tbuckley/cabot-search huggingface dataset:
Detection of Shared Balancing Selection in the Absence of Trans-Species Polymorphism
Authors: Xiaoheng Cheng, Michael DeGiorgio
Journal: Molecular Biology and Evolution (2018)

Trans-species polymorphism has been widely used as a key sign of long-term balancing selection across multiple species. However, such sites are often rare in the genome and could result from mutational processes or technical artifacts. Few methods are yet available to specifically detect footprints of trans-species balancing selection without using trans-species polymorphic sites. In this study, we develop summary- and model-based approaches that are each specifically tailored to uncover regions of long-term balancing selection shared by a set of species by using genomic patterns of intraspecific polymorphism and interspecific fixed differences. We demonstrate that our trans-species statistics have substantially higher power than single-species approaches to detect footprints of trans-species balancing selection, and are robust to those that do not affect all tested species. We further apply our model-based methods to human and chimpanzee whole-genome sequencing data. In addition to the previously established major histocompatibility complex and malaria resistance-associated FREM3/GYPE regions, we also find outstanding genomic regions involved in barrier integrity and innate immunity, such as the GRIK1/CLDN17 intergenic region, and the SLC35F1 and ABCA13 genes. Our findings not only echo the significance of pathogen defense but also reveal novel candidates in maintaining balanced polymorphisms across human and chimpanzee lineages. Finally, we show that these trans-species statistics can be applied to and work well for an arbitrary number of species, and integrate them into open-source software packages for ease of use by the scientific community.
Nanoparticle-drug conjugates treating bacterial infections
Authors: Pavlina Jelinkova, Aninda Mazumdar, Vishma Pratap Sur, Silvia Kociova, Kristyna Dolezelikova, Ana Maria Jimenez Jimenez, Zuzana Koudelkova, Pawan Kumar Mishra, Kristyna Smerkova, Zbynek Heger, Marketa Vaculovicova, Amitava Moulick, Vojtech Adam
Journal: Journal of Controlled Release (2019)
PF313 NEW TREATMENT FOR DOUBLE/TRIPLE HIT LYMPHOMA WITH DOSE INTENSE PROTOCOL: RITUXIMAB,DOXORUBICIN,ETOPOSIDE,PREDNISOLONE/GEMCITABINE+OXALIPLATIN SHAWING BETTER SURVIVAL RATE
Authors: M. Salamoon, M. balti, M. kenj
Journal: HemaSphere (2019)

Background: unclassifiable B‐cell lymphoma with features between diffuse large B‐cell and Burkitt, Burkitt‐like with a complex karyotype involving MYC and BCL‐2 genes (double hit) and BCL‐6 gene (triple hit). This kind of lymphoma shows high mitotic rates and an aggressive course for which no definitive treatment have been established so far. Aims: the study is aiming at evaluating a new dose intense chemotherapy in patients with double/triple hit lymphoma with end points including progression free and overall survival at 5 years. Methods: this is a multicenter study with Al Bairouni university cancer center in Damascus, Syria as the main investigator performed between 2014 and 2018 where we recruited 66 patients with ages between 18 and 65 years having double/triple hit lymphoma confirmed by immuno‐histochemistry as well as FISH technique. Patients received a dose intense protocol as follows: (Rituximab 375 mg/m 2 with Doxorubicin 75 mg/m 2 , Cyclophosphamide 1200 mg/m 2 , Etopdside 300 mg/m 2 and Prednisolone 1 mg/kg for 5 days) repeated every 21 days for 6 cycles with 5 days G‐csf support. Then partial and complete responders were given (Gemcitabine 1gr/m 2 + Oxaliplatin 85 mg/m 2 ) for 6 cycles repeated every 14 days. End‐points were progression free survival and overall survival at 5 years. Results: overall response rate (ORR) was documented in 58 patients (87.8%) (42 complete responders and 16 partial responders). 12 patients progressed at different stages of follow up with a progression free survival (PFS) of 82% (95% CI 77–88). However, 51 patients were found to still alive at 5 years with an overall survival (OS) rate of 77.2(95% CI 71–82). Survival was shorter in those presented with synchronous central nervous system and abdominal localizations (P value 0.02). The most frequent toxicities were, neutropenia and thromcytopenia of different grades, tumorlysis syndrome in few patients and different degrees of mucositis and peripheral neuropathy, however, no documented death was attributed to toxicity profile. Summary/Conclusion: double/triple hit lymphoma is a new subtype of lymphoma involving a 2–3 genes abnormalities which increase the aggressiveness course of disease with most patients resisting the old standards. Recently, patients were responding to the classical R‐CHOP as well as to R‐EPOCH in both young and elderly patients, however, survival rates were not exceeding 65% at 5 years. That is why we have developed this protocol with high dose chemotherapy in order to overcome resistance and consolidate the primary response. Compared with studies published in the literature, our protocol confers better progression free and overall survival rates, however, bigger trials should be performed to validate our results
Antimicrobial resistance of Helicobacter pylori in Germany, 2015 to 2018
Authors: B. Bluemel, H. Goelz, B. Goldmann, J. Grüger, H. Hamel, K. Loley, T. Ludolph, J. Meyer, S. Miehlke, A. Mohr, K. Tüffers, H. Usadel, S. Wagner, H. Wenzel, L. Wiemer, J. Vorreiter, B. Eisele, D. Hofreuter, E.-O. Glocker
Journal: Clinical Microbiology and Infection (2019)
Cardiovascular Events and Mortality in White Coat Hypertension
Authors: Jordana B. Cohen, Michael J. Lotito, Usha K. Trivedi, Matthew G. Denker, Debbie L. Cohen, Raymond R. Townsend
Journal: Annals of Internal Medicine (2019)

