tbuckley/cabot-search huggingface dataset:
An open, multicentre, randomized clinical study in patients with bullous pemphigoid comparing methylprednisolone and azathioprine with methylprednisolone and dapsone
Authors: M. Sticherling, A. Franke, E. Aberer, R. Gläser, M. Hertl, C. Pfeiffer, B. Rzany, S. Schneider, I. Shimanovich, T. Werfel, A. Wilczek, D. Zillikens, E. Schmidt
Journal: British Journal of Dermatology (2017)

Current treatment of bullous pemphigoid (BP) is based on the long‐term use of topical and/or systemic corticosteroids, which are associated with a high rate of adverse events and increased mortality. To study the corticosteroid‐sparing potential of azathioprine and dapsone. This was a prospective, multicentre, randomized, nonblinded clinical trial that compared the efficacy and safety of two parallel groups of patients with BP treated with oral methylprednisolone 0·5 mg kg−1 per day in combination with either azathioprine 1·5–2·5 mg kg−1 per day or dapsone 1·5 mg kg−1 per day. Nine German and Austrian departments of dermatology included 54 patients based on clinical lesions, positive direct immunofluorescence (IF) microscopy and detection of serum autoantibodies by indirect IF microscopy, immunoblotting or enzyme‐linked immunosorbent assay. The primary end point was the time until complete tapering of methylprednisolone, and the most important secondary end point was the cumulative corticosteroid dose. In eight patients (five azathioprine, three dapsone), methylprednisolone could be discontinued after a median time of 251 days in the azathioprine group and 81 days in the dapsone group. The median cumulative corticosteroid dose was 2·65 g for azathioprine compared with 1·92 g for dapsone (P =0·06). The median numbers of days when corticosteroids were applied were 148 and 51, respectively (P =0·24). No significant difference in the number of adverse events was seen between the treatment arms. Four patients (8%) died within the observation period of 12 months. Due to the lower than intended number of patients, the results of the primary and secondary end points were not or only barely significant. Dapsone appeared to have a moderately higher corticosteroid‐sparing potential than azathioprine. The combination regimen of either drug with oral methylprednisolone is associated with a relatively low 1‐year mortality in this vulnerable patient population.
Does in-house availability of multidisciplinary teams increase survival in upper GI cancer?
Authors: Christian Kersten, Milada Cvancarova, Geir Boehler, Svein Mjaaland, Odd Mjaaland
Journal: Journal of Clinical Oncology (2012)

4066 Background: Treatment of esophageal, gastric and pancreatic cancers (UGI) is recommended to be discussed by a multidisciplinary team (MDT), despite lack of evidence that this approach leads to increased survival. In 2001, a cancer centre with irradiation and chemotherapy facilities was established in the Norwegian county of West Agder (WA), providing the potential for local in-house MDT meetings. Our primary objective was to evaluate the effect of the establishment of in-house MDT availability (iMDTa) on survival in a cohort of UGI patients in WA. We compared survival figures for WA with those of other Norwegian counties with complete, less complete and without iMDTa. Methods: We defined “iMDTa” as a single administrative institution with all departments on one campus, serving the population of one county. We compared cause-specific survival rates for 2000-04 and 2005-08 for UGI patients living in counties with (MDT-Yes), without (MDT-No) and with a mix (MDT-mix) of iMDTa, with the county of WA which had a change in iMDTa (MDT-Change) during the study period. Crude survival was modelled with Kaplan-Meier method and Cox regression analysis was used to adjust for age and region (sex and stage distributions were similar in all counties). Results: We analyzed 12530 UGI patients living in five Norwegian regions. Median age was 74 (17-98) yrs and median follow-up was 5 (0-138) months. The regions with the highest level of iMDTa achieved the largest increases in survival, compared to the counties with limited or no iMDTa. Median overall survival for all UGI patients in WA/MDT-Change increased from 129 to 300 days from 2000-8, p=0.001. Compared to the county with MDT-Mix, the county with MDT-Change reached a statistically significant reduction in the risk of death (HR) for both esophageal (1.12- 0.60) and stomach cancers (0.87-0.63), but not for pancreatic cancers (1.04-1.01). Conclusions: In parallel with an increasing use of in-house MDT, we found a striking and more than two-fold increase in survival in the Norwegian county of WA/MDT-Change. This survival gain is partly explained by increased use of chemotherapy. During the same time period, no increase in survival was found in the MDT-No or MDT-Mix counties.
