tbuckley/cabot-search huggingface dataset:
Indirect treatment comparison of dabrafenib plus trametinib versus vemurafenib plus cobimetinib in previously untreated metastatic melanoma patients
Authors: Adil Daud, Japinder Gill, Sheily Kamra, Lei Chen, Amit Ahuja
Journal: Journal of Hematology & Oncology (2017)

Metastatic melanoma is an aggressive form of skin cancer with a high mortality rate and the fastest growing global incidence rate of all malignancies. The introduction of BRAF/MEK inhibitor combinations has yielded significant increases in PFS and OS for melanoma. However, at present, no direct comparisons between different BRAF/MEK combinations have been conducted. In light of this, an indirect treatment comparison was performed between two BRAF/MEK inhibitor combination therapies for metastatic melanoma, dabrafenib plus trametinib and vemurafenib plus cobimetinib, in order to understand the relative efficacy and toxicity profiles of these therapies. A systematic literature search identified two randomized trials as suitable for indirect comparison: the coBRIM trial of vemurafenib plus cobimetinib versus vemurafenib and the COMBI-v trial of dabrafenib plus trametinib versus vemurafenib. The comparison followed the method of Bucher et al. and analyzed both efficacy (overall survival [OS], progression-free survival [PFS], and overall response rate [ORR]) and safety outcomes (adverse events [AEs]). The indirect comparison revealed similar efficacy outcomes between both therapies, with no statistically significant difference between therapies for OS (hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.68 − 1.30), PFS (HR 1.05, 95% CI 0.79 − 1.40), or ORR (risk ratio [RR] 0.90, 95% CI 0.74 − 1.10). Dabrafenib plus trametinib differed significantly from vemurafenib plus cobimetinib with regard to the incidence of treatment-related AE (RR 0.92, 95% CI 0.87 − 0.97), any AE grade ≥3 (RR 0.71, 95% CI 0.60 − 0.85) or dose interruption/modification (RR 0.77, 95% CI 0.60 − 0.99). Several categories of AEs occurred significantly more frequently with vemurafenib plus cobimetinib, while some occurred significantly more frequently with dabrafenib plus trametinib. For severe AEs (grade 3 or above), four occurred significantly more frequently with vemurafenib plus cobimetinib and no severe AE occurred significantly more frequently with dabrafenib plus trametinib. This indirect treatment comparison suggested that dabrafenib plus trametinib had comparable efficacy to vemurafenib plus cobimetinib but was associated with reduced adverse events.
Prognostic Factors in Adult Patients up to 60 Years with AML and Translocations of Chromosome 11q23: Individual Patient Data Based Analysis of the German AML-Intergroup.
Authors: Jürgen Krauter, Katharina Wagner, Irina Schäfer, Rolf Marschalek, Claus Meyer, Gerhard Heil, Markus Andreas Schaich, Gerhard Ehninger, Dietger W. Niederwieser, Rainer Krahl, Thomas Buchner, Cristina Sauerland, Brigitte Schlegelberger, Konstanze Dohner, Hartmut Dohner, Richard Schlenk, Arnold Ganser
Journal: Blood (2007)
Abstract 15727: Platelet Inhibition With Ticagrelor and Clopidogrel in Comatose Survivors of Out-of-Hospital Cardiac Arrest
Authors: Klemen Steblovnik, Ales Blinc, Mojca B Mijovski, Misa Fister, Ursa Mikuz, Marko Noc
Journal: Circulation (2015)

Comatose survivors of out-of-hospital cardiac arrest (OHCA) nowadays frequently undergo immediate percutaneous coronary intervention (PCI) which is associated with the need for antiplatelet therapy with P2Y12 inhibitors. In the present study we investigated platelet inhibition in 19 comatose survivors of OHCA undergoing PCI and hypothermia (32-34 o C) who were randomized to clopidogrel 600 mg loading followed by 75 mg/day (n=6) or ticagrelor 180 mg loading followed by 90mg bid (n=13) administered as crushed and dissolved tablets via nasogastric tube. Platelet inhibition was measured by VerifyNow® and Multiplate® aggregometry at baseline, and 2, 4, 12, 22 and 48 hours after loading dose. VerifyNow® revealed greater platelet inhibition with ticagrelor becoming statistically significant 12 hours after the loading (Figure). Also Multiplate ADPtest revealed greater platelet inhibition after ticagrelor at 4 hours (21.5±13.9 vs. 38.7±16.8, p=0.03), 12 hours (15.4±12.0 vs. 36.3±8.7, p&lt;0.01) and 22 hours (14.3±6.1 vs. 26.3±4.3, p&lt;0.01). Accordingly, our preliminary results indicate that ticagrelor has faster and stronger antiplatelet effect than clopidogrel during the initial 48 hours of postresuscitation phase and maybe a P2Y12 of choice in comatose survivors of OHCA undergoing PCI.
