Regulation of human sphingomyelin synthase 1 translation through its 5'-untranslated region.

Bcr-abl1 oncogene causes a shift in the transcription start site of the SMS1 gene (SGMS1) encoding the sphingomyelin (SM) synthesizing enzyme, sphingomyelin synthase 1 (SMS1). This results in an mRNA with a significantly shorter 5'-UTR, called 7-SGMS1, which is translated more efficiently than another transcript (IIb-SGMS1) with a longer 5'UTR in Bcr-abl1-positive cells. Here, we determine the effects of these alternative 5'UTRs on SMS1 translation and investigate the key features underlying such regulation. First, the presence of the longer IIb 5'UTR is sufficient to greatly impair translation of a reporter gene. Deletion of the upstream open reading frame (-164 nt) or of the predicted stem-loops in the 5'UTR of IIb-SGMS1 has minimal effects on SGMS1 translation. Conversely, deletion of nucleotides -310 to -132 enhanced transcription of IIb-SGMS1 to reach that of 7-SGMS1. We thus suggest that regulatory features within nucleotides -310 and -132 modulate IIb-SGMS1 translation efficiency.

Clinical and Molecular Predictors of Response to Immune Checkpoint Inhibitors in Patients with Advanced Esophagogastric Cancer.

PURPOSE: Immune checkpoint inhibitors (ICI) are effective in only a minority of patients with esophagogastric cancer (EGC). Here, we aimed to identify predictors of durable clinical benefit to ICI in EGC. EXPERIMENTAL DESIGN: Patients with advanced EGC treated with ICIs at Memorial Sloan Kettering Cancer Center (New York, NY) were identified. Clinicopathologic variables were assessed. In patients profiled by MSK-IMPACT-targeted sequencing, outcomes were correlated with tumor genomic features. RESULTS: One-hundred sixty-one patients were treated with ICIs (110 with anti-PD-1/PD-L1 antibodies and 51 with anti-CTLA-4 and PD-1/PD-L1 antibodies). The median progression-free survival (PFS) and overall survival (OS) were 1.7 and 4.9 months, respectively. Greater number of disease sites (≥3), liver metastases, treatment with ≥3 prior therapies and ECOG performance status ≥2 were associated with poorer PFS and OS. Patients treated with combination ICI and those with PD-L1-positive tumors had improved outcomes. There was no difference in outcomes between patients treated with antibiotics during or in the 2 months preceding ICI treatment versus those who were not. Occurrence of irAEs was associated with improved OS. In genomically profiled tumors (n = 89), survival was associated with increasing tumor mutation burden (TMB). However, in multivariable analyses and when microsatellite unstable (MSI) patients were excluded, a significant association was no longer observed. CONCLUSIONS: In patients with advanced EGC, heavily pretreated patients, those with high-volume disease and/or poor PS were less likely to benefit from ICI. irAEs were associated with improved OS. TMB correlated with improved survival, but this association was not observed when MSI-high patients were excluded.

Regional isolation in the right atrium with disruption of intra-atrial conduction after catheter ablation of atrial tachycardia.

BACKGROUND: Ablation of atrial tachycardia (AT) that occurs after cardiac surgery or prior ablation often requires complex lesion sets. In combination with the pre-existing atrial scar, these lesion sets may result in inadvertent intra-atrial conduction block. This study reports the phenomenon of incidental isolation of right atrial (RA) regions that occurs secondary to AT ablation, which in some cases results in profound bradycardia due to sinus exit block. METHODS AND RESULTS: Intracardiac electrograms were examined in consecutive patients who underwent AT ablation in the RA. Cases of localized isolation of the RA were defined as areas that developed electrical dissociation during ablation. Of 132 patients having ablation in both the RA free wall and the cavotricuspid isthmus (CTI), 10 (7.6%) developed unintentional isolation of the lateral RA. Five of these patients had prior mitral valve surgery, comprising 12.2% of all 41 patients with mitral surgery who underwent ablation in the CTI and the RA free wall. All patients with regional isolation had a pre-existing scar in the lateral wall of the RA. In six patients, isolation of the lateral RA resulted in profound bradycardia due to exit block from the peri-sinus node myocardium. CONCLUSIONS: Complex ablation lesions in patients with prior valve surgery, prior ablation, or atrial myopathy may result in unintended localized conduction block in the RA. In some cases, isolation of the lateral RA can result in complete sinus exit block with profound bradycardia requiring pacemaker implantation.

Oncogenic Signaling Pathways in The Cancer Genome Atlas.

Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFß signaling, p53 and ß-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy.