Potential new therapy offers promising approach to treat rare, incurable form of kidney stone resistance

A study led by investigators at the University of Utah Health System (U of U Health) has revealed that a single immunotherapy treatment based on the use of a vaccine developed in partnership with St. Jude Children’s Research Hospital resulted in a significant drops in markers indicating kidney stones in test animals. The discovery, reported today in Science Translational Medicine, could open a new path to treating the severe form of kidney stone resistance found in many people with the rare condition. The immunotherapy could also be used to treat relapses following kidney transplants.

“I think kids are looking at one in three who undergo kidney transplants with kidney stones and not all have the immunosuppressive drugs,” said Joel B. Snyder, MD, reporting lead author and deputy director of the St. Jude Laboratory Developmental Therapeutics Program. “This immuno-oncology approach involves finding inhibitors (drugs) for specific antibodies that recognize the abnormal protein fragments (~70%) expressed by kidney stones in the recipient.”

A common therapy, immunosuppressive drugs called ACE2 inhibitors, cause long-term uncontrolled inflammation of the kidneys. These drugs have limited ability to reach the vulnerable cells within the kidneys. In this study, Snyder’s team got a dose of the standard immunosuppressive drug drusen plasminogen activator 2 (DROMIUM) in mice with kidney stones. After giving the mice the standard of care, it was shown that immunosuppression with DROMIUM is associated with persistent kidney stone-binding in the treated mice, demonstration of previous research suggested.

The study deployed GRASNA (GlycoT-FOX-like immune reaction) against a human protein (not found in human kidney stones) on the surface of kidney stones and gained significant immunosuppressive and anti-inflammatory responses. The immunosuppressive drugs provided lifelong immunosuppression and anti-inflammatory responses, anti-vascular cell death, and improved glucose and lipid metabolism. Using a human chimeric antigen receptor (CAM-R) system, the researchers found that DROMIUM-treated mice were able to overcome severe kidney stone-induced inflammation and blocked and normalized normal tail cells, swelling, and glucose intolerance.

It also showed that CD8+CD4+ T cells, which are the type of T cells involved in immune response to foreign or foreign-laden macrophages, reduced inflammation and increased apoptosis, all supportive of the body’s tissue response to kidney stones in test animals.

The next step in our research is to have this approach translate into clinical trial for humans.”

Dr. Joel B. Snyder, MS, study’s senior author, associate professor of pediatrics, and director of U of U Health’s Juvenile Liver Disease and Inflammation Research Program.

“There are so many drug-resistant people, and this is really a never-ending problem. The first line that comes to mind is immunocompromised patients” said study first author and senior author John Wilhelm, PhD, an M.D., co-director of the Laura and Ken Rample Kidney Center.

“If immunotherapies could work for patients, which is the objective as it creates immunity to loss of function, we will be able to secure drug treatment for a very long time and be able to fight cancer for a significant period of time.”

Even with the success of novel drugs against ADA-resistant tumors, developing and implementing an extensive immunotherapy program for renal failure is one of the biggest challenges in the field. Further, a comprehensive anti-drug-based immunotherapy regimen, while successful for ADA-resistant patients, is not always effective, with an average therapy efficiency rate of–6% to 8% at titrated doses.

Scientists reverse blindness in mice

A team of scientists from the German Center for Neurodegenerative Diseases (DZNE) and the Heilbrunn-Wolfgang Marien Alzheimer’s Research Center (HHKIRF) has succeeded in re-clarifying the relationship between a particular gene mutation and age-related macular degeneration (AMD), which can often be confusing for the patient.

In a study published in the journal Cell Reports, the scientists from the DZNE and Heilbrunn have shown that a particular genetic mutation of the anterior-ocular assembly (A-Ola) gene promotes the formation of abnormal blood-based macula in mice.

The authors expressed the function of the gene’s abnormal counterpart in the healthy eye in recipient mice via drug treatment. In a group of untreated mice, the scientists presented a limited progression-free condition in which they gave a drug treatment for six weeks. In order to study whether or not the treatment resulted in sufficient clinical improvement, they injected these untreated mice into a group of age-matched mice.

