tbuckley/cabot-search huggingface dataset:
Personalized and graph genomes reveal missing signal in epigenomic data
Authors: Cristian Groza, Tony Kwan, Nicole Soranzo, Tomi Pastinen, Guillaume Bourque
Journal: Genome biology (2020)

Epigenomic studies that use next generation sequencing experiments typically rely on the alignment of reads to a reference sequence. However, because of genetic diversity and the diploid nature of the human genome, we hypothesize that using a generic reference could lead to incorrectly mapped reads and bias downstream results.We show that accounting for genetic variation using a modified reference genome or a de novo assembled genome can alter histone H3K4me1 and H3K27ac ChIP-seq peak calls either by creating new personal peaks or by the loss of reference peaks. Using permissive cutoffs, modified reference genomes are found to alter approximately 1% of peak calls while de novo assembled genomes alter up to 5% of peaks. We also show statistically significant differences in the amount of reads observed in regions associated with the new, altered, and unchanged peaks. We report that short insertions and deletions (indels), followed by single nucleotide variants (SNVs), have the highest probability of modifying peak calls. We show that using a graph personalized genome represents a reasonable compromise between modified reference genomes and de novo assembled genomes. We demonstrate that altered peaks have a genomic distribution typical of other peaks.Analyzing epigenomic datasets with personalized and graph genomes allows the recovery of new peaks enriched for indels and SNVs. These altered peaks are more likely to differ between individuals and, as such, could be relevant in the study of various human phenotypes.
Abstract MP61: Body Mass Index and Mortality among Adults with Incident Type Diabetes: Results from Two Prospective US Cohort Studies
Authors: Deirdre K Tobias, An Pan, Eric Ding, Chandra L Jackson, Eilis J O’Reilly, JoAnn E Manson, Walter C Willett, Frank B Hu
Journal: Circulation (2013)

Background: Recent evidence suggests that having normal weight at time of diagnosis of type 2 diabetes (T2D) is associated with an increased risk of premature death, compared to being overweight or obese; these studies were limited in their sample size and ability to adequately address residual confounding by smoking and reverse causation. Objective: To prospectively evaluate the association between body mass index (BMI) at T2D diagnosis and mortality in two large cohorts. Methods: Women and men with incident T2D from the Nurses’ Health Study (1978-2010; N=8,984) and Health Professionals Follow-up Study (1988-2010; N=2,443) were included if they were free of major chronic disease (cardiovascular disease [CVD], cancer) at T2D diagnosis. Participants’ self-reported body weight preceding diagnosis (mean 11 months) and height was used to calculate BMI (kg/m2). Cox proportional hazards models estimated the relative risk (HR) and 95% confidence interval (CI) for mortality across BMI categories. Multivariable models adjusted for age, smoking, baseline comorbidities (high blood pressure, cholesterol), and several other lifestyle factors. Fixed-effects meta-analyses were used to combine individual cohort estimates. Results: In all, 3,119 total deaths were observed over a follow-up of 36 years in women (18.7 deaths/1,000 person-years) and 26 years in men (25.2 deaths/1,000 person-years). A J-shaped association was observed across BMI categories (18.5-22.4, 22.5-24.9, 25.0-27.4, 27.5-29.9, 30.0-34.9, &gt;35.0) and all-cause mortality (HR [CI] by category: 1.26[1.03, 1.55], 1[reference], 1.11[0.97, 1.28], 1.08[0.94, 1.25], 1.19[1.04, 1.37], 1.33[1.15, 1.55]). After stratifying by smoking status, a direct linear association was present among never smokers and a J-shaped relationship persisted among ever smokers. Excluding deaths in the first 4 years of follow-up and adjusting for BMI change prior to diagnosis further accentuated the linear relationship between BMI and all-cause mortality among never smokers (0.90[0.57, 1.43], 1.00 [reference], 1.19[0.91, 1.57], 1.20[0.91, 1.58], 1.27[0.97, 1.65], 1.50[1.14, 1.99]; p-trend&lt;0.001). The association across BMI categories and CVD mortality was also linear among never smokers, and flat among ever smokers. In addition, among ever smokers, cancer mortality was highest among those with BMI 18.5-22.5. No clear trend was observed between BMI and mortality due to other causes. Excluding insulin users did not appreciably modify the associations. Conclusions: We found no evidence to support lower mortality rates among diabetics who were overweight or obese at diagnosis, compared to their normal-weight counterparts. In contrast, after accounting for confounding by smoking, we observed direct linear relationships between BMI and both all-cause and CVD mortality in our cohorts. Reducing other biases strengthened these relationships.
Distinct genomic profiles of 589 Chinese early-stage breast cancer.
Authors: Ning Liao, Guo-Chun Zhang, Xiaoqing Chen, Weikai Xiao, Jianguo Lai, Yulei Wang, Bo Chen, Chong-Yang Ren, XueRui Li, Kai Li, Ling-Zhu Wen, Li Cao, Minghan Jia, Guangnan Wei, Jiali Lin, Min Li, Analyn Lizaso, Han Han-Zhang, Jing Liu, Zhou Zhang
Journal: Journal of Clinical Oncology (2020)

