StemCell Therapy

Ending Disease, a forthcoming documentary directed by Emmy award-winning filmmaker Joe Gantz, explores the controversial world of stem cell researchand why it's on the frontlines of combatting incurable disease.

The four-part series follows 10 patients who suffer from debilitating illnesses including paralysis, blindness, and terminal cancer. Each patient participated in the first FDA-approved clinical trials using stem cell and CAR T-cell therapy to treat conditions that were previously deemed incurable.

Stem cells are cells with the ability to develop into other cells, allowing them to repair damaged areas of the body. Stem cell therapy, also known as regenerative medicine, involves using these cells to heal diseased, injured, or dysfunctional tissue. CAR T-cell therapy, on the other hand, is a form of immunotherapy in which a patient's T cells are collected from the blood and modified into chimeric antigen receptors (CARs).

In this exclusive Ending Disease trailer, a high school senior becomes paralyzed after suffering a neck injury during a basketball game. His parents view stem cell therapy as their son's only option to recovery:

Another woman learns that her cancer has returned, after an MRI shows lesions on her breast and lungs. "It seemed like it was a death sentence," she says in the video, and then she begins the process of CAR T-cell therapy.

"I became legally blind when I was 26; this could potentially restore my vision," a second woman shares of the revolutionary clinical trial.

Later, the documentary shows the teenage boy regaining his strength in a wheelchair, while the formerly blind woman goes rock climbing. The woman with cancer is seen playing soccer with young children.

"We have in our own bodies the cells that know how to regenerate our own bodies, so this is a real medical revolution," a healthcare worker says.

The documentary promises to be an exciting look at an ambitious clinical trial that aims to change lives for the better. Ending Disease is set to release on Friday, November 13.

You can catch a virtual screening by purchasing tickets at one of the following local participating cinemas: Gathr Films, Laemmle Virtual Cinema (Los Angeles, C.A.), The Lark (Marin County, C.A.), Tampa Theater (Tampa, F.L.), Grail Movie House (Asheville, N.C.), Cinema Art Theater (Lewes, D.E.), Real Art Ways (Hartford, C.T.), The Neon (Dayton, O.H.), Oxford Film Society (Oxford, M.S.).

Support from readers like you helps us do our best work. Go here to subscribe to Prevention and get 12 FREE gifts. And sign up for our FREE newsletter here for daily health, nutrition, and fitness advice.

This content is created and maintained by a third party, and imported onto this page to help users provide their email addresses. You may be able to find more information about this and similar content at piano.io

Continued here:
Exclusive: "Ending Disease" Documentary Explores How Stem Cell Therapy Aims to Cure the Incurable - Prevention.com

DURHAM, N.C. -- A team of Duke University researchers has developed a lab-grown living lung model that mimics the tiny air sacs of the lungs where coronavirus infection and serious lung damage take place. This advance has enabled them to watch the battle between the SARS-CoV-2 coronavirus and lung cells at the finest molecular scale.

The virus damages the delicate, balloon-like air sacs, known as alveoli, leading to pneumonia and acute respiratory distress, the leading cause of death in Covid-19 patients. But scientists have been hampered in Covid-19 studies by the lack of experimental models that mimic human lung tissues.

Now, a team led by Duke cell biologist Purushothama Rao Tata has developed a model using lung organoids, also dubbed mini-lungs in a dish. The organoids are grown from alveolar epithelial type-2 cells (AT2s) which are the stem cells that repair the deepest portions of the lungs where SARS-CoV-2 attacks.

Earlier research at Duke had shown that just one AT2 cell, isolated into tiny dishes, could multiply to produce millions of cells that assemble themselves into balloon-like organoids that look just like alveoli. However, the soup in which the cells were grown contained complex ingredients such as serum from cows that is not completely defined.

Tatas group took on the big challenge of predicting and testing many combinations of chemically pure factors that would do the job just as well, a problem that required close co-operation with Dukes shared computing cluster.

The result is a purely human organoid without any helper cells. Mini-lungs grown in tiny wells will enable high throughput science, in which hundreds of experiments can be run simultaneously to screen for new drug candidates or to identify self-defense chemicals produced by lung cells in response to infection.

This is a versatile model system that allows us to study not only SARS-CoV-2, but any respiratory virus that targets these cells, including influenza, Tata said. A paper describing the development of the mini-lungs and some early experiments with coronavirus infection appeared early online Oct. 21 in the journal Cell Stem Cell.

In using mini-lungs to study SARS-CoV-2 infection, Tatas team collaborated with virology colleagues at Duke and the University of North Carolina in Chapel Hill. To safely handle these deadly viruses, the researchers utilized state-of-the art biosafety level 3 facilities at Duke and UNC-CH to infect lung organoids. The researchers watched the gene activity and chemical signals that are produced by the lung cells after infection.

This is a major breakthrough for the field because we were using cells that didnt have purified cultures, said Ralph Baric, a co-author on the paper who is a distinguished professor of epidemiology, microbiology and immunology at UNC and world authority on coronaviruses. The Duke mini-lungs are 100 percent human with no supporting cells that could confuse findings. This is incredibly elegant work to figure out how to purify and grow AT2 cells in culture in pure form, Baric said.

Barics lab is capable of changing any nucleotide of the Covid-19 viruss genetic code at will, so it produced a glowing version that would reveal where it went in the mini-lungs, confirming that it did indeed home in on the crucial ACE2 cell surface receptor, leading to infection.

When infected with the virus, the organoids were shown to launch an inflammatory response mediated by interferons. The researchers have also witnessed the cytokine storm of immune molecules the lungs launch in response to the virus.

It was thought cytokine storm happened due to the large influx of immune cells, but we can see it also happens in the lung stem cells themselves, Tata said.

Tatas lab found the cells produced interferons and experienced self-destructive cell death, just as samples from Covid-19 patients have shown. The signal for cell suicide was sometimes triggered in uninfected neighboring lung cells as well, as the cells struggled to get ahead of the virus. The researchers also compared the gene activity patterns between the mini-lungs and samples from six severe Covid-19 patients and found they agreed with striking similarity.

Weve only been able to see this from autopsies until now, Tata said. Now we have a way to figure out how to energize the cells to fight against this deadly virus.

In another series of experiments, mini-lungs treated with low doses of interferons before infection were able to slow viral copying. But suppressing interferon activity before infection led to increased viral replication.

Tata, who is a part of Dukes regenerative medicine initiative, Regeneration Next, said his lab was working on growing the mini lungs in mid-2019 and had achieved a working model just as the coronavirus pandemic emerged. He said his group will be working with both academic and industry partners to use these cells for cell-based therapies and eventually to try to grow a complete lung for transplantation.

Baric said his lab will probably be using the mini-lungs to better understand a new strain of SARS-CoV-2 called D614G that has become the dominant version of the virus. This strain, which emerged in Italy, has a spike protein that is apparently more efficient at recognizing the ACE2 receptor on lung cells, making it even more infectious.

This research was performed with support from the Chan Zuckerberg Foundation, the U.S. National Institutes of Health (UC6-AI058607, AI132178, AI149644, R00HL127181, R01HL146557, R01HL153375, R21GM1311279, F30HL143911, DK065988), Duke University and United Therapeutics Corporation.

CITATION: Human Lung Alveolospheres Provide Insights Into SARS-Cov-2 Mediated Interferon Responses and Pneumocyte Dysfunction, Hiroaki Katsura*, Vishwaraj Sontake*, Aleksandra Tata*, Yoshihiko Kobayashi*, Caitlin E. Edwards*, Brook E. Heaton, Arvind Konkimalla, Takanori Asakura, Yu Mikami, Ethan J. Fritch, Patty J. Lee, Nicholas S. Heaton, Richard C. Boucher, Scott H. Randell, Ralph S. Baric, Purushothama Rao Tata.* indicates co-first authors. Cell Stem Cell, early online Oct. 21, 2020. DOI: 10.1016/j.stem.2020.10.005

View original post here:
Lab-Grown Mini-Lungs Mimic the Real Thing Right Down to Covid Infection - Duke Today

The Patio Patrol program allows residents with home security systems register their devices to help police investigate crimes in their area more efficiently. Fort Collins Coloradoan

A Colorado man will likely go to trial formurder in the deaths of his ex-girlfriend and her new love interest ina double homicide that spanned one week andtwo Colorado counties earlier this year.

Kevin Eastman, 48, will appear in court in Weld County on Dec. 7 for an arraignment on 2 charges each of first-degree murder, tampering with a deceased human body and tampering withphysical evidence. He also faces on charge of possession of a weapon by a previous offender.

The charges seven in all stem from the early February death of 53-year-old Greeley musician Scott Sessions and, later, the death of Eastman's on-again, off-again ex-girlfriendHeatherFrank, also of Greeley.

In interviews with investigators, Eastman denied involvement in Frank's and Sessions' deaths,Eastman's defense attorney Ashley Morriss argued during the conclusion of Eastman's preliminary hearingMonday.

Sessions' body was found Feb. 10 wrapped in plastic and burned near a smoldering log along Old Flowers and Pingree Park roads about 40miles west of Fort Collins in Larimer County. He haddied from sharp force injuries to the back of his neck, Larimer County Sheriff's Office Investigator Justin Atwoodtestified during a preliminary hearing in the case.

Frank's body was foundFeb. 16 wrapped in plastic and bound with baling wire on the rural Weld County property of Eastman's former employer, Troy Bonnell. She had been shot twice in the chest at close range.

Investigators determined Sessions was last heard from by his father in a phone call around 6:12 p.m. Feb. 8. Sessions told his father he wasdriving to meet an unknown person. Facebook messages and location data from his cell phoneindicate thatSessions met Frank, 48, at her Greeley apartment that night, according to testimony from Eastman's hybrid in-person and virtual preliminary hearing, which concluded Monday.The first portion of the preliminary hearing was held Oct. 15.

Eastman later told investigators he showed up to Frank's apartment unannounced on Feb.8 to discuss the possibility of the two getting back together. Frank told Eastman he had to leave because she had a date, according to investigators'testimony.

Facebook messages between Frank and Sessions indicate they met on Jan. 22 at a Wednesday night blues jam concert and that there had later been at least one date before they made plans to meet up again on Feb. 8, Weld County Chief DeputyDistrict AttorneySteveWrenn said.

Sessions, a well-known singer and trumpet player in Denver bandThe Movers & Shakers, had recently returned from a music contest in Memphis, Tennessee, when he and Frank agreed to reconnect, Wrenn added.

COVID-19 in Colorado tracker: Larimer and state case, death and hospital data for October

Tracking the location data of their cellphones, investigators determined Sessions, Frank and Eastman were all in the same area of Greeley near Frank's apartment around 20th Street and 35th Avenue on the night of Feb. 8.

Using that same phone tracking data, investigators determined Scott Sessions' phone went dead or was turned off around 5 a.m. Feb. 9. It was last recorded in the area of Frank's apartment.

Eastman's and Frank's phonesremained active into Feb. 9, and location data showsthe phonestraveled in the area of Ted's Place in Laporte and up the Poudre Canyon that morning.

Surveillance footage at the Mishawaka Amphitheatre also showed a Subaru Crosstrek matching the description of Eastman's passing by the venue twiceonce when it was traveling westbound up the canyon and again as it traveled east down the canyon,Atwood testified.

Sessions' Ford Escape was later seen in surveillance footagebeing driven from Frank's cul-de-sac and left by an unknown person at a nearby King Soopers grocery store on Feb. 11.

A camera placed outside of Frank's cul-de-sac showed her and Eastman leaving her apartment and getting into Eastman's vehicle on Feb. 15, Larimer County Sheriff's Office Sgt. Donald Robbins testified Monday.

A GPS trackerplaced on Eastman's vehicle indicates it then traveled, without stopping, to Bonnell's property that afternoon leaving and coming back three times until early the next morning, when it returned again, Robbins said.

Robbins said he observed Eastman tending to a fireon the property the morning of Feb. 16. By that time, there were active warrants forEastman and Frankon suspicion of first-degree murder in Sessions' case.

From Fort Collins: Police make arrest in downtown stabbing incident

Robbins later followed Eastman to a Kersey gas station, where Eastman was arrested while trying to fill up a portable gasoline tank.

He was found in possession of a sheathed, fixed-blade knife as well as three live rounds and two spent rounds of .22 caliber shell casings, according to Wrenn.

Frank's body was found wrapped in plastic on the Bonnell property after Eastman's arrest onFeb. 16 as law enforcement searched the area where he had previously been spotted by Robbins.

Investigators have not found the gun used in Frank's death.

Investigators later found a large pool of suspected blood near the front entryway of Frank's apartment. As Eastman's preliminary hearing concluded Monday,Wrenn theorized the blood belonged to Sessions and was the result of anambush-style killing by Eastman on Feb. 8.

Wrenn theorized that Eastman then shot and killed Frank the only witness to Sessions'death, Wrenn surmised just over a week later on Feb. 15. Eastmanwas taking steps to burn her body when arrested by law enforcement, Wrenn alleged.

Weld District Court Judge Marcelo Kopcow ruled Monday to bind over all of Eastman's charges for trial. An arraignment of those charges was set for 9 a.m. Dec. 7 in Weld County. Eastman will remain in custodywith no possibility of bond.

All suspects are innocent until proven guilty in court. Arrests and charges are merelyaccusations by law enforcement until, and unless, a suspect is convicted of a crime.

Erin Udell reports on news, culture, history and more for the Coloradoan. Contact her at ErinUdell@coloradoan.com. The only way she can keep doing what she does is with your support. If you subscribe, thank you. If not, sign up for a subscription to the Coloradoan today.

Read or Share this story: https://www.coloradoan.com/story/news/2020/10/27/kevin-eastman-likely-going-trial-murders-heather-frank-greeley-musician-scott-sessions/6043488002/

Follow this link:
Man accused of killing Greeley musician Scott Sessions, ex-girlfriend likely going to trial - Coloradoan

Denmark-based Genmab A/S announced positive topline data from the second part of the Phase III CASSIOPEIA trial. The study is evaluating daratumumab monotherapy as maintenance treatment compared to observation, in other words, no treatment, for patients with newly diagnosed multiple myeloma that are eligible for autologous stem cell transplant (ASCT).

The second part of the trial is being conducted by the French Intergroupe Francophone du Myelome (IFM) in collaboration with the Dutch-Belgian Cooperative Trial Group for Hematology Oncology (HOVON) and Janssen Research & Development, a Johnson & Johnson company.

The trials primary endpoint was improved progression free survival (PFS), which the trial met at a pre-planned interim analysis. It demonstrated a 47% decrease in the risk of progression or death in the patients receiving daratumumab. The safety profile was consistent with previous studies and no new safety signals were seen.

An Independent Data Monitoring Committee (IDMC) has recommended the study results be unblinded. Janssen Biotech licensed the drug from Genmab in 2012 and indicates it plans to meet with regulators to discuss a possible submission for this indication. It also plans to present the data at an upcoming medical conference and submit it for a peer-reviewed scientific journal.

