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A new generation of target-specific inhibitors of the coagulation enzymes thrombin and factor Xa has been approved for a number of indications, but the clinical use of these drugs is hindered by the lack of a way to reverse bleeding, should it occur. An antidote to these new oral anticoagulants has now been designed and shows promise in small-animal models of blood loss (pages 446–451).
A recent study shows that, like cancer cells, cells lacking the Pdk1 gene reprogram their metabolism to use aerobic glycolysis—the 'Warburg effect'. Targeting this pathway using a glucose analog that cannot be metabolized resulted in slower disease progression in mouse models of polycystic kidney disease. This work thus suggests a new potential therapeutic approach for autosomal dominant polycystic kidney disease (pages 488–493).
The treatment of acute lymphoblastic leukemia (ALL) is one of the great success stories in oncology. However, patients who fail to achieve remission or relapse after chemotherapy continue to have a very poor prognosis, and the mechanisms underlying therapy failures are largely unknown. A new study suggests that gain-of-function mutations in NT5C2, a gene that encodes an enzyme that metabolizes chemotherapeutic drugs used against ALL, contribute to chemotherapy resistance (pages 368–371).
The long-term behavioral deficits observed in depression are associated with altered spine synapses in specific neuronal circuits. A new study shows that chromatin remodeling decreases the expression of Ras-related C2 botulinum toxin substrate 1 (Rac1) and that the deficit in this small Rho GTPase is sufficient and necessary for altered spines and behavioral abnormalities in mice after social defeat (pages 337–344).
Metabolically driven, chronic, low-grade inflammation has a crucial role in the pathogenesis of obesity and type 2 diabetes, and multiple stress-signaling cascades link insulin resistance and the immune response. An approved immunomodulatory drug is now shown to inhibit the kinases IKKε and TBK1, suppress inflammation and improve metabolic homeostasis in mouse models of obesity (pages 313–321).
Regulatory T (Treg) cells are important for protecting against pathogenic T cell responses, and impaired Treg functions have been linked with autoimmune diseases. A recent study reveals a new mechanism for the inflammatory cytokine tumor necrosis factor-α (TNF-α) in rheumatoid arthritis, showing that it disables Treg cells by affecting the phosphorylation and function of a key transcription factor expressed in these cells (pages 322–328).
Left ventricular noncompaction (LVNC) cardiomyopathy is a clinically and genetically heterogeneous disease that can be associated with substantial cardiovascular morbidity and mortality. A new study shows that mice with myocardial deletion of Mib1, which encodes a ubiquitin ligase in the Notch signaling pathway, have LVNC phenotypes and identifies MIB1 mutations in humans with LVNC (pages 193–201).
There has been much focus on DNA mutations in tumorigenesis and tumor progression, but now a new study highlights a role for post-transcriptional changes in RNA in cancer. The authors show increased RNA editing of antizyme inhibitor 1 (AZIN1) in tumor tissues from patients with hepatocellular carcinoma and characterize a mechanism through which the expression of edited AZIN1 protein leads to increased cell proliferation (pages 209–216).
BH3 mimetics are a class of anticancer agents that hold the promise to trigger the central apoptotic machinery to set cancer cells on the road to ruin. Now, a new agent that selectively targets BCL-2, ABT-199, has been developed, with exciting preclinical and clinical results (pages 202–208).
Several physiological and pathological events taking place postnatally in or around the pancreatic islets of Langerhans have been implicated in the initiation of type 1 diabetes. A new study highlights the contribution of neutrophils and how they, together with B1a cells and plasmacytoid dendritic cells (pDCs), may start the autoimmune process (pages 65–73).
Cells and tissues are often subjected to stressful environments that challenge homeostasis and can include oxidative, nutrient or metabolic stress. Cell survival requires the recruitment of stress pathways that 'defend' the internal homeostatic environment of the cell. Recent studies indicate that activation of some of these existing pathways is beneficial to whole-body metabolism. Now, mice with a muscle-specific autophagy deficiency are shown to adapt to stress through a newly discovered endocrine pathway involving fibroblast growth factor 21 (FGF21) (pages 83–92).
The anticancer efficacy of conventional chemotherapies seems to be due, in part, to augmentation of the host immune reactivity. However, a new study reveals that two common chemotherapeutic agents, gemcitabine and 5-fluorouracil, can also activate immune regulatory cells, which stimulates the emergence of protumorigenic cytokines via inflammasome pathways, limiting the antitumor efficacy of the drugs (pages 57–64).
Production of the amyloid-β peptide in Alzheimer's disease by the γ-secretase complex can be regulated by certain G protein–coupled receptors. This regulation seems to be mediated by β-arrestin-2, whose expression was found to be elevated in Alzheimer's disease brains (pages 43–49).
