tbuckley/cabot-search huggingface dataset:
Discordant Haplotype Sequencing Identifies Functional Variants at the 2q33 Breast Cancer Risk Locus
Authors: Nicola J. Camp, Wei-Yu Lin, Alex Bigelow, George J. Burghel, Timothy L. Mosbruger, Marina A. Parry, Rosalie G. Waller, Sushilaben H. Rigas, Pei-Yi Tai, Kristofer Berrett, Venkatesh Rajamanickam, Rachel Cosby, Ian W. Brock, Brandt Jones, Dan Connley, Robert Sargent, Guoying Wang, Rachel E. Factor, Philip S. Bernard, Lisa Cannon-Albright, Stacey Knight, Ryan Abo, Theresa L. Werner, Malcolm W.R. Reed, Jason Gertz, Angela Cox
Journal: Cancer Research (2016)

The findings from genome-wide association studies hold enormous potential for novel insight into disease mechanisms. A major challenge in the field is to map these low-risk association signals to their underlying functional sequence variants (FSV). Simple sequence study designs are insufficient, as the vast numbers of statistically comparable variants and a limited knowledge of noncoding regulatory elements complicate prioritization. Furthermore, large sample sizes are typically required for adequate power to identify the initial association signals. One important question is whether similar sample sizes need to be sequenced to identify the FSVs. Here, we present a proof-of-principle example of an extreme discordant design to map FSVs within the 2q33 low-risk breast cancer locus. Our approach employed DNA sequencing of a small number of discordant haplotypes to efficiently identify candidate FSVs. Our results were consistent with those from a 2,000-fold larger, traditional imputation-based fine-mapping study. To prioritize further, we used expression-quantitative trait locus analysis of RNA sequencing from breast tissues, gene regulation annotations from the ENCODE consortium, and functional assays for differential enhancer activities. Notably, we implicate three regulatory variants at 2q33 that target CASP8 (rs3769823, rs3769821 in CASP8, and rs10197246 in ALS2CR12) as functionally relevant. We conclude that nested discordant haplotype sequencing is a promising approach to aid mapping of low-risk association loci. The ability to include more efficient sequencing designs into mapping efforts presents an opportunity for the field to capitalize on the potential of association loci and accelerate translation of association signals to their underlying FSVs. Cancer Res; 76(7); 1916-25. ©2016 AACR.
T-cell epitope conservation across allergen species is a major determinant of immunogenicity
Authors: Luise Westernberg, Véronique Schulten, Jason A. Greenbaum, Sara Natali, Victoria Tripple, Denise M. McKinney, April Frazier, Heidi Hofer, Michael Wallner, Federica Sallusto, Alessandro Sette, Bjoern Peters
Journal: Journal of Allergy and Clinical Immunology (2016)

Patients with pollen allergies are frequently polysensitized. Pollens contain epitopes that are conserved across multiple species.
Absolute bioavailability of PF-01367338 tablets following oral administration in cancer patients.
Authors: D. D. Wang, K. A. Kern, M. Carpentieri, S. Zhang, B. Hee, M. R. Middleton, J. F. Spicer, L. R. Molife, R. Plummer
Journal: Journal of Clinical Oncology (2011)

