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An international phase 3 clinical trial, done in participation with Weill Cornell Medicine and NewYork-Presbyterian, found that a new targeted treatment called zolbetuximab, given in combination with a standard chemotherapy, extended survival for patients with advanced gastric or gastroesophageal junction cancer that overexpressed a specific biomarker.
Results from the GLOW study, published July 31 in Nature Medicine, together with results from the parallel SPOTLIGHT study that evaluated zolbetuximab with an alternative standard chemotherapy, prompted the United States Food and Drug Administration to grant priority review to the manufacturer’s biologic license application and set January 12, 2024, as the target decision date.
If approved, zolbetuximab will be the first targeted therapy in the U.S. for patients with previously untreated advanced gastric or esophageal junction cancer that is human epidermal growth factor receptor 2 (HER2)-negative and overexpresses the protein claudin-18 isoform 2 (CLDN 18.2).
Gastric cancer is the fifth most diagnosed cancer globally, and its incidence has increased markedly in the last few decades. Patients with cancer of the stomach or at the junction where the esophagus joins the stomach, known as the gastroesophageal junction, typically have few symptoms in early disease stages, so most are diagnosed after the cancer has advanced or become metastatic. According to the National Cancer Institute, the five-year survival rate for patients with metastatic disease is about 7 percent.
There are few targeted treatments available for patients with gastric and gastroesophageal cancers: Patients with tumors expressing the programmed cell death ligand 1 protein can be treated with immunotherapy, and those with HER2-positive tumors can be treated with trastuzumab, also known by the trade name Herceptin. There is another group of HER2-negative patients who fit neither category, and for whom targeted therapies aren’t generally used. However, these gastric cancers tend to have higher levels of CLDN 18.2, which is normally found in gastric mucosa cells and becomes more exposed as gastric cancer develops. Zolbetuximab is a monoclonal antibody, administered intravenously, that binds to CLDN18.2, killing the dividing cancer cells directly and also alerting the immune system to respond.
“Currently, standard chemotherapy regimens are the only treatment options for many patients with HER2-negative and low PD-L1 gastric and gastroesophageal cancer, and survival is about 12 months,” said lead study author and trial co-principal investigator Dr. Manish Shah, the Bartlett Family Professor of Gastrointestinal Oncology and director of the Gastrointestinal Oncology Program in the Division of Hematology and Medical Oncology at Weill Cornell Medicine. “A new treatment for these patients would address a significant unmet need to extend survival.”
The GLOW study was conducted between November 2018 and February 2022 at 166 sites, including NewYork-Presbyterian/Weill Cornell Medical Center, across 18 countries. A total of 507 patients with previously untreated HER2-negative locally advanced or metastatic gastric or gastroesophageal junction cancer expressing CLDN18.2 were randomized to receive zolbetuximab in combination with capecitabine plus oxaliplatin chemotherapy (CAPOX) or a placebo plus CAPOX.

Almost everything about insects called kissing bugs is revolting, from the insidious way they bite people’s faces at night to drink their blood while they sleep to the way they spread disease through their poop.
Some carry a parasite called Trypanosoma cruzi that causes Chagas disease, a leading cause of disability and premature death in the Americas. Left untreated, Chagas disease can cause serious heart and digestive problems. It’s showing up more and more in patients in the United States.
Now researchers at the University of Cincinnati are investigating what makes the parasite so resilient.
UC researchers are studying the signaling pathway that leads the parasite to transform and reproduce. They follow that pathway from the beginning when an uninfected kissing bug acquires the parasite by biting an infected mammal host all the way to the time the parasite develops in the insect’s gut to be spread to people or animals through the bug’s poop.
The study was published in the journal mBio.
“The best way of treating the disease is understanding the biology of the parasite so we can find better drugs to kill the parasite before it’s too late for the patient,” said Noelia Lander, an assistant professor of biological sciences in UC’s College of Arts and Sciences.
In her molecular parasitology lab at UC, Lander and her research team examined the ways T. cruzi survives in different hostile environments. They deployed technology such as the gene-editing tool CRISPR/Cas9, immunofluorescence analysis and electron microscopy for the study.

In a groundbreaking endeavor, researchers at the University of Rochester have successfully transferred a longevity gene from naked mole rats to mice, resulting in improved health and an extension of the mouse’s lifespan.
