tbuckley/cabot-search huggingface dataset:
IFCT-GFPC-0701 MAPS trial, a multicenter randomized phase III trial of pemetrexed-cisplatin with or without bevacizumab in patients with malignant pleural mesothelioma (MPM).
Authors: Gerard Zalcman, Julien Mazieres, Arnaud Scherpereel, Jacques Margery, Denis Moro-Sibilot, Jean-Jacques Parienti, Valérie Gounant, Alain Riviere, Isabelle Monnet, Oliver Molinier, Hervé Lena, Sylvie Friard, Jean-Paul Duhamel, Clarisse Audigier-Valette, Gilles Robinet, Christian Creveuil, Catherine Ligeza-poisson, Franck Morin
Journal: Journal of Clinical Oncology (2012)

TPS7112 Background: MPM median OS does not exceed 13 months with pem/CDDP doublet. U.S. Intergroup phase II trial of gemcitabine/CDDP, with or without bevacizumab, gave an appealing 15.6 months median OS in the bevacizumab arm. French Intergroup aimed to test pem/CDDP with bevacizumab (PCB), in a randomized phase III trial. Methods: Eligible patients had unresectable histologically proved MPM, no prior chemo, PS 0-2, no thrombosis, nor bleeding. Primary endpoint: The primary outcome will be survival. The secondary endpoint will be Progression-Free Survival. Patients received pem 500 mg/m 2 , CDDP 75 mg/m 2 (PC),at D1, and vitamin B12 +B9 substitution, with (arm B) or without bevacizumab (arm A), 15 mg/kg Q21D, for 6 cycles. Arm B nonprogressive patients received bevacizumab maintenance therapy until progression or toxicity. 445 patients to be recruited during a period 48 months, with at least 24 months of follow-up, and 385 events (deaths), will be needed to assure a power of 80% and detect at least a 4.3 months of median survival increase. This hypothesis leads to a Hazard Ratio (HR) of 1.33 and a 3-years survival of 14.7% in control arm and 23.6 % in experimental arm, with an absolute difference of 8.9% in survival rates. Accrual status: The first patient was included in February 2008. On January 31, 2012, 257 patients from 85 French centers had been enrolled. The end of accrual can be expected for September 2013. Ancillary studies: For molecular biomarker analyses, thoracoscopic tissue specimens (TS, ERCC1, MSH2, TUBB3, NF2, p16, RASSF1A methylation,15 microRNAs ) and blood samples (micro-RNAS, VEGF, osteopontin, SRMP) at diagnosis are centrally collected. Finally, a prospective study comparing PET-CT to standard CT with central blinded analysis, is currently on-going for evaluation of response, and accuracy of modified RECIST criteria for mesothelioma.
Identification and Characterization of Tyrosine Kinase Nonreceptor 2 Mutations in Leukemia through Integration of Kinase Inhibitor Screening and Genomic Analysis
Authors: Julia E. Maxson, Melissa L. Abel, Jinhua Wang, Xianming Deng, Sina Reckel, Samuel B. Luty, Huahang Sun, Julie Gorenstein, Seamus B. Hughes, Daniel Bottomly, Beth Wilmot, Shannon K. McWeeney, Jerald Radich, Oliver Hantschel, Richard E. Middleton, Nathanael S. Gray, Brian J. Druker, Jeffrey W. Tyner
Journal: Cancer Research (2016)

