tbuckley/cabot-search huggingface dataset:
Risk Of Acute and Chronic Leukemias Following Radiation Treatment For Locoregional Prostate Cancer In The United States Over 35-Years
Authors: Sudipto Mukherjee, Chandana A. Reddy, Jay P. Ciezki, Ramon V. Tiu, Anjali S. Advani, Yogen Saunthararajah, Jaroslaw P. Maciejewski, Brian J. Bolwell, Matt Kalaycio, Eric A. Klein, Mikkael A. Sekeres
Journal: Blood (2013)
Abstract 1386: Clinical research results for a NGS-based kit for targeted detection of clinically relevant gene rearrangements in lung tumor samples
Authors: Jeoffrey J. Schageman, José Luis Costa, Orla Sheils, John E. Glassco, David Chi, Jon Sherlock, John Bishop, Rosella P. Petraroli, Kelli S. Bramlett
Journal: Cancer Research (2016)

Abstract In recent years, advances in next-generation sequencing (NGS) technologies have enabled faster and cheaper methods for uncovering the genetic basis of disease. For cancer, NGS based screening for known tumor subtypes may inform diagnosis and allow the clinician to tailor a specific therapeutic approach in the future. Here, we present the testing results of one such NGS based kit used to detect specific chromosomal translocations in retrospective non-small cell lung cancer (NSCLC) samples by targeting specific breakpoints in known fusion transcripts. The included panel tested consists of a single primer pool containing amplicon designs to simultaneously screen for over 75 specific rearrangements involving the receptor tyrosine kinase (RTK) genes ALK, RET and ROS1 as well as NTRK1. The panel was compatible with formalin-fixed paraffin-embedded (FFPE) lung tumor research samples and achieved high-sensitivity down to 10 ng of RNA input. In addition, amplicon assays designed at the 5’ and 3’ ends the RTK genes provide non-specific evidence that a translocation exists in a sample by comparing expression imbalance between the two ends. Testing was carried out at three external clinical research laboratories. In addition to positive and negative control samples, each site contributed FFPE lung tumor research samples for which ALK fusion status was known prior to NGS library preparation carried out using the Ion AmpliSeq™ workflow. For site-specific samples (n = 144, 16 samples per sequencing run), high concordance, sensitivity and specificity were measured at 97.2%, 90.5% and 98.4%, respectively. Citation Format: Jeoffrey J. Schageman, José Luis Costa, Orla Sheils, John E. Glassco, David Chi, Jon Sherlock, John Bishop, Rosella P. Petraroli, Kelli S. Bramlett. Clinical research results for a NGS-based kit for targeted detection of clinically relevant gene rearrangements in lung tumor samples. [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 1386.
Kinome Profiling in Acute Myeloid Leukemia as a New Approach for Target Discovery.
Authors: Arja ter Elst, Maikel P Peppelenbosch, Sander H Diks, Rob Ruijtenbeek, Piet J Boender, Rik de Wijn, Frank J.G. Scherpen, Willem A Kamps, Evelina S De Bont
Journal: Blood (2008)
Oncologic Outcomes of Kidney-sparing Surgery Versus Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma: A Systematic Review by the EAU Non-muscle Invasive Bladder Cancer Guidelines Panel
Authors: Thomas Seisen, Benoit Peyronnet, Jose Luis Dominguez-Escrig, Harman M. Bruins, Cathy Yuhong Yuan, Marko Babjuk, Andreas Böhle, Maximilian Burger, Eva M. Compérat, Nigel C. Cowan, Eero Kaasinen, Joan Palou, Bas W.G. van Rhijn, Richard J. Sylvester, Richard Zigeuner, Shahrokh F. Shariat, Morgan Rouprêt
Journal: European Urology (2016)
A large delayed esophageal perforation due to chicken bone impaction treated by over-the-scope clipping
Authors: Ahmet Yozgat, Faruk Cetin, Yucel Akkas, Enver Avci, Ersan Ozaslan
Journal: Endoscopy (2016)

A 73-year-old man was admitted to the emergency clinic with a 7-day history of dysphagia after eating chicken. He had no significant medical history. On admission, he was tachypneic and tachycardic, but otherwise there were no significant findings on physical examination. His laboratory results showed a creatinine of 1.6 mg/dL and white blood count of 22 400/mm3 but other measurements were within normal limits. Cervical and thoracic computed tomography (CT) scanning showed a foreign body in the esophagus and evidence of mediastinitis. Upper gastrointestinal endoscopy revealed a chicken bone in the cervical esophagus ([Fig. 1]). This was removed with a snare ([Fig. 2]) and, once this had been done, an esophageal perforation was revealed ([Fig. 3 a]). We applied an over-the-scope clip (OTSC; Ovesco) for the esophageal perforation 2 days after admission using an endoscope with a diameter of 12 mm, cap depth of 6 mm, and a clip with pointed teeth (OTSC t) ([Fig. 3 b]).
