tbuckley/cabot-search huggingface dataset:
Association of BRCA2 K3326* With Small Cell Lung Cancer and Squamous Cell Cancer of the Skin
Authors: Thorunn Rafnar, Gudbjorg R Sigurjonsdottir, Simon N Stacey, Gisli Halldorsson, Patrick Sulem, Luba M Pardo, Hannes Helgason, Stefan T Sigurdsson, Thorkell Gudjonsson, Laufey Tryggvadottir, Gudridur H Olafsdottir, Jon G Jonasson, Kristin Alexiusdottir, Asgeir Sigurdsson, Julius Gudmundsson, Jona Saemundsdottir, Jon K Sigurdsson, Hrefna Johannsdottir, Andre Uitterlinden, Sita H Vermeulen, Tessel E Galesloot, Dawn C Allain, Martin Lacko, Bardur Sigurgeirsson, Kristin Thorisdottir, Oskar T Johannsson, Fridbjorn Sigurdsson, Gunnar B Ragnarsson, Helgi Isaksson, Hronn Hardardottir, Tomas Gudbjartsson, Daniel F Gudbjartsson, Gisli Masson, Lambertus A M L Kiemeney, Amanda Ewart Toland, Tamar Nijsten, Wilbert H M Peters, Jon H Olafsson, Steinn Jonsson, Unnur Thorsteinsdottir, Gudmar Thorleifsson, Kari Stefansson
Journal: JNCI Journal of the National Cancer Institute (2018)

Most pathogenic mutations in the BRCA2 gene carry a high risk of hereditary breast and ovarian cancer (HBOC). However, a stop-gain mutation, K3326* (rs11571833), confers risk of lung cancer and cancers of the upper-aero-digestive tract but only a modest risk of breast or ovarian cancer. The Icelandic population provides an opportunity for comprehensive characterization of the cancer risk profiles of K3326* and HBOC mutations because a single mutation, BRCA2 999del5, is responsible for almost all BRCA2-related HBOC in the population.
At the Crossroads of Fate—Somatic Cell Lineage Specification in the Fetal Gonad
Authors: Emmi Rotgers, Anne Jørgensen, Humphrey Hung-Chang Yao
Journal: Endocrine Reviews (2018)

The reproductive endocrine systems are vastly different between males and females. This sexual dimorphism of the endocrine milieu originates from sex-specific differentiation of the somatic cells in the gonads during fetal life. Most gonadal somatic cells arise from the adrenogonadal primordium. After separation of the adrenal and gonadal primordia, the gonadal somatic cells initiate sex-specific differentiation during gonadal sex determination with the specification of the supporting cell lineages: Sertoli cells in the testis vs granulosa cells in the ovary. The supporting cell lineages then facilitate the differentiation of the steroidogenic cell lineages, Leydig cells in the testis and theca cells in the ovary. Proper differentiation of these cell types defines the somatic cell environment that is essential for germ cell development, hormone production, and establishment of the reproductive tracts. Impairment of lineage specification and function of gonadal somatic cells can lead to disorders of sexual development (DSDs) in humans. Human DSDs and processes for gonadal development have been successfully modeled using genetically modified mouse models. In this review, we focus on the fate decision processes from the initial stage of formation of the adrenogonadal primordium in the embryo to the maintenance of the somatic cell identities in the gonads when they become fully differentiated in adulthood.
A Contemporary Prostate Biopsy Risk Calculator Based on Multiple Heterogeneous Cohorts
Authors: Donna P. Ankerst, Johanna Straubinger, Katharina Selig, Lourdes Guerrios, Amanda De Hoedt, Javier Hernandez, Michael A. Liss, Robin J. Leach, Stephen J. Freedland, Michael W. Kattan, Robert Nam, Alexander Haese, Francesco Montorsi, Stephen A. Boorjian, Matthew R. Cooperberg, Cedric Poyet, Emily Vertosick, Andrew J. Vickers
Journal: European Urology (2018)
Broad Genomic Sampling Reveals a Smut Pathogenic Ancestry of the Fungal Clade Ustilaginomycotina
Authors: Teeratas Kijpornyongpan, Stephen J Mondo, Kerrie Barry, Laura Sandor, Juna Lee, Anna Lipzen, Jasmyn Pangilinan, Kurt LaButti, Matthieu Hainaut, Bernard Henrissat, Igor V Grigoriev, Joseph W Spatafora, M Catherine Aime
Journal: Molecular Biology and Evolution (2018)

