Compelling evidence supports a genetic component to prostate cancer susceptibility and aggressiveness. Recent genome-wide association studies have identified more than 30 single-nucleotide ...polymorphisms associated with prostate cancer susceptibility. It remains unclear, however, whether such genetic variants are associated with disease aggressiveness--one of the most important questions in prostate cancer research today. To help clarify this and substantially expand research in the genetic determinants of prostate cancer aggressiveness, the first National Cancer Institute Prostate Cancer Genetics Workshop assembled researchers to develop plans for a large new research consortium and patient cohort. The workshop reviewed the prior work in this area and addressed the practical issues in planning future studies. With new DNA sequencing technology, the potential application of sequencing information to patient care is emerging. The workshop, therefore, included state-of-the-art presentations by experts on new genotyping technologies, including sequencing and associated bioinformatics issues, which are just beginning to be applied to cancer genetics.
Abstract Obtaining rigorous baseline density estimates of species of conservation interest is key when assisting landowners to achieve management goals on private lands. Northern bobwhite ( Colinus ...virginianus ) populations are declining throughout their range and despite being the focus of numerous private land conservation initiatives, baseline density estimates in privately owned pine forests are lacking. We sought to address this knowledge gap across the Southeastern United States by sampling 105 privately owned pine stands throughout 2018 to 2020 using observer point count and autonomous recording unit (ARU) sampling data. Using Bayesian hierarchical models, we investigated the influence of stand management (brush management or applied fire) on bobwhite density, as well as four landscape‐scale environmental variables. These included percentage cover of forest, herbaceous, agricultural or burnt land area across six different spatial scales ranging from 500‐m to 10‐km around each pine stand. Baseline density on sites with no management was estimated to be 2.24 coveys per 100 ha (1.00–5.03, 95% BCI), with little impact of applying brush management, but a trend for a positive effect of fire management (0.19, −0.01 to 0.38 95% BCI). This impact of fire was seen at both the stand‐scale, correlated with an increase in acreage of applied prescribed burn management, and across the greater landscape area, correlated with cover of burnt area within a 2‐km buffer around each site. There were also strong positive influences of herbaceous vegetation and a strong negative influence of forest cover on bobwhite density. Practical implication: our sampling efforts fill an important information gap regarding densities throughout private lands in the Southeastern United States. Our study also highlights the necessity of landscape scale planning for Northern Bobwhite conservation initiatives because the efficacy of conservation practices (i.e. prescribed fire and brush management) could be altered by the landscape surrounding the treated forest stand.
Genetic studies have identified single nucleotide polymorphisms (SNPs) associated with the risk of prostate cancer (PC). It remains unclear whether such genetic variants are associated with disease ...aggressiveness. The NCI-SPORE Genetics Working Group retrospectively collected clinicopathologic information and genotype data for 36 SNPs which at the time had been validated to be associated with PC risk from 25,674 cases with PC. Cases were grouped according to race, Gleason score (Gleason ≤6, 7, ≥8) and aggressiveness (non-aggressive, intermediate, and aggressive disease). Statistical analyses were used to compare the frequency of the SNPs between different disease cohorts. After adjusting for multiple testing, only PC-risk SNP rs2735839 (G) was significantly and inversely associated with aggressive (OR = 0.77; 95 % CI 0.69–0.87) and high-grade disease (OR = 0.77; 95 % CI 0.68–0.86) in European men. Similar associations with aggressive (OR = 0.72; 95 % CI 0.58–0.89) and high-grade disease (OR = 0.69; 95 % CI 0.54–0.87) were documented in African-American subjects. The G allele of rs2735839 was associated with disease aggressiveness even at low PSA levels (<4.0 ng/mL) in both European and African-American men. Our results provide further support that a PC-risk SNP rs2735839 near the KLK3 gene on chromosome 19q13 may be associated with aggressive and high-grade PC. Future prospectively designed, case-case GWAS are needed to identify additional SNPs associated with PC aggressiveness.