The amount of genomic information about leukemia cells currently far exceeds our overall understanding of the precise genetic events that ultimately drive disease development and progression. Effective implementation of personalized medicine will require tools to distinguish actionable genetic alterations within the complex genetic landscape of leukemia. In this study, we performed kinase inhibitor screens to predict functional gene targets in primary specimens from patients with acute myeloid leukemia and chronic myelomonocytic leukemia. Deep sequencing of the same patient specimens identified genetic alterations that were then integrated with the functionally important targets using the HitWalker algorithm to prioritize the mutant genes that most likely explain the observed drug sensitivity patterns. Through this process, we identified tyrosine kinase nonreceptor 2 (TNK2) point mutations that exhibited oncogenic capacity. Importantly, the integration of functional and genomic data using HitWalker allowed for prioritization of rare oncogenic mutations that may have been missed through genomic analysis alone. These mutations were sensitive to the multikinase inhibitor dasatinib, which antagonizes TNK2 kinase activity, as well as novel TNK2 inhibitors, XMD8-87 and XMD16-5, with greater target specificity. We also identified activating truncation mutations in other tumor types that were sensitive to XMD8-87 and XMD16-5, exemplifying the potential utility of these compounds across tumor types dependent on TNK2. Collectively, our findings highlight a more sensitive approach for identifying actionable genomic lesions that may be infrequently mutated or overlooked and provide a new method for the prioritization of candidate genetic mutations.
Prognostic value of thymidylate synthase (TS) expression on failure-free survival of fluorouracil-treated metastatic colorectal cancer patients
Authors: S. Richman, M. S. Braun, J. W. Adlard, C. Daly, F. Turner, J. Barrett, A. Meade, M. Parmar, P. Quirke, M. T. Seymour
Journal: Journal of Clinical Oncology (2006)

10011 Background: We previously presented (ASCO 04 #9506) an exploratory analysis of 13 molecular markers in relation to clinical outcomes in 846 patients treated with fluorouracil (FU), or FU+irinotecan, or FU+oxaliplatin in a large UK-based randomized controlled trial (FOCUS - ASCO ’05 #3518). High TS IHC expression and tumor grade were highly significantly associated with reduced failure-free survival (FFS) in a multivariable model. We now present data from an independent validation set of 449 FOCUS patients and on the combined test and validation sets. Methods: Formalin-fixed, paraffin embedded blocks were retrieved from consenting patients and tissue microarrays made for IHC assessment. Factors assessed for the effect on FFS of first-line therapy were: liver metastases; ALP; grade; mucoid status; age; and IHC for dUTPase and TS. Log-rank univariate analyses and Cox Model multivariable analysis was performed. Results: Univariate analysis of the validation set failed to confirm evidence of the previously observed association between high TS expression and FFS (p=0.2); however high dUTPase IHC (p=0.01), ALP (p&lt;0.0001) and grade (p=0.001) showed significant associations. Table 1 illustrates the results of univariate and multivariable analysis of the combined test and validation sets. In the Cox Model, high TS IHC expression, tumor grade and baseline serum ALP were highly significant predictors of reduced FFS. Conclusions: We failed to confirm a significant association between high TS expression and reduced FFS in an independent validation set. However, in an exploratory analysis of the combined validation and test sets (n&gt;1000), TS IHC expression remained a highly significant predictor of FFS. Overall, our results cannot be taken to demonstrate a powerful and clinically useful influence of TS on treatment efficacy, but are consistent with a moderate effect. [Table: see text] No significant financial relationships to disclose.
Endovascular aneurysm repair with the AneuRx stent-graft is safe, but is it effective?∗∗Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Timothy A.M Chuter
Journal: Journal of the American College of Cardiology (2001)
Reproductive Issues for Cancer Patients/Survivors
Authors: Marc R. Laufer
Journal: Journal of Clinical Oncology (1999)

Article Tools EDITORIAL Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1999.17.9.2631 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 10561335 Reproductive Issues for Cancer Patients/Survivors Marc R. LauferxMarc R. LauferSearch for articles by this author Show More Children's Hospital-Boston, Brigham and Women's Hospital, Boston, MA https://doi.org/10.1200/JCO.1999.17.9.2631 Full Text PDF Figures and Tables "Reproductive Issues for Cancer Patients/Survivors." Journal of Clinical Oncology, 17(9), p. 2631© 1999 by American Society of Clinical Oncology
3-D Maps and Compasses in the Brain
Authors: Arseny Finkelstein, Liora Las, Nachum Ulanovsky
Journal: Annual Review of Neuroscience (2016)

