tbuckley/cabot-search huggingface dataset:
Rebound Syndrome in Multiple Sclerosis After Fingolimod Cessation
Authors: Martin Merschhemke, Davorka Tomic, Norman Putzki
Journal: JAMA Neurology (2016)

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P1302 : Evidence for the ICG-clearance-test as a relevant predictor of post hepatectomy liver failure
Authors: S. Haegele, F. Offensperger, E. Lahner, A. Assinger, E. Fleischmann, B. Gruenberger, T. Gruenberger, C. Brostjan, P. Starlinger
Journal: Journal of Hepatology (2015)
Synthetic lethality in lung cancer and translation to clinical therapies
Authors: Ada W. Y. Leung, Tanya de Silva, Marcel B. Bally, William W. Lockwood
Journal: Molecular Cancer (2016)

Lung cancer is a heterogeneous disease consisting of multiple histological subtypes each driven by unique genetic alterations. Despite the development of targeted therapies that inhibit the oncogenic mutations driving a subset of lung cancer cases, there is a paucity of effective treatments for the majority of lung cancer patients and new strategies are urgently needed. In recent years, the concept of synthetic lethality has been established as an effective approach for discovering novel cancer-specific targets as well as a method to improve the efficacy of existing drugs which provide partial but insufficient benefits for patients. In this review, we discuss the concept of synthetic lethality, the various types of synthetic lethal interactions in the context of oncology and the approaches used to identify these interactions, including recent advances that have transformed the ability to discover novel synthetic lethal combinations on a global scale. Lastly, we describe the specific synthetic lethal interactions identified in lung cancer to date and explore the pharmacological challenges and considerations in translating these discoveries to the clinic.
Heterozygous Germ Line Deletion of a 2Mb Interval in Mice That Models Loss of 7q22 in Human Myeloid Malignancies Results in Defective Hematopoietic Stem Cell Function Reminiscent of Premature Aging
Authors: Jasmine C. Wong, Kelley Weinfurtner, Yan Zhang, Pilar Alzamora, Eugene Hwang, Scott C. Kogan, Kevin M. Shannon
Journal: Blood (2011)
Association Between Pediatric Psoriasis and Waist-to-Height Ratio in the Absence of Obesity
Authors: Andrew Lee, Saxon D. Smith, Esther Hong, Sarah Garnett, Gayle Fischer
Journal: JAMA Dermatology (2016)

<h3>Importance</h3> Increasing evidence suggests that psoriasis poses a cardiometabolic risk in children, as in adults. The best way to screen for this has not yet been established. Waist-to-height ratio (WtHR) can easily identify children with increased central adiposity and is a simpler alternative to body mass index (BMI) that does not require growth charts or percentiles. Having a WtHR of 0.5 or greater is associated with future cardiovascular risk. <h3>Objective</h3> To determine whether children with psoriasis are more likely to have increased WtHR, obesity, and metabolic syndrome relative to children without psoriasis. <h3>Design, Setting, and Participants</h3> This multicenter cross-sectional prospective case-control study was conducted from February 7, 2014, to July 15, 2015, in a tertiary referral center pediatric dermatology clinic and in 2 private consultant rooms of specialist dermatologists, all located in Sydney and Gosford, New South Wales, Australia. Participants were children (110 girls and 98 boys) aged from 5 to 16 years, 135 children with psoriasis and 73 controls with noninflammatory skin conditions. <h3>Main Outcomes and Measures</h3> Increased central adiposity indicated by WtHR of 0.5 or higher, metabolic syndrome, and increased BMI. <h3>Results</h3> Of the 208 children evaluated (110 girls and 98 boys) aged from 5 to 16 years (mean age, 8.9 years), 135 had psoriasis and 73 were controls with noninflammatory skin conditions. Children with psoriasis were more likely to have increased central adiposity, with WtHR of 0.5 or greater (29% [n = 39] vs 11% [n = 8];<i>P</i> = .002). Four of 53 children older than 10 years with psoriasis were found to have metabolic syndrome compared with none of 29 in the control group (8% vs 0%;<i>P</i> = .29). Three of 15 children with moderate to severe psoriasis had metabolic syndrome compared with 1 of 38 children with mild psoriasis (20% vs 3%;<i>P</i> = .06). Children with moderate to severe psoriasis had a higher mean WtHR than children with mild psoriasis (0.48 vs 0.46;<i>P</i> = .04). Overweight and obesity according to BMI did not vary significantly between children with psoriasis and controls (17% [n = 23] vs 16% [n = 12];<i>P</i> = .91). <h3>Conclusions and Relevance</h3> In this Australian cohort of children with psoriasis, elevated WtHR was significantly more common in patients with psoriasis than in controls, while proportions of participants with metabolic syndrome or BMI-determined obesity were not significantly different between the 2 groups.
