tbuckley/cabot-search huggingface dataset:
Responses of Isolator-Derived and Conventional Chickens to Marek's Disease Herpesvirus and Avian Leukosis Virus 2
Authors: Jack W. Frankel, Wendall M. Farrow, Cavett O. Prickett, Mary E. Smith, William F. Campbell, Vincent Groupé
Journal: JNCI Journal of the National Cancer Institute (1974)

A flock of isolator-derived, barrier-sustained specific-pathogen-free, White Leghorn chickens (LSI-SPF) was developed to provide definitive biologic materials for the study of avian tumor viruses, particularly Marek's disease herpesvirus (MDHV) and avian leukosis virus (ALV). Unlike conventional birds, LSI-SPF chickens inoculated with MDHV died as early as 10 days afterward and mortality reached 100% within 12–22 days post inoculation. The time to death was related to the dose of MDHV. Typical Marek's disease (MD) symptoms and gross tumors were not seen before death. In sharp contrast, neither mortality nor tumors were observed among LSI-SPF chickens contact-exposed to birds with MD. Persistent viremia and neutralizing antibodies demonstrated that infection had occurred in LSI-SPF birds. LSI-SPF chickens kept 8 weeks in an ALV-monocontaminated environment had neither symptoms nor tumors, although ALV viremia was demonstrated. The only experimental condition in which mortality (81%) and tumor development (100%) occurred in LSI-SPF chickens was concurrent exposure to both MDHV and ALV.
Safety and efficacy of everolimus in patients with non-clear cell renal cell carcinoma refractory to VEGF-targeted therapy: Subgroup analysis of REACT.
Authors: Christian U. Blank, Petri Bono, James M. G. Larkin, Svetozar Gogov, Ashok Panneerselvam, Carlos A. Garay, Viktor Grünwald
Journal: Journal of Clinical Oncology (2012)

402 Background: Metastatic non-clear cell renal cell carcinoma (mncRCC), which accounts for about 25% of all RCCs, is characterized by resistance to treatment and poor overall survival. Despite recent advances in targeted therapies for patients with mRCC, effective therapies for patients with mncRCC remain limited. The REACT (RAD001 Expanded Access Clinical Trial in RCC) study was initiated to provide patients with mRCC of any histology refractory to VEGF-targeted therapy access to everolimus in advance of regulatory approval. Methods: REACT, an open-label, international, expanded-access program (Clinicaltrials.gov: NCT00655252 ) enrolled patients with measurable or nonmeasurable mRCC of any histology who were intolerant of, or progressed while on, VEGFR-TKI therapy in order to evaluate the long-term safety of everolimus 10 mg daily. Overall incidence of grade 3/4 and serious adverse events (AEs) were recorded, as was tumor response to everolimus according to RECIST criteria. A subgroup analysis of safety and efficacy in patients with mncRCC was performed. Results: Of 1367 patients enrolled, 75 patients (5.5%) had mncRCC. Median everolimus treatment duration in the mncRCC subgroup was 12.14 weeks (range, 0.9–49.0 weeks) and in the overall REACT population it was 14.0 weeks (range, 0.1–83.7 weeks). In the mncRCC subgroup, most commonly reported grade 3/4 AEs were anemia (17.3%), dyspnea (10.7%), pleural effusion (9.3%), fatigue (8.0%), and hyperglycemia (6.6%). Best overall response was similar in the mncRCC subgroup and overall population: respectively, 1.3% and 1.7% had partial response and 49.3% and 51.6% had stable disease. Conclusions: Although patients with mncRCC had a slightly lower treatment duration than the overall REACT population, approximately 50% of these patients achieved disease control on treatment. In this subgroup, everolimus was well tolerated, no new safety issues were observed, and the AE profile was consistent with that of the overall population. These encouraging results of the safety and efficacy of everolimus in patients with mncRCC support further evaluation of everolimus in these patients.