e13615 Background: PF‐01367338 is a poly (ADP‐ribose) polymerase (PARP) inhibitor. The phosphate salt of PF‐01367338 (PF‐01367338‐09) was formerly known as AG‐014699. Its safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity following IV administration in combination with temozolomide has been previously evaluated in phase I and II studies. An oral formulation (the camphorsulfonic acid salt) is currently under study to allow for chronic/continuous dosing of PF-01367338 as single agent treatment or in combination with chemotherapeutic agents. One of the objectives of this study was to evaluate the absolute bioavailability of PF-01367338 following oral (PO) administration. Methods: In an ongoing phase I study of PF-01367338 in combination with several chemotherapeutic agents in adult patients (pts) with advanced solid tumors, a single IV dose and PO dose were administered on Day -10 and Day -5, respectively, during a lead-in phase of Cycle 1, to evaluate the bioavailability of PF-01367338. All PO doses were given under fasting conditions with 8 ounces of water. PK samples were collected at 0, 0.25, 0.5, 1, 1.5, 2.5, 4, 6, 10, 24, and 48 hours (h) after the start of the PF‐01367338 infusion or PO administration. The PK data were analyzed using Non-Compartmental Analysis (NCA). Results: To date, PK data from 6 pts at 12-18 mg IV dose and 12 to 48 mg PO dose have been analyzed. The key PK parameters are shown in the table below. The absolute bioavailability of the PF-01367338 immediate release tablet was estimated to be 34% and was independent of dose administered in the dose range studied. No DLTs occurred after single PO dosing. Conclusions: PF-01367337 was well tolerated after oral administration with an average absolute bioavailability of 34%. Preliminary summary of key plasma PF-01367338 PK parameters (N=6). CL (L/hr) Vdss (L) F (%) t1/2, IV (h) t1/2, Oral (h) Tmax, Oral (h) Mean* 18.1 230 34.1 16.6 20.1 1.0 CV (%) 8 77 23 26 19 0.5-2.5 * Geometric mean for all except: median (range) for Tmax, arithmetic mean (CV%) for t1/2.
L-アルギニン/アシンメトリックジメチルアルギニン(ADMA),ホモシステイン,葉酸,ビタミンBレベルと冠動脈拡張の関係
Authors: Koc Fatih, Ardic Idris, Erdem Sami, Kalay Nihat, Ozbek Kerem, Yarlioglues Mikail, Ceyhan Koksal, Celik Atac, Kadi Hasan, Taner Alpaslan, Sahin Semsettin, Onalan Orhan, Kaya Mehmet
Journal: Circulation (2011)
Randomized phase III study of irinotecan (CPT-11) versus weekly paclitaxel (wPTX) for advanced gastric cancer (AGC) refractory to combination chemotherapy (CT) of fluoropyrimidine plus platinum (FP): WJOG4007 trial.
Authors: Shinya Ueda, Shuichi Hironaka, Hirofumi Yasui, Tomohiro Nishina, Masahiro Tsuda, Takehiko Tsumura, Naotoshi Sugimoto, Hideki Shimodaira, Shinya Tokunaga, Toshikazu Moriwaki, Taito Esaki, Michitaka Nagase, Kazumasa Fujitani, Kensei Yamaguchi, Takashi Ura, Yasuo Hamamoto, Satoshi Morita, Isamu Okamoto, Narikazu Boku, Ichinosuke Hyodo
Journal: Journal of Clinical Oncology (2012)

4002 Background: A combination CT of FP has been regarded as the standard first-line treatment for AGC. Although two randomized trials showed a survival benefit of second-line CT (CPT-11 or docetaxel) compared with best supportive care, no standard regimen has been established. In Japan, wPTX has been used more frequently than docetaxel as the second‑line CT. The objective of this study was to compare CPT-11 with wPTX in patients (pts) with AGC refractory to FP. Methods: Patients with AGC refractory to the first‑line FP regimen were randomized 1:1 to either CPT-11 (150 mg/m 2 , q2w) or wPTX (80 mg/m 2 , days 1, 8, 15, q4w). The primary endpoint was overall survival (OS) and secondary endpoints were progression‑free survival (PFS), overall response rate (ORR), adverse events and receiving rates of third-line CT. To demonstrate an increase in median OS from 5 months (wPTX) to 7.5 months (CPT-11) with 2-sided alpha 5% and 80% power, 220 pts were required. Results: Between Aug 2007 and Aug 2010, 223 pts were enrolled; 112 pts were randomized to CPT-11 and 111 pts to wPTX. Baseline characteristics were well balanced between arms. Median OS was 8.4 months for CPT-11 and 9.5 months for wPTX (HR 1.132; 95% CI, 0.86-1.49; p=0.38). Median PFS was 2.3 months for CPT-11 and 3.6 months for wPTX (HR 1.14; 95% CI, 0.88-1.49; p=0.33). The ORR was 13.6% (12/88) for CPT-11 and 20.9% (19/91) for wPTX (p=0.20). The most common grade 3/4 adverse events were neutropenia (39.1% for CPT-11 vs. 28.7% for wPTX), anemia (30.0% vs. 21.3%), anorexia (17.3% vs. 7.4%) and fatigue (12.7% vs. 6.5%). Four (4%) CPT-11 and three (3%) wPTX recipients died within 30 days after the last administration. Subsequent CT was performed in 80 pts (71%) for CPT-11 and 97 pts (89%) for wPTX. Seventy-five pts (67%) in the CPT-11 group and 87 pts (80%) in the wPTX group received the crossover CT. Conclusions: The WJOG4007 trial, the first phase III study comparing second-line CT regimens for AGC, did not demonstrate the superiority of CPT-11 over wPTX. Thus, wPTX can be adopted as a control arm of future phase III trials of second-line CT for AGC.
Assessing the Health Impact of Water Quality Interventions in Low-Income Settings: Concerns Associated with Blinded Trials and the Need for Objective Outcomes
Authors: Thomas Clasen, Sophie Boisson
Journal: Environmental Health Perspectives (2015)