Ustilaginomycotina is home to a broad array of fungi including important plant pathogens collectively called smut fungi. Smuts are biotrophs that produce characteristic perennating propagules called teliospores, one of which, Ustilago maydis, is a model genetic organism. Broad exploration of smut biology has been hampered by limited phylogenetic resolution of Ustilaginiomycotina as well as an overall lack of genomic data for members of this subphylum. In this study, we sequenced eight Ustilaginomycotina genomes from previously unrepresented lineages, deciphered ordinal-level phylogenetic relationships for the subphylum, and performed comparative analyses. Unlike other Basidiomycota subphyla, all sampled Ustilaginomycotina genomes are relatively small and compact. Ancestral state reconstruction analyses indicate that teliospore formation was present at the origin of the subphylum. Divergence time estimation dates the divergence of most extant smut fungi after that of grasses (Poaceae). However, we found limited conservation of well-characterized genes related to smut pathogenesis from U. maydis, indicating dissimilar pathogenic mechanisms exist across other smut lineages. The genomes of Malasseziomycetes are highly diverged from the other sampled Ustilaginomycotina, likely due to their unique history as mammal-associated lipophilic yeasts. Despite extensive genomic data, the phylogenetic placement of this class remains ambiguous. Although the sampled Ustilaginomycotina members lack many core enzymes for plant cell wall decomposition and starch catabolism, we identified several novel carbohydrate active enzymes potentially related to pectin breakdown. Finally, ∼50% of Ustilaginomycotina species-specific genes are present in previously undersampled and rare lineages, highlighting the importance of exploring fungal diversity as a resource for novel gene discovery.
Abstract 19023: Is there a Correlation Between Bleeding Risk Score and Platelet Aggregability?
Authors: Flavia B Arantes, Remo H Furtado, Carlos J Barbosa, André Franci, Fernando R Menezes, Talia D Falcao, Carlos A Nakashima, Luciano M Baracioli, Jose A Ramires, Jose C Nicolau
Journal: Circulation (2014)

Background: Clinically relevant bleeding in ACS patients is strongly associated with mortality, with an HR similar to that of stent thrombosis. Although recent data have suggested that on-treatment platelet reactivity after PCI is an independent predictor of bleeding events, this correlation is not as clearly established as for HPR and stent thrombosis, with very few conflicting publications in the literature. The main objective of the present analysis was to evaluate the relationship between platelet reactivity and bleeding risk score in ACS patients submitted to PCI. Methods: In a prospective way, we assessed platelet aggregability using VerifyNow P2Y12® assay from 131 ACS patients submitted to PCI, at their discharge from the Coronary Care Unit. All patients were on DAPT with aspirin 100mg + clopidogrel 75mg daily. Low platelet reactivity (LPR) was defined as VerifyNow &lt;85 P2Y12 Reaction Units (PRU). The ACUITY/HORIZONS-AMI bleeding risk score was used to assess the population’s bleeding risk. Results: The mean age of the population was 64 years. Low platelet reactivity was observed in 25 patients (19%). There was no significant difference between LPR and no-LPR groups in relation to the mean bleeding risk score (14,6±7,7 PRU vs 15,3±6,9 PRU respectively, p=0.453). By linear regression, a very poor correlation was detected between VerifyNow P2Y12® values and bleeding score risk values (figure 1). By multivariable analysis, only hypertension (OR 0,23; 95% CI 0.093 to 0.73, p=0.01) and previous PCI (OR 2,9; 95% CI 1.05 to 8,2, p=0.04) correlated independently with LPR. Conclusion: In post-PCI ACS patients, there is no correlation between platelet aggregability and bleeding risk score. Although the latter is an important toll to minimize bleeding complications, more data is necessary to assess the role of platelet aggregability in the decision making process of this population.
Abstract 14219: Efficacy and Safety of Direct Oral Anticoagulants in Patients With Atrial Fibrillation in the Real-world: The Fushimi AF Registry
Authors: Yugo Yamashita, Ryuji Uozumi, Masahiro Esato, Yeong-Hwa Chun, Hiromichi Wada, Koji Hasegawa, Hisashi Ogawa, Mitsuru Abe, Satoshi Morita, Masaharu Akao
Journal: Circulation (2016)