Addendum: The schizophrenia risk gene product miR-137 alters presynaptic plasticity
Authors: Sandra Siegert, Jinsoo Seo, Ester J Kwon, Andrii Rudenko, Sukhee Cho, Wenyuan Wang, Zachary Flood, Anthony J Martorell, Maria Ericsson, Alison E Mungenast, Li-Huei Tsai
Journal: Nature Neuroscience (2016)
Prevention of rebleeding: high-dose PPIs, second-look endoscopy or both?
Authors: Angel Lanas
Journal: Endoscopy (2016)

The main objective of medical and endoscopic therapy in patients with peptic ulcer bleeding (PUB) is to reduce mortality, need for surgery, and recurrence of bleeding. Endoscopic therapy in patients with high-risk stigmata (active bleeding, visible vessel or adherent clot) within the first 24 hours after hospital admission is probably the most determinant measure to reduce these three outcomes. This instrumental procedure followed by intravenous (I.V.) administration of high-dose proton pump inhibitor (PPI) for 3 days has become current standard therapy for this type of patient [1].
Abstract 53: Epigenetic silencing of krebs cycle metabolism in kidney cancer
Authors: Eun-Young Kho, Carolina B. Livi, Phillip Buckhaults, Francesca Carobbio, Hye-Young Nam, Richard Kirkman, David Crossman, Praveen K. Vayalil, Shi Wei, Ralph J. DeBerardinis, Sunil Sudarshan
Journal: Cancer Research (2016)

Abstract Mounting evidence points to alterations in mitochondrial metabolism in renal cell carcinoma (RCC) including recent large-scale transcriptomic data demonstrating loss of tricarboxylic acid (TCA) cycle enzyme expression with aggressive tumors. Using a metabolomics/transcriptomics approach, we identified loss of mRNA expression of PGC-1α and ERR-γ is associated with tumor progression and worsened outcomes in RCC patients. PGC-1α both induces and cooperates with ERR-γ to promote TCA cycle enzyme expression. Additionally, PGC-1α reconstitution in RCC cells reverses the glycolytic phenotype and suppresses invasive phenotypes. Loss of PGC-1α and ERR-γ is through DNA and histone repressive silencing of the transcription factor PRDM16. Loss of PRDM16 is among the most prominent transcriptional changes in metastatic tumor sites. PRDM16 expression in RCC cells restorers TCA cycle enzyme expression, mitigates the Warburg phenotype, and suppresses in vivo tumorigenesis. Collectively, our data uncover a transcription factor network epigenetically silenced in renal cancer resulting in suppression of mitochondrial metabolism. Citation Format: Eun-Young Kho, Carolina B. Livi, Phillip Buckhaults, Francesca Carobbio, Hye-Young Nam, Richard Kirkman, David Crossman, Praveen K. Vayalil, Shi Wei, Ralph J. DeBerardinis, Sunil Sudarshan. Epigenetic silencing of krebs cycle metabolism in kidney 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 53.
Patterns of PD-L1 expression on circulating tumor cells in Japanese patients with advanced lung cancer.
