StemCell Therapy

After an accident, its all too easy to say that workplace hazards should have been handled better. But preventing accidents at work - spotting hazards and countering them before anyone gets hurt - will always be first prize. So says Gary Rodney, a behavioural optometrist who assists businesses with vision-related questions pertaining to the workplace.

The most serious workplace eye injuries are likely to occur in specific work environments. When theres dust, compressed air, tools, and especially power tools, extremely bright light or UV light, or work involving the use of chemicals, eyes can be at risk, and eye protection will be especially important.

Were usually looking at situations in which the surface of the eye gets scratched, foreign bodies become embedded in the eye, the eye is punctured, or chemicals have burned eye tissue. Welding flashes give off very bright UV light, and theyre also responsible for many eye injuries in the workplace. says Gary.

Effective eye protection in the workplace isnt just a matter of identifying areas where its needed and making sure its available - although thats a good start. Both employers and employees need to be educated and aware, says Gary. There are often instances in which eye protection is provided, but not worn, or the eye protection is inadequate, incorrect, or poorly-fitting.

Making employers and employees aware of workplace hazards, and sustaining that awareness is very important. When people work in hazardous situations every day, it becomes the norm. They get careless, and thats a very dangerous state of affairs.

Once there is awareness coupled with the provision of adequate eye protection, and a safety-oriented workplace culture that enforces the use of safety equipment and safety protocols, the risk of eye injuries in the workplace is substantially reduced.

Choosing the right eye protection to use at work is rather more complicated than it may initially seem. As a basic guideline, it should comply with Australian Standards which cover the types of safety gear that should be used to guard against impacts (high, medium, or low), dust, chemical handling accidents and UV light from welding equipment.

Apart from being effective, the equipment should also be comfortable and fit well. Personal Protective Equipment (PPE) should ideally be just that - personal, says Gary. If its comfortable to wear, theres a greater chance of compliance. As an employee, you should ask for help if you feel that your equipment isnt right for you. For example, if you wear glasses, your eye protection should fit over them, and if theres a chance of chemicals or debris entering your eyes from the sides, there shouldnt be any gaps.

The three steps towards reducing the chance of workplace injuries are the same regardless of the type of accidents that is being guarded against. Knowing where the risks are is the first step, the provision of adequate protective equipment is the next one, and compliance in using it closes the loop.

Your eyesight is too important to risk because you dont want to engage with workplace safety officers or simply dont feel like wearing your PEE, says Gary. Take the necessary steps, report problems, and be informed as to what to do in the event of an accident.

HEAR: Ultra106.5FM Interview with Gary Rodney Covid and Myopia: What you need to know!

For more information on eye injuries and impairments, and how they can be treated, or to make an appointment for a regular eye check, visit the Smart Vision website:Optometrists Sydney: Optometry Services For Children and Adults | Smart Vision; for specific information about Myopia treatment and prevention visitMyopia Prevention: Solutions, Control And Treatment In Sydney; and for detailed information about Myopia Treatment visitOrthokeratology In Sydney: The Non Surgical Alternative.

To book an appointment for a thorough eye check-up,click hereor Call the Bondi clinic on (02) 9365 5047 or the Mosman clinic on (02) 9969 1600.

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Sydney Optometrist Mosman Eye Injury Protection Vision Therapy Myopia Prevention - PRWire

Charenton-le-Pont and Paris, France (July 5, 2021 1:00 pm CEST) EssilorLuxottica and theFdration Internationale de lAutomobile (FIA) today announced the renewal of their partnership to raise awareness of the importance of regular eye checks for all road users and, more broadly, to promote good vision for safer roads. Together, EssilorLuxottica and the FIA will roll out a comprehensive plan mobilising public and private stakeholders, and leveraging both innovation and their global reach.

In August 2020, the United Nations General Assembly (UNGA) adopted Resolution A/RES/74/299, proclaiming 2021-2030 as a new Decade of Action for Road Safety, with the objective of halving the number of road victims by 2030. To achieve this goal, the United Nations (UN) issued a set of recommendations1, including a call for countries to implement appropriate, effective and evidence-based legislation on risk factors related to distracted or impaired driving. Adopting measures to ensure good vision for all road users is part of these recommendations. The UN also encouraged Member States to take measures to promote road safety knowledge and awareness among the population through education, training and advertising campaigns, especially among youth, and to share good road safety practice.

With 1.4 million people killed in road crashes and 50 million more seriously injured each year, safe mobility is a global priority and a key pillar to achieve the United Nations Sustainable Development Goals (SDGs). Since eyesight is a key element to make safe decisions and anticipate potential risks on the road, good vision is critical. It is part of the road safety culture and can help reduce any potential danger on the road. And even more so today, as the COVID-19 crisis has significantly accelerated the transformation of mobility, resulting in a boom of bikes, scooters and other forms of individual mobility joining cars on the road, reinforcing the need for good vision in all situations.

As part of their renewed three-year partnership within the new #PurposeDriven movement launched by the FIA, EssilorLuxottica and the FIA will continue to mobilise the general public, institutions, mobility players and eye care professionals, to address the UNs strong call for action. Together, they will roll out a wide range of initiatives focused on: reinforcing awareness campaigns and advocacy in the run-up to the 2022 UNGA dedicated to the road safety global plan of actions;accelerating innovation in the areas of eye exams, visual solutions and other road safety-related products such as helmets, leveraging racing expertise to apply it to the roads and scaling up access to visual equipment in close collaboration with FIA Member Clubs all over the world. This will include joint actions with the United Nations Road Safety Fund.

EssilorLuxottica will kick off this partnership with a global Action for good vision on the road campaign, calling upon all eye care professionals to play a key role in raising awareness and addressing the crucial and reinforced need for good vision in all conditions, day and night. As part of this partnership, the Company will also collaborate with FIA Member Clubs and engage its own extensive network of retail footprint in Italy, North America and Australia.

Vision is vital on the road. EssilorLuxotticas commitment for safer roads is part of our wider responsibility as the industry leader and our mission to help people see more, be more and live life to its fullest. Public awareness about the importance of good vision remains low while the need for access to suitable eyewear continues to grow. This issue concerns everyone low and middle-income countries as well as mature countries, from underserved communities to professional drivers. We are confident that together with the FIA, and with the support of public and private stakeholders across the globe, we will be able create a positive and meaningful impact as part of our plan, commented Francesco Milleri, CEO of EssilorLuxottica, and Paul du Saillant, Deputy CEO of EssilorLuxottica.

At the FIA, we are committed to improving global road safety, which includes the promotion of responsible driving. To do that, we need to build a comprehensive set of interventions, with a strong focus on prevention. Our renewed partnership with EssilorLuxottica will contribute to building a culture of safety by raising awareness on the importance of good vision for all road users, said Jean Todt, FIA President and UN Secretary-Generals Special Envoy for Road Safety.

Watch the official partnership video here.

CONTACTSHead of Investor Relations Head of Corporate CommunicationsGiorgio Iannella Marco Catalanie-mail: ir@essilorluxottica.com e-mail: media@essilorluxottica.com

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EssilorLuxottica and the FIA reinforce their commitment to promote good vision for safer roads - GlobeNewswire

EDMOND, Okla. (KFOR) Edmond 10-year-old, Miller Hines enjoys soccer, his scooter, constructing Legos, and playing with his younger brother.

Miller is a lover of life, I like to say that hes a world shaker and game changer, says his mother, Miranda.

Two years ago, Miranda remembers the cascade of bad news that started with swollen lymph nodes.

He was swollen in his neck area which was concerning but Id also seen that with him when hed had strep throat, she recalls.

But when Miller went to the doctor, the strep test came back negative. Thats when they ran blood tests which revealed alarming results.

Miranda remembers, I did somethingyoure not supposed to do, which is google what this means.

Miller had AML leukemia with an added genetic mutation which made it even more dangerous.

He had a very aggressive form of leukemia. I knew Miller was really, really sick, Miranda recalls. Preparing for his bone marrow transplant and then having the transplant was really brutal.

In the middle of the pandemic, mother and son leaned on each other for dear life.

Miller is such a sweet boy. He made me a mom, and were buddies, and he would often encourage me by saying Mom, Im OK,' Miranda shakes her head as she remembers his efforts to ease her fears.

Holding them both up with medical support and emotional encouragement was their medical team at OU Childrens Hospital, and Jimmy Everest Cancer Center.

Miranda doesnt hold back the tears as she expresses her gratitude, We absolutely adore them. Theres no doubt that they saved Miller.

His treatments included a stem cell transplant, chemotherapy, and gene therapy.

Working in tandem, his treatment plan proved to be successful.

His blood work shows hes free of cancer 17 months after his transplant.

Despite the pain, and even boredom that comes from months of treatment, Miller has happy memories of playing with therapy dogs at the clinic and joking around with the nurses.

Miranda says, We miss them, but we are happiest to run into them outside of the clinic!

Miller wants to get on with the hobbies he had to put on the sidelines.

Hes getting to be a 10-year-old. Hes playing soccer again.And the best thing thats ever happened in my whole life is Miller, so for him to be here and be healthy is incredible, says Miranda.

Its been almost a three-year roller coaster ride the Hines are happy to step off, grateful for a new chapter of childhood ahead.

If youd like to help children like Miller fight cancer, consider donating to JECFriends.org.

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Oklahoma 10-year-old in remission after being diagnosed with rare form of leukemia 2 years ago - KFOR Oklahoma City

This gives Scotland an opportunity, and a pressing need, to chart a different course. This is not political hyperbole. It is based on an NHS career in cancer care where infection prevention and control are a daily struggle for patients with suppressed immune systems.

Having led bone marrow and stem cell transplantation services at both University College Hospital and the Royal Marsden, I have a strong grasp of the systematic approach needed for effective infection protection, control, and treatment.

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While most people are not as vulnerable as transplant patients, with a novel virus like Covid we simply cannot predict how and when the virus will mutate or how this could impact the general population.

There are three interdependent strands to consider: controls such as mask wearing, social distancing and hand hygiene; surveillance testing and genomic studies that chart the progress and development of the virus; and treatment the use of dexamethasone and vaccination programmes.

Get one element wrong and the whole approach could fail.

Until now weve diligently been following guidance across a range of control measures, and the vaccination programme delivered by the ever-valiant NHS workforce has been a great success but weve still seen a sharp rise in Delta-variant cases. This brings me to surveillance.

The problem is the UK and devolved governments have relied on Innova lateral-flow devices (LFDs) as the method of rapid-test surveillance.

This means taxpayers money is being spent to prop up Chinese imports that are being used in a potentially dangerous way, while our domestic diagnostics industrys superior tests have been cast adrift.

As a result, we are now at a perilous crossroads. Failure to use effective controls or robust surveillance risks the Delta variant spreading ever more rapidly, presenting a significant risk of further mutation.

I am already seeing this in my constituency where people have received repeated negative results with Innova LFD tests, only to insist on a PCR test and discover they are Covid positive and at the centre of a new cluster of infections.

To be blunt, the Prime Ministers desire to appease some Tory backbenchers with cries of Freedom Day has endangered all the advances made to date.

Thats why the Scottish government must chart an independent course. Maintain all the sensible controls, continue the vaccination roll-out, but abandon the inappropriate use of these Chinese tests in favour of superior tests made here in Scotland.

There is no good reason to follow Boris over the cliff on his Covid surrender strategy.

Neale Hanvey is the Alba Party MP for Kirkcaldy and Cowdenbeath

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Covid: There's a serious problem with how we are testing people for the virus Neale Hanvey MP - The Scotsman

Introduction

Profilin 1 (PFN1) is a ubiquitous small-molecule protein that exists in all eukaryotes.1 PFN1 was first identified as a G-actin sequestering molecule,2 and subsequently, its true functions in actin polymerization and F-actin dynamics were revealed.3 In the following decades, the structure of PFN1 was recognized to have 3 domains: an actin-binding domain,4 a poly-L-proline (PLP)-binding domain,5 and a phosphoinositide-binding domain.6

PFN1 plays a vital role in many cell functions, including membrane trafficking, endocytosis, cell cycle, motility, proliferation, cell survival, transcription, stemness, and autophagy (Figure 1). Abnormal expression or deletion of PFN1 can affect the normal physiological activity of cells and lead to disease development. PFN1 has been deeply studied in a variety of diseases, some genetic (eg, amyotrophic lateral sclerosis)7 and some chronic (eg, hypertension).8

In the past 10 years, PFN1s role in cancer has received increasing attention. In this review, we summarize the studies of PFN1 in cancer that have been completed in recent years, discuss the roles of PFN1 in cancer, and discuss the implications for tumor diagnosis and therapy in the future.

