tbuckley/cabot-search huggingface dataset:
Phase I study of pazopanib (PAZ) in combination with abexinostat (ABX) in patients (Pts) with metastatic solid tumors.
Authors: Rahul Raj Aggarwal, Jennifer A. Grabowsky, Anne Reinert, Scott Thomas, Paromita Raha, Thierry Marie Jahan, Alain Patrick Algazi, Terence W. Friedlander, Thach-Giao Truong, Saloni Mathur, Pamela N. Munster
Journal: Journal of Clinical Oncology (2014)

2577 Background: PAZ is a tyrosine kinase inhibitor of VEGFR, PDGFR, and C-KIT approved for use in renal cell carcinoma (RCC) and soft tissue sarcoma (STS). ABX is a potent pan-HDAC inhibitor (HDACi). Pre-clinical models suggest that epigenetic modulation with an HDACi potentiates PAZ’s efficacy and prevents the outgrowth of a resistant phenotype. We therefore designed a Phase I clinical trial combining ABX with PAZ in pts with advanced solid tumors. Methods: The primary objective was to determine the maximal tolerated dose (MTD) of PAZ plus ABX in pts with advanced solid tumor malignancies. Secondary objectives included pharmacokinetics (PK) and efficacy. Altered histone acetylation post treatment denoted HDACi activity and served as pharmacodynamic (PD) markers in peripheral blood mononuclear cells. PAZ was dosed daily and ABX on days 1-5, 8-12, 15-19 of a 28-day cycle, at a starting dose of 400 mg/day and 45 mg/m2 orally twice daily for PAZ and ABX respectively. Results: 22 patients with advanced solid tumors were enrolled. There were five dose-limiting toxicities (DLTs) (fatigue: N = 2, thrombocytopenia: N = 2; grade 2 elevated AST with fever: N = 1). The MTD was PAZ 600 mg/day + ABX 30 mg/m2 BID. The most common grade ≥ 3 drug regimen-related adverse events observed include thrombocytopenia (12%), fatigue (12%), and diarrhea (8%). 3 of 15 evaluable pts (20%) (including 2 RCC pts) had a confirmed objective partial tumor response, including one pt with prior progression in single agent PAZ. 5 out of 17 evaluable pts (29%) have experienced disease stabilization or better for ≥ 6 months. PK and PD analyses are ongoing. An alternate dosing schedule is being explored with ABX administered on D1-4, 8-11,15-18 of a 28-day cycle. The current dose level is 45 mg/m2 BID and PAZ at 600 mg/day with no DLTs observed thus far (N = 2). Conclusions: This is the first trial to explore the combination of ABX with PAZ in RCC and other solid tumor malignancies. The optimal dosing schedule may be ABX taken 4 days/week but requires further investigation. Encouraging preliminary evidence of anti-tumor activity was observed including in a pt with prior disease resistance to PAZ monotherapy. An expansion cohort with 20 pts in RCC and sarcoma is planned. Clinical trial information: NCT01543763.
JAK2 Rearrangements, Including the Novel SEC31A-JAK2 Fusion, Are Recurrent in Classical Hodgkin Lymphoma.
Authors: Katrien Van Roosbroeck, Luk Cox, Idoya Lahortiga, Olga Gielen, Thomas Tousseyn, Barbara Cauwelier, Pascale De Paepe, Peter Vandenberghe, Peter Marynen, Chris De Wolf-Peeters, Jan Cools, Iwona Wlodarska
Journal: Blood (2009)
Finally, An Apoptosis-Targeting Therapeutic for Cancer
Authors: Carlo M. Croce, John C. Reed
Journal: Cancer Research (2016)

Abstract Resistance to cell death represents one of the hallmarks of cancer. Various genetic and epigenetic changes in malignant cells afford cytoprotection in the face of genomic instability, oncogene activation, microenvironment stress, chemotherapy, targeted anticancer drugs, and even immunotherapy. Central among the regulators of cell life and death are Bcl-2 family proteins, with the founding member of the family (B-cell lymphoma/leukemia-2) discovered via its involvement in chromosomal translocations in lymphomas. The quest for therapeutics that target cell survival protein Bcl-2 represents a long road traveled, with many dead-ends, disappointments, and delays. Finally, a Bcl-2–targeting medicine has gained approval as a new class of anticancer agent. Cancer Res; 76(20); 5914–20. ©2016 AACR.
