Body

Bluestar Genomics, an innovative company leading the development of next-generation epigenomic approaches to early cancer detection, announced today the publication of study results in the peer-reviewed journal Nature Communications. The study demonstrates the power of the company's platform to detect pancreatic cancer in its early stages, addressing the unmet need of more than 60,000 patients diagnosed with the disease each year in the United States alone. The research shows that utilizing Bluestar's epigenomic technology to analyze a simple blood draw effectively identifies the presence of pancreatic cancer in patients' DNA circulating in their blood, enabling non-invasive, precise detection of the disease, which could lead to more timely treatment and improved patient survival.

"Pancreatic cancer is a deadly disease with no current screening methods for the larger population," said Samuel Levy, Ph.D., chief executive and chief scientific officer at Bluestar Genomics, and the senior author of the study. "The Nature Communications publication demonstrates that our technology provides a crucial foundation for the development of a screening test that will set a new standard for liquid biopsies and the future of cancer screening."

Published results from a study of 307 patients, including both men and women ages 40 or older, showed that Bluestar Genomics' technology identified distinctive patterns in thousands of genes that could serve as a biomarker for blood-based pancreatic cancer detection to enable the development of a future cancer screening test. The study includes application of the detection strategy to novel samples not included in the development set, providing validation that holds promise for early-stage detection in larger patient groups.

"Pancreatic cancer is the third leading cause of cancer death in the U.S. and the absence of a robust screening test in clinical care means that this cancer is often detected at an advanced stage, leaving patients with fewer treatment options," said Kelly Bethel, M.D., chief medical officer at Bluestar Genomics. Gulfem Guler, Ph.D, the lead author of the study and Bluestar Genomics' lead scientist on pancreatic cancer research further stated, "This publication demonstrates that the utilization of our epigenetics platform can identify tumor biology in plasma earlier, which can bring the possibility of earlier treatment options to patients, potentially increasing their survival."

In pancreatic cancer patients, circulating tumor cells and circulating tumor DNA are shed into the blood and can be easily obtained through a blood draw, providing a unique potential for early diagnosis, forecasting disease prognosis, and monitoring of therapeutic response.

Unlike current diagnostic methods that rely on disease tissue to characterize the condition, Bluestar Genomics' blood-based 5hmC assay is able to detect signals of disease in a patient's plasma via DNA-based changes found in gene and gene regulatory regions.

This study's results strongly suggest that a clinical test employing newly identified biomarkers may promote more effective early-stage pancreatic cancer screening, which has significant value since many patients do not show symptoms until the disease has advanced to a late stage. Based on the results published in Nature Communications and inspired by the collaboration with its research and patient advocate partners, Bluestar will continue its development work required to commercialize a test in the coming years.

Someday, scientists may be able to prevent cancer by controlling two proteins that operate deep inside the quagmire of epigenetic cell fate transitions, a new paper suggests.

Published by Nature Communications, the article describes a dynamic push and pull between the proteins ANP32E and H2AZ. Their relationship is significant because too little of H2AZ promotes cell division and aggressive tumors, while high levels of H2AZ promotes chaos and metastatic cancer -- and ANP32E acts as a "chaperone" that directs H2AZ, said the study's corresponding author, Patrick Murphy, Ph.D. He is an assistant professor of Biomedical Genetics at the University of Rochester Medical Center and a Wilmot Cancer Institute investigator.

Abundant levels of H2AZ are often found in people with breast and brain cancer and melanoma.

With a "normal" amount of H2AZ, Murphy said, healthy cells can turn off the signals that permit cancer cells to divide and tumors to grow.

Epigenetics is at the root of Murphy's work. The field has been around for 80 years but is getting a lot of buzz more recently. Scientists and cancer patients are learning what biological factors influence inherited gene changes and predisposition to diseases, and how lifestyle behaviors passed down through generations and chemical exposures can also switch the function of genes and lead to cancer and other illnesses.

The core of epigenetics is understanding how two cells can have the same DNA but have different functions in the body. The work by the Murphy lab adds a critical bit of information as scientists clamor to find the factors that activate or silence genes during cell transitions.

His lab showed that when they eliminated ANP32E from connective tissue of mice, H2AZ spreads wildly. Therefore, if researchers can find a way to inhibit ANP32E and control the H2AZ protein in humans, it might make cancer cells more sensitive to anti-cancer drugs or immune-system attack.

Taking advantage of advanced technology, researchers can study cell transitions in specific regions of DNA. The Wilmot team was able to hone in on exactly how ANP32E and H2AZ coordinate to control DNA activity and cellular instructions.

