Anticancer compounds for B cell cancer therapy targeting cellular stress response — ScienceDaily

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Researchers at The Wistar Institute and collaborators from the University of Notre Dame are developing anticancer compounds targeting a pathway of the endoplasmic reticulum (ER) stress response implicated in the development of multiple myeloma (MM), chronic lymphocytic leukemia (CLL) and lymphoma. The study was published online today in Molecular Cancer Therapeutics, a journal of the American Association for Cancer Research.

The ER is an important organelle in our cells that oversees the quality control of protein folding under normal conditions and responds to the accumulation of misfolded proteins found under stressful conditions by activating specific mechanisms and signaling pathways such as the IRE-1/XBP-1 pathway that triggers a cascade of events that brings cells back to normal physiological conditions.

The laboratory of Chih-Chi Andrew Hu, Ph.D., professor in the Immunology, Microenvironment & Metastasis Program at Wistar, and collaborators show that targeting the ER stress signaling response is an effective strategy against various B cell cancers that rely upon ER stress signaling response to survive under stressful conditions.

The Wistar Institute and Notre Dame teams are working together to advance a new class of compounds to inhibit IRE-1 protein and block the function of the IRE-1/XBP-1 pathway, which promotes survival of malignant B cells such as MM and CLL cells. The IRE-1 inhibitors being developed by Hu and collaborators have shown promising activity in several preclinical cancer models, compared to other commercially available IRE-1 inhibitors having variable and inconsistent ability to selectively target ER stress signaling in vitro and in vivo.

“We carefully compared many published inhibitors of the IRE-1/XBP-1 pathway with our own inhibitors, showing that our compounds are the most reliable small molecule inhibitors for targeting this pathway in malignant B cells and that many of the other published inhibitors we tested have subpar activity or adverse off-target effects,”

Experimental glioblastoma therapy shows curative powers in mice models — ScienceDaily

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Houston Methodist researchers found that mice harboring human glioblastoma tumors in their brains had greatly enhanced survival and weight gain when given a newly developed prodrug. This mitochondrial-targeted prodrug — an inactive compound that cancer cells selectively metabolize to produce an active toxic drug — also greatly improves outcomes when coupled with standard therapies of radiation and/or chemotherapy. The drug selectively targets and destroys the DNA inside the glioblastoma cell mitochondria (the energy factory of the cancer cell) leaving normal cells intact.

In an Oct. 8 study published online in Molecular Cancer Therapeutics, a journal of the American Association for Cancer Research, investigators used a second generation prodrug called MP-Pt(IV) to target the deadly cells of glioblastoma tumors, a brain cancer that is almost always fatal and has no cure. Life expectancy in humans with glioblastoma ranges from a few months to two years.

Human glioma cells were removed from patients during surgical excision and isolated within 10 minutes after removal. The glioblastoma cells were injected into the brains of 48 female mice for a 300-day study. The prodrug was well tolerated, and, when given on its own, extended survival by more than a factor of three. However, when combined with standard chemotherapy and radiotherapy, the drug was curative in nature, allowing 90% of mice to survive, thrive and gain weight during the 10 months of observation.

“This study tells us that adding MP-Pt(IV) to a chemoradiotherapy protocol could address a critical need in glioblastoma treatment,” said David S. Baskin, M.D., FACS, FAANS, corresponding author and director of the Kenneth R. Peak Center for Brain and Pituitary Tumor Treatment in the Department of Neurosurgery at Houston Methodist. “We now know that MP-Pt(IV) is an excellent candidate for preclinical development.”

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Materials provided by Houston Methodist. Note: Content

With ‘Cure’ Comment, Trump Exaggerates Known Benefits of Another Covid-19 Therapy

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Experts think monoclonal antibodies, like the cocktail taken by Mr. Trump, could fare better than hydroxychloroquine and convalescent plasma.

The treatment is “super promising, and all of us are excited from a theoretical perspective,” Dr. Ranney said. “But it’s just too early,” she added, to tell if theory will translate into practice.

Monoclonal antibodies are synthetic, mass-produced mimics of the molecules the human body produces in response to an infection. Some antibodies are powerful enough to block the coronavirus from infiltrating cells. Administered to people battling the coronavirus, the monoclonal antibodies could help naturally produced immune molecules fend off the virus.

Just days before Mr. Trump tested positive for the coronavirus and was admitted to the hospital, Regeneron announced a batch of preliminary results, collected from ongoing trials, via news release. They suggested Regeneron’s monoclonal antibody cocktail could tamp down the amount of virus found in the nasal cavity, and hasten recovery in people who had contracted the virus but hadn’t been hospitalized.