Abstract 15500: The Proteasome is a Target of Protein Kinase G
Authors: Erin J Terpstra, Mark J Ranek, Eduardo Callegari, Xuejun Wang
Journal: Circulation (2013)

The ubiquitin-proteasome system (UPS) plays a central role in maintaining protein quality control and degradation in the cell. A characteristic phenotype of most heart diseases is abnormal protein aggregation and increased ubiquitinated proteins, indicative of UPS dysfunction. More importantly, experimental studies have demonstrated that cardiac proteasome functional insufficiency plays a major pathogenic role in heart failure resulting from a large subset of heart disease.  Clinical trials and studies on animal models reveal that cGMP-dependent kinase (PKG) activation by inhibition of phosphodiesterase type 5 (e.g., sildenafil) protects against a variety of cardiac pathological conditions. We have recently reported that PKG activation facilitates proteasome-mediate degradation of misfolded proteins and slows down the progression of cardiac proteinopathy in mice (Ranek MJ et al, Circulation 2013). To investigate further the mechanism by which PKG regulates proteasome function, we performed in vitro tests with purified proteasomes treated with active PKG. We found that 26S proteasomes showed increased chymotrypsin-like peptidase activity relative to untreated proteasomes. “Gel-free” 2D nano-LC MS/MS analysis identified increased phosphorylation at proteasome subunits including 19S regulatory subunit Rpn2 and 20S catalytic subunit β-7. Sites of phosphorylation were within predicted PKG targeted sequences. Neonatal rat ventricular myocytes (NRVMs) were employed for in vivo investigation. NRVMs were treated with sildenafil or vehicle control and proteasomes were immunoprecipitated against α-3 subunit. We found that PKG was co-precipitated with the 26S proteasome and that this interaction was augmented by sildenafil. Additionally, we found that NRVM 26S proteasome chymotrypsin-like activity was significantly increased by sildenafil treatment.  These findings suggest that proteasome activity may be positively regulated by PKG and that the mechanism may be through direct interaction.
Megestrol acetate versus tamoxifen in advanced breast cancer: 5-year analysis--a phase III trial of the Piedmont Oncology Association.
Authors: H B Muss, H B Wells, E H Paschold, W R Black, M R Cooper, R L Capizzi, R Christian, J M Cruz, D V Jackson, B L Powell
Journal: Journal of Clinical Oncology (1988)

One hundred thirty-eight patients with recurrent or metastatic breast cancer were randomized to receive megestrol acetate 40 mg orally four times daily or tamoxifen 10 mg orally twice a day. Upon treatment failure patients were crossed over to the alternate treatment. Eligibility required that either the estrogen receptor (ER) or progesterone receptor (PR) be positive or that both values be unknown, and that the patients be at least 2 years post-spontaneous menopause or over 50 years of age. Pretreatment characteristics including performance status (PS), disease-free interval (DFI), receptor status, and prior treatment were similar for both groups. Only three patients had previous hormonal therapy while one third had prior chemotherapy. Objective response was determined using strict International Union Against Cancer (UICC) criteria. Seventeen of 61 patients achieved complete response (CR) or partial response (PR) on megestrol (28%) while 20 of 64 patients achieved CR or PR on tamoxifen (31%). Responses of skin and bone lesions were similar for both agents; however, more patients with visceral disease responded to tamoxifen. Response did not correlate with the level of ER or PR but was correlated with age. Both unadjusted and adjusted analysis of time to progression and adjusted analysis (for pretreatment variables) of survival showed significant differences favoring tamoxifen. Six of 44 patients (14%) crossed from megestrol to tamoxifen achieved CR or PR while only two of 38 patients (5%) crossed from tamoxifen to megestrol achieved response. Only one of the original patients randomized to megestrol remains on study, while 12 patients still remain on tamoxifen. These data indicate similar response rates for megestrol and tamoxifen; however, time to progression and overall survival significantly favor tamoxifen when used as first-line therapy in this trial.