Following the positive data from the first part of the CASSIOPEIA study, we are very pleased to see this benefit, said Jan van de Winkel, chief executive officer of Genmab. We are appreciative of the efforts of the IFM, of HOVON and of Janssen for their work on this study.

Darzalex (daratumumab) is indicated for treatment of adults in the U.S. in combination with carfilzomib and dexamethasone for relapsed/refractory multiple myeloma patients who have received one to three earlier lines of therapy; in combination with bortezomib, thalidomide and dexamethasone for patients newly diagnosed with multiple myeloma who are eligible for autologous stem cell transplant; in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant, and for several other combinations and as a monotherapy for various stages of multiple myeloma.

The drug is a human IgG1k monoclonal antibody. It binds strongly to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. The drug causes an individuals own immune system to attack the cancer cells, causing rapid tumor cell death via multiple immune-mediated mechanisms of action and through immunomodulatory effects, as well as direct tumor cell death by way of apoptosis.

Net sales of Darzalex in the first quarter of 2020 totaled $937 million, with $463 million in the U.S. and $474 in the rest of the world.

The CASSIOPEIA Phase III trial included 1,085 newly diagnosed patients with previously untreated symptomatic multiple myeloma who were eligible for high-dose chemotherapy and ASCT. In the first part of the trial, patients received induction and consolidation treatment with daratumumab combined with bortezomib, thalidomide and dexamethasone (VTd) or VTd alone. The primary endpoint was the number of patients that achieved a stringent complete response (sCR).

In the second part of the study, which is what is being reported on today, patients that achieved a response in the first part underwent a second randomization to receive either maintenance treatment of 1i6 mg/kg every eight weeks for up to two years of daratumumab, or no further treatment. The primary endpoint was progression-free survival.

Read the original:
J&J's Darzalex Proves Effective in Yet Another Multiple Myeloma Indication - BioSpace

Even before the spread of COVID-19, scientists had declared we were in the midst of an air pollution pandemic, with bad air responsible for 8.8 million premature deaths every year. Now, researchers better understand how these two crises are converging. Across the world, more than 1.1 million people have died of COVID-19, and 15% of those deaths, researchers estimate, could be attributed to long-term air pollution exposure.

The study, conducted by experts at the Max Planck Institute for Chemistry, the German Center for Cardiovascular Research, and more, builds on a previous report from Harvard University that found that someone living in an area with high pollution levels for decades is 8% more likely to die from COVID-19 than someone living with less pollution.

That Harvard study accounted for other mortality factors, such as the number of hospital beds available or comorbidities such as obesity and smoking, and looked at more than 3,000 counties across the U.S, comparing air pollution levels and coronavirus deaths in each area. The authors of this most recent study, published in the journal Cardiovascular Research, applied that same relationship to the rest of the world, using satellite data on global particulate matter exposure and epidemiological data gathered up to June 2020.

Globally, the study found that air pollution exposure may account for 15% of COVID-19 deaths. At the country level, the impact is even more pronounced. In the Czech Republic, researchers estimated that air pollution contributed to 29% of coronavirus deaths; in China, 27%; and in Germany, 26%. In the U.S., 18% of all COVID-19 deaths could be attributed to air pollution. In countries with lower levels of air pollution, the effect was smaller; in Australia, for instance, only 3% of COVID-19 deaths could be attributed to air pollution, researchers estimated.

This doesnt mean theres a direct cause-and-effect relationship between air pollution and COVID-19 deaths, the researchers write; rather, there is some relationship between the two that affects health outcomes. People that have a precondition in terms of lung diseases or heart diseases have a much higher risk of dying from COVID-19. Air pollution affects the same types of mortality and the same diseases, says Jos Lelieveld, an atmospheric chemist at the Max Planck Institute and one of the authors of this latest study. Its not coincidental that these effects are sort of enhancing each other.

When we breathe polluted air, PM2.5particulate matter 2.5 micrometers or less in sizecan enter into our lungs and travel through our bloodstream, damaging our arteries and causing inflammation and oxidative stress, which has been linked to cancer, diabetes, high blood pressure, asthma, and other health impacts. SARS-CoV-2, the coronavirus that causes the disease COVID-19, does the same: entering our bodies through our lungs, traveling through our bloodstream, and damaging our arteries.

Air pollution also makes receptors on our cells called ACE-2 more active. Those receptors are involved in the way COVID-19 infects our bodies. What happens then is a double hit, the researchers explain: Air pollution damages the lungs and increases the activity of those receptors, which then take even more of the SARS-CoV-2 virus into the lungs and bloodstream.

Its important that people realize that air pollution really plays an important role in determining your overall level of health, Lelieveld says. Even though you may not immediately notice that theres something wrong when youre exposed to high levels of air pollution, it causes conditions that make you more sensitive to disease and dying from these diseases.

Lelieveld hopes this research supports that realization and pushes people to do more to stem air pollution. While soon there may be a COVID-19 vaccine, theres no vaccine for poor air or the effects of climate change. When the COVID-19 pandemic has passed, and the next pandemic comes, we may be at risk of more deaths again if we havent addressed pollution. Its extremely important that these vaccines and better cures are being developed, he says. But its also important that people realize that some of the factors that affect your health can only be dealt with if we start realizing that the way were treating our planet is not sustainable.

Follow this link:
How air pollution is making COVID-19 worse - Fast Company

Trophoblast cell surface antigen 2 (Trop-2) is a glycoprotein that spans the epithelial membrane surface and plays a role in cell self-renewal, proliferation, and transformation.1,2 Encoded by the TACSTD2 gene, Trop-2 is a 35-kDa protein composed of a large extracellular domain, a single transmembrane domain, and a short intracellular tail that is the functionally dominant part of the protein.1-4

Under physiological conditions, Trop-2 plays an essential role in embryonic development, placental tissue formation, embryo implantation, stem cell proliferation, and organ development.2 A low basal expression level of Trop-2 is found on the surface of multiple normal epithelial tissues, including skin and oral mucosa.1,3 Trop-2 can promote tumor growth and its overexpression is common in many types of malignant epithelial tumors.1,2,4

Expression of Trop-2 is regulated by several pro-oncogenic transcription factors (eg, CREB1, nuclear factor [NF]B, and HOXA10) via positive feedback relationships.2 Trop-2 expression may be upregulated because of the inactivation of several transcription factors (eg, HNF4A, TP63/TP53L, ERG, HNF1A/TCF-1, and FOXP3).1,2 Overexpression of Trop-2 accelerates the cancer cell cycle and drives cancer growth. Knocking out the TACSTD2 gene disturbs the proliferation of tumor cells, further validating the role of Trop-2 in tumorigenesis.1

Trop-2 was first elucidated as a transducer of intracellular calcium signals; however, it is now known to function in a variety of cell signaling pathways associated with tumorigenesis (Figure 1).1,2,4 Expression of Trop-2, as a calcium signal transducer, causes calcium to be mobilized from internal stores. Increased intracellular calcium levels activate MAPK, which in turn increases levels of phosphorylated ERK1 and ERK2.2,4 ERK1 and ERK2 are important mediators of cell cycle progression, angiogenesis, cell proliferation, cell invasion, and metastasis.2,4 Intracellular calcium also activates the NF-B pathway, which is involved in stimulation of cell growth, and the RAF pathway, which is essential for the upregulation of FOXM1, one of the most commonly overexpressed genes in human solid tumors.2

In addition to stimulating calcium release and MAPK signaling, Trop-2 is involved in several other pro-oncogenic signaling pathways, leading to tumor cell growth and proliferation. Activation of cyclin E and D further promotes cell cycle progression.4Alteration of the Notch, Hedgehog, and Wnt pathways may discourage appropriate stem cell proliferation and differentiation.2,4 Trop-2 signaling also appears to be dependent on -catenin.5 Direct interaction between -catenin and the intracellular domain of Trop-2, through -catenin signaling, enhances stem celllike properties (eg, self-renewal and transformation) of cancer cells.5 Attenuation of IGF-1 receptor signaling by Trop-2 encourages cancer growth and malignancy, particularly in lung cancers.2

Trop-2 is inextricably linked to cancer progression and metastasis because of its role as a key regulator of the hallmarks of cancer, including cell growth, proliferation, migration, invasion, and survival.4 A variety of human epithelial cancer cells are characterized by Trop-2 overexpression, including breast, lung, urothelial, gastric, colorectal, pancreatic, prostatic, cervical, head and neck, and ovarian carcinomas.2,3 In an analysis of 702 tissue samples from patients with breast cancer, Trop-2 expression was detected via immunohistochemistry (IHC) across a wide range of breast cancer subtypes.6 Trop-2 expression is substantially higher in hormone receptorpositive/HER2-negative (HR+/HER2-) disease and triple-negative breast cancer (TNBC) compared with other breast cancer subtypes, including HER2-positive disease.7

Trop-2 overexpression is also common in nonsmall cell lung cancer (NSCLC).8 Using IHC on tissues collected from the tumors of 68 patients with NSCLC, Trop-2 expression was significantly higher in NSCLC tissues compared with matched healthy tissues (P < .05). Moreover, its overexpression was associated with worse tumor, node, metastasis stage (P = .012), lymph node metastasis (P = .038), and histologic grade (P = .013).9

Bladder cancer, the most common urothelial cancer, is also marked by elevated Trop-2 expression.10,11 In a study of 102 transitional cell bladder cancer samples, IHC staining for Trop-2 demonstrated increased Trop-2 expression compared with noncancerous samples, and this expression pattern was significantly associated with worsened tumor grade (P = .001), stage (P < .0 01), and bladder cancer recurrence (P = .0 3).11

Molecular markers that influence the biological progress of tumors often serve as important prognostic indicators. Overexpression of Trop-2 has been associated with more aggressive disease, poorer overall survival (OS), and worse disease-free survival in patients with solid tumors.4 A meta-analysis conducted in 2016 explored the association of Trop-2 expression and prognosis in patients with a variety of solid tumors (N = 2569). Results from the study showed that high Trop-2 expression negatively affected OS (hazard ratio, 1.896; 95% CI, 1.599-2.247; P < .001) and disease-free survival (pooled hazard ratio, 2.336; 95% CI, 1.596-3.419; P < .0 01).12

Specific to breast cancers, increased Trop-2 mRNA is a strong predictor of lymph node involvement, distant metastasis, and poor OS.13,14 Trop-2 is expressed across all breast cancer subtypes; however, overexpression appears more common in aggressive disease subtypes, including HR+/HER2- disease and TNBC.7

Trop-2 overexpression is also associated with poor outcomes in patients with urothelial cancer. In an analysis of 102 tissue samples collected from patients with noninvasive bladder cancer, Trop-2 expression was higher in samples from patients who experienced disease recurrence compared with those who did not have recurrent disease (P = .0 3). Additionally, patients with Trop-2 overexpression had significantly lower rates of recurrence-free survival (P = .0 01).11 In a separate study, high Trop-2 expression analyzed by IHC was strongly correlated with bladder cancer severity and worsened disease prognosis, with particularly strong Trop-2 expression in muscle-invasive bladder cancer tissues compared with normal bladder tissues (P < .0 01).15

Taken together, the data indicate that Trop-2 is a potentially valuable therapeutic target, given the connection between its overexpression and poor prognosis in various solid tumors.4,15 Its value as a prognostic indicator and potential target for therapeutic development is particularly evident in advanced cancers that have limited or few treatment options available, such as TNBC and metastatic urothelial cancers.

Metastatic TNBC

TNBC is an aggressive form of invasive breast cancer that accounts for 15% to 20% of all breast cancers and a disproportionate number of deaths due to breast cancer.16-18 Its prevalence is particularly high in premenopausal women and those of African American and Hispanic descents.17,19 TNBC is characterized by a lack of estrogen and progesterone receptors and a low expression of HER2; therefore, TNBC cannot be effectively treated with standard hormone-based therapies and HER2-targeted agents.16, 20Although chemotherapy has shown promising results in early TNBC, the majority of patients relapse and progress to metastatic TNBC within the first 3 to 5 years after initial treatment.18 The treatment of metastatic TNBC remains a clinical challenge, as no standard-of-care chemotherapy exists for previously treated patients.17,18 There is an urgent unmet need for effective treatment options in patients with metastatic TNBC.18

Metastatic Urothelial Cancer

In the United States, an estimated 81,400 new cases of urothelial cancer will be diagnosed in 2020, and approximately 18,000 Americans will die from the disease.21 The majority of urothelial cancers arise in the bladder, and established risk factors for bladder cancer include older age, male gender, Caucasian race, family history, and smoking.22,23 Muscle-invasive and meta-static urothelial cancers represent 25% of urothelial carcinoma cases and are characterized by substantially worse prognostic outcomes.23,24 Current chemotherapeutic options for metastatic disease offer a modest median OS of 15 months and a 5-year survival of less than 5%.23,24 Long-term survival is infrequent, and newer treatment modalities that target distinct molecular biomarkers are warranted.24,25

As Trop-2 is a clinically relevant cell surface antigen among several solid tumor types, its overexpression on cancer cells makes it an ideal candidate for targeting by specific therapies.26 One targeted approach involves the use of antibody-drug conjugates (ADCs), a technology that has revolutionized the approach to cancer chemo-therapy over the past 2 decades.26

An ADC is designed to contain 3 components: a monoclonal antibody (mAb), a cytotoxic drug called a payload, and a linker that connects the mAb to the cytotoxin. The mAb binds specifically to its tumor-associated antigen (eg, Trop-2), thereby delivering the cytotoxin to the surface of the tumor cell. Once bound, the ADC is internalized through receptor-mediated endocytosis. Lysosomal degradation of the ADC ensues, facilitating the release of the cytotoxin and enabling it to bind to its intracellular target and induce apoptotic cell death (Figure 2).26,27 The targeted nature of ADCs allows potent therapy to be delivered to the cancer cell itself, limiting systemic exposure. The result is fewer adverse effects (AEs), a wider therapeutic window, and reduced exposure of the drug to efflux mechanisms that can increase drug resistance.26,27

Sacituzumab govitecan-hziy is the only FDA-approved Trop-2targeted ADC, and several other agents are under preclinical and clinical development.28

Sacituzumab govitecan-hziy is an ADC that binds to Trop-2 and delivers a potent cytotoxic drug into tumor cells.29,30 The FDA recently granted it accelerated approval for the treatment of metastatic TNBC, and it has also received fast track designation for metastatic urothelial carcinoma, NSCLC, and small cell lung cancer.28,30-32

The composition of sacituzumab govitecan-hziy has been optimized to effectively target tumors expressing Trop-2. A humanized monoclonal antibody (hRS7) binds to Trop-2 and delivers govitecan (SN-38) to the cell surface. SN-38 is the active metabolite of irinotecan and functions as a DNA topoisomerase I inhibitor. A hydrolysable CL2a linker covalently binds SN-38 to h R S 7.30 When released intracellularly, SN-38 causes double-stranded DNA breaks that lead to apoptosis.29 Additionally, the hydrolysable linker allows a portion of the SN-38 payload to be released into the tumor microenvironment, leading adjacent tumor cells to be killed via a bystander effect.31,32

