Co-targeting SOS1 enhances the antitumor effects of KRAS inhibitors by addressing intrinsic and acquired resistance.

Combination approaches are needed to strengthen and extend the clinical response to KRAS inhibitors (KRASi). Here, we assessed the antitumor responses of KRAS mutant lung and colorectal cancer models to combination treatment with a SOS1 inhibitor (SOS1i), BI-3406, plus the KRAS inhibitor, adagrasib. We found that responses to BI-3406 plus adagrasib were stronger than to adagrasib alone, comparable to adagrasib with SHP2 (SHP2i) or EGFR inhibitors and correlated with stronger suppression of RAS-MAPK signaling.

Efficacy and NSAID-sparing effect of secukinumab 150 mg in ankylosing spondylitis: results from phase IV ASTRUM study.

Background: Radiographic axial spondyloarthritis (r-axSpA), formerly known as ankylosing spondylitis (AS), is a chronic, inflammatory rheumatic disease associated with symptoms such as inflammatory back pain, morning stiffness, and arthritis. First-line recommendations for patients with AS include treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) for reducing pain and stiffness.

Objectives: The objective of our study is to evaluate the efficacy and short-term NSAID-sparing effect of secukinumab in patients with AS currently treated with NSAIDs.

[Nonpharmacological treatment measures, rehabilitation services and membership in patient support groups in axial spondylarthritis (The ATTENTUS axSpA study)].

Background: The treatment of axial spondylarthritis (axSpA) includes pharmacological treatment measures (PTM) and nonpharmacological treatment measures (NPTM) as well as supporting resources, such as rehabilitation services (RS) and membership in patient support groups (PSG). Nevertheless, there are significant participation restrictions in patients with axSpA in Germany.

Objective: Investigation of functional deficits, participation restrictions and utilization of PTM, NPTM, RS and PSG membership in patients with axSpA.

Work participation in patients with axial spondyloarthritis: high prevalence of negative workplace experiences and long-term work impairment.

Introduction: Axial spondyloarthritis (axSpA) is a chronic inflammatory disease that typically affects people in their second and third decades of life, which are important years for establishing a professional career. We aim to study outcomes of work participation (WP) and their associations with demographic and clinical confounders, in addition to prevalence of negative workplace experiences in axSpA.

Methods: In total, 770 patients with axSpA participated in the multicentre, observational ATTENTUS-axSpA survey in Germany.

Ocrelizumab-induced colitis and cytomegalovirus infection and their disadvantageous interaction with underlying multiple sclerosis.

Ocrelizumab is a humanized monoclonal antibody against the B-lymphocyte antigen CD20 and the only approved treatment option in primary progressive multiple sclerosis. Herpesvirus-related infections like cytomegalovirus (CMV) infections are common in patients receiving ocrelizumab, whereas gastrointestinal side effects with inflammatory bowel disease (IBD) like esophagitis or colitis are very rare. This case report describes the challenging clinical, endoscopic, and histologic features of an ocrelizumab-induced colitis overlapping with CMV infection and their disadvantageous interaction with the underlying multiple sclerosis.

Atezolizumab Plus Bevacizumab in Patients with Advanced and Progressing Hepatocellular Carcinoma: Retrospective Multicenter Experience.

Atezolizumab plus bevacizumab is the standard of care for first-line systemic therapy for advanced hepatocellular carcinoma (aHCC). Data on the efficacy and safety of atezolizumab plus bevacizumab in patients with aHCC who have received prior systemic therapy are not available. Patients with aHCC who received atezolizumab plus bevacizumab after at least one systemic treatment between December 2018 and March 2022 were retrospectively identified in 13 centers in Germany and Austria.

Discovery of potent and selective HER2 inhibitors with efficacy against HER2 exon 20 insertion-driven tumors, which preserve wild-type EGFR signaling.

Oncogenic alterations in human epidermal growth factor receptor 2 (HER2) occur in approximately 2% of patients with non-small cell lung cancer and predominantly affect the tyrosine kinase domain and cluster in exon 20 of the ERBB2 gene. Most clinical-grade tyrosine kinase inhibitors are limited by either insufficient selectivity against wild-type (WT) epidermal growth factor receptor (EGFR), which is a major cause of dose-limiting toxicity or by potency against HER2 exon 20 mutant variants. Here we report the discovery of covalent tyrosine kinase inhibitors that potently inhibit HER2 exon 20 mutants while sparing WT EGFR, which reduce tumor cell survival and proliferation in vitro and result in regressions in preclinical xenograft models of HER2 exon 20 mutant non-small cell lung cancer, concomitant with inhibition of downstream HER2 signaling.