Early diagnosis of cancers is still a major challenge worldwide, and early detection can notably reduce their associated morbidity and mortality.9 PFN1, a critical actin-binding protein, is found to be dysregulated in many cancers, which makes it possible to use it as a biomarker for diagnosis and prognosis. PFN1 mainly plays a role in the cytoplasm, but it can also be found in the nucleus and can even be secreted into the extracellular space. The rich knowledge in the proteomics field makes the detection of proteins for new diagnostic markers and targets for therapy possible.10

In some tumor types (such as renal cell carcinoma [RCC], gastric cancer, and others), high expression of PFN1 indicates later stage and worse prognosis. Via differential proteomics, PFN1 has been identified in metastatic and primary RCC, and further analysis indicated that high PFN1 expression was associated with poor outcome and that PFN1 could be used as a potential prognostic marker in RCC.11 In clear-cell RCC (ccRCC), the expression of PFN1 was decreased in early-stage tumors compared with normal tissues. However, its expression in stage IV ccRCC was significantly increased. PFN1 was selected as a candidate marker of late-stage ccRCC.12 Results of a recent study determined that the vast majority of ccRCC tumors tend to be selectively PFN1-positive in stromal cells only; dramatic transcriptional upregulation of PFN1 was found in tumor-associated vascular endothelial cells in clinical specimens of ccRCC.13 Tissue microarray results also showed that PFN1 was increased in metastatic ccRCC compared with primary tumors. Univariate analysis suggested that higher PFN1 expression was associated with shorter disease-free survival (HR, 7.36; P = .047) and lower overall survival.14

In gastric cancer, Tanaka et al found that PFN1 was highly expressed in fetal rat stomach. Additionally, PFN1 was overexpressed in some human and rat gastric cancers.15 The results of later studies indicated that PFN1 expression was higher in gastric cancer tissues than in adjacent normal tissues. High PFN1 expression was correlated with tumor infiltration, lymph node metastasis, and tumor-node-metastases (TNM) stage. Functional assays confirmed that silencing PFN1 could inhibit the invasion and migration of gastric cancer cell lines.16

In addition, PFN1 expression was higher in nonsmall cell lung cancer (NSCLC). Lower expression of PFN1 was associated with better prognosis and a higher survival rate in NSCLC.17 Proteomic analysis revealed that PFN1 was differentially expressed in laryngeal carcinoma tissues compared with adjacent normal tissues. Further study results revealed that PFN1 was increased in laryngeal carcinoma tissues compared with adjacent normal tissues, indicating that PFN1 was a novel potential biomarker for the diagnosis of laryngeal carcinoma.18

However, in some other tumors (such as colorectal cancer [CRC], oral carcinoma, and others), the opposite is true. PFN1 was downregulated in pancreatic cancer.19-20 Lower expression of PFN1 was significantly associated with a shorter survival period.20 In late-stage oral squamous cell carcinoma, PFN1 expression was lower than that in normal oral epithelium, and loss of PFN1 expression was related to invasion into and metastasis of lymph nodes.21 PFN1 was also decreased in late advanced hepatocellular carcinoma (HCC) and was associated with a poor survival rate of patients.22-23 In addition, PFN1 was found to be downregulated in nasopharyngeal carcinoma24 and breast cancer.25 Combined with another 4 actin-binding proteins, PFN1 could be used to construct a model for predicting poor prognosis of esophageal squamous cell carcinoma.26

Under normal physiological conditions, PFN1 is involved in multiple cellular functions, such as cell motility, migration, adhesion, and transduction signaling pathways.27 PFN1 is differentially expressed in various types of tissues and cells, which may explain its variable tumorigenic mechanisms in different tumors, even in different stages of the same cancer (Figure 2). Because PFN1 plays important roles in tumorigenesis and progression, targeting PFN1 dysregulation could to some extent influence the prognosis of patients with cancer. Determining the expression of PFN1 could thus be used to distinguish high-risk disease from lower-risk disease. Combination with other indices could further improve the diagnostic and prognostic value of PFN1.

In addition to dysregulation in tumor tissues, PFN1 was also found to bedifferentially expressed in the serum, urine, and extracellular vesicles of patients with cancer, which makes it possible to utilize PFN1 in liquid biopsy analysis of tumors. Compared with tumor tissue biopsy, liquid biopsy is a more practical method for real-time monitoring of patients with cancer.28 In addition, PFN1 was detected in the supernatants of cultured cells.

It has been shown that PFN1 gene expression is increased in peripheral blood cells of patients with HCC compared with healthy controls.29 A 9-gene expression system (including PFN1) was used to discriminate patients with HCC from healthy people.30 Proteomic analysis of serum proteins showed that PFN1 was increased in patients with gallbladder cancer. The expression difference between these patients and healthy controls was more than 2-fold.31 PFN1 was differentially expressed in the urine of patients with invasive and noninvasive bladder cancer. Further studies confirmed that PFN1 was notably decreased in the epithelium of invasive bladder tumors compared with noninvasive tumors, which was associated with the clinical outcomes of bladder cancer.32 In in vitro pancreatic cancer cell lines, PFN1 was downregulated in secretomes compared with nonneoplastic pancreatic ductal cells.33 In invitro cultured RCC cell lines, PFN1 was differentially regulated in the supernatant. Further studies revealed that PFN1 was upregulated in RCC tissues.34 Apart from its dysregulation in serum and urine, PFN1 was found to be downregulated in the circulating leukocytes of patients with breast cancer compared with healthy controls, which provides a new paradigm for highly sensitive and less invasive approaches for the diagnosis of breast cancer.35 Studies have already revealed that PFN1 can be secreted via exosomes or other secretory pathways.36-38

Extracellular PFN1 in the tumor microenvironment can be taken up by recipient cells and execute its function in recipient cells, which in turn may influence the biological behavior of cells in the microenvironment, ultimately affecting tumorigenesis and progression of cancers. As mentioned above, PFN1 is expressed differentially in the serum and urine of patients with cancer, which enables its application as a biomarker for diagnosis and prognosis in liquid biopsy (Table 1).

Cell motility involves membrane protrusion, cell matrix adhesion, cell body translocation, and rear detachment. Many of these processes require the actin cytoskeleton and its regulators. By facilitating the exchange of ATP for ADP on G-actin, PFN1 plays a major role in actin polymerization, thus influencing motility in numerous cells.39 PFN1 also participates in cell motility by regulating actin polymerization and interactions with other regulators of actin cytoskeletons, such as ARP3, VASP, and proteins of cell signaling pathways. Cell-cell adhesion and cell-matrix adhesion are critical contributors to maintaining tissue architecture. Dysregulation of cell-cell adhesion is an important sign in tumor initiation and progression of malignancy. PFN1 can modulate cell adhesion and epithelial-to-mesenchymal transition (EMT) in cancer cells. However, the mechanisms by which PFN1 regulates cell adhesion are still not very clear. Undoubtedly, learning more about the roles of PFN1 in cell adhesion and motility will help us better understand its roles in modulating tumor invasion and migration.

Since PFN1 plays a critical role in actin polymerization, it is an indispensable regulator of cell motility. PFN1 participates in the invasion and metastasis of multiple cancers. However, the roles of PFN1 in regulating cell motility are context specific.27 Exogenous PFN1 with intact actin-binding abilities can ameliorate the adherence and spreading capabilities of cancer cells and exert tumor-suppressive effects in breast cancer.40 Consistent with the results of the study by Wittenmayer et al, Zou et al found that PFN1 overexpression could revert MDA MB-231 cells to an epithelioid phenotype, with restored adherence junctions.41 In addition, PFN1 overexpression could promote AMPK activation and p27 phosphorylation, which in turn induces epithelial morphological reversion of mesenchymal breast cancer through restoration of adherens junctions.42 These studies highlighted the involvement of PFN1 in epithelial adhesion and differentiation, which helped us better understand its roles in cancer cell motility.

Invadopodia are actin-driven membrane protrusions that can deliver matrix metalloproteinases to degrade the matrix and support invasion and dissemination of tumor cells. Any dysregulation of the actin cytoskeleton can impair the formation and maturation of invadopodia.43-46 PFN1 can regulate PI(3,4)P2, which in turn negatively regulates lamellipodin at the leading edge of breast cancer cells and thus inhibits those cells motility.47 The depletion of PFN1 leads to an increase in the level of PI(3,4)P2 in invadopodia and its interacting adaptor Tks5. The interaction of PI(3,4)P2-Tks5 has been shown to promote the anchorage, maturation, and turnover of invadopodia, which in turn enhances the invasiveness and motility of breast cancer.48 Breast cancer is an invasive adenocarcinoma, and numerous studies have found that PFN1 is downregulated in breast cancer tissues.49-54 Overexpression of PFN1 reduces the invasion and migration of breast cancer cells, while loss of PFN1 significantly enhances breast cancer cell motility and invasion. Mechanisms involved in PFN1s negative roles in breast cancer metastasis include Enabled (Ena)/vasodilator stimulated phosphoprotein (VASP)-dependent lamellipodial protrusion,51 miRNA-182 regulation,52 and regulation of PFN1 degradation.53 Mouneimne et al found that PFN1 knockdown (KD) could increase F-actin bundles and enhance stress fiber formation. In that study, the numbers of protrusions in PFN1-KD cells were markedly decreased, and PFN1-KD could inhibit the motility of breast cancer.55 Moreover, Liu et al indicated that the interaction of LMO2-PFN1 and LMO2-ARP3 could promote the formation of lamellipodia/filopodia in basal-type breast cancer cells.56 Ena/VASP is a critical regulator of the actin cytoskeleton at the leading edge of cells, which controls membrane protrusions and cell motility. Cell-substrate adhesion and downregulation of Protein Kinase A (PKA) promote interactions of PFN1 with VASP, which is another mechanism by which PFN1 regulates cell motility.57-58 Knockdown of PFN-1 has been shown to abrogate the inhibitory effect of tyrphostin A9, suggesting that modulating PFN1 expression could have therapeutic potential in the treatment of metastatic breast cancer.59

As in breast cancer, PFN1 was found to be a suppressor of migration in HCC.22,23,60 All-trans retinoic acid60 and guttiferone K22 could inhibit hepatocellular cell migration and proliferation by upregulating the expression of PFN1. In prostate cancer, cathepsin X can inactivate PFN1, thus promoting adhesion, invasion, and migration of cancer cells.61 In CRC, elevated expression of PFN1 obviously inhibited invasion and migration. PFN1 was suppressed by the HLA-F-AS1/miRNA-330-3p/PFN1 or HCP5/miRNA-299-3p/PFN1/AKT axis.62-63

Interestingly, Ding et al showed that in the early stages of metastasis, breast cancer cells exhibit a hyperinvasive phenotype characterized by upregulation of MMP-9 and by faster invasion when PFN1 expression is downregulated. However, in the late stages of metastasis, loss of PFN1 markedly inhibits the growth of metastatic colonies of breast cancer cells.54 Rizwani et al reported that PFN1 expression was elevated in breast cancer tissues and that overexpression of PFN1 could inhibit the migration of breast cancer cells. The phosphorylation of S137 mutants abrogated PFN1s promotion of migration. These studies provided a different vision of PFN1s role in breast cancer metastasis.64

In gastric cancer, silencing PFN1 inhibited the invasion and migration of cells, and the PFN1 expression level in cancer tissue was positively correlated with tumor infiltration and lymph node metastasis.16 However, different conclusions were drawn from the study of Ma et al. The authors found that PFN1 expression was inversely correlated with lymph node metastasis.65 In the lung cancer cell line A549, downregulation of PFN1 inhibited migration.17 In addition, in vitro studies support the importance of PFN1 in the proliferation and migration of RCC cells, and treatment with a novel computationally designed PFN1-actin interaction inhibitor reduced the proliferation and migration of RCC cells in vitro and RCC tumor growth in vivo.13 Additional studies have demonstrated that downregulation of PFN1 can also suppress the migration of laryngeal cancer18 and bladder cancer.66

Although more studies on PFN1 have been completed recently, its roles in cancer metastasis are still unclear. The concentrations of actin and PFN1 are time- and space-specific, and so is the regulation of the actin cytoskeleton (Table 2). Additional thorough studies are needed to comprehend the mechanisms and laws regulating the actin cytoskeleton. More importantly, in addition to actin dependence, PFN1 affects cell migration in an actin-independent manner by interacting with proteins with PIP2 or PLP domains. Furthermore, lncRNAs and microRNAs also modulate the functions of PFN1. All of these proteins and RNAs interact with PFN1 and indirectly influence the functions of cancer cells, which makes understanding the roles of PFN1 in cancer metastasis and other functions more complicated (Table 3).

In yeast, the gene encoding PFN1 is essential for cytokinesis.67 Early studies revealed that PFN1/ embryos died as early as the 2-cell stage, while PFN1/+ embryos displayed reduced survival during embryogenesis compared with wild-type embryos; this indicates that PFN1 is essential for cell division and survival during embryogenesis.68 PFN1 silencing in endothelial cells inhibits proliferation.69 In addition, homozygous deletion of PFN1 in chondrocytes failed to complete abscission at late-stage cytokinesis.70 The results of all these studies imply that PFN1 plays a role in cell proliferation. In breast cancer, PFN1 overexpression (PFN1-OE) has been shown to inhibit cell growth and exert an inhibitory effect on tumorigenesis,25,40,52,71-75 and PFN1-OE suppresses the activation of AKT, which in turn inhibits the growth of tumor cells.71 PFN1-OE cells arrested at the G1 phase, which was partly attributed to the upregulation of P27kip1.72 miRNA-182 could downregulate PFN1 expression and promote triple-negative breast cancer cell proliferation.52 However, Yap et al put forward opposite views. The authors research results revealed that silencing PFN1 resulted in a multinucleation phenotype of breast cancer cells, thus inhibiting proliferation.76 Recent studies from Chakraborty et al also reported that PFN1 knockdown could upregulate SMAD3 and inhibit the proliferation of breast cancer.77 Results of single-cell studies on the extracellular matrix revealed that stiff extracellular matrix led to upregulation of PFN1, possibly promoting the proliferation of breast cancer.78 Apart from breast cancer, PFN1 was also found to suppress proliferation in pancreatic adenocarcinoma,20 endometrial cancer,79 and HCC.23,60 In gastric cancer, silencing PFN1 caused cell cycle arrest at G0/G1 phase, thus restraining cell proliferation.16 Knockdown of PFN1 could also inhibit the proliferation of laryngeal cancer.18 Our previous studies found that overexpression of PFN1 could promote the proliferation of multiple myeloma cells by accelerating the cell cycle from G1 to S phase.80 PFN1 is indispensable for cytokinesis. Nevertheless, PFN1 is involved in regulating cell proliferation not only by impacting cytokinesis but also by modulating cell cyclerelated proteins. Otherwise, PFN1 could also interact with cell signaling pathways and indirectly influence cell proliferation.