A dramatic disparity between the results of blinded versus open trial designs has raised questions about the effectiveness of water quality interventions and other environmental interventions to prevent diarrhea, a leading killer of young children in low-income countries.We summarize the results of blinded versus open trials of water quality interventions, describe evidence from a recent placebo-controlled trial in India suggesting that control households were put at risk from their participation, and suggest alternatives to blinded trials that could resolve continued uncertainty about the magnitude of the protective effect of water, sanitation, and hygiene (WASH) interventions without presenting ethical questions.Concerns about reporting bias in open trial designs continue to cause uncertainty about the effectiveness of WASH interventions. However, evidence suggests that despite instructions to the contrary, placebos may encourage control group participants in blinded trials to cease practicing traditional water treatment practices in the mistaken belief that they are protected by an active intervention. Although objective outcomes such as pathogen incrimination, seroconversion, biomarkers, and anthropometry can be helpful, these are often costly, nonspecific, and unsuitable for evaluating programmatic interventions.Unless researchers can be assured that a placebo will not cause those in a control group to change their behavior in a manner that increases their risk, it is incumbent on researchers to use alternatives. Validated objective measures are needed for assessing the health impact of WASH interventions that are reliable, affordable, and suitable both for research and program evaluation.Clasen T, Boisson S. 2016. Assessing the health impact of water quality interventions in low-income settings: concerns associated with blinded trials and the need for objective outcomes. Environ Health Perspect 124:886-889; http://dx.doi.org/10.1289/ehp.1510532.
VEGF serum levels during bevacizumab plus paclitaxel combination in metastatic melanoma
Authors: S. Viteri, A. Diaz-Lagares, A. González, S. Martin Algarra, P. Redondo, J. Espinos, M. González Cao
Journal: Journal of Clinical Oncology (2007)

8534 Background: Angiogenesis has an important role in melanoma progression. A prognostic value has been suggested for serum VEGF in melanoma. The novel agent bevacizumab (Bev) has demonstrated in combination with chemotherapy high activity in other tumors. We studied the combination of weekly paclitaxel (TXL) and bevacizumab (Bev) in previously treated metastatic melanoma patients (pts) and analyzed serum VEGF levels before and during treatment. Methods: TXL 70 mg/m 2 weekly and Bev 10 mg/kg biweekly during 5 consecutive weeks every six weeks. VEGF levels pre-treatment and at response evaluation were analyzed with enzyme-linked immunoassays. Results: 13 pts have been treated: male/female: 4/9, median age: 45 (29–71), median PS ECOG: 2 (0–3), stage distribution M1b/ M1c: 2/11, high LDH levels: 8 pts. Median number of previous lines: 3 (1–6). Hematological toxicity: G III lymphopenia in 6 pts, G III leucopenia in 2 pts, G III thrombocytopenia in 1 pt and G I anemia in 3 pts. Non-hematological toxicities: alopecia in 7 pts, diarrhea G I in 4 pts, epistaxis G I in 8 pts. Response (and time to progression, months [m]): 2/12 PR (6 m and 4 m), 1/12 MR (6 m), 7/12 SD (7+ m, 7 m, 4 m, 4+ m, 3 m, 3 m, 3+ m), 2/12 PD. Responses were seen in soft tissue, lung and brain metastases. Overall survival at 12 months was 43.3%. Pre-treatment serum levels were high in five patients and they became negative at response evaluation (1 pt achieved MR, 3 pts SD and 1 pt PD). Unexpectedly patients with high pre-treatment VEGF levels had long survival: 4/5 patients remain alive and 2 pts have survived over one year: 12+ m, 12+ m, 5 m, 3+ m, 3.5+ m.VEGF was undetectable pre-treatment and at response evaluation in 7 pts, only 2/7 pts remained alive: 15+ m, 8 m, 7.5 m, 7 m, 6.8+ m, 3 m, 2.6 m. Conclusions: The combination of Bev and weekly TXL is active in melanoma and it has a good tolerance profile. Serum VEGF could be a good marker in this setting. Further research is needed to confirm these results. No significant financial relationships to disclose.
Rare ovarian tumors (ROT). Impact of an interactive website on medical practice and inclusions in a clinical trial. Results after 1 year
Authors: I. Ray-Coquard, P. Cassier, I. Treilleux, J.-P. Lotz, C. Tournigand, Z. Merad, H. Jprovencal, D. Mayeur, P. Bougnoux, J. P. Guastalla
Journal: Journal of Clinical Oncology (2004)

