tbuckley/cabot-search huggingface dataset:
Open‐Label, Phase II Study to Assess the Efficacy and Safety of Canakinumab Treatment in Active Hyperimmunoglobulinemia D With Periodic Fever Syndrome
Authors: Juan I. Arostegui, Jordi Anton, Inmaculada Calvo, Angel Robles, Estibaliz Iglesias, Berta López‐Montesinos, Romain Banchereau, Seunghee Hong, Yolandi Joubert, Guido Junge, Virginia Pascual, Jordi Yagüe
Journal: Arthritis & Rheumatology (2017)

Objective To evaluate the efficacy and safety of canakinumab treatment in active hyperimmunoglobulinemia D with periodic fever syndrome (HIDS). Methods This was a 3‐part open‐label study with an initial 6‐month treatment period in which patients with HIDS (n = 9) received canakinumab subcutaneously at a dose of 300 mg (or 4 mg/kg for those weighing ≤40 kg) every 6 weeks (period 1 [P1]), followed by a 6‐month withdrawal period (period 2 [P2]), and then a 24‐month extension treatment period with canakinumab at the same dose (period 3 [P3]). The primary end point was reduction in the frequency of attacks during treatment periods as compared to the historical period (HP; defined as the period in which patients did not receive drugs other than nonsteroidal antiinflammatory drugs and/or steroids). Results All 9 patients completed P1 and P2, whereas only 8 patients completed P3. All patients achieved a complete response during P1, and only 2 required dose adjustments. The number of attacks per patient decreased from a median of 5 (range 3–12) during the HP to a median of 0 (range 0–2) during P1. During P2, 7 of 9 patients experienced a disease flare within a median of 110 days (range 62–196) after the last canakinumab dose. Laboratory findings were normalized by day 15 of treatment and remained at normal levels throughout the study. Analysis of blood transcriptome profiles, assessed during P1, showed up‐regulated levels of interferon and myeloid‐related inflammatory responses in untreated patients compared to healthy controls, and these rapidly decreased following canakinumab injection, reaching levels comparable to those of healthy controls. At least 1 adverse event (AE) was detected in all 9 patients. Most of the AEs were mild in intensity, with infections being the most frequent AE. Serious AEs were reported in 4 patients. Conclusion The results of this study demonstrate the efficacy and safety of canakinumab treatment to control active HIDS and to suppress inflammation‐related transcriptional responses.
A First-in-Human, Phase I, Dose-Escalation Study of TAK-117, a Selective PI3Kα Isoform Inhibitor, in Patients with Advanced Solid Malignancies
Authors: Dejan Juric, Johann S. de Bono, Patricia M. LoRusso, John Nemunaitis, Elisabeth I. Heath, Eunice L. Kwak, Teresa Macarulla Mercadé, Elena Geuna, Maria Jose de Miguel-Luken, Chirag Patel, Keisuke Kuida, Serap Sankoh, Eric H. Westin, Fabian Zohren, Yaping Shou, Josep Tabernero
Journal: Clinical Cancer Research (2017)

Purpose: To evaluate the safety, MTD, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of TAK-117 (MLN1117/INK1117), an investigational PI3Kα-selective inhibitor, in patients with advanced solid tumors.Experimental Design: Seventy-one patients received oral TAK-117 once daily [100-300 mg (n = 24)] or 3 days per week [Monday-Wednesday-Friday (MWF), 200-1,200 mg (n = 27); Monday-Tuesday-Wednesday (MTuW), 200-900 mg (n = 20)], in 21-day cycles. Dose escalation proceeded via a 3 + 3 design.Results: TAK-117 once-daily dosing was associated with dose-limiting grade ≥3 alanine/aspartate aminotransferase (ALT/AST) elevations, resulting in a narrow range of tolerable doses (100-150 mg once daily). With MWF/MTuW dosing, no dose-limiting ALT/AST elevations occurred until the MTD of 900 mg; total weekly dose was 2.6-fold that of 150 mg once daily. Drug-related grade ≥3 adverse events occurred in 25%/22%/35% (including hyperglycemia in 0%/7%/15%) of once-daily/MWF/MTuW patients. TAK-117 (100-1,200 mg) exhibited moderately fast oral absorption, a generally dose proportional increase in exposure, and plasma half-life of approximately 11 hours. Total weekly exposures with 900 mg MWF/MTuW dosing were approximately 4 times greater than with 150 mg once daily. Skin pS6 expression was suppressed at ≥200 mg. There were 3/1/0 partial responses (once daily/MWF/MTuW) and 5/7/5 patients had stable disease lasting ≥3 months (all PIK3CA mutated).Conclusions: Intermittent dosing of TAK-117 had an acceptable safety profile and enabled higher doses and total weekly exposures versus once-daily dosing. Although the potential for TAK-117 as single-agent therapy appears limited, further evaluation in combination approaches for advanced solid tumors is warranted. Clin Cancer Res; 23(17); 5015-23. ©2017 AACR.