Tumor growth is not only about uncontrolled proliferation but also resistance to apoptosis.81 Actin dynamics have notable impacts on multiple stages of apoptosis.82 PFN1, as a critical actin-binding protein, is an indispensable regulator of actin dynamics, through which PFN1 participates in regulating apoptosis. PFN1 overexpression could upregulate the most common tumor-associated hotspot mutation of p53p53R273Hthus sensitizing cancer cells to apoptosis via the intrinsic apoptotic pathway.83 PFN1 has been shown to facilitate apoptosis of breast cancer cells, thus exerting a suppressive effect on tumorigenesis.73,75,83,84 By inducing apoptosis and reducing autophagy, PFN1 has also been shown to sensitize pancreatic cancer cells to irradiation. Additionally, overexpression of PFN1 can significantly elevate apoptotic markers such as cleaved caspase-3 and cleaved PARP after irradiation, suggesting that PFN1 can modulate radiosensitivity partly by regulating apoptosis.85

Given that PFN1 is involved in cell proliferation and apoptosis, it is not difficult to understand its roles in the drug resistance of tumor cells. PFN1 was found to be downregulated in butyrate-treated CRC cells,86 and proteomics studies revealed that PFN1 was differentially expressed in erinacine Atreated CRC cells,87 which suggested the roles of PFN1 in drug-mediated cell death and inhibition of proliferation. In addition, proteomics showed that PFN1 was differentially expressed in mitotane-treated adrenocortical carcinoma,88 and PFN1 was found to be increased in tocotrienol-treated MDA-MB-231 cells,89 indicating its roles in predicting the response to anticancer therapies. Compared with temozolomide (TMZ)-treated glioblastoma cells, PFN1 was downregulated in OKN-007 combined with TMZ-treated glioblastoma cells. Further study results revealed that PFN1 is involved in TMZ resistance.90 Results of our previous studies showed that PFN1 could interact with the Beclin 1 complex and participate in bortezomib resistance in multiple myeloma.80 Since PFN1 is involved in multiple cell processes, including proliferation, apoptosis, and proteomics, it was recognized as a biomarker for therapy sensitivity, and it is worth further exploring its roles in drug resistance. In addition, PFN1 was found to participate in angiogenesis,91-92 initiation of tumors,93 and autophagy.80 Loss of PFN1 in A549 cell lines resulted in fewer early apoptotic cells after treatment with piperlongumine, and PFN1 sensitized A549 cells to anticancer agents.17 PFN1 serves as a bridge for actin-cytoskeleton and cell signaling pathways and is involved in multiple biological and physiological processes. Dysregulation of PFN1 in cancer cells has a notable impact on sensitivity to chemotherapy or radiotherapy and may be a new target for the treatment of drug-resistant or radioresistant patients.

Studies have already confirmed that PFN1 is essential for cell survival in early embryos, as PFN1-KN could induce Drosophila embryos to die at the 2-cell stage.94 For further investigation of PFN1s roles in tissue-specific stem cells, Zheng et al established PFN1flox/flox mice that inducibly delete PFN1 in HSCs. Results showed that PFN1 was essential for the retention and metabolism of mouse hematopoietic stem cells in bone marrow partially through the axis of PFN1/G13/EGR1.95 These study results implied important roles of PFN1 in stem cell function, which were still unclear and deserved further research. Later study results have found that both overexpression and depletion of PFN1 could reduce the stem-like phenotype of MDA-MB-231 (MDA-231) triple-negative breast cancer cells, suggesting that a balanced expression of PFN1 was required for maintenance of optimal stemness and tumor-initiating ability of breast cancer cells.93 Considering that tumor heterogeneity is still an ongoing challenge for cancer treatment and that cancer stem cells (CSC) are considered to be a determining factor of tumor heterogeneity,96 intensive studies on PFN1s roles in CSC may provide us new insight into tumor initiation.

As mentioned above, PFN1 has been shown to be a critical participator of actin dynamics and to play important roles in cell migration. For cytotoxic T lymphocytes (CTLs), migration abilities are essential for patrolling tissues and locating targeted cells.97-98 Schoppmeyer et al thus studied PFN1s roles in CTL functions. The authors found that PFN1 negatively regulated CTL-mediated elimination of target cells and that PFN1 downregulation promoted CTL invasion into a 3D matrix in vitro. In patients with pancreatic cancer, PFN1 expression was substantially decreased in peripheral CD8+ T cells.99 However, considering the complexity of immune responses in vivo, the exact roles of PFN1 in tumor immunity remain unclear and need to be further explored.

Based on previous studies, we found that PFN1participates in multiple biological processes of tumor development and progression. Meanwhile, it is noteworthy that PFN1 plays opposite roles in different tumors and at different periods of tumor, potentially leading to the conclusion that PFN1s function in tumor has spatial and temporal specificity. Future studies on PFN1 should take this into account. PFN1 was shown to be of great significance for diagnosis and prognosis prediction and for monitoring the therapeutic effect of anticancer drugs, and PFN1s roles in tumor stemness and immunity may provide a new avenue for cancer therapy. Although much research has been done on PFN1 and cancer, puzzles still need to be solved. With deepening research, the function of PFN1 in cancer would be further clarified and its clinical value would be more prominent.

Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

Conflicts of Interest: Authors declare no conflicts of interest for this article.

Acknowledgment: The authors are thankful for financial support from the Doctoral Fund Project of Hunan Provincial Peoples Hospital (program number BSJJ201812).

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3. Goldschmidt-Clermont PJ, Furman MI, Wachsstock D, Safer D, Nachmias VT, Pollard TD. The control of actin nucleotide exchange by thymosin beta 4 and profilin: a potential regulatory mechanism for actin polymerization in cells. Mol Biol Cell. 1992;3(9):1015-1024. doi:10.1091/mbc.3.9.1015

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31. Tan Y, Ma S-Y, Wang F-Q, et al. Proteomic-based analysis for identification of potential serum biomarkers in gallbladder cancer. Oncol Rep. 2011;26(4):853-859. doi:10.3892/or.2011.1353

32. Zoidakis J, Makridakis M, Zerefos PG, et al. Profilin 1 is a potential biomarker for bladder cancer aggressiveness. Mol Cell Proteomics. 2012;11(4):M111.009449. doi:10.1074/mcp.M111.009449

33. Grnborg M, Zakarias Kristiansen T, Iwahori A, et al. Biomarker discovery from pancreatic cancer secretome using a differential proteomic approach. Mol Cell Proteomics. 2006;5(1):157-171. doi:10.1074/mcp.M500178-MCP200

34. Minamida S, Iwamura M, Kodera Y, et al. Profilin 1 overexpression in renal cell carcinoma. Int J Urol. 2011;18(1):63-71. doi:10.1111/j.1442-2042.2010.02670.x

35. Braun M, Fountoulakis M, Papadopoulou A, et al. Down-regulation of microfilamental network-associated proteins in leukocytes of breast cancer patients: potential application to predictive diagnosis. Cancer Genomics Proteomics. 2009;6(1):31-40.

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37. Makridakis M, Vlahou A. Secretome proteomics for discovery of cancer biomarkers. J Proteomics. 2010;73(12):2291-2305. doi:10.1016/j.jprot.2010.07.001

38. Pavlou MP, Diamandis EP. The cancer cell secretome: a good source for discovering biomarkers? J Proteomics. 2010;73(10):1896-1906. doi:10.1016/j.jprot.2010.04.003

39. Small JV, Stradal T, Vignal E, Rottner K. The lamellipodium: where motility begins. Trends Cell Biol.2002;12(3):112-120. doi:10.1016/s0962-8924(01)02237-1

40. Wittenmayer N, Jandrig B, Rothkegel M, et al. Tumor suppressor activity of profilin requires a functional actin binding site. Mol Biol Cell. 2004;15(4):1600-1608. doi:10.1091/mbc.e03-12-0873

41. Zou L, Hazan R, Roy P. Profilin-1 overexpression restores adherens junctions in MDA-MB-231 breast cancer cells in R-cadherin-dependent manner. Cell Motil Cytoskeleton. 2009;66(12):1048-1056. doi:10.1002/cm.20407

42. Jiang C, Veon W, Li H, Hallows KR, Roy P. Epithelial morphological reversion drives Profilin-1-induced elevation of p27(kip1) in mesenchymal triple-negative human breast cancer cells through AMP-activated protein kinase activation. Cell Cycle. 2015;14(18):2914-2923. doi:10.1080/15384101.2015.1069929

43. Beaty BT, Wang Y, Bravo-Cordero JJ, et al. Talin regulates moesinNHE-1 recruitment to invadopodia and promotes mammary tumor metastasis. J Cell Biol. 2014;205(5):737-751. doi:10.1083/jcb.201312046

44. Beaty BT, Sharma VP, Bravo-Cordero JJ, et al. 1 integrin regulates Arg to promote invadopodial maturation and matrix degradation. Mol Biol Cell. 2013;24(11):1661-1675,S1-S11. doi:10.1091/mbc.E12-12-0908

45. Mader CC, Oser M, Magalhaes MAO, et al. An EGFRSrcArgcortactin pathway mediates functional maturation of invadopodia and breast cancer cell invasion. Cancer Res. 2011;71(5):1730-1741. doi:10.1158/0008-5472.CAN-10-1432

46. Oser M, Yamaguchi H, Mader CC, et al. Cortactin regulates cofilin and N-WASp activities to control the stages of invadopodium assembly and maturation. J Cell Biol. 2009;186(4):571-587. doi:10.1083/jcb.200812176

47. Baea YH, Dinga ZJ, Das T, Wells A, Gertler F, Roy P. Profilin1 regulates PI(3,4)P2 and lamellipodin accumulation at the leading edge thus influencing motility of MDA-MB-231 cells. Proc Natl Acad Sci U S A.2010;107(50):21547-21552. doi:10.1073/pnas.1002309107

48. Valenzuela-Iglesias A, Sharma VP, Beaty BT, et al. Profilin1 regulates invadopodium maturation in human breast cancer cells. Eur J Cell Biol. 2015;94(2):78-89. doi:10.1016/j.ejcb.2014.12.002

49. Roy P, Jacobson K. Overexpression of profilin reduces the migration of invasive breast cancer cells. Cell Motil Cytoskeleton. 2004;57(2):84-95. doi:10.1002/cm.10160

50. Zou L, Jaramillo M, Whaley D, et al. Profilin-1 is a negative regulator of mammary carcinoma aggressiveness. Br J Cancer. 2007;97(10):1361-1371. doi:10.1038/sj.bjc.6604038

51. Bae YH, Ding Z, Zou L, Wells A, Gertler F, Roy P. Loss of profilin-1 expression enhances breast cancer cell motility by Ena/VASP proteins. J Cell Physiol. 2009;219(2):354-364. doi:10.1002/jcp.21677

52. Liu H, Wang Y, Li X, et al. Expression and regulatory function of miRNA-182 in triple-negative breast cancer cells through its targeting of profilin 1. Tumour Biol. 2013;34(3):1713-1722. doi:10.1007/s13277-013-0708-0

53. Choi YN, Lee SK, Seo TW, Lee JS, Yoo SJ. C-terminus of Hsc70-interacting protein regulates profilin1 and breast cancer cell migration. Biochem Biophys Res Commun. 2014;446(4):1060-1066.doi:10.1016/j.bbrc.2014.03.061

54. Ding Z, Joy M, Bhargava R, et al. Profilin-1 downregulation has contrasting effects on early vs late steps of breast cancer metastasis. Oncogene. 2014;33(16):2065-2074. doi:10.1038/onc.2013.166

55. Mouneimne G, Hansen SD, Selfors LM, et al. Differential remodeling of actin cytoskeleton architecture by profilin isoforms leads to distinct effects on cell migration and invasion. Cancer Cell. 2012;22(5):615-630.doi:10.1016/j.ccr.2012.09.027

56. Liu Y, Wu C, Zhu T, Sun W. LMO2 enhances lamellipodia/filopodia formation in basal-type breast cancer cells by mediating ARP3-profilin1 interaction. Med Sci Monit. 2017;23:695-703. doi:10.12659/msm.903261

57. Gau D, Veon W, Shroff SG, Roy P. The VASPprofilin1 (Pfn1) interaction is critical for efficient cell migration and is regulated by cellsubstrate adhesion in a PKA-dependent manner. J Biol Chem.2019;294(17):6972-6985. doi:10.1074/jbc.RA118.005255

58. Gau D, Ding ZJ, Baty C, Roy P. Fluorescence resonance energy transfer (FRET)-based detection of profilinVASP interaction. Cell Mol Bioeng. 2011;4(1):1-8. doi:10.1007/s12195-010-0133-z

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Profilin 1 Protein and Its Implications for Cancers - Cancer Network

Han Xiao, a protein chemist at Rice University, and Shawn Zhang, a cancer biologist at Baylor College of Medicine, received an email with a big question: When will your drug go to clinical trials? The question came from a patient eager to try out a drug for breast cancer that had metastasized to the bone. When cancer spreads beyond the tissue where it developed, especially to bone, patients outcomes become less optimistic. More than hope hung on the patients email.

Xiao and Zhang developed an innovative therapeutic technology that sends medicine right to cancerous bone tissue by combining two drugs the U.S. Food and Drug Administration (FDA) has already approved. By delivering therapy to tissues such as bone that are notoriously difficult for medicines to access, the new technology, dubbed BonTarg, could be a game changer for patients with metastasized breast cancers and other cancers and bone diseases.

Its quite exciting, particularly because bone metastasis is such a huge problem in breast cancer, said Alana Welm, a breast cancer biologist at the University of Utahs Huntsman Cancer Institute, who was not involved with the new research.

A new technology targets an FDA-approved antibody therapy to cancer in the bone.

Baylor College of Medicine and Rice University

Metastasis to Metastasis

Bone is often the first site of metastasis. Once cancer spreads to bone it will almost inevitably spread to other organs such as the lung, liver, and brain. Metastasis makes cancer difficult or impossible to cure. Metastatic breast cancer, for example, is incurable.

Most metastases originate from other metastases, not the primary tissue. Zhangs group recently showed that bone can act as a launchpad for further metastases.1 They seeded invasive and less aggressive human breast and prostate cancer cell lines in the hind limbs of mice. Within four to eight weeks, they saw metastases in the rodents lungs, livers, kidneys, brains, and additional bones.

Follow-up experiments revealed that once cancer cells are growing in the bone microenvironment, they become more plastic and take on stem cell-like properties. These features allow cancer cells to better adapt to new environments. They leave the bone and spread to other organs, which further advances the disease. Zhang and his team also found that primary metastases in bone can remain small, indicating that further metastases could spread to other organs before the first ones are detectable.

Anything we can do to keep the disease either not going to bones, or to really treat it well once its in the bones, could actually have outcomes for overall survival, Welm said. Treating bone metastases could also alleviate bone pain, spinal compression, and fractures that can make patients lives quite awful, Welm said. To intervene when cancer has only spread to bone represents a huge therapeutic opportunity.