The Prognosis of Limited Stage Peripheral T-Cell Lymphoma (PTCL): A Population-Based Analysis and Comparison to Diffuse Large B-Cell Lymphoma (DLBCL)
Authors: Kerry Joanne Savage, Hilary M O'Leary, Joseph M Connors, Mukesh Chhanabhai, Belinda Campbell, Laurie H Sehn, Randy D. Gascoyne, R. Gregory Bociek, James O. Armitage, Dennis D. Weisenburger, Julie M. Vose, Martin Bast, Philip Bierman
Journal: Blood (2010)
Experience with colorectal cancer: Analysis of patient web forums.
Authors: Kathy Beusterien, Sarah Tsay, Yun Su, Mitra Corral, Shadi Gholizadeh, Samuel Wagner
Journal: Journal of Clinical Oncology (2012)

496 Background: Patient-reported outcomes are typically collected through structured questionnaires. Patient web forums provide a unique opportunity for patients to spontaneously post their experiences and thoughts about diseases and treatments. This study explored the impact of colorectal cancer (CRC) treatments in these forums. Methods: This was a cross-sectional qualitative analysis of web data. Two of the most active CRC web forums were identified using 4 criteria: site active for &gt; 5 years, &gt; 12,000 total posts on the forum, &gt;20 individuals currently browsing, and &gt; 10 new posts/day. All posts posted in Jul and Dec 2010 and Feb-Mar 2011 on the two forums were abstracted for review and coding using MaxQDA software. Results: A total of 1,654 posts, posted by 264 individuals, were identified on the two CRC web forums. Demographic and /or tumor information were identified for 83% of the posters. Of these, 83% were CRC patients and 17% were family members; 76% were females, and the mean age of the patients was 49 years. The majority had advanced cancer (44% stage IV or metastatic, 40% stage III). The most common topics were a variety of side effects (62.3% of posts), treatment response (13%), and impact on personal, social, and work lives, income and life styles, and resulting emotional distress (23.9%). The posters came to the online forums in part to have an emotional outlet. Another key motive was sharing experiences and seeking advice. Formal knowledge regarding the likelihood of response, magnitude of benefit, or side effects was absent however, leading to senses of uncertainty, anxiety, sometimes shock, and unrealistic expectations. On balance, although patients reported difficulties being on treatment, they also expressed resilience and appreciation for the availability of treatment options and the hope they provide. Conclusions: Online CRC communities provide patients with convenient and valuable emotional support and disease and treatment information. The profound impact of CRC and treatments goes beyond efficacy, toxicity, and structured quality of life scores. Systematic information and decision tools are needed to minimize uncertainties and help patients manage expectations and emotional distress.
