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CARM1 (coactivator-associated arginine methyltransferase 1) belongs to a family of enzymes known as PRMTs (protein arginine methyltransferases), which can introduce arginine methylation. CARM1 is also referred to as PRMT4. Protein methylation, the addition of a methyl group to target proteins, is one type of post-translational modification that can change the function of the target proteins.
CARM1 has been reported to be overexpressed in breast cancer, and its overexpression is associated with high-grade tumors and poorer prognosis. So CARM1-specific inhibitors are considered a promising breast cancer therapy. However, until now only few targets of CARM1 have been identified, and how it recognizes these targets remains unclear.
Now, a team of researchers from the University of Wisconsin – Madison has mapped out the profile of CARM1 targets in breast cancer, by using the quantitative mass spectrometry. This may aid in the development of CARM1-spcific inhibitors for breast cancer treatment.
Study leader Prof. Wei Xu previously found two targets of CARM1: BAF155 and MED12. Additionally, CARM1-mediated BAF155 methylation correlates with breast cancer progression and metastasis. Other researchers include Evgenia Shishkova, Hao Zeng, Fabao Liu, Nicholas Kwiecien, Alexander Hebert, and Joshua Coon.
In this work, Xu's team employed multiple techniques including high-resolution mass spectrometry to globally profile CARM1 targets in two human breast cancer cell lines. They identified more than 300 CARM1-dependent arginine methylation events, and verified about 130 new CARM1 protein targets, many of which have cancer-related functions. Further, they also found that the N-terminus of CARM1 is necessary for target recognition and methylation. The researchers hypothesized that the design of CARM1-specific inhibitors should focus on the N-terminus of CARM1.

A study in the Proceedings of the National Academy of Sciences (GRP78 haploinsufficiency suppresses acinar-to-ductal metaplasia, signaling, and mutant-driven pancreatic tumorigenesis in mice) shows that inhibiting a specific protein may be a way to combat the deadly pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC), which accounts for 95% of all cases of pancreatic cancer, remains an aggressive type of malignant tumor in need of more effective therapies. The five-year survival rate is only about 5%, though surgery offers the only opportunity for a cure. In the United States alone, PDAC killed 39,590 people in 2014.

Mutations in the KRAS oncogene are present in 90% of PDACs. Previous studies have shown that KRAS mutations drive pancreatic tumorigenesis and is required for tumor maintenance, suggesting KRAS as a promising therapeutic target. However, the effect of drugs directly targeting KRAS turned out to be disappointing, highlighting the need to identify new therapeutic targets.

PDAC is very difficult to treat due to its excessive local invasion and early systemic dissemination. The glucose-regulated protein (GRP) is over-expressed in a variety of cancers including pancreatic cancer and associated with invasion and metastasis. Elevated GRP78 expression promotes the proliferation, migration, and invasion of pancreatic cancer cells and may predict poor prognosis in PDAC.

The new study describes an approach to stop the development of pancreatic cancer. In the work, the researchers demonstrated in a genetically engineered mouse model that expressing only 50% of the amount of GRP78 (a mechanism called haploinsufficiency ) stopped KRAS-driven pancreatic tumorigenesis. Further investigation showed that GRP78 haploinsufficiency in the pancreata led to reduction of epidermal growth factor receptor (EGFR), a protein that plays essential roles in both normal physiological conditions and cancerous conditions.

