tbuckley/cabot-search huggingface dataset:
A phase 1b study of oral rapamycin (sirolimus) in patients with advanced malignancies
Authors: M. J. Ratain, K. L. Napoli, K.Knightley Moshier, X. Jiang, G. F. Fleming, T. F. Gajewski, E. Jacobsen, E. E. Cohen
Journal: Journal of Clinical Oncology (2007)

3510 Background: Rapamycin (R) analogues are being studied as cancer therapies since mTOR is recognized as a relevant target in several cancer types. However, R is readily available, has been well-studied in organ transplant patients, was the first recognized mTOR inhibitor, and demonstrates efficacy in preclinical cancer models. The aims of this study were to define R’s maximum tolerated dose (MTD), observed toxicities, dose-limiting toxicities (DLT), pharmacokinetics and effect on inhibition of phosphorylation of p70 S6 kinase (S6K) in peripheral T-cells (PTL). Methods: R was administered orally once weekly to successive cohorts of patients using an adaptive escalation design based on whole blood concentrations ([R]), using a validated HPLC procedure. S6K was assessed by stimulating CD3+ cells ex-vivo with PMA and ionomycin for 1 hour, followed by Western blot analysis using antibodies directed against phospho-Thr389 of S6K versus total S6K as a loading control. Results: 24 subjects have been enrolled in dose cohorts of 10 mg, 20 mg, 30 mg, and 60 mg. The mean [R] observed on day 2 of week 1 (24 hr after 1 st dose) was 5.5±2.7, 11.6±6.0 and 22.6±10.7 ng/mL, for dose levels 10 mg, 20 mg and 30 mg, respectively. [R] decreased by ∼50% by day 4 of week 1 (2.7±1.0, 6.9±4.0 and 11.0±7.7 ng/mL, respectively). By day 1 of week 2 (prior to the next dose of R), [R] had decreased below the limit of quantitation (2 ng/mL) for all subjects at 10 mg, 3 of 7 at 20 mg, and 4 of 6 at 30 mg. Preliminary analysis suggests that sustained phospho-S6K inhibition was achieved in some patients at 30 mg. The most common toxicities observed included nausea (50%), diarrhea (42%), asthenia (38%), hyperglycemia (58%), anemia (46%), and lymphopenia (33%). DLTs observed include 1 patient with grade 3 pneumonia at 20 mg, 1 patient with grade 3 dehydration at 30 mg, and 1 patient with grade 3 asthenia at 60 mg. Stable disease has been observed in 46% of evaluable patients. Conclusions: R can be feasibly administered orally on a once weekly schedule with a similar toxicity and pharmacokinetic profile compared with other mTOR inhibitors. Preliminary evidence suggests that prolonged suppression of phospho-S6K in PTL is possible at well-tolerated doses. No significant financial relationships to disclose.
Can the Epworth sleepiness score predict the apnoea-hypopnoea index in obstructive sleep apnoea and hypopnoea syndrome: A comparitive audit of patient and partner scoring
Authors: Caroline Hughes
Journal: European Respiratory Journal (2011)

Obstructive sleep apnoea and hypopnoea syndrome (OSAHS) is characterised by sleep-disordered breathing and daytime sleepiness. The Epworth Sleepiness Score subjectively quantifies sleep propensity whilst the Apnoea-Hypopnoea Index (AHI) is an objective value for the severity of OSAHS. An audit was undertaken to test whether standards held true regarding OSAHS remain so in a Gloucestershire population. Firstly, that mean ESS varies between patients and partners according to their perceptions of patient sleep propensity. Secondly that there is no correlation between patient ESS and AHI and a weak correlation between partner perspective ESS and AHI as shown by previous studies. The audit also aimed to test whether severity levels of ESS were found to be independent of severity levels of AHI when the data were placed in severity categories according to guidelines.  During the audit, 40 sets of patient-partner data were collected retrospectively from a sleep database and analysed. It was found that there was no mean difference between patient and partner perspective ESS scores (p=0.906), disputing the first standard. The partner perspective ESS (r=0.464), but not the patient ESS (r=0.305) correlated with AHI therefore the second standard held true. An additional test found that severity levels of ESS were independent of severity levels of AHI both for patient and partner scoring. ESS was found to be a poor predictor of AHI. To improve this, an alternative questionnaire was devised which combines subjective and objective risk factors for OSAHS. Evaluation of this questionnaire requires stratification.
A Phase II Dose-Escalation Study of Allogeneic Mesenchymal Precursor Cells in Patients With Ischemic or Nonischemic Heart Failure
Authors: Emerson C. Perin, Kenneth M. Borow, Guilherme V. Silva, Anthony N. DeMaria, Oscar C. Marroquin, Paul P. Huang, Jay H. Traverse, Henry Krum, Donna Skerrett, Yi Zheng, James T. Willerson, Silviu Itescu, Timothy D. Henry
Journal: Circulation Research (2015)

