Medulloblastoma: Improving cure rates in tandem with reduction in short-term toxicities and long-term treatment-related morbidities.
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ABSTRACT:
SUBMITTER: Gajjar A
PROVIDER: S-EPMC8637651 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:To study rates and predictors of hepatitis C virus (HCV) cure among human immunodeficiency virus (HIV)/HCV-coinfected patients, and then to evaluate the effect of attendance at clinic visits on HCV cure.Retrospective cohort study of adult HIV/HCV-coinfected patients who initiated and completed treatment for HCV with direct-acting antivirals (DAAs) between January 1, 2014, and June 30, 2015.Eighty-four participants reported completing treatment. The median age was 58 years (interquartile ratio, 50-66); 88% were male and 50% were black. One-third were cirrhotic and half were HCV-treatment-experienced. The most commonly used regimen was sofosbuvir/ledipasvir (40%) followed by simeprevir/sofosbuvir (30%). Cure was achieved in 83.3%, 11.9% relapsed, and 2.3% experienced virological breakthrough. Two patients (2.3%) did not complete treatment based on pill counts and follow-up visit documentation. In multivariable analysis, cure was associated with attendance at follow-up clinic visits (odds ratio [OR], 9.0; 95% CI, 2.91-163) and with use of an integrase-based HIV regimen versus other non-integrase regimens, such as non-nucleoside analogues or protease inhibitors (OR, 6.22; 95% CI 1.81-141). Age, race, genotype, presence of cirrhosis, prior HCV treatment, HCV regimen, and pre-treatment CD4 counts were not associated with cure.Real-world HCV cure rates with DAAs in HCV/HIV coinfection are lower than those seen in clinical trials. Cure is associated with attendance at follow-up clinic visits and with use of an integrase-based HIV regimen. Future studies should evaluate best antiretroviral regimens, predictors of attendance at follow-up visits, impact of different monitoring protocols on medication adherence, and interventions to ensure adequate models of HIV/HCV care.
| S-EPMC5942559 | biostudies-literature
Project description:BackgroundAberrant hedgehog (HH) signaling is implicated in the development of various cancer entities such as medulloblastoma. Activation of GLI transcription factors was revealed as the driving force upon pathway activation. Increased phosphorylation of essential effectors such as Smoothened (SMO) and GLI proteins by kinases including Protein Kinase A, Casein Kinase 1, and Glycogen Synthase Kinase 3 β controls effector activity, stability and processing. However, a deeper and more comprehensive understanding of phosphorylation in the signal transduction remains unclear, particularly during early response processes involved in SMO activation and preceding GLI target gene regulation.MethodsWe applied temporal quantitative phosphoproteomics to reveal phosphorylation dynamics underlying the short-term chemical activation and inhibition of early hedgehog signaling in HH responsive human medulloblastoma cells. Medulloblastoma cells were treated for 5.0 and 15 min with Smoothened Agonist (SAG) to induce and with vismodegib to inhibit the HH pathway.ResultsOur phosphoproteomic profiling resulted in the quantification of 7700 and 10,000 phosphosites after 5.0 and 15 min treatment, respectively. The data suggest a central role of phosphorylation in the regulation of ciliary assembly, trafficking, and signal transduction already after 5.0 min treatment. ERK/MAPK signaling, besides Protein Kinase A signaling and mTOR signaling, were differentially regulated after short-term treatment. Activation of Polo-like Kinase 1 and inhibition of Casein Kinase 2A1 were characteristic for vismodegib treatment, while SAG treatment induced Aurora Kinase A activity. Distinctive phosphorylation of central players of HH signaling such as SMO, SUFU, GLI2 and GLI3 was observed only after 15 min treatment.ConclusionsThis study provides evidence that phosphorylation triggered in response to SMO modulation dictates the localization of hedgehog pathway components within the primary cilium and affects the regulation of the SMO-SUFU-GLI axis. The data are relevant for the development of targeted therapies of HH-associated cancers including sonic HH-type medulloblastoma. A deeper understanding of the mechanisms of action of SMO inhibitors such as vismodegib may lead to the development of compounds causing fewer adverse effects and lower frequencies of drug resistance. Video Abstract.
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Project description:Bacterial vaginosis (BV) is one of the great enigmas in women's health, a common condition of unknown aetiology, which is associated with significant morbidity and unacceptably high recurrence rates. While it remains unclear whether BV recurrence is predominantly due to failure of current antibiotic regimens to eradicate BV-associated bacteria (BVAB) and biofilm, a failure of some women to re-establish a resilient Lactobacillus-dominant vaginal microbiota, reinfection from sexual partners, or a combination of these factors, it is inherently challenging to make significant inroads towards this goal. In this review, we will outline why BV is such a clinical and epidemiologic conundrum, and focus on several key approaches that we believe merit discussion and clinical research, including strategies to: i) prevent reinfection (partner treatment trials), ii) boost favourable vaginal Lactobacillus species and promote a Lactobacillus-dominant vaginal microbiome (hormonal contraceptive and probiotic trials) and iii) disrupt vaginal BV-associated biofilm.