Loss of muscular force in isolated rat diaphragms is related to changes in muscle fibre size.

Objective: Passivity of the diaphragm during prolonged mechanical ventilation can lead to ventilation-induced diaphragmatic dysfunction reasoned by a reduction of diaphragmatic muscle strength. Electrical stimulation may be utilised to modulate diaphragm muscle strength. Therefore we intended to investigate diaphragmatic muscle strength based on stimulation with electric impulses.

Filopodia-based contact stimulation of cell migration drives tissue morphogenesis.

Cells migrate collectively to form tissues and organs during morphogenesis. Contact inhibition of locomotion (CIL) drives collective migration by inhibiting lamellipodial protrusions at cell-cell contacts and promoting polarization at the leading edge. Here, we report a CIL-related collective cell behavior of myotubes that lack lamellipodial protrusions, but instead use filopodia to move as a cohesive cluster in a formin-dependent manner.

Structure of the helicase core of Werner helicase, a key target in microsatellite instability cancers.

Loss of WRN, a DNA repair helicase, was identified as a strong vulnerability of microsatellite instable (MSI) cancers, making WRN a promising drug target. We show that ATP binding and hydrolysis are required for genome integrity and viability of MSI cancer cells. We report a 2.

BI-3406, a Potent and Selective SOS1-KRAS Interaction Inhibitor, Is Effective in KRAS-Driven Cancers through Combined MEK Inhibition.

is the most frequently mutated driver of pancreatic, colorectal, and non-small cell lung cancers. Direct KRAS blockade has proved challenging, and inhibition of a key downstream effector pathway, the RAF-MEK-ERK cascade, has shown limited success because of activation of feedback networks that keep the pathway in check. We hypothesized that inhibiting SOS1, a KRAS activator and important feedback node, represents an effective approach to treat KRAS-driven cancers.

STAG1 vulnerabilities for exploiting cohesin synthetic lethality in STAG2-deficient cancers.

The cohesin subunit has emerged as a recurrently inactivated tumor suppressor in human cancers. Using candidate approaches, recent studies have revealed a synthetic lethal interaction between and its paralog To systematically probe genetic vulnerabilities in the absence of STAG2, we have performed genome-wide CRISPR screens in isogenic cell lines and identified STAG1 as the most prominent and selective dependency of STAG2-deficient cells. Using an inducible degron system, we show that chemical genetic degradation of STAG1 protein results in the loss of sister chromatid cohesion and rapid cell death in STAG2-deficient cells, while sparing -wild-type cells.

The Florida Mobile Health Adherence Project for People Living With HIV (FL-mAPP): Longitudinal Assessment of Feasibility, Acceptability, and Clinical Outcomes.

Background: For people living with HIV (PLWH), antiretroviral therapy (ART) adherence is crucial to attain better health outcomes. Although research has leveraged consumer health information technologies to enhance ART adherence, no study has evaluated feasibility and clinical outcomes associated with the usage of a commercially available, regularly updated mobile health (mHealth) app for improving ART adherence among PLWH.

Objective: This study aimed to assess the feasibility, acceptability, and clinical outcomes of Care4Today, an existing, free, biprogrammatic mHealth app for improving ART adherence among PLWH.

Attitudes, Beliefs, and Willingness Toward the Use of mHealth Tools for Medication Adherence in the Florida mHealth Adherence Project for People Living With HIV (FL-mAPP): Pilot Questionnaire Study.

Background: Antiretroviral (ART) adherence among people living with HIV (PLWH) continues to be a challenge despite advances in HIV prevention and treatment. Mobile health (mHealth) interventions are increasingly deployed as tools for ART adherence. However, little is known about the uptake and attitudes toward commercially available, biprogrammatic mobile apps (ie, designed for both smartphone and short message service [SMS] messaging) among demographically diverse PLWH.

Werner syndrome helicase is a selective vulnerability of microsatellite instability-high tumor cells.

Targeted cancer therapy is based on exploiting selective dependencies of tumor cells. By leveraging recent functional screening data of cancer cell lines we identify Werner syndrome helicase (WRN) as a novel specific vulnerability of microsatellite instability-high (MSI-H) cancer cells. MSI, caused by defective mismatch repair (MMR), occurs frequently in colorectal, endometrial and gastric cancers.

Racial/Ethnic Disparities in Failure to Initiate HIV Care: Role of HIV Testing Site, Individual Factors, and Neighborhood Factors, Florida, 2014-2015.

