Frandsenshoemaker3417

PURPOSE The role of plasma-based tumor mutation burden (pTMB) in predicting response to pembrolizumab-based first-line standard of care therapy for metastatic non-small cell lung cancer (mNSCLC) has not been explored. EXPERIMENTAL DESIGN A 500-gene next-generation sequencing (NGS) panel was used to assess pTMB. Sixty-six patients with newly diagnosed mNSCLC starting first-line pembrolizumab-based therapy, either alone or in combination with chemotherapy, were enrolled (Clinicaltrial.gov identifier NCT03047616).Response was assessed using RECIST 1.1. Associations were made for patient characteristics, 6-month durable clinical benefit (DCB), progression free survival (PFS), and overall survival (OS). RESULTS Of 66 patients, 52 (78.8%) were pTMB-evaluable. Median pTMB was 16.8 mutations per megabase (mut/Mb; range 1.9-52.5) and was significantly higher for patients achieving DCB compared to no durable benefit 21.3 mut/Mb vs. 12.4 mut/Mb, P=0.003. For patients with pTMB greater than or equal to16 mut/Mb, median PFS was 14.1 vs. 4.7 months for patients with pTMB less then 16 mut/Mb (HR 0.30 [0.16-0.60]) P less then 0.001. Median OS for patients with pTMB greater than or equal to 16 was not reached vs. 8.8 months for patients with pTMB less then 16 mut/Mb (HR 0.48 [0.22-1.03]) P=0.061. Mutations in ERBB2exon 20, STK11, KEAP1, or PTENwere more common in patients with no DCB. A combination of pTMB greater than or equal to 16 and absence of negative predictor mutations was associated with PFS (HR 0.24 [0.11-0.49]) P less then 0.001 and OS (HR 0.31 [0.13-0.74]) P=0.009. CONCLUSIONS pTMB greater than or equal to 16 mut/Mb is associated with improved PFS after first-line standard of care pembrolizumab-based therapy in mNSCLC. STK11/KEAP1/PTENand ERBB2mutations may help identify pTMB-high patients unlikely to respond. These results should be validated in larger prospective studies. Copyright ©2020, American Association for Cancer Research.The impact on survival of steroids and TNF-alpha blockade to treat immune-related toxicity from checkpoint blockade with ipilimumab, nivolumab/pembrolizumab or combined ipilimumab and nivolumab was assessed using data from a large national database. Using steroids was associated with better survival than the use of TNF-alpha blocking antibodies such as infliximab. Copyright ©2020, American Association for Cancer Research.Tobacco smoking is the primary risk factor for lung cancer, driven by the addictive nature of nicotine and the indisputable carcinogenicity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) as well as other compounds. The integration of lung cancer chemoprevention with smoking cessation is one potential approach to reduce this risk and mitigate lung cancer mortality. Experimental data from our group suggest that kava, commonly consumed in the South Pacific Islands as a beverage to promote relaxation, may reduce lung cancer risk by enhancing NNK detoxification and reducing NNK-derived DNA damage. Building upon these observations, we conducted a pilot clinical trial to evaluate the effects of a 7-day course of kava on NNK metabolism in active smokers. The primary objective was to compare urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL plus its glucuronides, major metabolites of NNK) before and after kava administration as an indicator of NNK detoxification. Secondary objectives included determining kava's safety, its effects on DNA damage, tobacco use, and cortisol (a biomarker of stress). Kava increased urinary excretion of total NNAL and reduced urinary 3-methyladenine (3-mA) in participants, suggestive of its ability to reduce the carcinogenicity of NNK. Kava also reduced urinary total nicotine equivalents (TNE), indicative of its potential to facilitate tobacco cessation. check details Plasma cortisol and urinary total cortisol equivalents (TCE) were reduced upon kava use, which may contribute to reductions in tobacco use. These results demonstrate the potential of kava intake to reduce lung cancer risk among smokers. Copyright ©2020, American Association for Cancer Research.Mammographic breast density is a strong risk factor for breast cancer. We comprehensively investigated the associations of body mass index (BMI) change from ages 10, 18, and 30 to age at mammogram with mammographic breast density in postmenopausal women. We used multivariable linear regressions, adjusted for confounders, to investigate the associations of BMI change with volumetric percent density, dense volume, and non-dense volume, assessed using Volpara in 367 women. At the time of mammogram, the mean age was 57.9 years. Compared to women who had a BMI gain of 0.1-5 kg/m2 from age 10, women who had a BMI gain of 5.1-10 kg/m2 had a 24.4% decrease (95% confidence interval [95% CI], 6.0%-39.2%) in volumetric percent density; women who had a BMI gain of 10.1-15 kg/m2 had a 46.1% decrease (95%CI, 33.0%-56.7%) in volumetric percent density; and women who had a BMI gain of >15 kg/m2 had a 56.5% decrease (95%CI, 46.0%-65.0%) in volumetric percent density. Similar, but slightly attenuated associations were observed for BMI gain from ages 18 and 30 to age at mammogram and volumetric percent density. BMI gain over the life course was positively associated with non-dense volume, but not dense volume. We observed strong associations between BMI change over the life course and mammographic breast density. The inverse associations between early life adiposity change and volumetric percent density suggest that childhood adiposity may confer long-term protection against postmenopausal breast cancer via its effect of mammographic breast density. Copyright ©2020, American Association for Cancer Research.Vitamin D may influence prostate cancer risk, but evidence is inconsistent. We conducted a nested