Prognostic value of CD44s in the NCI randomized trial on breast conservation with 25-year follow-up.
Authors: T. D. Dan, D. Ly, S. M. Hewitt, B. P. Soule, A. S. Nowacki, J. Gillespie, D. N. Danforth, J. B. Mitchell, K. A. Camphausen, N. L. Simone
Journal: Journal of Clinical Oncology (2010)

634 Background: Prognostic markers can be used in the management of early breast cancer to help determine which patients may benefit from either conservative or aggressive management. Breast tumor tissue from patients enrolled on the NCI randomized trial of Breast Conservation was analyzed to determine if a good prognostic marker could be identified. CD44s is a transmembrane glycoprotein typically bound to hyaluronan in the stroma that has been identified in the literature as having an association with tumor progression and metastasis because of its function as a cell adhesion molecule. Methods: 237 early stage breast cancer patients were randomized between 1979 and 1989 at the National Cancer Institute to receive mastectomy or lumpectomy followed by definitive radiation. Formalin- fixed paraffin embedded tumor specimens from 63 of these patients were available for study. Immunohistochemical staining was performed using a monoclonal antibody to the CD44s isoform of CD44, and was scored as negative or positive staining by 2 independent pathologists. Survival distributions were calculated by the Kaplan-Meier method and statistical significance was determined by the log-rank test. Results: The median age of patients included in this study was 53 years. Ten patients were Stage I, 21 Stage IIA, 13 Stage IIB, 7 Stage IIIA, and 9 Stage IIIC. Thirty patients were lymph node negative and 33 were positive. After 25.2 years of median follow up, overall median survival was 13.8 years, and 40 patients had experienced a recurrence. CD44s was positive in 49% of patients and negative in 51%. The presence of CD44s was significantly associated with an increase in time to first event which was typically a recurrence (11.5 years vs. 4.5 years, p=0.01) and overall survival (21.1 vs. 10.0, p=0.04). Conclusions: Positive expression of CD44s is associated with better prognosis in patients with early stage breast cancer. The assessment of CD44s expression levels in breast cancer may be a clinically useful target for identifying a subgroup of patients at higher risk of recurrence and death. However, further studies are needed to validate this finding in a larger cohort of patients. No significant financial relationships to disclose.
Everolimus in patients with advanced pancreatic neuroendocrine tumors (pNET): Multivariate analysis of progression-free survival from the RADIANT-3 trial.
