Researchers within the Biomedicine Discovery Institute at Monash University have made a breakthrough in understanding the role played by high-risk immune genes associated with the development of rheumatoid arthritis (RA).
The findings, published inScience Immunology, were the result of a seven-year collaboration led by Monash University, involving Janssen Research and Development, U.S. and the Karolinska Institute, Sweden.
Certain immune system genes, called Human Leukocyte antigen (HLA)-DR4, cause an increased susceptibility to RA. In this study, using mice genetically modified to express the human HLA-DR4 molecule, the team examined, at the molecular and cellular levels, how T cells recognise these HLA-DR4 molecules. The team also showed that highly similar T cell receptors, likely with similar recognition characteristics, are also present in "RA-susceptible" humans expressing these HLA molecules.
"This suggests that there may be an immune signature of RA development, providing a potential avenue for diagnostic development or a window of opportunity for therapeutic development," says Dr. Hugh Reid, who co-led the study with Professor Jamie Rossjohn and Professor Nicole La Gruta at Monash University.
With the assistance of the Australian Synchrotron, the researchers were able to determine the structure of the molecular complexes that form during the interaction between T cell receptors and altered joint proteins bound to HLA-DR4. Armed with this information, they were able to work out what was important in this deleterious T cell response.
"This research is an excellent example of how collaborative efforts between major academic and industrial partners can lead to breakthroughs in basic science that in turn provide avenues for the development of better therapeutics for common diseases," says Dr. Reid.
Rheumatoid arthritis is an autoimmune disease affecting about one percent of the world's population. It is characterised by swollen, painful, stiff joints, and consequently, restricted mobility in sufferers. By working out how T cells recognise altered joint proteins in complex with 'susceptibility' HLA molecules, Monash scientists have advanced our understanding of how these HLA molecules may predispose individuals to the development of disease. The insight provided may greatly assist in achieving the long-term goal of producing personalised medicines and/or preclinical interventions to treat RA.
Scientists at Sanford Burnham Prebys have identified a set of human genes that fight SARS-CoV-2 infection, the virus that causes COVID-19. Knowing which genes help control viral infection can greatly assist researchers' understanding of factors that affect disease severity and also suggest possible therapeutic options. The genes in question are related to interferons, the body's frontline virus fighters.
The study was published in the journal Molecular Cell.
"We wanted to gain a better understanding of the cellular response to SARS-CoV-2, including what drives a strong or weak response to infection," says Sumit K. Chanda, Ph.D., professor and director of the Immunity and Pathogenesis Program at Sanford Burnham Prebys and lead author of the study. "We've gained new insights into how the virus exploits the human cells it invades, but we are still searching for its Achille's heel so that we can develop optimal antivirals."
Soon after the start of the pandemic, clinicians found that a weak interferon response to SARS-CoV-2 infection resulted in some of the more severe cases of COVID-19. This knowledge led Chanda and his collaborators to search for the human genes that are triggered by interferons, known as interferon-stimulated genes (ISGs), which act to limit SARS-CoV-2 infection.
Based on knowledge gleaned from SARS-CoV-1, the virus that caused a deadly, but relatively brief, outbreak of disease from 2002 to 2004, and knowing that it was similar to SARS-CoV-2, the investigators were able to develop laboratory experiments to identify the ISGs that control viral replication in COVID-19.
"We found that 65 ISGs controlled SARS-CoV-2 infection, including some that inhibited the virus' ability to enter cells, some that suppressed manufacture of the RNA that is the virus's lifeblood, and a cluster of genes that inhibited assembly of the virus," says Chanda. "What was also of great interest was the fact that some of the ISGs exhibited control across unrelated viruses, such as seasonal flu, West Nile and HIV, which leads to AIDS."
"We identified eight ISGs that inhibited both SARS-CoV-1 and CoV-2 replication in the subcellular compartment responsible for protein packaging, suggesting this vulnerable site could be exploited to clear viral infection," says Laura Martin-Sancho, Ph.D., a senior postdoctoral associate in the Chanda lab and first author of this study. "This is important information, but we still need to learn more about the biology of the virus and investigate if genetic variability within these ISGs correlates with COVID-19 severity."
