Purpose Many dietary factors have either pro- or anti-inflammatory properties. We previously developed a dietary inflammatory index (DII) to assess the inflammatory potential of diet. In this study we conducted a construct validation of the DII based on data from a food frequency questionnaire and three inflammatory biomarkers in a subsample of 2,567 postmenopausal women in the Women’s Health Initiative Observational Study. Methods We used multiple linear and logistic regression models, controlling for potential confounders, to test whether baseline DII predicted concentrations of interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor alpha receptor 2 (TNFα-R2), or an overall biomarker score combining all three inflammatory biomarkers. Results The DII was associated with the four biomarkers with beta estimates (95%CI) comparing the highest with lowest DII quintiles as follows: IL-6: 1.26 (1.15, 1.38), Ptrend<0.0001; TNFα-R2: 81.43 (19.15, 143.71), Ptrend=0.004; dichotomized hs-CRP (odds ratio for higher versus lower hs-CRP): 1.30 (0.97, 1.67), Ptrend=0.34); and the combined inflammatory biomarker score: 0.26 (0.12, 0.40), Ptrend=0.0001. Conclusion The DII was significantly associated with inflammatory biomarkers. Construct validity of the DII indicates its utility for assessing the inflammatory potential of diet and for expanding its use to include associations with common chronic diseases in future studies.
This study demonstrates that greater oral abundance of commensal Corynebacterium and Kingella is associated with decreased risk of HNSCC, with potential implications for cancer prevention.
IMPORTANCE Prospective studies are needed to examine the temporal relationship between oral human papillomavirus (HPV) detection and risk of head and neck squamous cell carcinoma (HNSCC). Moreover, the oral cavity contains a wide spectrum of α-, β-, and γ- HPV types, but their association with risk of HNSCC is unknown. OBJECTIVE To prospectively examine associations between α-, β-, and γ-HPV detection in the oral cavity and incident HNSCC. DESIGN A nested case-control study was carried out among 96 650 participants, cancer free at baseline, with available mouthwash samples in 2 prospective cohort studies: (1) the American Cancer Society Cancer Prevention Study II Nutrition Cohort and (2) the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Incident cases of HNSCC (n = 132) were identified duringan average 3.9 years of follow-up in both cohorts. Three controls per case (n = 396) were selected through incidence density sampling and matched on age, sex, race/ethnicity, and time since mouthwash collection. METHODS Through a next-generation sequencing assay, DNA from α-, β-, and γ-HPV types were detected. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% CIs, adjusting for smoking history, alcohol consumption, and detection of HPV-16 for β- and γ-HPVs. MAIN OUTCOMES AND MEASURES Incident HNSCC, which includes cancers of the oropharynx, oral cavity, and larynx. RESULTS A total of 132 participants developed HNSCC during the follow-up period (103 men and 29 women; average age at baseline, 66.5 years). Oral HPV-16 detection was associated with incident HNSCC (OR, 7.1; 95% CI, 2.2–22.6), with positive association for oropharyngeal SCC (OR, 22.4; 95% CI, 1.8–276.7), but not for oral cavity (OR, 4.5; 95% CI, 0.6–34.7) or laryngeal SCCs (OR, 0.11; 95% CI, 0.01–834.80). Detection of β1-HPV-5 and β2-HPV-38 types, as well as γ-11 and γ-12 species, had ORs for HNSCC that ranged from 2.64 to 5.45 (P < .01 for all comparisons). Detection of β1-HPV-5 type was associated with oropharyngeal (OR, 7.42; 95% CI, 0.98–56.82; P = .054), oral cavity (OR, 5.34; 95% CI, 1.51–18.80; P = .01), and laryngeal SCCs (OR, 2.71; 95% CI, 1.00–7.43; P = .05), whereas γ11- and γ12-HPV species were associated with both oral cavity (OR, 7.47; 95% CI, 1.21–46.17; P = .03; and OR, 6.71; 95% CI, 1.47–30.75; P = .01, respectively) and laryngeal SCCs (OR, 7.49; 95% CI, 1.10–51.04; P = .04 and OR, 5.31; 95% CI, 1.13–24.95; P = .03, respectively). CONCLUSIONS AND RELEVANCE This study demonstrates that HPV-16 detection precedes the incidence of oropharyngeal SCC. Associations of other HPVs, including γ11- and γ12-HPV species and β1-HPV-5 type suggest a broader role for HPVs in HNSCC etiology.
