Body

For the first time, scientists from the German Cancer Consortium (DKTK) partner site in Essen/Düsseldorf have discovered stem cells of the hematopoietic system in glioblastomas, the most aggressive form of brain tumor. These hematopoietic stem cells promote division of the cancer cells and at the same time suppress the immune response against the tumor. This surprising discovery might open up new possibilities for developing more effective immunotherapies against these malignant brain tumors.

The DKTK is a consortium centered around the German Cancer Research Center (DKFZ) in Heidelberg, which has long-term collaborative partnerships with specialist oncological centers at universities across Germany.

Glioblastomas are the most common dangerous brain tumor in adults; they grow diffusely into healthy brain tissue and are therefore almost impossible to completely remove by surgery. They defy the combination of surgery, radiotherapy, and chemotherapy and usually continue to grow unchecked. Even immunotherapies, which achieve good results in some cases in other types of cancer, have had no effect on these malignant brain tumors to date.

"Glioblastomas apparently create an environment that actively suppresses the immune response," explained Björn Scheffler, DKTK Professor of Translational Oncology at the West German Tumor Center in Essen, partner site Essen/Düsseldorf. "They produce immunosuppressive messengers, and in the immediate environment of the tumors we find certain types of immune cells that specifically suppress the immune defense."

Researchers were not previously aware of the variety of immune cells in the microenvironment of glioblastomas in any detail. Yet Scheffler and his colleagues realized that a precise knowledge of the cellular composition of glioblastomas was necessary in order to be able to overcome tumor-related immunosuppression using appropriate treatments.

In tissue samples of 217 glioblastomas, 86 WHO grade II and III astrocytomas, and 17 samples from healthy brain tissue, the DKTK researchers used computer-assisted transcription analyses to draw up profiles of the cellular composition. The tissue samples were taken directly from the resection margins - where remaining tumor cells and immune cells meet.

The team were able to distinguish between signals from 43 cell types, including 26 different types of immune cells. To their great surprise, the researchers discovered hematopoietic stem and precursor cells in all the malignant tumor samples, while this cell type was not found in healthy tissue samples. "Blood stem cells are actually found in bone marrow, from where they supply the body with all kinds of mature blood cells - obviously including all the different types of immune cells. Blood stem cells of the brain tumor itself have never been described before now," remarked lead author Celia Dobersalske.

An even more surprising observation was that these blood stem cells seem to have fatal characteristics: They suppress the immune system and at the same time stimulate tumor growth. When the researchers cultured the tumor-associated blood stem cells in the same petri dish as glioblastoma cells, cancer cell division increased. At the same time, the cells produced large amounts of the PD-L1 molecule, known as an "immune brake", on their surface.

Tumor organoids - tiny tumors grown in a petri dish from the brain tumor cells of individual patients - reacted to the blood stem cells too. In the presence of these cells, the cancer cells formed a network of cell processes that connects them. Only a few years ago, scientists from the DKFZ and Heidelberg University Hospital discovered that glioblastoma cells communicate using these connections and can thus protect themselves against treatment-related damage.

All these observations suggested that the blood stem cells found in glioblastomas have a negative impact on the course of disease. This was confirmed in a study of 159 glioblastoma patients for whom data were available on the clinical course of disease. In this group of patients, it was consistently observed that the more blood stem cells a tumor contained, the more immunosuppressive messengers were released and the more immunosuppressive markers the cancer cells formed - and the lower the overall survival of the patients was.

In order to investigate brain tumor blood stem cells in more detail, the authors teamed up with the Department of Neurosurgery at Essen University Hospital (Director: Ulrich Sure) to extract individual cells from fresh patient tissue. Using gene expression sequencing in 660 individual cells, the researchers created a profile and compared it with cells from healthy bone marrow and blood. Analysis of these data led to several specific new suggestions as to how this tumor-promoting cell population could be made harmless.

It was already known from research reports that the blood stem cells in bone marrow tend to mature into immunosuppressive cell types during differentiation in the course of cancer. It appears that they are programmed by the tumor to do so. Expert and last author Igor Cima suspects that a similar phenomenon might be responsible for the observations in the glioblastoma-associated blood stem cells: "We can now see an opportunity to intervene in order to modify the differentiation process of the glioma-associated blood stem cells, for example through particular cell messengers, and hence prevent the immune system from being blocked as a result of the tumor. Immunotherapies would then have a better chance of being effective against glioblastomas."

Announcing a new article publication for BIO Integration journal. In this article the authors Chunxiong Zheng, Mingqiang Li and Jianxun Ding from Sun Yat-sen University, Guangzhou, China and Changchun Institute of Applied Chemistry, Changchun, China discuss the challenges and opportunities of nanomedicines in clinical translation.

Researchers are rapidly gaining a much deeper understanding of the challenges and opportunities of nanomedicines allowing for improvements in disease treatment and improved patient survival.

Deep exploration of the connections between preclinical and clinical modeling will facilitate the development of unique animal-based disease models remarkably similar to the human pathological mechanism to elevate the accuracy of predicting therapeutic efficacy in human clinical trials. Integration of active-targeting ligands and smart stimuli-responsive materials as well as the bio?nano interface interactions will endow nanomedicines with advanced functionalities to pioneer new-concept nanoparticle-based drugs.

By overcoming the obstacles of controllable, reproducible, as well as scalable nanoparticle production, cost, and toxicity, the next generation of nanomedicines that are incorporated with unique molecular modules and therapeutic agents, including cell-based therapeutics, siRNA, mRNA, DNA, protein, and so forth, will be accelerated into clinical development.

