New Dual Endothelin Receptor Antagonist Aprocitentan in Hypertension: A Systematic Review and Meta-Analysis.

Hypertension is one of the most common disorders encountered, yet pharmacotherapy for resistant hypertension has limited effective options. Aprocitentan is postulated to be a novel antihypertensive. The main goal was to determine the effect of aprocitentan on blood pressure among patients with hypertension. A thorough search of 5 electronic databases, including PubMed Central, PubMed, EMBASE, Springer, and Google Scholar, was carried out. The study included eight articles. With doses exceeding 25 mg, plasma ET-1(endothelin-1) concentrations, which show ETB (Endothelin receptor type B) receptor antagonism, significantly rose. Aprocitentan significantly reduced systolic and diastolic blood pressure with both doses of 10mg and 25mg in patients with hypertension. Further research is warranted to evaluate the efficacy, safety, and long-term outcomes of aprocitentan and its synergistic effect with other antihypertensives.

Discovery, Preclinical Characterization, and Early Clinical Activity of JDQ443, a Structurally Novel, Potent, and Selective Covalent Oral Inhibitor of KRASG12C.

Covalent inhibitors of KRASG12C have shown antitumor activity against advanced/metastatic KRASG12C-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 KRASG12C-mutated cell lines, including those with G12C/H95 double mutations. In vivo, JDQ443 induces AUC exposure-driven antitumor efficacy in KRASG12C-mutated cell-derived (CDX) and patient-derived (PDX) tumor xenografts. In PDX models, single-agent JDQ443 activity is enhanced by combination with inhibitors of SHP2, MEK, or CDK4/6. 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 KRASG12C-mutated tumors. SIGNIFICANCE: JDQ443 is a structurally novel covalent KRASG12C inhibitor with a unique binding mode that demonstrates potent and selective antitumor activity in cell lines and in vivo models. In preclinical models and patients with KRASG12C-mutated malignancies, JDQ443 shows potent antitumor activity as monotherapy and in combination with the SHP2 inhibitor TNO155. This article is highlighted in the In This Issue feature, p. 1397.

Utility of two-dimensional echocardiography in pregnancy and post-partum period and impact on management in an inner city hospital.

AIM: Evaluate the practice and appropriateness of requesting echocardiograms in patients with suspected or documented cardiac disease during gestation and puerperium, using the American College of Cardiology Foundation (ACCF) appropriateness criteria, in conjunction with clinical picture. METHODS: Retrospective observational study, to analyze echocardiograms performed during pregnancy and puerperium at a teaching hospital from 2001 to 2006 for appropriateness criteria and studying its impact on management. Sixty-seven patients pregnant or in the puerperal stage had an echocardiogram performed during that period; 58 met our criteria for inclusion. RESULTS: Based on clinical information and criteria of the ACCF, 51 of the 58 echocardiograms met the appropriateness criteria. Of the 51, results of 40 impacted on management; 14 of the 40 echocardiograms that had an impact were abnormal. CONCLUSIONS: Although the ACCF appropriateness criteria have not been specifically studied in pregnancy, our study demonstrates that the criteria are applicable if used appropriately in pregnancy. Most indications in our study correlated with the appropriateness criteria. Although most findings were normal, information from echocardiograms impacted on management in the majority of patients, contributing to therapeutic decision-making. The reliability of echocardiograms performed according to appropriate criteria to assist clinical decisions was excellent even in patients with physiologic cardiovascular changes.

A Simple and Flexible Computational Framework for Inferring Sources of Heterogeneity from Single-Cell Dynamics.

Single-cell time-lapse data provide the means for disentangling sources of cell-to-cell and intra-cellular variability, a key step for understanding heterogeneity in cell populations. However, single-cell analysis with dynamic models is a challenging open problem: current inference methods address only single-gene expression or neglect parameter correlations. We report on a simple, flexible, and scalable method for estimating cell-specific and population-average parameters of non-linear mixed-effects models of cellular networks, demonstrating its accuracy with a published model and dataset. We also propose sensitivity analysis for identifying which biological sub-processes quantitatively and dynamically contribute to cell-to-cell variability. Our application to endocytosis in yeast demonstrates that dynamic models of realistic size can be developed for the analysis of single-cell data and that shifting the focus from single reactions or parameters to nuanced and time-dependent contributions of sub-processes helps biological interpretation. Generality and simplicity of the approach will facilitate customized extensions for analyzing single-cell dynamics.

An Orthogonal Permease-Inducer-Repressor Feedback Loop Shows Bistability.

Feedback loops in biological networks, among others, enable differentiation and cell cycle progression, and increase robustness in signal transduction. In natural networks, feedback loops are often complex and intertwined, making it challenging to identify which loops are mainly responsible for an observed behavior. However, minimal synthetic replicas could allow for such identification. Here, we engineered a synthetic permease-inducer-repressor system in Saccharomyces cerevisiae to analyze if a transport-mediated positive feedback loop could be a core mechanism for the switch-like behavior in the regulation of metabolic gene networks such as the S. cerevisiae GAL system or the Escherichia coli lac operon. We characterized the synthetic circuit using deterministic and stochastic mathematical models. Similar to its natural counterparts, our synthetic system shows bistable and hysteretic behavior, and the inducer concentration range for bistability as well as the switching rates between the two stable states depend on the repressor concentration. Our results indicate that a generic permease-inducer-repressor circuit with a single feedback loop is sufficient to explain the experimentally observed bistable behavior of the natural systems. We anticipate that the approach of reimplementing natural systems with orthogonal parts to identify crucial network components is applicable to other natural systems such as signaling pathways.

Tolerability of Antihypertensive Medications in Older Adults.

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.

Prescribing warfarin appropriately to meet patient safety goals.

The anticoagulant warfarin is increasingly used in a variety of disorders associated with risk of thromboembolism. The drug is undoubtedly effective but is linked to numerous nutrient, disease, and drug interactions; safe use of warfarin therefore necessitates close patient monitoring, using the international normalized ratio. The predominant adverse effect is bleeding, and individuals respond to warfarin in different ways. Both high and subtherapeutic international normalized ratios warrant attention, whereas a high international normalized ratio, with or without bleeding, mandates prompt patient evaluation. The 2008 National Patient Safety Goals require medical institutions to develop processes to ensure the safe use and monitoring of anticoagulant use. Last August, the US Food and Drug Administration revised the prescribing information for warfarin to include genetic testing before initiating therapy, although this is still not covered by most health plans.

Pericardial fat mimicking pericardial effusion on two-dimensional echocardiography.

A 78-year-old overweight woman with diabetes mellitus, bronchial asthma, and Sheehan's syndrome on chronic steroid therapy presented with mild short-lived hematemesis, significant hypotension disproportionate to the degree of bleeding and radiographic evidence of cardiomegaly. Endoscopy showed duodenal ulcer. During evaluation of the unexplained brief hypotension and cardiomegaly, 2D-echocardiogram demonstrated anterior and posterior echo-free spaces consistent with large pericardial effusion (PE). However, subsequent elective surgical pericardiotomy unexpectedly revealed large amounts of pericardial fat. Pericardial fat was also noted on magnetic resonance imaging of the chest. Our case illustrates a potential pitfall of 2D-echocardiography in the diagnosis of PE.