552 Background: Extensive efforts by The Cancer Genome Atlas (TCGA) Network had provided much of our current understanding of the molecular profile of various solid tumors including breast tumors; however, Asian patients were underrepresented in this cohort. In this study, we aimed to elucidate the comprehensive genetic alteration profile of early-stage breast tumors among Chinese patients. Methods: Surgical tissue samples from 589 Chinese women with stage I-III breast cancer with various histology and molecular subtype consecutively diagnosed at Guangdong Provincial People’s Hospital were sequenced using a panel targeting 520 cancer-related genes spanning 1.64Mb of the human genome. Clinical and genomic data from our cohort was compared with publicly-available data from 1,046 stage I-III breast cancer patients from the TCGA dataset. Results: Based on the analysis of the genetic alteration profile from our cohort, at least one genetic alteration was observed from 98% of the tumor samples, with TP53 (47%), PIK3CA (45%), ERBB2 (30%), and CDK12 (18%) as the most commonly altered genes. The most common genetic alteration types were copy number amplification (43.6%) and missense mutations (36.8%). As compared with the TCGA dataset, our cohort is mostly composed of women 50 years and younger (59.1% vs. 30.4%, P&lt; 0.001), with significantly fewer patients with lobular carcinoma histology (2.4% vs. 19.0%, P&lt; 0.001), and significantly more patients with pathologic stage I tumors (23.3% vs. 17.3%, P= 0.012). Consistently, genetic alterations detected from our cohort affected genes involved in PI3K (63% vs. 56%, P= 0.009) and cell cycle (23% vs. 35%, P&lt; 0.001) pathways, with statistically different genetic alteration rates as compared with the TCGA dataset. Comparison of genetic alteration profile between the two cohorts revealed that our cohort had more frequent genetic alterations in genes including PIK3CA ( P&lt; 0.001), TP53, particularly in hotspot mutations Q192* ( P&lt; 0.001) and A307V/del ( P= 0.02), and ERBB2 amplification ( P&lt; 0.001). Conclusions: Our study contributes to the understanding of the key pathways and specific genetic alterations harbored by Chinese patients with early-stage breast cancer that could potentially be developed as markers of treatment response to targeted therapeutics.
Pattern of prescribing after disease progression following upfront docetaxel in metastatic hormone-naïve prostate cancer within the UK: Results from a national study.
Authors: Prantik Das, Sarah Taylor, Sadia Abdullah, Kiran Das
Journal: Journal of Clinical Oncology (2020)

