tbuckley/cabot-search huggingface dataset:
Dose-Response Studies to Polyoma Virus in Rats&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: J. S. Flocks, T. P. Weis, D. C. Kleinman, W. H. Kirsten
Journal: JNCI Journal of the National Cancer Institute (1965)

Newborn, inbred, polyoma-free Wistar/Furth (W/Fu) rats were inoculated intravenously with 0.05 ml of increasing dilutions (10−0.3–10−4) from a common pool of polyoma virus. The response of W/Fu rats to polyoma virus was measured with respect to three parameters: tumor frequency, survival times, and histologic types of polyoma tumors. As expected, tumor frequency was markedly increased and survival times were markedly decreased with increasing virus dose. The histologic types of polyoma tumors also varied with virus concentration. The inoculation of the highest virus doses (100 and 10−0.3) resulted in the formation of multiple capillary, cystic, or cavernous hemangiomas in the brain or spinal cord. Massive hemorrhages from these hemangiomas caused death within 14 to 29 days after birth. Medium virus doses (10−1–10−2.3 dilutions) induced multiple tumors including renal sarcomas, hemangiomas, mesenchymomas, osteogenic sarcomas, exostoses of bones, and an occasional subcutaneous fibromatosis. The mean survival times for rats receiving intermediate doses ranged from 28 to 42 days post partum. Low virus doses (10−3–10−3.3 dilutions) caused a single tumor, usually a renal sarcoma, after long survival times (63–110 days). Hemangiomas did not occur in the low virus-dose groups. The three dose-dependent response patterns were referred to as “hemangiomatous response,” “multiple tumor response,” and “late tumor response.” To detect strain differences in the tumor frequency from polyoma virus, the standard polyoma virus pool was inoculated intravenously in dilutions 100 or 10−2 into newborn Wistar, noninbred Sprague-Dawley, and inbred August rats. No strain differences were found with the undiluted virus pool. Tumor frequency after injection of a 10−2 dilution was 84 to 86 percent for the two noninbred strains as opposed to 35 percent for the inbred strain. Susceptibility of rats to oncogenesis by polyoma virus ceased after the 7th day post partum.
Presurgical bevacizumab in patients with metastatic clear cell renal cell carcinoma: A phase II study
Authors: E. Jonasch, C. G. Wood, S. Matin, P. Tamboli, K. Do, L. C. Pagliaro, A. M. Aparicio, J. C. Araujo, N. M. Tannir
Journal: Journal of Clinical Oncology (2008)

5104 Background: The increasing use of targeted therapies in metastatic renal cell carcinoma (mRCC) has raised questions about the timing of cytoreductive nephrectomy. We initiated a phase II trial to evaluate the safety and efficacy of presurgical bevacizumab (bev) in newly diagnosed patients (pts) with mRCC, with the hope of improving clinical outcomes and to obtain tissue for correlative studies. Methods: Pts with conventional-type mRCC with PS 0/1, resectable primary tumor and no brain metastasis received bev 10 mg/kg iv q2wks (plus erlotinib 150 mg daily for the first 25 pts) for 8 wks, followed 4 weeks later by cytoreductive nephrectomy. Primary endpoints: progression free survival (PFS) and safety. Secondary endpoints: response rate (RR), overall survival (OS) and correlative studies. Responding or stable pts resumed bev 4 weeks postoperatively. Response was defined by RECIST. PFS was measured from registration to date of progressive disease (PD) or death from any cause. Overall survival (OS) was measured from registration to date of death from any cause. Results: Forty-eight of fifty pts have been enrolled. Two pts did not receive study drug and were excluded from the analyses. Median age was 61 (range 35–83). 89% had at least two sites of metastatic disease. 83% had intermediate risk disease, and 17% had poor risk disease. Among the 46 pts who received at least one dose of study drug, 1 achieved a complete response in his target lesion (cCR) but stability in a bone lesion, 4 achieved a partial response (PR), and 27 achieved stable disease (SD). Seven patients did not undergo nephrectomy. Three patients died in the perioperative period. The response rate (cCR + PR) was 10.9% (95% C.l., 3.6–23.6). The clinical benefit rate (cCR + PR + SD) was 69.6% (95% C.I.,54–82.3%). Thirty pts developed PD or died, with median PFS of 6.0 mos (95% C.I,4.9–16.5). Sixteen pts died, with median OS of 25.4 mos (95% C.I.,13.3-Not Estimable). Common adverse events included hypertension, diarrhea, anemia, and abdominal pain. There were no major perioperative complications clearly attributable to study drug. Conclusions: Presurgical treatment of mRCC patients with bevacizumab is safe and feasible. Clinical outcomes were acceptable considering the relatively high disease burden of the study population. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Antigenics, Ethicon, Pfizer Oncology Antigenics, Bayer, Bristol-Myers Squibb, Ethicon, Onyx, Pfizer Oncology
More on follicular lymphomas.
