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Find video protocols related to scientific articles indexed in Pubmed.
Sample-Averaged Biexciton Quantum Yield Measured by Solution-Phase Photon Correlation.
Nano Lett.
PUBLISHED: 11-20-2014
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The brightness of nanoscale optical materials such as semiconductor nanocrystals is currently limited in high excitation flux applications by inefficient multiexciton fluorescence. We have devised a solution-phase photon correlation measurement that can conveniently and reliably measure the average biexciton-to-exciton quantum yield ratio of an entire sample without user selection bias. This technique can be used to investigate the multiexciton recombination dynamics of a broad scope of synthetically underdeveloped materials, including those with low exciton quantum yields and poor fluorescence stability. Here, we have applied this method to measure weak biexciton fluorescence in samples of visible-emitting InP/ZnS and InAs/ZnS core/shell nanocrystals, and to demonstrate that a rapid CdS shell growth procedure can markedly increase the biexciton fluorescence of CdSe nanocrystals.
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Long-Term Safety and Efficacy of Factor IX Gene Therapy in Hemophilia B.
N. Engl. J. Med.
PUBLISHED: 11-20-2014
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Background In patients with severe hemophilia B, gene therapy that is mediated by a novel self-complementary adeno-associated virus serotype 8 (AAV8) vector has been shown to raise factor IX levels for periods of up to 16 months. We wanted to determine the durability of transgene expression, the vector dose-response relationship, and the level of persistent or late toxicity. Methods We evaluated the stability of transgene expression and long-term safety in 10 patients with severe hemophilia B: 6 patients who had been enrolled in an initial phase 1 dose-escalation trial, with 2 patients each receiving a low, intermediate, or high dose, and 4 additional patients who received the high dose (2×10(12) vector genomes per kilogram of body weight). The patients subsequently underwent extensive clinical and laboratory monitoring. Results A single intravenous infusion of vector in all 10 patients with severe hemophilia B resulted in a dose-dependent increase in circulating factor IX to a level that was 1 to 6% of the normal value over a median period of 3.2 years, with observation ongoing. In the high-dose group, a consistent increase in the factor IX level to a mean (±SD) of 5.1±1.7% was observed in all 6 patients, which resulted in a reduction of more than 90% in both bleeding episodes and the use of prophylactic factor IX concentrate. A transient increase in the mean alanine aminotransferase level to 86 IU per liter (range, 36 to 202) occurred between week 7 and week 10 in 4 of the 6 patients in the high-dose group but resolved over a median of 5 days (range, 2 to 35) after prednisolone treatment. Conclusions In 10 patients with severe hemophilia B, the infusion of a single dose of AAV8 vector resulted in long-term therapeutic factor IX expression associated with clinical improvement. With a follow-up period of up to 3 years, no late toxic effects from the therapy were reported. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00979238 .).
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In Vitro Study of Genes and Molecular Pathways Differentially Regulated by Synchrotron Microbeam Radiotherapy.
Radiat. Res.
PUBLISHED: 11-20-2014
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The aim of this study was to identify genes and molecular pathways differentially regulated by synchrotron-generated microbeams (MRT) versus conventional radiotherapy (CRT) beams in vitro using cultured EMT6.5 cells. We hypothesized (based on previous findings) that gene expression and molecular pathway changes after MRT are different from those seen after CRT. We found that at 24 h postirradiation, MRT exerts a broader regulatory effect on multiple pathways than CRT. MRT regulated those pathways involved in gene transcription, translation initiation, macromolecule metabolism, oxidoreductase activity and signaling transduction in a different manner compared to CRT. We also found that MRT/CRT alone, or when combined with inflammatory factor lipopolysaccharide, upregulated expression of Ccl2, Ccl5 or Csf2, which are involved in host immune cell recruitment. Our findings demonstrated differences in the molecular pathway for MRT versus CRT in the cultured tumor cells, and were consistent with the idea that radiation plays a role in recruiting tumor-associated immune cells to the tumor. Our results also suggest that a combination of MRT/CRT with a treatment targeting CCL2 or Csf2 could repress the tumor-associated immune cell recruitment, delay tumor growth and/or metastasis and yield better tumor control than radiation alone.
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Association of Geographic and Seasonal Variation With Diverticulitis Admissions.
JAMA Surg
PUBLISHED: 11-20-2014
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The incidence of diverticulitis has been associated with geographic and seasonal variation. Low levels of circulating vitamin D are associated with diverticulitis. We investigated the association between UV light and diverticulitis.
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Clinical Outcomes of Splenectomy in Children: Report of the Splenectomy in Congenital Hemolytic Anemia (SICHA) Registry.
Am. J. Hematol.
PUBLISHED: 10-28-2014
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The outcomes of children with congenital hemolytic anemia (CHA) undergoing total splenectomy (TS) or partial splenectomy (PS) remain unclear. In this study, we collected data from 100 children with CHA who underwent TS or PS from 2005-2013 at 16 sites in the Splenectomy in Congenital Hemolytic Anemia (SICHA) consortium using a patient registry. We analyzed demographics and baseline clinical status, operative details, and outcomes at 4, 24, and 52 weeks after surgery. Results were summarized as hematologic outcomes, short-term adverse events (AEs) (? 30 days after surgery), and long-term AEs (31-365 days after surgery). For children with hereditary spherocytosis, after surgery there was an increase in hemoglobin (baseline 10.1 ± 1.8 gm/dl, 52 week 12.8 ± 1.6 gm/dl; mean ± SD), decrease in reticulocyte and bilirubin as well as control of symptoms. Children with sickle cell disease had control of clinical symptoms after surgery, but had no change in hematologic parameters. There was an 11% rate of short-term AEs and 11% rate of long-term AEs. As we accumulate more subjects and longer follow-up, use of a patient registry should enhance our capacity for clinical trials and engage all stakeholders in the decision-making process.
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Red meat intake, NAT2, and risk of colorectal cancer: A pooled analysis of 11 studies.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 10-25-2014
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Background: Red meat intake has been associated with risk of colorectal cancer (CRC), potentially mediated through heterocyclic amines. The metabolic efficiency of N-acetyltransferase 2 (NAT2) required for the metabolic activation of such amines is influenced by genetic variation. The interaction between red meat intake, NAT2 genotype, and CRC has been inconsistently reported. Methods: We used pooled individual-level data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Red meat intake was collected by each study. We inferred NAT2 phenotype based on polymorphism at rs1495741, highly predictive of enzyme activity. Interaction was assessed using multiplicative interaction terms in multivariate-adjusted models. Results: From 11 studies, 8,290 CRC cases and 9,115 controls were included. The highest quartile of red meat intake was associated with increased risk of CRC compared to the lowest quartile (OR 1.41, 95%CI 1.29 - 1.55). However, a significant association was observed only for studies with retrospective diet data, not for studies with diet prospectively assessed before cancer diagnosis. Combining all studies, high red meat intake was similarly associated with CRC in those with a rapid/intermediate NAT2 genotype (OR 1.38, 95%CI 1.20 - 1.59) as with a slow genotype (OR 1.43, 95%CI 1.28 - 1.61) (p- interaction=0.9). Conclusions: We found that high red meat intake was associated with increased risk of CRC only from retrospective case-control studies and not modified by NAT2 enzyme activity. Impact: Our results suggest no interaction between NAT2 genotype and red-meat intake in mediating risk of CRC.
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Tumor LINE-1 methylation level and microsatellite instability in relation to colorectal cancer prognosis.
J. Natl. Cancer Inst.
PUBLISHED: 09-04-2014
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Hypomethylation in long interspersed nucleotide element-1 (LINE-1) and high-degree microsatellite instability (MSI-high) in colorectal cancer (CRC) have been associated with inferior and superior survival, respectively; however, it remains uncertain whether the prognostic association of LINE-1 hypomethylation differs by MSI status. We hypothesized that the adverse prognostic association of LINE-1 hypomethylation might be stronger in MSI-high CRCs than in microsatellite stable (MSS) CRCs.
