Mutations in ap1b1 Cause Mistargeting of the Na(+)/K(+)-ATPase Pump in Sensory Hair Cells.

The hair cells of the inner ear are polarized epithelial cells with a specialized structure at the apical surface, the mechanosensitive hair bundle. Mechanotransduction occurs within the hair bundle, whereas synaptic transmission takes place at the basolateral membrane. The molecular basis of the development and maintenance of the apical and basal compartments in sensory hair cells is poorly understood. Here we describe auditory/vestibular mutants isolated from forward genetic screens in zebrafish with lesions in the adaptor protein 1 beta subunit 1 (ap1b1) gene. Ap1b1 is a subunit of the adaptor complex AP-1, which has been implicated in the targeting of basolateral membrane proteins. In ap1b1 mutants we observed that although the overall development of the inner ear and lateral-line organ appeared normal, the sensory epithelium showed progressive signs of degeneration. Mechanically-evoked calcium transients were reduced in mutant hair cells, indicating that mechanotransduction was also compromised. To gain insight into the cellular and molecular defects in ap1b1 mutants, we examined the localization of basolateral membrane proteins in hair cells. We observed that the Na(+)/K(+)-ATPase pump (NKA) was less abundant in the basolateral membrane and was mislocalized to apical bundles in ap1b1 mutant hair cells. Accordingly, intracellular Na(+) levels were increased in ap1b1 mutant hair cells. Our results suggest that Ap1b1 is essential for maintaining integrity and ion homeostasis in hair cells

Relacorilant + Nab-Paclitaxel in Patients With Recurrent, Platinum-Resistant Ovarian Cancer: A Three-Arm, Randomized, Controlled, Open-Label Phase II Study

Relacorilant; Cáncer de ovario recurrente; PlatinoRelacorilant; Càncer d'ovari recurrent; PlatíRelacorilant; Resistant ovarian cancer; PlatinumPURPOSE Despite therapeutic advances, outcomes for patients with platinum-resistant/refractory ovarian cancer remain poor. Selective glucocorticoid receptor modulation with relacorilant may restore chemosensitivity and enhance chemotherapy efficacy. METHODS This three-arm, randomized, controlled, open-label phase II study (ClinicalTrials.gov identifier: NCT03776812) enrolled women with recurrent, platinum-resistant/refractory, high-grade serous or endometrioid epithelial ovarian, primary peritoneal, or fallopian tube cancer, or ovarian carcinosarcoma treated with ≤4 prior chemotherapeutic regimens. Patients were randomly assigned 1:1:1 to (1) nab-paclitaxel (80 mg/m2) + intermittent relacorilant (150 mg the day before, of, and after nab-paclitaxel); (2) nab-paclitaxel (80 mg/m2) + continuous relacorilant (100 mg once daily); or (3) nab-paclitaxel monotherapy (100 mg/m2). Nab-paclitaxel was administered on days 1, 8, and 15 of each 28-day cycle. The primary end point was progression-free survival (PFS) by investigator assessment; objective response rate (ORR), duration of response (DOR), overall survival (OS), and safety were secondary end points. RESULTS A total of 178 women were randomly assigned. Intermittent relacorilant + nab-paclitaxel improved PFS (hazard ratio [HR], 0.66; log-rank test P = .038; median follow-up, 11.1 months) and DOR (HR, 0.36; P = .006) versus nab-paclitaxel monotherapy, while ORR was similar across arms. At the preplanned OS analysis (median follow-up, 22.5 months), the OS HR was 0.67 (P = .066) for the intermittent arm versus nab-paclitaxel monotherapy. Continuous relacorilant + nab-paclitaxel showed numerically improved median PFS but did not result in significant improvement over nab-paclitaxel monotherapy. Adverse events were comparable across study arms, with neutropenia, anemia, peripheral neuropathy, and fatigue/asthenia being the most common grade ≥3 adverse events. CONCLUSION Intermittent relacorilant + nab-paclitaxel improved PFS, DOR, and OS compared with nab-paclitaxel monotherapy. On the basis of protocol-prespecified Hochberg step-up multiplicity adjustment, the primary end point did not reach statistical significance (P < .025). A phase III evaluation of this regimen is underway (ClinicalTrials.gov identifier: NCT05257408)