Sacituzumab govitecan-hziy delivers SN-38 in its most active nonglucuronidated form. Because of its moderate toxicity profile, SN-38 is conjugated to hRS7 at a high drug-to-antibody ratio of up to 8 SN-38 molecules per antibody, allowing for greater drug delivery than systemic irinotecan can achieve.29,32 Irinotecan causes grade 3 to 4 diarrhea in approximately one-third of patients, whereas the lower toxicity of SN-38 may confer an improved therapeutic index.29,30 This high level of drug delivery may overcome the ability of Trop-2expressing tumors to repair DNA breaks.30

On April 22, 2020, sacituzumab govitecan-hziy received accelerated approval from the FDA for the treatment of adult patients with metastatic TNBC who have received at least 2 prior therapies for metastatic disease.28 Approval was based on findings of the phase 1/2, single-arm, multicenter IM-T-IMMU-132-01 trial (NCT01631552), in which sacituzumab govitecan-hziy produced durable responses in a subset of patients with heavily pretreated metastatic TNBC.31,33

The IM-T-IMMU-132-01 trial enrolled 108 patients with metastatic TNBC who had received at least 2 prior treatments for metastatic disease. In the study population, the median number of prior systemic therapies in the metastatic setting was 3, and the majority of patients received prior taxanes (98%) and anthracyclines (86%) in the neoadjuvant or metastatic setting. The median age of study patients was 55 years (range 31-80); 99% were female, and 76% were Caucasian.31Brain metastases were present in 23% of patients, and visceral metastases were present in 77% of patients; these included metastases in the lung/pleura (57%), the liver (42%), and other visceral organs (adrenal glands, pancreas, and kidney; 7%).31

Patients received sacituzumab govitecan-hziy 10 mg/kg administered intravenously on days 1 and 8 of 21-day cycles. Treatment continued until disease progression or unacceptable toxicity. The primary efficacy end point was objective response rate (ORR) assessed according to RECIST 1.1 tumor criteria. The secondary efficacy end points included time to response, duration of response, clinical benefit rate (defined as a complete or partial response or stable disease for 6 months), progression-free survival (PFS), and OS.31

After a median follow-up duration of 9.7 months, an objective response occurred in 36 of 108 patients (ORR, 33.3%; 95% CI, 24.6%-43.1%), including a complete response in 3 patients.31 The median time to response was 2 months (range 1.6-13.5). The median response duration was 7.7 months (95% CI, 4.9-10.8), with 55.6% of patients responding at 6 months and 16.7% of patients still responding at 12 months.31,34 An independent central review of the data found a similar ORR and median response duration (34.3% and 9.1 months, respectively).31 The clinical benefit rate, including stable disease for at least 6 months, was 45.4%. Median PFS was 5.5 months; the estimated probability of PFS at 6 and 12 months was 41.9% and 15.1%, respectively. Median OS was 13 months (95% CI, 11.2-13.7); the estimated probability of survival at 6 and 12 months was 78.5% and 51.3%, respectively.31

The most common AEs of any grade were nausea (67%), neutropenia (64%), diarrhea (62%, predominantly grade 1), and fatigue (55%). Of grade 3 or 4 AEs, the most common were neutropenia, decreased white cell count, and anemia (occurring in 42%, 11%, and 11% of patients, respectively).31 Serious AEs occurred in 32% of patients, with the most common being febrile neutropenia (7%), vomiting (6%), nausea (4%), diarrhea (3%), and dyspnea (3%). Occurrence of AEs led to treatment interruption in 44% of patients, dose reductions in 34%, and discontinuation of treatment in 3%.31,34

IM-T-IMMU-132-01 Trial HR+/HER2- Subpopulation Analysis

Treatment with sacituzumab govitecan-hziy showed encouraging results in a prespecified subpopulation of patients with histologically confirmed HR+/HER2- metastatic breast cancer from the IM-T-IMMU-132-01 trial.32

A total of 54 patients with histologically confirmed HR+/HER2- metastatic breast cancer were enrolled. Eligible patients had received at least 1 line of hormone-based therapy and at least 1 prior chemotherapy in the metastatic setting. The median age of enrollees was 54 years (range, 33-79); aside from required prior hormone-based therapy, previous chemotherapies included a taxane (85%), an anthracycline (67%), capecitabine (65%), a CDK4/6 inhibitor (61%), an mTOR inhibitor (44%), and an immune checkpoint inhibitor (1.9%). After a washout period of at least 2 weeks since prior treatment, sacituzumab govitecan-hziy was dosed at 10 mg/kg via intravenous infusion on days 1 and 8 of 21-day cycles.32

The primary efficacy end point was ORR. Of the 54 patients enrolled, 17 patients achieved partial responses during a median follow-up duration of 11.5 months (ORR, 31.5%; 95% CI, 19.5%-45.6%). In the key secondary outcomes, patients experienced a median PFS of 5.5 months (95% CI, 3.6-7.6) and a median OS of 12.0 months (95% CI, 9.0-18.2). The median time to response was 2.1 months (95% CI, 1.4-7.8), and median duration of response was 8.7 months (95% CI, 3.7-12.7). Of the 17 responders, 4 achieved a response lasting more than 12 months (24%). The clinical benefit rate was 44.4% (95% CI, 30.9%-58.6%), with 7 patients showing stable disease for at least 6 months.32

Safety analyses showed a manageable AE profile for sacituzumab govitecan-hziy. There were no reports of cardiac toxicity or severe peripheral neuropathy. The most common grade 3 or higher treatment-related AE was neutropenia, which occurred in 50% of patients. The incidence of diarrhea was 46% and was mild overall. Grade 3 diarrhea was reported in 4 patients, with no reports of grade 4.32 Serious AEs occurred in 2 patients, who experienced febrile neutropenia and 1 case each of neutropenia, viral pneumonia, sepsis, diarrhea, nausea, vomiting, dehydration, and acute respiratory failure.32

ESMO 2020 Data: ASCENTTrial in Metastatic TNBC (NCT02574455)

Final results of the international, multicenter, open-label ASCENT trial (NCT02574455) were presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020. ASCENT was the first phase 3 study of an ADC to show improvement in PFS and OS compared with standard-of-care chemotherapy in patients with previously treated metastatic TNBC.35,36

A total of 529 patients with metastatic TNBC were randomized 1:1 to receive either sacituzumab govitecan-hziy or physicians choice of single-agent chemotherapy (capecitabine, eribulin, vinorelbine, or gemcitabine). The dose of sacituzumab govitecan-hziy was 10 mg/kg intravenously on days 1 and 8 of 21-day cycles. All patients had histologically or cytologically confirmed TNBC refractory to or relapsed after at least 2 prior chemotherapies including a taxane. The median age of the study population was 54 years, and the median number of prior chemotherapies received was 4.

In the primary end point, sacituzumab govitecan-hziy significantly improved median PFS (hazard ratio, 0.41; P< .0001) compared with chemotherapy. The sacituzumab govitecan-hziy treatment group achieved a median PFS of 5.6 months compared with 1.7 months in the chemotherapy treatment group. Compared with chemotherapy, sacituzumab govitecan-hziy treatment also significantly improved key secondary end points of OS (12.1 vs 6.7 months; hazard ratio, 0.48; P < .0001) and ORR (35% vs 5%; P < .0001).35,36

The most common treatment-related grade 3 or higher AEs with sacituzumab govitecan-hziy compared with chemotherapy were neutropenia (51% vs 33%, respectively), diarrhea (10.5% vs < 1.0%), anemia (8% vs 5%), and febrile neutropenia (6% vs 2%). No treatment-related deaths were reported, and no cases of neuropathy or interstitial lung disease greater than grade 3 occurred with sacituzumab govitecan-hziy.35

ESMO 2020 Data: Sacituzumab Govitecan-hziy in Combination with Talazoparib for Patients with Metastatic TNBC (NCT04039230)

At the ESMO Virtual Congress 2020, investigators presented the trial design, objectives, and status of a phase 1/2, open-label study that will investigate the efficacy and safety of sacituzumab govitecan-hziy in combination with the PARP inhibitor talazoparib for patients with metastatic TNBC.37 PARP is involved in repairing damaged DNA and is required for clearance of Trop-2 cleavage complexes; thus, PARP inhibitors may be complementary therapeutic partners with sacituzumab govitecan-hziy.37, 38

This study will include a dose escalation in phase 1b followed by a dose expansion in phase 2. Patients will receive sacituzumab govitecan-hziy on days 1 and 8 of 21-day cycles and talazoparib daily on days 15 to 21 of each cycle.38 The primary objective of phase 1b is to assess the dose-limiting toxicity rate and maximum tolerated dose of sacituzumab govitecan-hziy when given in combination with talazoparib. From these data, investigators will determine the recommended phase 2 dose. During phase 2, investigators will assess the ORR, PFS, OS, and clinical benefit rate. As of August 30, 2020, the trial was undergoing active recruitment, and a total of 20 patients were enrolled.37, 38

ESMO 2020 Data: Sacituzumab Govitecan-hziy for Breast Cancer Brain Metastases (NCT03995706)

SN-38, the cytotoxic payload delivered by sacituzumab govitecan-hziy, crosses the blood-brain barrier and is often included in central nervous system (CNS) cancer regimens.39 Investigators hypothesized that sacituzumab govitecan-hziy would yield therapeutically relevant SN-38 concentrations within the CNS of patients under-going craniotomy for breast cancer brain metastases or recurrent glioblastoma.39,40

In this single-center, nonrandomized, phase 0 study (NCT03995706), patients receive a single 10-mg/kg intravenous dose of sacituzumab govitecan-hziy the day prior to craniotomy and then resume therapy (on days 1 and 8 of 21-day cycles) after recovery. To date, 14 patients have been treated. For patients with recurrent glioblastoma (n = 7), the mean SN-38 concentration was 420 nM; for patients with breast cancer brain metastases (n = 7), the mean SN-38 concentration was 626 nM. Among those patients with residual measurable disease, 2 partial intracranial responses have been observed in each group after 12 weeks of treatment (ORR, 28% and 50% for glioblastoma and breast cancer brain metastases, respectively). As of September 2020, recruitment for this trial was ongoing.39,40

The metastatic urothelial cancer cohort of the IM-T-IMMU-132-01 trial reported encouraging activity with sacituzumab govitecan-hziy monotherapy (ORR, 31%; median PFS, 7.3 months; and median OS, 18.9 months).41Sacituzumab govitecan-hziy has FDA fast track desig-nation for metastatic urothelial cancer and is currently under further investigation in the phase 2 TROPHY U-01 trial (NCT03547973) and the upcoming phase 3 TROPiCS-04 trial (NCT04527991).42-45

Final data for cohort 1 and the trial design for cohort 3 were presented at the ESMO Virtual Congress 2020 for the pivotal phase 2, open-label, multicohort TROPHY U-01trial. The TROPHY U-01trial is investigating the safety and efficacy of sacituzumab govitecan-hziy in patients with heavily pretreated metastatic urothelial cancer across several cohorts. The study population across the TROPHY U-01 trial includes patients with disease progression despite treatment with platinum (PLT)-based chemotherapy, checkpoint inhibitors, or both. For all cohorts, the primary efficacy end point is ORR, and key secondary end points include PFS, OS, duration of response, and safety analyses.44,45

Cohort 1

Cohort 1 included a total of 113 patients who were treated with sacituzumab govitecan-hziy. The study population included patients who experienced disease progression after both PLT-based chemotherapy and checkpoint inhibitor therapy.44 Overall, patients in cohort 1 were previously treated with a median of 3 therapies and were a median of 66 years of age. In the results presented at ESMO 2020, a total of 31 patients had achieved an objective response (ORR, 27%; 95% CI, 19%-37%), of which 6 were complete responses and 25 were partial responses. The median duration of response was 5.9 months (95% CI, 4.7-8.6); median PFS and OS were 5.4 months (95% CI, 3.5-6.9) and 10.5 months (95% CI, 8.2-12.3), respectively. Sacituzumab govitecan-hziy demonstrated manageable toxicity. Key grade 3 or higher AEs were neutropenia (35%), anemia (14%), febrile neutropenia (10%), and diarrhea (10%).44

Cohort 3

As of March 2020, cohort 3 had started enrollment and is ongoing. The study plans to enroll a total of 61 patients with metastatic urothelial cancer who are nave to checkpoint inhibitor agents and have experienced disease progression or recurrence after PLT-based chemotherapy.45 As checkpoint inhibitors are the stan-dard-of-care therapy for patients who have failed on PLT-based chemotherapy, this study will investigate combination therapy with sacituzumab govitecan-hziy and the checkpoint inhibitor pembrolizumab. Exclusion criteria include active autoimmune disease or a history of interstitial lung disease, given the coadministration of pembrolizumab. A 10-patient lead-in cohort will determine standard the recommended phase 2 dose of sacituzumab govitecan-hziy (given on days 1 and 8 of 21-day cycles), to be given along with pembrolizumab 200 mg on day 1 of each cycle. The primary end point of ORR and secondary end points of PFS, OS, clinical benefit rate, duration of response, and safety will be assessed.45

The phase 3, global, open-label TROPiCS-04trial aims to enroll 482 patients to investigate the efficacy and safety of sacituzumab govitecan-hziy in patients with metastatic or locally advanced unresectable urothelial cancer who have progressed despite prior therapy with PLT-based chemotherapy and a PD-1 or PD-L1 checkpoint inhibitor. Sacituzumab govitecan-hziy will be compared with physicians choice of chemotherapy (paclitaxel, docetaxel, or vinflunine). The primary outcome measure will be OS; secondary outcomes will include PFS, ORR, safety, and quality of life. As of August 2020, the trial was not yet recruiting patients.43

Evaluation of novel and existing ADCs has revealed that success is not based on the use of any one particular cytotoxic compound or conjugate platform. Factors such as the consistency and level of target-antigen expression, tumor progression, and specific properties of the cancer and stage of disease also play important roles.46 Several additional Trop-2targeted ADCs are currently being investigated in solid tumors (Table).33,36,37,40,42,43,47-51

DS-1062a is a Trop-2directed ADC that contains the cytotoxic compound DXd, a derivative of exatecan that acts as a DNA topoisomerase I inhibitor.52 It is currently being investigated for the treatment of advanced NSCLC in an ongoing phase 1, multicenter, open-label study (NC T 03 401385).48

The study involves a dose-escalation phase and a dose-expansion phase. Dose-limiting toxicity, maximum tolerated dose, and AEs will be explored in both phases.47 Eligible patients have experienced disease progression or recurrence despite previous treatments, have measurable disease per RECIST 1.1 criteria, and are able to provide a sufficient tumor tissue sample for Trop-2 measurement. Patients with multiple primary malignancies or untreated brain metastases are ineligible for the study.48

