tbuckley/cabot-search huggingface dataset:
Abstract 3540: Exploring novel treatment agent in GIST by using connectivity map
Authors: Chueh-Chuan Yen, Li-Tzong Chen, Chien-Feng Li
Journal: Cancer Research (2016)

Abstract Gastrointestinal stromal tumors (GIST) is gastrointestinal tract sarcoma which commonly contains a mutation in the KIT or PDGFRA. Imatinib mesylate, a specific tyrosine kinase inhibitor of the KIT and PDGFRA, causes regression or stabilization of disease in most of the patients with metastatic GIST. However, acquired resistance to imatinib is inevitable. Recently, E26 variant 1 (ETV1) pathway was found to be a key downstream effector of KIT. In this study, we explored the role of ETVI and its downstream effectors pathway in GIST by bioinformatics analysis, and identified potential novel agents that target ETV1 pathway of GISTs by using expression profile and a pattern-matching software “Connectivity Map” (CMAP), and confirmed the efficacy of novel agents by using GIST cell line in vitro assay. By using CMAP, four drugs with potential ETV1-inhibition effect were identified: suberanilohydroxamic acid (SAHA,Vorinostat) and trichostatin, two histone deacetylase inhibitors (HDACI), and trifluoperazine (TFP) and thioridazine (TDZ), two drugs of phenothiazine class. All four drugs were found to have ETV1-down regulating effect by immunoblotting. Phenothiazine could induce apoptosis and autophagy in GIST. Treatment of phenothiazine was found paradoxically up-regulate MEK activity. Combination of MEK inhibitor and phenothiazine showed great synergistic effect in exerting cytotoxicity against GIST cell lines. Our study established phenothiazine as a new class of agent with therapeutic effect in GIST, and combination of phenothiazine and MEK inhibitor showed great potential in GIST treatment. Citation Format: Chueh-Chuan Yen, Li-Tzong Chen, Chien-Feng Li. Exploring novel treatment agent in GIST by using connectivity map. [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 3540.
Myeloablative busulfan with cyclophosphamide (BuCy) versus busulfan with fludarabine (BuFlu) in myeloid neoplasms.
Authors: Renju V. Raj, Lindsay Dozeman, Anna M Button, Margarida De Magalhaes-Silverman
Journal: Journal of Clinical Oncology (2014)

7041 Background: BuCy is considered a standard myeloablative conditioning regimen for allogeneic hematopoietic stem cell transplantation (HSCT). However its use is limited by significant regimen related toxicity. Several reports suggest that the combination of busulfan and fludarabine(BuFlu) in ablative doses may provide effective control of myeloid neoplasms with less toxicity. This study evaluated the effect of replacing BuCy with BuFlu for myeloablative conditioning in myeloid neoplasms. Methods: Retrospective analysis of patients (pts) with myeloid neoplasms who underwent allogeneic HSCT after myeloablative conditioning regimen with BuFlu or BuCy between 2006 and 2012 was done. Forty five pts received BuFlu and 38 BuCy. Ten (22.2%) pts in BuFlu and 3 (8%) pts with BuCy had an HLA mismatched transplant. Median age was 58 (range 22-68) in BuFlu group and 53 (range 19-68) in BuCy. Disease risk by CIBMTR classification was advanced in 27 (60%) pts in BuFlu group and 10 (26.3%) in the BuCy. HSCT Comorbidity Index score was high in 24 (53.3%) pts in BuFlu and 17(44.7%) in BuCy. GVHD prophylaxis consisted of tacrolimus and methotrexate in all pts in BuFlu and in 81.6 % pts in BuCy with 7 pts receiving cyclosporine and mycophenolate. Thymoglobulin was administered in unrelated and mismatched donor grafts. Cox proportional hazard models were used to obtain the hazard ratios and 95% confidence intervals. Results: All pts engrafted except 1 in the BuCy group. Mortality at day 100 post-transplant was 4.4% in BuFlu and 21% in BuCy (p=0.038). Grade 3 and 4 GVHD was diagnosed in 6.6% in BuFlu and 21% in BuCy group. Risk of relapse or death for pts in the BuCy group was 2.17 times (95% CI 1.08-4.355, p=0.028) higher than for pts in the BuFlu group with a median follow up of 554 days. The trend for overall survival(OS) was better in BuFlu group compared to BuCy (HR 1.97, 95% CI 0.97-3.97, p=0.059). Relapse free survival was also favored in BuFlu pts compared to BuCy (HR 1.550, 95% CI 0.607-3.960, p=0.359) Conclusions: In our experience we found that conditioning with BuFlu is better tolerated, has better 100 day mortality, improved time to progression and OS, in spite of the fact that the pts in BuCy group had a higher CIBMTR disease risk score.
Immunoglobulin Heavy/Light Chain Immunoassays for Response Evaluation in Multiple Myeloma: Comparison with Immunofixation, Serum Free Light Chain, and Multicolor Flow- Cytometry
Authors: Yasuhito Suehara, Keisuke Seike, Kouta Fukumoto, Manabu Fujisawa, Masafumi Fukaya, Hiroki Sugihara, Masami Takeuchi, Hiroyuki Takamatsu, Kelly Endean, Stephen Harding, Kosei Matsue
Journal: Blood (2014)
Acidosis and Urinary Calcium Excretion: Insights from Genetic Disorders
Authors: R. Todd Alexander, Emmanuelle Cordat, Régine Chambrey, Henrik Dimke, Dominique Eladari
Journal: Journal of the American Society of Nephrology (2016)