Spinal Muscular Atrophy (SMA) presents challenges in (i) monitoring disease activity and predicting progression, (ii) designing trials that allow rapid assessment of candidate therapies, and (iii) ...understanding molecular causes and consequences of the disease. Validated biomarkers of SMA motor and non-motor function would offer utility in addressing these challenges. Our objectives were (i) to discover additional markers from the Biomarkers for SMA (BforSMA) study using an immunoassay platform, and (ii) to validate the putative biomarkers in an independent cohort of SMA patients collected from a multi-site natural history study (NHS).
BforSMA study plasma samples (N = 129) were analyzed by immunoassay to identify new analytes correlating to SMA motor function. These immunoassays included the strongest candidate biomarkers identified previously by chromatography. We selected 35 biomarkers to validate in an independent cohort SMA type 1, 2, and 3 samples (N = 158) from an SMA NHS. The putative biomarkers were tested for association to multiple motor scales and to pulmonary function, neurophysiology, strength, and quality of life measures. We implemented a Tobit model to predict SMA motor function scores.
12 of the 35 putative SMA biomarkers were significantly associated (p<0.05) with motor function, with a 13(th) analyte being nearly significant. Several other analytes associated with non-motor SMA outcome measures. From these 35 biomarkers, 27 analytes were selected for inclusion in a commercial panel (SMA-MAP) for association with motor and other functional measures.
Discovery and validation using independent cohorts yielded a set of SMA biomarkers significantly associated with motor function and other measures of SMA disease activity. A commercial SMA-MAP biomarker panel was generated for further testing in other SMA collections and interventional trials. Future work includes evaluating the panel in other neuromuscular diseases, for pharmacodynamic responsiveness to experimental SMA therapies, and for predicting functional changes over time in SMA patients.
Abstract
A nationwide tuberculosis outbreak linked to a viable bone allograft product contaminated with Mycobacterium tuberculosis was identified in June 2021. Our subsequent investigation identified ...73 healthcare personnel with new latent tuberculosis infection following exposure to the contaminated product, product recipients, surgical instruments, or medical waste.
Bipolar disorder Bauer, Mark; Unützer, Jürgen; Pincus, Harold A ...
Mental health services research
4, Številka:
4
Journal Article
Recenzirano
Manic-depressive (bipolar) disorder is a severe, relapsing mental illness that shares characterstics both with major depressive disorder and with serious mental illnesses such as schizophrenia. Like ...schizophrenia, it is a chronic disorder, and is treated primarily in the specialty mental health sector. Rates of appropriate treatment are low. Functional outcome is compromised for the majority of individuals who have this disorder. Societal costs are exceeded only by those for schizophrenia. Existing cost calculations likely underestimate societal costs because of underestimating functional impact and neglecting to account for the substantial proportion of individuals who are institutionalized outside of the health care system (e.g., in prison). Little is known as yet regarding manic-depressive disorder in historically underserved groups and in vulnerable groups such as the elderly. There are major lacunae with regard to this disorder in the grant portfolios of all federal agencies mandated to address the needs of Americans with serious mental illnesses. The authors in the context of the Wider NIMH Affective Disorders Workgroup propose several specific recommendations to address the needs of this costly and underresearched disorder.
