Publisher Health

McGill University researchers identify proteins that drive cancer stem cells. Targeting and supressing a particular protein called galectin1 could provide a more effective treatment for glioblastoma, in combination with radiation therapy.
Due to its resistance to therapy, glioblastoma is the most common and aggressive cancerous brain tumour in adults. It grows fast and spreads quickly. While treatments such as surgery, radiation, and chemotherapy can help ease symptoms for a few months, in most cases tumour cells regrow after treatment and the cancer recurs.
According to the researchers, no matter how low the weeds are cut, if the roots are not pulled out, the weeds will just grow back.
Getting to the root of the problem
Among all cancerous cells, some act as stem cells that reproduce themselves and sustain the cancer, much like normal stem cells typically renew and sustain our organs and tissues, say the researchers. By targeting the way the cells operate, they discovered a new way to disrupt the production of new tumours.
“What we found was really astonishing for us. After we inhibited the galectin1 protein, the brain tumours simply didn’t grow for several months,” says Arezu Jahani-Asl, an Associate Professor of Medicine at McGill University. “To improve patient response to therapy, we must exploit these newly identified vulnerabilities in cancer stem cells.”
The researchers discovered that a protein called galectin1 interacts with another protein called HOXA5 to control the genetic programs that drive cancer stem cell behaviour. By supressing galectin1 in preclinical models, they found a significant improvement in tumour response to radiation therapy, resulting in expanded lifespan.
The researchers also analyzed patient databases and found that glioblastoma patients with low expression of galectin1 and HOXA5 proteins had the best prognosis. Together, these proteins along with another called STAT3 activate mechanisms that promote a particularly aggressive type of glioblastoma.
Paving the way for new therapies
The discovery sheds light on the mechanisms that regulate cancer stem cells. The findings provide evidence that targeting galectin1 protein, in combination with radiation therapy, can pave the way for future clinical trials to treat glioblastoma tumours. The next step is to compare the effectiveness of different approaches to supressing the galectin1 and HOXA5 complex in the brain, with advances in gene therapy through CRISPR technology.
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A rare but serious inflammatory condition that affects children who contract COVID-19 produces a distinctive pattern of biomarkers that may help physicians predict disease severity and also aid researchers in developing new treatments, according to a study led by Cedars-Sinai.
The study focused on multisystem inflammatory syndrome in children (MIS-C), an inflammatory response involving multiple organs that can occur weeks after infection with SARS-CoV-2, the virus that causes COVID-19. Although most patients improve with medical care, more than half the MIS-C cases in the U.S. require ICU admission, and the condition can be deadly.
A total of 4,404 MIS-C cases and 37 fatalities in the U.S. had been reported to the federal Centers for Disease Control and Prevention as of Aug. 15. The median age of MIS-C patients was 9 years, and more than 60% of the cases were in Black or Latinx children, according to the report.
“It is crucial to improve our understanding of MIS-C in the current environment, given reports of rising rates of children being hospitalized with COVID-19 in the U.S. and the return of many students to school for the fall term,” said Moshe Arditi, MD, director of the Pediatric Infectious Diseases Division at Cedars-Sinai. “The disproportionate impact of MIS-C related to race and ethnicity is especially troubling.”
Arditi, professor of pediatrics and the GUESS?/Fashion Industries Guild Chair in Community Child Health, is co-senior author of the new study, published in the peer-reviewed Journal of Clinical Investigation. The other co-senior authors are Jennifer Van Eyk, PhD, director of the Advanced Clinical Biosystems Research Institute in the Smidt Heart Institute at Cedars-Sinai, and Mascha Binder, MD, from Martin Luther University Halle-Wittenberg in Germany.
The investigators examined a small group of patients to identify an array of pathogenic pathways culminating in MIS-C, along with proteins in the blood with potential to act as biomarkers to forecast the severity of the syndrome and help drive treatment decisions.

About one-fourth of people with diabetes develop painful foot ulcers, which are slow to heal due to low oxygen in the wound from impaired blood vessels and increased inflammation. These wounds can become chronic, leading to poor quality of life and potential amputation.
Jianjun Guan, a professor of mechanical engineering & materials science in the McKelvey School of Engineering at Washington University in St. Louis, has developed a hydrogel that delivers oxygen to a wound, which decreases inflammation, helps remodel tissue and accelerates healing. Results of the work, which were in a mouse model, are published Aug. 28 in Science Advances. Ya Guan, a doctoral student, and Hong Niu, a postdoctoral research associate, both in Guan’s lab, are co-first authors.
“The oxygen has two roles: one, to improve skin cell survival under the low-oxygen condition of the diabetic wound; and two, oxygen can stimulate the skin cells to produce growth factors necessary for wound repair,” Guan said.
