tbuckley/cabot-search huggingface dataset:
Abstract 5042: A CRISPR/Cas9 knockout screen identify novel drug resistance genes in AML
Authors: Jian Huang
Journal: Cancer Research (2016)

Abstract Acute myeloid leukemia (AML) is a malignant hematopoietic disease and the most common type of acute leukemia in adults. Despite remarkable progress made in the therapy of AML, the mainstays of treatment have not significantly changed over the last 20 years. Technological advances have greatly accelerated genomic discovery and precision medicine holds promise to better tailor medications to AML with specific mutations. Importantly, one major obstacle to greater success with target therapy of leukemia is drug resistance. But the mechanisms underlying drug resistance in AML are poorly understood. The activating mutations of FLT3 are now recognized as the most common molecular abnormality in AML and FLT3ITD mutations are found in nearly 30% of AML patients. The poor prognosis of patients harboring FLT3 mutations renders FLT3 an obvious target of therapy. Quizartinib (AC220) is a potent and selective second-generation inhibitor of FLT3. It is in clinical trials for the treatment of relapsed or refractory FLT3ITD positive and negative AML patients and as a maintenance therapy. So far, those clinical trials have showed very promising result. However, drug resistance to AC220 has also been reported through the early clinical studies. To understand the underlying mechanisms of drug resistance to AC220, we undertook an unbiased approach with a novel CRISPR pooled library to screen new genes whose loss of function confer resistance to AC220. In our screen, we identified SPRY3 and GSK3 as positive hits and the related Wnt and FGF-Ras-ERK signaling activation as the major mechanisms to cause resistance to the FLT3 inhibitor AC220. In the next step, we will explore the detailed underlying mechanisms by which SPRY3 and GSK3 mutations lead to drug resistance to AC220. We will also confirm our findings in primary AML patient samples. Taken together, our study will provide new insight into signaling pathways that contribute to the acquired resistance in AML. The knowledge learned from this study may lead to the development of more efficient therapeutic avenues for AML. Citation Format: Jian Huang. A CRISPR/Cas9 knockout screen identify novel drug resistance genes in AML. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5042.
Abstract 2783: Integrated genomics and epigenomics analysis reveals genome-wide effect of the DNA methyltransferase inhibitor 5-azacitidine (Aza) on regulation of transcription
Authors: Yuchen Bai, Emanuele Palescandolo, John Whitaker, Vinod Krishna, Vipul Bhargava, Satya Saxena, Xiang Yao, David Pocalyko, Kurtis Bachman
Journal: Cancer Research (2016)

Abstract DNA methyltransferase inhibitors (DNMTi) such as 5-azacytidine(Aza) are clinically used in treating hematologic malignancies. Promising effects were also observed in solid tumors, although the exact mechanism underlining the efficacy was unclear. There has been accumulating evidence suggesting an enhanced immune response to the tumor cells following such epigenetic therapies. Cancer immunotherapies targeting checkpoint inhibition in combination with epigenetic agents such as a DNMTi could hold promise for those patients that do not respond to immunotherapies alone. Aza was also found to stimulate an interferon response in tumor cells via inducing expression of endogenous retroviruses. In this study, we were interested to further explore the mechanisms of AZA on transcription regulation across the whole regulome. HCT-116 is a colon cancer cell line genetically defined by microsatellite instability (MSI) and mutations in KRAS(G13D) and PIK3CA(H1047R). In this study, HCT-116 cells were treated with DMSO (control) or 1μM Aza for 42 and 96 hours. RNA-seq, Mass spectrometry proteomics, RRBS, Chip-Seq, ATAC-Seq and Hi-C data was collected. Data was analyzed by integrative computational methods. Treatment with Aza resulted in global demethylation at CpG islands(CGI), which was moderately correlated with increased expression of the corresponding genes. DNA methylation, DNA accessibility, H3K4me3 (active promoter histone mark), H3K27me3 (repressive histone mark) and RNA expression revealed and cross-verified different states of genomic regions. Pathway and gene set enrichment analysis found activation of anti-viral defense and interferon pathways, as well as increased expression of cancer-testis antigens. IRF7 expression was increased by Aza, and IRF binding motifs were the most enriched TF motifs at the immediate promoter regions of the up-regulated genes. The data also suggested that Aza may remove gene repression by disrupting the scaffolding function of DNMTs. The effects of Aza on promoter-enhancer interactions were also examined by Hi-C. In conclusion, we found that DNMTi such as Aza regulates gene transcription through multiple modes of actions. Citation Format: Yuchen Bai, Emanuele Palescandolo, John Whitaker, Vinod Krishna, Vipul Bhargava, Satya Saxena, Xiang Yao, David Pocalyko, Kurtis Bachman. Integrated genomics and epigenomics analysis reveals genome-wide effect of the DNA methyltransferase inhibitor 5-azacitidine (Aza) on regulation of transcription. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2783.
Abstract 1786: One in four Hispanic women with early onset breast cancer carry BRCA1, BRCA2, or PALB2 mutations: Results from a population-based study in South America
Authors: Anna Marie Tuazon, Mabel Bohorquez, Carolina Ramirez, Paul Lott, Ana Estrada, Angel Criollo, Cathy Wang, Magdalena Echeverry, John Suarez, Luis G. Carvajal Carmona
Journal: Cancer Research (2016)