As of November 2018, a total of 22 patients had been treated with 1 of 3 escalating doses of DS-1062a. Nearly 82% of patients experienced at least 1 treatment-emergent AE, with fatigue being the most common complaint. Fatigue was the only reported grade 3 or higher AE and was reported by 1 patient. Of 18 tumor-evaluable patients, 1 showed a partial response and 8 showed stable disease. Maximum-tolerated dose has not been achieved, and investigators will continue to monitor for safety and disease progression.47, 48

RN927C

RN927C, also known as PF-06664178, is an ADC composed of a Trop-2directed antibody conjugated with the cytotoxic microtubule inhibitor PF-06380101. Release of PF-06380101 leads to mitotic arrest, apoptosis, and cell death.3 Preclinical studies demonstrated the ability of RN927C to induce cell death among various tumor cell lines, including those from the skin, lung, head and neck, breast, ovary, and colon.3

RN927C was investigated in a phase 1, open-label, nonrandomized dose-escalation study (NCT02122146)of patients with advanced or metastatic solid tumors that were unresponsive to current therapies or for whom no standard therapy was available. The primary objective of the study was to determine the maximum tolerated dose and recommended phase 2 dose. Secondary outcomes included safety and preliminary evidence of antitumor activity. A total of 31 patients were enrolled and received treatment with escalating doses of RN927C. Stable disease was noted in 11 patients (39%), but no partial or complete responses were seen. Doses of 3.6 mg/kg, 4.2 mg/kg, and 4.8 mg/kg were considered intolerable, primarily because of skin reactions and development of neutropenia. The next-lower dose of 2.4 mg/kg was well tolerated, but the study was terminated early because of minimal anti-tumor activity and excessive toxicities.50

BAT8003

BAT8003 is an ADC composed of a Trop-2directed antibody conjugated to a potent cytotoxic maytansine derivative. The ADC has been optimized to facilitate site-specific conjugation, which allows for a more controllable drug-antibody ratio. In addition, a fucosylation of the Fc region of the antibody enhances its antibody-dependent cell-mediated cytotoxicity effect. In preclinical xenograft and primate models, BAT8003 demonstrated strong inhibition of tumor growth at doses of 5 mg/kg and 15 mg/kg, with a highest nonseverely toxic dose of 20 mg/kg given once every 3 weeks.51, 53

Given the promising preclinical data, a phase 1 dose-escalation study (NCT03884517) is currently investigating the safety, tolerability, and pharmacokinetics of BAT8003 in patients with advanced epithelial cancer who are either ineligible for standard therapy or have disease refractory to standard therapy.Eligible patients will receive escalating doses of BAT8003 (0.2-10.0 mg/kg) on day 1 of each 21-day cycle. The study will be divided into 3 periods: (1) the first 21-day cycle, which will examine the safety of a single BAT8003 administration, observe for dose-limiting toxicities, and establish preliminary pharmacokinetic parameters; (2) cycles 2 through 8, which will examine safety, immunogenicity, and preliminary efficacy of escalating doses of BAT8003; and (3) an expansion period, which could include an additional 10 to 30 cases to further assess safety and efficacy once a safe and effective dose has been established. As of the last update on March 21, 2019, the trial was actively recruiting patients.51

Trop-2 has established itself as a clinically meaningful biomarker among several types of solid malignancies. Its ability to promote self-renewal, proliferation, and cell invasion makes it an ideal candidate for targeted anti-tumor therapies, including ADCs.

Sacituzumab govitecan-hziy is the first Trop-2directed ADC to receive FDA approval for the treatment of metastatic TNBC. In the pivotal IM-T-IMMU-132-01 trial, sacituzumab govitecan-hziy showed encouraging results in patients with multiple difficult-to-treat solid tumor types, including TNBC, HR+/HER2- metastatic breast cancer, and metastatic urothelial cancer.31,32,41 Sacituzumab govitecan-hziy and other Trop-2directed ADCs represent a novel strategy to improve outcomes among these populations of patients with few therapeutic options. Data from additional trials of sacituzumab govitecan-hziy were presented at the ESMO Virtual Congress 2020. In the ASCENT trial, sacituzumab govitecan improved response rates and survival outcomes in patients with metastatic TNBC compared with standard-of-care therapy.35 Data from a cohort of patients with metastatic urothelial cancer in the TROPHY U-01 trial indicated positive survival impacts with manageable toxicity.44 Additional trials of sacituzumab-govitecan-hziy (as monotherapy or in combination with PARP inhibitors or checkpoint inhibitors) are under way in patients with metastatic TNBC, breast cancer brain metastases, and metastatic or locally advanced urothelial cancer.37,40,43,45 Other Trop-2directed ADCs are under investigation in NSCLC and advanced epithelial cancers.47, 51

See the original post:
Role of Trop-2 as an Actionable Biomarker in Solid Tumors - OncLive

Written by Kabir Firaque | New Delhi | Updated: October 25, 2020 11:18:59 amMedical workers check a X-ray photo of a lung of a patient suffering of Covid-19 in the Nouvel Hopital Civil of Strasbourg, eastern France, Thursday, Oct.22, 2020. (AP Photo: Jean-Francois Badias, File)

The novel coronavirus is known to attack primarily the lungs, but how the attack unfolds is still a subject of research. Now, two studies have thrown light on these processes by using the same approach. Scientists have developed lung models in the lab, infected these with SARS-CoV-2, and watched the battle between the lung cells and the virus.

Both papers are published in the journal Cell Stem Press. One study is by South Korean and UK researchers, including from the University of Cambridge; the other is by researchers from Duke University and University of North Carolina.

In both studies, scientists observed how the virus damages the alveoli in the lungs. Alveoli are balloon-like air sacs that take up the oxygen we breathe and release the carbon dioxide we exhale. Damage to alveoli causes pneumonia and acute respiratory distress the leading cause of death in Covid-19.

Both teams developed the model using mini-lungs or lung organoids. The organoids were grown from the stem cells that repair the deepest portions of the lungs where SARS-CoV-2 attacks. These are called AT2 cells. Follow Express Explained on Telegram

The UK and South Korean team reprogramed the AT2 cells back to their earlier stem cell stage. They grew self-organising, alveolar-like 3D structures that mimic the behaviour of key lung tissue. When the 3D models were exposed to SARS-CoV-2, the virus began to replicate rapidly.

In six hours, cells began to produce interferonsproteins that act as warning signals to neighbouring cells. After 48 hours, the cells started fighting back. And after 60 hours from infection, some of the alveolar cells began to disintegrate, leading to cell death and damage to the tissue.

In the other study, led by Duke University cell biologist Purushothama Rao Tata, the team got a single lung cell to multiply into thousands of copies and create a structure that resembles breathing tissues of the human lung. Once infected with the virus, the model showed an inflammatory response.

The team also witnessed the cytokine storm the hyper reaction of immune molecules the lungs launch to fight the infection.

The Indian Express is now on Telegram. Click here to join our channel (@indianexpress) and stay updated with the latest headlines

For all the latest Explained News, download Indian Express App.

The Indian Express (P) Ltd

Read the rest here:
Scientists grow mini-lungs in a lab, infect them with coronavirus and watch battle in real time - The Indian Express

DetailsCategory: Proteins and PeptidesPublished on Tuesday, 27 October 2020 18:20Hits: 344

WALTHAM, MA, USA and STOCKHOLM, Sweden I October 27, 2020 I Apellis Pharmaceuticals, Inc. (Nasdaq: APLS) and Swedish Orphan Biovitrum AB (publ) (Sobi) (STO:SOBI) today announced a strategic collaboration to accelerate the advancement of systemic pegcetacoplan, a targeted C3 therapy, for the treatment of multiple rare diseases with high unmet need that impact more than 275,000 patients globally.

Sobi will receive global co-development and exclusive ex-US commercialization rights for systemic pegcetacoplan. Apellis retains U.S. commercialization rights for systemic pegcetacoplan and worldwide commercial rights for ophthalmological pegcetacoplan, which is being evaluated by Apellis in two fully enrolled Phase 3 studies in geographic atrophy (GA). Pegcetacoplan targets excessive activation of C3 in the complement cascade, part of the bodys immune system, which can lead to the onset and progression of many serious diseases.

Apellis and Sobi plan to jointly advance the clinical development of systemic pegcetacoplan in five parallel registrational programs across hematology, nephrology, and neurology. These include new registrational programs in cold agglutinin disease (CAD) and hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA), both of which are expected to start in 2021. By controlling complement activation centrally, pegcetacoplan offers the potential to become a transformative new therapy in several rare diseases where patients have few or no treatment options today.

This collaboration enables us to further expand on the broad platform potential of targeting C3 for serious rare diseases that impact hundreds of thousands of patients around the world, said Cedric Francois, M.D., Ph.D., co-founder and chief executive officer of Apellis. We evaluated numerous companies, medium and large, and chose Sobi because of their global leadership in hematology and rare diseases, track record of successful product launches, and deep commitment to patients. Together, we will quickly advance systemic pegcetacoplan in multiple registrational programs across hematology, nephrology, and neurology while also preparing for our first potential U.S. launch in PNH. Financially, this transaction also strengthens our position, with our cash runway expected to extend into the second half of 2022.

We are excited to collaborate with Apellis, a leader in targeted C3 therapies. The collaboration will significantly strengthen and broaden our late-stage R&D portfolio and be a catalyst for further internationalization. The products have an excellent fit with our strategic focus on hematology and immunology, said Guido Oelkers, chief executive officer and president of Sobi. Given the central role of C3 in the complement cascade, pegcetacoplan has the potential to become the foundation for a broader platform in rare diseases. With positive Phase 3 data in PNH, pegcetacoplan can elevate the standard of care for this debilitating blood disorder.

As part of the collaboration, Apellis and Sobi will co-develop systemic pegcetacoplan in the following rare diseases:

Hematology Paroxysmal nocturnal hemoglobinuria (PNH), CAD, and HSCT-TMAPNH represents the first potential indication to market for systemic pegcetacoplan. Marketing applications for pegcetacoplan for the treatment of PNH were submitted to the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) based on positive results from the Phase 3 PEGASUS study. Top-line results from the Phase 3 PRINCE study, which is evaluating pegcetacoplan in treatment-nave patients with PNH, are expected in the first half of 2021.

Sobi will lead development activities for the Phase 3 study in CAD and a potentially registrational Phase 2 study in HSCT-TMA, both planned to start in 2021.

Nephrology Immune complex membranoproliferative glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G)Apellis has initiated and will continue to lead a registrational program in IC-MPGN and C3G, which includes Phase 2 and Phase 3 studies.

Neurology Amyotrophic lateral sclerosis (ALS)Apellis has initiated and will continue to lead a potentially registrational Phase 2 study in ALS. Multiple other neurological conditions are under consideration for future clinical development.

About the TransactionSobi will make an upfront payment of $250 million to Apellis and up to $915 million in other regulatory and commercial milestone payments, and will contribute $80 million in reimbursement payments over a four-year period for research and development to support the initial development plan, which includes ongoing studies in PNH, IC-MPGN/C3G, and ALS and new studies in CAD and HSCT-TMA. Apellis will also be eligible for tiered double-digit royalties on sales ranging from high teens to high twenties. Sobi intends to finance these payments with available funds. Sobi will receive reimbursement payments for the costs incurred by Sobi in connection with the CAD and HSCT-TMA trials that Sobi will conduct. The parties have agreed to split costs 50/50 for any future global studies beyond the initial development plan.

Per the terms of the agreement, Apellis will be responsible for all regulatory and commercial activities in the United States and the ongoing Marketing Authorization Application (MAA) review for PNH in the European Union, which will be subsequently transferred to Sobi. Sobi will be responsible for regulatory and commercial activities for systemic pegcetacoplan in ex-US markets. The co-development of systemic pegcetacoplan will be overseen by a joint development committee, and the commercial strategy will be overseen by a joint commercial committee.

Conference Call and WebcastApellis will host a conference call and webcast to discuss its collaboration with Sobi today, October 27, 2020, at 8:30 a.m. ET. To access the conference call, please dial (866) 774-0323 (local) or (602) 563-8683 (international) at least 10 minutes prior to the start time and refer to conference ID 5774165. A live audio webcast of the event and accompanying slides may also be accessed through the Events and Presentations page of the Investors and Media section of the companys website at http://investors.apellis.com/events-and-presentations. A replay of the webcast will be available for 30 days following the event.

About Pegcetacoplan (APL-2)Pegcetacoplanis an investigational, targeted C3 therapy designed to regulate excessive complement activation, which can lead to the onset and progression of many serious diseases.Pegcetacoplanis a synthetic cyclic peptide conjugated to a polyethylene glycol polymer that binds specifically to C3 and C3b.Apellis is evaluatingpegcetacoplanin several clinical studies across hematology, ophthalmology, nephrology, and neurology.Pegcetacoplanwas granted Fast Track designation by the U.S. Food and Drug Administration (FDA) forthe treatment of PNH and the treatment of geographic atrophy and received orphan drug designation for the treatment of C3G by the FDA and European Medicines Agency.

About Pegcetacoplan for Paroxysmal Nocturnal Hemoglobinuria (PNH)In October, the European Medicines Agency validated the Marketing Authorization Application (MAA) for pegcetacoplan in PNH, and an opinion from the Committee for Medicinal Products for Human Use is expected in 2021. A decision by the U.S. Food and Drug Administration regarding the acceptance of the New Drug Application (NDA) and a Prescription Drug User Fee Act (PDUFA) target action date is expected in the fourth quarter of 2020. Top-line results from the Phase 3 PRINCE study, which is evaluating pegcetacoplan in treatment-nave patients with PNH, are expected in the first half of 2021.

The NDA and MAA submissions for pegcetacoplan for the treatment of PNH are based on positive results from the Phase 3 PEGASUS study (APL2-302; NCT03500549), a multi-center, randomized, active-comparator controlled Phase 3 study in 80 adults with PNH. The primary objective of PEGASUS was to establish the efficacy and safety of pegcetacoplan compared to eculizumab. Pegcetacoplan is also being evaluated in the Phase 3 PRINCE study (APL2-308; NCT04085601), a randomized, multi-center, controlled study evaluating pegcetacoplan in 53 patients with PNH who had not received a complement inhibitor within three months before entering the study.