Corneal epithelial homeostasis and regeneration are sustained by limbal stem cells (LSCs), and LSC deficiency is a major cause of blindness worldwide. Transplantation is often the only therapeutic ...option available to patients with LSC deficiency. However, while transplant success depends foremost on LSC frequency within grafts, a gene allowing for prospective LSC enrichment has not been identified so far5. Here we show that ATP-binding cassette, sub-family B, member 5 (ABCB5) marks LSCs and is required for LSC maintenance, corneal development and repair. Furthermore, we demonstrate that prospectively isolated human or murine ABCB5-positive LSCs possess the exclusive capacity to fully restore the cornea upon grafting to LSC-deficient mice in xenogeneic or syngeneic transplantation models. ABCB5 is preferentially expressed on label-retaining LSCs in mice and p63α-positive LSCs in humans. Consistent with these findings, ABCB5-positive LSC frequency is reduced in LSC-deficient patients. Abcb5 loss of function in Abcb5 knockout mice causes depletion of quiescent LSCs due to enhanced proliferation and apoptosis, and results in defective corneal differentiation and wound healing. Our results from gene knockout studies, LSC tracing and transplantation models, as well as phenotypic and functional analyses of human biopsy specimens, provide converging lines of evidence that ABCB5 identifies mammalian LSCs. Identification and prospective isolation of molecularly defined LSCs with essential functions in corneal development and repair has important implications for the treatment of corneal disease, particularly corneal blindness due to LSC deficiency.
Aquifer overexploitation could significantly impact crop production in the United States because 60% of irrigation relies on groundwater. Groundwater depletion in the irrigated High Plains and ...California Central Valley accounts for ∼50% of groundwater depletion in the United States since 1900. A newly developed High Plains recharge map shows that high recharge in the northern High Plains results in sustainable pumpage, whereas lower recharge in the central and southern High Plains has resulted in focused depletion of 330 km ³ of fossil groundwater, mostly recharged during the past 13,000 y. Depletion is highly localized with about a third of depletion occurring in 4% of the High Plains land area. Extrapolation of the current depletion rate suggests that 35% of the southern High Plains will be unable to support irrigation within the next 30 y. Reducing irrigation withdrawals could extend the lifespan of the aquifer but would not result in sustainable management of this fossil groundwater. The Central Valley is a more dynamic, engineered system, with north/south diversions of surface water since the 1950s contributing to ∼7× higher recharge. However, these diversions are regulated because of impacts on endangered species. A newly developed Central Valley Hydrologic Model shows that groundwater depletion since the 1960s, totaling 80 km ³, occurs mostly in the south (Tulare Basin) and primarily during droughts. Increasing water storage through artificial recharge of excess surface water in aquifers by up to 3 km ³ shows promise for coping with droughts and improving sustainability of groundwater resources in the Central Valley.
Brequinar sodium is a quinoline carboxylic acid derivative that has shown antitumor activity in a number of in vivo murine and human tumor xenograft models. Its mechanism of action is blockade of de ...novo pyrimidine biosynthesis by inhibition of dihydroorotic acid dehydrogenase. In vitro and in vivo studies demonstrate the superiority of prolonged drug exposure in achieving tumor growth inhibition. This phase I study evaluated the administration of brequinar sodium by short, daily i.v. infusion for 5 days repeated every 4 weeks. Fifty-four subjects were enrolled in the study and received drug in doses ranging from 36-300 mg/m2. The dose-limiting toxicities were mucositis and diffuse skin rash. Other toxicities included myelosuppression, nausea, vomiting, malaise, and burning at the infusion site. The maximum tolerated dose on the "daily times 5" schedule was 300 mg/m2. The recommended phase II dose is 250 mg/m2. Pharmacokinetic analysis of the day 1 drug clearance curves in 51 subjects showed slight nonlinearity in the relationship between dose and area under the clearance curve (AUC). The dose versus AUC relationship was well described using a Michaelis-Menten model of brequinar elimination kinetics with Vmax = 45 (micrograms/ml)/h and Km = 123 micrograms. Analysis of the day 5 drug clearance curves revealed a diminution in Vmax to 30 (micrograms/ml)/h. As a consequence of the reduction in Vmax brequinar plasma concentrations on day 5 were higher than predicted from day 1 drug kinetics. Pharmacodynamic analysis of the day 1 kinetic parameters and the toxicities occurring during the first cycle of drug therapy revealed significant correlations between mucositis and dose, AUC, and peak brequinar concentration; between leukopenia and AUC and peak drug concentration; and between thrombocytopenia and beta elimination rate.
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