The long-term cardiovascular risk of isolated elevated office blood pressure (BP) is unclear.To summarize the risk for cardiovascular events and all-cause mortality associated with untreated white coat hypertension (WCH) and treated white coat effect (WCE).PubMed and EMBASE, without language restriction, from inception to December 2018.Observational studies with at least 3 years of follow-up evaluating the cardiovascular risk of WCH or WCE compared with normotension.2 investigators independently extracted study data and assessed study quality.27 studies were included, comprising 25 786 participants with untreated WCH or treated WCE and 38 487 with normal BP followed for a mean of 3 to 19 years. Compared with normotension, untreated WCH was associated with an increased risk for cardiovascular events (hazard ratio [HR], 1.36 [95% CI, 1.03 to 2.00]), all-cause mortality (HR, 1.33 [CI, 1.07 to 1.67]), and cardiovascular mortality (HR, 2.09 [CI, 1.23 to 4.48]); the risk for WCH was attenuated in studies that included stroke in the definition of cardiovascular events (HR, 1.26 [CI, 1.00 to 1.54]). No significant association was found between treated WCE and cardiovascular events (HR, 1.12 [CI, 0.91 to 1.39]), all-cause mortality (HR, 1.11 [CI, 0.89 to 1.46]), or cardiovascular mortality (HR, 1.04 [CI, 0.65 to 1.66]). The findings persisted across several sensitivity analyses.Paucity of studies evaluating isolated cardiac outcomes or reporting participant race/ethnicity.Untreated WCH, but not treated WCE, is associated with an increased risk for cardiovascular events and all-cause mortality. Out-of-office BP monitoring is critical in the diagnosis and management of hypertension.National Institutes of Health.
AB1403-HPR INVESTIGATION OF SPINE POSTURE, MOBILITY AND POSTURAL COMPETENCY IN LOW BACK PAIN PATIENTS WITH MODERATE TO SEVERE DISABILITY: A CASE-CONTROL STUDY
Authors: Derya Ozer Kaya, Seyda Toprak Celenay
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Low back pain (LBP) is the most common musculoskeletal complaint especially in women that causing disability and growing as a global burden (1,2). Changes in spine structures and alignment have been important in the occurrence of LBP (3,4). <h3>Objectives</h3> This study aimed to investigate spine posture, mobility and postural competency in women with and without LBP. <h3>Methods</h3> Thirty-four women with LBP having moderate to severe disability (age: 50.509.26 years; body mass index (BMI): 34.765.42 kg/m<sup>2</sup>) and age-gender matched 37 asymptomatic healthy women (age: 48.948.99 years; BMI: 31.976.88 kg/m<sup>2</sup>) were included. Oswetry Disability Index (ODI) was used for disability assessment (higher scores indicated more severe disability (0-50)). Overall spine posture, mobility, postural competency and spine check scores were evaluated using the Spinal Mouse (Idiag, Fehraltorf, Switzerland) device in standing position. The scores were evaluated between as poor "0" and "100" as perfect. T test was used for analysis. <h3>Results</h3> The mean score of ODI was 32.258.27 (moderate to severe disability). The scores of spine posture, mobility, postural competency and total spine check of women with LBP were found 24.7615.65; 25.1114.60; 36.6421.58; 30.2612.06, respectively; while, the scores of asymptomatic women were found 34.6716.27; 34.4521.47; 38.2115.18; 38.7215.06, respectively. Lower posture (p=0.011), mobility (p=0.037) and total spine check scores (p=0.011) were found in women with LBP compared to the controls; however, the postural competency was similar (p=0.722). <h3>Conclusion</h3> Women with LBP had poor spine posture, mobility and total spine check scores, but similar postural competency in comparison to controls. In the clinics, considering these parameters might be important while planning the optimal treatment for LBP. <h3>References</h3> [1] Hoy D, Bain C, Williams G, March L, Brooks P, Blyth F, Woolf A, Vos T, Buchbinder R. A systematic review of the global prevalence of low back pain. Arthritis Rheum 2012;64:2028-2037. [2] Buchbinder R, van Tulder M, berg B, Costa LM, Woolf A, Schoene M, Croft P; Lancet Low Back Pain Series Working Group. Low back pain: a call for action. Lancet. 2018 9;391(10137):2384-2388. [3] Alricsson M, Bjrklund G, Cronholm M, Olsson O, Viklund P, Svantesson U. Spinal alignment, mobility of the hip and thoracic spine and prevalence of low back pain in young elite cross-country skiers. J Exerc Rehabil. 2016;12(1):21-8. [4] Misir A, Kizkapan TB, Tas SK, Yildiz KI, Ozcamdalli M, Yetis M. Lumbar spine posture and spinopelvic parameters change in various standing and sitting postures. Eur Spine J. 2018 Nov 29. doi: 10.1007/s00586-018-5846-z. <h3>Disclosure of Interests</h3> None declared
Chromosome-scale comparative sequence analysis unravels molecular mechanisms of genome dynamics between two wheat cultivars
Authors: Anupriya Kaur Thind, Thomas Wicker, Thomas Müller, Patrick M. Ackermann, Burkhard Steuernagel, Brande B. H. Wulff, Manuel Spannagl, Sven O. Twardziok, Marius Felder, Thomas Lux, Klaus F. X. Mayer, Beat Keller, Simon G. Krattinger
Journal: Genome biology (2018)

