Arena Pharmaceuticals (United States)

Globally, fourteen percent adolescents suffer from mental health issues. Among the many contributing factors to mental health problems, parenting is considered to have a significant effect on both the physical and psychological health of adolescents. This study aimed to assess depression, anxiety, stress, and self-esteem among adolescents and their relationship with parenting style. A community-based cross-sectional study with multistage proportionate sampling was conducted among 583 school-going adolescents from September 2022 to March 2023 in Bheemdatt Municipality, Kanchanpur, Nepal. This study used the previously validated Depression Anxiety and Stress Scale-21 (DASS-21), Rosenberg Self-Esteem Scale, and Parenting Style and Dimension Questionnaire to assess the status and relationships. Variables were analyzed using a multivariate logistic regression model, and a p-value of <0.05 was considered statistically significant. The prevalence of depression, anxiety, and stress among adolescents was found to be 37.39% (95% CI: 33.46 to 41.32), 42.19% (95% CI: 38.18 to 46.19), and 24.69% (95% CI: 21.18 to 28.19), respectively. Likewise, the mean self-esteem score among adolescents was found to be 22.26 ± 3.56. The authoritative parenting style was positively associated with DAS, while the authoritarian and permissive parenting styles were negatively associated with DAS and positively associated with self-esteem. Parent’s age, parent’s education, social support, and bullying, showed strong effects on the research outcomes. These findings highlight the crucial role of parental involvement and support in shaping adolescent mental health, underscoring the need for interventions that encourage positive parenting practices to improve mental health outcomes for adolescents. It is highly recommended that school-based programs focus on raising awareness of mental health issues and offer interventions such as stress management and student counseling. There is a pressing need to effectively monitor and enforce anti-bullying policies within educational settings.

Heterogeneity in the cell population of cancer tissues poses many challenges in cancer diagnosis and treatment. Studying the heterogeneity in cell populations from gene expression measurement data in the context of cancer research is a problem of paramount importance. In addition, reducing the computation time of the algorithms that deal with high volumes of data has its obvious merits. Parallelizable models using Markov chain Monte Carlo methods are typically slow. This article presents a novel, computationally efficient, and parallelizable model to analyze heterogeneity in cancer tissues using GPUs. Because our model is parallelizable, the input data size does not affect the computation time much, provided the hardware resources are not exhausted. Our model uses qPCR (quantitative polymerase chain reaction) gene expression measurements to study heterogeneity in cancer tissue. We compute the cell proportion breakup by accelerating variational methods on a GPU. We test this model on synthetic and real-world gene expression data collected from fibroblasts and compare the performance of our algorithm with those of Markov chain Monte Carlo and expectation maximization. Our new model is computationally less complex and faster than existing Bayesian models for estimating cancer tissue heterogeneity.

Background and AimsEtrasimod is an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis [UC]. This post-hoc analysis of the phase 2 OASIS trial [NCT02447302] evaluated its efficacy for endoscopic improvement–histologic remission [EIHR] and assessed correlation between faecal calprotectin [FCP] and C-reactive protein [CRP] levels with efficacy outcomes.MethodsIn total, 156 adults with moderately to severely active UC received once-daily etrasimod (1 mg [n = 52]; 2 mg [n = 50]) or placebo [n = 54] for 12 weeks. Clinical, endoscopic, and histologic variables were evaluated at baseline and Week 12. EIHR was defined as achievement of endoscopic improvement [endoscopic subscore ≤ 1, without friability] and histologic remission [Geboes score < 2.0]. Outcomes included the relationships between FCP and CRP concentration and clinical, endoscopic, and histologic variables.ResultsAchievement of EIHR was significantly higher in patients who received etrasimod 2 mg versus placebo [19.5% vs 4.1%; Mantel–Haenszel estimated difference, 15.4%; p = 0.010]. In the etrasimod 2 mg group, median FCP and CRP levels at Week 12 were significantly lower in patients who achieved clinical remission, endoscopic improvement, histologic remission, and EIHR versus patients who did not [all p < 0.05]. An FCP concentration cutoff of 250 µg/g achieved optimum sensitivity and specificity for efficacy, including EIHR [0.857 and 0.786, respectively; κ coefficient, 0.3584]. Higher proportions of patients with FCP ≤ 250 µg/g achieved efficacy outcomes at Week 12 versus patients with FCP > 250 µg/g.ConclusionsEtrasimod was effective for inducing EIHR in patients with UC. FCP and CRP may be useful, noninvasive biomarkers to monitor treatment response.ClinicalTrials.gov numberNCT02447302.