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Project description:We show that, statistically, the simple linear regression (SLR)-determined rate of temporal change in seawater pH (?pH), the so-called acidification rate, can be expressed as a linear combination of a constant (the estimated rate of temporal change in pH) and SLR-determined rates of temporal changes in other variables (deviation largely due to various sampling distributions), despite complications due to different observation durations and temporal sampling distributions. Observations show that five time series data sets worldwide, with observation times from 9 to 23 years, have yielded ?pH values that vary from 1.61 × 10(-3) to -2.5 × 10(-3) pH unit yr(-1). After correcting for the deviation, these data now all yield an acidification rate similar to what is expected under the air-sea CO2 equilibrium (-1.6 × 10(-3)?~?-1.8 × 10(-3) pH unit yr(-1)). Although long-term time series stations may have evenly distributed datasets, shorter time series may suffer large errors which are correctable by this method.
| S-EPMC4648385 | biostudies-literature
Project description:Short tandem repeats (STRs) are hotspots of genomic variability in the human germline because of their high mutation rates, which have long been attributed largely to polymerase slippage during DNA replication. This model suggests that STR mutation rates should scale linearly with a father's age, as progenitor cells continually divide after puberty. In contrast, it suggests that STR mutation rates should not scale with a mother's age at her child's conception, since oocytes spend a mother's reproductive years arrested in meiosis II and undergo a fixed number of cell divisions that are independent of the age at ovulation. Yet, mirroring recent findings, we find that STR mutation rates covary with paternal and maternal age, implying that some STR mutations are caused by DNA damage in quiescent cells rather than polymerase slippage in replicating progenitor cells. These results echo the recent finding that DNA damage in oocytes is a significant source of de novo single nucleotide variants and corroborate evidence of STR expansion in postmitotic cells. However, we find that the maternal age effect is not confined to known hotspots of oocyte mutagenesis, nor are postzygotic mutations likely to contribute significantly. STR nucleotide composition demonstrates divergent effects on de novo mutation (DNM) rates between sexes. Unlike the paternal lineage, maternally derived DNMs at A/T STRs display a significantly greater association with maternal age than DNMs at G/C-containing STRs. These observations may suggest the mechanism and developmental timing of certain STR mutations and contradict prior attribution of replication slippage as the primary mechanism of STR mutagenesis.
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Project description:Osteoporosis is a major health concern in aging populations, where 54% of the U.S. population aged 50 and older have low bone mineral density (BMD). Increases in inflammation and oxidative stress play a major role in the development of osteoporosis. Men are at a greater risk of mortality due to osteoporosis-related fractures. Our earlier findings in rodent male and female models of osteoporosis, as well as postmenopausal women strongly suggest the efficacy of prunes (dried plum) in reducing inflammation and preventing/reversing bone loss. The objective of this study was to examine the effects of two doses of prunes, daily, on biomarkers of inflammation and bone metabolism in men with some degree of bone loss (BMD; t-score between -0.1 and -2.5 SD), for three months. Thirty-five men between the ages of 55 and 80 years were randomized into one of three groups: 100 g prunes, 50 g prunes, or control. Consumption of 100 g prunes led to a significant decrease in serum osteocalcin (p < 0.001). Consumption of 50 g prunes led to significant decreases in serum osteoprotegerin (OPG) (p = 0.003) and serum osteocalcin (p = 0.040), and an increase in the OPG:RANKL ratio (p = 0.041). Regular consumption of either 100 g or 50 g prunes for three months may positively affect bone turnover.