Tissues in the body require oxygen to survive and need even more when tissue is injured. While there are several existing treatments for chronic wounds in people with diabetes, the most common treatment is dozens of sessions in a hyperbaric oxygen chamber, but its effectiveness is inconsistent and includes the risk of oxygen toxicity.
Guan’s hydrogel delivers oxygen to the wound using microspheres that gradually release oxygen to interact with the cells through an enzyme on their surface that converts what is inside of the microsphere into oxygen. The oxygen is delivered to the wound over about a two-week period, and inflammation and swelling decrease, prompting healing.
In the mice, wounds treated with the hydrogel containing the oxygen-releasing microspheres had a greater rate of closure than wounds treated with only the gel or those with no treatment. By day 16, the wounds treated with the hydrogel had reduced to 10.7%. Those treated with the gel only were reduced to 30.4%, and those with no treatment had reduced to 52.2%.

Sequential treatment using antibiotics that are similar but swapped around frequently is an effective way to kill bacteria and prevent drug resistance, a study in eLife reports.
The results challenge a broad assumption that using similar antibiotics promotes cross-resistance to drugs, and show that available antibiotics could offer unexplored, highly potent treatment options.
“We are currently in an antibiotic crisis, where the overuse of antibiotics is leading to increased antibiotic resistance and certain infections have become difficult and even impossible to treat,” says first author Aditi Batra, a graduate student at the Max Planck Institute for Evolutionary Biology and the University of Kiel, Germany. “It is the ability of pathogens to evolve and adapt to drugs that underlies this resistance, but evolutionary theory predicts that adaptation is difficult when the environment changes rapidly. We wanted to test if we could use sequential antibiotic treatment to slow down the evolution of human pathogens and limit drug resistance.”
The team used bacteria called Pseudomonas aeruginosa (P. aeruginosa), which can cause pneumonia and other infections in humans. They tested three different sequences of antibiotics under laboratory conditions and measured their potency at killing off different sub-populations of evolved bacterial cells. Two sets of antibiotics belonged to a class of drugs called β-lactams, which have a common structural component — a β-lactam ring. The other set of antibiotics all worked by different mechanisms.
To the team’s surprise, treatment with both sets of β-lactam antibiotics was better at killing off bacterial populations than some of the unrelated antibiotics. Moreover, switching rapidly between the individual antibiotics produced much better extinction of bacterial populations than when the switch between antibiotics was slower. This suggests that fast switching between antibiotics constrained the bacteria’s ability to adapt to the drugs. Given this unexpected result, the team explored the mechanisms that cause this evolutionary constraint.
They studied the changes in growth, resistance profiles and whole genome sequences of the P. aeruginosa populations treated with the most potent sequence of β-lactam antibiotics, which combined carbenicillin, doripenem and cefsulodin. They noted that when the sequences were switched quickly, bacterial growth during a switch to doripenem was much lower than for the other two antibiotics, indicating that resistance to this drug might emerge more slowly.
They also looked at whether physiological changes that occur as a result of drug treatment made the bacteria resistant or more susceptible to the other drugs in the sequence. They found that spontaneous development of resistance was much lower for doripenem than the other two drugs. There was also less cross-resistance towards this drug than the other two antibiotics. This lack of cross-resistance may indicate the presence of so-called collateral sensitivity; this means that the mutant cells, which have become resistant to one drug, maintain at least ancestral levels of susceptibility against the second drug. Collateral sensitivity is known to be important for the effectiveness of sequential treatment.
“Although sequential treatments with such similar antibiotics should have sped up resistance evolution, we found this is not the case if resistance to one of the antibiotics cannot emerge easily, and if the antibiotics show collateral sensitivity to each other,” says senior author Hinrich Schulenburg, Fellow of the Max Planck Institute for Evolutionary Biology and Professor at the University of Kiel. “It is ironic that the differential cross-resistance profile of the β-lactam drugs was a key factor to treatment potency, even though this is usually used to reject treatment that exclusively uses these drugs. Our study shows that spontaneous resistance rates of component antibiotics could be used as a guiding principle for sequential treatments and could improve the potency of sequential protocols.”
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Therapies should be highly effective and as free as possible of side effects — a big challenge, particularly in the case of cancer. A Chinese research team has now developed a novel form of photodynamic tumor therapy for the treatment of deep tumors that works without external irradiation. The light source is built into the drug and is “switched on” selectively in the microenvironment of tumors, as they report in the journal Angewandte Chemie.
Classic photodynamic therapy is a noninvasive cancer treatment that is relatively gentle because of its specific spatial and temporal selectivity. To start with, a photosensitizer is administered, then the region where the tumor is located is irradiated with light. The photosensitizer is excited by the light and transfers some of the absorbed energy to oxygen molecules, resulting in reactive oxygen species that destroy tumor cells. Because of the limited depth of penetration of the necessary visible or UV light in tissues, this method is only useful for shallow tumors.
