Carcinoma Matrix Controls Resistance to Cisplatin through Talin Regulation of NF-kB

Extracellular matrix factors within the tumor microenvironment that control resistance to chemotherapeutics are poorly understood. This study focused on understanding matrix adhesion pathways that control the oral carcinoma response to cisplatin. Our studies revealed that adhesion of HN12 and JHU012 oral carcinomas to carcinoma matrix supported tumor cell proliferation in response to treatment with cisplatin. Proliferation in response to 30 µM cisplatin was not observed in HN12 cells adherent to other purified extracellular matrices such as Matrigel, collagen I, fibronectin or laminin I. Integrin β1 was important for adhesion to carcinoma matrix to trigger proliferation after treatment with cisplatin. Disruption of talin expression in HN12 cells adherent to carcinoma matrix increased cisplatin induced proliferation. Pharmacological inhibitors were used to determine signaling events required for talin deficiency to regulate cisplatin induced proliferation. Pharmacological inhibition of NF-kB reduced proliferation of talin-deficient HN12 cells treated with 30 µM cisplatin. Nuclear NF-kB activity was assayed in HN12 cells using a luciferase reporter of NF-kB transcriptional activity. Nuclear NF-kB activity was similar in HN12 cells adherent to carcinoma matrix and collagen I when treated with vehicle DMSO. Following treatment with 30 µM cisplatin, NF-kB activity is maintained in cells adherent to carcinoma matrix whereas NF-kB activity is reduced in collagen I adherent cells. Expression of talin was sufficient to trigger proliferation of HN12 cells adherent to collagen I following treatment with 1 and 30 µM cisplatin. Talin overexpression was sufficient to trigger NF-kB activity following treatment with cisplatin in carcinoma matrix adherent HN12 cells in a process disrupted by FAK siRNA. Thus, adhesions within the carcinoma matrix create a matrix environment in which exposure to cisplatin induces proliferation through the function of integrin β1, talin and FAK pathways that regulate NF-kB nuclear activity

Genome-Wide Association Study of Lp-PLA2 Activity and Mass in the Framingham Heart Study

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an emerging risk factor and therapeutic target for cardiovascular disease. The activity and mass of this enzyme are heritable traits, but major genetic determinants have not been explored in a systematic, genome-wide fashion. We carried out a genome-wide association study of Lp-PLA2 activity and mass in 6,668 Caucasian subjects from the population-based Framingham Heart Study. Clinical data and genotypes from the Affymetrix 550K SNP array were obtained from the open-access Framingham SHARe project. Each polymorphism that passed quality control was tested for associations with Lp-PLA2 activity and mass using linear mixed models implemented in the R statistical package, accounting for familial correlations, and controlling for age, sex, smoking, lipid-lowering-medication use, and cohort. For Lp-PLA2 activity, polymorphisms at four independent loci reached genome-wide significance, including the APOE/APOC1 region on chromosome 19 (p = 6×10−24); CELSR2/PSRC1 on chromosome 1 (p = 3×10−15); SCARB1 on chromosome 12 (p = 1×10−8) and ZNF259/BUD13 in the APOA5/APOA1 gene region on chromosome 11 (p = 4×10−8). All of these remained significant after accounting for associations with LDL cholesterol, HDL cholesterol, or triglycerides. For Lp-PLA2 mass, 12 SNPs achieved genome-wide significance, all clustering in a region on chromosome 6p12.3 near the PLA2G7 gene. Our analyses demonstrate that genetic polymorphisms may contribute to inter-individual variation in Lp-PLA2 activity and mass

Impact of magnetic field on the stability of the CMS GE1/1 GEM detector operation

The Gas Electron Multiplier (GEM) detectors of the GE1/1 station of the CMS experiment have been operated in the CMS magnetic field for the first time on the 7$^{th}$ of October 2021. During the magnetic field ramps, several discharge phenomena were observed, leading to instability in the GEM High Voltage (HV) power system. In order to reproduce the behavior, it was decided to conduct a dedicated test at the CERN North Area with the Goliath magnet, using four GE1/1 spare chambers. The test consisted in studying the characteristics of discharge events that occurred in different detector configurations and external conditions. Multiple magnetic field ramps were performed in sequence: patterns in the evolution of the discharge rates were observed with these data. The goal of this test is the understanding of the experimental conditions inducing discharges and short circuits in a GEM foil. The results of this test lead to the development of procedure for the optimal operation and performance of GEM detectors in the CMS experiment during the magnet ramps. Another important result is the estimation of the probability of short circuit generation, at 68 % confidence level, p$_{short}$$^{HV}$ $^{OFF}$ = 0.42$^{-0.35+0.94}$% with detector HV OFF and p$_{short}$$^{HV}$ $^{OFF}$ < 0.49% with the HV ON. These numbers are specific for the detectors used during this test, but they provide a first quantitative indication on the phenomenon, and a point of comparison for future studies adopting the same procedure

