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BOSTON - Many patients with cancer receive immune checkpoint inhibitors that strengthen their immune response against tumor cells. While the medications can be life-saving, they can also cause potentially life-threatening side effects in internal organs. This double-edged sword makes it challenging for clinicians to decide who should be considered candidates for treatment. A new analysis led by researchers at Massachusetts General Hospital (MGH) indicates which patients are at elevated risk of side effects severe enough to require hospitalization. The findings are published in the Journal for ImmunoTherapy of Cancer.

"Understanding the risk factors for predicting high-grade toxicities will help in appropriately selecting patients most likely to tolerate immune checkpoint inhibitor therapy," says co-senior author Yevgeniy R. Semenov, MD, an investigator in the Department of Dermatology at MGH. "It will also help to identify higher risk patients who should be carefully monitored if they initiate this therapy."

To this end, Semenov and his colleagues analyzed information from a national health insurance claims database, identifying 14,378 patients with cancer who received immune checkpoint inhibitors in the United States between 2011 and 2019. The team found that 3.5% of patients who received immune checkpoint inhibitors experienced side effects that required patients to be hospitalized and to receive immunosuppression treatments (to counteract the effects of the immune checkpoint inhibitors).

"We found that younger age, melanoma, and kidney cancer were each predictive of the development of severe immunotherapy toxicities," says Semenov. Patients also faced a higher risk if they received multiple immune checkpoint inhibitors, rather than just one type.

"This study provides the foundation for studying severe immunotherapy toxicities using a Big Data analytic framework, which will be necessary when understanding the impact of these life-saving medications across diverse populations," says Semenov. "Also, it is the first step in developing robust clinical risk prediction models to identify patients at highest risk for the development of life-threatening treatment complications."

BOSTON - Immune checkpoint inhibitors, which boost the immune system's response against tumor cells, have transformed treatment for many advanced cancers, but short-term clinical trials and small observational studies have linked the medications with various side effects, most commonly involving the skin. A more comprehensive, population-level analysis now provides a thorough look at the extent of these side effects and provides insights on which patients may be more likely to experience them. The research was led by investigators at Massachusetts General Hospital (MGH) and is published in the Journal of the American Academy of Dermatology.

"Immunotherapies, which include immune checkpoint inhibitors, are an increasingly common treatment modality for advanced cancers, with more than 200,000 patients being started on these therapies annually," says co-senior author Yevgeniy R. Semenov, MD, an investigator in the Department of Dermatology at MGH. "As the use of immune checkpoint inhibitors increases, so will the incidence of adverse events, underscoring the importance of research into their incidence, type and severity."

Semenov and his colleagues used a "Big Data" approach to study the U.S. prevalence of skin-related side effects, as well as when they arise and how they're treated, in a large population of patients who received immune checkpoint inhibitors.

The study involved analyzing information from a national health insurance claims database pertaining to 8,637 patients who were treated with immune checkpoint inhibitors as well as an equal number of patients with cancer who did not receive these medications. The overall incidence of skin-related side effects was 25.1%, with a median time of onset of 113 days. "We found that only 10 of more than 40 skin conditions previously reported to be linked to immune checkpoint inhibitors are actually seen at a higher incidence among patients on these medications compared with other patients who were matched by demographics, cancer type and comorbidities," says Semenov.

These conditions manifested with symptoms of itching, inflammation, rash, skin color loss, swelling or blisters. Patients with melanoma or kidney cancer and those receiving multiple types of immune checkpoint inhibitors were at an especially high risk of developing these skin problems.

The investigators' real-world data also found that skin-related symptoms tended to arise later than those noted in clinical trials. In addition, they found that clinicians often prescribed systemic corticosteroids to treat them even though these drugs should generally be avoided due to concerns that they may blunt the anti-tumor effects of immunotherapy.

"These findings are of particular clinical relevance to both dermatologists and oncologists caring for patients receiving immune checkpoint inhibitors," says Semenov. For example, clinicians should be on the lookout for the 10 conditions identified in this analysis as patients continue taking these medications. "The real-world delays in the time to presentation of many of these conditions should also revise clinicians' understanding of when to expect patients to present with these toxicities and not to rule out a delayed onset of symptoms as being unrelated to immunotherapy," adds Semenov.

The findings also suggest an opportunity for improving care for patients, he says: "Dermatologists can work with oncologists to facilitate evaluations of these vulnerable patients so that they can take steps to prevent progression to more severe toxicities."

Moving endangered species to new locations is often used as part of species conservation strategies, and can help to restore degraded ecosystems. But scientists say there is a high risk that these relocations are accidentally spreading diseases and parasites.

The new report published today in the journal Conservation Letters focuses on freshwater mussels, which the researchers have studied extensively, but is applicable to all species moved around for conservation purposes.

Mussels play an important role in cleaning the water of many of the world's rivers and lakes, but are one of the most threatened animal groups on Earth. There is growing interest in moving mussels to new locations to boost threatened populations, or so they can be used as 'biological filters' to improve water quality.

A gonad-eating parasitic worm, Rhipidocotyle campanula, which can leave mussels completely sterile, was identified as a huge risk for captive breeding programmes where mussels from many isolated populations are brought together.

"We need to be much more cautious about moving animals to new places for conservation purposes, because the costs may outweigh the benefits," said Dr David Aldridge in the Department of Zoology at the University of Cambridge, senior author of the report.

He added: "We've seen that mixing different populations of mussels can allow widespread transmission of gonad-eating worms - it only takes one infected mussel to spread this parasite, which in extreme cases can lead to collapse of an entire population."

Pathogens can easily be transferred between locations when mussels are moved. In extreme cases, the pathogens may cause a population of mussels to completely collapse. In other cases infections may not cause a problem unless they are present when other factors, such as lack of food or high temperatures, put a population under stress leading to a sudden outbreak.

The report recommends that species are only relocated when absolutely necessary and quarantine periods, tailored to stop transmission of the most likely pathogens being carried, are used.

It identifies four key factors that determine the risk of spreading pathogens when relocating animals: proportion of infected animals in both source and recipient populations; density of the resulting population; host immunity; and the life-cycle of the pathogen. Pathogens that must infect multiple species to complete their life-cycle, like parasitic mites, will only persist if all of the species are present in a given location.

