tbuckley/cabot-search huggingface dataset:
High mobility group box 1 orchestrates tissue regeneration via CXCR4
Authors: Mario Tirone, Ngoc Lan Tran, Chiara Ceriotti, Andrea Gorzanelli, Monica Canepari, Roberto Bottinelli, Angela Raucci, Stefania Di Maggio, César Santiago, Mario Mellado, Marielle Saclier, Stéphanie François, Giorgia Careccia, Mingzhu He, Francesco De Marchis, Valentina Conti, Sabrina Ben Larbi, Sylvain Cuvellier, Maura Casalgrandi, Alessandro Preti, Bénédicte Chazaud, Yousef Al-Abed, Graziella Messina, Giovanni Sitia, Silvia Brunelli, Marco Emilio Bianchi, Emilie Vénéreau
Journal: The Journal of Experimental Medicine (2017)

Inflammation and tissue regeneration follow tissue damage, but little is known about how these processes are coordinated. High Mobility Group Box 1 (HMGB1) is a nuclear protein that, when released on injury, triggers inflammation. We previously showed that HMGB1 with reduced cysteines is a chemoattractant, whereas a disulfide bond makes it a proinflammatory cytokine. Here we report that fully reduced HMGB1 orchestrates muscle and liver regeneration via CXCR4, whereas disulfide HMGB1 and its receptors TLR4/MD-2 and RAGE (receptor for advanced glycation end products) are not involved. Injection of HMGB1 accelerates tissue repair by acting on resident muscle stem cells, hepatocytes, and infiltrating cells. The nonoxidizable HMGB1 mutant 3S, in which serines replace cysteines, promotes muscle and liver regeneration more efficiently than the wild-type protein and without exacerbating inflammation by selectively interacting with CXCR4. Overall, our results show that the reduced form of HMGB1 coordinates tissue regeneration and suggest that 3S may be used to safely accelerate healing after injury in diverse clinical contexts.
De Novo Gene Evolution of Antifreeze Glycoproteins in Codfishes Revealed by Whole Genome Sequence Data
Authors: Helle Tessand Baalsrud, Ole Kristian Tørresen, Monica Hongrø Solbakken, Walter Salzburger, Reinhold Hanel, Kjetill S Jakobsen, Sissel Jentoft
Journal: Molecular Biology and Evolution (2017)

New genes can arise through duplication of a pre-existing gene or de novo from non-coding DNA, providing raw material for evolution of new functions in response to a changing environment. A prime example is the independent evolution of antifreeze glycoprotein genes (afgps) in the Arctic codfishes and Antarctic notothenioids to prevent freezing. However, the highly repetitive nature of these genes complicates studies of their organization. In notothenioids, afgps evolved from an extant gene, yet the evolutionary origin of afgps in codfishes is unknown. Here, we demonstrate that afgps in codfishes have evolved de novo from non-coding DNA 13-18 Ma, coinciding with the cooling of the Northern Hemisphere. Using whole-genome sequence data from several codfishes and notothenioids, we find higher copy number of afgp in species exposed to more severe freezing suggesting a gene dosage effect. Notably, antifreeze function is lost in one lineage of codfishes analogous to the afgp losses in non-Antarctic notothenioids. This indicates that selection can eliminate the antifreeze function when freezing is no longer imminent. In addition, we show that evolution of afgp-assisting antifreeze potentiating protein genes (afpps) in notothenioids coincides with origin and lineage-specific losses of afgp. The origin of afgps in codfishes is one of the first examples of an essential gene born from non-coding DNA in a non-model species. Our study underlines the power of comparative genomics to uncover past molecular signatures of genome evolution, and further highlights the impact of de novo gene origin in response to a changing selection regime.
Whole-exome sequencing (WES) of HER2+ metastatic breast cancer (MBC) from patients (pts) treated with prior trastuzumab (T): A correlative analysis of TBCRC003.
Authors: Nikhil Wagle, Nancy U. Lin, Andrea L. Richardson, Ignaty Leshchiner, Ingrid A. Mayer, Andres Forero-Torres, Timothy J. Hobday, Elizabeth Claire Dees, Rita Nanda, Mothaffar F. Rimawi, Hao Guo, William Thomas Barry, Antonio C. Wolff, Stacey B. Gabriel, Levi A. Garraway, Eric P. Winer, Ian E. Krop
Journal: Journal of Clinical Oncology (2014)

