tbuckley/cabot-search huggingface dataset:
Pharmacodynamics of decitabine 5 days/week x 2 weeks in advanced cancers
Authors: D. J. Stewart, R. Kurzrock, Y. Oki, K. Kehr, S. Gupta, I. I. Wistuba, L. H. Camacho, J.-P. Issa
Journal: Journal of Clinical Oncology (2005)

3110 Background: Decitabine decreases DNA methylation by inhibiting DNA methyltransferase & may up-regulate tumor suppressor genes & pro apoptotic genes silenced by hypermethylation. In vitro prolonged decitabine is more effective than brief exposure. In leukemia patients, DNA demethylation plateaus at a dose of 15 mg/m2/day (IV over 1 hr) x 5 days/week x 2 weeks & this dose schedule appears substantially more effective than other schedules or higher or lower doses. Methods: We initiated a phase I trial of this decitabine schedule in advanced solid tumor & lymphoma patients. Planned dose levels are 2.5, 5, 10, 15 & 20 mg/m2/day (6 patients/level). Patients have tumor biopsies pre day 1 & shortly after last decitabine dose cycle 1 to assess global DNA methylation (% CpG methylation by Alu & LINE assays), & to assess methylation of selected specific genes. Peripheral blood mononuclear cells (PBMCs) collected concurrently assess their reliability as a surrogate of tumor DNA methylation. Results: From 9/27–11/15/04, cohort 1 (2.5 mg/m2/day) accrued 6 patients (3 males, 3 females; age 26–71 [median 52]; 2–6 [median 3] prior regimens). In preliminary analyses decitabine reduced PBMC DNA methylation in all 6 patients by 3–23% (mean 52.7% pre vs 45.5% post, p=0.02). Baseline methylation was higher in PBMCs than tumor (mean, 41.0%, p=0.03). 2 patients had >10% decrease in tumor DNA methylation after 1 cycle decitabine & 1 of these had 20% decreased tumor size. Decitabine effect on methylation did correlate in tumors & PBMCs (r=0.50). Toxicity has been minimal. Conclusions: Early results suggest that even very low decitabine doses exert biological effect on PBMCs & some tumors. As dose escalation continues, we will define dose-response relationships & biologically optimum dose. Support in part by NIH grant UO1 CA062461–10. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration SuperGen, MGI SuperGen, MGI
Mechanical strain- and high glucose-induced alterations in mesangial cell collagen metabolism
Authors: B L Riser, P Cortes, J Yee, A K Sharba, K Asano, A Rodriguez-Barbero, R G Narins
Journal: Journal of the American Society of Nephrology (1998)

Cultured mesangial cells (MC) exposed to cyclic mechanical strain or high glucose levels increase their secretion of transforming growth factor-beta1 (TGF-beta1) and collagen, suggesting possible mechanisms for the development of diabetic renal sclerosis resulting from intraglomerular hypertension and/or hyperglycemia. This study examines whether glucose interacts with mechanical strain to influence collagen metabolism and whether this change is mediated by TGF-beta. Accordingly, rat MC were grown on flexible-bottom plates in 8 or 35 mM glucose media, subjected to 2 to 5 d of cyclic stretching, and assayed for TGF-beta1 mRNA, TGF-beta1 secretion, and the incorporation of 14C-proline into free or protein-associated hydroxyproline to assess the dynamics of collagen metabolism. Stretching or high glucose exposure increased TGF-beta1 secretion twofold and TGF-beta1 mRNA levels by 30 and 45%, respectively. However, the combination of these stimuli increased secretion greater than fivefold without further elevating mRNA. In 8 mM glucose medium, stretching significantly increased MC collagen synthesis and breakdown, but did not alter accumulation, whereas those stretched in 35 mM glucose markedly increased collagen accumulation. TGF-beta neutralization significantly reduced baseline collagen synthesis, breakdown, and accumulation in low glucose, but had no significant effect on the changes induced by stretch. In contrast, the same treatment of MC in high glucose medium greatly reduced stretch-induced synthesis and breakdown of collagen and totally abolished the increase in collagen accumulation. These results indicate that TGF-beta plays a positive regulatory role in MC collagen synthesis, breakdown, and accumulation. However, in low glucose there is no stretch-induced collagen accumulation, and the effect of TGF-beta is limited to basal collagen turnover. In high glucose media, TGF-beta is a critical mediator of stretch-induced collagen synthesis and catabolism, and, most importantly, its net accumulation. These data have important implications for the pathogenesis and treatment of diabetic glomerulosclerosis.
A phase I study evaluating the effect of CDHP as a component of S-1 on the pharmacokinetics (PK) of 5-fluorouracil (5-FU)
Authors: M. W. Saif, L. S. Rosen, J. Zhang, C. Zergebel, L. Ravage-Mass, P. D. Urrea, M. S. Gordon
Journal: Journal of Clinical Oncology (2008)

