Cancer incidence increases with age and is a leading cause of death. Caloric restriction (CR) confers benefits on health and survival and delays cancer. However, due to CR's stringency, dietary ...alternatives offering the same cancer protection have become increasingly attractive. Short cycles of a plant-based diet designed to mimic fasting (FMD) are protective against tumorigenesis without the chronic restriction of calories. Yet, it is unclear whether the fasting time, level of dietary restriction, or nutrient composition is the primary driver behind cancer protection. Using a breast cancer model in mice, we compare the potency of daily CR to that of periodic caloric cycling on FMD or an isocaloric standard laboratory chow against primary tumor growth and metastatic burden. Here, we report that daily CR provides greater protection against tumor growth and metastasis to the lung, which may be in part due to the unique immune signature observed with daily CR.
Abstract
Background
Histone lactylation has been recently described as a novel histone post-translational modification linking cellular metabolism to epigenetic regulation.
Results
Given the expected ...relevance of this modification and current limited knowledge of its function, we generate genome-wide datasets of H3K18la distribution in various in vitro and in vivo samples, including mouse embryonic stem cells, macrophages, adipocytes, and mouse and human skeletal muscle. We compare them to profiles of well-established histone modifications and gene expression patterns. Supervised and unsupervised bioinformatics analysis shows that global H3K18la distribution resembles H3K27ac, although we also find notable differences. H3K18la marks active CpG island-containing promoters of highly expressed genes across most tissues assessed, including many housekeeping genes, and positively correlates with H3K27ac and H3K4me3 as well as with gene expression. In addition, H3K18la is enriched at active enhancers that lie in proximity to genes that are functionally important for the respective tissue.
Conclusions
Overall, our data suggests that H3K18la is not only a marker for active promoters, but also a mark of tissue specific active enhancers.
High-grade serous ovarian carcinoma (HGSOC) is the most common and aggressive form of epithelial ovarian cancer, for which few targeted therapies exist. To search for new therapeutic target proteins, ...we performed an in vivo shRNA screen using an established human HGSOC cell line growing either subcutaneously or intraperitoneally in immunocompromised mice. We identified genes previously implicated in ovarian cancer such asAURKA1, ERBB3, CDK2, andmTOR, as well as several novel candidates includingBRD4, VRK1, andGALK2.We confirmed, using both genetic and pharmacologic approaches, that the activity ofBRD4,an epigenetic transcription modulator, is necessary for proliferation/survival of both an established human ovarian cancer cell line (OVCAR8) and a subset of primary serous ovarian cancer cell strains (DFs). Among the DFs tested, the strains sensitive to BRD4 inhibition revealed elevated expression of eitherMYCNorc-MYC, withMYCNexpression correlating closely with JQ1 sensitivity. Accordingly, primary human xenografts derived from high-MYCN or c-MYC strains exhibited sensitivity to BRD4 inhibition. These data suggest that BRD4 inhibition represents a new therapeutic approach for MYC-overexpressing HGSOCs.
The Asian tiger mosquito (Aedes albopictus) is an important vector for pathogens that affect human health, including the viruses that cause dengue and Chikungunya fevers. It is also one of the ...world's fastest-spreading invasive species. For these reasons, it is crucial to identify strategies for controlling the reproduction and spread of this mosquito. During mating, seminal fluid proteins (Sfps) are transferred from male mosquitoes to females, and these Sfps modulate female behavior and physiology in ways that influence reproduction. Despite the importance of Sfps on female reproductive behavior in mosquitoes and other insects, the identity of Sfps in Ae. albopictus has not previously been reported. We used transcriptomics and proteomics to identify 198 Sfps in Ae. albopictus. We discuss possible functions of these Sfps in relation to Ae. albopictus reproduction-related biology. We additionally compare the sequences of these Sfps with proteins (including reported Sfps) in several other species, including Ae. aegypti. While only 72 (36.4%) of Ae. albopictus Sfps have putative orthologs in Ae. aegypti, suggesting low conservation of the complement of Sfps in these species, we find no evidence for an elevated rate of evolution or positive selection in the Sfps that are shared between the two Aedes species, suggesting high sequence conservation of those shared Sfps. Our results provide a foundation for future studies to investigate the roles of individual Sfps on feeding and reproduction in this mosquito. Functional analysis of these Sfps could inform strategies for managing the rate of pathogen transmission by Ae. albopictus.
