tbuckley/cabot-search huggingface dataset:
Modulation of Leukotriene Signaling Affecting Cell Growth in Chronic Myeloid Leukemia: A Key Pathway to Cure?
Authors: Elham Yektaei, Anders Nilsson, Barbro Näsman-Glaser, Marja Ekblom, Hong Qian, Olof Rådmark, Ana Zovko, Lena Kanter, Jonas Wallvik, Leif Stenke
Journal: Blood (2015)
Women with the Prothrombophilic HPA-1b Genotype of Platelet Integrin αIIbβ3 Are at Increased Risk of Intrauterine Growth Restriction.
Authors: Andrea Gerhardt, Nadja Howe, Jan S. Kruessel, Hans G. Bender, Rudiger E. Scharf, Rainer B. Zotz
Journal: Blood (2006)
Abstract PR07: Mechanisms of stromal reprogramming mediated by heat shock factor 1
Authors: Ruth Scherz-Shouval, Marc L. Mendillo, Giorgio Gaglia, Irit Ben-Aharon, Andrew H. Beck, Luke Whitesell, Susan Lindquist
Journal: Cancer Research (2016)

Abstract For tumors to form, progress and metastasize, they must recruit and reprogram normal cells in their microenvironment into a pro-tumorigenic stroma. Yet little is known about the pathways leading to stromal reprogramming. We hypothesized that such reprogramming would not be mediated by classic oncogenes, since the stroma is relatively genetically stable. Instead we propose that cancer cells hijack normal cytoprotective stress responses, and subvert them to enable stromal reprogramming. We found that Heat-shock factor 1 (HSF1), master regulator of the heat-shock response, plays a crucial role in this process. Across a broad range of human cancers, HSF1 is activated in cancer-associated fibroblasts (CAFs). In early stage breast and lung cancer, high stromal HSF1 activation is strongly associated with poor patient outcome. In fibroblasts co-cultured with cancer cells, HSF1 drives a transcriptional program that supports cancer phenotypes. This program is profoundly different from the transcriptional program it drives in cancer cells or in heat-shocked cells. Here we characterize mechanisms leading to activation of this unique stromal program and describe the contribution of cancer cells to this process. We then explore the stromal HSF1 program in patients. We apply computational and experimental approaches to define independent cancer and stromal HSF1 signatures and highlight the prognostic value of these signatures in human breast cancer. Billions of years of evolution through changing environments led organisms to develop an arsenal of cytoprotective pathways to promote their survival under stressful conditions. Our work provides insights into the ways by which tumors co-opt these normal biological networks to support their survival in the stressful tumor microenvironment. This abstract is also presented as Poster B40. Citation Format: Ruth Scherz-Shouval, Marc L. Mendillo, Giorgio Gaglia, Irit Ben-Aharon, Andrew H. Beck, Luke Whitesell, Susan Lindquist. Mechanisms of stromal reprogramming mediated by heat shock factor 1. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr PR07.
