Infants born at full term have better health outcomes. However, one in ten babies in the United States are born via a medically unnecessary early elective delivery: induction of labor, a cesarean ...section, or both before thirty-nine weeks gestation. In 2011 the Texas Medicaid program sought to reduce the rate of early elective deliveries by denying payment to providers for the procedure. We examined the impact of this policy on clinical care practice and perinatal outcomes by comparing the changes in Texas relative to comparison states. We found that early elective delivery rates fell by as much as 14 percent in Texas after this payment policy change, which led to gains of almost five days in gestational age and six ounces in birthweight among births affected by the policy. The impact on early elective delivery was larger in magnitude for minority patients. Other states may look to this Medicaid payment reform as a model for reducing early elective deliveries and disparities in infant health.
Mass cytometry, or cytometry by TOF (CyTOF), provides a robust means of determining protein-level measurements of more than 40 markers simultaneously. While the functional states of immune cells ...occur along continuous phenotypic transitions, cytometric studies surveying cell phenotypes often rely on static metrics, such as discrete cell-type abundances, based on canonical markers and/or restrictive gating strategies. To overcome this limitation, we applied single-cell trajectory inference and nonnegative matrix factorization methods to CyTOF data to trace the dynamics of T cell states. In the setting of cancer immunotherapy, we showed that patient-specific summaries of continuous phenotypic shifts in T cells could be inferred from peripheral blood-derived CyTOF mass cytometry data. We further illustrated that transfer learning enabled these T cell continuous metrics to be used to estimate patient-specific cell states in new sample cohorts from a reference patient data set. Our work establishes the utility of continuous metrics for CyTOF analysis as tools for translational discovery.
With its Leading-Edge Cluster Competition (in German: Spitzencluster-Wettbewerb; LECC), the Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung, BMBF) is ...supporting innovation clusters in a nationwide contest for the first time. In three waves, 15 cluster initiatives were selected and provided with funds to support them on their way to becoming international leaders in their field of technology. This paper presents the results of empirical studies regarding several important aspects of the LECC. The analysis of network relations shows that the LECC's short-term goal of intensifying or enhancing networking between innovative stakeholders in the cluster regions has been achieved. At the same time, certain types of regional impulses of the LECC can already be observed, primarily an improved visibility of the Leading-Edge Cluster regions and enhanced regional R&D activity. When looking at causal programme effects, we find that the programme increases firm-level R&D expenditure, but also that the programme design influences the programme impulse, e.g. by promoting additional activities of SMEs.
Abstract Objective The objective of this study was to examine cognitive and quality-of-life measures/quality of life outcomes with adjunctive lacosamide therapy in patients with treatment-resistant ...partial epilepsy. Methods This was a prospective, open-label, nonblinded, adjunctive therapy test–retest (within subjects) study of patients with treatment-resistant partial epilepsy in which outcome (cognitive functioning and mood/quality of life) was measured in the same subject before and after adjunctive lacosamide administration for 24 weeks. The cognitive assessment included the following: Controlled Oral Word Association Test, Buschke Selective Reminding Test, Brief Visuospatial Memory Test—Revised, Stroop Color Word Test, Symbol Digit Modalities Test, Digit Span, Digit Cancellation, and Trails A and B. The quality-of-life measures/quality-of-life assessment included the following: Beck Depression Inventory—II, Profile of Mood States, and Quality of Life Inventory—89. Lacosamide was started at 100 mg (50 mg twice daily) and could be titrated as needed up to 400 mg/day (200 mg twice daily). Baseline concomitant AEDs were kept constant. Composite scores were calculated for a pre–post difference score for the cognitive and mood/quality-of-life measures separately and used in regression analyses to correct for the effects of age, education, seizure frequency, seizure severity, dose of lacosamide, and number of AEDs at baseline. Results Thirty-four patients were enrolled (13 males, 21 females). Mean age was 38.8 ± 2.43 years. Mean seizure frequency decreased significantly from 2.0 ± 2.55 seizures per week at baseline to 1.02 ± 1.72 seizures per week at posttreatment (t = 4.59, p < .0001) with a 50% responder rate seen in 18 patients (52.9%). No significant differences were found on the composite scores of the cognitive or the mood/quality-of-life measures after 6 months of lacosamide. Significance Lacosamide appeared to have low risks of significant changes in cognition or mood/quality of life. In addition, the present study supports prior studies that have proven lacosamide as an effective adjunctive therapy for the treatment of resistant partial epilepsy.
