StemCell Therapy

Trends Cell Biol. 2010 Dec; 20-206(12-6): 715722.

1Department of Craniofacial Development and MRC Centre for Transplantation, Kings College London; NIHR comprehensive Biomedical Research Centre at Guys and St Thomas NHS Foundation Trust and Kings College London, London, UK

1Department of Craniofacial Development and MRC Centre for Transplantation, Kings College London; NIHR comprehensive Biomedical Research Centre at Guys and St Thomas NHS Foundation Trust and Kings College London, London, UK

2Advanced Centre for Biochemical Engineering, University College London, London, UK

1Department of Craniofacial Development and MRC Centre for Transplantation, Kings College London; NIHR comprehensive Biomedical Research Centre at Guys and St Thomas NHS Foundation Trust and Kings College London, London, UK

1Department of Craniofacial Development and MRC Centre for Transplantation, Kings College London; NIHR comprehensive Biomedical Research Centre at Guys and St Thomas NHS Foundation Trust and Kings College London, London, UK

2Advanced Centre for Biochemical Engineering, University College London, London, UK

Teeth exhibit limited repair in response to damage, and dental pulp stem cells probably provide a source of cells to replace those damaged and to facilitate repair. Stem cells in other parts of the tooth, such as the periodontal ligament and growing roots, play more dynamic roles in tooth function and development. Dental stem cells can be obtained with ease, making them an attractive source of autologous stem cells for use in restoring vital pulp tissue removed because of infection, in regeneration of periodontal ligament lost in periodontal disease, and for generation of complete or partial tooth structures to form biological implants. As dental stem cells share properties with mesenchymal stem cells, there is also considerable interest in their wider potential to treat disorders involving mesenchymal (or indeed non-mesenchymal) cell derivatives, such as in Parkinson's disease.

Teeth are complex organs containing two separate specialized hard tissues, dentine and enamel, which form an integrated attachment complex with bone via a specialized (periodontal) ligament. Embryologically, teeth are ectodermal organs that form from sequential reciprocal interactions between oral epithelial cells (ectoderm) and cranial neural crest derived mesenchymal cells. The epithelial cells give rise to enamel forming ameloblasts, and the mesenchymal cells form all other differentiated cells (e.g., dentine forming odontoblasts, pulp, periodontal ligament) (Box 1). Teeth continue developing postnatally; the outer covering of enamel gradually becomes harder, and root formation, which is essential for tooth function, only starts to occur as part of tooth eruption in children.

Tooth development

Tooth development is traditionally considered a series of stages that reflect key processes (). The first step is induction, in which signals from the epithelium to the mesenchyme initiate the developmental process. As localized proliferation of the dental epithelial cells takes place, the cells form a bud around which the mesenchymal cells condense. Differentiation and localized proliferation of the epithelial cells in the bud leads to the cap stage. It is at this stage that crown morphogenesis is initiated by the epithelial signalling centre, an enamel knot regulating the folding of the epithelium. By the bell stage, the precursors of the specialized tooth cells, ameloblasts, coordinate enamel deposition, and odontoblasts, which produce dentine, are formed. Tooth eruption involves the coordination of bone resorption and root development, and occurs postnatally.

Throughout tooth development, signals are exchanged between epithelial and mesenchymal cells to coordinate each process. The key initial signals occur at induction (epithelium) and bud formation (mesenchyme). Once the mesenchymal cells receive signals from the epithelium, the mesenchyme sends reciprocal signals back to the epithelium. Strategies for biological replacement teeth aim to utilize these first signal exchanges by identifying either epithelial cells that can induce a naive mesenchyme or mesenchymal cells that can induce a naive epithelium to stimulate tooth development.

Repair, restoration and replacement of teeth is unique among clinical treatments because of the huge numbers of patients involved. Paradoxically, although teeth are nonessential for life and thus not considered a major target for regenerative medicine research, in comparison with neural or cardiac diseases, for example, this very fact makes teeth ideal for testing new cell-based treatments. Because the patients are not usually ill, if anything goes wrong it is far less life threatening, and the accessibility of teeth means that treatment does not require major surgery. Added to this is the existence of highly proliferative stem cell populations in teeth, which can be easily obtained from naturally lost or surgically removed teeth. These stem cells can be used for tooth repair, restoration and regeneration and, significantly, non-dental uses, such as developing stem cell-based therapies for major life-threatening diseases. An important but often overlooked advantage of teeth as a source of stem cells is that postnatal root formation (a rich source of dental stem cells) is a developmental process, and thus cells involved in root formation are more embryonic-like than other sources of dental stem cells. The humble tooth clearly has a very important role to play in future developments in regenerative medicine.

In this review, we outline the important biological properties of dental stem cells and illustrate examples of research showing the rapid progress being made in using these cells for tooth repair. We also highlight the major obstacles that need to be overcome before any form of usable, cell-based tooth replacement becomes available to practising dentists.

Several populations of cells with stem cell properties have been isolated from different parts of the tooth. These include cells from the pulp of both exfoliated (children's) and adult teeth, from the periodontal ligament that links the tooth root with the bone, from the tips of developing roots and from the tissue (dental follicle) that surrounds the unerupted tooth. All these cells probably share a common lineage of being derived from neural crest cells and all have generic mesenchymal stem cell-like properties, including expression of marker genes and differentiation into mesenchymal cell lineages (osteoblasts, chondrocytes and adipocytes) in vitro and, to some extent, in vivo. The different cell populations do, however, differ in certain aspects of their growth rate in culture, marker gene expression and cell differentiation, although the extent to which these differences can be attributed to tissue of origin, function or culture conditions remains unclear.

The possibility that tooth pulp might contain mesenchymal stem cells was first suggested by the observation that severe tooth damage that penetrates both enamel and dentine and into the pulp stimulates a limited natural repair process, by which new odontoblasts are formed, which produce new dentine to repair the lesion [1,2]. Putative stem cells from the tooth pulp and several other dental tissues have now been identified (Box 2) [38].

Human third molar as a source of dental stem cells

Human third molars (wisdom teeth) start their development postnatally, during childhood (ages of 56 years) and begin their calcification process from the age of 710 years. By the age of 1825 years, the roots of the third molars have completed their development. These teeth are most commonly extracted and discarded in the dental clinic, but because they are still undergoing root development, they provide an excellent source of dental stem cells including DPSC, PDL cells and SCAP cells ().

The first stem cells isolated from adult human dental pulp were termed dental pulp stem cells (DPSCs) [3]. They were isolated from permanent third molars, and exhibited high proliferation and high frequency of colony formation that produced sporadic, but densely calcified nodules. Additionally, in vivo transplantation into immunocompromised mice demonstrated the ability of DPSCs to generate functional dental tissue in the form of dentine/pulp-like complexes [4]. Further characterization revealed that DPSCs were also capable of differentiating into other mesenchymal cell derivatives in vitro such as odontoblasts, adipoctyes, chondrocytes and osteoblasts [912]. DPSCs differentiate into functionally active neurons, and implanted DPSCs induce endogenous axon guidance, suggesting their potential as cellular therapy for neuronal disorders [1315].

Stem cells isolated from the pulp of human exfoliated deciduous (children's milk) teeth (SHED) have the capacity to induce bone formation, generate dentine and differentiate into other non-dental mesenchymal cell derivatives in vitro[1620]. In contrast to DPSCs, SHED exhibit higher proliferation rates [21], increased population doublings, osteoinductive capacity in vivo and an ability to form sphere-like clusters [16]. SHED seeded onto tooth slices/scaffolds and implanted subcutaneously into immunodeficient mice differentiated into functional odontoblasts capable of generating tubular dentine and angiogenic endothelial cells [18].

Studies using SHED as a tool in dental pulp tissue engineering in vivo, where pulp removed because of infection is replaced with stem cells, have revealed that the tissue formed has architecture and cellularity closely resembling that of dental pulp, a tissue important for tooth vitality [19]. Another interesting clinical application has been suggested by investigations of the therapeutic efficacy of SHED in alleviating Parkinson's disease (PD) [20]. Transplantation of SHED spheres into the striatum of parkinsonian rats partially improved the apomorphine evoked rotation of behavioural disorders. The results of this study indicate that SHED might be a useful source of postnatal stem cells for PD treatment. SHED are isolated from children's exfoliated teeth, however, so autologous stem cell therapy for a disease such as PD would require that these cells be stored from childhood. DPSCs, which are obtained from adult tooth pulp, might well have similar properties, however, and collection and expansion of these autologous cells would simply require removal of a tooth from the patient.

SHED and other dental stem cells are derived from cranial neural crest ectomesenchyme, and so developmentally and functionally would appear identical, but studies have shown that they do differ and have different gene expression profiles. SHED have significantly higher proliferation rates compared with DPSC and bone marrow-derived mesenchymal stem cells [21]. Comparison of the gene expression profiles showed 4386 genes that are differentially expressed between DPSC and SHED by two-fold or more. Higher expression in SHED was observed for genes that participate in pathways related to cell proliferation and extracellular matrix formation, including several growth factors such as fibroblast growth factor and transforming growth factor (TGF)- [21]. TGF- in particular is important, because it is released after damage to dentine and might act to mobilize pulp stem cells to differentiate into odontoblasts [1,22].

DPSC are highly proliferative and retain their stem cell characteristics after prolonged culture [23]. They could therefore be used as a generic allogeneic source of mesenchymal stem cells. Their use as autologous cells, however, is currently restricted to children who have not yet lost all their deciduous teeth. Commercial banking of these cells is thus becoming widespread to enable them to be used once the child becomes an adult. Limited studies have shown that frozen SHED cells do maintain their properties after cryopreservation for 2 years [24], but one caveat is that the effects of long-term storage (10 years, plus) have not yet been assessed. Because children naturally lose 20 deciduous teeth, there are multiple opportunities to bank these cells, unlike cord blood, for example.

The periodontal ligament (PDL) is a fibrous connective tissue that contains specialized cells located between the bone-like cementum and the inner wall of the alveolar bone socket that acts as a shock absorber during mastication (Box 2). The PDL has long been recognized to contain a population of progenitor cells [25] and recently, several studies [26] identified a population of stem cells from human periodontal ligament (PDLSC) capable of differentiating along mesenchymal cell lineages to produce cementoblast-like cells, adipocytes and connective tissue rich in collagen I in vitro and in vivo[2629].

The periodontal ligament is under constant strain from the forces of mastication, and thus PDLSC are likely to play an endogenous role in maintaining PDL cell numbers. This might explain why they are better than other dental stem cell populations at forming PDL-like structures [17].

A unique population of dental stem cells known as stem cells from the root apical papilla (SCAP) is located at the tips of growing tooth roots (Box 2). The apical papilla tissue is only present during root development before the tooth erupts into the oral cavity [30]. SCAP have the capacity to differentiate into odontoblasts and adipocytes [27]. These cells are CD24+ but expression is downregulated upon odontogenic differentiation in vitro coincident with alkaline phosphatase upregulation. SCAP cells exhibit higher rates of proliferation in vitro than do DPSC [27]. By co-transplanting SCAP cells (to form a root) and PDLSC (to form a periodontal ligament) into tooth sockets of mini pigs, dentine and periodontal ligament was formed. These findings suggest that this population of cells, together with PDLSC, could be used to create a biological root that could be used in a similar way as a metal implant, by capping with an artificial dental crown. Most human tissues from early in their development are not clinically available for stem cell isolation; however, because roots develop postnatally, the root apical papilla is accessible in dental clinical practice from extracted wisdom teeth. Thus, a very active source of stem cells with embryonic-like properties (i.e., in the process of development) can be readily obtained. Further experiments on the properties of these cells obtained from human teeth following expansion in culture are needed.

The dental follicle is a loose ectomesenchyme-derived connective tissue sac surrounding the enamel organ and the dental papilla of the developing tooth germ before eruption [31]. It is believed to contain progenitors for cementoblasts, PDL and osteoblasts. Dental follicle cells (DFC) form the PDL by differentiating into PDL fibroblasts that secrete collagen and interact with fibres on the surfaces of adjacent bone and cementum. DFC can form cementoblast-like cells after transplantation into SCID mice [32,33].

Dental follicle progenitor cells isolated from human third molars are characterized by their rapid attachment in culture, expression of the putative stem cell markers Nestin and Notch-1, and ability to form compact calcified nodules in vitro[34]. When DFC were transplanted into immunocompromised mice, however, there was little indication of cementum or bone formation [34]. DFC, in common with SCAP, represent cells from a developing tissue and might thus exhibit a greater plasticity than other dental stem cells. However, also similar to SCAP, further research needs to be carried out on the properties and potential uses of these cells.

There are several areas of research for which dental stem cells are currently considered to offer potential for tissue regeneration. These include the obvious uses of cells to repair damaged tooth tissues such as dentine, periodontal ligament and dental pulp [1619,3236]. Even enamel tissue engineering has been suggested [37], as well as the use of dental stem cells as sources of cells to facilitate repair of non-dental tissues such as bone and nerves [1215,20,38,39].

The periodontium is a set of specialized tissues that surround and support the teeth to maintain them in the jaw. Periodontitis is an inflammatory disease that affects the periodontium and results in irreversible loss of connective tissue attachment and the supporting alveolar bone. The challenge for cell-based replacement of a functional periodontium is therefore to form new ligament and bone, and to ensure that the appropriate connections are made between these tissues, as well as between the bone and tooth root. This is not a trivial undertaking, as these are very different tissues that form in an ordered manner (spatially and temporally) during tooth development. One aim of current research is to use different populations of dental stem cells to replicate the key events in periodontal development both temporally and spatially, so that healing can occur in a sequential manner to regenerate the periodontium [34].

A conceptually simpler approach to periodontal regeneration methods involves engineered cell sheets to facilitate human periodontal ligament (HPDL) cell transplantation [35]. Periodontal ligament cells isolated from a human third molar tooth were cultured on poly(N-isopropylacryl-amide) (PIPAAm)-grafted dishes that induce spontaneous detachment of the cells as viable cell sheets upon low temperature treatment. HPDL cells sheets were implanted into athymic rats that had the periodontium and cementum removed from their first molars. Fibril anchoring resembling native periodontal ligament fibres, together with an acellular cementum-like layer, was observed, indicating that this technique could be applicable to future periodontal regeneration. Although promising, this approach does not take into account any replacement of bone that might be required.

The outstanding issue with these approaches is the extent to which any reconstituted periodontium can maintain integrity and function during mastication over long periods of time. Current treatments for severe periodontitis are poor, however, and thus, despite their flaws, any new dental stem cell-based treatments are likely to be the subject of intensive clinical research in the near future.

Dental pulp needs to be removed when it becomes infected, and this is particularly problematic for root pulp that requires endodontic (root canal) treatment. The restoration of tooth pulp is thus a much sought after goal in dentistry because the current practice of replacing infected pulp with inorganic materials (cements) results in a devitalized (dead) tooth. A recent study demonstrated de novo regeneration of dental pulp in emptied root canal space using dental stem cells [36]. DPSC and SCAP isolated from the human third molars were seeded onto a poly-D,L-lactide/glycolide scaffold and inserted into the canal space of root fragments, followed by subcutaneous transplantation into SCID mice. Subsequent histological analysis of the tooth fragments 34 months after surgery indicated that the root canal space was completely filled with pulp-like tissue with well established vascularization. Moreover, a continuous layer of mineralized tissue resembling dentine was deposited on the existing dentinal walls of the canal [36]. Recent studies using genetically marked cells in mice have suggested that adding stem cells makes little difference to the extent to which an empty pulp cavity regenerates because the majority of cells are provided by the vasculature (Sharpe P.T, unpublished data). Stem cell pulp restoration might therefore not be a problem of providing exogenous stem cells but one of surgically ensuring that an adequate blood supply is maintained after pulp removal.

The current state of the art in tooth replacement is a dental implant that involves screwing a threaded metal rod into a predrilled hole in the bone, which is then capped with a plastic or ceramic crown. Implant use requires a minimum amount of bone to be present. Because these implants attach directly to the bone without the PDL shock absorber, the forces of mastication are transmitted directly to the bone, which is one reason implants can fail. In cases where there is insufficient bone for implants, such as tooth loss as a consequence of the bone loss that occurs in postmenopausal osteoporosis, implants have to be preceded by bone grafts. The ultimate goal in dentistry is to have a method to biologically replace lost teeth; in essence, a cell-based implant rather than a metal one. The minimum requirement for a biological replacement is to form the essential components required for a functional tooth, including roots, periodontal ligament, and nerve and blood supplies. Paradoxically, the visible part of the tooth, the crown, is less important because, although essential for function, synthetic tooth crowns function well, and can be perfectly matched for size, shape and colour. The challenge, therefore, for biological tooth replacement is ultimately one of forming a biological root.

Currently, the major challenges in whole tooth regeneration are to identify non-embryonic sources of cells with the same properties as tooth germ cells and to develop culture systems that can expand cells that retain tooth forming potential (). This is even more challenging when considering the fact that tooth development requires two cell types, epithelial and mesenchymal [4042].

Tooth formation in vitro from combinations of mouse epithelial and mesenchymal cells. The epithelium (red arrow) and mesenchyme (black arrow) are separated from pre-bud stage tooth primordia,and cells dissociated in single cell populations. (a) The cells are recombined (as shown in this figure) and grown in vitro for 6 days. (b) Gross appearance after 9 days in culture with higher magnification of a tooth primordium. (c) Sections of tooth primordia from (a), showing development to the bell stage.

The induction of odontogenic potential lies in the dental epithelium [4345]. Dental epithelium from pre-bud stages can induce tooth formation when combined with nonodontogenic mesenchyme as long as the mesenchymal cells have stem cell-like properties in common with neural crest cells [46]. After epithelial induction of the mesenchyme, this becomes the inductive tissue and reciprocates inductive signals back to the now noninductive epithelium. Tooth regeneration can thus be approached in one of two ways; identification of either epithelial or mesenchymal cells than can induce tooth formation in the other cell type.

No sources of epithelial cells capable of inducing odontogenesis have been identified to date, other than the endogenous dental epithelium of early stage embryos. The main limitation for identifying sources of epithelial cells that can be grown in culture and form teeth after association with inducing mesenchymal cells is that these epithelial cells retain an immature state.

The epithelial rests of Malassez (ERM) are a group of cells that remain during root formation; thus, these cells are present in adult teeth and can be isolated and cultured [5155]. When ERM cells are maintained in vitro on feeder layers, they can be induced to form enamel-like tissues following recombination with primary (uncultured) dental pulp cells [55].

