tbuckley/cabot-search huggingface dataset:
A phase 1b/2b multicenter study of oral panobinostat plus azacitidine in adults with MDS, CMML or AML with ⩽30% blasts
Authors: G Garcia-Manero, M A Sekeres, M Egyed, M Breccia, C Graux, J D Cavenagh, H Salman, A Illes, P Fenaux, D J DeAngelo, R Stauder, K Yee, N Zhu, J-H Lee, D Valcarcel, A MacWhannell, Z Borbenyi, L Gazi, S Acharyya, S Ide, M Marker, O G Ottmann
Journal: Leukemia (2017)

Treatment with azacitidine (AZA), a demethylating agent, prolonged overall survival (OS) vs conventional care in patients with higher-risk myelodysplastic syndromes (MDS). As median survival with monotherapy is <2 years, novel agents are needed to improve outcomes. This phase 1b/2b trial (n=113) was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of panobinostat (PAN)+AZA (phase 1b) and evaluate the early efficacy and safety of PAN+AZA vs AZA monotherapy (phase 2b) in patients with higher-risk MDS, chronic myelomonocytic leukemia or oligoblastic acute myeloid leukemia with <30% blasts. The MTD was not reached; the RP2D was PAN 30 mg plus AZA 75 mg/m2. More patients receiving PAN+AZA achieved a composite complete response ([CR)+morphologic CR with incomplete blood count+bone marrow CR (27.5% (95% CI, 14.6–43.9%)) vs AZA (14.3% (5.4–28.5%)). However, no significant difference was observed in the 1-year OS rate (PAN+AZA, 60% (50–80%); AZA, 70% (50–80%)) or time to progression (PAN+AZA, 70% (40–90%); AZA, 70% (40–80%)). More grade 3/4 adverse events (97.4 vs 81.0%) and on-treatment deaths (13.2 vs 4.8%) occurred with PAN+AZA. Further dose or schedule optimization may improve the risk/benefit profile of this regimen.
Type 2 diabetes and obesity induce similar transcriptional reprogramming in human myocytes
Authors: Leif Väremo, Tora Ida Henriksen, Camilla Scheele, Christa Broholm, Maria Pedersen, Mathias Uhlén, Bente Klarlund Pedersen, Jens Nielsen
Journal: Genome Medicine (2017)

Skeletal muscle is one of the primary tissues involved in the development of type 2 diabetes (T2D). The close association between obesity and T2D makes it difficult to isolate specific effects attributed to the disease alone. Therefore, here we set out to identify and characterize intrinsic properties of myocytes, associated independently with T2D or obesity.We generated and analyzed RNA-seq data from primary differentiated myotubes from 24 human subjects, using a factorial design (healthy/T2D and non-obese/obese), to determine the influence of each specific factor on genome-wide transcription. This setup enabled us to identify intrinsic properties, originating from muscle precursor cells and retained in the corresponding myocytes. Bioinformatic and statistical methods, including differential expression analysis, gene-set analysis, and metabolic network analysis, were used to characterize the different myocytes.We found that the transcriptional program associated with obesity alone was strikingly similar to that induced specifically by T2D. We identified a candidate epigenetic mechanism, H3K27me3 histone methylation, mediating these transcriptional signatures. T2D and obesity were independently associated with dysregulated myogenesis, down-regulated muscle function, and up-regulation of inflammation and extracellular matrix components. Metabolic network analysis identified that in T2D but not obesity a specific metabolite subnetwork involved in sphingolipid metabolism was transcriptionally regulated.Our findings identify inherent characteristics in myocytes, as a memory of the in vivo phenotype, without the influence from a diabetic or obese extracellular environment, highlighting their importance in the development of T2D.
Efficacy of fexofenadine in preventing tyrosine kinase inhibitor (TKI)-induced interstitial lung disease.
Authors: Ryo Ko, Shinichi Sasaki, Yukiko Namba, Ayako Ishimori, Masakata Yoshioka, Yasuko Yoshioka, Shigeru Tominaga, Kazuhisa Takahashi
Journal: Journal of Clinical Oncology (2012)