536 Background: Although several large sequencing studies have elucidated the spectrum of genomic alterations in primary, treatment-naïve HER2+ cancers, the genomic landscape in metastatic tumors after progression on anti-HER2 therapy remains largely unknown. Methods: We performed WES on baseline metastatic tumor biopsies from 57 pts enrolled on TBCRC003 (NCT00470704), a phase II study evaluating combined lapatinib (L) and T that included pts with varying degrees of prior T exposure. Tumors were analyzed for point mutations, insertions/deletions, and copy number alterations. Results: Across 57 tumors, the median depth of coverage was 99-fold (range 37-160). The median number of coding mutations per sample was 55 (Range: 1-716). Significant recurrently mutated genes were TP53 (n=30; 53%) and PIK3CA (n=19; 33%). The incidence of mutant TP53 and PIK3CA was not significantly different from 104 primary, treatment-naïve HER2+ tumors sequenced in the TCGA study (53% and 28%, respectively). Comparing the 40 pts who received prior T with the 17 pts who did not, there was no significant difference in the incidence of mutant PIK3CA (35% vs 29%, p=0.8) and TP53 (53% vs 53%, p=1.0). Significant recurrent copy number alterations included amplifications in FGFR1, MYC, CCND1, and MDM2 and deletions in NF1, also similar to TCGA data. In 3/40 pts who had received prior T (8%), we identified a HER2 L755S kinase domain mutation. HER2 mutations have been seen in ~2% of HER2-negative cancers and <1% of primary HER2+ cancers. HER2 L755S has been shown to be resistant to L and sensitive to irreversible HER2 inhibitors. 5 additional pts, 2 of whom received prior T, had uncharacterized HER2 mutations at low allelic fractions, including a novel kinase domain mutation in a pt who had received prior T. No HER2 kinase domain mutations were seen in T-naïve pts. Conclusions: We present the first genomic landscape of HER2+ MBC using WES data. WES of matched primary tumor tissue is underway. The presence of HER2 mutations in pts with HER2+ MBC treated with prior T suggests that these mutations may be involved in the development of resistance to T. Novel therapeutic approaches may be required for these pts.
Characteristics of 809 Patients with Essential Thrombocythemia in Real-World Clinical Practice: A Chart Review Study in the United States
Authors: Jingbo Yu, Philomena Colucci, Dilan Chamikara Paranagama, Smitha Sivaraman, Pavel Atanasov, Becky Hanna, Jackson Tang, Shreekant V. Parasuraman
Journal: Blood (2017)
Frequency of multiple PIK3CA and PK3R1 concurrent mutations in endometrial cancers.
Authors: Will Jeck, Dario R. Roque, David N. Hayes, A. Mitch Dizon, Leslie Horn Clark, Stuart Pierce, Weiya Zhang Wysham, Paola A. Gehrig, Victoria Lin Bae-Jump
Journal: Journal of Clinical Oncology (2015)

e16522 Background: Endometrial cancers (ECs) frequently harbor mutations in PI3K pathway genes. Our objective was to determine the mutation frequency of the PIK3 pathway in the tumors of EC patients enrolled on UNCseq and correlate these findings with clinical outcomes. Methods: Snap-frozen and FFPE tissue samples were collected from EC patients enrolled on UNCseq (NCT01457196). DNA was isolated using the Puregene DNA purification system, and Illumina libraries were prepared separately from tumor and a matched normal sample from each patient. Relevant targets, were enriched by a custom designed Agilent SureSelect hybrid capture enrichment library using standard protocols. Samples were sequenced on Illumina HiSeq machines in a variety of formats. Statistical analysis of clinical correlates was performed in R (v 3.1.1). Results: Data was collected from 73 EC patients. Fifteen tumors (20.5%), 14 of which were endometrioid, had 2 or more mutations in PIK3CA or PIK3R1. Of 73 patients, 6 patients had 2 PIK3CA mutations (8.2%), 7 patients had two PIK3R1 mutations (9.6%), 1 had three PIK3R1 mutations (1.4%) and 1 (1.4%) had 2 PIK3CA mutations as well as 2 PIK3R1 mutations. In all cases, multiple mutations of PIK3R1 or PIK3CA overlapped with PTEN mutation (p = 0.002731). Single mutations in PIK3CA and PIK3R1 were not significant predictors of overall survival (OS) or progression free survival (PFS), after accounting for tumor stage and grade. There was a trend suggesting that multiple PIK3CA mutations may be associated with a decrease in OS and PFS of 7.6 months (p = 0.17) and 8.1 months (p = 0.14), respectively. Conclusions: We did not find a strong relationship between mutated PIK3 pathway genes and clinical outcomes in EC patients. However, mutations in the PIK3 pathway were common and when present, were often multiple and involved more than one gene. This has not been previously reported for EC, but may have been detected in the tumors of UNCseq patients due to the more in depth ultra-sequencing used on this trial. Given the overlap between PTEN mutation and multiple PIK3R1 or PIK3CA concurrent mutations, PTEN mutation may be a necessary antecedent to the emergence of multiple PIK3CA or PIK3R1 mutations, and this may have relevance for targeted therapies in EC.
Association of Rare Predicted Loss-of-Function Variants in Cellular Pathways with Sub-Phenotypes in Age-Related Macular Degeneration
Authors: Alexandra Pietraszkiewicz, Freekje van Asten, Alan Kwong, Rinki Ratnapriya, Goncalo Abecasis, Anand Swaroop, Emily Y. Chew
Journal: Ophthalmology (2017)
Outcomes of a Coaching-Based WHO Safe Childbirth Checklist Program in India
Authors: Katherine E.A. Semrau, Lisa R. Hirschhorn, Megan Marx Delaney, Vinay P. Singh, Rajiv Saurastri, Narender Sharma, Danielle E. Tuller, Rebecca Firestone, Stuart Lipsitz, Neelam Dhingra-Kumar, Bhalachandra S. Kodkany, Vishwajeet Kumar, Atul A. Gawande
Journal: New England Journal of Medicine (2017)