The world has a complex, three-dimensional (3-D) spatial structure, but until recently the neural representation of space was studied primarily in planar horizontal environments. Here we review the emerging literature on allocentric spatial representations in 3-D and discuss the relations between 3-D spatial perception and the underlying neural codes. We suggest that the statistics of movements through space determine the topology and the dimensionality of the neural representation, across species and different behavioral modes. We argue that hippocampal place-cell maps are metric in all three dimensions, and might be composed of 2-D and 3-D fragments that are stitched together into a global 3-D metric representation via the 3-D head-direction cells. Finally, we propose that the hippocampal formation might implement a neural analogue of a Kalman filter, a standard engineering algorithm used for 3-D navigation.
A phase II trial of AZD2171 (cediranib), an oral pan-VEGF receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma
Authors: T. Batchelor, A. G. Sorensen, M. Ancukiewicz, D. G. Duda, D. N. Louis, S. R. Plotkin, P. Ivy, P. Y. Wen, J. S. Loeffler, R. Jain
Journal: Journal of Clinical Oncology (2007)

2001 Background: AZD2171 (cediranib) is a potent, oral pan-VEGF receptor tyrosine kinase inhibitor with a half-life of 20 hours compatible with once-daily dosing. A primary target of AZD2171, VEGFR2, is expressed on glioblastoma endothelium. We have demonstrated normalization of tumor vessels in recurrent glioblastoma patients treated with daily doses of AZD2171. Normalization has rapid onset, is reversible and is associated with alleviation of brain edema [Cancer Cell 2007; 11: 83]. Methods: In this phase II study of 30 recurrent glioblastoma subjects the primary endpoint was the proportion of patients alive and progression-free at 6 months (APF6). Secondary endpoints include radiographic response proportion; progression-free survival; overall survival and toxicity. At this time we are presenting radiographic response data and toxicity on the first 16 consecutive patients and APF6, PFS and OS on all 30 patients. Complete information will be available on all 30 patients at the time of presentation. Results: Twenty-eight patients have experienced disease progression and two patients remain in follow-up without progression. The primary and secondary endpoints are tabulated below: Only one of the first 16 patients was removed from the study due to toxicity (fatigue). Dose limiting toxicities of hypertension, fatigue and diarrhea were observed in 9/16 patients. There were no intracerebral hemorrhages. AZD2171 alleviated brain edema, a major cause of morbidity in glioblastoma patients, and had a steroid-sparing effect in the first 16 patients enrolled. Blood biomarkers were serially assessed and elevated levels of bFGF, SDF1a and viable circulating endothelial cells correlated with disease progression. Conclusions: AZD2171 has activity in patients with recurrent glioblastoma. Combination studies of AZD2171 with radiation and chemotherapy are planned. [Table: see text] [Table: see text]
High Levels of Antifibrinolytic Proteins Are Found in Plasma of Older Octogenarians With Cardiovascular Disease and Cognitive Decline
Authors: Judit Cubedo, Teresa Padró, Esther Peña, Rosa Aledo, Francesc Formiga, Assumpta Ferrer, Glòria Padrós, Lina Badimon
Journal: Journal of the American College of Cardiology (2015)
High density methylation QTL analysis in human blood via next-generation sequencing of the methylated genomic DNA fraction
Authors: Joseph L. McClay, Andrey A. Shabalin, Mikhail G. Dozmorov, Daniel E. Adkins, Gaurav Kumar, Srilaxmi Nerella, Shaunna L. Clark, Sarah E. Bergen, Christina M. Hultman, Patrik K. E. Magnusson, Patrick F. Sullivan, Karolina A. Aberg, Edwin J. C. G. van den Oord
Journal: Genome biology (2015)

