Activity of a Novel bcl-2/bcl-xL-Bispecific Antisense Oligonucleotide Against Tumors of Diverse Histologic Origins

Background: Increased expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL is involved in the development and progression of many tumors. We recently reported that the bcl-2/bcl-xL-bispecific antisense oligonucleotide 4625 induces apoptosis in lung carcinoma cells. To further assess the therapeutic potential of oligonucleotide 4625, we investigated its effect on a series of human tumor cell lines of diverse histologic origins in vitro and in vivo. Methods: Oligonucleotide 4625-mediated inhibition of bcl-2 and bcl-xL expression in vitro was measured in breast carcinoma cells with the use of reverse transcription-polymerase chain reaction (PCR), real-time PCR, and western blotting. Cytotoxicity was assessed in several different cell lines by measurement of tumor cell growth, propidium iodide uptake, and nuclear apoptosis. The in vivo activity of oligonucleotide 4625 was determined by the inhibition of growth of established tumor xenografts in nude mice, immunohistochemical staining of Bcl-2 and Bcl-x proteins in the tumors, and western blotting of tumor lysates. Apoptosis in tumor xenografts was detected with the use of in situ TUNEL (i.e., terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-digoxigenin nick end labeling) staining. All statistical tests are two-sided. Results: In breast carcinoma cells, oligonucleotide 4625 treatment reduced bcl-2 and bcl-xL messenger RNA levels in a dose-dependent manner. At 600 nM, oligonucleotide 4625 reduced Bcl-2 and Bcl-xL protein levels to 25% (95% confidence interval [CI] = 16% to 34%) and 20% (95% CI = 14% to 26%), respectively, of the levels in untreated cells and it decreased viability in all cell lines mainly by inducing apoptosis. In vivo, oligonucleotide 4625 statistically significantly inhibited the growth of breast and colorectal carcinoma xenografts by 51% (95% CI = 28% to 74%) and 59% (95% CI = 44% to 74%), respectively, relative to those treated with control oligonucleotide 4626; it also reduced Bcl-2 and Bcl-xL protein levels and induced tumor cell apoptosis. Conclusion: The bcl-2/bcl-xL-bispecific antisense oligonucleotide 4625 merits further study as a novel compound for cancer therap

Predicting Venous Thromboembolic Events in Patients with Coronavirus Disease 2019 Requiring Hospitalization: an Observational Retrospective Study by the COVIDIC Initiative in a Swiss University Hospital.

Coronavirus disease 2019 (COVID-19) can result in profound changes in blood coagulation. The aim of the study was to determine the incidence and predictors of venous thromboembolic events (VTE) among patients with COVID-19 requiring hospital admission. Subjects and Methods. We performed a retrospective study at the Lausanne University Hospital with patients admitted because of COVID-19 from February 28 to April 30, 2020. Among 443 patients with COVID-19, VTE was diagnosed in 41 patients (9.3%; 27 pulmonary embolisms, 12 deep vein thrombosis, one pulmonary embolism and deep vein thrombosis, one portal vein thrombosis). VTE was diagnosed already upon admission in 14 (34.1%) patients and 27 (65.9%) during hospital stay (18 in ICU and nine in wards outside the ICU). Multivariate analysis revealed D-dimer value > 3,120 ng/ml (P < 0.001; OR 15.8, 95% CI 4.7-52.9) and duration of 8 days or more from COVID-19 symptoms onset to presentation (P 0.020; OR 4.8, 95% CI 1.3-18.3) to be independently associated with VTE upon admission. D-dimer value ≥ 3,000 ng/l combined with a Wells score for PE ≥ 2 was highly specific (sensitivity 57.1%, specificity 91.6%) in detecting VTE upon admission. Development of VTE during hospitalization was independently associated with D-dimer value > 5,611 ng/ml (P < 0.001; OR 6.3, 95% CI 2.4-16.2) and mechanical ventilation (P < 0.001; OR 5.9, 95% CI 2.3-15.1). VTE seems to be a common COVID-19 complication upon admission and during hospitalization, especially in ICU. The combination of Wells ≥ 2 score and D - dimer ≥ 3,000 ng/l is a good predictor of VTE at admission

Transcriptomic Signature Differences Between SARS-CoV-2 and Influenza Virus Infected Patients.