Authors: T. J. Hobday, J. Capdevila, S. Saletan, A. Panneerselvam, R. F. Pommier
Journal: Journal of Clinical Oncology (2011)

e21091 Background: In the phase III RADIANT-3 trial, everolimus, an oral mTOR inhibitor, demonstrated superiority in progression-free survival (PFS) with a median of 11.0 versus 4.6 months for placebo (HR=0.35; p<0.0001) in patients with advanced pNET (ESMO 2010, abstract LBA9). In order to determine the factors that significantly influence PFS, a prespecified multivariate analysis was performed. Methods: Patients with progressive advanced low- or intermediate-grade pNET were randomized to receive everolimus 10 mg/d orally (n=207) or placebo (n=203); both arms received best supportive care. Primary endpoint was PFS. Multivariate analysis using a Cox-proportional hazards model was performed on the following factors: treatment; age; sex; WHO performance status; geographic region; prior somatostatin use; baseline CgA; baseline NSE; Ki67; years since diagnosis; liver, bone, or extrahepatic involvement; and number of organs involved. Significant factors (p<0.05) were determined after a stepwise elimination of nonsignificant factors from the model. Results: Multivariate analysis indicated that significant prognostic factors of PFS were treatment (everolimus vs placebo) (p<0.001), WHO performance status (p<0.001), baseline NSE level (p<0.001), and liver involvement (p=0.048). Conclusions: Multivariate analysis of the RADIANT-3 trial has allowed, for the first time, evaluation of prognostic factors associated with PFS in a large phase III, placebo-controlled trial in patients with advanced pNET. A better understanding of these risk factors can help clinicians in the treatment of their patients. Multivariate analysis of PFS. n Events n (%) Median PFS (95% CI) Hazard ratio (95% CI) P Treatment 0.33 (0.26, 0.43) <0.001 Everolimus 207 109 (52.7) 11.04 (8.41, 13.86) Placebo 203 165 (81.3) 4.60 (3.06, 5.39) WHO performance status 1.58 (0.49, 0.82) <0.001 0 272 173 (63.6) 8.15 (5.78, 8.51) ≥1 138 101 (73.2) 5.45 (4.37, 8.75) Baseline NSE 1.95 (1.49, 2.55) <0.001 Elevated 104 81 (77.9) 3.91 (2.83, 5.42) Nonelevated 293 183 (62.5) 8.08 (5.78, 8.54) Liver involvement 1.68 (1.01, 2.80) 0.048 Yes 377 257 (68.2) 5.75 (5.55, 7.98) No 32 17 (53.1) 8.94 (6.18, NA)
A three-stage intrathymic development pathway for the mucosal-associated invariant T cell lineage
Authors: Hui-Fern Koay, Nicholas A Gherardin, Anselm Enders, Liyen Loh, Laura K Mackay, Catarina F Almeida, Brendan E Russ, Claudia A Nold-Petry, Marcel F Nold, Sammy Bedoui, Zhenjun Chen, Alexandra J Corbett, Sidonia B G Eckle, Bronwyn Meehan, Yves d'Udekem, Igor E Konstantinov, Martha Lappas, Ligong Liu, Chris C Goodnow, David P Fairlie, Jamie Rossjohn, Mark M Chong, Katherine Kedzierska, Stuart P Berzins, Gabrielle T Belz, James McCluskey, Adam P Uldrich, Dale I Godfrey, Daniel G Pellicci
Journal: Nature Immunology (2016)
Prospective randomized trial comparing postoperative adjuvant concurrent versus sequential hormonal and different radiation fractionation schedule in breast cancer patients.
Authors: M. S. Barsoum, M. M. El Mongi, E. M. Khalil, H. E. Eisa, I. M. Hamed, G. A. Attia
Journal: Journal of Clinical Oncology (2010)

544 Background: To evaluate the optimal sequencing of tamoxifen (T) and radiation therapy (RT) after surgery (S) in breast cancer (BC) patients regarding pulmonary fibrosis (PF), breast cosmesis (BC) and tt outcome and to compare the acute, late toxicity and tt outcome resulting from two different fractionation schedules. Methods: This prospective randomized study included 308 female patients who underwent S followed by chemotherapy if indicated, subsequently randomized to receive p/o conventional fractionation (CF) (50 Gy in 25 fractions over 35 days - 200 cGy/fraction) concomitant or sequentialwith T or to receivehypofractionated protocol (HF) (40 Gy in 15 fractions over 3 weeks - 267 cGy /fraction) concomitantor sequentially with T (Patients with conservative surgery less than 50 years received boost to tumor bed 1600 cGy in 8 fractions over 1.5 weeks). Results: There was no statistical significant difference between the early, late skin reactions, BC grades,and symptomatic cough among the concurrent and sequential T treatment sub-groups. CT lung fibrosis at 1 year increased from 13.6% to 22.7% in the concurrent T (p = 0.039). The sequence of T did not influence 4year OS (concurrent 82.4%; sequential 81.7%; p = 0.831),or that of locoregional DFS (concurrent 94.8%; sequential 96.2%; p = 0.555), as well as distant-free survival (concurrent 73.4%; sequential 72.4%; p = 0.911). There was statistical significant difference between early skin reactions of the two different fractionation groups. The maximum early skin reactions, in CR occurred during the fifth week of tt, while in HF occurred during the second and third week of tt. There was no difference between the 2 groups regarding late skin toxicity, cosmetic grades, occurrence of cough and PF as proved by CT.The different fractionation schedules did not influence 4year OS (CF 79.2%; HF 84.8%; p = 0.408), or locoregional DFS (CF 94.1%;HF 97%; p = 0.265) and DFS (CF 70.2%; HF 75.7%; p = 0.248). Conclusions: The use of T concurrently with RT does not compromise the early or late skin reactions, BC, local control or OS however the incidence of PF was increased. HF appear to be as favorable as the standard CF. No significant financial relationships to disclose.
