tbuckley/cabot-search huggingface dataset:
Combinatorial genetics in liver repopulation and carcinogenesis with a in vivo CRISPR activation platform†
Authors: Kirk J. Wangensteen, Yue J. Wang, Zhixun Dou, Amber W. Wang, Elham Mosleh‐Shirazi, Max A. Horlbeck, Luke A. Gilbert, Jonathan S. Weissman, Shelley L. Berger, Klaus H. Kaestner
Journal: Hepatology (2017)

Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 activation (CRISPRa) systems have enabled genetic screens in cultured cell lines to discover and characterize drivers and inhibitors of cancer cell growth. We adapted this system for use in vivo to assess whether modulating endogenous gene expression levels can result in functional outcomes in the native environment of the liver. We engineered the catalytically dead CRISPR-associated 9 (dCas9)-positive mouse, cyclization recombination-inducible (Cre) CRISPRa system for cell type-specific gene activation in vivo. We tested the capacity for genetic screening in live animals by applying CRISPRa in a clinically relevant model of liver injury and repopulation. We targeted promoters of interest in regenerating hepatocytes using multiple single guide RNAs (gRNAs), and employed high-throughput sequencing to assess enrichment of gRNA sequences during liver repopulation and to link specific gRNAs to the initiation of carcinogenesis. All components of the CRISPRa system were expressed in a cell type-specific manner and activated endogenous gene expression in vivo. Multiple gRNA cassettes targeting a proto-oncogene were significantly enriched following liver repopulation, indicative of enhanced division of cells expressing the proto-oncogene. Furthermore, hepatocellular carcinomas developed containing gRNAs that activated this oncogene, indicative of cancer initiation events. Also, we employed our system for combinatorial cancer genetics in vivo as we found that while clonal hepatocellular carcinomas were dependent on the presence of the oncogene-inducing gRNAs, they were depleted for multiple gRNAs activating tumor suppressors.
Pharmacological inhibition of the transcription factor PU.1 in leukemia
Authors: Iléana Antony-Debré, Ananya Paul, Joana Leite, Kelly Mitchell, Hye Mi Kim, Luis A. Carvajal, Tihomira I. Todorova, Kenneth Huang, Arvind Kumar, Abdelbasset A. Farahat, Boris Bartholdy, Swathi-Rao Narayanagari, Jiahao Chen, Alberto Ambesi-Impiombato, Adolfo A. Ferrando, Ioannis Mantzaris, Evripidis Gavathiotis, Amit Verma, Britta Will, David W. Boykin, W. David Wilson, Gregory M.K. Poon, Ulrich Steidl
Journal: Journal of Clinical Investigation (2017)

The transcription factor PU.1 is often impaired in patients with acute myeloid leukemia (AML). Here, we used AML cells that already had low PU.1 levels and further inhibited PU.1 using either RNA interference or, to our knowledge, first-in-class small-molecule inhibitors of PU.1 that we developed specifically to allosterically interfere with PU.1-chromatin binding through interaction with the DNA minor groove that flanks PU.1-binding motifs. These small molecules of the heterocyclic diamidine family disrupted the interaction of PU.1 with target gene promoters and led to downregulation of canonical PU.1 transcriptional targets. shRNA or small-molecule inhibition of PU.1 in AML cells from either PU.1lo mutant mice or human patients with AML-inhibited cell growth and clonogenicity and induced apoptosis. In murine and human AML (xeno)transplantation models, treatment with our PU.1 inhibitors decreased tumor burden and resulted in increased survival. Thus, our study provides proof of concept that PU.1 inhibition has potential as a therapeutic strategy for the treatment of AML and for the development of small-molecule inhibitors of PU.1.
Neoadjuvant versus adjuvant chemotherapy with taxanes and anthracycline-based regimen: Which leads to better outcome in patients with different subtype breast cancer?
Authors: Houpu Yang, Shu Wang, Lixin Zhou, Jiajia Guo, Yingming Cao, Bo Zhou, Lin Cheng, Fei Xie, Hongjun Liu, Fuzhong Tong, Miao Liu, Peng Liu, Siyuan Wang, Deqi Yang, Jiaqing Zhang
Journal: Journal of Clinical Oncology (2013)