"Moving animals to a new location is often used to protect or supplement endangered populations. But we must consider the risk this will spread pathogens that we don't understand very well at all, which could put these populations in even greater danger," said Josh Brian, a PhD student in the Department of Zoology at the University of Cambridge and first author of the report.

Different populations of the same species may respond differently to infection with the same pathogen because of adaptations in their immune system. For example, a pack of endangered wolves moved to Yellowstone National Park died because the wolves had no immunity to parasites carried by the local canines.

The researchers say that stocking rivers with fish for anglers, and sourcing exotic plants for home gardens could also move around parasites or diseases.

"Being aware of the risks of spreading diseases between populations is a vital first step towards making sure we avoid unintentional harm in future conservation work," said Isobel Ollard, a PhD student in the Department of Zoology at the University of Cambridge, who was also involved in the study.

Good cholesterol, which is transported in HDLs (high-density lipoproteins), plays a key part in the prevention of atherosclerosis and thus the risk of cardiovascular disease. However, according to a new paper co-authored by researchers at Karolinska Institutet in Sweden and published in the journal Circulation, the anti-inflammatory properties of HDLs could be an even better biomarker for future cardiovascular events.

Atherosclerosis is considered a chronic local inflammation that leads to plaques in the blood vessels and that, if left untreated, can cause cardiovascular disease, the most common cause of death in the world.

The inflammation, while unnoticeable, can cause considerable damage to the blood vessels, so it is important to identify at-risk individuals as early as possible to curb progression of the disease.

HDLs carry away surplus cholesterol from the vessel wall to the liver. Today, the value for blood HDL cholesterol is used to help predict an individual's risk of cardiovascular disease.

HDLs are commonly referred to as "good" cholesterol but HDL particles have several important functions, amongst them anti-inflammatory properties.

Researchers at Karolinska Institutet and the University of Groningen in the Netherlands have for the first time interrogated whether the anti-inflammatory activity of HDL particles can predict the future risk of myocardial infarction and other cardiovascular events.

For their data, the researchers used blood samples from participants of the Prevend (Prevention of REnal and Vascular End stage Disease) study in Groningen.

Of the 8,592 participants, a selection was made of 369 who were healthy when the study began but who, on a 10.5-year follow-up, were recorded as having experienced a cardiovascular event.

These individuals were then matched according to age, gender, smoking habit and levels of HDL cholesterol with healthy individuals from the same cohort.

Despite identical HDL cholesterol levels, the participants who had suffered a cardiovascular event showed lower anti-inflammatory activity in their HDL particles, and this read-out of HDL function predicted the occurrence of cardiovascular events independent of conventional risk factors.

Further, adding this value to all other parameters, the results for the conventional Framingham model for predicting cardiovascular risk improved. Also, risk prediction improved when the HDL cholesterol value was replaced by the anti-inflammatory HDL value in the Framingham score.

"Our results point to new opportunities for improved cardiovascular risk assessment by using a biologically meaningful functional biomarker for HDL instead of its cholesterol content," says the study's last author, Professor Uwe Tietge at the Department of Laboratory Medicine, Karolinska Institutet. "However, the method for analysing the anti-inflammatory activity of HDLs is currently rather complex and difficult. Our next goal is therefore to make the method simpler and more clinically implementable."

HOUSTON -- Early phase clinical trials conducted by researchers from The University of Texas MD Anderson Cancer Center show promising results for patients with RET fusion-positive cancers, high-grade (HGG) and low-grade glioma (LGG) and ovarian cancer.

The results, presented today at the virtual American Association for Cancer Research (AACR) Annual Meeting 2021, showcase the researchers' ongoing efforts to advance clinical studies and expand potential indications of approved drugs to develop a platform for more effective treatments and to improve patient outcomes.

FDA-approved selpercatinib shows clinical benefits for RET fusion-positive cancers beyond lung and thyroid cancers (Abstract CT011)

Clinical trial results of RET kinase inhibitor selpercatinib show that the targeted therapy was effective in preventing or inhibiting the growth of tumors in RET fusion-positive cancers other than lung and thyroid cancers. The results, derived from a cohort of patients enrolled in the phase 1/2 LIBRETTO-001 trial, were presented by Vivek Subbiah, M.D., associate professor of Investigational Cancer Therapeutics.

Selpercatinib became the first treatment approved by the Food and Drug Administration (FDA) to treat RET fusion-positive lung and thyroid cancers, as well as RET-mutant medullary thyroid cancer (MTC), in May 2020. However, because RET alterations also have been shown to be oncogenic drivers in the pathogenesis of other cancers, it was postulated that selpercatinib could be used to treat other advanced solid tumors in which RET alterations occur.

"Selpercatinib demonstrates promising activity across a variety of non-lung and non-thyroid RET fusion-positive advanced solid tumors, including treatment-refractory GI malignancies," Subbiah said. "Although RET fusions are rare, this undoubtedly has conferred clinical benefit and the gift of time to these patients."

Thirty-two patients with RET fusion-positive non-lung or non-thyroid cancers participated in the study, representing 12 unique tumor types -- including pancreatic, colon, breast, salivary, sarcoma and pulmonary carcinosarcoma. Twenty-nine of the patients were previously treated with systemic therapy.

The objective response rate in this heavily pretreated patient population was 47%, including complete responses observed in two patients. Responses were observed across nine unique cancer types and a spectrum of fusion partners. Responses were ongoing in 73% of the patients, and the median duration of response was not reached at a follow-up of 13 months. The safety profile of this cohort is consistent with the known profile of selpercatinib in the overall LIBRETTO-001 population.

The LIBRETTO-001 trial, which spans 16 countries and 89 sites, continues to enroll patients with RET-altered non-lung cancer.

"These are definitely impactful data for precision oncology from the clinical and translational perspective," Subbiah emphasized. "These analyses reiterate the importance of broad-based genomic profiling to identify actionable oncogenic drivers, including RET fusions."

This research was supported by Eli Lilly and Company. A full list of collaborating authors and their disclosures can be found with the abstract.

