Syndicate content

Archive - Jan 2017

January 6th

New Treatment for Rare Form of Encephalitis

“Anti-NMDA-receptor encephalitis” is an inflammatory disease that affects the central nervous system. It is a rare autoimmune disease that results in the body producing antibodies against the NMDA receptor (image), a protein that plays an important role in signal transduction in the brain. Using a new treatment regimen, researchers from Charité-Universitätsmedizin Berlin and the German Center for Neurodegenerative Diseases (DZNE) have recorded significant progress in treating the disease, including in patients who did not previously respond to treatment. Results from this study were published online on December 21, 2016 in the journal Neurology. The article is titled “Bortezomib for Treatment of Therapy-Refractory Anti-NMDA Receptor Encephalitis.” Anti-NMDA-receptor encephalitis is a serious autoimmune disease. It is characterized by an inflammation of the brain, which can result in neurological and psychiatric symptoms, including psychoses, epileptic seizures, and movement disorders. Standard treatments currently available are often either inadequate or ineffective in patients with severe forms of the disease. This treatment resistance may be caused by certain anti-NMDA-receptor antibody-producing plasma cells that remain inaccessible to current immunotherapies. In a study led by Dr. Franziska Scheibe and Professor Dr. Andreas Meisel from the Department of Neurology and the NeuroCure Cluster of Excellence, Charité-based researchers recorded outcomes obtained using a new treatment regimen. In addition to standard treatment, patients received bortezomib, a drug known as a proteasome inhibitor that has proven successful in treating patients with plasmacytoma, a specific type of blood cancer.

Comprehensive Interactome Map of Human Receptor Tyrosine Kinases and Phosphatases Is Released; Paves Way for Future Cancer Research and Drug Discovery

In 2011, Igor Stagljar, Ph.D., a professor in the University of Toronto's Donnelly Centre, came across a study that genetically linked two genes in the cell to a hard-to-treat (triple negative) breast cancer. It was not clear how the proteins encoded by these genes worked, but Dr. Stagljar had a unique way to find out. One of the proteins, called epidermal growth factor receptor (EGFR), belonged to a group called receptor tyrosine kinases (RTKs), which tell the cell to grow and divide in response to signals from the cell's environment. The other one (PTPN12) was from the protein tyrosine phosphatase (PTP) class, which mainly work by shutting the RTKs down. However, the EGFR is wedged within the cell's outer envelope, or membrane, making it difficult to study by traditional methods. But with the help of MYTH and MaMTH, technologies developed in Stagljar's lab, Dr. Zhong Yao, a senior research associate in the lab, was able to show that the two proteins came into direct contact with each other. This led further support to the thinking that some breast cancers progress when the link between this particular RTK and PTP is broken, unleashing unchecked RTK signalling and, consequently, cell proliferation. But Dr. Yao did not stop there. The high-throughput power of MYTH and MaMTH allowed him to investigate interactions between almost all human RTKs and PTPs. The resulting map charts more than 300 RTK-PTP interactions, most of which were unknown. The study was published online in the journal Molecular Cell on January 5, 2017. The article is titled “A Global Analysis of the Receptor Tyrosine Kinase-Protein Phosphatase Interactome.” "We tested interactions between almost all 58 RTKs and 144 PTPs that exist in human cells. Our map reveals new and surprising ways in which these proteins work together.

Researchers Find Key Genetic Driver for Rare Type of Triple-Negative Breast Cancer