1084 Background: Neoadjuvant chemotherapy was reported to lead to equal outcome with adjuvant therapy in operable breast cancer. However, different molecular subtypes show variant response to chemotherapy, which is associated with different long-term prognosis. This study was to clarify whether molecular subtypes lead to different outcome between neoadjuvant and adjuvant chemotherapy. Methods: We identified 406 patients with stage II-III breast cancer who were treated with neoadjuvant or adjuvant chemotherapy between 2000 and 2008. To minimize the confounding bias, only patients received taxanes and anthracycline based regimen (TA) were included. Cases were divided according to receipt of neoadjuvant and adjuvant therapy. Data were compared using χ 2 test and analysis of variance. Kaplan-Meier Curves were generated. Results: Of the 406 patients, 201(49.5%) received neoadjuvant chemotherapy and 205(50.5%) received adjuvant TA regimen. The pCR rate was 12.9%(26/201) in total, and 7%, 14%, 33.3%, 19.4% for Luminal A, Luminal B, HER2+ and Triple negative breast cancer(TNBC), respectively. The HER2+ and TNBC have significantly higher rates of pCR than Luminal type (p&lt;0.05). In general the two groups showed little survival variance (p=0.073 for DFS and p=0. 601 for OS). In Luminal B, neoadjuvant settings led to worse disease free survival (DFS) and overall survival (OS) than adjuvant settings after controlling for the covariates associated with survival in unadjusted tests (HR=0.41, p=0.028 for DFS; HR=0.32, p=0.020 for OS). In HER2+ subtype, neoadjuvant group corresponded to better DFS and OS (HR=5.65, p=0.024 for DFS; HR=10.52, p=0.010 for OS). On the contrary, patients with TNBC and Luminal A undergoing neoadjuvant chemotherapy had equal DFS and OS compared with patients receiving adjuvant therapy (p&gt;0.05). Conclusions: The results demonstrate survival difference between patients receiving neoadjuvant and adjuvant cytotoxic therapy in variant subtypes. Prospective studies are necessary to determine if the finding is durable and optimize the timing of chemotherapy for breast cancer with different molecular background.
Reprogramming of stromal fibroblasts by SNAI2 contributes to tumor desmoplasia and ovarian cancer progression
Authors: Zongyuan Yang, Xin Yang, Sen Xu, Ping Jin, Xiaoting Li, Xiao Wei, Dan Liu, Kecheng Huang, Sixiang Long, Ya Wang, Chaoyang Sun, Gang Chen, Junbo Hu, Li Meng, Ding Ma, Qinglei Gao
Journal: Molecular Cancer (2017)

Molecular profiling in ovarian cancer (OC) revealed that the desmoplasia subtype presented the poorest prognosis, highlighting the contribution of stromal fibroblasts in tumor progression. This study aimed to investigate the molecular characteristics of SNAI2 driving the transcriptional reprogramming of fibroblasts within tumors.SNAI2 expression was evaluated in microdissected profiles of various cancers and in various molecular subtypes of OC. Gene set enrichment analysis (GSEA) and single sample GSEA (ssGSEA) were performed to explore the correlation between SNAI2 and stromal fibroblast activation. The SNAI2 defined signature in the mesenchymal OC subtype was identified through an integrative analysis of the TCGA and the Tothill datasets. The predictive value of this signature was validated in independent datasets. SNAI2 expression alteration influence of tumor growth in primary CAFs was evaluated in 3D organotypic and murine xenograft models.We demonstrated that SNAI2 was frequently activated in the tumor stroma, correlated with fibroblast activation and worse patient outcome in OC. SNAI2 transformed normal fibroblasts to a CAF-like state and boosted their tumor-supporting role in 3D organotypic culture and in OC xenograft model. SNAI2 drove a transcriptional signature in the mesenchymal subtype of OC that contributed to tumor desmoplasia, which fed back to increase SNAI2 expression and sustain fibroblast activation.Our results address the role of SNAI2 in reprogramming stromal fibroblasts. The identified SNAI2 mesenchymal signature has both a predictive value and biological relevance and might be a therapeutic target for stroma-oriented therapy against the desmoplasia OC subtype.
Evaluação da frequência das doações de sangue contaminadas por VHB, VHC e VIH nos bancos de sangue no Reino-Unido, 1996-2003
Authors: K Soldan, K Davison, B Dow
Journal: Eurosurveillance (2005)