As a next step, the researchers will look at the biology of SARS-CoV-2 variants that continue to evolve and threaten vaccine efficacy. Martin-Sancho notes that they have already started gathering variants for laboratory investigation,
"It's vitally important that we don't take our foot off the pedal of basic research efforts now that vaccines are helping control the pandemic," concludes Chanda. "We've come so far so fast because of investment in fundamental research at Sanford Burnham Prebys and elsewhere, and our continued efforts will be especially important when, not if, another viral outbreak occurs."
Additional study authors include Lars Pache, Anshu P. Gounder, Courtney Nguyen, Yuan Pu, Heather M. Curry, Paul D. De Jesus, Ariel Rodriguez-Frandsen and Xin Yin at Sanford Burnham Prebys. Other authors include Mary K. Lewinski, Charlotte A. Stoneham, Aaron L. Oom, and John Guatelli at the University of California at San Diego and the VA San Diego Healthcare System; Mark Becker, Thomas J. Hope and Judd F. Hultquist at the Northwestern University Feinberg School of Medicine; Dexter Pratt, Christopher Churas, Sara B. Rosenthal, Sophie Liu, Fan Zheng, Max W. Chang, Christopher Benner, Trey Ideker and Alan M. O'Neill at the University of California San Diego; Lisa Miorin, Matthew Urbanowski, Megan L. Shaw and Adolfo García-Sastre at the Icahn School of Medicine at Mount Sinai; Stuart Weston and Matthew B. Frieman at the University of Maryland School of Medicine; and Chunxiang Wu and Yong Xiong at Yale University.
Laura Martin-Sancho, Mary K. Lewinski, Lars Pache, Charlotte A. Stoneham, Xin Yin, Mark E. Becker, Dexter Pratt, Christopher Churas, Sara B. Rosenthal, Sophie Liu, Stuart Weston, Paul D. De Jesus, Alan M. O’Neill, Anshu P. Gounder, Courtney Nguyen, Yuan Pu, Heather M. Curry, Aaron L. Oom, Lisa Miorin, Ariel Rodriguez-Frandsen, Fan Zheng, Chunxiang Wu, Yong Xiong, Matthew Urbanowski, Megan L. Shaw, Max W. Chang, Christopher Benner, Thomas J. Hope, Matthew B. Frieman, Adolfo García-Sastre, Trey Ideker, Judd F. Hultquist, John Guatelli, Sumit K. Chanda. Functional Landscape of SARS-CoV-2 Cellular Restriction. Molecular Cell, 2021; DOI: 10.1016/j.molcel.2021.04.008
Researchers have found a long-sought enzyme that prevents cancer by enabling the breakdown of proteins that drive cell growth, and that causes cancer when disabled.
Publishing online in Nature on April 14, the new study revolves around the ability of each human cell to divide in two, with this process repeating itself until a single cell (the fertilized egg) becomes a body with trillions of cells. For each division, a cell must follow certain steps, most of which are promoted by proteins called cyclins.
Led by researchers at NYU Grossman School of Medicine, the work revealed that an enzyme called AMBRA1 labels a key class of cyclins for destruction by cellular machines that break down proteins. The work finds that the enzyme's control of cyclins is essential for proper cell growth during embryonic development, and that its malfunction causes lethal cell overgrowth. Moreover, the study further suggests that an existing drug class may be able to reverse such defects in the future.
As in a developing fetus, restraints on cell division are central to the prevention of abnormal, aggressive growth seen in cancers, and the new study finds that cells have evolved to use AMBRA1 to defend against it.
"Our study clarifies basic features of human cells, provides insights into cancer biology, and opens new research avenues into potential treatments," says corresponding study author Michele Pagano, MD, chair of the Department of Biochemistry and Molecular Pharmacology at NYU Langone Health, and an investigator with the Howard Hughes Medical Institute.