Patients with Churg-Strauss Syndrome (CSS) may benefit from an anti-IL5 monoclonal antibody. This is the result of a study (Mepolizumab or Placebo for Eosinophilic Granulomatosis with Polyangiitis) published May 18, 2017 in New England Journal of Medicine.
Churg-Strauss Syndrome (CSS), also known as Eosinophilic granulomatosis with polyangiitis (EGPA), is an extremely rare autoimmune condition marked by blood vessel inflammation. It can impair multiple organ systems, such as the lungs, skin, nerves and stomach. The disease generally affects individuals with a history of asthma or allergies. Asthma, eosinophils, fevers, shortness of breath, cough, wheezing, runny nose, sinusitis, and rashes are common symptoms. Left untreated, the disease can be life-threatening.
Mepolizumab, an anti–interleukin-5 monoclonal antibody, reduces blood eosinophil counts. It is used to treat severe eosinophilic asthma, and works by blocking interleukin-5 (IL-5), a protein that functions as a key mediator in eosinophil activation. This protein is known to correlate with several allergic diseases, such as allergic rhinitis and asthma. There is a hyperthesis that anti-IL5 antibodies may not only treat asthma but other diseases. (PODXL Monoclonal Antibody can be offered by CusAb.)
The aim of this study is to test the effect of mepolizumab in CSS. A total of 136 people with CSS participated in the study, and were randomly assigned to receive mepolizumab or a lacebo. Results showed that patients receiving mepolizumab showed accrued weeks of remission, and more patients receiving mepolizumab showed remission. These findings demonstrated the theapeutic effects of the antibody mepolizumab in CSS.

Alzheimer's disease (AD) was firstly described and named after a psychiatrist and pathologist Dr. Alois Alzheimer in 1906. It is an irreversible, progressive brain disorder that affects cognitive functions. Symptoms usually starts in patients’ mid-60s, but can also occur earlier. According to estimated, 5 million people in the USA have the disease, for which currently there are no treatments to stop or reverse the progression. Exiting therapies only temporarily improve symptoms. Its incidence is rising in line with the aging population. Mechanisms of AD have yet completely understood.

Published 26 April 2017 in Alzheimer’s Research and Therapy, a new study, carried out by Doris Lambracht-Washington, Min Fu, Pat Frost and Roger Rosenberg at UT Southwestern Medical Center, now reports a DNA vaccine that could protect against toxic proteins associated with AD. The researchers demonstrated that a DNA Aβ42 trimer vaccine led to high levels of antibody responses in rhesus macaques.

The accumulation of amyloid plaques between neurons in the brain is one of the markers of AD. This study showed that a vaccine that contains DNA of the toxic beta-amyloid (Aβ) protein can elicit a protective immune response. In the study, 6 rhesus monkeys received two different doses of the DNA Aβ42 trimer vaccine. The researchers monitored the humoral and cellular immune response in the animals. Results showed that the vaccine triggered high titer antibody responses (anti-Aβ42 IgG and IgA antibodies) in the monkeys. Moreover, these antibodies were able to detect amyloid plaques in the brain of an AD mouse model. Importantly, the vaccine did not accompany inflammatory interferon (IFN)-γ- and interleukin (IL)-17-producing T-cell responses. The researchers hope that their vaccine has protective effects in patients with early AD. (Cusabio produces and offers FITC conjugated antibody.)

In the past, there are limited treatment options for people with advanced kidney cancer. These patients tend to have poor outcomes. In recent years, the emergence of novel combination treatments, such as the combination of nivolumab and ipilimumab, have prolonged the survival of some patients. However, there are a still a subpopulation of patients who do not respond to these combination treatments.
Nivolumab is a human IgG4 anti-PD-1 monoclonal antibody used in the treatment of several cancers such as inoperable or metastatic melanoma, metastatic squamous non-small cell lung cancer, primary or metastatic urothelial carcinoma, and renal cell carcinoma. It works by blocking a signal that would have prevented activated T cells from attacking the cancer. Ipilimumab is a also monoclonal antibody and it activates the immune system by a protein that downregulates that immune system, CTLA-4. (Cusabio offers polyclonal antibody.)
Evidence shows that immunotherapy agents improve the survival and life quality of some kidney cancer patients, but almost have no effects in other patients. A lot of research groups are conducting clinical trials to test the effectiveness of a new immunotherapy combination: nnivolumab and other investigational immunotherapy agent. One such group is from Rush University Medical Center. They analyzed blood samples of cancer patients receiving immunotherapy treatments in order to identify immune-biomarkers in the blood that can be used to indicate the presence of a disease, or predict patients’ response to a treatment. But the interactions between a tumor and the body’s immune system are complex. Identifying a immune-biomarker is not a easy task. More research is needed to solve this problem.

