Prenatal development is linked to bronchial reactivity: epidemiological and animal model evidence

Chronic cardiorespiratory disease is associated with low birthweight suggesting the importance of the developmental environment. Prenatal factors affecting fetal growth are believed important, but the underlying mechanisms are unknown. The influence of developmental programming on bronchial hyperreactivity is investigated in an animal model and evidence for comparable associations is sought in humans. Pregnant Wistar rats were fed either control or protein-restricted diets throughout pregnancy. Bronchoconstrictor responses were recorded from offspring bronchial segments. Morphometric analysis of paraffin-embedded lung sections was conducted. In a human mother-child cohort ultrasound measurements of fetal growth were related to bronchial hyperreactivity, measured at age six years using methacholine. Protein-restricted rats' offspring demonstrated greater bronchoconstriction than controls. Airway structure was not altered. Children with lesser abdominal circumference growth during 11-19 weeks' gestation had greater bronchial hyperreactivity than those with more rapid abdominal growth. Imbalanced maternal nutrition during pregnancy results in offspring bronchial hyperreactivity. Prenatal environmental influences might play a comparable role in humans

Trapping and Wiggling: Elastohydrodynamics of Driven Microfilaments

We present a general theoretical analysis of semiflexible filaments subject to viscous drag or point forcing. These are the relevant forces in dynamic experiments designed to measure biopolymer bending moduli. By analogy with the ``Stokes problems" in hydrodynamics (fluid motion induced by that of a wall bounding a viscous fluid), we consider the motion of a polymer one end of which is moved in an impulsive or oscillatory way. Analytical solutions for the time-dependent shapes of such moving polymers are obtained within an analysis applicable to small-amplitude deformations. In the case of oscillatory driving, particular attention is paid to a characteristic length determined by the frequency of oscillation, the polymer persistence length, and the viscous drag coefficient. Experiments on actin filaments manipulated with optical traps confirm the scaling law predicted by the analysis and provide a new technique for measuring the elastic bending modulus. A re-analysis of several published experiments on microtubules is also presented.Comment: RevTex, 24 pages, 15 eps figs, uses cite.sty, Biophysical

Expedition 306 summary

The overall aim of the North Atlantic paleoceanography study of Integrated Ocean Drilling Program Expedition 306 is to place late Neogene–Quaternary climate proxies in the North Atlantic into a chronology based on a combination of geomagnetic paleointensity, stable isotope, and detrital layer stratigraphies, and in so doing generate integrated North Atlantic millennial-scale stratigraphies for the last few million years. To reach this aim, complete sedimentary sections were drilled by multiple advanced piston coring directly south of the central Atlantic “ice-rafted debris belt” and on the southern Gardar Drift. In addition to the North Atlantic paleoceanography study, a borehole observatory was successfully installed in a new ~180 m deep hole close to Ocean Drilling Program Site 642, consisting of a circulation obviation retrofit kit to seal the borehole from the overlying ocean, a thermistor string, and a data logger to document and monitor bottom water temperature variations through time

Nitrifying Microorganisms Linked to Biotransformation of Perfluoroalkyl Sulfonamido Precursors from Legacy Aqueous Film-Forming Foams

Drinking water supplies across the United States have been contaminated by firefighting and fire-training activities that use aqueous film-forming foams (AFFF) containing per- and polyfluoroalkyl substances (PFAS). Much of the AFFF is manufactured using electrochemical fluorination by 3M. Precursors with six perfluorinated carbons (C6) and non-fluorinated amine substituents make up approximately one-third of the PFAS in 3M AFFF. C6 precursors can be transformed through nitrification (microbial oxidation) of amine moieties into perfluorohexane sulfonate (PFHxS), a compound of regulatory concern. Here, we report biotransformation of the most abundant C6 sulfonamido precursors in 3M AFFF with available commercial standards (FHxSA, PFHxSAm, and PFHxSAmS) in microcosms representative of the groundwater/surface water boundary. Results show rapid (\u3c1 day) biosorption to living cells by precursors but slow biotransformation into PFHxS (1–100 pM day–1). The transformation pathway includes one or two nitrification steps and is supported by the detection of key intermediates using high-resolution mass spectrometry. Increasing nitrate concentrations and total abundance of nitrifying taxa occur in parallel with precursor biotransformation. Together, these data provide multiple lines of evidence supporting microbially limited biotransformation of C6 sulfonamido precursors involving ammonia-oxidizing archaea (Nitrososphaeria) and nitrite-oxidizing bacteria (Nitrospina). Further elucidation of interrelationships between precursor biotransformation and nitrogen cycling in ecosystems would help inform site remediation efforts