Allogeneic mesenchymal precursor cells (MPCs) have been effective in large animal models of ischemic and nonischemic heart failure (HF).To evaluate the feasibility and safety of 3 doses (25, 75, or 150 million cells) of immunoselected allogeneic MPCs in chronic HF patients in a phase 2 trial.We sequentially allocated 60 patients to a dosing cohort (20 per dose group) and randomized them to transendocardial MPC injections (n=15) or mock procedures (n=5). The primary objective was safety, including antibody testing. Secondary efficacy end points included major adverse cardiac events (MACE; cardiac death, myocardial infarction, or revascularization), left ventricular imaging, and other clinical-event surrogates. Safety and MACE were evaluated for up to 3 years. MPC injections were feasible and safe. Adverse events were similar across groups. No clinically symptomatic immune responses were noted. MACE was seen in 15 patients: 10 of 45 (22%) MPC-treated and 5 of 15 (33%) control patients. We found no differences between MPC-treated and control patients in survival probability, MACE-free probability, and all-cause mortality. We conducted a post hoc analysis of HF-related MACE (HF hospitalization, successfully resuscitated cardiac death, or cardiac death) and events were significantly reduced in the 150 million MPC group (0/15) versus control (5/15; 33%), 25 million MPC group (3/15; 20%), and 75 million MPC group (6/15; 40%); the 150 million MPC group differed significantly from all groups according to Kaplan-Meier statistics >3 years (P=0.025 for 150 million MPC group versus control).Transendocardial injections of allogeneic MPCs were feasible and safe in chronic HF patients. High-dose allogeneic MPCs may provide benefits in this population.
Detection of high-risk HPV in urine of high- and low-risk populations in India
Authors: D. Robbins, D. Garg, J. Li, H. Melkonyan
Journal: Journal of Clinical Oncology (2009)

5581 Background: Infection with high-risk HPV is involved in 90%-100% of cervical cancers. HPV detection in cervical cells, used as a supporting test for Pap smear positive patients, are much more sensitive than cytology but less specific for ongoing cervical cancer. Cervical cancer is one of the most common female tumors in countries lacking a screening program such as India. In this study we investigate the feasibility of a urine-based HPV DNA test. Methods: Matching urine and cervical samples were collected from 270 high-risk subjects from STD clinics or district brothels in West Bengal, and 50 low-risk subjects with no known predisposition to disease recruited in Mumbai. The Xenomics HPV DNA test involves isolation of DNA from urine and specific PCR amplification of the HPV E1 region to detect the presence of high-risk HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. Results were compared to the hc2 high-risk HPV DNA Test (QIAGEN). Discordant samples were resolved by DNA sequencing. Results: Of 320 patients, 248 samples (77.5%) were concordant between the Xenomics and hc2 assays. Of the discordant samples reactive by Xenomics but nonreactive by hc2, 31/38 (81.6%) contained high-risk HPV by DNA sequencing. 10 out of 34 (29.4%) of samples detected by hc2 but not by Xenomics were shown to contain high-risk HPV. Using DNA sequencing as the gold standard, the Xenomics test false negative and false positive rates were 10/180 (5.6%) and 7/140 (5.0%), respectively. The hc2 assay had a false negative and false positive rate of 31/184 (16.8%) and 24/136 (17.6%), respectively. Conclusions: HPV DNA can be isolated from urine samples and detected with sensitivity and specificity equal to or better than current assays based on cervical scraping. [Table: see text]
Intra and interobserver variability in cancer patients' performance status assessed according to Karnofsky and ECOG scales
Authors: F. Roila, M. Lupattelli, M. Sassi, C. Basurto, S. Bracarda, M. Picciafuoco, E. Boschetti, G. Milella, E. Ballatori, M. Tonato, A. Del Favero
Journal: Annals of Oncology (1991)
Pilot trial of murine monoclonal antibodies in patients with advanced melanoma.
Authors: G E Goodman, P Beaumier, I Hellström, B Fernyhough, K E Hellström
Journal: Journal of Clinical Oncology (1985)