A team led by Xiaolian Sun (China Pharmaceutical University, Nanjing) and Guoqiang Shao (Nanjing Medical University) has now developed a new photodynamic tumor therapy that works for deep tumors. It does not need external irradiation because the photosensitizer brings its own “lamp” along and “switches it on” on its own once it reaches the tumor.
This “intelligent” drug consists of four components linked into a single molecule: a photosensitizer (pyropheophorbide-a), a pH sensor (diisopropylamino group), a polymer (polyethylene glycol), and the “lamp” (the amino acid tyrosine carrying a radioactive iodine-131 isotope). At the pH values found in healthy tissues, the molecules are tightly aggregated into nanoparticles. In this compact form, the “irradiation” is switched off (quenched) and the drug has no effect. However, tumorous tissue has a somewhat more acidic pH value. This environment causes the pH sensor to change structure, and the nanoparticles fall apart — the irradiation is switched on, and reactive oxygen species are formed that kill the tumor cells.
How does this “built-in light” work? As it decays, the radioactive iodine isotope I-131 releases β-radiation (electrons) and γ-radiation. As the electrons move, their charges polarize atoms, thereby causing dipole oscillations that send out electromagnetic waves, which means light. Usually, these waves cancel one another immediately. Yet, in the dense aqueous environment of the cells (other than in vacuo), the electrons sent out by I-131 are faster than light. In this case, the quenching of the waves is incomplete, resulting in a bluish light known as Cherenkov radiation. This excites the photosensitizers enough to destroy tumor cells. In cell cultures and animal models, the new drug demonstrated powerful tumor inhibition with low toxicity and minimal side effects on healthy tissue.
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As several Republican-controlled states confront their worst outbreaks yet, their leaders — following the base — have doubled down on resisting vaccine and mask requirements.As a new coronavirus wave accelerated by the Delta variant spreads across the United States, many Republican governors have taken sweeping action to combat what they see as an even more urgent danger posed by the pandemic: the threat to personal freedom.In Florida, Ron DeSantis has prevented local governments and school districts from enacting mask mandates and battled in court over compliance. In Texas, Greg Abbott has followed a similar playbook, renewing an order last week to ban vaccine mandates.And in South Dakota, Kristi Noem, who like Mr. DeSantis and Mr. Abbott is a potential 2024 candidate for president, has made her blanket opposition to lockdowns and mandates a key selling point. Arriving by horseback and carrying the American flag, she advertised the state’s recent Sturgis Motorcycle Rally, which drew half a million people, as a beacon of liberty.Ms. Noem brushed aside criticism from Democrats and public health experts about the gathering, which was followed by a local Covid spike, saying on Fox News that the left was “accusing us of embracing death when we’re just allowing people to make personal choices.”The actions of Republican governors, some of the leading stewards of the country’s response to the virus, reveal how the politics of the party’s base have hardened when it comes to curbing Covid. As some Republican-led states, including Florida, confront their most serious outbreaks yet, even rising death totals are being treated as less politically damaging than imposing coronavirus mandates of almost any stripe.“Freedom is good policy and good politics,” Senator Ted Cruz, a Texas Republican and ally of Mr. Abbott’s who has introduced federal legislation to end mask decrees and to forbid federal vaccine passports, said in an interview.Mr. DeSantis has become a symbolic face of the battle, as President Biden has urged Republican governors opposed to mandates to at least “get out of the way.” This week, Mr. DeSantis’s education commissioner withheld funds from two school districts that made masks mandatory.Most top Republicans, including every Republican governor, have been vaccinated and have encouraged others to do so. But most have also stopped short of supporting inoculation requirements and have opposed masking requirements.In many ways, Republican leaders are simply following Republican voters.Skepticism about masks, vaccines and the rules governing them is increasingly intertwined with the cultural issues that dominate the modern Republican Party. The fear over losing “medical freedom” has become part of the broader worry that “cancel culture” is coming for conservatives’ way of life.And while opposing pandemic edicts is a limited-government stance, the forceful approach of governors is at odds with the long-held principle of local control, making it the latest Republican Party orthodoxy to be cast aside since the beginning of the Trump era, along with free trade and limited spending.Gov. Ron DeSantis of Florida wants to open antibody treatment sites for those who contract the coronavirus.Andrew West/The News-Press, via Associated PressThe intensifying conservative mistrust of the news media and opposition to the directives of elite institutions and experts — Dr. Anthony S. Fauci is now so reviled by some that Mr. DeSantis sold merchandise saying “Don’t Fauci My Florida” — have cleaved the country into two factions guided by alternative sets of beliefs.One outlier among Republican governors is Larry Hogan, a moderate who leads Democratic-dominated Maryland. He recently required that hospital and nursing home employees be vaccinated.