Abstract Oxaloacetate (OAA) inhibits the Warburg effect by reducing the glucose-derived lactate levels in human cancer cell lines. In dose ranging IC50 experiments with human hepatocellular carcinoma (HCC) cell lines, OAA inhibited cell growth in the concentration range 1.7 - 2.4 mM. Previously, we showed that in the presence of OAA, [U-13C]glucose derived lactate was reduced by 48.8% in GBM cells. OAA also increased survival in mouse models of GBM. Here, we are showing an evidence for the direct utilization of OAA by Glioblastoma (GBM) cells, using uniformly 13C-labeled oxaloacetate ([U-13C]OAA) as a metabolic tracer. Patient-derived GBM cells were grown in DMEM medium containing 11.0 mM glucose and 2.0 mM glutamine. When cells reached confluency, were treated with 4.0 mM [U-13C]OAA in the above DMEM medium. GC-MS based 13C isotopomer analysis showed that [U-13C]OAA entered the cells and get metabolized to generate distinct 13C-labeled isotopomers of aspartate, citrate, glutamate, malate and fumarate. Upon entering TCA cycle, [U-13C]OAA generated M+4 aspartate (3.0%) and citrate (3.2%), and M+3 glutamate (4.1%). During the first turn of the TCA cycle, it produced M+2 aspartate (13.9%), malate (10.5%), and fumarate (8.8%), and after multiple turns, [U-13C]OAA led to the production of the following 13C-labeled isotopomers: M+2 citrate (21.5%), M+2 glutamate (17.2%), M+1 glutamate (5.6%) and M+4 glutamate (2.2%). In addition, [U-13C]OAA also produced [U-13C]pyruvate (17.0%) through PEPCK/PK/ or malic enzyme which further generated similar amount of [U-13C]lactate (17.0%) and [U-13C]alanine (12%). These data demonstrate that GBM cells utilize [U-13C]OAA to perturb TCA cycle and glycolytic pathways, and support our previous observation that OAA-derived pyruvate lead to an increase in the total pyruvate pool and associated decrease in glycolytic flux including the glucose-derived lactate. OAA may metabolically reduce tumor growth in difficult to treat cancers.

The ever-increasing use of Internet of Things (IoT) devices results in the implementation of multiple wireless technologies that would not only cater their data rate requirements but also support various applications. To optimize the energy efficiency and security of the wireless transmission, it is imperative to identify the wireless technologies in various IoT implementations. Many of the existing approaches are based on measuring only the receiving signal strength indicator (RSSI). However, such approaches may not work well because of transmit power control and complex channel variations among different wireless technologies. In this article, we propose an autonomous wireless detection scheme that considers multiple distinguishable physical (PHY)-layer settings for real-time identification of wireless technologies for real-time applications. Specifically, the proposed scheme relies on the PHY-layer measurements of the targeted spectrum. Transmission settings, such as bandwidth, carrier frequency, and RSSI are estimated from the raw in-phase and quadrature-phase (I/Q) measurements. In addition, a symbol-level extraction scheme is implemented to extract unique features of modulation settings. These aforementioned features are applied to a machine learning process to identify the received wireless technologies. Compared with raw I/Q measurements, the extracted features are much simplified and, thus, the machine learning classifier can be designed with a simple structure for fast processing on IoT nodes. Finally, the proposed schemes are primarily evaluated theoretically, followed by implementing them on a USRP software-defined radio (SDR)-based hardware testbed. The evaluation results demonstrate high accuracy in the real-time detection of different wireless technologies for seamless IoT applications.

