tbuckley/cabot-search huggingface dataset:
Family history record and hereditary cancer risk perception after the creation of a heredofamilial cancer unit in a Spanish hospital.
Authors: Ivan Marquez-Rodas, Sara Perez Ramirez, Mercedes Cavanagh Podesta, Beatriz Moya, Ana Belen Ruperez Blanco, Daniel Lopez-Trabada Ataz, Sara Custodio Cabello, Maria Orera Clemente, Felipe A. Calvo, Miguel Martin
Journal: Journal of Clinical Oncology (2012)

e12003 Background: A comprehensive family history and consideration of the criteria for hereditary cancer risk are essential for oncology practice, since patients and relatives at risk could benefit from further genetic counseling (GC). The objective of this work is to compare the family history record and the hereditary cancer perception risk according to national cancer institute (NCI) criteria before and after the creation of a heredofamilial cancer unit (HFCU). Methods: We retrospectively analyze the clinical records from new incoming patients of our medical oncology service in two cohorts: Cohort 1, from January 2009 to December 2009 (before HFCU creation); and cohort 2, from May 2010 to August 2010 (first four months after HFCU creation). Family history record (yes/no) and NCI general hereditary cancer criteria (unusually early age; one or more first-degree relatives affected with the same or a related tumor; synchronous, bilateral or metachronous cancer in the same individual; atypical presentations; suggestive pathology report) were collected. Results were compared using chi-square test. p &lt;0.05 was considered significant. Results: The table summarizes the results. In cohort 1, 28% (175/621) of clinical records contained the family history, while in cohort 2 this percentage increased to 54% (92/171), (p&lt;0.001). 17% (106/621) patients in cohort 1 and 23% (40/171) in cohort 2, met NCI risk criteria (N.S.) In cohort 1, 13% (14/106) of these patients were referred to GC, while in cohort 2 this percentage increased to 38% (15/40) (p&lt;0.01). Conclusions: The creation of a multidisciplinary HFCU significantly increased the quality of family history records and the referral of patients at risk to GC. However, the percentages still remain limited and further efforts must be made in order to remark the importance of family history in oncology. [Table: see text]
A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest
Authors: Gavin D. Perkins, Chen Ji, Charles D. Deakin, Tom Quinn, Jerry P. Nolan, Charlotte Scomparin, Scott Regan, John Long, Anne Slowther, Helen Pocock, John J.M. Black, Fionna Moore, Rachael T. Fothergill, Nigel Rees, Lyndsey O’Shea, Mark Docherty, Imogen Gunson, Kyee Han, Karl Charlton, Judith Finn, Stavros Petrou, Nigel Stallard, Simon Gates, Ranjit Lall
Journal: New England Journal of Medicine (2018)

Concern about the use of epinephrine as a treatment for out-of-hospital cardiac arrest led the International Liaison Committee on Resuscitation to call for a placebo-controlled trial to determine whether the use of epinephrine is safe and effective in such patients.
Building Bridges for Asthma Care: Reducing school absence for inner-city children with health disparities
Authors: Stanley J. Szefler, Michelle M. Cloutier, Miguel Villarreal, Jessica P. Hollenbach, Melanie Gleason, Christy Haas-Howard, Carol Vinick, Agustin Calatroni, Lisa Cicutto, Marty White, Shann Williams, Meghan McGinn, Christine Langton, Donna Shocks, Herman Mitchell, David A. Stempel
Journal: Journal of Allergy and Clinical Immunology (2018)
Abstract 182: Medical Comorbidities and Age Both Predict Neurological Outcomes in Survivors of Cardiac Arrest Treated With Hypothermia
Authors: Samuel W Terman, Benjamin D Hume, Robert Silbergleit
Journal: Circulation (2013)