Gene Expression Profiling for Molecular Features of Response in a Phase I Trial of Alisertib Plus Romidepsin for Relapsed/Refractory Aggressive B- and T-Cell Lymphomas
Authors: Michelle A. Fanale, Zhiqiang Wang, Wencai Ma, Yasuhiro Oki, Fredrick B. Hagemeister, Luis E. Fayad, Nathan Fowler, Jorge E. Romaguera, Nina Shah, Hubert H Chuang, Feng Lei, Sandra B. Horowitz, Dai Chihara, Emily Wesson, Toni Y Hutto, Charnelle Ruben, Felipe Samaniego, Tariq Muzzafar, Richard Piekarz, R Eric Davis
Journal: Blood (2015)
Abstract 457: Depletion of glioma infiltrating myeloid derived suppressor cells promotes anti-tumor T cell responses
Authors: Neha Kamran, Youping Li, Mariela Moreno-Ayala, Hikmat Assi, Marianela Candolfi, Marta Dzaman, Pedro Lowenstein, Maria Castro
Journal: Cancer Research (2015)

Abstract MDSCs represent a population of immature myeloid cells at various stages of differentiation that have the potential to inhibit anti-tumor T cell immunity. We demonstrate the accumulation of MDSCs in GL26 and M7-induced glioma (GBM) bearing mice. Absolute numbers of Ly-6G+ (Gr-1high) MDSCs showed a 200 fold increase within the tumor microenvironment (TME) 28 days post-tumor implantation. The numbers of Ly-6C+ (Gr-1low) MDSCs also showed a similar trend within the TME. While this massive influx of MDSCs was noted within intracranial tumors, MDSC levels did not increase in the dLNs, spleen or bone marrow (BM) of intracranial tumor bearing mice. MDSC numbers were significantly elevated in the blood of GL26 and M7 intracranial tumor bearing mice at 28 days. While both Gr-1high and Gr-1low MDSCs isolated from the TME of GL26 intracranial tumor bearing mice inhibited antigen-specific T cell proliferation, Gr-1low MDSC were found to be more efficient. Gr-1high or Gr-1low MDSCs from the bone marrow of intracranial tumor bearing mice failed to suppress antigen-specific T cell proliferation suggesting that TME derived factors may activate MDSCs to exert their immune-suppressive properties. In vivo, depletion of Gr-1+ cells enhanced the median survival of GBM bearing mice. Furthermore, when combined with Ad-TK + Ad-FLT3L immune-gene therapy, Gr-1+ depletion significantly enhanced the frequency of tumor-specific T cells within the TME and spleen and increased IFN-γ production by splenic T cells. Our data therefore indicates that inhibiting the accumulation of MDSCs with in the GBM TME promotes the generation of robust anti-tumor immunity. Preliminary experiments to determine the mechanism of MDSC trafficking to the TME point towards the receptor CXCR2 and its ligand CXCL1. Microarray analysis of glioma cell lines showed elevated levels of CXCL1 mRNA. Additionally a culture of primary mixed glial cells also produced CXCL1 when stimulated with GBM cell lysates. SB225002, a CXCR2 inhibitor suppressed the migration of MDSCs towards GBM cells in an in vitro migration assay. Overall, our data suggests that strategies that inhibit MDSC recruitment to the GBM TME and/or block their activity could enhance the T cell mediated tumor clearance and provide survival benefit. Work supported by grants from NIH-NINDS Citation Format: Neha Kamran, Youping Li, Mariela Moreno-Ayala, Hikmat Assi, Marianela Candolfi, Marta Dzaman, Pedro Lowenstein, Maria Castro. Depletion of glioma infiltrating myeloid derived suppressor cells promotes anti-tumor T cell responses. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 457. doi:10.1158/1538-7445.AM2015-457
591. The OTTC Plasmid Manager: A Comprehensive Database for Archiving Plasmid DNA Sequence
Authors: Emily J. Heathward, Giun Sun, Ron U. Domingo, Calvin A. Thomas, Christopher T. Richie, Brandon Harvey
Journal: Molecular Therapy (2016)

A freely available plasmid database that is interoperable with popular freeware (such as a Plasmid Editor, or ApE [1]) has been developed for our research group. Our group has accrued a wealth of data that can no longer be efficiently analyzed without a comprehensive cataloging system. The OTTC Plasmid Manager provides an intuitive plasmid database with analytical and search capabilities, offering a versatile platform for the storage and organization of plasmid sequences and their associated metadata. The database has been designed with informatics and visualization support to enhance the efficiency and analytic capabilities of the user, with a user-friendly interface. Annotations performed in ApE can be imported directly into the database, and unlike most commercially available and free DNA editing software, the Plasmid Manager also includes a mechanism to standardize the annotations of uploaded sequences, facilitating the direct comparison of multiple plasmids at the feature level. The visualization component generates a graphic representation of the plasmid map together with its features and annotations, allowing the visual comparison of multiple plasmids side-by-side. The contents of the database can be browsed and searched using a variety of criteria, including plasmid name, database accession number and associated features. This innovative plasmid database presents a new platform for molecular biologists to catalog plasmids relevant to their laboratory, saving time and enhancing the analytical capabilities of researchers. [1] Davis W. A Plasmid Editor. Retrieved September 9, 2014, from http://biologylabs.utah.edu/wayned/ape/
OSU-DY7, a Novel D-Tyrosinol Derivative, Mediates Cytotoxicity in Chronic Lymphocytic Leukemia and Lymphoblastic Lymphoma through p38 Mitogen-Activated Protein Kinase Pathway.