Naked mole rats, known for their long lifespans and exceptional resistance to age-related diseases, have long captured the attention of the scientific community. By introducing a specific gene responsible for enhanced cellular repair and protection into mice, the Rochester researchers have opened exciting possibilities for unlocking the secrets of aging and extending human lifespan.
“Our study provides a proof of principle that unique longevity mechanisms that evolved in long-lived mammalian species can be exported to improve the lifespans of other mammals,” says Vera Gorbunova, the Doris Johns Cherry Professor of biology and medicine at Rochester. Gorbunova, along with Andrei Seluanov, a professor of biology, and their colleagues, report in a study published in Nature that they successfully transferred a gene responsible for making high molecular weight hyaluronic acid (HMW-HA) from a naked mole rat to mice. This led to improved health and an approximate 4.4 percent increase in median lifespan for the mice.
A unique mechanism for cancer resistance
Naked mole rats are mouse-sized rodents that have exceptional longevity for rodents of their size; they can live up to 41 years, nearly ten times as long as similar-size rodents. Unlike many other species, naked mole rats do not often contract diseases — including neurodegeneration, cardiovascular disease, arthritis, and cancer — as they age. Gorbunova and Seluanov have devoted decades of research to understanding the unique mechanisms that naked mole rats use to protect themselves against aging and diseases.
The researchers previously discovered that HMW-HA is one mechanism responsible for naked mole rats’ unusual resistance to cancer. Compared to mice and humans, naked mole rats have about ten times more HMW-HA in their bodies. When the researchers removed HMW-HA from naked mole rat cells, the cells were more likely to form tumors.
Gorbunova, Seluanov, and their colleagues wanted to see if the positive effects of HMW-HA could also be reproduced in other animals.

Mallinckrodt Pharmaceuticals had promised $1.7 billion to governments, individuals and others harmed by the opioid crisis.A major opioid manufacturer that had promised to pay $1.7 billion as compensation over its role in the opioid crisis disclosed on Wednesday that it had reached an agreement with its creditors to reduce the settlement payments by $1 billion.The manufacturer, Mallinckrodt Pharmaceuticals, had originally agreed to pay the $1.7 billion over eight years to state and local governments, individuals and others that had sued the company for helping fuel the opioid crisis. The funds had been earmarked for addiction victims to rebuild their lives and for governments to pay for priorities like drugs to reverse opioid overdoses.In a regulatory filing on Wednesday, Mallinckrodt disclosed that it had reached a plan to file for bankruptcy for the second time in three years. The plan would cancel a majority of the $1.25 billion that the company still owes under the original settlement agreement, in exchange for a final payment of $250 million that would be made before the company enters its second bankruptcy.The plan to cancel a majority of the outstanding payments was devised with backing from hedge funds that would control the company under a second bankruptcy. The funds had lent money to Mallinckrodt and were in a position to force the company to prioritize paying back its lenders over compensating victims.The revised plan still requires bankruptcy court approval. The company’s chief executive, Siggi Olafsson, said in a news release that the company “remained committed to ensuring that we achieved a meaningful resolution” for the trust set up to disburse settlement payments to victims. Mallinckrodt did not immediately return a request for additional comment.The original settlement plan, finalized last year as Mallinckrodt exited its first bankruptcy, protected the company and its former executives from future liability related to its opioid sales.Mallinckrodt last year made its first and only payment, of $450 million, under the original settlement agreement. The company is late on a second payment, which was due in June.The revised plan was agreed to by a master trust that oversees the distribution of payments to subordinate trusts tasked with disbursing money to victims. Governments have begun receiving the initial funds. The money earmarked for individuals has not yet been disbursed but is expected to go out soon.Joseph Steinfeld, a lawyer representing about half of the approximately 40,000 individuals who had been promised payments as part of the settlement, said that the revised plan would reduce the amount going to that group by about $100 million.“What was promised was a significant amount to many of the victims that were counting on it,” Mr. Steinfeld said. “They’re losing about 70 percent of what they were promised.”Mallinckrodt is among a number of manufacturers, pharmacy chains and distributors that have agreed to large settlements with governments and other victims who accused them of seeding a public health disaster by pushing prescription opioids and downplaying their addiction risks.While Purdue Pharma has become a household name for its role in the opioid crisis, Mallinckrodt has been less recognized, even as its product known as Roxicodone became one of the widely misused legal painkillers. Documents that were made public through the company’s first bankruptcy filing showed how Mallinckrodt aggressively promoted its prescription painkillers as the opioid crisis took hold in communities around the country.