Introduction: Age is a known predictor of outcome in comatose survivors of out of hospital cardiac arrest (OHCA), but it is unknown whether this is inherent or because age is a marker for overall health status. In a cohort treated with hypothermia, we hypothesized that age and pre-arrest comorbidities would both contain unique neurological prognostic information. Methods: We conducted a retrospective cohort study, reviewing electronic medical records of all patients treated with mild therapeutic hypothermia (MTH) in the University of Michigan Emergency Department for OHCA. We categorized patients’ past medical history into a Charlson Comorbidity Index (CCI). Age was analyzed by decade. Neurologic outcomes were determined 6-12 months post-discharge by Cerebral Performance Category (CPC). Logistic models were evaluated by c-statistics and likelihood ratio tests. Trends were evaluated using one-sided Cochrane Armitage tests. Results: After exclusions, 123 patients received MTH between 7/1/2006 and 9/14/2012. Favorable neurological outcomes in patients with CCI 0, 1-2, 3-4, and ≥5 are shown (figure). Odds ratio (95% confidence intervals) by CCI category were 1 (ref), 0.4 (0.1-1.0), 0.5 (0.2-1.7), and 0.2 (0.03-0.9) (c = 0.65, p for trend=0.04). Combined Charlson-age index had slightly higher predictive ability (c=0.71, p=0.0004). CCI added significant predictive ability when added onto a model containing only age (c-statistic increased from 0.71 to 0.78; likelihood ratios p=0.0073). Similarly, age added significant predictive ability when added onto a model containing CCI alone (c-statistic increased from 0.65 to 0.78; p=0.0001) Conclusions: Both age and pre-arrest comorbidities are associated with outcome in comatose survivors of cardiac arrest, but the former appears to be a stronger predictor. This may reflect limitations of the health index used, but more likely that age is an independent predictor of prognosis rather than a marker for comorbidity.
In vivo evaluation of post-operative pain reduction on rat model after implantation of intraperitoneal PET meshes functionalised with cyclodextrins and loaded with ropivacaine
Authors: Feng Chai, Mickael Maton, Stephanie Degoutin, Guillaume Vermet, Nicolas Simon, Christelle Rousseaux, Bernard Martel, Nicolas Blanchemain
Journal: Biomaterials (2018)
Clinical and genetic differences between pustular psoriasis subtypes
Authors: Sophie Twelves, Alshimaa Mostafa, Nick Dand, Elias Burri, Katalin Farkas, Rosemary Wilson, Hywel L. Cooper, Alan D. Irvine, Hazel H. Oon, Külli Kingo, Sulev Köks, Ulrich Mrowietz, Luis Puig, Nick Reynolds, Eugene Sern-Ting Tan, Adrian Tanew, Kaspar Torz, Hannes Trattner, Mark Valentine, Shyamal Wahie, Richard B. Warren, Andrew Wright, Zsuzsa Bata-Csörgő, Marta Szell, Christopher E.M. Griffiths, A. David Burden, Siew-Eng Choon, Catherine H. Smith, Jonathan N. Barker, Alexander A. Navarini, Francesca Capon
Journal: Journal of Allergy and Clinical Immunology (2018)