Colonic mucosal DNA methylation, immune response, and microbiome patterns in Toll-like receptor 2-knockout mice
Authors: Dorottya Nagy-Szakal, Richard Kellermayer
Journal: Gut Microbes (2011)

The stunning complexity of the resident microbiota and the intricate pathways of microbial and host interactions provide a massive adaptive capacity for mammals. In this addendum we reflect on our recent publication on Toll-like receptor 2 deficiency related colonic mucosal epigenetic, immunologic and microbiomic changes. Our findings underscored the tremendous flexibility of the gut and its microbiota. This flexibility can provide means to overcome significant environmental or genetic challenges. In the meantime, the challenged intestinal system may become vulnerable to otherwise tolerable insults. In such instances, the fine-tuned mutualistic balance between the gut and its microflora may collapse leading to dysbiosis and disease. The ultimate challenge for biomedical research in these cases is to find optimal means for the restoration and maintenance of healthy host physiology.
Development of LMB763, a novel, orally bioavailable, clinical farnesoid X receptor agonist for the treatment of non-alcoholic steatohepatitis and hepatobiliary disorders
Authors: B. Laffitte, B. Liu, Y. Kim, D. Bao, J. Zoll, X. Wu, M. Badman, J. Nelson, P. Rucker, X. Liu, D. Chianelli, D. Tully, J. Roland, V. Molteni
Journal: Journal of Hepatology (2017)
Induction of an aggressive phenotype and poor survival in early-stage lung adenocarcinoma and epigenetic inactivation of microRNA-34b/c.
Authors: Ernest Nadal, Marc Gallegos, Guoan Chen, Ramon Palmero, Gabriel Capella, Felipe Cardenal, David G. Beer
Journal: Journal of Clinical Oncology (2013)

11056 Background: The microRNA-34b/c (miR-34b/c) is a transcriptional target of TP53 that is frequently mutated in primary lung adenocarcinoma (AC). We investigated the clinical implications of miR-34b/c methylation in early stage lung AC patients and the functional role of miR-34b/c re-expression in lung AC cell lines. Methods: DNA methylation of miR-34b/c promoter was assessed by real-time PCR temperature dissociation in 15 lung AC cell lines and 140 early stage lung AC resected at the Bellvitge Hospital (Barcelona) and at the University of Michigan (Ann Arbor). Patient characteristics: 65% males, 88% smokers, 68.5% stage I and 31.5% stage II. Expression of miR-34b/c was determined by TaqMan RT-PCR. Two lung AC cell lines (NCI-H1838 and SK-LU-1) were transfected with an expression vector containing both miRs and the effects upon cell proliferation, migration and invasion were determined. Results: MiR-34b/c was methylated in 40% of cell lines and in 46% of primary tumors with significant association with higher tumor stage (P=0.033), recurrence (P=0.017) and death (P=0.005). In the training set (n=58), patients with higher levels of miR-34b/c methylation had significantly shorter median DFS (28.5 months) compared to low to medium levels (not reached, log-rank P=0.016). In the test set (n=82), higher levels of miR-34b/c methylation were also associated to shorter median DFS (19 months) compared to patients with low to medium levels (not reached, log-rank P=0.005). MiR-34b/c methylation remained an independent prognostic marker for DFS after adjusting by age, gender and stage. Tumors harboring TP53 mutations and miR-34b/c methylation expressed significantly lower levels of miR-34b/c (P≤0.001). Stable cells expressing miR-34b/c had lower proliferation rate relative to cells transfected with empty vector (P≤0.001). Expressing miR-34b/c in SK-LU-1 cells reduced migration and invasion ability. Conclusions: Epigenetic inactivation of miR-34b/c by DNA methylation is an independent prognostic marker in early stage lung AC. Ectopic expression of miR-34b/c generated a less aggressive phenotype in lung AC cell lines suggesting a potential for therapeutic targeting.