Oral mucosa epithelial cells from embryos and adults have been used in recombination experiments and shown to give rise to complex dental structures, but not whole functional teeth, when combined with embryonic dental mesenchyme [56,57]. Some evidence of tooth formation was seen when oral epithelial lines established from p-53-deficient mouse embryos at embryonic day (E)18 were combined with fetal E16.5 molar mesenchymal tissues and transplanted for 23 weeks [56]. Postnatal oral mucosal epithelium might also offer some potential as a replacement for embryonic dental epithelium, because cells isolated from young animals, grown as cell sheets and re-associated with dental mesenchyme from E12.5 embryos, can give rise to tooth-like structures [57].

There are sources of epithelial cells that can contribute to tooth formation following culture, suggesting that exogenously adding factors to these cells could make them inducible. Such factors, include signalling proteins of the fibroblast growth factor bone morphogenetic protein and Wnt families, but the issue of reproducing the temporal, spatial and quantitative delivery of these, as seen in vivo, is daunting. Identification of key intracellular factors (e.g., kinases, transcription factors.) is likely to be a more fruitful direction because these are more easily manipulated.

The ability of non-dental mesenchymal cell sources to respond to odontogenic epithelial signals following in vitro expansion was demonstrated when it was shown that expanded adult bone marrow stromal cells would form teeth in vitro when combined with inductive embryonic oral epithelium [46]. This study also showed that embryonic tooth primordia could develop into complete teeth, following transplantation into the adult oral cavity. Such transplants, when left for sufficient time, will form roots and erupt [47,58]. The issues with producing inductive epithelium in vitro illustrated in the above section suggest that the alternative approach of identifying mesenchymal cells with inductive capacity might be more fruitful. The cells that have this capacity in vivo are the early embryonic neural crest-derived ectomesenchyme cells that have already received the first inductive signals from the dental epithelium (Box 1). Bone marrow mesenchymal cells, although able to respond to odontogenic signals from the epithelium, are only able to induce tooth formation after receiving these epithelial signals. Such priming of bone marrow mesenchymal cells by inducing factors or embryonic dental epithelium is possible, but in reality too laborious and difficult to be of any clinical value.

If ectomesenchyme cells have odontogenic-inducing capacity, can this be maintained in vitro? Embryonic tooth primordia mesenchymal cells from mice have been shown to retain their potential to respond to odontogenic signals following in vitro culture after immortalization but it is uncertain if cells with inducing capacity can retain this following culture (Jung H.-S., personal communication). Similarly, equivalent cells from human embryos have been isolated and shown to form teeth in re-association experiments (Volponi A.A. and Sharpe P.T., unpublished data).

Adult dental pulp mesenchymal stem cells are an obvious source of cells to replace embryonic ectomesenchyme because they are derived from cranial neural crest and are dental cells. Indeed, these cells retain expression of many genes expressed in neural crest, in addition to a number of stem cell marker genes. However, it has yet to be shown that adult dental pulp mesenchymal stem cells retain any odontogenic inductive or responsive capacity. One interesting direction is to identify the factors expressed by ectomesenchyme cells (embryonic dental mesenchyme) that render them capable of forming teeth that are not expressed by adult dental stem cells. Approaches similar to those developed for producing induced pluripotent stem cells can be used to convert adult dental stem cells into ectomesenchyme cells that can form teeth.

Functional teeth can be experimentally bioengineered in mice by re-association of dissociated tooth cells [4851]. These experiments actually demonstrate the ability of dissociated cells to re-aggregate, however, rather than the bioengineering of whole teeth. The cells used are obtained from embryonic tooth primordia, many of which are required to produce one tooth. When tooth germs are dissociated and allowed to re-associate in an extracellular matrix (scaffold), they sort out and re-aggregate to reform the tooth germs [48,51]. The re-aggregation produces multiple small toothlets, whose shape bears no resemblance to that of the scaffold used (). Similarly, the tooth germ epithelial and mesenchymal cell components can be physically separated, the cells dissociated and recombined, whereupon they sort and re-aggregate to reform the tooth germ [48,51]. In this case, 5104 cells dissociated from multiple tooth germs are required to generate a single new tooth germ [48]. The large cell numbers required necessitate in vitro expansion of epithelial and mesenchymal cells that will retain their odontogenic properties.

Diagrammatic representation of the generation of biological replacement teeth. Suitable sources of epithelial and mesenchymal cells are expanded in culture to generate sufficient cells. The two cell populations are combined to bring the epithelial and mesenchymal cells into direct contact, mimicking the in vivo arrangement. Interaction between these cell types leads to formation of an early stage tooth primordium, equivalent to a tooth bud or cap, around which the mesenchyme cells condense (dark blue dots) (see also Box 1). The tooth primordium is surgically transplanted into the mouth and left to develop.

Despite some progress, there remain major obstacles to formulating safe, simple and reproducible cell-based approaches for tooth repair and regeneration that could be used on patients. It is clear that there is both a clinical need for such treatments and a vast patient resource. Dental stem cells have many advantages, and results to date suggest that teeth are a viable source of adult mesenchymal stem cells for a wide range of clinical applications. Ultimately, the use of these dental stem cells over other sources of mesenchymal stem cells for therapeutic use will not only depend on ease of use and accessibility, but also on the efficiency and quality of repair in relation to cost. Dental pulp cells grow well in culture and, unusually, the proportion of cells with stem cell properties appears to increase with passage. The molecular basis of this phenomenon needs to be investigated because it might provide a paradigm for increasing stem cell numbers in cultures of other cell types.

For whole tooth regeneration, there remain many major issues that will take considerable time to resolve. Most immediate is the identification of epithelial and mesenchymal cell populations that can be maintained and expanded in culture to provide the large numbers needed to make a tooth. Related to this is the issue of whether the cells will need to be autologous (expensive, but safe) or allogeneic (cheaper, but with possible rejection problems). Finally, an additional fundamental issue that needs to be considered is that human tooth development is a much slower process than in mice. Human tooth embryogenesis is approximately eight times slower, and postnatal development lasts several years. Thus, whereas growth, implantation and eruption of bioengineered mouse teeth might take a few weeks, the equivalent time to create a functional human tooth might be many months or even years. Research thus needs to be done to investigate ways of possibly accelerating human tooth development.

Diagrammatic representation of tooth development.

Photograph and diagram of a human third molar tooth following extraction. A hemisected tooth showing the internal tissues is shown on the right. Because the tooth was in the process of erupting, root growth is incomplete, and the apical papilla is visible. A diagrammatic representation of this tooth is shown on the left.

Research in the author's laboratory is supported by the MRC, Wellcome Trust and the Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guys. YP is supported by the UK Stem Cell Foundation. We are grateful to Han-Sung Jung for his permission to cite unpublished work and to Andrea Mantesso for comments on the manuscript.

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Stem cell-based biological tooth repair and regeneration - PMC

Stem cells are found throughout the body

The term stem cell may conjure up thoughts of some rare type of cell that can only be found in very specific locations. The opposite is really true. Stem cells are pretty ubiquitous in the body, appearing in many different organs and tissues including the brain, blood, bone marrow, muscle, skin, heart, and liver tissues. In these areas, they lie dormant until needed to regenerate lost or damaged tissue. They can do this because of their unique abilities to become many different types of cells and to replicate rapidly. (You can read more about the unique traits of stem cells here.)

As stem cells can be found throughout the body, it may seem as though they can easily be harvested for transplantation and regenerative medicine, but its the volume and the age of stem cells that are the main driving factors in where they are collected. Volume is important because there is no conclusive way to spur replication, so as of now, what you get is what you get. Age is also a factor because as stem cells age, they lose their ability to reproduce and differentiate into other cell types, they may become contaminated with a latent virus or affected by a disease, or they may have been exposed to toxins and have undergone mutation. They are also more likely to cause an autoimmune response, which is when your body attacks itself.

Found in large numbers during gestation, embryonic stem cells are by far the youngest stem cells and have the unique ability to become any type of cell in the body. There is a lot of controversy and ethical considerations concerning the embryonic stem cell. Thankfully, we can also acquire stem cells that form just a little bit later down the road and can be found in the umbilical cord blood and cord tissue. These stem cells are more limited in the types of cells they can become, something known as being tissue-specific, and they stay with us throughout our lives, which is why they are referred to as adult stem cells.

Extracting the cord blood is painless and risk-free

The second to youngest stem cells are still called adult stem cells even though they can be collected at the time of delivery. Cord blood stem cells were discovered in 1978, and after the first cord blood transplant in 1988, the cord blood banking industry was formed. Cord tissue stem cells were discovered in the late '90s, and this discovery spurred cord tissue banking for many cord blood banks. Cord blood and cord tissue stem cells have the special quality of being the purest and youngest tissue-specific stem cells you can collect and function more quickly and effectively than adult stem cells from other sources. They are also easily collected at the time of birth. (Dive into the differences between cord blood and cord tissue.)

Placental tissue can also be easily collected at the time of birth

The placenta and other amniotic tissues are also a rich source of the same type of stem cells found in cord tissue, and as with cord tissue, they can be easily collected at the time of birth. Despite these similarities to cord tissue, the major difference is that the placental tissue has a mix of the baby's and the mother's stem cells, and in order for these to be properly utilized in a stem cell treatment, they need to be separated. As the mother's stem cells often replicate more quickly than the fetal stem cells, placental stem cells are more likely to be preserved for the exclusive use of the mother.

A bone marrow draw requires the use of anesthesia and usually takes 20 days to fully recover

There are also areas where stem cells can be collected later in life. Bone marrow is rich in the blood-forming stem cells like those found in cord blood. To collect bone marrow stem cells, a needle is inserted into the soft center of the bone and requires the donor to undergo anesthesia. While it would be best to obtain bone marrow stem cells right from the person who needs them, the bone marrow procedure could be too much for the patient or the patients bone marrow could be too diseased. If this is the case, a matching donor must be found. A matching donor may be hard to obtain, and unfortunately, all non-related stem cell transplants come with a high degree of risk for an autoimmune response like graft-versus-host disease. (Read more about how cord blood and bone marrow compare.)

The procedure for capturing peripheral blood stem cells is like a long blood donation

As noted earlier, blood contains stem cells, just not too many. To gather a large number of stem cells from blood, the blood- and immune systemforming stem cells in bone marrow need to be coaxed out and collected. The non-surgical procedure is called apheresis. It begins days before the stem cell transplant with injections to get the stem cells in the bone marrow to enter the blood stream. The blood is then drawn from one arm and filtered through a machine to catch the stem cells from the peripheral blood. The rest of the blood is returned to the donor's other arm through another needle. Unfortunately, these stem cells have proven less effective compared with cord blood and bone marrow stem cells. In a meta-analysis of 9 trials totaling 1,111 patients, researchers found time to engraftment was slower and the frequency of graft-versus-host disease was greater in transplantations using peripheral blood than bone marrow. Researchers believe this has something to do with the removal of the stem cells from their bone marrow environment although the exact reason is not clear.

Obtaining adipose-derived stem cells requires a liposuction-like procedure that may itself take weeks of healing

Adipose stem cells are collected from fat tissue by way of an invasive liposuction-like procedure and are not the same as those found in cord blood or bone marrow. This means they are not used to treat the blood cancers and diseases that cord blood or bone marrow treat. The adipose tissue is more abundant in the same kind of stem cells found in cord tissue. These stem cells show promise for heart and kidney disease, ALS, wound healing and some autoimmune diseases.

Because stem cells taken from the patient and re-infused within 48 hours fall under different guidelines than stem cells collected through other methods, a market has sprung up for adipose stem cells, with many clinics touting their benefits in treatments that go well beyond current research. There is an inherit risk in using stem cell therapies neither approved by the FDA nor a part of an FDA-approved clinical trial.

Dental pulp can be collected as a child loses his or her baby teeth

A relatively new discovery is the stem cells in dental pulp. Teeth contain the same type of stem cells as adipose tissue and umbilical cord tissue, so once again, they are not used to treat the blood cancers and diseases that cord blood or bone marrow treat. Like cord tissue, however, dental pulp could hold future potential for heart and kidney disease, ALS, wound healing and some autoimmune diseases, and collection could involve simply saving all the teeth that fall out as the child grows.

Its too early to know if dental pulp will prove to be an quality source of these types of stem cells, and the volume of stem cells is known to be small. As cord tissue stem cells are plentiful and have been being used in clinical trials for the past 20 years, comparing its progress to that of dental pulp is akin to comparing a great 9-year-old tee ball player to the upcoming major league superstar. Dental pulp as a source of stem cells is a new idea, and maybe it has potential, but it's still has to undergo years of trials, data collection and analysis before it will be a proven science.

Stem cells can be found throughout the body, but the volume of the stem cells, the age and purity of the stem cells, the ease of collecting, the degree to which they have proven successful in transplants and clinical data and any ethical considerations are all major factors as to which is the preferred source. These are all factors where cord blood and cord tissue prove superior.

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Where Stem Cells Are Found, & the Difference That Makes | Cryo-Cell

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Human Umbilical Cord Mesenchymal Stem Cell-Derived Extracellular Vesicles Carrying MicroRNA-181c-5p Promote BMP2-Induced Repair of Cartilage Injury through Inhibition of SMAD7 Expression

Qiang Zhang|Le Cao|...|Yongping Wu

The therapy role of mesenchymal stem cell- (MSC-) derived extracellular vesicles (EVs) in cartilage regeneration has been well studied. Herein, we tried to analyze the role of human umbilical cord MSC- (hUCMSC-) EVs carrying microRNA- (miR-) 181c-5p in repair of cartilage injury. After successful isolation of hUCMSCs, the multidirectional differentiation abilities were analyzed. Then, the EVs were isolated and identified. After coculture of PKH26-labled EVs with bone marrow MSCs (BMSCs), the biological behaviors of which were detected. The relationship between the predicted early posttraumatic osteoarthritis-associated miRNA, miR-181c-5p, and SMAD7 was verified. Gain- and loss-of functions were performed for investing the role of miR-181c-5p and SMAD7 in BMP-induced chondrogenesis in vitro and in vivo. hUCMSC-EVs could be internalized by BMSCs and promote the proliferative, migratory, and chondrogenic differentiation potentials of BMSCs. Additionally, miR-181c-5p could target and inhibit SMAD7 expression to promote the bone morphogenic protein 2- (BMP2-) induced proliferative, migratory, and chondrogenic differentiation potentials of BMSCs. Also, overexpression of SMAD7 inhibited the repairing effect of BMP2, and overexpression of BMP2 and miR-181c-5p further promoted the repair of cartilage injury in vivo. Our present study highlighted the repairing effect of hUCMSC-EVs carrying miR-181c-5p on cartilage injury.

Research Article

22 Jun 2022

Human Placental Mesenchymal Stem Cells for the Treatment of ARDS in Rat

Zurab Kakabadze|Nicholas Kipshidze|...|David Chakhunashvili

The acute respiratory distress syndrome (ARDS) is one of the main causes of high mortality in patients with coronavirus (COVID-19). In recent years, due to the coronavirus pandemic, the number of patients with ARDS has increased significantly. Unfortunately, until now, there are no effective treatments for ARDS caused by COVID-19. Many drugs are either ineffective or have a low effect. Currently, there have been reports of efficient use of mesenchymal stem cells (MSCs) for the treatment of ARDS caused by COVID-19. We investigated the influence of freeze-dried human placenta-derived mesenchymal stem cells (HPMSCs) in ARDS rat model. All animals have received intratracheal injection of 6mg/kg of lipopolysaccharide (LPS). The rats were randomly divided into five groups: I: LPS, II: LPS+dexamethasone, III: LPS+HPMSCs, IV: HPMSC, and V: saline. ARDS observation time was short-term and amounted to 168 hours. The study has shown that HPMSCs are able to migrate and attach to damaged lung tissue, contributing to the resolution of pathology, restoration of function, and tissue repair in the alveolar space. Studies have also shown that the administration of HPMSCs in animals with ARDS model significantly reduced the levels of key cytokines such as IL-1, IL-6, and TNF-. Freeze-dried placental stem cell is a very promising biomaterial for the treatment of ARDS. The human placenta can be easily obtained because it is considered as a medical waste. At the same time, a huge number of MSCs can be obtained from the placental tissue, and there is no ethical controversy around their use. The freeze-dried MSCs from human placental tissue can be stored sterile at room temperature for a long time before use.

Research Article

20 Jun 2022

GMP Compliant Production of a Cryopreserved Adipose-Derived Stromal Cell Product for Feasible and Allogeneic Clinical Use

Mandana Haack-Srensen|Ellen Mnsted Johansen|...|Annette Ekblond

The emerging field of advanced therapy medicinal products (ATMP) holds promise of treating a variety of diseases. Adipose-derived stromal cells (ASCs) are currently being marketed or tested as cell-based therapies in numerous clinical trials. To ensure safety and efficacy of treatments, high-quality products must be manufactured. A good manufacturing practice (GMP) compliant and consistent manufacturing process including validated quality control methods is critical. Product design and formulation are equally important to ensure clinical feasibility. Here, we present a GMP-compliant, xeno-free, and semiautomated manufacturing process and quality controls, used for large-scale production of a cryopreserved off-the-shelf ASC product and tested in several phase I and II allogeneic clinical applications.

Research Article

18 Jun 2022

Human Umbilical Cord Mesenchymal Stem Cells Encapsulated with Pluronic F-127 Enhance the Regeneration and Angiogenesis of Thin Endometrium in Rat via Local IL-1 Stimulation

Shuling Zhou|Yu Lei|...|Jiang Gu

Thin endometrium (< 7mm) could cause low clinical pregnancy, reduced live birth, increased spontaneous abortion, and decreased birth weight. However, the treatments for thin endometrium have not been well developed. In this study, we aim to determine the role of Pluronic F-127 (PF-127) encapsulation of human umbilical cord mesenchymal stem cells (hUC-MSCs) in the regeneration of thin endometrium and its underlying mechanism. Thin endometrium rat model was created by infusion of 95% ethanol. Thin endometrium modeled rat uterus were treated with saline, hUC-MSCs, PF-127, or hUC-MSCs plus PF-127 separately. Regenerated rat uterus was measured for gene expression levels of angiogenesis factors and histological morphology. Angiogenesis capacity of interleukin-1 beta (IL-1)-primed hUC-MSCs was monitored via quantitative polymerase chain reaction (q-PCR), Luminex assay, and tube formation assay. Decreased endometrium thickness and gland number and increased inflammatory factor IL-1 were achieved in the thin endometrium rat model. Embedding of hUC-MSCs with PF-127 could prolong the hUC-MSCs retaining, which could further enhance endometrium thickness and gland number in the thin endometrium rat model via increasing angiogenesis capacity. Conditional medium derived from IL-1-primed hUC-MSCs increased the concentration of angiogenesis factors (basic fibroblast growth factor (bFGF), vascular endothelial growth factors (VEGF), and hepatocyte growth factor (HGF)). Improvement in the thickness, number of glands, and newly generated blood vessels could be achieved by uterus endometrium treatment with PF-127 and hUC-MSCs transplantation. Local IL-1 stimulation-primed hUC-MSCs promoted the release of angiogenesis factors and may play a vital role on thin endometrium regeneration.