The "precise control of ANP32E levels and H2A positioning may be critical for preventing carcinogenesis," the paper stated. "Thus, it will be important for future studies to investigate the mechanisms described here in the context of human diseases, including cancer."

HAMILTON, Oct. 8, 2020 -- Researchers at McMaster and Brock universities have created the prototype for a hand-held device to measure a biomarker for cancer, paving the way for home-based cancer monitoring and to improve access to diagnostic testing.

The device works much like the monitors that diabetics use to test their blood-sugar levels and could be used in a medical clinic or at home, all without lab work, greatly simplifying the process for testing blood for cancer's signature.

A user would mix a droplet of blood in a vial of reactive liquid, then place the mixture onto a strip and insert it into a reader. In minutes, the device would measure an antigen that indicates the degree to which cancer is present.

The prototype has been designed to monitor prostate specific antigen (PSA) and the technology can readily be adapted to measure other markers, depending on the form of cancer or other chronic disease.

The ability to collect such information at home would make the daily lives of patients much easier while also generating accurate, shareable, up-to-the-minute results to guide their doctors in shaping care and treatment - all at a lower cost to the health-care system.

The device would also allow patients to continue to monitor their health after treatment.

The prototype was created by a research collaboration led by McMaster's Leyla Soleymani, a biomedical engineer and Canada Research Chair in Miniaturized Biomedical Devices, and Brock's Feng Li, an associate professor of chemistry who leads a bioanalytical chemistry lab.

Soleymani's team (also including Sarah Traynor and Richa Pandey) was responsible for the hardware, including the chip that reads the sample, while Li's team (also including Guan Wang) created the technology that analyzes the sample.

"This is another step toward truly personalized medicine," Soleymani says. "We're getting away from centralized, lab-based equipment for this kind of testing. This would make monitoring much more accessible and cut down on the number of times patients need to leave home to provide blood samples."

"Once commercialized, this device will be a paradigm shift for cancer diagnosis and prognosis," Li says. "Since this device is a lot more accessible and user-friendly than conventional technologies, patients will be more willing to use it, which can improve clinical outcomes and save lives."

The researchers' proof-of-concept work is described in an article published in the journal Angewandte Chemie. The invention will need to be tested more broadly before earning the regulatory approvals that would permit commercial manufacturing.

Traumatic brain injury (TBI) is a leading cause of cognitive impairment that affects millions of people worldwide. Despite growing awareness about the debilitating and lifelong progressive consequences of TBI, there are currently no treatments that slow the deteriorative process. TBI survivors are currently treated with extensive physical and cognitive rehabilitation, accompanied by medications that may mitigate symptoms yet do not halt or slow neurodegeneration.

Now, researchers have found for the first time that this process can be pharmacologically reversed in an animal model of this chronic health condition, offering an important proof of principle in the field and a potential path to new therapy. The findings from Harrington Discovery Institute at University Hospitals (UH), Case Western Reserve University (CWRU) School of Medicine, and Louis Stokes Cleveland VA Medical Center were recently published in the Proceedings of the National Academy of Sciences (PNAS) USA.

"TBI can lead to lifelong detrimental effects on multiple aspects of health," explains Andrew A. Pieper, MD, PhD, senior author on the study and Director of the Harrington Discovery Institute at UH Neurotherapeutics Center, Morley-Mather Chair in Neuropsychiatry, Professor of Psychiatry at CWRU, and Psychiatrist at the Louis Stokes Cleveland VA Medical Center Geriatrics Research Education and Clinical Center (GRECC). "Adverse long-term outcomes of TBI commonly include sensorimotor impairment, cognitive dysfunction, or emotional dysregulation, such as depression and anxiety, including worsened post-traumatic stress disorder. In addition, TBI significantly increases the risk of later developing aging-related forms of dementia, such as Alzheimer's and Parkinson's diseases."

Dr. Pieper and his team set out to test whether it was possible to reverse the lifelong chronic neurodegeneration and associated cognitive deficits after TBI, which had never been demonstrated before. They utilized a mouse model that mimicked concussive impact in middle-aged people suffering a TBI decades prior, and administered an energy-elevating neuroprotective compound, known as P7C3-A20, that they had previously shown to have therapeutic value in acute TBI. The research team waited for one year after injury and then administered the compound daily to mice for one month.

Strikingly, this brief treatment with P7C3-A20 restored normal cognitive function. They continued to observe the mice for an additional four months, during which time they did not administer any more compound. Remarkably, at the end of this period the mice still showed normal cognitive function. Thus, after just one month of treatment, cognitive function remained improved four months later.