Adults with One or More Functional Disabilities — United States, 2011–2014
Authors: Alissa C. Stevens, Dianna D. Carroll, Elizabeth A. Courtney-Long, Qing C. Zhang, Michelle L. Sloan, Shannon Griffin-Blake, Georgina Peacock
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

Nearly 40 million persons in the United States have a disability, as defined by responses to six questions recommended by the U.S. Department of Health and Human Services as the national standard for identifying disabilities in population-based health surveys (1). Although these questions have been used to estimate prevalence of functional disabilities overall, as well as types of functional disabilities (disability type), no study has yet investigated the characteristics of U.S. adults by number of disability types. Knowing the characteristics of persons living with multiple disability types is important for understanding the overall functional status of these persons. CDC analyzed data from the family component of the National Health Interview Survey (NHIS) for the years 2011-2014 to estimate the percentage of adults aged 18-64 years with one, two, three, or four or more disability types, by selected demographic and socioeconomic characteristics. Overall, 22.6 million (11.9%) working-age adults were found to have any disability, and in this population, most (12.8 million) persons had only one disability type. A generally consistent pattern between increasing indicators of low socioeconomic status and the number of disability types was observed. Understanding the demographic and socioeconomic characteristics of working-age adults with disabilities, including those with multiple disability types, might help to further the inclusion of persons with disabilities in public health programs and policies.
Genome-wide identification of Drosophila dorso-ventral enhancers by differential histone acetylation analysis
Authors: Nina Koenecke, Jeff Johnston, Bjoern Gaertner, Malini Natarajan, Julia Zeitlinger
Journal: Genome biology (2016)

Drosophila dorso-ventral (DV) patterning is one of the best-understood regulatory networks to date, and illustrates the fundamental role of enhancers in controlling patterning, cell fate specification, and morphogenesis during development. Histone acetylation such as H3K27ac is an excellent marker for active enhancers, but it is challenging to obtain precise locations for enhancers as the highest levels of this modification flank the enhancer regions. How to best identify tissue-specific enhancers in a developmental system de novo with a minimal set of data is still unclear.Using DV patterning as a test system, we develop a simple and effective method to identify tissue-specific enhancers de novo. We sample a broad set of candidate enhancer regions using data on CREB-binding protein co-factor binding or ATAC-seq chromatin accessibility, and then identify those regions with significant differences in histone acetylation between tissues. This method identifies hundreds of novel DV enhancers and outperforms ChIP-seq data of relevant transcription factors when benchmarked with mRNA expression data and transgenic reporter assays. These DV enhancers allow the de novo discovery of the relevant transcription factor motifs involved in DV patterning and contain additional motifs that are evolutionarily conserved and for which the corresponding transcription factors are expressed in a DV-biased fashion. Finally, we identify novel target genes of the regulatory network, implicating morphogenesis genes as early targets of DV patterning.Taken together, our approach has expanded our knowledge of the DV patterning network even further and is a general method to identify enhancers in any developmental system, including mammalian development.
Patterns of Bone Marrow Micro Vessel Morphology in AML and High Risk MDS Predict Treatment Outcome Following Intensive Chemotherapy and Bevacizumab
Authors: Alida C. Weidenaar, Arja ter Elst, Cees AGM van Montfort, Tiny G.J. Meeuwsen-de Boer, Stefano Rosati, Mario Bargetzi, Carlos Graux, Alois Gratwohl, Bob Lowenberg, Gert Ossenkoppele, Evelina S. De Bont
Journal: Blood (2011)
Outcomes of adjuvant chemoradiotherapy after a radical gastrectomy and D2 node dissection for gastric adenocarcinoma in INEN (Lima, Peru).
