Oncogene-triggered suppression of DNA repair leads to DNA instability in cancer

DNA instability is an important contributor to cancer development. Previously, defects in the chromosome segregation and excessive DNA double strand breaks due to the replication or oxidative stresses were implicated in DNA instability in cancer. Here, we demonstrate that DNA instability can directly result from the oncogene-induced senescence signaling. Expression of the activated form of Her2 oncogene, NeuT, in immortalized breast epithelial cells led to downregulation of the major DNA repair factor histone H2AX and a number of other components of the HR and NHEJ double strand DNA breaks repair pathways. H2AX expression was regulated at the transcriptional level via a senescence pathway involving p21-mediated regulation of CDK and Rb1. The p21-dependent downregulation of H2AX was seen both in cell culture and the MMTV-neu mouse model of Her2-positive breast cancer. Importantly, downregulation of H2AX upon Her2/NeuT expression impaired repair of double strand DNA breaks. This impairment resulted in both increased DNA instability in the form of somatic copy number alterations, and in increased sensitivity to the chemotherapeutic drug doxorubicin. Overall, these findings indicate that the Her2/NeuT oncogene signaling directly potentiates DNA instability and increases sensitivity to DNA damaging treatments

Clinical Study Bedside Endoscopic Ultrasound in Critically Ill patients

Background. The aim of this study was to evaluate the role and impact of EUS in the management of critically ill patients. Methods. We retrospectively identified all patients at our institution over a 68-month period in whom bedside inpatient EUS was performed. EUS was considered to have a significant impact if a new diagnosis was established and/or the findings altered subsequent clinical management. Results. Fifteen patients (9 male; mean age 58 ± 15 years) underwent bedside EUS without complications. EUS-FNA (median 4 passes; range 2–7) performed in 12 (80%) demonstrated a malignant mediastinal mass/lymph node (5), pancreatic abscess (1), excluded a pelvic abscess (1), established enlarged gastric folds as benign (1) and excluded malignancy in enlarged mediastinal (1) and porta hepatis adenopathy (1). In two patients, EUS-FNA failed to diagnose mediastinal histoplasmosis (1) and a hemorrhagic pancreatic pseudocyst (1). In three diagnostic exams without FNA, EUS correctly excluded choledocholithaisis (n = 1) and cholangiocarcinoma (1), and found gastric varices successfully thrombosed after previous cyanoacrylate injection (1). EUS was considered to have an impact in 13/15 (87%) patients. Conclusions. In this series, bedside EUS in critically ill patients was technically feasible, safe and had a major impact on the majority of patients. 1

Bedside Endoscopic Ultrasound in Critically Ill patients

Background. The aim of this study was to evaluate the role and impact of EUS in the management of critically ill patients. Methods. We retrospectively identified all patients at our institution over a 68-month period in whom bedside inpatient EUS was performed. EUS was considered to have a significant impact if a new diagnosis was established and/or the findings altered subsequent clinical management. Results. Fifteen patients (9 male; mean age 58 ± 15 years) underwent bedside EUS without complications. EUS-FNA (median 4 passes; range 2–7) performed in 12 (80%) demonstrated a malignant mediastinal mass/lymph node (5), pancreatic abscess (1), excluded a pelvic abscess (1), established enlarged gastric folds as benign (1) and excluded malignancy in enlarged mediastinal (1) and porta hepatis adenopathy (1). In two patients, EUS-FNA failed to diagnose mediastinal histoplasmosis (1) and a hemorrhagic pancreatic pseudocyst (1). In three diagnostic exams without FNA, EUS correctly excluded choledocholithaisis (n = 1) and cholangiocarcinoma (1), and found gastric varices successfully thrombosed after previous cyanoacrylate injection (1). EUS was considered to have an impact in 13/15 (87%) patients. Conclusions. In this series, bedside EUS in critically ill patients was technically feasible, safe and had a major impact on the majority of patients

Performance characteristics of EUS for locoregional evaluation of ampullary lesions