Authors: J R Anderson, J O Armitage, D D Weisenberger
Journal: Journal of Clinical Oncology (1993)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1993.11.9.1834 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 8355051 More on follicular lymphomas. J R AndersonxJ R AndersonSearch for articles by this author , J O ArmitagexJ O ArmitageSearch for articles by this author , D D WeisenbergerxD D WeisenbergerSearch for articles by this author https://doi.org/10.1200/JCO.1993.11.9.1834 First Page PDF © 1993 by American Society of Clinical Oncology
Abstract 15302: Genetic Enhancement of Insulin-Like Growth Factor-1 in Human Cardiac Stem Cells Prevents Cell Death and Enhances Ischemic Myocardial Repair
Authors: Robyn Jackson, Everad L Tilokee, Nicholas Latham, Bin Ye, Munir Boodhwani, Vincent Chan, Marc Ruel, Erik J Suuronen, Duncan J Stewart, Darryl R Davis
Journal: Circulation (2013)

Insulin-like growth factor (IGF-1) activates pro-survival pathways and improves post ischemic cardiac function but this key cytokine is not expressed by  ex vivo  proliferated human cardiac stem cells (CSCs). Here, we explore the influence of an IGF-1 enhanced paracrine signature on CSC-mediated cardiac repair.   Methods/Results:  To rationalize the timing of IGF-1 delivery to infarcted myocardium, the expression of the IGF-1 receptor (IGF-1R) transcript was screened in myocardial samples from C57 mice taken 1, 7, 14 and 21 days after experimental myocardial infarction (MI). Seven days after LAD ligation, IGF-1R expression was increased by 1.4±0.7 and 3.0±0.8 fold in the infarct and border zones (p≤0.05) and remained elevated throughout the sampling period. Based on these data, human CSCs underwent lentivirus-mediated somatic gene transfer to overexpress human IGF-1 (CSC IGF-1 ) or the GFP reporter alone (CSC GFP ). Genetic engineering enhanced the IGF-1 content within hypoxic conditioned media by 8.1±1.9 fold (p=0.01) with no discernible effects on population doubling time (1.1±0.3 vs. 1.2±0.1 days, p=ns). With the exception of enhanced IGF-1, a proteomic array of 59 cardioprotective/pro-angiogenic cytokines demonstrated that CSC IGF-1  engineering improved the secretion of additional cytokines compared to CSC GFP . Culture of CSC IGF-1  within conditions designed to mimic the ischemic border zone improved proliferation and reduced the expression of annexin V compared to CSC GFP  or non-transduced CSCs (proliferation: 30±13% vs. -14±15% or -19±12% change in cell numbers, p≤0.05; annexin V: 30±6% vs. 74±9% or 77±1%, respectively; p≤0.05). These results may be partially explained through the enhancement of downstream activators within the AKT, ERK and MAPK pro-survival pathways (p≤0.05 vs. CSC GFP ). Intra-myocardial injection of CSC IGF-1  into immunodeficient mice one week after MI enhanced cardiac repair as compared to CSC GFP  and vehicle controls. (echocardiographic left ventricular ejection fraction 28 days post LAD ligation: 41±1% vs. 37±1% or 25±1%, respectively; p   Conclusions:  Paracrine engineering of CSCs to over-express IGF-1 boosts CSC resistance to hypoxia and improves cell-mediated cardiac repair.