Review Article

18 Jun 2022

Role of Primary Cilia in Skeletal Disorders

Xinhua Li|Song Guo|...|Ziqing Li

Primary cilia are highly conserved microtubule-based organelles that project from the cell surface into the extracellular environment and play important roles in mechanosensation, mechanotransduction, polarity maintenance, and cell behaviors during organ development and pathological changes. Intraflagellar transport (IFT) proteins are essential for cilium formation and function. The skeletal system consists of bones and connective tissue, including cartilage, tendons, and ligaments, providing support, stability, and movement to the body. Great progress has been achieved in primary cilia and skeletal disorders in recent decades. Increasing evidence suggests that cells with cilium defects in the skeletal system can cause numerous human diseases. Moreover, specific deletion of ciliary proteins in skeletal tissues with different Cre mice resulted in diverse malformations, suggesting that primary cilia are involved in the development of skeletal diseases. In addition, the intact of primary cilium is essential to osteogenic/chondrogenic induction of mesenchymal stem cells, regarded as a promising target for clinical intervention for skeletal disorders. In this review, we summarized the role of primary cilia and ciliary proteins in the pathogenesis of skeletal diseases, including osteoporosis, bone/cartilage tumor, osteoarthritis, intervertebral disc degeneration, spine scoliosis, and other cilium-related skeletal diseases, and highlighted their promising treatment methods, including using mesenchymal stem cells. Our review tries to present evidence for primary cilium as a promising target for clinical intervention for skeletal diseases.

Research Article

18 Jun 2022

Global Research Trends in Tendon Stem Cells from 1991 to 2020: A Bibliometric and Visualized Study

Huibin Long|Ziyang Yuan|...|Ai Guo

Background. Tendinopathy is a disabling musculoskeletal disorder affecting the athletics and general populations. There have been increased studies using stem cells in treating tendon diseases. The aim of this bibliometric and visualized study is to comprehensively investigate the current status and global trends of research in tendon stem cells. Methods. Publications related to tendon stem cells from 1991 to 2020 were retrieved from Web of Science and then indexed using a bibliometric methodology. VOSviewer software was used to conduct the visualized study, including coauthorship, cocitation, and cooccurrence analysis and to analyze the publication trends of research in tendon stem cells. Results. In total, 2492 articles were included and the number of publications increased annually worldwide. The United States made the largest contribution to this field, with the most publications (938 papers, 37.64%), citation frequency (68,195 times), and the highest -index (103). The most contributive institutions were University of Pittsburgh (96 papers), Zhejiang University (70 papers), Shanghai Jiao Tong University, and Chinese University of Hong Kong (both 64 papers). The Journal of Orthopaedic Research published the most relative articles. Studies could be classified into five clusters: Animal study, Tissue engineering, Clinical study, Mechanism research, and Stem cells research, which show a balanced development trend. Conclusion. Publications on tendon stem cells may reached a platform based on current global trends. According to the inherent changes of hotspots in each cluster and the possibilities of cross-research, the research in tendon stem cells may exist a balanced development trend.

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Stem Cells International | Hindawi

However, breast milk is a constantly changing fluid so in a way it's a moving target, with some components still not fully understood, says Fewtrell, the professor of paediatric nutrition at University College London.

"We can quite successfully produce formulas to provide adequate and safe nutrition so the baby grows and develops as expected," she says. "Indeed, there have been improvements to the composition of formulas in recent years so that they can more closely reproduce the growth patterns and some outcomes seen in breast-fed infants. However I think it would be impossible to ever mimic the 'non-nutrient' components in this complex fluid."

As for my investigation into my own body's toxic load, and the harmful chemicals that were perhaps present in my breastmilk, Bloxam, the dietician, reassures me: "I'd encourage breastfeeding wherever possible as the benefits for mother and baby would far outweigh any risks [from contamination]."

Still it appears I'm not the only one wondering about the ingredients in my own milk. Stephanie Canale, previously a family medical doctor, is the founder of Lactation Lab in California, a private company that analyses breast milk for nutritional content as well as environmental toxics.Mothers send in frozen samples of their breast milk to check the levels of various ingredients including minerals and vitamins. The idea is that they can then adapt their diet accordingly.

Canale says that when we look at a baby's nutrition, we need to include everything from prenatal vitamins to the food a breastfeeding mother consumes and the meals a weaning baby eats. Formula may be one part of that mosaic, in families where it is used.

"It's this holistic approach," says Canale who would like to see stricter regulations in the US about the contents of formula. "I'm from Canada and it still surprises how much high-fructose corn syrup is present in US products, including formula. Moms are going to drive this change by saying we need to be better aware of what is going into these products, especially formula because that child is eating the same thing every single day there's no variation [like there is naturally with breast milk]."

In the case of the toxic chemicals whether they find their way into breast milk or into formula the question is clearly not just about how we can provide our children with safe nutrition. It is also about how we can provide them and future generations with a safe, liveable environment, and reduce pollution along the entire food chain. One answer, surely, is to start by using fewer harmful chemicals in the first place.

* Listen toMy Toxic Cocktail, Anna Turns's investigation for BBC Radio 4's Costing the Earth series on BBC Sounds.Go Toxic Free: Easy and Sustainable Ways to Reduce Chemical Pollutionby Anna Turns is out now

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The surprising science of breast milk - BBC

Stem cell supplements are usually composed of natural materials and ingredients that helps support your bodys stem cells.

Stem cells, which can be easily described as the bodys building blocks or raw-material cells, are the cells responsible for all healing and growth processes in the body (1).

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Actif Stem Cell Mega Support is one of the most complete and advanced formulas on the market, using 15 factors to support stem cell growthand decrease DNA damage.It has been clinically proven to support stem cell renewal, boost cognitive function, and assist in circulation while decreasing the signs of aging and offering regeneration to your system.

Their enhanced formula includes L-carnosine for neurons, L-leucine to boost muscles and prevent fatigue, organic methylfolate to enhance the metabolism of cells. Actif Stem Cell Mega Support is also non-GMO, gluten free, and made in the USA, in GMP (Good Manufacturing Process) certified facilities. For these reasons, its our #1 pick.

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Stem Cell Worx Intra-oral Spray, is formulated by scientists and biochemists to activate your own adult stem cells instead of inserting new ones. The spray provides a 95% absorption rate versus the 20% average from pills and capsules.Over 50% of this product is protein and it has one of the highest content formulas on the market in terms of natural immune factors.

Its manufactured in the USA using GMP certified facilities that have been inspected and approved by the FDA.When it comes to independent clinical studies, this product has several to back up its claims (which can be found on the companys website).

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Enzymedica Stem XCellis a potent, research-backed formula that is designed to help boost and protect your stem cells from free radicals.This formula contains powerful stem cell supporting ingredients including glutathione, SOD, and alpha-lipoic acid along with 6 more enzymes that are designed to enhance the effectiveness and potency of the pure Stem XCell formula.

Their patented NT020 blend has been studied extensively and proven to promote health and growth in your bodys cells. Enzymedica Stem XCell contains no fillers andis vegetarian friendly. The company also supports the Autism Hope Alliance, Vitamin Angels, and Green Mountain Energy.

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Enzyme Science Stem XCell Proincludes antioxidants likegreen tea, red wine, and blueberry in a special and powerful formulathat helps boost immune and cellular health while preventing oxidative damage from free radicals.This product is designed with a patented NT-020 blend that was developed by researchers and scientists and studied for the ability to maintain and produce stem cells.

Enzyme Science Stem XCell Procontains no egg, soy, yeast, dairy, preservatives, salt, sucrose, casein, potato, rice, corn, wheat, nuts, artificial colors, or flavors. It is also gluten free and doesnt use any ingredients that are produced using biotechnology.

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Nu-Derm Cell Biotic Complete Complex offers powerful gastrointestinal and anti-aging support for older adults through the use of. DE111TM, lactobacillus rhamnosus, lactobacillus casei, and more.

Each capsule contains 5.75 billion probiotic bacteria that will help improve your digestive health without a prescription. Nu-Derm Cell Biotic Complete Complex is made in the USA and manufactured using GMP (Good Manufacturing Practice).

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Regenexx Advanced Stem Cell Support Formula has an 8 in 1 regenerative formula thatcan help your joint mobility. This supplement is tested in vitro using real human mesenchymal stem cells. The laboratory studies showed that these supplements help to maintain a healthy cell environment thanks to the special formula.

Regenexx Advanced Stem Cell Support Formula is oneof the rare stem cell supplements that is drinkable and comes in delicious flavors like strawberry and banana.

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Healthycell AC-11 repairs your DNA using Amazonian Uncaria tomentosa, Cats claw, and other natural ingredients. Over 40 peer-reviewed studies and nearly 20 years of research have backed this supplement up and it has 10 US patents.

Healthycell AC-11 isvertically integrated, sustainably sourced, located from the Peruvian Amazon Rainforest origin, and extracted in Brazil. It has no preservatives, no fillers, no flow agents, and no GMOs.

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BioXcell Stem Cell Enhanceris 100% AFA (Aphanizomenon flos-aquae) with blue green algae.This natural product has been shown to provide a variety of fantastic benefits for your health.

It helps regenerate your DNA, restore broken stem cells and increase adult cell metabolism, decrease intestinal problems, and keeps your mental health boosted as you have improved cognition and memory.

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Digestacute Autoimmune-X Advanced Formula isrecommended by some of the nations most respected immune restoration practitioners, including Dr. C. Nomal Shealy, who is the President of the American Holistic Medical Association.It is organically grown and does not contain any soy, GMOs, fillers, L-glutamine, and other ingredients.

Digestacute Autoimmune-X Advanced Formula is cruelty-free and does not test on animals.

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Stem Vida StemAliveis made in the USA and is 100% natural, non-stimulating and caffeine free.Stem Vida StemAlive rejuvenates your your stem cells and repairs your tissues and organs.

The first thing we looked at, when formulating our rankings for the best stem cell supplements, was the clinical trials. If a product was not backed by clinical trial data, it did not meet our purity requirement and was thus axed. All of the products on our list are independently tested and examined by scientists. In the case of Healthycell, over 2 decades of clinical study has gone into ensuring this product was safe and effective.

Another requirement we looked at was the ingredients. Making sure that the ingredients were all natural and pure, while still being potent, was very important. Organic and biologically sourced ingredients, like those found inActif Stem Cell Mega SupportandDigestacute Autoimmune-X Advanced Formula,are crucial when it comes to healthy and reliable stem cell supplements.

We also looked at the manufacturing process. Many low-quality supplements will come from China, which can be damaging and even dangerous to ones health especially when something as potent as stem cells are involved. It was important to us that products only originated from the USA and were manufactured in certified labs. Youll find on our list thatStem Cell Worxwas manufactured in an FDA-certified lab, andEnzymedicais manufactured in GMP-certified labs, among others.

Another thing we looked at was the cost. Stem cell supplements can be costly, especially ones with quality materials. However, the supplement industry has a bad habit of creating 10-20x markups, so we know that very expensive supplements are not necessarily always the best. As such, we tried to balance our rankings between price, quality, and affordability to ensure everyone was able to afford stem cell supplements.

1. Stem cell supplements can favorably alter gene expression.This translates to regulating and lowering the possibility of cells replicating in error. Gene expression is given a chance to mutate positively or harmfully each time that a cell divides. By taking stem cell supplements, you can tip the scales in your favor and lessen the chance that stem cells will divide poorly(2).

In addition, stem cell supplements can also help your stem cells replicate more frequently (3).

Because the stem cells are positively linked with a reduction in the signs of aging, causing your stem cells to replicate more often will lead to a better aging process, fewer side effects associated with aging, and overall better quality of life.

Having more stem cells can lead to looking and feeling younger for a more extended time. Stem cells are directly related to an adult bodys ability to heal from injury and natural degradation as a result of telomere shortening, otherwise known as aging.

2.The stem sell supplement vitaminD can support those who have multiple sclerosis. As an autoimmune disease that hinders the ability of nerve cells to send signals from one place to another, multiple sclerosis is thought to be currently incurable.However, vitamin D supplementation may possess the ability to reverse nerve cell damage caused by multiple sclerosis (4).

While this is not technically curing multiple sclerosis, this does offer victims of the autoimmune disease a fighting chance and can potentially extend their lifespan to natural levels so they can live out the rest of their life normally. In addition, it may provide patients with enough time for a cure to be found in the future.

3. Certain stem cell supplements may improve stem cells in the brain. During one study, animals were provided with blueberry, vitamin D, green tea, and carnosine as stem cell supplements. This resulted in a reduction of inflammatory effects, such as pro-inflammatory cytokines, that improved brain function and health overall (5).

In addition, this indicates that nutritional supplements can improve the overall environment for brain stem cells and lower the risk that they will change into sick or diseased cells in the future. As functioning stem cells are directly related to greater overall health, particularly when it comes to neurological function, this indicates that better brain health can safely be attributed as a benefit to stem cell supplements.

A healthier brain is already at a lower risk of suffering from neurodegenerative diseases in the future (6).

In this way, stem cell supplements can be seen as effective agents which reduce the likelihood of a person developing a neurodegenerative disease.

4. Stem cells supplements can provide improved cognitive and memory function.A study during which certain animals were provided with various nutritional supplements showed that sufficient supplementation could cause the proliferation of new stem cells (7).

This is likely due to an increase in overall healthy brain cells as described above but is specific enough that it warrants its own attention.Memory loss is a major concern for anyone leaving middle-age. Taking good nutritional supplements to assist with stem cell reproduction and function is a good way to combat this effect.

5. Stem cellsupplementscan lead to increased energy and endurance.As stem cells are chiefly responsible for the restoration of the body, those who supplement their stem cells with the right nutritional additives can expect greater recovery time from workouts and greater energy reserves to draw upon during times of stress or excess energy release (8).

This effect can allow people to build muscle more quickly or remain fit for longer; even as they start to ascend in age. The bodys physical capabilities naturally decline as it grows older, but increased stem cell production can truncate this effect or delay it for longer than normal. This can lead to improved physical ability and function.

6. Stem cell supplements can provide faster recovery times from injuries or sicknesses.Those who suffer from chronic illnesses or from major bodily injuries can expect faster recovery times if they have an excess of stem cells(9).

Because stem cells are responsible for physical repair, having extra cells may lead to quicker overall recovery time and fewer long-term side effects as a result of the initial injury.In addition, a plethora of reparative stem cells can lead to fewer mistakes during the healing process or a better healing process in general.

While certain major injuries have a tendency to cause permanent damage or lower function depending on injury location, excess stem cells, bolstered by a good nutritional environment, may result in near-perfect healing of the wounded area. This effect has applications for cancer patients or victims of regular physical trauma from everyday accidents.

7. Stem cells supplements may delay the onset of aging.Regular aging side effects, ranging from common symptoms like the wrinkling of the skin to serious problems like diseases that affect the elderly, may be truncated or reduced thanks to healthy stem cell abundance.

Taking stem cell supplements will make your stem cells more plentiful and more effective in general. Both of these will result in a gentler aging process than is normal. Although stem cells cannot stop the aging process permanently, lessening the negative aspects of growing older will allow people to enjoy their later years more fully and allow them to maintain healthy lifestyles for longer. In many cases, aging side effects are exacerbated as older people become less active or stop making healthy choices as a result of chronic pain or discomfort. By remaining healthy for longer, this potentially destructive loop is delayed as well.

8. Stem cell supplements can lead to more effective stem cell activity, preventing the body from being as vulnerable to certain illnesses.The human body is naturally under attack from various viruses and other diseases at all times. While the immune system is normally quite effective at keeping out these potential threats, minor damage incurred from daily activity or normal cell replication can breach these defenses.

Having help from your stem cells can allow these gaps to be closed more quickly and lessen the chances of various viruses infiltrating a bodily system. While stem cells cannot directly stop diseases from entering a body, they can promote a greater immune response and a faster recovery time in the events that it does become infected (10).

9. Stem cell supplements can promote healthy weight due tothebodys greater ability to maintain itself.It is still important to maintain a good exercise routine and dietary guidelines, but many people struggle with staying within a healthy weight range even when keeping these factors in consideration.

Stem cells already work to keep a healthy body in a homeostatic condition, where will function most optimally. Boosting the number of stem cells in the bloodstream beyond their regular number will improve this effect and make it harder for your body to fall out of balance (11).

In addition, stem cells ability to improve muscle growth will allow for easier exercise improvements and consistency (12). Because stem cells passively boost overall energy, keeping up a healthy exercise routine will be more achievable for many people.

Combined with a good exercise routine and smart nutritional practices, lots of people can experience a body within a healthy weight much more easily.

10. Stem cells improved through supplements can help increase alertness. Research shows that stem cells that grow healthily and in good environments, boost brain function and cognitive effectiveness, this directly translates to a better attention span and greater alertness (13).

The possible uses for improved attention span and alertness are limitless. People suffering from chronic fatigue or who have to work a job during the nighttime hours can benefit from being more awake and being able to think more clearly than before. This can be particularly effective for professions such as doctors for emergency response personnel, where their jobs and the lives of others often depend on their alertness levels.

Greater attention span can also assist people who suffer from attention-based disorders, such as ADD, who may face greater challenges in life due to their condition.

1. Stem cell supplements may be harmful for the liver. Stem cell supplements which use blue-green algae as one of their key ingredients may impose certain side effects on their users (14).

While most people should be able to take blue-green algae without worry, some blue-green algae products may contain certain contaminants that can damage the liver. These negative components can be things like harmful bacteria, certain toxic metals, or microcystins.

2. Children should not take stem cell supplements in any form but especially those which contain blue-green algae. Children are generally more sensitive to blue-green algae products and may react negatively to ingesting or absorbing the substance in any way (15).

3. Stem cell supplements can cause IBS like symptoms. If contaminated blue-green algae are consumed by a supplement user, they may experience liver damage, weakness, rapid heartbeat, shock, thirst, vomiting, nausea, or stomach pain. More extreme reactions may result in death, so it is critical that anyone considering taking a stem cell supplement product ensures that the product uses cleared and contamination-free blue-green algae.

4. Women who are pregnant should avoid blue-green algae stem cell supplementation products due to the unforeseen side effects that stem cell production may have on an unborn fetus. Pregnant women already have more stem cells in their body due to the developing baby in their uterus and adding more stem cells to this process may complicate factors or lead to unforeseen developments that can cause negative health effects for either the mother or the child (16).