e19190 Background: Upfront docetaxel is now standard of care for men with newly diagnosed metastatic hormone naïve prostate cancer .After disease progression following upfront docetaxel, various treatment agents including further lines of chemo or novel hormonal agents are used but there have been no convincing evidence or consensus opinion about optimal sequencing. Methods: We have conducted a national study in the UK by approaching oncologists who treat prostate cancer with systemic therapies. The oncologists were requested to complete a web based survey about their treatment decisions . Aim were to gain an insight about current practice following docetaxel in the UK and to identify the various disease and patients related factors which could influence the decision-making process. Results: 114 oncologists were invited and 59 have responded, 80% clinical oncologist and 20% medical oncologists respectively. At the point of castrate-resistant disease progression, following docetaxel, abiraterone was most commonly used agents (63%), followed by Enzalutamide (29%), cabazitaxel (6%) and docetaxel re-challenge respectively. Time difference between finishing docetaxel and disease progression was considered the most important deciding factor to choose next agents. Other important factors as per responders were volume of the disease, patients current symptoms, co morbidities and site of metastases . Most oncologists felt initial PSA and Gleason scores were two least important deciding factors. Patients with low volume disease, 92 % oncologist preferred abiraterone or enzalutamide as opposed to chemotherapy. When disease progressed within 6 months of completion of docetaxel, only one fifth of responder would use further chemo in next line .After novel hormone agents, cabazitaxel was the most commonly prescribed agents. 81% of clinicians would consider re-challenging with Docetaxel at some point of treatment sequencing; of these the majority would only consider this after a minimal interval of 12-18 months following upfront treatment. Conclusions: Our study has demonstrated a wide variation of practice in the UK. It has reflected that the decision is complex and there is clear need for further evidence or guideline for sequencing.
Cognitive status of Beijing suburban residents in tobacco harm and the study of intervention strategy
Authors: Fang An, Xing Guan, Gao Li, Ji-chuan Wang, Zhi-li Zhang, Jiao Chen, Meng-die Chen, Shu-xiao Shi
Journal: BMJ (2012)

Through random sampling,a total of 300 residents of Beijing Changping Ming Tombs Town were selected for home-based questionnaires.The smoking rate of interviewed residents was 21.4％ (53/248).The rate in men (42/125,33.6％ ) was bigber than that in women ( 11/123,8.9％ ).The rate in those with higher education was lower than that in those with lower educational level ( x2 =27.12,P ＜ 0.05 ).The population awareness of tobacco hazards was 80.6％ (200/248).Awareness in smokers was lower than the average awareness of ex-smokers and nonsmokers ( x2 =5.07,P ＜ 0.05 ).The higher the education level,the higher the awareness of tobacco health hazards ( x2 ≈ 19.72,P ＜ 0.05 ).There were differences in awareness among different age groups (x2 =13.37,P ＜ 0.05 ).

Key words: 
Tobacco use disorder; Questionnaires
Clinical analysis of 210 esophageal carcinoma patients undergoing dual-incision surgery of left neck and chest
Authors: She-lu Chu
Journal: BMJ (2008)

This investigation was to analyze surgical treatment data of 210 patients undergoing mid- upper-esophagectomy and esophagogastroplasty through esophagus bed during June 1996 and June 2006 to evaluate the efficacy of this alternative strategy.No death was reported.Fistula occurred in 5 patients (2.4%) and cured by suture and dressing change.Thirteen patients (6.2%) developed stricture and received endoscopic balloon ductal dilatation.Of them,9 patients completely recovered,2 improved,and 2 showed no response.These findings suggest that our surgical procedure is simple,fits for physiological function,and results in fewer pest-operative complications and lower mortality,thus could be an ideal treatment option for mid-upper esophageal carcinoma.

Key words: 
Esophageal neoplasms; Thoracic surgical procedres
Research progress on relationship between intestinal microbiota and chronic liver diseases
Authors: Shuoyi Ma
Journal: BMJ (2018)

The relationship of intestinal microbiota with multifarious diseases becomes a hot spot of research in recent years, and accumulated evidence indicates that the intestinal microbiota also plays a key role in chronic liver diseases. Due to special anatomical location between the liver and the intestinal tract, the conditions of liver and intestinal microbiota are extensively interacted. This article reviews the current research progress on the relationship between intestinal microbiota and chronic liver diseases.


Key words: 
Gastrointestinal microbiome; Liver disease
Blocking pro-invasive signaling and inflammatory activation in triple-negative breast cancer with nucleic-acid scavengers (NASs).
Authors: Elias Eteshola, Karenia Landa, Eun-Sil Shelley Hwang, Smita Nair, Bruce Sullenger
Journal: Journal of Clinical Oncology (2020)