Genetic analysis of PSORS1 single nucleotide polymorphisms in guttate psoriasis and palmoplantar pustulosis.
Authors: M Allen, K Asumalahti, M Ameen, J Evans, C Veal, J Leman, A D Burden, C E M Griffiths, R C Trembath, J Kere, J N W N Barker
Journal: British Journal of Dermatology (2002)
FOXA2 overexpressed adipose derived stem cells attenuated acute liver injury model
Authors: Y.J. Chae, D.W. Jun, S.B. Ahn, W.K. Saeed, J.S. Lee, H.W. Oh, J.Y. Jeong, H.T. Kang, J.H. Sohn, E.C. Jang
Journal: Journal of Hepatology (2017)
Nivolumab in sorafenib-experienced patients with advanced hepatocellular carcinoma (HCC) with or without chronic viral hepatitis: CheckMate 040 study
Authors: B. Sangro, T. Yau, C. Hsu, M. Kudo, T.S. Crocenzi, S.-P. Choo, T. Meyer, T.H. Welling, W. Yeo, A. Chopra, A. Baakili, C. dela Cruz, L. Lang, J. Neely, I. Melero, A.B. El-Khoueiry, J. Trojan
Journal: Journal of Hepatology (2017)
Efficient Prophylaxis with Defibrotide for Sinusoidal Obstruction Syndrome (SOS) after Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)
Authors: Yves Chalandon, Federico Simonetta, Carole Dantin, Aikaterini Koutsi, Anne-Claire Mamez, Yan Beauverd, Olga Tsopra, Audrey Simon, Stijn Bex, Caroline Stephan, Juan Felipe Rodriguez Morales, Karolina Polchlopek, Marc Ansari, Yordanka Tirefort, Eddy Roosnek, Stavroula Masouridi-Levrat
Journal: Blood (2016)
Methotrexate-induced epidermal necrosis: A case series of 24 patients
Authors: Ting-Jui Chen, Wen-Hung Chung, Chun-Bing Chen, Rosaline Chung-Yee Hui, Yu-Huei Huang, Yueh-Tsung Lu, Chang-Wei Wang, Kuo-Hsien Wang, Li-Cheng Yang, Shuen-Iu Hung
Journal: Journal of the American Academy of Dermatology (2017)
A randomized, prospective, phase II study to determine the efficacy of BCG given in combination with panvac versus BCG alone in adults with high grade non-muscle invasive bladder cancer who failed at least one induction course of BCG.
Authors: Sam Joseph Brancato, Lambros Stamatakis, Andrea Borghese Apolo, Sarah Fowler, Jeffrey Schlom, James L. Gulley, Piyush K. Agarwal
Journal: Journal of Clinical Oncology (2014)

TPS4590 Background: High grade non-muscle invasive bladder cancer (NMIBC) has a 70% recurrence rate and rate of 15-30% progression. The standard of care is an induction course of bacillus Calmette-Guerin (BCG). A second induction course can be used in patients who fail the initial course, however only 35% of patients will experience a 12 month disease free survival. For those patients failing a second induction course, radical cystectomy is the gold standard treatment, although the morbidity rate is high. Therefore there is an unmet need for localized treatment for patients who fail an initial induction course of BCG. Recently, a pox viral vector-based vaccine, PANVAC, has been shown to induce a CD4 and CD8 antigen-specific immune response against the tumor-associated antigens, carcinoembryonic antigen (CEA) and mucin-1 (MUC-1). This vaccine also contains transgenes for three human T cell co-stimulatory molecules that can potentially augment an immune response. We hypothesize that the combined administration of BCG and PANVAC may augment the BCG-induced cytotoxic T lymphocyte response against bladder cancer cells expressing MUC-1 and/or CEA and potentially reverse BCG failure. MUC-1 is over-expressed in 93% and CEA is over-expressed in 76% of high grade bladder tumors and therefore PANVAC may enhance BCG response. Methods: This is a randomized, prospective Phase II study in subjects with NMIBC who have failed at least one induction course of intravesical BCG. Patients will be randomized to one of the following arms: BCG + PANVAC or BCG alone. All subjects will receive intravesical BCG as per usual standard of care once weekly for a total of 6 weeks. The combination arm will receive the pox viral vaccines (rV-PANVAC and rFPANVAC) that contain the transgenes for CEA and MUC-1 as well as 3 human T-cell costimulatory molecules. We will test the hypothesis that subjects in the BCG + PANVAC arm have a better disease-free survival at 12 months than subjects in the BCG alone arm. Secondary endpoints include disease progression, treatment-related toxicities, and immunologic correlates. Clinical trial information: NCT02015104.
C reactive protein contributes to the early prediction of 90-day mortality risk in acutely decompensated cirrhotic patients
Authors: A. Clemente, M. Romero, C. Martínez, A. Bueno, M. Antona, M. Salcedo, A. Fernández, M.V. Catalina, G. Clemente, D. Rincón, R. Bañares
Journal: Journal of Hepatology (2017)
Effect of hepatitis E virus infection on the human hepatic innate immune response in human liver chimeric mice
Authors: I.M. Sayed, L. Verhoye, L. Cocquerel, F. Abravanel, L. Foquet, C. Montpellier, Y. Debing, A. Farhoudi, C. Wychowski, J. Dubuisson, G. Leroux-Roels, J. Neyts, J. Izopet, T. Michiels, P. Meuleman
Journal: Journal of Hepatology (2017)
Concurrent driver mutations in non-small cell lung cancer (NSCLC) patients (p) on targeted therapy uncovered by comprehensive molecular profiling.
Authors: Collin M. Blakely, Luping Lin, Saurabh Asthana, Nikoletta Sidiropoulos, Tyrrell Nelson, Boris C. Bastian, Matthew A. Gubens, Barry S. Taylor, Trever Grant Bivona
Journal: Journal of Clinical Oncology (2013)

11004 Background: NSCLC p with EGFR mutations respond initially to EGFR tyrosine kinase inhibitors (TKIs) but invariably develop acquired EGFR TKI resistance. Prior studies identified the EGFR T790M mutation and activation of MET, PI3K, AXL, HER2 and the MAPK pathway as drivers of acquired EGFR TKI resistance. To date, comprehensive molecular profiling to identify actionable modifiers of EGFR TKI response has not been conducted in NSCLC p on therapy. Methods: We performed next generation sequencing (NGS) using a 263-gene Nimblegen custom cancer panel on DNA isolated from primary patient lung adenocarcinoma FFPE specimens prior to initiating standard erlotinib treatment and upon the development of acquired erlotinib resistance after only 3 months of therapy. Results: In the pretreatment sample, we confirmed the presence of the EGFRL858R mutation in 95% of the sequencing reads and discovered a concurrent BRAF V600E mutation with a frequency of ~ 6%. NGS performed on the acquired erlotinib resistance sample revealed acquisition of the EGFR T790M mutation with a frequency of ~ 14%. Notably, the frequency of the BRAF V600E mutation increased 10-fold upon acquired erlotinib resistance from ~ 6% in the pretreatment tumor to ~ 60% in the recurrent tumor. We found that overexpression of BRAF V600E in H3255 human NSCLC, which harbor EGFR L858R (but not BRAF V600E) and are erlotinib sensitive, caused resistance to erlotinib treatment (10-fold increase in erlotinib IC50). BRAF V600E-mediated erlotinib resistance was reversed by treatment with the BRAF inhibitor vemurafenib. Additional functional studies are ongoing and the complete dataset will be presented. Conclusions: These results indicate that EGFR-mutant NSCLC can harbor additional oncogenic driver mutations in BRAF at low frequencies prior to therapy. EGFR TKI treatment can lead to expansion of BRAF V600E expressing tumor cells, resulting in acquired EGFR TKI resistance that can be reversed by BRAF inhibitor treatment. The data demonstrate the utility of routine molecular profiling of NSCLC p on targeted therapy and offer unprecedented insight into the genetic basis of therapeutic resistance.