5, Finally, all boosts to stem cell production can inadvertently cause cancer, even in people that have not developed cancer in their life.The inherent risk of stem cells is that they can become any type of cell at all, including cancer cells(17).

Those with a family history of cancer should be careful when considering taking a stem cell supplement as this may increase their chances of developing cancer inadvertently.

Most stem cell supplements are taken either pill or spray form. Regardless of whichever method is used, dosages should not go above 500 mg taken twice daily, or 1000 mg in total per day. Depending on the exact product used, some stem cell supplements will have all of this limit reached with a single pill or tablet while others will require two or three tablets or capsules to reach 500-1000 mg.

Sprays are somewhat different. Recommended dosage varies by product and is harder to measure due to the application method used. However, users should avoid spraying too much of the supplement on to their skin at any one time. This will prevent oversaturation of compounds (such as blue-green algae) in the body and give the body time to adapt to the improvement of its stem cells.

How long does it take for stem cell supplements to work?The length of time between supplement administration and results varies greatly from product to product. This is because every persons stem cells are unique and will respond to boosting from supplementation differently. However, stem cell production occurs all the time, so results should not take very long to experience in some capacity.

What does stem cell pills do? Stem cell therapy, also known as regenerative medicine, promotes the repair response of diseased, dysfunctional, or injured tissue using stem cells or their derivatives.

Does fasting increase stem cells? Yes, MIT researchers have found that fastingdramatically improves stem cells ability to regenerate, in both aged and young mice.

Where do stem cells come from?Stem cells that are boosted by supplements come from bone marrow or other organs which may possess stem cell niches (18). These niches are where reparative stem cells reside in advance of damage for a particular organ or part of the body. In this way, stem cells are always around where they are needed to begin the healing process.

How long do stem cells live? Some stem cells have lasted five months and others for more than three years.

Do supplements create new stem cells?No. Stem cells are technically never truly replicated. This is because stem cells transform into the cells required for correct healing and restoration of damaged tissue (19).

Therefore, stem cells dont really replicate: they produce new cells which then perform the required task to ensure bodily health.New stem cells are made in the bone marrow or in stem cell niches throughout various internal organs or tissues (20).

Stem cell supplements boost stem cells by improving their effectiveness or creating positive environments where they can flourish and remain healthier for longer.Stem cells that are more effective have greater health benefits on the body, which is why supplements are effective.

Do stem cell supplements and therapywork for back pain? Yes, stem cell therapy may have the potential to be an alternative to invasive spine surgery.

Are stem cell supplements safe?Stem cell supplements do not have negative side effects as of yet. There have been no recorded medical issues as a result of ingesting or absorbing stem cell supplements. However, stem cells may cause cancer on their own, so promoting stem cell growth and activity may cause cancer down the road.

Overall, stem cell supplements by themselves are not dangerous or harmful. Children should not take stem cell supplements due to their developmental progress and an increase in possible side effects.

Does insurance pay for stem cell supplements and therapy? Medicare also does not cover stem cell injections. To be clear, proven bone marrow transplants/hematopoietic stem cell therapies such as for leukemia, which are established therapies covered by insurance, are a different story.

How long can you live after a stem cell transplant? A stem cell transplant may help you live longer. In some cases, it can even cure blood cancers. About 50,000 transplantations are performed yearly, with the number increasing 10% to 20% each year. More than 20,000 people have now lived five years or longer after having a stem cell transplant.

Does radiation kill stem cells? Radiation therapy and chemotherapy aimed at killing cancer cells may have the undesirable effect of helping to create cancer stem cells, which are thought to be particularly adept at generating new tumors and are especially resistant to treatment, researchers say.

How much are stem cell injections? The cost can vary, but is usually around $3,000 to inject one body area and $5000 for two areas. The final cost of the treatments will ultimately be determined by what particular injections are being done. Stem cell therapy and fat grafts are typically not covered by your insurance company.

How do stem cells start? Stem cells start off as a basic, undeveloped cell, that is sent to an area in need of new material. Once there, stem cells become the required cell to ensure proper organ or tissue function. Stem cells can become muscle cells, skin cells, blood cells, brain cells, or more. Because of this unique transformative ability, stem cells possess unparalleled healing capabilities.

The body naturally wears itself down from daily activity and from experiencing various damages and illnesses. Over time, these maladies pile up and impair function or lead to a lower quality of life. Ingesting or absorbing stem cell supplements can lessen these effects and improve many aspects of living.

How do stem cells affect gene expression? Stem cell supplements can favorably alter gene expression, lowering the possibility of cells replicating in error. In addition, stem cell supplements can also help your stem cells replicate more frequently which can lead to a better aging process, and a better quality of life.

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Top 10 Best Stem Cell Supplement Brands - Healthtrends

This formula has been utilized by Doctors and Professionals for decades and is now available to you. It provides you with natural and powerful support to power up your immune system against attacks.

Stronger, more powerful immune defense. Experience expedited healthy injury recovery. Healthy regeneration. Less sick days and a revitalized energy level.

IMMU-STEM is crafted with the most potent, all-natural ingredients for a stronger, powerful immune system. Spirulina has been clinically proven as a primary active ingredient to enhance and support the bodys response to viral contagion, for fast-acting protection, in an ever-changing world. Combined with other powerhouse botanicals you can enjoy less downtime due to sick days and extract more life enjoyment!

FIGHT VIRAL ATTACKS

Natural ingredients

Designed for optimal absorption

Complete trace mineral support

Made with Natural Ingredients with Health-Enhancing Properties

UNPARALLELED RESULTS

Supports Healthy Lifestyle

Naturally Supports the Body

Works at a cellular level to activate your own potential

Rich in antioxidants to fight free radicals

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Stem Cell Wellness Kit

Human stem cells are essential for the growth and maintenance of our organs, bones, and systems. They are also amazing tools of discovery for scientists at the Institute for Stem Cell and Regenerative Medicine and researchers around the world studying how to stop diseases. However, predatory businesses across the country are misusing the term stem cells to market unapproved, unproven, and unsafe procedures that are often expensive and largely ineffective. Its important to understand what stem cell therapy really means.

Lets start by creating two categories of stem cell therapies approved (by the FDA) and unapproved. Whether a stem cell therapy is approved or unapproved has critical implications for the science, effectiveness, and safety of the procedure.

(In addition to blood stem cell transplants), the FDA lists a limited number of additional approved products on its website.)

More recently, hundreds of businesses around the country referring to themselves as clinics have begun marketing various versions of stem cell therapy that promise to help patients with serious conditions like Parkinsons disease and more common ailments like joint pain. In reality, most of these types of stem cell therapy do not use stem cells at all. Rather, they remove tissues that presumably contains adult stem cells from one body part and inject those cells into another part of the body.

Furthermore, there is no proof that any stem cell therapy offered by stem cell clinics is effective or safe. Unlike FDA-approved procedures, which are subject to years of rigorous trials, unapproved treatments marketed directly to patients are developed and performed with little oversight. While stem cell clinics often tout testimonials from satisfied customers, there has never been a large-scale clinical trial to demonstrate that the perceived benefits of a stem cell therapy arent the result of a placebo effect. In recent years, the FDA has begun to expand regulations and enforcement of these clinics.

Thanks to decades of data, we know much more about the effectiveness of blood stem cell transplants. We also know they are not instant cures. While the procedure itself only lasts a few hours, recovery can take weeks. During this period, patients are monitored closely by physicians and nurses for side effects and for evidence of recovery.

There are side effects associated with approved and unapproved stem cell therapies. The possible side effects of blood stem cell transplants are detailed on the Cancer.org website. Patients considering an unapproved stem cell therapy should be aware that these procedures carry serious risks and that these risks may not be managed by a qualified care team. Injecting even a persons own tissue in a different body part has resulted in severe illness and, in some cases, blindness.

Therapies offered by stem cell clinics come with financial risk as well. Because these procedures are generally not covered by insurance, people seeking treatment are required to pay large out-of-pocket fees with no guarantee of improved health.

In their advertising, stem cell clinics promise unsubstantiated relief or even cures for everything from knee pain to Parkinsons disease, often taking advantage of vulnerable individuals who may feel they have nowhere else to turn. In reality, there is no strong evidence to back up claims that any stem cell therapy works let alone has lasting benefits.

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How Does Stem Cell Therapy Work and What Are the Risks? | ISCRM

The new report by Expert Market Research titled, GlobalHuman Embryonic Stem Cell MarketReport and Forecast 2022-2027, gives an in-depth analysis of the global human embryonic stem cell market, assessing the market based on its segments like applications and major regions. The report tracks the latest trends in the industry and studies their impact on the overall market. It also assesses the market dynamics, covering the key demand and price indicators, along with analysing the market based on the SWOT and Porters Five Forces models.

Get a Free Sample Report with Table of Contents:

The key highlights of the report include:https://bit.ly/3A1uYjO

Market Overview (2017-2027)

Historical Market Size (2020): USD 0.7 billion Forecast CAGR (2022-2027): 10%

The human embryonic stem cell market is being driven by the thriving medical sector. The rising demand for embryonic stem cells can be attributed to the increasing prevalence of chronic diseases around the world owing to the rising adoption of unhealthy and sedentary lifestyle among the youth and middle-class population. The increased risk of premature death as a result of chronic diseases is a growing concern. Therefore, human embryonic stem cells are gaining popularity in the medical sector. Furthermore, the increase in research grants and private as well as public funding for the development of effective and safe stem cell therapy products is further aiding the market growth. The rising investments from key players towards enhancing human embryonic cell therapy is expected to aid the market growth in the forecast period. In post-COVID days, as the various sectors recover from the negative impacts of the pandemic, human embryonic stem cells are likely to witness a rise in demand.

Industry Definition and Major Segments

Human embryonic stem cells, also known as human embryonic stem cells are self-replicating cells derived from human fetal tissue or human embryos that develop into tissues and cells of 3 primary layers. Furthermore, human embryonic stem cells are pluripotent and are roughly 3-5 days old. It is highly versatile, as it may split into new stem cells and even transform into any type of cell in the human body, allowing it to regenerate or repair any diseased organ or tissue.

Read Full Report with Table of Contents: https://bit.ly/3bor4HA

The human embryonic stem cell market, on the basis of application, can be segmented into:

Regenerative Medicine Stem Cell Biology Research Tissue Engineering Toxicology Testing

The regional markets for human embryonic stem cell include:

North America Europe Asia Pacific Latin America Middle East and Africa

Among these, North America represents a significant share of the human embryonic stem cell market.

Market Trends

The rising population along with the rapidly evolving medical infrastructure of emerging economies like India and China is expected to provide an impetus to the human embryonic stem cell market. Furthermore, technological advancements and increasing research and development investments and initiatives are expected to generate opportunities in the market. Researchers and scientists are increasingly leaning toward the transformation of human embryonic stem cells into a number of mature cell types that represent various tissues and organs in the body, as embryonic cells provide unequalled data relating to a variety of disorders. The increasing efforts by the governments of various nations towards enhancing human embryonic stem cell therapy is likely to be another key trend bolstering the market growth in the forecast period.

Key Market Players

The major players in the market Astellas Pharma Inc, Stemcell Technologies Inc., Biotime INC, Thermo Fisher Scientific, Inc., among others. The report covers the market shares, capacities, plant turnarounds, expansions, investments and mergers and acquisitions, among other latest developments of these market players.

About Us:

Expert Market Research (EMR) is a leading market research and business intelligence company, ensuring its clients remain at the vanguard of their industries by providing them with exhaustive and actionable market data through its syndicated and custom market reports, covering over 15 major industry domains. The companys expansive and ever-growing database of reports, which are constantly updated, includes reports from industry verticals like chemicals and materials, food and beverages, energy and mining, technology and media, consumer goods, pharmaceuticals, agriculture, and packaging.

EMR leverages its state-of-the-art technological and analytical tools, along with the expertise of its highly skilled team of over 100 analysts and more than 3000 consultants, to help its clients, ranging from Fortune 1,000 companies to small and medium-sized enterprises, easily grasp the expansive industry data and help them in formulating market and business strategies, which ensure that they remain ahead of the curve.

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Global Human Embryonic Stem Cell Market to be Driven by the Rapid Technological Advancements in the Forecast Period of 2022-2027 Designer Women -...

Kangstem Biotech said Monday that it has voluntarily withdrawn a phase 1 and 2a clinical trial investigational new drug (IND) approval for "FURESTEM-OA Kit Inj.," a candidate material for stem cell-based osteoarthritis (OA) treatment.

The company decided to withdraw its plans after determining that it required further data reinforcement concerning establishing a cell bank for clinical trial drugs after the government started enforcing the "Advanced Regenerative Medicine and Advanced Biopharmaceuticals Safety and Support Act."

The Ministry of Food and Drug Safety had requested the results of the adventitious virus-negative test from Kangstem Biotech. The test proves that even when the test drug used in clinical trials is manufactured using a cell bank, the quality and safety are the same, and there is no scientific risk factor.

Accordingly, the company confirmed that there is no adventitious virus by completing the virus test by the qPCR test method following the ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) regulations at Korean institutions.

Also, the company entrusted the test to the additional culture method of Charles River, an American consignment testing institution.

However, the company decided to voluntarily withdraw its IND approval, confirming it would be difficult to complete the test and analysis to secure additional data within the administrative processing period required for review of the clinical trial plan approval period.

"The IND application for the FURESTEM-OA Kit was for the first clinical trial for a stem cell-based fusion drug under the Advanced Regenerative Medicine and Advanced Biopharmaceuticals Safety and Support Act," Kangstems Clinical Development Division Director Bae Yo-han said. "Therefore, the IND approval process was somewhat delayed as the Ministry of Food and Drug Safety had to review its safety from various angles thoroughly."

During the delay period, additional test data that did not need to be initially submitted became a requirement, Bae added.

However, Bae stressed that the Ministry of Food and Drug Safety also believes that there are no additional problems in the clinical trial plan itself, other than a review on securing safety related to adventitious factors by ingredients used in the manufacturing process of the drug.

"Therefore, the company is aiming to re-apply for the phase 1 and 2a IND of the FURESTEM-OA Kit in July at the earliest and get approval within October," he said.

Due to the company's explanation, the company's shares rebounded on Wednesday after dropping about 5 percent the previous day.

As of 1:40 p.m. Tuesday, the company's stock price stood at 2,860 won ($2.22) per share, up 2.33 percent from the previous trading day.

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Kangstem Biotech withdraws trial application for stem cell-based osteoarthritis treatment - KBR

SEATTLE, June 13, 2022 (GLOBE NEWSWIRE) -- Sana Biotechnology, Inc. ( SANA), a company focused on creating and delivering engineered cells as medicines, today announced that the company will present data from its hypoimmune platform at the International Society for Stem Cell Research (ISSCR) 2022 Annual Meeting taking place from Wednesday, June 15 through Sunday, June 19 in San Francisco.

About Sana BiotechnologySana Biotechnology, Inc. is focused on creating and delivering engineered cells as medicines for patients. We share a vision of repairing and controlling genes, replacing missing or damaged cells, and making our therapies broadly available to patients. We are a passionate group of people working together to create an enduring company that changes how the world treats disease. Sana has operations in Seattle, Cambridge, South San Francisco, and Rochester.

Cautionary Note Regarding Forward-Looking StatementsThis press release contains forward-looking statements about Sana Biotechnology, Inc. (the Company, we, us, or our) within the meaning of the federal securities laws, including those related to the companys vision, progress, and business plans, the Companys participation at the ISSCR Annual Meeting, and the subject matter of the Companys presentations and data being presented at ISSCR Annual Meeting. All statements other than statements of historical facts contained in this press release, including, among others, statements regarding the Companys strategy, expectations, cash runway and future financial condition, future operations, and prospects, are forward-looking statements. In some cases, you can identify forward-looking statements by terminology such as aim, anticipate, assume, believe, contemplate, continue, could, design, due, estimate, expect, goal, intend, may, objective, plan, positioned, potential, predict, seek, should, target, will, would and other similar expressions that are predictions of or indicate future events and future trends, or the negative of these terms or other comparable terminology. The Company has based these forward-looking statements largely on its current expectations, estimates, forecasts and projections about future events and financial trends that it believes may affect its financial condition, results of operations, business strategy and financial needs. In light of the significant uncertainties in these forward-looking statements, you should not rely upon forward-looking statements as predictions of future events. These statements are subject to risks and uncertainties that could cause the actual results to vary materially, including, among others, the risks inherent in drug development such as those associated with the initiation, cost, timing, progress and results of the Companys current and future research and development programs, preclinical and clinical trials, as well as the economic, market and social disruptions due to the ongoing COVID-19 public health crisis. For a detailed discussion of the risk factors that could affect the Companys actual results, please refer to the risk factors identified in the Companys SEC reports, including but not limited to its Quarterly Report on Form 10-Q dated May 10, 2022. Except as required by law, the Company undertakes no obligation to update publicly any forward-looking statements for any reason.

Investor Relations & Media:Nicole Keith[emailprotected][emailprotected]

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Sana Biotechnology Announces Multiple Preclinical Data Presentations to Showcase Its Hypoimmune Platform, Including in Type 1 Diabetes, at the...

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Efficient terminal erythroid differentiation requires the APC/C cofactor Cdh1 to limit replicative stress in erythroblasts | Scientific Reports -...

MELBOURNE, Australia--(BUSINESS WIRE)--Propanc Biopharma, Inc. (OTCQB: PPCB) (Propanc or the Company), a biopharmaceutical company developing novel cancer treatments for patients suffering from recurring and metastatic cancer, today announced that the results from a small trial of just 18 rectal cancer patients in complete remission using an immunotherapy called dostarlimab are impressive, whilst acknowledging theres more work to be done. Chief Scientific Officer and Co-Founder, Dr Julian Kenyon MD, MB, ChB, believes that the fields biggest challenge remains that immunotherapies work inconsistently across cancers. Oncologists estimate a response rate of 20% across cancer types, according to the Wall Street Journal (WSJ). The drugs can wipe out cancers from some people, but fail to work for others. It is also uncertain whether the cancer may eventually return once a patient is in remission, even after a prolonged period of time.

Immunotherapies like dostarlimab, known as a checkpoint inhibitor, seek to inhibit key regulators of the immune system that when stimulated, reduces the bodys immune response to fight cancer. Given that immunotherapies target specific gene sequences, it often means they can encounter resistance, due to mutations that occur and genetic variation even within the primary tumor of a patient. As a result, Dr Cercek, from Memorial Sloan Kettering, who conducted the study for dostarlimab, estimates only 10% of rectal cancer patients and about 4% of all cancers will respond to treatment, according to the WSJ.