case-control study in the Prostate Cancer Prevention Trial (PCPT). Cases (n=1,128) and controls (n=1,205) were frequency matched on age, first-degree relative with prostate cancer and PCPT treatment arm (finasteride/placebo); African-Americans were oversampled and case/control status was biopsy-confirmed. We selected 21 SNPs in vitamin D-related genes (VDR, GC, C10orf88, CYP2R1, CYP24A1, CYP27B1, DHCR7, NADSYN1) to test genotype and genotype-treatment interactions in relation to prostate cancer. We also tested mean serum 25(OH)D differences by minor allele distributions and tested for serum 25(OH)D-genotype interactions in relation to prostate cancer risk. Log-additive genetic models (Bonferroni-corrected within genes) adjusted for age, BMI, PSA, and family history of prostate cancer revealed a significant interaction between treatment arm and GC/rs222016 (finasteride OR=1.37, placebo OR=0.85, p-interaction less inimal associations of vitamin D with total or high-grade prostate cancer. Copyright ©2020, American Association for Cancer Research.The bacterium Escherichia coli can initiate replication in the absence of the replication initiator protein DnaA and/or the canonical origin of replication oriC in a ΔrnhA background. This phenomenon, which can be primed by R-loops, is called constitutive stable DNA replication (cSDR). Whether DNA replication during cSDR initiates in a stochastic manner through the length of the chromosome or at specific sites and how E. coli can find adaptations to loss of fitness caused by cSDR remain inadequately answered. We use laboratory evolution experiments of ΔrnhA-ΔdnaA strains followed by deep sequencing to show that DNA replication preferentially initiates within a broad region located ∼0.4 to 0.7 Mb clockwise of oriC. This region includes many bisulfite-sensitive sites, which have been previously defined as R-loop-forming regions, and includes a site containing sequence motifs that favor R-loop formation. Initiation from this region would result in head-on replication-transcription conflicts at rRNA loci. Inversiom this site will result in more head-on collisions of DNA polymerase with RNA polymerase operating on rRNA loci. The bacterium adapts to this problem by inverting a region of the genome including several rRNA loci such that head-on collisions between the two polymerases are minimized. Understanding such evolutionary strategies in the context of cSDR can provide insights into the potential causes of resistance to antibiotics that target initiation of DNA replication. Copyright © 2020 Veetil et al.The existence of a placental microbiota and in utero colonization of the fetus have been the subjects of recent debate. The objective of this study was to determine whether the placental and fetal tissues of mice harbor bacterial communities. Bacterial profiles of the placenta and fetal brain, lung, liver, and intestine samples were characterized through culture, quantitative real-time PCR (qPCR), and 16S rRNA gene sequencing. These profiles were compared to those of the maternal mouth, lung, liver, uterus, cervix, vagina, and intestine, as well as to background technical controls. Positive bacterial cultures from placental and fetal tissue samples were rare; of the 165 total bacterial cultures of placental tissue samples from the 11 mice included in this study, only nine yielded at least a single colony, and five of those nine positive cultures came from a single mouse. Cultures of fetal intestinal tissue samples yielded just a single bacterial isolate, Staphylococcus hominis, a common skin bacterium. Bacterent. Given the established causal role of microbial invasion of the amniotic cavity (i.e., intra-amniotic infection) in pregnancy complications, especially preterm birth, if the in utero colonization hypothesis were true, there are several aspects of current understanding that will need to be reconsidered; these aspects include the magnitude of intra-amniotic microbial load required to cause disease and its potential influence on the ontogeny of the immune system. However, acceptance of the in utero colonization hypothesis is premature. Herein, we do not find consistent evidence for placental and fetal microbiota in mice using culture, qPCR, and DNA sequencing. Copyright © 2020 Theis et al.Hypoxia is the predominant condition that the human opportunistic fungus Candida albicans encounters in the majority of the colonized niches within the host. So far, the impact of such a condition on the overall metabolism of this important human-pathogenic yeast has not been investigated. Here, we have undertaken a time-resolved metabolomics analysis to uncover the metabolic landscape of fungal cells experiencing hypoxia. Our data showed a dynamic reprogramming of many fundamental metabolic pathways, such as glycolysis, the pentose phosphate pathway, and different metabolic routes related to fungal cell wall biogenesis. The C. albicans lipidome was highly affected by oxygen depletion, with an increased level of free fatty acids and biochemical intermediates of membrane lipids, including phospholipids, lysophospholipids, sphingolipids, and mevalonate. The depletion of oxygen-dependent lipids such as ergosterol or phosphatidylcholine with longer and polyunsaturated lateral fatty acid chains was observed only aroutes for the adaptation of this yeast to oxygen depletion. The fungal hypoxic metabolome identified in this work provides a framework for future investigations to assess the contribution of relevant metabolic pathways in the fitness of C. albicans and other human eukaryotic pathogens with similar colonized human niches. As hypoxia is present at most of the fungal infection foci in the host, hypoxic metabolic pathways are thus an attractive target for antifungal therapy. Copyright © 2020 Burgain et al.