e18019 Background: Tyrosine kinase inhibitors (TKIs; gefitinib and erlotinib) are widely indicated in NSCLC patients, especially those harboring an active mutation of EGFR, and have shown excellent efficacy. However, severe interstitial lung disease (ILD) can occur as an adverse event with TKIs, and is sometimes fatal. Fexofenadine has been used to prevent TKI-induced skin rash in all patients, who received EGFR-TKIs, since April 2009 in our hospital, and seems to reduce the incidence of ILD. Therefore, we retrospectively analyzed the efficacy of fexofenadine in preventing TKI-induced ILD. Methods: 145 NSCLC patients, in whom TKIs were administered, were analyzed in the study, comprising 54 and 91 patients with and without concomitant administration of fexofenadine, respectively. Univariate and multivariate analyses with logistic regression model were used to investigate whether fexofenadine could prevent EGFR-TKIs-induced ILD or not. Results: ILD occurred in 21 patients (14.5%), and was fatal in 5 (3.4%). The number of ILD patients with/without fexofenadine was 4 out of 54 (8.5%)/17 out of 91 (18.7%), and the mortality was 1 out of 54 patients (1.9%)/4 out of 91 (4.4%), respectively. Fexofenadine appears to reduce the ILD event (p=0.062). Interestingly, severe ILD events (grades 2, 3, 4, or 5) were significantly reduced in patients with fexofenadine compared to patients without fexonadine (p=0.031, Table). Although the administration of fexofenadine was not independent predictive factor for EGFR-TKIs-induced ILD according to multivariate analysis, it seems to reduce the ILD events (p= 0.061). Conclusions: Our data suggest that fexofenadine seem to reduce the incidence of TKI-induced ILD. However, the prospective study needs to be performed to confirm our result. [Table: see text]
FOLFIRI plus bevacizumab (bev) as second-line therapy in patients (pts) with metastatic colorectal cancer (mCRC) who have failed first-line bev plus oxaliplatin-based therapy: The randomized phase III EAGLE study.
Authors: Hiroshi Tamagawa, Shigeyoshi Iwamoto, Takao Takahashi, Masato Nakamura, Yoshinori Munemoto, Takeshi Kato, Taishi Hata, Tadamichi Denda, Yoshitaka Morita, Michio Inukai, Katsuyuki Kunieda, Naoki Nagata, Kiyotaka Kurachi, Kenji Ina, Takashi Oshiro, Tatsu Shimoyama, Hideo Baba, Koji Oba, Junichi Sakamoto, Hideyuki Mishima
Journal: Journal of Clinical Oncology (2013)