The prevalence of facility-based childbirth in low-resource settings has increased dramatically during the past two decades, yet gaps in the quality of care persist and mortality remains high. The World Health Organization (WHO) Safe Childbirth Checklist, a quality-improvement tool, promotes systematic adherence to practices that have been associated with improved childbirth outcomes.
Comparison of Neoadjuvant Nab-Paclitaxel+Carboplatin vs Nab-Paclitaxel+Gemcitabine in Triple-Negative Breast Cancer: Randomized WSG-ADAPT-TN Trial Results
Authors: Oleg Gluz, Ulrike Nitz, Cornelia Liedtke, Matthias Christgen, Eva-Maria Grischke, Helmut Forstbauer, Michael Braun, Mathias Warm, John Hackmann, Christoph Uleer, Bahriye Aktas, Claudia Schumacher, Nikola Bangemann, Christoph Lindner, Sherko Kuemmel, Michael Clemens, Jochem Potenberg, Peter Staib, Andreas Kohls, Raquel von Schumann, Ronald Kates, Ronald Kates, Johannes Schumacher, Rachel Wuerstlein, Hans Heinrich Kreipe, Nadia Harbeck
Journal: JNCI Journal of the National Cancer Institute (2017)

Pathological complete response (pCR) is associated with improved prognosis in triple-negative breast cancer (TNBC). The optimal chemotherapy regimen is unclear. Weekly nab-paclitaxel vs conventional paclitaxel or addition of carboplatin to anthracycline-taxane results in higher pCR rates with uncertain survival impact. We evaluated carboplatin vs gemcitabine with a nab-paclitaxel backbone as a short 12-week A-free regimen with a focus on early response.Patients with TNBC (estrogen receptor/progesterone receptor < 1%, human epidermal growth factor receptor 2-negative, cT1c-cT4c, cN0/+) were randomly assigned to A: nab-paclitaxel 125 mg/m2/gemcitabine 1000 mg/m2 d1,8 three times weekly (q3w); vs B: nab-paclitaxel 125 mg/m2/carboplatin AUC2 day 1,8 q3w. The trial was powered for a pCR (ypT0/is ypN0) comparison by therapy arm and early response (defined as Ki-67 decrease >30% or < 500 invasive tumor cells in the three-week serial biopsy). All statistical tests were two-sided.A total of 336 patients were enrolled (48 centers, arms A/B: n = 182/154). The median age was 50 years. At baseline (A vs B), 62.6% and 62.9% had cT2-4c tumors; 86.8% and 90.9% completed therapy per protocol, respectively. pCR favored arm B (28.7%, 95% CI = 0.22 to 0.36, vs 45.9%, 95% CI = 0.38 to 0.54; 95% CI(dBA) = 6.2% to 27.9%, P = .002) and was lower in nonresponders than in early responders (19.5% vs 44.4%, P < .001) or in patients with unclassifiable early response (50.0%). The nab-paclitaxel/gemcitabine was associated with more frequent dose reductions (20.6% vs 11.9%, P = .04), treatment-related serious adverse events (11.1% vs 5.3%, P = .07), grade 3-4 infections (7.2% vs 2.6%, P = .07), and grade 3-4 ALAT elevations (11.7 vs 3.3%, P = .01).This first large randomized trial suggests high efficacy and excellent tolerability of a neoadjuvant nab-paclitaxel/carboplatin regimen, superior to nab-paclitaxel/gemcitabine in TNBC. De-escalation of further chemotherapy in patients with early pCR after a short anthracycline-free regimen is a promising field of future research. Early necrotic morphological changes and/or proliferation decrease after the first therapy cycle seem to be associated with subsequent pCR.
CD271 Confers an Invasive and Metastatic Phenotype of Head and Neck Squamous Cell Carcinoma through the Upregulation of Slug
Authors: Man Ki Chung, Young Ho Jung, Joon Kyoo Lee, Soo Youn Cho, Oihana Murillo-Sauca, Ravindra Uppaluri, June Ho Shin, John B. Sunwoo
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Head and neck squamous cell carcinoma (HNSCC) is comprised of heterogeneous populations of cells, and CD271 (NGFR; p75NTR) has been associated with a tumor-initiating cell subpopulation. This study assessed the role of CD271 in modulating metastatic behavior in HNSCC. Experimental Design: CD271 was overexpressed in murine and human oral squamous cell carcinoma cells to assess the impact of CD271 activation on the invasive and metastatic phenotype of these cells, using in vitro and orthotopic in vivo modeling. Treatment with human nerve growth factor (NGF) to activate CD271, as well as shRNA