Efficacy and Safety in Tania, a Randomised Phase III Trial of Continued or Reintroduced Bevacizumab (Bev) After 1St-Line Bev for Her2-Negative Locally Recurrent/Metastatic Breast Cancer (Lr/Mbc)
Authors: G. von Minckwitz, F. Puglisi, J. Cortes, E. Vrdoljak, N. Marschner, C. Zielinski, C.B. Villanueva, G. Romieu, I. Láng, E. Ciruelos, M. De Laurentiis, C. Veyret, S. De Ducla, U. Freudensprung, S. Srock, J. Gligorov
Journal: Annals of Oncology (2014)
Association of DNA promoter hypermethylation of decoy receptor 1 (DCR1) with poor response to irinotecan in metastatic colorectal cancer.
Authors: Wim Van Criekinge, Linda JW Bosch, Geert Trooskens, Petur Snaebjornsson, Josien Haan, Lorraine Cheryl Pelosof, Miriam Koopman, Jolien Tol, Joost Louwagie, Luc Dehaspe, Nicole C.T. van Grieken, Bauke Ylstra, Henk M.W. Verheul, Manon van Engeland, Iris D. Nagtegaal, James Gordon Herman, Cornelis J. A. Punt, Beatriz Carvalho, Gerrit A. Meijer
Journal: Journal of Clinical Oncology (2013)

3552 Background: Heterogeneity in the biology of colorectal cancer (CRC) is associated with variable responses to standard chemotherapy. We aimed to identify DNA hypermethylated genes as predictive biomarkers for irinotecan treatment of patients with metastatic CRC. Methods: The presence of DNA methylation for a selected panel of 22 genes was assessed by methylation specific PCR (MSP) on primary tumors of 185 patients with metastatic CRC treated with first-line capecitabine (CAP, n=90) or a combination of capecitabine and irinotecan (CAPIRI, n=95) in the phase 3 CAIRO trial. Methylation status of each gene was correlated to progression free survival (PFS) by treatment regimen. Genes for which methylation status associated with response to irinotecan, were validated in 166 patients treated with first-line CAP (n=78) or CAPIRI (n=88). Results: Decoy Receptor 1 (DCR1) was identified as a novel hypermethylated gene in CRC. In CAPIRI treated patients, DCR1 methylation was correlated to a shorter PFS compared to patients with unmethylated DCR1 (hazard ratio [HR]=0.4 (95%CI =0.3-0.7), p = 0.0009). In patients with methylated DCR1 PFS did not improve with CAPIRI treatment, compared to treatment with CAP (discovery set: HR=0.8 (95%CI=0.5-1.3, p=0.4); validation set: HR=1.1 (95%CI 0.7-1.7, p=0.6)), in contrast to patients with unmethylated DCR1 (discovery set: HR=2.5 (95%CI 1.7-3.3, p=0.00004); validation set: HR=1.7 (95%CI 1.1-2.0, p=0.004)). Conclusions: CRC patients with methylated DCR1 did not benefit from adding irinotecan to capecitabine therapy, indicating that DCR1 methylation status may guide selecting metastatic CRC patients for irinotecan-based therapy.
Distribution of Certain Autoantibodies in Monozygotic and Dizygotic Twins
Authors: W. Watson Buchanan, J. A. Boyle, W. R. Greig, R. McAndrew, M. Barr, J. R. Anderson, R. B. Goudie
Journal: Annals of the Rheumatic Diseases (1966)

It is now well established that autoantibodies are found in a number of disease conditions such as
Biologic significance of TS, TK, and OPRT activities in renal cell carcinoma.