Epidemiologic studies of statin use in relation to prostate cancer risk have been inconclusive. Recent evidence, however, suggests that longer-term use may reduce risk of more advanced disease. The authors conducted a population-based study of 1,001 incident prostate cancer cases diagnosed in 2002-2005 and 942 age-matched controls from King County, Washington, to evaluate risk associated with statin use. Logistic regression was used to generate odds ratios for ever use, current use, and duration of use. No overall association was found between statin use and prostate cancer risk (odds ratio (OR) ¼ 1.0, 95% confidence interval (CI): 0.8, 1.2 for current use; OR ¼ 1.1, 95% CI: 0.7, 1.8 for >10 years' use), even for cases with more advanced disease. Risk related to statin use, however, was modified by body mass index (interaction p ¼ 0.04). Obese men (BMI !30 kg/m 2 ) who used statins had an increased risk (OR ¼ 1.5, 95% CI: 1.0, 2.2) relative to obese nonusers, with a stronger association for longer-term use (OR ¼ 1.8, 95% CI: 1.1, 3.0 for !5 years' use). Although statin use was not associated with overall prostate cancer risk, the finding of an increased risk associated with statin use among obese men, particularly use for extended durations, warrants further investigation. case-control studies; hydroxymethylglutaryl-CoA reductase inhibitors; obesity; odds ratio; prostatic neoplasms Abbreviations: BMI, body mass index; CI, confidence interval; OR, odds ratio; PSA, prostate-specific antigen.Statin drugs are competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the enzyme that controls conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, an essential precursor of cholesterol (1-3). Statins are used to treat hypercholesterolemia and have been shown to reduce cardiovascular disease incidence and mortality (4-7). Thus, use of statins has increased exponentially in the United States over the last decade (8).Statin use in relation to prostate cancer etiology is of interest because 1) these drugs inhibit the synthesis of cholesterol, a precursor of androgens that also plays a role in cell signaling pathways (9); 2) mevalonate is necessary for the prenylation of proteins involved in signal transduction cascades downstream of membrane receptors that are crucial in cell growth and apoptosis (10, 11); and 3) in experimental models, statins inhibit cell proliferation, inflammation, oxidative stress, angiogenesis, and metastasis (2,3,11,12).Some studies suggest that statins may alter prostate cancer risk. Randomized clinical trials of statin use to prevent cardiovascular disease reported no associations with prostate cancer incidence (13-15), but such trials were limited by the short durations of use and brief follow-up periods (16,17).
Background: The presence of the TMPRSS2-ERG fusion gene in prostate tumors has recently been associated with an aggressive phenotype, as well as recurrence and death from prostate cancer. These associations suggest the hypothesis that the gene fusion may be used as a prognostic indicator for prostate cancer.
The trillions of microbes that colonize our adult intestine are referred to as the gut microbiome (GMB). Functionally it behaves as a metabolic organ that communicates with, and complements, our own human metabolic apparatus. While the relationship between the GMB and kidney stone disease (KSD) has not been investigated, dysbiosis of the GMB has been associated with diabetes, obesity and cardiovascular disease. In this pilot study we sought to identify unique changes in the GMB of kidney stone patients compared to patients without KSD. With an IRB-approved protocol we enrolled 29 patients into our pilot study. 23 patients were kidney stone formers and six were non-stone forming controls. Specimens were collected after a 6h fast and were flash frozen in dry ice and then stored at -80 °C. Microbiome: determination of bacterial abundance was by analysis of 16 s rRNA marker gene sequences using next generation sequencing. Sequencing of the GMB identified 178 bacterial genera. The five most abundant enterotypes within each group made up to greater than 50 % of the bacterial abundance identified. Bacteroides was 3.4 times more abundant in the KSD group as compared to control (34.9 vs 10.2 %; p = 0.001). Prevotella was 2.8 times more abundant in the control group as compared to the KSD group (34.7 vs 12.3 %; p = 0.005). In a multivariate analysis including age, gender, BMI, and DM, kidney stone disease remained an increased risk for high prevalence for Bacteroides (OR = 3.26, p = 0.033), whereas there was an inverse association with Prevotella (OR = 0.37, p = 0.043). There were no statistically significant differences in bacterial abundance levels for Bacteroides or Prevotella when comparing patients with and without DM, obesity (BMI >30), HTN or HLD. 11 kidney stone patients completed 24 h urine analysis at the time of this writing. Looking at the bacterial genuses with at least 4 % abundance in the kidney stone group, Eubacterium was inversely correlated with oxalate levels (r = -0.60, p < 0.06) and Escherichia trended to an inverse correlation with citrate (r = -0.56, p < 0.08). We also compared bacterial abundance between uric acid (UA) stone formers (n = 5) and non UA stone formers (n = 18) and found no significant difference between them. We identified two genus of bacteria in the GMB that had significant association with KSD. Interestingly, components of the 24-h urine appear to be correlated to bacterial abundance. These preliminary studies for the first time associate differences in the GMB with kidney stone formation. Further studies are warranted to evaluate the potential causative role of preexisting dysbiosis in kidney stone disease.
