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A new, bio-inspired drug restores the effectiveness of immune cells in fighting cancer, a team led by researchers at The University of Texas at Austin has found. In mouse models of melanoma, bladder cancer, leukemia and colon cancer, the drug slows the growth of tumors, extends lifespan and boosts the efficacy of immunotherapy. The research is published in the journal Cancer Cell and could be a game changer for many cancer patients.
Many cancers delete a stretch of DNA called 9p21, which is the most common deletion across all cancers, occurring in 25%-50% of certain cancers such as melanoma, bladder cancer, mesothelioma and some brain cancers. Scientists have long known that cancers with the 9p21 deletion mean worse outcomes for patients and resistance to immunotherapies — the treatment strategies designed to supercharge a patient’s natural immune response to cancer.
The deletion helps cancer cells avoid getting detected and wiped out by the immune system, in part by prompting the cancer to pump out a toxic compound called MTA that impairs normal functioning of immune cells and also blocks the effectiveness of immunotherapies.
“In animal models, our drug lowers MTA back down to normal, and the immune system comes back on,” said Everett Stone, a research associate professor in the Department of Molecular Biosciences and associate professor of oncology at Dell Medical School, who led the work. “We see a lot more T cells around the tumor, and they’re in attack mode. T cells are an important immune cell type, like a SWAT team that can recognize tumor cells and pump them full of enzymes that chew up the tumor from the inside out.”
Stone envisions the drug being used in combination with immunotherapies to boost their effectiveness.
The study’s co-first authors are Donjeta Gjuka, a former UT postdoctoral researcher and currently a scientist at Takeda Oncology, and Elio Adib, formerly a postdoctoral researcher at Brigham and Women’s Hospital and the Dana-Farber Cancer Institute, and currently a resident physician at Mass General Brigham.
The 9p21 deletion leads to the loss of some key genes in cancer cells. Gone are a pair of genes that produce cell cycle regulators — proteins that keep healthy cells growing and dividing at a slow, steady rate. When those genes are lost, cells can grow unchecked. That’s what makes them cancerous. Also deleted is a housekeeping gene that produces an enzyme that breaks down the toxin MTA. It’s this loss, according to Stone, that lets cancer cells acquire a new superpower: the ability to deactivate the immune system.

A new combination of treatments safely decreased growth of pancreatic cancer in mice by preventing cancer cells from scavenging for fuel, a new study finds.
Led by researchers at NYU Grossman School of Medicine, its Department of Radiation Oncology, and the Perlmutter Cancer Center, the work builds on prior discoveries at NYU Langone that revealed how pancreatic cancer cells, to avert starvation and keep growing, find alternate fuel sources. Normally supplied by the bloodstream, oxygen, blood sugar, and other resources become scarce as the increasing density of fast-growing pancreatic tumors cuts off their own blood supply. In this environment, the ability to switch fuels contributes to the deadliness of pancreatic cancers.
Published online October 9 in Nature Cancer, the new study involves a drug designed to prevent pancreatic ductal adenocarcinoma (PDAC) cells from one such switch. PDAC cells use the enzyme glutaminase to convert the amino acid glutamate into glutamine, a form that can be burned for fuel to sustain rapid tumor growth. Drugs designed to block glutaminase, however, have been shown to cause cancer cells to switch to still other scavenging pathways.
For this reason, the field next looked at experimental treatments like DRP-104, designed by Dracen Pharmaceuticals, a new “prodrug” form of the compound 6-Diazo-5-oxo-L-norleucine (DON) that is preferentially activated within tumors to overcome toxicity issues seen with DON. DON was designed to starve cancer cells by mimicking glutamine, which unlike glutaminase blockers, broadly inhibits all metabolic pathways that use glutamine. Currently in clinical trials against non-small cell lung cancer, DRP-104 cannot be burned as fuel, but clings to the same enzymes as glutamine.