Since 2014, the lethal Ebola virus has swept many countries on the planet, particularly Liberia, Sierra Leone, and Guinea in West Africa. Ebola becomes an emerging infectious disease for which there is no known cure. Now, making progress toward a vaccine and therapy against Ebola, researchers reporting in Cell have identified natural human antibodies with the potential to provide broad protection against Ebolaviruses.
Therapies based on monoclonal antibody has shown promise for treatment of Ebola infections. However, one thing that limits their application is that most antibody therapies target just one specific ebolavirus due to their species-specific recognition of the viral glycoprotein (GP). One experimental therapy called ZMappTM, which comprises thress chimeric monclonal antibodies, is specific for Ebola virus, or called Zaire ebolavirus, but is ineffective against two other ebolaviruses known as Sudan virus and Bundibugyo virus. (CusAb strives to provide the excellent products such as Biotin conjugated antibody for researchers.)
The genus Ebolavirus is included in the family Filoviridae, order Mononegavirales. In addition to Zaire ebolavirus, Sudan virus and Bundibugyo virus, there are two other virus species that belong to this genus: Ta  Forest ebolavirus and Reston ebolavirus. Essentially, it is very difficult to predict which species will cause the next epidemic. So developing a broadly effective therapy that treats all ebolaviruses is a reasonable strategy in the fight against these lethal pathogens.
The new study, led by John Dye at U.S. Army Medical Research Institute of Infectious Diseases, Kartik Chandran at Albert Einstein College of Medicine, and Zachary Bornholdt at Mapp Biopharmaceutical, showed that two potent antibodies from a human survivor might be used as broadly effective immunotherapeutics and vaccines.
The team previously separated 349 different monoclonal antibodies from a survivor of the 2013-16 Ebola epidemic. For this work, by analyzing these antibodies, the team discovered two antibodies, ADI-15878 and ADI-15742, that effectively neutralized all the five ebolavirus species. Treatment with the antibodies protected animals that were exposed to Ebola virus, Bundibugyo virus and Sudan virus.

PD-1, a 55 kDa transmembrane protein, is an immune checkpoint receptor expressed by activated T cells, B cells, and myeloid cells. It is important for the induction of immune tolerance. Mice lacking PD-1 exhibit a breakdown of peripheral tolerance and show multiple autoimmune features. Tumor cells often express elevated levels of PD-L1, which is the ligand for PD-1, and this help them to evade the body’s immune attacks. Monoclonal antibodies targeting PD-1/PD-L1 interaction are promise in treating various cancers. These antibodies have already been known to unleash T cells, but how they affect macrophages remains unclear. (Cusabio offers Biotin conjugated antibody.)

Now, researchers from Stanford University School of Medicine, University Hospital Basel, and Yale University School of Medicine have found that those antibodies also prompt immune cells to engulf and devour cancer cells. In a paper published online 17 May 2017 in Nature, the researchers report how they made the discovery, which will expand the use of PD-1/PD-L1 blockade antibodies in cancer treatment.

PD-1/PD-L1 blockade antibodies have become an important immunotherapy. It is well established that these antibodies work by stimulating T cells to fight cancer cells. The new study provides a new mechanism by which these antibodies combat cancer.

Irving Weissman, corresponding author of the paper, and colleagues demonstrated that both mouse and human tumour-associated macrophages express PD-1, and this expression increases over time and is associated with poor macrophage phagocytosis ability. Inhibiting PD-1/PD-L1 interaction enhances macrophage phagocytosis, decreases cancer growth, and improve outcome of experimental mice.

Investigators from Germany have revealed the protective role of a protein in inflammatory bowel disease (IBD). The protein, called CD14, could be targeted to treat or prevent this debilitating and even life-threatening disease.

Inflammatory bowel disease (IBD), a group of diseases that involve inflammation of part or all of the digestive tract and predominantly include ulcerative colitis and Crohn disease, is a result of genetic, microbial, and environmental factors. Many genetic loci have been implicated in IBD development in both humans and mouse models. In particular, a gene called Cd14, which encodes the CD14 protein, has been suggested to be a candidate gene for IBD susceptibility.