Authors: Y. Mizutani, H. Azuma, Y. Katsuoka
Journal: Journal of Clinical Oncology (2011)

e15003 Background: Thymidylate synthase (TS), thymidine kinase (TK) and orotate phosphoribosyltransferase (OPRT) are the key enzymes in the de novo and salvage DNA synthetic process. 5-FU is a prodrug and OPRT is the principal enzyme which directly converts 5-FU to an active anticancer metabolite, FdUMP. TS is a target for FdUMP. Little is known about the significance of TS, TK and OPRT activities in various cancers including renal cell carcinoma (RCC). We measured TS, TK and OPRT activities in 83 RCCs and normal kidneys, and evaluated the association between the enzymatic activities and the stage/grade status of RCC. Furthermore, prognostic significance was also examined in patients with RCC. Methods: TS, TK and OPRT activities in 83 non-fixed fresh frozen RCCs and normal kidneys were determined enzymatically by the FdUMP binding assay, the DEAE cellulose disc method and the 5-FU phosphorylation assay, respectively. Results: TS activity was 5-fold higher in RCC compared to normal kidney. TS activity in Stage III/IV RCC was 3-fold higher than that in Stage I/II RCC. In addition, TS activity in Grade 3 RCC was 2-fold higher than that in Grade 1 and Grade 2 RCC. TK activity was approximately 4-fold higher in normal kidney compared with RCC. TK activity in Stage IV RCC was 2-fold higher than that in Stage I-III RCC. Furthermore, TK activity in Grade 3 RCC was 2-fold higher than that in Grade 1 and Grade 2 RCC. OPRT activity was approximately 7-fold higher in RCC compared to normal kidney. OPRT activity in Stage III/IV RCC was 2-fold higher than that in Stage I/II RCC. OPRT activity in Grade 3 RCC was 3-fold higher than those in Grade 1 and Grade 2 RCCs. The level of OPRT activity was positively correlated with those of TS and TK activities. Higher TS, TK and OPRT activities predicted worse prognosis in patients with RCC. Higher TS activity, lower TK activity and higher OPRT activity in RCC cells were positively correlated with higher sensitivity to 5-FU. Conclusions: The present study has demonstrated that TS, TK and OPRT activities were prognostic parameters in patients with RCC. Moreover, TS, TK and OPRT activities were predictive indicators for 5-FU efficacy in RCC. The present study has shown that TS, TK and OPRT activities may be molecular targets for the therapy against RCC.
Semi-physiological pharmacokinetic-pharmacodynamic (PK/PD) models for troxacitabine-induced neutropenia and thrombocytopenia
Authors: C. M. Ng, B. Muralidhar, C. H. Takimoto, C. Lin, A. Patnaik
Journal: Journal of Clinical Oncology (2007)

13002 Background: Neutropenia and thrombocytopenia are the dose-limiting toxicities of troxacitabine in Phase 1 studies. The present study’s aim was to develop a novel semi-physiological PK/PD model that can simultaneously describe the time course of the absolute neutrophil and platelet count changes in cancer patients receiving troxacitabine. Methods: The mixed-effect modeling was performed using the Monte-Carlo Parametric Expectation Maximization algorithm implemented in SADAPT program. The analysis was based on PK/PD data from 31 subjects who received troxacitabine/cisplatin combination every 28 days at five different dose levels (4.8/50, 4.8/75, 6.4/50, 6.4/75, 8.0/75 mg/m 2 ). The PD model consisted of 1) a troxicatabine-sensitive uncommitted progenitor cell compartment, which differentiates into committed neutrophil and platelet progenitor cells that are also sensitive to the troxacitabine, and 2) transit compartments for neutrophils and platelets that represent maturation stages in bone marrow. To capture the rebound phenomena and maintain the hemostasis, the model included a feedback mechanism for both neutrophils and platelets. The troxacitabine concentrationtion-time profiles affected the proliferation of sensitive progenitor cells through an inhibitory sigmoidal Emax model. A three-compartment linear pharmacokinetic model was developed to describe the troxaicibatine concentration-time profile. Results: The PD model described the time-course of troxacitabine- induced neutrophil and platelet cytopenias and accounted for the large observed inter-patient variability. The model predicted that neutrophil progenitor cells were more sensitive to troxacitabine therapy compared to platelet progenitor cells. Furthermore, the model suggested that the troxacitabine-induced neutropenia and thrombocytopenia are reversible and non-cumulative events. Conclusions: This novel model can describe both the intensity and duration of troxacitabine-induced thrombocytopenia and neutropenia rather than simply considering the nadir values. It may be valuable for selecting treatment regimens that minimize troxacitabine’s dose-limiting hematological toxicities. No significant financial relationships to disclose.