Introduction: Etrasimod (ETR), is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 modulator in development for the treatment of moderately to severely active ulcerative colitis (UC). Previous reports in healthy volunteers demonstrated selective effects of ETR on adaptive immune cell subsets with little effect on innate cells; however, the impact is unknown in patients with UC. Here, we report the effect of ETR on circulating immune cells in adults with moderately to severely active UC from the Phase 3 ELEVATE UC 52 and ELEVATE UC 12 trials. Methods: In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), adults (16-80 years) with moderately to severely active UC and documented history of inadequate response, loss of response, or intolerance to ≥1 treatment for UC were randomized 2:1 to once-daily treatment with ETR 2 mg or placebo (PBO). In this exploratory analysis, whole blood was collected throughout the studies for characterization of immune cell subsets by flow cytometry. Mean (SE) percent change from baseline (in cells/μL) to Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 in ELEVATE UC 52 and Weeks 2, 4, 8, and 12 in ELEVATE UC 12 were compared between ETR 2 mg and PBO using 2-sided t tests. Results: Whole blood from 433 patients in ELEVATE UC 52 (ETR 2 mg, n=289; PBO, n=144) and 349 patients in ELEVATE UC 12 (ETR 2 mg, n=236; PBO, n=113) was included for immunophenotyping. Treatment with ETR 2 mg resulted in rapid mean (SE) percent reductions (in cells/μL) from baseline to Week 2, with nadir or near nadir changes from baseline reached by Week 4 in ELEVATE UC 52 and ELEVATE UC 12, respectively, for total T cells (CD3+: −55.6% [1.50] and −55.9% [1.65]), T helper cells (CD3+CD4+: −71.1% [1.33] and −72.5% [1.30]), cytotoxic T cells (CD3+CD8+: −35.7% [1.94] and −33.8% [2.60]), and B cells (CD3−CD19+: −74.5% [1.05] and −75.2% [1.18]); reductions were maintained through Week 52 in ELEVATE UC 52 and Week 12 in ELEVATE UC 12. There were no notable changes in natural killer cells (CD3−CD56+CD16+) or monocytes (CD14+) during the treatment period of either study. Conclusion: Treatment with ETR has a rapid and differential effect on the frequency of circulating immune cell subsets in peripheral blood in patients with moderately to severely active UC. These findings may help explain the 5 serious infections in PBO and 3 in ETR observed in the ELEVATE UC 52 and ELEVATE UC 12 trials and the balanced overall infection rates across treatment arms in both studies.

<h3>Introduction</h3> Etrasimod (ETR) is a once-daily (QD), oral, selective sphingosine 1-phosphate receptor modulator in clinical development for immune-mediated inflammatory disorders including inflammatory bowel disease (IBD). At diagnosis, ~50% of patients with IBD are &lt;35 years old. Oral contraceptives (OC) are the most common birth control among women in the US. It’s important to ensure an IBD therapy does not impact the pharmacokinetic (PK) or pharmacodynamic (PD) performance of an OC. This study evaluated the effect of coadministration of ETR on the PK and PD performance of a monophasic OC. <h3>Methods</h3> This open-label Phase 1 study enrolled 21 premenopausal healthy females (18-40 years). On Days 1–21 of Period 1 (Days 1–28), participants received OC containing 30mcg ethinylestradiol (EE) and 50mcg levonorgestrel (LVG). On Day 23, participants initiated ETR 2mg QD such that steady-state concentrations were achieved by Day 28 and thereafter. On Days 29–49 of Period 2 (Days 29–50), OC was coadministered with ETR 2mg QD. Samples for measuring the pharmacologically active components of the OC (EE and LVG) were collected over 24 hours on Days 21 and 49. Log-transformed primary PK parameters were calculated and compared using analysis of variance with treatment as fixed effect and participant as random effect. PD markers (follicle-stimulating hormone [FSH], luteinizing hormone [LH], estradiol, progesterone) were measured at baseline (Days 1 and 29) and throughout Periods 1 and 2. Sex hormone–binding globulin (SHBG) levels were measured on Days 1, 21, 29, and 49. Largest ovarian follicle size measured by transvaginal ultrasound (TVUS) and Hoogland score were measured on Days 1, 11, 29, and 39. <h3>Results</h3> Only minor-to-mild increases in EE and LVG C_max,ss and AUC_tau,ss exposure measures were observed when the OC was coadministered with ETR vs when the OC was administered alone (<b>Table</b>). These changes were not considered clinically relevant. Markers of ovarian activity (FSH, LH, estradiol, progesterone, SHBG, TVUS/Hoogland score) demonstrated no clinically relevant impact of coadministration of ETR on the PD performance of the OC. All treatments were generally well tolerated. Most treatment-emergent adverse events (AEs) were mild (grade 1) or moderate (grade 2); 2 participants had severe (grade 3) AEs (attributed to the OC). No abnormalities in laboratory parameters, vital signs, or 12-lead electrocardiogram were noted. <h3>Conclusions</h3> The PK and PD performance of the monophasic OC was not altered to a clinically relevant extent; thus contraceptive efficacy was maintained during coadministration with ETR. ETR and the monophasic OC, administered alone or in combination, were generally well tolerated.

