Covalent inhibitors of KRASG12C have shown antitumor activity against advanced/metastatic KRAS G12C-mutated cancers, though resistance emerges and additional strategies are needed to improve outcomes. JDQ443 is a structurally unique, covalent inhibitor of GDP-bound KRASG12C that forms novel interactions with the switch II pocket. JDQ443 potently inhibits KRASG12C-driven cellular signaling and demonstrates selective antiproliferative activity in KRAS G12C-mutated cell lines, including those with G12C/H95 double mutations. In vivo, JDQ443 induces AUC exposure-driven antitumor efficacy in KRAS G12C-mutated cell-derived (CDX) and patient-derived (PDX) tumor xenografts. In PDX models, single-agent JDQ443 activity is enhanced by combination with SHP2, MEK or CDK4/6 inhibitors. Notably, the benefit of JDQ443 plus the SHP2 inhibitor TNO155 is maintained at reduced doses of either agent in CDX models, consistent with mechanistic synergy. JDQ443 is in clinical development as monotherapy and in combination with TNO155, with both strategies showing antitumor activity in patients with KRAS G12C-mutated tumors.

Objective: To evaluate a 4-hour ultrasonography course in the setting of an emergency medicine (EM) training program. Methods: EM residents and faculty at a large urban center were provided a 4-hour emergency ultrasonography course. Then, during an 18-month period, a nonconsecutive sample of ultrasonographic examinations were videotaped and later reviewed. The interpretations of the emergency physician examinations were compared with the following reference standards: 1) an official ultrasound performed and interpreted by the departments of radiology or cardiology; 2) an operative report; 3) A CT scan or IV pyelogram (IVP); or 4) a cardiologist's or a radiologist's interpretation of the videotaped examinations. Results: Of 258 examinations reviewed, 28 (1 1%) of these were excluded because the cardiologist or radiologist reviewing the videotape determined them to be "technically limited" studies. There is a growing body of literature demonstrating the efficacy of ultrasonography to answer these questions in the ED setting.'-'' This study evaluates an instructional model for emergency ultrasonography in the setting of an emergency medicine (EM) residency training program.

The SIB Swiss Institute of Bioinformatics (www.isb-sib.ch) provides world-class bioinformatics databases, software tools, services and training to the international life science community in academia and industry. These solutions allow life scientists to turn the exponentially growing amount of data into knowledge. Here, we provide an overview of SIB's resources and competence areas, with a strong focus on curated databases and SIB's most popular and widely used resources. In particular, SIB's Bioinformatics resource portal ExPASy features over 150 resources, including UniProtKB/Swiss-Prot, ENZYME, PROSITE, neXtProt, STRING, UniCarbKB, SugarBindDB, SwissRegulon, EPD, arrayMap, Bgee, SWISS-MODEL Repository, OMA, OrthoDB and other databases, which are briefly described in this article.

Several guidelines for hypertension have recently undergone revisions to incorporate an approach providing choices of medications based on age, race, and specific situations where hypertension may co-exist with disorders such as diabetes, coronary artery disease, heart failure and chronic kidney disease. Initial recommendations include diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers; beta blockers are favored in some guidelines and are a choice in specific settings. Within the classes of drugs, several antihypertensive agents provide options. This review discusses antihypertensive drugs by class, including adverse effects and tolerability, with preferences in older adults and specific settings. Adverse drug events from antihypertensive medications are discussed by class and where applicable for specific agents. Data from select studies pertinent to tolerability and adverse effects are presented in tables for several classes of drugs. The rationale for nonadherence to medication is reviewed, including the roles played by tolerability and adverse drug effects. Antihypertensive therapy in typical settings in older adults is discussed; they include hypertension in association with impaired cognition, depression, diabetes, sexual dysfunction, and falls. The key to successful therapy and tolerability is to promote a healthy lifestyle in conjunction with medications as the approach, thereby also lowering the adverse drug effects. The eventual choice of the specific drug(s) is based on risks, benefits, and patient preferences, and is best tailored for each older adult.