Authors: Yasuhiro Koh, Hiroaki Akamatsu, Woong Kim, Satomi Yagi, Ayaka Tanaka, Kuninobu Kanai, Atsushi Hayata, Nahomi Tokudome, Masayuki Higuchi, Hisashige Kanbara, Keiichiro Akamatsu, Masanori Nakanishi, Hiroki Ueda, Nobuyuki Yamamoto
Journal: Journal of Clinical Oncology (2016)

e23036 Background: Immune-checkpoint blockage with anti-PD-1 antibodies is effective against human malignancies including lung cancer. Although the expression of PD-L1 on tumor cells is expected as a predictive biomarker, detection of PD-L1 expression level on tissues remains challenging due to its dynamic and unstable expression. Here, we isolated circulating tumor cells (CTCs) and then evaluated the expression of PD-L1 on them in patients with advanced non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Methods: Immuno-staining for PD-L1 was established using NSCLC cell lines H820, H441, A549 and H23, spiked in the peripheral blood obtained from healthy donors. For clinical evaluation, 3 ml of peripheral whole blood was collected from 41 advanced lung cancer patients prior to the initiation of chemotherapy. Cells were captured and stained by using MCA system (Hitachi Chemical Co., Ltd). CTCs were defined as those positive for DAPI and cytokeratin (CK) and negative for CD45. Results: Characteristics of 41 lung cancer patients enrolled in clinical study were as follows: median age 70 (range, 39 to 86); male 66 %; stage II/III/IV, 2/7/91 %; NSCLC/SCLC, 80/20 %. More than 5 CTCs were detected in 32 patients (median 21.5; range, 7 to 58), and PD-L1-positive CTCs were detected in 22 patients (median 4; range, 1 to 15). All the patients bearing PD-L1-positive CTCs also had PD-L1-negative CTCs concurrently. We found a total of 49 CTC clusters from 24 patients and most of clusters contained PD-L1-positive CTCs (44/49 clusters, 90%). On top of that, CTCs forming clusters were more likely to be PD-L1-positive than those detected as a single CTC (28/80, 35% versus 104/769, 14%, respectively. p = 0.001). We also found that CTC-interacting white blood cells were more intensively bound with clustered CTCs than with single CTCs (15/77, 19% versus 55/598, 9%, respectively. p = 0.016). Conclusions: Our data suggest that PD-L1 expression on CTCs have diverse intrapatient heterogeneity in advanced lung cancer. Further investigation is warranted to address its clinical significance in response to PD-1/PD-L1 blockade and to clarify the biology of the aggregated CTCs and those interacting with white blood cells.
Abstract 684: Targeting an unconventional kinase-invasion axis in breast cancer metastasis
Authors: Margarite D. Matossian, Steven Elliott, Van T. Hoang, Hope E. Burks, Theresa B. Phamudy, Doug Chrisey, William J. Zuercher, David H. Drewry, Carrow Wells, Bridgette Collins-Burow, Matthew E. Burow
Journal: Cancer Research (2016)

Abstract Triple negative breast cancer (TNBC) is associated with poor survival, metastatic recurrence, increased mortality, and has few viable therapeutic options. Given the high mortality associated with metastasis of this disease, discovery of therapeutics targeting the metastasis axis is imperative. Kinases have been demonstrated to have an essential role in regulation of epithelial-mesenchymal transition (EMT), a process involved in the initiation of cancer metastasis. Elucidating specific signaling pathways that promote EMT has the potential to provide novel targeting strategies in the treatment of TNBC. Here we demonstrate a partially non-selective polo-like kinase 1 (PLK1) inhibitor, GSK346294, is capable of EMT reversal in phenotypically mesenchymal TNBC cell lines, as evidenced by enhanced E-cadherin expression and loss of cellular migration potential. Structurally analogous but highly specific PLK inhibitors did not exhibit similar EMT changes, which led us to investigate off-target kinases inhibited by GSK346294. Follow-up kinase profiling studies revealed members of the NEver-in-mitosis-related Kinase family (NEK5 and NEK9) as additional kinases inhibited by GSK346294, leading us to investigate their individual roles in the progression of EMT. NEK5 overexpression in a non-invasive breast cancer cell line increased both migration and invasion in trans-well assays. Additionally, enhanced NEK5 expression altered the TNBC gene expression profile, enhancing expression of genes associated with growth factor signaling (MET, EGFR) and the mesenchymal gene signature (SLUG, VIM). To date, no studies exist which delineate the regulatory roles of NEK5 and NEK9 in EMT or cellular invasion/motility. Further investigation into the function of NEK5 and/or NEK9 in the metastatic progression may provide novel therapeutic targets for the treatment of TNBC, the implication of which could impact the treatment and management of neoplastic disease and metastasis beyond breast cancer. Citation Format: Margarite D. Matossian, Steven Elliott, Van T. Hoang, Hope E. Burks, Theresa B. Phamudy, Doug Chrisey, William J. Zuercher, David H. Drewry, Carrow Wells, Bridgette Collins-Burow, Matthew E. Burow. Targeting an unconventional kinase-invasion axis in breast cancer metastasis. [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 684.