2514 Background: S-1 is an oral fixed combination drug composed of a prodrug of 5-FU (tegafur [FT]), a reversible dihydropyrimidine dehydrogenase (DPD) inhibitor (gimeracil [CDHP]), and an inhibitor of 5-FU phosphorylation (Oxo), primarily in the lower GI tract. The presence of CDHP in S-1 is expected to reduce 5-FU degradation mediated by DPD and therefore maintain therapeutic exposure to 5- FU converted from FT. The purpose of this study was to investigate the effect of CDHP on the PK of 5-FU and other related metabolites by comparing the pharmacokinetic profile of S-1 (FT + CDHP + Oxo) to that of FT alone. Methods: Patients with advanced solid tumors received single oral doses of 50 mg S-1 (dose expressed as FT equivalents) and 800 mg FT 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, 8, 12, 24, and 48 hours post-dose. Single-dose PK parameters were determined for FT, 5-FU, and α-fluoro-β-alanine (FBAL). Following the single-dose crossover period, patients could enter an extension phase and receive treatment with S-1 30 mg/m2 bid for 14 days followed by a 7-day rest, repeated every 3 weeks. Results: 12 patients (7M, 5F) were enrolled; median age was 59 years and mean BSA was 1.94 m2. Results of the PK analyses are shown in the table. In the extension phase, the most common treatment related G3/4 AE was diarrhea (3/12, 25%). Conclusions: Following S-1 administration, 5-FU exposure was significantly greater (∼3 fold) as compared to FT alone (800 mg) despite the lower dose of FT administered as S-1 (50 mg), while plasma concentrations of FT and FBAL were significantly lower with S-1. These results confirm the DPD inhibitory effect of CDHP as a component of S-1. PK Analysis of Pateints Treated on S-1 Study Analyte S-1 Geometric Mean (CV); N=12 FT Geometric Mean (CV); N=12 Cmax, ng/mL AUC0-inf, ng * hr/mL Cmax, ng/mL AUC0-inf, ng * hr/mL 5-FU 111 (44)* 498 (41)* 29 (103) 179 (45) FT 1368 (31)* 13165 (56)* 20218 (34) 237481 (47) FBAL 79 (34)* 1245 (29)* 1676 (45) 24649 (28) * Significant difference between S-1 and FT (p<0.0001); CV=coefficient of variation Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Taiho Pharma USA, Inc Taiho
Epidermoid Carcinomas of Esophagus and Forestomach Induced in Syrian Hamsters by N-Nitroso-N-Methylurethan
Authors: Katherine McD. Herrold
Journal: JNCI Journal of the National Cancer Institute (1966)

The effect of intragastric administration of N-nitroso-N-methylurethan was studied in Syrian hamsters. All animals developed epidermoid carcinomas of the forestomach which locally invaded the peritoneum, liver, and diaphragm. Thirteen of the 16 animals had epidermoid carcinomas of the esophagus. The malignant tumors were multicentric in origin. In addition to the tumors, the entire surface epithelium of the esophagus and forestomach revealed diffuse histopathological changes including hyperkeratosis, basal-cell hyperplasia, epithelial atypism, and papillomas. These findings indicate that the mode of action of N-nitroso-N-methylurethan is not local. A few of the animals revealed thecomas of the ovary, papillomas of the vagina, and stromal hyperplasia of the endometrium. The significance of these lesions is not known. When compared with the effects of N-nitroso-N-methylurea in Syrian hamsters, the finding suggests that though there are decided differences in the local effect of these two carcinogens, there may be similarities in regard to the metabolic pathway and metabolites formed by them.
Challenges in the Elimination of Pediatric HIV-1 Infection
Authors: Katherine Luzuriaga, Lynne M. Mofenson
Journal: New England Journal of Medicine (2016)