We have performed a pilot trial with two murine monoclonal antibodies (MAbs) directed against two surface membrane antigens, p97 (MAb 96.5) and a proteoglycan antigen (MAb 48.7) primarily expressed in human melanoma. Five patients with disseminated melanoma were studied, all of whom had multiple cutaneous metastases. Four patients received 212 mg each of antibodies 96.5 and 48.7, and one patient received 424 mg of antibody 96.5 alone. MAbs were administered in escalating doses over ten days in four patients and over six days in one patient. There was no clear treatment-related toxicity. Immunohistologic studies on biopsies taken two to 240 hours after treatment showed extensive binding of murine immunoglobulin to melanoma cells, but not to normal cells in the same section. The intensity of antibody binding was uniform across the diameter of the tumor nodules. In two patients, no murine immunoglobulin was detected in biopsies taken ten days after the last treatment. The mean initial elimination half-life (T1/2) of infused MAbs was 40.5 hours in two patients who received a combination of both antibodies and 53.0 hours in a third patient who received only antibody 96.5; none of these patients had previously been exposed to mouse immunoglobulin. The elimination T1/2 was 21 hours in a fourth patient, who three months previously had tumor imaging with 2-mg radiolabeled antigen-binding fragments (Fab) prepared from antibody 48.7. Serum from this patient appeared to contain anti-idiotypic antibodies which specifically bound Fabs of antibody 48.7. Three other patients also developed human anti-mouse antibodies. There were no objective tumor regressions, and no histologic changes were noted on biopsy.
The Effect of Physician'S Characteristics on Adjuvant Chemotherapy (Ct) Decisions for Early Stage Hr + , Her2– Breast Cancer (Bc) Patients (Pts)
Authors: M. De Laurentiis, M. Aapro, C. Markopoulos, T. Mamounas, R. Rouzier, C. Thomssen, J.E. Bargallo Rocha, D. Rea, P. Neven, B. Linderholm, V. Smit, L. Landherr, A. Petrovsky, C. Svedman, M. Martin
Journal: Annals of Oncology (2014)
Should we ban boxing?
Authors: Shaun Rudd, James Hodge, Rachael Finley, Peter Lewis, Michael Wang
Journal: BMJ (2016)

The death of professional boxer Braydon Smith after a fight last year prompted renewed calls for the sport to be banned, including from <b>Shaun Rudd and colleagues</b>. But <b>Peter Lewis</b> and <b>Michael Wang</b> say that this would restrict individual autonomy and is impractical
Influence of the K-ras status on outcome in cholangiocarcinoma.
Authors: D. Niedersuess-Beke, T. Gruenberger, D. Tamandl, F. Wrba, H. Feichtinger, K. Kaczirek, J. G. Meran, B. Gruenberger
Journal: Journal of Clinical Oncology (2010)

e21076 Background: Mutation of the K-ras oncogene was identified as predictive and potentially prognostic in colorectal and pancreatic cancer. Less is known about the influence of the K-ras status in cholangiocarcinoma. The purpose of this study was to investigate the K-ras status and to evaluate its prognostic role in patients with cholangiocarcinoma. Methods: Mutation analysis was performed on tumor samples of patients diagnosed with cholangiocarcinoma by extraction of genomic DNA. We studied the incidence of K-ras mutations and analyzed the influence of a K-ras mutation on progression-free survival (PFS) and overall survival (OS). Results: A total of 69 patients, 39 female and 30 male, with a median age of 67 (range 37-89) were evaluated. 39 (56%) patients were treated with curative intent and 30 (44%) patients received palliative treatment.Out of 69 patients, 41 (60%) had intrahepatic cholangiocarcinomas, 19 (27%) extrahepatic cholangiocarcinomas and 9 (13%) patients suffered from gallbladder cancer. K-ras mutation was detected in 8 (11.5%) patients. 5 (7%) of these patients had an extrahepatic cholangiocarcinoma and 3 (4%) patients an intrahepatic cholangiocarcinoma. None of the patients with gallbladder cancer had a mutation of the K-ras gene. Curatively resected patients had a median PFS of 19.2 months (95% CI: 6.6-31.8) and a mean OS of 61 months (95% CI: 42.7-79.4). Patients under palliative chemotherapy had a median PFS of 8.8 months (95% CI 5.1-12.5) and a median OS of 15.2 months (95% CI 9.9-20.5). Neither PFS nor OS was affected by K-ras status in both groups (p > 0.5). Conclusions: In our study the incidence of K-ras mutations was lower than expected and previously described in small patient cohorts. K-ras status does not seem to have a prognostic value in patients with cholangiocarcinoma. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck, Roche Merck, Roche, sanofi-aventis Merck, Roche, sanofi-aventis
Abstract 17991: The Cardiolipin-targeting Peptide Bendavia Protects Post-ischemic Myocardium by Preserving Mitochondrial Membrane Fluidity
Authors: Saame R Shaikh, Mitchel Harris, Hetal Patel, David A Brown
Journal: Circulation (2013)