The power of the biomarker for cervical cancer control
Authors: N. S. Markovic, O. Markovic, E. S. Henderson
Journal: Journal of Clinical Oncology (2006)

11001 Background: At ASCO 2001, the Cervical Acid Phosphatase - Papanicolaou Test (CPT) was introduced as a biomarker-based technology as a potential in vitro diagnostic device. At ASCO 2004 and 2005, we reported results from clinical trials on 2,000 subject/specimens. In a setting of standard cervical cancer screening, the safety and effectiveness of CPT (MarkPap® Test) was compared with control Pap smear and LBP. The favorable results motivated us to expand this translational research in areas where this biomarker is crucial: self-sampling and digital evaluation. We report a pilot study designed to assess whether upgrading CPT with digital image processing (IT technology) could create a new device for an effective telecytopathology. Methods: Material: Cervical specimens self-obtained by volunteers, specimens collected in prior clinical trials (Library of MarkPap slides), and control slides. Instruments and methods: We have assembled a set of instruments and procedures to create images from microscopic slides, to convert analog into digital images, to capture and store digital images and clinical data in computer files, to transfer image files via Internet to a central server for evaluation by cytotechnologist/pathologists, and to return the reports within hours. At the end, the results of reading digital and direct images were available for comparison. Results: Since each instrument was “fit-for-use”, we have tested different “conditions-for-use” for providing digital images comparable to direct images. Images of self-sampled specimens, controls and existing slides were processed through a new setup of five modules: image acquisition, image and data transferring, image evaluation, results reporting and quality control. It was made possible by upgrading software. There was no difference between results obtained after evaluation of digital or direct images. Conclusion: Using CPT and available instruments and software, we have developed a prototype in vitro diagnostic medical device, which could permit expert evaluation of cervical specimens to be performed rapidly and at affordable cost for developing countries. This device should be able to use self-obtained specimens, field laboratory personnel and equipment, but to provide high-qualified evaluation within hours for an easy affordable cost. [Table: see text]
Verification of imatiNib cost-effectiveness in advanced gastrointestinal stromal tumor in British Columbia (VINCE)
Authors: V. Mabasa, S. C. Taylor, C. C. Chu, V. Moravan, S. Peacock, M. Knowling
Journal: Journal of Clinical Oncology (2007)

10049 Background: To evaluate the cost-effectiveness of imatinib in British Columbia Cancer Agency (BCCA) patients with advanced gastrointestinal stromal tumors (GIST) in terms of median overall survival (OS) and median progression-free survival (PFS). Results were also compared to imatinib literature reports. Methods: A pragmatic, retrospective medical record review identified BCCA patients with advanced GIST who received imatinib or historical treatment during successive, pre-specified time periods. Data was collected on survival, duration of therapy, progression free status, and cost of drug, labour and supplies. Primary outcome was the cost-effectiveness of imatinib based on median-OS (Kaplan Meier method). Secondary outcomes were cost-effectiveness based on median overall-PFS, cost of therapy per patient, 1-year OS, and 1-year PFS. This study was conducted from the perspective of the BCCA. Sensitivity analyses varying effectiveness over the 95% CI, cost over the range of treatment duration, discounting level at 0, 3 and 5%, and comparing effectiveness to literature controls were performed. Life expectancy (mean survival), was also calculated and used in the CE sensitivity analysis. Results: Forty-six and 47 patients in the imatinib and historical groups respectively were analyzed. Median-OS in the imatinib group was 66.7 months (95% CI 61.7, infinity) compared to 7.7 months (95% CI 6.0, 12.6) in the historical group. Median-PFS was 45.3 months (95% CI 24.4, infinity) and 5.6 months (95% CI 3.5, 8.5) respectively. The 1-year OS and 1-year PFS for the imatinib group was 95.4% (95% CI 82.9, 99.2) and 81.4% (95% CI 66.1, 91.1) compared to 32.6% (95% CI 20.0, 48.1) and 17.4% (95% CI 8.3 - 32.0) in the historical group. No difference was seen between the imatinib study results and literature reports. The annual incremental cost-effectiveness ratio was $15,882 per median life year gained and $23,603 per median year of PFS for imatinib. Conclusions: Imatinib for advanced GIST is a cost- effective treatment in BC. Results were robust across the range of sensitivity analyses performed. No significant financial relationships to disclose.
