tbuckley/cabot-search huggingface dataset:
Global Prospective Safety Analysis of Rivaroxaban
Authors: Paulus Kirchhof, Ghazi Radaideh, Young-Hoon Kim, Fernando Lanas, Sylvia Haas, Pierre Amarenco, Alexander G.G. Turpie, Miriam Bach, Marc Lambelet, Susanne Hess, A. John Camm
Journal: Journal of the American College of Cardiology (2018)

The efficacy of direct oral anticoagulants (DOACs) for stroke prevention in patients with atrial fibrillation (AF) has been established in clinical trials. However, well-conducted, prospective, real-world observational studies of the safety and effectiveness of DOACs are needed. This study sought to assess the real-world safety profile of rivaroxaban through a pooled analysis of patients with AF enrolled in the XANTUS (Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation) program worldwide. A pre-planned pooled analysis of the XANTUS, XANAP (Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation in Asia), and XANTUS-EL (Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation in Latin America and EMEA Region) registries was performed. Patients with AF newly starting rivaroxaban for stroke prevention were followed for 1 year. Primary outcomes were treatment-emergent major bleeding, adverse events (AEs)/serious AEs, and all-cause death. Secondary outcomes included treatment-emergent thromboembolic events and nonmajor bleeding. Major outcomes were centrally adjudicated. Overall, 11,121 patients were included (mean age 70.5 ± 10.5 years; female 42.9%). Comorbidities included heart failure (21.2%), hypertension (76.2%), and diabetes (22.3%). Event rates were: events/100 patient-years: major bleeding 1.7 (95% confidence interval [CI]: 1.5 to 2.0; lowest: Latin America 0.7; highest: Western Europe, Canada, and Israel 2.3); all-cause death 1.9 (95% CI: 1.6 to 2.2; lowest: Eastern Europe 1.5; highest: Latin America, Middle East, and Africa 2.7); and stroke or systemic embolism 1.0 (95% CI: 0.8 to 1.2; lowest: Latin America 0; highest: East Asia 1.8). One-year treatment persistence was 77.4% (lowest: East Asia 66.4%; highest: Eastern Europe 84.4%). This large, prospective, real-world analysis in 11,121 patients from 47 countries showed low bleeding and stroke rates in rivaroxaban-treated patients with AF, with low treatment discontinuation in different regions of the world. Results were broadly consistent across regions. (Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation [XANTUS]; NCT01606995; Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation in Latin America and EMEA Region [XANTUS-EL]; NCT01800006; and Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation in Asia [XANAP]; NCT01750788)
Abstract 1088: Defining bone metastatic potential of Abi1 CRISPR prostate cancer cell lines
Authors: Alexander Nappi, Dawn Post, Disharee Das, Ishita Joshi, Megan Oest, Gennady Bratslavsky, Leszek Kotula
Journal: Cancer Research (2018)

Abstract Prostate cancer is the second most common cancer in American men, and it is the third leading cause of cancer-related deaths in American men. Distant stage and metastatic disease is often treated with androgen-deprivation therapy (ADT); however, this treatment ultimately fails, leading to castration-resistant prostate cancer (CRPC). This further emphasizes the need for better therapeutic targets. Our work focuses on understanding the role of the Abi1 gene in prostate cancer tumor progression. Our current in vitro data demonstrate an invasive phenotype with our CRISPR-mediated Abi1 knockout (KO) cell lines. In total, using CRISPR-mediated technology we have generated four Abi1 gene KO cell lines, PC-3, DU145, LnCaP, and RWPE-1. Importantly, the androgen-dependent cell line, LNCaP, demonstrated upregulation of Abi1 to the androgen receptor stimulation and the opposite response to the receptor inhibition upon treatment with enzalutamide. These data indicated that low Abi1 level could be induced by ADT therapies and are consistent with our previous observation of low Abi1/WAVE complex in prostate tumor samples. To learn more about this mechanism, we set out to investigate the role of Abi1 in castrated mice. The overall goal of the experiment is to compare the ability of cells lacking the Abi1 gene to engraft in bone under androgen deprivation condition and compare it to the control cells and examine any change in the engraftment phenotype. It is hoped that this research will lead to better understanding of the Abi1/WAVE complex role in CRPC. Supported by NCI R01 CA16101. Citation Format: Alexander Nappi, Dawn Post, Disharee Das, Ishita Joshi, Megan Oest, Gennady Bratslavsky, Leszek Kotula. Defining bone metastatic potential of Abi1 CRISPR prostate cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1088.
DeepCRISPR: optimized CRISPR guide RNA design by deep learning
Authors: Guohui Chuai, Hanhui Ma, Jifang Yan, Ming Chen, Nanfang Hong, Dongyu Xue, Chi Zhou, Chenyu Zhu, Ke Chen, Bin Duan, Feng Gu, Sheng Qu, Deshuang Huang, Jia Wei, Qi Liu
Journal: Genome biology (2018)