In the current study, DRP-104 treatment alone decreased PDAC growth in mouse models of pancreatic cancer. Importantly, the current team also found that PDAC cells pushed into metabolic crisis by DRP-104 increase signaling through a protein called extracellular signal-regulated kinase or ERK, to make up for their loss of glutamine metabolism. When the team combined DRP-104 with an existing drug that blocks the ERK signaling pathway, trametinib, it further improved survival in pancreatic cancer mouse models compared to DRP-104 treatment alone.
“Despite a decade of advances in understanding how cancer cells switch fuel sources, we have not yet effectively translated this into clinically relevant therapies,” says corresponding study author Alec Kimmelman, M.D., Ph.D., the Anita Steckler and Joseph Steckler Chair of Radiation Oncology at NYU Langone Health. “Broad antagonism of metabolic pathways with glutamine analogs may provide another mode of attack against these highly resistant tumor cells. The fact that such drugs are already being tested in the clinic makes us hopeful that we may finally see patient outcomes improve, if this approach proves to be effective in clinical trials.”
Moving forward, the research team will seek to understand how glutamine antagonism impacts other adaptive nutrient scavenging mechanisms in pancreatic cancers and whether these could be targeted as well. The success of such approaches will depend on careful balancing of improved therapeutic efficacy and toxicity from the potential effects on normal tissues, Kimmelman adds.
Along with Kimmelman, authors from Perlmutter Cancer Center and the Department of Radiation Oncology at NYU Langone were Joel Encarnación-Rosado, Albert Sohn, Douglas Biancur, Elaine Lin, Victoria Osorio-Vasquez, and Diana González-Baerga. Also Perlmutter authors were Ende Zhao and Diane Simeone. Also authors of the study were Tori Rodrick and Drew Jones from the Division of Advanced Research Technologies at NYU Grossman School of Medicine; Seth Parker from the Department of Biochemistry & Molecular Biology at University of British Columbia in Vancouver, and Yumi Yokoyama and Robert Wild from Dracen Pharmaceuticals, Inc., of San Diego.
Funding for the study came from Perlmutter Cancer Center support grant P30CA016087 and National Cancer Institute grants P01A1080192, P01CA117969, R35CA232124, P30CA016087-38, 1R01CA251726-01A1; as well as from the Lustgarten Foundation, Stand Up to Cancer, and the Howard Hughes Medical Gilliam Fellowships.
Kimmelman has financial interests in Vescor Therapeutics, is on the scientific advisory board of Rafael/Cornerstone Pharmaceuticals and OncoRev, and has been a consultant for Deciphera and Abbvie. These relationships are being managed according with the policies of NYU Langone Health. Yokoyama and Wild are employees of, and have ownership in, Dracen Pharmaceuticals, maker of DRP-104.

The intricate control of cellular metabolism relies on the coordinated and harmonious interplay between the nucleus and mitochondria. On the one hand, mitochondria are the hub for the production of essential metabolites, which aside from being required to meet the energy demands of the cell, also serve as the building blocks for constructing both genetic and epigenetic landscapes in the nucleus. On the other hand, the majority of mitochondrial metabolic enzymes are encoded by the nuclear genome, making the function of these two organelles highly interdependent on one another. Inter-organellar communication is aided by molecules that shuttle between these two compartments. The histone acetyltransferase MOF, an enzyme and a classical epigenetic regulator, is such a wanderer between these two worlds.
A team of researchers from the Max Planck Institute of Immunobiology and Epigenetics, in collaboration with scientists from the Universities of Freiburg and Bonn, now reveals the critical impact of MOF on the cellular physiology and function in compartments outside the nucleus. The study, published in the journal Nature Metabolism, uncovers the critical role of MOF in maintaining mitochondrial integrity through a process called protein acetylation. The findings shed light on the specific machinery responsible for regulating protein acetylation of mitochondrial proteins and deepens the understanding of how cells fine-tune their metabolic output.