For many cancers, multiple factors can drive growth, making it hard to effectively match one biomarker, or a particular gene sequence, to a single drug. On the other hand, a therapeutic approach like our lead product candidate, PRP, which alters the characteristics of the cancer cell, by enforcing it to express proteins it normally wouldnt, means the treatment is less likely to encounter resistance through mutations, which is what we have observed in the lab as well as in clinical practice, said Dr Julian Kenyon.

In addition to specifically selecting the 18 rectal cancer patients according to their genetic biomarker, the trial included patients that were pre-metastatic, where tumors were locally advanced in one area, but not spread to other organs. This means patients identified with metastatic cancer were excluded from the trial. Therefore, the treatment and prevention of metastatic cancer, the main cause of patient death for sufferers, still remains the unsolved, final frontier. Cancer stem cells, which are the cells responsible for spreading to other parts of the body, remains a key focus for Dr Kenyon.

Dr Kenyon said, PRP is a proenzyme treatment that targets and eradicates cancer stem cells by altering multiple pathways of a cancerous cell rather than a single genetic sequence. Weve observed that once they are treated with PRP, the effects are irreversible and are more easily recognizable by the immune system, therefore potentially improving the response rates of standard approaches like immunotherapy, to overcome advanced cancers. We look forward to testing the utility of PRP with these approaches as we further advance into the clinic.

PRP is a mixture of two proenzymes, trypsinogen and chymotrypsinogen from bovine pancreas administered by intravenous injection. A synergistic ratio of 1:6 inhibits growth of most tumor cells. Examples include kidney, ovarian, breast, brain, prostate, colorectal, lung, liver, uterine and skin cancers.

About Propanc Biopharma, Inc.

Propanc Biopharma, Inc. (the Company) is developing a novel approach to prevent recurrence and metastasis of solid tumors by using pancreatic proenzymes that target and eradicate cancer stem cells in patients suffering from pancreatic, ovarian and colorectal cancers. For more information, please visit http://www.propanc.com.

The Companys novel proenzyme therapy is based on the science that enzymes stimulate biological reactions in the body, especially enzymes secreted by the pancreas. These pancreatic enzymes could represent the bodys primary defense against cancer.

To view the Companys Mechanism of Action video on its anti-cancer lead product candidate, PRP, please click on the following link: http://www.propanc.com/news-media/video

Forward-Looking Statements

All statements other than statements of historical facts contained in this press release are forward-looking statements, which may often, but not always, be identified by the use of such words as may, might, will, will likely result, would, should, estimate, plan, project, forecast, intend, expect, anticipate, believe, seek, continue, target or the negative of such terms or other similar expressions. These statements involve known and unknown risks, uncertainties and other factors, which may cause actual results, performance or achievements to differ materially from those expressed or implied by such statements. These factors include uncertainties as to the Companys ability to continue as a going concern absent new debt or equity financings; the Companys current reliance on substantial debt financing that it is unable to repay in cash; the Companys ability to successfully remediate material weaknesses in its internal controls; the Companys ability to reach research and development milestones as planned and within proposed budgets; the Companys ability to control costs; the Companys ability to obtain adequate new financing on reasonable terms; the Companys ability to successfully initiate and complete clinical trials and its ability to successful develop PRP, its lead product candidate; the Companys ability to obtain and maintain patent protection; the Companys ability to recruit employees and directors with accounting and finance expertise; the Companys dependence on third parties for services; the Companys dependence on key executives; the impact of government regulations, including FDA regulations; the impact of any future litigation; the availability of capital; changes in economic conditions, competition; and other risks, including, but not limited to, those described in the Companys periodic reports that are filed with the Securities and Exchange Commission and available on its website at http://www.sec.gov. These forward-looking statements speak only as of the date hereof and the Company disclaims any obligations to update these statements except as may be required by law.

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Propanc Biopharma's CSO Hails Dostarlimab's Impressive Results Whilst Acknowledging More Work to Be Done in the Fight Against Cancer - Business Wire

DURHAM, N.C.--(BUSINESS WIRE)--Precision BioSciences, Inc. (Nasdaq: DTIL), a clinical stage gene editing company developing ARCUS-based ex vivo allogeneic CAR T and in vivo gene editing therapies, today announced it has entered into an exclusive worldwide in vivo gene editing research and development collaboration and license agreement with Novartis Pharma AG (the Agreement). As part of the Agreement, Precision will develop a custom ARCUS nuclease that will be designed to insert, in vivo, a therapeutic transgene at a safe harbor location in the genome as a potential one-time transformative treatment option for diseases including certain hemoglobinopathies such as sickle cell disease and beta thalassemia.

Under the terms of the Agreement, Precision will develop an ARCUS nuclease and conduct in vitro characterization, with Novartis then assuming responsibility for all subsequent research, development, manufacturing and commercialization activities. Novartis will receive an exclusive license to the custom ARCUS nuclease developed by Precision for Novartis to further develop as a potential in vivo treatment option for sickle cell disease and beta thalassemia. Precision will receive an upfront payment of $75 million and is eligible to receive up to an aggregate amount of approximately $1.4 billion in additional payments for future milestones. Precision is also eligible to receive certain research funding and, should Novartis successfully commercialize a therapy from the collaboration, tiered royalties ranging from the mid-single digits to low-double digits on product sales.

We are excited to collaborate with Novartis to bring together the precision and versatility of ARCUS genome editing with Novartis gene therapy expertise and commitment to developing one-time, potentially transformative treatment for hard-to-treat inherited blood disorders, said Michael Amoroso, Chief Executive Officer at Precision BioSciences. This collaboration will build on the unique gene insertion capabilities of ARCUS and illustrates its utility as a premium genome editing platform for potential in vivo drug development. With this Agreement, Precision, either alone or with world-class partners, will have active in vivo gene editing programs for targeted gene insertion and gene deletions in hematopoietic stem cells, liver, muscle and the central nervous system showcasing the distinctive versatility of ARCUS.

We identify here a collaborative opportunity to imagine a unique therapeutic option for patients with hemoglobinopathies, such as sickle cell disease and beta thalassemia a potential one-time treatment administered directly to the patient that would overcome many of the hurdles present today with other therapeutic technologies, said Jay Bradner, President of the Novartis Institutes for Biomedical Research (NIBR), the Novartis innovation engine. We look forward to working with Precision and leveraging the ARCUS technology platform, which could bring a differentiated approach to the treatment of patients with hemoglobinopathies."

The in vivo gene editing approach that we are pursuing for sickle cell disease could have a number of significant advantages over other ex vivo gene therapies currently in development, said Derek Jantz, Ph.D., Chief Scientific Officer and Co-Founder of Precision BioSciences. Perhaps most importantly, it could open the door to treating patients in geographies where stem cell transplant is not a realistic option. We believe that the unique characteristics of the ARCUS platform, particularly its ability to target gene insertion with high efficiency, make it the ideal choice for this project, and we look forward to working with our partners at Novartis to bring this novel therapy to patients.

Upon completion of the transaction, Precision expects that existing cash and cash equivalents, expected operational receipts, and available credit will be sufficient to fund its operating expenses and capital expenditure requirements into Q2 2024.

Precision BioSciences Conference Call and Webcast Information

Precision's management team will host a conference call and webcast tomorrow, June 22, 2022, at 8:00 AM ET to discuss the collaboration. The dial-in conference call numbers for domestic and international callers are (866)-996-7202 and (270)-215-9609, respectively. The conference ID number for the call is 6252688. Participants may access the live webcast on Precision's website https://investor.precisionbiosciences.com/events-and-presentations in the Investors page under Events and Presentations. An archived replay of the webcast will be available on Precision's website.

About ARCUS and Safe harbor ARCUS Nucleases

ARCUS is a proprietary genome editing technology discovered and developed by scientists at Precision BioSciences. It uses sequence-specific DNA-cutting enzymes, or nucleases, that are designed to either insert (knock-in), remove (knock-out), or repair DNA of living cells and organisms. ARCUS is based on a naturally occurring genome editing enzyme, I-CreI, that evolved in the algae Chlamydomonas reinhardtii to make highly specific cuts in cellular DNA. Precision's platform and products are protected by a comprehensive portfolio including nearly 100 patents to date.

Precision can use an ARCUS nuclease to add a healthy copy of a gene (or payload) to a persons genome. The healthy copy of the gene can be inserted at its usual site within the genome, replacing the mutated, disease-causing copy. Alternatively, an ARCUS nuclease can be used to insert a healthy copy of the gene at another site within the genome called a safe harbor that enables production of the healthy gene product without otherwise affecting the patients DNA of gene expression patterns.

About Sickle Cell Disease and Beta Thalassemia

Sickle cell disease (SCD) is a complex genetic disorder that affects the structure and function of hemoglobin, reduces the ability of red blood cells to transport oxygen efficiently and, early on, progresses to a chronic vascular disease.1-4 The disease can lead to acute episodes of pain known as sickle cell pain crises, or vaso-occlusive crises, as well as life-threatening complications.5-7 The condition affects 20 million people worldwide.8 Approximately 80% of individuals with SCD globally live in sub-Saharan Africa and it is estimated that approximately 1,000 children in Africa are born with SCD every day and more than half will die before they reach five.9,10 SCD is also a multisystem disorder and the most common genetic disease in the United States, affecting 1 in 500 African Americans. About 1 in 12 African Americans carry the autosomal recessive mutation, and approximately 300,000 infants are born with sickle cell anemia annually.11 Even with todays best available care, SCD continues to drive premature deaths and disability as this lifelong illness often takes an extreme emotional, physical, and financial toll on patients and their families.12,13

Beta thalassemia is also an inherited blood disorder characterized by reduced levels of functional hemoglobin.14 The condition has three main forms minor, intermedia and major, which indicate the severity of the disease.14 While the symptoms and severity of beta thalassemia varies greatly from one person to another, a beta thalassemia major diagnosis is usually made during the first two years of life and individuals require regular blood transfusions and lifelong medical care to survive.14 Though the disorder is relatively rare in the United States, it is one of the most common autosomal recessive disorders in the world.14 The incidence of symptomatic cases is estimated to be approximately 1 in 100,000 individuals in the general population.14, 15 The frequency of beta-thalassemia mutations varies by regions of the world with the highest prevalence in the Mediterranean, the Middle-East, and Southeast and Central Asia. Approximately 68,000 children are born with beta-thalassemia.16

About Precision BioSciences, Inc.

Precision BioSciences, Inc. is a clinical stage biotechnology company dedicated to improving life (DTIL) with its novel and proprietary ARCUS genome editing platform. ARCUS is a highly precise and versatile genome editing platform that was designed with therapeutic safety, delivery, and control in mind. Using ARCUS, the Companys pipeline consists of multiple ex vivo off-the-shelf CAR T immunotherapy clinical candidates and several in vivo gene editing candidates designed to cure genetic and infectious diseases where no adequate treatments exist. For more information about Precision BioSciences, please visit http://www.precisionbiosciences.com.

Forward-Looking Statements

This press release contains forward-looking statements, as may any related presentations, within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this herein and in any related presentation that do not relate to matters of historical fact should be considered forward-looking statements, including, without limitation, statements regarding the goal of providing a one time, potentially curative treatment for certain hemoglobinopathies, the success of the collaboration with Novartis, including the receipt of any milestone, royalty, or other payments pursuant to and the satisfaction of obligations under the Agreement, clinical and regulatory development and expected efficacy and benefit of our platform and product candidates, expectations about our operational initiatives and business strategy, expectations about achievement of key milestones, and expected cash runway. In some cases, you can identify forward-looking statements by terms such as aim, anticipate, approach, believe, contemplate, could, estimate, expect, goal, intend, look, may, mission, plan, potential, predict, project, should, target, will, would, or the negative thereof and similar words and expressions. Forward-looking statements are based on managements current expectations, beliefs and assumptions and on information currently available to us. Such statements are subject to a number of known and unknown risks, uncertainties and assumptions, and actual results may differ materially from those expressed or implied in the forward-looking statements due to various important factors, including, but not limited to: our ability to become profitable; our ability to procure sufficient funding and requirements under our current debt instruments and effects of restrictions thereunder; risks associated with raising additional capital; our operating expenses and our ability to predict what those expenses will be; our limited operating history; the success of our programs and product candidates in which we expend our resources; our limited ability or inability to assess the safety and efficacy of our product candidates; our dependence on our ARCUS technology; the initiation, cost, timing, progress, achievement of milestones and results of research and development activities, preclinical studies and clinical trials; public perception about genome editing technology and its applications; competition in the genome editing, biopharmaceutical, and biotechnology fields; our or our collaborators ability to identify, develop and commercialize product candidates; pending and potential liability lawsuits and penalties against us or our collaborators related to our technology and our product candidates; the U.S. and foreign regulatory landscape applicable to our and our collaborators development of product candidates; our or our collaborators ability to obtain and maintain regulatory approval of our product candidates, and any related restrictions, limitations and/or warnings in the label of an approved product candidate; our or our collaborators ability to advance product candidates into, and successfully design, implement and complete, clinical or field trials; potential manufacturing problems associated with the development or commercialization of any of our product candidates; our ability to obtain an adequate supply of T cells from qualified donors; our ability to achieve our anticipated operating efficiencies at our manufacturing facility; delays or difficulties in our and our collaborators ability to enroll patients; changes in interim top-line and initial data that we announce or publish; if our product candidates do not work as intended or cause undesirable side effects; risks associated with applicable healthcare, data protection, privacy and security regulations and our compliance therewith; the rate and degree of market acceptance of any of our product candidates; the success of our existing collaboration agreements, and our ability to enter into new collaboration arrangements; our current and future relationships with and reliance on third parties including suppliers and manufacturers; our ability to obtain and maintain intellectual property protection for our technology and any of our product candidates; potential litigation relating to infringement or misappropriation of intellectual property rights; our ability to effectively manage the growth of our operations; our ability to attract, retain, and motivate key executives and personnel; market and economic conditions; effects of system failures and security breaches; effects of natural and manmade disasters, public health emergencies and other natural catastrophic events; effects of COVID-19 pandemic and variants thereof, or any pandemic, epidemic or outbreak of an infectious disease; insurance expenses and exposure to uninsured liabilities; effects of tax rules; risks related to ownership of our common stock and other important factors discussed under the caption Risk Factors in our Quarterly Report on Form 10-Q for the quarterly period ended March 31, 2022, as any such factors may be updated from time to time in our other filings with the SEC, which are accessible on the SECs website at http://www.sec.gov and the Investors page of our website under SEC Filings at investor.precisionbiosciences.com.

References

1 Saraf SL, et al. Paediatr Respir Rev. 2014;15(1):4-12.2 Stuart MJ, et al. Lancet. 2004;364(9442):1343-1360.3 National Institutes of Health (NIH). Sickle cell disease. Bethesda, MD. U.S. National Library of Medicine. 2018:1-7.4 Conran N, Franco-Penteado CF, Costa FF. Hemoglobin. 2009;33(1):1-16.5 Ballas SK, et al. Blood. 2012;120(18):3647-3656.6 Elmariah H, et al. Am J Hematol. 2014(5):530-535.7 Steinberg M. Management of sickle cell disease. N Engl J Med. 1999;340(13):1021-1030.8 National Heart Lung and Blood Institute: What Is Sickle Cell Disease? 9 Odame I. Perspective: We need a global solution. Nature. 2014 Nov;515(7526):S1010 Scott D. Grosse, Isaac Odame, Hani K. Atrash, et al. Sickle Cell Disease in Africa: A Neglected Cause of Early Childhood Mortality. American Journal of Preventive Medicine 41, no. S4 (December 2011): S398-40511 Sedrak A, Kondamudi NP. Sickle Cell Disease. [Updated 2021 Nov 7]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-.12 Sanger M, Jordan L, Pruthi S, et al. Cognitive deficits are associated with unemployment in adults with sickle cell anemia. Journal of Clinical and Experimental Neuropsychology. 2016;38(6):661-671.13 Anim M, Osafo J, Yirdong F. Prevalence of psychological symptoms among adults with sickle cell disease in Korie-Bu Teaching Hospital, Ghana. BMC Psychology. 2016;4(53):1-9.14 NORD Rare Disease Database: Beta Thalassemia 15 Galanello R, Origa R. Orphanet J Rare Dis. 2010;5:1116 Needs T, Gonzalez-Mosquera LF, Lynch DT. Beta Thalassemia. [Updated 2022 May 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-.

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Precision BioSciences Announces In Vivo Gene Editing Collaboration with Novartis to Develop Potentially Curative Treatment for Disorders Including...

The last decade of immunotherapy progress was based on decades of prior research, including other forms of immunotherapy.

Until recent years, cancer treatment revolved around surgery, chemotherapy, and radiation. But the FDA approval of ipilimumab (Yervoy) in 2011 led to a fourth leg of that treatment stool: immunotherapy. This enabled new treatment paradigms, sometimes with shocking levels of success.

The types of immunotherapy treatments available are proliferating, with approved immune checkpoint inhibitors (ICIs) and cellular therapies like chimeric antigen receptor (CAR) T cells as well as other modalities in the research and discovery phases. Some even include more established approaches like vaccines that are being revisited with new information and iterations.

The last decade of immunotherapy progress was based on decades of prior research, including other forms of immunotherapy. The Bacillus Calmette-Gurin vaccine, used to prevent tuberculosis for a century, has also been used as an immunotherapy to treat nonmuscle invasive bladder cancer since 1990.1 And rituximab (Rituxan), a monoclonal antibody therapy approved in 1997 for B-cell malignancies, is seen by some as an early immunotherapy as well.2

What many clinicians think of in terms of immunotherapy, however, are treatments targeting CTLA-4 and PD-1/PD-L1 pathways, brought from the bench by James P. Allison, PhD, and Tasuku Honjo, PhD, respectively, leading to a Nobel Prize awarded jointly to them in 2018.3

Immune responses are tightly controlled by T cells, and these T cells have on/off switches that help control their responses, according to Padmanee Sharma, MD, PhD, a professor in the Department of Genitourinary Medical Oncology in the Division of Cancer Medicine and the scientific director of the James P. Allison Institute at The University of Texas MD Anderson Cancer Center in Houston. Previously, she said, clinicians were not aware of the off switches. Allison showed that CTLA-4 was an inhibitory pathway and that by blocking it, the T cells could stay longer to eradicate the tumors.

With 8 ICIs approved for immunotherapy in hematological and solid tumors,4 researchers are not only investigating newer forms of therapy, but also combining them to fi nd more effective and durable treatments and introducing them into earlier lines of treatment (TIMELINE). Current research is also attempting to predict who will respond to which therapy based on current and emerging biomarkers.

