A phase 2, multicenter, open‐label study of sepantronium bromide (YM155) plus docetaxel in patients with stage III (unresectable) or stage IV melanoma

Survivin is a microtubule‐associated protein believed to be involved in preserving cell viability and regulating tumor cell mitosis, and it is overexpressed in many primary tumor types, including melanoma. YM155 is a first‐in‐class survivin suppressant. The purpose of this Phase 2 study was to evaluate the 6‐month progression‐free survival (PFS) rate in patients with unresectable Stage III or IV melanoma receiving a combination of YM155 plus docetaxel. The study had two parts: Part 1 established the dose of docetaxel that was tolerable in combination with YM155, and Part 2 evaluated the tolerable docetaxel dose (75 mg/m2) in combination with YM155 (5 mg/m2 per day continuous infusion over 168 h every 3 weeks). The primary endpoint was 6‐month PFS rate. Secondary endpoints were objective response rate (ORR), 1‐year overall survival (OS) rate, time from first response to progression, clinical benefit rate (CBR), and safety. Sixty‐four patients with metastatic melanoma were treated with docetaxel and YM155. Eight patients received an initial docetaxel dose of 100 mg/m2 and 56 patients received 75 mg/m2 of docetaxel. Six‐month PFS rate per Independent Review Committee (IRC) was 34.8% (n = 64; 95% CI, 21.3–48.6%), and per Investigator was 31.3% (n = 64; 95% CI, 19.5–43.9%). The best ORR (complete response [CR] + partial response [PR]) per IRC was 12.5% (8/64). The stable disease (SD) rate was 51.6% (33/64), leading to a CBR (CR + PR + SD) of 64.1% (41/64). Estimated probability of 1‐year survival was 56.3%. YM155 is a novel agent showing modest activity when combined with docetaxel for treating patients with melanoma. YM155 was generally well tolerated, but the predetermined primary efficacy endpoint (i.e., 6‐month PFS rate ≥20%) was not achieved.YM155 is a first‐in‐class agent that suppresses surviving. Though YM155 combined with docetaxel was generally well‐tolerated in this study, it showed limited efficacy in the treatment of metastatic melanoma.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111757/1/cam4363.pd

A Phase 2b Randomised Trial of the Candidate Malaria Vaccines FP9 ME-TRAP and MVA ME-TRAP among Children in Kenya

OBJECTIVE: The objective was to measure the efficacy of the vaccination regimen FFM ME-TRAP in preventing episodes of clinical malaria among children in a malaria endemic area. FFM ME-TRAP is sequential immunisation with two attenuated poxvirus vectors (FP9 and modified vaccinia virus Ankara), which both deliver the pre-erythrocytic malaria antigen construct multiple epitope–thrombospondin-related adhesion protein (ME-TRAP). DESIGN: The trial was randomised and double-blinded. SETTING: The setting was a rural, malaria-endemic area of coastal Kenya. PARTICIPANTS: We vaccinated 405 healthy 1- to 6-year-old children. INTERVENTIONS: Participants were randomised to vaccination with either FFM ME-TRAP or control (rabies vaccine). OUTCOME MEASURES: Following antimalarial drug treatment children were seen weekly and whenever they were unwell during nine months of monitoring. The axillary temperature was measured, and blood films taken when febrile. The primary analysis was time to a parasitaemia of over 2,500 parasites/μl. RESULTS: The regime was moderately immunogenic, but the magnitude of T cell responses was lower than in previous studies. In intention to treat (ITT) analysis, time to first episode was shorter in the FFM ME-TRAP group. The cumulative incidence of febrile malaria was 52/190 (27%) for FFM ME-TRAP and 40/197 (20%) among controls (hazard ratio = 1.52). This was not statistically significant (95% confidence interval [CI] 1.0–2.3; p = 0.14 by log-rank). A group of 346 children were vaccinated according to protocol (ATP). Among these children, the hazard ratio was 1.3 (95% CI 0.8–2.1; p = 0.55 by log-rank). When multiple malaria episodes were included in the analyses, the incidence rate ratios were 1.6 (95% CI 1.1–2.3); p = 0.017 for ITT, and 1.4 (95% CI 0.9–2.1); p = 0.16 for ATP. Haemoglobin and parasitaemia in cross-sectional surveys at 3 and 9 mo did not differ by treatment group. Among children vaccinated with FFM ME-TRAP, there was no correlation between immunogenicity and malaria incidence. CONCLUSIONS: No protection was induced against febrile malaria by this vaccine regimen. Future field studies will require vaccinations with stronger immunogenicity in children living in malarious areas