Abstract Breast cancer is the leading cause of cancer incidence and mortality among Hispanic women, who are often diagnosed with late stage tumors and are more likely to die after diagnosis when compared to non-Hispanic whites. While strides have been made in understanding Hispanic breast cancer genetics, most studies have been limited to investigating cases from high-risk clinics. In this study, we aimed to assess the prevalence of pathogenic mutations in three most important breast cancer genes (BRCA1, BRCA2 and PALB2) in an unselected Hispanic breast cancer cohort. Initially, six hundred and forty-six unselected Colombian breast cancer cases were screened for four known Hispanic BRCA1/2 mutations by genotyping. Subsequently, cases that remained mutation negative, as well as 186 cancer-free controls, were screened for BRCA1, BRCA2 and PALB2 mutations using targeted next generation sequencing. We identified 67 cases with pathogenic mutations, one case with a likely-pathogenic variant, and 16 carriers of variants of unknown significance. Among the pathogenic mutation carriers, 88.1% harbored a founder mutation (n = 59), which includes the known BRCA1 3450del4 mutation, strikingly found in 32 unrelated cases. Remarkably, we found that 1 in 4 of the cases diagnosed with breast cancer by age 40 years, regardless of family history of cancer, carried a pathogenic mutation. The high frequency of pathogenic mutations in this unselected cohort (10.4%), in particular those with an early age of onset (25.3%), suggests that population-based genetic testing among Hispanic communities can identify most carriers who would otherwise ineligible for testing. Identifying mutation carriers of these genes has implications in clinical management and surveillance for Hispanic women, a population that is vulnerable to breast cancer disparities in the U.S. and Latin America. Citation Format: Anna Marie Tuazon, Mabel Bohorquez, Carolina Ramirez, Paul Lott, Ana Estrada, Angel Criollo, Cathy Wang, Magdalena Echeverry, John Suarez, COLUMBUS Consortium, LaFamilia Consortium, Luis G. Carvajal Carmona. One in four Hispanic women with early onset breast cancer carry BRCA1, BRCA2, or PALB2 mutations: Results from a population-based study in South America. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1786.
Quality and Safety in Health Care, Part XV
Authors: Jay A. Harolds
Journal: Clinical Nuclear Medicine (2016)

Infections that are associated with health care are a major problem that results in many deaths, suffering, and a great deal of extra monetary costs. Fortunately, there is much that can be done to prevent these infections. This article is a brief introduction to prevention of some of the common hospital acquired infections, such as surgical site infection, ventilator-associated pneumonia, central line-associated bloodstream infections, and catheter-associated urinary tract infections.
Gas7 Induces The Proliferation Of Ph+ ALL Cells and Prevents The Differentiation Of Early B Cell Progenitors Into CD25high Small Pre-B Cells
Authors: Jaewoong Lee, Maike Buchner, Huimin Geng, Srividya Swaminathan, Eugene Park, Lars Klemm, Sue Lin-Chao, Chi Wai So, Markus Muschen
Journal: Blood (2013)
Abstract 1291: Applicability of integrative tumor response assays for recurrent colorectal cancer
Authors: Yong Sik Yoon, Jin Cheon Kim
Journal: Cancer Research (2016)