Metabolic acidosis is associated with increased urinary calcium excretion and related sequelae, including nephrocalcinosis and nephrolithiasis. The increased urinary calcium excretion induced by metabolic acidosis predominantly results from increased mobilization of calcium out of bone and inhibition of calcium transport processes within the renal tubule. The mechanisms whereby acid alters the integrity and stability of bone have been examined extensively in the published literature. Here, after briefly reviewing this literature, we consider the effects of acid on calcium transport in the renal tubule and then discuss why not all gene defects that cause renal tubular acidosis are associated with hypercalciuria and nephrocalcinosis.
Abstract 168: Contribution of Vascular Endothelial Growth Factor Signaling to Fate Specification in Cardiomyocytes
Authors: Taylor Y Lu, Courtney K Domigan, Vaspour Antanesian, Yasuhiro Nakashima, Atsushi Nakano, Luisa Iruela-Arispe
Journal: Circulation Research (2014)

Vascular endothelial growth factor (VEGF) is one of the pivotal proangiogenic growth factors that has long contributed to our knowledge of blood vessel and circulatory maintenance as well as angiogenesis in both pathology and pathophysiology. However, the non-canonical functions of VEGF in cardiac morphogenesis have not been well characterized. Here, we examined how VEGF regulates cardiomyocyte cell fate. Using chimeric embryos harboring both wild type and VEGF-null embryonic stem cells, we observed that derivatives of VEGF null cells were preferentially recruited to the atrium of the heart in comparison to the ventricles. To further provide physiologic context of this finding, we used reporter-LacZ staining and RT-PCR and found that endogenous VEGF was indeed expressed at much lower levels in the atrium but highly expressed in the ventricle early in cardiac morphogenesis. These data lead to our hypothesis that cell-autonomous expression of VEGF is a determinant of atrial vs. ventricular cardiomyocyte cell fate. To test this hypothesis, we used a VEGF knock-in mouse model of Sm22Cre x Rosa 26 VEGF. VEGF overexpression in cardiomyocytes (and smooth muscle) at E8.5 resulted in lethality by P1 and thickened atrial and ventricular walls in mutant embryos as characterized by histology (H&amp;E, IF). We further explored the molecular changes underlying this phenotype via microarray and RT-PCR and find disruptions in molecular markers necessary for wall development, specifically: Notch-1, BMP10, Nrg-1. Taken together, our data indicates that aberrant embryonic VEGF signaling disrupts several critical signaling pathways and that overexpression leads to disruption of cardiomyocyte proliferation and cardiac morphogenesis. These findings add to the foundation of better understanding heart development, laying the groundwork for future therapy of congenital and acquired cardiac disease.
Abstract 1831: Cancer genomic resources and needs in the Latin American region
Authors: Javier Oliver, Sandra Perdomo, Felipe Vaca
Journal: Cancer Research (2016)