It remains unclear whether causal, rather than merely correlational, relationships in molecular networks can be inferred in complex biological settings. Here we describe the HPN-DREAM network ...inference challenge, which focused on learning causal influences in signaling networks. We used phosphoprotein data from cancer cell lines as well as in silico data from a nonlinear dynamical model. Using the phosphoprotein data, we scored more than 2,000 networks submitted by challenge participants. The networks spanned 32 biological contexts and were scored in terms of causal validity with respect to unseen interventional data. A number of approaches were effective, and incorporating known biology was generally advantageous. Additional sub-challenges considered time-course prediction and visualization. Our results suggest that learning causal relationships may be feasible in complex settings such as disease states. Furthermore, our scoring approach provides a practical way to empirically assess inferred molecular networks in a causal sense.
Background: Despite advances in developing medications to treat alcohol dependence, few such medications have been approved by the Food and Drug Administration. Identified molecular targets are ...encouraging and can lead to the development and testing of new compounds. Atypical antipsychotic medications have been explored with varying results. Prior research suggests that the antipsychotic quetiapine may be beneficial in an alcohol‐dependent population of very heavy drinkers.
Methods: In this double‐blind, placebo‐controlled trial, 224 alcohol‐dependent patients who reported very heavy drinking were recruited across 5 clinical sites. Patients received either quetiapine or placebo and Medical Management behavioral intervention. Patients were stratified on gender, clinical site, and reduction in drinking prior to randomization.
Results: No differences between the quetiapine and placebo groups were detected in the primary outcome, percentage heavy‐drinking days, or other drinking outcomes. Quetiapine significantly reduced depressive symptoms and improved sleep but had no effect on other nondrinking outcomes. Results from a subgroup analysis suggest that patients who reduced their drinking prior to randomization had significantly better drinking outcomes during the maintenance phase (p < 0.0001). No significant interactions, however, were observed between reducer status and treatment group. Finally, quetiapine was generally well tolerated. Statistically significant adverse events that were more common with quetiapine versus placebo include dizziness (14 vs. 4%), dry mouth (32 vs. 9%), dyspepsia (13 vs. 2%), increased appetite (11 vs. 1%), sedation (15 vs. 3%), and somnolence (34 vs. 9%).
Conclusions: This multisite clinical trial showed no efficacy for quetiapine compared with placebo at reducing alcohol consumption in heavy‐drinking alcohol‐dependent patients.
The scaling exponent (ScE) of the ventricular fibrillation (VF) waveform correlates with duration of VF and predicts defibrillation outcome. We compared 4 therapeutic approaches to the treatment of ...VF of various durations.
Seventy-two swine (19.5 to 25.7 kg) were randomly assigned to 1 of 9 groups (n=8 each). VF was induced and left untreated until the ScE reached 1.10, 1.20, 1.30, or 1.40. Animals were treated with either immediate countershock (IC); 3 minutes of CPR before the first countershock (CPR); CPR for 2 minutes, then drugs given with 3 more minutes of CPR before the first shock (CPR-D); or drugs given at the start of CPR with 3 minutes of CPR before the first shock (Drugs+CPR). Return of spontaneous circulation (ROSC) and 1-hour survival were analyzed with chi2 and Kaplan-Meier survival curves. IC was effective when the ScE was low but had decreasing success as the ScE increased. No animals in the 1.30 or 1.40 groups had ROSC from IC (0 of 16). CPR did not improve first shock outcome in the 1.20 CPR group (3 of 8 ROSC). Kaplan-Meier survival analyses indicated that IC significantly delayed time to ROSC in both the 1.3 (P=0.0006) and the 1.4 (P=0.005) groups.
VF of brief to moderate duration is effectively treated by IC. When VF is prolonged, as indicated by an ScE of 1.3 or greater, IC was not effective and delayed time to ROSC. The ScE can help in choosing the first intervention in the treatment of VF.
Mutations in the androgen receptor (AR), that alter steroid hormone specificity have been identified in a series of androgen-independent prostate cancers. To address the functional properties of ...these mutant ARs that may have contributed to their selection in vivo, responses to a series of steroid hormones and antiandrogens were assessed. CV-1 cells were cotransfected with wild-type or mutant ARs and a luciferase reporter plasmid regulated by an androgen-responsive element. Dose-response curves were analyzed for 5alpha-dihydrotestosterone, the most active androgen in normal prostate, and androstenedione, a major androgen derived from the adrenals. Although the mutant ARs responded to both of these steroids, the responses were equivalent to or less than the wild-type AR. In contrast, responses to flutamide, a competitive antagonist of the wild-type AR, were markedly increased by three of the mutations. Similar responses were observed with a second antiandrogen, nilutamide. Bicalutamide, another antiandrogen related to flutamide, remained an antagonist for these mutant ARs. Finally, flutamide was observed to be a weak partial agonist of the wild-type AR in this system. These results indicate that flutamide used in conjunction with androgen ablation therapy for prostate cancer may select for tumor cells with flutamide-inducible ARs.