BackgroundCurrently available urate lowering therapies (ULTs) are limited in their use for gout patients with advanced CKD based on dosing restrictions, tolerability, safety concerns, and reduced effectiveness, compared to options for the broader gout population. In gout patients with advanced CKD, the intestinal tract becomes the major route of urate elimination, as opposed to in healthy people with normal kidney function where kidneys are the primary route of uric acid excretion.1 Considering some of the limitations of present urate-lowering therapies (ULTs) in gout & CKD and the extra-renal pathway of urate secretion, a new oral therapy, ALLN-346 (engineered urate oxidase), is under development as a non-absorbed, urate specific enzyme, designed to enhance degradation and secretion of urate in the intestinal tract.2ObjectivesTo assess the safety, tolerability, and initial bioactivity data of ALLN-346 in adults with hyperuricemia and CKD.MethodsThis one-week inpatient Phase 2a study (NCT04987242) was conducted at a clinical pharmacology unit. Eleven otherwise healthy adult patients with hyperuricemia (sUA ≥ 6.8 mg/dL) and normal to Stage 2 CKD (eGFR ≥60), not on concurrent ULTs, were randomized (2:1) to receive either 5 capsules of ALLN-346 or matching placebo, three times daily for 7 days. Serum urate was measured daily, and urine uric acid was assessed on days -2, -1, 1, 4, and 7. Safety was monitored throughout the study. To assess possible ALLN-346 systemic absorption, a specific ELISA was used on serum samples collected pre- and post-dose over 7 days.ResultsOf the 11 patients 7 received ALLN-346 and 4 received placebo. Most patients had Stage 2 CKD, including 5 of the 7 subjects treated with ALLN-346. A statistically significant reduction in mean sUA was recorded with ALLN-346 compared to placebo [Figure 1]. The largest mean % reduction in sUA was observed among patients with stage 2 CKD; sUA reduction was correlated with eGFR in the ALLN-346 group (r=0.95; P=0.003), but not the placebo group (r=-0.2; P=0.91). No serious adverse events were reported, and clinical and laboratory parameters revealed no significant safety signals. Lack of systemic absorption of ALLN-346 was confirmed by ELISA assays.Figure 1.Absolute and Percent Change from Baseline in Serum Urate over 7 -days of TreatmentConclusionIn this study, oral therapy with ALLN-346 for 7 days was well tolerated and resulted in a significant reduction in sUA. Consistent with the known pathophysiologic adaptation of increased intestinal elimination of uric acid in patients with impaired kidney function and the intestinal-based mechanism of action of ALLN-346, there was a strong correlation between the effect of ALLN-346 on sUA reduction and the level of kidney function. The generated data support proof of pharmacology for the intestinal mechanism of action of ALLN-346 to degrade urate either formed or secreted in the gut. Future studies in the larger gout population with CKD are underway.

Localized flushing after alcohol ingestion is a reported adverse effect of 2 topical calcineurin inhibitors, tacrolimus and pimecrolimus, which are approved to treat atopic dermatitis and used off label for other dermatologic conditions. We propose techniques for alleviating this phenomenon.