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A proteolytically derived fragment of the epigenetic regulator HDAC4 protects the heart through transcriptional repression of the hexosamine biosynthetic pathway, thereby inhibiting protein O-GlcNAcylation and maintaining normal calcium handling and contractility of cardiomyocytes.
ALOX12-mediated generation of 12-HETE leads to GPR31 activation and liver injury in ischemia–reperfusion, which can be targeted in a nonhuman primate model to improve outcome.
Through injection of human Alzheimer's disease (AD) brain extracts containing pathological tau protein into transgenic mouse lines harboring different levels of amyloid plaque burden, the authors find that the presence of amyloid plaques modifies endogenous pools of tau protein, creating a unique environment required for the seeding and spreading of distinct tau pathologies.
Degeneration of the retinal pigment epithelium is a hallmark of geographic atrophy, a type of age-related macular degeneration. Kerur et al. show that this degeneration results from a multistep pathway in which mitochondrial dysfunction in RPE cells, triggered by accumulation of Alu RNA, leads to activation of the noncanonical inflammasome via a cGAS–STING–IRF3 signaling axis.
Fry et al. report the first results from a human trial of a CD22-directed chimeric antigen receptor (CAR) T cell therapy providing evidence of efficacy in the treatment of pre–B cell acute lymphoblastic leukemia that is immunotherapy-naive or resistant to CD19-directed CAR T cells.
Tumor organoids derived from the most common subtypes of primary liver cancer recapitulate the histologic and molecular features of the tissues of origin, even after long-term culture. These in vitro models, as well as those for colorectal cancer reported in Crespo et al. in a previous issue, are amenable for drug screening and allow the identification of therapeutic approaches with potential for cancer treatment.
Pule and colleagues identify the TCR β-chain constant region as a new target for chimeric antigen receptor (CAR) T cells in treatment of T cell cancers while potentially preserving a healthy T cell repertoire. They demonstrate that anti-TCRB1 CAR T cells eliminate cancerous TCRB1+ T cells while sparing nearly one-third of normal TCRB2+ T cells.
Hosen et al. identify an active conformation of integrin beta-7 as a cancer-associated antigen in multiple myeloma, and engineer a CAR-T cell that shows efficacy against MM in a mouse model. These findings describe the first conformation-specific CAR-T cell and highlight the potential of conformational targets in cancer immunotherapy.
TGF-β induces expression of ADAM10, which results in greater shedding of ephrin-B2. This shedding promotes the chemotaxis and activation of myofibroblasts and thus the progression of organ fibrosis.
Huot et al. investigate the differences in natural killer (NK) cells in lymph nodes during pathogenic and nonpathogenic simian immunodeficiency virus (SIV) infection of cynomolgus macaques and African green monkeys (AGMs), respectively. Their findings suggest that NK cells are specifically recruited to follicles in AGMs and regulate SIV replication in the lymph node.
Concomitant overexpression of microRNAs miR-100 and miR-125b-1 within the host long non-coding RNA MIR100HG induces cetuximab resistance in cancer in the absence of previously associated genetic alterations. miR-100 and miR-125b target negative regulators of Wnt/β-catenin signaling and sustain drug resistance through feedback inhibition of GATA6 expression and this resistance can be overcome by pharmacological inhibition of Wnt activity. These findings, together with those by Tan et al. in the previous issue, highlight the emerging functional role of non-coding RNAs in modulating the response to anti-cancer therapies.
Microenvironmental pressures in glioblastoma select for glioma stem cells (GSCs) subpopulations that are maintained through preferential activation of BMI1 and EZH2 in different niches. Given the high degree of intratumor heterogeneity, combined pharmacological inhibition of Polycomb repressive complexes targets proneural and mesenchynmal GSCs and expands lifespan in mice, warranting the therapeutic evaluation of this approach in patients with glioblastoma.
Hiroyuki Arai and colleagues characterize a new group of epoxy ω-3 fatty acid–derived proinflammatory lipid mediators, an enzyme mediating their biosynthesis and a signaling pathway by which they regulate a threshold of mast cell activation and anaphylaxis, revealing new targets for mast cell–mediated diseases.
Combined inhibition of oncogene-driven glucose uptake and induction of cytoplasmic-p53 activity induces apoptosis in a subset of glioblastoma samples. In mice, PET imaging of glucose uptake predicts glioblastoma response to this combination therapy.