Introduction:  Oral anticoagulants (OAC) are essential for stroke prevention in patients with atrial fibrillation (AF). Due to the preferable results of randomized clinical trials and use of ease in daily clinical practice, direct oral anticoagulants (DOAC) have become widespread use. These changes in OAC therapy may have influenced the outcomes of AF, but it has not been fully characterized in unselected patients of the real-world.   Methods:  The Fushimi AF Registry is a community-based prospective survey of AF patients who visited the participating institutions in Fushimi district, Japan. Follow-up data with OAC therapy status were available for 3,731 patients by the end of November 2015. We evaluated stroke/systemic embolism (SE) and major bleeding events according to OAC therapy status.   Results:  After the release of DOACs, the proportion of DOACs increased gradually. The incidence rates of stroke/SE and major bleeding events in the entire cohort during a median follow-up of 3.0 years were 2.3%/year and 1.8%/year. There was no significant difference in the incidence of stroke/SE or major bleeding events according to OAC therapy status at baseline. Cox proportional hazards model incorporating the transition of OAC therapy status as a time-dependent covariate for stroke/SE and major bleeding events revealed that use of DOACs was not associated with stroke/SE events, compared with use of warfarin or non-OAC treatment [HR, 0.95 (0.59-1.51), P=0.82; vs. warfarin: HR, 0.99 (0.61-1.61), P=0.98; vs. no-OAC, respectively] (Figure). Similarly, use of DOACs was not associated with major bleeding events, compared with use of warfarin or non-OAC treatment [HR, 0.82 (0.50-1.36), P=0.45; vs. warfarin: HR, 1.24 (0.73-2.10), P=0.43; vs. no-OAC, respectively] (Figure).   Conclusions:  In the real-world, use of DOACs neither showed significant differences in stroke/SE events nor major bleeding events compared with use of warfarin or non-OAC treatment in Japanese patients with AF.
Effect of More vs Less Frequent Follow-up Testing on Overall and Colorectal Cancer–Specific Mortality in Patients With Stage II or III Colorectal Cancer
Authors: Peer Wille-Jørgensen, Ingvar Syk, Kenneth Smedh, Søren Laurberg, Dennis T. Nielsen, Sune H. Petersen, Andrew G. Renehan, Erzsébet Horváth-Puhó, Lars Påhlman, Henrik T. Sørensen
Journal: JAMA (2018)