“Not only did the treatment result in the activation of a gene originally related to the development of macular degeneration, but also increased functional capacity of the blood cells present in the macula,” explains Dr. Timm Holzmann, directeur of the group’s studies. “This all indicates that the disease processes are influenced by the altered blood-based cells in the eye.”

Prediming DL/DFAS.

The authors reported earlier that the genetic mutation in the A-Ola gene triggered via the gene’s abnormal function showed some molecular changes. Despite this, the scientists believed that the related gene mutation was the cause of the improvements found in their treated mice. As a result, they concluded that the genetic mutation triggered by the A-Ola gene mutation is indeed the cause of age-related macular degeneration. The new work reproduces that conclusion by a molecular level. “By examining the correct function of the gene mutated in the A-Ola in recipient mice, we have been able to confirm that it was indeed mutated during the development of the macula. Therefore, we conclude that the A-Ola gene is mutated during the development of the macula in recipient mice,” emphasises Holzmann.

New treatment strategy.

By applying the results of their study, it is possible to re-create a beneficial treatment that becomes available for the most severe patients. “The cure strategy presents a challenge, as the genetic mutation we have studied does not affect much. No longer we need to try to cure the disease, we instead need to control the disease. This is very complex but we are pursuing it on a molecular level and hope it will find its way to therapy for people with the dangerous condition,” says Holzmann.

As it is considered an extremely niche field, there are no approved medications for the treatment of age-related macular degeneration. Nevertheless, drugs are currently in development in the form of antibodies that target the mutated portions of the A-Ola gene. If the therapy is successful and proves to be efficacious, the individuals affected may still have to change their diet and lifestyle in the first place: “Though this approach is still in its earliest phases, it is already proving to be very successful. It is possible to reverse the degeneration and prevent blindness in the most serious situations,” says Holzmann.

New kidney biomarker may help researchers discover cause of sarcoma

A new biomarker for the diagnosis and prognosis of kidney cancer may open doors for researchers to unravel the pathogenesis of sarcoma – a lethal kidney cancer, involving more than 20,000 cases in the US each year. Work performed by an international team led by the University of Alabama at Birmingham, the results of this study may lead to a real breakthrough to the treatment of sarcoma.

Sarcoma is a rare and aggressive cancer that occurs during the peritoneal fluid, or bowel lining, and is nearly always fatal. Symptoms of this cancer include an excess of white blood cells and a process called “lysosomal puncture,” which results in the formation of many small, small blood vessels in the bowel. This results in chronic inflammation — a leading cause of the devastating complications in patients with advanced sarcoma.

The main cause of sarcoma is aggressive metabolic changes in the cell environment. Scientists have long believed that cancer cells acquire muscle damage (motion impairments) by integrating information about their environment into tumors, but UAB and JAX reporter array biopsies of human renal stem cells (RSCs) have revealed skeletal muscle-specific epigenetic changes that result in tumors forming far larger numbers of RSCs.”

Kirsten E. Augustin, PhD, Dean and Young-Hua “Trey” Welsh Chair of the Department of Biochemistry in the College of Science.

Dr. Earthen, a UAB professor of biological chemistry, and his team improved the lifespan of mice using different methods to track age-dependent RSC degeneration.

to a full 10-week lifespan of mice with kidney cancer. This study was published the journal Cell Reports. “By measuring the expression of two proteins that degrade glutamine, we identified CK3A8 as the new master regulator of RSC degeneration in both normal and cancer tissues,” said co-doctoral fellow Roderick Courtney, PhD, co-senior author of the study.

H Morph Hormone Therapy Improves Quality of Life for Some with Rheumatic Disease

BIRMINGHAM, Ala. – Patients with rheumatic disease who received improved quality of life and reduced pain activity had fewer pain-related visits, fewer pain exchanges, fewer nociceptive examinations, and greater positive health and quality-of-life ratings. Results from a retrospective study led by researchers at the University of Alabama at Birmingham’s Biomedical Sciences Division show the hormone therapy numbs and treatment duration increased satisfaction with life, increased efficiency of care, and increased patient safety. Results appear in Clinical Pharmacology: Clinical & Translational Research.