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Multiplication of microbes below 0.690 water activity: implications for terrestrial and extraterrestrial life.
Environ. Microbiol.
PUBLISHED: 08-20-2014
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Since a key requirement of known life forms is available water (water activity; aw ), recent searches for signatures of past life in terrestrial and extraterrestrial environments have targeted places known to have contained significant quantities of biologically available water. However, early life on Earth inhabited high-salt environments, suggesting an ability to withstand low water-activity. The lower limit of water activity that enables cell division appears to be ??0.605 which, until now, was only known to be exhibited by a single eukaryote, the sugar-tolerant, fungal xerophile Xeromyces bisporus. The first forms of life on Earth were, though, prokaryotic. Recent evidence now indicates that some halophilic Archaea and Bacteria have water-activity limits more or less equal to those of X.?bisporus. We discuss water activity in relation to the limits of Earth's present-day biosphere; the possibility of microbial multiplication by utilizing water from thin, aqueous films or non-liquid sources; whether prokaryotes were the first organisms able to multiply close to the 0.605-aw limit; and whether extraterrestrial aqueous milieux of ??0.605?aw can resemble fertile microbial habitats found on Earth.
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Plasma 25-hydroxyvitamin D and risk of colorectal cancer after adjusting for inflammatory markers.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 08-08-2014
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Despite the substantial epidemiologic evidence on the inverse association between circulating 25-hydroxyvitamin D [25(OH)D] and colorectal cancer, it remains controversial whether this relationship is causal or due to confounding by inflammation. We reevaluated the association between plasma 25(OH)D and colorectal cancer risk by additionally accounting for inflammatory markers in a prospective case-control study nested within the Nurses' Health Study and Health Professionals Follow-up Study (615 cases and 1,209 matched controls). Conditional logistic regression was used to estimate relative risk (RR) and 95% confidence interval (CI) of colorectal cancer in relation to quartiles of plasma 25(OH)D. Results were compared before and after adjusting for inflammatory markers in the multivariable model. Plasma 25(OH)D was associated with reduced risk of colorectal cancer (multivariable RR comparing extreme quartiles = 0.71; 95% CI, 0.52-0.97; Ptrend = 0.01). Additional adjustment for C-reactive protein, IL6, soluble tumor necrosis factor receptor 2, or a composite inflammatory score did not change the results [multivariable (including inflammatory score) RR = 0.72; 95% CI, 0.53-0.98; Ptrend = 0.02). Our findings suggest that confounding by inflammation, as reflected by circulating inflammatory markers, does not appear to account for the inverse association between plasma 25(OH)D and colorectal cancer.
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Water and temperature relations of soil Actinobacteria.
Environ Microbiol Rep
PUBLISHED: 08-05-2014
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Actinobacteria perform essential functions within soils, and are dependent on available water to do so. We determined the water-activity (aw ) limits for cell division of Streptomyces albidoflavus, Streptomyces rectiviolaceus, Micromonospora grisea and Micromonospora (JCM 3050) over a range of temperatures, using culture media supplemented with a biologically permissive solute (glycerol). Each species grew optimally at 0.998 aw (control; no added glycerol) and growth rates were near-optimal in the range 0.971-0.974 (1?M glycerol) at permissive temperatures. Each was capable of cell division at 0.916-0.924 aw (2?M glycerol), but only S.?albidoflavus grew at 0.895 or 0.897 aw (3?M glycerol, at 30 and 37°C respectively). For S.?albidoflavus, however, no growth occurred on media at ??0.870 (4?M glycerol) during the 40-day assessment period, regardless of temperature, and a theoretical limit of 0.877 aw was derived by extrapolation of growth curves. This level of solute tolerance is high for non-halophilic bacteria, but is consistent with reported limits for the growth and metabolic activities of soil microbes. The limit, within the range 0.895-0.870 aw , is very much inferior to those for obligately halophilic bacteria and extremely halophilic or xerophilic fungi, and is inconsistent with earlier reports of cell division at 0.500 aw . These findings are discussed in relation to planetary protection policy for space exploration and the microbiology of arid soils.
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MicroRNA-21 promotes glioblastoma tumorigenesis by down-regulating insulin-like growth factor-binding protein-3 (IGFBP3).
J. Biol. Chem.
PUBLISHED: 07-24-2014
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Despite advances in surgery, imaging, chemotherapy, and radiation, patients with glioblastoma multiforme (GBM), the most common histological subtype of glioma, have an especially dismal prognosis; >70% of GBM patients die within 2 years of diagnosis. In many human cancers, the microRNA miR-21 is overexpressed, and accumulating evidence indicates that it functions as an oncogene. Here, we report that miR-21 is overexpressed in human GBM cell lines and tumor tissue. Moreover, miR-21 expression in GBM patient samples is inversely correlated with patient survival. Knockdown of miR-21 in GBM cells inhibited cell proliferation in vitro and markedly inhibited tumor formation in vivo. A number of known miR-21 targets have been identified previously. By microarray analysis, we identified and validated insulin-like growth factor (IGF)-binding protein-3 (IGFBP3) as a novel miR-21 target gene. Overexpression of IGFBP3 in glioma cells inhibited cell proliferation in vitro and inhibited tumor formation of glioma xenografts in vivo. The critical role that IGFBP3 plays in miR-21-mediated actions was demonstrated by a rescue experiment, in which IGFBP3 knockdown in miR-21KD glioblastoma cells restored tumorigenesis. Examination of tumors from GBM patients showed that there was an inverse relationship between IGFBP3 and miR-21 expression and that increased IGFBP3 expression correlated with better patient survival. Our results identify IGFBP3 as a novel miR-21 target gene in glioblastoma and suggest that the oncogenic miRNA miR-21 down-regulates the expression of IGFBP3, which acts as a tumor suppressor in human glioblastoma.
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SMO Expression in Colorectal Cancer: Associations with Clinical, Pathological, and Molecular Features.
Ann. Surg. Oncol.
PUBLISHED: 07-15-2014
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Smoothened, frizzled family receptor (SMO) is an important component of the hedgehog signaling pathway, which has been implicated in various human carcinomas. However, clinical, molecular, and prognostic associations of SMO expression in colorectal cancer remain unclear.
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The role of FDG-PET/CT in the evaluation of residual disease in paediatric non-Hodgkin lymphoma.
Br. J. Haematol.
PUBLISHED: 07-07-2014
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(18) F-labelled-fluorodeoxyglucose positron emission tomography (FDG-PET) findings are challenging to interpret for residual disease versus complete response in paediatric patients with non-Hodgkin lymphoma (NHL). A biopsy is often warranted to confirm the presence or absence of viable tumour if there is clinical or radiographic evidence of residual disease. In this study, we compared conventional imaging and FDG-PET/computerized tomography (CT) findings with biopsy results in 18 children with NHL. Our goal was to provide additional data to establish more reliable criteria for response evaluation. Residual disease was suspected after conventional imaging alone in eight patients, after FDG-PET/CT alone in three and after both modalities in seven patients. Biopsy confirmed the presence of viable tumour in two patients. Two additional patients experienced progressive disease or relapse. The sensitivity and negative predictive value of FDG-PET/CT using the London criteria to indicate residual tumour detectable by biopsy were 100%, but specificity was low (60%), as was the positive predictive value (25%). Thus, in this study, a negative FDG-PET/CT finding was a good indicator of complete remission. However, because false-positive FDG-PET/CT findings are common, biopsy and close monitoring are required for accurate determination of residual disease in individual patients.
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Gene-environment interaction involving recently identified colorectal cancer susceptibility Loci.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 07-03-2014
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Genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) that are associated with risk of colorectal cancer. Prior research has evaluated the presence of gene-environment interaction involving the first 10 identified susceptibility loci, but little work has been conducted on interaction involving SNPs at recently identified susceptibility loci, including: rs10911251, rs6691170, rs6687758, rs11903757, rs10936599, rs647161, rs1321311, rs719725, rs1665650, rs3824999, rs7136702, rs11169552, rs59336, rs3217810, rs4925386, and rs2423279.