Abstract 10882: Serum Levels of Vascular Endothelial Growth Factor-C are Inversely Correlated with Future Cardiovascular Events
Authors: Nobutoyo Masunaga, Hiromichi Wada, Masaharu Akao, Shuichi Ura, Mitsuru Ishii, Takashi Unoki, Mitsuru Abe, Mikhiko Kanasaki, Yasuyo Nakashima, Koh Ono, Tatsuya Morimoto, Noriko Asahara, Akira Shimatu, Koji Hasegawa
Journal: Circulation (2012)
Tariquidar (XR9576) is a potent and effective P-glycoprotein (Pgp) inhibitor that can be administered safely with chemotherapy
Authors: M. E. Menefee, C. Fan, M. Edgerly, D. Draper, C. Chen, R. Robey, F. Balis, W. D. Figg, S. Bates, A. T. Fojo
Journal: Journal of Clinical Oncology (2005)

3093 Background: Inhibition of P-glycoprotein (Pgp) as a means to improve chemotherapeutic efficacy remains a valid but unproven hypothesis. Two recent trials in patients with lung cancer using the Pgp inhibitor, tariquidar (XR9576), closed prematurely due to toxicity concerns. We report our experience using tariquidar with chemotherapy. Methods: Patients with refractory or metastatic adrenocortical cancer (ACC) received tariquidar on days 1 & 3 with a 96-hour infusion of doxorubicin, vincristine, and etoposide with mitotane (X-MAVE) every 21 days. Patients with refractory ovarian, cervical & lung cancer received tariquidar with a docetaxel infusion every 21 days. Study participants had two 99mTc-sestamibi scans. Time-activity curves were generated and areas under the curve calculated to compare 99mTc-sestamibi accumulation at baseline to that 1 h after tariquidar. Rhodamine efflux from CD56+ cells was measured before and after tariquidar to assess Pgp inhibition. Results: To date, 15 patients with ACC have received 71 cycles of X-MAVE, and 16 patients with ovarian, cervical or lung cancer have received 66 cycles of docetaxel. Grade 3 non-hematologic toxicities (# of cycles) observed with X-MAVE include: abdominal pain/constipation (4), arthralgia (4), nausea/vomiting (2), diarrhea (1), esophagitis (1), fatigue (6), hand-foot reaction (1), and hyponatremia (3); those with docetaxel include: diarrhea (1), dyspnea (1) fatigue (6), hyponatremia (3), pain (3) and tearing (2). 99mTc-sestamibi accumulation increased 39 to 129%, compared to a mean increase of 106% in the liver, in 6 of 8 patients with ACC whose lesions could be visualized. Quantitation for the 10 such patients with ovarian, cervical or lung cancer is ongoing. Rhodamine efflux from CD56+ cells assayed in 30 patients was reduced by a mean of 85% after tariquidar and was sustained even after 48 h. Pharmacokinetic sampling before and after tariquidar has been performed. Conclusions: Tariquidar is a potent and highly effective Pgp inhibitor that can be administered safely with a combination of doxorubicin, etoposide and vincristine or with docet axel. The efficacy in patients with refractory cancers continues to be evaluated. No significant financial relationships to disclose.
The Expanding Complexity of Estrogen Receptor Signaling in the Cardiovascular System
Authors: Sara Menazza, Elizabeth Murphy
Journal: Circulation Research (2016)

Estrogen has important effects on cardiovascular function including regulation of vascular function, blood pressure, endothelial relaxation, and the development of hypertrophy and cardioprotection. However, the mechanisms by which estrogen mediates these effects are still poorly understood. As detailed in this review, estrogen can regulate transcription by binding to 2 nuclear receptors, ERα and ERβ, which differentially regulate gene transcription. ERα and ERβ regulation of gene transcription is further modulated by tissue-specific coactivators and corepressors. Estrogen can bind to ERα and ERβ localized at the plasma membrane as well as G-protein–coupled estrogen receptor to initiate membrane delimited signaling, which enhances kinase signaling pathways that can have acute and long-term effects. The kinase signaling pathways can also mediate transcriptional changes and can synergize with the ER to regulate cell function. This review will summarize the beneficial effects of estrogen in protecting the cardiovascular system through ER-dependent mechanisms with an emphasis on the role of the recently described ER membrane signaling mechanisms.