GW26-e4511 Blockade of Histone Demethylase JMJD2A Stimulates Endothelial Repair in Denuded Aorta of diabetic Rat
Authors: Qi Hu, Jing Zhang, Changwu Xu, Shuo Yang, Xiaorong Hu, Jian Yang, Jing Chen, Hong Jiang
Journal: Journal of the American College of Cardiology (2015)
Randomized phase II trial of the neurokinin-1 receptor antagonist (NK-1 RA) casopitant mesylate with ondansetron (ond)/dexamethasone (dex) for chemotherapy-induced nausea/vomiting (CINV) in patients (pts) receiving highly emetogenic chemotherapy (HEC)
Authors: J. Rolski, R. Ramlau, M. Dediu, M. W. Russo, G. A. Ross, R. A. Mather, R. R. Bandekar, S. M. Grunberg
Journal: Journal of Clinical Oncology (2006)

8513 Background: A combination of a 5-HT3 receptor antagonist (5-HT3 RA) + dex is standard for prevention of CINV due to HEC. However, NK-1 RAs are now also of interest. The current trial evaluated casopitant mesylate, a potent, oral, selective NK-1 RA, in a triple therapy regimen with a 5-HT3 RA and dex in pts receiving HEC. Methods: In this multicenter, randomized, double-blind, placebo-controlled, dose-ranging, parallel group study, pts receiving HEC were stratified by gender and randomized among six arms. HEC consisted of regimens including cisplatin ≥ 70 mg/m 2 IV over 1–4 hours (h) day 1 (D1). All pts received ond 32mg IV D1 and dex PO D1–4 with either placebo control, casopitant 50mg QD D1–3, casopitant 100mg QD D1–3, or casopitant 150mg QD D1–3. Pts on exploratory arms received ond/dex plus either casopitant 150 mg D1 only or aprepitant 125mg D1 and 80mg D2–3. The primary endpoint was complete response (CR) rate (no vomiting, retching, rescue medications or premature withdrawals) during the first 120 h following initiation of HEC. Target intent-to-treat (ITT) group enrollment was 82 pts per arm. Results: 493 enrolled patients comprised the ITT group. CR rate was 60% in the control arm; 76% for casopitant 50mg; 86% for 100mg; and 77% for 150mg (p=.0036, Cochran-Armitage trend test). CR rate was 75% with casopitant 150 mg D1 and 72% for 3-day aprepitant. CR rates at 24 h were similar in all groups (86%-96%). Casopitant prolonged time to emesis (p=.0029) and increased the proportion of pts without vomiting (p=.0122) relative to control. There were no differences in rates of nausea or use of rescue medication among groups. Adverse events were similar across all arms, with neutropenia, nausea, and hiccups (≤ 17%) as most common. All casopitant doses were generally well tolerated. Conclusions: The addition of casopitant to ond/dex at all doses tested and in 1- or 3-day administration regimens was well tolerated and significantly reduced CINV rates over a 5-day period in pts receiving HEC. The results of the exploratory 1-day regimen are of particular interest for future evaluation. [Table: see text]
Characteristic Macrocytic Anemia, Ineffective Erythropoiesis, and Iron Overload in 5q-Mice and Effect of Exogenous Transferrin
Authors: Maria Feola, Tenzin Choesang, Weili Bao, Li Huihui, Huiyong Chen, Shuming Sun, Petra Pham, Guiyuan Li, Amit Verma, Antonia Follenzi, Yelena Ginzburg
Journal: Blood (2015)
Effect of combinations of EGF-R antibodies on complement-dependent tumor cell lysis
Authors: M. Dechant, W. Weisner, S. Berger, M. Peipp, J. J. Lammerts van Bueren, W. K. Bleeker, P. W. Parren, J. G. van de Winkel, T. Valerius
Journal: Journal of Clinical Oncology (2008)

14005 Background: Therapeutic EGF-R antibodies have advanced the treatment of colon and head & neck tumors and bear great promise for other cancers. While several methods of action have been identified for EGF-R antibodies, induction of complement depending cytotoxicity (CDC) has so far not been observed. We asked whether antibody combinations might provide benefit for this mechanism. Methods and Results: We investigated 8 EGF-R antibodies of human IgG1 (cetuximab, matuzumab, zalutumumab, 003, 005, 008, 011 and 018) and 1 of human IgG2 isotype (panitumumab). Select combinations led to increased C1q and C4c fixation - determined by immunofluorescence - and correspondingly induced strong CDC of A431 and A1207 cells in 51-Cr release assays. Experiments with Ca++/Mg++ depletion and heat inactivation of serum