Bendavia is a mitochondria-targeting peptide currently being tested in the EMBRACE-STEMI trial for reducing injury during acute coronary syndromes. Across pre-clinical models, Bendavia preserves mitochondrial function by targeting the mitochondrial phospholipid cardiolipin, but it is not understood how targeting cardiolipin ultimately leads to cardioprotection. Membrane fluidity, which regulates the assembly of mitochondrial proteins, is directly influenced by cardiolipin levels/content. We recently observed augmented fluidity with Bendavia in cardiolipin-enriched lipid vesicles, but the pathophysiological relevance has not been established. We hypothesized that mitochondrial membrane fluidity would be decreased after cardiac reperfusion, and that targeting cardiolipin with Bendavia protects tissue by sustaining mitochondrial membrane fluidity. Following ex vivo ischemia-reperfusion, rat left ventricular mitochondria were isolated and mitochondrial membrane fluidity was assessed. We utilized two different probes to comprehensively assess mitochondrial membrane fluidity: one that detects acyl side fluidity (DPH polarization; n=6-15 per group), and another that reports on phospholipid headgroup fluidity (MC540 fluorescence (AU); n=3-4 per group). Mitochondrial acyl side chain fluidity decreased after cardiac ischemia-reperfusion (DPH polarization increased 74±16% from control). Phospholipid headgroup fluidity was also decreased following ischemia-reperfusion (mean fluorescence was 535,371 versus 940,139 AU in control). Post-ischemic Bendavia administration improved mitochondrial membrane fluidity in both acyl side chains (mean polarization was increased by only 4% compared to non-ischemic mitochondria) and phospholipid headgroups (mean MC540 fluorescence significantly increased to 804,109 AU). Upcoming studies will determine if improved supercomplex-dependent reparation is a direct consequence of sustaining mitochondrial membrane fluidity. In conclusion, these studies are the first to show clear declines in mitochondrial fluidity during acute coronary syndromes, and highlight the promise of therapies that improve cardiolipin-dependent fluidity.
Hormonal therapy for localized prostate cancer in Japan: The outcome of J-CaP database.
Authors: Shiro Hinotsu, Hideyuki Akaza, Osamu Ogawa, Mototsugu Oya, Tadaichi Kitamura, Kazuhiro Suzuki, Taiji Tsukamoto, Seiji Naito, Mikio Namiki, Kazuo Nishimura, Yoshihiko Hirao
Journal: Journal of Clinical Oncology (2012)

54 Background: In Japan, the J-CaP database was established in 2001 when the Japan Study Group of Prostate Cancer (J-CaP Study Group), commenced a study to gather information about hormone therapy administered to Japanese patients and to analyze the outcomes of treatment. From the results of prostate cancer registry conducted by Japanese Urological Association revealed that 45% of localized prostate cancer patients diagnosed in the year of 2000 treated by hormonal therapy in Japan. The J-CaP database is the largest cohort of over 20,000 prostate cancer patients treated by hormonal therapy. Therefore, the objective of the current study was to estimate the outcome of hormonal therapy for the localized prostate cancer patients in the J-CaP database. Methods: The study cohort included 9,127 men with localized prostate cancer who treated by hormonal therapy. All patients were diagnosed by biopsy as having prostate cancer and began to receive hormonal therapy between January 2001 and December 2003. In this study, initial hormonal treatment contained anti-androgen monotherapy, surgical castration only, LHRH agonist monothrerapy, LHRH agonist plus short-term anti-androgen, surgical castration plus anti-androgen, and LHRH agonist plus anti-androgen. All patients evaluated risk category of D’Amico classification. The percentage of Low-risk, intermediate-risk, and high-risk was 19%, 22%, and 59% of men, respectively. Prognosis analyses were performed using Kaplan–Meier methods. Progression-free survival and overall survival were estimated for each risk classification. Results: After a median follow-up of 2.9 years (interquartile range, 1.5-5.3 years) and five year progression-free survival of low-risk, intermediate-risk and high risk were 74.5%, 68.1%, and 57.1%, respectively. The five-year overall survival of low-risk, intermediate-risk, and high risk were 90.0%, 87.2%, and 81.8%, respectively. Conclusions: Comparing the results of radical prostatectomy in US, the five-year progression free survival was 54.6% in high-risk patients. Japanese patients with localized prostate cancer who treated hormonal therapy were comparable outcome of radical treatment in US considering the patients’ risk classification.
Roles of the N and C Terminal Domains of the Interleukin-3 Receptor α Chain in Receptor Function
Authors: S.C. Barry, E. Korpelainen, Q. Sun, F.C. Stomski, P.A.B. Moretti, H. Wakao, R.J. D'Andrea, M.A. Vadas, A.F. Lopez, G.J. Goodall
Journal: Blood (1997)
A phase I study evaluating the effect of oxonic acid (Oxo) as a component of S-1 on the pharmacokinetics (PK) of 5-fluorouracil (5-FU)
Authors: J. Zhang, M. R. Lichinitser, M. Abramov, E. Borisova, A. Lud, P. Scigalla, C. Zergebel, P. D. Urrea, M. S. Gordon
Journal: Journal of Clinical Oncology (2008)