Benchmarking LHC background particle simulation with the CMS triple-GEM detector

In 2018, a system of large-size triple-GEM demonstrator chambers was installed in the CMS experiment at CERN\u27s Large Hadron Collider (LHC). The demonstrator\u27s design mimicks that of the final detector, installed for Run-3. A successful Monte Carlo (MC) simulation of the collision-induced background hit rate in this system in proton-proton collisions at 13 TeV is presented. The MC predictions are compared to CMS measurements recorded at an instantaneous luminosity of 1.5 ×10$^{34}$ cm$^{-2}$ s$^{-1}$. The simulation framework uses a combination of the FLUKA and GEANT4 packages. FLUKA simulates the radiation environment around the GE1/1 chambers. The particle flux by FLUKA covers energy spectra ranging from 10$^{-11}$ to 10$^{4}$ MeV for neutrons, 10$^{-3}$ to 10$^{4}$ MeV for γ\u27s, 10$^{-2}$ to 10$^{4}$ MeV for e$^{±}$, and 10$^{-1}$ to 10$^{4}$ MeV for charged hadrons. GEANT4 provides an estimate of the detector response (sensitivity) based on an accurate description of the detector geometry, the material composition, and the interaction of particles with the detector layers. The detector hit rate, as obtained from the simulation using FLUKA and GEANT4, is estimated as a function of the perpendicular distance from the beam line and agrees with data within the assigned uncertainties in the range 13.7-14.5%. This simulation framework can be used to obtain a reliable estimate of the background rates expected at the High Luminosity LHC

Modeling the triple-GEM detector response to background particles for the CMS Experiment

An estimate of environmental background hit rate on triple-GEM chambers is performed using Monte Carlo (MC) simulation and compared to data taken by test chambers installed in the CMS experiment (GE1/1) during Run-2 at the Large Hadron Collider (LHC). The hit rate is measured using data collected with proton-proton collisions at 13 TeV and a luminosity of 1.5$\times10^{34}$ cm$^{-2}$ s$^{-1}$. The simulation framework uses a combination of the FLUKA and Geant4 packages to obtain the hit rate. FLUKA provides the radiation environment around the GE1/1 chambers, which is comprised of the particle flux with momentum direction and energy spectra ranging from $10^{-11}$ to $10^{4}$ MeV for neutrons, $10^{-3}$ to $10^{4}$ MeV for $\gamma$'s, $10^{-2}$ to $10^{4}$ MeV for $e^{\pm}$, and $10^{-1}$ to $10^{4}$ MeV for charged hadrons. Geant4 provides an estimate of detector response (sensitivity) based on an accurate description of detector geometry, material composition and interaction of particles with the various detector layers. The MC simulated hit rate is estimated as a function of the perpendicular distance from the beam line and agrees with data within the assigned uncertainties of 10-14.5%. This simulation framework can be used to obtain a reliable estimate of background rates expected at the High Luminosity LHC.Comment: 16 pages, 9 figures, 6 table

Triple-GEM discharge probability studies at CHARM: Simulations and experimental results

The CMS muon system in the region with 2.03<|η|<2.82 is characterized by a very harsh radiation environment which can generate hit rates up to 144 kHz/cm$^{2}$ and an integrated charge of 8 C/cm$^{2}$ over ten years of operation. In order to increase the detector performance and acceptance for physics events including muons, a new muon station (ME0) has been proposed for installation in that region. The technology proposed is Triple—Gas Electron Multiplier (Triple-GEM), which has already been qualified for the operation in the CMS muon system. However, an additional set of studies focused on the discharge probability is necessary for the ME0 station, because of the large radiation environment mentioned above. A test was carried out in 2017 at the Cern High energy AcceleRator Mixed (CHARM) facility, with the aim of giving an estimation of the discharge probability of Triple-GEM detectors in a very intense radiation field environment, similar to the one of the CMS muon system. A dedicated standalone Geant4 simulation was performed simultaneously, to evaluate the behavior expected in the detector exposed to the CHARM field. The geometry of the detector has been carefully reproduced, as well as the background field present in the facility. This paper presents the results obtained from the Geant4 simulation, in terms of sensitivity of the detector to the CHARM environment, together with the analysis of the energy deposited in the gaps and of the processes developed inside the detector. The discharge probability test performed at CHARM will be presented, with a complete discussion of the results obtained, which turn out to be consistent with measurements performed by other groups