Phase I trial of intermittent administration of sorafenib (BAY 43–9006) for patients (pts) with refractory/relapsed acute myelogenous leukemia (AML)
Authors: A. Quintas-Cardama, H. Kantarjian, M. Andreef, S. Faderl, J. Wright, W. Zhang, M. Konopleva, S. Verstovsek, G. Borthakur, J. Cortes
Journal: Journal of Clinical Oncology (2007)

7018 Background: Fms-like tyrosine kinase 3 (FLT3) mutations, both internal tandem duplication (ITD) and point mutations, occur in approximately 30% of pts with AML and confer poor prognosis. Sorafenib is an oral multi-kinase inhibitor highly potent against mutant FLT3 (IC 50 1–3 nM). Based on preclinical data, this study was initiated to assess two intermittent administration schedules of sorafenib. Methods: This phase I trial evaluated the safety and efficacy of sorafenib in 15 pts with refractory/relapsed AML (n=14) or high-risk myelodysplastic syndrome (n=1). Pts were randomized to sorafenib for 5 days per week (arm A; n=8) or for 14 days every 21 days (arm B; n=7). In both arms, dose level (DL) 1 was 200 mg twice daily in 21-day cycles. Successive DLs were 600, 800, and 1,200 mg daily on a standard 3+3 design. Pre- and post-treatment peripheral blood (PB) and bone marrow (BM) samples were obtained for evaluation of FLT3 status and phospho and total FLT3 and ERK expression. Results: 10 (67%) of 15 pts (all with AML) received at least 1 cycle of sorafenib (5 in arm A, 5 in arm B) and 5 discontinued sorafenib (3 in arm A, 2 in arm B): 3 due to disease progression, and 2 due to infectious complications. Pts who received at least 1 cycle were treated at DL-1 (n=4) or DL-2 (n=6). Median age was 61 years (range, 51–81), number of prior therapies 4 (range, 1–6), and time from diagnosis to sorafenib 9 months (range, 5–46). Sorafenib was well tolerated; the MTD has not been reached. Six (60%) of 10 pts receiving at least 1 cycle of sorafenib (3 in arm A, 3 in arm B) responded. Responses were transient and only occurred in pts with FLT3-ITD mutation. The median blast percentage before and after sorafenib start was 59% and 0% in PB (p=0.008) and 66% and 32% in BM (p=0.03). Serial determinations of phosphorylation status following sorafenib (at 0, 2, 24,120 hours) in pts with FLT3-ITD, demonstrated inhibition of phospho-FLT3 in 3/3 and phospho-ERK in 5/5 pts. Conclusions: Sorafenib is safe in AML and has encouraging activity at the relatively low doses tested thus far, particularly in pts with FLT3-ITD mutation. Clinical studies of sorafenib in combination with chemotherapy or other targeted agents are warranted in pts with AML expressing this abnormality. [Table: see text]
K-ras and EGFR mutations in 24 Chinese patients with non-small-cell lung cancer (NSCLC) treated with gefitinib
Authors: Z. Wang, Y. Wu, G. Zhang, J. Lin, Q. Zhou, C. Xu, A. Guo
Journal: Journal of Clinical Oncology (2006)

17109 Background: It was previously reported that K-ras mutations could behave as a resistance marker for response to gefitinib while EGFR mutations make NSCLC more responsive to this medication. And it is known that Asians and Westerners have different responses to gefitinib. Therefore, we are to identify the mutational status of K-ras and EGFR in the group of Chinese patients with NSCLC especially adenocarcinoma treated with gefitinib to find some helpful information. Methods: Genomic DNA was extracted from tumor specimens, including liquid nitrogen frozen tumor, paraffin blocks and fine needle biopsies from 24 patients with advanced NSCLC, who failed at least one platinum-based regimen, treated with gefitinib. Nested polymerase chain reaction products of codons 12, 13, 59, and 61 of K-ras and exon 18 through 21 of EGFR were directly sequenced at least twice. Results: Patients’ age ranges from 24 to 71 years (54.8 ± 10.2). Male/female was 14/10. Thirteen patients were smokers and 11 were non-smokers. Eighteen were adenocarcinomas, 2 were bronchioloalveolar carcinomas, 2 were squamous cell carcinomas and 2 were large cell carcinomas. The disease control (CR+PR+SD) rate was 79.2% (19/24) and the objective response (CR+PR) rate was 50.0% (12/24). No K-ras gene mutation was found in all patients. Fifteen patients (62.5%, 15/24) harbored EGFR mutations, which were delE746-A750 (8), delE746-A751 (1), delE746-A751insA (1), L861Q (1), L858R (5) and A871G (1). Two patients had double mutations (delE746-A750 and L858R). The disease control rate for wild type and mutant EGFR were 66.7% (6/9) and 86.7% (13/15), and the objective response rate were 33.3% (3/9) and 60.0% (9/15). Median time to progress (TTP) for wild type and mutant EGFR were 439 days (SE 249.8) and 367 days (SE 108.8). However, no statistically significant differences were found between these two groups regarding the response rates and TTP. Conclusions: K-ras mutation may occur at a low frequency in Chinese NSCLC groups despite the pathology, status of smoking, gender and EGFR mutations. And the relationship between the response to gefitinib and K-ras mutation might still remain to be determined at least in Chinese NSCLC. And the role of EGFR mutations in prediction of response to gefitinib should be further studied. No significant financial relationships to disclose.