e13096 Background: Breast cancers remain the most lethal malignancies amongst women worldwide and the second leading cause of cancer-related mortalities in the US. Subtype heterogeneity and aggressive invasive potential are believed to be the major contributors of these outcomes. Triple-negative breast cancer (TNBC) are notoriously aggressive, difficult-to-treat, and metastatic. Inflammation-driven tumorigenesis has been shown to correlate with cell-free DNA (cfDNA) and other damage-associated molecular patterns (DAMPs) in cancer patient sera. We showed that nucleic-acid scavengers (NAS) can block pro-inflammatory signals elicited by DAMP-activation of innate immune sensors (e.g. toll-like receptors). Treatment with the NAS PAMAM-G3 drastically reduced liver metastatic burden in an immunocompetent murine model of pancreatic cancer. Methods: TNBC cells lines were treated with a cocktail of standard-of-care chemotherapeutic agents and the conditioned media (CM) from these cells served as an in vitro DAMP source. Downstream function of TLR activation was tested via a HEK293-TLR reporter cell line measuring absorbance at 655nm. The in vitro invasive phenotype was tested and quantified using a Transwell-Matrigel invasion assay. Cytokine secretion was measured using a BioLegend cytokine array. Results: TNBC CM greatly increased TNBC cell invasion in vitro and that treatment with the NAS PAMAM-G3 significantly inhibits this effect. Treatment of human monocytes (THP-1) with TNBC CM elicited a strong pro-inflammatory response with elevated levels of IL-8, IL-6, CCL2, and IL-1β. Other biologically immune responders including human PBMCs will be tested to determine the potential impact on the tumor immune microenvironment during tumorigenesis and treatment. Conclusions: To elucidate the mechanism by which this NAS works in these tumor settings, our lab has developed several PAMAM-G3 derivatives, including biotin, IR-, and near-IR fluorophore labeled molecules. These molecules will allow us to capture and characterize DAMPs and do in vivo live imaging experiments to gain insight into NAS PK/PD properties. This insight into NAS capabilities will enhance our understanding of metastatic progression and its interplay with the immune system. Moreover, these principles will aid in the development of novel of anti-metastatic therapies to improve TNBC patient outcomes.
Prevalence and outcomes of <i>pneumocystis</i> pneumonia in patients with T-cell lymphoma.
Authors: Natalia Castillo Almeida, Pooja Gurram, Steven R Hwang, Nora N Benanni, Jason Barreto, Pritish Tosh, John W Wilson
Journal: Journal of Clinical Oncology (2020)

e20057 Background: T-cell lymphomas (TCL) are a heterogeneous group of rare, but aggressive non-Hodgkin lymphomas. CD4+ and CD8+ T-cell function plays a vital role in the immunologic response to P.jirovecii infection. Our study aims to define the prevalence of Pneumocystis jirovecii pneumonia (PJP) in HIV-uninfected TCL patients. Methods: All patients at Mayo Clinic, Rochester MN diagnosed with TCL and a positive Pneumocystis PCR assay from either bronchoalveolar lavage (BAL) fluid or other respiratory specimens were identified from March 2005 until November 2019. Patients with TCL and a diagnosis of PJP made outside of our medical center were identified through Advanced Cohort Explorer, a query building tool. Results: A total of 922 patients with TCL were identified, and only 14 cases (1.5%) had confirmed PJP. In confirmed PJP cases, the median age of TCL diagnosis was 62 years (IQR 51-70 years), 79% were male, and the median number of chemotherapy lines was 1.5 (IQR of 1-3). Half of the cases (6/12) received CHOP as first-line of therapy, followed by CHOEP (25%, 3/12). The median time to PJP diagnosis relative to chemotherapy was 18 days (IQR 14-27 days). Peripheral TCL, not otherwise specified was the most common TCL, followed by angioimmunoblastic TCL, and CD30+ T-cell lymphoproliferative disorders (64%, 29% and 7%, respectively). The primary specimen type sampled for PJP diagnosis was BAL fluid (n = 9, 64%), followed by sputum (n = 3, 22%), induced sputum (n = 1, 7%), and transbronchial lung biopsy (n = 1, 7%). Three patients had a prior autologous stem cell transplant (ASCT), and all three cases had relapsed TCL one year after ASCT. 77% of cases received oral prednisone equivalents (median dose of 25 mg, IQR 20-40 mg) 30 days prior to PJP diagnosis. Two patients developed PJP despite anti- Pneumocystis prophylaxis with aerosolized pentamidine. At the time of PJP diagnosis, most patients had lymphopenia (88%, 8/9), and CD4+ T-cells measurement was obtained only in one patient (CD4+ of 100 cells/mL). 71% of the cases were treated with trimethoprim/sulfamethoxazole (TMP/SMX). After the initial PJP episode, 36% of the cases were transitioned to TMP/SMX for secondary prophylaxis. All cause 30-day and 90-day mortality was 7% and 29%, respectively. Mortality attributed to PJP was 7% (n = 1). Conclusions: In our TCL cohort, the occurrence of PJP was low. Primary prophylaxis should be individualized in this population.
用力肺活量测试的质量控制
Authors: 高怡
Journal: BMJ (2011)