Preventing mother-to-child transmission of HIV-1 requires a series of steps in the care of women and their infants during pregnancy, delivery, and the postpartum period. This review outlines the steps and summarizes progress in resource-limited countries and elsewhere.
Genetic analysis, phenotypic diagnosis, and risk of venous thrombosis in families with inherited deficiencies of protein S
Authors: Michael Makris, Michael Leach, Nick J. Beauchamp, Martina E. Daly, Peter C. Cooper, Kingsley K. Hampton, Pauline Bayliss, Ian R. Peake, George J. Miller, F. Eric Preston
Journal: Blood (2000)
Chronology and Pattern of Human Chromosome Replication. Ill. Autoradiographic Studies on Cells From Cancer Effusions&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: Kiyomi Yamada, Avery A. Sandberg
Journal: JNCI Journal of the National Cancer Institute (1966)

There has been an almost total lack of information on the replicatory pattern of chromosomes in human cancer cells. The availability of a pseudodiploid female cancer cell line afforded us the unusual opportunity of comparing chromosome replication in cancer cells with that of normal cells. The chronology of chromosomal replication has been studied autoradiographically with cells from the effusions of cancer patients. In cells cultured for 5 days, it was shown that the order in which certain chromosomes duplicated their DNA was not greatly changed in pseudodiploid cancer cells when compared to that exhibited by diploid cells (leukocytes) present in the same effusions. Thus, a late-labeling X chromosome was found in the female cancer cells comparable to that of the normal cells. A pair of autosomes of groups B and D replicated late in both types of cells. The pseudodiploid cancer cells could be easily differentiated from the diploid cells by the presence of a marker chromosome in the former. The data seem to indicate that a grossly abnormal chronology of chromosomal replication did not characterize the pseudodiploid cancer cells studied.
<i>The BMJ</i>editors respond
Authors: Elizabeth Loder, Trish Groves, Sara Schroter, Jose G Merino, Wim Weber, Fiona Godlee
Journal: BMJ (2016)

We appreciate the vigour and thoughtfulness of responders to Greenhalgh and colleagues’ open letter and our editorial.1 2 We will consult on recognising the best qualitative work, and will call for research methods and reporting articles on this.3 …
Injury prevention strategies, coach compliance and player adherence of 33 of the UEFA Elite Club Injury Study teams: a survey of teams’ head medical officers
Authors: Alan McCall, Gregory Dupont, Jan Ekstrand
Journal: British Journal of Sports Medicine (2016)

Purpose (1) To quantify current practice at the most elite level of professional club football in Europe with regard to injury prevention strategy; (2) to describe player adherence and coach compliance to the overall injury prevention programme. Methods A structured online survey was administered to the Head medical officers of 34 elite European teams currently participating in the UEFA Elite Club Injury Study. The survey had 4 sections; (1) risk factors for injury, (2) assessment and monitoring of injury risk, (3) prevention strategies and (4) coach compliance and player adherence to the injury prevention process. Results 33 (97%) Medical officers of the teams responded. The most important perceived injury risk factor was previous injury. Four of the top 6 risk factors—physical fitness, accumulated fatigue, reduced recovery time between matches and training load—were related to player workload. The top 3 preventative exercises were eccentric, balance/proprioception and core training. Regarding monitoring, the top 3 tools implemented were measurement of workload, subjective wellness and a general medical screen. The subjectively rated level of coach compliance in UEFA teams was perceived as ‘high’, while the player adherence varied from none at all to perfect. Summary and conclusion Medical officers place importance on workload-related variables as risk factors for injury in elite European football players. A lack of consistently high player adherence may limit the effects of contemporary injury prevention programmes in elite European footballers.
Safety and efficacy of MPDL3280A (anti-PDL1) in combination with platinum-based doublet chemotherapy in patients with advanced non-small cell lung cancer (NSCLC).
Authors: Stephen V. Liu, John D. Powderly, D. Ross Camidge, Neal Ready, Rebecca Suk Heist, F. Stephen Hodi, Giuseppe Giaccone, Bo Liu, Jeffrey Wallin, Roel Peter Funke, Daniel Waterkamp, Scott N. Gettinger
Journal: Journal of Clinical Oncology (2015)