Combining dabrafenib and trametinib to treat BRAF V600E-mutant high-grade (HGG) and low-grade glioma (LGG) shows significant antitumor activity (Abstract CT025)

In a nonrandomized, open-label phase 2 study, MD Anderson researchers showed that the combination of BRAF inhibitor dabrafenib and MEK inhibitor trametinib had promising efficacy in patients with BRAF V600 mutation-positive HGG and LGG.

BRAF mutations occur in approximately 3% of glioblastomas and 15% of low-grade gliomas.

The FDA approved a combination therapy of BRAF inhibitor dabrafenib and MEK inhibitor trametinib, which blocks proteins that facilitate cancer cell growth, to treat patients with BRAF V600-positive melanoma, non-small cell lung carcinoma and anaplastic thyroid cancer.

"Glioblastoma is a very difficult-to-treat tumor and has historically shown resistance to therapies, and this is the first time that a targeted therapy has shown significant activity in these challenging tumors," said Subbiah, who presented these findings.

The HGG arm of the trial enrolled 45 patients previously treated with radiotherapy, surgery or chemotherapy. A majority of patients had glioblastoma, while the rest had anaplastic pleomorphic xanthoastrocytoma and anaplastic astrocytoma.

After undergoing the combination therapy, patients showed a 33% objective response rate. The tumors continued to respond to treatment without cancer growth or spread for 36.9 months.

While 13 patients were enrolled in the LGG cohort, eight patients -- who were previously treated with surgery, radiotherapy and chemotherapy -- were evaluated in the study and achieved an objective response rate of 69%. The median duration of response, median progression-free survival and median overall survival rates were not reached.

Among both cohorts, 54 patients (93%) experienced a common adverse event -- including fatigue, headache, nausea and fever -- and 31 patients (53%) experienced a Grade 3 or greater adverse event -- such as fatigue, decreased neutrophil count, headache and neutropenia. No new safety signals were detected.

Ultimately, results from this basket trial show that dabrafenib combined with trametinib achieved meaningful response rates in patients with recurrent gliomas with BRAF V600E mutations, regardless of glioma subtype.

"Molecular screening strategies that include BRAF V600E mutations will be crucial for identifying patients who may benefit from these therapies," Subbiah said. "We recommend that testing is adopted in clinical practice for patients with glioma."

This research was supported by Novartis. A full list of collaborating authors and their disclosures can be found with the abstract.

Newly discovered metabolic vulnerability may offer treatment strategy for certain patients with ovarian cancer (Abstract 87)

Researchers from MD Anderson's Therapeutics Discovery division previously reported the discovery and development of IACS-6274, a novel small-molecule inhibitor targeting the metabolic enzyme glutaminase (GLS1). Through a patient-driven translational biology effort, the researchers now have identified and validated asparagine synthetase (ASNS) as a candidate biomarker to predict those most likely to benefit from the therapy.

The new findings were shared in a minisymposium presentation by Nakia D. Spencer, institute associate scientist IV with the Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform and one of the GLS1 project leads.

The development of IACS-6274, previously known as IPN60090, was initiated and advanced by a team of scientists in the Institute for Applied Cancer Science (IACS) and TRACTION platforms, both engines within Therapeutics Discovery. The drug is now under investigation in a Phase I trial for advanced solid tumors.

"Ovarian cancer remains an area of unmet medical need for our patients," Spencer said. "Utilizing team science to drive patient-focused research, we discovered that ovarian tumors lacking ASNS respond to IACS-6274 treatment, pointing us toward a significant number of patients who may benefit from this therapy."

Disruptions in normal cellular metabolism are distinguishing characteristics of many cancers, and the GLS1 enzyme is critical to many metabolic processes. In the preclinical development of IACS-6274, TRACTION researchers demonstrated promising activity in certain ovarian cancer preclinical models.

In ovarian cancer cell lines that respond to IACS-6274, treatment disrupts normal metabolism of specific amino acids and antioxidants, resulting in the accumulation of DNA damage and inhibiting tumor growth. By comparing sensitive and resistant cell lines, the researchers discovered that high expression of the metabolic enzyme ASNS predicted resistance to IACS-6274.

These results were confirmed in animal models, where ovarian cancers with low ASNS expression were responsive to IACS-6274 treatment and those with high ASNS expression where not. Working with the Division of Pathology and Laboratory Medicine, the team created a CLIA-certified assay to quantify ASNS levels in tumor samples.

“Advancing treatments that provide the greatest benefits to patients requires a strong translational and drug discovery package that complements the clinical efforts,” said Spencer. “Applying what we are learning from our on-going clinical study, we continue to develop multiple biomarker-driven patient stratification strategies to identify those most likely to benefit from IACS-6274.”

Therapeutics Discovery researchers will share additional updates on IACS-6274 development in poster sessions, including the identification of rational combination strategies for GLS1 inhibitors and the effects of IACS-6274 on the antitumor immune response.

PHILADELPHIA--Giving early-stage pancreatic cancer patients a CD40 immune-stimulating drug helped jumpstart a T cell attack to the notoriously stubborn tumor microenvironment before surgery and other treatments, according to a new study from researchers in the Abramson Cancer Center (ACC) at the University of Pennsylvania. Changing the microenvironment from so-called T cell "poor" to T cell "rich" with a CD40 agonist earlier could help slow eventual progression of the disease and prevent cancer from spreading in more patients.

The data--which included 16 patients treated with the CD40 agonist selicrelumab--was presented today by Katelyn T. Byrne, PhD, an instructor of Medicine in the division of Hematology-Oncology in the Perelman School of Medicine at the University of Pennsylvania, during a plenary session at the American Association for Cancer Research annual meeting (Abstract #CT005).

"Many patients with early-stage disease undergo surgery and adjuvant chemotherapy. But it's often not enough to slow or stop the cancer," Byrne said. "Our data supports the idea that you can do interventions up front to activate a targeted immune response at the tumor site--which was unheard of five years ago for pancreatic cancer--even before you take it out."

The purpose of CD40 agonists is to help "push the gas" on the immune system both by activating antigen-presenting cells, such as dendritic cells, to "prime" T cells and by enhancing immune-independent destruction of the tumor site. The therapies have mostly been investigated in patients with metastatic pancreatic cancer patients in combination with other therapies, such as chemotherapy or other immunotherapies. This is the first time the drug has been shown to drive an immune response in early-stage patients both at the tumor site and systemically--which mirrors what researchers found in their mouse studies.