Bone Barriers

To get ahead of the metastatic launchpad in the bone, Zhang and Xiao planned to specifically target breast cancer-derived bone metastases. They started with a proven drug called trastuzumab. Commonly referred to by its brand name Herceptin, trastuzumab is an antibody therapy that targets human epidermal growth factor 2 (HER2), a protein that cells make too much of in about a quarter of breast cancers. The antibody prevents HER2-expressing cancer cells from initiating a cascade of events that leads to proliferation, and may also induce cytotoxicity by attracting the immune systems natural killer cells.

Trastuzumab is a proven therapy that, when given in combination with chemotherapy, has extended overall survival in metastatic breast cancer patients to nearly five years.2 But the drug is not a cure. For many patients, their cancer continues to progress while they are under treatment, and for most, remission rarely lasts.

Bone metastases do not kill patients as often as metastases to internal organs such as the lung or liver, so they do not receive a lot of attention in research. But according to Zhang, Targeting bone metastasis not just kills cancer cells in the bone, it has the potential to prevent cancer cells from going other places in the body.

One difficulty lies in getting drugs to the bone. Despite making billions of blood cells every day, bone tissue holds few blood vessels. Where it does have vasculature, a bone marrow-blood barrier makes it hard for therapies delivered through the circulatory system to arrive at their destination. In addition, antibodies are big molecules. The mineralized matrix structure of bone prevents big molecules from gaining access to the tissue, limiting how effective a drug can be.

In the past, patients were given high doses of antibody therapies to overcome hurdles of getting them to bone. But then the drug ended up in tissues besides the bone, leading to unwanted and sometimes systemic side effects.

People think of antibody drugs as magic bullets that only target cancer cells while missing healthy cells, Xiao said. But research in the clinic has shown that not to be true.

That discrepancy drove Xiao to increase the specificity of the bullet so that it goes to the cancer, but not the healthy tissues. In the new research, he equipped the antibody therapy with a homing device.

Targeting Tumors

Alendronate is a bisphosphonate drug with high affinity for the highly mineralized bone matrix. It has been used to selectively deliver imaging probes, nuclear medicines, and nanoparticles to the bone, and the FDA has approved it to treat bone maladies such as osteoporosis. Xiao joined alendronate to the monoclonal antibody trastuzumab to target the therapy to bone.

Next, Zhang and his team injected the modified drug into the intra-iliac artery, a branch of a major artery in the lower abdomen, of mice with tumors in the hind limb bone derived from a breast cancer cell line.

Within 24 hours, the drug accumulated in the bone and remained there for a week. In contrast, injection with unmodified antibody did not remain in bone past the first day of treatment. The bone-targeted drug also accumulated much more substantially in cancerous bone compared with healthy bone, thanks in part to alendronates affinity for the highly acidic environment of bone metastatic sites.

The conjugated antibody therapy also prevented the development of secondary metastases in most other organs. Zhang and his team let the bone tumors grow for about eight to 12 weeks. Mice treated with trastuzumab harbored metastases in the heart, liver, spleen, lungs, kidney, and brain. Mice treated with alendronate conjugated trastuzumab, however, were mostly devoid of secondary tumors, Zhang and Xiao reported in Science Advances.3

Scans of rodents treated with alendronate-conjugated trastuzumab, individual components, or a salt solution.

Baylor College of Medicine and Rice University

Translatable Technology

The work that theyve done here is quite translatable [to the clinic], Welm said. She added that a trial will likely be straightforward as long as Xiao and Zhang can create a clinical grade version of the compound. The next step is to see whether the therapy works in models with cells derived from patients rather than established cell lines.

She is curious whether the technology could be used with other breast cancer therapies. The FDA recently approved another antibody therapy called Sacituzumab govitecan to treat triple-negative breast cancer. Theoretically, the chemistry Xiao and his team developed to attach alendronate to trastuzumab should work with Sacituzumab govitecan.

For these antibody drugs, even though [trastuzumab] is an older drug, people can modify the antibody, like what we are doingand get more potential from this drug, he said.

The technology allows scientists like Xiao and Zhang to come one step closer to the magic bullet that will take out cancer cells while leaving healthy cells alone. This conjugated antibody is one of the most perfect, best solutions in my mind, to help us gather the bullets to where they need to be, Zhang said.

The team hopes to be ready in time to help the patient who emailed them. This drug can be the next wave of drugs for this patient, Xiao said. We can get a better outcome for her. We want to push this drug to clinical trials as soon as possible, and hopefully this patient can benefit from it.

References

Read more from the original source:
Homing Technology Delivers Therapy to Cancerous Bone - The Scientist

After closing a merger with GX Acquisition Corp., Celularity Inc., a clinical-stage cellular medicine company, is taking the next step in its evolution to enable further development of novel, off-the-shelf allogeneic placentaderived cellular therapies.1

Celularity aims to transform the way we approach the treatment of cancer and other diseases by harnessing the versatility, unique immune biology, and innate stemness of placental-derived cells, Robert J. Hariri, MD, PhD, found, chairperson, and chief executive officer of Celularity, stated in a press release. We are immensely proud of our clinical development results so far as well as the state-of-the-art manufacturing capabilities we built to support rapid scaling and a competitive cost structure for our placental-derived cell therapeutics. We believe off-the-shelf, allogeneic cell therapies will drive a paradigm shift in how clinicians approach the treatment of cancer and other serious diseases.

CYNK-001, the companys lead product candidate, is the only cryopreserved, allogeneic, off-the-shelf natural killer (NK) cell therapy to be developed from placental hematopoietic stem cells. The agent expresses perforin and granzyme B, has showcased cytotoxic activity against hematological tumors and solid tumor cell lines, and can secrete immunomodulatory cytokines in the presence of tumor cells.

The novel therapy is under investigation as a potential option in multiple myeloma, acute myeloid leukemia (AML), and glioblastoma multiforme; it is also being evaluated in infectious diseases like COVID-19 (NCT04365101).

An ongoing, open-label, multi-dose, phase 1 trial (NCT04310592) is examining the maximum-tolerated dose (MTD) or maximum planned dose of CYNK-001 in an estimated 22 patients with acute myeloid leukemia (AML).2 To participate, patients need to have primary or secondary AML and be in first or second morphological clinical response (CR), morphological CR with incomplete hematologic recovery, or a morphologic leukemia-free state per European LeukemiaNet recommendations for AML Response Criteria.

Patients also need to have MRD positivity, be aged between 18 and 80 years old, have an ECOG performance status of 0 to 2, and be able to be off immunosuppressive therapy for at least 3 days before infusion with the therapy. Patients who previously had central nervous system involvement are allowed to enroll if they had been treated and their cerebral spinal fluid is clear for at least 2 weeks before undergoing lymphodepletion.

Exclusion criteria include significant medical conditions, laboratory abnormalities, bi-phenotypic acute leukemia, acute promyelocytic leukemia, unacceptable organ function, autoimmune disease, uncontrolled graft-vs-host disease (GVHD), and GVHD that requires corticosteroids.

Participants are first given cyclophosphamide plus fludarabine. Then, they are administered CYNK-001 at 3 varying dose levels1.8 billion, 3.6 billion, and 5.4 billion CYNK-001 cellson days 0, 7, and 14. The primary objectives of the research include dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and frequency and severity of adverse effects. Important secondary objectives include the number of patients who convert from MRD-positive to -negative status; time to, and duration of, MRD response; progression-free survival; time to progression; duration of morphologic complete remission; and overall survival.

In June 2021, the study was expanded to include patients with relapsed/refractory AML following a case of conversion to MRD negativity, when the therapy was delivered at its highest dose level.3

The decision to expand the trial followed observations of a patient with NPM-1positive, FLT3-negative AML and good-risk cytogenetics who had been administered 5.4 billion CYNK-001 cells. The patient converted from MRD-positive to -negative status, without experiencing any DLTs.

For this patient, primary induction treatment with 7+3 chemotherapy had failed, and so they had gone on to receive second induction therapy followed by high-dose cytarabine consolidation. At this time point, the patient achieved a complete CR, but MRD was found to be persistent; it did not clear following 4 months of treatment with azacitidine. MRD positivity was confirmed on a marrow biopsy.

The patient went on to enter the phase 1 trial, where they received lymphodepletion, and then received 1.8 billion CYNK-001 cells on days 0, 7, and 14 in the outpatient setting, which totaled to 5.4 billion CYNK-001 cells. On day 28, the patient had converted from MRD positivity to negativity. CYNK-001 cells were present in both the peripheral blood and bone marrow.

Notably, no DLTs have been observed with the therapy at any of the dose levels examined thus far.

The company also shared plans to continue dose escalation with the therapy in the MRD indication up to 9.0 billion CYNK-001 cells. To strengthen the persistence of the treatment, the expansion arms of MRD and relapsed/refractory AML will include an augmented lymphodepletion protocol comprised of cyclophosphamide at 3600 mg and fludarabine at 120 mg over 4 days vs cyclophosphamide at 900 mg plus fludarabine at 75 mg over 3 days.

In April 2021, the FDA granted an orphan drug designation to CYNK-001 as a potential therapeutic option for patients with malignant gliomas.4 As such, the therapy is also under investigation in patients with glioblastoma multiforme as part of another phase 1 trial (NCT04489420).5

To be eligible for enrollment, patients need to have historically confirmed disease at first or second relapse, measurable disease, a Karnofsky performance status of 60 or higher, and acceptable organ function, among other criteria.

Patients who previously received radiation within 12 weeks of their screening MRI; those who were on growth factors with less than 4 weeks of a washout period; those treated with radiotherapy, chemotherapy, or other investigational drugs within 4 weeks; those who received prior cellular or gene therapy; and those with active autoimmune disease, were excluded.

Cohort 1A of the trial will enroll up to 6 patients with recurrent glioblastoma multiforme who will receive intravenous CYNK-001 at a dose of 1.2 x 109 cells on days 0, 7, and 14. From the initial infusion of therapy, patients will be followed for a 42-day DLT period. No other interventions are planned between the last day of treatment.

If DLTs are experienced, cohort 1C, the de-escalation cohort, will include up to 6 patients with recurrent glioblastoma multiforme who will receive the therapy at a dose of 600 x 106 cells on days 0, 7, and 14. These patients will also be followed for DLTs for 42 days post infusion. Cohort 1B, the surgical cohort, will also enroll up to 6 patients, who will be given CYNK-001 at a maximum safe dose of either 1.2 x 109 cells or 600 x 106 cells at days 0, 7, and 14. Patients in this cohort will undergo resection following the last dose of the therapy in the DLT period.

Treatment of cohorts 2A or 2C will only begin after the safety data from cohorts 1A or 1C are determined to be acceptable. Here, patients will first have the Ommaya catheter placement in accordance with institutional policy within 1 week before CYNK-001 infusion on day 0. Cohort 2A will enroll up to 6 patients with recurrent glioblastoma multiforme who will be given the therapy at a dose of 200 x 106 cells +/- 50 x 106 cells intratumorally on day 0, 7, and 14.

Cohort 2C will also include up to 6 patients with recurrent disease who will receive the product at a dose of 200 x 106 cells +/- 50 x 106 cells intratumorally on day 0 and day 7. Lastly, cohort 2B, the surgical intratumoral cohort, will include 6 patients with glioblastoma multiforme who will receive the cellular therapy at a maximum safe dose of either 200 x 106 cells +/- 50 x 106 cells on day 0 and 7.

The primary objectives of the trial are to examine the number of patients who report DLTs with the therapy and toxicities. Important secondary objectives are to evaluate the overall response rate, duration of response, progression-free survival, time to progression, and overall survival.

The safety and efficacy of the cell therapy is also being explored in newly diagnosed patients with multiple myeloma after autologous stem cell transplant, as part of another phase 1 trial (NCT04309084).6 The objective of the program is to achieve durable responses with the therapy in these patients with multiple myeloma who are eligible for transplant in the first-line setting.

Another novel agent in the pipeline is CYNK-101, which is manufactured from NK cells extracted from postpartum placentas. The cells are then genetically engineered to boost cell-killing activity when given with a monoclonal antibody.7 Preclinical data with the product in combination with an antibody showed that the regimen resulted in cell-killing activity when administered to lymphoma cells in vitro.

Additionally, CYNK-CAR products are being developed as allogeneic, off-the-shelf strategies by modifying genes of the human placental hematopoietic stem cellderived NK cells. Several CAR constructs that are designed to target hematologic and solid tumor indications are currently under investigation.

More here:
Developmental Interest in Allogeneic PlacentaDerived Cell Therapies Expands - OncLive

This article was originally published here

J Control Release. 2021 Jul 14:S0168-3659(21)00357-6. doi: 10.1016/j.jconrel.2021.07.014. Online ahead of print.

ABSTRACT

Triple negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC) are amongst the most aggressive forms of solid tumors. TNBC is highlighted by absence of genetic components of progesterone receptor, HER2/neu and estrogen receptor in breast cancer. NSCLC is characterized by integration of malignant carcinoma into respiratory system. Both cancers are associated with poor median and overall survival rates with low progression free survival with high incidences of relapse. These cancers are characterized by tumor heterogeneity, genetic mutations, generation of cancer-stem cells, immune-resistance and chemoresistance. Further, these neoplasms have been reported for tumor cross-talk into second primary cancers for each other. Current chemotherapeutic regimens include usage of multiple agents in tandem to affect tumor cells through multiple mechanisms with various such combinations being clinically tested. However, lack of controlled delivery and effective temporospatial presence of chemotherapeutics has resulted in suboptimal therapeutic response. Consequently, passive targeted albumin bound paclitaxel and PEGylated liposomal doxorubicin have been clinically used and tested with newer drugs for improved therapeutic efficacy in these cancers. Active targeting of nanocarriers against surface overexpressed proteins in both neoplasms have been explored. However, use of single agent nanoparticulate formulations against both cancers have failed to elicit desired outcomes. This review aims to identify clinical unmet need in these cancers while establishing a correlation with tested nano-formulation approaches and issues with preclinical to clinical translation. Lipid and polymer-based drug-drug and drug-gene combinatorial nanocarriers delivering multiple chemotherapeutics simultaneously to desired site of action have been detailed. Finally, emerging opportunities such as pharmacological targets (immune check point and epigentic modulators) as well as gene-based modulation (siRNA/CRISPR/Cas9) and the nano-formulation challenges for effective treatment of both cancers have been explored.