Recentemente, foram introduzidos varios novos testes nos servicios ingleses de transfusao de sangue para melhorar a seguranca dos componentes do sangue. A frequencia (ou o risco) de introduzir doacoes de sangue infectadas pelo virus da hepatite B (VHB), o virus da hepatite C (VHC) ou o VIH nos bancos de sangue, foi estimada sobre o periodo 1996-2003. Nestes anos foram instaurados os testes de acidos nucleicos (NAT) para o VHC, e o teste combinado VIH antigeno-anticorpo e NAT para o VIH. 
Foi evaluada a frequencia de introduccao de uma doacao contaminada nos bancos de sangue ligada 1) ao periodo janela, 2) as falhas do teste, e 3) aos errores humanos e tecnicos durante o teste. Estimou-se o risco devido ao periodo janela basandose na incidencia da infeccao nos dadores e a duracao do periodo janela para os testes utilisados, ajustando os intervalos entre doacoes atipicas em dadores seroconvertores. 
A frequencia das doacoes infecciosas presentes nos bancos de sangue entre 1996 e 2003 foi estimada em 1,66; 0,80 e 0,14 por milhao para oVHB, o VHC e o VIH respectivamente. Os resultados do NAT tem mostrado uma reduccao de 95% do risco de VHC. Em cuando ao risco estimado para o VIH, foi reduzido de 10% depois da introduccao do teste combinado VIH antigeno-anticorpo e do NAT. No Reino-Unido, o risco de transmissao do VHB, VHC e HIV por transfusao baixou desde 1996 devido aos progressos no teste dos componentes do sangue, embora seja poco importante a reduccao dos riscos. A melhoria da seguranca dos componentes do sangue respeito ao VHB, VHC e VIH se conseguira com a reduccao do periodo janela dos testes e talvez ainda mais reforcanda a vigilância dos errores tecnicos e da seleccao dos dadores.
TCT-186 Impact of pulmonary hypertension on the outcome after transcatheter aortic valve implantation - results from a prospective single-center registry
Authors: Stephan Haussig, Norman Mangner, Felix Woitek, Georg Stachel, Philipp Kiefer, Sergey Leontyev, David Michael Holzhey, Friedrich-Wilhelm Mohr, Gerhard Schuler, Axel Linke
Journal: Journal of the American College of Cardiology (2017)
Frequency, Predictors, and Impact of Combined Antiplatelet Therapy on Venous Thromboembolism in Patients With Symptomatic Atherosclerosis
Authors: Ilaria Cavallari, David A. Morrow, Mark A. Creager, Jeffrey Olin, Deepak L. Bhatt, P. Gabriel Steg, Robert F. Storey, Marc Cohen, Benjamin S. Scirica, Gregory Piazza, Erica L. Goodrich, Eugene Braunwald, Marc S. Sabatine, Marc P. Bonaca
Journal: Circulation (2017)

Background: Observational studies suggest that symptomatic atherosclerosis may be associated with risk of venous thromboembolism (VTE). Prior randomized studies have demonstrated a significant reduction in recurrent VTE with aspirin monotherapy. Whether VTE risk is associated with more severe symptomatic atherosclerosis and more intensive antiplatelet therapy reduces VTE risk beyond aspirin monotherapy is unknown. Methods: TRA2P-TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events–Thrombolysis in Myocardial Infarction) (vorapaxar) and PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54) (ticagrelor) were blinded, randomized placebo-controlled trials of antiplatelet therapy for the prevention of ischemic events in stable patients with symptomatic atherosclerosis. Two blinded vascular specialists systematically identified symptomatic venous thromboembolic events in both trials. Results: Of 47 611 patients with stable vascular disease followed for 3 years in both studies there were 343 VTE events in 301 patients (Kaplan-Meier rate at 3 years, 0.9% for placebo). The risk of VTE was independently associated with age, body mass index, polyvascular disease, chronic obstructive pulmonary disease, and malignancy. The burden of atherosclerosis manifested as an increasing number of symptomatic vascular territories was associated with a graded increase in the 3-year rates of VTE (0.76% for 1, 1.53% for 2, and 2.45% for 3 territories). More intensive antiplatelet therapy (vorapaxar and ticagrelor pooled) significantly reduced the risk of VTE by 29% compared with background antiplatelet therapy, from 0.93% to 0.64% at 3 years (hazard ratio, 0.71; 95% confidence interval, 0.56–0.89; P =0.003). Conclusions: The rate of VTE in patients with atherosclerosis is ≈0.3% per year while on treatment with ≥1 antiplatelet agent, with increased risk independently associated with the number of symptomatic vascular territories. More intensive antiplatelet therapy reduces the risk of VTE. These data suggest a relationship between atherosclerosis burden and VTE risk, and they support inclusion of VTE as a prospective end point in long-term secondary prevention trials evaluating the risks and benefits of antiplatelet therapies in patients with atherosclerosis. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01225562.
Salm-Net : red europea de vigilancia de salmonelosis humana
Authors: I. S.T. Fisher
Journal: Eurosurveillance (1995)