Since the trial of Lucy Letby, a nurse who murdered babies in her care, experts have warned of a culture of hostility toward whistle-blowers in Britain’s National Health Service.It was June 2016, and almost a year had passed since Stephen Brearey, the lead doctor at a neonatal unit in northwest England, first became concerned about a spate of troubling and unexpected deaths on his ward.Five babies had died, and at least six others had experienced unusual complications. The neonatal ward at the Countess of Chester Hospital cared for premature and vulnerable babies, but the number of deaths was far above average for the unit. Something was desperately wrong.Then, in the early evening of June 23, a baby boy — one of a set of newborn triplets — suddenly became sick and died. The following night, as the parents were still reeling, another of the triplets died.The infants had been in the care of Lucy Letby, a seemingly conscientious and well-liked nurse. Dr. Brearey had noticed that she was present in every other suspicious case and raised that fact multiple times with executives, but he felt his concerns were dismissed.After the second triplet died, he phoned a hospital executive and demanded that Ms. Letby be removed from the ward. The executive said there was no clear evidence against the nurse and insisted she was safe to work with, Dr. Brearey later told a court.It would be another week before Ms. Letby, now considered the most prolific killer of children in modern British history, was moved to clerical duties, and months before the hospital’s senior managers contacted the police.She was finally convicted last week of killing those boys by injecting air into their bodies, murdering five other babies and attempting to murder six others in her care.The harrowing case has not only horrified the nation but raised profound questions about the workplace culture that allowed her to continue working, even after doctors raised alarms.Since the trial, clinicians who worked alongside Ms. Letby have spoken out, describing a culture of hostility toward whistle-blowers and a fear of scandal that they say meant their alerts were ignored.A November 2020 police photograph of Lucy Letby.Cheshire Constabulary, via Getty ImagesThe hospital delayed contacting the police.In England, hospitals that are part of the National Health Service, or NHS, are operated by individual trusts that have their own management teams. The Countess of Chester Hospital Foundation Trust did not contact the Cheshire Constabulary, the police force responsible for the area, until early May 2017, a year and a half after doctors first began reporting their suspicions.During the trial, the court heard that a number of pediatricians who worked alongside Ms. Letby, 33, including Dr. Brearey, had repeatedly alerted hospital executives to their concerns about the nurse.Dr. John Gibbs, who worked in the department, told Channel 4 news that there had been “resistance on the senior management side to involving the police, but I don’t know quite why.” He added, “We pediatricians were certainly concerned that someone — and suspicions fell on Lucy Letby — could have been harming and perhaps killing patients on the unit.”After Ms. Letby left the unit, she began a grievance case against the hospital, claiming she was being victimized. In January 2017, some of the doctors were made to apologize to the nurse and asked to attend mediation sessions, including Dr. Brearey and Dr. Ravi Jayaram, a pediatrician at the hospital for nearly two decades.Dr. Jayaram had spoken up about Ms. Letby as early as October 2015 and recently told ITV he believed “babies could have been saved” if the situation had been reported to the police earlier.“There are things that need to come out about why it took several months from concerns being raised to the top brass before any action was taken to protect babies,” Dr. Jayaram said in a statement on Facebook on Friday, “and why from that time it then took almost a year for those highly paid senior managers to allow the police to be involved.” He declined an interview request from The New York Times.The case highlights a problematic culture in the health service, experts say.Medical professionals say the fact that the trust failed to involve the police sooner underlines a broader failing in the NHS. Rob Behrens, an ombudsman who investigates complaints about government departments and the health service in England, said the trial revealed how, for too long, nobody listened despite repeated alarms.Mr. Behrens was clear that the type of intentional killing seen in Ms. Letby’s case was extremely rare in the health service. But he said that senior managers’ ignoring warnings was “depressingly familiar.”“I see this time and time again in the cases I investigate,” he said, noting that a number of independent reports in recent years pointed to a defensive culture and hostility to those who disclosed safety issues.Dr. Claudia Paoloni, an executive member of the hospital doctors’ union in Britain, said that the case followed a longtime pattern in which whistle-blower clinicians were ignored or victimized.“Every single trust should be reviewing their existing systems to make sure they are robust and effective,” she said.Dr. Jayaram said in his Facebook statement that there was a long history of whistle-blowers in the NHS, “not only being ignored but then being portrayed as the problem, sometimes to the point of their careers being destroyed.”