Spaceflight Causes Increased Virulence of Serratia Marcescens on a Drosophila Melanogaster Host

Drosophila melanogaster, or the fruit fly, has long been an important organism for Earth-based research, and is now increasingly utilized as a model system to understand the biological effects of spaceflight. Studies in Drosophila melanogaster have shown altered immune responses in 3rd instar larvae and adult males following spaceflight, changes similar to those observed in astronauts. In addition, spaceflight has also been shown to affect bacterial physiology, as evidenced by studies describing altered virulence of Salmonella typhimurium following spaceflight and variation in biofilm growth patterns for the opportunistic pathogen Pseudomonas aeruginosa during flight. We recently sent Serratia marcescens Db11, a Drosophila pathogen and an opportunistic human pathogen, to the ISS on SpaceX-5 (Fruit Fly Lab-01). S. marcescens samples were stored at 4degC for 24 days on-orbit and then allowed to grow for 120 hours at ambient station temperature before being returned to Earth. Upon return, bacteria were isolated and preserved in 50% glycerol or RNAlater. Storage, growth, and isolation for ground control samples were performed using the same procedures. Spaceflight and ground samples stored in 50% glycerol were diluted and injected into 5-7-day-old ground-born adult D. melanogaster. Lethality was significantly greater in flies injected with the spaceflight samples compared to those injected with ground bacterial samples. These results indicate a shift in the virulence profile of the spaceflight S. marcescens Db11 and will be further assessed with molecular biological analyses. Our findings strengthen the conclusion that spaceflight impacts the virulence of bacterial pathogens on model host organisms such as the fruit fly. This research was supported by NASA's ISS Program Office (ISSPO) and Space Life and Physical Sciences Research and Applications (SLPSRA)

Barriers and facilitators to screen for and address social needs in primary care practices in Maryland: a qualitative study

BackgroundSocial needs screening can help modify care delivery to meet patient needs and address non-medical barriers to optimal health. However, there is a need to understand how factors that exist at multiple levels of the healthcare ecosystem influence the collection of these data in primary care settings.MethodsWe conducted 20 semi-structured interviews involving healthcare providers and primary care clinic staff who represented 16 primary care practices. Interviews focused on barriers and facilitators to awareness of and assistance for patients' social needs in primary care settings in Maryland. The interviews were coded to abstract themes highlighting barriers and facilitators to conducting social needs screening. The themes were organized through an inductive approach using the socio-ecological model delineating individual-, clinic-, and system-level barriers and facilitators to identifying and addressing patients' social needs.ResultsWe identified several individual barriers to awareness, including patient stigma about verbalizing social needs, provider frustration at eliciting needs they were unable to address, and provider unfamiliarity with community-based resources to address social needs. Clinic-level barriers to awareness included limited appointment times and connecting patients to appropriate community-based organizations. System-level barriers to awareness included navigating documentation challenges on the electronic health record.ConclusionsOvercoming barriers to effective screening for social needs in primary care requires not only practice- and provider-level process change but also an alignment of community resources and advocacy of policies to redistribute community assets to address social needs

Integrated Multi-Tumor Radio-Genomic Marker of Outcomes in Patients with High Serous Ovarian Carcinoma.

Purpose: Develop an integrated intra-site and inter-site radiomics-clinical-genomic marker of high grade serous ovarian cancer (HGSOC) outcomes and explore the biological basis of radiomics with respect to molecular signaling pathways and the tumor microenvironment (TME). Method: Seventy-five stage III-IV HGSOC patients from internal (N = 40) and external factors via the Cancer Imaging Archive (TCGA) (N = 35) with pre-operative contrast enhanced CT, attempted primary cytoreduction, at least two disease sites, and molecular analysis performed within TCGA were retrospectively analyzed. An intra-site and inter-site radiomics (cluDiss) measure was combined with clinical-genomic variables (iRCG) and compared against conventional (volume and number of sites) and average radiomics (N = 75) for prognosticating progression-free survival (PFS) and platinum resistance. Correlation with molecular signaling and TME derived using a single sample gene set enrichment that was measured. Results: The iRCG model had the best platinum resistance classification accuracy (AUROC of 0.78 [95% CI 0.77 to 0.80]). CluDiss was associated with PFS (HR 1.03 [95% CI: 1.01 to 1.05], p = 0.002), negatively correlated with Wnt signaling, and positively to immune TME. Conclusions: CluDiss and the iRCG prognosticated HGSOC outcomes better than conventional and average radiomic measures and could better stratify patient outcomes if validated on larger multi-center trials