Salm-Nettiene por objetivo prevenir las salmonelosis humanas en la Union Europeamediante el refuerzo de la vigilancia internacional con la creacion delaboratorios y de una base de datos disponible a todos los participantes. Salm-Netesta financiada por el programa BIOMED 1 de la DG XII de la ComisionEuropea. La red esta compuesta por microbiologos y epidemiologos responsablesde la vigilancia nacional de salmonelosis en 14 paises europeos. Salm-Nettambien tiende a armonizar los metodos de tipificacion de fagos deSalmonella enteriditis, S. typhimurium y S. virchow
Interleukin-10 from CD4 <sup>+</sup> follicular regulatory T cells promotes the germinal center response
Authors: Brian J. Laidlaw, Yisi Lu, Robert A. Amezquita, Jason S. Weinstein, Jason A. Vander Heiden, Namita T. Gupta, Steven H. Kleinstein, Susan M. Kaech, Joe Craft
Journal: Science Immunology (2017)

CD4+ follicular regulatory T (Tfr) cells suppress B cell responses through modulation of follicular helper T (Tfh) cells and germinal center (GC) development. We found that Tfr cells can also promote the GC response through provision of interleukin-10 (IL-10) after acute infection with lymphocytic choriomeningitis virus (LCMV). Sensing of IL-10 by B cells was necessary for optimal development of the GC response. GC B cells formed in the absence of Treg cell-derived IL-10 displayed an altered dark zone state and decreased expression of the transcription factor Forkhead box protein 1 (FOXO1). IL-10 promoted nuclear translocation of FOXO1 in activated B cells. These data indicate that Tfr cells play a multifaceted role in the fine-tuning of the GC response and identify IL-10 as an important mediator by which Tfr cells support the GC reaction.
Comparison of Nutrition and Lung Function Outcomes in Patients with Cystic Fibrosis Living in Canada and the United States
Authors: Christopher H. Goss, Jenna Sykes, Sanja Stanojevic, Bruce Marshall, Kristofer Petren, Josh Ostrenga, Aliza Fink, Alexander Elbert, Bradley S. Quon, Anne L. Stephenson
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Rationale: A 10-year gap in the median age of survival for patients with cystic fibrosis (CF) was reported between patients living in Canada compared with patients living in the United States.Objectives: Because both malnutrition and poor lung function are associated with an increased risk of mortality in CF, we investigated the temporal and longitudinal trends in lung function and nutrition between Canada and the United States.Methods: This cohort study used Canadian CF Registry and U.S. CF Foundation Patient Registry data from 1990 to 2013. A unified dataset was created to harmonize the variables collected within the two registries for the purpose of comparing outcomes between the two countries.Measurements and Main Results: We conducted three analyses: survival differences by birth cohort; population trends for FEV1 and body mass index (BMI) over time; and individual patient FEV1 and BMI trajectories. The study included a total of 37,772 patients in the United States and 5,149 patients in Canada. Patients with CF experienced significant improvements in nutritional status and lung function in both Canada and the United States during the study. In addition, the survival gap between the two countries is narrowing within younger birth cohorts. The improvements for the patients within the United States were most prominent in the BMI trajectories, where patients born after 1990 in the United States have higher BMI that has persisted over time.Conclusions: The reasons for the observed improvements, and catch-up in the United States, are likely multifactorial and include the introduction of high-fat, high-calorie diets; introduction of newborn screening; and/or improved access to care for CF children in the United States.
Inotuzumab ozogamicin in pediatric patients with relapsed/refractory acute lymphoblastic leukemia (R/R ALL).
Authors: Deepa Bhojwani, Richard Sposto, Nirali Shah, Vilmarie Rodriguez, Maureen Megan O'Brien, Jennifer Lynn McNeer, Mignon L. Loh, Susan R. Rheingold
Journal: Journal of Clinical Oncology (2017)