A global leading cause of death today is a class of dreaded disorders called cardiovascular diseases (CVD), which are ailments of the heart and blood vessels, such as arrhythmia, stroke, coronary artery diseases, cardiac arrest, and so on. The causes for each CVD are different and can be genetic or lifestyle related; but one key risk factor is hypertension, also known as high blood pressure (BP). For instance, as a recent paper published in Chinese Medical Journal notes, in 2017, hypertension was a factor in over 2.5 million deaths in China alone, 95.7% of which were due to CVD.

In this paper, Dr. Jing Liu, expert in the epidemiology of cardiovascular diseases at the Beijing Institute of Heart, Lung, and Blood Vessel Diseases, along with a team of researchers, explores exactly how much hypertension puts a person at significant risk of CVD. As the 2017 statistic shows, the team's study comes at a time when there is a pressing need to make informed decisions on managing hypertension appropriately.

The team began their research at the heels of recent findings in other studies, where it was observed that CVD risk can be elevated for a person even if their BP is below the clinical threshold of hypertension, and having hypertension for longer periods of time, such as several years, can amplify the risk of CVD. So, perhaps, the cumulative BP over a certain period of time, instead of the BP measured at only one point of time, would be a better indicator of the risk of CVD? Studies seemed to indicate as such, but exactly how much cumulative BP meant significant risk of CVD remained a mystery.

To find out, Dr. Liu's team analyzed data from a 26-year follow-up of the Chinese Multi-provincial Cohort Study-Beijing Project. From the data for the first 15 years from 1992 to 2007, they calculated the cumulative BP levels of 2429 participants who were free of CVD at 2007. From the data for 2007 to 2018, the number of CVD incidents among these participants were registered.

Between 2007 to 2018, 207 CVD events had occurred. The incidence of these events was greater among participants with higher cumulative BP. This suggested that cumulative BP was indeed a reliable measure of the risk of CVD.

Further, it appeared that having a cumulative BP level higher than 1970.8/1239.9 mmHg·year--equivalent to maintaining a BP level higher than 131/83 mm/Hg for 15 years--was associated with increased CVD risk. The team had arrived at the elusive threshold value they had set out to find. This value remained true even for participants whose BP values were within limits when measured in 2007. Conversely, if a participant's BP was high in 2007 but their cumulative BP over the 15 years preceding was low, their risk of CVD was low. Thus, cumulative BP was a better indicator of CVD risk than BP measured at one time.

Highlighting a key practical implication of this last finding, Dr. Liu says, "Our findings show that long-term exposure to high blood pressure may increase your risk of cardiovascular disease, although your current blood pressure level is lower than the diagnostic criterion of hypertension. For example, a person with current blood pressure level of 120/70 mmHg, which is within the normal range, could still be at a higher risk of contracting a cardiovascular disease in the future if his/her blood pressure level used to be higher than 130/80 mmHg for a long time, say years, in the past."

"This study underscores the importance of starting BP management early," Dr. Liu continues. Lifestyle changes to keep BP in check, coupled with regular monitoring can go a long way. In addition, waiting to medicate until the BP levels have become chronically high is not wise.

Dr. Liu also suggests a paradigm shift in the way hypertension is monitored by medical professionals. "We wish for our research to guide health care providers to pay attention to a patient's previous blood pressure levels and duration for which BP has been high, in addition to current levels. This will help to identify individuals at a higher risk of cardiovascular disease in the future."

Indeed, if we are to reduce the global burden of cardiovascular diseases, a paradigm shift is just what is needed.

ATLANTA - JUNE 28, 2021 - A new study finds evidence for adverse effects of the COVID-19 pandemic on declines in cancer detection and surgical treatments. The study, appearing in JNCI: The Journal of the National Cancer Institute, finds a 10.2% decline in real-time electronic pathology reports from population-based cancer registries in 2020 compared with those in 2019.

This study observation period, through December 2020, is one of the longest to date for evaluating the effects of the COVID-19 pandemic on cancer-related trends. To learn more about the indirect effects of the pandemic on cancer care, investigators led by Robin Yabroff, PhD, MBA of the American Cancer Society used electronic pathology data from population-based SEER cancer registries from Georgia and Louisiana that included information about cancers from all age groups. Trends for breast, colorectal, lung, and prostate cancers, the most common cancers, were assessed separately, as were trends by age group.

The study found initial patterns of declines were generally like those reported elsewhere, with greatest differences in April 2020 relative to April 2019, the first peak in COVID-19 mortality rates in Georgia and Louisiana. Declines in pathology reports in August, November, and December coincided with later peaks in COVID-19 mortality rates.

"We observed substantial declines in 2020 among cancers with effective screening tests, including breast and colorectal cancers, as well as across cancer sites and age groups without effective screening tests, including cancers among children and young adults," said Dr. Yabroff. "Declines across cancer sites and age groups suggest that in addition to delays in cancer screening, there were also delays in routine well-child and primary care, evaluation of signs and symptoms, and treatment initiation for most cancers."

Notably, the number of pathology reports in 2020 never consistently exceed those in 2019 after initial declines, which might be expected if a backlog of diagnoses were being resolved. By cancer type, percentage declines were greatest for lung (17.4%) and colorectal (12.0%) cancers, followed by breast (9.0%) and prostate (5.8%) cancers. Declines were observed in all age groups, including children and adolescents younger than 18 years. Patterns of declines were similar by cancer site and age group, with some variation in timing, magnitude, and duration of declines.