3516 Background: The phase III ML18147 study (NCT00700102) showed a survival benefit for the continuation of bev after 1st-line bev-containing therapy in pts with mCRC. Continuation of bev beyond disease progression in this setting was approved by the FDA in Jan 2013. In the randomized, phase II SPIRITT study (NCT00418938) assessing 2nd-line treatment for mCRC, progression-free survival (PFS) was longer in the bev arm compared with the panitumumab arm, but the difference was not statistically significant. We describe the results of EAGLE, a multicenter, randomized phase III study evaluating the optimal dose of 2nd-line bev in Japan (UMIN000002557). Methods: Pts were randomized 1:1 to receive bev 5 mg/kg (Arm A) or 10 mg/kg (Arm B) plus FOLFIRI Q2W. Key eligibility criteria: age ≥20 years, mCRC, ECOG PS ≤1, and treatment failure to prior 1st-line bev plus oxaliplatin-based therapy (≥4 cycles). The primary endpoint was PFS. Secondary endpoints included time to treatment failure (TTF), PFS from 1st-line therapy, response rate (RR) and safety. The planned sample size was 370 pts to detect 30% risk reduction with 90% power assuming a two-sided significance level of 0.05. Results: 387 pts were randomized between Sep 2009 and Jan 2012; 367 pts formed the full analysis set (Arm A 179 pts; Arm B 188 pts). Baseline characteristics were well balanced between the treatment arms. Respectively for Arm A and B, PFS was 6.2 and 6.3 months (HR 1.03, 95% CI: 0.82-1.30; p=0.815), TTF 5.3 and 5.3 months (HR 1.08, 95% CI: 0.87-1.33; p=0.485), PFS from 1st-line therapy 17.6 and 17.8 months (HR 0.99, 95% CI: 0.78-1.25; p=0.919) and RR 11.7% and 10.1%. Frequently reported AEs in Arm A and B, respectively, were: hypertension (13.0%, 18.1%), proteinurea (36.8%, 35.2%), GI perforation (4.7%, 3.1%), grade 3/4 neutropenia (46.1%, 39.9%), grade 3/4 fatigue (7.8%, 10.9%), and grade 3/4 anorexia (5.7%, 5.2%). Treatment-related deaths occurred in 2 pts in each arm. Conclusions: The study did not meet its primary endpoint. PFS in Arm A was comparable to that reported in the ML18147 study. Safety in both arms was consistent with previously reported studies. Clinical trial information: UMIN000002557.
Evolution of the Banana Genome (Musa acuminata) Is Impacted by Large Chromosomal Translocations
Authors: Guillaume Martin, Françoise Carreel, Olivier Coriton, Catherine Hervouet, Céline Cardi, Paco Derouault, Danièle Roques, Frédéric Salmon, Mathieu Rouard, Julie Sardos, Karine Labadie, Franc-Christophe Baurens, Angélique D’Hont
Journal: Molecular Biology and Evolution (2017)

Most banana cultivars are triploid seedless parthenocarpic clones derived from hybridization between Musa acuminata subspecies and sometimes M. balbisiana. M. acuminata subspecies were suggested to differ by a few large chromosomal rearrangements based on chromosome pairing configurations in intersubspecies hybrids. We searched for large chromosomal rearrangements in a seedy M. acuminata ssp. malaccensis banana accession through mate-pair sequencing, BAC-FISH, targeted PCR and marker (DArTseq) segregation in its progeny. We identified a heterozygous reciprocal translocation involving two distal 3 and 10 Mb segments from chromosomes 01 and 04, respectively, and showed that it generated high segregation distortion, reduced recombination and linkage between chromosomes 01 and 04 in its progeny. The two chromosome structures were found to be mutually exclusive in gametes and the rearranged structure was preferentially transmitted to the progeny. The rearranged chromosome structure was frequently found in triploid cultivars but present only in wild malaccensis ssp. accessions, thus suggesting that this rearrangement occurred in M. acuminata ssp. malaccensis. We propose a mechanism for the spread of this rearrangement in Musa diversity and suggest that this rearrangement could have played a role in the emergence of triploid cultivars.
Analyse médico-économique prospective de la pratique de la dissection sous-muqueuse en CHU: la création d'un acte CCAM spécifique est indispensable!
Authors: E Pauliat, R Legros, S Brischoux, D Sautereau, A Tailleur, V Richard, L Merle, S Chatton, P Carrier, V Loustaud-Ratti, J Jacques
Journal: Endoscopy (2016)

La dissection sous-muqueuse endoscopique (DSE) est une technique innovante permettant la résection en un seul bloc d'importantes lésions tumorales superficielles du tractus digestif. L'évaluation de son efficacité et de sa sécurité est retrouvée dans la littérature mais aucune étude n'évalue le coût de cet acte nécessitant des dispositifs médicaux stériles (DMS) coûteux. Cette intervention, bien plus longue que les actes d'endoscopie classique, ne possède pas de cotation spécifique dans la classification commune des actes médicaux (CCAM). Le séjour du patient ne peut donc pas être orienté vers un groupe homogène de malades (GHM) spécifique permettant de couvrir les coûts liés à cette procédure.
Phase I/II multicenter study of phy906/capecitabine in hepatocellular carcinoma
Authors: Yun Yen, Samuel So, Michal Rose, Wasif Saif, Edward Chu, Li-Tzong Cheng, Shwu-Huey Liu, Angeline Foo, Robert Tilton, Yung-Chi Cheng
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