Abstract Introduction Drug response assays use autologous viable tumors to evaluate susceptibility to specific agents in vitro. Histoculture drug reponse assay (HDRA) is a representative methyl thiazolyl-diphenyl-tetrazolium bromide (MTT) assay, which has the advantage of more correctly reflecting the in vivo microenvironment. Many studies showed 66-92% of accuracy rates for clinical correlation of chemotherapy in solid tumors including colorectal cancer (CRC). However, in recurrent cases of metastatic CRC, there is no usable assay to predict second-line chemo-sensitivity. Thus, authors invented novel technique, the integrative tumor response assay (ITRA), can identify drug responses for both first- and second-line chemotherapy simultaneously. We investigated the chemo-sensitivity to clinically used regimens using ITRA of samples from patients with metastatic CRC, and compared their chemo-sensitivity with the observed clinical response. Methods A total of 129 patients with metastatic CRC were prospectively enrolled. First-stage HDRAs were performed using 5-fluorouracil with leucovorin and oxaliplatin (FX) or irinotecan (FR). Second-stage HDRAs (ITRA) were done for survived cells after first-stage HDRA, using FX, FR, and their combinations with bevacizumab and cetuximab. The inhibition rate of tumor growth (IR) cut-off value for a positive response was determined to be ≥ 30%. For clinical validation, treatment responses of chemotherapy were evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST). The primary endpoint of this study was a correlation between the ITRA results and the clinical response in the response rate (RR). This was defined as positive for the effect of chemotherapy for tumor responses between complete response (CR) and partial response (PR). Results Among 129 used samples, ITRA failure was 9 (7%), due to deficient volume of samples. Out of 79 evaluated first-line chemotherapeutic regimes, RR was 53% (42/79). The correlation rate of HDRA for first-line chemotherapy was 70.9% (56/79), with a 71.4% (30/42) of sensitivity and 70.3% (26/37) of specificity. For 42 cases completing second-line chemotherapy, RR was 43% (18/42). The accuracy rate of ITRA for second-line chemotherapy was 61.9% (26/42), with a 44.4% (8/18) of sensitivity and 75% (18/24) of specificity. Conclusions ITRA might be further developed to be a feasible and useful technique for predicting therapy efficacy and selecting the appropriate anticancer regimen for individual patients despite its relatively low accuracy. Citation Format: Yong Sik Yoon, Jin Cheon Kim. Applicability of integrative tumor response assays for recurrent colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1291.
Abstract 722: MYB promotes pancreatic tumor associated-desmoplasia by up-regulating Sonic hedgehog and adrenomedullin
Authors: Arun Bhardwaj, Sanjeev K. Srivastava, Nikhil Tyagi, Sumit Arora, Seema Singh, James E. Carter, Ajay P. Singh
Journal: Cancer Research (2016)

Abstract Pancreatic cancer (PC) stands as the fourth leading cause of cancer-related death in the United States. Unfortunately, even with the emergence of tumor-targeted therapies, the 5-year survival rate of PC continues to remain very dismal (∼ 7.0%). The presence of dense desmoplastic region at the tumor site is a prominent pathological characteristic of PC, and tumor-associated desmoplasia is suggested to limit the therapeutic efficacy by acting as a physical barrier for drug delivery. In addition, it plays pivotal roles in promoting the survival and aggressive phenotypes of tumor cells. Therefore, it is of utmost importance that we identify novel gene targets and associated molecular mechanisms accountable for the development of desmoplasia in pancreatic tumors. Our recent study provided first evidence for a role of MYB, an oncogenic transcription factor, in pancreatic tumor growth and metastasis. Upon histological examination of orthotopic tumor xenografts derived from MYB-overexpressing and -silenced pancreatic tumor cells, we noticed a positive association of MYB expression with the extent of desmoplastic reaction. This finding was further confirmed by staining the tumor xenograft sections with Collagen-I, fibronectin and á-SMA, the well-characterized markers of desmoplasia. In a co-culture experiment, we observed that MYB-overexpressing pancreatic tumor cells promoted greater proliferation of pancreatic stellate cells (PSCs) as compared to the MYB-silenced cells further supporting a role of MYB in desmoplasia. From the mechanistic standpoint, we identified MYB to be novel direct regulator of Sonic hedgehog (SHH) and Adrenomedullin (ADM) expression in PC cells as confirmed by chromatin immunoprecipitation (ChIP) analysis. Treatments of pancreatic tumor (high or low MYB) and stellate cells co-culture with specific inhibitors and/or recombinant SHH and ADM demonstrated that both SHH and ADM cooperatively mediated the effect of MYB on PC and stellate cells via autocrine and/or paracrine mechanisms. Together, our studies suggest that MYB promotes malignant phenotype of PC not only by directly impacting the tumor cells, but also by altering the tumor microenvironment. Citation Format: Arun Bhardwaj, Sanjeev K. Srivastava, Nikhil Tyagi, Sumit Arora, Seema Singh, James E. Carter, Ajay P. Singh. MYB promotes pancreatic tumor associated-desmoplasia by up-regulating Sonic hedgehog and adrenomedullin. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 722.
Abstract 2014: Alternative splicing is a frequent event in mouse PTEN-deficient prostate cancer
Authors: Marco A. De Velasco, Yurie Kura, Kazuko Sakai, Yoshihiko Fujita, Yosuke Togashi, Masato Terashima, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura
Journal: Cancer Research (2016)