Authors: Paola Catherine Montenegro, Lourdes Lopez, Shirley Quintana, Luis Augusto Casanova, Victor Castro, Raul Mantilla
Journal: Journal of Clinical Oncology (2012)

150 Background: Adjuvant chemoradiotherapy is the standard treatment in Western countries in gastric cancer patients submitted to curative resection. INT 0116 pivotal trial established adyuvant chemoradiation as the standar care for resected high risk adenocarcionoma of the stomach in US however was hampered by suboptimal surgery. There is controversial data about efficacy of this adjuvant therapy in patients who have undergone D2 lymphadenectomy predominantly. In our hospital D2 lymphadenectomy is standar surgery for gastric cancer. Methods: Retrospective study with gastric adenocarcinoma patients stage II to IV M0 who underwent curative resection at Instituto Nacional de enfermedades Neoplasicas Lima- Peru between 2001 and 2006 Standard treatment at institution is D2 lymphadenectomy. Chemoradiotherapy according to INT 0116 was given like adjuvant therapy. Survival curves were calculated according to Kaplan-Meier method and compared with log-rank test. Multivariate analysis of prognostic factors related to survival was performed by Cox proportional hazards model adjusted for age, stage and adjuvant chemoradiotherapy. Results: 84 patients were included 60.3% male and 39.3% female. Median age was 40.5 years old. The patologic stage were T1-T2 (12.3%), T3-T4 ( 50% ), N0-N1 (10.7%), N2-N3 (89.3%). D2 lymphadenectomy was performed in all patients. The 3-year DFS was 17% and 3-year overall survivall was 23.9% years.However when we analized by subgroups the overal survival was significantly longer in group N1 ( 61%) and N2 (58.9%) that N3 (18.3%) and DFS were N1 (60%), N2 (55%) and N3 (16.3%). Conclusions: Adjuvant chemoradiotherapy decreased risk of death and relapse in patients with node positive N1-N2 , who underwent curative resection with D2 lymphadenectomy, but recurrence was most frecuent in N3 node positive, maybe is necesary improve the chemotherapy in this group of patientes for dicrease the rate of relapse.
An Expansible Aortic Ring For A Physiological Approach Of Aortic Valve Repair
Authors: Emmanuel Lansaic, Isabelle Di Centa, Francois Raoux, Neil Bulman-Fleming, Adrian Ranga, Aicha Abed, Maguette Ba, Anthony Paolitto, Didier Letourneur, Anne Meddahi
Journal: Circulation (2008)
Efficacy and safety of bevacizumab combined with fluoropyrimidine monotherapy in unfit or older metastatic colorectal cancer patients: A systematic review and pooled-analysis.
Authors: Lorenzo Antonuzzo, Giuseppe Aprile, Sandro Barni, Evaristo Maiello, Gianluca Masi, Fausto Petrelli, Luca Porcu, Mario Scartozzi, Valter Torri, Carmine Pinto
Journal: Journal of Clinical Oncology (2016)