Abstract 11526: Intraprocedural Thrombotic Events During PCI for ACS Are Associated With Increased Adverse Ischemic Events at 30 Days: A Meta-Analysis of Randomized Trials
Authors: Ramez Nairooz, Partha Sardar, Saurav Chatterjee, Zubair Ahmed, Dmitriy N Feldman
Journal: Circulation (2014)

Background: Data regarding intraprocedural thrombotic events (IPTE) including slow reflow or no reflow, distal embolization, intraprocedural stent thrombosis and abrupt vessel closure during PCI for acute coronary syndrome (ACS) are scarce. Their association with subsequent adverse ischemic events needs further investigation. Aim: To evaluate effect of IPTE on in-hospital and at 30-days clinical outcomes after PCI for ACS. Hypothesis: IPTE during PCI are associated with adverse ischemic events while in-hospital and at 30 days. Methods: We performed a literature search of all published full-length articles of randomized trials that reported data on patients with IPTE compared with no IPTE during PCI for patients with ACS. We calculated odd ratios via random effects model for in-hospital ischemic outcomes and 30 day outcomes. Results: Our literature search yielded 3 randomized trials reporting clinical outcomes with IPTE and no IPTE for ACS patients undergoing PCI: ACUITY, HORIZONS-AMI and EARLY-ACS trials. We report clinical outcomes (in-hospital and at 30 days) in 8,043 patients in total, of those 673 had IPTE. At 30 days, patients with IPTE had more major adverse cardiovascular events (MACE) (Odds ratio (OR) 3.97, 95% Confidence interval (CI) [1.81-8.69]; p=0.0006), mortality (OR 4.54, 95% CI [1.99, 10.39]; p=0.0003), myocardial infarction (OR 4.54, 95% CI [1.99, 10.39]; p=0.0003), repeat revascularization (OR 4.54, 95% CI [1.99, 10.39]; p=0.0003), total stent thrombosis (OR 4.54, 95% CI [1.99, 10.39]; p=0.0003) and non-CABG related major bleeding (OR 4.54, 95% CI [1.99, 10.39]; p=0.0003) than those with no IPTE. Similarly, in-hospital clinical outcomes were all significantly higher in patients with IPTE than those without. Conclusion: IPTE during PCI is associated with more adverse ischemic events, including mortality, both in-hospital and at 30 days.
우리나라 비알코올지방간 환자에서 혈중 철분 과잉의 빈도와 HFE 유전자(H63D) 변이의 존재
Authors: 이동훈 ( Don Hun Lee ), 정숙향 ( Sook Hyang Jeong ), 이명진 ( Myung Jin Lee ), 조영애 ( Young Ae Cho ), 김진욱 ( Jin Wook Kim ), 박영수 ( Young Soo Park ), 황진혁 ( Jin Hyuk Hwang ), 김나영 ( Na Young Kim ), 이동호 ( Doug Ho Lee )
Journal: Clinical and Molecular Hepatology (2007)