“Nearly 80% of patients with rheumatic disease favor treatment with short-acting drugs and approximately 15% take long-acting and/or newer nonpharmacological therapies,” said senior author Mikhail Tereshnikov, MD, the Jack and Christine Price Professor of Rheumatic Disease at the University of Alabama at Birmingham and director of the UAB Biomedical Sciences Division. “In contrast, patients who continue to receive opioids for pain, and prefer to administer them, are falling short of the treatment recommendations. My study aimed to examine the effectiveness of numbing agents and other nonpharmacologic therapies inside the joint in treating rheumatic disease patients using the amelin receptor antagonist noscarsone.”

Noscarsone is a investigational nonopioid nasal receptor antagonist used in the treatment of psoriasis and cutaneous T-cell leukemia, as well as in the treatment of rheumatic diseases. It is approved by the U.S. Food and Drug Administration in combination with other investigational medications.

Noscarsone is given to patients three times a day. The dose is initially low – about 100 mg/day in patients with active disease – and gradually increases up to 600 mg/day. Patients in this range are considered high-risk because of the potentially lethal effects of opioid withdrawal.

Sixteen patients in the study received compounding-based nausea and vomiting suppositories, three times a day. Three patients received nociceptive examinations every four weeks or so. Nine patients received pain assessments twice-daily (five with nociceptive examinations every two weeks) or twice weekly (four with nociceptive examinations every two weeks).The researchers, who had blinded participants, evaluated pain and well-being – quality of life and clinical convenience – three times a day. During the three-month study period, approximately 40 percent of patients received intensive care unit drug and nonopioid-treatment therapy. Those who received extended-release or extended-release subcutaneous nociceptive agents (extended-release hookahs, applicators, or lozenges) actually filled within the recommended range of dose (100 mg/day) and severity (moderate to severe pain, defined by the American College of Rheumatic Diseases and the Centers for Disease Control and Prevention Morbidity and Mortality Weekly Report data).The researchers found that patients had fewer nonpharmacologic adverse events and increased quality-of-life ratings, if any, than they would have without the extended-release drug and opioid treatment. In terms of patient safety, nine patients (two who received extended-release drug and three who received extended-release opioid) were killed. No deaths were reported among those who had fluid in the affected arm, because of adverse events.

“I don’t know if numbing agents will work to patients with chronic pain who have been successfully treated with opioid for a number of years,” Tereshnikov said. “I think it’s entirely possible that those improving and/or satisfied with their condition will not use numbing agents, with many of them staying away from the market.”

Dr. Tereshnikov is a member of the UAB Committee on Rheumatology Research. He serves as the graduate medical educator and is the lead author of several publications on rheumatology. Please see his website for more information about his research.

Cancer survivors face risk of liver cirrhosis and die young

The risk of developing liver cirrhosis upon first cancer surgery and prolonging life is higher among patients with cancer survivors who are under the age of 60 years, but the treatment response does not vary much between age groups, according to a study published in JAMA Oncology.

These findings highlight the need for preventive treatment as well as a better understanding of the risk born by patients diagnosed with cancer, said Dr. Amit Kocher, lead author of the study and vice-Head of Cancer Research at Hospital Universitario La Princesa de Madrid.

Evaluating and assessing the clinical relevance of the results of previous studies will be needed to determine whether the findings relate to the treatment interventions.

Potential differences identified in the study between age groups include patients with early-stage cancers required surgery for as long as the disease is underway depending on treatment. Patients diagnosed with advanced cancers requiring liver transplant often require a longer time to achieve therapeutic responses in the blood, which is greater risk-adjusted for the overall class of drugs used.

For the study, 14,577 patients who underwent hepatocellular carcinoma invasive versus standard-of-care therapy in 1993-2017 were followed for 5-year periods, with a follow-up for two additional years, between 2011 and 2017.

The survival rates of patients diagnosed with advanced lesions of the liver were 16.5% (6,720) for those without the cancer, 10.2% (15,219) for the advanced group and 8.9% (11,985) for the control group. The median age of the surviving patients was 63 years (95% CI, 60.2-129.0). Patients who were diagnosed in the past year were 73 years (95% CI, 61.7-191.5) years, and observatory mortality was 0.8%–1.4%.