"The findings suggest substantial delays in diagnosis and treatment services for cancers during the pandemic, and that ongoing evaluation can inform public health efforts to minimize any lasting adverse effects of the pandemic on cancer diagnosis, stage, treatment, and survival," write the authors. "As data become available, evaluation of the effects of the pandemic on cancer stage at diagnosis and survival will be important, as will evaluation of racial/ethnic, socioeconomic, and geographic disparities in access to care and outcomes."

The U.S. Food and Drug Administration's controversial decision to approve aducanumab for the treatment of Alzheimer's disease raises at least three major ethical issues that need to be addressed, states a new article in the Hastings Center Report:

Billions of dollars in Medicare resources (which is to say, taxpayer dollars) are at risk of being unjustly squandered.

Physicians must choose between facilitating this unjust squandering and denying desperate patients and families access to this drug.

Patients and families are having false hopes legitimated and encouraged when physicians prescribe aducanumab.

The drug's approval was contrary to the nearly unanimous judgment of an FDA advisory committee that there was little reliable evidence of significant benefit. And given the drug's $56,000 annual price and the 3.1 million people who are candidates for the drug, the total cost to Medicare or a private insurer would be $174 billion per year. An additional $93 billion in health care costs would be needed to cover infusion costs and the brain scans needed to monitor the risk of drug side effects, which include brain swelling or small-vessel brain bleeds.

"If the drug reversed and cured Alzheimer's, it would make ethical and economic sense to fully fund access to it, in my view," writes Leonard Fleck, a professor in the Center for Bioethics and Social Justice at Michigan State University. "But it does not do that."

Fleck concludes with a proposal to minimize the ethical issues cited above and set an important precedent for similar drugs in the pipeline. Medicare should require Biogen, the manufacturer, to provide aducanumab at cost--between $2,500 and $5,000 per year--(plus a modest profit) while it conducts further research to establish whether the drug is safe and effective.

Fleck suggests that "this is the best nonideal resolution we can achieve, given competing pressures form intense patient demands and the need for the just and prudent allocation of limited health care resources."

He adds, "Other pharmaceutical companies could expect the same crimped profits . . . if they could not prove decisively that their drug yielded substantial clinical benefits at a reasonable cost. This would be unforgettable tough love."

San Francisco, CA, June 28, 2021 - A new study by Pendulum Therapeutics was presented at the American Diabetes Association's (ADA) 81st (Virtual) Scientific Sessions, the preeminent global conference for diabetes clinicians, researchers, and professionals where cutting-edge science and advances in diabetes research, prevention, and care are discussed. The findings shine a light on proprietary probiotic formulations that may be used to help patients with Type 2 Diabetes (T2D).

The research report entitled, "Changes in Circulating Metabolites, Including Butyrate, Points to Underlying Mechanism of a Probiotic Intervention That Improves Postprandial Hyperglycemia in Type 2 Diabetes," is believed to be the first of its kind. Its findings show Pendulum Glucose Control increases circulating butyrate and ursodeoxycholic acid (UDCA), a secondary bile acid in people with T2D, and supports the mechanism for improvement in glucose control.

According to the Centers for Disease Control and Prevention (CDC), more than 30 million Americans have T2D. New research shows that T2D is linked to an imbalance in the gut microbiome. Over time, people with T2D lose functionality of the beneficial bacteria strains that help digest dietary fiber and produce butyrate, a key molecule needed for managing insulin secretion and action, encouraging glucose regulation.

Previous studies have shown that there are three pillars to managing diabetes without the use of drugs: diet, exercise, and the microbiome. This new research helps explain why microbiome management is critical to keeping blood glucose under control.

"This study, part of an ongoing series, is adding to the body of knowledge on the microbiome and its role in metabolic disease including Type 2 Diabetes," said Orville Kolterman, MD, Chief Medical Officer at Pendulum Therapeutics and Principal Investigator of the study. "This data builds upon the research Pendulum Therapeutics presented at ADA's 79th Scientific Sessions two years ago. Our initial presentation showcased the efficacy of Pendulum's proprietary microbiome synbiotic formulation (Pendulum Glucose Control) and its ability to improve glucose control in patients with Type 2 Diabetes. This newest data will further inform the development of a portfolio of products that target the microbiome as a pathway to augment the dietary management of impaired glucose metabolism and other metabolic diseases."

Pendulum Glucose Control, Pendulum Therapeutics' ground-breaking, flagship product, is featured in the American Diabetes Association's selection of thought-leadership videos that will debut at ADA's 81st Scientific Sessions.

"The microbiome is proving to be an exciting and provocative area of study. Multiple studies to date point to the microbiome's integral role in disease management," said Colleen Cutcliffe, Pendulum's Co-Founder and Chief Executive Officer. "At Pendulum Therapeutics, we are committed to a methodical, rigorous, science-based approach to developing microbiome interventions. These data are affirming as we continue to pursue a portfolio of products to improve overall health."

(Philadelphia, PA) - Like a blocked water line, obstructions in blood vessels in the human circulatory system can cause serious problems. This is especially the case in superior vena cava syndrome (SVCS), in which oxygen-depleted blood returning from the head, upper chest, and arms is partially or completely prevented from reaching the heart. The result, however, is far more serious than the inconvenience of low water pressure from a clogged pipe - SVCS requires immediate attention.

Each year, some 15,000 people in the United States are affected by SVCS, symptoms of which include facial swelling, difficulty breathing, chest pain, mental confusion, and sometimes coma. A tumor compressing the superior vena cava vessel is the most common cause, but the condition can also result from intravascular devices, such as catheters and pacemakers, that may compress or obstruct the vessel.

