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

Role of endoscopic ultrasound fine-needle aspiration evaluating adrenal gland enlargement or mass

AIM: To report the clinical impact of adrenal endoscopic ultrasound fine-needle aspiration (EUS-FNA) in the evaluation of patients with adrenal gland enlargement or mass. METHODS: In a retrospective single-center case-series, patients undergoing EUS-FNA of either adrenal gland from 1997-2011 in our tertiary care center were included. Medical records were reviewed and results of EUS, cytology, adrenal size change on follow-up imaging ≥ 6 mo after EUS and any repeat EUS or surgery were abstracted. A lesion was considered benign if: (1) EUS-FNA cytology was benign and the lesion remained < 1 cm from its original size on follow-up computed tomography (CT), magnetic resonance imaging or repeat EUS ≥ 6 mo after EUS-FNA; or (2) subsequent adrenalectomy and surgical pathology was benign. RESULTS: Ninety-four patients had left (n = 90) and/or right (n = 5) adrenal EUS-FNA without adverse events. EUS indications included: cancer staging or suspected recurrence (n = 31), pancreatic (n = 20), mediastinal (n = 10), adrenal (n = 7), lung (n = 7) mass or other indication (n = 19). Diagnoses after adrenal EUS-FNA included metastatic lung (n = 10), esophageal (n= 5), colon (n = 2), or other cancer (n = 8); benign primary adrenal mass or benign tissue (n = 60); or was non-diagnostic (n = 9). Available follow-up confirmed a benign lesion in 5/9 non-diagnostic aspirates and 32/60 benign aspirates. Four of the 60 benign aspirates were later confirmed as malignant by repeat biopsy, follow-up CT, or adrenalectomy. Adrenal EUS-FNA diagnosed metastatic cancer in 24, and ruled out metastasis in 10 patients. For the diagnosis of malignancy, EUS-FNA of either adrenal had sensitivity, specificity, positive predictive value and negative predictive value of 86%, 97%, 96% and 89%, respectively. CONCLUSION: Adrenal gland EUS-FNA is safe, minimally invasive and a sensitive technique with significant impact in the management of adrenal gland mass or enlargement

Rescue Endoscopic Ultrasound (EUS)-Guided Trucut Biopsy Following Suboptimal EUS-Guided Fine Needle Aspiration for Mediastinal Lesions

Background/Aims Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) and Trucut biopsy (TCB) are sensitive techniques for diagnosing mediastinal lesions, but it is unclear how either one or both should be used to obtain a pathologic diagnosis. The objective of our study was to evaluate whether EUS-TCB impacts the diagnosis of mediastinal lesions after the initial on-site review of EUS-FNA specimen suggests a suboptimal result. Methods We enrolled consecutive patients with mediastinal lesions who underwent EUS-TCB during the same procedure if the initial EUS-FNA demonstrated an inadequate FNA sample or suggested that histopathology was required for diagnosis. Diagnostic accuracies between procedures were compared as the main outcome. Results Twenty-seven patients (14 men; median age, 56 years; range, 19 to 82 years) underwent EUS-FNA and EUS-TCB to evaluate a mediastinal lymphadenopathy or mass (n=17), to determine the cancer stage (n=3) or to exclude tumor recurrence or metastasis (n=7). The overall diagnostic accuracies of EUS-FNA and EUS-TCB were 78% and 67%, respectively (p=0.375). The combined diagnostic accuracy of EUS-FNA plus EUS-TCB was 82%. In six patients with nondiagnostic EUS-FNA, EUS-TCB provided a final diagnosis in one patient (17%). Conclusions In the current series of patients with mediastinal masses or adenopathy, the administration of EUS-TCB following suboptimal results for the on-site cytology review did not increase the diagnostic yield

Evaluation of Social Impact of Traffic Noice in Amman, Jordan

Few road traffic studies were conducted in Jordan, but the issue is drawing an increasing attention due to its growing magnitude and various impacts as a result of the high increase in vehicular traffic. This study further investigates the issue with the aim of providing an understanding of its social impact on residents of Amman, the capital of Jordan. Traffic noise levels were measured at selected locations along urban arterials and a social survey was performed to examine the reactions and attitudes of the neighboring residents towards these levels of traffic noise. The survey included social characteristics of individuals, and their attitudes towards traffic noise, and how it impacted their daily activities. A predesigned questionnaire was used for this purpose which included questions to evaluate the awareness of respondents of the problem and its environmental and health impacts. The financial impact that residents perceive of noise and the need for attenuation measures were also addressed. The results of the study also revealed that the impact of traffic noise on people can cause annoyance while performing daily activities were 24% of respondents reported that they get annoyed by traffic while working, 49% while resting, 34% while talking to others, 31% while talking on the phone, 39% while reading, 38% while watching TV and 53% of respondents get annoyed while sleeping. The respondents have also pointed out the following effects of noise: twist in mood (53%), headache (36%), and difficulty in concentration (40%). About 57% of respondents think traffic noise reduces the value of their properties and a total of 31% are willing to sell their house at reduced cost. About 59% of respondents consider attenuation measures necessary, and in order to reduce the noise, about 54% of respondents were willing to pay for attenuation measures which reflects the public awareness of the issue magnitude

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

Student Misconceptions about Cybersecurity Concepts: Analysis of Think-Aloud Interviews

We conducted an observational study to document student misconceptions about cybersecurity using thematic analysis of 25 think-aloud interviews. By understanding patterns in student misconceptions, we provide a basis for developing rigorous evidence-based recommendations for improving teaching and assessment methods in cybersecurity and inform future research. This study is the first to explore student cognition and reasoning about cybersecurity. We interviewed students from three diverse institutions. During these interviews, students grappled with security scenarios designed to probe their understanding of cybersecurity, especially adversarial thinking. We analyzed student statements using a structured qualitative method, novice-led paired thematic analysis, to document patterns in student misconceptions and problematic reasoning that transcend institutions, scenarios, or demographics. Themes generated from this analysis describe a taxonomy of misconceptions but not their causes or remedies. Four themes emerged: overgeneralizations, conflated concepts, biases, and incorrect assumptions. Together, these themes reveal that students generally failed to grasp the complexity and subtlety of possible vulnerabilities, threats, risks, and mitigations, suggesting a need for instructional methods that engage students in reasoning about complex scenarios with an adversarial mindset. These findings can guide teachers’ attention during instruction and inform the development of cybersecurity assessment tools that enable cross-institutional assessments that measure the effectiveness of pedagogies

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

InterCells: A Generic Monte-Carlo Simulation of Intercellular Interfaces Captures Nanoscale Patterning at the Immune Synapse

Molecular interactions across intercellular interfaces serve to convey information between cells and to trigger appropriate cell functions. Examples include cell development and growth in tissues, neuronal and immune synapses (ISs). Here, we introduce an agent-based Monte-Carlo simulation of user-defined cellular interfaces. The simulation allows for membrane molecules, embedded at intercellular contacts, to diffuse and interact, while capturing the topography and energetics of the plasma membranes of the interface. We provide a detailed example related to pattern formation in the early IS. Using simulation predictions and three-color single molecule localization microscopy (SMLM), we detected the intricate mutual patterning of T cell antigen receptors (TCRs), integrins and glycoproteins in early T cell contacts with stimulating coverslips. The simulation further captures the dynamics of the patterning under the experimental conditions and at the IS with antigen presenting cells (APCs). Thus, we provide a generic tool for simulating realistic cell-cell interfaces, which can be used for critical hypothesis testing and experimental design in an iterative manner