The Endothelin Receptor Etb Plays a Crucial Role for Recruitment of Neutrophils to the Vascular Wall in Sickle Cell Disease
Authors: Bérengere Koehl, Pierre Nivoit, Wassim El Nemer, Catia Pereira, Valentine Brousse, Lea Guyonnet, Anna Chipont, Olivia Lenoir, Malika Benkerrou, Yves Colin Aronovicz, Pierre-Louis Tharaux, Caroline Le Van Kim
Journal: Blood (2016)
Human hepatocellular carcinomas with a periportal phenotype have the lowest potential for early recurrence after curative resection
Authors: Romain Désert, Florian Rohart, Frédéric Canal, Marie Sicard, Mireille Desille, Stéphanie Renaud, Bruno Turlin, Pascale Bellaud, Christine Perret, Bruno Clément, Kim-Anh Lê Cao, Orlando Musso
Journal: Hepatology (2017)

Hepatocellular carcinomas (HCCs) exhibit a diversity of molecular phenotypes, raising major challenges in clinical management. HCCs detected by surveillance programs at an early stage are candidates for potentially curative therapies (local ablation, resection, or transplantation). In the long term, transplantation provides the lowest recurrence rates. Treatment allocation is based on tumor number, size, vascular invasion, performance status, functional liver reserve, and the prediction of early (&lt;2 years) recurrence, which reflects the intrinsic aggressiveness of the tumor. Well‐differentiated, potentially low‐aggressiveness tumors form the heterogeneous molecular class of nonproliferative HCCs, characterized by an approximate 50% β‐catenin mutation rate. To define the clinical, pathological, and molecular features and the outcome of nonproliferative HCCs, we constructed a 1,133‐HCC transcriptomic metadata set and validated findings in a publically available 210‐HCC RNA sequencing set. We show that nonproliferative HCCs preserve the zonation program that distributes metabolic functions along the portocentral axis in normal liver. More precisely, we identified two well‐differentiated, nonproliferation subclasses, namely periportal‐type (wild‐type β‐catenin) and perivenous‐type (mutant β‐catenin), which expressed negatively correlated gene networks. The new periportal‐type subclass represented 29% of all HCCs; expressed a hepatocyte nuclear factor 4A–driven gene network, which was down‐regulated in mouse hepatocyte nuclear factor 4A knockout mice; were early‐stage tumors by Barcelona Clinic Liver Cancer, Cancer of the Liver Italian Program, and tumor–node–metastasis staging systems; had no macrovascular invasion; and showed the lowest metastasis‐specific gene expression levels and TP53 mutation rates. Also, we identified an eight‐gene periportal‐type HCC signature, which was independently associated with the highest 2‐year recurrence‐free survival by multivariate analyses in two independent cohorts of 247 and 210 patients. Conclusion: Well‐differentiated HCCs display mutually exclusive periportal or perivenous zonation programs. Among all HCCs, periportal‐type tumors have the lowest intrinsic potential for early recurrence after curative resection. (H epatology 2017;66:1502–1518).
Safety and efficacy of anti-CD19 chimeric antigen receptor (CAR)-modified autologous T cells (CTL019) in advanced multiple myeloma.