New Tumor Suppressor
The current study addresses the three D-type cyclins, the subset that must link up with enzymes called cyclin-dependent kinases (CDKs), specifically CDK4 and CDK6, if cells are to divide. The authors found that AMBRA1, as a ligase, attaches molecular tags to all three D-type cyclins, labeling them for destruction. Previously proposed mechanisms for how D-type cyclins are eliminated by the cell could not be reproduced by the scientific community. Thus, prior to the new study, a central regulator of D-type cyclins had remained elusive for a quarter of a century, Pagano says.
The new work also revealed the role of AMBRA1 in development. Mice lacking the AMBRA1 gene, which codes for the AMBRA1 enzyme, developed uncontrolled, lethal tissue growth that distorted the developing brain and spinal cord. The researchers also found for the first time that treating with a CDK4/6 inhibitor pregnant mice carrying embryos without the AMBRA1 gene reduced these neuronal abnormalities.
In terms of cancer, the authors analyzed patient databases to conclude that those with lower-than-normal expression of AMBRA1 were less likely to survive diffuse large B-cell lymphoma, the most common form of non-Hodgkin lymphoma in the United States. The causes of lower expression of AMBRA1 may include random changes that delete the gene or make its encoded instructions harder to read.
To confirm the role of AMBRA1 as a tumor suppressor, the researchers monitored cancer cell growth in mouse models of diffuse large B-cell lymphoma, in collaboration with study author Luca Busino, PhD, at the University of Pennsylvania. When human B-cell lymphoma cells were transplanted into mice, for instance, tumors without the AMBRA1 gene grew up to three times faster than those with the gene. While the NYU Langone-led study looked at diffuse large B-cell lymphoma, two other studies led by Stanford University and the Danish Cancer Society Research Center, published in the same issue of Nature, found missing or disabled AMBRA1 to be a key factor in lung cancer.
Further, D-type cyclins are known to assemble with CDK4 and CDK6 into enzymes that encourage both normal and abnormal cell growth. Drugs that inhibit CDK4 and CDK6 have been FDA-approved in recent years as cancer therapies, but some patients have a weaker response to the drugs. Providing insight into this problem, the current team found that lymphomas lacking AMBRA1 are less sensitive to CDK4/6 inhibitors. When the AMBRA1 gene is missing, levels of D-type cyclins become high enough to form complexes with another CDK (CDK2), which, due to its structure, cannot be inactivated by CDK4/6 inhibitors.
"This makes AMBRA1 a potential marker for the selection of patients best suited for CDK4/6 inhibitor therapy," says first author Daniele Simoneschi, PhD, a senior research coordinator in the Department of Biochemistry and Molecular Pharmacology at NYU Langone Health. As a next step, he says the team plans to study the effect of combining CDK4/6 inhibitors with CDK2 inhibitors in tumors with low AMBRA1, as well as in those with mutations in D-type cyclins that make them insensitive to AMBRA1.
Daniele Simoneschi, Gergely Rona, Nan Zhou, Yeon-Tae Jeong, Shaowen Jiang, Giacomo Milletti, Arnaldo A. Arbini, Alfie O’Sullivan, Andrew A. Wang, Sorasicha Nithikasem, Sarah Keegan, Yik Siu, Valentina Cianfanelli, Emiliano Maiani, Francesca Nazio, Francesco Cecconi, Francesco Boccalatte, David Fenyö, Drew R. Jones, Luca Busino, Michele Pagano. CRL4AMBRA1 is a master regulator of D-type cyclins. Nature, 2021; DOI: 10.1038/s41586-021-03445-y
Michigan will expand its use of a COVID-19 treatment in the hopes of substantially reducing its rising numbers of hospitalizations and deaths, state officials announced Wednesday amid their efforts to bring down the nation’s highest infection rate.
Additional doses of monoclonal antibodies will be given to hospitals and other providers, which will be asked to expand the number of sites where patients can get infusions from the more than 70 that are operating in 37 of Michigan’s 83 counties.
The drugs, delivered intravenously and made by Regeneron Pharmaceuticals and Eli Lily, have concentrated doses of lab-made antibodies to fight COVID-19 and are geared toward people who are at high risk for severe symptoms or having to be hospitalized.