Ipilimumab, which kicked off the current era of cancer immunotherapy treatment with FDA approval in 2011, targets CTLA-4 for newly diagnosed or previously treated unresectable or metastatic melanoma.5 Ipilimumab blocks CTLA-4, removing its inhibitory signals. This allows the T cells to activate and launch an immune response to the tumors antigens.

CTLA-4 is basically the fi rst inhibitory pathway that comes up on the T cells, Sharma said. CTLA-4 is a member of an immunoglobulin-related receptor family responsible for some immune regulation aspects of T cells.6 It is thought to regulate T-cell proliferation mostly in lymph nodes, early in an immune response, by having an inhibitory role.7

What ipilimumab really did and what the immune checkpoint inhibitors really did is they opened up this whole different way to approach the immune system, Elizabeth Buchbinder, MD, a medical oncologist at Dana-Farber Cancer Institute and an assistant professor of medicine at Harvard Medical School in Boston, Massachusetts, said. Ipilimumab provided amazing durable responses in patients with melanoma with widely metastatic disease, some of whom were alive 10 years later, she said.

The PD-1 and PD-L1 blockades build on ipilimumabs success. Like CTLA-4, PD-1 is a negative regulator of T-cell immune function, inhibiting the target to increase immune system activation. PD-1 suppresses T cells mostly in the peripheral tissues.7 As of November 2021, 8 ICIs have been approved that target CTLA-4, PD-1, and PD-L1 pathways and treat 18 types of cancer.3

AntiPD-1 inhibitors

The percentage of people who benefi tted from ipilimumab was on the low side, Buchbinder said, with only an 11% response rate and 20% of people doing well long term in clinical trials. With PD-1 inhibition, however, there was approximately a 40% response rate and many more patients doing well long term, as demonstrated in clinical trials. So [PD-1 inhibition is] both far more effective and also less toxic, Buchbinder said.

When choosing an agent in the PD-1 class, we dont need to differentiate them. Theyre all antiPD-1, Sharma explained. There arent any data to indicate that patients will respond any differently to pembrolizumab [Keytruda] vs nivolumab [Opdivo]. The mechanism of action for both drugs [is] exactly the same.

Instead, clinicians should consider the FDA approvals for each drugs indications and combinations. But from a scientific standpoint, theres no distinguishing between [them], Sharma said.

AntiPD-L1 inhibitors

PD-1 and PD-L1 targeting drugs were found to work beyond melanoma and kidney cancer, the early indications for treatments targeting the CTLA-4 pathway, Buchbinder said. That was a huge opening up of this fi eld to all of these other cancers, like lung cancer, head and neck cancer, GI [gastrointestinal] cancer, breast [cancer], and beyond, she said.

Before receiving these immunotherapies, patients may need to show PD-1 or PD-L1 expression, although this may not identify all patients who can benefi t from the treatments. Researchers continue to try to identify additional and better biomarkers to indicate which patients may respond.13

In March, the FDA approved the newest ICI, nivolumab and relatlimab-rmbw (Opdualag), for adult and pediatric patients (12 years and older) with unresectable or metastatic melanoma. 3 Nivolumab is a PD-1 inhibitor, and relatlimab blocks LAG3 proteins on immune cells. It is being tested in a lot of other tumors, Buchbinder noted.

Another target in the discovery phase is T cell immunoglobulin and mucin domain 3, which is a checkpoint receptor expressed by many immune cells and leukemic stem cells.14 It is activated by several ligands and is being tested in different cancer types.

Also in clinical trials are tumor-infiltrating lymphocytes (TIL) that recognize cancer cells as abnormal, entering the tumor to kill the cells. TILs already recognize the targets because they originate from the tumor itself.15 Although they need to be expanded, they are not the same as CAR T cells, which must be engineered to recognize the targets.

In addition, older therapies are experiencing a resurgence, with research underway to make interleukin 2 (IL-2) help cytokines function better. That work is trying to optimize what those cytokines do in the body and the immune system, Buchbinder said. There are so many areas where the goal of the therapy is activation of the immune system.

One of these areas includes a return to vaccines. In earlier vaccine therapy, We had no idea that while we were giving therapy to turn on the cells, we were also rapidly turning off the cells because an on switch will automatically drive an off switch for the immune system, Sharma said. The yin and the yang of the immune response is very important to understand because when the immune response is driven in one direction, it will always try to control itself. With that in mind, newer vaccines might work better if given in combination with an antiCTLA-4, for example, to block the inhibitory pathways, she said.

Vaccines are taking many forms, including the mRNA vaccine used for COVID-19, peptide vaccines that include a tiny bit of protein that is expected to be expressed on the tumor surface, and vaccines constructed from dendritic cells, which stimulate T cells, Buchbinder said.

There are also viral therapies injected directly into tumor vaccines, such as talimogene laherparepvec (Imlygic) approved in 2015 for the treatment of some patients with metastatic melanoma that cannot be surgically removed.16 It is a is a modifi ed herpes virus directly injected into the tumor to bring about a local immune response, Buchbinder said.

According to Sharma, approximately 60 targets are currently being evaluated for immunotherapy development.

The FDA has approved 2 CAR T-cell therapies, both in 2017: tisagenlecleucel (Kymriah) for patients 25 years and younger with relapsed B-cell precursor acute lymphoblastic leukemia17 and axicabtagene ciloleucel (Yescarta) for the treatment of adult patients with large B-cell lymphoma that is refractory to fi rst-line chemoimmunotherapy or that relapses within 12 months of fi rst-line chemoimmunotherapy.18 These treatments involve collecting T cells from the patient and engineering them to express CARs that recognize the patients cancer cells. The cells are then enlarged and infused back into the patient, where they can target the antigen- expressing cancer cells. CARs have been shown to greatly improve clinical response and disease remission in some patients.19

I think CAR T cells are clearly building on the concept that T cells are the soldiers of immune response. They are basically engineering the cell to have an antibody that recognizes a specifi c antigen, Sharma said, adding that its important to ensure the targeted antigen is part of the cancer.

CAR T cells have had limited effectiveness in treating solid tumors, given the low T-cell infiltration and immunosuppressive environment that challenges the immune system from successfully reaching and killing solid tumor cancer cells.20

Natural killer (NK) cells are another cell type being researched to attempt tumor eradication, and this therapy is in the early stages, according to Sharma. CAR NK cells can be generated from allogenic donors, making them more attractive as off the shelf treatments compared with CAR T cells, which are collected from the patient. As of early 2021, more than 500 CAR T-cell trials and 17 CAR T-cell/NK-cell trials were in the works globally.21

A major consideration when choosing any treatment, including immunotherapies, is the adverse event (AE) profile. Immunotherapy drugs have different AEs than oncology treatments like chemotherapy or radiation. [With immunotherapy,] what we see is infl ammation because youre turning on the immune system in such a powerful way, Sharma said. Inflammatory reactions include a skin rash or dermatitis, infl ammation in the colon (colitis and diarrhea), and/or infl ammation in the lung with pneumonitis. Clinicians are now aware of these AEs and can monitor them closely, stopping therapy if needed to control them before they become severe, Sharma said.

Toxicities with ipilimumab can be severe, and patients requiring hospital admission might need high-dose steroids, Buchbinder noted. Common AEs for the CTLA-4 inhibitor are typically GI related, including diarrhea, colitis, and hepatitis. Some patients may experience fatigue or a small rash, but most generally make it through treatment with minimal AEs.

The stronger AEs with ipilimumab can be seen from a trial comparing ipilimumab plus nivolumab to nivolumab and relatlimab. Almost 60% of patients experienced AEs with the ipilimumab combination vs 20% in the latter group.17

PD-1 and PD-L1 inhibition typically involve AEs that cause lung issues rather than GI. The types of organ systems affected by immunotherapy AEs can vary based upon which checkpoint inhibitor you use but in some ways, the mechanism by which these occur is very similar, Buchbinder said. Its all an overactivation of the immune system leading to infl ammation in an organ, and there are very few organs that we have not seen toxicity from immunotherapy.

Buchbinder noted that cellular therapies can cause more severe AEs, such as cytokine release syndrome (CRS). Patients can get very sick very quickly, she said, because the therapies given with the cellsincluding the chemotherapy given before and the IL-2 given aftercause most of the AEs. With a lot of the injection therapies, the AEs are related to delivery method, like injection-site issues, but there are also potential systemic AEs like fever, chills, and reactions someone would get to a virus. Its really a huge range in terms of the different [adverse] effects, Buchbinder said.

CRS is the most common AE of CAR T-cell therapy, and it is caused by large numbers of T cells activating, which releases inflammatory cytokines. Although this demonstrates that the therapy is working, it can cause worrisome symptoms. The CRS and the related neurotoxicity can be treated with tocilizumab (Actemra).

One question in the immunotherapy world is whether the development of immune-related AEs predicts a positive or negative response to treatment. With melanoma, we think the data have been very tricky, Buchbinder said. Early trials appeared to show a higher response rate for patients who developed severe symptoms, but as trials developed, that signal was not always there. I think the overall impression is that yes, severe AEs are associated with a better response, she said. A cosmetic AE that clinicians who treat melanoma are excited to see, she said, is vitiligo. It suggests that the immune system is attacking normal melanocytes and that it is attacking cancer cells as well. Those patients generally do far better than patients who dont get vitiligo.

A meta-analysis of 30 studies on the topic, including 4971 individuals, showed that patients who developed immune-related AEs experienced an overall survival benefi t and a progression-free survival benefi t using ICI therapy compared with those who did not. The authors stated that more studies are needed and that the results are controversial.22

Melanoma has been the proving ground for ICIs, Buchbinder said, But now the bar is higher in terms of immunotherapy.

ICIs are now being tested in more immuneresistant tumors. Although there are huge hurdles in terms of some cancers where its going to be hard for immune therapy to do muchlike pancreatic cancer or prostate cancerthere are still diseases where theres opportunity and a possibility that the correct approach or combination might get to some great therapy for those diseases, Buchbinder said

Immunotherapies are being combined with conventional therapies to better integrate treatment. We dont see cancer as a death sentence anymore, Sharma said. We really do see a lot of hope, [and patients with cancer] should be encouraged to discuss immunotherapy with their physician either in a clinical trial or an FDA-approved agent. If you do have a response, its a pretty phenomenal response.

REFERENCES:

1. Lobo N, Brooks NA, Zlotta AR, et al. 100 years of Bacillus Calmette- Gurin immunotherapy: from cattle to COVID-19. Nat Rev Urol. 2021;18(10):611-622. doi:10.1038/s41585-021-00481-1

2. Pierpont TM, Limper CB, Richards KL. Past, present, and future of rituximab-the worlds fi rst oncology monoclonal antibody therapy. Front Oncol. 2018;8:163. doi:10.3389/fonc.2018.00163

3. Kruger S, Ilmer M, Kobold S, et al. Advances in cancer immunotherapy 2019 - latest trends. J Exp Clin Cancer Res. 2019;38(1):268. doi:10.1186/s13046-019-1266-0

4. Lee JB, Kim HR, Ha SJ. Immune checkpoint inhibitors in 10 years: contribution of basic research and clinical application in cancer immunotherapy. Immune Netw. 2022;22(1):e2. doi:10.4110/in.2022.22.e2

5. FDA approves Yervoy (ipilimumab) for the treatment of patients with newly diagnosed or previously-treated unresectable or metastatic melanoma, the deadliest form of skin cancer. News release. Bristol Myers Squibb. March 25, 2011. Accessed May 11, 2022. https://bit.ly/3PFp7q2

6. Rowshanravan B, Halliday N, Sansom DM. CTLA-4: a moving target in immunotherapy. Blood. 2018;131(1):58-67. doi:10.1182/ blood-2017-06-741033

7. Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol. 2016;39(1):98-106. doi:10.1097/COC.0000000000000239

8. Keown A. Keytruda approvals: a timeline. BioSpace. Aug 13, 2019. Accessed May 11, 2022. https://bit.ly/3yHvfrL

9. Stewart J. Opdivo FDA approval history. Drugs.com. Updated March 15, 2022. Accessed May 20, 2022. https://bit.ly/3lnmtar

10. Markham A, Duggan S. Cemiplimab: fi rst global approval. Drugs. 2018;78(17):1841-1846. doi:10.1007/s40265-018-1012-5

11. FDA grants accelerated approval to dostarlimab-gxly for dMMr endometrial cancer. FDA. Updated April 22, 2021. Accessed May 20, 2022. https://bit.ly/38BSJns

12. Pierpont TM, Limper CB, Richards KL. Past, present, and future of rituximab-the worlds first oncology monoclonal antibody therapy. Front Oncol. 2018;8:163. doi:10.3389/fonc.2018.00163

13. Opdualag becomes fi rst FDA-approved immunotherapy to target LAG-3. National Cancer Institute. April 6, 2022. Accessed May 11, 2022. https://bit.ly/3FZWaAp

14. Acharya N, Sabatos-Peyton C, Anderson AC. TIM-3 finds its place in the cancer immunotherapy landscape. J Immunother Cancer. 2020;8(1):e000911. doi:10.1136/jitc-2020-000911

15. Boldt C. TIL Therapy: 6 things to know. MD Anderson Cancer Center. April 15, 2021. Accessed May 11, 2022. https://bit.ly/3wmguJb

16. FDA approves talimogene laherparepvec to treat metastatic melanoma. National Cancer Institute. November 25, 2015. Accessed May 20, 2022. https://bit.ly/3woTDwA

17. OLeary MC, Lu X, Huang Y, et al. FDA approval summary: tisagenlecleucel for treatment of patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Clin Cancer Res. 2019;25(4):1142-1146. doi:10.1158/1078-0432.CCR-18-2035

18. FDA approves CAR-T cell therapy to treat adults with certain types of large B-cell lymphoma. News release. FDA. Oct. 18, 2017. Accessed May 11, 2022. https://bit.ly/3wpECL1

19. FDA approves fi rst CAR T-cell therapy the evolution of CAR T-cell therapy. Cell Culture Dish. October 24, 2017. Accessed May 10, 2022. https:// bit.ly/3LlDD2B

20. Albinger N, Hartmann J, Ullrich E. Current status and perspective of CAR-T and CAR-NK cell therapy trials in Germany. Gene Ther. 2021;28:513-527. doi:10.1038/s41434-021-00246-w

21. Ahmad A, Uddin S, Steinhoff M. CAR-T cell therapies: an overview of clinical studies supporting their approved use against acute lymphoblastic leukemia and large B-cell lymphomas. Int J Mol Sci. 2020;21(11):3906. doi:10.3390/ijms21113906

22. Zhou X, Yao Z, Yang H, Liang N, Zhang X, Zhang F. Are immune-related adverse events associated with the efficacy of immune checkpoint inhibitors in patients with cancer? a systematic review and meta-analysis. BMC Med. 2020;18(1):87. doi:10.1186/s12916-020-01549-2

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10 Years of Immunotherapy: Advances, Innovations, and Better Patient Outcomes - Targeted Oncology

Why do some heavy smokers never get lung cancer? And why do some people who never smoke get lung cancer? Answers are emerging for both of those questions. In both cases, much depends on our individual genetic make-up.

Lung cancer is the second most common cancer worldwide, accounting for2.2 million new cases and 1.8 million deaths in 2020. It is also the most commonly occurring cancer for which the major cause is both known and preventable. Yet there remain mysteries about causation of lung cancer. How do some heavy smokers manage to avoid lung cancer? And what accounts for the occurrence of lung cancer in people who have never smoked?

In a just-published study, researchers at the Albert Einstein College of Medicine in the Bronx have found that some smokers DNA appears to become accustomed to the cancer-causing agents in cigarettes. This may help prevent dangerous mutations that result in lung cancer.

The heaviest smokers did not have the highest mutation burden, lead study author Dr. Simon Spivack said in a statement. Our data suggests these individuals may have survived for so long in spite of their heavy smoking because they managed to suppress further mutation accumulation. This leveling off of mutations could stem from these people having very proficient systems for repairing DNA damage or detoxifying cigarette smoke.

While this explanation may account for one mystery, another remains: What about the hundreds of thousands of people throughout the world who get lung cancer every year but never so much as took a drag?

Cigarette smoking accounts for between 80 and 90 percent of lung cancer cases in the West. The vast majority of lung cancers in high-income countries could be prevented if all smokers gave up their habit. While this is not likely to happen, just noting this fact is a crucial starting point for any discussion of lung cancer.

The only other common non-skin cancer for which the predominant cause has been identified is cervical cancer, which is caused by the human papilloma virus (HPV), and which can be almost totally prevented by vaccination.

There are striking differences in the epidemiologic, clinical, and biological characteristics of lung cancer in different parts of the world. In the U.S., where nearly 240,000 cases of lung cancer are diagnosed each year and where there are 130,000 deaths annually from the disease, lung cancer rates are roughly comparable in men and women, and are decreasing in both sexes. In contrast, in China, lung cancer rates are increasing in both sexes, but are roughly twice as high in males compared to females.

While most lung cancer in the West is associated with smoking, worldwide, it has been estimated that 15 percent of men and 53 percent of all women with lung cancer worldwide are never smokers.

Lung cancer in never smokers (LCINS), which tends to be of the adenocarcinoma cell type, is found predominantly in women and in East Asians. In contrast, the most common cell types found in lung cancer occurring in smokers are squamous cell and small cell types.

When considered as a distinct disease entity, lung cancer in never smokers ranked as the 7th most common cause of cancer death and the 11th or 12th most common incident type of cancer.

For at least 40 years, we have tried to identify environmental risk factors that might explain the occurrence of lung cancer in people who have never smoked. Potential factors that have been studied include passive smoking; residential exposure to radon gas; exposure to cooking fumes from coal and other fuels (particularly, in low-income countries); general air pollution; pre-existing lung disease; hormonal/reproductive factors (that might help account for the more frequent occurrence in women who never smoked); and inherited susceptibility. Other potential risk factors include asbestos and oncogenic viruses.

Although numerous studies have examined these factors, they appear to have relatively weak effects and are unlikely to account for the majority of cases (here, here, and here).

A 2012 review of the epidemiology of lung cancer in never smokers concluded that, In any event, a large fraction of lung cancers occurring in never smokers cannot be definitively associated with established environmental risk factors, highlighting the need for additional epidemiologic research in this area.

If strong environmental risk factors that account for lung cancer in never smokers are lacking, research examining molecular markers and driver mutations has produced novel and potentially clinically actionable results. Current evidence indicates that LCINS is a distinct disease with unique molecular and genetic characteristics.