705 Background: Bevacizumab (BEV) improves progression-free survival (PFS) and overall survival (OS) of metastatic colorectal cancer (mCRC) patients (pts) when added to doublets in first-line setting. Yet, its use in unfit and older mCRC pts remains controversial. This systematic review and pooled-analysis evaluated the efficacy and safety data of BEV combined with first-line fluoropyrimidine monochemotherapy in unfit or elderly mCRC pts. Methods: A literature search to identify studies using first-line fluoropyrimidine monochemotherapy plus BEV in unfit pts was performed in PubMed and EMBASE databases up to May 2015. Unfit pts were selected based on age, comorbities and health status, along with monochemotherapy as the only therapeutic option. The random-effects model was used to combine the effect estimates and the I 2 index to quantify the between-study heterogeneity unexplained by sampling error. Results: We screened 1,304 papers and, after a double check, 56 were considered for full text evaluation: 38 were excluded and 10 were deemed not evaluable for lack of data on unfit pts, whereas 8 (3 RCTs, 4 single arm phase II trials and 1 prospective cohort study), including 782 pts, were considered eligible for the meta-analysis. Administered monochemotherapy was capecitabine in 531 (67.9%) pts and 5-fluorouracil (5-FU) in 251 (32.1%); 500 (63.9%) pts also received BEV. Median age was 75 years, 441 (56.4%) pts were male, ECOG performance status was 0-1 in 684 (87.7%) pts. The combination with BEV produced advantages in terms of both OS (HR 0.79; 95% CI: 0.64-0.98, P = 0.03; I 2 = 0%) and PFS (HR 0.52; 95% CI: 0.43-0.64, P &lt; 0.00001; I 2 = 0%; pooled effect estimates of RCTs have been previously reported). As expected, higher rates of all grade hypertension (27% vs 4.9%), bleeding (24% vs 6.4%), thromboembolic events (10% vs 5%) and proteinuria (25.6% vs 8.2%) were observed in the BEV combination. Conclusions: Adding BEV to first-line fluoropyrimidine monochemotherapy, either capecitabine or 5-FU, significantly improved PFS and OS in unfit and elderly pts with mCRC, with a manageable safety profile and no unexpected side effects.
Very Small Embryonic/Epiblast-Like Stem Cells (VSELs) – Novel Supporting Evidence for An Existence of Developmentally Distinct Mobile Pool of Oct-4 + Pluripotent Stem Cells in Embryonic and Adult Tissues: Emerging Concept for a Potential 4th Migratory Germ Layer.
Authors: Mariusz Z Ratajczak, Dong-Myung Shin, Ewa Zuba-Surma, Rui Liu, Momoko Yoshimoto, Mervin C. Yoder, Magdalena Kucia
Journal: Blood (2009)
P1013 : Chronic intermittent hypoxia is associated with liver damage and atherosclerosis in patients with non-alcoholic fatty liver disease
Authors: S. Petta, O. Marrone, D. Torres, M. Buttacavoli, C. Cammà, V. Di Marco, A. Licata, A. Lo Bue, G. Parrinello, A. Pinto, A. Selvaggio, A. Tuttolomondo, A. Craxì, M.R. Bonsignore
Journal: Journal of Hepatology (2015)
Common genetic heterogeneity of human interleukin-37 leads to functional variance
Authors: Jingjing Yan, Yuling Zhang, Shimeng Cheng, Bin Kang, Jinbiao Peng, Xiaodan Zhang, Meichun Yuan, Wenqi Chu, Wen Zhang, Jiayin Shen, Shuye Zhang
Journal: Cellular and Molecular Immunology (2016)
Results of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Advanced Chronic Myeloid Leukemia (CML) Patients (pts) Who Failed Tyrosine Kinase Inhibitors (TKIs) after Developing BCR-ABL Kinase Domain (KD) Mutations.