8030 Background: MPDL3280A, which preserves the PD-L2/PD-1 interaction to potentially diminish autoimmune lung toxicity, has promising activity in advanced NSCLC. Platinum-based doublet chemotherapy (chemo) remains standard first-line (1L) treatment for NSCLC with ORRs historically of ≈ 30%. Preclinical data show that chemo may prompt tumor antigen release and enhance MPDL3280A activity. Thus, we studied MPDL3280A + chemo in untreated NSCLC pts. Methods: This Ph Ib study evaluated MPDL3280A combined with carboplatin + either paclitaxel (Arm C), pemetrexed (Arm D) or weekly nab-paclitaxel (Arm E) in pts with chemonaive locally advanced or metastatic NSCLC. Pts received MPDL3280A 15 mg/kg IV q3w with standard chemo dosing for 4-6 cycles followed by MPDL3280A maintenance therapy until progression. Unconfirmed ORRs were assessed by RECIST v1.1 in pts dosed by Jun 29, 2014 (data cutoff Sep 29, 2014). PD-L1 expression was centrally assayed using the SP142 IHC antibody. Results: 37 pts were safety evaluable (Arm C, 8; Arm D, 14; Arm E, 15). Across arms, 54% of pts were male, median age was 65 y (range, 40-82 y), 81% had non-squamous and 19% had squamous NSCLC. Median follow-up for safety was 154 d (range, 1-346 d). The most frequent all-grade AEs regardless of attribution across arms included those commonly associated with chemo, such as nausea (Arms C & D, 50%; Arm E, 73%), fatigue (Arm C, 38%; Arm D, 36%; Arm E, 73%) and constipation (Arm C, 25%; Arm D, 71%; Arm E, 27%). The most common MPDL3280A-related G3-4 AEs included anemia (Arms D & E, 7%), neutropenia (Arm C, 13%; Arm D, 7%) and thrombocytopenia (Arms D & E, 7%). No pneumonitis was seen. One MPDL3280A-related G5 AE due to candidemia after prolonged neutropenia was seen in Arm D. 30 pts were efficacy evaluable (Arm C, 5; Arm D, 12; Arm E, 13). Across all arms, the ORR (95% CI) was 67% (48%-82%): 60% (19%-92%) in Arm C (3 PRs), 75% (45%-93%) in Arm D (9 PRs) and 62% (33%-83%) in Arm E (6 PRs & 2 CRs). Responses were seen in each arm independent of PD-L1 expression. Conclusions: MPDL3280A + standard 1L chemo was well tolerated with no unexpected toxicities, showing promising clinical activity in advanced NSCLC pts. Ph III studies are ongoing. Clinical trial information: NCT01633970.
Immunodynamics: a cancer immunotherapy trials network review of immune monitoring in immuno-oncology clinical trials
Authors: Holbrook E. Kohrt, Paul C. Tumeh, Don Benson, Nina Bhardwaj, Joshua Brody, Silvia Formenti, Bernard A. Fox, Jerome Galon, Carl H. June, Michael Kalos, Ilan Kirsch, Thomas Kleen, Guido Kroemer, Lewis Lanier, Ron Levy, H. Kim Lyerly, Holden Maecker, Aurelien Marabelle, Jos Melenhorst, Jeffrey Miller, Ignacio Melero, Kunle Odunsi, Karolina Palucka, George Peoples, Antoni Ribas, Harlan Robins, William Robinson, Tito Serafini, Paul Sondel, Eric Vivier, Jeff Weber, Jedd Wolchok, Laurence Zitvogel, Mary L. Disis, Martin A. Cheever
Journal: Journal for ImmunoTherapy of Cancer (2016)

The efficacy of PD-1/PD-L1 targeted therapies in addition to anti-CTLA-4 solidifies immunotherapy as a modality to add to the anticancer arsenal. Despite raising the bar of clinical efficacy, immunologically targeted agents raise new challenges to conventional drug development paradigms by highlighting the limited relevance of assessing standard pharmacokinetics (PK) and pharmacodynamics (PD). Specifically, systemic and intratumoral immune effects have not consistently correlated with standard relationships between systemic dose, toxicity, and efficacy for cytotoxic therapies. Hence, PK and PD paradigms remain inadequate to guide the selection of doses and schedules, both starting and recommended Phase 2 for immunotherapies. The promise of harnessing the immune response against cancer must also be considered in light of unique and potentially serious toxicities. Refining immune endpoints to better inform clinical trial design represents a high priority challenge. The Cancer Immunotherapy Trials Network investigators review the immunodynamic effects of specific classes of immunotherapeutic agents to focus immune assessment modalities and sites, both systemic and importantly intratumoral, which are critical to the success of the rapidly growing field of immuno-oncology.
Early Cardiopulmonary Resuscitation in Out-of-Hospital Cardiac Arrest
Authors: Ingela Hasselqvist-Ax, Gabriel Riva, Johan Herlitz, Mårten Rosenqvist, Jacob Hollenberg, Per Nordberg, Mattias Ringh, Martin Jonsson, Christer Axelsson, Jonny Lindqvist, Thomas Karlsson, Leif Svensson
Journal: New England Journal of Medicine (2015)