A New Analysis of 8 Spitzer Phase Curves and Hot Jupiter Population Trends: Qatar-1b, Qatar-2b, WASP-52b, WASP-34b, and WASP-140b

With over 30 phase curves observed during the warm Spitzer mission, the complete data set provides a wealth of information relating to trends and three-dimensional properties of hot Jupiter atmospheres. In this work we present a comparative study of seven new Spitzer phase curves for four planets with equilibrium temperatures of T$_{eq}\sim$ 1300K: Qatar-2b, WASP-52b, WASP-34b, and WASP-140b, as well as the reanalysis of the 4.5 \micron Qatar-1b phase curve due to the similar equilibrium temperature. In total, five 4.5 \micron phase curves and three 3.6 \micron phase curves are analyzed here with a uniform approach. Using these new results, in combination with literature values for the entire population of published Spitzer phase curves of hot Jupiters, we present evidence for a linear trend of increasing hot spot offset with increasing orbital period, as well as observational evidence for two classes of planets in apparent redistribution vs. equilibrium temperature parameter space, and tentative evidence for a dependence of hot spot offset on planetary surface gravity in our $\sim$ 1300 K sample. We do not find trends in apparent heat redistribution with orbital period or gravity. Non-uniformity in literature Spitzer data analysis techniques precludes a definitive determination of the sources or lack of trends.Comment: 22 pages, 13 figures, 6 tables. Accepted for publication in AAS journal

Smaller than expected bright-spot offsets in Spitzer phase curves of the hot Jupiter Qatar-1b

We present \textit{Spitzer} full-orbit thermal phase curves of the hot Jupiter Qatar-1b, a planet with the same equilibrium temperature---and intermediate surface gravity and orbital period---as the well-studied planets HD 209458b and WASP-43b. We measure secondary eclipse of $0.21 \pm 0.02 \%$ at $3.6~\mu$m and $0.30 \pm 0.02 \%$ at $4.5~\mu$m, corresponding to dayside brightness temperatures of $1542^{+32}_{-31}$~K and $1557^{+35}_{-36}$~K, respectively, consistent with a vertically isothermal dayside. The respective nightside brightness temperatures are $1117^{+76}_{-71}$~K and $1167^{+69}_{-74}$~K, in line with a trend that hot Jupiters all have similar nightside temperatures. We infer a Bond albedo of $0.12_{-0.16}^{+0.14}$ and a moderate day-night heat recirculation efficiency, similar to HD 209458b. General circulation models for HD 209458b and WASP-43b predict that their bright-spots should be shifted east of the substellar point by tens of degrees, and these predictions were previously confirmed with \textit{Spitzer} full-orbit phase curve observations. The phase curves of Qatar-1b are likewise expected to exhibit eastward offsets. Instead, the observed phase curves are consistent with no offset: $11^{\circ}\pm 7^{\circ}$ at $3.6~\mu$m and $-4^{\circ}\pm 7^{\circ}$ at $4.5~\mu$m. The discrepancy in circulation patterns between these three otherwise similar planets points to the importance of secondary parameters like rotation rate and surface gravity, and the presence or absence of clouds, in determining atmospheric conditions on hot Jupiters.Comment: 14 pages, 8 figures. Accepted for publication in A

Identification, replication, and fine-mapping of loci associated with adult height in individuals of African ancestry

Adult height is a classic polygenic trait of high heritability (h 2 ~0.8). More than 180 single nucleotide polymorphisms (SNPs), identified mostly in populations of European descent, are associated with height. These variants convey modest effects and explain ~10% of the variance in height. Discovery efforts in other populations, while limited, have revealed loci for height not previously implicated in individuals of European ancestry. Here, we performed a meta-analysis of genome-wide association (GWA) results for adult height in 20,427 individuals of African ancestry with replication in up to 16,436 African Americans. We found two novel height loci (Xp22-rs12393627, P = 3.4×10 -12 and 2p14-rs4315565, P = 1.2×10 -8). As a group, height associations discovered in European-ancestry samples replicate in individuals of African ancestry (P = 1.7×10 -4 for overall replication). Fine-mapping of the European height loci in African-ancestry individuals showed an enrichment of SNPs that are associated with expression of nearby genes when compared to the index European height SNPs (P\u3c0.01). Our results highlight the utility of genetic studies in non-European populations to understand the etiology of complex human diseases and traits. © 2011 N\u27Diaye et al

Pathobiological signatures of dysbiotic lung injury in pediatric patients undergoing stem cell transplantation.