The phase 1b clinical trial was conducted at four sites, including the ACC, Fred Hutchinson Cancer Research Center at the University of Washington, Case Western Reserve University, and Johns Hopkins University.

Sixteen patients were treated with selicrelumab before surgery. Of those patients, 15 underwent surgery and received adjuvant chemotherapy and a CD40 agonist. Data collected from those patients' tumors and responses were compared to data from controls (patients who did not receive the CD40 agonist before surgery) treated at Oregon Health and Science University and Dana Farber Cancer Institute.

Multiplex imaging of immune responses revealed major differences between the two groups. Eighty-two percent of tumors in patients who received the CD40 agonist before surgery were T-cell enriched, compared to 37 percent of untreated tumors and 23 percent chemotherapy or chemoradiation-treated tumors. Selicrelumab tumors also had less tumor-associated fibrosis (bundles of tissue that prevent T cells and traditional therapies from penetrating tumors), and antigen-presenting cells known as dendritic cells were more mature.

In the treatment group, disease-free survival was 13.8 months and median overall survival was 23.4 months, with eight patients alive at a median of 20 months after surgery.

"This is a first step in building a backbone for immunotherapy interventions in pancreatic cancer," Byrne said.

Based on these findings, researchers are now investigating how other therapies combined with CD40 could help strengthen the immune response even further in pancreatic cancer patients before surgery.

"We're starting to turn the tide," said Robert H. Vonderheide, MD, DPhil, director of the ACC and senior author. "This latest study adds to growing evidence that therapies such as CD40 before surgery can trigger an immune response in patients, which is the biggest hurdle we've faced. We're excited to see how the next-generation of CD40 trials will take us even closer to better treatments."

LOS ANGELES -- Early results from a new, pioneering chimeric antigen receptor (CAR) T cell immunotherapy trial led by researchers at the UCLA Jonsson Comprehensive Cancer Center found using a bilateral attack instead of the conventional single-target approach helps minimizes treatment resistance, resulting in long-lasting remission for people with non-Hodgkin's B-cell lymphoma that has come back or has not responded to treatment.

The new approach, which will be presented at the American Association for Cancer Research Annual Meeting during one of the clinical oral plenary sessions (ABSTRACT CT007), achieves a more robust defense and helps avoid relapse by simultaneously recognizing two targets - CD19 and CD20 - that are expressed on B-cell lymphoma.

In the small trial, four out of the five patients enrolled demonstrated a complete metabolic response, with minimal toxicity. While the median duration of the response, progression-free survival and overall survival endpoints have not yet been reached, the results are very promising.

"These responses are overall very impressive," said lead author Sanaz Ghafouri, MD, a hematology/oncology fellow at the David Geffen School of Medicine at UCLA. "We are hopeful that dual targeting CD19/CD20 CARs in naïve memory T-cells will provide patients with relapsed or refractory aggressive B-cell lymphomas, that are otherwise chemotherapy-refractory, a chance at a possible cure or at the very least a lasting long-term remission."

Patients diagnosed with relapsed or refractory B-cell lymphoma tend to have poor outcomes with second-line therapies. While CAR T cell therapy has been a game-changer for many people with this disease, recurrence is still a common phenomenon -- approximately 50% of patients relapse by six months.

"One of the reasons CAR T cell therapy can stop working in patients is because the cancer cells escape from therapy by losing the antigen CD19, which is what the CAR T cells are engineered to target," said Sarah Larson, MD, assistant professor of hematology/oncology at the David Geffen School of Medicine at UCLA and the principal investigator on the trial. "One way to keep the CAR T cells working is to have more than one antigen to target. So by using both CD19 and CD20, the thought is that it will be more effective and prevent the loss of the antigen, which is known as antigen escape, one of the common mechanisms of resistance."

The patients enrolled in the trial all had measurable disease after either undergoing two or more lines of therapy for primary mediastinal B-cell lymphoma, or three or more lines of therapy for mantle cell lymphoma or follicular lymphoma. All patients had CD19/CD20 positive B-cell malignancy on tissue biopsies prior to the CAR T therapy.

Each patient had their T cells (a type of white blood cells) collected intravenously then reengineered in the laboratory so the T cells can produce tumor-specific receptors (CARs), which allow the T cells to recognize and attack the CD19 and CD20 proteins on the surface of tumor cells. The new "smarter and stronger" T cells are then infused back into the patient and primed to recognize and kill cancer cells.

The engineered CARs used in the study were developed by Yvonne Chen, PhD, co-director of the UCLA Jonsson Comprehensive Cancer Center's Tumor Immunology Program and the sponsor of the trial.

Dr. Chen, who is also part of the UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research and a Parker Institute of Cancer Immunotherapy research member, and her team designed the CARs based on the molecular understanding of the CAR's architecture, the antigen structure and the CAR/antigen binding interaction to achieve optimal T cell function. This design helps the T cells have dual-antigen recognition to help prevent antigen escape.

The median follow up is 13 months, with four of the patients in ongoing complete remission. The one patient who did not respond had early disease progression at day 14 after the infusion.

"The goal of the study was to determine a safe therapeutic dose," said Dr. Ghafouri. "And we can safely say that bispecific anti-CD19/CD20 CAR in naïve/memory T-cells are safe and effective in patients with relapsed or refractory B-cell lymphomas."

"We believe that this investigational anti-CD19/CD20 CAR product has substantial potential to become standard of care in the armamentarium of therapeutics for patients with aggressive B-cell lymphomas," noted Dr. Larson.

While these findings are encouraging, the team notes the need to continue enrolling patients in the dose expansion phase and diversify the B-cell lymphoma disease subtypes.

WASHINGTON, April 9, 2021 -- For the millions of people worldwide who have sickle cell disease, there are only a few treatment options, which include risky bone marrow transplants, gene therapy or other treatments that address a subset of symptoms. Today, researchers will describe the discovery of a small molecule with the potential to address the root cause of sickle cell disease by boosting levels of fetal hemoglobin, a healthy form that adults normally do not make. The drug could be formulated into a convenient daily tablet.