knockdown of the CD271-upregulated Snai2 expression, was used to assess the mechanism of the CD271-induced invasive phenotype. Relevance of CD271 expression in human HNSCC was evaluated in patient-derived xenografts (PDX) and primary human oral cancers, annotated with clinical behavior characteristics and survival data. Results: Forced expression of CD271 resulted in a more invasive and metastatic phenotype. Slug, an epithelial-to-mesenchymal transition (EMT)-related transcription factor, encoded by Snai2, was highly expressed in MOC2-CD271 and HSC3-CD271, compared with respective parental cells. CD271 activation by NGF conferred enhanced invasiveness in CD271-overexpressing cells, which was abrogated by Snai2 knockdown. In PDXs and primary human HNSCC, CD271 expression correlated with higher Snai2 expression, greater nodal metastasis, and shorter disease-free survival. Conclusions: Activation of CD271 results in upregulation of Snai2/Slug, which, in turn, results in a more invasive phenotype and an enhanced capacity for metastasis to regional lymph nodes. These findings point to CD271 as a promising, therapeutic target for oral cancer metastasis. Clin Cancer Res; 24(3); 674–83. ©2017 AACR.
Correction to: Efficacy and safety of stress ulcer prophylaxis in critically ill patients: a network meta-analysis of randomized trials
Authors: Waleed Alhazzani, Fayez Alshamsi, Emilie Belley-Cote, Diane Heels-Ansdell, Romina Brignardello-Petersen, Mustafa Alquraini, Anders Perner, Morten Hylander Møller, Mette Krag, Saleh Almenawer, Bram Rochwerg, Joanna Dionne, Roman Jaeschke, Mohammed Alshahrani, Adam Deane, Dan Perri, Lehana Thebane, Awad Al-Omari, Simon Finfer, Deborah Cook, Gordon Guyatt
Journal: Intensive Care Medicine (2017)
Abstract 15277: Long-term Mortality Following Minimally Invasive Coronary Artery Bypass Surgery in Diabetics.
Authors: Emad A Barsoum, Basem Azab, Masood Shariff, John Nabagiez, James Lafferty, Joseph T McGinn
Journal: Circulation (2016)

Background:  Cardiovascular disease is the main cause of death in patients with diabetes mellitus, which increases the risk of diffuse, progressive atherosclerosis in coronary arteries. Diabetic patients with multivessel disease have a significant survival benefit after coronary artery bypass graft (CABG). The long term outcome after minimally invasive coronary artery bypass grafting (MC) has not been fully evaluated. The aim of our study was to explore the long term outcome after MC and sternotomy CABG (SC) in diabetics with coronary artery disease.   Method:  This is a retrospective study of 2073 patients that underwent CABG between 2005 and 2011. Patients were divided into diabetics (n=762) and non-diabetics (n=1,311) and divided further for a subgroup analysis according to type of procedure, MC (left lateral thoracotomy) and SC. Propensity score matching utilized to evaluate all-cause mortality. The diabetics (n=195 per group) and non-diabetics (n=359 per group) were evaluated with average number of bypasses per procedure and Kaplan-Meier estimate for survival.   Result:  All patients were followed for a maximum of 10 years, with a mean of 6.4±2.7 years. Total number of bypasses performed in diabetics was 3.2±1.1 in SC and 2.5±0.9 in MC (p   Conclusion:  Sternotomy CABG demonstrates significantly lower long-term mortality and improved survival compared to minimally invasive CABG in diabetic patients with coronary artery disease. Survival was comparable between non-diabetics, regardless of surgical approach. Therefore, the presence of diabetes mellitus should be considered carefully when choosing surgical approach for CABG. Further study is required to determine whether completeness of revascularization plays a greater role in the survival of diabetics than for non-diabetics.
Investigation using whole genome sequencing of a prolonged restaurant outbreak of Salmonella Typhimurium linked to the building drainage system, England, February 2015 to March 2016
Authors: John Mair-Jenkins, Roberta Borges-Stewart, Caroline Harbour, Judith Cox-Rogers, Tim Dallman, Philip Ashton, Robert Johnston, Deborah Modha, Philip Monk, Richard Puleston
Journal: Eurosurveillance (2017)