Authors: Alfred L. Garfall, Marcela Valderrama Maus, Simon F. Lacey, Yolanda D. Mahnke, Jan J. Melenhorst, Zhaohui Zheng, Dan T. Vogl, Adam D. Cohen, Brendan M. Weiss, Karen Dengel, Naseem D.S. Kerr, Wei-Ting Hwang, Bruce Levine, Carl H. June, Edward Allen Stadtmauer
Journal: Journal of Clinical Oncology (2015)

8517 Background: CTL019, a 2nd-generation anti-CD19 CAR transduced via lentiviral vector, can induce regression of refractory B cell malignancies. Though multiple myeloma (MM) is reported to be CD19-negative, we hypothesized that CTL019 would exhibit efficacy in MM due to low-level CD19 expression on MM plasma cells (PC) or CD19 expression in drug-resistant, disease-propagating subsets of the MM clone. Here, we report initial results of an ongoing phase 1 study of CTL019 in patients with advanced MM. Methods: MM patients are eligible if they experienced disease progression within one year of a prior autologous stem cell transplantation (ASCT) and are medically fit to undergo second ASCT. Study therapy consists of 1-5x107CTL019 cells infused 12-14 days after high-dose melphalan + ASCT. Results: 4 subjects have been treated and have completed 30-220 days of follow-up. Median prior lines of therapy is 7.5 (range 3-10). 3/4 have unfavorable cytogenetics; 1/4 had PC leukemia. Adverse events have included hypogammaglobulinemia (4/4) and grade 1 cytokine release syndrome (1/4). 3 subjects are evaluable for response. In all 3 subjects, CTL019 engraftment was achieved (peak 0.1-0.6% of peripheral blood T cells at days 30-42), and B cells were not detectable by flow cytometry in blood or marrow at day 42. At day 100, subject #1 attained MRD-negative stringent complete response (CR), and Subject #2 attained MRD-negative unconfirmed (due to unevaluable bone marrow core) CR. Response duration in Subject #1 has surpassed the response duration after this subject's prior ASCT (i.e., remission inversion). 99.95% of Subject #1's MM PC were CD19-negative by flow cytometry and RTPCR, indicating that efficacy in this subject is not due to direct cytotoxicity of CTL019 against the dominant MM PC population. Subject #3 experienced disease progression at day 43. Updated results on the first 5 subjects will be presented. Conclusions: Preliminary data suggest that CTL019 can be manufactured from and safely administered to refractory MM patients. CTL019 can engraft and induce B cell aplasia after salvage ASCT. Ongoing, deep responses in 2 of 3 evaluable subjects are encouraging with respect to potential efficacy. Clinical trial information: NCT02135406.
Viral load at 15 days after liver transplantation as a good predictor of fast liver fibrosis progression
Authors: M. Llorens, J. Gregori, C. Dopazo, F. Rodriguez-Frías, D. Garcia-Cehic, M.E. Soria, C. Perales, S. Bergamo, G. Ruiz, Q. Chen, L. Ordeig, R. Esteban, J.I. Esteban, J. Quer, I. Bilbao
Journal: Journal of Hepatology (2017)
High efficacy and tolerability of hepatitis C genotype 2 treatment with direct-acting antivirals in real world: analysis of the Hepa-C Registry
Authors: E.B. Aranda, Z. Mariño, S. Calvo, J.A. Carrión, I. Fernández, J. García-Samaniego, C. Baliellas, J.M. Pascasio, A. Albillos, C.F. Carrillo, A.C. Iglesias, J.M.M. Planas, C.P. Giner, J.J.M. Palomares, J. Llaneras, J. Arenas, M. Fernández-Bermejo, C. Fernández, R.M.G. Lopez, P.B. García, M. Romero-Gómez, F. Sáez-Royuela
Journal: Journal of Hepatology (2017)
Smart Nanobiomaterials: Remote Control of Cellular Functions: The Role of Smart Nanomaterials in the Medicine of the Future (Adv. Healthcare Mater. 9/2017)
Authors: Giada Graziana Genchi, Attilio Marino, Agostina Grillone, Ilaria Pezzini, Gianni Ciofani
Journal: Advanced Healthcare Materials (2017)

In article number 1700002, Giada Graziana Genti, Gianni Ciofani, and co-workers describe the most recent and exciting developments related to the field of nanomedicine that relies on the control of cell functions through physical remote manipulation mediated by smart nanoparticles. Piezoelectric materials with micrometric and nanometric surface structuring provide smart interfaces to actively tune biological environment responses towards a favourite phenotype. Here, high-pressure hydrothermal conversion of corrugated titanium dioxide into barium titanate produces repeated microstructures mimicking Phalaenopsis genus morphology, working as anchoring points for neurons and active sites for voltage-gated calcium channel opening under mechanical stimulation.