"When we examined the brains under the microscope, we saw that chronic neurodegeneration after TBI had completely stopped in the mice that had been briefly-treated with P7C3-A20," said Edwin Vázquez-Rosa, PhD, co-first author on the study. "Then, under electron microscopy we discovered that P7C3-A20 had also facilitated repair of the endothelial cells lining the blood vessels of the brain."

"This is the first time we've seen that P7C3-A20 can protect endothelial cells at the interface of the cardiovascular system and the brain, known as the neurovascular unit (NVU)," explains Min-Kyoo Shin, PhD, co-first author on the study. Deterioration of the NVU occurs in almost all types of brain injury and disease, and is a well-known early and chronic feature of Alzheimer's disease. The team also showed that P7C3-A20 directly protects human brain microvascular endothelial cells cultured in the laboratory as well.

"Except for aging and genetics, TBI is the greatest risk factor for developing Alzheimer's disease," explains Matasha Dhar, PhD, co-first author on the study. "We speculate that preserving the blood-brain barrier at the NVU might be a way to protect TBI patients from this increased risk."

Robert A. Bonomo, MD, Associate Chief of Staff and Director of the Cleveland GRECC asserts, "These seminal findings have tremendous long-term impact on our veteran population that suffers from TBI."

There are currently no medicines available to patients that directly protect the blood brain barrier. A medicine with this property, such as one derived from the P7C3 series of compounds, would have broad applicability to numerous conditions of the brain, including TBI and Alzheimer's disease.

Announcing a new article publication for BIO Integration journal. In this editorial, Co-Editor-in-Chief, Pingtong Huang considers an integrated approach to ultrasound imaging in medicine and biology.

Ultrasound imaging is an important method for clinical disease screening, early diagnosis, and non-invasive guidance. The development and research pertaining to ultrasound contrast agents for ultrasound molecular imaging underlies the advancement of ultrasound targeted technologies and is the driving force for the progression of ultrasound molecular imaging.

The utilization of ultrasound-mediated microbubble cavitation to augment the movement of genes, drugs, and antibodies across the vascular endothelial barrier to realize intracellular delivery has created new opportunities for applications in biology and clinical transformation. Sonodynamic therapy has emerged as a favorable option for the minimally-invasive treatment of solid cancers. The compounded utilization of ultrasound and a sonosensitizer drug to produce cytotoxic reactive oxygen species in and around neoplastic cells forms the basis of sonodynamic therapy.

In the future, the rise in cross-disciplinary and interdisciplinary cooperation will continue to promote the advancement of ultrasound theranostic techniques with additional accomplishments in clinical trials and basic research which could have extensive benefits to human health.

Blood transfusions increase the survival of children admitted to the hospital with complications by severe malaria, and could be beneficial even at higher haemoglobin levels than those currently recommended. These are the main findings of a study led by ISGlobal, a centre supported by "la Caixa" Foundation, and published in The Lancet Haematology.

Mortality among children admitted to hospital with malaria is high, especially in cases with severe complications. Most of them die within the first 24 hours, which leaves a limited time-window to intervene. In addition to starting antiparasitic treatment, one of the most frequent interventions is performing a blood transfusion. The World Health Organisation recommends transfusing children with malaria when the haemoglobin levels are under 4og /litre, or 60g / litre in case of complications such as impaired consciousness or acidosis. Despite these recommendations, there is still considerable uncertainty regarding which patients may benefit - and which may be harmed - from blood transfusion.

In this study, the team led by ISGlobal researcher Climent Casals-Pascual analysed the association between blood transfusion and death in almost 26,000 patients from five different sub-Saharan countries, with the aim of identifying the optimal haemoglobin threshold for transfusing children with severe malaria. "The value of this study is that it includes countries where adherence to international guidelines varies, which allowed us to compare results across a wide range of haemoglobin values," explains Casals-Pascual.

The data used for the study involved 25,893 patients under 15 years of age that were admitted to hospital with confirmed infection by P. falciparum between 200 and 2005, in six hospital centres (in The Gambia, Ghana, Malawi, Gabon and Kenya) belonging to the SMAC (Severe Malaria in African Children) network. Thirty-three per cent of these patients (8,513) received a blood transfusion.

The results show that blood transfusion increased the survival of patients with severe disease. In cases with complications, such as impaired consciousness or elevated lactate in blood, transfusion improved survival even in children whose levels of haemoglobin were higher the recommended threshold of 60g /l. For example, among patients with impaired consciousness, the authors observed improved survival upon transfusion with haemoglobin levels as high as 105 g / l. However, in the case of mild cases, transfusion was associated with an increase in mortality.

"This study provides valuable evidence to guide blood transfusions in African children with severe malaria, and highlights the need to perform controlled clinical tirals to establish higher thresholds for those cases with complications," concludes Casals-Pascual.