Capecitabine (XE) plus Irinotecan (IRI) as second-line treatment (XELIRI) for metastatic colorectal cancer (MCRC) in elderly patients: Feasibility and safety results from a Phase II study
Authors: G. Fiorentini, P. Dentico, M. Cantore, S. Rossi, P. Pacetti, P. Bernardeschi, R. Della Seta, S. Tumolo, U. de Giorgi
Journal: Journal of Clinical Oncology (2005)

3676 Background: the oral fluoropyrimidine XE has a well defined efficacy and improved safety compared to 5-FU/LV in MCRC. Twice daily oral XE mimics 5-FU infusion and is substituting this drug in combination regimens.The safety and efficacy of XE plus IRI (XELIRI) were evaluated in second line MCRC. Methods: recommended doses from other indipendent previous phase I trials were IRI 250 mg/m2 i.v. on day 1 and XE 1000 mg/m2 orally twice daily on days 1–15, every 3 weeks.Eigtheen Patients (pts) >70 received lower doses of IRI and XE (150 mg/m2 on day 1 and 750 mg/m2 twice daily on days 1–15, respectively). Results: 26 pts enrolled from Dec. 2002 and Sept. 2003: M/F=14/12; median WHO PS 1 (0–2), median age 69.3 (66–82); right colon cancer 20%,sigmoid cancer 60%,rectal cancer 20%. Tumor differentiation was 30% poor, 50% moderate and 20% well. Most common metastastic sites were the liver 80%, abdominal lymph nodes (30%), lung 20% and bone 10%, with 6 pts having stage IV disease at initial diagnosis. All pts, except 6 stage IV, received 5-FU/LV as adjuvant therapy. All received first line chemotherapy (FOLFOX 4 in16 cases, group A; FOLFIRI in 4, group B; and 5-FU/LV/MTX in 6 cases, group C) with evidence of clinical control (PR+SD) in 50% group A, 50% group B and 20% group C. The median number of treatment cycles was 8. In the 26 pts evaluable for feasibility and safety the most common side effect grade 3 was diarrhea (40%) nausea & vomiting (20%), HFS 10%. Grade 3–4 neutropenia was seen in 40% of pts. No treatment related death was reported. Eight of 24 evaluable pts (33%) showed a response to treatment and a control of the disease (PR+SD) was observed in15 pts (63%; 9 group A, 1 group B, 5 group C). Median time to progression was 5.5 months and overall survival was 11.5 months. Conclusions: XELIRI is active and well tolerated as second line therapy for MCRC in elderly pts. We stress that efficacy is quite interesting also in pts already pretreated with FOLFOX 4. XE should replace 5-FU in combination with IRI as second line therapy to obtain an effective,safe and well accepted opportunity in second line MCRC elderly pts. No significant financial relationships to disclose.