| S-EPMC8779167 | biostudies-literature
Project description:Marine hydrocarbon seeps are ecosystems that are rich in methane, and, in some cases, short-chain (C2-C5) and longer alkanes. C2-C4 alkanes such as ethane, propane, and butane can be significant components of seeping fluids. Some sulfate-reducing microbes oxidize short-chain alkanes anaerobically, and may play an important role in both the competition for sulfate and the local carbon budget. To better understand the anaerobic oxidation of short-chain n-alkanes coupled with sulfate-reduction, hydrocarbon-rich sediments from the Gulf of Mexico (GoM) were amended with artificial, sulfate-replete seawater and one of four n-alkanes (C1-C4) then incubated under strict anaerobic conditions. Measured rates of alkane oxidation and sulfate reduction closely follow stoichiometric predictions that assume the complete oxidation of alkanes to CO2 (though other sinks for alkane carbon likely exist). Changes in the δ(13)C of all the alkanes in the reactors show enrichment over the course of the incubation, with the C3 and C4 incubations showing the greatest enrichment (4.4 and 4.5‰, respectively). The concurrent depletion in the δ(13)C of dissolved inorganic carbon (DIC) implies a transfer of carbon from the alkane to the DIC pool (-3.5 and -6.7‰ for C3 and C4 incubations, respectively). Microbial community analyses reveal that certain members of the class Deltaproteobacteria are selectively enriched as the incubations degrade C1-C4 alkanes. Phylogenetic analyses indicate that distinct phylotypes are enriched in the ethane reactors, while phylotypes in the propane and butane reactors align with previously identified C3-C4 alkane-oxidizing sulfate-reducers. These data further constrain the potential influence of alkane oxidation on sulfate reduction rates (SRRs) in cold hydrocarbon-rich sediments, provide insight into their contribution to local carbon cycling, and illustrate the extent to which short-chain alkanes can serve as electron donors and govern microbial community composition and density.
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Project description:It is well established in theory that short-term environmental fluctuations could affect the long-term growth rates of wildlife populations, but this theory has rarely been tested and there remains little empirical evidence that the effect is actually important in practice. Here we develop models to quantify the effects of daily, seasonal, and yearly temperature fluctuations on the average population growth rates, and we apply them to long-term data on the endangered Black-faced Spoonbill (Platalea minor); an endothermic species whose population growth rates follow a concave relationship with temperature. We demonstrate for the first time that the current levels of temperature variability, particularly seasonal variability, are already large enough to substantially reduce long-term population growth rates. As the climate changes, our results highlight the importance of considering the ecological effects of climate variability and not just average conditions.
| S-EPMC4564168 | biostudies-literature
Project description:Methanotrophs, which help regulate atmospheric levels of methane, are active in diverse natural and man-made environments. This range of habitats and the feast-famine cycles seen by many environmental methanotrophs suggest that methanotrophs dynamically mediate rates of methane oxidation. Global methane budgets require ways to account for this variability in time and space. Functional gene biomarker transcripts are increasingly being studied to inform the dynamics of diverse biogeochemical cycles. Previously, per-cell transcript levels of the methane oxidation biomarker, pmoA, were found to vary quantitatively with respect to methane oxidation rates in model aerobic methanotroph, Methylosinus trichosporium OB3b. In the present study, these trends were explored for two additional aerobic methanotroph pure cultures, Methylocystis parvus OBBP and Methylomicrobium album BG8. At steady-state conditions, per cell pmoA mRNA transcript levels strongly correlated with per cell methane oxidation across the three methanotrophs across many orders of magnitude of activity (R2 = 0.91). Additionally, genome-wide expression data (RNA-seq) were used to explore transcriptomic responses of steady state M. album BG8 cultures to short-term CH4 and O2 limitation. These limitations induced regulation of genes involved in central carbon metabolism (including carbon storage), cell motility, and stress response.
2021-11-17 | GSE188821 | GEO
Project description:Background and objectivesObesity precedes and is strongly linked to the development of type 2 diabetic nephropathy in most patients, yet little is known about the effects of weight reduction on this disease. This study aimed to establish proof of concept for the hypothesis that weight reduction ameliorates diabetic nephropathy.Design, setting, participants, & measurementsSix obese individuals with advanced diabetic nephropathy (estimated GFR <40 ml/min per 1.73 m(2), urine albumin excretion >30 mg/d) currently taking a renin-aldosterone axis inhibitor underwent a 12-week very low calorie ketogenic weight reduction diet with encouragement of exercise between March and September 2012. Albuminuria and other parameters of kidney health were the main outcome measures.ResultsThere was a 12% reduction in weight (median 118.5 versus 104.3 kg, P=0.03). The intervention was associated with a 36% reduction in albuminuria that did not reach statistical significance (2124 versus 1366 mg/24 h, P=0.08) and significant reductions in the filtration markers serum creatinine (3.54 versus 3.13 mg/dl, P<0.05) and cystatin C (2.79 versus 2.46 mg/l, P<0.05). Improvements were also noted for the diabetes markers fasting glucose (166 versus 131 mg/dl, P<0.05), fasting insulin (26.9 versus 10.4 μU/ml, P<0.05), and insulin resistance (9.6 versus 4.2, P=0.03). Physical function, general health, and the number of diabetes medications also showed statistically significant signs of improvement.ConclusionsAfter a short-term intensive weight reduction intervention in patients with advanced diabetic nephropathy, improvements were observed in markers of glomerular filtration, diabetes status, and risk factors for kidney disease progression, as well as other general indicators of health and well-being.
| S-EPMC3817909 | biostudies-literature