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Null association between vitamin D and PSA levels among black men in a vitamin D supplementation trial.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 06-28-2014
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Black men exhibit a high prevalence of vitamin D deficiency as well as a higher incidence of prostate cancer and higher mortality rates from prostate cancer than Whites. There are few data about the effect of vitamin D3 (cholecalciferol) supplementation on prostate-specific antigen (PSA) in healthy Black men.
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A review of the application of inflammatory biomarkers in epidemiologic cancer research.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 06-24-2014
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Inflammation is a facilitating process for multiple cancer types. It is believed to affect cancer development and progression through several etiologic pathways, including increased levels of DNA adduct formation, increased angiogenesis, and altered antiapoptotic signaling. This review highlights the application of inflammatory biomarkers in epidemiologic studies and discusses the various cellular mediators of inflammation characterizing the innate immune system response to infection and chronic insult from environmental factors. Included is a review of six classes of inflammation-related biomarkers: cytokines/chemokines, immune-related effectors, acute-phase proteins, reactive oxygen and nitrogen species, prostaglandins and cyclooxygenase-related factors, and mediators such as transcription factors and growth factors. For each of these biomarkers, we provide a brief overview of the etiologic role in the inflammation response and how they have been related to cancer etiology and progression within the literature. We provide a discussion of the common techniques available for quantification of each marker, including strengths, weaknesses, and potential pitfalls. Subsequently, we highlight a few under-studied measures to characterize the inflammatory response and their potential utility in epidemiologic studies of cancer. Finally, we suggest integrative methods for future studies to apply multifaceted approaches to examine the relationship between inflammatory markers and their roles in cancer development.
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Predicted 25(OH)D score and colorectal cancer risk according to vitamin D receptor expression.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 06-11-2014
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Despite accumulating evidence for the preventive effect of vitamin D on colorectal carcinogenesis, its precise mechanisms remain unclear. We hypothesized that vitamin D was associated with a lower risk of colorectal cancer with high-level vitamin D receptor (VDR) expression, but not with risk of tumor with low-level VDR expression.
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Cognitive styles and clinical correlates of childhood abuse in bipolar disorder.
Bipolar Disord
PUBLISHED: 05-26-2014
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In a relatively small number of previous studies, childhood abuse has been found to be associated with more severe symptom course, earlier onset, greater comorbidity, and greater suicidality in those diagnosed with bipolar disorder. There have been no prior reports looking for any association between childhood abuse and cognitive style. This study aimed to examine the relationship between cognitive factors, such as response styles to depressed mood and dysfunctional attitudes, clinical features, and childhood physical and sexual abuse in this population.
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Relating the metatranscriptome and metagenome of the human gut.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 05-19-2014
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Although the composition of the human microbiome is now well-studied, the microbiota's >8 million genes and their regulation remain largely uncharacterized. This knowledge gap is in part because of the difficulty of acquiring large numbers of samples amenable to functional studies of the microbiota. We conducted what is, to our knowledge, one of the first human microbiome studies in a well-phenotyped prospective cohort incorporating taxonomic, metagenomic, and metatranscriptomic profiling at multiple body sites using self-collected samples. Stool and saliva were provided by eight healthy subjects, with the former preserved by three different methods (freezing, ethanol, and RNAlater) to validate self-collection. Within-subject microbial species, gene, and transcript abundances were highly concordant across sampling methods, with only a small fraction of transcripts (<5%) displaying between-method variation. Next, we investigated relationships between the oral and gut microbial communities, identifying a subset of abundant oral microbes that routinely survive transit to the gut, but with minimal transcriptional activity there. Finally, systematic comparison of the gut metagenome and metatranscriptome revealed that a substantial fraction (41%) of microbial transcripts were not differentially regulated relative to their genomic abundances. Of the remainder, consistently underexpressed pathways included sporulation and amino acid biosynthesis, whereas up-regulated pathways included ribosome biogenesis and methanogenesis. Across subjects, metatranscriptional profiles were significantly more individualized than DNA-level functional profiles, but less variable than microbial composition, indicative of subject-specific whole-community regulation. The results thus detail relationships between community genomic potential and gene expression in the gut, and establish the feasibility of metatranscriptomic investigations in subject-collected and shipped samples.
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Urinary PGE-M levels are associated with risk of colorectal adenomas and chemopreventive response to anti-inflammatory drugs.
Cancer Prev Res (Phila)
PUBLISHED: 05-13-2014
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Prostaglandin E2 (PGE2) promotes colorectal carcinogenesis. Overall, systemic PGE2 production can be assessed by measuring its major metabolite, PGE-M, in urine. We examined the potential role of PGE-M as a biomarker for colorectal adenoma risk and chemopreventive response to anti-inflammatory drugs. We conducted a prospective case-control study nested within the Nurses' Health Study. Among women who previously provided a urine sample, we identified 420 cases diagnosed with colorectal adenoma during follow-up and matched them to 420 endoscopy-negative controls. We measured urinary PGE-M using an LC/MS assay. Compared with women in the lowest quartile of urinary PGE-M, women in the highest quartile had a multivariate OR of 1.40 (95% confidence interval (CI), 0.92-2.14) for any adenoma; 0.91 (95% CI, 0.48-1.72) for low-risk adenoma (solitary adenoma <1 cm in greatest diameter with tubular/unspecified histology); and 1.66 (95% CI, 1.04-2.67) for high-risk adenoma (adenoma ?1 cm in greatest diameter and/or tubulovillous, villous or high-grade dysplasia histology or multiple adenomas of any size or histology). Regular use of anti-inflammatory drugs (?2 standard tablets of aspirin/NSAIDs per week) was associated with a significant reduction in adenoma risk (multivariate OR, 0.61; 95% CI, 0.43-0.87) in women with high baseline PGE-M (quartiles 2-4), but not low PGE-M (quartile 1).Urinary PGE-M is associated with an increased risk of high-risk adenoma. Anti-inflammatory drugs seem to reduce adenoma risk among women with high, but not low PGE-M. Urinary PGE-M may serve as a biomarker to define subsets of the population who may obtain differential chemopreventive benefit from anti-inflammatory drugs.
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Microbiology of sugar-rich environments: diversity, ecology and system constraints.
Environ. Microbiol.
PUBLISHED: 05-09-2014
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Microbial habitats that contain an excess of carbohydrate in the form of sugar are widespread in the microbial biosphere. Depending on the type of sugar, prevailing water activity and other substances present, sugar-rich environments can be highly dynamic or relatively stable, osmotically stressful, and/or destabilizing for macromolecular systems, and can thereby strongly impact the microbial ecology. Here, we review the microbiology of different high-sugar habitats, including their microbial diversity and physicochemical parameters, which act to impact microbial community assembly and constrain the ecosystem. Saturated sugar beet juice and floral nectar are used as case studies to explore the differences between the microbial ecologies of low and higher water-activity habitats respectively. Nectar is a paradigm of an open, dynamic and biodiverse habitat populated by many microbial taxa, often yeasts and bacteria such as, amongst many others, Metschnikowia spp. and Acinetobacter spp., respectively. By contrast, thick juice is a relatively stable, species-poor habitat and is typically dominated by a single, xerotolerant bacterium (Tetragenococcus halophilus). A number of high-sugar habitats contain chaotropic solutes (e.g. ethyl acetate, phenols, ethanol, fructose and glycerol) and hydrophobic stressors (e.g. ethyl octanoate, hexane, octanol and isoamyl acetate), all of which can induce chaotropicity-mediated stresses that inhibit or prevent multiplication of microbes. Additionally, temperature, pH, nutrition, microbial dispersion and habitat history can determine or constrain the microbiology of high-sugar milieux. Findings are discussed in relation to a number of unanswered scientific questions.