“Frankly, it’s confusing to me as to why some of my colleagues are mandating why you can’t wear masks, or mandating that businesses can’t make their own decisions about vaccines, or mandating that school systems can’t make decisions for themselves,” Mr. Hogan said in an interview. “And then they’re talking about freedom? It just doesn’t make sense to me.”The pandemic, public health officials say, is now largely one of the unvaccinated, and the virus is raging particularly in conservative states with far lower inoculation rates and more relaxed attitudes toward group gatherings. Of the 10 states with the most cases per capita in recent days, nine voted Republican in last year’s presidential race and nine are led by Republican governors, according to The New York Times coronavirus database.Republican leaders’ posture, particularly on keeping schools from requiring masks, does not appear popular across the wider electorate. In Florida, a Quinnipiac poll released last week found that 60 percent of residents supported compulsory masks in schools.But among Republicans, that figure was inverted: 72 percent of Mr. DeSantis’s party said they opposed universal masking requirements in schools. The poll showed that a plurality of Republicans in the state also opposed a mask requirement for health care workers, a measure that is popular among independents.“Many Republicans are out on an island by themselves,” said Whit Ayres, a veteran G.O.P. pollster. “It may be a safe political place for some primary electorates at the moment. But ultimately you have to win a general election.”Governors nationwide almost uniformly reject the idea that political considerations have shaped their Covid policies. “Politics have played no role,” said Ian Fury, a spokesman for Ms. Noem.Gov. Kristi Noem of South Dakota attended the recent Sturgis Motorcycle Rally, which drew half a million people and was followed by a spike in local Covid cases.Scott Olson/Getty ImagesThe offices of Mr. DeSantis, Mr. Abbott, Ms. Noem and other Republican governors did not make them available for comment. But advisers to multiple Republican governors said the widespread distribution of vaccines had changed the governing calculus when it came to masks and shutdowns. Both Mr. DeSantis and Mr. Abbott have focused on opening antibody treatment sites for those who contract the virus.As Florida became the first state to reach a new peak in deaths since vaccines became freely available, Mr. DeSantis has remained steadfast in keeping schools from requiring masks without a parental opt-out.“We say unequivocally no to lockdowns, no to school closures, no to restrictions and no to mandates,” Mr. DeSantis said at a conservative conference in July.These choices by governors carry a range of risks.One Republican strategist privately lamented, only half-jokingly, that the party was going to kill off part of its own base with its vaccine hesitancy. Former President Donald J. Trump recently told donors at a New York Republican Party fund-raiser that he hoped his supporters would get vaccinated because “we need our people,” according to two attendees.Even Mr. Trump is not immune from blowback, however. He received a rare rebuke from his base at an August rally in Alabama after he urged people to get vaccinated. “Take the vaccines,” he said. “I did it. It’s good.”Some in the crowd began to jeer; Mr. Trump appeared to soften his stance.“That’s OK, that’s all right,” he said. “You got your freedoms, but I happened to take the vaccine.”Mr. Trump’s political operation has clearly assessed where his base stands. “FREEDOM PASSPORTS > VACCINE PASSPORTS,” read one recent fund-raising text, selling $45 American flag shirts that declare, “This is my freedom passport.”.css-1xzcza9{list-style-type:disc;padding-inline-start:1em;}.css-3btd0c{font-family:nyt-franklin,helvetica,arial,sans-serif;font-size:1rem;line-height:1.375rem;color:#333;margin-bottom:0.78125rem;}@media (min-width:740px){.css-3btd0c{font-size:1.0625rem;line-height:1.5rem;margin-bottom:0.9375rem;}}.css-3btd0c strong{font-weight:600;}.css-3btd0c em{font-style:italic;}.css-w739ur{margin:0 auto 5px;font-family:nyt-franklin,helvetica,arial,sans-serif;font-weight:700;font-size:1.125rem;line-height:1.3125rem;color:#121212;}#NYT_BELOW_MAIN_CONTENT_REGION .css-w739ur{font-family:nyt-cheltenham,georgia,’times new roman’,times,serif;font-weight:700;font-size:1.375rem;line-height:1.625rem;}@media (min-width:740px){#NYT_BELOW_MAIN_CONTENT_REGION .css-w739ur{font-size:1.6875rem;line-height:1.875rem;}}@media (min-width:740px){.css-w739ur{font-size:1.25rem;line-height:1.4375rem;}}.css-9s9ecg{margin-bottom:15px;}.css-16ed7iq{width:100%;display:-webkit-box;display:-webkit-flex;display:-ms-flexbox;display:flex;-webkit-align-items:center;-webkit-box-align:center;-ms-flex-align:center;align-items:center;-webkit-box-pack:center;-webkit-justify-content:center;-ms-flex-pack:center;justify-content:center;padding:10px 0;background-color:white;}.css-pmm6ed{display:-webkit-box;display:-webkit-flex;display:-ms-flexbox;display:flex;-webkit-align-items:center;-webkit-box-align:center;-ms-flex-align:center;align-items:center;}.css-pmm6ed > :not(:first-child){margin-left:5px;}.css-5gimkt{font-family:nyt-franklin,helvetica,arial,sans-serif;font-size:0.8125rem;font-weight:700;-webkit-letter-spacing:0.03em;-moz-letter-spacing:0.03em;-ms-letter-spacing:0.03em;letter-spacing:0.03em;text-transform:uppercase;color:#333;}.css-5gimkt:after{content:’Collapse’;}.css-rdoyk0{-webkit-transition:all 0.5s ease;transition:all 0.5s ease;-webkit-transform:rotate(180deg);-ms-transform:rotate(180deg);transform:rotate(180deg);}.css-eb027h{max-height:5000px;-webkit-transition:max-height 0.5s ease;transition:max-height 0.5s ease;}.css-6mllg9{-webkit-transition:all 0.5s ease;transition:all 0.5s ease;position:relative;opacity:0;}.css-6mllg9:before{content:”;background-image:linear-gradient(180deg,transparent,#ffffff);background-image:-webkit-linear-gradient(270deg,rgba(255,255,255,0),#ffffff);height:80px;width:100%;position:absolute;bottom:0px;pointer-events:none;}.css-uf1ume{display:-webkit-box;display:-webkit-flex;display:-ms-flexbox;display:flex;-webkit-box-pack:justify;-webkit-justify-content:space-between;-ms-flex-pack:justify;justify-content:space-between;}.css-wxi1cx{display:-webkit-box;display:-webkit-flex;display:-ms-flexbox;display:flex;-webkit-flex-direction:column;-ms-flex-direction:column;flex-direction:column;-webkit-align-self:flex-end;-ms-flex-item-align:end;align-self:flex-end;}.css-12vbvwq{background-color:white;border:1px solid #e2e2e2;width:calc(100% – 40px);max-width:600px;margin:1.5rem auto 1.9rem;padding:15px;box-sizing:border-box;}@media (min-width:740px){.css-12vbvwq{padding:20px;width:100%;}}.css-12vbvwq:focus{outline:1px solid #e2e2e2;}#NYT_BELOW_MAIN_CONTENT_REGION .css-12vbvwq{border:none;padding:10px 0 0;border-top:2px solid #121212;}.css-12vbvwq[data-truncated] .css-rdoyk0{-webkit-transform:rotate(0deg);-ms-transform:rotate(0deg);transform:rotate(0deg);}.css-12vbvwq[data-truncated] .css-eb027h{max-height:300px;overflow:hidden;-webkit-transition:none;transition:none;}.css-12vbvwq[data-truncated] .css-5gimkt:after{content:’See more’;}.css-12vbvwq[data-truncated] .css-6mllg9{opacity:1;}.css-qjk116{margin:0 auto;overflow:hidden;}.css-qjk116 strong{font-weight:700;}.css-qjk116 em{font-style:italic;}.css-qjk116 a{color:#326891;-webkit-text-decoration:underline;text-decoration:underline;text-underline-offset:1px;-webkit-text-decoration-thickness:1px;text-decoration-thickness:1px;-webkit-text-decoration-color:#326891;text-decoration-color:#326891;}.css-qjk116 a:visited{color:#326891;-webkit-text-decoration-color:#326891;text-decoration-color:#326891;}.css-qjk116 a:hover{-webkit-text-decoration:none;text-decoration:none;}In Arkansas, Gov. Asa Hutchinson, a Republican, saw his party’s pushback firsthand on a 16-stop tour to promote vaccination.Mr. Hutchinson signed a law this spring banning mask mandates, but with cases rising again this month, he said he regretted it. In Siloam Springs, he was pelted with questions from frustrated constituents, including one woman who told him that she had been “praying that God himself will step in so that Christians are not forced by their employers and a mandate to get the vaccine.”“Yet even if God does not, I will not bow,” she said to raucous cheers.Gov. Asa Hutchinson of Arkansas spoke about the state’s high hospitalization rates during a news conference in late July.Andrew Demillo/Associated PressThen there is Ms. Noem, who last month accused other Republican governors of “pretending they didn’t shut down their states, that they didn’t close their regions, that they didn’t mandate masks.” The remarks were widely interpreted to be aimed at potential 2024 rivals.Mr. Cruz, who ran for president in 2016 and could again in 2024, predicted a reckoning for politicians, including Republicans, who had embraced pandemic edicts. “There’s a range of politicians in terms of how long they shut things down,” he said. “In my view, the shorter the better. But that will certainly be a legitimate topic for discussion and debate.”Mr. Ayres, the Republican pollster, said that governors trying to control the virus policies of schools, employers and local officials were breaking with years of tradition on free enterprise and local control.“Liberty has never meant the freedom to threaten the health” of others, Mr. Ayres said. “That is a perversion of the definition of liberty and freedom.”Some governors who imposed mandates and lockdowns last year have even been targeted by state legislators who want to trim their powers.In Ohio, the G.O.P.