Historically, radiation therapy, aimed at killing tumor cells, was the treatment of choice for SVCS. But in recent decades minimally invasive endovascular stenting, in which a tubular support is placed inside the collapsed or obstructed vessel, has become the preferred option of care. Whether it is the best option has been unclear, but now, a new analysis by researchers at the Lewis Katz School of Medicine at Temple University shows that endovascular therapy currently is the safest and most effective treatment for SVCS.

"Endovascular stenting has emerged as a first-line treatment for SVCS," said Riyaz Bashir, MD, FACC, RVT, Professor of Medicine at the Lewis Katz School of Medicine at Temple University and Director of Vascular and Endovascular Medicine at Temple University Hospital. "But until our recent work, there had been no systematic review carried out to assess the actual success rate of stenting."

The review by Dr. Bashir and colleagues was published online June 28 in the journal EClinicalMedicine.

The team's analysis was carried out by first conducting a systematic review of medical literature databases such as PubMed and Cochrane Library. Collaborator Stephanie Clare Roth, MLIS, Biomedical & Research Services Librarian at the Ginsburg Health Sciences Library at Temple University, performed searches targeted specifically at identifying studies on endovascular therapy and SVCS. Dr. Bashir's team then evaluated the studies for various endpoints of therapy, including success rate, restenosis rate, and SVCS recurrence after stenting.

Statistical analyses indicated that endovascular stenting was successful nearly 99 percent of the time, with relatively low restenosis and recurrence rates. "Our analyses really highlight the success of endovascular therapy for SVCS, showing that it is highly effective, safe, and durable," Dr. Bashir said.

Dr. Bashir and colleagues plan next to look at the use of endovascular therapy in clinical practice. "We would like to understand more about how SVCS patients in the United States are currently treated," he said. "Little is known about current clinical practices for SVCS, despite the severity of the condition."

PITTSBURGH, June 28, 2021 - It was a nagging mystery: A rare-disease expert at UPMC Children's Hospital of Pittsburgh had found a successful treatment for two of the deadliest symptoms of one of the more common classes of rare diseases diagnosed by newborn screenings, but one symptom--painful episodes of muscle breakdown that land victims in intensive care--persisted.

Today, the scientists announce in the journal Clinical & Translational Immunology that they've gotten to the bottom of the self-destructive syndrome and have a good lead on a treatment.

"These episodes looked a lot like inflammatory muscle disease, but usually that is persistent and doesn't wax and wane, so it wasn't a perfect fit," said senior author Jerry Vockley, M.D., Ph.D., chief of Genetic and Genomic Medicine and director of the Center for Rare Disease Therapy at UPMC Children's and professor of pediatrics and human genetics at the University of Pittsburgh School of the Health Sciences. "Still, I couldn't shake the thought that there was some inflammatory link, so we tested patient blood samples. Sure enough, when the episodes were happening, certain inflammatory markers were high, and when the patients were well, they were lower. Knowing this will allow us to try to figure out why this inflammation is happening and prevent it."

Very long chain acyl-CoA dehydrogenase deficiency--VLCADD--is a genetic disease where a mutation prevents an enzyme from breaking down fatty acids into energy. It afflicts about one in 40,000 people but is part of a class of diseases that affect four times that number, making it one of the more common of the rare genetic diseases that U.S. doctors now universally test for in newborns.

If untreated, the disease can cause heart failure and low blood sugar--two life-threatening conditions. When coupled with a modified diet, a recently approved drug that Vockley was involved in developing can manage those symptoms. But patients still experience rhabdomyolysis--muscle breakdown--indicating that the disease acts through another pathway.

With his hunch that inflammation might be behind the rhabdomyolysis, Vockley consulted with Abbe de Vallejo, Ph.D., associate professor of pediatrics, immunology and rheumatology in Pitt's School of Medicine and director of the Flow Cytometry Core Facility at the John G. Rangos Sr. Research Center located at UPMC Children's.

Their teams tested patient blood samples that Vockley had stored from his previous research and obtained additional samples from new patients. One patient--Bella Linz, 15, of Meadville, Pa.--had particularly persistent bouts of rhabdomyolysis requiring week-long hospitalizations more than a dozen times per year. She consented to give blood samples over several years and participate in the study. Regular infusions of an anti-inflammatory medication kept her from needing to be hospitalized for nearly 10 months, and then only irregularly since.

"Bella is a very empathetic child, very caring," said her mother, Carrie Linz. "So, when she was going through trying out the different medications and the pain that came with the shots, we'd talk about the other children this would help--how what she was doing would benefit other kids, quicker and for a longer period of time. That helped us find purpose."

The team found that when the patients were experiencing episodes of rhabdomyolysis, they were having what's known as a "cytokine storm"--when various inflammatory molecules are produced by immune cells in excessive quantities, leading them to attack the body. Even when they weren't having these episodes, the patients had elevated inflammatory markers, though at lower numbers than when they were symptomatic.

Still, the solution isn't so clear-cut, de Vallejo said.

"The cytokines activate cells, but those cells aren't following the rules," he said. "In the immune system, cytokines and cells 'talk' to each other to regulate and counter-regulate their actions accordingly. But that's not happening the way you'd expect in VLCADD patients. It's paradoxical and is our next challenge. If we can find the disconnect, we may be able to learn what is triggering the inflammatory response and stop it from happening altogether."

In the meantime, the team also is exploring the off-label and compassionate use of certain anti-inflammatory medications to treat acute, symptomatic rhabdomyolysis and prevent it from occurring.

A discovery by a team of researchers, led by a Geisinger professor, could yield a potential new treatment for breast cancer.

In a study published this month in Cell Reports, the team used small molecules known as peptides to disrupt a complex of two proteins, RBM39 and MLL1, that is found in breast cancer cells but not in normal cells.