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Double small bowel intussusception complicating bilateral partial nephrectomies.
J Pediatr Surg Case Rep
PUBLISHED: 05-06-2014
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An 11.5-month-old male, diagnosed with bilateral Wilms tumor at 10 months of age, received 6 weeks of chemotherapy and subsequently underwent bilateral partial nephrectomies. On postoperative day 5, he had crampy abdominal pain and bilious vomiting. Abdominal ultrasound confirmed the presence of an intussusception in the right lower quadrant. Laparotomy demonstrated two separate areas of small intestinal intussusception located at jejuno-jejunal and ileo-ileal locations. The patient was successfully treated with manual reduction. A high index of suspicion is necessary to diagnose and treat patients with two different points of intussusception.
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Aspirin and the risk of colorectal cancer in relation to the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD).
Sci Transl Med
PUBLISHED: 04-25-2014
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Aspirin use reduces the risk of colorectal neoplasia, at least in part, through inhibition of prostaglandin-endoperoxide synthase 2 (PTGS2, cyclooxygenase 2)-related pathways. Hydroxyprostaglandin dehydrogenase 15-(nicotinamide adenine dinucleotide) (15-PGDH, HPGD) is down-regulated in colorectal cancers and functions as a metabolic antagonist of PTGS2. We hypothesized that the effect of aspirin may be antagonized by low 15-PGDH expression in the normal colon. In the Nurses' Health Study and the Health Professionals Follow-Up Study, we collected data on aspirin use every 2 years and followed up participants for diagnoses of colorectal cancer. Duplication-method Cox proportional, multivariable-adjusted, cause-specific hazards regression for competing risks data was used to compute hazard ratios (HRs) for incident colorectal cancer according to 15-PGDH mRNA expression level measured in normal mucosa from colorectal cancer resections. Among 127,865 participants, we documented 270 colorectal cancer cases from which we could assess 15-PGDH expression. Compared with nonuse, regular aspirin use was associated with lower risk of colorectal cancer that developed within a background of colonic mucosa with high 15-PGDH expression [multivariable HR, 0.49; 95% confidence interval (CI), 0.34 to 0.71], but not with low 15-PGDH expression (multivariable HR, 0.90; 95% CI, 0.63 to 1.27) (P for heterogeneity = 0.018). Regular aspirin use was associated with lower incidence of colorectal cancers arising in association with high 15-PGDH expression, but not with low 15-PGDH expression in normal colon mucosa. This suggests that 15-PGDH expression level in normal colon mucosa may serve as a biomarker that may predict stronger benefit from aspirin chemoprevention.
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Large-scale genetic study in East Asians identifies six new loci associated with colorectal cancer risk.
Nat. Genet.
PUBLISHED: 04-21-2014
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Known genetic loci explain only a small proportion of the familial relative risk of colorectal cancer (CRC). We conducted a genome-wide association study of CRC in East Asians with 14,963 cases and 31,945 controls and identified 6 new loci associated with CRC risk (P = 3.42 × 10(-8) to 9.22 × 10(-21)) at 10q22.3, 10q25.2, 11q12.2, 12p13.31, 17p13.3 and 19q13.2. Two of these loci map to genes (TCF7L2 and TGFB1) with established roles in colorectal tumorigenesis. Four other loci are located in or near genes involved in transcriptional regulation (ZMIZ1), genome maintenance (FEN1), fatty acid metabolism (FADS1 and FADS2), cancer cell motility and metastasis (CD9), and cell growth and differentiation (NXN). We also found suggestive evidence for three additional loci associated with CRC risk near genome-wide significance at 8q24.11, 10q21.1 and 10q24.2. Furthermore, we replicated 22 previously reported CRC-associated loci. Our study provides insights into the genetic basis of CRC and suggests the involvement of new biological pathways.
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Progress and opportunities in molecular pathological epidemiology of colorectal premalignant lesions.
Am. J. Gastroenterol.
PUBLISHED: 04-18-2014
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Molecular pathological epidemiology (MPE) is an integrative molecular and population health science that addresses the molecular pathogenesis and heterogeneity of disease processes. The MPE of colonic and rectal premalignant lesions (including hyperplastic polyps, tubular adenomas, tubulovillous adenomas, villous adenomas, traditional serrated adenomas, sessile serrated adenomas/sessile serrated polyps, and hamartomatous polyps) can provide unique opportunities for examining the influence of diet, lifestyle, and environmental exposures on specific pathways of carcinogenesis. Colorectal neoplasia can provide a practical model by which both malignant epithelial tumor (carcinoma) and its precursor are subjected to molecular pathological analyses. KRAS, BRAF, and PIK3CA oncogene mutations, microsatellite instability, CpG island methylator phenotype, and LINE-1 methylation are commonly examined tumor biomarkers. Future opportunities include interrogation of comprehensive genomic, epigenomic, or panomic datasets, and the adoption of in vivo pathology techniques. Considering the colorectal continuum hypothesis and emerging roles of gut microbiota and host immunity in tumorigenesis, detailed information on tumor location is important. There are unique strengths and caveats, especially with regard to case ascertainment by colonoscopy. The MPE of colorectal premalignant lesions can identify etiologic exposures associated with neoplastic initiation and progression, help us better understand colorectal carcinogenesis, and facilitate personalized prevention, screening, and therapy.
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Complex phylogeography and historical hybridization between sister taxa of freshwater sculpin (Cottus).
Mol. Ecol.
PUBLISHED: 04-11-2014
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Species ranges that span different geographic landscapes frequently contain cryptic species- or population-level structure. Identifying these possible diversification factors can often be accomplished under a comparative phylogeographic framework. However, comparisons suffer if previous studies are limited to a particular group or habitat type. In California, a complex landscape has led to several phylogeographic breaks, primarily in terrestrial species. However, two sister taxa of freshwater fish, riffle sculpin (Cottus gulosus) and Pit sculpin (Cottus pitensis), display ranges based on morphological identifications that do not coincide with these breaks. Using a comprehensive sampling and nuclear, mitochondrial and microsatellite markers, we hypothesized that proposed species ranges are erroneous based on potential hybridization/gene flow between species. Results identified a phylogeographic signature consistent with this hypothesis, with breaks at the Coast Range Mountains and Sacramento/San Joaquin River confluence. Coastal locations of C. gulosus represent a unique lineage, and 'true' C. gulosus were limited to the San Joaquin basin, both regions under strong anthropogenic influence and potential conservation targets. C. pitensis limits extended historically throughout the Sacramento/Pit River basin but currently are restricted to the Pit River. Interestingly, locations in the Sacramento River contained low levels of ancestral hybridization and gene flow from C. gulosus but now appear to be a distinct population. The remaining population structure was strongly correlated with Sierra Nevada presence (high) or absence (low). This study stresses the importance of testing phylogeographic breaks across multiple taxa/habitats before conservation decisions are made, but also the potential impact of different geographic landscapes on evolutionary diversification.
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Genome-wide diet-gene interaction analyses for risk of colorectal cancer.
PLoS Genet.
PUBLISHED: 04-01-2014
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Dietary factors, including meat, fruits, vegetables and fiber, are associated with colorectal cancer; however, there is limited information as to whether these dietary factors interact with genetic variants to modify risk of colorectal cancer. We tested interactions between these dietary factors and approximately 2.7 million genetic variants for colorectal cancer risk among 9,287 cases and 9,117 controls from ten studies. We used logistic regression to investigate multiplicative gene-diet interactions, as well as our recently developed Cocktail method that involves a screening step based on marginal associations and gene-diet correlations and a testing step for multiplicative interactions, while correcting for multiple testing using weighted hypothesis testing. Per quartile increment in the intake of red and processed meat were associated with statistically significant increased risks of colorectal cancer and vegetable, fruit and fiber intake with lower risks. From the case-control analysis, we detected a significant interaction between rs4143094 (10p14/near GATA3) and processed meat consumption (OR = 1.17; p = 8.7E-09), which was consistently observed across studies (p heterogeneity = 0.78). The risk of colorectal cancer associated with processed meat was increased among individuals with the rs4143094-TG and -TT genotypes (OR = 1.20 and OR = 1.39, respectively) and null among those with the GG genotype (OR = 1.03). Our results identify a novel gene-diet interaction with processed meat for colorectal cancer, highlighting that diet may modify the effect of genetic variants on disease risk, which may have important implications for prevention.