Background
Study results vary on whether depressive symptoms are associated with worse prognosis for low back pain (LBP). We assessed the association between depressive symptoms or depression and ...health outcomes in persons with LBP.
Methods
We searched MEDLINE, Embase, CINAHL, and PsycINFO from inception to June 2020. Eligible studies were cohort and case-control studies assessing the association between depressive symptoms (questionnaires) or depression (diagnoses) and health outcomes in persons aged ≥16 years with LBP in the absence of major pathology. Reviewers independently screened articles, extracted data, and assessed risk of bias using the Quality in Prognosis Studies tool. We classified exploratory versus confirmatory studies based on phases of prognostic factor investigation. We conducted random-effects meta-analyses and descriptive synthesis where appropriate.
Results
Of 13,221 citations screened, we included 62 studies (63,326 participants; 61 exploratory studies, 1 confirmatory study). For acute LBP, depressive symptoms were associated with self-reported disability (descriptive synthesis: 6 studies), worse recovery (descriptive synthesis: 5 studies), and slower traffic injury–related claim closure (1 study), but not pain or work-related outcomes. Depressive symptoms were associated with greater primary healthcare utilization for acute LBP (1 confirmatory study). For chronic LBP, depressive symptoms were associated with higher pain intensity (descriptive synthesis: 9 studies; meta-analysis: 3 studies, 2902 participants,
β
=0.11, 95% confidence interval (CI) 0.05–0.17), disability (descriptive synthesis: 6 studies; meta-analysis: 5 studies, 3549 participants,
β
=0.16, 95% CI 0.04–0.29), and worse recovery (descriptive synthesis: 2 studies; meta-analysis: 2 studies, 13,263 participants, relative risk (RR)=0.91, 95% CI 0.88–0.95), but not incident chronic widespread pain (1 study).
Discussion
Depressive symptoms may be associated with self-reported disability and worse recovery in persons with acute and chronic LBP, and greater primary healthcare utilization for acute LBP. Our review provides high-quality prognostic factor information for LBP. Healthcare delivery that addresses depressive symptoms may improve disability and recovery in persons with LBP. Confirmatory studies are needed to assess the association between depressive symptoms and health outcomes in persons with LBP.
Protocol Registration
PROSPERO database (CRD42019130047)
Recent studies demonstrate the role of the tumor microenvironment in tumor progression. However, strategies used to overcome the malignant phenotypes of cancer cells modulated by the microenvironment ...have not been thoroughly explored. In this study, we evaluated the therapeutic efficacy of a newly developed mAb targeting microfibril-associated protein 5 (MFAP5), which is secreted predominately by cancer-associated fibroblast (CAF), in ovarian and pancreatic cancer models.
MAbs were developed using human MFAP5 recombinant protein as an antigen in mice, and antibodies from hybridoma clones were evaluated for their specificity to human and murine MFAP5. An Octet RED384 system was used to determine the kinetics of binding affinity and the specificity of the antibody clones, which were followed by epitope mapping and functional characterization by
assays. The therapeutic efficacy of a lead anti-MFAP5 antibody clone 130A in tumor suppression was evaluated by ovarian tumor- and pancreatic tumor-bearing mouse models.
Three hybridoma clones, which produced antibodies with high affinity and specificity to MFAP5, were selected for functional studies. Antibody clone 130A, which recognizes a common epitope shared between human and murine MFAP5 protein, was further selected for
studies. Results showed that clone 130A downregulated MFAP5-induced collagen production in CAFs, suppressed intratumoral microvessel leakiness, and enhanced paclitaxel bioavailability in both ovarian and pancreatic cancer mouse models.
These data suggest that MFAP5 blockade using an immunologic approach inhibits fibrosis, induces tumor vessel normalization, and enhances chemosensitivity in ovarian and pancreatic cancer, and can be used as a novel therapeutic agent.
Adults with back pain commonly consult chiropractors, but the impact of chiropractic use on medical utilization and costs within the Canadian health system is unclear. We assessed the association ...between chiropractic utilization and subsequent medical healthcare utilization and costs in a population-based cohort of Ontario adults with back pain.