On Wednesday evening, Regeneron announced it was seeking an emergency approval from the F.D.A. for its antibody cocktail.

The data so far for monoclonal antibodies looks “very promising,” said Dr. Phyllis Tien, an infectious disease physician at the University of California, San Francisco. But it’s crucial, she added, to let the trials run to completion to fully assess safety and efficacy. Unanticipated side effects could crop up, or the treatment might not perform as well in certain people as it does in others.

Mr. Trump’s allusions to making monoclonal antibodies “free” for widespread use are also probably off base. Monoclonal antibodies are expensive and difficult to produce in large quantities. Regeneron estimated that it would initially have enough doses for only 50,000 people, though the company plans to scale up production in coming months.

What’s cheaper, Dr.

Simple sugar possible therapy for repairing myelin in multiple sclerosis — ScienceDaily

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N-acetylglucosamine, a simple sugar found in human breast milk and sold as an over-the-counter dietary supplement in the United States, promotes myelin repair in mouse models and correlates with myelination levels in multiple sclerosis patients according to a new University of California, Irvine-led study.

Published in the Journal of Biological Chemistry, the study also demonstrates that in mice, delivering N-acetylglucosamine orally to lactating mothers drove primary myelination in their nursing offspring. N-acetylglucosamine is a simple sugar that is metabolically attached to proteins at the cell surface to control cellular function.

“We found that N-acetylglucosamine activates myelin stem cells to promote primary myelination and myelin repair,” said Michael Demetriou, MD, PhD, FRCP(C), professor of neurology, microbiology and molecular genetics at UCI School of Medicine and leader of the study. “Our data raises the intriguing possibility that N-acetylglucosamine may be a simple therapy to promote myelin repair in multiple sclerosis patients.” Formal human studies will be required to test this theory.

The failure of robust re-myelination following inflammatory demyelination in multiple sclerosis leads to chronic disability and neurodegeneration. Myelin insulates the long, cable-like nerve cell branches called axons, and serves to increase the speed of electrical signal conduction between neurons. Myelination in the central nervous system also plays an important role in cognitive development during childhood.

“Interestingly, since N-acetylglucosamine is a major component of human breast milk but not baby formula, it may explain some of the cognitive function and myelination benefits realized by children fed breast milk as opposed to formula.” said Michael Sy, MD, PhD, assistant professor of neurology at UCI School of Medicine, co-director of the regional MS program at the VA Long Beach Healthcare System, and first author of the study.

Dr. med. Alexander Brandt, MD, who led the clinical parts of the study together with Dr.

CRB USA Designs New Research and Gene Therapy Center for Amicus Therapeutics

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Glass doors and floor-to-ceiling windows stream natural light into the new Amicus Center, creating a positive energy in the space. Photography courtesy of CRB USA. 

In addition to the classic “Philly” moniker and being known as the city of brotherly love, “Cellicon Valley” is emerging as a popular nickname for Philadelphia, Pennsylvania, with many new genetic research firms establishing labs within the metropolis. Amicus Therapeutics, a biotechnology company that specializes in researching medications for rare metabolic diseases, recently opened their Global Research and Gene Therapy Center of Excellence in West Philadelphia’s University City neighborhood. Located near distinguished universities and hospitals, Amicus recruited CRB USA, an architecture, engineering, and construction firm dedicated to creating advanced science and technology facilities, to design a state-of-the-art office and laboratory. 

Informal quiet zones are set up throughout the office to facilitate collaboration. Photography courtesy of CRB USA. 

Encompassing a total of 75,000 square feet, CRB devised an inviting, open space that celebrates the researchers and lab technicians by design. Scientists—often cooped up in artificially lit windowless labs—work surrounded by natural light and views of the Philadelphia skyline on the 13th and 14th floor of an urban high-rise. The royal blue of the Amicus logo is used as a bright color motif throughout the entire space, adding a lively edge via furniture, carpets, and transparent panel dividers.

Organization and transparency form symbiotic relationship throughout the space. Photography courtesy of CRB USA. 

From zones filled with heavy-duty machinery and technology to the areas that include traditional workplace features such as meeting rooms and lounge areas, the CRB designers focused on layering humanity into the design. Safety, being of utmost importance, is achieved by giving scientists freedom to move through the clearly identifiable zones—creating a defined path that’s obstacle free. Because not all workers are involved