4466 

PHY906, prepared under GMP conditions, is a multi-herbal, 1700-year-old Chinese medicine formula with claims for the treatment of diarrhea, vomiting, noxia, stomach cramps, and fever. PHY906 was found to enhance the antitumor efficacy of capecitabine against HepG2 (hepatocellular carcinoma) cells implanted in mice. Accordingly, a Phase I/II clinical study has been conducted with the combination of capecitabine and PHY906 in patients with hepatocellular carcinoma (HCC). The objective of the Phase I study was to determine the safety and tolerability of the two-drug combination given on a 21-day course of treatment as follows: capecitabine - BID for 14 consecutive days then 1 week drug-free; PHY906 - BID on days 1-4 and 8-11. In addition to antitumor response, objectives of the Phase II study included assessment of patients’ quality of life (QoL).    The Phase I/II study, begun November 2003, was a multicenter, open-label, dose-escalation, safety and efficacy study of a fixed dose of capecitabine in combination with variable doses of PHY906. Four centers in the US and two in Taiwan were used. Patients were required to have measurable, recurrent, metastatic, or unresectable HCC, a Karnofsky status of 70% or above, adequate organ and hematological functions, and not to have had additional optimal chemotherapy regimens. Patients were considered evaluable after two cycles of treatment. The initial dose regimen (capecitabine 1000 mg/m2 BID; PHY906 1000 mg BID) was found to have unfavorable toxicities. Consequently, capecitabine was reduced to 750 mg/m2 BID and combined with PHY906 600 mg BID initially. Subsequently, a new cohort of 750 mg/m2 BID capecitabine plus 800 mg BID PHY906 was added. Both of the latter regimens were well tolerated (N=4 for PHY906 600 mg BID, N=26 for PHY906 800 mg BID).    The Phase II study was conducted using the regimen of capecitabine 750 mg/m2 BID and PHY906 800 mg BID; it was completed in August, 2007. Thirty patients were evaluated, 27 at US sites and 3 at Taiwan sites. Three (10%) patients achieved minor response (MR), 15 (50%) had stable disease (SD), and 12 (40%) exhibited progressive disease after two cycles of treatment. Overall median survival time was 9.1 months. For Child-Pugh A patients (N=20), median survival time was 10.9 months. Asian patients had a higher overall 12-month survival rate than non-Asians. QoL data implied that the HCC patients’ quality of life does not deteriorate significantly during the combination therapy.    Based on the median survival time and QoL data obtained with Child-Pugh A patients in this study, additional Phase II studies in which patients treated with the combination of capecitabine and PHY906 are compared to those treated with sorefinib (recently-approved for HCC treatment) appear warranted.
Mutations in KATNB1 Cause Complex Cerebral Malformations by Disrupting Asymmetrically Dividing Neural Progenitors
Authors: Ketu Mishra-Gorur, Ahmet Okay Çağlayan, Ashleigh E. Schaffer, Chiswili Chabu, Octavian Henegariu, Fernando Vonhoff, Gözde Tuğce Akgümüş, Sayoko Nishimura, Wenqi Han, Shu Tu, Burçin Baran, Hakan Gümüş, Cengiz Dilber, Maha S. Zaki, Heba A.A. Hossni, Jean-Baptiste Rivière, Hülya Kayserili, Emily G. Spencer, Rasim Ö. Rosti, Jana Schroth, Hüseyin Per, Caner Çağlar, Çağri Çağlar, Duygu Dölen, Jacob F. Baranoski, Sefer Kumandaş, Frank J. Minja, E. Zeynep Erson-Omay, Shrikant M. Mane, Richard P. Lifton, Tian Xu, Haig Keshishian, William B. Dobyns, Neil C. Chi, Nenad Šestan, Angeliki Louvi, Kaya Bilgüvar, Katsuhito Yasuno, Joseph G. Gleeson, Murat Günel
Journal: Neuron (2015)
Abstract 111: Blood Lipoproteins May Be Implicated in Blood Pressure Regulation
Authors: Janna Lendner, Stephan Krohn, Agnes Jumar, Daniel Grün, Andreas Zakrzewicz, Eugeny Ermilov, Günter Siegel
Journal: Circulation Research (2013)