Hematopoietic cell transplantation (HCT) uses cytotoxic chemotherapy and/or radiation followed by intravenous infusion of stem cells to cure malignancies, bone marrow failure and inborn errors of immunity, hemoglobin and metabolism. Lung injury is a known complication of the process, due in part to disruption in the pulmonary microenvironment by insults such as infection, alloreactive inflammation and cellular toxicity. How microorganisms, immunity and the respiratory epithelium interact to contribute to lung injury is uncertain, limiting the development of prevention and treatment strategies. Here we used 278 bronchoalveolar lavage (BAL) fluid samples to study the lung microenvironment in 229 pediatric patients who have undergone HCT treated at 32 childrens hospitals between 2014 and 2022. By leveraging paired microbiome and human gene expression data, we identified high-risk BAL compositions associated with in-hospital mortality (P = 0.007). Disadvantageous profiles included bacterial overgrowth with neutrophilic inflammation, microbiome contraction with epithelial fibroproliferation and profound commensal depletion with viral and staphylococcal enrichment, lymphocytic activation and cellular injury, and were replicated in an independent cohort from the Netherlands (P = 0.022). In addition, a broad array of previously occult pathogens was identified, as well as a strong link between antibiotic exposure, commensal bacterial depletion and enrichment of viruses and fungi. Together these lung-immune system-microorganism interactions clarify the important drivers of fatal lung injury in pediatric patients who have undergone HCT. Further investigation is needed to determine how personalized interpretation of heterogeneous pulmonary microenvironments may be used to improve pediatric HCT outcomes

Prior knowledge transfer across transcriptional data sets and technologies using compositional statistics yields new mislabelled ovarian cell line

Here, we describe gene expression compositional assignment (GECA), a powerful, yet simple method based on compositional statistics that can validate the transfer of prior knowledge, such as gene lists, into independent data sets, platforms and technologies. Transcriptional profiling has been used to derive gene lists that stratify patients into prognostic molecular subgroups and assess biomarker performance in the pre-clinical setting. Archived public data sets are an invaluable resource for subsequent in silico validation, though their use can lead to data integration issues. We show that GECA can be used without the need for normalising expression levels between data sets and can outperform rank-based correlation methods. To validate GECA, we demonstrate its success in the cross-platform transfer of gene lists in different domains including: bladder cancer staging, tumour site of origin and mislabelled cell lines. We also show its effectiveness in transferring an epithelial ovarian cancer prognostic gene signature across technologies, from a microarray to a next-generation sequencing setting. In a final case study, we predict the tumour site of origin and histopathology of epithelial ovarian cancer cell lines. In particular, we identify and validate the commonly-used cell line OVCAR-5 as non-ovarian, being gastrointestinal in origin. GECA is available as an open-source R package

Genome-Wide Association of Bipolar Disorder Suggests an Enrichment of Replicable Associations in Regions near Genes

Although a highly heritable and disabling disease, bipolar disorder's (BD) genetic variants have been challenging to identify. We present new genotype data for 1,190 cases and 401 controls and perform a genome-wide association study including additional samples for a total of 2,191 cases and 1,434 controls. We do not detect genome-wide significant associations for individual loci; however, across all SNPs, we show an association between the power to detect effects calculated from a previous genome-wide association study and evidence for replication (P = 1.5×10−7). To demonstrate that this result is not likely to be a false positive, we analyze replication rates in a large meta-analysis of height and show that, in a large enough study, associations replicate as a function of power, approaching a linear relationship. Within BD, SNPs near exons exhibit a greater probability of replication, supporting an enrichment of reproducible associations near functional regions of genes. These results indicate that there is likely common genetic variation associated with BD near exons (±10 kb) that could be identified in larger studies and, further, provide a framework for assessing the potential for replication when combining results from multiple studies