Gov. Gretchen Whitmer said the treatment could save lives, adding that it “very likely” helped then-President Donald Trump when he was infected last fall. People who qualify — an estimated 30% of infected residents — include seniors and those with preexisting or underlying health risks.
“If you are diagnosed with COVID, talk to a physician to see if you are eligible for this treatment,” the governor said. “Time is of the essence with these therapeutics. The sooner you receive them after you test positive, the more effective they will be.”
More than 6,600 residents have been treated with the drugs since they were approved for emergency use in November, with 65% reporting they felt better within two days and less than 5% requiring hospitalization. Whitmer said her administration also was working with the federal government to add doses of remdesivir, an antiviral medicine given to hospitalized patients through an IV.
The state health department on Wednesday reported nearly 8,000 additional COVID-19 cases and 33 deaths from the disease. The number of hospitalized adults with confirmed cases, about 4,000, dipped slightly but remained near the state’s record high. Some hospitals reported being at or near capacity. Case rates and positivity rates have quintupled since mid-February.
The seven-day average of daily confirmed and probable cases was highest for people ages 20 to 39. Hospitalizations were highest among 50- to 69-year-old residents.
“Patients are again lining our hallways like they were last spring. This situation is very serious,” said Dr. Joneigh Khaldun, the state’s chief medical executive and an emergency room doctor in Detroit. “We need to be using every tool in our toolbox right now to get these cases and hospitalizations down.”
She asked every doctor in Michigan to check whether their COVID-19 patients are eligible for the antibody treatment.Whitmer, a Democrat, continued to push vaccines and masks — not tougher restrictions — as the way out. At least 42% of residents ages 16 and up have received at least one dose. Earlier this week, the director of the Centers for Disease Control and Prevention said Michiganshould “close things down”to address the outbreak.
Republicans who have criticized the governor for limits on business capacity and gathering sizes supported her for not tightening them. In a tweet, Senate Majority Leader Mike Shirkey, of Clarklake, applauded Whitmer “for resisting the tremendous pressure to lock our state down and trusting Michiganders to do the right thing.”
In Detroit, Mayor Mike Duggan made a desperate plea to residents to get vaccinated. He said the seven-day positive rate climbed this week to 20.7% compared to 3.5% in mid-March.
“The worst is still ahead of us,” Duggan said.
He displayed a photo of suburban residents in Sterling Heights willing to stand in rain for three hours last week to get a shot. Duggan reminded Detroiters that there was immediate access to drive-up vaccinations at a convention center as well as neighborhood clinics at schools.
About 24% of Detroit residents 16 or older have at least one dose, well below suburban and statewide results. Duggan said his staff is considering whether incentives offered by companies to get people vaccinated would help.
Taiwan has beenwidely applaudedfor its management of the pandemic, with one of the lowest per capita COVID-19 rates in the world and life on the island largely returning to normal.
Just 11 people have died from COVID-19 in Taiwan since the pandemic began, an impressive feat for a country that never went into lockdown.
At the start of the pandemic, Taiwan was considered a high-risk country for COVID-19 due to its proximity to China and the frequent travel that takes place between the two countries.
A new study in the Journal of the American Medical Association has examined further just why Taiwan did so well at conquering COVID-19. The study’s authors, from a range of health institutes and hospitals in Taiwan and the US, compared the estimated effectiveness of two types of COVID-19 policy in the early months of the pandemic: case-based and population-based measures.
Case-based measures include the detection of infected people through testing, isolation of positive cases, contact tracing and 14-day quarantining of close contacts. The population-based measures included face mask policies, personal hygiene and social distancing.
The effects of these policies were quantified by estimating the effective reproduction number (R number).
The R number is a way of rating an infectious disease’s ability to spread – it represents the average number of people that one infected person will pass a virus onto. An R number of greater than 1 means the virus will continue to spread and outbreaks will continue. An R number below 1 means that case numbers will start to reduce.
While previous studies in other countries have simulated hypothetical scenarios, this paper combined transmission modelling with detailed real data to estimate effectiveness.