PMID:34273417 | DOI:10.1016/j.jconrel.2021.07.014

The rest is here:
Triple negative breast cancer and non-small cell lung cancer: Clinical challenges and nano-formulation approaches - DocWire News

Gourmey uses stem cells taken from a fertilized duck egg which are isolated and then fed on a diet of proteins, amino acids, and fats. "The cells multiply as if they are in the egg, then you adjust the nutrients to trigger the cell type that you want," company CEO and cofounder Nicolas Morin-Forest tellsSifted."So if you want liver cells, or muscle cells, you adjust the inputs and the cells react to that. We then harvest muscle cells, fat cells, or liver cells and craft our products."The company says its end product is so successful that an unnamed Michelin-star chef has not been able to tell the lab grown foie gras from its natural counterpart, and that he would cook with the synthesized meat product.

Morin-Forest says their company began with foie gras because it is complex, hard to find due to bans, and it carries premium pricing. But the company wants to do more with what they've created. "Foie gras is just the first application of our current know-how," says Morin-Forest. "With the same starting cells, we can create any type of poultry meat product."

Gourmey's product has been so convincing it's been able to pull together $10 million in additional funding. Fortune notes that with this money, this specialty lab-meat maker expects to begin selling its foie gras before the end of 2022 at the earliest, and by 2023 at the latest.

Read the original:
The World's First Lab-Grown Foie Gras Could Solve This Major Concern - Mashed

KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced positive event-free survival (EFS) data from the pivotal neoadjuvant/adjuvant Phase 3 study KEYNOTE-522. The trial investigated neoadjuvant KEYTRUDA, Mercks anti-PD-1 therapy, plus chemotherapy followed by adjuvant KEYTRUDA as monotherapy (the KEYTRUDA regimen) compared with neoadjuvant chemotherapy followed by adjuvant placebo (the chemotherapy-placebo regimen) in patients with high-risk early-stage triple-negative breast cancer (TNBC). This is the first time an anti-PD-1/L1 therapy has demonstrated a statistically significant EFS result as combined neoadjuvant and adjuvant therapy for these patients. These results are being presented today during a European Society for Medical Oncology (ESMO) Virtual Plenary.

After a median follow-up of 39 months, the KEYTRUDA regimen reduced the risk of EFS events by 37% (HR=0.63 [95% CI, 0.48-0.82]; p=0.00031) versus the chemotherapy-placebo regimen a statistically significant and clinically meaningful EFS result. EFS was defined as the time from randomization to the first occurrence of either disease progression that precluded definitive surgery, a local/distant recurrence, a second primary cancer, or death from any cause. As previously announced, KEYNOTE-522 met the dual primary endpoint of pathological complete response (pCR) at the first interim analysis. The trial is continuing to allow for additional follow-up of overall survival (OS), a key secondary endpoint. At this fourth interim analysis, although these data have not crossed the boundary for statistical significance, there was a 28% reduction in the risk of death with the KEYTRUDA regimen versus the chemotherapy-placebo regimen (HR=0.72 [95% CI, 0.51-1.02]; p=0.03214). The safety profile of the KEYTRUDA regimen was consistent with the known profiles of each regimen, and no new safety concerns were identified.

Given the high rates of recurrence within the first five years of diagnosis, patients with high-risk early-stage TNBC need new treatment options, said Dr. Peter Schmid, lead, Centre for Experimental Cancer Medicine, Barts Cancer Institute in London, England. KEYNOTE-522 was designed to study whether the combined neoadjuvant and adjuvant regimen with KEYTRUDA could help treat the cancer earlier. Now, with more than three years of follow-up, we see the potential of this approach. These event-free survival data are very encouraging for patients and show that this combination of KEYTRUDA plus chemotherapy as neoadjuvant therapy, followed by single-agent KEYTRUDA as adjuvant therapy, may offer women with high-risk early-stage TNBC a new treatment option for this aggressive disease.

These highly anticipated event-free survival results in this TNBC population build upon earlier findings from the KEYNOTE-522 trial and further support the potential use of KEYTRUDA in these patients, said Dr. Vicki Goodman, vice president, clinical research, Merck Research Laboratories. KEYNOTE-522 is the first large randomized Phase 3 study to report a statistically significant and clinically meaningful EFS result among patients with stage II and stage III TNBC. We have submitted these data to the FDA and are working closely with the agency on its review of our application.

KEYTRUDA is currently approved under accelerated approval in the U.S. in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (Combined Positive Score [CPS] 10) as determined by an FDA-approved test.

Merck is rapidly advancing a broad portfolio in womens cancers with an extensive clinical development program for KEYTRUDA and several other investigational and approved medicines across multiple gynecologic and breast cancers. The KEYTRUDA clinical development program for TNBC encompasses several internal studies and external collaborative trials, including the ongoing studies KEYNOTE-242 and KEYNOTE-355.

Study Design and Additional Data From KEYNOTE-522

KEYNOTE-522 is a Phase 3, randomized, double-blind trial (ClinicalTrials.gov, NCT03036488). The dual primary endpoints are pCR, defined as pathological stage ypT0/Tis ypN0 at the time of definitive surgery, and EFS, defined as the time from randomization to the first occurrence of either disease progression that precluded definitive surgery, a local/distant recurrence, a second primary cancer, or death from any cause in all patients randomized. Secondary endpoints include pCR rate using alternative definitions, OS in all patients randomized, pCR rate according to all definitions, EFS and OS in patients whose tumors express PD-L1 (CPS 1), safety and health-related quality of life assessments. The study enrolled 1,174 patients who were randomized 2:1 to receive either:

As previously announced, KEYNOTE-522 met the success criterion for the dual primary endpoint of pCR at the first interim analysis; pCR was observed in 64.8% of patients treated with KEYTRUDA plus chemotherapy (n=401), an increase of 13.6% (p=0.00055) from 51.2% in patients treated with placebo plus chemotherapy (n=201). At the fourth interim analysis, KEYNOTE-522 met the success criterion for the dual primary endpoint of EFS. The study is continuing to allow for additional follow-up of OS.

At three years, 84.5% of patients treated with the KEYTRUDA regimen were alive and did not experience an EFS event compared to 76.8% of patients treated with the chemotherapy-placebo regimen.

In pre-specified exploratory subgroup analyses of EFS, the EFS benefit seen with the KEYTRUDA regimen was independent of PD-L1 expression. In the PD-L1-positive subgroup (n=973), defined as CPS 1, treatment with the KEYTRUDA regimen reduced the risk of EFS events by 33% (HR=0.67 [95% CI, 0.49-0.92]) versus the chemotherapy-placebo regimen. In the PD-L1-negative subgroup (n=197), defined as CPS <1, treatment with the KEYTRUDA regimen reduced the risk of EFS events by 52% (HR=0.48 [95% CI, 0.28-0.85]) versus the chemotherapy-placebo regimen.

In a pre-specified but non-randomized exploratory analysis of EFS by pCR outcome, the reduction in EFS events with the KEYTRUDA regimen was observed independent of pCR outcome at definitive surgery.

Treatment-related adverse events (TRAEs) were examined in the neoadjuvant phase, the adjuvant phase and the combined phases. TRAEs in the neoadjuvant phase have been previously reported. At the time of this data cutoff, no patients were still receiving protocol treatment. For the combined neoadjuvant and adjuvant phases, TRAEs occurred in 98.9% of patients receiving the KEYTRUDA regimen (n=783) and 99.7% of patients receiving the chemotherapy-placebo regimen (n=389); Grade 3-5 TRAEs occurred in 77.1% versus 73.3%, respectively. TRAEs led to death in 0.5% of patients receiving the KEYTRUDA regimen (n=4) and 0.3% of patients receiving the chemotherapy-placebo regimen (n=1). No new safety concerns were identified. In the adjuvant phase, TRAEs occurred in 53.7% of patients receiving adjuvant KEYTRUDA (n=588) and 48.6% of patients receiving adjuvant placebo (n=331), including 6.3% and 2.7%, respectively, who had at least one Grade 3 event.

Immune-mediated adverse events (AEs) and infusion reactions of any grade in the combined neoadjuvant and adjuvant phases occurred in 43.6% of patients receiving the KEYTRUDA regimen and 21.9% of patients receiving the chemotherapy-placebo regimen. The most common of these events (occurring in 10% of patients) were infusion reactions (18.0%) and hypothyroidism (15.1%) in patients receiving the KEYTRUDA regimen and infusion reactions (11.6%) in patients receiving the chemotherapy-placebo regimen. Immune-mediated AEs led to death in 0.3% of patients receiving the KEYTRUDA regimen (n=2) and no patients receiving the chemotherapy-placebo regimen. In the adjuvant phase, immune-mediated AEs and infusion reactions occurred in 10.2% of patients receiving adjuvant KEYTRUDA and 6.0% of patients receiving adjuvant placebo, including 2.9% and 0.3%, respectively, who had at least one Grade 3 event.

About Triple-Negative Breast Cancer (TNBC)

Triple-negative breast cancer is an aggressive type of breast cancer that characteristically has a high recurrence rate within the first five years after diagnosis. While some breast cancers may test positive for estrogen receptors, progesterone receptors or overexpression of human epidermal growth factor receptor 2 (HER2), TNBC tests negative for all three. Approximately 10-15% of patients with breast cancer are diagnosed with TNBC. TNBC tends to be more common in people who are younger than 40 years of age, who are African American or who have a BRCA1 mutation.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,500 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is:

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or mUC who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Cancer

KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma.

Tumor Mutational Burden-High Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDASevere and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of antiPD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.

KEYTRUDA with Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen, at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT 3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT 3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT 3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism.

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with antiPD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other antiPD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after antiPD-1/PD-L1 treatment. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between antiPD-1/PD-L1 treatment and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using antiPD-1/PD-L1 treatments prior to or after an allogeneic HSCT.

Increased Mortality in Patients With Multiple Myeloma

In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with an antiPD-1/PD-L1 treatment in this combination is not recommended outside of controlled trials.

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KEYTRUDA (pembrolizumab) Plus Chemotherapy Before Surgery and Continued as a Single Agent After Surgery Showed Statistically Significant Event-Free...

Bayer subsidiary BlueRock Therapeutics has been granted a fast-track review by the FDA for DA01, its stem cell-based therapy for Parkinsons disease which is currently in early-stage clinical testing.

The FDA designation allows for benefits such as more frequent meetings and communication with the regulator during clinical development, and a truncated six-month review time.

Those are all considerations for the future as the first patients only started to be treated with DA01 in a phase 1 trial aimed primarily at showing the safety of the therapy, which is trying to replenish the dopaminergic neurons that progressively die away in Parkinsons and lead to slow, laboured movement, tremors and other symptoms.

The therapy involves implantation of dopamine-producing cells under general anaesthesia into a part of the brain called the putamen, which is particularly affected by neuron loss in Parkinsons and is responsible for regulating movement as well as some types of learning.

Patients take immune-suppressing drugs to prevent their body rejecting the transplanted cells, and the safety and tolerability of the procedure as well as the ability of the transplant to survive will be monitored for two years.

BlueRock is also hoping to demonstrate some evidence of efficacy, and will look at clinical measures such as motor function over the same time period. It is the first trial in the US to study pluripotent stem cell-derived dopaminergic neurons in patients with Parkinsons, according to the company.

The first patient in the trial, which will eventually enrol 10 subjects with advanced Parkinsons, was treated at Memorial Sloan Kettering Cancer Centre in June, and others will be recruited at Weill Cornell Medical Centre, the University of California, Irvine, and the University of Toronto.

Our objective is to use authentic cells, to have them integrate entirely into the brain and restore lost physiologic function, said BlueRock chief executive Emile Nuwaysir, as the first patient was treated.

If successful, this new therapeutic modality could have implications for the Parkinsons community and beyond, he added.

Bayer took control of BlueRock in 2019, three years after backing the formation of the company as joint venture with private equity group Versant, in a deal that valued the biotech at $1 billion.

DA01 is Bluerocks lead cell therapy programme, but the company is also working on treatments for other neurological disorders, degenerative heart disease, and autoimmune disorders.

Bayer is also developing a gene therapy for Parkinsons originated by Asklepios Bio (AskBio), which it acquired for $2 billion upfront last year with another $2 billion tied to milestones, and has pledged to make cell and gene therapies a pillar of its R&D strategy.

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FDA gives speedy review to Bayer's Parkinson's stem cell therapy - - pharmaphorum

The report published on the Stem Cell Therapy Market Analysis of Key Players, End User, Demand and Consumption By 2026 by Zion Market Research facilitates a closer outlook on opportunities, revenue growth, and current market trends. The report is focused to offer qualitative and quantitative analysis of dynamics and market opportunities prevailing during the forecast period. Also, the report encompasses an in-depth study on the prominent leaders in theStem Cell Therapy Market.

The Leading Market Players Covered in this Report are:

Anterogen Co., Ltd., RTI SurgicalInc., Pharmicell Co., Ltd., MEDIPOST Co., Ltd., JCR Pharmaceuticals Co., Ltd., Holostem Terapie Avanzate S.r.l., NuVasiveInc., and AlloSource.

The market report additionally gives a to-the-point evaluation of the techniques and plans of action that are being executed by the players and companies to contribute to the global Stem Cell Therapy Market growth. Some of the most conspicuous measures taken by the organizations are partnerships, mergers & acquisitions, and collaborations to extend their overall reach. The players are likewise presenting newer product varieties in the market to improve the product portfolio by embracing the new innovation and carrying out it in their business.

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The report provides extensive insights into the key strategies and market development dynamics along with the macro and micro factors in the current market landscape. Also, the report comprises the Covid-19 and post-Covid-19 market landscape to let users identify the upcoming patterns and trends in the global Stem Cell Therapy Market. Our analysts have prepared the report as an indispensable guide for enabling our customers to take qualitative decisions and reap the best results out of it.