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Rejection sensitivity and pain in bipolar versus unipolar depression.
Bipolar Disord
PUBLISHED: 03-19-2014
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Recent neuroimaging studies support the contention that depression, pain distress, and rejection distress share the same neurobiological circuits. In two recently published studies we confirmed the hypothesis that the perception of increased pain during both treatment-refractory depression (predominantly unipolar) and difficult-to-treat bipolar depression was related to increased state rejection sensitivity (i.e., rejection sensitivity when depressed). In the present study, we aimed to compare the correlates of pain and rejection sensitivity in individuals with bipolar versus unipolar depression and test the hypothesis that bipolar disorder may be distinguished from unipolar depression both by an increased perception of pain and heightened rejection sensitivity during depression.
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Long-term pulmonary function after metastasectomy for childhood osteosarcoma: a report from the St Jude lifetime cohort study.
J. Am. Coll. Surg.
PUBLISHED: 03-04-2014
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Complete resection of lung metastases improves survival in patients with osteosarcoma. We evaluated the long-term effect of metastasectomy on pulmonary function of patients treated for osteosarcoma during childhood.
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Sleep Duration Affects Risk for Ulcerative Colitis: A Prospective Cohort Study.
Clin. Gastroenterol. Hepatol.
PUBLISHED: 03-04-2014
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Sleep deprivation is associated with production of inflammatory cytokines. Disturbed sleep quality has been associated with increased risk of disease flare in patients with Crohn's disease (CD) or ulcerative colitis (UC). However, the association between sleep and risk of incident CD and UC has not been previously examined.
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Analyses of clinicopathological, molecular, and prognostic associations of KRAS codon 61 and codon 146 mutations in colorectal cancer: cohort study and literature review.
Mol. Cancer
PUBLISHED: 02-16-2014
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KRAS mutations in codons 12 and 13 are established predictive biomarkers for anti-EGFR therapy in colorectal cancer. Previous studies suggest that KRAS codon 61 and 146 mutations may also predict resistance to anti-EGFR therapy in colorectal cancer. However, clinicopathological, molecular, and prognostic features of colorectal carcinoma with KRAS codon 61 or 146 mutation remain unclear.
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Etiologic field effect: reappraisal of the field effect concept in cancer predisposition and progression.
Mod. Pathol.
PUBLISHED: 02-12-2014
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The term 'field effect' (also known as field defect, field cancerization, or field carcinogenesis) has been used to describe a field of cellular and molecular alteration, which predisposes to the development of neoplasms within that territory. We explore an expanded, integrative concept, 'etiologic field effect', which asserts that various etiologic factors (the exposome including dietary, lifestyle, environmental, microbial, hormonal, and genetic factors) and their interactions (the interactome) contribute to a tissue microenvironmental milieu that constitutes a 'field of susceptibility' to neoplasia initiation, evolution, and progression. Importantly, etiological fields predate the acquisition of molecular aberrations commonly considered to indicate presence of filed effect. Inspired by molecular pathological epidemiology (MPE) research, which examines the influence of etiologic factors on cellular and molecular alterations during disease course, an etiologically focused approach to field effect can: (1) broaden the horizons of our inquiry into cancer susceptibility and progression at molecular, cellular, and environmental levels, during all stages of tumor evolution; (2) embrace host-environment-tumor interactions (including gene-environment interactions) occurring in the tumor microenvironment; and, (3) help explain intriguing observations, such as shared molecular features between bilateral primary breast carcinomas, and between synchronous colorectal cancers, where similar molecular changes are absent from intervening normal colon. MPE research has identified a number of endogenous and environmental exposures which can influence not only molecular signatures in the genome, epigenome, transcriptome, proteome, metabolome and interactome, but also host immunity and tumor behavior. We anticipate that future technological advances will allow the development of in vivo biosensors capable of detecting and quantifying 'etiologic field effect' as abnormal network pathology patterns of cellular and microenvironmental responses to endogenous and exogenous exposures. Through an 'etiologic field effect' paradigm, and holistic systems pathology (systems biology) approaches to cancer biology, we can improve personalized prevention and treatment strategies for precision medicine.Modern Pathology advance online publication, 13 June 2014; doi:10.1038/modpathol.2014.81.
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Measures of adiposity are associated with increased risk of peptic ulcer.
Clin. Gastroenterol. Hepatol.
PUBLISHED: 02-10-2014
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Obesity is associated with systemic inflammation, alterations in the intestinal microbiome, and decreased epithelial integrity. The association between obesity and peptic ulcer has not been investigated thoroughly.
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Seven In Absentia Homolog 2 (SIAH2) downregulation is associated with tamoxifen resistance in MCF-7 breast cancer cells.
J. Surg. Res.
PUBLISHED: 02-07-2014
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A significant percentage of estrogen receptor (ER)-positive breast cancers are resistant to tamoxifen therapy. Seven in Absentia Homolog 2 (SIAH2), an E3 ubiquitin protein ligase, has been shown to be associated with resistance to antiestrogens. We sought to assess its role in the resistance of a breast cancer cell line, MCF-7, to the ER antagonist, tamoxifen.
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Dietary patterns during high school and risk of colorectal adenoma in a cohort of middle-aged women.
Int. J. Cancer
PUBLISHED: 02-05-2014
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Adolescent diet may be etiologically relevant for later risk of colorectal adenoma, a precursor of colorectal cancer. We aimed to examine associations between adolescent dietary patterns (derived using factor analysis) and risk of colorectal adenoma in middle adulthood. We analyzed data from 17,221 women participating in the Nurses' Health Study II, who had completed a validated high school (HS) food frequency questionnaire in 1998 when they were 34-51 years old, and had subsequently undergone at least one lower bowel endoscopy. Between 1998 and 2007, 1,299 women were diagnosed with at least one colorectal adenoma. In multivariable models adjusted for adult dietary patterns, a higher "prudent" pattern during HS, characterized by high consumption of vegetables, fruit and fish was associated with a statistically significantly lower risk of rectal (odds ratio [OR] highest vs. lowest quintile, 0.45, 95% CI 0.27-0.75, p-trend?=?0.005), but not colon adenomas. A higher "Western" pattern during HS, characterized by high consumption of desserts and sweets, snack foods and red and processed meat, was significantly associated with rectal (OR 1.78, 95% CI 1.12-2.85, p-trend?=?0.005) and advanced (OR 1.58, 95% CI 1.07-2.33, p-trend?=?0.08), but not associated with colon or non-advanced adenomas. This study suggests that overall eating patterns during high school may influence later risk of rectal and advanced adenoma, independent of adult diet. Our results support the hypothesis that diet during early life may influence colorectal carcinogenesis.
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Risk of hypercalcemia in blacks taking hydrochlorothiazide and vitamin D.
Am. J. Med.
PUBLISHED: 02-04-2014
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Hydrochlorothiazide, an effective antihypertensive medication commonly prescribed to blacks, decreases urinary calcium excretion. Blacks have significantly higher rates of hypertension and lower levels of 25-hydroxyvitamin D. Thus, they are more likely to be exposed to vitamin D supplementation and thiazide diuretics. The risk for hypercalcemia among blacks using vitamin D and hydrochlorothiazide is undefined.
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Repeat nephron-sparing surgery for children with bilateral Wilms tumor.
J. Pediatr. Surg.
PUBLISHED: 01-21-2014
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Renal insufficiency is a significant complication of Wilms tumor treatment in the 5% with bilateral disease. Nephron-sparing surgery (NSS) is recommended after neoadjuvant chemotherapy initially. However, the role of NSS in recurrent disease is unknown. We reviewed our experience to assess the feasibility and oncologic and functional outcomes of repeat NSS for children with recurrent disease.