Taiwan combined case-based policies like quarantine with population polices like masking to fight COVID-19.David Chang
The authors collected data on 158 cases between January 10 and June 1 2020 from the Taiwan Centers for Disease Control, and all cases were confirmed by PCR testing. The data related to locally acquired cases, confirmed clusters, and imported cases in people who entered Taiwan before March 21 2020.
They then compared the outcomes they found in Taiwan with an estimated R number of 2.5, based on the estimated equivalent number in nearby China at the beginning of its COVID-19 outbreak.
The winning combination
The study found that the case-based policies alone, like contact tracing and quarantining, could lower the R number from 2.5 to 1.53. Quarantine contributed the most to lowering the R number.
Case-based interventions could not substantially prevent transmission from one person to another, but could reduce transmission onwards from those secondary cases to a third or fourth person, as long as close contacts quarantined.
Population-based policies like social distancing and face masks, meanwhile, reduced the R number from 2.5 to 1.3.
The authors concluded that it was the combination of case-based and population-based policies, along with widespread adherence, that led to Taiwan’s success in containing COVID. Combining both approaches led to an R number estimated using two different methods to be 0.82 and as low as 0.62. They also found that considerable population-based policies were needed to achieve containment even though the number of circulating infections was small.
Neither approach would have been sufficient alone, even in a country with an effective public health system and sophisticated contact tracing.
What does this mean for other countries?
Acknowledging that all models make assumptions, and this analysis is no different, this paper does confirm that the full suite of public health measures we have been using fairly consistently across the world – to varying degrees of length and stringency – have been necessary. Though it’s worth noting that the results in the study reflects a time when new variants with greater transmissibility were not a problem.
Taiwan was reporting zero COVID cases as early as April 2020.David Chang/EPA
The authors assumed that testing and isolation occurred simultaneously. This was the case in Taiwan, but not in other countries, for example England, where delays between testing, results and isolation diminish the effectiveness of case-based measures.
Taiwan is an island nation with the ability to control the introduction of new cases through border control, and the authors acknowledge the findings of this study may not be fully applicable to other countries. This is the reason the authors focused on the effectiveness of case-based and population-based interventions on local transmission, rather than on border controls on the number of introductions of COVID-19.
The authors conclude that intensive contact tracing is not possible when public health systems are overwhelmed. This never happened in Taiwan due to the success of its strategies, but it did, for example, take place in Ireland in January 2021, which experienced a damaging third wave of COVID-19.
This paper also found similar results for seven-day and 14-day quarantine and suggest that the quarantine period could be shortened. This is being considered by some countries, including the USA, but it has not been introduced on a widespread basis to date.
We already knew there was much to be learned from Taiwan’s success in preventing COVID-19 from taking hold. Now, as vaccines roll out and new variants emerge, we have more information about the comparative and combined contributions of public health measures.
Full Professor of Epidemiology & Biomedical Statistics, University College Dublin
Disclosure statement
Patricia Fitzpatrick does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.
Thecoronavirus crisishas had a devastating impact on many families’ finances.
And some students were forced to sacrifice college as a result.
One quarter of last year’s high-school graduates delayed their college plans, according to a survey from Junior Achievement and Citizens, largely because their parents or guardians were less able to provide financial support due to the pandemic.
The survey polled 2,000 teenagers in the U.S. between the ages of 13 and 19 who are not in college and 500 teens who graduated high school in 2020.
Increasingly, the sky-high price is the problem.
Students and their families are starting to question the return on investment, saidJack Kosakowski, president and CEO of Junior Achievement.
“We’ve had this ‘college thing’ up on a pedestal,” he said. “As costs have gone up, it’s forcing people to take a more realistic view.”
A separate survey of high school students found that the likelihood of attending a four-year school sank nearly 20% in less than a year — down to 53%, from 71%, according to ECMC Group, a nonprofit aimed at helping student borrowers.
High schoolers are putting more emphasis on career training and post-college employment, the report found.
More than half said they can achieve professional success with three years or less of college, and just one-fourth believe a four-year degree is the only route to a good job. ECMC Group polled more than 1,000 high school students three times over the last year.