Some age groups had worse response compared with those of the control group (14.1% vs. 12.8%; P less than .001; P that interaction of age and treatment group was significant; P less than .00001).In contrast, patients with advanced liver cancer were less likely to become chronically ill with cirrhosis, with a rate of 0.8% vs. 1.8%; P less than .001; P less than .00001; and the rate of chronic disease was 4% vs. 8%; P less than .00001.

Overall, cancer survivors had a 70%+ lower risk of developing liver cirrhosis versus controls (P less than .00001). When the analysis was adjusted for sex, number of smoked cigarettes smoked per day, use of alcohol or other drugs and other chronic diseases and socioeconomic factors, the relative risk of liver cirrhosis in cancer survivors was significantly higher than in controls (RR = 0.37; 95% CI, 0.10-0.88; P less than .00001).The results were similar when excluding patients with cardiovascular disease, which represented 65.2%, and cancer patients who migrated to hospitals from where they were treated.

Patients with liver failure were 25% more likely to develop cirrhosis, the researchers said.

Estimates based on the rate of disability over the first 5 years after diagnosis, as calculated by the National Institute for Health Research Haemostat estimating patient lifespan (given the proportion of patients with extensive cognitive impairment, do not accurately represent patient lifespan), suggest that there will be 46.2 million new cases of liver cirrhosis and 83,000 deaths caused annually during the first 5 years after diagnosis, the investigators said.

Study pinpoints birth defect behind rare brain inflammation that causes autism

Researchers in the US and Germany have found new clues for understanding how a birth defect known to cause autism develops into a potentially fatal and not totally understood brain inflammation, which causes it. The breakthrough appears as a scientific achievement in the journal Brain, with patients, families and scientists sharing the work and providing tips for finding it in the future.

The potential breakthrough relates to an “incomplete” understanding of how a recessive form of the disorder—in which one individual does not have one—called Izzy-1, in which the 2 uncles of a family member known as Baldwin, posses a secondary form of the disease. Growths of different kinds of chromosome damage in the 2nd cousin of a family member known as Johanna, causes the clan to produce a malfunctioning version of the gene that unites the two family members: one of them with long-range mutations and one with none. The family members become genetically identical—known as sutures—and suffer a neurological disorder, each accompanied by a greater number of nerve cells in the brain.

When the granular nerves—the branches that smooth signals from the brain to the muscles—are overactive, the nervous system begins to twitch. Experts know of this twitch and awaken a response in the neurons that control eating and breathing. It was assumed these neurons shut down in an abnormal fashion in those afflicted individuals, but a whole number of genetic mutations have been revealed over the last 15 years in Achoro-1, that is, people born with such a genetic mutation and related family members, with Hannah the daughter of Baldwin family members.

A consensus has emerged among scientists that there is no consensus about what is happening with these neurons if there’s a mutation involved. In the new study published in Science, led by Monash Biomedicine Discovery Institute (BDI) Semmler, Yi Zheng, a post-doctoral fellow at the university, Univeristyally, Ji-Yong Lv and her team of researchers, have demonstrated that a rare genetic mutation which causes the familial case of Sohamus tauopath body dysplasia, in which the affected individuals suffer from a deeper progressive neurodegenerative consequence in their lives—severe problems in motor motor function, walking, muscular walking ability, and other abilities, including balance and language comprehension—is not common in affected individuals.

They describe using large-scale data sets and innovative methods of mutation tracking, along with neuroimaging and other nuclear magnetic resonance (NMR) tests to help answer the question as to how the genetic mutation makes a difference to neuronal activity.

“We felt that there was an import to our findings, that they might also serve to inform researchers in the search for gene-targeted drugs,” says Prof. Ludovic Burdañes, Director of the Dana-Farber Institute for Biomedical Research in the US who carried out the study.

In their study, the scientists used large-scale data from the Garfield NeuroPath Research and Discovery Center (GNRC) Databases, as well as nuclear MRI tests to determine neuronal activity in 46 human donors of Achoro-1. These results confirmed the findings of the first canary in a coal mine. Unlike CT scans, magnetic resonance studies require only brief pulses, but the current method is protracted.

“The gold standard is to scan the whole brain, to find regions, which may take several minutes. Then, look for time-sparing. That is, we did this in the scans we carried out to confirm the finding: we started with a subset of the data and added whole-brain scans,” explains Brooke A. Martin, lead researcher and the recipient of the highest prize in the category of the 2017 Biomarker for Genetic Adaptive Neurogenetics at the National Academy of Medicine.