Cancer results from the binding of mutagens to the DNA of critical genes, including tumor suppressor genes, proto-oncogenes, and genes involved in DNA repair. If the damage is not repaired, the transformed cell can go on to produce a clone, which can go on to develop into a full-blown (i.e., clinical) cancer. Tobacco smoke contains more than 60 mutagens that bind to, and chemically modify, DNA, leaving a distinctive mutational imprint on the lung cancer genome.

However, identifying the specific mutations that account for the potent carcinogenic effect of smoking on lung cancer has proved a challenge. The recent study from Albert Einstein College of Medicine used a new method to identify mutations in the progenitor cells that give rise a cell type that is susceptible to lung cancer (basal lung epithelial cells).

The researchers examined normal lung tissue from 14 never smokers and 19 smokers. Only one of the former had lung cancer, whereas 13 of the latter had lung cancer. The number of mutations increased with age in both smokers and never smokers, and with increasing pack-years of smoking up to 23 pack-years among smokers, but with no further increase in heavy smokers. However, the one never smoker who developed lung cancer did not have more mutations in normal lung cells than the never smokers who were free of lung cancer.

Notably, the smokers who developed lung cancer did not have more mutations in their normal lung tissue than the smokers who did not develop lung cancer. Thus, it is not clear which mutations associated with smoking determine who goes on to develop lung cancer, or whether it is a matter of susceptibility factors or just bad luck.

Although smoking is a powerful risk factor for lung cancer, its also known that susceptibility genes also play a role in lung cancer, as well as in cancer generally. This is apparent from the fact that most smokers never develop lung cancer.

Its been long recognized that the pattern of lung cancer in Asia differs from that seen in the West. Smoking rates have been much lower in Asian women compared to Asian men, and women tend to develop the adenocarcinoma cell type, which occurs in the periphery of the lung, as opposed to squamous cell and small cell lung cancer, which occur in the main bronchi.

In the early 2000s it was noted that the response to treatment with epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitors, such as gefitinib and erlotinib, among patients with non-small cell lung cancer (NSCLC) was markedly more effective in never smokers than in smokers. The benefit of treatment included statistically significant increased response rates, longer interval to progression, and/or longer median overall survival. This improved clinical response was most evident in patients from East Asia, in women, and in cases with the adenocarcinoma cell type.

Thus, lung cancer in smokers and that occurring in never smokers, particularly in East Asian women, appear to present two contrasting facets of lung cancer. In the first case, a potent carcinogen has been identified, but the precise way in which it causes cancer is unclear. In the second instance, a driver mutation which leads to cancer has been identified in a large proportion of cases, but evidence for environmental triggers is either weak or lacking. (A driver mutation is a genetic alteration that is responsible for both the initiation and progression of cancer).

Other research has identified a number of striking differences in genomic signatures and driver mutations between lung cancers occurring in smokers versus in those who have never smoked. For example, mutations in the tumor suppressor gene TP53 are more common in lung cancers in smokers than in LCINS. In addition, mutations in the KRAS oncogene are also common in lung cancers occurring in smokers but are rare in LCINS (43% vs. 0%). Conversely, EGFR mutations are common in LCINS but rare in lung cancer occurring in smokers (in one large study: 54% vs. 16%).

In addition, next generation sequencing studies indicate that the total number of mutations involving genes in protein coding regions was significantly higher in smokers than in never smokers (median 209 vs. 18). This represents a 90 percent lower incidence of mutations in never smokers.

The smaller number of genetic alterations identified in lung cancer in never smokers suggests that the majority, if not all, may play a role in the carcinogenic process. For this reason, it has been suggested that lung cancer in never smokers may provide a relatively enriched and easily identified set of oncogenic drivers for lung cancer.

The more frequent occurrence of EGFR mutations in LCINS has been found in different populations and geographic regions. The discovery of activating EGFR-TK mutations led to a number of randomized clinical trials comparing EGFR-TK inhibitors to chemotherapy in the front-line treatment of patients with EGFR-TK mutations. These trials have now established EGFR-TK inhibitors as the standard front-line treatment for patients with advanced-stage NSCLC that is positive for EGFR-TK mutation. Patients who harbor an EGFR-TK mutation have a 60% response rate to erlotinib (Tarceva).

Two researchers involved the treatment of LCINS concluded their review as follows, With the advances in sequencing technology and decreasing costs it is possible that, in the near future, advanced-stage LCINS may be primarily treated with molecularly targeted therapy, and it would be possible to achieve prolonged periods of disease control similar to the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST).

In spite of these advances, it must be emphasized that the landscape of mutations in lung cancer is complex, and there is a tendency for these cancers to develop resistance to the first-line targeted therapy. For this reason, intensive work is focused on new targeted treatments, combinations of several agents, and use of immunotherapies in addition.

First, epidemiologic studies investigating low-level, hard-to-measure, or subtle exposures, such as environmental tobacco smoke, radon exposure, and asbestos should focus on validated lifetime non-smokers, since smoking is such a powerful risk factor for lung cancer. (The risk of lung cancer posed by smoking is much stronger than that posed by asbestos).

Because so little is known about the causes of LCINS, there may be a tendency to overstate the importance of associations with potential risk factors that have been studied, rather than acknowledge that the findings of these studies are unlikely to account for a large proportion of LCINS.

In regard to passive smoking, a French study that examined major mutations associated with lung cancer in never smokers and smokers found no clear association between passive smoke exposure and a smoker-like mutation profile in lifelong, never-smokers with lung cancer. They concluded that, Passive smoking alone appeared to be insufficient to determine a somatic profile in lung cancer.

Second, characterizing the common and divergent mechanisms of malignant transformation in lung cancer occurring among smokers and that in never smokers could contribute to a better understanding of the genomic changes underlying malignant transformation and progression. As one group of researchers wrote, The mutually exclusive nature of certain mutations is a strong argument in favor of separate genetic paths to cancer for ever smokers and never smokers.

Third, the difficulty of identifying major causal factors in LCINS reminds us, that for many cancers, in spite of fifty years of epidemiologic research, we still have not identified major causal factors (exposures) for many common cancers, which might lend themselves to prevention. This is true for colorectal cancer, breast cancer, pancreatic cancer, prostate cancer, brain cancer, leukemia, and others.

This, in turn, underscores how difficult it is to pinpoint external causes of cancers that in most cases take decades to develop. Smoking as a cause of lung cancer and human papillomavirus as a cause of cervical cancer are exceptions to be noted and appreciated.

That said, we are seeing that identifying driver mutations that give rise to a particular cancer can lead to the development of effective targeted therapies that can greatly extend survival. These therapies represent long-sought, dramatic progress in treating serious cancers. This progress is independent of identifying the causal factor responsible for the cancer.

Geoffrey Kabat is a cancer epidemiologist and the author of Hyping Health Risks: Environmental Hazards in Daily Life and the Science of Epidemiology and Getting Risk Right: Understanding Science of Elusive Health Risks. He has a long-standing interest in lung cancer and, particularly, lung cancer occurring in never smokers, and has published on risk factors associated with that condition, including passive smoking, hormonal factors, and body weight.

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Unraveling the mystery of who gets lung cancer and why - Genetic Literacy Project

image:Jordan Kharofa, MD. view more

Credit: Photo/University of Cincinnati

While recommended screenings beginning at age 45 have helped decrease colorectal cancer cases in older adults, cancer rates are continuing to increase in younger populations.

Since 2009, the rate of new colorectal cancer diagnoses in patients under age 50 has increased by 2% each year.

"When I started practice and residency around 2010, Id uncommonly see patients who were less than 50 years old," said Jordan Kharofa, MD, associate professor in the Department of Radiation Oncology in the University of Cincinnatis College of Medicine, a University of Cincinnati Cancer Center member and a UC Health physician. "But more and more were seeing these patients in our clinics now to the point where it doesnt strike us as an exception to the rule."

The research is still unclear exactly what is causing increased cancer rates in young people, but Kharofa said one hypothesis is that patients diets and the bacteria in their gut are contributing factors. This led he and his colleagues to research the relationship between bacteria in the fecal microorganisms, or microbiome, and rates of colorectal cancer in younger populations.

Kharofa delivered a poster presentation on his findings at the recent American Society of Clinical Oncology annual meeting in Chicago.

The microbiome is a term used for the collection of microbes, including microorganisms like bacteria, that live on or in the human body. Kharofa said advances in DNA sequencing have allowed researchers to better characterize what species of bacteria are present in the microbiome, leading to a boom in research over the past 10 years.

In the past, wed have to culture specific bacteria and isolate them, and thats really complicated, he said. But now with the genetics and the cost of sequencing going down, we can quickly characterize what species are where and try to understand if they have implications for normal health and disease.

Kharofa said previous studies have shown that certain bacteria species present in the gut are associated with colorectal cancer. The research team then asked the question if these cancer-causing bacteria were elevated specifically in younger colorectal cancer patients compared to older patients and to healthy patients.

Kharofa collaborated with a team including Nicholas J. Ollberding, PhD, a Cincinnati Childrens Hospital Medical Center bioinformatician and associate professor in the UC Department of Pediatrics. Using genetic data from 11 previous studies, the team analyzed microbiome data from 609 patients who were healthy and 692 patients with colorectal cancer.

The research found two species of bacteria most closely associated with causing colorectal cancer were not found in higher levels among young patients, meaning these bacteria are unlikely to be responsible for increased cancer rates in young people.

Five other bacteria were found in higher levels in young people, including one species that is associated with a sulfur microbial diet, or a diet that is both high in processed meats, low-calorie drinks and liquor and low in raw fruits, vegetables and legumes.

Other epidemiologic studies without access to stool have revealed connections between a sulfur microbial diet and a higher increased risk of cancer in younger people, and Kharofa said this study is consistent with these previous findings.

Although these patients arent obese, there may be dietary patterns that happen early in life that enrich for certain bacteria such as this one, Kharofa said. Its not that what youre eating has carcinogens in them, but the byproducts produced during bacteria metabolism may lead to carcinogenic chemicals. Its possible that interactions between diet and the microbiome may mediate the formation of colorectal cancer cells and heightened risk in younger populations over the last several decades.

While more research is needed, Kharofa said a tangible takeaway from the study is for young people to eat more raw fruits and vegetables and legumes and less processed meats in their diets.

Theres still a lot we dont understand about how the diet influences the microbiome and how that might influence cancer, but this is a small sneak peek at something that might be going on, he said. Theres a lot of reasons to eat less processed foods and diets rich in raw fruits, vegetables and legumes, and this might be one more.

Kharofa said further research will look to learn more about the bacteria species that were found in higher levels in younger patients and how these species contribute both to the development of cancer and to the cancers response to treatment.

As the role of bacteria becomes clearer, there is also the potential for more advanced and tailored screening for younger patients.

Its really difficult to just screen everybody because the rates are pretty low in the entire population of individuals less than 45 years old, he said. But if you are able to profile the microbiome and maybe do targeted screening in some patients who had higher risk based on their stool, that might be a worthwhile investigation.

Even if a person is younger, Kharofa said anyone with symptoms should be evaluated by a doctor. Signs and symptoms of colorectal cancer include rectal bleeding or blood in the stool; persistent abdominal discomfort, including gas, bloating, fullness or cramps; diarrhea, constipation or feeling that the bowel does not fully empty; unknown weight loss; fatigue and vomiting.

Screening is for asymptomatic people, and anyone with symptoms needs to be evaluated, Kharofa said. We unfortunately see these patients presenting later at diagnosis because their symptoms were ignored. If youre young and you have symptoms, you need to be evaluated.

Other contributing authors to the research were Senu Apewokin, MD, associate professor in the UC College of Medicine, and Theresa Alenghat, PhD, member of Cincinnati Childrens Hospital Medical Centers Division of Immunobiology and an associate professor in the UC Department of Pediatrics.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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How diet and the microbiome affect colorectal cancer - EurekAlert

Researchers have recently successfully treated Type 1 diabetes by transplanting insulin-producing pancreas cells into the patient.

University of Missouri scientists are partnering with Harvard and Georgia Tech to create a new diabetes treatment that involves transplanting insulin-producing pancreatic cells

Type 1 diabetes is estimated to affect around 1.8 million Americans. Although type 1 diabetes often develops in childhood or adolescence, it can occur in adulthood.

Despite active research, type 1 diabetes has no cure. Treatment methods include taking insulin, monitoring your diet, managing blood sugar levels, and exercising regularly. Scientists have also recently discovered a new treatment method that holds promise.

A group of researchers from the University of Missouri, Georgia Institute of Technology, and Harvard University has proved the successful use of a novel Type 1 diabetes treatment in a large animal model in a new study published in Science Advances on May 13th. Their method includes transferring insulin-producing pancreas cells, known as pancreatic islets, from a donor to a recipient without the need for long-term immunosuppressive medicines.

According to Haval Shirwan, a professor of child health and molecular microbiology and immunology at the MU School of Medicine and one of the studys primary authors, people with Type 1 diabetes immune system may malfunction, leading it to target itself.

The immune system is a tightly controlled defense mechanism that ensures the well-being of individuals in an environment full of infections, Shirwan said. Type 1 diabetes develops when the immune system misidentifies the insulin-producing cells in the pancreas as infections and destroys them. Normally, once a perceived danger or threat is eliminated, the immune systems command-and-control mechanism kicks in to eliminate any rogue cells. However, if this mechanism fails, diseases such as Type 1 diabetes can manifest.

Diabetes impairs the bodys ability to produce or utilize insulin, a hormone that aids in the regulation of blood sugar metabolism. People with Type 1 diabetes are unable to manage their blood sugar levels because they do not produce insulin. This lack of control may result in life-threatening problems including heart disease, kidney damage, and vision loss.

Shirwan and Esma Yolcu, a professor of child health and molecular microbiology and immunology at the MU School of Medicine, have spent the last two decades targeting an apoptosis mechanism that prevents rogue immune cells from causing diabetes or rejection of transplanted pancreatic islets by attaching a molecule called FasL to the islets surface.

A type of apoptosis occurs when a molecule called FasL interacts with another molecule called Fas on rogue immune cells, and it causes them to die, said Yolcu, one of the studys first authors. Therefore, our team pioneered a technology that enabled the production of a novel form of FasL and its presentation on transplanted pancreatic islet cells or microgels to prevent being rejected by rogue cells. Following insulin-producing pancreatic islet cell transplantation, rogue cells mobilize to the graft for destruction but are eliminated by FasL engaging Fas on their surface.

Haval Shirwan and Esma Yolcu work in their lab at the Roy Blunt NextGen Precision Health building. Credit: University of Missouri

One advantage of this new method is the opportunity to potentially forgo a lifetime of taking immunosuppressive drugs, which counteract the immune systems ability to seek and destroy a foreign object when introduced into the body, such as an organ, or in this case, cell, transplant.

The major problem with immunosuppressive drugs is that they are not specific, so they can have a lot of adverse effects, such as high instances of developing cancer, Shirwan said. So, using our technology, we found a way that we can modulate or train the immune system to accept, and not reject, these transplanted cells.

Their method utilizes technology included in a U.S. patent filed by the University of Louisville and Georgia Tech and has since been licensed by a commercial company with plans to pursue FDA approval for human testing. To develop the commercial product, the MU researchers collaborated with Andres Garca and the team at Georgia Tech to attach FasL to the surface of microgels with proof of efficacy in a small animal model. Then, they joined with Jim Markmann and Ji Lei from Harvard to assess the efficacy of the FasL-microgel technology in a large animal model, which is published in this study.

Haval Shirwan looks at a sample through a microscope in his lab at the Roy Blunt NextGen Precision Health building. Credit: University of Missouri

This study represents a significant milestone in the process of bench-to-bedside research, or how laboratory results are directly incorporated into use by patients in order to help treat different diseases and disorders, a hallmark of MUs most ambitious research initiative, the NextGen Precision Health initiative.

Highlighting the promise of personalized health care and the impact of large-scale interdisciplinary collaboration, the NextGen Precision Health initiative is bringing together innovators like Shirwan and Yolcu from across MU and the UM Systems three other research universities in pursuit of life-changing precision health advancements. Its a collaborative effort to leverage the research strengths of MU toward a better future for the health of Missourians and beyond. The Roy Blunt NextGen Precision Health building at MU anchors the overall initiative and expands collaboration between researchers, clinicians, and industry partners in the state-of-the-art research facility.

I think by being at the right institution with access to a great facility like the Roy Blunt NextGen Precision Health building, will allow us to build on our existing findings and take the necessary steps to further our research, and make the necessary improvements, faster, Yolcu said.

Haval Shirwan and Esma Yolcu. Credit: University of Missouri

Shirwan and Yolcu, who joined the faculty at MU in the spring of 2020, are part of the first group of researchers to begin working in the NextGen Precision Health building, and after working at MU for nearly two years they are now among the first researchers from NextGen to have a research paper accepted and published in a high-impact, peer-reviewed academic journal.

Reference: FasL microgels induce immune acceptance of islet allografts in nonhuman primates by Ji Lei, Mara M. Coronel, Esma S. Yolcu, Hongping Deng, Orlando Grimany-Nuno, Michael D. Hunckler, Vahap Ulker, Zhihong Yang, Kang M. Lee, Alexander Zhang, Hao Luo, Cole W. Peters, Zhongliang Zou, Tao Chen, Zhenjuan Wang, Colleen S. McCoy, Ivy A. Rosales, James F. Markmann, Haval Shirwan and Andrs J. Garca, 13 May 2022, Science Advances.DOI: 10.1126/sciadv.abm9881

Funding was provided by grants from the Juvenile Diabetes Research Foundation (2-SRA-2016-271-S-B) and the National Institutes of Health (U01 AI132817) as well as a Juvenile Diabetes Research Foundation Post-Doctoral Fellowship and a National Science Foundation Graduate Research Fellowship. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.

The studys authors would also like to acknowledge Jessica Weaver, Lisa Kojima, Haley Tector, Kevin Deng, Rudy Matheson, and Nikolaos Serifis for their technical contributions.

Potential conflicts of interest are also noted. Three of the studys authors, Garca, Shirwan, and Yolcu, are inventors on a U.S. patent application filed by the University of Louisville and the Georgia Tech Research Corporation (16/492441, filed Feb. 13, 2020). In addition, Garca and Shirwan are co-founders of iTolerance, and Garca, Shirwan, and Markmann serve on the scientific advisory board for iTolerance.

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Harvard Scientists Have Developed a Revolutionary New Treatment for Diabetes - SciTechDaily

Upon receiving a diagnosis of type 1 diabetes (T1D), many people have the same reaction: But why me?

Some people have T1D that runs in their family, while others have no idea how or why they received a diagnosis. Often, to their frustration, those questions go unanswered.

But some people can seemingly link their T1D diagnosis to a previous virus they had endured directly before their onset of T1D.