Disruption of the blood-brain barrier (BBB) is a defining and early feature of multiple sclerosis (MS) that directly damages the central nervous system (CNS), promotes immune cell infiltration, and influences clinical outcomes. There is an urgent need for new therapies to protect and restore BBB function, either by strengthening endothelial tight junctions or suppressing endothelial vesicular transcytosis. Although wingless integrated MMTV (Wnt)/β-catenin signaling plays an essential role in BBB formation and maintenance in healthy CNS, its role in BBB repair in neurologic diseases such as MS remains unclear. Using a Wnt/β-catenin reporter mouse and several downstream targets, we demonstrate that the Wnt/ β-catenin pathway is up-regulated in CNS endothelial cells in both human MS and the mouse model experimental autoimmune encephalomyelitis (EAE). Increased Wnt/β-catenin activity in CNS blood vessels during EAE progression correlates with up-regulation of neuronal Wnt3 expression, as well as breakdown of endothelial cell junctions. Genetic inhibition of the Wnt/β-catenin pathway in CNS endothelium before disease onset exacerbates the clinical presentation of EAE, CD4 + T-cell infiltration into the CNS, and demyelination by increasing expression of vascular cell adhesion molecule-1 and the transcytosis protein Caveolin-1 and promoting endothelial transcytosis. However, Wnt signaling attenuation does not affect the progressive degradation of tight junction proteins or paracellular BBB leakage. These results suggest that reactivation of Wnt/β-catenin signaling in CNS vessels during EAE/MS partially restores functional BBB integrity and limits immune cell infiltration into the CNS.blood-brain barrier | endothelial cell | Wnt/β-catenin signaling | MS | EAE I n both multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), leukocytes infiltrate the central nervous system (CNS) across a damaged blood-brain barrier (BBB) to mediate myelin destruction and neuronal damage (1). BBB breakdown is a contributing factor to the pathogenesis of both MS and EAE (2-4). Structural and functional BBB degradation precedes lesion development in both MS and EAE (5-9), and focal BBB abnormalities correlate with clinical exacerbations in the relapsing-remitting form of MS (10). Moreover, BBB leakage precedes the entry of T cells and monocytes into the brain parenchyma (7, 11) and coincides with early infiltration of neutrophils before the onset of EAE (12). Although the severity of barrier leakage decreases over time for most relapsing-remitting MS lesions, as assessed by gadoliniumenhancing magnetic resonance imaging (7, 13-15), whether BBB recovery is an active process and, if so, which pathways mediate its repair, remain unclear.The BBB achieves its highly selective permeability through the presence of (i) tight junctions (TJs) that prevent paracellular diffusion of small molecules and immune cells between endothelial cells (ECs), (ii) very few endocytotic vesicles that restrict movement of large mo...
The genetic contributions to breast cancer development among Latinas are not well understood. Here, we carry out a genome-wide association study of breast cancer in Latinas and identify a genome-wide significant risk variant, located 5’ of the Estrogen Receptor 1 gene (ESR1) (6q25 region). The minor allele for this variant is strongly protective (rs140068132: OR 0.60, 95%CI 0.53-0.67, P=9×10−18), originates from Indigenous Americans, and is uncorrelated with previously reported risk variants at 6q25. The association is stronger for estrogen receptor negative disease (OR 0.34 95% CI 0.21-0.54) than estrogen receptor positive disease (OR 0.63 95% CI 0.49-0.80) (P heterogeneity=0.01) and is also associated with mammographic breast density, a strong risk factor for breast cancer (P=0.001). rs140068132 is located within several transcription factor binding sites and electrophoretic mobility shift assays with MCF-7 nuclear protein demonstrate differential binding of the G/A alleles at this locus. These results highlight the importance of conducting research in diverse populations.
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