Three million people in Sweden are trained in cardiopulmonary resuscitation (CPR). Whether this training increases the frequency of bystander CPR or the survival rate among persons who have out-of-hospital cardiac arrests has been questioned.We analyzed a total of 30,381 out-of-hospital cardiac arrests witnessed in Sweden from January 1, 1990, through December 31, 2011, to determine whether CPR was performed before the arrival of emergency medical services (EMS) and whether early CPR was correlated with survival.CPR was performed before the arrival of EMS in 15,512 cases (51.1%) and was not performed before the arrival of EMS in 14,869 cases (48.9%). The 30-day survival rate was 10.5% when CPR was performed before EMS arrival versus 4.0% when CPR was not performed before EMS arrival (P<0.001). When adjustment was made for a propensity score (which included the variables of age, sex, location of cardiac arrest, cause of cardiac arrest, initial cardiac rhythm, EMS response time, time from collapse to call for EMS, and year of event), CPR before the arrival of EMS was associated with an increased 30-day survival rate (odds ratio, 2.15; 95% confidence interval, 1.88 to 2.45). When the time to defibrillation in patients who were found to be in ventricular fibrillation was included in the propensity score, the results were similar. The positive correlation between early CPR and survival rate remained stable over the course of the study period. An association was also observed between the time from collapse to the start of CPR and the 30-day survival rate.CPR performed before EMS arrival was associated with a 30-day survival rate after an out-of-hospital cardiac arrest that was more than twice as high as that associated with no CPR before EMS arrival. (Funded by the Laerdal Foundation for Acute Medicine and others.).
Correlation of serum sex hormone levels with the Gail model risk of breast cancer in postmenopausal women
Authors: H. Liang, S. S. Lo, F. Ye, J. P. Costantino, A. Hudson, V. G. Vogel
Journal: Journal of Clinical Oncology (2008)

1517 Background: Several prospective studies have shown that a woman's estradiol and/or testosterone level predicts her risk of developing breast cancer. These hormone levels are also related to the risk of developing ER+ breast cancer in women >65 years. The Gail model is the most widely accepted definition of breast cancer risk, and has shown its ability to predict overall breast cancer risk. The objective of this study was to determine whether serum estradiol and free testosterone levels in post-menopausal women correlated with their predicted risk of breast cancer. Methods: One hundred twenty women who were screened for the NSABP P-2 STAR trial and found to have an elevated 5-year Gail breast cancer risk (at least 1.66%), agreed to participate and signed a consent form to undergo a repeat risk assessment by the NSABP for their Gail risk. Serum 17-beta-estradiol (E2), free testosterone, and sex hormone binding globulin (SHBG) were measured by using immunoassay. The correlations between the hormone levels and the Gail score were analyzed. Results: The median age was 62 years (42–83). The mean Gail score was 2.56% [95% confident interval (CI) 2.34% -2.79%]. The mean serum level of E2 was 37 pmol/L (95% CI 24.7–50.1), and that of free testosterone 0.85 nmol/L (95% CI 0.73–0.97). The mean serum SHBG concentration was 50.1 nmol/L (95% CI 46.3–53.8). There was a statistically significant negative linear association of testosterone level with the Gail score (Pearson correlation coefficient, r = -0.18235, p = 0.0462). There was no statistically significant correlation of serum SHBG level and Gail risk in this cohort of postmenopausal women, nor between E2 and Gail risk. However, a non-linear association was detected between E2 level and high Gail score only (≥3.255%, 75th percentile). Conclusions: These data do not support the use of endogenous sex hormone levels to identify postmenopausal women who are at particularly high risk of breast cancer based on the Gail model. Serum sex hormones may be an independent predictor of risk in low to moderate-risk women. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Eli Lilly and Company Eli Lilly and Company Eli Lilly and Company