Recruitment Of T Cells and Macrophages To The Eyes In Recipients Of Allogeneic Hematopoietic Stem Cell Transplants Correlate With Inflammatory Cytokine Presence In Ocular Gvhd
Authors: Samantha Herretes, Juan C. Murillo, Duncan Ross, Tan Yaohong, Henry Barreras, Ali M. Saeed, Krishna V. Komanduri, Victor L. Perez, Robert B. Levy
Journal: Blood (2013)
Excellent Long-Term Survival of Patients with Waldenström‘s Macroglobulinemia (WM) treated in Private Oncology Practices and a University hospital with different Treatment Strategies
Authors: Manfred Hensel, Jürgen Brust, Christoph Plöger, Dieter Schuster, Marie-Luise Memmer, Michael Rieger, Lara Hensel, Solveigh Mosthaf, Judith Franz-Werner, Hans-Peter Feustel, Franz Mosthaf, Andreas Karcher, Stefan Fuxius, Anthony D. Ho, Mathias Witzens-Harig
Journal: Blood (2011)
Phase II study of biweekly docetaxel and cisplatin combination chemotherapy in first-line advanced gastric cancer
Authors: G. Quintero, M. Jorge, J. Casal, M. Salgado, S. Candamio, R. López, J. R. Mel
Journal: Journal of Clinical Oncology (2008)

15601 Background: Docetaxel and cisplatin, as single agents, have demonstrated activity in patients with advanced gastric cancer. Docetaxel and cisplatin have shown a different toxicity profile; consequently the combination of these drugs could be a safe and effective treatment. Therefore, we conducted a phase II study to assess efficacy and toxicity of a biweekly regimen of docetaxel plus cisplatin in patients with advanced gastric cancer who have never been treated with palliative chemotherapy. Methods: Fifty-two patients with advanced gastric cancer were enrolled, histologically confirmed of gastric adenocarcinoma, at least one measurable lesion, ECOG PS ≤2, no prior palliative chemotherapy and adequate bone marrow, renal and hepatic function. Docetaxel 50 mg/m2 and cisplatin 50 mg/m2 were administered every two weeks until progression disease, unbearable toxicity or a maximum of 12 cycles. The objective response was evaluated according to RECIST criteria and toxicity was assessed according to the NCI-CTC 2.0. Results: In total, 392 cycles were administered (median 8, range 1–12 cycles), with a median dose intensity of 91% for docetaxel and cisplatin. The median age was 66 years (range 37–84), 71% were male, 6.5% had ECOG 0 and 78.3% ECOG 1. The objective response rate was 37.0% (95% CI, 23.0–50.9) with one complete response and 16 partial responses, over 46 evaluable patients. Sixteen patients had stable disease. Median time to progression was 5.5 months (95% CI, 4.0–7.0) and median overall survival 8.9 months (95% CI: 6.0–11.9). The most common grade 3–4 toxicities per cycle were neutropenia (5.9%), anaemia (1.8%), asthenia (1.8%), vomiting (1.0%), nausea (0.8%) and thrombocytopenia (0.8%). Conclusions: Biweekly administration of docetaxel and cisplatin in advanced gastric cancer has a manageable toxicity profile and shows a promising antitumor activity as a first-line therapy. No significant financial relationships to disclose.