The report is segregated into different sections of which few are overview, growth factors, segmentation, regional analysis, and competitive analysis. The only aim to bifurcate the report into different sections is to put forth an in-depth assessment of each parameter and let our users understand the most probable and even the finest trend prevailing in the current landscape. Also, the structure of a report is curated to reveal the future trends and opportunities in the global Stem Cell Therapy Market in the forthcoming years.

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The overview section reveals the potential, opportunities, and scope of the Stem Cell Therapy Market along with its market size and volume. Also, the section encompasses an in-depth study on value chain analysis and the core working of the market. The growth factor segment elaborates the financial position, technology dynamics, and product portfolio expected in the forthcoming year. Also, the segmentation section bifurcates the whole market landscape into different classes to identify the market size and volume of each segment. However, the regional analysis segment reveals the extensive potential of each region in the global Stem Cell Therapy Market along with its size and volume.

Our analysts have tried to maintain the highest level of transparency and accuracy in the report. Also, the report offers business intelligence solutions for helping our clients to achieve a competitive edge in the global Stem Cell Therapy Market. Moreover, it will help our users to curate effective business strategies to promulgate the growth rate of their business in the forthcoming years. However, all the statistical and quantitative analysis mentioned in the report reflects the real-time data. It covers all the market landscapes to help users understand the present positioning of the global Stem Cell Therapy Market along with the probable market trends in the future.

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Moving to the drivers and restraints, one will be given all factors that are indirectly or directly helping the development of the global Stem Cell Therapy Market. To get to know the markets development measurements, it is important to evaluate the drivers of the market. Furthermore, the report likewise analyses the current patterns alongside new and plausible growth openings for the global market. Additionally, the report incorporates the components that can restrict the market growth during the forecast period. Understanding these elements is also mandatory as they help in grasping the markets shortcomings.

Primary and secondary methodologies are being utilized by the research analysts to gather the information. Along these lines, this global Stem Cell Therapy Market report is planned at guiding the readers to a superior, clearer viewpoint and information about the global market.

Thanks for reading this article; you can also get individual chapter wise section or region wise report version like North America, Europe or Asia

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Stem Cell Therapy Market Analysis of Key Players, End User, Demand and Consumption By 2026 26 Sports - 2x6 Sports

Chop a three-banded panther worm in half, and the head and tail will swirl around as if nothing had happened. Even more astonishing, a few days later, the halves will grow to become two complete and almost indistinguishable worms.

Loeb associate professor of the natural sciences Mansi Srivastava has studied this process of healing and regeneration for more than a decade. Together with members of her research group, she has been working to uncover the molecular and cellular mechanisms underlying whole-body regeneration, and tracing their evolutionary history. Understanding both these aspects of regeneration, she believes, could aid in efforts to develop the field of human regenerative medicine.

Srivastava chose to study the three-banded panther worm because this tiny, carnivorous Bermuda native is especially adept at whole-body regeneration: able to heal and then recreate an entire organism from even a small fragment of its body. Moreover, the species is sufficiently similar to planarians, worms widely studied in the field of regeneration biology, that scientists can make comparisons between the two species, whose last common ancestor lived 550 million years ago. If there are similarities in the molecular mechanisms they use to regenerate, Srivastava explains, identifying and investigating these shared elements could lead to an understanding of the fundamental principles controlling this feat.

An advance in this direction came in 2019 when her research group reported the discovery of a pioneer factor, a molecular agent responsible for initiating the cascade of genetic signals necessary for regeneration. In the moments after an injury, she explains, cells around the damaged site sound an alarm by generating proteins that activate the choreography of regeneration. But what intracellular factor causes the genes encoding those proteins to switch on? How does an incomplete animal know what is missing, and how to recreate it? Who or what decides how to proceed?

Her team probed these questions using a technique known as ATACseq that allowed them to zoom in on the structure of chromatinthe packaging material of cellular DNA. They focused on regions of the chromatin structure that opened up soon after amputation. These sites marked genes likely activated in response to injury. By analyzing the commonalities among multiple regions of open chromatin across many cells found near the damage site, Srivastava and colleagues were able to identify one such decision-maker, or factor responsible for the observed changes in the products of these activated genes. Known as EGR, the protein proved crucial for regeneration: when the researchers turned off its production, many of the genes that should have been switched on werentand the worm never regenerated.

This work provided a broad look, Srivastava says, at the early steps following amputation. Her team is currently developing a more detailed picture of these molecular events. To do so, they have applied the same analysis of the chromatin structure to individual cells of the worm. By looking at chromatin changes within single cells, they hope to learn exactly how the process that directs regeneration unfolds.

By tagging a single potentially pluripotent cell (above, at far left) with a red fluorescent protein, researchers can watch as it divides, eventually becoming a complete worm.

Courtesy of Mansi Srivastava

At the same time, Srivastava has turned her attention to the raw material the worms use to regenerate tissues, a form of adult stem cell called a neoblast. In response to amputation, these typically dormant cells wake up and undergo rapid bursts of division. A sort of cellular alchemy ensues, she explains: like embryonic stem cells, which are active during development, the neoblasts turn into neurons, muscles, skin, whatever you need. This ability to become any cell type, known as pluripotency, is a well-described feature of embryonic stem cells. But panther worms are somehow able to maintain pluripotency of neoblasts into adulthood.

By investigating the cellular origins of the worms embryonic and adult pluripotent stem cells, and characterizing the differences and similarities between the two, Srivastava hopes to learn how neoblasts persist and reawaken, and why human and other mammalian stem cells are limited in their regenerative capacities.

Using ultraviolet light to tag cells of interest and follow them during their life cycle, her team has made significant progress toward identifying the cellular lineage that gives rise to stem cells during the worms early development. We now want to use that same approach in adults, she says, to understand how the worms make and then maintain a neoblast, to keep it hanging out, happily pluripotent, in its body. I dont think my work is going to help anyone grow a limb five years from now, she adds, but I do think it could lead to an understanding of pluripotency, and how genomes are regulated during regeneration. That could lead to breakthroughs in the nascent field of human regenerative medicine.

Continued here:
Could Regenerative Biology Work in Humans? - Harvard Magazine

Newly Report on Opthalmology Drugs and Devices Market 2021, Growth, Share Types and Key Players | Merck (US), Pfizer (US), Roche Holdings (Switzerland), Santen Pharmaceutical(Japan), Abbott Medical Optics (US), Alcon (Switzerland), Bausch& Lomb (US), Carl Zeiss Meditec (Germany), Essilor International S.A. (France), Johnson& Johnson (US), Nidek(Japan), Topcon Corporation (Japan)

COVID-19 Impact on Global Opthalmology Drugs and Devices Market Research Report 2021-2028

The global Opthalmology Drugs and Devices market report examines the market position and viewpoint of the market worldwide, from various angles, such as from the key players point, geological regions, types of product and application. This Opthalmology Drugs and Devices report highlights the key driving factors, constraint, opportunities, challenges in the competitive market. It also offers thorough Opthalmology Drugs and Devices analysis on the market stake, classification, and revenue projection. The Opthalmology Drugs and Devices market report delivers market status from the readers point of view, providing certain market stats and business intuitions. The global Opthalmology Drugs and Devices industry includes historical and futuristic data related to the industry. It also includes company information of each market player, capacity, profit, Opthalmology Drugs and Devices product information, price, and so on.

The latest Opthalmology Drugs and Devices market report published by Cognitive Market Research offers a competency-based analysis and global market estimate, developed using evaluable methods, to provide a clear view of current and expected growth patterns. The report also contains market analysis by geographic location across the globe as well as major markets.

The key manufacturers covered in this report areMerck (US), Pfizer (US), Roche Holdings (Switzerland), Santen Pharmaceutical(Japan), Abbott Medical Optics (US), Alcon (Switzerland), Bausch& Lomb (US), Carl Zeiss Meditec (Germany), Essilor International S.A. (France), Johnson& Johnson (US), Nidek(Japan), Topcon Corporation (Japan)

The product type segment discusses the different kinds of products made available by the Global Opthalmology Drugs and Devices market:Device, Drug

The product application segment examines the different end-users operational in the Global {Opthalmology Drugs and Devices} market:Hosptial, Clinic, Others

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The report also inspects the financial standing of the leading companies, which includes gross profit, revenue generation, sales volume, sales revenue, manufacturing cost, individual growth rate, and other financial ratios.

Research MethodologyThe data that has been collected is from a multitude of different services that include both primary and secondary sources. The data also includes a list of the different factors that affect the Opthalmology Drugs and Devices market either positively or negatively. The data has been subjected to a SWOT analysis that can be used to accurately predict the various parameters that are used to measure a companys growth. The strengths along with various weaknesses faced by a company are included in the report along with a comprehensive analysis of the different threats and opportunities that can be exploited.

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To understand the global Opthalmology Drugs and Devices market dynamics, the market is analyzed across major global regions and countries. Cognitive Market Research provides customized specific regional and country-wise analysis of the key geographical regions as follows:North AmericaEuropeAsia Pacific CounterMiddle East & AfricaLatin AmericaAmerica Country (United States, Canada)South AmericaAsia Country (China, Japan, India, Korea)Europe Country (Germany, UK, France, Italy)Other Country (Middle East, Africa, GCC)

About Author:Cognitive Market Research is the new buzzword in the market, which helps in understanding the market potential of any product in the market. This helps in understanding the market players and the growth forecast of the products and so the company. This is where market research companies come into the picture. It offers premium progressive statistical surveying, market research reports, analysis & forecast data for a wide range of sectors both for the government and private agencies all across the world.

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Coronavirus Impact Editon of Opthalmology Drugs and Devices Coronavirus Impact Editon of Insights with COVID-19 Impact Analysis by 2020Merck (US),...

This Tissue Ablation market report depicts industrial analysis, growth factors, driving factors and recent market trends, which greatly benefit to the newly entering key players in the industry. This market report is very important for them as it covers all the profit making related factors that play a major role in driving the growth of the market. These factors include technological progressions, confronts, opportunities for the players and modern inclinations. One can get a detailed review of the market and also a brief insight of the market evolution. All this information is provided in the form of an overview on the current market trends and upcoming projections. This research analysis further proceeds with growth aspects, volume of the industry and market share.

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For the better understanding of the market, considering market experts opinions is very important. This Tissue Ablation market report discusses the expert opinions in detail. Additionally, it also consists of type wise and application wise sections. Every type describes about the production for the forecast period 2021 to 2027. Every section understanding greatly aids to recognize the significance of elements that work effectively in market growth. This market report sheds light on key players of the market to know about the strategies they are following in the market which include new product launchings, collaborations, acquisitions and mergers.

Major Manufacture:St. Jude Medical Boston Scientific Johnson & Johnson Medtronic

20% Discount is available on Tissue Ablation market report:https://www.globalmarketmonitor.com/request.php?type=3&rid=726930

Market Segments by Application:Oncology Cardiology Gynecology Cosmetology Urology Opthalmology

Worldwide Tissue Ablation Market by Type:Radiofrequency Ablation Ultrasound Ablation Laser-Based Ablation Irreversible Electroporation Cryoablation Devices Microwaves Ablation Hydrothermal Ablation External Beam Radiation Therapy (EBRT)

Table of Content1 Report Overview1.1 Product Definition and Scope1.2 PEST (Political, Economic, Social and Technological) Analysis of Tissue Ablation Market2 Market Trends and Competitive Landscape3 Segmentation of Tissue Ablation Market by Types4 Segmentation of Tissue Ablation Market by End-Users5 Market Analysis by Major Regions6 Product Commodity of Tissue Ablation Market in Major Countries7 North America Tissue Ablation Landscape Analysis8 Europe Tissue Ablation Landscape Analysis9 Asia Pacific Tissue Ablation Landscape Analysis10 Latin America, Middle East & Africa Tissue Ablation Landscape Analysis 11 Major Players Profile

This Tissue Ablation market report also includes specific sections by application and type. These market variables include, for example, the evolving needs of clients in diverse regions such as East Asia, North America, Latin America, and the Middle East and Africa, among others. The classification to drivers is depicted by a systematic evaluation of the controls, which also allows for key arranging. In addition, insights into the opinions of market experts have been used to gain a better picture of the overall market. To examine critical information and insight from the partnerships with a specific purpose in mind, equipment and programming exploration arrangements are used. This specific Tissue Ablation market report, also known as the global report, includes a broad analysis of the market in several regions of North America, Latin America, Asia Pacific, the Middle East & Africa, and Europe. The study includes details such as current market trends, past performance, and future prospects. Its an inside and out report in this sense.

Tissue Ablation Market Intended Audience: Tissue Ablation manufacturers Tissue Ablation traders, distributors, and suppliers Tissue Ablation industry associations Product managers, Tissue Ablation industry administrator, C-level executives of the industries Market Research and consulting firms

The significant findings mentioned in this global Tissue Ablation market research analysis are obtained from different trustworthy sources. Every minute detail about market scenario and business strategies are provided in this market report. With the help of significant data provided in this market report is greatly help new entrants to get overall idea about market strategies. Market data provided here is of great use as it forecasts future productivity and helps in business related decision making. This comprehensive Tissue Ablation market analysis gives precise data about market constraints, segment analysis, region wise market size, competitive landscape and growth factors. It also forecasts the global market scenario for the period 2021-2027.

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Tissue Ablation Market Value Projected to Expand by 2027 26 Sports - 2x6 Sports

Historically, most large-scale immunogenomic studies those exploring the association between genes and disease were conducted with a bias toward individuals of European ancestry. Corey T. Watson, assistant professor in the University of Louisville Department of Biochemistry and Molecular Genetics, is leading a call to actively diversify the genetic resources he and fellow immunogenomics researchers use in their work to advance genomic medicine more equitably.

Watson, along with UofL post-doctoral fellow Oscar Rodriguez, and visiting fellow Yana Safonova, are part of an international group of researchers who say the narrow studies limit their ability to identify variation in human adaptive immune responses across populations.

We need to better understand how genetics influences immune system function by studying population cohorts that better represent the diversity observed across the globe if we are to fully understand disease susceptibility, as well as design more tailored treatments and preventative measures, Watson said.