The research team discovered that the abnormal interaction between RBM39 and MLL1 is required for breast cancer cells to multiply and survive. The team developed non-toxic peptides that prevent these proteins from interacting in breast cancer cells, disrupting their growth and survival.

"Because these proteins do not interact in normal cells, the peptides we developed are not harmful to them," said Anne M. Moon, M.D., Ph.D., professor at Geisinger's Department of Molecular and Functional Genomics and senior author of the study. "This offers promise for future non-toxic cancer treatment."

Further laboratory tests are needed before the treatment could be trialed in humans, Moon said.

Anxiety, commonly termed as a feeling of fear, dread, and restlessness, is a perfectly normal reaction to stressful situations. However, a state of heightened anxiety, which is the reality for thousands of people who struggle to cope with these feelings, is called anxiety disorder. Anxiety disorder can invoke debilitating fear or apprehension, even without any immediate threat. Though intensive research over the years has yielded a plethora of information, and effective drugs like selective serotonin reuptake inhibitors have been used to alleviate this condition, a lot remains to be understood about this complex condition and its treatment.

For a group of Japanese researchers from Tokyo University of Science and University of Tsukuba, endeavoring in this line of research is not new. In a previous study, they used a drug called KNT-127, which acts by activating specific receptors in the brain, called "delta opioid receptors." The researchers found KNT-127 to reduce anxiety-like behavior in mice. They found that KNT-127 caused the reduction of an excitatory neurotransmitter, called glutamate, in the extracellular regions of a part of the brain that controls several emotional states, called the "prelimbic subregion of the medial prefrontal cortex" (PL-PFC). The researchers went on to study this phenomenon in a new study published in Biochemical and Biophysical Research Communications.

According to Professor Akiyoshi Saitoh, from the Faculty of Pharmaceutical Sciences, Tokyo University of Science, and corresponding author of this study, there is a good reason to have investigated the glutamate levels specifically in PL-PFC. He says, "The medial prefrontal cortex (mPFC) plays a vital role in the processing of emotional events. It has been shown that activation of the glutamatergic transmission in PL-PFC evoked anxiety-like behavior in rodents."

Accordingly, Professor Saitoh and his colleagues conducted electrophysiological studies at a single-neuron level in mice. The team measured spontaneous excitatory currents from the glutamate-releasing presynapse region of various important neurons treated with and without KNT-127, in the PL-PFC of mice that had been induced to exhibit anxious behavior.

For neurons treated with KNT-127, the results showed that release of glutamate was reduced at the PL-PFC synapses. Since this excitatory neurotransmitter relays information from one neuron to the other, at the synapse region, the corresponding brain activity was also found to be lowered. Interestingly, the team found that KNT-127 treatment made the PL-PFC neurons less excitable. The researchers considered these findings to be a consequence of the anxiolytic effects of KNT-127.

Overall, this study proposes a novel pathway--and a novel drug candidate--that can be targeted for treating anxiety disorder. Commenting on the clinical potential of drugs like KNT-127, Dr. Daisuke Yamada, one of the investigators in the study from Tokyo University of Science, says, "There is a need for the development of new therapeutic agents that have different mechanisms of action from existing drugs. The results of this study are expected to lead to the development of evidence-based antipsychotics with a new mechanism of action, targeting opioid delta receptors."

Indeed, the world can hope for groundbreaking anxiolytic drugs to enter the market, taking after the results of this promising study!

The first two COVID-19 vaccines authorized for emergency use by the Food and Drug Administration (FDA) employed a technology that had never before been used in FDA-approved vaccines. Both vaccines performed well in clinical trials, and both have been widely credited with reducing disease, but concerns remain over how long immunity induced by the new vaccine technology will last.

Now, a study from researchers at Washington University School of Medicine in St. Louis, published June 28 in the journal Nature, has found evidence that the immune response to such vaccines is both strong and potentially long-lasting. Nearly four months after the first dose, people who received the Pfizer vaccine still had so-called germinal centers in their lymph nodes churning out immune cells directed against SARS-CoV-2, the virus that causes COVID-19. Germinal centers, which form as the result of natural infection or vaccination, are boot camps for immune cells, a place where inexperienced cells are trained to better recognize the enemy and weapons are sharpened. A better germinal center response may equal a better vaccine.

Moreover, vaccination led to high levels of neutralizing antibodies effective against three variants of the virus, including the Beta variant from South Africa that has shown some resistance to vaccines. Vaccination induced stronger antibody responses in people who had recovered from SARS-CoV-2 infection compared to those who had never been infected.

In April, both Pfizer and Moderna reported that their vaccines provided at least six months of protection. Their reports were based on tracking whether vaccinated people came down with COVID-19. Other groups have monitored antibody levels in the blood and concluded that the vaccine provides at least months of protection. But nobody had looked to see how the immune response was developing in the body, which could provide important clues to the strength and persistence of the immune response without requiring years of follow-up.

"Germinal centers are the key to a persistent, protective immune response," said senior author Ali Ellebedy, PhD, an associate professor of pathology & immunology, of medicine and of molecular microbiology. "Germinal centers are where our immune memories are formed. And the longer we have a germinal center, the stronger and more durable our immunity will be because there's a fierce selection process happening there, and only the best immune cells survive. We found that germinal centers were still going strong 15 weeks after the vaccine's first dose. We're still monitoring the germinal centers, and they're not declining; in some people, they're still ongoing. This is truly remarkable."