Part I of GANNET53: A multicenter phase I/II trial of the Hsp90 inhibitor ganetespib (G) combined with weekly paclitaxel (P) in women with high-grade serous, high-grade endometrioid, or undifferentiated, platinum-resistant epithelial ovarian, fallopian tube or primary peritoneal cancer.
Authors: Isabelle Ray-Coquard, Ioana Braicu, Regina Berger, Sven Mahner, Jalid Sehouli, Alain G Zeimet, Eric Pujade Lauraine, Philippe Alexandre Cassier, Utemartha Moll, Hanno Ulmer, Karin Leunen, Christian Marth, Ignace Vergote, Nicole Concin
Journal: Journal of Clinical Oncology (2015)

5578 Background: Stabilized mutant p53 protein (mutp53) is a novel target in epithelial ovarian cancer (EOC). Due to aberrant conformation, mutp53 proteins depend on folding support by the Hsp90 chaperone. Hsp90 blockade induces degradation of mutp53, resulting in tumor cell cytotoxicity and increased sensitivity to chemotherapeutics. Preclinical synergy of the Hsp90 inhibitor G combined with P provided the rationale for testing the combination in relapsed platinum resistant EOC patients (pts) in the GANNET53 trial (EUDRACT 2013-003868-31). Methods: Eligiblepts had platinum resistant EOC. Pts with > 4 prior chemotherapy and low grade carcinoma were not eligible. Weekly P (80 mg/m²) and increasing doses of G (100, 150 mg/m²) were given i.v. on days 1, 8, 15 in a 28 days cycle until disease progression or unacceptable toxicity. End points were safety and determination of phase II dose. Dose limiting toxicity (DLT) was defined as grade (gr) 4 toxicity (with exceptions) occurring in cycles 1 & 2. Results: Ten pts (median age 57 years; range 43-70) were enrolled. No DLT occurred in cohort 1 (4 pts treated with P + G 100 mg/m²), nor in cohorts 2 and 3 (6 pts treated with P + G 150mg/m²). The most common adverse events (AEs) related to G were transient gr 1/2 diarrhea (n = 9). The most frequent gr 1/2 AEs were diarrhea (n = 9), nausea (n = 5), anemia (n = 6), fatigue (n = 4), headache (n = 5), and QTc prolongation (n = 6). AEs ≥ gr 3 were anemia (n = 3), neutropenia (n = 2), and acute cardiac failure (n = 1). There was 1 death on study (after DLT period) due to digestive tract hemorrhage from duodenal ulcer. Two pts discontinued due to SAEs (digestive hemorrhage n = 1, cardiac failure n = 1), 4 due to progressive disease, one due to physicians decision. Three pts are still on study at time of abstract submission. Conclusions: The combination of ganetespib 150 mg/m² with paclitaxel 80 mg/m² once weekly for 3 out of 4 weeks was generally well tolerated with no DLTs, and therefore chosen for the planned randomized phase II trial. Clinical trial information: 2013-003868-31.
Myeloablative Intravenous Busulfan/Fludarabine Conditioning Does Not Facilitate Reliable Engraftment of Dual Umbilical Cord Blood Grafts in Adult Recipients.
Authors: Mitchell Horwitz, John Chute, Cristina Gasparetto, Gwynn Long, David Rizzieri, Ashley Morris, Jackie McPherson, Keith Sullivan, Nelson Chao
Journal: Blood (2007)
The increase of type IIFN serum activity by treatment with etanercept, but not infliximab, does not influence the induction of anti-nuclear antibodies in spondyloarthritis
Authors: Tineke Cantaert, C Mavragani, L De Rycke, Theo Niewold, C Wijbrandts, T. Van der Pouw Kraan, M. K Crow, P. P Tak, D Baeten
Journal: Annals of the Rheumatic Diseases (2008)
FTY720 but Not Its Immunosuppressive Phosphorylated Form FTY720-P Exerts Anti-Leukemic Activity towards Ph(+) and Ph(−) Myeloproliferative Disorders through Reactivation of the PP2A Tumor Suppressor.