For more than a decade, Celina Kleer, M.D., has been studying how a poorly understood protein called CCN6 affects breast cancer. To learn more about its role in breast cancer development, Dr. Kleer's lab designed a special mouse model - which led to something unexpected. The scientists deleted CCN6 from the mammary gland in the mice. This type of model allows researchers to study effects specific to the loss of the protein. As Dr.Kleer and her team checked in at different ages, they found delayed development and mammary glands that did not develop properly. "After a year, the mice started to form mammary gland tumors. These tumors looked identical to human metaplastic breast cancer, with the same characteristics. That was very exciting," says Dr. Kleer, Harold A. Oberman Collegiate Professor of Pathology and Director of the Breast Pathology Program at the University of Michigan Comprehensive Cancer Center. Metaplastic breast cancer is a very rare and aggressive subtype of triple-negative breast cancer - a type considered rare and aggressive of its own. Up to 20 percent of all breast cancers are triple-negative. Only 1 percent are metaplastic. "Metaplastic breast cancers are challenging to diagnose and treat. In part, the difficulties stem from the lack of mouse models to study this disease," Dr. Kleer says. So not only did Dr, Kleer gain a better understanding of CCN6, but her lab's findings open the door to a better understanding of this very challenging subtype of breast cancer. The study was published on November 7, 2016 in Oncogene. The article is titled "MMTV-cre;Ccn6 Knockout Mice Develop Tumors Recapitulating Human Metaplastic Breast Carcinomas." "Our hypothesis, based on years of experiments in our lab, was that knocking out this gene would induce breast cancer.

Chance Meeting Leads to Creation of Antibiotic Spider Silk

A chance meeting between a spider expert and a chemist has led to the development of antibiotic synthetic spider silk. After five years' work, an interdisciplinary team of scientists at The University of Nottingham (UK) has developed a technique to produce chemically functionalized spider silk that can be tailored to applications used in drug delivery, regenerative medicine, and wound healing. The Nottingham research team has shown for the first time how “click-chemistry” can be used to attach molecules, such as antibiotics or fluorescent dyes, to artificially produced spider silk synthesized by E.coli bacteria. The research, funded by the Biotechnology and Biological Sciences Research Council (BBSRC) is published online on December 28, 2018 in Advanced Materials. The article is titled “Antibiotic Spider Silk: Site-Specific Functionalization of Recombinant Spider Silk Using “Click” Chemistry. The chosen molecules can be “clicked” into place in soluble silk protein before it has been turned into fibres, or after the fibres have been formed. This means that the process can be easily controlled and more than one type of molecule can be used to “decorate” individual silk strands. In a laboratory in the Centre of Biomolecular Sciences, Professor Neil Thomas from the School of Chemistry in collaboration with Dr. Sara Goodacre from the School of Life Sciences, has led a team of BBSRC DTP-funded Ph.D. students starting with David Harvey who was then joined by Victor Tudorica, Leah Ashley and Tom Coekin. They have developed and diversified this new approach to functionalizing “recombinant” -- artificial -- spider silk with a wide range of small molecules.

January 5th

Using DNA Nanotubes for Molecular Bridge-Building at the Nanoscale Level

In a microscopic feat that resembled a high-wire circus act, collaborating Johns Hopkins researchers and a scientist from Rockefeller University have coaxed DNA nanotubes to assemble themselves into bridge-like structures arched between two molecular landmarks on the surface of a lab dish. The team captured examples of this unusual nanoscale performance on video (https://www.youtube.com/watch?v=VETd3znn3eE&feature=youtu.be). This self-assembling bridge process, which may someday be used to connect electronic medical devices to living cells, was reported by the team in an article published online on December 19, 2016 in Nature Nanoteechnology. To describe this process, senior author Rebecca Schulman, Ph.D., an Assistant Professor of Chemical and Biomolecular Engineering in the Johns Hopkins Whiting School of Engineering, referred to a death-defying stunt shown in the movie "Man on Wire." The film depicted Philippe Petit's 1974 high-wire walk between the World Trade Center's Twin Towers. Dr. Schulman pointed out that the real-life crossing could not have been accomplished without a critical piece of old-fashioned engineering: Petit's hidden partner used a bow and arrow to launch the wire across the chasm between the towers, allowing it to be secured to each structure. "A feat like that was hard to do on a human scale," Dr. Schulman said. "Could we ask molecules to do the same thing? Could we get molecules to build a 'bridge' between other molecules or landmarks on existing structures?" The paper's lead author, Abdul Mohammed, Ph.D., a postdoctoral fellow in Schulman's lab, used another analogy to describe the molecular bridge-building feat they demonstrated at the nanoscale level. "If this process were to happen at the human scale," Dr.

Cancers Evade Immunotherapy by “Discarding the Evidence” of Tumor-Specific Mutations, Hopkins Study Shows; Findings Could Explain Widespread Acquired Resistance Among Patients Treated with Immune Checkpoint Blockade Drugs

Results of an initial study of tumors from patients with lung cancer or head and neck cancer suggest that the widespread acquired resistance to immunotherapy drugs known as checkpoint inhibitors may be due to the elimination of certain genetic mutations needed to enable the immune system to recognize and attack malignant cells. The study, conducted by researchers on the cells of five of their patients treated at the Johns Hopkins Kimmel Cancer Center, is described in an article published online on December 28, 2016 in Cancer Discovery. The article is titled “Evolution of Neoantigen Landscape During Immune Checkpoint Blockade in Non-Small Cell Lung Cancer.” "Checkpoint inhibitors are one of the most exciting recent advances for cancers, but the mechanism by which most patients become resistant to these therapies has been a mystery," says Victor E. Velculescu (photo), M.D., Ph.D., Program Leader in the Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins and Professor of Oncology. Clinical trials with the drugs to date have shown that nearly half of patients with lung cancers eventually develop resistance to this class of drugs for reasons that have been unclear. Checkpoint inhibitors, such as nivolumab and ipilimumab, approved by the FDA for use against lung cancer, metastatic melanoma, head and neck cancer, and Hodgkin lymphoma, help the immune system recognize cancer cells by revealing evidence of mutated proteins called neoantigens on the surface of cancer cells. To investigate why checkpoint inhibitors so often stop working, Dr. Velculescu; Valsamo Anagnostou, M.D., Ph.D., Instructor of Oncology at the Johns Hopkins University School of Medicine; Kellie N.

Apligraf® Cell Therapy Shows Promise in Wound Healing

Apligraf®, an FDA-approved, bioengineered living-cell therapy from Organogenesis Inc., has become the first wound-healing therapy to demonstrate a significant change in the genomic profile of a treated non-healing wound, according to new research published in the January 4, 2016 isssue of Science Translational Medicine. The analysis from a multidisciplinary research team at the University of Miami, titled "A Bioengineered Living Cell Construct Activates an Acute Wound Healing Response In Venous Leg Ulcers," provides new insight on what happens to a wound's genomic profile when Apligraf is applied to a chronic venous leg ulcer (VLU), when compared to standard care with compression therapy alone. The analysis found that the application of Apligraf in conjunction with compression therapy altered specific molecular and cellular responses in the wound environment, converting the chronic wound profile to resemble an acute, healing wound profile. "This is the first time this type of detailed gene expression analysis has been conducted to evaluate the response to a wound-healing modality," said Marjana Tomic-Canic, Ph.D., Director of the Wound Healing and Regenerative Medicine Research Program at the University of Miami. "Our findings show that Apligraf can shift the gene expression profile of a chronic, non-healing ulcer to resemble a profile similar to that of an acute, healing wound. This is important as we now can use this as a guiding tool to understand healing of a chronic wound and mechanisms by which therapies can work." The research consisted of a prospective, randomized, controlled clinical trial that analyzed VLUs with less than 40 percent area reduction after four weeks of treatment with standard care with compression therapy.

Inhibitor of 12/15-Lipoxygenase Shows Effectiveness in Mouse Model of Alzheimer’s Disease

Treatment with an inhibitor of 12/15-lipoxygenase (image), an enzyme elevated in patients with Alzheimer's disease (AD), reverses cognitive decline and neuropathology in an AD mouse model, according to a new study published as a priority communication in the January 15, 2017 issue of Biological Psychiatry. The article is titled “12/15-Lipoxygenase Inhibition Reverses Cognitive Impairment, Brain Amyloidosis, and Tau Pathology by Stimulating Autophagy in Aged Triple Transgenic Mice.” The positive effects of the inhibitor were observed after the AD-like phenotype was already established in the mice, which is promising for the inhibitor’s potential therapeutic use, as neuropathology tends to develop many years before the appearance of AD symptoms in patients. The study, by senior author Domenico Praticò, Ph.D., and colleagues at Temple University in Philadelphia, Pennsylvania, offers some hope for a new treatment for patients with AD, who currently have no effective therapy options. Past research has focused on prevention of the disease by reducing the levels of proteins that cause brain plaques and tangles and kill nerve cells. "In this exciting new study, the authors provide support for a new experimental treatment approach that works by helping nerve cells digest toxic proteins that might otherwise cause cell death," said John Krystal, Editor of Biological Psychiatry. First author Antonio Di Meco, Ph.D., and colleagues used a triple transgenic (3xTg) mouse model that displays an AD-like phenotype, including cognitive decline, and Aβ and tau neuropathology characteristic of the disease in humans. The scientists had already shown that early administration of the 12/15-lipoxygenase inhibitor PD146176 could prevent the onset of these features in mice.