Authors: Elias Jabbour, Jorge Cortes, Leandro de Padua Silva, Marcos De Lima, Dan Jones, Susan O’Brien, Gabriela Rondon, Uday Popat, Sergio Giralt, Hagop Kantarjian, Richard Champlin
Journal: Blood (2008)
Systematic Review of the Performance of Noninvasive Tests in Diagnosing Bladder Outlet Obstruction in Men with Lower Urinary Tract Symptoms
Authors: Sachin Malde, Arjun K. Nambiar, Roland Umbach, Thomas B. Lam, Thorsten Bach, Alexander Bachmann, Marcus J. Drake, Mauro Gacci, Christian Gratzke, Stephan Madersbacher, Charalampos Mamoulakis, Kari A.O. Tikkinen, Stavros Gravas
Journal: European Urology (2016)
Inhibition of Complement Activation by Pexelizumab reduces Death in Patients undergoing combined Aortic Valve Procedure and Coronary Artery Pypass Surgery
Authors: M Carrier, KM Taylor, A Haverich, JC Chen, SK Shernan, MF Newman, JH Levy, Frans Van de Werf, van, er, Lm, TG Todaro, PX Adams, ED Verrier
Journal: Circulation (2004)
Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma
Authors: Larry Mansouri, Daniel Noerenberg, Emma Young, Elena Mylonas, Maysaa Abdulla, Mareike Frick, Fazila Asmar, Viktor Ljungström, Markus Schneider, Kenichi Yoshida, Aron Skaftason, Tatjana Pandzic, Blanca Gonzalez, Anna Tasidou, Nils Waldhueter, Alfredo Rivas-Delgado, Maria Angelopoulou, Marita Ziepert, Christopher Maximilian Arends, Lucile Couronné, Dido Lenze, Claudia D. Baldus, Christian Bastard, Jessica Okosun, Jude Fitzgibbon, Bernd Dörken, Hans G. Drexler, Damien Roos-Weil, Clemens A. Schmitt, Helga D. Munch-Petersen, Thorsten Zenz, Martin-Leo Hansmann, Jonathan C. Strefford, Gunilla Enblad, Olivier A. Bernard, Elisabeth Ralfkiaer, Martin Erlanson, Penelope Korkolopoulou, Magnus Hultdin, Theodora Papadaki, Kirsten Grønbæk, Armando Lopez-Guillermo, Seishi Ogawa, Ralf Küppers, Kostas Stamatopoulos, Niki Stavroyianni, George Kanellis, Andreas Rosenwald, Elias Campo, Rose-Marie Amini, German Ott, Theodoros P. Vassilakopoulos, Michael Hummel, Richard Rosenquist, Frederik Damm
Journal: Blood (2016)
A Wilms Tumor 1 (WT1) Mutation Causes Myelodysplastic Syndrome in a Knock-in Mouse Model, and a Mixed Myelodysplastic/Myeloproliferative Neoplam in Double Knock-in Mice with WT1 and FLT3/ITD Mutations
Authors: Colleen E. Annesley, Amy S. Duffield, Rachel E. Rau, Gregory McCarty, Daniel Magoon, Li Li, Vicki Huff, Donald Small, David Loeb, Patrick Brown
Journal: Blood (2015)
Stimulatory Effects of Mesenchymal Stem Cells on cKit <sup>+</sup> Cardiac Stem Cells Are Mediated by SDF1/CXCR4 and SCF/cKit Signaling Pathways
Authors: Konstantinos E. Hatzistergos, Dieter Saur, Barbara Seidler, Wayne Balkan, Matthew Breton, Krystalenia Valasaki, Lauro M. Takeuchi, Ana Marie Landin, Aisha Khan, Joshua M. Hare
Journal: Circulation Research (2016)

Culture-expanded cells originating from cardiac tissue that express the cell surface receptor cKit are undergoing clinical testing as a cell source for heart failure and congenital heart disease. Although accumulating data support that mesenchymal stem cells (MSCs) enhance the efficacy of cardiac cKit(+) cells (CSCs), the underlying mechanism for this synergistic effect remains incompletely understood.To test the hypothesis that MSCs stimulate endogenous CSCs to proliferate, migrate, and differentiate via the SDF1/CXCR4 and stem cell factor/cKit pathways.Using genetic lineage-tracing approaches, we show that in the postnatal murine heart, cKit(+) cells proliferate, migrate, and form cardiomyocytes, but not endothelial cells. CSCs exhibit marked chemotactic and proliferative responses when cocultured with MSCs but not with cardiac stromal cells. Antagonism of the CXCR4 pathway with AMD3100 (an SDF1/CXCR4 antagonist) inhibited MSC-induced CSC chemotaxis but stimulated CSC cardiomyogenesis (P<0.0001). Furthermore, MSCs enhanced CSC proliferation via the stem cell factor/cKit and SDF1/CXCR4 pathways (P<0.0001).Together these findings show that MSCs exhibit profound, yet differential, effects on CSC migration, proliferation, and differentiation and suggest a mechanism underlying the improved cardiac regeneration associated with combination therapy using CSCs and MSCs. These findings have important therapeutic implications for cell-based therapy strategies that use mixtures of CSCs and MSCs.