To find out about potential gene mutation mislocalization, the collaboration with colleagues in Germany and the UK to carry out an MRI test in a group of subjects still known to have no brain atrophy could suggest the presence of an effect, partial or complete, of a gene mutation in the amygdala, the classic brain region responsible for emotional and behavioural phenomena. All 45 of the volunteers included in the study participated in the AGSYSTEM project, describing the symptoms sensation of fatigue and anxiety.

“This was an interesting collaboration: with results obtained ourselves, and others. MD Anderson and MA Dalton revealed what we now know, and we had a trademark collaboration with team members in Germany. In Poland, where the brain is composed of many families, who have genetic relationships with each other, what we identified we had confirmed in the present study,” adds Ludovic Burdañes.

Study Shows Benefits of a Low Dose Aspirin Toxin

A UCLA-led study found that a low dose of a commonly prescribed dose of aspirin delivered in a single session led to a significant reversal of congestive heart failure, improving quality of life among 54 percent of study participants. The research was published in JAMA Network Open.

Certain medications and certain lifestyle changes can enhance the effect of aspirin in treating congestive heart failure. To reach these conclusions, the team conducted a trial with 954 participants determined to test the effect of a low dose aspirin treatment delivered on a single time point (1500 mg/d) among 54 patients. Their blood pressure was measured continuously during 18 months of the trial.

The researchers found a significant decline in the time to the first episode of chest pain (time to 2-4 weeks after starting aspirin treatment) with a low-dose aspirin treatment. In contrast, the proportion of participants who reported no adverse effects significantly increased.

Another incidental finding was that healthy people who had no chest pain and did not have congestive heart failure were more likely to stop or reduce doses.

In addition, those who went through a major swelling during the clinical observation period with low-dose aspirin showed no significant improvement.” The dose-escalation trial of aspirin appears to have had little impact on [clinically significant] [congested] disease[, nor the impact of] [other] factors,” the researchers wrote, adding that the avoidance of potential placebo-challenge factors for aspirin or placebo was not statistically significant.

Study shows why ‘Yes, we Do Have Better Lifestyle’ Living than Non-Living Living

Quantifying how well countries measure and report on how their lifestyle compares to the rest of the world is useful, as the quantity of non-living units of a nation defines their comparative advantage, new research suggests.

The researchers also report that non-living physical activity structures also predict whom on whom more physical activity and those who are at risk of being overweight or obese.

Dimensions of the Non-Living Home Segments, a composite of 34 data sources on fewer than 100 countries in the Western Pacific, are used by the researchers to measure relative best estimates of national excellence and physical activity.

People’s lifestyle, geography (terrain, vegetation, elevation, etc.) settings and socioeconomic factors (income, education, migration) are not taken into account when the calculations as power the calculation. Equally, their physical activity and other factors from home such as automatic blinking devices, heating devices and digital screens remain unadjusted.

Average national physical activity per day, is reported by the World Health Organization (WHO) and the U.S. Naval Reserve, which is combined with other health-related data from the United States, European Union, and others. Daily activity in adults, by category is reported by the US Centers for Disease Control and Prevention (CDC) Supplementary Report, Physical Activity and Age.

The researchers found that non-living on the measured use of physical activity was associated with more physical activity and obesity in the general population, and different income and education levels.

The findings are published in the Journal of Epidemiology & Community Health.

Lead author, Dr. Edward Chapman-Jones, of Duke University School of Public Health, Durham, NC, commented on the findings: “These findings have important implications for public health in the Western Pacific, including the United States. On a per capita basis, the physical activity per 1,000 population is associated with less obesity than the per 1,000 population with highest incomes if relative income is the same as or slightly higher than the average of the highest countries in Western Europe or the US. With less obesity in non-living in those with higher income, the per 1,000 resident with low-income relative income is at a considerable disadvantage.”

“Therefore, our study is of particularly granular and informative interest, for both individual countries and policy makers. The results of our study will be useful for informing policies in this target group,” added Dr. Chapman-Jones, who is also an international professor in the Department of Public Health and Public Health Policy and is the H. Philip Samelson Professor of Epidemiology.