CD14 is preferentially expressed by monocytes and macrophages. Some other types of cells such as dendritic cells, neutrophils, and epithelial cells can also express the protein. It has two forms, a membrane form and a soluble form. As part of the innate immune system, it functions to enhance activation of cells by bacterial LPS. Evidence shows that CD14 is present at a low level in the uninflamed intestine and is increased in the inflamed intestine. Additioanlly, mice experiments demonstrate the impact of genetics on gut CD14 level.

The new study, led by investigators from Hannover Medical School, University of Veterinary Medicine Hannover, and University of Erlangen-Nürnberg, have uncovered that CD14 has a protective role in the development of IBD by enhancing intestinal barrier function. Findings of their study are described in The American Journal of Pathology.

The team used a mouse-model system for IBD to better elucidate the disease's pathogenesis. Genetic and candidate gene analyses confirmed that Cd14 is a potentially protective candidate gene. Mice lacking CD14 exhibited more severe inflammation in their gut in comparison to the controls. In contrast, increasing CD14 expression strengthened the integrity of the intestinal barrier.

Liver disease, which includes is more than a hundred different kinds of diseases of the liver, constitutes one of the most common causes of death worldwide. In Australia alone, approximately 6 million people are suffering from liver disease, putting an enormous burden on the health care system. It is imperative to develop more effective therapeutic agents for liver disease.

One type of liver disease, hepatitis, is an inflammation of the liver tissue. It is most frequently caused by viruses, although the condition can also be caused by other factors, such as heavy alcohol use, certain medications, toxins, other infections, and autoimmune diseases. Over time, hepatitis may progress to liver fibrosis, cirrhosis, liver failure, and liver cancer.

Now a study “IFN-λ3, not IFN-λ4, likely mediates IFNL3–IFNL4 haplotype–dependent hepatic inflammation and fibrosis” appearing in the journal Nature Genetics shows that the protein IFN-λ3 seems to be responsible for liver fibrosis, a discovery that will open an avenue for treating liver disease. (Cusabio offers interferon (IFN) and other proteins like Recombinant Itgb5.)

The study is carried out by an international team consisting of scientists from Australia, Italy, Germany, Egypt, UK, Denmark and Spain. Prof. Jacob George at Sydney's Westmead Institute for Medical Research is the study leader.

Previously, the team located liver fibrosis-related genetic variations on chromosome 19 between the IFNL3 and IFNL4 (interferon-λ3 and interferon-λ4) genes. But whether IFN-λ3 or IFN-λ4 protein drives the disease is unknown. In this work, the team set out to address this question. Using multiple methods, they examined liver samples from 2000 patients with Hepatitis C and found that liver inflammation, fibrosis stage, fibrosis progression rate, liver infiltration of immune cells, IFN-λ3 expression are greater in patients with the IFNL3–IFNL4 risk haplotype that does not produce IFN-λ4, but produces IFN-λ3. This suggests that it is IFN-λ3 but not IFN-λ4 that likely mediates liver inflammation and fibrosis. The IFN-λ3 protein is a naturally occurring antiviral agent and modulates functions of the immune system. With these information, doctors may be able to predict which people are at risk of developing liver disease and then take effective measures to deal with it. The precise mechanism by which IFN-λ3 contributes to liver disease development needs further investigation.

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease and motor neurone disease (MND), is a fatal disorder of motor neurons. It is the most common adult-onset motor neuron disease and is characterized by progressive paralysis and death. Currently, no treatment substantially slows disease progression. The etiological underpinnings of ALS are complex and not fully understood. A lot of genes have been implicated in ALS, including C9orf72, SOD1, TARDBP, and FUS, which are key to the normal function of motor neurons and other cells.

Now a new study shows that a variant in UBQLN4 gene is associated with ALS. The study, led by Dr Yongchao Ma from Northwestern University Feinberg School of Medicine, reveals that UBQLN4 gene variant disrupts a pathway that drives motor neuron development.

Previous studies suggest that mutations in UBQLN4 gene can trigger ALS and ALS/dementia in humans. In the current study, Dr Ma and colleagues screened the UBQLN family of genes in patients with familial ALS and identified a novel variant in UBQLN4 that is associated with ALS. They further demonstrated that the UBQLN4 gene variant impairs a pathway involved in breaking down a protein called beta catenin, leading to the buildup of the protein. This, in turn, impairs motor neuron structure.