Genetic influence on DNA methylation is potentially an important mechanism affecting individual differences in humans. We use next-generation sequencing to assay blood DNA methylation at approximately 4.5 million loci, each comprising 2.9 CpGs on average, in 697 normal subjects. Methylation measures at each locus are tested for association with approximately 4.5 million single nucleotide polymorphisms (SNPs) to exhaustively screen for methylation quantitative trait loci (meQTLs). Using stringent false discovery rate control, 15 % of methylation sites show genetic influence. Most meQTLs are local, where the associated SNP and methylation site are in close genomic proximity. Distant meQTLs and those spanning different chromosomes are less common. Most local meQTLs encompass common SNPs that alter CpG sites (CpG-SNPs). Local meQTLs encompassing CpG-SNPs are enriched in regions of inactive chromatin in blood cells. In contrast, local meQTLs lacking CpG-SNPs are enriched in regions of active chromatin and transcription factor binding sites. Of 393 local meQTLs that overlap disease-associated regions from genome-wide studies, a high percentage encompass common CpG-SNPs. These meQTLs overlap active enhancers, differentiating them from CpG-SNP meQTLs in inactive chromatin. Genetic influence on the human blood methylome is common, involves several heterogeneous processes and is predominantly dependent on local sequence context at the meQTL site. Most meQTLs involve CpG-SNPs, while sequence-dependent effects on chromatin binding are also important in regions of active chromatin. An abundance of local meQTLs resulting from methylation of CpG-SNPs in inactive chromatin suggests that many meQTLs lack functional consequence. Integrating meQTL and Roadmap Epigenomics data could assist fine-mapping efforts.
Effect of 1α,25-Dihydroxyvitamin D&lt;sub&gt;3&lt;/sub&gt; on Proliferation of Activated T-Cells and Established Human Lymphotropic Virus Type I-Positive T-Cell Lines&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Yoshinobu Nakao, Tamio Koizumi, Toshimitsu Matsui, Shuichi Matsuda, Toshitaro Nakagawa, Yuko Katakami, Takuo Fujita, Sakan Maeda, Shigeru Morikawa, Yohei Ito
Journal: JNCI Journal of the National Cancer Institute (1987)

The effects of 1α,25-dihydroxyvitamin D3 [1,25-(OH)2D3] on proliferation and de novo DNA synthesis were studied in the following established human leukemia cell lines: lymphoblastic T-cell lines HPB-ALL, CCRF-HSB-2, p12/Ichikawa, and HPB-MLT; adult T-cell leukemia- (ATL) and human lymphotropic virus type I (HTLV-I)-infected T-cell lines HUT102, HUT-102B2, MT-1, MT-2, MJ, C2/MJ, KH-2, KH-2Lo, HPB-CTL-1, and ATN-C1; ATL-derived B-cell lines ATL-BK9 and ATL-BK10; lymphoblastic B-cell line Daudi; and myelocytic-monocytic lineage cell lines HL-60 and U937. 1,25(OH)2D3 inhibited proliferation and de novo DNA synthesis of phytohemagglutinin-P-activated T-cells and certain established HTLV-I-positive T-cells. However, it did not inhibit immature lymphoblastic T- and B-cells or ATL-derived B-cells. The degree of inhibition depended on the dose of 1,25(OH)2D3 and the heterogeneity of the established HTLV-I-positive T-cells. KH-2 and subclone KH-2Lo were markedly inhibited, and HPB-CTL-1 was moderately inhibited. Marked inhibition of DNA synthesis in KH-2Lo cells was observed in the proliferative phase of the cell cycle. No inhibition of KH-2Lo proliferation or expression of interleukin-2 and transferrin receptor was noted after removal of 1,25(OH)2D3 from the culture medium. 1,25(OH)2D3 inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced multinucleated cell formation of various HTLV-I-positive T-cell lines and TPA-induced HTLV-I p19 expression in KH-2Lo cells.
Phosphoinositide 3-kinase-δ regulates fungus-induced allergic lung inflammation through endoplasmic reticulum stress
Authors: Kyung Sun Lee, Jae Seok Jeong, So Ri Kim, Seong Ho Cho, Narasaiah Kolliputi, Yun Hee Ko, Kyung Bae Lee, Suk Chul Park, Hae Jin Park, Yong Chul Lee
Journal: Thorax (2015)