MOF as a molecular bridge between epigenetics and metabolism
“MOF is a highly conserved protein. We find it in Drosophila, in mice and in humans. Together with other molecules, it forms a complex that acetylates histone proteins and thereby promotes transcriptional activation. In the nucleus, our DNA is wrapped around these histones and forms chromatin. The activity of MOF attaches acetyl groups to the histones relaxing the compaction of chromatin in the nucleus and makes genes readable,” explains Asifa Akhtar. Akhtar is Director at the MPI of Immunobiology and Epigenetics in Freiburg and member of the Cluster of Excellence CIBSS — Centre for Integrative Biological Signalling Studies at the University of Freiburg.
In previous studies, Asifa Akhtar’s lab was able to detect MOF and several of its protein partners in mitochondria. However, the precise impact of MOF’s enzymatic activity on mitochondrial function and cellular metabolism remained unknown. “The observation that MOF was localized outside the nucleus spurred our further interest to explore what this acetyltransferase does to mitochondrial proteins and to study protein acetylation as a broader phenomenon in mitochondria,” says Sukanya Guhathakurta, first author of the study.
Protein acetylation beyond histone proteins
Now, a collaboration between Asifa Akhtar’s team and the groups of Thomas Becker (Uni Bonn), and Nikolaus Pfanner (Uni Freiburg and CIBSS) found a pivotal role for MOF in regulating mitochondrial physiology and function. “In our studies in mice, we identified a unique set of mitochondrial proteins that undergo a change in acetylation status upon loss of MOF and its associated complex members, leading to a cascade of mitochondrial defects, including fragmentation and reduced cristae density, and impaired oxidative phosphorylation,” says Guhathakurta. Mitochondria are the “powerhouses” of the cell. Their function is essential for cellular energy production and many physiological processes. Dysregulation of mitochondrial physiology and function has been implicated in several diseases such as cancer, heart failure and neurodegenerative disorders.

If global temperatures increase by 1 degree Celsius (C) or more than current levels, each year billions of people will be exposed to heat and humidity so extreme they will be unable to naturally cool themselves, according to interdisciplinary research from the Penn State College of Health and Human Development, Purdue University College of Sciences and Purdue Institute for a Sustainable Future.
Results from a new article published today (Oct. 9) in Proceedings of the National Academy of Sciences indicated that warming of the planet beyond 1.5 C above preindustrial levels will be increasingly devastating for human health across the planet.
Humans can only withstand certain combinations of heat and humidity before their bodies begin to experience heat-related health problems, such as heat stroke or heart attack. As climate change pushes temperatures higher around the world, billions of people could be pushed beyond these limits.
Since the start of the industrial revolution, when humans began to burn fossil fuels in machines and factories, temperatures around the world have increased by about 1 C, or 1.8 degrees Fahrenheit (F). In 2015, 196 nations signed the Paris Agreement which aims to limit worldwide temperature increases to 1.5 C above pre-industrial levels.
The researcher team modeled global temperature increases ranging between 1.5 C and 4 C — considered the worst-case scenario where warming would begin to accelerate — to identify areas of the planet where warming would lead to heat and humidity levels that exceed human limits.
“To understand how complex, real-world problems like climate change will affect human health, you need expertise both about the planet and the human body,” said co-author W. Larry Kenney, professor of physiology and kinesiology, the Marie Underhill Noll Chair in Human Performance at Penn State and co-author of the new study. “I am not a climate scientist, and my collaborators are not physiologists. Collaboration is the only way to understand the complex ways that the environment will affect people’s lives and begin to develop solutions to the problems that we all must face together.”
A threat to billions
The ambient wet-bulb temperature limit for young, healthy people is about 31 C, which is equal to 87.8 F at 100% humidity, according to work published last year by Penn State researchers. However, in addition to temperature and humidity, the specific threshold for any individual at a specific moment also depends on their exertion level and other environmental factors, including wind speed and solar radiation. In human history, temperatures and humidity that exceed human limits have been recorded only a limited number of times — and only for a few hours at a time — in the Middle East and Southeast Asia, according to the researchers.