Scientists don't fully understand why some vaccines, such as the one for smallpox, induce strong protection that lasts a lifetime, while others, such as the vaccine for whooping cough, require regular boosters. But many suspect that the difference lies in the quality of the germinal centers induced by different vaccines.

The Pfizer and Moderna vaccines were created with mRNA technology. Unlike most vaccines, which provide bits of viral or bacterial proteins to trigger an immune response, mRNA-based vaccines provide instructions for the body to build and release foreign proteins, such as the spike protein in the case of the SARS-CoV-2 virus. To assess whether this new kind of vaccine induces a good germinal center response, Ellebedy and co-first author Jackson Turner, PhD, an instructor in pathology & immunology, teamed up with co-senior author Rachel Presti, MD, PhD, an associate professor of medicine, and co-first author Jane O'Halloran, MD, PhD, an assistant professor of medicine, and started the study once the first COVID-19 vaccine became available in mid-December 2020.

The team enlisted the help of co-authors Sharlene Teefey, MD, and William Middleton, MD, both professors of radiology, to perform ultrasound-guided sampling of the minuscule germinal centers in lymph nodes in the armpit. Teefey and Middleton extracted cells from 14 people who received the Pfizer vaccine. Samples were obtained three weeks after the first dose (just prior to administration of the second dose), and at weeks four, five and seven. Ten of the participants gave additional samples 15 weeks after the first dose. None of the participants previously had been infected with the virus that causes COVID-19.

Three weeks after the first dose, all 14 participants had formed germinal centers with B cells producing antibodies that target a key SARS-CoV-2 protein. The response expanded greatly after the booster shot and then stayed high. Even 15 weeks after the first dose, eight of 10 people still had detectable germinal centers containing B cells targeting the virus.

"This is evidence of a really robust immune response," Presti said. "Your immune system uses germinal centers to perfect the antibodies so they can bind well and last as long as possible. The antibodies in the blood are the end result of the process, but the germinal center is where it is happening."

The researchers also obtained blood samples from 41 people who received the Pfizer vaccine, including eight who previously had been infected with the virus that causes COVID-19. Samples were obtained prior to the administration of each dose of the vaccine, as well as at weeks four, five, seven and 15 after the first dose. In people without prior exposure to the virus, antibody levels rose slowly after the first dose and peaked one week after the second. People who previously had been infected already had antibodies in their blood before the first dose. Their levels shot up quickly after the first dose and peaked higher than the uninfected participants' levels.

"We didn't set out to compare the effectiveness of vaccination in people with and without a history of infection, but when we looked at the data we could see an effect," O'Halloran said. "If you've already been infected and then you get vaccinated, you get a boost to your antibody levels. The vaccine clearly adds benefit, even in the context of prior infection, which is why we recommend that people who have had COVID-19 get the vaccine."

A new national study finds that children in the United States with greater screen time usage at ages 9-10 are more likely to gain weight one year later.

The study, publishing in Pediatric Obesity on June 28, found that each additional hour spent on virtually all forms of screen time was associated with a higher body mass index (BMI) one year later. In particular, researchers found that each extra hour spent watching or streaming television, YouTube videos, video games, video chat, and texting led to a higher risk of weight gain one year later. At the start of the study, 33.7% of children were considered overweight or obese, and this increased to 35.5% one year later, a proportion that is expected to rise in the late teens and early adulthood.

BMI is calculated based on height and weight. Researchers analyzed the BMI z-scores, which is relative weight adjusted for a child's age and sex, of 11,066 preteens who are part of the Adolescent Brain Cognitive Development Study, the largest long-term study of brain development in the United States. The children answered questions about their time spent on six different screen time modalities, including television, social media, and texting.

"Screen time is often sedentary and may replace time for physical activity. Children are exposed to more food advertisements and are prone to snacking and overeating while distracted in front of screens," said lead author, Jason Nagata, MD, assistant professor of pediatrics at the University of California, San Francisco.

"A negative body image and subsequent overeating may be a result of exposure to social media and unattainable body ideals," said senior author, Kyle T. Ganson, PhD, assistant professor at the University of Toronto's Factor-Inwentash Faculty of Social Work. "This study emphasizes the need for more research on how screen time impacts the well-being of young people now and in the future."

"The study was conducted prior to the COVID-19 pandemic, but its findings are especially relevant for the pandemic," noted Nagata. "With remote learning, the cancellation of youth sports and social isolation, children have been exposed to unprecedented levels of screen time."

"Screen time can have important benefits such as education and socialization during the pandemic, but parents should try to mitigate risks from excessive screen time including increased sedentary time and decreased physical activity. Parents should regularly talk to their children about screen-time usage and develop a family media use plan," said Nagata.

In first-of-its kind research led by a University of Massachusetts Amherst psychotherapy researcher, mental health care patients matched with therapists who had a strong track record of treating the patients' primary concerns had better results than patients who were not so matched.

In addition, this "match effect" was even more beneficial and pronounced for patients with more severe problems and for those who identified as racial or ethnic minorities.

The findings are published in JAMA Psychiatry and the Journal of Consulting and Clinical Psychology.

"One of the things we've been learning in our field is that who the therapist is matters," says lead author Michael Constantino, professor of clinical psychology and director of the Psychotherapy Research Lab, who seeks to understand the variability of outcomes among patients receiving mental health treatment. "We've become very interested in this so-called therapist effect. Earlier on, there was a heavier emphasis on what the treatment was as opposed to who was delivering it."

Constantino and colleagues have discovered, for example, that psychotherapists possess relative strengths and weaknesses in treating different types of mental health problems. Such performance "report cards" hold promise, then, for personalizing treatment toward what therapists do well.