Abstract In 2012, approximately 1,005,255 new cancer cases and 550,164 deaths from cancer occurred in both sexes in central and South American region, by 2025 and increment of nearly 30% of new cases and 35% of deaths from cancer are predicted. One of the priorities of cancer control within the region is to reduce avoidable deaths from cancer by improving early detection and personalized treatment. The development of cancer genomics and their integration to cancer care has shown a great improvement in cancer control worldwide; however, all these key advances have been mainly concentrated in highly developed nations and little is known about the capacities and needs of cancer genomics in the Latin-American (LA) context. In order to evaluate the capacity and development of cancer genomic applications in the LA we collected available information for all countries in central, South America and Cuba. Data reviewed included: number of cancer research institutions, number of NGS platforms, research groups working in cancer genetics, publications on cancer genetics for the last 10 years, educational programs on genomics and related health policies. In average 15 Research groups per country were registered as conducting cancer-genetics related projects. In the las 10 years, 206 publications on cancer genetics including reviews were led by (1st, 2nd or corresponding) authors affiliated to LA institutions and only publications in the last 2 years included cancer genomic analysis. Most publications related to breast, gastric and hematological cancers were underrepresented in general. In the past 5 years physical resources have grown markedly by the acquisition of nearly 150 NGS platforms in 9 countries, the majority installed in medical related services and universities. Participation in large genomic consortia has only included two countries Mexico (as partner) and Brazil (as leading). Educational programs in genomics are scarce, almost exclusive of graduate programs and few are applied to cancer. Despite the recent advances in introducing cancer genomics knowledge and application in LA, the region lacks development of integrated genomic research projects, improved use of platforms dedicated to cancer, educational programs and health policies that focus on the most frequent cancers and could impact cancer care. Citation Format: Javier Oliver, Sandra Perdomo, Felipe Vaca. Cancer genomic resources and needs in the Latin American region. [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 1831.
Differentiation stage of myeloma plasma cells: biological and clinical significance
Authors: B Paiva, N Puig, M T Cedena, B G de Jong, Y Ruiz, I Rapado, J Martinez-Lopez, L Cordon, D Alignani, J A Delgado, M C van Zelm, J J M Van Dongen, M Pascual, X Agirre, F Prosper, J I Martín-Subero, M-B Vidriales, N C Gutierrez, M T Hernandez, A Oriol, M A Echeveste, Y Gonzalez, S K Johnson, J Epstein, B Barlogie, G J Morgan, A Orfao, J Blade, M V Mateos, J J Lahuerta, J F San-Miguel
Journal: Leukemia (2016)
Disciplined approach to drug discovery and early development
Authors: Robert M. Plenge
Journal: Science Translational Medicine (2016)

Our modern health care system demands therapeutic interventions that improve the lives of patients. Unfortunately, decreased productivity in therapeutics research and development (R&D) has driven drug costs up while delivering insufficient value to patients. Here, I discuss a model of translational medicine that connects four components of the early R&D pipeline-causal human biology, therapeutic modality, biomarkers of target modulation, and proof-of-concept clinical trials. Whereas the individual components of this model are not new, technological advances and a disciplined approach to integrating all four areas offer hope for improving R&D productivity.
Evolution de l‘asthme en Suisse : le réseau suisse de surveillance sentinelle, 1988-1996
Authors: U Bollag, J Cloetta, J Oberreich, W J Paget
Journal: Eurosurveillance (1999)

L‘asthme pose un vrai probleme de sante publique chez les enfants et les adultes dans le monde. D‘apres des etudes de populations, la prevalence des dyspnees expiratoires et du diagnostic de l‘asthme augmente avec le temps (1). Cette augmentation apparente peut en partie resulter d‘une plus grande sensibilite du public a l‘egard de l‘asthme et d‘une tendance croissante des parents a consulter un medecin pour un traitement de l‘asthme lorsque leurs enfants presentent une respiration sifflante. La toux, symptome principal des maladies respiratoires virales, peut etre attribuee a l‘asthme alors qu‘en realite elle fait partie d’un processus infectieux et correspond a une constriction non specifique de l‘arbre bronchique (2).
Abstract 654: Impact of epithelial cell-specific deletion of mPGES-1 on colon carcinogenesis
Authors: Masako Nakanishi, Daniel W. Rosenberg
Journal: Cancer Research (2016)