Longitudinal changes in liver stiffness by magnetic resonance elastography (MRE), liver fibrosis, and serum markers of fibrosis in a multi-center clinical trial in nonalcoholic steatohepatitis (NASH)
Authors: R. Loomba, E. Lawitz, R. Ghalib, M. Elkhashab, S. Caldwell, M. Abdelmalek, K. Kowdley, R. Xu, G. Chen, C.S. Djedjos, R.P. Myers, G.M. Subramanian, Z. Goodman, M. Charlton, C. Sirlin, M.S. Middleton
Journal: Journal of Hepatology (2017)
Normal values of liver stiffness as measured by transient elastography: pooled individual participant data meta-analysis from 26 studies and 14,883 participants
Authors: F. Bazerbachi, S. Haffar, Z. Wang, J.C. González, M.T. Arias-Loste, J. Crespo, S. Darwish-Murad, M.A. Ikram, S. Petta, A. Berzuini, D. Prati, V. de Lédinghen, V. Wong, P. Del Poggio, N.C. Chávez-Tapia, Y.-P. Chen, P.-N. Cheng, M.-F. Yuen, K. Das, A. Chowdhury, L. Caballería, N. Fabrellas, P. Ginès, M. Kumar, S.K. Sarin, F. Conti, P. Andreone, R. Sirli, H. Cortez-Pinto, S. Carvalhana, T. Sugihara, S.-U. Kim, P. Parikh, K. Chayama, C. Corpechot, K.-M. Kim, G. Papatheodoridis, A. Alsebaey, J.K. Olynyk, E. Gan, P. Kamath, K.D. Watt, M.H. Murad
Journal: Journal of Hepatology (2017)
A recurring theme in pulmonary fibrosis genetics
Authors: Paul J. Wolters
Journal: European Respiratory Journal (2017)

In 1980, the question "Is there a fibrotic gene?" was posed in an editorial [1] commenting on a report about pulmonary fibrosis in monozygotic twins. Over the next 37 years, the identification of kindreds of families with pulmonary fibrosis and advances in DNA sequencing provided answers to this question. An early example of a gene associated with pulmonary fibrosis involved a case of familial pulmonary fibrosis (FPF) that was linked to a heterozygous mutation in the surfactant protein C (SFTPC) gene, which is expressed predominantly by alveolar type-II (ATII) cells in the lung [2]. This was followed by reports that mutations in other ATII cell associated genes (ABCA3 and SFTPA) had been identified in patients with FPF. Similarly, candidate gene and whole-genome linkage scanning approaches identified mutations in TERT and TERC, two genes required for telomere maintenance, in kindreds of pulmonary fibrosis patients. These findings were followed by the association of other genes involved in telomere maintenance (DKC1, RTEL1, PARN, TIN2, and NAF1) to FPF. Overall, mutations in these ten ATII cell and telomere associated genes are predicted to account for up to 25% of genes associated with FPF [3, 4], which can present as different clinical syndromes including idiopathic pulmonary fibrosis (IPF), chronic hypersensitivity pneumonitis, pleuroparenchymal fibroelastosis, interstitial pneumonia with autoimmune features, or idiopathic nonspecific interstitial pneumonia [5, 6]. Genetic abnormalities in epithelial and telomere-associated genes contribute to the development of lung fibrosis <http://ow.ly/dx1q30aCL4V>
The Rapid Evolution of an Ohnolog Contributes to the Ecological Specialization of Incipient Yeast Species
Authors: Chris Eberlein, Lou Nielly-Thibault, Halim Maaroufi, Alexandre K Dubé, Jean-Baptiste Leducq, Guillaume Charron, Christian R Landry
Journal: Molecular Biology and Evolution (2017)

Identifying the molecular changes that lead to ecological specialization during speciation is one of the major goals of molecular evolution. One question that remains to be thoroughly investigated is whether ecological specialization derives strictly from adaptive changes and their associated trade-offs, or from conditionally neutral mutations that accumulate under relaxed selection. We used whole-genome sequencing, genome annotation and computational analyses to identify genes that have rapidly diverged between two incipient species of Saccharomyces paradoxus that occupy different climatic regions along a south-west to north-east gradient. As candidate loci for ecological specialization, we identified genes that show signatures of adaptation and accelerated rates of amino acid substitutions, causing asymmetric evolution between lineages. This