“There are phenomenal opportunities for people to build great careers that may not be a full four-year degree and you don’t have to borrow $100,000,” said Christine Roberts, the head of student lending at Citizens.
But students are not choosing these programs, either.
For starters, community college is significantly less expensive. At two-year public schools, tuition and fees are $3,770 for the 2020-2021 school year, according to the College Board. Alternatively, at in-state four-year public schools, tuition is $10,560 and at four-year private universities it averages $37,650.
A two-year program is not necessarily an alternative to a four-year degree. Increasingly, students transfer from community college to a four-year school to keep costs down.
Today, about half of all bachelor’s degree earners began their education at a community college, according to data from the National Student Clearinghouse Research Center.
Community college enrollment spiked during the last recession, but as the economy improved, enrollments steadily declined every year since, according to Martha Parham, senior vice president of public relations at the American Association of Community Colleges.
This time, in the aftermath of the Covid outbreak and the economic shock that followed, even fewer students enrolled.
Across the board, community college enrollment fell roughly 10%, according to Thomas Brock, director of the Community College Research Center, or CCRC. Although for some groups, including Black men, enrollment sank more than 20%.
“This is a trend that alarms everyone,” he said.
Community college students likely are older, lower-income and often balancing work, children and other obligations. They are also disproportionately students of color — all groups that the pandemic hit especially hard.
The Junior Achievement report found that 60% of Black and 59% of Hispanic teens in 11th or 12th grade said that Covid affected how they will pay for college, compared to 45% of white teenagers.
“If you look at our students and who we serve, you can extrapolate that they have challenges,” Parham said.
When these students drop out, it is even harder to them get back on track, she added. Community colleges don’t have the same resources for outreach, Parham said. “That becomes a challenge.”
Although early indicators show four-year college enrollment will bounce back in the coming year, it’s too soon to tell if community college students will also return.
Since community colleges are open access, students can sign up for classes right up until the start of the semester, or even later, Brock said. “We won’t know until early fall.”
If students forgo this pathway to a career or a four-year degree, it could have dramatic consequences for their upward mobility, according to Barbara Mistick, president of the National Association of Independent Colleges and Universities.
“The higher education experience is a great equalizer,” she said.
In fact, studies show that postponing a higher education has a steep economic cost.
The earnings gap experienced by delayers compared with on-time enrollees is at least $41,000 in the first 13 years after high school graduation, according to a report by the Community College Research Center. The lifetime penalty is at least three times higher.
Of course, those who put college on hold are less likely to return at all.
Historically, only 13% of college dropouts come back within five years, a separate National Student Clearinghouse report found, and even fewer graduate.
Talaris Therapeutics, a phase 3 biotech developing methods for allogeneic hematopoietic stem cell transplantation, filed on Friday with the SEC to raise up to $100 million in an initial public offering.
Talaris Therapeutics is a late-clinical stage, cell therapy company developing methods of allogeneic hematopoietic stem cell transplantation (allo-HSCT) that are aimed to transform the standard of care in solid organ transplantation, certain severe autoimmune diseases, and certain severe non-malignant blood, immune, and metabolic disorders. The company's initial focus is a proprietary therapeutic approach called Facilitated Allo-HSCT Therapy that could prevent organ rejection without the morbidity and mortality that has been associated with the use of lifelong anti-rejection medicines. The lead product candidate, FCR001, is a novel allogeneic cell therapy comprised of stem and immune cells that are procured from a healthy donor, who is also the organ donor in the case of organ transplantation. Patients are currently being enrolled in FREEDOM-1, a randomized, controlled, open-label Phase 3 registration trial in the US of FCR001 in 120 adult living donor kidney transplant (LDKT) recipients.
The Louisville, KY-based company was founded in 2002 and plans to list on the Nasdaq under the symbol TALS. Talaris Therapeutics filed confidentially on February 26, 2021. Morgan Stanley, SVB Leerink, Evercore ISI and Guggenheim Securities are the joint bookrunners on the deal. No pricing terms were disclosed.