Abstract 16011: An Outcomes Assessment of Vasodilator Therapy in Pulmonary Arterial Hypertension Through Meta-Analysis of 31 Randomized Controlled Trials
Authors: John J Ryan, Saurav Chatterjee, Nathan Hatton, Neel Patel, Josef Stehlik, Emily Bucholz, Harlan Krumholz
Journal: Circulation (2014)

Introduction: Pulmonary Arterial Hypertension (PAH) is a rapidly progressive disease with high mortality. We reviewed randomized controlled trials (RCTs) to evaluate the effect of pulmonary vasodilators on mortality in PAH. Hypothesis: Our objective was to determine the effect of PAH medicines on survival, and the impact of trial design on outcomes. Methods: We conducted a meta-analysis using MEDLINE, EMBASE, Cochrane Library, Web of Science, and Scopus (inceptions-May 2014) of all RCTs treating PAH with pulmonary vasodilators. Data on all-cause mortality and hemodynamics were abstracted. Summary relative risks (RR) and 95% confidence intervals (CI) for outcomes were calculated using a random effects model comparing various pulmonary vasodilators with control. Results: The analysis included 31 RCTs (6,271 patients, 77% female, range of mean age 30-57 years). Median follow up was 12 weeks (18 trials had ≤ 12 weeks follow up, and only 5 followed patients ≥ 6 months). When analyzed together (n = 14), FDA-approved pulmonary vasodilators demonstrated a mortality benefit with RR = 0.77 (95% CI = 0.60 - 099, I 2 = 0%). When analyzed by vasodilator type, prostacyclins were the only class of agents with significant mortality benefit, RR = 0.61 (95% CI 0.38-0.98, I 2 = 1%). Oral pulmonary vasodilators demonstrated no significant benefit on PAH mortality, RR = 0.85 (95% CI 0.65-1.12, I 2 = 0.0%), but we could not exclude a clinically meaningful benefit or harm. Many studies reported ≤1 death in at least one treatment arm. When we limited the analysis to only studies with at least 2 deaths in both treatment arms (n=9), the mortality benefit for pulmonary vasodilators was no longer significant (RR 0.86, CI 0.66-1.12, I 2 =0%), but the point estimate was below 1 and we could not exclude a reduction or increase in risk. For studies with the shorter follow up of ≤ 12 weeks, the RR of mortality for active treatment arm was 0.54 (95% CI 0.35-0.83), compared to trials with &gt; 12 weeks of follow up where the RR of mortality was not significant at 0.91 (95% CI 0.67-1.22). Conclusion: There is an observed mortality benefit for prostacyclins in PAH. For the oral pulmonary vasodilators, there is no observed mortality benefit based on either design of trials, length of follow up or efficacy of the agents studied.
Trabectedin (Tr) in the treatment of advanced uterine leiomyosarcomas (U-LMS): Results of a pooled analysis of five single-agent phase II studies using the recommended dose.
Authors: I. R. Judson, J. Blay, S. P. Chawla, J. A. Radford, A. Le Cesne, J. Verweij, M. von Mehren, J. Pontes, E. Bayever, G. D. Demetri
Journal: Journal of Clinical Oncology (2010)

10028 Background: Trabectedin is approved in Europe and 19 other countries around the world for second-line treatment of advanced soft tissue sarcomas (STS), with activity documented in several phase II studies. Uterine sarcoma represent 1% of all gynecological malignancies and 30% of all uterine sarcoma are U-LMS. A pooled analysis of activity and tolerability of Tr in U-LMS patients (pts) from five phase II trials is presented. Methods: Retrospective analysis was done on data from 5 different trials, with a total of 62 generally pretreated pts with advanced U-LMS (prior anthracycline-based chemotherapy: 91.9%; prior surgery: 98.4%; prior radiotherapy: 48.4%), exposed to a median of two prior chemotherapy lines (range 0-6), received iv Tr 1.5 mg/m2 24-h q3wk. Efficacy endpoints were response rate (RR) by investigator assessment (IA), progression-free survival (PFS) and overall survival (OS). Safety was also analyzed. Results: Median age 53 (range:34-75) years; median No. cycles 3 (1-38); median relative dose intensity 90%. Eleven pts achieved PR (17.7%) and 20 pts