The researchers will present their results today at the spring meeting of the American Chemical Society (ACS). ACS Spring 2021 is being held online April 5-30. Live sessions will be hosted April 5-16, and on-demand and networking content will continue through April 30. The meeting features nearly 9,000 presentations on a wide range of science topics.

"Using our proprietary small molecule probe and CRISPR guide RNA libraries, we screened a disease-relevant cell model that allowed us to pinpoint a treatment target," says Ivan V. Efremov, Ph.D., senior director, head of medicinal chemistry of Fulcrum Therapeutics, who is presenting the work.

Sickle cell disease occurs when the gene responsible for instructing cells to produce two of hemoglobin's four proteins contains an error. The mutation causes hemoglobin to adopt a rigid, sickle-like shape, which results in reduced oxygen transport throughout the body. The irregularly shaped cells get stuck in the blood vessels, causing painful episodes known as vaso-occlusive crises. The cells also die much sooner than normal red blood cells, leading to anemia. In addition to these symptoms, patients are at high risk of developing stroke, heart disease, kidney failure and other life-threatening conditions.

Interestingly, sickle cell patients don't begin life with malfunctioning hemoglobin. While in the womb, humans make "fetal" hemoglobin that carries oxygen normally. Three or four months after birth, however, cells stop expressing fetal hemoglobin and switch to an adult version. The adult hemoglobin expressed by sickle cell patients is defective, but they still carry stem cells in their bone marrow with the potential to produce fetal hemoglobin.

Patients that have what is called a hereditary persistence of fetal hemoglobin tap this resource automatically. "They have the sickle cell mutation, but additional mutations result in continued expression of fetal hemoglobin into adulthood," says Christopher Moxham, Ph.D., chief scientific officer of Fulcrum Therapeutics. With fetal hemoglobin levels around 25-30%, he says, enough red blood cell function is restored so that these patients may become asymptomatic.

The team developed a drug, called FTX-6058, that mimics the effect seen in patients with the hereditary persistence of fetal hemoglobin, as demonstrated in human-derived cell assay systems and mouse models. The drug attaches to a protein inside bone marrow stem cells destined to become mature red blood cells and reinstates their fetal hemoglobin expression. "What is really key is FTX-6058 upregulates fetal hemoglobin across all red blood cells, a pancellular distribution," Efremov says. "If some red blood cells did not express this, they could still sickle and cause disease symptoms." Fulcrum began a phase 1 safety trial in healthy adult volunteers last year after preclinical experiments showed an increase in fetal hemoglobin levels to around 25-30%.

"What distinguishes FTX-6058 is that we are targeting the root cause of sickle cell disease," Moxham says. "Other drugs approved in this space, particularly since 2019, are treating the disease's symptoms, either the anemia or the vaso-occlusive crises." Preclinical experiments comparing FTX-6058 with another fetal hemoglobin booster, hydroxyurea, approved in the 1990s, showed the new drug candidate outperforms the current treatment and, according to Moxham, offers the potential for a transformative therapy.

The team is currently designing a phase 2 clinical trial for people living with sickle cell disease that they plan to initiate by the end of 2021. They are also in the process of characterizing the therapeutic molecule further, using genomic technologies and additional cell assay systems to fill in the details of exactly how it works. Beyond sickle cell disease, Fulcrum is also considering a clinical strategy to explore the use of FTX-6058 in people living with β-thalassemia, a blood disorder in which hemoglobin production is reduced.

Obesity is linked to heavier periods and may be caused by delayed repair of the womb lining, according to a study published in the Journal of Endocrinology. Using a combined approach, assessing both women and mice, the study suggests an association between higher body weight and greater menstrual blood loss that may result from increased inflammation in the womb lining, delaying its repair. Although the study did not examine whether weight loss or anti-inflammatory medications may be useful in treating women with obesity and heavy periods, this is a step towards developing more successful and personalised treatments for those suffering with heavy periods, which can be distressing and debilitating.

Heavy menstrual bleeding affects up to 1 in 3 women at some point in their reproductive lives and, although common and debilitating, its causes are poorly defined. Periods can be so heavy that women are unable to go out without leaking through their menstrual protection or in extreme cases may require a blood transfusion. Heavy menstrual bleeding can result in more work or school absences, an increased financial burden from buying more menstrual products and an inability to carry out normal daily activities. Problematic menstrual bleeding can have far reaching negative impacts on quality of life for sufferers. The number of women of reproductive age who have obesity is also increasing, with levels in England up to 33% in 2019. Menstrual disorders are common but they are under-researched. Understanding how obesity may impact menstrual blood loss is an important step towards improving prevention and treatment of heavy periods.

In this study, Dr Jacqueline Maybin and colleagues at the MRC Centre for Reproductive Health at the University of Edinburgh, examined how body mass index (BMI) may affect womb function during menstruation in women, and also in female mice. The researchers measured the BMI and menstrual blood loss of 121 women, with regular menstrual cycles, who were attending gynaecology clinics and not taking any hormone medications. A weak but statistically significant association between increasing BMI and more menstrual blood loss was found. Since many other factors in women may also affect menstrual blood loss, the investigation was extended to a mouse study, where conflicting variables could be limited.

Mice were fed a normal diet or a high-fat diet prior to simulation of menstruation. Mice on high-fat diet had significantly higher body weight than those on a normal diet. After shedding their womb lining, the mice on a high-fat diet showed delayed repair of the remaining womb lining in comparison to mice on a normal diet. Further examination of womb tissue from the mice indicated that inflammatory factors were also higher in mice with greater body weight.

Dr Maybin comments, "Our findings suggest that women with obesity may experience heavier periods due to increased local inflammation and delayed repair of their womb lining. It would be really interesting to investigate the reasons behind this to further our understanding of womb function in the presence of obesity and develop more effective, evidence-based treatments."

These findings suggest that weight loss and anti-inflammatory medications may be useful interventions for treatment of heavy periods in women with obesity. However, this research was carried out on a small number of women with regular periods, who were attending gynaecology clinics and may not be representative of the general population. Additional, larger studies are needed to confirm these findings.