In an article published in Nature Methods, Diversity in immunogenomics: the value and the challenge, the group advocates for resources used in immunogenomics research to actively include and specifically identify additional populations and minority groups. They say such diversity will make their research more relevant and help in understanding population and ancestry-specific gene-associated disease, leading to improvements in patient care.

As scientists, we have a say in which populations are investigated. Therefore, it is critical for us to be actively inclusive of individuals representative of the world we live in. This is especially critical for genes that are as diverse and clinically relevant as those that encode antibodies and T cell receptors, Rodriguez said.

Watsons research focuses on immune function and molecular genetics. His team is studying a specific area of the genetic code that controls antibody function to better understand how differences in an individuals genes determine their susceptibility to certain diseases or immune responses to vaccines.

In collaboration with Melissa Smith, assistant professor in the Department of Biochemistry and Molecular Genetics, the team is conducting the largest sequencing efforts of the antibody gene regions in humans and in animal models, Watson said.

Specifically in humans, we are working to build catalogs of genetic variation in samples from multiple ethnic backgrounds and are engaged in projects that seek to understand how this genetic variation influences the immune response in infection, vaccination and other disease contexts, he said.

Watson is involved in efforts to improve the resources and data standards for antibody and T cell receptor genes for immunogenomics researchers around the world.

The article in Nature Methods was co-authored by researchers from the United States, Canada, Norway, France, Sweden, the United Kingdom, Russia, Saudi Arabia, Israel, South Africa, Nigeria, Chile, Peru, China, Japan, Taiwan and French Polynesia with expertise in biomedical and translational research, population and public health genetics, health disparities and computational biology as well as immunogenomics.

Continued here:
UofL researchers lead the call to increase genetic diversity in immunogenomics - uoflnews.com

NEW YORK Foundation Medicine and Flatiron Health announced this week that Foundations comprehensive genomic profiling tests will be available to order through Flatiron's OncoEMR platform. The integration will allow clinicians to electronically order, track, and receive Foundations test through OncoEMR, the companies said. Both Flatiron and Foundation are planning further integrations with the others comprehensive genomic profiling tests and electronic medical record systems, respectively.

Myriad Genetics this week said it has completed the sale of its Myriad RBM unit which specializes in providing laboratory research services to pharmaceutical companies to IQVIA subsidiary Q2 Solutions. When Myriad announced its intent to sell this business unit in May, it did not disclose the deal's financial details.

GenetronHealth said this week that it has entered a new partnership with the World Economic Forum under its Health and Healthcare Platform, where it is contributing its research insights, technologies, and industry experience. The platform's overall goal is to ensure worldwide equal access to the highest standards of health and healthcare.Genetroniscurrentlyparticipating in a sub-project,dubbedMoving Genomics to the Clinic, which seeks to promote the use of genetic testing in routine clinical practices by proving its utility and efficacy.

AccessHope, a City of Hope subsidiary, said this week that it has partnered with the Dana-Farber Cancer Institute to bring the latest cancer care expertise to patients and oncologists in the community. By partnering withAccessHope, Dana-Farber's experts will support oncologistswiththe latest advances in oncology,includingpersonalized treatments, clinical trials, promising investigational medications, and molecular testing. Patients in Massachusetts, Maine, New Hampshire, Vermont, Connecticut, Rhode Island, New York,and New Jersey, as well asthosein other parts of the country,can access these services through their employee benefits programs. City of Hope and Northwestern University's Robert H. Lurie Comprehensive Cancer Center are also foundational members ofAccessHope.

Molecular breath analysis startup Deep Breath Intelligencesaid this week that it has entered a collaboration with Lwenstein Medical, a sleep and respiratory medicine firm based inRheinland-Pfalz, Germany.Rotkreuz, Switzerland-based DBI said that it is applying artificial intelligence to identify breath biomarkers related to obstructive sleep apnea syndrome. DBIsaid ithas initiated a study on OSASin collaboration with Lwenstein Medical,using participantsbreath samples and applying DBIs patterned analytical algorithms to provide results.

Enable Biosciences said this week it is partnering with the California Department of Public Health to survey state residents for the presence of antibodies against SARS-CoV-2. As part of the program, more than 200,000 households in California will be invited to submit dried blood samples collected at home using kits developed by Enable Bio andtheCDPH. The samples will then be tested by Enable Bio for the presence of antibodies against SARS-CoV-2 to distinguish antibody response fromviralinfection versusresponse fromvaccination. Test results will provide information about the spread of COVID-19 in California and the uptake of vaccines for the disease, South San Francisco, California-based Enable Bio said. The project is a collaboration betweenthe company,theCDPH, Stanford University, and Gauss Surgical. The first survey period concluded June 15 with the second and third enrollment periods slated tobeginat the start of 2022.

NeoGensaid this week that it has extended itsglobalanimal genomicspartnership withGencove. Thepartnership allowsNeoGento offerGencove'sSkimSeeklow-pass sequencing technology to customers in the agricultural sector, including those in the bovine, canine,poultry, and swine industries. UsingGencove'ssequencingimputationplatform,NeoGensaid it can deliver increased genomics data with improved accuracy and flexibility.

Bioceptsaid this week ithas been added to the Russell Microcap Index. Michael Nall, Biocept's president and CEO,called the nodexceptionally exciting, as a driver ofawarenessfor the cancer liquid biopsy firm within thelargerglobal investment community.

Immunoviasaid this week that its American subsidiary hasreceived a CLIA Certificate of Registration,which isan important step in the accreditation of its laboratory in Marlborough, Massachusetts, and a prerequisite to receiving clinical laboratory licensure fromtheMassachusetts Department of Public Health. Clinical laboratory licensure is required beforeImmunoviacan begin testing patients with itsImmrayPanCan-d test, the firm said.According to the Centers for Medicare and Medicaid Services, a Certificate of Registration allows a laboratory toconduct moderate and/or high complexity testing until it is inspected to determine its compliance with the CLIA regulations.

In Brief This Week is a selection of news items that may be of interest to our readers but had not previously appeared onGenomeWeb.

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In Brief This Week: Foundation Medicine, Myriad Genetics, Genetron Health, and More - GenomeWeb

Flies have discriminating taste. Like a gourmet perusing a menu, they spend much of their time seeking sweet nutritious calories and avoiding bitter, potentially toxic food. But what happens in their brains when they make these food choices?

Yale researchers discovered an interesting way to find out. They tricked them.

In a study that could also help illuminate how people make food choices, the researchers gave hungry fruit flies the choice between sweet, nutritious food laced with bitter quinine and a less sweet, but not bitter, food containing fewer calories. Then, using neuroimaging, they tracked neural activity in their brains as they made these tough choices.

So which won? Calories or better taste?

It depends on how hungry they are, said Michael Nitabach,professor of cellular and molecular physiology, genetics, and neuroscience at Yale School of Medicine and senior author of the study.The hungrier they are, the more likely they will tolerate bitter taste to obtain more calories.

But the real answer to how flies make these decisions is a little more complex, according to the study published July 5 in the journal Nature Communications.

According to the research team, led by Preeti Sareen, associate research scientist at Yale, flies relay sensory information to a portion of their brain called the fan-shaped body, where signals are integrated, triggering what amounts to the insect version of an executive decision. The researchers found that patterns of neuronal activity in the fan-shaped body change adaptively when novel food choices are introduced, which dictates the flys decision over what food to eat.

But researchers went a step further. And things got even stranger. They found they could change a flys choice by manipulating neurons in areas of the brain that feed into the fan-shaped body. For example, when they caused a decrease in activity in the neurons involved in metabolism, they found that it made hungry flies choose the lower calorie food.

It is one big feedback loop, not just top-down decision making, Nitabach said.

And this is where there are connections to food choices of humans, he said. Neural activity in both a flys brain and a humans brain are regulated by the secretion of neuropeptides and the neurotransmitter dopamine, which in humans helps regulate sensations of reward. Changes in this network may alter how the brain responds to different types of food. In other words, neurochemistry may sometimes dictate food choices we think we are making consciously.

The study provides a template to understand how it is that things like hunger and internal emotional states influence our behavior, Nitabach said.

Sareen and Li Yan McCurdy, a graduate student at Yale School of Medicine, are co-authors of the paper.

Read more from the original source:
More filling? Tastes great? How flies, and maybe people, choose their food - Yale News

Introduction

Fragile X syndrome (FXS), OMIM # 300624, is a X-linked inherited genetic disease classified as a triplet repeat condition. FXS is the most common cause of inherited intellectual disability and autism in the world. It has a prevalence of 1 in 5000 men and 1 in 8000 women. Affected individuals are characterized by intellectual disability, autism, language deficit, typical facies, and macroorchidism.1,2

Alterations in the FMR1 gene with locus Xq27.3 are causative of Fragile X Syndrome and other disorders. This gene harbors a CGG repeat within the 5 untranslated region and, depending on the number of repetitions, 4 types of alleles are defined with different clinical manifestations:3 Normal alleles, which have up to 44 CGG repeats; grey zone or intermediate alleles that contain between 45 and 54 repeats; premutation (PM) alleles with between 55 and 200 repeats; and full mutation (FM) alleles, with more than 200 repeats. In most cases, this is due to an expansion of the CGG triplet from one generation to the next.4

The Fragile Mental Retardation Protein (FMRP) is coded by the FMR1 gene. The absence of FMRP expression is usually secondary to the methylation of the FMR1 gene that occurs when more than 200 CGG repeats are present in the 5UTR region; this can also be explained by a point mutation in the coding region for FMR1 or a deletion that includes this gene, but these changes have only been reported in a few cases. The absence of FMRP is related to the classic FXS phenotype.5,6

FMRP expression is slightly lower in the carriers of a PM allele. Lower levels of FMRP are found particularly in the upper premutation (PM) range however, they typically do not present the classic FXS syndrome phenotype.7 Furthermore, they have elevated FMR1 mRNA levels between 2 to 8 times normal levels, which also leads to RNA toxicity. These elevated levels of mRNA are a risk for a number of medical conditions that are not explained by decreased FMRP.2,4,8

FMRP has roles in chromatin dynamics, RNA binding, mRNA transport, and mRNA translation9,10 and for certain subgroups of cerebral transcripts.11

This protein is involved in the regulation of RNA stability, subcellular transport and translation of neural mRNAs that codify proteins involved in synapsis development, neural plasticity and brain development.8

In addition, FMRP interacts with at least 180 proteins expressed in the brain and connective tissue. This interactome comprises known FMRP-binding proteins, including the ribosomal proteins FXR1P, NUFIP2, Caprin-1, and other novel FMRP-interacting candidate proteins located in different subcellular compartments, including CARF, LARP1, LEO1, NOG2, G3BP1, NONO, NPM1, SKIP, SND1, SQSTM1 and TRIM28. This interactome suggests that, besides its known functions, FMRP is involved in transcription, RNA metabolism, ribonucleoprotein stress granule formation, translation, DNA damage response, chromatin dynamics, cell cycle regulation, ribosome biogenesis, miRNA biogenesis and mitochondrial organization.9

Several studies have shown that in the absence of FMRP, a wide range of neural mRNAs are affected, boosting neural protein synthesis, which results in dendritic spine dysmorphogenesis and glutamate/GABA imbalance, which in turn produce variations in neural excitation/inhibition, phenomena that are present in FXS. Dendritic spine dysmorphogenesis plays a role in the intellectual deficits and behavioral problems, due to the weak synaptic connections found in this syndrome.12,13

Fragile X syndrome (FXS) has incomplete penetrance and variable expressivity and biological sex is a decisive factor of the phenotype. Full mutation of the FMR1 gene has a 100% penetrance of intellectual disability in males and 60% in females. Other characteristics associated with FXS Appear with varying frequencies in affected individuals. Autism spectrum disorder (ASD) symptoms appear during early childhood in 50% to 60% of males and 20% of females with FXS.1417

Physical features include elongated face, large and prominent ears (7578% of affected males), mandibular prognathism (80% of adult men), hyperlaxity and macroorchidism (95% of adult men). Other characteristics also vary in their frequency of presentation: seizures (23%), strabismus (8%), and cardiac abnormalities such as abnormal aortic root dimensions (18%) and mitral valve prolapse (55%). In general, the female phenotype is less severe and less specific.4,18

The variation in the phenotype of monogenic diseases is common,19,20 it is explained by a combination of genetic, environmental, and lifestyle factors,21 and FXS is not an exception.

Here, we present a review of the knowledge about the molecular factors involved in the variable expressivity of FXS.

The presence of a full mutation in FMR1 is associated with the hypermethylation of a CpG island located in the promoter of the FMR1 gene. Methylation of DNA regions (mDNA) is one of the main epigenetic modifications related to transcription regulation.22 A CpG island is located proximal to the CGG repeat tract, which is expanded in FXS. Hypermethylation of the CpG island generates transcriptional silencing of the FMR1 gene.23 As a consequence, the Fragile Mental Retardation Protein (FMRP), codified by the FMR1 gene, is not produced24 and in turn, the absence or low expression of FMRP causes FXS.