Delayed initiation of human immunodeficiency virus (HIV) care affects disease progression. To determine the role of HIV testing site and neighborhood- and individual-level factors in racial/ethnic disparities in initiation of care, we examined Florida population-based HIV/AIDS surveillance system records. We performed multilevel Poisson regression to calculate adjusted prevalence ratios (APR) for non-initiation of care by race/ethnicity adjusting for HIV testing site type and individual- and neighborhood-level characteristics.

Triple Angiokinase Inhibitor Nintedanib Directly Inhibits Tumor Cell Growth and Induces Tumor Shrinkage via Blocking Oncogenic Receptor Tyrosine Kinases.

The triple-angiokinase inhibitor nintedanib is an orally available, potent, and selective inhibitor of tumor angiogenesis by blocking the tyrosine kinase activities of vascular endothelial growth factor receptor (VEGFR) 1-3, platelet-derived growth factor receptor (PDGFR)- and -, and fibroblast growth factor receptor (FGFR) 1-3. Nintedanib has received regulatory approval as second-line treatment of adenocarcinoma non-small cell lung cancer (NSCLC), in combination with docetaxel. In addition, nintedanib has been approved for the treatment of idiopathic lung fibrosis.

Synthetic lethality between the cohesin subunits and in diverse cancer contexts.

Recent genome analyses have identified recurrent mutations in the cohesin complex in a wide range of human cancers. Here we demonstrate that the most frequently mutated subunit of the cohesin complex, , displays a strong synthetic lethal interaction with its paralog . Mechanistically, STAG1 loss abrogates sister chromatid cohesion in mutated but not in wild-type cells leading to mitotic catastrophe, defective cell division and apoptosis.

Retention in HIV Care and Viral Suppression: Individual- and Neighborhood-Level Predictors of Racial/Ethnic Differences, Florida, 2015.

The objective of this study was to estimate racial/ethnic differences in retention in HIV care and viral suppression and to identify related individual and neighborhood determinants. Florida HIV surveillance records of cases aged ≥13 years diagnosed during the years 2000-2014 were analyzed. Retention in care was defined as evidence of ≥2 or more laboratory tests, receipts of prescription, or clinical visits at least 3 months apart during 2015.

Missed Opportunities for Preventing Perinatal Transmission of Human Immunodeficiency Virus, Florida, 2007-2014.

Objectives: Despite declining numbers of perinatally exposed infants, an increase in perinatal human immunodeficiency virus (HIV) infections from 2011 to 2013 prompted this study to identify missed perinatal HIV prevention opportunities.

Methods: Deidentified records of children born from 2007 through 2014, exposed to HIV perinatally, and reported to the Florida Department of Health were obtained. Crude relative risks (RRs) and 95% confidence intervals (CIs) for factors associated with perinatal transmission, nondiagnosis of maternal HIV infection, and nonreceipt of antiretroviral medication were calculated.

[Dialectical Behavioral Therapy for Male Adolescents with Borderline Symptomatology].

Dialectical Behavioral Therapy for Male Adolescents with Borderline Symptomatology The efficacy of Dialectical Behavior Therapy for adolescents (DBT-A) in patients with borderline symptomatology has mainly been shown in female adolescents. However, male adolescents with borderline symptoms are characterized by more aggressive, disruptive, and antisocial behavior. Therefore, the efficacy of the DBT-A has to be investigated in male adolescents.

Black-White and Country of Birth Disparities in Retention in HIV Care and Viral Suppression among Latinos with HIV in Florida, 2015.

The study's purpose was to identify HIV, Black-White race, and birth country disparities in retention in HIV care and HIV viral load (VL) suppression among Latinos, in 2015. Florida's surveillance data for Latinos diagnosed with HIV (2000-2014) were merged with American Community Survey data. Multi-level (random effects) models were used to estimate adjusted odds ratios (aOR) for non-retention in care and non-viral load suppression.

Label-free versus conventional cellular assays: Functional investigations on the human histamine H receptor.

A set of histamine H receptor (HR) agonists and antagonists was characterized in functional assays, using dynamic mass redistribution (DMR), electric cell-substrate impedance sensing (ECIS) and various signaling pathway specific readouts (Fura-2 and aequorin calcium assays, arrestin recruitment (luciferase fragment complementation) assay, luciferase gene reporter assay). Data were gained from genetically engineered HEK293T cells and compared with reference data from GTPase assays and radioligand binding. Histamine and the other HR agonists gave different assay-related pEC values, however, the order of potency was maintained.