Is now a good time?
Researchers from Harvard Medical School have shown that the combination of DNA damaging agents and MDMX inhibitors could either synergize or cancel each other, depending on the timing of their administration. MDMX is an oncogene, and its overexpression inhibits the tumor suppressor p53, suggesting that MDMX inhibition might reactivate p53. Because p53 is activated by DNA damage, MDMX inhibition might synergize with DNA damaging agents. However, when the authors tested the relationship between MDMX inhibition and DNA damaging agents, they found that MDMX inhibition led to oscillatory levels of p53 in cells. "The results presented here unexpectedly show that the combination of DNA damage with MDMX inhibitors for cancer therapy has the potential either to improve cancer therapy or to blunt its effects," the authors wrote. "Our results have implications for the design of MDMX-combination drug regimes and perhaps for the design of combination therapies in general." They published their findings in the March 10, 2016, issue of Science.
A team from Beijing Mabworks Biotech Co. Ltd. and the Institute of Basic Medical Sciences, both of China, and the Public Health Agency of Canada, has reported on a cocktail of two antibodies that protected monkeys against Ebola virus. The antibodies used in the cocktail were based on two antibodies in the cocktail Zmapp, which has been used under compassionate use guidelines in the West Africa Ebola outbreak and is currently in a randomized controlled clinical trial in West Africa. In their work, the authors tested a two-antibody cocktail based on two antibodies of the Zmapp cocktail that had been modified so they could be produced in Chinese hamster ovary cells. The cocktail, MIL77E, was fully protective in three monkeys when given three days after Ebola virus infection. The authors said that "the addition of a third potent Sudan virus (SUDV)–specific [antibody] could lead to the generation of a single product targeting both [Ebola virus] and SUDV, the causative agents of most of the [Ebola virus disease] outbreaks in Africa." In addition, a two-antibody cocktail would "simplify the production and approval processes as well as increase the safety profile of the treatment." Their findings appeared in the March 9, 2016, issue of Science Translational Medicine.
Enzyme could be Alzheimer's target
A team from Columbia University has reported that the activity of protein phosphatase 2A (PP2A) affected the sensitivity of mice to high levels of amyloid beta, making them potential targets for the treatment of Alzheimer's disease (AD). Phosphatases are a class of enzymes that remove phosphate tags from proteins, and much like the kinases, which add phosphate tags, their activity is important to control the activity of their substrates. PP2A is active in many pathways that have been implicated in the progression of AD, and the authors tested whether its activity was affected by amyloid beta. Transgenic mice overexpressing PP2A were protected from electrophysiological and cognitive consequences of high amyloid beta levels. Neither of two transgenes affected A-beta production or the electrophysiological response to low concentrations of A-beta, "suggesting that these manipulations selectively affect the pathological response to elevated A-Beta levels. Together these data identify a molecular mechanism linking PP2A to the development of AD-related cognitive impairments that might be therapeutically exploited to target selectively the pathological effects caused by elevated A-beta." The work appeared in the March 7, 2015, advance online issue of the Proceedings of the National Academy of Sciences.
Gut microbiome metabolite activates platelets
Researchers at the Cleveland Clinic Foundation have shown that the gut microbiome metabolite trimethyalmine N-oxide (TMAO) had a direct and detrimental effect on the cardiovascular system by contributing to platelet hyperreactivity and enhanced risk of clotting. Previous work had shown that TMAO and its precursors, choline and carnitine, increased the risk of heart disease, and the authors set out to understand those effects at the molecular level. They showed that direct exposure to TMAO enhanced the platelet's propensity to clot and, hence, thrombosis risk in vulnerable patients. In more than 4,000 patients, plasma TMAO levels in subjects predicted the three-year risk of thrombosis, heart attack and stroke. "Collectively, the present results reveal a previously unrecognized mechanistic link between specific dietary nutrients, gut microbes, platelet function, and thrombosis risk," the authors wrote. They published their findings in the March 10, 2016, online issue of Cell.
Zika virus infects neural progenitors
Scientists at Florida State University and Johns Hopkins University have demonstrated that Zika virus infected human cortical progenitor cells and affected their growth and proliferation. The emerging Zika virus and its possible link to microcephaly is an urgent global public health concern, but little is known about what happens during Zika virus infection, or why microcephaly should be a particular risk. In their experiments, the authors generated human neural progenitor cells from induced pluripotent stem (iPS) cells. They showed that the virus was able to infect such cells, and global gene regulation in infected cells was disturbed, particularly with respect to cell cycle genes. In addition to the demonstration that neural progenitors are a direct target of Zika virus, the authors noted that "we establish a tractable experimental model system to investigate the impact and mechanism of [Zika virus] on human brain development and provide a platform to screen therapeutic compounds." Their work appeared in the March 4, 2016, online issue of Cell Stem Cell.