Homozygous<i>SLCO2A1</i>translation initiation codon mutation in a Pakistani family with recessive isolated congenital nail clubbing
Authors: K. Shah, T.M. Ferrara, A. Jan, M. Umair, None Irfanullah, S. Khan, W. Ahmad, R.A. Spritz
Journal: British Journal of Dermatology (2016)

Isolated congenital nail clubbing (ICNC; OMIM 119900) is a rare genodermatosis in which bilateral, symmetric enlargement of the nail plate and terminal segments of fingers and/or toes results from excessive proliferation of connective tissue between the nail matrix and distal phalanx. Loss of the normal angle between the nail and posterior nail fold is associated with a shiny, hypoplastic, thick-ended, long, broad nail. The thumbs are almost always involved, though some fingers or toes may be spared. Both autosomal dominant and autosomal recessive forms of ICNC have been described, sometimes associated with other systemic anomalies, which may include primary hypertrophic osteoarthropathy (PHO), the similar disorder pachydermoperiostitis (PDP), as well as cardiovascular, gastrointestinal, pulmonary and metabolic disorders.1,2

This article is protected by copyright. All rights reserved.
Mutational Status of the TP53 Gene as a Predictor of Response and Survival in CLL Patients with and without 17p Deletion
Authors: David Gonzalez, Pilar Martinez, Rachel Wade, Sarah Lorna Hockley, Vasantha Brito-Babapulle, David Graham Oscier, Estella Matutes, Claire E Dearden, Sue Richards, Daniel Catovsky, Gareth J Morgan
Journal: Blood (2008)
The novel thiosemicarbazone, di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), inhibits neuroblastoma growth in vitro and in vivo via multiple mechanisms
Authors: Zhu-Ling Guo, Des R. Richardson, Danuta S. Kalinowski, Zaklina Kovacevic, Kian Cheng Tan-Un, Godfrey Chi-Fung Chan
Journal: Journal of Hematology & Oncology (2016)

Neuroblastoma is a relatively common and highly belligerent childhood tumor with poor prognosis by current therapeutic approaches. A novel anti-cancer agent of the di-2-pyridylketone thiosemicarbazone series, namely di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), demonstrates promising anti-tumor activity. Recently, a second-generation analogue, namely di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), has entered multi-center clinical trials for the treatment of advanced and resistant tumors. The current aim was to examine if these novel agents were effective against aggressive neuroblastoma in vitro and in vivo and to assess their mechanism of action. Neuroblastoma cancer cells as well as immortalized normal cells were used to assess the efficacy and selectivity of DpC in vitro. An orthotopic SK-N-LP/Luciferase xenograft model was used in nude mice to assess the efficacy of DpC in vivo. Apoptosis in tumors was confirmed by Annexin V/PI flow cytometry and H&E staining. DpC demonstrated more potent cytotoxicity than Dp44mT against neuroblastoma cells in a dose- and time-dependent manner. DpC significantly increased levels of phosphorylated JNK, neuroglobin, cytoglobin, and cleaved caspase 3 and 9, while decreasing IkBα levels in vitro. The contribution of JNK, NF-ĸB, and caspase signaling/activity to the anti-tumor activity of DpC was verified by selective inhibitors of these pathways. After 3 weeks of treatment, tumor growth in mice was significantly (p < 0.05) reduced by DpC (4 mg/kg/day) given intravenously and the agent was well tolerated. Xenograft tissues showed significantly higher expression of neuroglobin, cytoglobin, caspase 3, and tumor necrosis factor-α (TNFα) levels and a slight decrease in interleukin-10 (IL-10). DpC was found to be highly potent against neuroblastoma, demonstrating its potential as a novel therapeutic for this disease. The ability of DpC to increase TNFα in tumors could also promote the endogenous immune response to mediate enhanced cancer cell apoptosis.