indicated the classical complement pathway to be responsible. Studies comparing a human IgG1 with its murine parental antibody, respective F(ab’)2 fragments, or its IgA1 variant demonstrated two human IgG1 antibodies to be mandatory for CDC. Immunofluorescence-based cross-competition studies identified two clusters of EGF-R binding epitopes (cluster 1: cetuximab, matuzumab, panitumumab, zalutumumab, 018; cluster 2: 003, 005, 008, 011). In cluster 1, three combinations were non-crossblocking, while the remaining combinations competed with each other. In cluster 2, all combinations were crossblocking. None of the combinations of cluster 1 and cluster 2 was crossblocking. All possible dual combinations of the 8 IgG1 antibodies were investigated for complement activation. Strong synergism was observed for all non-crossblocking combinations, whereas none of the crossblocking combinations triggered CDC. Conclusions: Here, we demonstrate a remarkable synergy for EGF-R antibodies. Antibody combinations were identified resulting in potent complement activation via the classical pathway and effective CDC of tumor cells. Studies on a large antibody panel indicated that the observed synergy is a general mechanism which can be activated by combining human IgG1 antibodies recognizing different, non-overlapping epitopes. Our findings demonstrate an unexpected quality of EGF-R antibodies which may be exploited to develop novel and more effective treatments for solid cancers. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genmab
Health and functional status of long-term adult medulloblastoma/PNet survivors: A report from the Childhood Cancer Survivor Study.
Authors: Allison A. King, Stephanie Mabry Perkins, Kristy Seidel, Chongzhi Di, Wendy M. Leisenring, Kevin R. Krull, Charles A. Sklar, Daniel M. Green, Gregory T. Armstrong, Lonnie K. Zeltzer, Elizabeth Wells, Marilyn Stovall, Nicole Ullrich, Kevin C. Oeffinger, Leslie L. Robison, Roger Packer
Journal: Journal of Clinical Oncology (2014)

9515 Background: Medulloblastoma is the most common malignant childhood CNS tumor. Survival rates increased from 40% to 70% during the past 30 years. The long-term risks of chronic medical conditions, adverse health status, and reduced psychosocial functioning in aging survivors of childhood medulloblastoma/PNET are not known. Methods: Using the Childhood Cancer Survivor Study cohort, we analyzed the long-term outcomes of 380 5+ year survivors of medullobastoma/PNET (median age at last follow-up: 30 years, range 7-53), diagnosed between 1970-1986. A sibling cohort (n=4031) served as a comparison population. Neurological outcomes and cataracts were analyzed as time-to-event data with cumulative incidence, with Cox regression models used to calculate hazard ratios (HR) and 95% confidence intervals (CI). Memory complications, educational status, marital status, independent living, employment status, income, and fertility were assessed cross-sectionally using generalized linear models. Comparisons were adjusted for age and sex. Results: By 30 years post diagnosis, mortality was 29% (CI 23-36). Cumulative incidence of second malignant neoplasm was 8% (CI 5-12), and recurrence of the original cancer 18% (CI 14-22) at 30 years. Cumulative incidence for hearing loss was 37% (CI 31-44), seizures 34% (CI 29-39), balance problems 72% (CI 67-77), tinnitus 30% (CI 23-37) and cataracts 14% (CI 9-18). Relative to siblings, survivors reported a higher risk of hearing loss (HR=36.0, CI 23.6-54.9), seizures (HR=12.8, CI 9.0-18.1), poor balance (HR=10.4, CI 6.7-15.9), tinnitus (HR=4.8, CI 3.5-6.8), and cataracts (HR=31.8, CI 16.7–60.5). Survivors were less likely to earn a bachelor’s degree (RR=0.49, CI 0.39-0.60), to marry (RR=0.35, CI 0.29–0.42), to live independently (RR=0.58, CI 0.52-0.66) and to have a pregnancy or a partner become pregnant (RR=0.23, CI 0.17–0.3). Conclusions: Among adult survivors of childhood medulloblastoma/PNET, significant neurologic morbidity and lower levels of educational attainment and social independence exist. Given the high survival rates for these children, interventions to reduce these sequelae and support the survivors should be a high priority.