Comprehensive pharmacogenetic profiling of the epidermal growth factor receptor pathway for biomarkers of response to, and toxicity from, cetuximab

Background Somatic mutations in the epidermal growth factor receptor (EGFR) intracellular signalling pathways predict non-response to cetuximab in the treatment of advanced colorectal cancer (aCRC). We hypothesized that common germline variants within these pathways may also play similar roles. Methods We analysed 54 potentially functional, common, inherited EGFR pathway variants in 815 aCRC patients treated with oxaliplatin-fluoropyrimidine chemotherapy +cetuximab. Primary endpoints were response and skin rash (SR). We had >85% power to detect ORs=1.6 for variants with minor allele frequencies >20%. Results We identified five potential biomarkers for response and four for SR, although none remained significant after correction for multiple testing. Our initial data supported a role for Ser313Pro in PIK3R2 in modulating response to cetuximab - in patients with KRAS wild type CRCs, 36.4% of patients with one allele encoding proline responded, as compared to 71.2% of patients homozygous for alleles encoding serine (OR 0.23, 95% CI 0.09-0.56, P=0.0014) and this association was predictive for cetuximab (Pinteraction=0.017); however, independent replication failed to validate this association. No previously proposed predictive biomarkers were validated. Conclusions Our study highlights the need to validate potential pharmacogenetic biomarkers. We did not find strong evidence for common germline biomarkers of cetuximab response and toxicity

Occupational exposure to magnetic fields and breast cancer among Canadian men

Occupational magnetic field (MF) exposure has been suggested as a risk factor for breast cancer in both men and women. Due to the rarity of this disease in men, most epidemiologic studies investigating this relationship have been limited by small sample sizes. Herein, associations of several measures of occupational MF exposure with breast cancer in men were investigated using data from the population-based case-control component of the Canadian National Enhanced Cancer Surveillance System. Lifetime job histories were provided by 115 cases and 570 controls. Average MF exposure of individual jobs was classified into three categories (<0.3, 0.3 to <0.6, or ≥0.6 μT) through expert blinded review of participant's lifetime occupational histories. The impact of highest average and cumulative MF exposure, as well as exposure duration and specific exposure-time windows, on cancer risk was examined using logistic regression. The proportion of cases (25%) with a highest average exposure of ≥0.3 μT was higher than among controls (22%)

Association of Frequent Aspirin Use With Ovarian Cancer Risk According to Genetic Susceptibility

IMPORTANCE: Frequent aspirin use is associated with reduced ovarian cancer risk, but it is unknown whether genetic factors modify this association. Understanding effect modifiers is important given that any use of aspirin for ovarian cancer chemoprevention will likely need to focus on specific higher-risk subgroups. OBJECTIVE: To evaluate whether the association between frequent aspirin use and ovarian cancer is modified by a polygenic score (PGS) for nonmucinous ovarian cancer. DESIGN, SETTING, AND PARTICIPANTS: We pooled individual-level data from 8 population-based case-control studies from the Ovarian Cancer Association Consortium conducted in the US, UK, and Australia between 1995 and 2009. We included case patients and control participants with both genetic data and data on frequent aspirin use. Case patients with mucinous ovarian cancer were excluded. Data were analyzed between November 1, 2021, and July 31, 2022. EXPOSURES: Frequent aspirin use, defined as daily or almost daily use for 6 months or longer. MAIN OUTCOMES AND MEASURES: The main outcome was nonmucinous epithelial ovarian cancer. We used logistic regression to estimate odds ratios (ORs) and 95% CIs and likelihood ratio tests to investigate effect modification by the PGS. RESULTS: There were 4476 case patients with nonmucinous ovarian cancer and 6659 control participants included in this analysis. At study enrollment, the median (IQR) age was 58 (50-66) years for case patients and 57 (49-65) years for control participants. Case patients and control participants self-reported that they were Black (122 [3%] vs 218 [3%]), White (3995 [89%] vs 5851 [88%]), or of other race and ethnicity (348 [8%] vs 580 [9%]; race and ethnicity were unknown for 11 [0%] vs 10 [0%]). There were 575 case patients (13%) and 1030 control participants (15%) who reported frequent aspirin use. The 13% reduction in ovarian cancer risk associated with frequent aspirin use (OR, 0.87 [95% CI, 0.76-0.99]) was not modified by the PGS. Consistent ORs were observed among individuals with a PGS less than (0.85 [0.70-1.02]) and greater than (0.86 [0.74-1.01]) the median. Results were similar by histotype. CONCLUSIONS AND RELEVANCE: The findings of this study suggest that genetic susceptibility to ovarian cancer based on currently identified common genetic variants does not appear to modify the protective association between frequent aspirin use and ovarian cancer risk. Future work should continue to explore the role of aspirin use for ovarian cancer prevention among individuals who are at higher risk for ovarian cancer