Authors: Li-Yuan Bai, Yihui Ma, Samuel K Kulp, Shu-Huei Wang, Chang-Fang Chiu, Frank Frissora, Xiaokui Mo, David Jarjoura, John C. Byrd, Ching-Shih Chen, Natarajan Muthusamy
Journal: Blood (2009)
503. Minimally Effective Dose of Systemic AAV8-MTM1 Needed To Prolong Survival and Correct Severe Muscle Pathology in a Canine Model of X-Linked Myotubular Myopathy
Authors: David L. Mack, Karine Poulard, Melissa Goddard, Jessica M. Snyder, Robert W. Grange, Jon Doering, Stefan Czerniecki, Jennifer L. Strande, Virginie Latournerie, Philippe Veron, Hui Meng, Lin Yang, Fujun Liu, Christine Le Bec, Laurine Buscara, Samia Martin, Philippe Moullier, Michael O'Callaghan, Federico Mingozzi, Alan H. Beggs, Michael W. Lawlor, Anna Buj-Bello, Fulvio Mavilio, Martin K. Childers
Journal: Molecular Therapy (2015)

Mutations in the myotubularin gene (MTM1) result in X-linked myotubular myopathy (XLMTM), a fatal pediatric disease characterized by small centrally nucleated myofibers. Patients typically present with severe hypotonia and respiratory failure. We previously reported that administration of adeno-associated virus serotype 8 vector (AAV8) expressing myotubularin under the muscle-specific desmin promoter delivered intravenously (i.v.) in Mtm1-KO mice and by regional hind limb perfusion in myotubularin-deficient dogs prolonged life and restored muscle function. Here we report the results of an i.v. dose escalation study testing the efficacy of AAV8-MTM1 in XLMTM dogs. Five groups were studied: Normal controls (N=6); affected dogs given saline only (N=4) or affected dogs given AAV8-MTM1 at the following dosages: (5E12 vg/kg, N=3), (2.5E13 vg/kg, N=3) or (8E13 vg/kg, N=3). AAV8-MTM1 was administered at 10 weeks of age and dogs were followed for 9 months. Blinded analyses included limb strength, gait, respiratory function, neurological assessment, histology, vector biodistribution, transgene expression and immune response over the nine month study. Pathology characteristic of XLMTM was moderately improved in the 5E12 vg/kg dosed group and was dramatically improved in the animals receiving (2.5E13 vg/kg) or (8E13 vg/kg) doses of AAV.