No one likes to think about their own mortality. But COVID-19 has shoved life's dark questions to the forefront: "What if I'm hooked to a ventilator and can't speak?" "If my heart stops beating, do I want to be resuscitated?" "Where do I want to die?"

West Virginia University researchers saw a sharp uptick in inquiries regarding end-of-life care in the first half of 2020, according to a study published in the Journal of Pain and Symptom Management.

Danielle Funk, program manager of the West Virginia Center for End-of-Life Care and lead author of the study, said calls to the Center spiked threefold in the early months of the COVID-19 pandemic. This indicates a new sense of urgency in advance care planning - such as completing directives and medical orders (i.e. Do-Not-Resuscitate forms) - in West Virginia.

"We average between 70 and 120 calls a month," Funk said. "But in March (2020), we had over 300 calls. COVID made a lot of people recognize that you never what's going to happen and you need to be prepared for your medical decisions."

The Center, housed in the WVU Health Sciences Center, was established in 2002 to provide resources to West Virginians seeking guidance on their preferences for care at the end of life.

For the study, Funk examined the first six months in 2020 of inquiries to the Center compared to the previous five years. Many of the callers this year specifically asked about COVID-19 and its impact on advance directives and medical orders, as well as how to respect patients' wishes via medical power of attorney or health care surrogate during social distancing.

The Center also distributed more advance directives - legal documents that outline how a patient wants medical decisions made for them if unresponsive - during the first half of 2020.

The Center's e-Directive Registry, which houses patients' advance directives and medical orders and makes them available to treating health care providers, also experienced COVID-19-related changes. Most remarkably, the Registry saw an increase in DNR cards by 77 percent between 2019 and 2020.

"Essentially, a DNR card says if your heart stops beating, no one's going to perform CPR on you," Funk said.

The Registry also accepted more Physician Orders for Scope of Treatment forms. A POST form is more wide-ranging and less black-and-white than a DNR card, Funk said. POST forms are also intended to relay the patient's wishes but leave wiggle room for various scenarios.

"There are different levels," Funk said. "For instance, if your heart stops beating, do you want full medical interventions? Or just certain, limited interventions? Or do you just want to be kept comfortable?"

The Center's e-Directive Registry has been lauded nationally and is viewed as one of the top two - along with Oregon - for its comprehensiveness, Funk said. Healthcare providers are able to access the Registry 24/7 through the West Virginia Health Information Network for their patients' advanced care documents.

"This has been very beneficial in situations where patients could not speak for themselves and could not provide documentation of their advance directives or medical orders," Funk said. "Many states have registries that only accept one type of form. We accept everything, even brain bank donations and human gift registry forms. All the documents are there and you don't have to worry about losing them."

Despite the enhanced awareness of end-of-life care during COVID-19, Funk believes anytime is a good time to start planning, for the sake of oneself and loved ones. And everything is available through the Center.

"I have the same call to action now than before COVID," Funk said. "I encourage everyone to begin advance care planning. There's no downside to it. It's just making your wishes known. I've had people call me and say, 'I'm doing this because my loved one didn't do it before me. And they had this horrific death.' When people spend the majority of their lives trying to please everyone else, you should be able to choose what happens to you when you're sick or when you die."

Rutgers researchers have discovered human gene markers that work together to cause metastatic prostate cancer - cancer that spreads beyond the prostate.

The study, published in the journal Nature Cancer, explored prostate cancer cells from people and mice and found a wide collaboration among 16 genes that leads to metastasis, which often leads to treatment challenges.

The gene markers identified can predict if a prostate cancer patient has a high probability of developing metastasis, including bone.

Prostate cancer is the second leading cause of cancer-related deaths among men in the United States with a five-year relative survival rate of near 100 percent when diagnosed early. Metastatic prostate cancer has a five-year survival rate of 30 percent. Current therapeutics like first- and next- generation anti-androgens that target male sex hormones alongside radiation, chemotherapy and others are not always effective, and it's impossible to predict which patients are at risk of developing the advanced late stage of the disease.

"People diagnosed with prostate cancer should now be screened for the protein markers discovered to help determine their risk of developing metastatic prostate cancer, which can help inform more personalized therapy," said Antonina Mitrofanova, an assistant professor at the Rutgers School of Health Professions and research member at Rutgers Cancer Institute of New Jersey. "Our results show that molecular profiling at the time of diagnosis can help inform more personalized therapy leading to better outcomes for those with this advanced form of disease."

Researchers say testing for these gene markers can also predict which patients will fail to respond to normally used androgen targeting therapies in metastatic disease and can decrease multiple treatment rounds for patients.