Assessing COVID-19 testing strategies in K-12 schools in underserved populations: Study protocol for a cluster-randomized trial

BACKGROUND: Since March 2020, COVID-19 has disproportionately impacted communities of color within the United States. As schools have shifted from virtual to in-person learning, continual guidance is necessary to understand appropriate interventions to prevent SARS-CoV-2 transmission. Weekly testing of students and staff for SARS-CoV-2 within K-12 school setting could provide an additional barrier to school-based transmission, especially within schools unable to implement additional mitigation strategies and/or are in areas of high transmission. This study seeks to understand the role that weekly SARS-CoV-2 testing could play in K-12 schools. In addition, through qualitative interviews and listening sessions, this research hopes to understand community concerns and barriers regarding COVID-19 testing, COVID-19 vaccine, and return to school during the COVID-19 pandemic. METHODS/DESIGN: Sixteen middle and high schools from five school districts have been randomized into one of the following categories: (1) Weekly screening + symptomatic testing or (2) Symptomatic testing only. The primary outcome for this study will be the average of the secondary attack rate of school-based transmission per case. School-based transmission will also be assessed through qualitative contact interviews with positive contacts identified by the school contact tracers. Lastly, new total numbers of weekly cases and contacts within a school-based quarantine will provide guidance on transmission rates. Qualitative focus groups and interviews have been conducted to provide additional understanding to the acceptance of the intervention and barriers faced by the community regarding SARS-CoV-2 testing and vaccination. DISCUSSION: This study will provide greater understanding of the benefit that weekly screening testing can provide in reducing SARS-CoV-2 transmission within K-12 schools. Close collaboration with community partners and school districts will be necessary for the success of this and similar studies. TRIAL REGISTRATION: NCT04875520 . Registered May 6, 2021

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

Pharmacogenetic analyses of 2,183 patients with advanced colorectal cancer; Potential role for common dihydropyrimidine dehydrogenase variants in toxicity to chemotherapy.

BACKGROUND: Inherited genetic variants may influence response to, and side-effects from, chemotherapy. We sought to generate a comprehensive inherited pharmacogenetic profile for oxaliplatin and 5FU/capecitabine therapy in advanced colorectal cancer (aCRC). METHODS: We analysed more than 200 potentially functional, common, inherited variants in genes within the 5FU, capecitabine, oxaliplatin and DNA repair pathways, together with four rare dihydropyrimidine dehydrogenase (DPYD) variants, in 2183 aCRC patients treated with oxaliplatin-fluoropyrimidine chemotherapy with, or without, cetuximab (from MRC COIN and COIN-B trials). Primary end-points were response, any toxicity and peripheral neuropathy. We had >85% power to detect odds ratios (ORs) = 1.3 for variants with minor allele frequencies >20%. RESULTS: Variants in DNA repair genes (Asn279Ser in EXO1 and Arg399Gln in XRCC1) were most associated with response (OR 1.9, 95% confidence interval [CI] 1.2-2.9, P = 0.004, and OR 0.7, 95% CI 0.5-0.9, P = 0.003, respectively). Common variants in DPYD (Cys29Arg and Val732Ile) were most associated with toxicity (OR 0.8, 95% CI 0.7-1.0, P = 0.008, and OR 1.6, 95% CI 1.1-2.1, P = 0.006, respectively). Two rare DPYD variants were associated with increased toxicity (Asp949Val with neutropenia, nausea and vomiting, diarrhoea and infection; IVS14+1G>A with lethargy, diarrhoea, stomatitis, hand-foot syndrome and infection; all ORs > 3). Asp317His in DCLRE1A was most associated with peripheral neuropathy (OR 1.3, 95% CI 1.1-1.6, P = 0.003). No common variant associations remained significant after Bonferroni correction. CONCLUSIONS: DNA repair genes may play a significant role in the pharmacogenetics of aCRC. Our data suggest that both common and rare DPYD variants may be associated with toxicity to fluoropyrimidine-based chemotherapy