The reason why most individuals with COVID-19 have relatively limited symptoms while other develop respiratory distress with life-threatening complications remains unknown. Increasing evidence suggests that COVID-19 associated adverse outcomes mainly rely on dysregulated immunity. Here, we compared transcriptomic profiles of blood cells from 103 patients with different severity levels of COVID-19 with that of 27 healthy and 22 influenza-infected individuals. Data provided a complete overview of SARS-CoV-2-induced immune signature, including a dramatic defect in IFN responses, a reduction of toxicity-related molecules in NK cells, an increased degranulation of neutrophils, a dysregulation of T cells, a dramatic increase in B cell function and immunoglobulin production, as well as an important over-expression of genes involved in metabolism and cell cycle in patients infected with SARS-CoV-2 compared to those infected with influenza viruses. These features also differed according to COVID-19 severity. Overall and specific gene expression patterns across groups can be visualized on an interactive website (https://bix.unil.ch/covid/). Collectively, these transcriptomic host responses to SARS-CoV-2 infection are discussed in the context of current studies, thereby improving our understanding of COVID-19 pathogenesis and shaping the severity level of COVID-19

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Estimation de la prévalence de la BPCO et de l'association BPCO-AOMI dans le service de médecine interne de l'HFR Fribourg

CONTEXTE : La bronchopneumopathie chronique obstructive (BPCO) est un problème majeur de santé publique dans le monde, responsable d'une morbidité et d'une mortalité considérables. En Suisse, sa prévalence varie entre 2 et 15% de la population, selon l'âge et le sexe. Son diagnostic requière une spirométrie montrant un trouble ventilatoire obstructif dont la réversibilité est incomplète. Or, nous constatons régulièrement dans notre pratique de la médecine interne que de nombreux patients portent ce diagnostic dans leur dossier médical sans avoir effectué d'examen respiratoire fonctionnel, et qu'un nombre significatif de patients à haut risque de BPCO n'a jamais été diagnostiqué. La prévalence réelle de cette maladie n'est donc pas connue. Par ailleurs, la BPCO est associée à de nombreuses maladies systémiques, notamment cardiovasculaires telles que l'insuffisance cardiaque et la maladie coronarienne. Cependant, son association avec l'artériopathie oblitérante des membres inférieurs (AOMI), avec laquelle elle partage plusieurs facteurs de risque comme le tabagisme, l'âge avancé, et la dyslipidémie, n'a que peu été étudiée. OBJECTFS : L'objectif principal de cette étude était de déterminer la prévalence de la BPCO confirmée parmi les patients âgés de 45 ans et plus, qui étaient admis dans le service de médecine interne de i'HFR Fribourg, et qui étaient "étiquetés" comme BPCO dans leur dossier médical ou présentaient des facteurs de risque et des symptômes typiques de la maladie. L'objectif secondaire était de déterminer, dans cette population de patients, la prévalence de l'association entre la BPCO et l'AOMI. METHODOLOGIE : Tous les patients consécutifs âgés de 45 ans et plus, admis dans le service de médecine interne de notre hôpital entre les mois de novembre 2013 and mars 2014 ont été évalués pour l'inclusion dans notre étude. Les patients dont le dossier médical informatisé mentionnait le diagnostic de BPCO, de bronchite chronique et/ou d'emphysème pulmonaire faisaient partie du groupe des "patients étiquetés comme BPCO". Les patients qui présentaient au moins un facteur de risque et un symptôme classiques de la BPCO, identifiés à leur arrivée sur une liste à cocher, faisaient partie du groupe des "patients à risque de BPCO". Une spirométrie, une mesure de l'index de pression systolique (IPS) cheville-bras, et une mesure de l'IPS orteil-bras lorsqu'elle était nécessaire, ont été effectuées chez chaque patient une fois leur état clinique stable. RESULTATS : Cent septante-deux des 888 patients évalués ont été inclus dans l'étude. Une BPCO a été retrouvée chez 81 patients au total. Parmi les "patients étiquetés comme BPCO", 65 (87%) souffraient réellement d'une BPCO et 10 (13%) portaient un diagnostic erroné. Une BPCO a été nouvellement diagnostiquée chez 16 (16%) des 97 "patients à risque de BPCO". Une AOMI a été identifiée chez 35 (43%) des patients souffrant d'une BPCO confirmée et chez 22 (24%) des patients sans BPCO. L'association entre la BPCO et l'AOMI était statistiquement significative (p<0.01). CONCLUSION : Une BPCO confirmée a été identifiée chez 9% des 888 patients évalués pour l'inclusion. La majorité des "patients étiquetés comme BPCO" était correctement diagnostiquée et une proportion non négligeable des "patients à risque de BPCO" était sous-diagnostiquée. Par ailleurs, une association significative entre la BPCO et l'AOMI a été retrouvée dans notre collectif de patients. Chez les patients fumeurs, une spirométrie mettant en évidence une BPCO semble être un test utile pour détecter les patients à haut risque cardiovasculaire, notamment ceux atteints d'AOMI. Nous pensons donc qu'il est indispensable d'utiliser la spirométrie de façon systématique pour le diagnostic de la BPCO, et suggérons de proposer un dépistage de l'AOMI à tous les patients tabagiques avec un diagnostic de BPCO confirmée