Tumor suppressor genes (TSGs) are commonly inactivated by somatic mutation and/or promoter methylation; yet, recent high-throughput genomic studies have not identified key TSGs inactivated by both ...mechanisms. We pursued an integrated molecular analysis based on methylation binding domain sequencing (MBD-seq), 450K Methylation arrays, whole exome sequencing, and whole genome gene expression arrays in primary head and neck squamous cell carcinoma (HNSCC) tumors and matched uvulopalatopharyngoplasty tissue samples (UPPPs). We uncovered 186 downregulated genes harboring cancer specific promoter methylation including PAX1 and PAX5 and we identified 10 key tumor suppressor genes (GABRB3, HOXC12, PARP15, SLCO4C1, CDKN2A, PAX1, PIK3AP1, HOXC6, PLCB1, and ZIC4) inactivated by both promoter methylation and/or somatic mutation. Among the novel tumor suppressor genes discovered with dual mechanisms of inactivation, we found a high frequency of genomic and epigenomic alterations in the PAX gene family of transcription factors, which selectively impact canonical NOTCH and TP53 pathways to determine cell fate, cell survival, and genome maintenance. Our results highlight the importance of assessing TSGs at the genomic and epigenomic level to identify key pathways in HNSCC, deregulated by simultaneous promoter methylation and somatic mutations.
BackgroundChimeric antigen receptor (CAR) T cell therapy has transformed the landscape of hematologic malignancy treatment. However, its successful translation to solid cancer treatment remains ...challenging, primarily due to the immunosuppressive tumor microenvironment (TME). Prostaglandin E2 (PGE2) has emerged as a pivotal player in TME immunosuppression, whereby its impact on T cell function has been recognized as a novel immune checkpoint. This study focuses on enhancing CAR T cell efficacy against solid tumors by disrupting PGE2 signaling through the targeted knockout of its receptors, EP2 and EP4.Materials and MethodsUtilizing CRISPR/Cas9 technology, we generated double knockout CAR T cells deficient in EP2 and EP4. In vitro analyses assessed the impact of PGE2 on CAR T cell functions, including proliferation, activation, and cytotoxicity. To translate these findings to a human system, we conducted tumor growth and survival experiments using a xenograft mouse model. Additionally, T cell tracking was performed to elucidate the fate of EP2-/-EP4-/- CAR T cells in vivo.ResultsWe could successfully generate murine as well as human EP2 and EP4 single and double knockout CAR T cells, which showed complete abrogation of PGE2 signaling, as indicated by suppressed cAMP production and CREB phosphorylation. While wild type CAR T cells were suppressed in their proliferative abilities by PGE2, their capacity to become activated remained unaffected. PGE2-induced reduction in CAR T cell numbers ultimately compromised their anti-tumor activity both in vitro and in vivo. This effect was rescued by the EP2 and EP4 double knockout, leading to increased EP2-/-EP4-/- T cell accumulation within tumors. As a consequence, bettered therapeutic efficacy and prolonged survival were achieved in a xenograft mouse model.ConclusionsOur findings underscore the detrimental impact of PGE2-mediated suppression on CAR T cell efficacy in the TME, highlighting the potential to rescue therapeutic cells through EP2 and EP4 knockout. Notably, single knockouts of either receptor proved insufficient to shield CAR T cells from PGE2. Genetic ablation of EP2 and EP4 presents a promising strategy to shield CAR T cells from PGE2 without disrupting healthy PGE2 signaling and encourages further exploration and development of this novel therapeutic strategy. J. Dörr: None. L. Gregor: None. S.B. Lacher: None. A. Öner: None. S. Lesch: None. S. Michaelides: None. L. Majed: None. L. Fertig: None. E. Carlini: None. D. Andreu Sanz: None. D. Briukhovetska: None. S. Stock: None. A. Gottschlich: None. J.P. Böttcher: None. S. Kobold: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Significant; TCR2 Inc, Catalym, Plectonic, Arcus Biosciences, Tabby Therapeutics. D. Speakers Bureau/Honoraria (speakers bureau, symposia, and expert witness); Significant; GSK, BMS, Novartis, Miltenyi Biotherapeutics, TCR2 Inc. E. Ownership Interest (stock, stock options, patent or other intellectual property); Significant; TCR2 Inc, Carina Biotech.
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