The researchers conducted a randomized clinical trial involving 48 therapists and 218 outpatients at six community clinics in a health care system in Cleveland, Ohio. They used a matching system based on how well a therapist has historically treated patients with the same concerns. The matching relied on a multidimensional outcomes tool called the Treatment Outcome Package (TOP), which assesses 12 symptomatic or functional domains: depression, quality of life, mania, panic or somatic anxiety, psychosis, substance misuse, social conflict, sexual functioning, sleep, suicidality, violence and work functioning. The matched group was compared to a group of patients who were case-assigned as usual, such as by therapist availability or convenience of office location.

"By collecting TOP data from enough patients treated by a given therapist, this outcomes tool can establish the domains in which that therapist is stably effective (historically, on average, their patients' symptoms reliably improved), neutral (historically, on average, their patients' symptoms neither reliably improved nor deteriorated), or ineffective
(historically, on average, their patients' symptoms reliably deteriorated)," the paper states.

To qualify for matching, the therapists had to have completed a minimum of 15 cases with patients who had completed the TOP before and after treatment. For the trial, neither the patients nor the therapists knew if they had been matched or were case-assigned as usual. "We think there would be an even stronger positive impact if the patients knew they were empirically well-matched versus assigned by chance," Constantino says. "Such knowledge might cultivate more positive expectations, which are generally associated with better therapy outcomes."

Post-therapy reports by patients showed that those in the matched group experienced significantly greater reductions in general impairment compared with those who were randomly assigned a therapist. "We showed that with this matching system you can get a big bump in improvement rates," Constantino says.

The finding that the improvement in the matched group was even greater among people who identified as racial or ethnic minorities may provide a way to address and improve mental health care access and quality in traditionally underserved populations, Constantino says.

The JAMA Psychiatry paper concludes, "Notably, the good fit in this study came not from changing what the therapists did in their treatment, but rather who they treated. Capitalizing on whatever it is that a therapist historically does well when treating patients with certain mental health problems, the current data indicate that our match system can improve the effectiveness of that care, even with neither therapist nor patient being aware of their match status."

Two recent collaborative publications by CU Cancer Center members provide insights into how chronic inflammation can serve as a key factor in the development of leukemia and other blood cancers.

Eric Pietras, PhD, CU Cancer Center member and assistant professor in the CU School of Medicine Division of Hematology, and James DeGregori, PhD, deputy director of the CU Cancer Center and professor in the Department of Biochemistry and Molecular Genetics, were corresponding authors on both papers.

Both papers provide support for the theory of adaptive oncogenesis, which was developed by DeGregori. The theory stipulates that chronic inflammation (such as the inflammation associated with aging or with chronic disease) reduces the fitness of normal cells, hindering their ability to reproduce and creating space for cells with cancer-causing mutations to proliferate.

Study challenges previous understandings

The first paper, "PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress," on which Pietras' laboratory technician, James Chavez, B.S., is the primary author, explores the effect of inflammation on the transcription factor PU.1 and its effect in turn on the production of hematopoietic stem cells (HSCs) -- the immature cells found in the bone marrow that can develop into blood cells.

Pietras says this research challenged his previous understanding of how inflammation impacts HSCs.

"We thought that introducing a proinflammatory cytokine like Interleukin (IL)-1 would make hematopoietic stem cells proliferate, because when you have inflammation, the body typically interprets it as a signal to produce more white blood cells to fight off an infection or injury," he explains.

Instead, Pietras and his team found that, in the presence of IL-1, genes that control the creation of additional hematopoietic stem cells were turned off rather than on, particularly genes related to the synthesis of proteins, the key building block for new cells.

After delving into the surprising findings, the team found that a transcription factor called PU.1 represses protein synthesis genes in HSCs during periods of inflammation.

"That made us wonder what would happen if we got rid of PU.1," Pietras says. The team used genetic mouse models that allowed them to reduce the amount of PU.1 in the HSCs or remove it altogether. They found that when PU.1 is reduced or removed, inflammation caused by the introduction of IL-1 triggers the proliferation and expansion of HSCs as Pietras previously predicted it would.

"Our findings point to an interesting mechanism for how inflammation can trigger differences in cell fitness when normal HSCs have to compete with HSCs harboring oncogenic mutations that are known to disable or reduce PU.1," Pietras says. "In this case, those PU.1- deficient HSCs act like normal cells as long as there's no inflammation. But as soon as you trigger an inflammatory response, it's like throwing gasoline on a fire. The HSCs with loss of PU.1 expand because there is no longer a mechanism to turn their protein synthesis off. And when that happens, you get uncontrolled growth of the PU.1-deficient hematopoietic stem cells, which can eventually lead to leukemia, a type of blood cancer."

As for the way his new findings contradicted his previous understanding of inflammation, Pietras says he's happy to have been proven wrong. "I think some of the best science is that which disproves your own notions and dogmas," he says.

Chronic inflammation and aging

The second paper, "Chronic interleukin-1 exposure triggers selection for Cebpa-knockout multipotent hematopoietic progenitors," co-led by DeGregori and Pietras, also studies the impact of the proinflammatory cytokine IL-1 on hematopoietic stem and progenitor cells (HSPCs). The primary author on this study was Kelly Higa, a student in CU's MD/PhD program co-mentored by DeGregori and Pietras.

DeGregori says one of the primary goals of the team's study was to better understand the factors that determine what kind of mature blood cells are produced from our blood stem cells (the HSPCs), particularly in response to chronic inflammation.

They studied this in mouse models by injecting them with IL-1, mimicking an infection and causing inflammation. As expected, this skewed blood cell production towards making granulocytes, a type of white blood cell that helps the immune system fight infections.