Abstract Castration-resistant prostate cancer (CRPC) remains an incurable disease and presents a major challenge for the development of novel treatment strategies. Alternative splicing occurs as a common natural phenomenon and promotes diversity, however, cancer-related alternative splicing events have been shown to contribute to disease progression and promote therapeutic escape. In prostate cancer, key genes required for normal biological function are frequently alternatively spliced resulting in altered phenotypes. Novel therapeutic strategies targeting the alternative splicing machinery are being developed and tested. Here, characterized the conditional PTEN-deficient mouse model of prostate cancer to determine its relevancy as preclinical tool for the development and efficacy determination of novel therapeutic strategies targeting aberrant alternative splicing. For this, we used the Affymetrix GeneChip mouse transcriptome assay to perform comparative analysis of the transcriptomes of normal prostate tissue and PTEN-deficient castration-naïve, castration-sensitive (4 weeks post-castration), and castration-resistant (10 weeks post-castration) prostate cancers. Clustering analysis revealed genes enriched with the functions involved in mRNA splicing and processing in mice with prostate tumors. Moreover, alternative splicing events were more prevalent in castration-sensitive tumors (&amp;gt;2.5-fold) compared to castration-naïve and castration resistant tumors. Exon skipping (cassette exon), was the most common splicing event observed in all conditions. Additionally, alternative splicing was observed in several genes frequently associated with human prostate cancer including CD44, AR, p53, Bcl2l1 and Klf6 among others. Collectively, our data shows that alternative mRNA splicing is a frequent event in mouse PTEN-deficient prostate cancer and supports a role for alternative splicing dysregulation and the pathogenesis of the disease. Furthermore, this mouse model may also provide a suitable platform to study current therapeutic approaches targeting alternative splicing. Citation Format: Marco A. De Velasco, Yurie Kura, Kazuko Sakai, Yoshihiko Fujita, Yosuke Togashi, Masato Terashima, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Alternative splicing is a frequent event in mouse PTEN-deficient prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2014.
Abstract 2574: Accuracy of Apical Rotation by Two-dimensional Speckle Tracking Echocardiography is Influenced by Apical Slice Location.
Authors: Celine Goffinet, Fabien Chenot, Patrick Montant, Anne-Catherine Pouleur, Jean-Benoît le Polain de Waroux, David Vancraeynest, Agnès Pasquet, Bernhard Gerber, Jean-Louis Vanoverschelde
Journal: Circulation (2007)