Authors: Joshua Oaks, Paolo Neviani, A. Mukhopadhyay, Ramasamy Santhanam, Y. Ma, Charlene Mao, Guido Marcucci, Ching-Shih Chen, Jorge Cortes, Michael A. Caligiuri, Peter Hokland, Claudia Huettner, Steffen Koschmieder, Jose Cancelas, Roger Briesewitz, Ravi Bhatia, Denis-Claude Roy, Besim Ogretmen, Danilo Perrotti
Journal: Blood (2009)
MicroRNA-223 ameliorates alcoholic liver injury by inhibiting the IL-6–p47<sup>phox</sup>–oxidative stress pathway in neutrophils
Authors: Man Li, Yong He, Zhou Zhou, Teresa Ramirez, Yueqiu Gao, Yanhang Gao, Ruth A Ross, Haixia Cao, Yan Cai, Mingjiang Xu, Dechun Feng, Ping Zhang, Suthat Liangpunsakul, Bin Gao
Journal: Gut (2016)

<h3>Objectives</h3> Chronic-plus-binge ethanol feeding activates neutrophils and exacerbates liver injury in mice. This study investigates how recent excessive drinking affects peripheral neutrophils and liver injury in alcoholics, and how miR-223, one of the most abundant microRNAs (miRNAs) in neutrophils, modulates neutrophil function and liver injury in ethanol-fed mice. <h3>Designs</h3> Three hundred alcoholics with (n=140) or without (n=160) recent excessive drinking and 45 healthy controls were enrolled. Mice were fed an ethanol diet for 10 days followed by a single binge of ethanol. <h3>Results</h3> Compared with healthy controls or alcoholics without recent drinking, alcoholics with recent excessive drinking had higher levels of circulating neutrophils, which correlated with serum levels of alanine transaminase (ALT) and aspartate transaminase (AST). miRNA array analysis revealed that alcoholics had elevated serum miR-223 levels compared with healthy controls. In chronic-plus-binge ethanol feeding mouse model, the levels of miR-223 were increased in both serum and neutrophils. Genetic deletion of the miR-223 gene exacerbated ethanol-induced hepatic injury, neutrophil infiltration, reactive oxygen species (ROS) and upregulated hepatic expression of interleukin (IL)-6 and phagocytic oxidase (phox) p47<sup>phox</sup>. Mechanistic studies revealed that miR-223 directly inhibited IL-6 expression and subsequently inhibited p47<sup>phox</sup> expression in neutrophils. Deletion of the p47<sup>phox</sup> gene ameliorated ethanol-induced liver injury and ROS production by neutrophils. Finally, miR-223 expression was downregulated, while IL-6 and p47<sup>phox</sup> expression were upregulated in peripheral blood neutrophils from alcoholics compared with healthy controls. <h3>Conclusions</h3> miR-223 is an important regulator to block neutrophil infiltration in alcoholic liver disease and could be a novel therapeutic target for the treatment of this malady.
Defining the Nutritional and Metabolic Context of FGF21 Using the Geometric Framework
Authors: Samantha M. Solon-Biet, Victoria C. Cogger, Tamara Pulpitel, Marika Heblinski, Devin Wahl, Aisling C. McMahon, Alessandra Warren, Jessica Durrant-Whyte, Kirsty A. Walters, James R. Krycer, Fleur Ponton, Rahul Gokarn, Jibran A. Wali, Kari Ruohonen, Arthur D. Conigrave, David E. James, David Raubenheimer, Christopher D. Morrison, David G. Le Couteur, Stephen J. Simpson
Journal: Cell Metabolism (2016)
A phase I trial of recombinant human interleukin-1 beta alone and in combination with myelosuppressive doses of 5-fluorouracil in patients with gastrointestinal cancer
Authors: J Crown, A Jakubowski, N Kemeny, M Gordon, C Gasparetto, G Wong, C Sheridan, G Toner, B Meisenberg, J Botet
Journal: Blood (1991)