Asthénie, vertiges et instabilité à la marche

Encéphalite auto-immun

Algorithm Development in Computational Materials Science

Researchers share their views on efforts being made to develop algorithms in computational materials science. The development of solution algorithms will enable the treatment of increasingly complex systems and materials over longer spans of simulated time in an acceptable amount of computational time. The complexity of multiscale and multiphysics models is the key issue, with the goal of improving the representation of the relevant physical and chemical processes being essential. Strategies to achieve this complexity vary from extending existing methods into foreign regimes of length time energy phase space to the coupling of multiple methods, each firmly rooted in its own regime. The hardware and techniques available to the experimental materials scientist have also evolved over time, necessitating algorithms that expand the frontiers of data acquisition and analysis

Legislative Documents

Also, variously referred to as: House bills; House documents; House legislative documents; legislative documents; General Court documents

Comparison of Traditional Upper Airway Surgery and Upper Airway Stimulation for Obstructive Sleep Apnea.

OBJECTIVE To compare patients with moderate-severe obstructive sleep apnea (OSA) undergoing traditional single and multilevel sleep surgery to those undergoing upper airway stimulation (UAS). STUDY DESIGN Case control study comparing retrospective cohort of patients undergoing traditional sleep surgery to patients undergoing UAS enrolled in the ADHERE registry. SETTING 8 multinational academic medical centers. SUBJECTS AND METHODS 233 patients undergoing prior single or multilevel traditional sleep surgery and meeting study inclusion criteria were compared to 465 patients from the ADHERE registry who underwent UAS. We compared preoperative and postoperative demographic, quality of life, and polysomnographic data. We also evaluated treatment response rates. RESULTS The pre and postoperative apnea hypopnea index (AHI) was 33.5 and 15 in the traditional sleep surgery group and 32 and 10 in the UAS group. The postoperative AHI in the UAS group was significantly lower. The pre and postoperative Epworth sleepiness scores (ESS) were 12 and 6 in both the traditional sleep surgery and UAS groups. Subgroup analysis evaluated those patients undergoing single level palate and multilevel palate and tongue base traditional sleep surgeries. The UAS group had a significantly lower postoperive AHI than both traditional sleep surgery subgroups. The UAS group had a higher percentage of patients reaching surgical success, defined as a postoperative AHI <20 with a 50% reduction from preoperative severity. CONCLUSION UAS offers significantly better control of AHI severity than traditional sleep surgery. Quality life improvements were similar between groups