“What happened here was history repeating itself,” he wrote, “but the patient-safety issue that was ignored was beyond anything that the NHS has tried previously to cover up.”The case has prompted calls for change.Tamlin Bolton, a lawyer at Switalskis Solicitors, is representing the families of seven babies who were victims of Ms. Letby in civil claims against the Countess of Chester trust.“We really need to look at what was known and what the trust knew during that timeline, to know what they could have done and what they should have done with what was presented,” Ms. Bolton said.Immediately after the Letby verdict, the British government ordered an independent inquiry “to ensure vital lessons are learned and to provide answers to the parents and families impacted.”But many experts, and representatives of the victims’ families, said this type of inquiry would not go far enough.Mr. Behrens, the ombudsman, sent a letter to the health secretary on Wednesday calling for the government to set up a statutory inquiry, which would compel those involved to give evidence, rather than the weaker independent inquiry, which will allow people to opt out. He also requested better protection for whistle-blowers.“This is a critical, pivotal moment in the history of our health service,” Mr. Behrens said. “And we need to understand why patient safety is not considered as important as the reputation of the trust.”

The number of procedures rose to roughly 13,000 in 2019 from about 4,550 in 2016 as access broadened, researchers estimated.The NewsThe number of gender-affirming surgeries, intended to align patients’ physical appearance with their gender identity, nearly tripled in the United States between 2016 and 2019, according to a new analysis published in JAMA Network Open on Wednesday.The number of procedures rose from about 4,550 in 2016 to about 13,000 in 2019, and then dipped slightly in 2020, according to the study’s estimates. Because of various data limitations, the researchers behind the study believe the true figures are higher.Surgeons performing a bilateral mastectomy on a transgender patient at a hospital in Boston in 2016.Christine Hochkeppel/Worcester Telegram & Gazette, via Associated PressThe Context: Transition care has become a political issue.Gender-affirming care has become a key political issue for conservatives in the run-up to the presidential election. At least 20 states led by Republicans have restricted or banned such care for minors.Gender-affirming surgery is endorsed by a wide array of medical groups. Yet surprisingly little has been known about how often these operations are performed.“There’s been a sense that more patients are asking about it, and ultimately pursuing it, but there wasn’t good data,” said Dr. Jason D. Wright, the chief of gynecologic oncology at Columbia University Vagelos College of Physicians and Surgeons, who led the research.“Ours is one of the first studies to quantify the age groups and the procedures they’re undergoing.”Past analyses have shown that such surgeries have been increasing. Health experts anticipated a sharper increase in recent years, in part because of changes in federal and state laws that often require coverage of transition-related care.The Numbers: What kinds of procedures do patients opt for?Dr. Wright and his colleagues drew patient counts from two databases maintained by the federal Agency for Healthcare Research and Quality in order to account for both inpatient and outpatient procedures, and weighted the figures to produce estimates for the entire country.According to the analysis, about 48,000 patients underwent surgeries from 2016 through 2020. Breast and chest surgeries were the most common: There were about 27,187, or 56.6 percent of all gender-affirming surgeries.Researchers estimated there were about 16,872 genital surgeries (35.1 percent of the total) during the period, and about 6,669 facial and cosmetic surgeries (13.9 percent).Just over half of all patients were ages 19 to 30; about 22 percent were ages 31 to 40; and almost 8 percent were ages 12 to 18. The number of genital surgeries in particular increased with age, which researchers attributed to the higher complexity and “definitive nature” of the procedure.The number of procedures overall rose from 2016 to 2019 but declined slightly in 2020, which the researchers said might have resulted from the onset of the Covid pandemic.The data accounted only for surgeries in inpatient and ambulatory settings, and did not include cases in which surgeons omitted certain gender-related diagnosis codes. As a result, the study’s findings are “almost certainly under-captures” of the real figures, Dr. Wright said.Background: Recent developments in gender-affirming care.Much of the national discussion has centered on treatment for adolescents. Earlier this month, the American Academy of Pediatrics reaffirmed its guidelines regarding the gender-affirming treatment but also commissioned a fresh review of the research, after European health authorities found uncertain evidence for its effectiveness.Here are articles to better understand the topic:Medical Group Backs Youth Gender Treatments, but Calls for Research ReviewEngland Limits Use of Puberty-Blocking Drugs to Research OnlyReport Reveals Sharp Rise in Transgender Young People in the U.S.