Researchers, in collaboration with Cory Abate-Shen's lab at Columbia University, have applied for a patent for their discovery and are looking to develop therapeutics and diagnostic tools.

ABBOTT PARK, IL., October 19, 2020 -- Researchers at the University of Illinois, Urbana-Champaign, Abbott and, the U.S. Air Force Research Lab announced today the results of a new study that found a direct link between physical fitness, cognitive performance, and optimal nutrition. The scientists revealed that getting the right nutrition not only fuels our bodies and improves fitness, but gives us an edge mentally, too.

The double-blind study, published this week in the journal Scientific Reports, examined the effectiveness of optimal nutrition and exercise to enhance fitness and cognitive performance among a population of active-duty men and women in the U.S. Air Force. Researchers divided the 148 study participants into two groups for 12 weeks. Both groups performed the same training program, which included a balanced exercise program comprised of aerobic and resistance training performed five days per week. In addition to the training program, one group was given a prototype nutritional drink, the other group received a placebo.

The study showed that exercise, along with the addition of a high-protein nutrition drink containing lutein, omega-3 fatty acids, phospholipids, vitamin D, and beta-hydroxy-beta-methylbutyrate (HMB), led to statistically significant changes to the following compared to exercise alone.

Improved working memory by 11% (i.e., information processing and problem-solving), which predicts multitasking and is often impaired under stress

Improved reaction time by 6% - participants became faster and more accurate

Increased muscle mass by more than two pounds

Lowered resting heart rate by 8% - a sign of increased cardiovascular fitness. Resting heart rate improved from 71 beats per minute to 65 beats per minute

"The physical and mental health benefits of exercise are well known, but this study demonstrates how optimal nutrition can help boost brain function as well," said lead study author, Chris Zwilling, Ph.D, a postdoctoral researcher working with the study's principal investigator Aron Barbey, Ph.D. at the Beckman Institute for Advanced Science and Technology at the University of Illinois. "We are excited by the results because they provide critical insights into how simple dietary changes can make a big difference in helping people be as efficient and productive as possible in today's world. "

FUELING BODY AND BRAIN

"Abbott has been researching the impact of nutrition on brain function for more than a decade," said Matthew Kuchan, Ph.D., a research fellow and brain health scientist at Abbott and co-author of the study. "These results confirm that by combining the right nutrition and exercise, people who are facing high-pressure situations can stay sharp physically and mentally when they need it most."

Abbott Research Fellow, Tapas Das, Ph.D., led the design of the innovative liquid nutritional drink used in the study. It contained DHA, an omega-3 fatty acid, lutein, a carotenoid, as well as phospholipids and micronutrients to support mental performance. The nutrition formulation also included protein, vitamin D, and HMB to support muscle health. Abbott will leverage these results and ingredients to design future nutritional products to allow individuals to live their lives to the fullest.

"It is clear that nutrition is a critical component for developing and maintaining the physical and cognitive performance of the men and women in the U.S. Air Force," said Adam Strang, Ph.D., and lead investigator with the Air Force Research Laboratory. "This research confirms that a nutritional supplement with the right nutrients can support and facilitate those improvements when paired with balanced exercise training. We hope to use this knowledge now and, in the future, to better prepare them for the complex and diverse mission sets they are facing."

PERFORM LIKE AN AIRMAN

Like U.S. Air Force personnel, healthy adults can prime their bodies and brains to work more efficiently and juggle multiple priorities:

Muscle gains: After a workout, make sure your muscles reap the benefits by consuming foods rich in protein to help build muscle, like lean meats and dairy, salmon, tuna, fortified milk, and egg yolks.

Mind your meals: Support memory and multitasking abilities by getting enough DHA, an omega-3 fatty acid in your diet. Adding more fatty fish like salmon and tuna can help tackle a growing to-do list

Focus foods: Support information processing and problem-solving acumen by opting for more lutein at meals. Lutein can be found in egg yolks, dark leafy greens like kale and spinach, and brightly colored fruits and vegetables, including bell peppers, carrots, corn, tomatoes, sweet potatoes, peas, avocados, oranges, and melons

A multisite study led by UC Davis Health found that two prominent early intervention models for autism had a similar impact. The researchers compared developmental and symptom improvements in toddlers with autism who received one year of one-on-one intervention sessions using either the Early Intensive Behavioral Intervention (EIBI) or Early Start Denver Model (ESDM). They found that the effect did not differ significantly whether delivered at 15-hours or 25-hours per week.