-controlled Legislature overrode a veto by Gov. Mike DeWine, a fellow Republican, of legislation that reined in his administration’s emergency powers to manage the pandemic. After requiring masks to be worn last year in schools, he has not renewed the order this fall.Mr. DeWine, who drew national attention for his fast and forceful response to Covid in early 2020, now faces a 2022 primary challenge from Jim Renacci, a former congressman. Mr. Renacci said the governor’s handling of the virus was “a big part” of his bid.He said Mr. DeWine had now “gone quiet” on mandates because “he realizes what he did the first time did not make Republicans happy.”A spokesman for Mr. DeWine said the need for mandates had changed since vaccines became freely available.The most severe Covid outbreaks have been most concentrated in the South, and the Republican governors of Alabama and Mississippi have largely embraced the no-mandate ethos even as cases have climbed to new heights.Gov. Tate Reeves of Mississippi renewed an emergency declaration in mid-August but set clear boundaries: “There will be no lockdowns and there will be no statewide mandates,” he said.The same week, two field hospitals were installed in the parking lots of Mississippi medical centers.Jennifer Medina contributed reporting.

COVID-19 vaccination elicited antibody responses in nearly nine out of 10 people with weakened immune systems, although their responses were only about one-third as strong as those mounted by healthy people, according to a study by researchers at Washington University School of Medicine in St. Louis.
The study, published Aug. 30 in the Annals of Internal Medicine, looked at people taking immunosuppressive medications to treat chronic inflammatory diseases such as inflammatory bowel disease and rheumatoid arthritis. Since a minimum level of antibodies needed for protection hasn’t been established, it has been difficult to say whether the levels achieved by people on immune suppressing drugs are high enough to protect them from severe COVID-19, the researchers said. The Centers for Disease Control and Prevention (CDC) recently recommended that people taking immunosuppressants receive a third dose of the vaccine to strengthen their immune responses.
Nonetheless, the discovery that COVID-19 vaccination elicits a response in people with compromised immune systems — even if not quite as strong a response — is encouraging news for a population that faces a high risk of serious illness.
“Some of our patients have been hesitant about getting vaccinated, which is unfortunate because they are at increased risk of having more severe cases of COVID-19 if they happen to get infected, compared to those not taking immune suppressing drugs,” said co-senior author Alfred Kim, MD, PhD, an assistant professor of medicine who treats patients with autoimmune conditions at Barnes-Jewish Hospital. “Some of them are worried that vaccination might cause their disease to flare, but we haven’t seen that happen. Others don’t see the point of vaccination, because they think the drugs they’re taking to treat their autoimmune condition will prevent them from producing an immune response to the vaccine. What we found here is that the vast majority of immunocompromised patients with autoimmune diseases are able to mount antibody responses following COVID-19 vaccination. There’s clearly a benefit for this population.”
When the first COVID-19 vaccines were authorized for emergency use in December 2020, Kim worried about how well they would work for his patients. Previous studies had shown that immunosuppressive medications can blunt people’s responses to other vaccines, such as those for influenza and pneumococcal diseases.
Kim and co-senior author Ali Ellebedy, PhD, an associate professor of pathology & immunology, of medicine and of molecular microbiology, set out to determine how well people taking immunosuppressive drugs respond to COVID-19 vaccination. Co-first authors Parakkal Deepak, MBBS, an assistant professor of medicine in the Division of Gastroenterology, Wooseob Kim, PhD, a postdoctoral researcher in Ellebedy’s lab, and Michael Paley, MD, PhD, an instructor in medicine in the Division of Rheumatology, with the help of other colleagues at Washington University and the University of California, San Francisco, pulled together a participant group comprising 133 patients and 53 healthy people for comparison. The patients each were taking at least one immune-suppressing medication for illnesses such as inflammatory bowel disease, rheumatoid arthritis, spondyloarthritis, lupus and multiple sclerosis.
Participants provided blood samples within two weeks before receiving the first dose of the Pfizer or Moderna vaccine and within three weeks after receiving the second dose. The researchers measured each participants’ antibody levels and counted the number of antibody-producing cells in their blood samples. All patients stayed on their prescribed drug regimens, except for three whose medications were paused within one week of immunization.
All healthy participants and 88.7% of the immunosuppressed participants produced antibodies against the virus that causes COVID-19. However, antibody levels and the number of antibody-producing cells in the immunosuppressed group were one-third as high as those in the healthy group.