The term pustular psoriasis indicates a group of severe skin disorders characterized by eruptions of neutrophil-filled pustules. The disease, which often manifests with concurrent psoriasis vulgaris, can have an acute systemic (generalized pustular psoriasis [GPP]) or chronic localized (palmoplantar pustulosis [PPP] and acrodermatitis continua of Hallopeau [ACH]) presentation. Although mutations have been uncovered in IL36RN and AP1S3, the rarity of the disease has hindered the study of genotype-phenotype correlations.We sought to characterize the clinical and genetic features of pustular psoriasis through the analysis of an extended patient cohort.We ascertained a data set of unprecedented size, including 863 unrelated patients (251 with GPP, 560 with PPP, 28 with ACH, and 24 with multiple diagnoses). We undertook mutation screening in 473 cases.Psoriasis vulgaris concurrence was lowest in PPP (15.8% vs 54.4% in GPP and 46.2% in ACH, P < .0005 for both), whereas the mean age of onset was earliest in GPP (31.0 vs 43.7 years in PPP and 51.8 years in ACH, P < .0001 for both). The percentage of female patients was greater in PPP (77.0%) than in GPP (62.5%; P = 5.8 × 10-5). The same applied to the prevalence of smokers (79.8% vs 28.3%, P < 10-15). Although AP1S3 alleles had similar frequency (0.03-0.05) across disease subtypes, IL36RN mutations were less common in patients with PPP (0.03) than in those with GPP (0.19) and ACH (0.16; P = 1.9 × 10-14 and .002, respectively). Importantly, IL36RN disease alleles had a dose-dependent effect on age of onset in all forms of pustular psoriasis (P = .003).The analysis of an unparalleled resource revealed key clinical and genetic differences between patients with PPP and those with GPP.
Photosensitivity and type I IFN responses in cutaneous lupus are driven by epidermal-derived interferon kappa
Authors: Mrinal K Sarkar, Grace A Hile, Lam C Tsoi, Xianying Xing, Jianhua Liu, Yun Liang, Celine C Berthier, William R Swindell, Matthew T Patrick, Shuai Shao, Pei-Suen Tsou, Ranjitha Uppala, Maria A Beamer, Anshika Srivastava, Stephanie L Bielas, Paul W Harms, Spiro Getsios, James T Elder, John J Voorhees, Johann E Gudjonsson, J Michelle Kahlenberg
Journal: Annals of the Rheumatic Diseases (2018)

Objective Skin inflammation and photosensitivity are common in patients with cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE), yet little is known about the mechanisms that regulate these traits. Here we investigate the role of interferon kappa (IFN-κ) in regulation of type I interferon (IFN) and photosensitive responses and examine its dysregulation in lupus skin. Methods mRNA expression of type I IFN genes was analysed from microarray data of CLE lesions and healthy control skin. Similar expression in cultured primary keratinocytes, fibroblasts and endothelial cells was analysed via RNA-seq. IFNK knock-out (KO) keratinocytes were generated using CRISPR/Cas9. Keratinocytes stably overexpressing IFN-κ were created via G418 selection of transfected cells. IFN responses were assessed via phosphorylation of STAT1 and STAT2 and qRT-PCR for IFN-regulated genes. Ultraviolet B-mediated apoptosis was analysed via TUNEL staining. In vivo protein expression was assessed via immunofluorescent staining of normal and CLE lesional skin. Results IFNK is one of two type I IFNs significantly increased (1.5-fold change, false discovery rate (FDR) q&lt;0.001) in lesional CLE skin. Gene ontology (GO) analysis showed that type I IFN responses were enriched (FDR=6.8×10 −04 ) in keratinocytes not in fibroblast and endothelial cells, and this epithelial-derived IFN-κ is responsible for maintaining baseline type I IFN responses in healthy skin. Increased levels of IFN-κ, such as seen in SLE, amplify and accelerate responsiveness of epithelia to IFN-α and increase keratinocyte sensitivity to UV irradiation. Notably, KO of IFN-κ or inhibition of IFN signalling with baricitinib abrogates UVB-induced apoptosis. Conclusion Collectively, our data identify IFN-κ as a critical IFN in CLE pathology via promotion of enhanced IFN responses and photosensitivity. IFN-κ is a potential novel target for UVB prophylaxis and CLE-directed therapy.
Abstract B45: Rab5C enhances resistance to ionizing radiation in rectal cancer
Authors: Antuani Rafael Baptistella, Marcos Vinicios Salles Dias, Fernanda Giudice, Bruna Roz Rodrigues, Petrus Paulo Combas Eufrazio Silva, Edson Kuatelela Cassinela, Tonielli Lacerda, Fabio Marchi, Adriana Franco Paes Leme, Maria Dirlei Begnami, Samuel Aguiar Junior, Vilma Regina Martins
Journal: Clinical Cancer Research (2018)