A major challenge for effective application of CRISPR systems is to accurately predict the single guide RNA (sgRNA) on-target knockout efficacy and off-target profile, which would facilitate the optimized design of sgRNAs with high sensitivity and specificity. Here we present DeepCRISPR, a comprehensive computational platform to unify sgRNA on-target and off-target site prediction into one framework with deep learning, surpassing available state-of-the-art in silico tools. In addition, DeepCRISPR fully automates the identification of sequence and epigenetic features that may affect sgRNA knockout efficacy in a data-driven manner. DeepCRISPR is available at http://www.deepcrispr.net/ .
Abstract 80: Glucocorticoids mediate DCIS transition to IDC through myoepithelial cell apoptosis
Authors: Arantzazu Zubeldia-Plazaola, Leire Recalde-Percaz, Núria Moragas, Mario Mancino, Aleix Noguera, Miquel Prats de Puig, Flavia Guzman, Pedro Gascón, Paloma Bragado, Gemma Fuster
Journal: Cancer Research (2018)

Abstract The most accepted theory in breast cancer evolution is the linear progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC). DCIS is defined by a clonal proliferation of epithelial cells that accumulate within the lumen of a duct and surrounded by the myoepithelial cells layer and the basement membrane. The challenge is to predict which of the DCIS lesions will eventually progress to IDC and which will remain stable for a long time. Understanding the progression from DCIS to IDC is crucial to properly treat DCIS patients and to develop new and more approachable therapeutic strategies in this stage. The microenvironment, as well as stress factors like glucocorticoids, exerts strong influences in DCIS to IDC transition. These factors have been previously implicated in breast cancer progression however its role in the first stages of breast cancer and particularly in myoepithelial cells regulation remains elusive. In order to clarify glucocorticoids role in this breast cancer stage, we evaluated the effects of corticosterone and cortisol in epithelial cells and myoepithelial cells using in vitro 2D and 3D and in vivo techniques. Glucocorticoids induced a decreased in laminin levels and favour the disruption of the myoepithelial cell layer through myoepithelial cells apoptosis promotion. In addition, increased corticosterone levels, in an in vivo stress murine model, fostered the transition from DCIS to IDC via myoepithelial cell apoptosis and basement membrane vanishing. Furthermore, myoepithelial cell apoptosis is a more frequent event in DCIS+IDC than in DCIS breast cancer patients. Our findings show that stress, through glucocorticoids, plays a role in the progression of DCIS to IDC, and particularly by promoting apoptosis of myoepithelial cells and the apoptosis in myoepithelial cells seems to be a requirement to achieve invasive features in breast cancer patients. Citation Format: Arantzazu Zubeldia-Plazaola, Leire Recalde-Percaz, Núria Moragas, Mario Mancino, Aleix Noguera, Miquel Prats de Puig, Flavia Guzman, Pedro Gascón, Paloma Bragado, Gemma Fuster. Glucocorticoids mediate DCIS transition to IDC through myoepithelial cell apoptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 80.
A traumatic wrist injury
Authors: Philip Beak, Shamim Umarji
Journal: BMJ (2018)

A 38 year old motorcyclist presented to the emergency department after colliding with a car at speed. He had landed on his outstretched right hand and was complaining of a painful, swollen right wrist. Motor and sensory neurological function of the right radian, ulnar, and median nerves was intact. Radial pulse was palpable.

Based on the radiographs of his wrist (fig 1), what is the diagnosis?



Fig 1 
(a) Anteroposterior radiograph of the wrist 





Fig 2 
Lateral radiographs of the wrist



The radiographs show volar dislocation of the lunate (fig 3). This injury classically occurs after a high-energy fall on an outstretched hand. On examination, the wrist is painful and there is diffuse swelling. …
Abstract 4313: Methylated BAF155 promotes cancer metastasis by cooperating with BRD4 to potentiate genes addicted to super-enhancers
Authors: Eui-Jun Kim, Yidan Wang, Li Lu, Lixin Rui, Xuehua Zhong, Kari B. Wisinski, Wei Xu
Journal: Cancer Research (2018)