Antibiotic effects on gut microbiota and metabolism are host dependent
Authors: Shiho Fujisaka, Siegfried Ussar, Clary Clish, Suzanne Devkota, Jonathan M. Dreyfuss, Masaji Sakaguchi, Marion Soto, Masahiro Konishi, Samir Softic, Emrah Altindis, Ning Li, Georg Gerber, Lynn Bry, C. Ronald Kahn
Journal: Journal of Clinical Investigation (2016)

Interactions of diet, gut microbiota, and host genetics play important roles in the development of obesity and insulin resistance. Here, we have investigated the molecular links between gut microbiota, insulin resistance, and glucose metabolism in 3 inbred mouse strains with differing susceptibilities to metabolic syndrome using diet and antibiotic treatment. Antibiotic treatment altered intestinal microbiota, decreased tissue inflammation, improved insulin signaling in basal and stimulated states, and improved glucose metabolism in obesity- and diabetes-prone C57BL/6J mice on a high-fat diet (HFD). Many of these changes were reproduced by the transfer of gut microbiota from antibiotic-treated donors to germ-free or germ-depleted mice. These physiological changes closely correlated with changes in serum bile acids and levels of the antiinflammatory bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) and were partially recapitulated by treatment with a TGR5 agonist. In contrast, antibiotic treatment of HFD-fed, obesity-resistant 129S1 and obesity-prone 129S6 mice did not improve metabolism, despite changes in microbiota and bile acids. These mice also failed to show a reduction in inflammatory gene expression in response to the TGR5 agonist. Thus, changes in bile acid and inflammatory signaling, insulin resistance, and glucose metabolism driven by an HFD can be modified by antibiotic-induced changes in gut microbiota; however, these effects depend on important interactions with the host's genetic background and inflammatory potential.
Unique pathological tau conformers from Alzheimer’s brains transmit tau pathology in nontransgenic mice
Authors: Jing L. Guo, Sneha Narasimhan, Lakshmi Changolkar, Zhuohao He, Anna Stieber, Bin Zhang, Ronald J. Gathagan, Michiyo Iba, Jennifer D. McBride, John Q. Trojanowski, Virginia M.Y. Lee
Journal: The Journal of Experimental Medicine (2016)

Filamentous tau aggregates are hallmark lesions in numerous neurodegenerative diseases, including Alzheimer’s disease (AD). Cell culture and animal studies showed that tau fibrils can undergo cell-to-cell transmission and seed aggregation of soluble tau, but this phenomenon was only robustly demonstrated in models overexpressing tau. In this study, we found that intracerebral inoculation of tau fibrils purified from AD brains (AD-tau), but not synthetic tau fibrils, resulted in the formation of abundant tau inclusions in anatomically connected brain regions in nontransgenic mice. Recombinant human tau seeded by AD-tau revealed unique conformational features that are distinct from synthetic tau fibrils, which could underlie the differential potency in seeding physiological levels of tau to aggregate. Therefore, our study establishes a mouse model of sporadic tauopathies and points to important differences between tau fibrils that are generated artificially and authentic ones that develop in AD brains.
Donor Dendritic Cells Home to Lymphoid Organs in Allogeneic Transplant Recipients, Enhance Donor T-Cell Chimerism, and Polarize Donor T-Cell Activation.
Authors: Kimberly T. Fan, Jian-Ming Li, Ying Lu, Wayne Harris, Kataryna A. Darlak, Parvin Forghani, Keihyun Shin, Chunzi Huang, Edmund K. Waller
Journal: Blood (2009)
Surgical practice patterns following NCCTG N0338 “Phase II trial of docetaxel and darboplatin administered every two weeks as induction therapy for stage II and stage III breast cancer.”