Following notification of a Salmonella enterica serovar Typhimurium gastroenteritis outbreak, we identified 82 cases linked to a restaurant with symptom onset from 12 February 2015 to 8 March 2016. Seventy-two cases had an isolate matching the nationally unique whole genome sequencing profile (single nucleotide polymorphism (SNP) address: 1.1.1.124.395.395). Interviews established exposure to the restaurant and subsequent case–control analysis identified an association with eating carvery buffet food (adjusted odds ratios (AOR): 20.9; 95% confidence interval (CI): 2.2 – ∞). Environmental inspections, food/water testing, and a food trace-back investigation were inconclusive. Repeated cycles of cleaning were undertaken, including hydrogen peroxide fogging, however, transmission continued. After 7 months of investigation, environmental swabbing identified 106 isolates from kitchen surfaces and restaurant drains matching the outbreak profile. We found structural faults with the drainage system and hypothesised that a reservoir of bacteria in drain biofilm and underfloor flooded areas may have sustained this outbreak. Ineffective drain water-traps (U-bends) may have also contributed by allowing transmission of contaminated aerosols into the kitchen environment. These findings suggest that routine swabbing of sink drain points and inspection of drainage systems should be considered in future outbreak scenarios.
Thorase variants are associated with defects in glutamatergic neurotransmission that can be rescued by Perampanel
Authors: George K. E. Umanah, Marco Pignatelli, Xiling Yin, Rong Chen, Joshua Crawford, Stewart Neifert, Leslie Scarffe, Adam A. Behensky, Noah Guiberson, Melissa Chang, Erica Ma, Jin Wan Kim, Cibele C. Castro, Xiaobo Mao, Li Chen, Shaida A. Andrabi, Mikhail V. Pletnikov, Ann E. Pulver, Dimitrios Avramopoulos, Antonello Bonci, David Valle, Ted M. Dawson, Valina L. Dawson
Journal: Science Translational Medicine (2017)

The AAA+ adenosine triphosphatase (ATPase) Thorase plays a critical role in controlling synaptic plasticity by regulating the expression of surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Bidirectional sequencing of exons of ATAD1, the gene encoding Thorase, in a cohort of patients with schizophrenia and healthy controls revealed rare Thorase variants. These variants caused defects in glutamatergic signaling by impairing AMPAR internalization and recycling in mouse primary cortical neurons. This contributed to increased surface expression of the AMPAR subunit GluA2 and enhanced synaptic transmission. Heterozygous Thorase-deficient mice engineered to express these Thorase variants showed altered synaptic transmission and several behavioral deficits compared to heterozygous Thorase-deficient mice expressing wild-type Thorase. These behavioral impairments were rescued by the competitive AMPAR antagonist Perampanel, a U.S. Food and Drug Administration-approved drug. These findings suggest that Perampanel may be useful for treating disorders involving compromised AMPAR-mediated glutamatergic neurotransmission.
White Adipose Tissue Is a Reservoir for Memory T Cells and Promotes Protective Memory Responses to Infection
Authors: Seong-Ji Han, Arielle Glatman Zaretsky, Vinicius Andrade-Oliveira, Nicholas Collins, Amiran Dzutsev, Jahangheer Shaik, Denise Morais da Fonseca, Oliver J. Harrison, Samira Tamoutounour, Allyson L. Byrd, Margery Smelkinson, Nicolas Bouladoux, James B. Bliska, Jason M. Brenchley, Igor E. Brodsky, Yasmine Belkaid
Journal: Immunity (2017)
Search Images and Extrapolation Risk
Authors: Robert S. Brown
Journal: JAMA Internal Medicine (2017)

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