Abstract Triple-negative breast cancers (TNBC) lack the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). TNBC is the most aggressive breast cancer subtype and is often associated with distant metastasis, poor prognosis, and lack of targeted treatment options. The failure to identify a few genes driving metastasis through sequencing of paired tumors at primary and metastatic sites implies that epigenetic mechanisms may play important roles in TNBC metastasis. Recently, we found that an epigenetic enzyme coactivator associated arginine methyltransferase 1 (CARM1) is highly expressed in TNBC and its high expression correlates with poor prognosis. Subsequently we identified BRG1-Associated Factor 155 (BAF155), a component of SWI/SNF chromatin remodeling complex, as a novel CARM1 substrate. Transcriptome analyses of BAF155 methylation competent and defective cell lines identified many genes involved in regulating cancer metastasis are methyl-BAF155 targets. Methylation of BAF155 was found to promote metastasis in the TNBC xenografted mouse models. We generated a methyl-BAF155 antibody that could specifically detect methylated BAF155 (me-BAF155) by IHC and chromatin immunoprecipitation followed by sequencing (ChIP-seq). We mapped global me-BAF155 genomic association sites using ChIP-seq and discovered that me-BAF155 was highly enriched in super-enhancers (SEs), regulatory elements on chromatin that are known to drive high transcription of many oncogenes. SEs are known to recruit BRD4, a BET family bromodomain protein. Indeed, global me-BAF155 binding peaks greatly overlap with those of BRD4 binding sites. Treatment of TNBC cells with either BRD4 inhibitor JQ1 or CARM1 inhibitor TP-064 significantly reduced the expression of me-BAF155 target genes. Together our data suggest that me-BAF155 is an important epigenetic target for treatment of cancer metastasis in TNBC cells. Citation Format: Eui-Jun Kim, Yidan Wang, Li Lu, Lixin Rui, Xuehua Zhong, Kari B. Wisinski, Wei Xu. Methylated BAF155 promotes cancer metastasis by cooperating with BRD4 to potentiate genes addicted to super-enhancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4313.
Paclitaxel Sensitivity of Ovarian Cancer Can be Enhanced by Knocking Down Pairs of Kinases that Regulate MAP4 Phosphorylation and Microtubule Stability
Authors: Hailing Yang, Weiqun Mao, Cristian Rodriguez-Aguayo, Lingegowda S. Mangala, Geoffrey Bartholomeusz, Lakesla R. Iles, Nicholas B. Jennings, Ahmed Ashour Ahmed, Anil K. Sood, Gabriel Lopez-Berestein, Zhen Lu, Robert C. Bast
Journal: Clinical Cancer Research (2018)

Purpose: Most patients with ovarian cancer receive paclitaxel chemotherapy, but less than half respond. Pre-treatment microtubule stability correlates with paclitaxel response in ovarian cancer cell lines. Microtubule stability can be increased by depletion of individual kinases. As microtubule stability can be regulated by phosphorylation of microtubule-associated proteins (MAPs), we reasoned that depletion of pairs of kinases that regulate phosphorylation of MAPs could induce microtubule stabilization and paclitaxel sensitization.Experimental Design: Fourteen kinases known to regulate paclitaxel sensitivity were depleted individually in 12 well-characterized ovarian cancer cell lines before measuring proliferation in the presence or absence of paclitaxel. Similar studies were performed by depleting all possible pairs of kinases in six ovarian cancer cell lines. Pairs that enhanced paclitaxel sensitivity across multiple cell lines were studied in depth in cell culture and in two xenograft models.Results: Transfection of siRNA against 10 of the 14 kinases enhanced paclitaxel sensitivity in at least six of 12 cell lines. Dual knockdown of IKBKB/STK39 or EDN2/TBK1 enhanced paclitaxel sensitivity more than silencing single kinases. Sequential knockdown was superior to concurrent knockdown. Dual silencing of IKBKB/STK39 or EDN2/TBK1 stabilized microtubules by inhibiting phosphorylation of p38 and MAP4, inducing apoptosis and blocking cell cycle more effectively than silencing individual kinases. Knockdown of IKBKB/STK39 or EDN2/TBK1 enhanced paclitaxel sensitivity in two ovarian xenograft models.Conclusions: Sequential knockdown of dual kinases increased microtubule stability by decreasing p38-mediated phosphorylation of MAP4 and enhanced response to paclitaxel in ovarian cancer cell lines and xenografts, suggesting a strategy to improve primary therapy. Clin Cancer Res; 24(20); 5072-84. ©2018 AACR.
Abstract 13479: New Heart, Old Arrhythmia: Atrial Arrhythmias After Orthotopic Heart Transplantation
Authors: Briana T Costello, Burhan Mohamedali, Enrique P Campos, Jessica E Sturgess, Anjan Deka
Journal: Circulation (2015)