Dr Maybin cautions, "Although it is difficult to make strong recommendations based on this study alone, a common-sense approach would be to offer weight-loss support to women with a high BMI experiencing heavy periods. However, this should not replace investigation and treatment of other underlying causes for heavy bleeding (e.g. fibroids, bleeding disorders, cancer). This should form part of personalised treatment recommendations to be considered by both patients and doctors."

Early results show that a new combination drug therapy is safe and effective against advanced skin cancer in patients who were not able to have their tumors surgically removed.

The drug combination is among the first, researchers say, to demonstrate the potential value of a live common cold virus, a coxsackievirus, to infect and kill cancer cells.

The Phase I study, led by a researcher at NYU Langone Health and its Perlmutter Cancer Center, is also among the first to show how such oncolytic viruses can safely boost the action of widely used cancer therapies that help the body's immune defense system detect and kill cancer cells. Currently, such immunotherapies are only effective in shrinking melanoma tumors in just over a third of patients who receive them.

The new study results showed that injections of experimental coxsackievirus drug V937, along with pembrolizumab, an immunotherapy drug known as pembro or Keytruda, was well tolerated. Moreover, the combined treatment shrank melanoma tumors in nearly half (47 percent) of 36 men and women who received the therapy every few weeks for at least two years.

Researchers say most side effects, such as rash and fatigue, were minimal, while 13 patients (36 percent) had serious immune reactions in the liver, stomach, or lungs, not unlike side effects that are known to happen with pembrolizumab alone.

Set for presentation at the annual meeting of the American Association for Cancer Research online April 10, the study also showed that eight patients who received both drugs (22 percent) experienced complete remission, with no remaining signs of skin cancer.

"Our initial study results are very promising and show that this oncolytic virus injection, a modified coxsackievirus, when combined with existing immunotherapy is not only safe but has the potential to work better against melanoma than immunotherapy alone," says study senior investigator and medical oncologist Janice Mehnert, MD.

Mehnert, a professor at NYU Grossman School of Medicine and associate director of clinical research at Perlmutter Cancer Center, cautions that further testing, already underway, would have to prove successful before the combination treatment could become a "standard of care," or go-to therapy, for patients with advanced melanoma, meaning melanoma that has spread to other parts of the body.

She adds that the next phase of clinical trials will involve patients with melanoma that has become widespread, as well as in patients whose tumors, if shrunken by the drug combination, could be more easily removed by surgery.

Among the study's other findings was that patients least likely to respond to immunotherapy alone were those who responded best to the combined treatment. Patients, for example, who responded best had less of the chemical receptors (PDL1) on the surfaces of cancer cells that are blocked by pembrolizumab than patients who did not respond as well.

Researchers say further experiments are needed to determine how V937 changes the molecular makeup of the tissues immediately surrounding tumors.

"Our goal is to determine if the virus turns the tumor microenvironment from 'friendly' to one that is 'unfriendly,' making the cancer cells more vulnerable to pembrolizumab," says Mehnert.

As part of the latest study, volunteers, mostly seniors, enrolled at three cancer clinics, including Rutgers Cancer Institute in New Brunswick, NJ; Gabrail Cancer Center in Canton, Ohio; and John Wayne Cancer Institute in Santa Monica, Calif.

Scientists have known since the 1800s that some cancer patients who suffered from infections, later tied to bacteria or viruses that cause measles and herpes, often experience tumor shrinkage. Recent technological advances in genetic engineering have allowed scientists to retool viruses to target specific molecules on the surface of cancer cells to more easily infect them.

As demonstrated by multiple studies over the years, women who breastfeed have a lower risk for developing cardiovascular disease and diabetes when compared to those who don't or can't. However, the mechanisms by which these risks are reduced for lactating women are still not fully understood.

Duke Appiah, Ph.D., an assistant professor of public health at the Texas Tech University Health Sciences Center and director of the university's master's program in public health, said the presence of excess fat, specifically visceral and pericardial fat could help explain this finding. Using that hypothesis, Appiah and a team of researchers recently completed a study titled, "The Association of Lactation Duration with Visceral and Pericardial Fat Volumes in Parous Women: The CARDIA Study." The Journal of Clinical Endocrinology & Metabolism published the results in its February issue.

The Appiah team included Cora E. Lewis, M.D., and James M. Shikany (University of Alabama at Birmingham); David R. Jacobs, Jr., Ph.D., and Myron Gross, Ph.D., (University of Minnesota); Jeff Carr, M.D., (Vanderbilt University Medical Center); and Charles P. Quesenberry, Jr., Ph.D., Stephen Sidney, M.D., and senior research scientist Erica P. Gunderson, Ph.D., (Kaiser Permanente Northern California). The National Institute of Diabetes and Digestive and Kidney Diseases provided funding to Gunderson, the study's senior author, for creating the pregnancy-related derived variables, and for the analysis of lactation and the development of cardiometabolic diseases in Coronary Artery Risk Development in Young Adults (CARDIA) study women.

Visceral fat, often referred to as active fat, potentially can increase the risk of developing dangerous health issues such as cardiovascular disease, heart attacks, Type 2 diabetes, stroke, breast and colorectal cancer and Alzheimer's disease. Though it can build up in the arteries, visceral fat typically is stored within the abdominal cavity near critical organs such as the stomach, liver and intestines.

Pericardial fat, a deposit of fatty tissue located on the outside of the heart, also may influence certain cardiovascular conditions.

"We know these two organ-related fats contribute to diabetes as well as cardiovascular disease, so we wanted to see how breastfeeding influences these types of fat," Appiah explained. "If breastfeeding does affect these fats, then it means it could provide a physiologic mechanism by which we can understand how breastfeeding actually affects these two main diseases. That was basically the motivation for this study."

Because these fats are related to insulin production and other cardio metabolic factors, Appiah said weight change could influence the relationship between breastfeeding and these fats. For instance, the visceral fat that builds up around the abdomen tends to also include adipokines, which are cytokines produced by fatty tissue. Adipokines also secrete hormones, which influence the insulin sensitivity of the muscles. When the amount of visceral fat increases, so too does the competition for insulin binding sites, which increases the risk of developing insulin resistance or glucose intolerance.