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Dietary intake of fish, ?-3 and ?-6 fatty acids and risk of colorectal cancer: A prospective study in U.S. men and women.
Int. J. Cancer
PUBLISHED: 01-19-2014
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The association between fish, ?-3 and ?-6 polyunsaturated fatty acid (PUFA) intake and risk of colorectal cancer (CRC) remains inconclusive. Recent prospective studies suggest that the relationship may vary by gender, subsite and duration of follow-up. We followed 123,529 US adults (76,386 women and 47,143 men) without a history of cancer at baseline for 24 to 26 years. Fish and PUFA intake was assessed at baseline and updated every 4 years by using a validated food-frequency questionnaire. We found no overall association between fish, ?-3 and ?-6 PUFA intake and CRC risk with hazard ratio (HR) of 1.03 [95% confidence interval (CI): 0.89-1.20] comparing marine ?-3 intake of ? 0.30 g/d versus <0.15 g/d among women and 1.05 (95% CI: 0.85-1.30) comparing intake of ? 0.41 g/d versus <0.16 g/d among men. However, fish and marine ?-3 PUFA intake appeared to be positively associated with risk of distal colon cancer in both men and women and inversely with risk of rectal cancer in men. In an analysis based on a limited number of cases, marine ?-3 PUFA intake assessed 12-16 years before diagnosis tended to be inversely associated with CRC risk in men (HR: 0.76; 95% CI: 0.52-1.10). In conclusion, although no overall association between fish, ?-3 or ?-6 PUFA intake was observed with CRC risk, marine ?-3 PUFA may be differentially associated with risk of distal colon and rectal cancers and a long latency may be needed for its protection against CRC in men.
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Progress towards gene therapy for haemophilia B.
Int. J. Hematol.
PUBLISHED: 01-03-2014
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Haemophilia B is an X-linked recessive bleeding disorder, arising from a deficiency of coagulation factor IX. It has been a target for gene therapy ever since the factor IX gene was cloned in 1982. Several distinct approaches have been evaluated in humans over the last 30 years, but none has resulted in tangible corrections of the bleeding phenotype in humans until recently. Our group has now shown that lasting clinical improvement of the bleeding phenotype in patients with haemophilia B is possible following a single systemic administration of a self-complementary adeno-associated virus vector to deliver an optimised factor IX expression cassette to the liver. Success in this trial raises hope for patients with severe haemophilia B as well as others with inherited monogenetic disorders of the liver where current treatment options are limited.
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Increased Extinction Potential of Insular Fish Populations with Reduced Life History Variation and Low Genetic Diversity.
PLoS ONE
PUBLISHED: 01-01-2014
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Theoretical work has shown that reduced phenotypic heterogeneity leads to population instability and can increase extinction potential, yet few examples exist of natural populations that illustrate how varying levels expressed diversity may influence population persistence, particularly during periods of stochastic environmental fluctuation. In this study, we assess levels of expressed variation and genetic diversity among demographically independent populations of tidewater goby (Eucyclogobius newberryi), show that reductions in both factors typically coincide, and describe how low levels of diversity contribute to the extinction risk of these isolated populations. We illustrate that, for this annual species, continuous reproduction is a safeguard against reproductive failure by any one population segment, as natural, stochastically driven salinity increases frequently result in high mortality among juvenile individuals. Several study populations deviated from the natural pattern of year-round reproduction typical for the species, rendering those with severely truncated reproductive periods vulnerable to extinction in the event of environmental fluctuation. In contrast, demographically diverse populations are more likely to persist through such periods through the continuous presence of adults with broader physiological tolerance to abrupt salinity changes. Notably, we found a significant correlation between genetic diversity and demographic variation in the study populations, which could be the result of population stressors that restrict both of these diversity measures simultaneously, or suggestive of a causative relationship between these population characteristics. These findings demonstrate the importance of biocomplexity at the population level, and assert that the maintenance of diversity contributes to population resilience and conservation of this endangered species.
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Methodological Challenges in Collecting Social and Behavioural Data Regarding the HIV Epidemic among Gay and Other Men Who Have Sex with Men in Australia.
PLoS ONE
PUBLISHED: 01-01-2014
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Behavioural surveillance and research among gay and other men who have sex with men (GMSM) commonly relies on non-random recruitment approaches. Methodological challenges limit their ability to accurately represent the population of adult GMSM. We compared the social and behavioural profiles of GMSM recruited via venue-based, online, and respondent-driven sampling (RDS) and discussed their utility for behavioural surveillance.
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Joint effects of colorectal cancer susceptibility loci, circulating 25-hydroxyvitamin D and risk of colorectal cancer.
PLoS ONE
PUBLISHED: 01-01-2014
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Genome wide association studies (GWAS) have identified several SNPs associated with colorectal cancer (CRC) susceptibility. Vitamin D is also inversely associated with CRC risk.
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Dose response to vitamin D supplementation in African Americans: results of a 4-arm, randomized, placebo-controlled trial.
Am. J. Clin. Nutr.
PUBLISHED: 12-24-2013
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Association studies have suggested that lower circulating 25-hydroxyvitamin D [25(OH)D] in African Americans may partially underlie higher rates of cardiovascular disease and cancer in this population. Nonetheless, the relation between vitamin D supplementation and 25(OH)D concentrations in African Americans remains undefined.
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Impact of Vitamin D Supplementation on Inflammatory Markers in African-Americans: Results of a Four-Arm, Randomized, Placebo-Controlled Trial.
Cancer Prev Res (Phila)
PUBLISHED: 12-10-2013
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African-Americans have a disproportionate burden of inflammation-associated chronic diseases such as cancer and lower circulating levels of 25-hydroxyvitamin D [25(OH)D]. The effect of vitamin D3 (cholecalciferol) supplementation on inflammatory markers is uncertain. We conducted a randomized, double-blind, placebo-controlled trial of supplemental oral vitamin D (Placebo; 1,000; 2,000; or 4,000 IU/day of vitamin D3 orally for 3 months) in 328 African-Americans (median age, 51 years) of public housing communities in Boston, MA who were enrolled over 3 consecutive winter periods (2007-2010). Change from 0 to 3 months of plasma levels of 25(OH)D, high-sensitivity C-reactive protein (CRP), interleukin (IL)-6, interleukin (IL)-10, and soluble tumor necrosis factor alpha receptor type 2 (sTNF-R2) in 292 (89%) participants were measured. Overall, no statistically significant changes in CRP, IL-6, IL-10, and sTNF-R2 were observed after vitamin D supplementation period. Baseline CRP was significantly inversely associated with baseline 25(OH)D level (p<0.001) in unadjusted and adjusted models. An interaction between baseline 25(OH)D and vitamin D supplementation was observed for outcome change in log CRP (Month 3-Month 0) (p for interaction=0.04). Within an unselected population of African-Americans, short-term exposure to vitamin D supplementation produced no change in circulating inflammatory markers. This study confirms the strong independent association of CRP with 25(OH)D status even after adjusting for BMI. Future studies of longer supplemental vitamin D3 duration are necessary to examine the complex influence of vitamin D3 on CRP and other chronic inflammatory cytokines for possible reduction of cancer health disparities in African-Americans.
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Aspirin Use, 8q24 Single Nucleotide Polymorphism rs6983267, and Colorectal Cancer According to CTNNB1 Alterations.
J. Natl. Cancer Inst.
PUBLISHED: 12-07-2013
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Regular aspirin use reduces the risk for colorectal cancer (CRC), possibly through inhibition of WNT/cadherin-associated protein ?1 (CTNNB1 or ?-catenin) signaling. The single nucleotide polymorphism (SNP) rs6983267 on chromosome 8q24 is a CRC susceptibility locus that affects binding activity of transcription factor 7 like-2 (TCF7L2) to CTNNB1, thereby altering expression of target oncogenes, including MYC.