Background The accuracy of EUS in the locoregional assessment of ampullary lesions is unclear. Objectives To compare EUS with ERCP and surgical pathology for the evaluation of intraductal extension and local staging of ampullary lesions. Design Retrospective cohort study. Setting Tertiary-care referral center. Patients All patients who underwent EUS primarily for the evaluation of an ampullary lesion between 1998 and 2012. Intervention EUS. Main Outcome Measurements Comparison of EUS sensitivity/specificity for intraductal and local extension with ERCP and surgical pathology by using the area under the receiver-operating characteristic (AUROC) curves and outcomes of the subgroup referred for endoscopic papillectomy. Results We identified 119 patients who underwent EUS for an ampullary lesion, of whom 99 (83%) had an adenoma or adenocarcinoma. Compared with ERCP (n = 90), the sensitivity/specificity of EUS for any intraductal extension was 56%/97% (AUROC = 0.77; 95% confidence interval [CI], 0.64-0.89). However, when using surgical pathology as the reference (n = 102), the sensitivity/specificity of EUS (80%/93%; AUROC = 0.87; 95% CI, 0.76-0.97) and ERCP (83%/93%; AUROC = 0.88; 95% CI, 0.77-0.99) were comparable. The overall accuracy of EUS for local staging was 90%. Of 58 patients referred for endoscopic papillectomy, complete resection was achieved in 53 (91%); in those having intraductal extension by EUS or ERCP, complete resection was achieved in 4 of 5 (80%) and 4 of 7 (57%), respectively. Limitation Retrospective design. Conclusions EUS and ERCP perform similarly in evaluating intraductal extension of ampullary adenomas. Additionally, EUS is accurate in T-staging ampullary adenocarcinomas. Future prospective studies should evaluate whether EUS can identify characteristics of ampullary lesions that appropriately direct patients to endoscopic or surgical resection. (Gastrointest Endosc 2015;81:380-8.

Utility of EUS following endoscopic polypectomy of high-risk rectosigmoid lesions

BACKGROUND: The utility of endoscopic ultrasound (EUS) compared with standard white light endoscopy (WLE) following recent polypectomy of high-risk colorectal polyps is unknown. OBJECTIVE: To assess the incremental yield of EUS after endoscopic polypectomy of a high-risk rectal lesion. DESIGN: Retrospective cohort. SETTING: Tertiary referral center. MATERIALS AND METHODS: Patients referred for EUS following attempted endoscopic resection of a high-risk rectal neoplasm, defined as a tubulovillous adenoma, tubular adenoma with high-grade dysplasia, carcinoid, carcinoma in-situ or adenocarcinoma (CA). INTERVENTIONS: Sigmoidoscopy ± mucosal biopsy and EUS ± fine-needle aspiration (FNA) to evaluate for: (1) Residual polyp/tumor in the rectal wall or (2) peritumoral adenopathy. MAIN OUTCOME: Sensitivity and specificity for detection of residual neoplasia for WLE ± biopsy (WLE/BX) and EUS ± FNA for cancer (CA group) or benign disease (non-CA group). The incremental yield of EUS defined as: (1) Residual intramural neoplasia not present on WLE ± BX and; (2) abnormal peritumoral adenopathy. RESULTS: A total of 70 patients (mean age 64 ± 11 years, 61% male) with a final diagnosis of CA (n = 38) and non-CA (n = 32) were identified. There was no difference between the sensitivity and specificity of WLE alone (65% and 84%), WLE with biopsy (71% and 95%), and EUS (59% and 84%), for the detection of residual neoplasia (P > 0.05 for all). EUS identified 3 masses missed by WLE, all in the CA group. A malignant (n = 2) or benign (n = 3) node was identified in 5 (13%) CA patients; EUS-FNA in two showed residual malignancy in one and a reactive lymph node (LN) in one. No LNs were identified in the non-CA patients. LIMITATIONS: Retrospective design, incomplete follow-up in some patients. CONCLUSION: Following endoscopic polypectomy of high-risk rectal neoplasia, the incremental yield of EUS compared with WLE/BX for evaluation of residual disease appears limited, especially in patients with benign disease

Effectiveness and safety of serial endoscopic ultrasound–guided celiac plexus block for chronic pancreatitis

