APOE4 strongly affects microglial function
Scientists at the University of Eastern Finland have investigated the effects of predisposing Alzheimer's disease (AD) mutations in induced pluripotent stem cell (iPSC)-derived microglia (iMGLs), and they found that APOE4 mutations had a much stronger effect that either presenilin (PSEN) or amyloid precursor protein (APP) in that cell type. "Using 16 iPSC lines from healthy donors, AD patients and isogenic controls, we reveal that the APOE4 genotype has a profound impact on several aspects of microglial functionality, whereas PSEN1deltaE9 and APPswe mutations trigger minor alterations," the authors wrote. "The APOE4 genotype impairs phagocytosis, migration, and metabolic activity of iMGLs but exacerbates their cytokine secretion. This indicates that APOE4 iMGLs are fundamentally unable to mount normal microglial functionality in AD." Their work appeared in the Sept. 12, 2019, issue of Stem Cell Reports.
Palbo prevents chemo hair loss
Researchers at the University of Manchester have demonstrated that inhibiting CDK4/6 with Ibrance (palbociclib, Pfizer Inc.) could prevent hair follicle damage induced by chemotherapy, suggesting that it might be able to prevent chemotherapy-induced hair loss. Such hair loss is a highly problematic side effect of taxanes, as nearly 10% of women decline chemotherapy for fear of hair loss. In their experiments, the authors first investigated the molecular effects of taxanes on hair follicles, and found that they induced "massive" apoptosis in the stem cell-rich compartment of the follicle. They then showed that treatment with Ibrance, which induces cell cycle arrest, could prevent progenitor cells from entering mitosis. Taxanes kill cells during mitosis, so the study provides "proof-of-principle of a novel therapeutic approach, i.e. pharmacological G1 arrest, that could mitigate taxane-induced hair follicle damage and prevent subsequent chemotherapy-induced alopecia, e.g. through the topical delivery of G1 arresting agents." The team reported its findings in the Sept. 12, 2019, issue of EMBO Molecular Medicine.
Inflammation stress induces red blood cell formation
Researchers from Pennsylvania State University have identified a signaling pathway through which inflammation can induce the production of red blood cells, or erythropoiesis. Inflammation tips the balance of blood cell production away from red blood cells and toward white blood cell infection fighters, which is adaptive in acute inflammation but can cause anemia in chronic inflammation. In their work, the authors showed that Toll-like receptor (TLR) signaling led to an increase in red blood cell-eating by macrophages, which disinhibited the transcription factor SPI-C and enabled stress erythropoiesis, an emergency production system that takes over when steady-state erythropoiesis is not producing enough cells. The authors concluded that "inflammatory signals induce stress erythropoiesis to maintain erythroid homeostasis when inflammation inhibits steady-state erythropoiesis.... treatments geared to decreasing inflammation and boosting stress erythropoiesis may be effective in treating chronic [anemia of inflammation]." They reported their results in the Sept. 10, 2019, issue of Science Signaling.
Methylation patterns, AI identify metastases
Patients with head and neck cancer (head and neck squamous carcinoma, HNSC) are at high risk of both lung metastases and developing an independent primary tumor in the lung (lung squamous carcinoma, LUSC). While treatment for metastatic HNSC is mainly palliative, primary LUSC can potentially be cured by surgery. But current diagnostic techniques cannot distinguish the two reliably. Researchers from Charite Comprehensive Cancer Center have trained a neural network to distinguish HNSC metastases from primary LUSCs by looking at their methylation patterns. The network "correctly classified 96.4% of the cases in a validation cohort of 279 patients with HNSC and LUSC as well as normal lung controls," outperforming other neural network methods, the authors wrote. Prediction accuracy, which was validated in an independent cohort, could be further increased by "applying thresholds to... probability scores and excluding samples with low confidence." The team published its findings in the Sept. 11, 2019, issue of Science Translational Medicine.
Rare eye disease gives clues to peripheral neuropathy
Scientists at The Scripps Research Institute have gained insights into the metabolic underpinnings of peripheral neuropathy by studying the rare eye disease macular telangiectasia type 2. Previous work had linked macular telangiectasia, which causes photoreceptor loss, to altered serine metabolism. In their work, the team sequenced the exome of a single macular telangiectasia patient, and discovered that he had a mutation in the gene SPTLC1, which has been linked to hereditary somatic and autonomic neuropathy. The team then looked at other patients with the same neuropathy and showed that nine out of 11 also had macular telangiectasia. Separately, they showed that macular telangiectasia had high levels of deoxysphingolipids, which are toxic to neurons and are formed when low serine levels force the increased metabolism of the related amino acid alanine. The team reported its results, establishing "a connection between central and peripheral neuropathies, as well as between plasma amino acid levels and these disorders," in the Sept. 11, 2019, issue of The New England Journal of Medicine.
Investigators at Columbia University have demonstrated that acute stress led to increased release of the hormone osteocalcin from bones. Osteocalcin, which is produced by bone-building osteoblast cells, has a diverse set of physiological roles that have been puzzling to tie together. The authors tested the idea that bone in general has protective functions that go beyond its mechanical protection of organs. They showed that stress led to the release of an as-yet unidentified signaling molecule from the brain that induced osteocalcin release, and the osteocalcin, in turn, shut off the "rest-and-digest" parasympathetic nervous system to clear the way for a fight-or-flight response. "The present characterization of osteocalcin as a stress hormone provides a conceptual framework that can capture most osteocalcin-regulated physiological processes," the authors wrote. "Indeed, the ability of osteocalcin to facilitate the ASR, favor memory, and enhance muscle function during exercise suggests that osteocalcin confers a survival advantage to bony vertebrates that live in a hostile environment such as the wild." They reported their findings in the Sept. 12, 2019, online issue of Cell Metabolism.
Mitochondria differ between cell types
Mitochondria are well known as the main source of ATP, the energy currency of the cell. But more recent research has shown that they also play a role in other cell functions, including organ and cell-specific functions, and that the protein catalog of mitochondria differs between different tissue types. Now, researchers at the Technical University of Munich have demonstrated that in the brain, mitochondria vary between cell types as well. They "developed an isolation approach to profile tagged mitochondria from defined cell types. We determined the mitochondrial proteome of the three major cerebellar cell types (Purkinje cells, granule cells and astrocytes) and identified hundreds of mitochondrial proteins that are differentially regulated. Thus, we provide markers of cell-type-specific mitochondria for the healthy and diseased mouse and human central nervous systems, including in amyotrophic lateral sclerosis and Alzheimer's disease." They reported their work in the Sept. 9, 2019, online issue of Nature Neuroscience.
Getting to the root of schizophrenia
Investigators at the University of Chicago and the Children's Hospital of Philadelphia have identified the transcription factor TCF4 as a "master regulator" of gene networks that appear to be altered in schizophrenia. While genome-wide association studies (GWAS) are beginning to identify genetic risk loci for schizophrenia and other neuropsychiatric disorders, which of those risk loci play the greatest role, and whether there are subtypes of major diseases like schizophrenia or depression, remains unknown. The team used a mix of bioinformatics and cell culture experiments to identify TCF4 as an originator and regulator of network changes in schizophrenia. "Compared to the commonly used weighted gene co-expression network analysis, the method used in our study aims to find MRs rather than to identify co-expression patterns, bearing a number of unique features, including the ability to elucidate potentially causal interactions, to illustrate the hierarchical structure of the identified transcriptional networks, and to identify potential feed-forward loops between [master regulators] that may cause synergistic effects in the network," the authors wrote. Their study was published in the Sept. 11, 2019, issue of Science Advances.
CAR relative CCR may offer targeting advantages
While CAR T cells have been a remarkable breakthrough for the treatment of B-cell cancers, in solid tumors they have performed much less well, showing both reduced efficacy and increased toxicity. Researchers at University College London and Memorial Sloan-Kettering Cancer Center have altered the type of T cell and co-stimulatory receptor used to engineer CAR T cells, and found that such cells avoided the on-target off-tumor toxicity that has made it so challenging to find appropriate targets for CAR T cells to attack solid tumors. The team used gamma-delta T cells, a subtype of T cells that can recognize targets not being presented by major histocompatibility complex (MHC) proteins, outfitted with a chimeric co-stimulatory receptor (CCR). "CCR-expressing gamma-delta-T cells may provide a means of improving the safety of cellular immunotherapy by avoiding on-target off-tumor toxicity," the authors wrote. "Furthermore, they may allow targeting of antigens, which to date have been off-limits due to toxicity concerns." They published their findings in the Sept. 10, 2019, issue of Science Signaling.
Waking up sleeping Xs
Investigators at KU Leuven have gained new insights into X chromosome reactivation by looking at the process in induced pluripotent stem cells (iPSCs). Female cells inactivate one copy of their X chromosomes early in embryonic development. Knowing how to reactivate the second X chromosome or, ideally, specific genes on the X chromosome, could be a therapeutic approach to certain disorders such as Rett syndrome. The researchers demonstrated that in iPSCs, X chromosome reactivation involved "the combined action of chromatin topology, pluripotency [transcription factors] and chromatin regulators. These findings are important for our understanding of gene silencing, maintenance of cell identity, reprogramming and disease." They published their work in the Sept. 12, 2019, issue of Genome Research.