“When parents receive the first diagnosis, they typically ask: What kind of treatment should I seek and for how many hours per week?” said Sally J. Rogers, professor emeritus of psychiatry and behavioral sciences at the UC Davis MIND Institute and lead author on the study. “As clinicians, we had no data from well-controlled experimental studies to answer these questions. This study is the first to ask these questions experimentally.”

Their study, published in the Journal of the American Academy of Child and Adolescent Psychiatry, found that neither the type of intervention nor the intensity of delivery led to significant differences in the children’s rate of progress.

EIBI and ESDM interventions for autism

The two interventions vary considerably in their delivery style and underlying theories. EIBI is based on applied behavior analysis and uses simple, structured instructions to teach the children. ESDM is naturalistic and based on developmental and behavioral sciences with an interactive style embedded in everyday activities, both play and typical routines.

Previous studies have documented that both treatment types can result in significant child gains in language understanding and use, learning rates, and cognitive and adaptive skills. However, recommendations for a specific number of hours per week of treatment have been based on assumptions rather than high-quality experimental evidence.

“We designed the trial to provide objective answers about the effect of initial child characteristics, treatment styles and treatment intensities on the child’s progress over time,” Rogers said. “We assessed this progress by measuring key developmental and symptom indicators.”

Researchers enrolled 87 toddlers with autism (between the ages of 12 and 30 months) from three university sites. Based on their age and development level, the children were randomly assigned to one of four intervention groups: 15 or 25 hours of ESDM; 15 or 25 hours of EIBI.

The researchers delivered one year of one-on-one interventions in homes and childcare settings. They also provided caregiver coaching to the families through two 1.5-hour sessions per month. According to Rogers, the ESDM and EIBI treatments were delivered at the highest quality.

“Therapists followed the treatment manuals and maintained high fidelity to the principles of each treatment. They also received frequent supervision and coached parents to use the interventions and to generalize child skills from therapy into everyday activities at home and in the community,” Rogers said.

The children received four clinic assessments from the time of enrollment, at six-month intervals. Therapists assessed progress daily and updated the intervention frequently to meet children’s changing developmental and behavioral needs.

More intervention hours not necessarily better

The researchers found that neither style nor intensity of intervention had a differing effect overall on the study’s four outcome measures: children’s progress in receptive language, expressive communication, nonverbal ability and autism symptom change. They also found that the treatment providers in both models used the models flexibly to meet individual children’s needs. Both models tended to provide greater structure and practice for children who needed it, and more child choice and naturalistic teaching for children who were ready for it.

“Parents may find it reassuring that even within highly specified treatment approaches like these two, therapists still adjust to individual child needs.”

The initial severity of developmental delay and autism symptom severity did not influence the impact of treatment style or intensity on any of the outcomes.

The current findings apply only to the toddler-aged children who were studied. They need to be validated through replication. The study approach also needs to be applied to older children to understand their responses to these differing treatments and intensities.

Irvine, CA - October 19, 2020 - A breakthrough study, led by researchers from the University of California, Irvine, results in the restoration of retinal and visual functions of mice models suffering from inherited retinal disease.

Published today in Nature Biomedical Engineering, the paper, titled, "Restoration of visual function in adult mice with an inherited retinal disease via adenine base editing," illustrates the use of a new generation CRISPR technology and lays the foundation for the development of a new therapeutic modality for a wide range of inherited ocular diseases caused by different gene mutations.

"In this proof-of-concept study, we provide evidence of the clinical potential of base editors for the correction of mutations causing inherited retinal diseases and for restoring visual function," said Krzysztof Palczewski, PhD, the Irving H. Leopold chair and a distinguished professor in the Gavin Herbert Eye Institute, Department of Ophthalmology at the UCI School of Medicine. "Our results demonstrate the most successful rescue of blindness to date using genome editing."

Inherited retinal diseases (IRDs) are a group of blinding conditions caused by mutations in more than 250 different genes. Previously, there was no avenue available for treating these devastating blinding diseases. Recently, the FDA approved the first gene augmentation therapy for Leber congenital amaurosis (LCA), a common form of IRD which originates during childhood.

"As an alternative to gene augmentation therapy, we applied a new generation of CRISPR technology, referred to as 'base editing' as a treatment for inherited retinal diseases," said first author Susie Suh, assistant specialist in the UCI School of Medicine Department of Ophthalmology.

"We overcame some of the barriers to the CRISPR-Cas9 system, such as unpredictable off-target mutations and low editing efficiency, by utilizing cytosine and adenine base editors (CBE and ABE). Use of these editors enabled us to correct point mutations in a precise and predictable manner while minimizing unintended mutations that could potentially cause undesirable side effects," said co-first author Elliot Choi, also an assistant specialist in the UCI Department of Ophthalmology.