A phase II study of durvalumab (MEDI4736) for previously treated patients with stage IV squamous NSCLC (SqNSCLC): Lung-MAP Sub-study SWOG S1400A
Authors: V. Papadimitrakopoulou, M.W. Redman, H. Borghaei, S.N. Waqar, F. Robert, G.J. Kiefer, S. McDonough, R.S. Herbst, K. Kelly, D.R. Gandara
Journal: Annals of Oncology (2017)
Nuclear NFATc1 Causes Development of Fms-like Receptor Tyrosine Kinase 3 Receptor (FLT3) Internal Tandem Duplication Mutation-Positive (FLT3-ITD) Acute Myeloid Leukemia (AML) and Mediates Drug Resistance
Authors: Maria A. Solovey, Ying Wang, Stefan Gattenloehner, Elisabeth Hessmann, Stephan Metzelder, Christian Michel, Volker Ellenrieder, Joachim R. Goethert, Andreas Neubauer, Andreas Burchert
Journal: Blood (2016)
Natural History of Relapsed Myeloma, Refractory to Immunomodulatory Drugs and Proteasome Inhibitors: A Multicenter IMWG Study
Authors: Shaji Kumar, Meletios A Dimopoulos, Efstathios Kastritis, Evangelos Terpos, Hareth Nahi, Hartmut Goldschmidt, Jens Hillengass, Xavier Leleu, Meral Beksac, Melissa Alsina, Albert Oriol, Michele Cavo, Enrique M. Ocio, Maria Victoria Mateos, Elizabeth K. O'Donnell, Ravi Vij, Henk M. Lokhorst, Niels W.C.J. van de Donk, Chang-Ki Min, Tomer Mark, Ingemar Turesson, Markus Hansson, Heinz Ludwig, Sundar Jagannath, Michel Delforge, Charalampia Kyriakou, Parameswaran Hari, Ulf-Henrik Mellqvist, Saad Z Usmani, Dominik Dytfeld, Ashraf Z Badros, Philippe Moreau, Kihyun Kim, Paula Rodriguez Otero, Jae Hoon Lee, Chaim Shustik, Daniel Waller, Wee Joo Chng, Shuji Ozaki, Je-Jung Lee, Javier de la Rubia, Hyeon Seok Eom, Laura Rosinol, Juan José Lahuerta, Anna Sureda, Jin Seok Kim, Brian G.M. Durie
Journal: Blood (2016)
Declining prevalence and increasing awareness of hepatitis C virus infection in Italy: a population-based survey
Authors: A. Andriulli, T. Stroffolini, M.R. Valvano, I. Grattagliano, A.M. Ippolito, A. Grossi, G. Brancaccio, C. Coco, M. Russello, A. Smedile, E. Petrini, S. Martini, G.B. Gaeta, M. Rizzetto
Journal: Journal of Hepatology (2017)
Repeated biopsy for mutational analysis on EGFR-mutated non-small cell lung cancer (EGFR-NSCLC): Feasibility and safety
Authors: G. Anguera, M. Riudavets, A. Torrego, V. Pajares, A. Gimenez, L. López-Vilaró, E. Martínez, J.C. Trujillo-Reyes, E. Lerma, M. Majem
Journal: Annals of Oncology (2017)
The role of integrin-linked kinase in the regulation of the Wnt signaling pathway
Authors: Arusha Oloumi, Shoukat Dedhar
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

3932 

Wnt pathways are involved in the control of many biological processes by acting through a core set of proteins that are highly conserved in evolution. The Wnt gene family encodes secreted signaling molecules, which play important roles in tumorigenesis and embryonic development. The downstream effect of this pathway is stabilization of the cytoplasmic pool of β-catenin and its nuclear translocation resulting in the regulation of a number of genes that modulate cell fate, proliferation and apoptosis. In addition, activation of integrin-linked kinase (ILK) has also been implicated in the regulation of β-catenin and its nuclear translocation. ILK is an ankyrin repeat containing serine-threonine protein kinase that can interact directly with the cytoplasmic domains of β1 and β3 integrin subunits. Over-expression of ILK has been shown to result in the translocation of β-catenin to the nucleus, formation of a complex between β-catenin and LEF, a high mobility transcription factor, and transcriptional activation by this LEF/β-catenin complex in mammary epithelial cells. Therefore, the downstream effect of both ILK and Wnt signalling pathways is the regulation of genes through activation of LEF/β-catenin transcription complex. In an attempt to determine whether ILK is a required component of the Wnt signaling pathway we have been able to show that molecular and pharmacological inhibition of ILK