Abstract Activation of the COX-2/mPGES-1/PGE2 signaling axis is a hallmark of many cancers, including colorectal cancer (CRC), prompting the implementation of cancer prevention strategies targeting COX-2 activity. We have shown that targeting the downstream terminal PGE2 synthase, mPGES-1, specifically reduces inducible PGE2 formation without disrupting synthesis of other essential prostanoids. Additionally, global deletion of mPGES-1 (gKO) confers dramatic protection against intestinal cancer development in several mouse models, including the AOM+DSS inflammation-associated colon cancer model. Understanding the role of PGE2 under inflammatory conditions, however, is complicated by the diverse cellular sources and context-dependence of inducible PGE2. To clarify the relative contribution of inducible PGE2 synthesis within distinct cell compartments in colon, we have recently created an mPGES-1 conditional knockout mouse (cKO), where exon 3 of the mPGES-1 gene (mPtges) is floxed for tissue-specific Cre-mediated deletion. To test the role of epithelial-derived PGE2 synthesis on inflammation-associated cancer, we crossed the cKO mice with carbonic anhydrase 1 (Car1)-controlled Cre mice (cKO:Car1), thereby inactivating mPGES-1 function specifically within colonic epithelial cells. Based on our recent observation that global inactivation mPGES-1 sensitizes the colonic mucosa to direct environmental injury, we first examined the sensitivity of the cKO:Car1 mice to DSS-induced acute colitis. Two days after a five-day treatment with 0, 0.5 or 1% DSS, clinical signs of colitis, including the extent of colonic ulceration were determined. Both cKO:Car1 and cKO:WT control mice showed a comparable extent of colonic ulceration, covering ∼60% of the epithelial surface. We next examined the impact of epithelial-specific deletion of mPGES-1 on DSS-induced colon carcinogenesis. KO:Car1 and cKO:WT control mice were treated with a single injection of AOM (10 mg/kg bw) followed by five days of 0, 0.5 or 1% DSS, and colons were examined five weeks after the end of DSS treatment. Surprisingly, epithelial deletion of mPGES-1 in the cKO:Car1 mice failed to provide against cancer development in comparison to the cKO:WT mice. This is the first study to show that genetic inactivation of inducible PGE2 formation within a specific cell lineage (e.g. epithelial cells) does not affect both the extent of acute colonic inflammation nor subsequent inflammation-associated carcinogenesis. Citation Format: Masako Nakanishi, Daniel W. Rosenberg. Impact of epithelial cell-specific deletion of mPGES-1 on colon carcinogenesis. [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 654.
Value of Donor–Specific Anti–HLA Antibody Monitoring and Characterization for Risk Stratification of Kidney Allograft Loss
Authors: Denis Viglietti, Alexandre Loupy, Dewi Vernerey, Carol Bentlejewski, Clément Gosset, Olivier Aubert, Jean-Paul Duong van Huyen, Xavier Jouven, Christophe Legendre, Denis Glotz, Adriana Zeevi, Carmen Lefaucheur
Journal: Journal of the American Society of Nephrology (2016)

The diagnosis system for allograft loss lacks accurate individual risk stratification on the basis of donor–specific anti–HLA antibody (anti-HLA DSA) characterization. We investigated whether systematic monitoring of DSA with extensive characterization increases performance in predicting kidney allograft loss. This prospective study included 851 kidney recipients transplanted between 2008 and 2010 who were systematically screened for DSA at transplant, 1 and 2 years post-transplant, and the time of post–transplant clinical events. We assessed DSA characteristics and performed systematic allograft biopsies at the time of post–transplant serum evaluation. At transplant, 110 (12.9%) patients had DSAs; post-transplant screening identified 186 (21.9%) DSA-positive patients. Post–transplant DSA monitoring improved the prediction of allograft loss when added to a model that included traditional determinants of allograft loss (increase in c statistic from 0.67; 95% confidence interval [95% CI], 0.62 to 0.73 to 0.72; 95% CI, 0.67 to 0.77). Addition of DSA IgG3 positivity or C1q binding capacity increased discrimination performance of the traditional model at transplant and post-transplant. Compared with DSA mean fluorescence intensity, DSA IgG3 positivity and C1q binding capacity adequately reclassified patients at lower or higher risk for allograft loss at transplant (category–free net reclassification index, 1.30; 95% CI, 0.94 to 1.67; P &lt;0.001 and 0.93; 95% CI, 0.49 to 1.36; P &lt;0.001, respectively) and post-transplant (category–free net reclassification index, 1.33; 95% CI, 1.03 to 1.62; P &lt;0.001 and 0.95; 95% CI, 0.62 to 1.28; P &lt;0.001, respectively). Thus, pre– and post–transplant DSA monitoring and characterization may improve individual risk stratification for kidney allograft loss.
P1316 : Effects of long-term administration of midodrine and albumin in the prevention of complications in patients with cirrhosis on waiting list for liver transplantation. A randomized, multicenter, double-blind, placebo-controlled trial. macht study
Authors: E. Sola, M. Simon Talero, M. Martin-Llahi, J. Castellote, A. Nazar, C. Solè, M. Ventura, R. Cela, N. Fabrellas, M. Torrens, E. Lopez, G. de Prada, P. Huelin, P. Suñé, M. Guevara, X. Xiol, V. Vargas, V. Arroyo, P. Gines
Journal: Journal of Hepatology (2015)
Cutaneous Necrosis of the Ears
Authors: Kim M. Phan, Katherine H. Nguyen, Nancy F. Crum-Cianflone
Journal: JAMA (2016)