Individual species of very different plant families produce special indole-derived defense compounds called benzoxazinoids. However, the biosynthetic pathway of these compounds was so far only known for grasses such as maize. A team from the Max Planck Institute for Chemical Ecology has now been able to show, by studying two distantly related plant species, the golden dead-nettle and zebra plant, that completely different enzymes are responsible for the formation of these special defense compounds. Hence, plants evolved the biosynthetic pathway for the same compounds several times independently.
Maize plants form special compounds derived from indole, the so-called benzoxazinoids. They are considered ecologically important because they act against a wide range of herbivores and reduce their feeding. Benzoxazinoids also exhibit antimicrobial properties and are thought to be involved in mediating plant-plant interactions. Their biosynthesis in maize has been known since the 1990s. Meanwhile, their biosynthetic pathway has been described in several grasses, but benzoxazinoids have also been found in other plant species. Their distribution is peculiar: While specialized metabolites often occur in specific evolutionary related plant species, benzoxazinoids show the opposite behavior and occur sporadically in many distantly related plant families. Several attempts to elucidate this metabolic pathway not only in maize but also in distantly related species were unsuccessful. Accordingly, the research goal of Tobias Köllner’s group in the Department of Natural Product Biosynthesis at the Max Planck Institute for Chemical Ecology was clear: “We wanted to find out whether the ability to form benzoxazinoids evolved independently in different species.”
The team used two distantly related eudicot plant species that produce benzoxazinoids for the studies: the golden dead-nettle Lamium galebodolon, which is found in sparse forests and forest edges on nutrient-rich soils in Europe, and the zebra plant Aphelandra squarrosa, a popular houseplant. For both species, the researchers created data sets of the compounds and genes expressed in different tissues and compared them to closely related species that do not produce benzoxazinoids. “This approach allowed us to identify candidate genes that may be involved in the formation of these compounds. We further characterized the candidate genes by expressing them in tobacco to find out if they are really involved in the production of benzoxazinoids,” says Matilde Florean, first author of the study, describing their methodological approach.
The researchers were able to show that the benzoxazinoid metabolic pathway evolved independently in maize and the two species under investigation. Tobias Köllner continues, “We found that, in contrast to maize where a number of closely related cytochrome P450 enzymes carry out specific steps of the metabolic pathway, different enzyme classes as well as unrelated enzyme families of cytochrome P450 were recruited.” In particular the discovery that the golden dead-nettle and the zebra plant use a dual-function flavin-containing monooxygenase, rather than two different cytochrome P450 enzymes as in grasses, was completely unexpected. Overall, the research team was surprised to find such a diversity of enzymes performing the same reactions.
“With this work, we have shown how flexible plant metabolism can be. We have shown that plants can independently invent very different strategies to make the same chemical compounds, and this has happened at least three times in the evolutionary history of benzoxazinoids” Sarah O’Connor, director of the Department of Natural Product Biosynthesis summarizes the research findings. In the future, the team hopes to elucidate the biosynthesis of these compounds in even more plant families.

Scientists at the UCL Institute for Neurology have developed new tools, based on AI language models, that can characterise subtle signatures in the speech of patients diagnosed with schizophrenia.
The research, published in PNAS, aims to understand how the automated analysis of language could help doctors and scientists diagnose and assess psychiatric conditions.
Currently, psychiatric diagnosis is based almost entirely on talking with patients and those close to them, with only a minimal role for tests such as blood tests and brain scans.
However, this lack of precision prevents a richer understanding of the causes of mental illness, and the monitoring of treatment.
The researchers asked 26 participants with schizophrenia and 26 control participants to complete two verbal fluency tasks, where they were asked to name as many words as they could either belonging to the category “animals” or starting with the letter “p,” in five minutes.