Using an LCA mouse model harboring a clinically relevant pathogenic mutation in the Rpe65 gene, the UCI team successfully demonstrated the therapeutic potential of base editing for the treatment of LCA and by extension other inherited blinding diseases. Among other results, the base editing treatment restored retinal and visual function in LCA mice to near-normal levels.

"After receiving treatment, the mice in our study could discriminate visual changes in terms of direction, size, contrast and spatial and temporal frequency," said Palczewski. "These results are extremely encouraging and represent a major advance towards the development of treatments for inherited retinal diseases."

Gene therapy approaches to treating inherited retinal diseases are of special interest given the accessibility of the eye, its immune-privileged status and the successful clinical trials of RPE65 gene augmentation therapy that led to the first US Food and Drug Administration-approved gene therapy. Now, as demonstrated in this study, base-editing technology can provide an alternative treatment model of gene augmentation therapy to permanently rescue the function of a key vision-related protein disabled by mutations.

DARIEN, IL - As we approach flu season, adults with obstructive sleep apnea may want to take extra precautions. A study published online as an accepted paper in the Journal of Clinical Sleep Medicine is the first to find that patients with sleep apnea who did not use CPAP therapy were more likely to be hospitalized with the flu.

Results of the retrospective study show that 61% of patients (17 of 28) who either weren't prescribed CPAP to treat their sleep apnea or weren't adherent to their CPAP treatment were hospitalized with the flu, compared with 24% of patients (6 of 25) who were adherent to CPAP therapy. Statistical analysis found that the patients who were non-adherent to CPAP were nearly five times more likely to be hospitalized with a flu infection, despite having a higher rate of flu vaccination.

"Our study would suggest that among patients with obstructive sleep apnea, those who use CPAP are less likely to be hospitalized because of an influenza infection than those who do not use CPAP," said study coinvestigator Dr. Glen Greenough, associate professor of medicine, psychiatry and neurology at the Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire.

Greenough said the study provides further evidence that sleep is essential to health.

"These results would suggest that use of a treatment, CPAP, that improves sleep quality reduces the severity of influenza infection as determined by rate of hospitalization," he said. "This might suggest that treating sleep apnea and thereby improving sleep quality has a beneficial effect on the immune system. It also suggests that treating sleep apnea with CPAP could help reduce hospitalizations thereby reducing health care costs."

Nearly 30 million adults in the U.S. have obstructive sleep apnea, a chronic disease that involves the repeated collapse of the upper airway during sleep. Common warning signs include snoring and excessive daytime sleepiness. A common treatment is CPAP therapy, which uses mild levels of air pressure, provided through a mask, to keep the throat open during sleep.

The researchers at Dartmouth-Hitchcock Medical Center analyzed the medical records of 53 patients who had sleep apnea and a confirmed case of the flu between 2016-2018. The 28 patients categorized as non-adherent to CPAP treatment had a mean age of 63 years and were 54% male; the 25 CPAP-adherent patients had a mean age of about 60 years and were 52% male. CPAP use was assessed by data download, with adherence defined as usage of at least four hours per night for at least 70% of nights.

The analysis also revealed that 75% of non-adherent patients received a flu vaccine, compared with 56% of regular CPAP users. While not a statistically significant difference, the authors suggest that poor sleep could have negatively impacted non-adherent patients' response to the vaccine.

According to the Centers for Disease Control and Prevention, October is a good time to get vaccinated for the flu. Learn more at cdc.gov/flu.

AURORA, Colo. (Oct. 18, 2020) - Success rates for in vitro fertilization are higher at clinics that voluntarily share more information than required by government regulators, according to new research by faculty at the University of Colorado School of Medicine.

In a review of data reported between 2014 and 2017, CU researchers found that clinics that reported more data than required by the Centers for Disease Control and Prevention (CDC) had higher rates of success in achieving pregnancy and birth.

"It was stunning to see the difference," said Alex J. Polotsky, MD, professor of obstetrics and gynecology in the Division of Advance Reproductive Medicine at CU. "The data showed that clinics with high transparency had greater success. When you go to a clinic with high transparency, it means you are much more likely to have healthy baby."

In a review presented Sunday, October 18, at the American Society for Reproductive Medicine's annual meeting, Polotsky and his colleagues compared the outcomes at clinics that report the minimum data required by the CDC and those clinics that share more information through a professional organization, the Society for Assisted Reproductive Technology (SART).

The review compared rates of pregnancy, live birth, good birth outcome, and cases when the IVF cycle is cancelled. The cancellation rates were higher at the clinics meeting the higher transparency standards required by SART, indicating that the procedure moves forward when the likelihood for success is higher. SART posts national data and reports from member clinics on its website.