Abstract 574: CD133 and LGR5 characterize stem-cell like subtype of colorectal cancer
Authors: Luka Stanisavljevic, Mette Pernille Myklebust, Olav Dahl
Journal: Cancer Research (2015)

Abstract Background: Colorectal cancer (CRC) has recently been divided into six subtypes with cluster mRNA expression analysis. The subtype characterized as stem-like subtype exhibit the highest degree of stemness with poorest prognosis. Prominin-1 (CD133) and leucine-rich-repeat-containing G protein-coupled receptor (LGR5) mark cancer stem cells. High CD133 expression is associated with higher rate of metastases and disease progression. In mouse models, tumor cells expressing CD133 are enriched in chemotherapeutic-resistant colorectal cancer. LGR5+ cells characterize fast-cycling columnar-based stem cells of colon which are instrumental in neoplasia formation. Further, the LGR5+ cells are associated with metastasis formation. Material and methods: A prospective randomized multicenter randomized trial in Norway recruited from December 1992 to October 1996. 412 colorectal cancer patients stage II and III were treated with surgery alone or 5-fluoruracil (5-FU) and levamisole (Lev) after surgical resection. The patients were followed up by routine clinical examination until five years after surgery. We constructed tissue microarrays from 409 patient samples. CD133 protein expression was assessed by mouse anti-CD133 ([clone AC133], Miltenyi Biotec, Bergisch Gladbach, Germany) at a dilution 1:10. LGR5 mRNA expression was assessed by RNAscope 2.0 HD Detection Kit-Brown (Advanced Cell Diagnostics, Hayward, CA, USA). Results: Colon cancer stage III patients negative for CD133 had better five-year disease-free survival (DFS) when they received 5-FU/Lev (P = .016). In contrast, the patients did not respond to adjuvant therapy when CD133 was expressed (P = .500). LGR5 was a prognostic marker for colon cancer stage II (P = .045). In colon stage III, mRNA expression of LGR5 was associated with better DFS (P = .046) and patients with positive LGR5 responded to chemotherapy (P = .025). In stage II, LGR5 mRNA expression was associated with lower tumor diameter (P = .005), while in stage III there was no statistically significant association. In conclusion, CD133 expression was associated with chemotherapy resistance in the colon stage III cohort. LGR5 was associated with a metastatic phenotype in CRC stage II and colon cancer stage III. In addition, LGR5 expression predicted response to chemotherapy in colon cancer stage III. Citation Format: Luka Stanisavljevic, Mette Pernille Myklebust, Olav Dahl. CD133 and LGR5 characterize stem-cell like subtype of colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 574. doi:10.1158/1538-7445.AM2015-574
Outcome of Treatment for Relapsed Acute Lymphoblastic Leukemia in Children with Down Syndrome
Authors: Franziska Meyr, Fabian Baumann, Gabriele Escherich, Georg Mann, Thomas Klingebiel, Andreas E Kulozik, Claudia Rossig, Martin Schrappe, Guenter Henze, Arend von Stackelberg, Johann K. Hitzler
Journal: Blood (2012)
Abstract 4997: Phosphorylation of SLAP by the KIT-D816V oncogenic mutant suppresses SLAP-mediated negative regulation of KIT signaling
Authors: Julhash U. Kazi, Jianmin Sun, Lars Rönnstrand
Journal: Cancer Research (2015)

Abstract The SRC-like-adaptor protein (SLAP) is a negative regulator of mitogenic signaling. SLAP shares considerable structural homology with SRC, apart from lacking a kinase domain. SLAP is known to be expressed in a variety of cells and regulates cell surface receptor signaling by direct association. Here we show that SLAP interacts with the type III receptor tyrosine kinase KIT and also with its oncogenic mutant KIT-D816V. This mutant has been described as a driving mutant in several cancers including mastocytosis and certain types of acute myeloid leukemia. The association is mediated through phosphotyrosine residues in KIT and the SLAP-SH2 domain. Despite high structural similarity between SLAP and SRC, these tyrosine residues are different from the ones mediating SRC binding to KIT. This association results in increased ubiquitination and degradation of KIT. siRNA-mediated depletion of SLAP selectively potentiates wild-type KIT downstream signaling but not KIT-D816V signaling. Although SLAP displays similar localization pattern with both ligand-stimulated KIT and KIT-D816V, only KIT-D816V can phosphorylate SLAP on three tyrosine residues (Y120, Y258 and Y273). This phosphorylation takes place when SLAP interacts with KIT-D816V. Mutations on these tyrosine residues in SLAP restores normal SLAP regulation on oncogenic KIT-D816V. Taken together, our data suggest that the oncogenic mutant of KIT can bypass normal cellular regulation of signaling by phosphorylating regulatory proteins such as SLAP. Citation Format: Julhash U. Kazi, Jianmin Sun, Lars Rönnstrand. Phosphorylation of SLAP by the KIT-D816V oncogenic mutant suppresses SLAP-mediated negative regulation of KIT signaling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4997. doi:10.1158/1538-7445.AM2015-4997
The Bi-Specific T-Cell Enhancer (BiTE) MT103 (MEDI-538) Induces Clinical Responses in Heavily Pre-Treated NHL Patients: Update from the Ongoing Phase I Study MT103-104.