Introduction: Arrhythmias after orthotopic heart transplantation (OHT) are common. However the influence of pre-transplant atrial arrhythmia on post-OHT atrial arrhythmia has not been established. In this study we analyzed the occurrence of post-OHT atrial arrhythmias in patients with prior atrial fibrillation or flutter (afib/flutter). Methods: In this retrospective single center study, 56 patients who underwent OHT from 2003-14 were enrolled. Patients were stratified based on history of pre-OHT afib/flutter. Baseline demographics, and post-transplant outcomes including atrial arrythmias were recorded. Post-OHT atrial arrhythmias were defined as afib/flutter, atrial tachycardia, multifocal atrial tachycardia, and wandering atrial pacemaker Data was analyzed using student’s t-test and X2 analysis. Results: The cohort comprised of 20 patients with pre-transplant history of afib/flutter and 36 patients without such diagnosis. There was no statistical difference in age, gender or BMI in patients between the two groups. Our analysis revealed that patients with afib/flutter prior to OHT had significantly more atrial arrhythmias at one year compared to those without afib/flutter (31.6% vs 8.8%, p=0.034), and this difference was maintained at five years follow-up (50% vs 11.1%, p=0.001). Additionally, there was a strong trend toward increased overall mortality in in this group (35% vs 13.9%, p=0.065). Discussion: Our results suggest a novel finding of a link between pre and post-OHT atrial arrhythmias, particularly in the first year after transplantation. This surprising finding may be related to residual recipient pulmonary vein activity, recipient atrial anastomotic tissue, or patient related factors. Further prospective research is indicated to confirm our findings.
Noninvasive Immunohistochemical Diagnosis and Novel MUC1 Mutations Causing Autosomal Dominant Tubulointerstitial Kidney Disease
Authors: Martina Živná, Kendrah Kidd, Anna Přistoupilová, Veronika Barešová, Mathew DeFelice, Brendan Blumenstiel, Maegan Harden, Peter Conlon, Peter Lavin, Dervla M. Connaughton, Hana Hartmannová, Kateřina Hodaňová, Viktor Stránecký, Alena Vrbacká, Petr Vyleťal, Jan Živný, Miroslav Votruba, Jana Sovová, Helena Hůlková, Victoria Robins, Rebecca Perry, Andrea Wenzel, Bodo B. Beck, Tomáš Seeman, Ondřej Viklický, Sylvie Rajnochová-Bloudíčková, Gregory Papagregoriou, Constantinos C. Deltas, Seth L. Alper, Anna Greka, Anthony J. Bleyer, Stanislav Kmoch
Journal: Journal of the American Society of Nephrology (2018)

Background Autosomal dominant tubulointerstitial kidney disease caused by mucin-1 gene ( MUC1 ) mutations (ADTKD- MUC1 ) is characterized by progressive kidney failure. Genetic evaluation for ADTKD- MUC1 specifically tests for a cytosine duplication that creates a unique frameshift protein (MUC1fs). Our goal was to develop immunohistochemical methods to detect the MUC1fs created by the cytosine duplication and, possibly, by other similar frameshift mutations and to identify novel MUC1 mutations in individuals with positive immunohistochemical staining for the MUC1fs protein. Methods We performed MUC1fs immunostaining on urinary cell smears and various tissues from ADTKD- MUC1– positive and –negative controls as well as in individuals from 37 ADTKD families that were negative for mutations in known ADTKD genes. We used novel analytic methods to identify MUC1 frameshift mutations. Results After technique refinement, the sensitivity and specificity for MUC1fs immunostaining of urinary cell smears were 94.2% and 88.6%, respectively. Further genetic testing on 17 families with positive MUC1fs immunostaining revealed six families with five novel MUC1 frameshift mutations that all predict production of the identical MUC1fs protein. Conclusions We developed a noninvasive immunohistochemical method to detect MUC1fs that, after further validation, may be useful in the future for diagnostic testing. Production of the MUC1fs protein may be central to the pathogenesis of ADTKD- MUC1 .
Are high‐ and low‐molecular‐weight sensitizing agents associated with different clinical phenotypes of occupational asthma?
Authors: Olivier Vandenplas, Julien Godet, Laura Hurdubaea, Catherine Rifflart, Hille Suojalehto, Marta Wiszniewska, Xavier Munoz, Joaquin Sastre, Pavlina Klusackova, Vicky Moore, Rolf Merget, Donatella Talini, Cecilie Svanes, Paola Mason, Marco dell'Omo, Paul Cullinan, Gianna Moscato, Santiago Quirce, Jennifer Hoyle, David L. Sherson, Paula Kauppi, Alexandra Preisser, Nicolas Meyer, Frédéric de Blay
Journal: Allergy (2018)