To analyse the answers given by participants, the team used an AI language model that had been trained on vast amounts of internet text to represent the meaning of words in a similar way to humans. They tested whether the words people spontaneously recalled could be predicted by the AI model, and whether this predictability was reduced in patients with schizophrenia.
They found that the answers given by control participants were indeed more predictable by the AI model than those generated by people with schizophrenia, and that this difference was largest in patients with more severe symptoms.

While a narrative emerged that the pandemic indiscriminately struck the young and healthy, new evidence suggests that frail young adults were most vulnerable.The flu typically kills the very young, the old and the sick. That made the virus in 1918 unusual, or so the story goes: It killed healthy young people as readily as those who were frail or had chronic conditions.Doctors of the time reported that, among those in the prime of their lives, good health and youth were no protection: The virus was indiscriminate, killing at least 50 million people, or between 1.3 and 3 percent of the world’s population. Covid, in contrast, killed 0.09 percent of the population.But a paper published on Monday in the Proceedings of the National Academy of Sciences challenges that persistent narrative. Using evidence in skeletons of people who died in the 1918 outbreak, researchers reported that people who suffered from chronic diseases or nutritional deficiencies were more than twice as likely to die as those who did not have such conditions, no matter their age.The 1918 virus did kill young people, but, the paper suggests, it was no exception to the observation that infectious diseases kill frail and sicker people most readily.Sharon DeWitte, an anthropologist at the University of Colorado, Boulder, and an author of the paper, said the finding had a clear message: “We should never expect any nonaccidental cause of death to be indiscriminate.”The analysis of skeletons, said J. Alex Navarro, a historian of the flu pandemic at the University of Michigan, makes for “a fascinating paper and a very interesting approach to studying this issue.”The lead author of the paper, Amanda Wissler, an anthropologist at McMaster University in Ontario, said she was intrigued by claims that the 1918 virus killed young and healthy people as readily as those with pre-existing conditions. In those days, there were no antibiotics or vaccines against childhood diseases, and tuberculosis was widespread among young adults.There was a puzzle about who died from that flu, though, which helped fuel speculation that health was no protection. The flu’s mortality curve was unusual, shaped like a W. Ordinarily, mortality curves are shaped like a U, indicating that babies with immature immune systems and older people have the highest death rates.The W arose in 1918 because death rates soared in people aged from about 20 to 40, as well as in babies and older people. That seemed to indicate that young adults were extremely vulnerable and, according to numerous contemporaneous reports, it did not matter if they were healthy or chronically ill. The flu was an equal opportunity killer.In one report, Colonel Victor Vaughn, an eminent pathologist, described a scene at Fort Devens in Massachusetts. He wrote that he had seen “hundreds of young men in uniforms of their country, coming into the wards in groups of 10 or more.” By the next morning, he added, “the dead bodies are stacked about the ward like cord wood.”The influenza pandemic, he wrote, “was taking its toll of the most robust, sparing neither soldier nor civilian, and flaunting its red flag in the face of science.”Dr. Wissler and Dr. DeWitte, who have done similar research on the Black Death, saw a way to test the hypothesis about young people. When people have had lingering illnesses like tuberculosis or cancer, or other stressors like nutritional deficiencies, their shin bones develop tiny bumps.Assessing frailty by looking for those bumps “is quite legitimate” as a method, said Peter Palese, a flu expert at the Icahn School of Medicine at Mount Sinai.The researchers used skeletons at the Cleveland Museum of Natural History. Its collection of 3,000 people’s remains, kept in large drawers in a massive room, includes each person’s name, age of death and date of death.Dr. Wissler said she treated the remains “with great respect,” as she examined the shin bones of 81 people aged 18 to 80 who died in the pandemic. Twenty-six of them were between the ages of 20 and 40.For comparison, the researchers examined the bones of 288 people who died before the pandemic.The results were clear: Those whose bones indicated they were frail when they got infected — whether they were young adults or older people — were, by far, the most vulnerable. Many healthy people were killed, too, but those who were chronically ill to start with had a much greater chance of dying.That makes sense, said Dr. Arnold Monto, an epidemiologist and professor emeritus at the University of Michigan’s School of Public Health. But, he said, although the new study makes “an interesting observation,” the skeletons were not a random sample of the population, so it can be difficult to be specific about the risk that came with frailty.“We are not used to the fact that younger healthy adults are going to die,” which often occurred in the 1918 pandemic, Dr. Monto said.Dr. Palese said there was a reasonable explanation for the W-shaped mortality curve of the 1918 flu. It means, he said, that people older than 30 or 40 had most likely been exposed to a similar virus that had given them some protection. Younger adults had not been exposed.