<h3>Importance</h3> Intensive follow-up of patients after curative surgery for colorectal cancer is common in clinical practice, but evidence of a survival benefit is limited. <h3>Objective</h3> To examine overall mortality, colorectal cancer–specific mortality, and colorectal cancer–specific recurrence rates among patients with stage II or III colorectal cancer who were randomized after curative surgery to 2 alternative schedules for follow-up testing with computed tomography and carcinoembryonic antigen. <h3>Design, Setting, and Participants</h3> Unblinded randomized trial including 2509 patients with stage II or III colorectal cancer treated at 24 centers in Sweden, Denmark, and Uruguay from January 2006 through December 2010 and followed up for 5 years; follow-up ended on December 31, 2015. <h3>Interventions</h3> Patients were randomized either to follow-up testing with computed tomography of the thorax and abdomen and serum carcinoembryonic antigen at 6, 12, 18, 24, and 36 months after surgery (high-frequency group; n = 1253 patients) or at 12 and 36 months after surgery (low-frequency group; n = 1256 patients). <h3>Main Outcomes and Measures</h3> The primary outcomes were 5-year overall mortality and colorectal cancer–specific mortality rates. The secondary outcome was the colorectal cancer–specific recurrence rate. Both intention-to-treat and per-protocol analyses were performed. <h3>Results</h3> Among 2555 patients who were randomized, 2509 were included in the intention-to-treat analysis (mean age, 63.5 years; 1128 women [45%]) and 2365 (94.3%) completed the trial. The 5-year overall patient mortality rate in the high-frequency group was 13.0% (161/1253) compared with 14.1% (174/1256) in the low-frequency group (risk difference, 1.1% [95% CI, −1.6% to 3.8%];<i>P</i> = .43). The 5-year colorectal cancer–specific mortality rate in the high-frequency group was 10.6% (128/1248) compared with 11.4% (137/1250) in the low-frequency group (risk difference, 0.8% [95% CI, −1.7% to 3.3%];<i>P</i> = .52). The colorectal cancer–specific recurrence rate was 21.6% (265/1248) in the high-frequency group compared with 19.4% (238/1250) in the low-frequency group (risk difference, 2.2% [95% CI, −1.0% to 5.4%];<i>P</i> = .15). <h3>Conclusions and Relevance</h3> Among patients with stage II or III colorectal cancer, follow-up testing with computed tomography and carcinoembryonic antigen more frequently compared with less frequently did not result in a significant rate reduction in 5-year overall mortality or colorectal cancer–specific mortality. <h3>Trial Registration</h3> clinicaltrials.gov Identifier:NCT00225641
Deterioration of hepatic function after locoregional therapy (LRT) for hepatocellular carcinoma (HCC) measured by hepatic cholate clearance: A pilot study.
Authors: Maarouf Hoteit, Christine Cho-Shing Hsu, Matthew H Levine, Kimberly A Forde, Kim Anna Reiss, Gregory Nadolski, Michael C. Soulen, Laura Kron, Steve Helmke, Gregory T Everson, Edgar Ben-Josef
Journal: Journal of Clinical Oncology (2018)

468 Background: LRT is used in treating HCC, but is associated with a risk of hepatotoxicity, which is not accurately predicted by traditional measures of liver function. In this pilot study, we evaluated the change in liver function after LRT as measured by a test using dual, oral and IV, cholate clearances (HepQuantSHUNT). Our hypothesis is that LRT would impose a significant reduction in the disease severity index (DSI) measured in the HepQuant SHUNT test, as an indicator of reduced liver function. Methods: We conducted a prospective cohort study of 11 subjects undergoing LRT for HCC. HepQuantSHUNT was performed at baseline (T0) and 4-10 weeks after LRT (T1). Clinical assessment was performed at T0 and T1, and at 12-18 weeks after LRT (T2). Decompensation was defined as either a new complication of cirrhosis or an increase in Child-Pugh (CP) score by ≥2 points. Results: Median age was 61 years, 73% were men, 55% had hepatitis C. Median CP score was 7[5-8], including 36%CP A and 64%CP B. Subjects had a BCLC stage A(64%) or BCLC stage B(36%) HCC. LRT modalities were TACE (45%) or SBRT (55%). From T0 to T1, there was a reduction in oral cholate clearance(422[235-768] vs 339[208-362], p = 0.03) and in IV cholate clearance(210[150-300] vs 191[144-203],p = 0.04) as well as a trend towards a worsening disease severity index (DSI) (32.0[19.5-37.8] vs 33.0[29.7-38.0],p = 0.10); however, there was no significant change in MELD(12[9-13]vs 11[10-12],p = 0.72) or CP score(7[5-8] vs 7[6-8],p = 0.15). 89% of the subjects had a reduction in oral and IV cholate clearance, and 78% had a worsening DSI; while 44% subjects had increase in CP score, and 56% had an increase in MELD. Decompensation was observed in 43% of CP B patients and none of CP A patients; and in 60% patients with a DSI &gt; 35, and none of the patients with DSI &lt; 35. Conclusions: The dual cholate clearance assay HepQuant-SHUNT detects a deterioration in liver function after LRT for HCC more frequently than clinical measures of liver function. DSI 35 might be a cutoff for risk of clinical decompensation after LRT for HCC. Additional research is needed to evaluate the role of the HepQuant SHUNT test in improving the selection of Child B patients for LRT.
Use of Direct Oral Anticoagulants for Treating Venous Thromboembolism in Patients With Cancer
Authors: Gerald A. Soff
Journal: Journal of the National Comprehensive Cancer Network (2018)