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T Lymphocytes Expressing a CD16 Signaling Receptor Exert Antibody-Dependent Cancer Cell Killing.
Cancer Res.
PUBLISHED: 11-06-2013
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To expand applications for T-cell-based immunotherapy in cancer, we designed a receptor that binds the Fc portion of human immunoglobulins and delivers activation signals. The construct included the high-affinity CD16 (FCGR3A) V158 variant, CD8? hinge, and transmembrane domains, along with signaling domains from CD3? and 4-1BB (TNFRSF9), forming a chimeric receptor termed CD16V-BB-?. After retrovirus-mediated expression in human T cells, CD16V-BB-? bound humanized antibodies with higher affinity than a control receptor containing the more common F158 variant. Engagement of CD16V-BB-? provoked T-cell activation, exocytosis of lytic granules, and sustained proliferation, with a mean cell recovery after 4-week coculture with Daudi lymphoma cells and rituximab of nearly 70-fold relative to input cells. In contrast, unbound antibody alone produced no effect. CD16V-BB-? T cells specifically killed lymphoma cells and primary chronic lymphocytic leukemia cells in combination with rituximab at a low effector:target ratio, even when assayed on mesenchymal cells. Trastuzumab triggered CD16V-BB-?-mediated killing of HER2 (ERBB2)(+) breast and gastric cancer cells; similar results were obtained with an anti-GD2 antibody in neuroblastoma and osteosarcoma cells. Furthermore, coadministration of CD16V-BB-? T cells with immunotherapeutic antibodies exerted considerable antitumor activity in vivo. Signaling mediated by 4-1BB-CD3? induced higher T-cell activation, proliferation, and cytotoxicity than CD3? or Fc?RI?, and the receptor was expressed effectively after mRNA electroporation without viral vectors, facilitating clinical translation. Our results offer preclinical proof of concept for CD16V-BB-? as a universal, next-generation chimeric receptor with the potential to augment the efficacy of antibody therapies for cancer. Cancer Res; 74(1); 1-11. ©2013 AACR.
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Long-term colorectal-cancer incidence and mortality after lower endoscopy.
N. Engl. J. Med.
PUBLISHED: 09-20-2013
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Colonoscopy and sigmoidoscopy provide protection against colorectal cancer, but the magnitude and duration of protection, particularly against cancer of the proximal colon, remain uncertain.
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Genetic predictors of circulating 25-hydroxyvitamin d and risk of colorectal cancer.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 08-27-2013
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Experimental evidence has demonstrated an antineoplastic role for vitamin D in the colon, and higher circulating 25-hydroxyvitamin D [25(OH)D] levels are consistently associated with a lower risk of colorectal cancer. Genome-wide association studies have identified loci associated with levels of circulating 25(OH)D. The identified single-nucleotide polymorphisms (SNPs) from four gene regions collectively explain approximately 5% of the variance in circulating 25(OH)D.
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Pleiotropic effects of genetic risk variants for other cancers on colorectal cancer risk: PAGE, GECCO and CCFR consortia.
Gut
PUBLISHED: 08-09-2013
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Genome-wide association studies have identified a large number of single nucleotide polymorphisms (SNPs) associated with a wide array of cancer sites. Several of these variants demonstrate associations with multiple cancers, suggesting pleiotropic effects and shared biological mechanisms across some cancers. We hypothesised that SNPs previously associated with other cancers may additionally be associated with colorectal cancer. In a large-scale study, we examined 171 SNPs previously associated with 18 different cancers for their associations with colorectal cancer.
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Constitutive activation of signal transducer and activator of transcription 3 (STAT3) and nuclear factor ?B signaling in glioblastoma cancer stem cells regulates the Notch pathway.
J. Biol. Chem.
PUBLISHED: 07-31-2013
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Malignant gliomas are locally aggressive, highly vascular tumors that have a dismal prognosis, and present therapies provide little improvement in the disease course and outcome. Many types of malignancies, including glioblastoma, originate from a population of cancer stem cells (CSCs) that are able to initiate and maintain tumors. Although CSCs only represent a small fraction of cells within a tumor, their high tumor-initiating capacity and therapeutic resistance drives tumorigenesis. Therefore, it is imperative to identify pathways associated with CSCs to devise strategies to selectively target them. In this study, we describe a novel relationship between glioblastoma CSCs and the Notch pathway, which involves the constitutive activation of STAT3 and NF-?B signaling. Glioma CSCs were isolated and maintained in vitro using an adherent culture system, and the biological properties were compared with the traditional cultures of CSCs grown as multicellular spheres under nonadherent culture conditions. Interestingly, both adherent and spheroid glioma CSCs show constitutive activation of the STAT3/NF-?B signaling pathway and up-regulation of STAT3- and NF-?B-dependent genes. Gene expression profiling also identified components of the Notch pathway as being deregulated in glioma CSCs, and the deregulated expression of these genes was sensitive to treatment with STAT3 and NF-?B inhibitors. This finding is particularly important because Notch signaling appears to play a key role in CSCs in a variety of cancers and controls cell fate determination, survival, proliferation, and the maintenance of stem cells. The constitutive activation of STAT3 and NF-?B signaling pathways that leads to the regulation of Notch pathway genes in glioma CSCs identifies novel therapeutic targets for the treatment of glioma.
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Cost-effectiveness analysis of chromoendoscopy for colorectal cancer surveillance in patients with ulcerative colitis.
Gastrointest. Endosc.
PUBLISHED: 07-30-2013
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Recent studies report that the risk of colorectal cancer (CRC) among patients with ulcerative colitis (UC) may be lower than previously estimated. Although white-light endoscopy (WLE) with random biopsies is recommended for dysplasia detection in patients with UC, several studies reported increased detection of dysplasia by chromoendoscopy.
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Plasma adiponectin and soluble leptin receptor and risk of colorectal cancer: a prospective study.
Cancer Prev Res (Phila)
PUBLISHED: 07-19-2013
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Adipokines are adipocyte-secreted hormones that may mediate the etiologic link between obesity and colorectal cancer; however, the evidence from large prospective studies is limited. We prospectively evaluated the association of plasma adiponectin and soluble leptin receptor (sOB-R) with colorectal cancer risk within the Nurses Health Study (1990-2008) and the Health Professionals Follow-up Study (1994-2008) among 616 incident colorectal cancer cases and 1,205 controls selected using risk-set sampling and matched on age and date of blood draw. In unconditional logistic regression with adjustment for matching factors and multiple risk factors, plasma adiponectin was significantly associated with reduced risk of colorectal cancer among men, but not among women. Compared with men in the lowest quartile of adiponectin, men in the highest quartile had a relative risk (RR) for colorectal cancer of 0.55 [95% confidence interval (CI), 0.35-0.86; Ptrend = 0.02]. The corresponding RR in women was 0.96 (95% CI, 0.67-1.39; Ptrend = 0.74). Plasma sOB-R was not associated with overall colorectal cancer risk in either men or women. A significant heterogeneity was noted in the association between sOB-R and colorectal cancer by subsite in women (Pheterogeneity = 0.004); sOB-R was significantly associated with increased risk of rectal cancer but not colon cancer. These findings support a role for adiponectin in colorectal carcinogenesis in men. Further studies are warranted to confirm these associations and elucidate potential underlying mechanisms.
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Long-term intake of dietary fat and risk of ulcerative colitis and Crohns disease.
Gut
PUBLISHED: 07-04-2013
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Dietary fats influence intestinal inflammation and regulate mucosal immunity. Data on the association between dietary fat and risk of Crohns disease (CD) and ulcerative colitis (UC) are limited and conflicting.
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Aspirin use and risk of colorectal cancer according to BRAF mutation status.