interferes with Wnt3a-mediated stabilization of β-catenin. In this study stabilization of β-catenin and activation of LEF/β-catenin transcription complex in L and HEK 293 cells was achieved by treatment with Wnt3a condition medium. However, transient transfection of the dominant negative form of ILK, which has a very limited kinase activity, or treatment with ILK inhibitors, which also blocks the kinase activity of ILK resulted in the inhibition of Wnt3a-induced activation of β-catenin demonstrated by western blot and a promoter-reporter luciferase assay. Deregulation of ILK by constitutive activation and/or over-expression has already been shown to inhibit the activity of GSK-3β in mammary epithelial cells. Therefore, these findings suggest that ILK is a required component of the canonical Wnt pathway by working upstream of GSK-3β and possibly as a kinase involved in the hyperphosphorylation of dvl, the downstream component of the Wnt transmembrane receptor. The understanding of the molecular mechanism behind the interaction between these two pathways particularly in cancer progression could lead to identification of novel therapeutic targets.
Early initiation of carvedilol is safe and cost effective in cirrhotic patients presenting with upper GI bleed following endoscopic therapy: results of a prospective randomized trial
Authors: A. Salim, M.O. Farooq, F.U.A. Mengal, A. Masood, K. Malik, A.K. Butt, A. Alam
Journal: Journal of Hepatology (2017)
Abstract IA29: Targeting undruggable proteins for degradation with small molecules
Authors: William G. Kaelin
Journal: Clinical Cancer Research (2017)

Abstract Many well-studied oncoproteins are currently viewed to be “undruggable”. The infamous teratogen thalidomide was serendipitously discovered to be a potent antimyeloma drug in the 1990s but its mechanism of action was unknown. In 2010 thalidomide was shown by Handa and coworkers to bind to cereblon, which is the substrate-recognition subunit of a cullin-dependent ubiquitin ligase. Moreover, thalidomide was found to inhibit this ligase in vitro, suggesting that thalidomide is a cereblon antagonist. However, it soon became apparent that loss of cereblon rendered myeloma cells resistant to thalidomide (and related drugs such as lenalidomide, collectively referred to as IMiDs). This suggested to us that cereblon, once bound to an IMiD, acquires a new (neomorphic) ability to target a myeloma-relevant protein for destruction. To look for such a protein we built a bicistronic expression vector that encodes both a protein open reading frame (ORF)-firefly luciferase fusion protein and, from the same mRNA, renilla luciferase for normalization purposes, with both proteins under the control of an internal ribosomal entry site (IRES). We then made a library of ~12,000 such ORF-luciferase fusions and introduced them into 293T cells in quadruplicate in multiwell plate format (1 ORF/well), treated the cells with lenalidomide or vehicle, and monitored changes in firefly luciferase/renilla luciferase as a surrogate for changes in ORF stability. In this way we discovered that cereblon, once bound to lenalidomide, destabilizes IKZF1 and IKZF3. We went on to show that downregulation of IKZF1 and IKZF3 is intimately linked to the antimyeloma activity of the IMiDs. Ben Ebert and his group working in parallel and using complimentary approaches reached the same conclusion. Published and unpublished work from investigators such as Jay Bradner and Craig Crews suggests IMiDs can be reengineered to serve as molecular matchmakers between cereblon and novel targets. We are currently developing new screening methodologies to identify chemicals and genetic perturbants that directly or indirectly destabilize proteins of interest. Citation Format: William G. Kaelin, Jr. Targeting undruggable proteins for degradation with small molecules. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA29.