Background Sensitisation with Aspergillus fumigatus ( Af ) is known to be associated with severe allergic lung inflammation, but the mechanism remains to be clarified. Phosphoinositide 3-kinase (PI3K)-δ and endoplasmic reticulum (ER) stress are suggested to be involved in steroid-resistant lung inflammation. We aimed to elucidate the role of PI3K-δ and its relationship with ER stress in fungus-induced allergic lung inflammation. Methods Using Af -exposed in vivo and in vitro experimental systems, we examined whether PI3K-δ regulates ER stress, thereby contributing to steroid resistance in fungus-induced allergic lung inflammation. Moreover, we checked expression of an ER stress marker in lung tissues isolated from patients with allergic bronchopulmonary aspergillosis. Results Af -exposed mice showed that ER stress markers, unfolded protein response (UPR)-related proteins, phosphorylated Akt, generation of mitochondrial reactive oxygen species (mtROS), eosinophilic allergic inflammation, and airway hyperresponsiveness (AHR) were increased in the lung. Similarly, glucose-regulated protein 78 was increased in lung tissues of patients with ABPA. A PI3K-δ inhibitor reduced Af -induced increases in ER stress markers, UPR-related proteins, allergic inflammation and AHR in mice. However, dexamethasone failed to reduce Af -induced allergic inflammation, AHR and elevation of ER stress. Administration of an ER stress inhibitor or a mtROS scavenger improved Af -induced allergic inflammation. The PI3K-δ inhibitor reduced Af -induced mtROS generation and the mtROS scavenger ameliorated ER stress. In primary cultured tracheal epithelial cells, Af -induced ER stress was inhibited by blockade of PI3K-δ. Conclusions These findings suggest that PI3K-δ regulates Af -induced steroid-resistant eosinophilic allergic lung inflammation through ER stress.
Improving the spatial resolution of epiretinal implants by increasing stimulus pulse duration
Authors: Andrew C. Weitz, Devyani Nanduri, Matthew R. Behrend, Alejandra Gonzalez-Calle, Robert J. Greenberg, Mark S. Humayun, Robert H. Chow, James D. Weiland
Journal: Science Translational Medicine (2015)

Retinal implants that deliver longer pulses of electrical current may markedly improve image sharpness for blind individuals.
An observational study using γ-H2AX foci to investigate cardiac doses of radiation following adjuvant radiotherapy for breast cancer: Standard external beam radiotherapy to the breast versus intraoperative radiotherapy.
Authors: D. Woolf, R. Bakhshi, S. Fawcitt, M. Worku, D. B. Ghosh, S. Sivabalasingham, N. R. Williams, S. Short, K. Pigott, M. R. Keshtgar
Journal: Journal of Clinical Oncology (2011)