10512 Background: Inotuzumab ozogamicin (InO), a CD22-targeting antibody linked to calicheamicin demonstrated exceptional activity in R/R ALL in adults. InO has been available to pediatric patients with R/R ALL via a compassionate access program. Methods: Participating international pediatric oncology centers received IRB approval to submit retrospective demographic, outcome and toxicity data on pediatric patients who received at least one dose of InO. Results: Thirty-four patients, age 2.3-21.4 yrs (median 11.7) received 1-4 cycles (3 weekly doses) of InO. Patients were heavily pretreated in 1 st -5 th relapse; 28 were refractory to their preceding regimen. Thirteen patients had prior hematopoietic stem cell transplant (HSCT), 27 received prior CD19 and 8 prior CD22-directed therapy. Pre-InO disease was M3 ( &gt; 25% blasts) in 26 patients, M2 (5-25%) in 3, and MRD only in 5 (1 with extramedullary disease). Of 29 patients with M2/M3 disease at baseline, 18 (62%) achieved a complete remission (CR), 13 of whom were MRD negative. Post-InO, 15 patients proceeded to HSCT and 5 to CAR T-cell therapy. Alterations in CD22 expression at subsequent relapse were noted in two patients with available blasts samples. No deaths were attributed to InO during therapy. The incidence of grade 3/4 infections was 38% and were of the expected types. Grade 1-4 hepatic toxicity was noted in 11/34 (32%) patients, primarily asymptomatic elevations in transaminases/bilirubin. There was no sinusoidal obstruction syndrome (SOS) during InO therapy but 8/15 patients who received HSCT post-InO developed SOS. One patient died from SOS, but the others recovered. The incidence of SOS was higher in patients who had undergone prior HSCT (6/8) versus no prior HSCT (2/7). SIRS (1), neurotoxicity (2) and hemorrhage (3) were infrequent. Three patients had musculoskeletal pain associated with edema. Conclusions: Single agent InO had a CR rate of 62% in heavily pretreated pediatric patients. Toxicities were similar to adults with hepatic and infectious toxicity being the most common. Overall InO was well tolerated, but the incidence of SOS was high in patients who underwent HSCT post-InO, particularly in those who had undergone a prior HSCT.
Methotrexate versus azathioprine in patients with atopic dermatitis: 2-year follow-up data
Authors: Evelien Roekevisch, Mandy Elvira Schram, Mariska Maria Geertruida Leeflang, Marijke Willemijn Dorothée Brouwer, Louise Anna Andrea Gerbens, Jan Dositheus Bos, Phyllis Ira Spuls
Journal: Journal of Allergy and Clinical Immunology (2017)
Effect of Pantothenic Acid on Growth of the Spontaneous Mammary Carcinoma in Female C3H Mice
Authors: Harold P. Morris, Stuart W. Lippincott
Journal: JNCI Journal of the National Cancer Institute (1941)

Effect of Pantothenic Acid on Growth of the Spontaneous Mammary Carcinoma in Female C3H Mice Get access Harold P. Morris, Harold P. Morris senior nutrition chemist Search for other works by this author on: Oxford Academic PubMed Google Scholar Stuart W. Lippincott Stuart W. Lippincott research fellow National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 2, Issue 1, August 1941, Pages 47–54, https://doi.org/10.1093/jnci/2.1.47 Published: 01 August 1941
Abstract 17406: Three Dimensional Echocardiographic Wall Motion Tracking Assessment of Right Ventricular Remodeling and Effects on Left Ventricular Function as Prognostic Predictors in Patients With Pulmonary Hypertension
Authors: Masataka Sugahara, Zhi Qi, Simon Marc, Michael Mathier, John Gorcsan
Journal: Circulation (2016)

Introduction: Progression of pulmonary hypertension (PH) may cause right ventricular (RV) remodeling and variable effects on left ventricular (LV) remodeling and function. The prognostic significan...
Step-up empiric elimination diet for pediatric and adult eosinophilic esophagitis: The 2-4-6 study
Authors: Javier Molina-Infante, Ángel Arias, Javier Alcedo, Ruth Garcia-Romero, Sergio Casabona-Frances, Alicia Prieto-Garcia, Ines Modolell, Pedro L. Gonzalez-Cordero, Isabel Perez-Martinez, Jose Luis Martin-Lorente, Carlos Guarner-Argente, Maria L. Masiques, Victor Vila-Miravet, Roger Garcia-Puig, Edoardo Savarino, Carlos Teruel Sanchez-Vegazo, Cecilio Santander, Alfredo J. Lucendo
Journal: Journal of Allergy and Clinical Immunology (2017)