Clinical trial experience with CA4P anticancer therapy: focus on efficacy, cardiovascular adverse events, and hypertension management

Combretastatin A4-phosphate (CA4P) is a vascular-disrupting agent (VDA) in clinical development for the treatment of ovarian and other cancers. In contrast to antiangiogenic agents, such as bevacizumab, which suppress the development of new tumor vasculature, VDAs target established tumor vasculature. These differing but complementary mechanisms of action are currently being explored in clinical trials combining CA4P and bevacizumab. Clinical experience to date has highlighted an important need to better understand the cardiovascular adverse events of CA4P, both alone and in combination with antiangiogenic agents, which can also be associated with cardiovascular adverse events. An acute but transient increase in blood pressure is often the most clinically relevant toxicity associated with CA4P. Increases in CA4P-related blood pressure typically occur 0.5 to 1&nbsp;h after initiation of the 10-min infusion, peak by 2&nbsp;h, and return to baseline 3 to 4&nbsp;h after the infusion. Post-infusion increases in blood pressure are likely to recur in subsequent treatment cycles; however, the severity does not appear to increase with successive cycles. Other cardiovascular adverse events, such as transient, predominantly grade 1-2 tachycardia, bradycardia, QTc prolongation, and in rare cases myocardial ischemia, have also been observed with CA4P but at markedly lower frequencies than hypertension. The clinical trial experience with CA4P suggests that cardiovascular assessment of patients prior to CA4P treatment and careful management of blood pressure during CA4P treatment can largely mitigate the risk of cardiovascular adverse events. Accordingly, we have developed a blood pressure management algorithm for use in the ongoing phase II/III FOCUS study of the triple combination of CA4P with physician's choice chemotherapy and bevacizumab

Clinical trial experience with CA4P anticancer therapy: focus on efficacy, cardiovascular adverse events, and hypertension management.

Combretastatin A4-phosphate (CA4P) is a vascular-disrupting agent (VDA) in clinical development for the treatment of ovarian and other cancers. In contrast to antiangiogenic agents, such as bevacizumab, which suppress the development of new tumor vasculature, VDAs target established tumor vasculature. These differing but complementary mechanisms of action are currently being explored in clinical trials combining CA4P and bevacizumab. Clinical experience to date has highlighted an important need to better understand the cardiovascular adverse events of CA4P, both alone and in combination with antiangiogenic agents, which can also be associated with cardiovascular adverse events. An acute but transient increase in blood pressure is often the most clinically relevant toxicity associated with CA4P. Increases in CA4P-related blood pressure typically occur 0.5 to 1 h after initiation of the 10-min infusion, peak by 2 h, and return to baseline 3 to 4 h after the infusion. Post-infusion increases in blood pressure are likely to recur in subsequent treatment cycles; however, the severity does not appear to increase with successive cycles. Other cardiovascular adverse events, such as transient, predominantly grade 1-2 tachycardia, bradycardia, QTc prolongation, and in rare cases myocardial ischemia, have also been observed with CA4P but at markedly lower frequencies than hypertension. The clinical trial experience with CA4P suggests that cardiovascular assessment of patients prior to CA4P treatment and careful management of blood pressure during CA4P treatment can largely mitigate the risk of cardiovascular adverse events. Accordingly, we have developed a blood pressure management algorithm for use in the ongoing phase II/III FOCUS study of the triple combination of CA4P with physician\u27s choice chemotherapy and bevacizumab