This makes sense, as T1D is an autoimmune disease. This means your bodys own immune system mistakenly attacks its own insulin-producing beta cells. Although scientists dont know the exact causes or reasons why T1D develops, some researchers believe this haywire immune system reaction is the result of a virus triggering your bodys defense system to go into overdrive.

Viruses are now one main hypothesis of the cause of T1D. In particular, coxsackievirus is on the rise in those with newly diagnosed T1D. That has led some to wonder if theres a direct correlation between this virus, or any virus for that matter.

Read on for more about coxsackievirus, how it materializes in people, and what research has to say about its potential for causing T1D.

Coxsackievirus is a virus thats part of the enterovirus family, which lives in the human digestive tract. This enterovirus family also includes polioviruses, hand, foot, and mouth disease (HFMD), and hepatitis A virus.

This virus spreads easily from person to person, usually through human touch or on surfaces contaminated with feces. The virus can live for several days without a host, making it extremely easy to spread.

When theres a coxsackievirus outbreak, its most likely to affect babies and children younger than 5 years old, as its easily spreadable in places such as daycare centers, schools, and summer camps. Youre most contagious the first week that youre sick, and the best preventive mechanism is hand washing.

Usually, infection with this virus results in these mild flu-like symptoms initially:

Many people have no symptoms at all, and most people recover without treatment. But sometimes the virus can trigger more serious conditions or reactions, such as with HFMD, where a blister-like rash may appear on your hands or feet or in your mouth.

Theres no specific treatment for this virus, and antibiotics dont help with viral infections.

When a virus invades your body, your immune system produces antibodies to fight off that infection. T cells are in charge of developing antibodies as well as fighting off the virus.

But if the virus has some of the same antigens (or substances that cause your immune system to produce antibodies against them) as your bodys own pancreatic beta cells (in the case of T1D), the T cells sometimes start attacking your bodys own beta cells.

This miscommunication is common and results in autoimmune diseases like T1D. Once all the beta cells have been destroyed, T1D is developed and diagnosed. This is why people sometimes receive a diagnosis of T1D a few months after recovering from a bad virus.

But it can sometimes take more than a year for your bodys T cells to destroy the majority of your beta cells (sometimes people experience the honeymoon phase of diabetes, where their pancreas is still producing a minimal amount of insulin), but that original viral infection is hypothesized to be a trigger in the development of T1D.

Not every virus can trigger this reaction ending in T1D. The virus must have antigens that are similar enough to the antigens in pancreatic beta cells. Those viruses include:

Theres mounting evidence that the coronavirus disease 19 (severe acute respiratory syndrome coronavirus 2) pandemic is causing a tidal wave of new T1D diagnoses to be received by both children and adults. But the full repercussions of the pandemic are yet to be seen.

A 2018 study showed that kids exposed to enteroviruses are more likely to develop T1D.

The Environmental Determinants of Diabetes in the Young study found, through nearly 8,000 stool samples of children in the United States and Europe, an association between an exposure and infection with coxsackievirus. This study followed participants for 30 days or longer and focused on the development of an autoimmune reaction that can lead to a T1D diagnosis.

In a Finland-based study, researchers tested more than 1,600 stool samples from 129 children who had recently developed T1D. They also tested 282 children without diabetes for enterovirus RNA, a marker of previous exposure to infection.

Researchers also found 60 percent of the control group showed signs of prior infection (without diabetes), compared with 75 percent of the group with T1D.

They also found that children who developed T1D were exposed to the virus more than a year before their diabetes was diagnosed. Taking this lag time of viral infection to T1D diagnosis into account, the researchers believed that children with diabetes are exposed to three times more enteroviruses than children without diabetes.

Viral infections arent the only hypothesized cause of T1D, but research is homing in on viruses as a common trigger. Studies have shown that even if pregnant people are exposed to enteroviruses, such as coxsackievirus, theyre more likely to give birth to children who eventually develop T1D.

Researchers arent exactly sure what the precise cause of T1D is, and the virus hypothesis is just one theory. Many people believe that T1D is caused by a mix of genetic and environmental factors and that the disease may just be finally triggered by catching a virus such as coxsackievirus or another enterovirus.

While preventing viral spread is always important, even if all enteroviruses were prevented, T1D wouldnt be prevented in everyone, but it would probably make a big difference.

Researchers are hopeful with new trials showing vaccines against enteroviruses could potentially prevent many new diagnoses of T1D, but they wont prevent all people from receiving diagnoses of course.

While theres no vaccine to prevent T1D, Dr. Denise Faustman, Director of the Massachusetts General Hospital Immunobiology Laboratory, is working on that research front. Her work focuses on the bacillus Calmette-Gurin (BCG) vaccine, traditionally used to prevent tuberculosis, and how it can help people with T1D. Specifically, this century-old BCG vaccine may boost a substance called tumor necrosis factor, which eliminates T cells and helps develop more beneficial cells called regulatory T cells.

If you have diabetes, this could help improve your blood sugar and A1C levels while lowering your insulin requirements even years after your initial vaccination. That research is expected to continue for at least several more years beyond 2022.

The exact causes of T1D arent known. But research shows enteroviruses, and in particular coxsackievirus, may play a part in the development of this autoimmune condition. Most researchers believe it to be a mix of both environmental and genetic factors, with perhaps a viral infection trigger. Research remains ongoing, and the development of a coxsackievirus vaccine could go a long way in preventing people worldwide from receiving diagnoses of T1D in the future.

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Do Viruses and Coxsackievirus Cause Type 1 Diabetes? - Healthline

While managing diabetes can be challenging, you can still do the things you enjoy in life. (Getty Images)

This diabetes week, and every week, it's important that just because diabetes is a hidden condition, it doesn't get ignored.

One in 14 of us live with the condition, while even more care for a loved one who does, according to Diabetes UK.

So, whether you might suspect you have diabetes, support someone else with it, are recently diagnosed, or just want to learn more about the condition, here are the basics of what there is to know.

Read more: Kate Moss' daughter Lila proudly sports blood glucose monitor in Fendace campaign

If you're diagnosed with diabetes, a medical professional will explain all you need to know about managing it. (Getty Images)

Diabetes is a lifelong condition that causes a person's blood glucose levels (also called blood sugar) to become too high, according to the NHS. There are two main types, Type 1 and Type 2, though some can also get Gestational diabetes.

Pre-diabetes is when people have blood glucose levels above the normal range, but are not high enough to be diagnosed with the condition itself. But it's important to keep in mind that if your levels are higher than most, your risk of developing full-scale diabetes is increased.

Getting diabetes diagnosed early is key to prevent it from getting progressively worse, which can happen if left untreated.

The finger-prick test has long been used to manage diabetes, though there are now more advanced methods. (Getty Images)

Type 1 diabetes is where the body's immune system attacks and destroys the cells that produce insulin. You need to take insulin every day to keep your blood glucose levels under control. Type 1 is not linked with age, being overweight or lifestyle factors, whereas Type 2 is.

The NHS website says you should see a GP if you have symptoms of type 1, which include:

feeling very thirsty

peeing more than usual, particularly at night

feeling very tired

losing weight without trying

thrush that keeps coming back

blurred vision

cuts and grazes that are not healing

fruity-smelling breath

Type 1 signs and symptoms can come on quickly, particularly in children.

To get tested, your GP will do a urine test and might also check your blood glucose level. If they suspect you have diabetes, you'll be advised to go to hospital immediately for further assessments, where you will stay until you get results (usually the same day).

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If you are diagnosed, then a specialist diabetes nurse will explain everything you need to know about the condition, including how to manage it, test your own blood glucose and how to inject insulin.

Finger-prick tests have long been used to manage diabetes, though you can now check your glucose levels at any time with a continuous glucose monitor (CGM) or flash monitor.

This involves using a sensor, a small device you attach to your arm or tummy that senses how much glucose is in the 'interstitial' fluid under your skin, and a reader or receiver, which shows the results (you can also read them on your smartphone). Some types have optional alarms to alert you if your levels go too low or high.

Read more: What types of dementia are there? Signs and symptoms to see your GP about

While interstitial fluid readings have made many people living with diabetes' lives much easier, it's important to remember they're a few minutes behind your blood glucose levels. This means you'll still need to do finger-prick checks every now and then, particularly when you drive or have a hypoglycaemia (when your blood glucose level is too low), as this tells you what your level is at that moment.

Although being diagnosed with and managing diabetes can be difficult at times, you can still do the things you enjoy. This useful NHS guide on being newly diagnosed provides information to help, including how to recognise and treat a hypo, useful websites, online courses and more.

Do you have the symptoms of diabetes? (Getty Images)

Type 2 diabetes is where the body does not produce enough insulin, or the body's cells do not react to insulin. It is far more common than type 1, with around 90% of all adults in the UK with diabetes living with it.

It can be linked to being overweight or inactive, or having a family history of type 2 diabetes. You're also more at risk of this type of diabetes if you're over 40 (or 25 for south Asian people), have a close relative with diabetes, are overweight or obese, are of Asian, African-Caribbean or black African heritage.

Many people can have type 2 diabetes without realising, because symptoms don't always make you feel unwell.

The NHS website says you should see a GP if you have symptoms of type 2 (similar to type 1), which include:

peeing more than usual, particularly at night

feeling thirsty all the time

feeling very tired

losing weight without trying to

itching around your penis or vagina, or repeatedly getting thrush

cuts or wounds taking longer to heal

blurred vision

You should also see a GP if you're worried you may have a higher risk of getting type 2. You check your risk here.

Some people find checking blood glucose levels with a continuous glucose monitor (CGM) or flash monitor easier. (Getty Images)

Gestational diabetes can also occur during pregnancy, when some women have such high levels of blood glucose that their body is unable to produce enough insulin to absorb it all.

While it can happen at any stage of pregnancy, it is more common in the second or third trimester. It usually disappears after giving birth.

That said, it can cause problems for you and your baby during pregnancy and after birth, but the risks can be reduced if the condition is detected early and well managed.

Read more: How to stay safe in hot weather: Top tips to avoid heatstroke this summer

With the causes of Type 1 and Type 2 different, a doctor will explain how management differs. (Getty Images)

Elaborating on the above, the amount of sugar in the blood is controlled by a hormone called insulin, which is produced by the pancreas (a gland behind the stomach), the NHS explains.

Normally, when food is digested and enters your bloodstream, insulin moves glucose out of the blood and into cells, where it's broken down to produce energy.

However, if you have diabetes, your body is unable to break down glucose into energy because there's either not enough insulin to move it, or the insulin produced doesn't work properly.

While there are no lifestyle changes you can make to lower your risk of of type 1 diabetes, you can help manage type 2 diabetes through healthy eating, regular exercise and achieving a healthy body weight.

There's nothing you can't eat if you have type 2 diabetes, but the NHS suggests limiting certain foods. You should eat a wide range of food (fruit, veg and some starchy foods like pasta), keep sugar, fat and salt to a minimum, and make sure you eat breakfast, lunch and dinner every day do not skip meals.

If you need to change your diet, it might be easier to make small changes every week, it adds.

Altering your lifestyle in small ways can go a long way to reduce your risk of type 2 diabetes. (Getty Images)

Diet, exercise and a healthy lifestyle can also help to reduce the likelihood of getting type 2 diabetes, with more than 13.6 million people in the UK at an increased risk.

"Fortunately even in people with a strong family history of diabetes making positive lifestyle choices can help avoid diabetes altogether," says Dr Sundhya Raman, Medical Doctor and Lifestyle Medicine Physician, Plant Based Health Professionals.

In terms of diet, Ruman says we should try to avoid "processed foods, sugar-sweetened foods and drinks, saturated fats (found in animal source foods and tropical oils), and red and processed meats".

On exercise, she explains it is never too late to start, and build up gradually. "Most people think they need to be quite fit before they get a benefit from exercising, but in fact going from doing nothing to doing something is when the biggest gains are achieved."

It seems sleep is very important too. "We should all be aiming for 7-8 hours of sleep a night, and people who chronically sleep less than this amount raise their risk of diabetes by about 30%," she says.

"When we dont get enough sleep we also have dysregulated levels of our hunger and satiety hormones so are more likely to eat more, particularly foods that are not good for us and make us put on weight, so sleep should also be a priority."

Of all lifestyle factors, Raman says poor diet is the biggest risk. "In studies, the dietary group who have the lowest rates of diabetes are whole-food plant based. They are also the group that tend to have the lowest BMI compared with any other dietary group such as pescatarians or omnivores, and we know that a high BMI is one of the most significant risk factors [for having diabetes].

Some believe food is medicine when it comes to reducing your risk of diabetes, or even reversing it. (Getty Images)

Plant-based diets can reduce the risk of type 2 diabetes by up to 60%, according to Plant Based Health Professionals. But how does this work?

Soluble fibre, she explains helps us to feel full and maintain a healthy weight, release the carbohydrate from our food into our bloodstream slowly, and is the superfood for bugs that live in our colon, of which a healthy balance of can lower the risk of diabetes.

"Plant foods are also full of antioxidants that help reduce the damage that happens to our cells from everyday activities, as well as some of the more damaging things we do such as eating the wrong kinds of foods or sitting for prolonged periods," Ruman adds. "We also know that some of the compounds in plant foods switch on genes that optimise our metabolism.

She also says wholegrains are the food type that have been shown in studies to be particularly important in reducing diabetes and cardiovascular risk. However, in the UK we don't have specific guidelines on how many portions to eat, or any legislation on what can be termed a wholegrain, so people can eat processed foods with few wholegrains, thinking they are improving their health, or think they're bad for people with diabetes, as are often grouped under carbs.

Read more: Earth Day 2022: 7 ways to reduce your carbon 'foodprint' to save the planet

"I would recommend 3 portions of wholegrains per day, ideally as unprocessed as possible." She also reccomends a variety of fruit and vegetables, as well as variety in your nuts, seeds, wholegrains, lentils, legumes, herbs and spices, while prioritising plant sources of proteins over those from animal sources.

In some cases, plant-based are also effective at reversing Type 2 diabetes, effective at reversing insulin resistance, which is thought to happen fat gets stored in our muscle and liver, and damages cells."One of the ways in which a whole-food plant-based diet is incredibly beneficial is that people tend to lose weight when they follow this dietary pattern, and we know that weight loss can reverse diabetes."

Make sure you consult a doctor before making any big dietary changes.

For more information, visit the NHS' website on diabetes, or seek support from Diabetes UK on 0345123 2399.

Watch: Diabetes drug leads to significant weight loss in those with obesity, study finds

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Great sex, anecdotally, is uninhibited and free of worry. Its a time to put aside the usual responsibilities that plague you and just enjoy the moment. But diabetes and sex have a slightly complicated relationship. For people with type 1 diabetes, fully detaching from responsibilities isnt an option in fact, it can be dangerous. Its no surprise then that a study conducted by Oxford University professors found that 62 percent of people with diabetes say their condition has negatively impacted their relationships with their partners.

Having to think about your type 1 diabetes during intimacy can be agitating and even disheartening. But its important to remember that many adults have to do some planning before sex. Some men have to take pills for erectile dysfunction. Tons of women need lubricant due to a hormonal imbalance. And lets not forget about all of the people who need a lumbar support pillow for missionary. Everyone deserves to enjoy sex. Heres what you need to know about having safe and enjoyable sex, when you have type 1 diabetes.

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There are several reasons that those with type 1 diabetes cant explore the Kama Sutra without some planning. First off, a lot of sex depending on how you go about it counts as a workout. It gets your blood pumping, it gets you sweating and, like any exercise, it impacts blood sugar levels. While people who dont have diabetes can handle these blood sugar fluctuations fairly well, people with diabetes need to be careful.

Next, theres the added factor of booze. Its common for people to enjoy a drink (or a few) before having sex. Alcohol helps loosen those inhibitions and make you feel relaxed. But, if you drink too much or dont stick to diabetic-friendly cocktails, your blood sugar levels can go on a roller coaster.

The ways sex plays on blood sugar levels dont stop there. Even if you stay sober for sex, the mere excitement of being with a partner can impact blood sugar levels. So, while its frustrating, the fact that sex affects blood sugar levels cannot be ignored.

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If you know that your night will likely end in sex, take steps to put your blood sugar levels in a healthy range by the time intimacy occurs. This means being careful about what you eat, using insulin when necessary and even monitoring other physical activity throughout the day. If your sessions in the sack are particularly active, then you might need to skip your afternoon workout. You dont want to put yourself at risk of low blood sugar mid-coitus due to over-exertion.

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Even if you eat right and monitor your blood sugar levels, things can still go awry after a few rounds with your partner. Be sure to keep snacks on the nightstand so you can reach for them if you feel your blood sugar levels dropping. Better yet, incorporate sexy foods like strawberries or chocolate sauce (sugar-free if necessary) into sex so it doesnt feel like snack time is putting a pause on the fun.

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Sex is always better when you can communicate with your partner. That is true about every topic, from what positions work for you to managing your blood sugar levels. Notify your partner in advance that sex can impact your blood sugar, and that you might need to pause during the activities to have a snack or take insulin. Additionally, if you can tell tonight is just not a good night to do the deed, speak up. Pushing yourself through sex when your blood sugar levels are off can be dangerous.

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If you wear an insulin pump or a blood glucose monitor, you might be tempted to remove this during sex. Some diabetics struggle to feel sexy when wearing these devices (and nothing else) in front of a partner. First off, theres no shame in wearing a device that keeps you alive and enables you to live the way that you enjoy. However, there are some practicalities to consider, like the fact that these devices can get tangled or fall off during sex.

If you want to remove your device during sex, make sure to get your blood sugar levels in a healthy range right before the activities. And then put the device back on immediately after sex. If your blood sugar levels arent stable enough for device removal, get creative and choose positions that let you keep the device on. Again, communication is key here.

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It is important to know that type 1 diabetes can impact sexual function in many ways. For women, high blood sugar can lead to vaginal dryness, according to the Journal of Natural Science, Biology and Medicine. For men, blood sugar issues can cause erectile dysfunction. And people of all genders can experience mood swings and a low libido in connection to type 1 diabetes.

While there are practical fixes for vaginal dryness like finding a lubricant you love the other symptoms can be more complicated to treat. If you are struggling with any of these issues, first off, know that its common for people with type 1 diabetes and is nothing to be embarrassed about. Then talk to your doctor about the best way to treat the problem.

Having type 1 diabetes doesnt have to mean the end of a fun, playful and even erotic sex life. It simply means you have to do a little extra planning. But when you have a partner with whom you can communicate openly, that planning wont feel like a burden. And when you know your body will be safe and taken care of, then you can let go and be in the moment.

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Diabetes And Sex: Have Safe Sex While Managing Diabetes - MadameNoire