Joint research groups at Tampere University, University of Helsinki, Lund University and Pi-Numerics, Salzburg, have established key early steps in the conversion of aromatic molecules, a major constituent of traffic and other urban volatile emissions, into aerosol. Their findings increase understanding of the chemical processes that degrade urban air quality and influence climate change.
Many aromatic molecules are carcinogenic and have negative impacts on health. Their primary source is exhaust fumes from motor vehicles. Aromatics can form aerosol particles when they collide in the atmosphere with the hydroxyl radical, a molecule colloquially dubbed “atmospheric detergent” due to its acute propensity to react chemically. When breathed in, aerosol particles can lead to a myriad of chronic health issues and even death. These particles also affect Earth’s climate by reflecting sun light and increasing the formation of clouds.
Despite their importance to the urban environment, details of the reaction processes that form aerosol from aromatics have until now remained unresolved.
The group of researchers used a combination of quantum mechanics, targeted experiments, and modeling, to establish the early steps in the reaction process of toluene, one of the most abundant aromatic molecules.
“We found out that a reaction product that was previously thought to be stable is in fact transient and converts to new hot molecules. These molecules have residual energy that makes subsequent chemistry fast and promptly lead to aerosol precursor products. This result bridges the gap between theory and observation and provides better understanding of the chemistry of aerosol formation in urban environments,” says Siddharth Iyer, Postdoctoral Research Fellow of Aerosol Physics at Tampere University.

Researchers from the University of Colorado Anschutz Medical Campus and Washington University in St. Louis have identified a way to assess brain activity in sleep that occurs in the earliest stages of Alzheimer’s disease, typically many years prior to developing symptoms of dementia.
The digital biomarker uses electroencephalography (EEG) that can be recorded from simple headband devices to detect brain wave patterns related to memory reactivation in sleep, which are part of a system that processes memories in deep sleep. Study results published today in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association identify a relationship between EEG readings and levels of specific molecular changes indicative of pre-symptomatic Alzheimer’s disease. Additional findings further demonstrate that early stages of mild cognitive impairment due to Alzheimer’s disease can be detected in the EEG signals.
“This digital biomarker essentially enables any simple EEG headband device to be used as a fitness tracker for brain health,” says Brice McConnell, MD, PhD, assistant professor of neurology at the University of Colorado School of Medicine and study senior author. “Demonstrating how we can assess digital biomarkers for early indications of disease using accessible and scalable headband devices in a home setting is a huge advancement in catching and mitigating Alzheimer’s disease at the earliest stages.”
In the largest study of its kind to date, researchers analyzed data from 205 aging adults, identifying measurable problems with memory reactivation in association with levels of proteins such as amyloid and tau that build up in Alzheimer’s Disease.
“What we found is these abnormal levels of proteins are related to sleep memory reactivations, which we could identify in people’s brainwave patterns before they experienced any symptoms,” says McConnell. “Identifying these early biomarkers for Alzheimer’s disease in asymptomatic adults can help patients develop preventative or mitigation strategies before the disease advances.”
Researchers say this is an exciting step towards using wearables as digital biomarkers for disease detection. “We are just scratching the surface with this work, paving the way for affordable and easy-to-use devices to monitor brain health,” says McConnell. “This is proof of principle that brain waves during sleep can be turned into a digital biomarker, and our next steps involve perfecting the process.”