Abstract Background High‐molecular‐weight ( HMW ) proteins and low‐molecular‐weight ( LMW ) chemicals can cause occupational asthma ( OA ) although few studies have thoroughly compared the clinical, physiological, and inflammatory patterns associated with these different types of agents. The aim of this study was to determine whether OA induced by HMW and LMW agents shows distinct phenotypic profiles. Methods Clinical and functional characteristics, and markers of airway inflammation were analyzed in an international, multicenter, retrospective cohort of subjects with OA ascertained by a positive inhalation challenge response to HMW (n = 544) and LMW (n = 635) agents. Results Multivariate logistic regression analysis showed significant associations between OA caused by HMW agents and work‐related rhinitis ( OR [95% CI ]: 4.79 [3.28‐7.12]), conjunctivitis (2.13 [1.52‐2.98]), atopy (1.49 [1.09‐2.05]), and early asthmatic reactions (2.86 [1.98‐4.16]). By contrast, OA due to LMW agents was associated with chest tightness at work (2.22 [1.59‐3.03]), daily sputum (1.69 [1.19‐2.38]), and late asthmatic reactions (1.52 [1.09‐2.08]). Furthermore, OA caused by HMW agents showed a higher risk of airflow limitation (1.76 [1.07‐2.91]), whereas OA due to LMW agents exhibited a higher risk of severe exacerbations (1.32 [1.01‐1.69]). There were no differences between the two types of agents in the baseline sputum inflammatory profiles, but OA caused by HMW agents showed higher baseline blood eosinophilia and a greater postchallenge increase in fractional nitric oxide. Conclusion This large cohort study describes distinct phenotypic profiles in OA caused by HMW and LMW agents. There is a need to further explore differences in underlying pathophysiological pathways and outcome after environmental interventions.
Maternal antibiotic use and child asthma: is the association causal?
Authors: Mingyu Zhang, Augusto A. Litonjua, Noel T. Mueller
Journal: European Respiratory Journal (2018)

<b>Maternal antibiotic use before, during and after pregnancy is associated with higher child asthma risk. Lack of specificity to the pregnancy period suggests the association is not causal or the window of susceptibility extends outside pregnancy.</b>http://ow.ly/U29f30kFD2I
FBXO22 Possesses Both Protumorigenic and Antimetastatic Roles in Breast Cancer Progression
Authors: Rui Sun, Hong-Yan Xie, Jin-Xian Qian, Yan-Ni Huang, Fan Yang, Fang-Lin Zhang, Zhi-Min Shao, Da-Qiang Li
Journal: Cancer Research (2018)

The molecular underpinnings behind malignant progression of breast cancer from a localized lesion to an invasive and ultimately metastatic disease are incompletely understood. Here, we report that F-box only protein 22 (FBXO22) plays a dual role in mammary tumorigenesis and metastasis. FBXO22 was upregulated in primary breast tumors and promoted cell proliferation and colony formation in vitro and xenograft tumorigenicity in vivo Surprisingly, FBXO22 suppressed epithelial-mesenchymal transition (EMT), cell motility, and invasiveness in vitro and metastatic lung colonization in vivo Clinical data showed that expression levels of FBXO22 were associated with favorable clinical outcomes, supporting the notion that metastasis, rather than primary cancer, is the major determinant of the mortality of patients with breast cancer. Mechanistic investigations further revealed that FBXO22 elicits its antimetastatic effects by targeting SNAIL, a master regulator of EMT and breast cancer metastasis, for ubiquitin-mediated proteasomal degradation in a glycogen synthase kinase 3β phosphorylation-dependent manner. Importantly, expression of SNAIL rescued FBXO22-mediated suppression of EMT, cell migration, and invasion. A patient-derived tryptophan-to-arginine mutation at residue 52 (W52R) within the F-box domain impaired FBXO22 binding to the SKP1-Cullin1 complex and blocked FBXO22-mediated SNAIL degradation, thus abrogating the ability of FBXO22 to suppress cell migration, invasion, and metastasis. Collectively, these findings uncover an unexpected dual role for FBXO22 in mammary tumorigenesis and metastatic progression and delineate the mechanism of an oncogenic mutation of FBXO22 in breast cancer progression.Significance: These findings highlight the paradoxical roles of FBXO22 in breast cancer, as it promotes breast tumor cell proliferation but prevents EMT and metastasis. Cancer Res; 78(18); 5274-86. ©2018 AACR.