An increase in pericardial fat also puts additional weight on the heart and can affect its contractivity, or how it beats, which also could influence other cardiovascular diseases. Though many studies have looked at visceral fat, or abdominal fat, and its influence on cardiometabolic health, Appiah said not as much is known about pericardial fat.

"However, there is still enough science showing that the more pericardial fat you have, the more likely you are to get cardiovascular disease," Appiah said. "What this really means is that breastfeeding affects weight gain, and so women who breastfeed typically will not gain more weight, which will also influences less fat buildup in the abdomen or around their heart."

Gunderson said previous studies on women in the 30-year CARDIA study have shown lactation duration is associated with a 50% lower relative risk of progression to Type 2 diabetes in women, independent of their metabolic profiles and body size before pregnancy, social factors and lifestyle behaviors. Lactation also may prevent future development of cardiovascular disease in women by reversing hypertriglyceridemia during pregnancy through the removal of excess fatty acids in the production of breast milk and by preventing the lowering of high-density lipoprotein cholesterol after delivery.

"This lower pericardial fat was mediated only partially by subsequent weight gain, indicating that there are powerful systemic metabolic changes independent of overall adiposity," Gunderson said. "Thus, lower fat deposition in the heart and other organs might potentially explain the protective benefits of lactation to prevent cardiovascular disease in women."

To generate data for his research, Appiah used the CARDIA study, with which he also is affiliated. CARDIA, sponsored by the National Institutes of Health-National Heart Lung and Blood Institute, is a long-term study of cardiovascular disease that includes more than 5,000 Black (48%) and white (52%) adult women who were aged 18 to 30 years when the study began in 1985-1986.

As one of the longest and continuous studies of its kind, the CARDIA study has continued to monitor these participants for more than 30 years and has aided researchers in understanding how factors that appear in early adulthood can increase the risk of cardiovascular disease later in life.

"There are not many studies out there which actually have followed young women all through their birth years and measured cardiovascular risk factors on all of them," Appiah said. "It also includes cumulative measures of lactation, which made CARDIA more unique to address this research because it's not just one episode of breastfeeding that is important. We wanted to look at the entire reproductive lifespan and CARDIA was the best study to do that."

Gunderson, who also is a professor of health systems science at the Kaiser Permanente Bernard J. Tyson School of Medicine, said the CARDIA data enabled the research team to account for biomarkers and metabolic risk factors before pregnancy that might influence future adiposity and cardiovascular health.

"After accounting for lifestyle behaviors and other risk factors across the life course, the lower visceral and pericardial fat among women with longer lactation persisted," Gunderson said. "This indicates lactation may have effects that persist many years through midlife."

After their initial enrollment in the study in 1985-1986, women in the CARDIA study update their measurements and other history approximately every five years, giving investigators a clearer picture of a woman's entire reproductive lifespan. The results, as Appiah discovered in his research, show that women who breastfed more over the duration of their reproductive years experienced less weight gain and tended to have less fat buildup around the abdomen or around the heart.

Appiah said these results support some of the findings made by the American College of Pediatricians (ACP), which recommends breastfeeding exclusively for the first six months of a child's life, and then combining breastfeeding with age-appropriate food between six months and 12 months the food can be mixed. However, ACP also recommends that women should breastfeed for two years or longer if they are able.

"Now we are showing that, yes, breastfeeding more is actually beneficial to a woman's health and can help to prevent cardiovascular disease," Appiah added. "This study is providing more proof for some of these recommendations that have been given previously."

Appiah said there are other issues related to lactation that his team is investigating, including looking at how lactation influences cytokines and other hormones.

"We know that these fats produce adipokines and other cytokines that are associated with plaque buildup in the arteries," Appiah said. "Therefore, we want to look at how these cytokines may be influenced by lactation. We also want to look at how lactation may affect left ventricular structure and function independent of pericardial fat. Those are the next steps for this project."

Exercise and a healthy diet in childhood leads to adults with bigger brains and lower levels of anxiety, according to new UC Riverside research in mice.

Though diet and exercise are consistently recommended as ways to promote health, this study is the first to examine the long-lasting, combined effects of both factors when they are experienced early in life.

"Any time you go to the doctor with concerns about your weight, almost without fail, they recommend you exercise and eat less," said study lead and UCR physiology doctoral student Marcell Cadney. "That's why it's surprising most studies only look at diet or exercise separately. In this study, we wanted to include both."

The researchers determined that early-life exercise generally reduced anxious behaviors in adults. It also led to an increase in adult muscle and brain mass. When fed "Western" style diets high in fat and sugar, the mice not only became fatter, but also grew into adults that preferred unhealthy foods.

These findings have recently been published in the journal Physiology and Behavior. To obtain them, the researchers divided the young mice into four groups -- those with access to exercise, those without access, those fed a standard, healthy diet and those who ate a Western diet.

Mice started on their diets immediately after weaning, and continued on them for three weeks, until they reached sexual maturity. After an additional eight weeks of "washout," during which all mice were housed without wheels and on the healthy diet, the researchers did behavioral analysis, measured aerobic capacity, and levels of several different hormones.

One of those they measured, leptin, is produced by fat cells. It helps control body weight by increasing energy expenditure and signaling that less food is required. Early-life exercise increased adult leptin levels as well as fat mass in adult mice, regardless of the diet they ate.

Previously, the research team found that eating too much fat and sugar as a child can alter the microbiome for life, even if they later eat healthier. Going forward, the team plans to investigate whether fat or sugar is more responsible for the negative effects they measured in Western-diet-fed mice.

Together, both studies offer critical opportunities for health interventions in childhood habits.

"Our findings may be relevant for understanding the potential effects of activity reductions and dietary changes associated with obesity," said UCR evolutionary physiologist Theodore Garland.

In other words, getting a jump start on health in the early years of life is extremely important, and interventions may be even more critical in the wake of the pandemic.

"During the COVID-19 lockdowns, particularly in the early months, kids got very little exercise. For many without access to a park or a backyard, school was their only source of physical activity," Cadney said. "It is important we find solutions for these kids, possibly including extra attention as they grow into adults."

Given that exercise was also shown to reduce adult anxiety, Cadney believes children who face these challenges may face unique physical and mental health issues as they become adults in the coming decade.