AboutPNHPNH is a rare, chronic, life-threatening blood disorder characterized by the destruction of oxygen-carrying red blood cells through extravascular and intravascular hemolysis. Persistently low hemoglobin can result in frequent transfusions and debilitating symptoms such as severe fatigue, hemoglobinuria, and difficulty breathing (dyspnea). A retrospective analysis shows that, even on eculizumab, approximately 72% of people with PNH have anemia, a key indicator of ongoing hemolysis.1 The analysis also finds that 36% of patients require one or more transfusions a year and 16% require three or more.1

About Cold Agglutinin Disease (CAD) CAD is a severe, chronic, rare blood disorder2 that currently has no approved therapies and impacts ~10,500 people across the United States and Europe.3 People living with CAD may suffer from chronic anemia, transfusion requirements, and an increased risk of life-threatening thrombotic events such as stroke.4 In people with CAD, immunoglobin M (IgM) autoantibodies cause red blood cells to agglutinate, or clump together, at temperatures below 30oC or as a result of a compromised immune system or infection.5 This activates the complement cascade to destroy healthy red blood cells through extravascular and intravascular hemolysis.6,7

About Hematopoietic Stem Cell Transplantation Thrombotic Microangiopathy (HSCT-TMA)HSCT-TMA is rare blood disease that can be a fatal complication of a bone marrow transplant or HSCT.8 In HSCT-TMA, microscopic blood clots form in small blood vessels, leading to organ damage. The kidneys are commonly affected, although any organ may be involved.8 HSCT-TMA occurs in up to 40% of HSCT recipients;9 every year, there are ~9,000 allogeneic transplants in the United States and ~18,000 in the EU+.10,11 Excessive complement activation is a high-risk feature in patients with HSCT-TMA,12 and C3 is believed to play a critical role in TMA based on proinflammatory and procoagulant properties of C3a and C3b.13

About Immune Complex Membranoproliferative Glomerulonephritis (IC-MPGN) and C3 Glomerulopathy (C3G) IC-MPGN and C3G are rare, debilitating kidney diseases that affect ~18,000 people in the United States and Europe.14 There are no approved therapies for the diseases, and symptoms include blood in the urine, dark foamy urine due to the presence of protein, swelling, and high blood pressure.15 Approximately 50% of people living with IC-MPGN and C3G ultimately suffer kidney failure within five to 10 years of diagnosis.16 Although IC-MPGN is considered a distinct disease from C3G, the underlying cause and progression of the two diseases are remarkably similar and include overactivation of the complement cascade, with excessive accumulation of C3 breakdown products in the kidney causing inflammation and damage to the organ. 17,18

About Amyotrophic Lateral Sclerosis (ALS)ALS is a devastating neurodegenerative disease that results in progressive muscle weakness and paralysis due to the death of nerve cells, called motor neurons, in the brain and spinal cord.19, 20 The death of motor neurons leads to theprogressive loss of voluntary muscle movement required forspeaking, walking, swallowing and breathing.19,20In individuals with ALS, high levels of C3 are present at the neuromuscular junction21 where motor neurons communicate directly to muscle cells. Numerous studies suggest that elevated levels of C3 present throughout the motor system of ALS patients are likely to contribute to chronic neuroinflammation and the death of motor neurons.21,22,23 There are no treatments that stop or reverse the progression of ALS, which impacts ~225,000 patients worldwide.24

About ApellisApellis Pharmaceuticals, Inc. is a global biopharmaceutical company that is committed to leveraging courageous science, creativity, and compassion to deliver life-changing therapies. Leaders in targeted C3 therapies, we aim to develop transformative therapies for a broad range of debilitating diseases that are driven by excessive activation of the complement cascade, including those within hematology, ophthalmology, nephrology, and neurology. For more information, please visithttp://apellis.com.

About SobiSobi is a specialized international biopharmaceutical company transforming the lives of people with rare diseases. Sobi is providing sustainable access to innovative therapies in the areas of hematology, immunology and specialty indications. Today, Sobi employs approximately 1,500 people acrossEurope,North America, theMiddle East,RussiaandNorth Africa. In 2019, Sobi's revenue amounted toSEK 14.2 billion. Sobi's share (STO:SOBI) is listed on Nasdaq Stockholm. You can find more information about Sobi atwww.sobi.com.

1 McKinley C. Extravascular Hemolysis Due to C3-Loading in Patients with PNH Treated with Eculizumab: Defining the Clinical Syndrome. Blood. 2017;130:3471.2 Sokol RJ, Hewitt S, Stamps BK. Autoimmune haemolysis: an 18-year study of 865 cases referred to a regional transfusion centre.Br Med J (Clin Res Ed).1981;282(6281):2023-2027.National Institute of Health (NIH), Genetic and Rare Diseases Information Center (GARD) 3 Catenion using physician and literature consensus4 Websitehttps://rarediseases.info.nih.gov/diseases/6130/cold-agglutinin-disease. Accessed November 21, 2019.5 Berentsen S, Ulvestad E, Langholm R, et al. Primary chronic cold agglutinin disease: a population based clinical study of 86 patients.Haematologica.2006;91(4):460-466.6 Cold agglutinin disease. Genetic and Rare Diseases Information Center Web site. https://rarediseases.info.nih.gov/diseases/6130/cold-agglutinin-disease. Accessed November 21, 2019.7 Reynaud Q, Durieu I, Dutertre M, et al. Efficacy and safety of rituximab in auto-immune hemolytic anemia: A meta-analysis of 21 studies.Autoimmun Rev.2015;14(4):304-313.8 Dvorak C, et al. Transplant-Associated Thrombotic Microangiopathy in Pediatric Hematopoietic Cell Transplant Recipients: A Practical Approach to Diagnosis and Management. Frontiers in Pediatrics. Vol 7, article 133. (2019)9 Jodele S, et al. Diagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study in children and young adults. Blood. 124(4): 645653 (2014)10 Current Uses and Outcomes of Hematopoietic Cell Transplantation (HCT): CIBMTR Summary Slides11 Passweg et al, BMT. 2019, 38: 1575158512 Jodele S, et al. Complement blockade for TA-TMA: lessons learned from a large pediatric cohort treated with eculizumab. Blood. 135 (13): 10491057. (2020)13 Noris M, et al. STEC-HUS, atypical HUS and TTP are all diseases of complement activation. Nature Reviews Nephrology. 8, 622633 (2012)14 ClearView Analysis using physician and literature consensus.15 Complement 3 Glomerulopathy (C3G). National Kidney Foundation Website.https://www.kidney.org/atoz/content/complement-3-glomerulopathy-c3g.Accessed November 21, 2019.16 C3 glomerulopathy. National Institute of Health, Genetics Home Reference.https://ghr.nlm.nih.gov/condition/c3-glomerulopathy#resources. Accessed November 21, 2019.17 Noris M, Donadelli R, Remuzzi G. Autoimmune abnormalities of the alternative complement pathway in membranoproliferative glomerulonephritis and C3 glomerulopathy. Pediatr Nephrol. 2019 Aug;34(8):1311-1323.18 Cook HT. Evolving complexity of complement-related diseases: C3 glomerulopathy and atypical haemolytic uremic syndrome. Curr Opin Nephrol Hypertens. 2018 May;27(3):165-170.19 National Institute of Neurological Disorders and Stroke. (2020). Amyotrophic Lateral Sclerosis Fact Sheet. Retrieved from https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Amyotrophic-lateral-Sclerosis-ALS-Fact-Sheet20 ALS Association. What is ALS? Retrieved June 2020 from https://www.als.org/understanding-als/what-is-als21 Bahia El Idrissi N, et al. J Neuroinflammation. 2016;13(1):72.4 Sta M, et al. Neurobiol Dis. 2011;42(3):211-220.22 Woodruff, et al., PNASJanuary 7, 2014111(1)E3-E423 Lee, et al Journal of Neuroinflammation volume 15: 171 (2018)25 Arthur K et al. Nat Commun, 2016, Vol 7, article 1240824 Arthur K et al. Nat Commun, 2016, Vol 7, article 12408

SOURCE: Apellis Pharmaceuticals

Read more:
Apellis and Sobi Enter Collaboration for Global Co-development and Ex-US Commercialization of Systemic Pegcetacoplan in Rare Diseases with Urgent Need...

Despite recent studies identifying invasive pulmonary aspergillosis (IPA) as a common complication of severe influenza, even in hosts who are immunocompetent, a retrospective look at the last 9 influenza seasons at 1 healthcare center in the United States tells a different tale.

In a poster presented virtually at ID Week 2020, investigators at Northwestern Universitys Feinberg School of Medicine determined the incidence of IPA among critically ill patients with influenza over multiple seasons and sought to track outcomes and hone in on predisposing risk factors.

Data were collected at a single healthcare center in Chicago, Illinois, across 9 influenza seasons (March 2009 March 2018), and included patients > age 18 who were admitted to the intensive care unit (ICU) with respiratory distress and had a positive influenza polymerase chain reaction test.

Investigators relied on criteria from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) to define IPA, as well as the revised AspICUcriteria.

The study population comprised 224 patients admitted to the ICU with influenza, and the overall rate of IPA was 3.1% (7/224). History of stem cell transplant was found to be a statistically significant risk factor for IPA (P = .015), with hematologic malignancy (P = .09), lung disease (P = .098), and obesity (P = .051) tending toward significance. Only 1 out of 7 patients with IPA was not immunosuppressed.

Length of hospital stay was significantly increased for patients with IPA (P = .046), but there was no significant difference in need for mechanical ventilation, renal replacement therapy, or death in these patients.

Other coinfections were common in these patients, with 31.3% bacterial, 7.6% viral, and 8.9% non-aspergillosis fungi infections reported.

The incidence of IPA was significantly lower (3.1%) in our study over 9 influenza seasons than has been reported in similar studies, investigators concluded. History of stem cell transplant was a risk factor strongly associated with the development of IPA. IPA did not significantly predict morbidity and mortality among critically ill influenza patients.

The poster, Aspergillosis Complicating Severe Influenza in ICU Patients: A Retrospective Cohort Study, was presented virtually at ID Week 2020.

Link:
Rates of Invasive Pulmonary Aspergillosis in ICU Patients With Influenza Far Lower Than Previously Thought - Contagionlive.com

Within the womb, a human fetus benefits from the protection of the placenta, limiting their contact with pathogens. However, once born, babies face a myriad of germs completely new to their bodies. Their immune system must rapidly develop to ensure early protection from infection. But what is exactly the dynamic of the immune system development in the first days of life?

To answer this question researchers from the Precision Vaccines Program at Boston Children's Hospital received funding from the Human Immunology Project Consortium (HIPC)/National Institute of Allergy and Infectious Diseases (NIAID) to study the timing of activation of different components of the immune system during the first week of life. For the first time, they observe an acute immune response starting right after the birth, followed by the progressive increase in key factors of innate immunity.

"Our study has revealed the developmental changes of the immune system during the defining first 7 days of life, in two independent cohorts. Furthermore, we provide insights into the development of the immune system which appears to be initiated by immunological triggers associated with birth" says Dr Hanno Steen lead author of the study published in the open-access journal Frontiers in Immunology.

The researchers studied the inventory of proteins present in newborn blood plasma, in two independent cohorts in The Gambia (West Africa) and in Papua New Guinea (PNG), at birth and after the first, third, and seventh day of life. This approach enabled them to follow, with high sensitivity, the dynamic of immune components in the blood across the first week of human life.

Firstly, the team observes, right after birth, an increase of plasma proteins involved in an acute inflammatory response, suggesting an activation of the immune system development. This is followed by an increase of components related to an innate immunity pathway called the complement system, starting as early as 24h after birth. The complement pathway has a major role in innate immunity, through the recruitment of several complexes of proteins (C1 to C9) it can induce direct destruction of pathogens. Furthermore, as the majority of the complement proteins are increasing concentrations of complement inhibitors is decreasing, until a new increase on day seven. Finally, the analysis also reveals that antibodies transmitted by the mother are declining rapidly over the first week of life while antibodies related to the complement pathway activation (IgM and IgG1) increase. Altogether, these results suggest that the complement pathway could have a central role in neonatal immunity and could be an important defense mechanism against pathogens in infancy.

A better understanding of the immune system and its development during the first week of life is particularly important given the prevalence of infections in early life. Neonatal infections cause 700,000 annual deaths, representing 40% of mortality in children under five years of age. "Having a better understanding of the immune system at the beginning of life will be pivotal for the development of precision vaccines for the newborns, which is one of the major goals of the Precision Vaccines Program at Boston Children's Hospital" says Steen.

ReferenceBjerg Bennike T et al/ Preparing for Life: Plasma Proteome Changes and Immune System Development During the First Week of Human Life. Frontiers Immunology. Accessed October 22, 2020.https://doi.org/10.3389/fimmu.2020.578505

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

Read the rest here:
How Do Our Immune Systems Develop in the First Days of Life? - Technology Networks

London, October 25

Some immune system molecules trigger the production of a non-functional variant of the human protein used by the novel coronavirus to enter and infect host cells, according to a study that sheds light on the body's natural defence against COVID-19.

The research, published in the journal Nature Genetics, examined the genetic information that codes for the ACE2 receptor, to which the SARS-CoV-2 virus must bind in order to enter and infect human cells.

In the study, scientists, including those from the Francis Crick Institute in London, analysed existing genetic databases and human cells to identify a new variant, or isoform, of ACE2 called MIRb-ACE2, which the SARS-CoV-2 virus cannot bind to.

"This variant of genetic information is the result of retroelements in our DNA, which can 'jump' around the genome impacting gene expression," said Kevin Ng, a co-author of the study from the Francis Crick Insitute.

"From looking at which other species also have this variant, it appears to be widely present in mammals, so it must have entered the human genome a long time ago," he added.

In order to understand the role this variant plays in the body's immune response to SARS-CoV-2, the scientists assessed the effects of exposing cells to interferons -- signalling proteins that are made and released by virus-infected cells.

They found that interferons increase the response and production specifically of MIRb-ACE2, while ACE2 is not affected.

According to the researchers, the findings allay concerns that interferon-based treatments for SARS-CoV-2 could inadvertently be helping the virus by bringing about an increase in coronavirus cell receptors in the body.

They said the coronavirus is not able to bind to MIRb-ACE2, which is also highly unstable.

"The non-functional MIRb-ACE2 isoform was likely responsible for results from previous studies that suggested interferons could be upregulating ACE2, as there was no distinction between these two isoforms," said George Kassiotis, another co-author of the study.

"This highlights how scientific knowledge about SARS-CoV-2 is constantly being revised and updated as new research is carried out. We still have a lot to learn, but we are making rapid progress," Kassiotis said.

The researchers also found that cells in the upper aero-digestive tract, including the mouth and the nose, express more MIRb-ACE2 than the functional ACE2, and this balance changes lower in this tract and in the intestines.

They believe more research is needed to understand why this difference occurs and the impact it might have on how the virus spreads in the body. PTI

See the article here:
Body's immune response drives production of non-functional coronavirus 'gateway protein': Study - The Tribune India

Playing through the greenery and litter of a mini forest's undergrowth for just one month may be enough to change a child's immune system, according to a small new experiment.

When daycare workers in Finland rolled out a lawn, planted forest undergrowth such as dwarf heather and blueberries, and allowed children to care for crops in planter boxes, the diversity of microbes in the guts and on the skin of young kids appeared healthier in a very short space of time.

Compared to other city kids who play in standard urban daycares with yards of pavement, tile and gravel, 3-, 4-, and 5-year-olds at these greened-up daycare centres in Finland showed increased T-cells and other important immune markers in their blood within 28 days.