Recent improvements in DNA sequencing and genome scaffolding have paved the way to generate high-quality de novo assemblies of pseudomolecules representing complete chromosomes of wheat and its wild relatives. These assemblies form the basis to compare the dynamics of wheat genomes on a megabase scale.Here, we provide a comparative sequence analysis of the 700-megabase chromosome 2D between two bread wheat genotypes-the old landrace Chinese Spring and the elite Swiss spring wheat line 'CH Campala Lr22a'. Both chromosomes were assembled into megabase-sized scaffolds. There is a high degree of sequence conservation between the two chromosomes. Analysis of large structural variations reveals four large indels of more than 100 kb. Based on the molecular signatures at the breakpoints, unequal crossing over and double-strand break repair were identified as the molecular mechanisms that caused these indels. Three of the large indels affect copy number of NLRs, a gene family involved in plant immunity. Analysis of SNP density reveals four haploblocks of 4, 8, 9 and 48 Mb with a 35-fold increased SNP density compared to the rest of the chromosome. Gene content across the two chromosomes was highly conserved. Ninety-nine percent of the genic sequences were present in both genotypes and the fraction of unique genes ranged from 0.4 to 0.7%.This comparative analysis of two high-quality chromosome assemblies enabled a comprehensive assessment of large structural variations and gene content. The insight obtained from this analysis will form the basis of future wheat pan-genome studies.
Chromatin loop anchors are associated with genome instability in cancer and recombination hotspots in the germline
Authors: Vera B. Kaiser, Colin A. Semple
Journal: Genome biology (2018)