However, the team also found that inflammation seemed to alter selection in the HSPCs toward oncogenic mutations of the Cebpa gene (a key transcription factor for making mature myeloid cells like granulocytes) that are often found in leukemia.

"For every good process that happens in your body, such as fighting infection, there can also be adverse reactions that create risk," DeGregori says. "And we think inflammation creates some level of risk, particularly if it's a chronic situation."

Examples of conditions that could cause long-term inflammation include arthritis and chronic infections such as colitis. But DeGregori says the most widespread cause of inflammation is simply old age.

"When we get old, many of us become chronically inflamed," he explains. "Not everyone experiences the same level of inflammation, but higher inflammation tends to coincide with worse outcomes for people. Our data would suggest that old age, and the inflammation associated with it, could contribute to the increased leukemia rates that occur in the elderly, particularly acute myeloid leukemia (AML)."

DeGregori says this finding "flies in the face" of what most people think, which is that cancer-causing mutations drive the over-proliferation of cancer cells. "But what we're saying is that the cancer-causing mutation doesn't do anything by itself," he says. "There needs to be a selective force, which in this case is inflammation."

Inflammation: friend and foe

But both DeGregori and Pietras stress that the solution is not as seemingly "simple" as wiping out inflammation altogether.

"Inflammation is critically important for surviving infections," DeGregori says. "Over evolutionary time, dying from infection was a major risk, so we evolved inflammation as a mechanism to avoid that. On the other hand, we've shown that chronic inflammation could promote selection for oncogenic events, such as through inhibition of Cebpa".

"Inflammation isn't always an enemy," Pietras agrees. "We need it to fight off pathogens and to help repair tissues. It's when inflammation becomes pathological that it becomes an enemy."

Pietras says the next step is to thoughtfully apply the findings to human biology.

"I think there are a few different implications for the work," Pietras says. "One is that we're learning more about when and where stem cells first gain mutations and the extent to which inflammation can impact the capacity of these mutant HSCs to eventually initiate leukemia. What this tells us is that if we can intervene at an early stage, we may be able to reduce the risk of getting blood cancer."

The researchers say the studies also indicate that both preventive measures for those at higher risk of developing cancer and treatments for those who have already been diagnosed could potentially be improved by addressing chronic "bad" inflammation while maintaining the immune system's ability to function.

"We don't want to limit someone's risk of getting leukemia and at the same time increase their risk of dying from an infection," DeGregori says. "But the more we learn about it, the better we might get at finding that happy balance."

Oncotarget published "Insulin-like growth factor 1/Child-Turcotte-Pugh composite score as a predictor of treatment outcomes in patients with advanced hepatocellular carcinoma treated with sorafenib" which reported that this study investigated the association of the IGF/CTP score with overall survival and progression-free survival of HCC patients treated with sorafenib.

The authors calculated the IGF/CTP score and used the Kaplan-Meier method and log-rank test to estimate and compare the time-to-event outcomes between patient subgroups.

171 patients were included, 116 of whom were CTP class A. Median PFS for IGF/CTP score AA and AB patients were 6.88 and 4.28 months, respectively.

Median OS for IGF/CTP score AA and AB patients were 14.54 and 7.60 months, respectively.

In CTP class A patients, IGF/CTP score B was associated with shorter PFS and OS, however, study was underpowered to reach statistical significance.

In CTP class A patients, IGF/CTP score B was associated with shorter PFS and OS

Dr. Ahmed O. Kaseb from The University of Texas MD Anderson Cancer Center said, "Accurate assessment of the functional hepatic reserve is important to the prognostic and treatment prediction for patients with liver disease."

Several prospective and retrospective studies have confirmed that HCC patients in CTP classes B and C showed worse prognoses and accelerated decline in liver function as compared with CTP A patients.

However, it is known now that the clinical outcomes for patients can vary even within those in the same CTP class, including class A. In addition, subjective variables, ascites and encephalopathy of the CTP scoring system have been considered its major shortcoming because they are difficult to grade, vary daily, and could be affected by symptomatic management.

Subsequently, the authors prospectively validated a revised CTP scoring system by replacing the subjective clinical assessment of ascites and encephalopathy in the CTP score with objectively quantified plasma IGF-1 levels to create new IGF/CTP score classes.

In addition, these results showed that a significant number of patients in the old CTP class A were reassigned as IGF/CTP-B or -C and had significantly poorer survival than did those in IGF/CTP-A, proving the usefulness of the IGF/CTP composite score to refine the CTP scoring system's prognostic accuracy.

Sorafenib, the first drug approved for the treatment of HCC, was approved after randomized, placebo-controlled trials demonstrated that it improved the overall survival of CTP class A patients with advanced HCC; the purpose of our current study was to investigate the usefulness of the IGF/CTP score in predicting overall survival and progression-free survival in CTP class A patients with advanced HCC who were treated with sorafenib.

The Kaseb Research Team concluded in their Oncotarget Research Output, "our results demonstrate that, in CTP class A patients with advanced HCC treated with sorafenib, the IGF/CTP scoring system provides more accurate associations with survival than the CTP score. This finding should be validated in studies with larger sample sizes. If our results are validated in independent future studies, our approach of computing CTP scores using IGF-1 levels and other laboratory-based parameters that are less subjective than the clinical assessments currently used may lead to a paradigm shift in predicting the efficacy and toxicity of systemic HCC therapies and in stratifying patients in HCC clinical trials. Our approach could also help differentiate between CTP class A patients who may benefit from active therapy and those in whom active therapy should be deferred to avoid unnecessary harm and save health care resources."