<section class="abstract"><p id="P1">For patients with cancer who experience venous thromboembolism (VTE), low-molecular-weight heparin (LMWH) remains the standard of care in the NCCN Guidelines for VTE, but under certain conditions direct oral anticoagulants (DOACs) are acceptable alternatives. A growing body of literature suggests that DOACs may more effective than LMWHs in preventing recurrences, but they do carry some increased risk of bleeding. Most of this risk is seen in patients with gastrointestinal or urinary pathology or implanted devices. DOACs are also acceptable when the pain, cost, and inconvenience of LMWHs are expected to be obstacles to compliance. Through careful patient selection, most patients can be treated successfully with a DOAC, although for most patients with gastrointestinal or urinary pathology, LMWH remains the safer choice. </section>
Development of a centrally vascularized tissue engineering bone graft with the unique core-shell composite structure for large femoral bone defect treatment
Authors: Le Wang, Li-xin Zhu, Zhao Wang, Ai-ju Lou, Yi-xi Yang, Yuan Guo, Song Liu, Chi Zhang, Zheng Zhang, Han-sheng Hu, Bo Yang, Ping Zhang, Hong-wei Ouyang, Zhi-yong Zhang
Journal: Biomaterials (2018)
Neutrophils recruited by leukotriene B4 induce features of plaque destabilization during endotoxaemia
Authors: Marie-Anne Mawhin, Peggy Tilly, Gaia Zirka, Anne-Laure Charles, Farid Slimani, Jean-Luc Vonesch, Jean-Baptiste Michel, Magnus Bäck, Xavier Norel, Jean-Etienne Fabre
Journal: Cardiovascular Research (2018)

Both leukotrienes and neutrophils have been linked to plaque destabilization. Despite being evoked, the role of leukotriene B4 (LTB4) in neutrophil recruitment to plaques and the concomitant effects of these two actors on plaque stability remain to be proven. Since both actors are elicited during endotoxaemia, a condition associated with the risk of cardiovascular events, we investigated whether endotoxaemia promotes LTB4-mediated neutrophil infiltration in plaques and explored the roles of LTB4 and neutrophils in plaque destabilization. Endotoxaemia induced by repeated peritoneal endotoxin injections at a non-lethal dose (1.5 mg/kg, 5 days) in chow-fed aged Apoe−/− mice (over 45 weeks old) resulted in neutrophil infiltration and activation in plaques. Subsequently to neutrophil invasion, plaques exhibited increased features of vulnerability: reduced collagen content, expanded necrotic cores, and thinned fibrous caps. These plaque features were reproduced by direct deposition of isolated neutrophils onto murine atheromatous carotid arteries in an in vivo assay. In endotoxemic mice, plaques produced increased amounts of LTB4. Genomic or pharmacological impairments of this production reduced neutrophil infiltration, collagenolysis, and apoptosis of smooth muscle cells in plaques of endotoxemic mice. Furthermore, conditioned media of human culprit plaques (CPs) contained more LTB4 than non-CPs and levels of LTB4 correlated to both neutrophil activation markers and endotoxin releases in CPs. These results show that the increased neutrophil recruitment elicited by LTB4 contributes to increase features of plaque destabilization in endotoxemic contexts and point out LTB4 as a potential therapeutic target in atherosclerosis.
The Role of Intercalated Cell Nedd4–2 in BP Regulation, Ion Transport, and Transporter Expression
Authors: Masayoshi Nanami, Truyen D. Pham, Young Hee Kim, Baoli Yang, Roy L. Sutliff, Olivier Staub, Janet D. Klein, Karen I. Lopez-Cayuqueo, Regine Chambrey, Annie Y. Park, Xiaonan Wang, Vladimir Pech, Jill W. Verlander, Susan M. Wall
Journal: Journal of the American Society of Nephrology (2018)