Chromatin loops form a basic unit of interphase nuclear organization, with chromatin loop anchor points providing contacts between regulatory regions and promoters. However, the mutational landscape at these anchor points remains under-studied. Here, we describe the unusual patterns of somatic mutations and germline variation associated with loop anchor points and explore the underlying features influencing these patterns.Analyses of whole genome sequencing datasets reveal that anchor points are strongly depleted for single nucleotide variants (SNVs) in tumours. Despite low SNV rates in their genomic neighbourhood, anchor points emerge as sites of evolutionary innovation, showing enrichment for structural variant (SV) breakpoints and a peak of SNVs at focal CTCF sites within the anchor points. Both CTCF-bound and non-CTCF anchor points harbour an excess of SV breakpoints in multiple tumour types and are prone to double-strand breaks in cell lines. Common fragile sites, which are hotspots for genome instability, also show elevated numbers of intersecting loop anchor points. Recurrently disrupted anchor points are enriched for genes with functions in cell cycle transitions and regions associated with predisposition to cancer. We also discover a novel class of CTCF-bound anchor points which overlap meiotic recombination hotspots and are enriched for the core PRDM9 binding motif, suggesting that the anchor points have been foci for diversity generated during recent human evolution.We suggest that the unusual chromatin environment at loop anchor points underlies the elevated rates of variation observed, marking them as sites of regulatory importance but also genomic fragility.
Comparative proteogenomic analysis of right-sided colon cancer, left-sided colon cancer and rectal cancer reveals distinct mutational profiles
Authors: Robin Imperial, Zaheer Ahmed, Omer M. Toor, Cihat Erdoğan, Ateeq Khaliq, Paul Case, James Case, Kevin Kennedy, Lee S. Cummings, Niklas Melton, Shahzad Raza, Banu Diri, Ramzi Mohammad, Bassel El-Rayes, Timothy Pluard, Arif Hussain, Janakiraman Subramanian, Ashiq Masood
Journal: Molecular Cancer (2018)

Right-sided colon cancer (RCC) has worse prognosis compared to left-sided colon cancer (LCC) and rectal cancer. The reason for this difference in outcomes is not well understood. We performed comparative somatic and proteomic analyses of RCC, LCC and rectal cancers to understand the unique molecular features of each tumor sub-types. Utilizing a novel in silico clonal evolution algorithm, we identified common tumor-initiating events involving APC, KRAS and TP53 genes in RCC, LCC and rectal cancers. However, the individual role-played by each event, their order in tumor development and selection of downstream somatic alterations were distinct in all three anatomical locations. Some similarities were noted between LCC and rectal cancer. Hotspot mutation analysis identified a nonsense mutation, APC R1450* specific to RCC. In addition, we discovered new significantly mutated genes at each tumor location, Further in silico proteomic analysis, developed by our group, found distinct central or hub proteins with unique interactomes among each location. Our study revealed significant differences between RCC, LCC and rectal cancers not only at somatic but also at proteomic level that may have therapeutic relevance in these highly complex and heterogeneous tumors.
Comparison of whole-genome bisulfite sequencing library preparation strategies identifies sources of biases affecting DNA methylation data
Authors: Nelly Olova, Felix Krueger, Simon Andrews, David Oxley, Rebecca V. Berrens, Miguel R. Branco, Wolf Reik
Journal: Genome biology (2018)