The NewsApproximately 20 percent of adolescents had symptoms of major depressive disorder in 2021 — the first full calendar year of the pandemic — but less than half who needed treatment received it, according to a new study.The research, published in JAMA Pediatrics, found that treatment was most lacking for minority adolescents, particularly those who are Latino and mixed-race.Christopher Capozziello for The New York TimesBackground: Depression was already on the riseMajor depressive disorder is a chronic condition that surfaces in episodes of depressed mood and loss of joy, with symptoms lasting at least two weeks. It is distinct from persistent depressive disorder, in which symptoms last two years or more.Previous research showed that the prevalence of major depressive disorder among adolescents nearly doubled recently, rising to 15.8 percent in 2019 from 8.1 percent in 2009. The Covid-19 pandemic amplified this trend as it caused isolation, uncertainty, loneliness and fear of illness among family members.The Findings: Treatment gaps persist, especially for minority teensThe new study on the prevalence of major depressive disorder in 2021 drew from a nationally representative sample of 10,700 adolescents, ages 12 to 17, whose experiences were recorded by the National Survey on Drug Use and Health.The study found some sharp differences in the prevalence of the condition across racial and ethnic groups. About 14.5 percent of Black adolescents, 14.6 percent of Asian adolescents and 20 percent of white adolescents reported symptoms of major depressive disorder. Latino adolescents experienced major depressive disorder at a slightly higher rate, around 23 percent.Though mixed-race and Latino adolescents had the highest rates of major depressive disorder, they had the lowest rates of treatment, the study found. Twenty-one percent of mixed-race adolescents and 29 percent of Latino adolescents with the condition received treatment for it, compared with nearly half of white adolescents. Treatment rates for Asian and Black adolescents fell in between.The study overlaps with previous research that found that adolescents from racial and ethnic minorities had fewer treatment options than their white peers did, with the most glaring gaps for teens living in lower-income communities.What’s Next: Addressing the inequitiesThe authors of the study called for policymakers to recognize the inequities in treatment that were “highlighted” by the pandemic. “As we move forward,” they concluded in the paper, “policy and clinical efforts should target adolescents as a whole and marginalized populations in particular, to ensure timely access to high-quality mental health treatment.”

Once thought to be the trash can of the cell, a little bubble of cellular stuff called the midbody remnant is actually packing working genetic material with the power to change the fate of other cells — including turning them into cancer.
It’s a surprise to many people, according to Ahna Skop, a University of Wisconsin-Madison genetics professor, that when one cell divides into two, a process called mitosis, the result is not just the two daughter cells.
“One cell divides into three things: two cells and one midbody remnant, a new signaling organelle,” says Skop. “What surprised us is that the midbody is full of genetic information, RNA, that doesn’t have much to do with cell division at all, but likely functions in cell communication.”
In a study published today in the journal Developmental Cell, Skop’s lab and collaborators from the Pasteur Institute in Paris, Harvard Medical School, Boston University and the University of Utah analyzed the contents of midbodies — which form between the daughter cells during division — and tracked the interactions of the midbody remnants set free after cell division. Their results point to the midbody as a vehicle for the spread of cancer throughout the body.