Immunotherapies for cancer aim to induce the immune system to combat cancer cells more effectively. In the journal Angewandte Chemie, a Chinese research team has now described a new, modular strategy for T-cell-based immunotherapy that manages to work without complex genetic modifications. Modulation of cell-cell communications through an ingenious regulatory circuit using various small, specially folded DNA molecules (aptamers) causes cancer cells to directly activate their mortal enemies, T cells.
For multicell organisms like our bodies to function correctly, the cells must “coordinate” with each other. In this complex communications network, signals are sent and received, processed, and passed on. The regulation of specific membrane receptors that bind to signal molecules plays an important role in this process. In a typical example, components of the immune system, known as antigen-presenting cells (APCs), sense the presence of cancer antigens. They transmit the signal to lymph nodes, in which specific T cells are activated by their receptors, move into the bloodstream, and kill the cancer cells. Unfortunately, cancer cells use a variety of “loopholes” to escape the immune system.
The team at Hunan University, Hangzhou Institute of Medicine, the Chinese Academy of Sciences, and Shanghai Jiao Tong University is working on ways to close these loopholes. Their goal is to establish new cellular interactions without having to produce genetically modified immune cells or receptors. The idea is to produce a “short circuit” in the communication pathways, by which the T cells are activated directly by the tumor cells, avoiding the detour through APCs.
Led by Weihong Tan and Liping Qiu, the team developed a “regulatory circuit” consisting of two modules: 1) “recognition-then-triggering” and 2) “aggregation-then-activation.” The circuit is based on different DNA aptamers — short DNA segments that fold into a “preprogrammed” 3D structure and “recognize” specific target molecules.
The DNA for module 1) is initially inactive and partially paired into a double strand. If cancer cells are present, the aptamer portion of the “recognition” single strand binds to protein tyrosinase kinase 7, a protein found in large numbers on the surface of many cancer cells. This splits the DNA double strand, releasing the “triggering strand,” which triggers module 2).
Module 2) requires two more types of aptamer. Both specifically bind to CD28 immunoreceptors on the surfaces of T cells. CD28 is a co-stimulator in the activation of T cells. This triggering strand binds to an additional “loop” on a type 1 aptamer. The loop opens and the newly released end binds to a type 2 aptamer, which then binds another type 1 aptamer, and so on (hybridization). This results in a double strand and the bound CD28 receptors aggregate, triggering a signal cascade that massively amplifies the activation of T cells. In this way, “short-circuited” cell communication causes cancer cells to very effectively directly induce T cells to kill them.

Figuring out how hundreds of different kinds of brain cells develop from their unique expression of thousands of genes promises to not only advance understanding of how the brain works in health, but also what goes wrong in disease. A new MIT study that precisely probes this “molecular logic” in two neuron types of the Drosophila fruit fly, shows that even similar cells push and pull many levers to develop distinct functions.
In the study in Neuron, a team of neurobiologists at The Picower Institute for Learning and Memory found that the two closely related neuronal subtypes differed from each other in how they expressed more than 800 genes, or ~5% of the total genes encoded in the fly genome. By manipulating genes whose expression differed most prominently, the scientists were then able to show how they produced several of the observable differences between the cells.
“There is a global effort in neuroscience to identify all the different types of neurons to define their unique properties and their gene expression profiles,” said study senior author Troy Littleton, Menicon Professor of Neuroscience in MIT’s Departments of Biology and Brain and Cognitive Sciences. “That information can be used as a toolkit for studying how newly found disease genes map on to those particular neurons to indicate which ones might be most affected in specific brain disorders.
“We wanted to use Drosophila as a way to see whether we can, in fact, determine how the transcriptome of two similar neurons is differentially used to understand which key genes specify their unique structural and functional properties.”
Under the microscope
The two neuron types compared in the study both emerge from the fly’s analog of a spinal cord to control muscles by releasing the neurotransmitter glutamate at connections called synapses. The neurons’ main functional differences are that “phasic” neurons connect to many muscles and emit big, occasional bursts of glutamate while “tonic” neurons each connect to only one muscle and provide more of a constant drip of the chemical. This duality, which is also found in neurons of the human brain, provides a flexible range of control.
Picower Institute postdoc Suresh Jetti led the effort in Littleton’s lab to determine how these two neurons develop their differences. The team began with an unusually deep characterization of how the two cell types differ in form and function and then took a highly precise look at the gene expression profiles, or transcriptomes.