Background: An increase in triglycerides, which comprise the main component of VLDL, belongs to definition criteria of the metabolic syndrome. We investigated the influence of VLDL (30 mg/dL) on flow-dilatation without and with α- (10 -7 mol/L) and β-blockers (10 -7 mol/L) to find out whether the VLDL effect is partly due to a possible α- and β-receptor interaction. Methods: Isometric tension, membrane potential and cAMP-cGMP were measured in 16 coronaries from heart transplantations. Results: Flow-dependent relaxation of 0.432 g in Krebs solution (T 3 - T 100 ) was reduced under VLDL by 15.3% to 0.366 g, and under VLDL + α/β-blockers by 20.1% to 0.345 g, thus practically no change. However, calculation of the difference in tension for the individual flow rates between Krebs and VLDL on the one hand, and Krebs and VLDL + α/β-blockers on the other, results in significant differences (Table). Setting the difference between Krebs and VLDL equal to 100%, leads to a 12.2% to 45.4% change in difference under α/β-blockers. Experiments under blockers yielded that α-receptor blockade alone is sufficient to explain the reduction of the VLDL-effect. β-effects were reflected by variation in [cAMP], α-effects in [cGMP]. Conclusion: About one third of the constricting VLDL-effect is due to a direct VLDL-inhibition of the β- receptor and/or stimulation of the α- receptor. We prove for the first time that blood lipoproteins exert their influence on arterial tone also via an interaction with the autonomic nervous system. We conclude that blood lipids may be implicated in blood pressure regulation. This unveiling could help in navigating the treatment options of both hypertension and hypercholesterolemia.
Analysis of MET expression in primary tumors and corresponding metastases in non-small cell lung cancer (NSCLC).
Authors: Babak Tamjid, Tom John, Carmel Murone, Khashayar Asadi, Simon Knight, Paul Mitchell
Journal: Journal of Clinical Oncology (2014)

e22197 Background: Hepatocyte Growth Factor and its corresponding receptor MET are potential therapeutic targets. In NSCLC MET is over expressed, activated and mutated and is involved in resistance to tyrosine kinase inhibitors. A high proportion of primary NSCLC cases show elevated MET expression on immunohistochemistry (IHC), however, it is not clear whether expression changes during the metastatic process. We investigated paired biopsies to determine whether MET receptor expression alters between primary NSCLC and its corresponding metastases. Methods: Tissue Microarrays (TMAs) were constructed using 1mm cores of primary and metastatic matched NSCLC archival paraffin tissues in triplicate. For IHC, TMAs were stained with the SP44 clone (Ventana) and an H-score calculated based on the percentage of cells stained and their intensity with a minimum of 0 and maximum of 300. The mean of triplicate values were calculated. Two independent scorers assessed the tissues. Discordance was defined as an H-score difference of greater than 100 between the primary and its metastasis. Results: Sixty one patients were included in the study with 38 (62%) male and brain the most common site of metastasis (27/61, 44%). Of these, 26 patients had adenocarcinoma, 21 had squamous cell and 14 had mixed NSCLC. The median H-score was 100 in primary tissue and 120 in metastatic tissue. Brain secondaries showed the highest median H-score (140) compared with other sites of the metastasis (105). The MET concordance rate was 82%. MET discordance between primary and secondary tumours was found in 11/61 tumours including 6/26 (23%) of adenocarcinomas, 2/21 (10%) of squamous carcinomas and 3/14 (21%) of mixed or large cell tumours. Discordant elevation in metastases was present in 6/61 (10 %) and reduction in 5/61 (8%). In 4 out of 11 discordant cases a complete loss of MET expression was observed in metastases. Conclusions: In this cohort of paired biopsies, increased MET expression in the primary was retained in a high proportion of metastases. These data indicate that MET expression in metastases can be predicted by expression in the primary and further suggests that treatment decisions can be based on archival primary tumour MET IHC results.
Collaborative research and development
Authors: Salvador Moncada
Journal: Journal of the Royal Society of Medicine (1998)