"We also found that the intestinal microbiota of children who received greenery was similar to the intestinal microbiota of children visiting the forest every day," saysenvironmental scientist Marja Roslund from the University of Helsinki.

One daycare before (left) and after introducing grass and planters (right). (University of Helsinki)

Prior research has shown early exposure to green space is somehow linked to a well-functioning immune system, but it's still not clear whether that relationship is causal or not.

The experiment in Finland is the first to explicitly manipulate a child's urban environment and then test for changes in their micriobiome and, in turn, a child's immune system.

While the findings don't hold all the answers, they do support a leading idea - namely that a change in environmental microbes can relatively easily affect a well-established microbiome in children, giving their immune system a helping hand in the process.

The notion that an environment rich in living things impacts on our immunity is known as the 'biodiversity hypothesis'. Based on that hypothesis,a loss of biodiversity in urban areascould be at least partially responsible for the recent rise in immune-related illnesses.

"The results of this study support the biodiversity hypothesis and the concept that low biodiversity in the modern living environment may lead to an un-educated immune system and consequently increase the prevalence of immune-mediated diseases," the authors write.

The study compared the environmental microbes found in the yards of 10 different urban daycares looking after a total of 75 kids between the ages of 3 and 5.

Some of these daycares contained standard urban yards with concrete and gravel, others took kids out for daily nature time, and four had their yards updated with grass and forest undergrowth.

Over the proceeding 28 days, kids in these last four daycares were given time to play in their new backyard five times a week.

When researchers tested the microbiota of their skin and gut before and after the trial, they found improved results compared to the first group of kids that played in daycares with less greenery for the same amount of time.

Even in that short duration of the study, researchers found microbes on the skin and guts of children who regularly played in green spaces had increased in diversity - a feature which is tied to an overall healthier immune system.

Their results largely matched the second group of kids at daycares who had outings for daily nature time.

Among kids who got outside, playing in the dirt, the grass and among the trees, an increase in a microbe called gammaproteobacteria appeared to boost the skin's immune defence, as well as increase helpful immune secretions in the blood and reduce the content of interleukin-17A, which is connected to immune-transmitted diseases.

"This supports the assumption that contact with nature prevents disorders in the immune system, such as autoimmune diseases and allergies," says Sinkkonen.

The results aren't conclusive and they will need to be verified among larger studies around the world. Still, the benefits of green spaces appear to go beyond our immune systems.

Researchshows getting outside is also good for a child's eyesight, and being in nature as a kid is linked to better mental health. Some recent studies have even shown green spaces are linked to structural changes in the brains of children.

What's driving these incredible results is not yet clear. It could be linked to changes to the immune system, or something about breathing healthy air, soaking in the sun, exercising more or having greater peace of mind.

Given the complexities of the real world, it's really hard to control for all the environmental factors that impact our health in studies.

While rural children tend to have fewer cases of asthma and allergies, the available literature on the link between green spaces and these immune disorders is inconsistent.

The current research has a small sample size, only found a correlation, and can't account for what children were doing outside daycare hours, but the positive changes seen are enough for scientists in Finland to offer some advice.

"It would be best if children could play in puddles and everyone could dig organic soil," encouragesenvironmental ecologist Aki Sinkkonen, also from the University of Helsinki.

"We could take our children out to nature five times a week to have an impact on microbes."

The changes are simple, the harms low, and the potential benefits widespread.

Bonding with nature as a kid is also good for the future of our planet's ecosystems.Studiesshow kids who spend time outdoors are more likely to want to become environmentalists as adults, and in a rapidly changing world, that's more important than ever.

Just make sure everyone's up to date on their tetanus vaccinations, Sinkkonen advises.

The study was published in the Science Advances.

Continue reading here:
Daycares in Finland Built a 'Forest Floor', And It Changed Children's Immune Systems - ScienceAlert

Across the world, immunologists who retooled their labs to join the fight against SARS-CoV-2 are furiously trying to explain why some people get so sick while others recover unscathed. The pace is dizzying, but some clear trends have emerged.

One area of focus has been the production of antibodies powerful proteins capable of disabling and killing invading pathogens like viruses. Of great concern has been the sporadic identification of so-called autoreactive antibodies that, instead of targeting disease causing microbes, target the tissues of individuals suffering from severe cases of COVID-19.

Early studies implicated these autoantibodies in dangerous blood clots forming in patients admitted to intensive care. More recently, they have been linked to severe disease by inactivating critical components of viral immune defenses in a significant fraction of patients with severe disease.

As an immunologist within the Lowance Center for Human Immunology at Emory University, I have been investigating the immune response responsible for producing antibodies in COVID-19. Under the direction of Dr. Ignacio Sanz, our group has previously investigated immune responses contributing to autoantibody production in autoimmune disorders like lupus, and more recently in severe cases in COVID-19. However, while we were able to characterize the response in COVID-19 patients as autoimmunelike, we could not confirm the production of autoantibodies hidden within their antiviral responses.

Now we can.

In a newly released study awaiting peer-review, we describe the alarming finding that in the sickest patients with COVID-19, autoantibody production is common a finding with large potential impact on both acute patient care and infection recovery.

Autoantibodies come in flavors that are usually associated with specific disease types. Patients with lupus, for example, will often have antibodies that target their own DNA the molecules that make up the human genome.

Patients with the autoimmune disorder rheumatoid arthritis are less likely to have those antibodies, but more likely to show positive tests for rheumatoid factor antibodies that target other antibodies.

In this study, the Lowance Center group analyzed the medical charts of 52 patients in intensive care who were diagnosed with COVID-19. None of them had a history of autoimmune disorders. However, they were tested during infection for autoantibodies found in a variety of disorders.

The results are stark. More than half of the 52 patients tested positive for autoantibodies. In patients with the highest levels of c-reactive protein (a marker of inflammation) in the blood, more than two-thirds displayed evidence that their immune system was producing antibodies attacking their own tissue.

While these findings raise concerns, there are things that our data dont reveal. Although patients with severe disease clearly display autoantibody responses, the data dont tell us to what extent these autoantibodies contribute to the most severe symptoms of COVID-19.

It could be that severe viral illness routinely results in the production of autoantibodies with little consequence; this could just be the first time were seeing it. We also dont know how long the autoantibodies last. Our data suggest that they are relatively stable over a few weeks. But, we need follow-up studies to understand if they are persisting routinely beyond infection recovery.

Importantly, we believe that the autoreactive responses we have identified here are specific to the SARS-CoV-2 infection there is no reason to believe that similar results would be expected through vaccination against the virus.

However, while it is possible that these autoantibodies are benign, or even helpful in a yet-unidentified manner, its also possible that they arent. Maybe these self-targeted antibody responses do indeed contribute to disease severity, helping explain the delayed onset of severe symptoms in some patients that may correlate with antibody production.

This could be a reason that treatment with dexamethasone, an immunosuppressant often used to quell flare-ups of autoimmune disorders, might be effective in treating patients with only the most severe disease. It is also possible that these responses are not short lived, outlasting the infection and contributing to ongoing symptoms now experienced by a growing number of long-hauler COVID-19 patients.

Most concerning, it is possible that these responses could self-perpetuate in some patients, resulting in the emergence of new, permanent autoimmune disorders.

My colleagues and I sincerely hope that this is not the case rather, that the emergence of autoantibodies in these patients is a red herring, a quirk of a viral immune response in some patients that will resolve on its own. But we need to do better than hope we need to ask the right questions and figure out the answers. Fortunately, this study also gives us the tools to do that.

The tests that were run on these patients to determine their autoreactive profile are not specialized. They are available to most hospital labs across the country. Indeed, the two most common antibodies that we find in these patients, antinuclear antibodies and rheumatoid factor, are detected by common tests used by rheumatologists.

Our study shows that by testing for just these two autoantibodies, and the inflammatory marker c-reactive protein, we may be able to identify patients more likely to be experiencing potentially dangerous immune responses that might benefit from more aggressive immune modulation.

[Get facts about coronavirus and the latest research. Sign up for The Conversations newsletter.]

Further, autoreactivity testing might help identify patients who might benefit from rheumotological follow-up to monitor recovery, and help us understand whether some cases of long-hauler COVID-19 might be related to persisting autoantibodies. If so, these patients might respond to the same immune-targeted therapies that have been successful in MIS-C where autoantibody production has now been documented.

Finally, by testing patients immediately following COVID-19 recovery, we can establish baselines and begin to track the possible emergence of new cases of autoimmunity following this terrible disease, and plan early rheumatological intervention if needed.

We now have the tools. Its time to start using them.

Original post:
COVID-19 causes some patients' immune systems to attack their own bodies, which may contribute to severe illness - The Conversation US

Winter is coming and a second wave of Covid-19 is already with us, so it has never been more important to strengthen your immunity.

Along with hand-washing, masks and social distancing, its the best defence we have against the coronavirus.

A vaccine is still some way off and scientists warn that without one there is no hope of achieving the herd immunity needed to end the pandemic.

Boosting your own immunity makes sense, and studies show there is lots you can do.

A balanced diet is key, but there are certain nutrients that are particularly important and scientists have been working hard to find the stars that can help in the Covid battle.

Take these simple steps to strengthen your immune system and keep you well through the tough winter ahead:

Vitamin D, which is essential for healthy bones and muscles, is often known as the sunshine vitamin giving a big clue as to why we dont get enough in winter.

While it can be found in some foods, including oily fish, red meat and eggs, our bodies grab the majority of what they need from exposure to sunlight.

One in five Brits is deficient, with the number increasing as the nights draw in.

And thats why the official advice is to consider taking a supplement containing 10mcg of vitamin D (the equivalent of 400IU) during winter.

But as well as keeping bones strong, this simple vitamin could also play a key role in the fight against Covid-19.

A super-study published earlier this year, which analysed results from 39 trials, found that taking 10mcg of the sunshine vitamin reduced the risk of respiratory infections by up to 23 per cent.

More recently, researchers at the University of Birmingham, who tested blood samples from 392 healthcare staff, found that 72per cent of those who were deficient in vitamin D had also caught Covid-19.

By contrast, only 51 per cent of those with good levels carried antibodies confirming they had been infected.

Covidence-UK, a study that uses monthly surveys of UK citizens to identify potential risk factors for Covid-19, has also identified a link.

Researchers are launching a randomised control trial to see if providing free vitamin D to people with low levels reduces their odds of catching the virus. To sign up and support the Covidence-UK search for ways to reduce the risk of Covid-19, visit qmul.ac.uk/covidence.

Some scientists believe its no accident that countries where cabbage and fermented vegetables, such as sauerkraut and kimchi, are popular, have reported lower coronavirus death rates.

Dr Jean Bousquet, Honorary Professor of Pulmonary Medicine at Montpellier University, France, has calculated that every gram of fermented vegetables eaten each day reduces the risk of dying of Covid-19 by 35 per cent.

A similar pattern was seen in countries where a lot of cabbage is consumed, and Professor Bousquet believes the benefits are down to high levels of the antioxidant sulforaphane in them.

He adds: Nutrition may play a role in the immune defence against Covid and may explain some of the differences seen in Covid across Europe. Ive now changed my diet, and it includes raw cabbage three times a week, sauerkraut once a week and pickled vegetables.

Dozens of studies have underlined the importance of zinc for strong immunity. And the World Health Organisation confirms it, saying: Zinc is thought to help decrease susceptibility to acute lower respiratory tract infections by regulating various immune functions.

Zinc can be found in shellfish, beans and lentils, but eight per cent of adults here in the UK do not get the recommended intake.

Research has shown that taking zinc within 24 hours of cold symptoms appearing cuts the duration of infections by a third.

Excitingly, studies have confirmed zinc inhibits Covid-19 and there is evidence it may boost levels of interferon, a protein that helps our immune system identify threats.

The balance of good and bad bacteria in our gut has a big impact on immunity. Dr Bousquets research has also identified a link between fermented dairy products, such as yoghurt and kefir, and a lower rate of deaths from the virus.

A recent Chinese study discovered that probiotic drinks that contained a combination of lactobacillus bacteria reduced the risk of respiratory infections by 59 per cent.

Another study, published in the European Journal of Public Health, found that children who were given daily probiotic supplements werearound a third less likely to needantibiotics.

A 150ml glass of orange juice provides more than 80 per cent of the immune-strengthening vitamin C that we need each day.

But there is growing scientific interest around another nutrient in orange juice, which could be even more important for our immunity.

Hesperidin, a micronutrient found in citrus fruit, slows the rate that viruses can replicate. Laboratory tests showed such strong antiviral activity that some scientists think it could be used to develop new drugs against dreaded influenza.

A recent study showed it locks on to key proteins on the Covid-19 virus, which could make it harder for infection to take hold.

Because the highest concentrations are found in the pith of fruit, juice will have more hesperidin in it than whole fruit. Shop-bought orange juice contains three times more hesperidin than juice squeezed at home.

Read the original post:
Strengthen your immune system against Covid with help of Vitamin D, zinc and pickles - Mirror Online

Immune boosting is a phrase that I really cant get along with, says leading nutritional therapist and healthy eating expert, Amelia Freer, when asked about the best immune-boosting advice for the coming winter months. In fact, according to Freer, weve been approaching it all wrong and when it comes to our immune system, the aim isnt to boost, but rather to balance it.

Read more: Feeling Low? Here Are 8 Ways To Ease Seasonal Affective Disorder

An overactive immune system can result in auto-immune disease, or a significant widespread inflammatory state, while an under-active or otherwise compromised immune system can increase our risk of infection neither of which is ideal. In the simplest of terms, says Freer, we want to be able to switch our immune function on appropriately, and then switch it off again when the infection risk has passed.

As for how we can do this best, Freer suggests nurturing and supporting our overall health and wellbeing. There are various nutrients that our body requires to mount and suppress an appropriate immune response, she comments. The best way to get these is through eating a balanced, nutritious, and abundant diet, so including a wide variety of different whole foods into our diets throughout the winter is a great place to start.

A variety of fresh green vegetables is key.

SCIENCE PHOTO LIBRARY

First up is dark-green vegetables such as kale, chard, spinach, rocket, Brussels sprouts, sprouting broccoli. They all provide a variety of beneficial phytonutrients, fibre, vitamin A, magnesium, folate and more. If there is one thing to add to our diets, it is this group of vegetables. Aim for at least one portion per day (remembering that when cooked, they tend to shrink considerably in terms of volume, making it easier to achieve this target).

Citrus fruits are a good source of vitamin C and perfect for the coldest winter months a little bit of concentrated sunshine just when we need it most. I particularly love the month or two that blood oranges are available [around December to April] I have one almost every day when I can, as the most deliciously simple dessert.

Citrus fruits such as oranges, grapefruits, and mandarins can provide, a little bit of concentrated sunshine just when we need it most, according to Freer.

voloshin311

This is a cheap and readily available oily fish and a source of long-chain omega-3 fatty acids, which can help to regulate inflammation in the body. It also contains some food-based vitamin D, as well as protein, and its a great speedy choice for lunches. Top tip: look out for unsmoked, frozen mackerel fillets in the freezer section of some supermarkets. Ive found that its the best fish to cook from frozen, and contains less salt than the smoked version.