When the researchers used a drug to inhibit beta-catenin function in a Zebrafish model, the defects in motor neurons caused by the UBQLN4 gene variant were reversed. The drug, called quercetin, is a flavonol found in many plants, used as an ingredient in supplements, and has been promoted for the treatment of many human diseases including cancer.

Collectively, the findings indicate that inhibition of beta-catenin function may a treatment strategy for patients with ALS who have the the UBQLN4 variant. “These findings provide a strong link between the regulation of axonal morphogenesis and a new ALS-associated gene variant mediated by protein degradation pathways,” the researchers concluded. The findings, if confirmed, may lead to new therapies for this devastating degenerative disease. 

Scientists from Australia and the Netherlands have identified a diagnostic biomarker of a rare childhood disease called mevalonate kinase deficiency (MKD). The study “Defective protein prenylation is a diagnostic biomarker of mevalonate kinase deficiency” is published online 10 May 2017 in the Journal of Allergy and Clinical Immunology.

MKD is a rare, inherited auto-inflammatory disease that disrupts the production of cholesterol and isoprenoids. The disease is most often caused by mutation of the MVK gene. This gene provides instructions for making the mevalonate kinase (MVK) enzyme, which plays an important role in the synthesis of cholesterol and isoprenoids. Patients usually experience recurrent episodes of high fever, which typically begin during infancy and can persist into adulthood. The severity of the disease varies from person to person. There two types of MKD: hyperimmunoglobulinemia D syndrome (HIDS) and mevalonic aciduria (MVA).

The new study provides new insights into MKD. The team, consisting of scientists from Garvan Institute of Medical Research, University of Queensland, St Vincent's Hospital, Sydney Children's Hospitals Network, and Radboud University Medical Center Australia and, found that a group of untethered proteins builds up in the cells of children with MKD. These defective proteins could be a diagnostic biomarker of MKD.

Professor Mike Rogers, who led the study, and colleagues analyzed blood cells from patients with MKD. Results showed that several Rab proteins did not have an isoprenoid 'tail', a molecule that is generally added to these proteins so that they can perform their functions. It is suspected that this tail may keep Rab proteins in a particular area of the cell. When the tail is lost, the Rab proteins become free to move to other parts of the cell, which the researchers believed might be the cause of inflammation in MKD.

The researchers developed an accurate method to detect untethered Rab proteins in blood samples, which enabled them to identify the accumulation of untethered Rab proteins in MKD cells. By contrast, this accumulation was absent in healthy controls and patients with other autoinflammatory diseases. The researchers noted that Rab proteins “appears to be a sensitive and specific diagnostic biomarker to distinguish MKD from other autoinflammatory diseases.” (Cusabio offers MVK and Rab related proteins and polyclonal antibody.)

Investigators, including Chung-Ping Liao, Reid C. Booker, Sean J. Morrison and Lu Q. Le from the University of Texas Southwestern Medical Center (UT Southwestern), have stumbled upon a finding that may lead to a cure for balding and hair graying.

The study, “Identification of hair shaft progenitors that create a niche for hair pigmentation,” appears in an advance online publication by the journal Genes & Development.

Baldness and gray hair are considered unfortunate but unavoidable products of aging. Generally, the risk of losing your hair is proportional to your age. Apparently, men are more prone to baldness than women. The American Hair Loss Association says that two-thirds of men will experience some degree of balding by age 35, and up to 85% of men will have noticeably thinner hair by age 50.

Hair is produced by the hair follicle, a skin organ that contains several structures including papilla, matrix, and bulge. Hair differentiates from follicle stem cells and is also pigmented by melanocytes in the follicle. However, the precise mechanism is not fully understood.

When UT Southwestern investigators studied how tumors form, they unexpectedly found why hair turns gray. They observed that a protein called KROX20 switches on in skin cells that develop into the hair shaft. These pre-hair cells then produce a protein called SCF, which the investigators showed is important for giving hair its color. The investigators said that SCF expression by these cells is necessary for the maintenance of differentiated melanocytes and for hair pigmentation.