Whole-genome bisulfite sequencing (WGBS) is becoming an increasingly accessible technique, used widely for both fundamental and disease-oriented research. Library preparation methods benefit from a variety of available kits, polymerases and bisulfite conversion protocols. Although some steps in the procedure, such as PCR amplification, are known to introduce biases, a systematic evaluation of biases in WGBS strategies is missing. We perform a comparative analysis of several commonly used pre- and post-bisulfite WGBS library preparation protocols for their performance and quality of sequencing outputs. Our results show that bisulfite conversion per se is the main trigger of pronounced sequencing biases, and PCR amplification builds on these underlying artefacts. The majority of standard library preparation methods yield a significantly biased sequence output and overestimate global methylation. Importantly, both absolute and relative methylation levels at specific genomic regions vary substantially between methods, with clear implications for DNA methylation studies. We show that amplification-free library preparation is the least biased approach for WGBS. In protocols with amplification, the choice of bisulfite conversion protocol or polymerase can significantly minimize artefacts. To aid with the quality assessment of existing WGBS datasets, we have integrated a bias diagnostic tool in the Bismark package and offer several approaches for consideration during the preparation and analysis of WGBS datasets.
Telemonitoring-supported exercise training, metabolic syndrome severity, and work ability in company employees: a randomised controlled trial
Authors: Sven Haufe, Arno Kerling, Gudrun Protte, Pauline Bayerle, Hedwig T Stenner, Simone Rolff, Thorben Sundermeier, Momme Kück, Ralf Ensslen, Lars Nachbar, Dirk Lauenstein, Dietmar Böthig, Christoph Bara, Alexander A Hanke, Christoph Terkamp, Meike Stiesch, Denise Hilfiker-Kleiner, Axel Haverich, Uwe Tegtbur
Journal: The Lancet Public Health (2019)

Metabolic syndrome is a predisposing factor for cardiovascular and metabolic disease, but also has socioeconomic relevance by affecting the health and productivity of workers. We tested the effect of regular telemonitoring-supported physical activity on metabolic syndrome severity and work ability in company employees.This was a prospective, randomised, parallel-group, and assessor-blind study done in workers in the main Volkswagen factory (Wolfsburg, Germany). Volunteers with diagnosed metabolic syndrome according to American Heart Association/National Heart, Lung, and Blood Institute criteria were randomly assigned (1:1) to a 6-month lifestyle intervention focusing on regular exercise (exercise group), or to a waiting-list control group, using a computer-based assignment list with variable block length. Participants in the exercise group received individual recommendations for exercise at face-to-face meetings and via a smartphone application, with the aim of doing 150 min physical activity per week. Activities were supervised and adapted using activity-monitor data, which were transferred to a central database. Participants in the control group continued their current lifestyle and were informed about the possibility to receive the supervised intervention after study completion. The primary outcome was the change in metabolic syndrome severity (metabolic syndrome Z score) after 6 months in the intention-to treat population. This trial is registered with ClinicalTrials.gov, number NCT03293264, and is closed to new participants.543 individuals were screened between Oct 10, 2017, and Feb 27, 2018, of whom 314 (mean age 48 years [SD 8]) were randomly assigned to receive the intervention (n=160; exercise group) or to a waiting list (n=154; control group). The mean metabolic syndrome Z score for the exercise group was significantly reduced after the 6-month intervention period (0·93 [SD 0·63] before and 0·63 [0·64] after the intervention) compared with the control group (0·95 [0·55] and 0·90 [0·61]; difference between groups -0·26 [95% CI -0·35 to -0·16], p<0·0001). We documented 11 adverse events in the exercise group, with only one event (a twisted ankle) regarded as directly caused by the intervention.A 6-month exercise-focused intervention using telemonitoring systems reduced metabolic syndrome severity. This form of intervention shows significant potential to reduce disease risk, while also improving mental health, work ability, and productivity-related outcomes for employees at high risk for cardiovascular and metabolic disease.Audi BKK health insurance and the German Research Foundation through the Cluster of Excellence REBIRTH.
Abstract 18744: Cost-effectiveness of Rheumatic Heart Disease Echocardiographic Screening in Brazil: Data From the PROVAR Study
Authors: Jasper Ubels, Klas-Göran Sahlen, Andrea Z Beaton, Maria do Carmo P Nunes, Adriana C Diamantino, Cassio M Oliveira, Isabella M Teixeira, Karlla C Lauriano, Julia P Santos, Ana Luísa M Costa, Antonio Luiz P Ribeiro, Craig Sable, Bruno R Nascimento
Journal: Circulation (2017)

Introduction: In recent years, new technologies have emerged that make it possible to screen for Rheumatic Heart Disease (RHD) with portable echocardiographic machines. We performed a cost-utility ...