Abstract Rectal cancer is currently the second most common cancer in the large intestine, and represents one-third of the colorectal cancers that are diagnosed. Neoadjuvant chemoradiation is a well-established protocol for rectal cancer treatment and it reduces the risk of local recurrence. However, a pathologic complete response is only achieved in 10–40% of cases and the mechanisms associated with chemoradiation resistance are poorly understood. To identify potential targets for preventing therapy resistance, a proteomic analysis of biopsy specimens collected from stage II and III rectal adenocarcinoma patients before neoadjuvant treatment was performed. These results were then compared with a proteomic analysis of residual rectal adenocarcinoma tissues that were removed by surgery after neoadjuvant therapy. Three proteins, Ku70, Ku80, and Rab5C, exhibited a significant increase in expression after chemoradiation treatment. To better understand the possible role of these proteins in therapy resistance, a rectal adenocarcinoma cell line was irradiated to generate a radiotherapy-resistant lineage. These cells overexpressed the same three proteins that were identified in the tissue samples. Furthermore, radiotherapy resistance in this in vitro model was found to involve modulation of epidermal growth factor receptor (EGFR) internalization by Rab5C in response to irradiation, and this affected expression of the DNA repair proteins, Ku70 and Ku80. Taken together, these findings indicate that EGFR and Rab5C are potential targets for the sensitization of rectal cancer cells to neoadjuvant treatment and they should be further investigated. Supported by FAPESP - Fundação de Amparo à Pesquisa do Estado de São Paulo. Note: This abstract was not presented at the conference. Citation Format: Antuani Rafael Baptistella, Marcos Vinicios Salles Dias, Fernanda Giudice, Bruna Roz Rodrigues, Petrus Paulo Combas Eufrazio Silva, Edson Kuatelela Cassinela, Tonielli Lacerda, Fabio Marchi, Adriana Franco Paes Leme, Maria Dirlei Begnami, Samuel Aguiar Junior, Vilma Regina Martins. Rab5C enhances resistance to ionizing radiation in rectal cancer [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B45.
Accelerating the reversal of inflammatory pain with NPD1 and its receptor GPR37
Authors: Lintao Qu, Michael J. Caterina
Journal: Journal of Clinical Investigation (2018)

Resolution of inflammation is a critical process that is facilitated by specialized proresolving mediators (SPMs). In this issue, Bang et al. show that the G protein-coupled receptor GPR37 is a receptor for one such SPM, neuroprotectin D1. They also show that GPR37 activation in macrophages enhances phagocytosis, shifts cytokine release toward an antiinflammatory profile, and thereby helps to reverse inflammatory pain.
CRL4DCAF2 negatively regulates IL-23 production in dendritic cells and limits the development of psoriasis
Authors: Tao Huang, Zhengjun Gao, Yu Zhang, Keqi Fan, Fei Wang, Yiyuan Li, Jiangyan Zhong, Heng Y. Fan, Qian Cao, Jiyong Zhou, Yichuan Xiao, Hongbo Hu, Jin Jin
Journal: The Journal of Experimental Medicine (2018)

The E3 ligase CRL4DCAF2 is believed to be a pivotal regulator of the cell cycle and is required for mitotic and S phase progression. The NEDD8-targeting drug MLN4924, which inactivates cullin ring-finger ubiquitin ligases (CRLs), has been examined in clinical trials for various types of lymphoma and acute myeloid leukemia. However, the essential role of CRL4DCAF2 in primary myeloid cells remains poorly understood. MLN4924 treatment, which mimics DCAF2 depletion, also promotes the severity of mouse psoriasis models, consistent with the effects of reduced DCAF2 expression in various autoimmune diseases. Using transcriptomic and immunological approaches, we showed that CRL4DCAF2 in dendritic cells (DCs) regulates the proteolytic fate of NIK and negatively regulates IL-23 production. CRL4DCAF2 promoted the polyubiquitination and subsequent degradation of NIK independent of TRAF3 degradation. DCAF2 deficiency facilitated NIK accumulation and RelB nuclear translocation. DCAF2 DC-conditional knockout mice displayed increased sensitivity to autoimmune diseases. This study shows that CRL4DCAF2 is crucial for controlling NIK stability and highlights a unique mechanism that controls inflammatory diseases.
Species Tree Inference with BPP Using Genomic Sequences and the Multispecies Coalescent
Authors: Tomáš Flouri, Xiyun Jiao, Bruce Rannala, Ziheng Yang
Journal: Molecular Biology and Evolution (2018)