There are a huge variety of orange-fleshed pumpkins to enjoy over winter. They provide a source of vitamin A, which, as a fat-soluble vitamin, is best absorbed alongside some healthy fats. I therefore tend to slow-roast my squash and pumpkins in a little olive oil, and then enjoy as they come, blended into sauces or soups, or tossed into salads with rocket, radicchio, some toasted hazelnuts and crumbled feta.

Brazil nuts are a key source of the micronutrient selenium, which is an important mineral for optimal immune response. Just four or five Brazil nuts per week can meet our selenium requirements. It is, however, one of the few whole food nutrients that we can over-consume, so its best to mix things up and eat just a few each week alongside a variety of other nuts and seeds, too.

Protein and pulses are important for enabling the body to mount an appropriate immune response.

Adl Bkefi

I adore pulses in all shapes and sizes, and I find them a convenient source of protein I aim to have roughly a palm-sized portion of protein at each meal of the day. Protein is important for enabling the body to mount an appropriate immune response, as well as for repair and growth of our bodys tissues, and for appetite and blood-sugar regulation. I buy pulses in bulk in jars and add them to soups, make them into hummus and other dips, throw them into curries and stews, or eat them cold with some olive oil, lemon and a few chopped herbs.

Shellfish is a good source of zinc and vitamin B12, and mussels and scallops are in season over the winter months. They are a bit of a treat, but its worth making the effort to cook them once in a while. Do check that they are sustainably sourced and if youre unsure about cooking them yourself, it might be a good option to consider ordering if eating out.

Rolled oats are a great choice and can provide not only a warming and delicious porridge breakfast, but also a hefty dose of fibre, too. Soaking oats overnight can help to make the nutrients they contain more absorbable, as well as speeding up the cooking time.

Eating eggs regularly is a simple way to introduce immunity balancing benefits into your diet.

Jody Louie took this picture

Eggs are such a versatile and useful ingredient to have on hand for quick meals and speedy snacks. They are also a source of vitamin B12, a little vitamin D, vitamin A, protein and some are even fortified with omega-3 fatty acids, all of which are important for balanced immune function.

Maintaining a good level of hydration can help to keep our mucosal barriers moist, such as those in our mouth and the lining of our nose. This might sound strange, but hydration of these tissues helps to support the natural immune function that exists within them, warding off infection before it has a chance to enter the body. Plus water wont spoil your appetite for the abundance of nourishing whole foods awaiting you at your next meal.

Good hydration supports muscles and skin tissues, enabling them to better fight off infection.

Dulin

The only supplement that is recommended for everyone to consider over the winter months is vitamin D. In some countries, the sunlight is not strong enough between October and early March for our skin to make enough vitamin D to meet our requirements.

I know its been said a thousand times before, but it really is what works: wash your hands, prioritise sleep, actively respond to and manage stress, move regularly, exercise, moderate alcohol and avoid smoking. Its not original, but it is effective.

More from British Vogue:

See original here:
Immunity Boosting Is Over, Its All About Balance - British Vogue

Findings from a new study showed an association between high serum immunoglobulin G (IgG) and immunoglobulin A (IgA) levels and milder cases of Clostridium difficile (C. difficile).

Specifically, this association was modulated by the two serum antibodies targeting of both toxins A (TcdA) and B (TcdB), which play an essential role in the pathogenesis of the disease.

Investigators from Tel Aviv University and Tel Aviv Sourasky Medican Center conducted a case-control study to determine the risk factors of C. difficile infection (CDI) and evaluate the link between humoral immune response and CDI severity.

Thus, their analysis consisted of a total of 50 patients with CDI, 62% of whom were female. This represented a subset of 140 total CDI patients who were enrolled in their study.

They categorized CDI patients according to severitysevere disease was defined as leukocytosis with a white blood cell count of 15,000 cells/L, decreased blood albumin (<30 g/L) or a rise in serum creatinine level 1.5 times the premorbid level. Any patient who did not fulfill any of these requirements were considered to have a mild case.

Additionally, they analyzed 52 patient controls who were not suffering from diarrhea, where 56% were female. In total, they had enrolled 140 controls.

Both CDI patients and controls were matched by age, sex, hospitalization ward (medical or surgical), and number of hospitalization stays.

The mean age between the CDI and control groups were 79.2% years and 82.7%, respectively.

The investigators collected stool specimens from the both groups to test for C. difficile. Blood samples were also collected, and the levels of serum IgG and IgA antibodies against TcdA and TcDB were measured.

Overall, they found that patients with CDI presented with higher geometric mean titers (GMT) values of serum IgG antibody against TcdA when compared with the control group (20.1 EU vs 11.6 EU, respectively; P = .0001).

The GMT values of serum IgG against TcdB were also higher for the CDI group than for the control (18.0 EU vs 12.0 EU, respectively; P = .04).

They also noted that similar trends were observed for IgA antibodies, but the differences were not statistically significant.

In terms of associations for C. diff severity, they found that GMT values of serum IgA against TcdB was significantly higher among CDI patients with mild disease as compared with patients with severe disease (9.2 EU vs 4.9 EU, respectively; P = .023).

Similar but non-statistically significant trends were noted found for IgA and IgG levels against TcdA, as well as for IgG against TcdB.

Limiting the analysis to sera that were collected at days 714 following the diagnosis of C. difficile showed significantly higher IgG levels against TcdA and TcdB in patients with mild CDI compared to patients with severe CDI, they wrote.

Furthermore, they found significant correlations between serum IgG levels and TcdA and TcdB (Spearmans r = 0.31). Other strong correlations included IgA levels against TcdA and TcDB (r = 0.53) and IgG and IgA levels against TcdB (r = 0.43).

Although there remains great uncertainty behind the mechanism that can explain the protective effect of serum IgA and IgG antibodies against C. diff toxins, the investigators nonetheless suggested implications for the findings.

Based on the current evidence from observational studies and our new findings, the concept of presenting antigens that can prime or boost the immune system towards the production of antitoxin circulating antibodies seems a sensible approach for developing preventive and therapeutic vaccines and technologies for CDI, the team wrote.

The study, "Enhanced Humoral Immune Responses against Toxin A and B of Clostridium difficile is Associated with a Milder Disease Manifestation," was publshed online in Journal of Clinical Medicine.

Read more here:
Increased Humoral Immune Response Against C. Diff Toxins Linked to Mild Disease - MD Magazine

We are still working to figure out why low levels of vitamin D are associated with worse outcomes in critical illness, noted Todd W. Rice, MD, FCCP, associate professor of medicine at Vanderbilt University Medical Center in Nashville, Tennessee.

Studies have shown that low levels of vitamin D are associated with worse outcomes in critical illnessfor instance, needing to be in the intensive care unit (ICU) morebut we are still working to figure out why, noted Todd W. Rice, MD, FCCP, associate professor of medicine at Vanderbilt University Medical Center in Nashville, Tennessee, in an interview for this years CHEST Annual Meeting.

Transcript

Tell us about your presentation on day 1 of CHEST, Vitamin D in Critical Illness: Helpful Fact or Hopeless Fiction.

This is a presentation in a session about vitamins and vitamins in the ICU. And obviously, based off of the title, Im going to talk about vitamin D. The short, brief story of vitamin D is that weve had a number of studies that have shown that low levels of vitamin D are associated with worse outcomes, including needing to be into the ICU more, having more infections in the ICU, and staying in the ICU longer, having higher mortality while youre in the ICU. And so the thought process is that repleting peoples vitamin D to normal levels may prevent some of these bad outcomes. And weve tried this in a number of trials and we havent had great success in improving outcomes by giving patients vitamin D. And the question then becomes, why is that the case? Is it that low vitamin D level is not the reason that people do worse, its just kind of associated with being sick and doing worse? Or is there something about vitamin D metabolism and vitamin D absorption that we dont yet understand? So were not really supplementing it right, were not really targeting the right levels, those sorts of things. And I think were still working to figure that out.

How do the pleiotropic effects of micronutrients affect critical illness?

Vitamin D has a number of kind of positive effects in the body. Obviously, its involved in bone metabolismthats probably not that relevant in critical illnessbut its very, very, very much involved in the immune system. And its sort of a cofactor for our immune cells in fighting infection. And its been shown in a number of other studies, not in the ICU, that low vitamin D levels result in less robust immune systems, more prone to get infections, and worse outcomes.

The other effects of it are that it seems to have some anti-inflammatory effects. We dont entirely understand exactly how it decreases inflammation, but it seems to decrease inflammation and also kind of has some effects on the endothelial lining of the lungs and the vasculature. So all of those effects kind of together are pleiotropic in the fact that they sort of grow these areas, stimulate these areas, and are beneficial to the body in that regard.

Read more:
Dr Todd Rice Explains the Anti-inflammatory Benefits of Vitamin D to Our Immune Systems - AJMC.com Managed Markets Network

People wear face masks in Times Square as the city continues the re-opening efforts following restrictions imposed to slow the spread of coronavirus on October 22, 2020 in New York City.

Noam Galai | Getty Images

Mandy Elmore, 47, has been wearing masks for more than 20 years. That's because she has cystic fibrosis, a hereditary disease that affects her lungs and digestive system.

Because of her illness, a cold or flu can land her in the hospital. Prior to the pandemic, Elmore, who lives in Dallas, Texas, had to stop going to church or traveling on planes to avoid strangers coughing and sneezing directly on her.

"Masks offer freedom for those of us who are sick," she said. "I would feel comfortable going to church in the winter or to movies or to birthday parties if people could think about those like me who truly suffer as a result of a simple cold virus."

For millions of Americans like Elmore, it would change their lives for the better if it became more of a cultural norm in the U.S. for people to wear masks when they're under the weather or in crowded areas. The West has stigmatized mask-wearing, but in countries like Japan or South Korea, residents might get dirty looks if they hop on a subway with a sniffle and no mask.

Still, there's reason for skepticism. Not everyone in America is wearing masks, even now, when public health officials are strongly encouraging them to do so. Rallies to protest masks have popped up across the country, with many Americans pointing out that it's a violation of their personal freedoms.

But for others, who potentially represent a less vocal majority, it could become the new normal. Since the start of the pandemic, many people bought a handful of masks for the first time and have gotten used to wearing them in public. Doctors and public health experts believe that American culture could fundamentally shift to embrace new hygiene practices.

"I think we do need a new culture of masks, at least any time not feeling well, and I think masks are in and handshakes out for the indefinite future," said Dr. Tom Frieden, the former director of the C.D.C. during the Obama Administration and the president of global health initiative Resolve to Save Lives.

"Post pandemic, there will be new social norms," added Dr. Panagis Galiatsatos, a pulmonary and critical care doctor, who treats patients with chronic respiratory conditions like COPD and cystic fibrosis, as well as Covid-19.

"I think face masks will continue to be used by the general public in times when they don't feel well, and honestly we're realizing that no one feels slighted without a handshake," he said.

Sometimes, it takes a pandemic to change behavior. Across East Asia, mask wearing really took off in the aftermath of the SARS outbreak in 2003. The U.S. was largely spared from SARS. But in Hong Kong, where more than 280 people died, there was widespread panic. All of that led to many countries developing practices around how to tamp down on potential disease outbreaks early, with measures like social distancing, travel bans, and masks.

Almost two decades later, this advanced planning gave the region an edge when it came to Covid-19. Many people already had a mask or two at home and had become used to wearing one. In countries like Taiwan, those who did not wear a mask were occasionally even publicly shamed on social media for failing to take proper precautions.

William Hsiao, emeritus professor of economics inthe Department of Health Policy and Management at the Harvard T.H. Chan School of Public Health, told CNBC that in these cultures, there's a strong feeling that sometimes people have to sacrifice their "individual desires and benefits" for the sake of their community. That helped countries like Taiwan and Vietnam, which have experienced relatively few cases of Covid-19, come together to face a threat in a more unified way. In Taiwan, only 7 people have died from the virus, while Vietnam has reported just 35 deaths.

In the West, it hasn't been as easy to disseminate public health measures. Not all Americans have eagerly embraced mask-wearing, even in the height of the pandemic. Research organizations like Brookings say that "a culture of individualism" is an obstacle. Americans aren't as used to putting the needs of the community ahead of themselves.

Still, some Americans say their perspective has fundamentally shifted. Rather than powering through illness by going to school or work as normal, they say they'd take extra precautions or stay home. And some say that they'd be comfortable wearing a mask in a crowded setting from now on.

"I grew up going to school, even if I was sick" said Spencer Guthrie, 45, from San Francisco. "I never missed a single day of school from K-12."

But Guthrie said his views have changed since the start of the pandemic. He would take greater precautions now if he felt under the weather. "Masks are not the slightest bit inconvenient for long periods of time if you find one that fits well," he said.

Others say they discovered unexpected benefits to wearing a mask. Hope King, a New York-based journalist, has found comfort in that moment on the street when people pull their mask up as they approach. She sees it as a sign of respect.

King has experienced the rise of anti-Asian racism during the pandemic. So wearing a mask makes her feel safer.

"I think maybe you can't tell immediately that I'm Asian from far away, especially if I'm wearing glasses," she said.

King envisions keeping her mask on as long as people around her continue to do so. She also plans to wear one if she starts to feel sick, as a signal to others that she's invested in protecting them.

For some young Americans, wearing a mask just isn't big deal. Gurdane Bhutani, 29, suspects that face coverings won't be perceived as a "strange thing to do" in the future at times when people are packed together. He already refrains from eating peanuts on an airplane in case someone has an allergy. So a mask doesn't seem any different.

"It's not hard to do, and it could make a difference for someone else," he said. "I know people with autoimmune conditions are feeling really relieved that everyone is wearing masks now."

Doctors like Krishna Komanduri, chief of the division of transplantation and cellular therapy at the University of Miami, has noticed an increased empathy for immunocompromised patients in recent months. People with weakened immune systems have long feared getting sick and that prospect is never far from their thoughts.

And now, with Covid-19, even young and healthy people are concerned about avoiding germs and spreading illness.

"For our cancer patients, nothing has really changed," he said. "Rather we have been drawn into their world."

Cancer patients, he said, or really anyone with a compromised immune system, are no strangers to masks and social distancing. Some received strange looks prior to the pandemic, he said. But not anymore. "More widespread adoption of these measures would be good in general," he explained.

For her part, Elmore, who suffers from cystic fibrosis, has never felt safer. And ironically, that's during a respiratory pandemic.

"Now, if someone coughs or sneezes with a mask on in the store, I'm not trying to run to get away," she said. "Pre-Covid, I would literally breathe out and walk as fast as possible to get away from the airflow."

Elmore said her entire family would keep their ears alerted for any hint of sickness at a time when very few people wore masks. "My husband used to say, 'cougher on the left,' to prevent me from breathing as they walked by," she said.

Elmore isn't expecting that everyone will wear masks at all times in the future. She is hoping that people will take more precautions, however, when they start feeling sick. "I do hope those that are having symptoms will consider them," she said.