“Nobody knows what minimum level of antibodies is needed for protection,” Ellebedy said. “We just don’t know whether people who had low but detectable levels of antibodies are protected or not. It’s that uncertainty that justifies the need for a third dose, especially since we have these highly infectious variants that are capable of causing breakthrough infections even among healthy people.”
Two classes of drugs led to particularly weak immune responses. Only 65% of people taking glucocorticoids and 60% of people taking B cell-depleting therapies developed detectable antibody responses. People taking antimetabolites such as methotrexate, TNF inhibitors or JAK inhibitors, on the other hand, did not generate significantly weaker immune responses than people not taking those drugs.
Alfred Kim, Ellebedy and colleagues are preparing to follow the same group of participants as they receive their third shots. If a third dose allows people on immunosuppressants to achieve the antibody levels seen in healthy people after a second dose, Alfred Kim said he would feel better about how well the vaccine protects his patients.
“Receiving this additional dose may help mitigate this loss of response,” he said. “It’s really important for people who are immunocompromised to receive this dose to maximize their ability to protect themselves from SARS-CoV-2.”

In all eukaryotic organisms, genetic material is stored in the cell nucleus in the form of DNA. In order to be used, this DNA is first transcribed into messenger RNA in the cell cytoplasm, then translated into protein with the help of ribosomes, small machines capable of decoding messenger RNA to synthesise the appropriate proteins. However, the speed with which this mechanism takes place is not uniform: it must adapt to allow the protein to adopt the right configuration. Indeed, a deregulation of the production rate leads to structural defects. The proteins, which are not correctly folded will aggregate, become unusable and often toxic for the cell. By analysing the rate of ribosome movement in yeast cells, a team from the University of Geneva (UNIGE), Switzerland, in collaboration with the University of Hamburg, has succeeded in demonstrating that the rate of protein synthesis is modulated by regulatory factors that modify at will the rate of translation of messenger RNA into proteins. These results can be found in the journal Cell Reports.
Proteins are 3D structures that, in order to act, must interlock with each other or interact with partners. In case of a structural defect, the proteins clump together, becoming toxic and potentially pathological. This phenomenon is actually observed in many neurodegenerative diseases, such as Alzheimer’s disease or amyotrophic lateral sclerosis. “We already knew that the rate at which proteins are made varies according to need: sometimes fast, sometimes very slow,” explains Martine Collart, a professor in the Department of Microbiology and Molecular Medicine at the UNIGE Faculty of Medicine, who led this research. “However, we did not yet know how this mechanism was controlled.”
Ribosome profiling
In order to understand this process, the scientists used a very innovative and still not well-known technique: ribosome profiling. “This methodology makes it possible to determine the position of ribosomes at a given moment in the cell,” explains Olesya Panasenko, a researcher in Martine Collart’s laboratory and head of the ‘BioCode: RNA to Proteins’ Core Facility at the Faculty of Medicine, who specialized in this technique. “It consists of degrading, at a specific moment, all the RNA that is not protected by the ribosome, to keep only the ribosome protected fragments (RPFs). We then sequence these RPFs in order to define how many ribosomes were on the mRNA, and at which positions, at that particular moment. This indicates the speed and efficiency of translation.”
The scientists observed the speed and dynamics of protein production in natural yeast cells as well as in genetically modified yeast, in order to identify possible differences depending on the genetic code. During synthesis, small condensates of RNA and proteins appear in the cell, with the function of slowing down the rate of ribosome production. “The formation of these condensates depends on the presence or absence of regulatory factors, called Not, which act as decelerators,” explains Martine Collart. In their absence, the mechanism accelerates in the wrong places and results in aggregated proteins.
A speed regulated by the genetic code
Thus, Not factors associate with the ribosome at precise moments during protein synthesis, to slow down the ribosome during translation by condensing the RNA and the nascent protein. “One may wonder whether this regulatory mechanism is affected during neurodegenerative diseases or with age,” the authors ask. It is therefore possible that small disturbances, when adding one to the other, may ultimately have a significant cumulative effect over time.
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A new mechanism that stops the progression of Huntington’s disease in cells has been identified by scientists at UCL and the University of Cambridge, as part of their research groups at the UK Dementia Research Institute.
Researchers say the breakthrough study, published in Cell Reports, could lead to much needed therapies for the rare genetic disease, which is currently incurable.
Huntington’s disease is a progressive and devastating neurodegenerative disorder, that affects about 1 in 10,000 people in the UK.
The disease is caused by the accumulation of toxic repetitive expansions of three DNA blocks called nucleotides (C, A and G) in the huntingtin (HTT) gene and is often termed a repeat expansion disorder. These CAG tri-nucleotide repeats are expanding by misuse of a cellular machinery that usually promotes DNA repair called ‘mismatch repair’. This overuse in mismatch repair drives Huntington’s disease onset and progression.