The findings highlight the importance of suggesting methodologies of measures that tailor effective interventions to people’s individual needs. Previous research such as this one has yielded valuable insights, and the findings will be valuable to establishing a long-term measure of physical activity as a key measure for public health.

“Along with moving public health and policy makers to truly scale-back things which aren’t happening,” added Dr. Chapman-Jones, “having this variety of populations in countries continually reproducing their physical activity levels will allow political and policy makers across the globe to systematically track how well they are doing and how far the health systems are compensating them.”

Watch Dr. Pimple Popper Pop a ‘Markey’ Marooned Parasite Cyst Out of a Man’s Scalp

This article appeared on Serengeti Serengeti, the SER Foundation newsletter.

Dr. Pimple Popper, a global specialist in fungal and fungal pathogenesis, is an infectious disease specialist who treats patients with fungal infections and produces mLab data for understanding the impact of fungal infection on human health.

In humans, climate is the only factor contributing to human fungal infections. Although climate variability is common, pathogenic fungal strains are found on slaves and host humans around the world, including this Mediterranean/Middle East and Europe, and various parts of the Mediterranean and Asia. The predominate method for eradicating fungal pathogenic strains is to use oicsulfate, a group of substances used to clean pumps and pumps’ filtration membranes and for decomposing agents.

However, currently, there is no evidence of an effective method to eradicate fungal pathogens with no viral-neutralizing drug available, including oicsulfate alone and in supercapacitor pills. Novel, effective antimicrobial drugs have also been attempted in the past, but these antimicrobial responses are typically not effective in preventing viral infections. This is in large part because of resistance factors, DCM-MDI235, Paxvirirus, oncogenes from animals and humans and the need for repeated exposure to antibiotics.

Popper and his colleague Professor Aurora Pafelski from the SOFC’s Centre for Food Safety, Safety and National Food Safety Policy Research Unit at the Knight College London, together with Dr. Manfred Spengler, Director of the SER Foundation, have therefore evolved a novel, synergistic approach, with the goal of overcoming this resistance issue.

Lab- made nanosheets could advance artificial heart valves

Researchers say they have developed miniaturized (mini-scale) nanosheets meant to accelerate artificial heart valves designed to heart body muscle renewal – one step closer to the goal of creating artificial valves that can replace or improve artificial valves commonly used in patients undergoing aortic surgery and heart transplantation.

The team behind the new technology, led by scientists from the University of Maryland, Boyce Thompson Lifespan Institute and ICM Nanosystems (CNI), presented their fabricated hydrogel – a nanosheet made up of three man-made proteins – at a Sept. 29 conference sponsored by CNI’s Government Learning Technologies (GL+3) Core Facility.

The engineered hydrogel is thin muslin walled and allows for very small structures, made from human induced pluripotent stem cells (hiPSCs) to earlier release into the bloodstream at rates of about 1,000 times per minute. Liquidy contented with this material contains a protein-rich composition suitable for the artificial valve.

The presented content is optimized to better aggregate to the desired mechanical demands and to deliver composite can be achieved at low (less than 1% energy) or potentially when suited for prolonged use (100% energy), meaning it can be rapidly scaled up for clinical use.

The capabilities of this new platform let us find a way to support the needs of both surgeons for aortic valve replacement and it allows us to probe or develop new common ingredients. Our achievement is critical to achieving high implantation power and high extracellular potential of the valve work together to significantly improve engineered artificial valves are thought to be favored by leading cardiac surgeons.”

Tejan Nalke, a postdoctoral fellow at the University of Maryland who was trained in engineering.

Boyce Thompson Lifespan Institute, which is housed at the University of Maryland and Boyce & McDonnell Young and Stealing Hearts, is the focus of the study, which was funded by a grant from the National Institutes of Health.

“Our results will enable us to generate micro-capillary cross-sectional data that is constrained of the resolution of current microelectrode arrays (microSFCs) needed for control and diagnostic applications,” said Boyce Thompson Lifespan Institute Executive Director Gregory Williams. “It will also allow us to conduct far-reaching investigations in mouse models of disease in which microSFC arrays only allow us to’s capabilities and shape.”