Authors: Ralf Bargou, R. Noppeney, M. Schuler, G. Hess, Ch Gerecke, F. Zettl, J. Birkmann, A. Viardot, P. Kirchinger, P. Baeuerle, C. Reinhardt, M. Klinger, M. Libicher, M. Goebeler, H. Einsele, P. Kufer, G. Zugmaier, E. Leo
Journal: Blood (2006)
Deferasirox Treatment for up to 3 Years in Iron-Overloaded Pediatric Patients Reduces Serum Ferritin with a Manageable Safety Profile
Authors: Amal El-Beshlawy, Mohsen Elalfy, Lee Lee Chan, Yongrong Lai, Kai-Hsin Lin, Yesim Aydinok, Renzo Galanello, Ali El-Ali, Nicolas Martin, M Domenica Cappellini
Journal: Blood (2012)
Shortened Antimicrobial Treatment for Acute Otitis Media in Young Children
Authors: Alejandro Hoberman, Jack L. Paradise, Howard E. Rockette, Diana H. Kearney, Sonika Bhatnagar, Timothy R. Shope, Judith M. Martin, Marcia Kurs-Lasky, Susan J. Copelli, D. Kathleen Colborn, Stan L. Block, John J. Labella, Thomas G. Lynch, Norman L. Cohen, MaryAnn Haralam, Marcia A. Pope, Jennifer P. Nagg, Michael D. Green, Nader Shaikh
Journal: New England Journal of Medicine (2016)

Limiting the duration of antimicrobial treatment constitutes a potential strategy to reduce the risk of antimicrobial resistance among children with acute otitis media.We assigned 520 children, 6 to 23 months of age, with acute otitis media to receive amoxicillin-clavulanate either for a standard duration of 10 days or for a reduced duration of 5 days followed by placebo for 5 days. We measured rates of clinical response (in a systematic fashion, on the basis of signs and symptomatic response), recurrence, and nasopharyngeal colonization, and we analyzed episode outcomes using a noninferiority approach. Symptom scores ranged from 0 to 14, with higher numbers indicating more severe symptoms.Children who were treated with amoxicillin-clavulanate for 5 days were more likely than those who were treated for 10 days to have clinical failure (77 of 229 children [34%] vs. 39 of 238 [16%]; difference, 17 percentage points [based on unrounded data]; 95% confidence interval, 9 to 25). The mean symptom scores over the period from day 6 to day 14 were 1.61 in the 5-day group and 1.34 in the 10-day group (P=0.07); the mean scores at the day-12-to-14 assessment were 1.89 versus 1.20 (P=0.001). The percentage of children whose symptom scores decreased more than 50% (indicating less severe symptoms) from baseline to the end of treatment was lower in the 5-day group than in the 10-day group (181 of 227 children [80%] vs. 211 of 233 [91%], P=0.003). We found no significant between-group differences in rates of recurrence, adverse events, or nasopharyngeal colonization with penicillin-nonsusceptible pathogens. Clinical-failure rates were greater among children who had been exposed to three or more children for 10 or more hours per week than among those with less exposure (P=0.02) and were also greater among children with infection in both ears than among those with infection in one ear (P<0.001).Among children 6 to 23 months of age with acute otitis media, reduced-duration antimicrobial treatment resulted in less favorable outcomes than standard-duration treatment; in addition, neither the rate of adverse events nor the rate of emergence of antimicrobial resistance was lower with the shorter regimen. (Funded by the National Institute of Allergy and Infectious Diseases and the National Center for Research Resources; ClinicalTrials.gov number, NCT01511107 .).