CAD-based computer vision: the automatic generation of recognition stragtegies

Journal ArticleThree-dimensional model-based computer vision uses geometric models of objects and sensed data to recognize objects in a scene. Likewise, Computer Aided Design (CAD) systems are used to interactively generate three-dimensional models during these fields. Recently, the unification of CAD and vision systems has become the focus of research in the context of manufacturing automation. This paper explores the connection between CAD and computer vision. A method for the automatic generation of recognition strategies based on the geometric properties of shape has been devised and implemented. This uses a novel technique developed for quantifying the following properties of features which compose models used in computer vision: robustness, completeness, consistency, cost, and uniqueness. By utilizing this information, the automatic synthesis of a specialized recognition scheme, called a Strategy Tree, is accomplished. Strategy Trees describe, in a systematic and robust manner. the search process used for recognition and localization of particular objects in the given scene. They consist of selected features which satisfy system constraints and Corroborating Evidence Subtrees which are used in the formation of hypotheses. Verification techniques, used to substantiate or refute these hypotheses, are explored. Experiments utilizing 3-D data are presented

EPIdemiology of Surgery-Associated Acute Kidney Injury (EPIS-AKI) : Study protocol for a multicentre, observational trial

More than 300 million surgical procedures are performed each year. Acute kidney injury (AKI) is a common complication after major surgery and is associated with adverse short-term and long-term outcomes. However, there is a large variation in the incidence of reported AKI rates. The establishment of an accurate epidemiology of surgery-associated AKI is important for healthcare policy, quality initiatives, clinical trials, as well as for improving guidelines. The objective of the Epidemiology of Surgery-associated Acute Kidney Injury (EPIS-AKI) trial is to prospectively evaluate the epidemiology of AKI after major surgery using the latest Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI. EPIS-AKI is an international prospective, observational, multicentre cohort study including 10 000 patients undergoing major surgery who are subsequently admitted to the ICU or a similar high dependency unit. The primary endpoint is the incidence of AKI within 72 hours after surgery according to the KDIGO criteria. Secondary endpoints include use of renal replacement therapy (RRT), mortality during ICU and hospital stay, length of ICU and hospital stay and major adverse kidney events (combined endpoint consisting of persistent renal dysfunction, RRT and mortality) at day 90. Further, we will evaluate preoperative and intraoperative risk factors affecting the incidence of postoperative AKI. In an add-on analysis, we will assess urinary biomarkers for early detection of AKI. EPIS-AKI has been approved by the leading Ethics Committee of the Medical Council North Rhine-Westphalia, of the Westphalian Wilhelms-University Münster and the corresponding Ethics Committee at each participating site. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and used to design further AKI-related trials. Trial registration number NCT04165369

Burnout among surgeons before and during the SARS-CoV-2 pandemic: an international survey

Background: SARS-CoV-2 pandemic has had many significant impacts within the surgical realm, and surgeons have been obligated to reconsider almost every aspect of daily clinical practice. Methods: This is a cross-sectional study reported in compliance with the CHERRIES guidelines and conducted through an online platform from June 14th to July 15th, 2020. The primary outcome was the burden of burnout during the pandemic indicated by the validated Shirom-Melamed Burnout Measure. Results: Nine hundred fifty-four surgeons completed the survey. The median length of practice was 10&nbsp;years; 78.2% included were male with a median age of 37&nbsp;years old, 39.5% were consultants, 68.9% were general surgeons, and 55.7% were affiliated with an academic institution. Overall, there was a significant increase in the mean burnout score during the pandemic; longer years of practice and older age were significantly associated with less burnout. There were significant reductions in the median number of outpatient visits, operated cases, on-call hours, emergency visits, and research work, so, 48.2% of respondents felt that the training resources were insufficient. The majority (81.3%) of respondents reported that their hospitals were included in the management of COVID-19, 66.5% felt their roles had been minimized; 41% were asked to assist in non-surgical medical practices, and 37.6% of respondents were included in COVID-19 management. Conclusions: There was a significant burnout among trainees. Almost all aspects of clinical and research activities were affected with a significant reduction in the volume of research, outpatient clinic visits, surgical procedures, on-call hours, and emergency cases hindering the training. Trial registration: The study was registered on clicaltrials.gov "NCT04433286" on 16/06/2020