Experts have uncovered a new molecular reason why faecal transplants are highly effective in treating infections such as C. difficile (a nasty bacteria that can infect the bowel), which could lead to more targeted treatments for this and other similar diseases.

The study, published today in Gastroenterology, was led by experts from the University of Nottingham and Nottingham Trent University.

Clostridium difficile, also known as C. difficile or C. diff, is a bacterium that can infect the bowel and cause diarrhoea. The infection most commonly affects people who have recently been treated with antibiotics. It can spread easily to others.
A stool transplant - or to give it its full title "a faecal microbiota transplant" (FMT) - aims to repopulate the patient's gut with the microbes from a healthy person, making it a successful therapy against C. diff and other similar diseases. An FMT is only considered if a patient suffers recurring bouts of the infection or has not responded to traditional treatments. FMT is effective in at least 80% of cases in treating the condition.

After a poo "sample" is produced, it is mixed with water. There are two routes for getting the sample into the required location in the bowel - down through the mouth straight into the stomach, or as a colonoscopy, up through the rectum.

Whilst the technique is highly effective in treating the infection, little is still known about how it does so. In this new study, a team of experts set out to understand how FMT works at a molecular level.

Dr Tanya Monaghan, Clinical Associate Professor, Honorary Consultant in Gastroenterology, and Anne McLaren Fellow in the School of Medicine at the University of Nottingham, and co-lead author of the research said: "It is not fully understood how an FMT works at a molecular level. That is a problem because if we knew how it worked at this level, then we could refine the treatment, which would mean a full transplant may not be needed."

The team used blood samples from two clinical FMT trials which were undertaken in Canada by co-lead Dr Dina Kao (University of Alberta) and collaborator Prof Christine Lee (University of British Columbia). From these data, they could see that following successful FMTs, there were alterations in patient microRNAs in the blood.

MicroRNAs are a class of short non-coding RNA molecules. With more than 2,000 microRNAs discovered in humans to date, many of them have already been implicated in common human disorders.

Dr Christos Polytarchou, Associate Professor in the School of Science and Technology at Nottingham Trent University, and co-author of the research, said: "MicroRNAs are characterised as master regulators of gene expression. A single microRNA can modulate multiple RNA and protein molecules, affecting a vast array of cell functions."

The researchers wanted to specifically look at whether microRNAs changed following a successful FMT.

The team, which also included investigators from the universities of Vanderbilt (Prof Borden Lacy and Dr Nick Markham) and Clemson (Dr Anna Seekatz), discovered that following successful transplant, there was an increase in specific microRNAs in the blood, which resembled similar changes also seen in the human and mouse intestine.

Dr Polytarchou added: "We found that C. diff utilises its toxins to highjack the molecular mechanism important for microRNA maturation, a process important for microRNA activity. We went on to identify specific microRNAs, which contribute to disease pathogenesis."

The team then looked at whether or not the combination of specific microRNAs could protect bowel cells from the damage that is induced by toxins from the bacteria, and they could.

Dr Monaghan said: "We have discovered a new mechanism by which the transplants work, which will now help us to develop a new method of therapeutics, which specifically target microRNAs. MicroRNA-based drugs are already being investigated to treat cancers, heart abnormalities, and kidney disease, but this is the first time microRNAs have been looked at as a means to treat C. diff infections. If used with antimicrobials, microRNA drugs could be extremely effective in treating C. diff and potentially other diseases"

What The Study Did: This survey study examines wh0 U.S. adults believe should be prioritized for access to COVID-19 vaccines.

Authors: Ezekiel J. Emanuel, M.D., Ph.D., of the University of Pennsylvania Perelman School of Medicine in Philadelphia, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamanetworkopen.2021.7943)

Editor's Note: The article includes conflict of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

Nine out of ten Danes say that they will accept the COVID-19 vaccine when offered. This is the same level as before the AstraZeneca vaccine was paused.

This is shown by a questionnaire-based survey collected by Søren Dinesen Østergaard and co-authors. He is professor at the Department of Clinical Medicine at Aarhus University and affiliated with the Department of Affective Disorders at Aarhus University Hospital, Psychiatry.

"In February 2021, we asked a sample of Danes whether they were willing to be vaccinated against the coronavirus, and 89 per cent replied that they would. This picture was unchanged when the same people were asked again after the pausing of the AstraZeneca vaccine," says Søren Dinesen Østergaard.

The approximately 1,500 participants answered the questions about vaccination for the first time in the period between 4-21 February and then again in the period between 15-25 March. Danish health authorities paused the use of the AstraZeneca vaccine on 11 March - initially for 14 days before extending it until 9 April.

The survey also shows that many Danes feel insecure about the safety of the AstraZeneca vaccine. On a scale from 0-10, where ten is the safest, AstraZeneca scored just over five on average, while the vaccine from Pfizer scored above eight. As could be expected, it is those who do are not willing to be vaccinated who feel most insecure about the AstraZeneca vaccine after the reported blood clots.

"The fact that 89 percent still maintain that they willing to be vaccinated testifies to the high degree of trust in the Danish healthcare system. The extended pause indicates that the healthcare system is thoroughly investigating the cases of blood clots and thus takes our safety seriously. I think the population sees this as due diligence. If anything, it will probably increase confidence in the healthcare system," says Søren Dinesen Østergaard.

On the other hand, the research group is uncertain that all the people who say they are willing to be vaccinated will actually roll up their sleeves for the jab. It is well-known from survey research that 'good behaviour' is often over-reported, because people give what they think is the 'right' answer. A phenomenon called social desirability bias.

"If this bias plays a role here, it likely means that the vaccine willingness has been overestimated in this study, but probably to the same extent before and after the pausing of the AstraZeneca vaccine," says Søren Dinesen Østergaard.

According to the researchers, the low level of confidence in the safety of the AstraZeneca vaccine is an important signal to the health authorities.

"The results indicate that there will be a need to rebuild the population's trust in the AstraZeneca vaccine if its use is resumed," he says. So far, more than 140,000 Danes have received the AstraZeneca vaccine. The Danish Medicines Agency is currently investigating reports of blood clots in combination with a low number of blood platelets occurring among individuals having received the AstraZeneca vaccine. One case in Denmark has had a fatal outcome, and this case resembles several deaths elsewhere in Europe.