用力肺功能检查是临床上最常用的肺功能检查项目,主要通过肺量计完成.多种因素如肺量计的技术性能、测试环境、技术员素质、患者的依从性及配合能力、测试结果的解读和分析等都可能对结果产生影响[1].因此,严格的质量控制是正确评估检查结果的必要前提[2]。
喫煙誘発性の炎症におけるレクチン様酸化低密度リポ蛋白質受容体-1(LOX-1)の役割 | 文献情報 | J-GLOBAL 科学技術総合リンクセンター
Authors: Takanabe-Mori Rieko, Ono Koh, Wada Hiromichi, Takaya Tomohide, Yamakage Hajime, Satoh-Asahara Noriko, Shimatsu Akira, Takahashi Yuko, Fujita Masatoshi, Fujita Yoshiko, Sawamura Tatsuya, Hasegawa Koji
Journal: Circulation (2012)
The impact of tobacco retail density on overall survival (OS) in lung cancer survivors.
Authors: Lawson Eng, Katrina Hueniken, Todd A Norwood, Gerald J Romme, M. Catherine Brown, Andrew J. Hope, Andrea Bezjak, Adrian G. Sacher, Penelope Ann Bradbury, Frances A. Shepherd, Natasha B. Leighl, Andrew Pierre, Peter Selby, David Paul Goldstein, Wei Xu, Meredith Elana Giuliani, William K. Evans, Michael Chaiton, Geoffrey Liu
Journal: Journal of Clinical Oncology (2020)

12058 Background: Continued smoking after a cancer diagnosis is associated with poorer outcomes. We previously identified that tobacco retail outlet density is negatively associated with cessation in lung cancer survivors (ASCO 2019). However, the impact of tobacco retail density on survival has not been evaluated. We evaluated the impact of tobacco retail density on OS in lung cancer patients (pts). Methods: Lung cancer pts diagnosed from 2009-2012 were recruited at diagnosis and completed a baseline questionnaire on their socio-demographics, ECOG and smoking history. Clinicopathologic data including stage, histology and OS data were collected. Validated tobacco retail location data obtained from Ministry of Health and pt home addresses were geocoded using ArcGIS 10.6.1, which calculated tobacco outlet density within 250 meters (m) and 500m from pts. Multivariable Cox proportional hazard models evaluated the impact of tobacco outlet density on OS adjusted for significant clinicodemographic covariates. Results: Among 1411 pts, median age 66, 53% female, 8% small cell/56% adenocarcinoma/17% squamous/19% other, 28% stage 1/9% stage 2/20% stage 3/35% stage 4, 38% were current smokers at diagnosis and 40% were ex-smokers; median OS was 24 months. On average, there was one vendor (range 0-23) within 250m and four vendors (range 0-44) within 500m from pts; 33% and 60% of pts lived within 250m and 500m from at least one vendor respectively. The final baseline multivariable model consisted of age, gender, stage, smoking status, ECOG and neighbourhood marginalization index ( P&lt; 0.05). Among all pts, not living within 250m to an outlet improved OS (aHR 0.84 [0.72-0.97] P= 0.02). Living near more outlets within 250 m (aHR 1.03 per outlet [1.00-1.05] P= 0.03) or 500 m (aHR 1.01 per outlet [1.00-1.02] P= 0.04) worsened OS. Subgroup analysis based on smoking status at diagnosis, identified that among current smokers, not living within 250m to an outlet improved OS (aHR 0.76 [0.60-0.97] P= 0.03), and among ex-smokers, living near more outlets within 500 m worsened OS (aHR 1.02 per outlet [0.99-1.03] P= 0.07); other associations showed similar directionality. Among 135 current smokers at diagnosis with follow-up smoking status, not living within 250m to an outlet continued to show a trend towards improved OS (aHR 0.57 [0.31-1.03] P= 0.06), after also adjusting for follow-up smoking status. Conclusions: Living near a greater density of tobacco outlets is associated with poorer OS among lung cancer pts. Reducing the density of tobacco outlets may be a strategy that can help improve lung cancer pt outcomes.