SD (32.3%; 13% ≥6 months), PD 43.5% and NE 6.5%. Median PFS was 2.5 months (95% CI:1.7-4.2); 30.7% (CI 95% 19-43) pts were progression free at 6 months. Median OS was 12.1 months, with 52% (CI 95% 39-64) and 20% (CI 95% 10-30) of pts alive at 12 and 24 months, respectively. Worst per patient grade 3-4 AEs included neutropenia (41.9%), thrombocytopenia (9.7%), anemia (9.7%), fatigue (8.1%) and febrile neutropenia (1.6%). G-CSF was used in 17.7% of pts. Transient G3-4 ALT and AST elevations occurred in 43.5% and 30.6% without symptoms/signs of hepatic failure. Alopecia (4.8%) and peripheral neuropathy (1.6%) were uncommon. Conclusions: Tr has activity and is reasonably safe for pts with advanced U-LMS. Nearly one-third of pts were progression-free for 6 months or more, and over half (52%) of these pretreated pts were alive at one year. RR, PFS and OS compare favorably to published outcomes with other single agents (e.g., doxorubicin). These results warrant further prospective studies in first-line U-LMS combining Tr with other active drugs. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Johnson & Johnson, PharmaMar Amgen, ARIAD, ArQule, Daiichi Sankyo, Genentech, GlaxoSmithKline, Infinity, Johnson & Johnson, Novartis, Pfizer, PharmaMar, Roche, ZIOPHARM Oncology Johnson & Johnson GlaxoSmithKline, Novartis, Pfizer, PharmaMar, Roche Amgen, ARIAD, ArQule, Daiichi Sankyo, Genentech, GlaxoSmithKline, infinity, Johnson & Johnson, Novartis, Pfizer, PharmaMar, Roche, ZIOPHARM Oncology ARIAD, ArQule, Daiichi Sankyo, Infinity, Johnson & Johnson, PharmaMar PharmaMar
The Head and Neck Radiotherapy Questionnaire: a morbidity/quality-of-life instrument for clinical trials of radiation therapy in locally advanced head and neck cancer.
Authors: G P Browman, M N Levine, D I Hodson, J Sathya, R Russell, P Skingley, C Cripps, L Eapen, A Girard
Journal: Journal of Clinical Oncology (1993)

PURPOSE The purpose of this study was to develop and validate an instrument for clinical trials to measure radiation-related acute morbidity and quality of life from the perspective of patients with head and neck cancer (HNC) treated with radiotherapy. METHODS The Head and Neck Radiotherapy Questionnaire (HNRQ) was developed by a panel of health care workers and patients, was pretested in a pilot study of HNC patients, and was validated in a randomized double-blind trial of concomitant fluorouracil (FUra) infusional therapy (1.2 g/m2 per 24 hours) or saline placebo administered for 72 hours in the first and third weeks of a 6 1/2-week course of radiation therapy. The HNRQ was validated against existing toxicity and performance status indices, all of which were measured weekly for the 6 1/2 weeks of treatment and for 4 weeks posttreatment. RESULTS There were three a priori constructs: (1) that the HNRQ scores would conform to a shallow U-shaped pattern to reflect declining quality of life (increasing morbidity) during radiation and recovery posttreatment; (2) that the HNRQ would correlate with existing toxicity indices (World Health Organization [WHO] stomatitis, Byfield stomatitis, WHO skin toxicity, Eastern Cooperative Oncology Group [ECOG] and Karnofsky performance status); and (3) that the HNRQ would discriminate between FUra and placebo groups. The HNRQ and its domain scores all showed a change from baseline reflecting increased morbidity during radiation (analysis of variance [ANOVA], P &lt; .00001). The HNRQ correlated well with all other indices (r &gt; or = .60), and domain scores correlated best with other indices that assess the same symptom complex (eg, HNRQ skin domain and WHO skin toxicity index, r = .77). There was a significant difference in HNRQ scores between the FUra and placebo groups during radiation (ANOVA, P = .0007), and all HNRQ domains also discriminated between the treatment groups. CONCLUSION The HNRQ is a valid measure of acute morbidity due to radiation therapy in patients with locally advanced HNC, and may be useful as an outcome measure for future clinical trials of radiation treatment strategies.