Read the rest here:
Will masks become the 'new normal' even after the pandemic has passed? Some Americans say so - CNBC

Summary

Two MSK-led studies published in the journal Nature support the idea of using immunotherapy drugs to treat the environment surrounding a tumor as an indirect way to combat cancer.

Despite the remarkable successes of immune-based treatments for cancer, not everyone responds to these approaches, and relapses do occur. Researchers around the world are racing to find ways to improve outcomes for people receiving immunotherapy. But new findings from scientists at Memorial Sloan Kettering suggest they may be focusing too narrowly on the problem.

According to Ming Li, an immunologist in the Sloan Kettering Institute, most existing immunotherapy approaches, including both checkpoint blockade and CAR T therapy, aim to prod the immune system into finding and killing cancer cells a kind of frontal attack on the disease.

But tumors also need supportive environments safe harbors in which to grow and thrive. They need the support of blood vessels that provide them with nutrients, Dr. Li says.

Could destroying these safe harbors be an indirect way to fight this internal enemy? Dr. Li thinks the answer is yes, and on October 21, he published two papers in the journal Nature in support of the concept.

We know that the immune system is incredibly adept at recognizing harmful invaders and attacking them with precision, he says. But thats not the only way our immune system protects us from threats. It also promotes healing of damaged tissue so that pathogens cant take root in the body. This latter role, we now show, can also be enlisted in the fight against cancer.

Dr. Li and his colleagues found they could thwart cancers in mice by encouraging immune cells to begin the process of wound repair around a tumor. In the process, blood vessels that feed the cancer are pruned away and cancer cells starve and die. Its an approach that Dr. Li has dubbed cancer environment immunotherapy.

To understand how wound healing can help curb cancer, consider what happens when someone gets an injury, say a cut from a knife. Early on, the site becomes inflamed red, hot, and swollen. During this phase of wound healing, blood vessels dilate and immune cells rush in to fight enemies that may cause infection and clean up the debris. But later on, the wound fills in with new tissue, and inflammation resolves.

An important player in the wound healing process is a molecule called TGF-beta, whose presence waxes and wanes with the inflammation cycle. In the context of a cancerous wound, TGF-beta persists and makes cancer growth worse. By contrast, blocking its action inhibits tumor development. This latter effect is dependent upon immune cells called T cells, previous research has shown.

Blocking the action of a molecule called TGF-beta in immune cells (right) triggers cell death (blue) in tumors in mice.

Dr. Li and his team wanted to find out more about which T cells were involved in curbing cancer growth when TGF-beta is blocked. They initially suspected that a subset of T cells called CD8 T cells, or killer T cells, were responsible for restraining tumor development. But when they genetically removed the receptor for TGF-beta from CD8 cells in mice, it had no effect on cancer growth.

Next, they asked whether a different subset of T cells, called CD4 T cells, or helper T cells, could explain the phenomenon of cancer suppression. Indeed, genetically removing the receptor for TGF-beta in CD4 T cells dramatically reduced cancer growth in mice.

How do CD4 T cells contribute to cancer control in this context? Dr. Li and his colleagues found that these cells promote wound healing around a tumor. As part of this process, the blood vessels supplying nutrients to a tumor are dramatically remodeled, and a kind of protective wall is formed around the tumor, depriving it of sustenance.

These results, reported in the first Nature paper, showed that blocking TGF-beta signaling in CD4 T cells could activate a powerful wound healing response that directly opposes cancer development.

But what about tumors that have already been growing? Could blocking TGF-beta restrain them? Dr. Li and his team explored this question in a second set of experiments, published in a second Nature article.

By blocking TGF-beta inhelper T cells, we allow the wound healing to run to completion. We heal the wound that is cancer.

They designed an antibody-based drug that can bind to both TGF-beta andhelper T cells. They found that this drug, which they called 4T-Trap, could dramatically reduce cancer in mice.

Previous attempts at blocking TGF-beta as a cancer treatment have not been successful, likely because this molecule has many effects in the body, and therefore blocking it completely can cause severe side effects such as heart problems or even the appearance of new cancers. But 4T-Trap targets the TGF-beta-blocking-molecule directly to CD4 T cells, so side effects are reduced. In other words, its a more targeted approach.

That fact that CD4helper T cells were the key players rather than CD8 killer T cells came as something of a surprise to the researchers. These days, CD8 cytotoxic T cells that recognize cancer cells are in the spotlight. Dr. Li says, Its almost become dogma that if its T cell mediated, then it must be CD8 T cells. That was our original hypothesis, too. But that turns out not to be the case.

Yet the findings are not completely unprecedented. In fact, the discovery that the promotion of wound healing can dramatically curb cancer progression meshes nicely with older work. In the mid-1980s, cancer researcher Harold Dvorak published a now-famous article in the New England Journal of Medicine, in which he argued that tumors are essentially wounds that do not heal. Tumors enlist normal wound healing to help themselves grow. They thrive by enlisting the early stages of the immune responses to tissue damage growth of new blood vessels, for example but then never get to later stages of wound healing when these blood vessels are normally pruned away.

By blocking TGF-beta inhelper T cells, we allow the wound healing to run to completion, Dr. Li says. We heal the wound that is cancer.

Reflecting on the way his results echo these earlier findings, Dr. Li says, Its an exciting homecoming.

He proposes that such cancer environment immunotherapy could be a powerful addition to current immune-based treatments for cancer. His lab is currently collaborating with physician-researchers at MSK to translate these new findings to patients.

Original post:
MSK-led Studies Support the Concept of Cancer Environment Immunotherapy - On Cancer - Memorial Sloan Kettering

Many of the symptoms experienced by people infected with SARS-CoV-2 involve the nervous system. Patients complain of headaches, muscle and joint pain, fatigue and brain fog, or loss of taste and smellall of which can last from weeks to months after infection. In severe cases, COVID-19 can also lead to encephalitis or stroke. The virus has undeniable neurological effects. But the way it actually affects nerve cells still remains a bit of a mystery. Can immune system activation alone produce symptoms? Or does the novel coronavirus directly attack the nervous system?

Some studiesincluding a recent preprint paper examining mouse and human brain tissueshow evidence that SARS-CoV-2 can get into nerve cells and the brain. The question remains as to whether it does so routinely or only in the most severe cases. Once the immune system kicks into overdrive, the effects can be far-ranging, even leading immune cells to invade the brain, where they can wreak havoc.

Some neurological symptoms are far less serious yet seem, if anything, more perplexing. One symptomor set of symptomsthat illustrates this puzzle and has gained increasing attention is an imprecise diagnosis called brain fog. Even after their main symptoms have abated, it is not uncommon for COVID-19 patients to experience memory loss, confusion and other mental fuzziness. What underlies these experiences is still unclear, although they may also stem from the body-wide inflammation that can go along with COVID-19. Many people, however, develop fatigue and brain fog that lasts for months even after a mild case that does not spur the immune system to rage out of control.

Another widespread symptom called anosmia, or loss of smell, might also originate from changes that happen without nerves themselves getting infected. Olfactory neurons, the cells that transmit odors to the brain, lack the primary docking site, or receptor, for SARS-CoV-2, and they do not seem to get infected. Researchers are still investigating how loss of smell might result from an interaction between the virus and another receptor on the olfactory neurons or from its contact with nonnerve cells that line the nose.

Experts say the virus need not make it inside neurons to cause some of the mysterious neurological symptoms now emerging from the disease. Many pain-related effects could arise from an attack on sensory neurons, the nerves that extend from the spinal cord throughout the body to gather information from the external environment or internal bodily processes. Researchers are now making headway in understanding how SARS-CoV-2 could hijack pain-sensing neurons, called nociceptors, to produce some of COVID-19s hallmark symptoms.

Neuroscientist Theodore Price, who studies pain at the University of Texas at Dallas, took note of the symptoms reported in the early literature and cited by patients of his wife, a nurse practitioner who sees people with COVID remotely. Those symptoms include sore throat, headaches, body-wide muscle pain and severe cough. (The cough is triggered in part by sensory nerve cells in the lungs.)

Curiously, some patients report a loss of a particular sensation called chemethesis, which leaves them unable to detect hot chilies or cool peppermintsperceptions conveyed by nociceptors, not taste cells. While many of these effects are typical of viral infections, the prevalence and persistence of these pain-related symptomsand their presence in even mild cases of COVID-19suggest that sensory neurons might be affected beyond normal inflammatory responses to infection. That means the effects may be directly tied to the virus itself. Its just striking, Price says. The affected patients all have headaches, and some of them seem to have pain problems that sound like neuropathies, chronic pain that arises from nerve damage. That observation led him to investigate whether the novel coronavirus could infect nociceptors.

The main criteria scientists use to determine whether SARS-CoV-2 can infect cells throughout the body is the presence of angiotensin-converting enzyme 2 (ACE2), a protein embedded in the surface of cells. ACE2 acts as a receptor that sends signals into the cell to regulate blood pressure and is also an entry point for SARS-CoV-2. So Price went looking for it in human neurons in a study now published in the journal PAIN.

Nociceptorsand other sensory neuronslive in discreet clusters, found just outside the spinal cord, called dorsal root ganglia (DRG). Price and his team procured nerve cells donated after death or cancer surgeries. The researchers performed RNA sequencing, a technique to determine which proteins a cell is about to produce, and they used antibodies to target ACE2 itself. They found that a subset of DRG neurons did contain ACE2, providing the virus a portal into the cells.

Sensory neurons send out long tendrils called axons, whose endings sense specific stimuli in the body and then transmit them to the brain in the form of electrochemical signals. The particular DRG neurons that contained ACE2 also had the genetic instructions, the mRNA, for a sensory protein called MRGPRD. That protein marks the cells as a subset of neurons whose endings are concentrated at the bodys surfacesthe skin and inner organs, including the lungswhere they would be poised to pick up the virus.

Price says nerve infection could contribute to acute, as well as lasting, symptoms of COVID. The most likely scenario would be that the autonomic and sensory nerves are affected by the virus, he says. We know that if sensory neurons get infected with a virus, it can have long-term consequences, even if the virus does not stay in cells.

But, Price adds, it does not need to be that the neurons get infected. In another recent study, he compared genetic sequencing data from lung cells of COVID patients and healthy controls and looked for interactions with healthy human DRG neurons. Price says his team found a lot of immune-system-signaling molecules called cytokines from the infected patients that could interact with receptors on neurons. Its basically a bunch of stuff we know is involved in neuropathic pain. That observation suggests that nerves could be undergoing lasting damage from the immune molecules without being directly infected by the virus.

Anne Louise Oaklander, a neurologist at Massachusetts General Hospital, who wrote a commentary accompanying Prices paper in PAIN, says that the study was exceptionally good, in part because it used human cells. But, she adds, we dont have evidence that direct entry of the virus into [nerve] cells is the major mechanism of cellular [nerve] damage, though the new findings do not discount that possibility. It is absolutely possible that inflammatory conditions outside nerve cells could alter their activity or even cause permanent damage, Oaklander says. Another prospect is that viral particles interacting with neurons could lead to an autoimmune attack on nerves.

ACE2 is widely thought to be the novel coronaviruss primary entry point. But Rajesh Khanna, a neuroscientist and pain researcher at the University of Arizona, observes that ACE2 is not the only game in town for SARS-CoV-2 to come into cells. Another protein, called neuropilin-1 (NRP1), could be an alternate doorway for viral entry, he adds. NRP1 plays an important role in angiogenesis (the formation of new blood vessels) and in growing neurons long axons.

That idea came from studies in cells and in mice. It was found that NRP1 interacts with the viruss infamous spike protein, which it uses to gain entry into cells. We proved that it binds neuropilin and that the receptor has infectious potential, says virologist Giuseppe Balistreri of the University of Helsinki, who co-authored the mouse study, which was published in Sciencealong with a separate study in cells. It appears more likely that NRP1 acts as a co-factor with ACE2 than that the protein alone affords the virus entry to cells. What we know is that when we have the two receptors, we get more infection. Together, its much more powerful, Balistreri adds.

Those findings piqued the interest of Khanna, who was studying vascular endothelial growth factor (VEGF), a molecule with a long-recognized role in pain signaling that also binds to NRP1. He wondered whether the virus would affect pain signaling through NRP1, so he tested it in rats in a study that was also published in PAIN. We put VEGF in the animal [in the paw], and lo and behold, we saw robust pain over the course of 24 hours, Khanna says. Then came the really cool experiment: We put in VEGF and spike at the same time, and guess what? The pain is gone.

The study showed what happens to the neurons signaling when the virus tickles the NRP1 receptor, Balistreri says. The results are strong, demonstrating that neurons activity was altered by the touch of the spike of the virus through NRP1.

In an experiment in rats with a nerve injury to model chronic pain, administering the spike protein alone attenuated the animals pain behaviors. That finding hints that a spike-like drug that binds NRP1 might have potential as a new pain reliever. Such molecules are already in development for use in cancer.

In a more provocative and untested hypothesis, Khanna speculates that the spike protein might act at NRP1 to silence nociceptors in people, perhaps masking pain-related symptoms very early in an infection. The idea is that the protein could provide an anesthetic effect as SARS-CoV-2 begins to infect a person, which might allow the virus to spread more easily. I cannot exclude it, says Balistreri. Its not impossible. Viruses have an arsenal of tools to go unseen. This is the best thing they know: to silence our defenses.

It still remains to be determined whether a SARS-CoV-2 infection could produce analgesia in people. They used a high dose of a piece of the virus in a lab system and a rat, not a human, Balistreri says. The magnitude of the effects theyre seeing [may be due to] the large amount of viral protein they used. The question will be to see if the virus itself can [blunt pain] in people.

The experience of one patientRave Pretorius, a 49-year-old South African mansuggests that continuing this line of research is probably worthwhile. A motor accident in 2011 left Pretorius with several fractured vertebrae in his neck and extensive nerve damage. He says he lives with constant burning pain in his legs that wakes him up nightly at 3 or 4 A.M. It feels like somebody is continuously pouring hot water over my legs, Pretorius says. But that changed dramatically when he contracted COVID-19 in July at his job at a manufacturing company. I found it very strange: When I was sick with COVID, the pain was bearable. At some points, it felt like the pain was gone. I just couldnt believe it, he says. Pretorius was able to sleep through the night for the first time since his accident. I lived a better life when I was sick because the pain was gone, despite having fatigue and debilitating headaches, he says. Now that Pretorius has recovered from COVID, his neuropathic pain has returned.

For better or worse, COVID-19 seems to have effects on the nervous system. Whether they include infection of nerves is still unknown like so much about SARS-CoV-2. The bottom line is that while the virus apparently can, in principle, infect some neurons, it doesnt need to. It can cause plenty of havoc from the outside these cells.

Read more about the coronavirus outbreak from Scientific American here. And read coverage from our international network of magazines here.

Follow this link:
What We Know So Far about How COVID Affects the Nervous System - Scientific American