Tumor Regression and Delayed Onset Toxicity Following B7-H4 CAR T Cell Therapy
Authors: Jenessa B Smith, Evripidis Lanitis, Denarda Dangaj, Elizabeth Buza, Mathilde Poussin, Caitlin Stashwick, Nathalie Scholler, Daniel J Powell
Journal: Molecular Therapy (2016)

B7-H4 protein is frequently overexpressed in ovarian cancer. Here, we engineered T cells with novel B7-H4-specific chimeric antigen receptors (CARs) that recognized both human and murine B7-H4 to test the hypothesis that B7-H4 CAR T cell therapy can be applied safely in preclinical models. B7-H4 CAR T cells specifically secreted IFN-γ and lysed B7-H4(+) targets. In vivo, B7-H4 CAR T cells displayed antitumor reactivity against B7-H4(+) human ovarian tumor xenografts. Unexpectedly, B7-H4 CAR T cell treatment reproducibly showed delayed, lethal toxicity 6-8 weeks after therapy. Comprehensive assessment of murine B7-H4 protein distribution uncovered expression in ductal and mucosal epithelial cells in normal tissues. Postmortem analysis revealed the presence of widespread histologic lesions that correlated with B7-H4(+) expression, and were inconsistent with graft versus host disease. Lastly, expression patterns of B7-H4 protein in normal human tissue were comparable to distribution in mice, advancing our understanding of B7-H4. We conclude that B7-H4 CAR therapy mediates control of cancer outgrowth. However, long-term engraftment of B7-H4 CAR T cells mediates lethal, off-tumor toxicity that is likely due to wide expression of B7-H4 in healthy mouse organs. This model system provides a unique opportunity for preclinical evaluation of safety approaches that limit CAR-mediated toxicity after tumor destruction in vivo.
Sex and Race/Ethnicity Differences in Implantable Cardioverter-Defibrillator Counseling and Use Among Patients Hospitalized With Heart Failure
Authors: Paul L. Hess, Adrian F. Hernandez, Deepak L. Bhatt, Anne S. Hellkamp, Clyde W. Yancy, Lee H. Schwamm, Eric D. Peterson, Phillip J. Schulte, Gregg C. Fonarow, Sana M. Al-Khatib
Journal: Circulation (2016)

Background: Previous studies have found that women and black patients eligible for a primary prevention implantable cardioverter-defibrillator (ICD) are less likely than men or white patients to receive one. Methods: We performed an observational analysis of the Get With The Guidelines-Heart Failure Program from January 1, 2011, to March 21, 2014. Patients admitted with heart failure and an ejection fraction ≤35% without an ICD were included. Rates of ICD counseling among eligible patients and ICD receipt among counseled patients were examined by sex and race/ethnicity. Results: Among 21 059 patients from 236 sites, 4755 (22.6%) received predischarge ICD counseling. Women were counseled less frequently than men (19.3% versus 24.6%, P &lt;0.001, adjusted odds ratio [OR], 0.84; 95% confidence interval [CI], 0.78–0.91). Racial and ethnic minorities were less likely to receive counseling than white patients (black 22.6%, Hispanic 18.6%, other race/ethnic group 14.4% versus white 24.3%, P &lt;0.001 for each): adjusted OR versus white, 0.69; 95% CI, 0.63 to 0.76 for black patients; adjusted OR, 0.62; 95% CI, 0.55 to 0.70 for Hispanic patients; adjusted OR, 0.53; 95% CI, 0.43 to 0.65 for other patients. Among the 4755 counseled patients, 2977 (62.6%) received an ICD or had one planned for placement after hospital stay. Among those counseled, women and men were similarly likely to receive an ICD (adjusted OR, 1.13; 95% CI, 0.99–1.29). However, black (adjusted OR, 0.70; 95% CI, 0.56–0.88) and Hispanic patients (adjusted OR, 0.68; 95% CI, 0.46–1.01) were less likely to receive an ICD. Conclusions: Up to 4 of 5 hospitalized patients with heart failure eligible for ICD counseling did not receive it, particularly women and minority patients. Among counseled patients, ICD use differences by race and ethnicity persisted.
Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn's disease: a phase 3 randomised, double-blind controlled trial
Authors: Julián Panés, Damián García-Olmo, Gert Van Assche, Jean Frederic Colombel, Walter Reinisch, Daniel C Baumgart, Axel Dignass, Maria Nachury, Marc Ferrante, Lili Kazemi-Shirazi, Jean C Grimaud, Fernando de la Portilla, Eran Goldin, Marie Paule Richard, Anne Leselbaum, Silvio Danese
Journal: The Lancet (2016)
Abstract 4851: Second generation 2,3-dihydroimidazo[1,2-c]quinazoline PI3K inhibitors: development of BAY 1082439, a novel balanced PI3Ká / PI3Kâ inhibitor
Authors: William J. Scott, Ningshu Liu, Andreas Hägebarth, Manfred Möwes, Ursula Mönning, Ulf Bömer, Dominik Mumberg, Franz von Nussbaum, Michael Brands, Julien Lafranc
Journal: Cancer Research (2016)

Abstract The phosphoinositide-3 kinase (PI3K) pathway plays critical roles in cancer cell growth and survival, as well as in intrinsic and acquired resistance to both chemotherapy and targeted agents. These essential roles of PI3K in human cancer have led to the clinical development of PI3K pathway inhibitors. Due to the complexity derived from the existence of various PI3K isoforms (á, ß, ã, ∂), and their differential roles in signal transduction as well as cancer pathology, investigation of PI3K inhibitors with differential isoform activity profiles would allow potential use in novel indications. Mutation or amplification of PIK3CA and/or activation of PI3Ká (e.g., through oncogenic RTKs) are found frequently in a variety of cancers, making this isoform a prime target for anti-cancer therapy. In addition, the role of PI3Kß in PTEN-deficient tumors, as well as in acquired resistance to PI3Ká, has been described. This led to the hypothesis that development of a dual PI3Ká / PI3Kß inhibitor might provide a unique efficacy profile. The discovery of a novel class of 2,3-dihydroimidazo[1,2]quinazoline PI3K inhibitors, and its optimization to afford the i.v. PI3Ká/∂ inhibitor copanlisib (IC50 ratio of 1:7 in biochemical assays of PI3Ká vs. PI3Kß) has been reported recently. Herein is described the structure-activity relationship (SAR) leading to potent oral 2,3-dihydroimidazo[1,2]quinazoline PI3K inhibitors with balanced PI3Ká and PI3Kß activity, and to the selection of BAY 1082439, as a clinical candidate. BAY 1082439 has an IC50 ratio of 1:3 in biochemical assays of PI3Ká (4.9 nM) vs. PI3Kâ (15.0 nM). In addition, BAY 1082439 has unique pharmacokinetic (PK) properties with very high plasma free fractions across all species tested (33-50%), large Vss, high clearance and intermediate T1/2. Thus, BAY 1082439 represents a PI3K inhibitor with a novel pharmacological profile, warranting exploration in clinical development. BAY 1082439 is currently being studied in a phase I trial for subjects with advanced malignancies (NCT01728311). Citation Format: William J. Scott, Ningshu Liu, Andreas Hägebarth, Manfred Möwes, Ursula Mönning, Ulf Bömer, Dominik Mumberg, Franz von Nussbaum, Michael Brands, Julien Lafranc. Second generation 2,3-dihydroimidazo[1,2-c]quinazoline PI3K inhibitors: development of BAY 1082439, a novel balanced PI3Ká / PI3Kâ inhibitor. [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 4851.