New Therapeutic Agent Proves Promising Treatment for Advanced Prostate Cancer

A German multicenter study, initiated by the German Society of Nuclear Medicine, demonstrates that lutetium-177 (Lu-177)-labeled PSMA-617 is a promising new therapeutic agent for radioligand therapy (RLT) of patients with metastatic castration-resistant prostate cancer (mCRPC). The study is published in the January 2017 issue of the Journal of Nuclear Medicine and is the featured article. The article is titled “German Multicenter Study Investigating 177Lu-PSMA-617 Radioligand Therapy in Advanced Prostate Cancer Patients.” Prostate-specific membrane antigen (PSMA) is overexpressed in prostate cancer and even more so with castration-resistant disease. This makes development of new tracers for PSMA-targeted radionuclide therapies a promising treatment approach. Prostate cancer deaths are usually the result of mCRPC, and the median survival for men with mCRPC has been less than two years. "Previous studies with a small number of patients have indicated the high potential of this new therapeutic option," explains Kambiz Rahbar, M.D., University Hospital Muenster. "This study of a large number of patients at multiple healthcare facilities, however, confirms the efficacy and safety of Lu-177-PSMA-617 radioligand therapy." At 12 therapy centers across Germany, 145 patients (median age 73 years, range 43-88) with mCRPC were treated with Lu-177-PSMA-617 between February 2014 and July 2015 with one to four therapy cycles. A total of 248 therapy cycles were performed in 145 patients. Efficacy was defined by a prostate-specific antigen (PSA) decline of 50 percent or more from baseline to at least two weeks after start of RLT. Overall, 45 percent of patients had a positive response following all therapy cycles, while 40 percent responded after a single cycle. Some adverse side effects were noted but manageable.

January 4th

Researchers Discover New Mechanism for Type IV Pili Retraction in Vibrio cholerae

Type IV pili, essential for many pathogens to cause disease, are hair-like appendages that grow out of and are retracted back into bacteria cells, enabling them to move and adhere to surfaces. Although pathogenic bacteria often rely on a specialized molecular motor to retract their pili, a new study, published online on December 19, 2016 in PLOS Pathogens, reveals that a minor pilin protein elicits pilus retraction in the cholera bacterium, Vibrio cholerae. The open-access PLOS Pathogens article is titled “The Vibrio cholerae Minor Pilin TcpB Initiates Assembly and Retraction of the Toxin-Coregulated Pilus.” Bacteria utilize a number of highly sophisticated molecular tools to colonize their hosts. One of the most ubiquitous of these tools is a complex nanomachine called the Type IV pilus. This nanomachine has as few as 10 to as many as 30 molecular components, producing exquisitely thin filaments that extend from the bacterial surface and that can be several times the length of the bacterium itself. These pilus filaments have a remarkable array of functions that rely on their ability to (i) adhere to many substrates, including host cell surfaces, pili from nearby bacteria, DNA and bacterial viruses (bacteriophage), and (ii) to depolymerize or retract, which pulls the bacteria along mucosal surfaces, pulls them close together in protective aggregates, and can even draw in substrates like DNA and bacteriophage for nutrition and genetic variation. In collaboration with researchers from Dartmouth College and Simon Fraser University, Dr. Nicolas Biais, Assistant Professor of Biology at Brooklyn College, City University of New York (CUNY), developed an assay in his laboratory that revealed for the first time that the V.