set of genes includes a glycyl-tRNA-synthetase, GRS2, which is known to be transcriptionally induced under heat stress in the model and sister species S. cerevisiae. Molecular modelling, expression analysis and fitness assays suggest that the accelerated evolution of this gene in the Northern lineage may be caused by relaxed selection. GRS2 arose during the whole-genome duplication (WGD) that occurred 100 million years ago in the yeast lineage. While its ohnolog GRS1 has been preserved in all post-WGD species, GRS2 has frequently been lost and is evolving rapidly, suggesting that the fate of this ohnolog is still to be resolved. Our results suggest that the asymmetric evolution of GRS2 between the two incipient S. paradoxus species contributes to their restricted climatic distributions and thus that ecological specialization derives at least partly from relaxed selection rather than a molecular trade-off resulting from adaptive evolution.
Effectiveness, safety and quality of life in patients treated with Ombitasvir/Paritaprevir/r ± Dasabuvir ± Ribavirin under real-life conditions – data from the German observational study LIFE-C
Authors: P. Buggisch, U. Naumann, R. Link, C. Antoni, G. Teuber, J. Huelsenbeck, K. Lohmann, M.R. Kraus
Journal: Journal of Hepatology (2017)
Prevalence of infection with multiple strains of hepatitis C virus (HCV) in patients enrolled in HCV clinical trials
Authors: T.M. Welzel, M. Ryan, C. Hedskog, N. Bhardwaj, R.H. Hyland, R. Martin, L.M. Stamm, D.M. Brainard, H. Mo, E. Svarovskaia, R.G. Nahass, E.R. Schiff, C. Katlama
Journal: Journal of Hepatology (2017)
Erratum: The 'battering syndrome': Prevalence and clinical characteristics of domestic violence in primary care internal medicine practices (Annals of Internal Medicine (1995) 123 (737-746))
Authors: J. McCauley, D. E. Kern, K. Kolodner, L. Dill, A. F. Schroeder, H. K. DeChant
Journal: Annals of Internal Medicine (1996)
Frequent mutations in <i>MLH1</i>, <i>MET</i>, <i>KIT</i>, <i>PDGFRA</i>, and <i>PIK3CA</i> genes in human gastrointestinal stromal tumors.
Authors: Zhi Xu, Xinying Huo, Chuanning Tang, Hua Ye, Feng Lou, Si-Yi Chen, Jinfei Chen
Journal: Journal of Clinical Oncology (2013)

10544 Background: Identifying mutations in individual tumor is critical to improve the efficacy of cancer therapy by matching targeted drugs to specific mutations. Gastrointestinal stromal tumor (GIST) is a stromal or mesenchymal subepithelial neoplasm affecting the gastrointestinal tract and it frequently contains an activating mutation in either the KIT or platelet-derived growth factor A (PDGFRA) gene. Although GIST is highly responsive to several selective tyrosine kinase inhibitors, combined use of inhibitors targeting other mutations is needed to further prolong survival. Methods: In this study, we aim to screen and identify genetic mutations in GIST for targeted therapy using the new Ion Torrent next-generation sequencing platform. Results: By utilizing the Ion Ampliseq Cancer Panel, we sequenced 737 loci from 45 cancer-related genes from DNA extracted from formalin-fixed and paraffin-embedded (FFPE) samples of 125 human gastrointestinal stromal tumors, set up stringent parameters for reliable variant calling by filtering out potential raw base calling errors, and identified frequent mutations in PDGFRA, KIT, APC, MLH1, MET, RET, and PIK3CA. Moreover, frequent missense mutations were detected in MLH1 (12%), MET (16.8%), KIT (51.2%), and PIK3CA (41.6%) genes. The mutations in MLH1 gene were frequently detected in the exon 14, while MET gene was frequently mutated in the exon 2. In addition, we identified missense mutations in other genes, including FLT3, KRAS, PDGFRA, and STK11, at lower frequencies. Conclusions: This study demonstrates the utility of using Ion Torrent sequencing to efficiently identify human cancer mutations. With the finding of the frequent mutations in MLH1 and MET genes, in addition to KIT, PDGFRA and PIK3CA, in GISTs, this study provides a molecular basis for clinically developing new drugs targeting these gene mutations for GIST therapy.