TPS129 Background: External beam radiotherapy is a gold standard adjuvant treatment after breast conserving surgery for localised breast cancer. A recent phase III trial has shown the non-inferiority of intraoperative radiotherapy compared with external beam radiotherapy (Vaidya J et al. Lancet 2010) with a reduction in radiotherapy toxicity in the intraoperative radiotherapy group (0.5% vs 2.1%; p = 0.002). Intraoperative radiotherapy also has advantages in cost saving and patient convenience, particularly for those living some distance from a cancer centre. There are data to suggest an increase in morbidity and mortality from stroke and heart disease in those exposed to radiation and this includes late effects from breast radiotherapy. Intraoperative radiotherapy uses low energy x-rays (50 KV) and is therefore likely to reduce the radiation exposure of the cardiovascular system compared with external beam radiotherapy. We are using γ-H2AX foci formation in peripheral blood lymphocytes as a surrogate marker of radiation dose to the heart and great vessels. The phosphorylated histone H2AX protein (γ-H2AX) is a very sensitive assay for the induction of double strand breaks caused by ionising radiation, which will be created as the lymphocytes pass through, and adjacent to, the irradiated field. We will study the induced foci number after patient radiotherapy treatment for localised breast cancer, as a surrogate for dose to the heart and great vessels using the different radiotherapy techniques. Methods: 36 patients are being recruited, having either external beam radiotherapy or intraoperative radiotherapy as part of their planned treatment program. We are collecting data including demographics, disease status and radiotherapy delivery variables, and γ-H2AX foci number with 12 patients having intraoperative radiotherapy and 24 having external beam radiotherapy. We will have equal numbers or right and left sided treatments and are comparing foci number between right and left external beam radiotherapy groups as well as intraoperative radiotherapy versus external beam radiotherapy.
Results of the phase III, placebo-controlled trial (SUCCEED) evaluating the mTOR inhibitor ridaforolimus (R) as maintenance therapy in advanced sarcoma patients (pts) following clinical benefit from prior standard cytotoxic chemotherapy (CT).
Authors: S. P. Chawla, J. Blay, I. L. Ray-Coquard, A. Le Cesne, A. P. Staddon, M. M. Milhem, N. Penel, R. F. Riedel, B. Bui Nguyen, L. D. Cranmer, P. Reichardt, E. Bompas, Y. Song, R. Lee, J. E. Eid, J. Loewy, F. G. Haluska, P. F. Dodion, G. D. Demetri
Journal: Journal of Clinical Oncology (2011)

10005 Background: The mTOR signaling pathway is activated in most sarcomas. R, an oral mTOR inhibitor, demonstrated activity in phase I-II trials in advanced sarcomas following failure of prior CT. Methods: This trial is an international, double-blind study randomized 1:1 between R (40 mg orally for 5 days/week) vs. placebo (P) as maintenance therapy in pts with metastatic sarcoma (stratified soft-tissue vs bone; 1st vs, 2nd/3rd line prior CT) following stable disease or better response to prior CT. Primary endpoint is progression-free survival (PFS) based on independent radiological review (IRR). Secondary endpoints include overall survival (OS), best target lesion response, cancer-related symptoms, and safety and tolerability. Results: 711 pts were randomized from Jun '07 to Jan '10 and analyzed for efficacy. At data cut-off, 53 pts remained on blinded drug. Baseline characteristics were well balanced between the study arms. Analysis of 552 PFS events per IRR showed that R met the prespecified study endpoint with a statistically significant improvement in PFS compared to P (Hazard Ratio HR=0.72, P=0.0001, stratified log-rank). Median PFS improved by 21% (17.7 wks R vs. 14.6 wks P). Based on local site assessment of PFS, R demonstrated an improvement with HR=0.69 (P<0.0001) and a 52% gain in median (22.4 wks R vs. 14.7 wks P). PFS benefit was noted across all prespecified strata. Follow-up for OS is ongoing; results at data cut-off (313 OS events) indicate a trend favoring R (median OS: 88.0 wks R vs. 78.7 wks P; HR=0.92, 95% CI (0.74, 1.15)). While incidence of stomatitis (52%) and other adverse events was higher in pts receiving R, the overall safety profile was consistent with other mTOR inhibitors. Conclusions: This randomized trial of ridaforolimus met the primary endpoint of improved PFS in pts with metastatic soft-tissue or bone sarcomas to maintain benefit from prior standard CT. The rapid progression of metastatic sarcomas demonstrates the aggressive nature of these malignancies, and maintenance therapy with R will provide a new option for pts with this life-threatening disease.