Calcium and Sudden Cardiac Death in End‐Stage Renal Disease

Sudden cardiac death (SCD) accounts for a quarter of all deaths in end‐stage renal disease (ESRD) patients. While causative mechanisms of SCD in this high risk population remain poorly defined, interaction of the vulnerable myocardium with dialysis‐related arrhythmic triggers is thought to play a major role. Recent evidence suggests that dialysis‐induced derangement of calcium concentrations contributes to the increased risk of all‐cause and cardiovascular mortality, vascular calcification, and SCD. Current KDIGO guidelines recommend avoiding high dialysate calcium concentrations as a precaution against adverse outcomes of increased calcium burden and vascular calcification. Conversely, low calcium concentration is also implicated in the development of SCD via increased QT dispersion and prolonged QT interval. Consequently, the optimal dialysate calcium concentration in dialysis patients remains debated and further studies are needed to establish the best strategy for managing calcium in dialysis patients.     

Alterations in Brain Polyribosomal RNA Translation and Lymphocyte Proliferation in Prenatal Ethanol-Exposed Rats

The long-term effects of prenatal ethanol exposure on the properties of brain polysomes and the proliferative responses of lymphocytes to mitogenic stimulation in adult offspring were assessed. Female Sprague-Dawley rats either ingested the control or 6.6% ethanol-containing Lieber-DeCarli liquid diet during the 3rd trimester of pregnancy. Controls were age-matched and pair-fed. At 42 to 72 days of age, ethanol effects were evaluated on the (1) polysomal properties in the cerebral hemispheres, cerebellum, and hippocampal regions of the brain after translation in a messenger RNA (mRNA)-dependent rabbit reticulocyte lysate system and (2) immunologic functions of lymphocytes cultured from spleen cells by measuring their responses to mitogenic stimulation. Results showed long-term adverse effects of in utero ethanol exposure on the polysomal RNA translation in each of the three brain regions tested with free polysomal mRNAs affected more than the bound polysomal mRNAs. Of these, the hippocampal region appeared to sustain the most injurious effects. In addition, a suppression of the mitogen-induced lymphocyte proliferative responses were present under these conditions. The degree of suppression varied with the specific mitogen used. Data suggest that the ethanol effects on the CNS and lymphocyte proliferation are most possibly irreversible, and in the case of the CNS, a post-translational modification by ethanol is indicated. The reduced lymphocyte responses are suggestive of a possible interference by ethanol of the synthesis of interleukin-2 (IL-2) and/or a reduced binding of IL-2 with its receptor (IL-2 receptors).     

RIG-I–like receptor LGP2 protects tumor cells from ionizing radiation

An siRNA screen targeting 89 IFN stimulated genes in 14 different cancer cell lines pointed to the RIG-I (retinoic acid inducible gene I)–like receptor Laboratory of Genetics and Physiology 2 (LGP2) as playing a key role in conferring tumor cell survival following cytotoxic stress induced by ionizing radiation (IR). Studies on the role of LGP2 revealed the following: (i) Depletion of LGP2 in three cancer cell lines resulted in a significant increase in cell death following IR, (ii) ectopic expression of LGP2 in cells increased resistance to IR, and (iii) IR enhanced LGP2 expression in three cell lines tested. Studies designed to define the mechanism by which LGP2 acts point to its role in regulation of IFNβ. Specifically (i) suppression of LGP2 leads to enhanced IFNβ, (ii) cytotoxic effects following IR correlated with expression of IFNβ inasmuch as inhibition of IFNβ by neutralizing antibody conferred resistance to cell death, and (iii) mouse embryonic fibroblasts from IFN receptor 1 knockout mice are radioresistant compared with wild-type mouse embryonic fibroblasts. The role of LGP2 in cancer may be inferred from cumulative data showing elevated levels of LGP2 in cancer cells are associated with more adverse clinical outcomes. Our results indicate that cytotoxic stress exemplified by IR induces IFNβ and enhances the expression of LGP2. Enhanced expression of LGP2 suppresses the IFN stimulated genes associated with cytotoxic stress by turning off the expression of IFNβ.Several studies have shown that the response of tumor cells to ionizing radiation (IR) is associated with IFN-mediated signaling (1–6). IFN signaling leads to the induction of multiple IFN stimulated genes (ISGs) (7, 8) and activates growth arrest and cell death in exposed cell populations (9). The precise mechanism of IR-mediated induction of IFN signaling is unknown. Tumor cell clones that survive an initial cytotoxic insult are subsequently resistant to exposure to both IR and prodeath components of IFN signaling (10). These clones express IFN-dependent enhanced levels of constitutively expressed ISGs, which overlap in part with ISGs initially induced by cytotoxic stress. Many of these constitutively expressed ISGs have been characterized as antiviral genes (11). Recently, enhanced levels of constitutively expressed ISGs have been reported in advanced cancers and were often associated with a poor prognosis related to aggressive tumor growth, metastatic spread, resistance to IR/chemotherapy, or combinations of these factors (11–18). The studies presented in this report are based on the hypothesis that a specific set of constitutively expressed ISGs, whose enhanced expression is by cytotoxic stress, confers a selective advantage to individual tumor clones (5, 9, 10, 13, 19).To test this hypothesis, we designed a targeted siRNA screen against 89 ISGs selected from two sources. The first included ISGs identified in our earlier screen and designated the IFN-Related DNA Damage Signature (IRDS) (1, 13). The second set included related ISG signatures that have been reported in the literature (as described in Methods and Dataset S1). The 89 genes were individually targeted in 14 tumor cell lines derived from malignant gliomas, lung, breast, colon, head and neck, prostate, and bladder cancers.The most significant finding from this screen was that the RNA helicase Laboratory of Genetics and Physiology 2 (LGP2) encoded by DHX58 [DEXH (Asp-Glu-X-His) box polypeptide 58] confers survival and mediates the response to IR of multiple tumor cell lines. LGP2 acts as a suppressor of the RNA-activated cytoplasmic RIG-I RIG-I (retinoic acid inducible gene I)–like receptor’s pathway (20, 21). This pathway is a subtype of pattern recognition receptors responsible for primary recognition of pathogen and host-associated molecular patterns and the subsequent activation of type I IFN production that orchestrates an innate immune response (22–24). In addition to its role in inhibiting IFNβ expression, Suthar et al. recently demonstrated that LGP2 governs CD8+ T-cell fitness and survival by inhibiting death-receptor signaling (25). Here we demonstrate that suppression of LGP2 leads to an enhanced IFNβ expression and increased killing of tumor cells. Our results thereby provide a mechanistic connection between IR-induced cytotoxic response in tumor cells and the LGP2–IFNβ pathway.     

Taking it up a notch in MCL

In this issue of Blood, Kridel et al describe recurrent NOTCH1 mutations in mantle cell lymphoma (MCL) by next-generation sequencing of patient samples and cell lines. They further demonstrate a negative prognostic impact of NOTCH1 mutation in their cohort of patients and sensitivity of MCL cells to NOTCH1 inhibition in vitro, suggesting a novel role for NOTCH1 in this disease.