BackgroundNedd4-2 is an E3 ubiquitin-protein ligase that associates with transport proteins, causing their ubiquitylation, and then internalization and degradation. Previous research has suggested a correlation between Nedd4-2 and BP. In this study, we explored the effect of intercalated cell (IC) Nedd4-2 gene ablation on IC transporter abundance and function and on BP.Methods We generated IC Nedd4-2 knockout mice using Cre-lox technology and produced global pendrin/Nedd4-2 null mice by breeding global Nedd4-2 null (Nedd4-2-/- ) mice with global pendrin null (Slc26a4-/- ) mice. Mice ate a diet with 1%-4% NaCl; BP was measured by tail cuff and radiotelemetry. We measured transepithelial transport of Cl- and total CO2 and transepithelial voltage in cortical collecting ducts perfused in vitro Transporter abundance was detected with immunoblots, immunohistochemistry, and immunogold cytochemistry.Results IC Nedd4-2 gene ablation markedly increased electroneutral Cl-/HCO3- exchange in the cortical collecting duct, although benzamil-, thiazide-, and bafilomycin-sensitive ion flux changed very little. IC Nedd4-2 gene ablation did not increase the abundance of type B IC transporters, such as AE4 (Slc4a9), H+-ATPase, barttin, or the Na+-dependent Cl-/HCO3- exchanger (Slc4a8). However, IC Nedd4-2 gene ablation increased CIC-5 total protein abundance, apical plasma membrane pendrin abundance, and the ratio of pendrin expression on the apical membrane to the cytoplasm. IC Nedd4-2 gene ablation increased BP by approximately 10 mm Hg. Moreover, pendrin gene ablation eliminated the increase in BP observed in global Nedd4-2 knockout mice.Conclusions IC Nedd4-2 regulates Cl-/HCO3- exchange in ICs., Nedd4-2 gene ablation increases BP in part through its action in these cells.
Small hypoxia-primed mesenchymal stem cells attenuate graft-versus-host disease
Authors: YongHwan Kim, Hye Jin Jin, Jinbeom Heo, Hyein Ju, Hye-Yeon Lee, Sujin Kim, Seungun Lee, Jisun Lim, Sang Young Jeong, JiHye Kwon, Miyeon Kim, Soo Jin Choi, Wonil Oh, Yoon Sun Yang, Hyun Ho Hwang, Hwan Yeul Yu, Chae-Min Ryu, Hong Bae Jeon, Dong-Myung Shin
Journal: Leukemia (2018)

Mesenchymal stem cells (MSCs) are of particular interest for the treatment of immune-related diseases due to their immunosuppressive capacity. Here, we show that Small MSCs primed with Hypoxia and Calcium ions (SHC-MSCs) exhibit enhanced stemness and immunomodulatory functions for treating allogeneic conflicts. Compared with naïve cultured human umbilical cord blood-derived MSCs, SHC-MSCs were resistant to passage-dependent senescence mediated via the monocyte chemoattractant protein-1 and p53/p21 cascade and secreted large amounts of pro-angiogenic and immunomodulatory factors, resulting in suppression of T-cell proliferation. SHC-MSCs showed DNA demethylation in pluripotency, germline, and imprinted genes similarly to very small embryonic-like stem cells, suggesting a potential mutual relationship. Genome-wide DNA methylome and transcriptome analyses indicated that genes related to immune modulation, cell adhesion, and the cell cycle were up-regulated in SHC-MSCs. Particularly, polo-like kinase-1 (PLK1), zinc-finger protein-143, dehydrogenase/reductase-3, and friend-of-GATA2 play a key role in the beneficial effects of SHC-MSCs. Administration of SHC-MSCs or PLK1-overexpressing MSCs significantly ameliorated symptoms of graft-versus-host disease (GVHD) in a humanized mouse model, resulting in significantly improved survival, less weight loss, and reduced histopathologic injuries in GVHD target organs compared with naïve MSC-infused mice. Collectively, our findings suggest that SHC-MSCs can improve the clinical treatment of allogeneic conflicts, including GVHD.
Abstract 15164: Characterizing the Incidence of Heart Failure Following Hospitalizations for Acute Myocardial Infarction
Authors: Ella Nkhoma, Agata Ptaszynska, Andres Gomez
Journal: Circulation (2016)

Introduction: The incidence of heart failure (HF) following acute myocardial infarction (AMI) in recent years is poorly characterized in the literature. We sought to estimate the long-term incidenc...