Breath analysis for early detection of lung cancer.
Authors: Geetha D. Vallabhaneni, Sheryl G. A. Gabram, Kichun Sky Lee, Taofeek Kunle Owonikoko, Johann Christoph Brandes, Scott Arthur Kono, Nabil F. Saba, Fadlo Raja Khuri, Suresh S. Ramalingam, Charlene W. Bayer
Journal: Journal of Clinical Oncology (2012)

7048 Background: Lung cancer (LC) is the leading cause of cancer death worldwide. Early detection is critical to reduce LC related mortality. Breath analysis can be used as a non invasive diagnostic tool in conjunction with CT screening. We assessed the diagnostic value of breath volatile organic compounds (BVOCs) in the alveolar breath of female non-small cell lung cancer (NSCLC) patients. Methods: This is a prospective case-control study that enrolled newly diagnosed NSCLC and cancer-free female controls. The study aims: 1) To compare the BVOC signature in female NSCLC patients to a control group without LC 2) To compare the BVOC signature between NSCLC and breast cancer (BC) patients. The study was restricted to women because the pilot data was generated from female subjects with BC. Consenting eligible patients provided a total of five deep breath samples into a proprietary breath sampler developed at the Georgia Tech Research Institute (GTRI) for collecting alveolar breath. Breath samples were collected five minutes apart from each subject. The collected samples were analyzed for BVOCs using thermal desorption/gas chromatographic/mass spectrometric (TD/GC/MS) technique. Statistical differences in BVOCs in breath samples from cases and controls were assessed using this technique. Support vector machine classification method was employed to compare the BVOCs pattern between LC and BC patients. Results: We enrolled 25 NSCLC and 25 cancer-free subjects. TD/GC/MS analysis identified a total of 422 BVOCs among the controls and NSCLC subjects. 75 unique BVOCs that were significantly different between cases and controls were employed for statistical modeling. This 75 BVOCs signature has a sensitivity of 0.75, a specificity of 0.75 and a classification accuracy of 75% for NSCLC and controls. Statistical analysis on the full BVOCs data set from NSCLC and previously collected BVOCs data from BC patients achieved a classification accuracy of 88%. Conclusions: Unique BVOCs pattern can identify patients with established NSCLC. Future studies in at-risk patients will assess the utility of this approach as a less invasive and minimal risk screening tool for early detection of NSCLC. Supported by the Kennedy Seed Grant awarded by the Winship Cancer Institute of Emory University.
Investigating the contribution of genetic risk variants to Attention 1 Deficit/Hyperactivity Disorder trajectories in the general population
Authors: Lucy Riglin, Stephen Collishaw, Ajay K Thapar, Soren Dalsgaard, Kate Langley, George Davey Smith, Evangelia Stergiakouli, Barbara Maughan, Michael O'Donovan, Anita Thapar
Journal: JAMA Psychiatry (2016)
Neutrophil-to-lymphocyte ratio as an independent predictor of mortality in critically ill cirrhotic patients
Authors: M. Giabicani, C. Lemaitre, E. Weiss, S. Grange, D. Carpentier, G. Beduneau, C. Girault, H. Montialoux, G. Riachi, O. Goria, C. Paugam-Burtz, F. Tamion
Journal: Journal of Hepatology (2017)