The multispecies coalescent provides a natural framework for accommodating ancestral genetic polymorphism and coalescent processes that can cause different genomic regions to have different genealogical histories. The Bayesian program BPP includes a full-likelihood implementation of the multispecies coalescent, using transmodel Markov chain Monte Carlo to calculate the posterior probabilities of different species trees. BPP is suitable for analyzing multilocus sequence data sets and it accommodates the heterogeneity of gene trees (both the topology and branch lengths) among loci and gene tree uncertainties due to limited phylogenetic information at each locus. Here, we provide a practical guide to the use of BPP in species tree estimation. BPP is a command-line program that runs on linux, macosx, and windows. This protocol shows how to use both BPP 3.4 (http://abacus.gene.ucl.ac.uk/software/) and BPP 4.0 (https://github.com/bpp/).
Circulating angiogenesis-related markers as predictors of benefit from regorafenib in metastatic colorectal cancer (mCRC) patients (pts).
Authors: Carlotta Antoniotti, Federica Marmorino, Marzia Pennati, Nadia Zaffaroni, Daniele Rossini, Beatrice Borelli, Gemma Zucchelli, Roberto Moretto, Filippo Pietrantonio, Gianluca Masi, Francesca Vannini, Camilla Colombo, Serenella Gini, Alessandra Saettini, Laura Delliponti, Isa Maura Brunetti, Elisabetta Pfanner, Alfredo Falcone, Chiara Cremolini
Journal: Journal of Clinical Oncology (2018)

675 Background: Regorafenib is a treatment option for refractory mCRC pts. Considering its limited clinical benefit and the palliative setting, patients’ selection is essential to optimize the cost-effectiveness ratio. We aimed to describe the modulation of selected circulating angiogenic factors by regorafenib and to investigate their correlation with clinical outcome. Methods: IL-8, Ang-2, PDGF, bFGF, Tie-2, sVEGFR2, sVEGFR3, PlGF, VEGF-A, VEGF-B were assessed by ELISA on plasma samples collected at baseline (d1), after 15 days of treatment (d15), at the best RECIST response, at disease progression (PD) in mCRC pts treated with regorafenib, as per indication. Comparisons among concentrations of each marker at different timepoints were performed by Wilcoxon test. Markers showing significant changes were analyzed for correlation with outcome. Results: 105 pts were included. Median PFS and OS were 2.1 and 7.0 months (mos), respectively. As compared to d1, IL-8 and Ang-2 levels increased at PD. An early decrease at d15 was observed for PDGF, Tie-2, sVEGFR2 and sVEGFR3 levels, followed by an increase at PD. Conversely, PlGF levels increased at d15 and then decreased at PD. Baseline levels of Ang-2 and Tie-2 below the median value were associated with longer PFS (HR:0.61 [0.37-0.83] p = 0.006; HR:0.69 [0.43-0.95] p = 0.04, respectively) and OS (HR:0.45 [0.26-0.60] p &lt; 0.0001; HR:0.68 [0.44-0.98] p = 0.04, respectively). With regard to Ang-2, 40 (45%) out of 89 pts with available plasma samples at d15 showed increased levels at d15 as compared to d1. Among them, 21 (53%) achieved disease control, as compared to 14 out of 49 (29%) pts with Ang-2 decreased levels (p = 0.03). Median PFS of pts with increased and decreased Ang-2 levels were 3.1 and 1.8 mos, respectively (HR:0.57 [0.33-0.78] p = 0.004). Conclusions: A dynamic modulation of plasma angiogenic factors occurs during the treatment with regorafenib. Low baseline Ang-2 and Tie-2 levels seem to be associated with good prognosis. The early modulation of Ang-2 levels may predict benefit from regorafenib. These results need validation in independent series.
Lower genomic stability of induced pluripotent stem cells reflects increased non‐homologous end joining
Authors: Minjie Zhang, Liu Wang, Ke An, Jun Cai, Guochao Li, Caiyun Yang, Huixian Liu, Fengxia Du, Xiao Han, Zilong Zhang, Zitong Zhao, Duanqing Pei, Yuan Long, Xin Xie, Qi Zhou, Yingli Sun
Journal: Cancer Communications (2018)

Induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) share many common features, including similar morphology, gene expression and in vitro differentiation profiles. However, genomic stability is much lower in iPSCs than in ESCs. In the current study, we examined whether changes in DNA damage repair in iPSCs are responsible for their greater tendency towards mutagenesis.Mouse iPSCs, ESCs and embryonic fibroblasts were exposed to ionizing radiation (4 Gy) to introduce double-strand DNA breaks. At 4 h later, fidelity of DNA damage repair was assessed using whole-genome re-sequencing. We also analyzed genomic stability in mice derived from iPSCs versus ESCs.In comparison to ESCs and embryonic fibroblasts, iPSCs had lower DNA damage repair capacity, more somatic mutations and short indels after irradiation. iPSCs showed greater non-homologous end joining DNA repair and less homologous recombination DNA repair. Mice derived from iPSCs had lower DNA damage repair capacity than ESC-derived mice as well as C57 control mice.The relatively low genomic stability of iPSCs and their high rate of tumorigenesis in vivo appear to be due, at least in part, to low fidelity of DNA damage repair.
Somatic Mutations in Renal Cyst Epithelium in Autosomal Dominant Polycystic Kidney Disease
Authors: Adrian Y. Tan, Tuo Zhang, Alber Michaeel, Jon Blumenfeld, Genyan Liu, Wanying Zhang, Zhengmao Zhang, Yi Zhu, Lior Rennert, Che Martin, Jenny Xiang, Steven P. Salvatore, Brian D. Robinson, Sandip Kapur, Stephanie Donahue, Warren O. Bobb, Hanna Rennert
Journal: Journal of the American Society of Nephrology (2018)

Autosomal dominant polycystic kidney disease (ADPKD) is a ciliopathy caused by mutations in PKD1 and PKD2 that is characterized by renal tubular epithelial cell proliferation and progressive CKD. Although the molecular mechanisms involved in cystogenesis are not established, concurrent inactivating constitutional and somatic mutations in ADPKD genes in cyst epithelium have been proposed as a cellular recessive mechanism.We characterized, by whole-exome sequencing (WES) and long-range PCR techniques, the somatic mutations in PKD1 and PKD2 genes in renal epithelial cells from 83 kidney cysts obtained from nine patients with ADPKD, for whom a constitutional mutation in PKD1 or PKD2 was identified.Complete sequencing data by long-range PCR and WES was available for 63 and 65 cysts, respectively. Private somatic mutations of PKD1 or PKD2 were identified in all patients and in 90% of the cysts analyzed; 90% of these mutations were truncating, splice site, or in-frame variations predicted to be pathogenic mutations. No trans-heterozygous mutations of PKD1 or PKD2 genes were identified. Copy number changes of PKD1 ranging from 151 bp to 28 kb were observed in 12% of the cysts. WES also identified significant mutations in 53 non-PKD1/2 genes, including other ciliopathy genes and cancer-related genes.These findings support a cellular recessive mechanism for cyst formation in ADPKD caused primarily by inactivating constitutional and somatic mutations of PKD1 or PKD2 in kidney cyst epithelium. The potential interactions of these genes with other ciliopathy- and cancer-related genes to influence ADPKD severity merits further evaluation.
What <i>have</i> we learned? What <i>can</i> we learn?
Authors: Fritz Strack, Wolfgang Stroebe
Journal: Behavioral and Brain Sciences (2018)

Abstract We advocate that replications should be an integral part of the scientific discourse and provide insights about the conditions under which an effect occurs. By themselves, mere nonreplications are not informative about the “truth” of an effect. As a consequence, the mechanistic continuation of multilab replications should be replaced by diagnostic studies providing insights about the underlying causes and mechanisms.