Professor Salvador Moncada was born in Honduras. He received a medical degree in El Salvador and came to London in 1971 to do a PhD on the mode of action of aspirin-like drugs at The Royal College of Surgeons. He joined the Wellcome Research Laboratories in 1975 where he worked on the unstable metabolites of arachidonic acid. He obtained a DSc in 1983 and in 1986 was appointed Director of Research at Wellcome. In 1988 he was made a Fellow of the Royal Society and in 1994 he became a Fellow of the Royal College of Physicians as well as a foreign member of the National Academy of Sciences of the USA. In the last decade his major research interest has been the biology of nitric oxide, a substance that he discovered in the cardiovascular system in 1987. In 1995 he became Director of the Cruciform project for Strategic Medical Research at UCL. He has published over 700 papers and edited a number of books on nitric oxide.
Clinical Relevant Alterations Identified By Comprehensive Genomic Profiling Can Potentially Improve Therapeutic Option and Change Prognosis in Hematologic Malignancies
Authors: Jie He, Minal Patel, Irene Phillip, Mark Bailey, Ellin Berman, Jae H. Park, Neerav N Shukla, Stephen S. Chung, Hugo Castro-Malaspina, Dan Douer, Michelle Nahas, Geoff Otto, Jo-Anne Vergilio, Tariq I Mughal, Jeff Ross, Phil Stephens, Martin S. Tallman, Vincent A. Miller, Marcel van den Brink, Doron Lipson, Ross L. Levine
Journal: Blood (2016)
Methods and Reporting Studies Assessing Fecal Microbiota Transplantation
Authors: Aïda Bafeta, Amelie Yavchitz, Carolina Riveros, Rui Batista, Philippe Ravaud
Journal: Annals of Internal Medicine (2017)

Fecal microbiota transplantation (FMT) could be a novel treatment option for several chronic diseases associated with altered gut microbiota.To examine the conduct and reporting of studies assessing FMT.Cochrane Central Register of Controlled Trials, PubMed, EMBASE, and Web of Science from inception to 31 January 2017.Two reviewers independently examined titles and abstracts to identify all English-language reports of human clinical studies assessing the safety or efficacy of FMT.Three reviewers independently assessed study types and characteristics and the reporting of important methodological components of the FMT intervention.Most (84%) of the 85 published reports found addressed the use of FMTs for Clostridium difficile infection or inflammatory bowel disease, and most (87%) were non-randomized controlled trials. Important methodological components that were not reported in published studies included the following: eligibility criteria for donors (47%), materials used for collecting stools and the period of collection (96%), methods used for conservation of stools (76%), the amount and type of stools used (for example, fresh or frozen), and duration of stool conservation (67%). Many (58%) did not report an analysis of microbiota composition.Lack of universal consensus regarding the most important methodological components of FMT and inability to assess the actual conduct of studies and whether the publication process affected the completeness of reporting.Key components of FMT interventions, which are necessary to replicate and understand study findings about efficacy and safety, are poorly reported.No specific funding.