Differential Platelet Levels Affect Response to Taxane-Based Therapy in Ovarian Cancer

We hypothesized that platelet levels during therapy could serve as a biomarker for response to therapy and that manipulation of platelet levels could impact responsiveness to chemotherapy

\u3cem\u3eABCC9\u3c/em\u3e Gene Polymorphism Is Associated with Hippocampal Sclerosis of Aging Pathology

Hippocampal sclerosis of aging (HS-Aging) is a high-morbidity brain disease in the elderly but risk factors are largely unknown. We report the first genome-wide association study (GWAS) with HS-Aging pathology as an endophenotype. In collaboration with the Alzheimer\u27s Disease Genetics Consortium, data were analyzed from large autopsy cohorts: (#1) National Alzheimer\u27s Coordinating Center (NACC); (#2) Rush University Religious Orders Study and Memory and Aging Project; (#3) Group Health Research Institute Adult Changes in Thought study; (#4) University of California at Irvine 90+ Study; and (#5) University of Kentucky Alzheimer\u27s Disease Center. Altogether, 363 HS-Aging cases and 2,303 controls, all pathologically confirmed, provided statistical power to test for risk alleles with large effect size. A two-tier study design included GWAS from cohorts #1-3 (Stage I) to identify promising SNP candidates, followed by focused evaluation of particular SNPs in cohorts #4-5 (Stage II). Polymorphism in the ATP-binding cassette, sub-family C member 9 (ABCC9) gene, also known as sulfonylurea receptor 2, was associated with HS-Aging pathology. In the meta-analyzed Stage I GWAS, ABCC9 polymorphisms yielded the lowest p values, and factoring in the Stage II results, the meta-analyzed risk SNP (rs704178:G) attained genome-wide statistical significance (p = 1.4 × 10-9), with odds ratio (OR) of 2.13 (recessive mode of inheritance). For SNPs previously linked to hippocampal sclerosis, meta-analyses of Stage I results show OR = 1.16 for rs5848 (GRN) and OR = 1.22 rs1990622 (TMEM106B), with the risk alleles as previously described. Sulfonylureas, a widely prescribed drug class used to treat diabetes, also modify human ABCC9 protein function. A subsample of patients from the NACC database (n = 624) were identified who were older than age 85 at death with known drug history. Controlling for important confounders such as diabetes itself, exposure to a sulfonylurea drug was associated with risk for HS-Aging pathology (p = 0.03). Thus, we describe a novel and targetable dementia risk factor

Revisiting the HD 21749 planetary system with stellar activity modelling

HD 21749 is a bright (V = 8.1 mag) K dwarf at 16 pc known to host an inner terrestrial planet HD 21749c as well as an outer sub-Neptune HD 21749b, both delivered by Transiting Exoplanet Survey Satellite (TESS). Follow-up spectroscopic observations measured the mass of HD 21749b to be 22.7 ± 2.2 M with a density of 7.0^{+1.6}_{-1.3} g cm-3, making it one of the densest sub-Neptunes. However, the mass measurement was suspected to be influenced by stellar rotation. Here, we present new high-cadence PFS RV data to disentangle the stellar activity signal from the planetary signal. We find that HD 21749 has a similar rotational time-scale as the planet's orbital period, and the amplitude of the planetary orbital RV signal is estimated to be similar to that of the stellar activity signal. We perform Gaussian process regression on the photometry and RVs from HARPS and PFS to model the stellar activity signal. Our new models reveal that HD 21749b has a radius of 2.86 ± 0.20 R, an orbital period of 35.6133 ± 0.0005 d with a mass of Mb = 20.0 ± 2.7 M and a density of 4.8^{+2.0}_{-1.4} g cm-3 on an eccentric orbit with e = 0.16 ± 0.06, which is consistent with the most recent values published for this system. HD 21749c has an orbital period of 7.7902 ± 0.0006 d, a radius of 1.13 ± 0.10 R, and a 3σ mass upper limit of 3.5 M. Our Monte Carlo simulations confirm that without properly taking stellar activity signals into account, the mass measurement of HD 21749b is likely to arrive at a significantly underestimated error bar

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Valuing student and community voices in the university : action research as a framework for community service-learning

The Community Service-learning Lab (the Lab) was initiated as a university-wide service-learning experience at an Australian university. The Lab engages students, academics, and key community organisations in interdisciplinary action research projects to support student learning and to explore complex and ongoing problems nominated by the community partners. The current study uses feedback from the first offering of the Lab and focuses on exploring student experiences of the service learning project using an action research framework. Student reflections on this experience have revealed some positive outcomes of the Lab such as an appreciation for positive and strengths-based change. These outcomes are corroborated by collected reflections from community partners and academics. The students also identified challenges balancing the requirements for assessment and their goals to serve the community partner’s needs. This feedback has provided vital information for the academic team, highlighting the difficulties in balancing the agenda of the academic framework and the desire to give students authentic experiences