"Nobody had compared clinics that adhered to higher standards of transparency," said Polotsky, who is the medical director for CU Advanced Reproductive Medicine. "This shows that it is better for patients when clinics share more information that is easier to understand."

Volume 11, Issue 30 of Oncotarget reported that previously, the authors showed that anti-estrogen drugs combined with a dendritic cell-based anti-HER-2 vaccine known to induce strong Th1-polarized immunity dramatically improved clinical response rates in patients with HER-2pos/ERpos early breast cancer.

Here, the Oncotarget authors show that the small molecule Akt antagonist MK-2206, when combined with the Th1 cytokines IFN-gamma and TNF-alpha, maximize indicators of apoptotic cell death in a panel of phenotypically-diverse human breast cancer lines.

These findings were mirrored by other, structurally-unrelated Akt-targeting drugs that work through different mechanisms. Interestingly, they found that MK-2206, as well as the other Akt antagonist drugs, also had a tendency to suppress Th1 cytokine expression in stimulated human and murine lymphocytes, potentially complicating their use in conjunction with active immunotherapy.

"They found that MK-2206, as well as the other Akt antagonist drugs, also had a tendency to suppress Th1 cytokine expression in stimulated human and murine lymphocytes, potentially complicating their use in conjunction with active immunotherapy"

After verifying that MK-2206 plus IFN-gamma could show similar combined effects against breast cancer lines, even in the absence of TNF-alpha, the authors tested in a rodent HER-2pos breast cancer model either a HER-2-based DC vaccine, or recombinant IFN-gamma with or without MK-2206 administration.

These findings suggest a combined therapy approach for Akt-targeting drugs that incorporates recombinant Interferon-gamma and is potentially translatable to humans.

Dr. Gary K. Koski from Kent State University said "Once existing only at the margins of cancer treatment, immunotherapy has now gained a strong claim as a distinct and accepted treatment modality, taking its place among the established approaches of surgery, radiation, cytotoxic agents and targeted drugs."

Consistent with this notion, the authors and others have found that paired Th1 cytokines IFN-γ and TNF-α induced senescence and/or apoptosis in vitro for a variety of cancer cell lines.

Subsequent in vitro studies showed that ERpos BT-474 cells were relatively resistant to Th1 cytokines while ERneg SK-BR3 cells were more sensitive.

However, addition of anti-estrogen drugs to cytokines for BT-474 cells had about the same impact as cytokines alone on SKBR3, i. e. the drugs that blocked estrogen signaling appeared to sensitize estrogen-dependent cells to the Th1 cytokines.

Because Akt sits at the nexus of such important growth and survival signaling pathways, and because we previously showed that Th1 cytokines also trigger apoptosis while lowering expression of HER family oncodriver expression, the authors hypothesized that the combination of Th1 cytokines and Akt antagonists might make a particularly effective pairing useful for immunotherapy of breast cancer.

Since MK-2206 is one of the most potent and best-studied Akt agonists, they designed a series of studies around this agent to determine whether a phenotypically diverse panel of breast cancer lines would be susceptible to combined action of Th1 cytokines and MK-2206, whether this combination would enhance cell death through an apoptotic mechanism, and determine the effect of this treatment on the expression of important oncodrivers by breast cancer cells.

The Koski Research Team concluded in their Oncotarget Research Paper that few studies have examined the impact of Akt antagonist drugs on T cell function.

In contrast, the authors focused their investigation on suppression on T cell function, namely the capacity of antigen- and mitogen-stimulated cells to produce IFN-γ.

They showed that MK-2206, as well as all other tested Akt antagonists, strongly suppressed IFN-γ production by stimulated lymphocytes.

It is entirely possible that one of the reasons Akt inhibitor drugs have underperformed expectations clinically is that they simultaneously suppress activated T cells, and particularly their capacity to produce cytokines like IFN-γ which might be critical for anti-tumor activity by the immune system.

In light of this developing clinical trial, in the present study the authors placed particular emphasis on trastuzumab- and lapatinib-resistant cell lines, positioning Akt antagonist drugs as possible ways to deal with resistance to these more established drugs, should they come to be used more routinely in conjunction with IFN-γ.

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DOI - https://doi.org/10.18632/oncotarget.27556

Full text - https://www.oncotarget.com/article/27556/text/

Correspondence to - Gary K. Koski - dendritic_cell@hotmail.com

Keywords -
breast cancer,
Akt kinase,
immunotherapy

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Journal

Oncotarget

DOI

10.18632/oncotarget.27556

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(doi:10.1001/jamapsychiatry.2020.3746)

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