Background : During the cardiac cycle, there is a systolic twist and an early diastolic untwist about LV long axis, because of opposite rotation of the basal and apical segments. Previous studies showed that speckle tracking echocardiography (STE) allows to measure the rotation of these segments and thereby to assess global LV torsion. Unfortunately, STE does not always allow visualization of the real apex, thus raising concerns about the reliability of LV torsion data using this approach. Methods : We compared LV apical rotation by tagged magnetic resonance (cMR) and STE in 30 patients with normal regional and global systolic function. With cMR, rotation was measured on serial contiguous 10 mm thick short-axis (SAX) sections, whereas with STE, it was only obtained on the most apical available SAX section. cMR and STE were compared using either the most apical cMR SAX slice or the cMR slice that best matched the end-diastolic internal dimensions of the available STE slice. Results : LV rotation measured by cMR decreased from apex to base (Fig 1 ). When using the best matched cMR SAX slice, cMR and STE were well correlated (r=0.7, Fig 2 , black dots). By contrast, when using the most apical cMR SAX slice, the correlation between cMR and STE was lost (Fig 2 , white dots). By comparing end-diastolic internal dimensions, the level of the STE slice was found to be at the real apex in 10% of pts, and at 10, 20 and 30 mm below the apex in 27%, 50% and 13% of pts, respectively. Conclusion : Although STE allows to measure LV apical rotation, it rarely does so at the level of the real apex. This results in an almost systematic and mostly unpredictable underestimation of apical rotation.
Efficacy and safety of sofosbuvir plus simeprevir therapy in Egyptian patients with chronic hepatitis C: a real-world experience
Authors: Hisham R El-Khayat, Yasser M Fouad, Mohsen Maher, Hussain El –Amin, Hala Muhammed
Journal: Gut (2016)

<h3>Background</h3> Simeprevir plus sofosbuvir (SIM/SOF) regimen was recommended by professional guidelines for certain patients with HCV genotype 1 infection and there is lack of data about this regimen in patients with genotype 4 infection. <h3>Aim</h3> To evaluate the efficacy and safety of this regimen in Egyptian patients with chronic HCV genotype 4 infection in the real world. <h3>Methods</h3> Multicentre observational study included 583 patients with HCV genotype 4 infection who began 12 weeks of treatment with SIM plus SOF. Demographic, clinical and virological data as well as adverse outcomes were collected. Treatment naïve patients were 342 (59%) of all included patients, 45% of patients had severe fibrosis (F3 and F4) while 55% had mild fibrosis (F1 and F2) and the primary outcome was sustained virological response (SVR). <h3>Results</h3> The overall SVR rate was 95.7% (558 out of 583 patients). In total, SVR12 in naïve patients with mild fibrosis score (F1 and F2) was achieved in 98.9% (94/95) for F1 and 98.1% (105/107) for F2, while naïve patients with severe fibrosis (F3 and F4) achieved SVR of 97.7% (86/88) for F3 and (42/52) 80.8% for F4. SVR in patients with previous interferon treatment achieved in 100% (45/45) for patients with F1 and 98.7% (74/75) for F2. While 94.7% (72/76) in experienced patients with F3; and 88.9% (40/45) for F4 achieved SVR12. Notable side effects included rash in 21 patients, photosensitivity in 18 patients, pruritus in 44 patients and hyperbilirubinemia in 42 patients. <h3>Conclusions</h3> A 12-week regimen of simeprevir/sofosbuvir was efficacious and well tolerated by treatment-naïve and treatment-experienced patients with chronic HCV genotype 4.
Computational Cardiology — A New Discipline of Translational Research
Authors: Benjamin Meder, Hugo A. Katus, Andreas Keller
Journal: Genomics Proteomics & Bioinformatics (2016)

Over the past two decades, improved diagnosis, pharmaceutical therapies, and interventional strategies have impressively improved the armamentarium of modern cardiologists in the fight against the most incident and lethal diseases: heart failure, ischemic heart disease, and arrhythmia.The innovations in the field have mostly been enabled by inventions based on hypothesis-driven approaches.The invention and development of key cardiac biomarkers, such as natriuretic peptides and cardiac-specific troponins, may serve as examples.Based on few candidate molecules, the discovery of these markers requires neither high-throughput molecular screening, nor advanced computational methodologies for interpretation and refinement of results.What has changed such that authors of this Special Issue on Computational Cardiology propose the requirement of a structured interaction of clinical, molecular, and bioinformatics experts?Evidence-based changes that have been implemented into current guidelines of cardiovascular medicine are mostly due to large-scale randomized clinical trials.Although this approach was hugely successful to improve prognosis of patients, in the future the treatment and outcome net-benefit