Lupus loop of B cells goes awry
Scientists at the British University College London have discovered a dysfunctional feedback loop between two immune cell types in the autoimmune systemic lupus erythematosus (lupus). Much like regulatory T cells inhibit other types of T cells, there is a type of regulatory B cell that exerts an inhibitory effect on immune responses. Such regulatory B cells usually develop in response to signals from another immune cell type, plasmacytoid dendritic cells (pDCs). Once they have developed, regulatory B cells inhibit the pDCs via production of interleukin-10. The authors showed that this feedback loop did not work in lupus patients, and that healthy B cells were exposed to high levels of interferon-alpha, which is a characteristic feature of lupus. The authors concluded that a defective feedback loop between pDCs and B cells contributes to pathology in lupus. Their work appeared in the March 10, 2016, online issue of Immunity.
Peptide shrinks ovarian cancer metastases
Scientists at Boston Children's Hospital have developed a peptide that promoted tumor regression in patient-derived xenografts of ovarian cancers. In previous work, the team had identified the peptide prosaposin as an inhibitor of metastases which acted by stimulating the tumor suppressor p53. Prosaposin works by stimulating an antitumor protein, thrombospondin-1, in the bone marrow. Ovarian cancer cells have thrombospondin-1 receptors, and when thrombospondin-1 binds ovarian cancer cells it triggers apoptosis. In animal models, treatment "resulted in apoptosis in the tumor cells and regression of established metastases," the authors wrote, leading them to conclude that "a therapeutic agent based on [the prosaposin peptide] would have efficacy in treating patients with metastatic ovarian cancer. Their work appeared in the March 9, 2016, issue of Science Translational Medicine.
A team at the Scripps Research Institute has identified a new isoform of a protein that appears to affect risk for bipolar disease. Previous studies had shown that there are multiple risk-affecting SNP's for bipolar disease that mapped to the PDE10A gene. In their studies, the authors used RNA sequencing from the brains of healthy controls and individuals with bipolar disorder to identify a primate-specific version of the gene. The protein affects cAMP-dependent signaling, a G protein-coupled receptor pathway that is important for proper communication between neurons. "These studies illustrate the complexity of PDE10A gene expression in the human brain and highlight the need to unravel the gene's complex and complete coding capabilities along with its transcriptional and translational regulation to guide the development of therapeutic agents that target the protein for the treatment of neuropsychiatric illness." The work appeared in the Feb. 23, 2016, online issue of Translational Psychiatry.
CRISPR turns reversible
A team from the Gladstone Institutes has engineered CRISPR to reversibly inhibit gene expression in induced pluripotent stem (iPS) cells. CRISPR is a genome engineering method that is derived from a primitive bacterial immune system. In their work, the team developed an inducible form of CRISPR, and combined it with an additional inhibitory protein, KRAB. The combination of Cas9 and KRAB blocked access to the DNA targeted by CRISPR without making the cuts to the DNA that are necessary for permanent editing. The authors said the system, which they have named CRISPRi, "provides a powerful platform to perform genome-scale screens in a wide range of iPSC-derived cell types and to dissect developmental pathways and model disease." Their work appeared in the March 10, 2016, online issue of Cell Stem Cell.
Myc regulates antitumor immunity
Scientists from Stanford University have discovered that the oncogene Myc affected the expression of immune checkpoint molecules, suggesting the Myc tumorigenesis may be driven in part by immune surveillance evasion. Two critical immune evasion molecules are PD-L1, which inhibits antitumor T cells, and CD47, which inhibits the innate immune system from attacking tumor cells. In their work, the authors showed that Myc regulated the expression of both PD-L1 and CD47. Suppressing Myc in tumor cells led to down-regulation of both PD-L1 and CD47, and in mouse models of cancer, that led to an enhanced antitumor immune response. The authors concluded that "MYC appears to initiate and maintain tumorigenesis in part through the modulation of immune regulatory molecules," and that "MYC-overexpressing human cancers may be especially vulnerable to an immune checkpoint blockade." Their work appeared in the March 11, 2016, online issue of Science.