2552 Background: S-1 is a fixed combination drug composed of a prodrug of 5-FU (tegafur [FT]), a dihydropyrimidine dehydrogenase inhibitor (gimeracil [CDHP]), and an inhibitor of 5-FU phosphorylation (Oxo). Through its gastrointestinal distribution, Oxo is expected to reduce 5-FU induced GI toxicity without affecting 5-FU systemic exposure. The purpose of this study was to investigate the effect of Oxo on the PK of 5-FU by comparing the PK profile of S-1 (FT + CDHP + Oxo) to that of CFT (FT + CDHP; no Oxo). Methods: Patients with advanced refractory/relapsed solid tumors received single oral doses of S-1 and CFT (50 mg expressed as FT equivalents) orally on Day 1 and Day 8 in a randomized crossover fashion. Plasma samples were collected on Days 1 and 8 pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 24 and 48 hours post-dose. Single-dose PK parameters (AUC and Cmax) were determined for FT, 5-FU, CDHP, and FBAL. Patients could enter an extension phase in which all patients received S-1 30 mg/m2 bid for 14 days followed by 7 days rest. Results: 28 patients were included in the PK analyses; median age was 59 years and mean BSA was 1.88 m2. The PK results are shown in the table; there were no differences in levels of 5-FU, FT, CDHP or FBAL between patients treated with S-1 versus CFT. During the PK phase, no unexpected toxicities were observed. In the subsequent extension phase, 26 patients received S-1; the most common treatment-related adverse events were nausea (23.1%), diarrhea and fatigue (19.2% each), and anemia and vomiting (11.5% each). Conclusions: The presence of Oxo as a component of S-1 does not affect the systemic exposure to 5-FU. S-1 was generally well tolerated in this population. Analyte S-1 geometric Mean (CV); N=28 CFT Geometric Mean (CV); N=28 Cmax, ng/mL AUC0-inf, ng*hr/mL Cmax, ng/mL AUC0-inf, ng*hr/mL 5-FU 130 (46) 635 (48) 128 (49) 605 (51) FT 1,353 (30) 12,316 (43) 1,362 (29) 13,531 (58) CDHP 323 (35) 1,458 (26) 305 (42) 1,421 (31) FBAL 85 (27) 1,396 (26) 81 (26) 1,440 (25) CV=coefficient of variation Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Taiho Taiho
Erythropoeitin Signaling in Macrophages Promotes Dying Cell Clearance and Immune Tolerance
Authors: Bangwei Luo, Woting Gan, Zongwei Liu, Zigang Shen, Jinsong Wang, Rongchen Shi, Yuqi Liu, Yu Liu, Man Jiang, Zhiren Zhang, Yuzhang Wu
Journal: Immunity (2016)
成人直肠脱垂、直肠内套叠、直肠前膨出及阴道肠疝的评估与处理
Authors: Oliver, Jones, Christopher, Cunningham, Ian, Lindsey, 苏万春, 陈雷
Journal: BMJ (2011)

直肠脱垂是指直肠全层肠壁突出于肛缘。直肠内脱垂或称直肠内套叠的定义为直肠全层肠壁脱垂但并没有突出于肛门外。直肠脱垂和内套叠常常与直肠前膨出（直肠阴道隔向前方疝人阴道）和阴道肠疝（直肠阴道腹膜形成深疝）同时存在。总地来说，这些问题常统称作“盆底功能障碍”。本综述的重点是后盆腔，即直肠，上述疾病均绕其发生。