CGG tract repetition expansion in the untranslated region (UTR) of exon 1 in the FMR1 gene generates instability of that region during the replication process, inducing size mosaicism, which is defined as the presence of premutation and mutation alleles in several cells.25

In males with FXS caused by full mutation, the detection of FMR1 mRNA levels in peripheral blood lymphocytes is common. This phenomenon is due to both size mosaicism and mDNA in the CpG island and nearby regions that vary between cells and tissues.26 Furthermore, longitudinal studies in women with FXS have shown that levels of mRNA transcribed from FMR1 decrease significantly with age.23 Complicating even more the behavior of mDNA and FXS, it has been found that in premutation alleles, a considerable number of cells have mDNA.27 The variation between methylation states of the CpG island and nearby regions among different cells and tissue of the same person is known as methylation mosaicism.28 It is estimated that around 50% of people with FXS have this type of mosaicism.29 In cells where mutated alleles are not methylated, they are transcriptionally active and can be expressed.30 However, in these cells there is no FMRP synthesis since mRNA with CGG expansion greater than 200 repeats is not translated efficiently in ribosomes.31,32

The absence or low levels of FMRP is a decisive factor for FXS development, as several studies have aimed to discover the relationship between protein levels and phenotypic characteristics of the patients. Since the late 1990s, correlations between FMRP levels and the neurological phenotype of FXS have been established.29,33,34 The first studies about this topic established the standard levels of FMRP in peripheral blood leucocytes through immunoblotting. When comparing protein levels with the allele type and the presence of size mosaicism, it was demonstrated that people with the lowest FMRP levels were males with FM. Males with size mosaicism and females with FM had slightly higher levels of FMRP than males with FM.33,35,36 Via multiple regression models, it was found that FMRP levels were significantly correlated with the intelligence quotient (IQ) of the patients in the study.33 However, studies did not identify the same relation between FMRP levels and behavioral symptoms.34,37 More recent evidence supports a partial overlap between the pathogenic mechanisms that lead to FXS and ASD.38 Lower FMRP levels have been documented in samples of individuals with FXS and ASD compared to patients with FXS only.29,34 The relation between FMRP levels and IQ in males and females with different expansions in CGG repeats was studied recently.39 This last study has two important advantages compared with previous studies: firstly, the use of fluorescence resonance energy transfer (FRET), which has a higher sensibility when measuring protein levels, and also FMRP levels were measured in dermal fibroblasts. Unlike leucocytes, fibroblasts derive from the ectoderm, the same germ layer from which nervous system cells originate. Researchers found a strong and positive relation between FMRP levels and cognitive skills in patients with levels below 30% of the standard levels in controls. Interestingly, above this level, there was a higher dependence between low FMRP levels and low IQ.39

In parallel with the aforementioned studies, researchers reported the incidence of size and methylation mosaicism in cognitive impairment severity.4042 The classic definition of premutation alleles behavior as non-methylated alleles, and mutated alleles as methylated or partially methylated ones in order to categorize premutation carriers and patients with FXS has been extended progressively to include a detailed classification that takes into account the existence of size and methylation mosaicisms.

Regarding size mosaicisms, different combinations have been described, including patients with some FM cells and other cells with PM. Indeed, patients with FM, PM, grey zone alleles and even alleles with normal size have been reported.40 The presence of size mosaicisms with PM and FM alleles is related with a less severe phenotype and a higher risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS).43

When exploring the possible relation between size mosaicisms and the intellectual functioning of patients with FXS disregarding sex, it was found that patients with FM/PM had better intellectual functioning and less maladaptive behavior, compared with FM-affected individuals.42 Interestingly, the same study found that ASD features and maladaptive behaviors were similar between FM-only and PM/FM mosaics within each sex, after controlling for overall intellectual functioning. A limitation of this study is that they used venous blood and real time PCR and Southern blot analysis to quantify the level of methylation.

Recently, methylation mosaicism has been taken into account as an important variable in phenotype traits. The most frequent mosaicism found in males is the presence of FM-methylated alleles and non-methylated FM and PM alleles (combination of size and methylation mosaicism).25,44 However, in patients with FM and not PM mosaicisms, methylated alleles do not express mRNA, while non-methylated alleles do. An aspect that highlights the importance of detecting the presence of this kind of mosaicism is the influence on phenotype severity. Additionally, according to some case reports, the presence of synthesized mRNA from PM and FM alleles increases the odds of developing the FXTAS phenotype.45,46 The final consequence of methylation mosaicism is the cells reduced ability to express FMR1 mRNA, measure mRNA and determine if there is a relation with phenotypic traits. When analyzing mRNA levels between males and females, it was found that females had higher levels. Also, in females, higher levels of FMR1 mRNA were related positively with age but not with intellectual functioning and autistic features. Males with FM that express FMR1 mRNA had significantly higher ADOS calibrated severity scores, when compared with males with fully methylated FM. Interestingly, no differences were found regarding intellectual functioning.41 Likewise, when contrasting FMR1 mRNA levels and scores on the Aberrant Behavior Checklist-Community-FXS version (ABC-CfX) it was found that in males with FM, higher values of FMR1 mRNA were related with elevated irritability and lower health-related quality of life scores.47 This association was not found in males with PM/FM, suggesting that for improved genotype/phenotype associations, it is essential to take into consideration not only sex but also size and methylation mosaicism.

Recent investigations explored simultaneously how FMR1 mRNA levels of FMRP are related to phenotypic alterations in males with PM and FM.48 In a study composed of 14 cases of patients with PM or PM and FM mosaicism and mental illnesses such as bipolar disorder, schizophrenia and psychosis, among others, low levels of FMRP and increased FMR1 mRNA were evident in these patients. This combination of characteristics in patients with FM, decreased FMRP, PM and increased FMR1 mRNA represents a dual mechanism of clinical significance that may generate characteristics of both FXS and FXTAS.48 In a clinic-based ascertained group of patients with FXS of both gender, a significant difference was found between FXS with ASD and low levels of FMRP when comparing concentrations of the protein in patients with FXS without ASD.29 They found that the mean full scale IQ and adaptive skills composite scores were significantly lower in males than in females (p = 0.016 and p = 0.001, respectively, MannWhitney). Additionally, all individuals with moderate or severe ID were males. Not surprisingly, ASD was present more frequently in males with FXS (46% vs 20% females). This association was not found in males with PM/FM, suggesting that for improved genotype/phenotype associations is essential to take into consideration not only sex but size and methylation mosaicism.29

There is a small proportion of FXS patients without expansions in the CGG-repeat tract. In this group, the condition is caused by missense or nonsense mutations,5,16 or deletions in FMR1.1,6 Patients with these mutations have similar physical, cognitive and behavioral characteristics to FXS patients. With the increasing availability of diagnostic methods based on next-generation sequencing and comparative genomic hybridization, a higher rate of diagnosis of mutations causing FMR1 function loss is expected. This will allow a clear delimitation of the phenotype caused by the loss of the protein in the absence of CGG tract expansions.

For many monogenic diseases it is known that, besides the allelic variance, the effect of modifier genes has an important role in incomplete penetrance and variable expressivity. The identification of modifier genes that affect the phenotype in monogenic diseases has many challenges that complicate their description. A genetic variant can modify the effect in the phenotype of another variant in many ways, including epistasis and genetic interactions.49,50

In studies using FXS murine models, important new evidence was acquired in order to establish the importance of potential modifier genes and their impact on FXS phenotype development. The knockout mouse model for FXS was generated in the last decade of the XX century. Fmr1 KO mice had learning deficits, abnormal synaptic connections, seizures, hyperactivity and macroorchidism.51,52 When describing the mouse phenotype in detail, it was evident that abnormal phenotypic characteristics depend, at least in some proportion, on their genetic background.53

During the identification of modifier genes in the FXS phenotype, a large proportion of the research has aimed towards the susceptibility to developing certain clinical behavioral characteristics, such as aggression, ASD and seizures.34,5459 All of the studies use a similar methodological design: they arrange groups of people with or without a specific phenotypic trait and establish the frequency of specific variants in modifier gene candidates.

The possibility that Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene may modulate the epilepsy phenotype in FXS patients has also been investigated. The replacement of a methionine for a valine in the 66th position of the BDNF protein interferes with normal intracellular traffic and BDNF dependent secretory activity in cortical neurons.60 This polymorphism has been related to cerebral anatomy alterations61 and neuropsychiatric disorders.62,63 In a sample of 27 males with FXS from Finland, it was found that all the patients with epilepsy (15%) had the Met66 allele, whereas the prevalence of this allele is 20% in the normal population. Research suggests that the Met66 allele in BDNF interacting with FM in FMR1 may partially explain the higher incidence of seizures in patients with FXS.56 In a more recent study with a higher number of males with FXS (77 patients), the results were not replicated and there was no association between seizures and Val66Met polymorphism.58 These results show the importance of validating studies about modifier genes in different populations.

In research about genes that affect mood and aggression, such as the serotonin transporter (5-HTTLPR), the monoamine oxidase A (MAOA-VNTR) and COMT, conflicting results were found. All of those genes are involved in regulatory pathways for different neurotransmitters, and their variants have been associated with the development of behavioral phenotypes in different contexts other than FXS. In one group of 50 males with FXS, the relationship of 5-HTTLPR and MAOA-VNTR polymorphisms with the frequency/severity of aggressive/destructive, self-injurious and stereotypic behaviors was studied. It was found that the high-transcribing long (L/L) genotype in 5-HTTLPR was related with a higher frequency of aggressive/destructive and stereotypic behavior, while patients with the short (S/S) genotype had less aggression. The MAOA-VNTR genotype had no effect on behavior.55 On the other hand, in a study of 64 males with FXS where the COMT gene was also included, the results of the previous study were not replicated. There was no association between behavioral characteristics and either 5-HTTL PR (serotonin) or MAOA genotypes. Nevertheless, the A/A genotype in COMT that modifies dopamine levels was associated with greater interest and pleasure in the environment, and with less risk of property destruction, stereotyped behavior and compulsive behavior.54 The authors of the study suggest that the non-reproducibility of the results regarding MAOA-VNTR can be explained by differences in the prevalence of aggressive and stereotyped behavior among the studied populations or by differences in the measurements used to characterize each behavior.

The importance of identifying potential modifier genes was explored in a clinical trial. The researchers investigated the relation between polymorphisms in several genes and the response of sertraline in 51 children. They found that BDNF, MAOA, 5-HTTLPR, Cytochrome P450 2C19 and 2D6 polymorphisms had significant correlations with treatment response.64

Currently the knowledge about molecular causes of the variable phenotype in patients with FXS include characteristics associated with the FMR1 gene itself and to secondary, modifying gene effects.

Regarding FMR1, when the diagnosis is established, the type of mutation causing FXS is identified: CGG repeat tract expansion vs pathological variant causing loss of function in FMR1.

When the CGG is identified, is it expected that about half of the patients have size or methylation mosaicism or both.29 The presence of any of those mosaicisms determines the expression or not of FMR1 mRNA and FMRP. The quantity of FMRP is directly related with IQ.34,37,39 While the presence of size mosaicism is related with better intellectual functioning and less maladaptive behavior,29,42 elevated concentrations of FMR1 mRNA in patients with FM have been associated with a higher risk of developing FXTAS45,46,48 and with the severity of behavioral symptoms.47

The search for modifier genes affecting the phenotype has been carried out using the candidate genes strategy. Because high impact clinical manifestations in FXS are related with neurologic phenotypes, the studied candidate genes are involved in CNS development and the appearance of seizures (BNDF)56,6062 and associated with mood and aggression (5-HTTLPR, MAOA-VNTR y COMT).54,55 Recent research has been done with small groups of patients and there are no conclusive results about the importance of these variants in modifier genes.

Scientific and clinical evidence about molecular causes of variable expressivity in FXS is growing quickly. It is evident that aspects of the mutation type in FMR1 and the behavior of the CGG repeat tract are relevant in the presentation of the condition. Research about modifier genes is still emerging. There are important limitations such as sample size and comparability of different studies, mainly due to smaller groups of selected patients and the use of different tools for measuring the phenotypes.

Independent cohorts of patients with FXS across different continents have shown evidence that mosaicism, FMR1 mRNA or FMRP quantification are associated with the severity of the phenotype. However, this information cannot currently be used effectively in the integral management of patients. When intervention strategies become available in order to prevent the development of FXTAS, or when certain molecules can regulate levels of FMRP expression to measure FMR1 mRNA and FMRP, they could be crucial for selecting patients and identifying the best therapeutic intervention.

In clinical trials there is an important window of opportunity. Identifying mosaicism, measuring transcription/translation activity of FMR1 and stratifying patients by modifier genotypes29,65 will permit the identification of subgroups of patients with greater potential to respond to specific treatments.

The authors report no conflicts of interest in this work.

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Genetic mapping of subsets of patients with fragile X syndro | TACG - Dove Medical Press

Danielle Lloyd recently revealed that she is expecting a baby girl after using a controversial sex-selection guide called The Babydust Method.

The mum-of-four shares Archie, 10, Harry, nine, and George, seven, with her ex-husband, footballer Jamie OHara, and Ronnie, three, with current husband Michael O'Neill.

She came across the guide, written and researched by Kathryn Taylor - who has a degree in Microbiology, Immunology, and Molecular Genetics from UCLA - and followed it in hopes of having a girl.

Danielle revealed she followed the book to a T, explaining to OK! magazine : "I tried it previously and I got pregnant but I had a miscarriage. So this time I was trying for a few months and nothing happened.

"When I got the negative result I felt really upset about it and Michael said, 'Come on, lets leave trying now and do the gender selection.'

"I had come to terms with the fact that we werent going to try any more and then two or three days later I found out I was pregnant."

The author, Kathryn, based her Babydust Method after Missionary Sister Dr Lonie McSweeney's 2011 study.

99 couples in Nigeria monitored their ovulation and then had intercourse with the exact timing and number of times placed depending on what sex they wanted their child to be.

For families that wanted a girl, sex could only happen only once, exactly two to three days before ovulation.

And if the couple wanted a boy, intercourse was meant to happen twice, as close to ovulation as possible.

Women chart their luteinising hormone twice a day and use ovulation predictor kits for three months before they want to conceive a child so that they could recognise patterns in their cycle.

The luteinising hormone surges at around day 14 in the menstrual cycle and ovulation, which is when an egg is released from the ovary.

Kathryn had taken to her Facebook to warn followers that she isn't a doctor but simply wanted to help people better understand the method.

She explained: "I have to mention, I am not a doctor, and I cannot guarantee you'll conceive the sex of your choice.

"All I can do is help you better understand how to implement the method, and give you encouragement along the way."

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Doctors have been sceptical about the method, explaining how the chances of getting a boy or girl are usually 50-50.

"There are some scientific ideas on how to improve your chances to get a boy and girl," Dr. Elena Trukhacheva, President and Medical Director of Reproductive Medicine Institute in Chicago, Ill., told Refinery29.

"But in real life, its 50-50. These ideas are not going to take you farther than 50-50, and its not going to work for some couples."

It is important to note that no exact method can promise the desired results.

Do you have a story to sell? Get in touch with us at webcelebs@trinitymirror.com or call us direct 0207 29 33033.

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What is The Babydust Method? Danielle Lloyd swears method helped her conceive girl - The Mirror