A 22-year-old woman presented with a 2-month history of fevers and pleuritic chest pain and a 2-day history of cutaneous necroses on her ears, without trauma. Evaluation revealed abnormal coagulation values and a deep vein thrombosis in one leg. What would you do next?
Case 50-1971
Authors: Richard C. Cabot, Benjamin Castleman, Betty U. McNeely, Kenneth E. W. Melvin, Benjamin Castleman
Journal: New England Journal of Medicine (1971)

Presentation of CaseA 50-year-old woman was admitted to the hospital because of hypercalcemia.She had been well until 20 months previously, when there was the onset of fatigue. Nine months before entry the fatigue increased, accompanied by generalized muscle weakness, anorexia and a loss of 11 kg in weight during the next four months. Periodic nausea developed, and six months before admission she began to vomit intermittently. Five months before admission she became aware of a lump in the right side of the neck, which slowly increased in size. Four months before entry a dull ache appeared in the . . .
Abstract 3510: Tolfenamic acid induces apoptosis and growth inhibition in anaplastic thyroid cancer: involvement of nonsteroidal anti-inflammatory drug-activated gene-1 expression and intracellular reactive oxygen species generation
Authors: Yeon Soo Kim, Jae Won Chang, SungUn Kang, JaeWon Choi, YooSeob Shin, Seung Joon Baek, Seong-Ho Lee, Kyoung Ho Oh, Chul-Ho Kim
Journal: Cancer Research (2016)

Abstract Nonsteroidal anti-inflammatory drugs (NSAIDs) are usually used for the treatment of inflammatory diseases. However, certain NSAIDs also have antitumor activities in various cancers, including head and neck cancer, through cyclooxygenase-dependent or independent pathways. Nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1), a TGF-β superfamily protein, is induced by NSAIDs and has been shown to be induced by several antitumorigenic compounds and to exhibit proapoptotic and antitumorigenic activities. In this report, we demonstrate for the first time that tolfenamic acid (TA) transcriptionally induced the expression of NAG-1 during TA-induced apoptosis of anaplastic thyroid cancer (ATC) cells. TA reduced the viability of ATC cells in a dose-dependent manner and induced apoptosis, findings that were coincident with NAG-1 expression. Overexpression of the NAG-1 gene using cDNA enhanced the apoptotic effect of TA, whereas suppression of NAG-1 expression by small interfering RNA attenuated TA-induced apoptosis. Subsequently, we found that intracellular ROS generation plays an important role in activating the proapoptotic protein NAG-1. Then, we confirmed antitumorigenic effects of TA in a nude mouse orthotopic ATC model, and this result accompanied the augmentation of NAG-1 expression and ROS generation in tumor tissue. Taken together, these results demonstrate that TA induces apoptosis via NAG-1 expression and ROS generation in in vitro and in vivo ATC models, providing a novel mechanistic explanation and indicating a potential chemotherapeutic approach for treatment of ATC. Citation Format: Yeon Soo Kim, Jae Won Chang, SungUn Kang, JaeWon Choi, YooSeob Shin, Seung Joon Baek, Seong-Ho Lee, Kyoung Ho Oh, Chul-Ho Kim. Tolfenamic acid induces apoptosis and growth inhibition in anaplastic thyroid cancer: involvement of nonsteroidal anti-inflammatory drug-activated gene-1 expression and intracellular reactive oxygen species generation. [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 3510.