In this study researchers investigated the role of FAN1 — a DNA repair protein, that has been identified as a modifier of Huntington’s disease in several genetic studies; however, the mechanism affecting disease onset has remained elusive.
Using human cells and techniques that can read DNA repeat expansions, the researchers found that FAN1 can block the accumulation of the DNA mismatch repair factors to stop repeat expansion thus alleviating toxicity in cells derived from patients.
Co-lead authors Dr Rob Goold and PhD researcher Joseph Hamilton, both UCL Queen Square Institute of Neurology and UK Dementia Research Institute at UCL, said: “Evidence for DNA repair genes modifying Huntington’s disease has been mounting for years. We show that new mechanisms are still waiting to be discovered, which is good news for patients.”
Medicines that could mimic or potentiate (increase the power of) FAN1 inhibition of mismatch repair would alter disease course. The team is now working with the biotechnology company Adrestia Therapeutics, based at the Babraham Research Campus near Cambridge, to translate these discoveries into therapies for substantial numbers of patients in the UK and worldwide.
Senior author of the study, Professor Sarah Tabrizi, director of the UCL Huntington’s Disease Centre, UCL Queen Square Institute of Neurology and UK Dementia Research Institute at UCL, stated: “Our next step is to determine how important this interaction is in more physiological models and examine if it is therapeutically tractable. We are now working with key pharma partners to try and develop therapies that target this mechanism and might one day reach the clinic.”
Joint senior author, Dr Gabriel Balmus from the UK Dementia Research Institute at the University of Cambridge, said: “There are currently more than fifty CAG repeat expansion disorders that are incurable. If viable, the field suggests that resulting therapies could be applied not only to Huntington’s disease but to all the other repeat expansion disorders.”
Professor Steve Jackson, CSO and Interim CEO of Adrestia, said: “My colleagues and I are delighted to be working with Professor Tabrizi, Dr Balmus and the UK Dementia Research Institute to seek ways to translate their exciting science towards new medicines for Huntington’s disease and potentially also other DNA-repeat expansion disorders.”
The study was funded by the CHDI Foundation and UK Dementia Research Institute.
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Genomic scientists at KAIST have revealed new insights into the process of human embryonic development using large-scale, whole-genome sequencing of cells and tissues from adult humans. The study, published in Nature on Aug.25, is the first to analyse somatic mutations in normal tissue across multiple organs within and between humans.
An adult human body comprises trillions of cells of more than 200 types. How a human develops from a single fertilized egg to a fully grown adult is a fundamental question in biomedical science. Due to the ethical challenges of performing studies on human embryos, however, the details of this process remain largely unknown.
To overcome these issues, the research team took a different approach. They analysed genetic mutations in cells taken from adult human post-mortem tissue. Specifically, they identified mutations that occur spontaneously in early developmental cell divisions. These mutations, also called genomic scars, act like unique genetic fingerprints that can be used to trace the embryonic development process.
The study, which looked at 334 single-cell colonies and 379 tissue samples from seven recently deceased human body donors, is the largest single-cell, whole-genome analysis carried out to date. The researchers examined the genomic scars of each individual in order to reconstruct their early embryonic cellular dynamics.
The result revealed several key characteristics of the human embryonic development process. Firstly, mutation rates are higher in the first cell division, but then decrease to approximately one mutation per cell during later cell division. Secondly, early cells contributed unequally to the development of the embryo in all informative donors, for example, at the two-cell stage, one of the cells always left more progeny cells than the other. The ratio of this was different from person to person, implying that the process varies between individuals and is not fully deterministic.
The researchers were also able to deduce the timing of when cells begin to differentiate into individual organ-specific cells. They found that within three days of fertilization, embryonic cells began to be distributed asymmetrically into tissues for the left and right sides of the body, followed by differentiation into three germ layers, and then differentiation into specific tissues and organs.
“It is an impressive scientific achievement that, within 20 years of the completion of human genome project, genomic technology has advanced to the extent that we are now able to accurately identify mutations in a single-cell genome,” said Professor Young Seok Ju from the Graduate School of Medical Science and Engineering at KAIST. “This technology will enable us to track human embryogenesis at even higher resolutions in the future.”
The techniques used in this study could be used to improve our understanding of rare diseases caused by abnormalities in embryonic development, and to design new precision diagnostics and treatments for patients.
The research was completed in collaboration with Kyungpook National University Hospital, the Korea Institute of Science and Technology Information, Catholic University of Korea School of Medicine, Genome Insights Inc, and Immune Square Inc. This work was supported by the Suh Kyungbae Foundation, the Ministry of Health and Welfare of Korea, the National Research Foundastion of Korea.