We conducted a population-based cohort study that included Ontario adult respondents of the Canadian Community Health Survey (CCHS) with back pain from 2003 to 2010 (n = 29,475), followed up to 2018. The CCHS data were individually-linked to individual-level health administrative data up to 2018. Chiropractic utilization was self-reported consultation with a chiropractor in the past 12 months. We propensity score-matched adults with and without chiropractic utilization, accounting for confounders. We evaluated back pain-specific and all-cause medical utilization and costs at 1- and 5-year follow-up using negative binomial and linear (log-transformed) regression, respectively. We assessed whether sex and prior specialist consultation in the past 12 months were effect modifiers of the association.
There were 6972 matched pairs of CCHS respondents with and without chiropractic utilization. Women with chiropractic utilization had 0.8 times lower rate of cause-specific medical visits at follow-up than those without chiropractic utilization (RR
= 0.82, 95% CI 0.68-1.00); this association was not found in men (RR
= 0.96, 95% CI 0.73-1.24). There were no associations between chiropractic utilization and all-cause physician visits, all-cause emergency department visits, all-cause hospitalizations, or costs. Effect modification of the association between chiropractic utilization and cause-specific utilization by prior specialist consultation was found at 1-year but not 5-year follow-up; cause-specific utilization at 1 year was lower in adults without prior specialist consultation only (RR
= 0.74, 95% CI 0.57-0.97).
Among adults with back pain, chiropractic use is associated with lower rates of back pain-specific utilization in women but not men over a 5-year follow-up period. Findings have implications for guiding allied healthcare delivery in the Ontario health system.
More doses of CoronaVac have been administered worldwide than any other COVID-19 vaccine. However, the effectiveness of COVID-19 inactivated vaccines in pregnant women is still unknown. We estimated ...the vaccine effectiveness (VE) of CoronaVac against symptomatic and severe COVID-19 in pregnant women in Brazil.
We conducted a test-negative design study in all pregnant women aged 18-49 years with COVID-19-related symptoms in Brazil from March 15, 2021, to October 03, 2021, linking records of negative and positive SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) tests to national vaccination records. We also linked records of test-positive cases with notifications of severe, hospitalised or fatal COVID-19. Using logistic regression, we estimated the adjusted odds ratio and VE against symptomatic COVID-19 and against severe COVID-19 by comparing vaccine status in test-negative subjects to test-positive symptomatic cases and severe cases.
Of the 19,838 tested pregnant women, 7424 (37.4%) tested positive for COVID-19 and 588 (7.9%) had severe disease. Only 83% of pregnant women who received the first dose of CoronaVac completed the vaccination scheme. A single dose of the CoronaVac vaccine was not effective at preventing symptomatic COVID-19. The effectiveness of two doses of CoronaVac was 41% (95% CI 27.1-52.2) against symptomatic COVID-19 and 85% (95% CI 59.5-94.8) against severe COVID-19.
A complete regimen of CoronaVac in pregnant women was effective in preventing symptomatic COVID-19 and highly effective against severe illness in a setting that combined high disease burden and marked COVID-19-related maternal deaths.
Low back pain (LBP) is a high-burden condition that lacks routine surveillance data. Health administrative data may be used for surveillance, but their validity for measuring LBP in the general ...population has not been established. We aimed to (1) determine the validity of health administrative data to measure LBP compared to self-reported LBP in a population-based sample of Ontario adults; and (2) describe the differences in characteristics of LBP cases based on data sources. Adult respondents (≥18 years) of the Canadian Community Health Survey (CCHS) from 2003 to 2012 were included (N = 150,695). Canadian Community Health Survey data were individually linked to health administrative data, including Ontario Health Insurance Plan and hospitalization data. The reference standard was defined as self-reported back problem diagnosed by a health professional in the CCHS. Measurement of LBP from billing records was defined as ≥1 physician billing or procedural code for LBP during the year preceding CCHS interview date. We measured concurrent validity by comparing prevalence, agreement (kappa), and accuracy (sensitivity, specificity, and positive and negative predictive values PV) of administrative data to measure LBP. Prevalence of LBP was higher using self-reported (21.2%) than administrative data (10.2%), and agreement was low (kappa = 0.21). Administrative data had sensitivity 23.9% (95% CI 23.1-24.6), specificity 93.4% (95% CI 93.2-93.7), positive PV 50.4% (95% CI 49.1-51.7), and negative PV 82.0% (95% CI 81.7-82.3). Characteristics of LBP cases based on data sources differed in sex, health/behaviour characteristics, and allied health care utilization. Using health administrative data significantly underestimates the prevalence of LBP. This can lead to misclassification bias that is likely nondifferential in epidemiological studies.
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