JAMA
PUBLISHED: 06-27-2013
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Aspirin use reduces the risk of colorectal carcinoma. Experimental evidence implicates a role of RAF kinases in up-regulation of prostaglandin-endoperoxide synthase 2 (PTGS2, cyclooxygenase 2), suggesting that BRAF-mutant colonic cells might be less sensitive to the antitumor effects of aspirin than BRAF-wild-type neoplastic cells.
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Higher Serum Levels of Vitamin D Are Associated With a Reduced Risk of Diverticulitis.
Clin. Gastroenterol. Hepatol.
PUBLISHED: 06-25-2013
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Recent studies have shown geographic and seasonal variations in hospital admissions for diverticulitis. Because this variation parallels differences in ultraviolet light exposure, the most important contributor to vitamin D status, we examined the association of prediagnostic serum levels of vitamin D with diverticulitis.
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A prospective study of duration of smoking cessation and colorectal cancer risk by epigenetics-related tumor classification.
Am. J. Epidemiol.
PUBLISHED: 06-20-2013
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The effect of duration of cigarette smoking cessation on colorectal cancer risk by molecular subtypes remains unclear. Using duplication-method Cox proportional-hazards regression analyses, we examined associations between duration of smoking cessation and colorectal cancer risk according to status of CpG island methylator phenotype (CIMP), microsatellite instability, v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation, or DNA methyltransferase-3B (DNMT3B) expression. Follow-up of 134,204 individuals in 2 US nationwide prospective cohorts (Nurses Health Study (1980-2008) and Health Professionals Follow-up Study (1986-2008)) resulted in 1,260 incident rectal and colon cancers with available molecular data. Compared with current smoking, 10-19, 20-39, and ?40 years of smoking cessation were associated with a lower risk of CIMP-high colorectal cancer, with multivariate hazard ratios (95% confidence intervals) of 0.53 (0.29, 0.95), 0.52 (0.32, 0.85), and 0.50 (0.27, 0.94), respectively (Ptrend = 0.001), but not with the risk of CIMP-low/CIMP-negative cancer (Ptrend = 0.25) (Pheterogeneity = 0.02, between CIMP-high and CIMP-low/CIMP-negative cancer risks). Differential associations between smoking cessation and cancer risks by microsatellite instability (Pheterogeneity = 0.02), DNMT3B expression (Pheterogeneity = 0.03), and BRAF (Pheterogeneity = 0.10) status appeared to be driven by the associations of CIMP-high cancer with microsatellite instability-high, DNMT3B-positive, and BRAF-mutated cancers. These molecular pathological epidemiology data suggest a protective effect of smoking cessation on a DNA methylation-related carcinogenesis pathway leading to CIMP-high colorectal cancer.
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Sexual risk behaviour, marriage and ART: a study of HIV-positive people in Papua New Guinea.
AIDS Res Ther
PUBLISHED: 06-19-2013
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The prevention of intimate partner transmission of HIV remains an important component of comprehensive HIV prevention strategies. In this paper we examine the sexual practices of people living with HIV on antiretroviral therapy (ART) in Papua New Guinea (PNG).
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A prospective study of long-term intake of dietary fiber and risk of Crohns disease and ulcerative colitis.
Gastroenterology
PUBLISHED: 05-14-2013
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Increased intake of dietary fiber has been proposed to reduce the risk of inflammatory bowel disease (Crohns disease [CD] and ulcerative colitis [UC]). However, few prospective studies have examined associations between long-term intake of dietary fiber and risk of incident CD or UC.
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Clinical management of infantile fibrosarcoma: a retrospective single-institution review.
Pediatr. Surg. Int.
PUBLISHED: 05-14-2013
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Infantile fibrosarcoma (IFS) is an uncommon soft-tissue sarcoma. Here we review our experience treating this tumor.
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Targeting oxidative stress in embryonal rhabdomyosarcoma.
Cancer Cell
PUBLISHED: 05-03-2013
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Rhabdomyosarcoma is a soft-tissue sarcoma with molecular and cellular features of developing skeletal muscle. Rhabdomyosarcoma has two major histologic subtypes, embryonal and alveolar, each with distinct clinical, molecular, and genetic features. Genomic analysis shows that embryonal tumors have more structural and copy number variations than alveolar tumors. Mutations in the RAS/NF1 pathway are significantly associated with intermediate- and high-risk embryonal rhabdomyosarcomas (ERMS). In contrast, alveolar rhabdomyosarcomas (ARMS) have fewer genetic lesions overall and no known recurrently mutated cancer consensus genes. To identify therapeutics for ERMS, we developed and characterized orthotopic xenografts of tumors that were sequenced in our study. High-throughput screening of primary cultures derived from those xenografts identified oxidative stress as a pathway of therapeutic relevance for ERMS.
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Is adrenalectomy necessary during unilateral nephrectomy for Wilms Tumor? A report from the Childrens Oncology Group.
J. Pediatr. Surg.
PUBLISHED: 04-26-2013
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To determine whether performing adrenalectomy at the time of nephrectomy for unilateral Wilms tumor impacts clinical outcome.
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Thoracoscopic resection of computed tomography-localized lung nodules in children.
J. Pediatr. Surg.
PUBLISHED: 04-16-2013
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Detection and treatment of small lung nodules are important in managing pediatric cancer. We studied the effectiveness of preoperative localization of pulmonary nodules by CT-guided needle hook wire placement followed by thoracoscopic resection in children with cancer.
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Phase I trial, pharmacokinetics, and pharmacodynamics of vandetanib and dasatinib in children with newly diagnosed diffuse intrinsic pontine glioma.
Clin. Cancer Res.
PUBLISHED: 03-27-2013
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Testing of promising drug combinations is crucial in the treatment of diffuse intrinsic pontine glioma (DIPG). As the VEGF and platelet-derived growth factor (PDGF) pathways are critical in gliomas, we evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of vandetanib, a VEGFR-2 inhibitor, combined with dasatinib, a potent PDGFR inhibitor, during and after radiotherapy in children with newly diagnosed DIPG.
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Anxiety, stress and perfectionism in bipolar disorder.
J Affect Disord
PUBLISHED: 03-26-2013
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Previous reports have highlighted perfectionism and related cognitive styles as a psychological risk factor for stress and anxiety symptoms as well as for the development of bipolar disorder symptoms. The anxiety disorders are highly comorbid with bipolar disorder but the mechanisms that underpin this comorbidity are yet to be determined.
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SBERIA: set-based gene-environment interaction test for rare and common variants in complex diseases.
Genet. Epidemiol.
PUBLISHED: 03-05-2013
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Identification of gene-environment interaction (G × E) is important in understanding the etiology of complex diseases. However, partially due to the lack of power, there have been very few replicated G × E findings compared to the success in marginal association studies. The existing G × E testing methods mainly focus on improving the power for individual markers. In this paper, we took a different strategy and proposed a set-based gene-environment interaction test (SBERIA), which can improve the power by reducing the multiple testing burdens and aggregating signals within a set. The major challenge of the signal aggregation within a set is how to tell signals from noise and how to determine the direction of the signals. SBERIA takes advantage of the established correlation screening for G × E to guide the aggregation of genotypes within a marker set. The correlation screening has been shown to be an efficient way of selecting potential G × E candidate SNPs in case-control studies for complex diseases. Importantly, the correlation screening in case-control combined samples is independent of the interaction test. With this desirable feature, SBERIA maintains the correct type I error level and can be easily implemented in a regular logistic regression setting. We showed that SBERIA had higher power than benchmark methods in various simulation scenarios, both for common and rare variants. We also applied SBERIA to real genome-wide association studies (GWAS) data of 10,729 colorectal cancer cases and 13,328 controls and found evidence of interaction between the set of known colorectal cancer susceptibility loci and smoking.
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Surgical treatment of pediatric desmoid tumors. A 12-year, single-center experience.
Ann. Surg. Oncol.
PUBLISHED: 03-04-2013
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Pediatric desmoid tumors (PDTs) represent a group of rare, distinct lesions. While sparse, available literature suggests that PDT are particularly aggressive and difficult to control when compared with their adult counterpart.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.