Background and study aims: Endoscopic ultrasound – guided celiac plexus block (EUS-CPB) is an established treatment for pain in patients with chronic pancreatitis (CP), but the effectiveness and safety of repeated procedures are unknown. Our objective is to report our experience of repeated EUS-CPB procedures within a single patient. , Patients and methods: A prospectively maintained EUS database was retrospectively analyzed to identify patients who had undergone more than one EUS-CPB procedure over a 17-year period. The main outcome measures included number of EUS-CPB procedures for each patient, self-reported pain relief, duration of pain relief, and procedure-related adverse events. , Results: A total of 248 patients underwent more than one EUS-CPB procedure and were included in our study. Patients with known or suspected CP (N = 248) underwent a mean (SD) of 3.1 (1.6) EUS-CPB procedures. In 76 % of the patients with CP, the median (range) duration of the response to the first EUS-CPB procedure was 10 (1 – 54) weeks. Lack of pain relief after the initial EUS-CPB was associated with failure of the next EUS-CPB (OR 0.17, 95 %CI 0.06 – 0.54). Older age at first EUS-CPB and pain relief after the first EUS-CPB were significantly associated with pain relief after subsequent blocks (P = 0.026 and P = 0.002, respectively). Adverse events included peri-procedural hypoxia (n = 2) and hypotension (n = 1) and post-procedural orthostasis (n = 2) and diarrhea (n = 4). No major adverse events occurred., Conclusions: Repeated EUS-CPB procedures in a single patient appear to be safe. Response to the first EUS-CPB is associated with response to subsequent blocks

Regulatory interactions between IRG resistance GTPases in the cellular response to Toxoplasma gondii

Members of the immunity-related GTPase (IRG) family are interferon-inducible resistance factors against a broad spectrum of intracellular pathogens including Toxoplasma gondii. The molecular mechanisms governing the function and regulation of the IRG resistance system are largely unknown. We find that IRG proteins function in a system of direct, nucleotide-dependent regulatory interactions between family members. After interferon induction but before infection, the three members of the GMS subfamily of IRG proteins, Irgm1, Irgm2 and Irgm3, which possess an atypical nucleotide-binding site, regulate the intracellular positioning of the conventional GKS subfamily members, Irga6 and Irgb6. Following infection, the normal accumulation of Irga6 protein at the parasitophorous vacuole membrane (PVM) is nucleotide dependent and also depends on the presence of all three GMS proteins. We present evidence that an essential role of the GMS proteins in this response is control of the nucleotide-bound state of the GKS proteins, preventing their GTP-dependent activation before infection. Accumulation of IRG proteins at the PVM has previously been shown to be associated with a block in pathogen replication: our results relate for the first time the enzymatic properties of IRG proteins to their role in pathogen resistance

Overfishing Drives Over One-Third of All Sharks and Rays Toward a Global Extinction Crisis

The scale and drivers of marine biodiversity loss are being revealed by the International Union for Conservation of Nature (IUCN) Red List assessment process. We present the first global reassessment of 1,199 species in Class Chondrichthyes-sharks, rays, and chimeras. The first global assessment (in 2014) concluded that one-quarter (24%) of species were threatened. Now, 391 (32.6%) species are threatened with extinction. When this percentage of threat is applied to Data Deficient species, more than one-third (37.5%) of chondrichthyans are estimated to be threatened, with much of this change resulting from new information. Three species are Critically Endangered (Possibly Extinct), representing possibly the first global marine fish extinctions due to overfishing. Consequently, the chondrichthyan extinction rate is potentially 25 extinctions per million species years, comparable to that of terrestrial vertebrates. Overfishing is the universal threat affecting all 391 threatened species and is the sole threat for 67.3% of species and interacts with three other threats for the remaining third: loss and degradation of habitat (31.2% of threatened species), climate change (10.2%), and pollution (6.9%). Species are disproportionately threatened in tropical and subtropical coastal waters. Science-based limits on fishing, effective marine protected areas, and approaches that reduce or eliminate fishing mortality are urgently needed to minimize mortality of threatened species and ensure sustainable catch and trade of others. Immediate action is essential to prevent further extinctions and protect the potential for food security and ecosystem functions provided by this iconic lineage of predators