“People thought the midbody was a place where things died or were recycled after cell division,” Skop says. “But one person’s trash is another person’s treasure. A midbody is a little packet of information cells use to communicate.”
The midbody’s involvement in cell signaling and stimulating cell proliferation has been investigated before, but Skop and her collaborators wanted to look inside the midbody remnants to learn more.
What the researchers found inside midbodies was RNA — which is a kind of working copy of DNA used to produce the proteins that make things happen in cells — and the cellular machinery necessary to turn that RNA into proteins. The RNA in midbodies tends to be blueprints not for the cell division process but for proteins involved in activities that steer a cell’s purpose, including pluripotency (the ability to develop into any of the body’s many different types of cells) and oncogenesis (the formation of cancerous tumors).

It started with a bout of dry, itchy skin. Soon everything hurt. A specialist found a way to find some relief.The 49-year-old woman knew as soon as she got out of bed that something was very wrong. A quick survey of her body revealed the source: Sprinkled around her bellybutton were a half dozen blisters. They were small — the largest maybe the size of a pencil eraser — and painful. They looked like the kind of blister you might get on your heel after wearing a new pair of shoes. Except they were on her belly. She dressed carefully, choosing a pair of slacks that were a little loose around the middle. She put a long T-shirt under her sweater and hoped for the best. It was hard to concentrate at her job: The fleshy bubbles shot painful reminders every time she shifted position. When she got home, she immediately changed into a loosefitting dress. One of the blisters had ruptured, leaving an angry-looking raw red mark. She tried not to worry about it. It was September 2021; this was her first week back in the office after months of working at home, and she had too much on her mind already. But the next day, there were a couple of more blisters. And the day after that. By the end of the week, her back and belly were dotted with a dozen of these odd bubbles. Another dozen had burst, leaving sores that seeped a clear fluid. At night, the opened blisters soaked through the gauze she applied, then through her pajamas and into the sheets. Every movement she made ripped open the weeping wounds that had dried, marrying flesh to fabric.After a week of this, she took a sick day and began searching online for a dermatologist; after many calls, she found a practice where she could be seen the next day. The physician assistant who saw her was immediately concerned. After 40 years in practice, she had mastered the routine stuff — and this wasn’t routine. The patient told the P.A. that her skin had been extremely dry and itchy for months, but these blisters were new. As the P.A. examined the woman, she saw a few intact blisters but much of the woman’s torso was dotted with open splotches. This could be acne, she said. She would give her a cream for that. But it could also be a skin infection, and for that she prescribed an antibiotic. The patient should follow up in a couple of weeks so she could make sure things were moving in the right direction.They weren’t. At the woman’s next appointment, her skin hadn’t improved. The P.A. brought in one of the dermatologists. This was clearly some kind of blistering disease, the doctor said. Possibly a type of disseminated infection called eczema herpeticum, which is caused by the herpes simplex virus. The doctor prescribed a potent steroid cream along with an antiviral medication to be taken for a week. That should clear things up, she told the woman confidently. Blisters EverywhereBut over the next week, the blisters and the seeping spots that followed kept appearing. A second antibiotic was prescribed. More steroid creams. At this point, everything she did hurt. The blisters were everywhere: on her arms, her legs and all over her back and stomach. They were even in her mouth and on her scalp. Sitting down was impossible. All she could do was perch at the very edge of the chair. When she went back, the determined P.A. brought in another dermatologist. He examined the woman closely and said: “I think this may be something called bullous pemphigoid. If it is, we can treat you.” The P.A. explained that bullous pemphigoid (B.P.) is a rare autoimmune disease in which the body’s white blood cells create antibodies that attack the connection between the skin and the tissue below, causing these blisters. B.P. is treated with high-dose steroids, and when the disease cools off and blisters stop appearing, the steroids can be tapered down and sometimes stopped completely. The disease often resolves in a few months but can last for years. She started taking 60 milligrams of prednisone every day. The drug was awful. She couldn’t sleep. She felt constantly hungry but at the same time bloated and full. She was weak. Her legs felt like each weighed 100 pounds. But the results were amazing. There were fewer new blisters. And the raw spots marking where old blisters had once been started healing. She took the prednisone for two months. Her skin got better, but she gained more than 20 pounds, and the weakness was so profound she could hardly get out of bed in the morning. The weight gain was depressing, but the weakness was intolerable. Seeing how disabled she was, and how much her skin had improved, the P.A. lowered her dose. Almost immediately new crops of blisters arose. The P.A. increased the dose, but this woman clearly needed a different approach. She needed a doctor who specialized in these kinds of autoimmune diseases. There are internet groups for patients with B.P., the P.A. told the patient. They will know the best doctors for you. She was right. Through the International Pemphigus and Bullous Pemphigoid Foundation, she found a group of fellow sufferers online who lived not far from her on Long Island. They were unanimous in their recommendation: Dr. Allireza Alloo, an associate professor and attending physician at the Zucker School of Medicine at Hofstra/Northwell. Photo illustration by Ina JangHitting the Reset ButtonWhen Alloo entered the exam room to meet his new patient, he could see how tired she was. And frustrated. She had been uncomfortable in her own skin for months, and the treatment was almost as bad as the disease. It started with the itch, she reported. She always suffered from dry skin in the icy depths of winter, but a couple of years earlier her skin got that same dry itchiness while she was vacationing with friends in balmy Hawaii. She bought her usual wintertime creams — moisturizers and low-dose steroid creams — and slathered herself at regular intervals. It helped, but the itch never went away completely. Then she started getting canker sores — huge and painful ones. It hurt to eat. When one erupted in her mouth, she had to limit her diet to soups and shakes. And then the blisters started. Alloo had her change into a gown and then did a full exam of her skin. Her blisters ranged from the size of a BB pellet to the size of a quarter. He could push down on them and they wouldn’t rupture or spread outward, as you might see with bullous pemphigoid. The skin over these blisters was thin, almost translucent. And they were delicate. Alloo could understand why the first dermatologists had thought she had B.P. That disease often starts with an intense itchiness before the blisters appear. But the disrupted tissue is deep, so the skin forming the blisters is thicker. And the blisters themselves are tense and not soft like these. This wasn’t B.P. “You have pemphigus vulgaris,” Alloo told her, “and you are going to get better.” Pemphigus gets its name from the Greek word for blister. It was first described in the 18th century, and until the 20th century, with all its advances, every disease that caused blisters (and there are many) was called pemphigus. Pemphigus vulgaris is an autoimmune disorder, like B.P., but even rarer. In this disease, antibodies attack the connection between cells in the topmost layers of the skin so that it is easily separated from the layers below. An old test for the disease, called the Nikolsky test, was to rub the normal-appearing skin next to the blisters. In pemphigus, that skin often sheers off in thin sheets. Mouth sores are usually the disorder’s first symptom. Until recently the diagnosis was made solely by biopsy. Now a blood test can help identify the specific antibodies that do the damage. As with B.P., Alloo explained to the patient, pemphigus can often be treated with steroids. But when these are not sufficient or cause intolerable side effects, the next step is often a medication called rituximab. This powerful immune-suppressing drug destroys the antibody-producing white blood cells. When the next generation of these cells are created, they no longer make the abnormal antibodies. It’s like hitting the reset button at a cellular level.The patient had her first two doses of rituximab soon after that. Over the next few months her skin began to clear. It has been a year and a half since she started treatment, and she still hasn’t fully recovered; she expects she’ll need a couple of more doses of rituximab. But she is confident Alloo was right. She is going to get well again.Lisa Sanders, M.D., is a contributing writer for the magazine. Her latest book is “Diagnosis: Solving the Most Baffling Medical Mysteries.” If you have a solved case to share, write her at Lisa.Sandersmdnyt@gmail.com.