Authors: H. Apsey, V. Roy, B. Pockaj, D. Northfelt, R. Sticca, D. A. Nikcevich, B. Mattar, T. Fitch, E. A. Perez
Journal: Journal of Clinical Oncology (2009)

623 Background: Neoadjuvant therapy plays an important role in breast cancer treatment. Unlike patients who undergo surgery followed by adjuvant therapy,there are no established guidelines for surgical management following neoadjuvant therapy. Methods: Surgical practice patterns from 50 patients in N0338 “Phase II trial of Docetaxel and Carboplatin administered every two weeks as induction therapy for Stage II and Stage III breast cancer” were reviewed. The protocol did not mandate surgical therapy leaving the decision to the treating surgeon and patient. Results: 66% of patients underwent mastectomy (M) and 33% underwent breast conservation therapy (BCT). Three (9%) had immediate reconstruction. Eight (24%) underwent contralateral prophylactic M. Residual tumor size did not always impact primary surgical therapy. In the M group 4 (12%) had no residual disease, 15 (45%) &lt; 2cm and 14 (42%) &gt; 2cm; whereas, in the BCT group 1 (6%) had no residual disease, 12 (70%) &lt; 2cm and 4 (24%) &gt; 2cm. Axillary lymph node (ALN) staging varied tremendously. Three (6%) patients presented with palpable lymphadenopathy and proceeded to complete axillary lymph node dissection (ALND) after chemotherapy (CT). Fine needle aspiration (8) or core needle biopsy (7) of the axilla was performed in 15 (30%) patients before CT; 1 was negative and went on to have sentinel lymph node biopsy (SLNB) after CT; 14 (94%) were positive with 13 (86%) going on to ALND and 1 SLNB after CT. Five (10%) underwent SLNB prior to CT. One (20%) was positive and went on to have ALND after CT; 4 (8%) were negative and had no further ALN staging. A total of 19 (39%) had SLNB after neoadjuvant therapy; 13 (68%) were positive and underwent ALND; 1 SLNB failed; 2 of 5 that were negative underwent ALND with 1 having a positive lymph node. Ten (20%) underwent ALND with no pre-operative staging with 8 being positive for ALN metastases. Conclusions: Review of study data from multiple institutions revealed no consistent criteria in selection of surgical intervention for the breast tumor or ALN staging. There remains a need for further research in this area to establish standard practice guidelines. Support from NIH, sanofi-aventis, Amgen, Breast Cancer Research Foundation. No significant financial relationships to disclose.
Prediction of Poor Outcome After Transcatheter Aortic Valve Replacement
Authors: Suzanne V. Arnold, Jonathan Afilalo, John A. Spertus, Yuanyuan Tang, Suzanne J. Baron, Philip G. Jones, Michael J. Reardon, Steven J. Yakubov, David H. Adams, David J. Cohen
Journal: Journal of the American College of Cardiology (2016)
Acetylation of PGK1 promotes liver cancer cell proliferation and tumorigenesis
Authors: Hongli Hu, Wenwei Zhu, Jun Qin, Min Chen, Liyan Gong, Long Li, Xiangyuan Liu, Yongzhen Tao, Huiyong Yin, Hu Zhou, Lisha Zhou, Dan Ye, Qinghai Ye, Daming Gao
Journal: Hepatology (2016)

Phosphoglycerate kinase 1 (PGK1) is an important enzyme in the metabolic glycolysis pathway. In this study, we observed a significant overexpression of PGK1 in liver cancer tissues and a negative correlation between PGK1 expression and liver cancer patient survival. Furthermore, depletion of PGK1 dramatically reduced cancer cell proliferation and tumorigenesis, indicating an oncogenic role of PGK1 in liver cancer progression. Moreover, we identified acetylation at the K323 site of PGK1 as an important regulatory mechanism for promoting its enzymatic activity and cancer cell metabolism. And we further characterized P300/cyclic adenosine monophosphate response element binding protein-binding protein-associated factor (PCAF) and Sirtuin 7 as the enzymes regulating K323 acetylation from both directions in liver cancer cells.These findings demonstrate a novel regulation of PGK1 as well as its important role in liver cancer progression. (Hepatology 2017;65:515-528).