Abstract 246: Role for ATP7A copper transporter in cisplatin resistance, tumorigenesis and metastasis
Authors: Vinit Shanbhag, Nikita Gudekar
Journal: Cancer Research (2016)

Abstract Copper is a trace metal with a ready capacity to gain or donate electrons. This property is harnessed by numerous enzymes to perform vital functions in the body. In humans, copper is required for various biochemical processes including cellular respiration, connective tissue development, iron transport, and pigmentation. The same redox property which makes copper useful can also have deleterious effects if the proper balance is not maintained. Hence a delicate balance of copper should be maintained in the body. Cellular copper homeostasis is maintained by several different proteins. Ctr1 (copper transporter 1) has high affinity for copper and aids in copper uptake into the cell. ATP7A and ATP7B are copper exporting ATPases, which share 60% identity, are functionally homologous. Under low intracellular copper concentrations, ATP7A is localized to the TGN (trans-Golgi network), where it transports copper to newly synthesized cuproenzymes. Under elevated copper concentrations, ATP7A traffics to post TGN vesicles and to the plasma membrane, subsequently releasing the copper load by fusion with the plasma membrane. There are emerging studies implicating a role of ATP7A in resistance against the platinum-based chemotherapy agent, cisplatin, which is widely used to treat cancer. Previous studies have correlated ATP7A expression to the sensitivity of cultured cells to cisplatin. Here, we report that deletion of the Atp7a gene in isogenic RAS-transformed mouse embryonic fibroblast (MEF) cells not only confers sensitivity to cisplatin, but markedly prevents tumor formation in the absence of chemotherapy agent. Deletion of Atp7a in the breast cancer cell line, 4T1, was also found to suppress tumorigenesis and markedly reduce metastasis to the lungs. The ATP7A knockout 4T1 cells showed a significant decrease in Lysyl Oxidase (LOX) activity as compared to the 4T1WT cells. Given the numerous studies showing that LOX family involved in breast tumor metastasis, ATP7A might play a role in tumor progression by virtue of its requirement for metallating LOX. The ATP7A knockout 4T1 cells exhibited reduced survival as compared to the 4T1WT cells in the presence of physiological concentrations of hydrogen peroxide or hypoxia, suggesting that hyper-accumulation of copper sensitizes these cells to ROS production. Taken together, these findings identify the ATP7A copper transporter at the nexus of platinum-drug resistance, tumorigenesis and metastatic pathways, underscoring its potential as a therapeutic drug target at multiple stages of carcinogenesis. Citation Format: Vinit Shanbhag, Nikita Gudekar. Role for ATP7A copper transporter in cisplatin resistance, tumorigenesis and metastasis. [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 246.
DNA Based Detection and Quantification of BCR-ABL1 Gene Using Patient-Specific qPCR and Droplet Digital PCR Tests in Chronic Myeloid Leukemia
Authors: Hana Zizkova, Eliska Motlova, Karla Zemanova, Hana Klamova, Lenka Hovorkova, Jan Zuna, Jan Zach, Susanne Saussele, Francois-Xavier Mahon, Katerina Machova Polakova
Journal: Blood (2015)
B-Cell Anergy Underlies Indolent Clinical Behavior Of CLL Stereotyped Subset #4
Authors: Stavroula Ntoufa, Nikos Papakonstantinou, Benedetta Apollonio, Maria Gounari, Achilles Anagnostopoulos, Chrysoula Belessi, Marta Muzio, Paolo Ghia, Kostas Stamatopoulos
Journal: Blood (2013)