5110 Background: ROT are by nature rare. The lack of experience outside specialized centers leads to wide variations in management and treatment. A specialized website (www.ovaire-rare.org) was developed in France in 2002. Objectives were: to delineate prognostic factors of these very rare diseases, to favor patient inclusion in a clinical trial available online, to provide access to online medical expert forum (disease-related) for complex cases, and finally to demonstrate the impact of these tools on improving medical practice. Methods: Since 04/2002, a prospective study accessible on the website has proposed inclusion of patients online. All new adult patients with ORT in first or second-line treatment were eligible (70 pts/year expected in France). Results: Since 2002, 30 patients have been included in the online clinical trial. 29 medical records were evaluated for initial treatment and for second opinion histological diagnosis. Patients characteristics were: median age 36y (16–69), FIGO stage I 60%, II 10%, III 20%, IV 10% (metastatic sites: liver 2, lung 2), median tumor size 11 cm (3–24), most frequent histology: adult granulosa (10/29), dysgerminoma (7/29). Second opinion histological diagnosis was validated for 24 pts. Discordance was total (no same tumor subtype, no same prognosis) for 7/24 (29%) and partial (same tumor, different prognosis) for 2/24 (8%). Second opinion changes initial diagnosis in 38% of the patients. Conclusions: After one year, the use of the website is effective and enables to recruit patients with ROT. Histological discrepancies between initial diagnosis and second opinion suggest that this tool is useful for including patients in the clinical trial. The website provides very interesting data for a better knowledge of these rare tumors and will possibly help improve medical practice. No significant financial relationships to disclose.
The effect of chronic intermittent hypoxia on hepatic injury and mechanism in lean mice and mice with diet-induced obesity
Authors: Hyeon Hui Kang, In Kyoung Kim, Joong Hyun Ahn, Ki Hoon Park, Soon Seog Kwon, Hwa Sik Moon
Journal: European Respiratory Journal (2014)

Background: The purpose of this study was to investigate the effects of CIH on the liver in lean mice and mice with diet-induced obesity (DIO).  Methods: Eight-week old C57BL/6J mice were divided into two groups and then exposed to control conditions (room air, n = 16) or CIH (n = 16) for 4 weeks. Each group was divided into two groups again, and then was fed a regular diet or high-fat, high-cholesterol diet for 4 weeks. At the end of the exposure, several genes including hypoxia inducible factor (HIF-1α), vascular endothelial growth factor (VEGF), nuclear factor kappa B (NF-κB), Toll-like receptor 4(TLR4) in liver were examined.  Results:There was a significant reduction in body weight in mice exposed to CIH steadily through 4 weeks compared with the control group (P  Conclusions: CIH is associated with enhanced expression and signaling events downstream of TLR4 in livers of DIO mice.  Our data indicates that CIH causes significant inflammation and liver injury in DIO mice, via TLR4-mediated NF-kB activation. These results suggest that TLR4 may play a critical role in CIH-induced hepatic inflammation.
Reproductive and endocrine gonadal functions in adults following multidrug chemotherapy for acute lymphoblastic or undifferentiated leukemia.
Authors: E D Kreuser, W D Hetzel, W Heit, D Hoelzer, E Kurrle, N Xiros, H Heimpel
Journal: Journal of Clinical Oncology (1988)

The impact of aggressive chemotherapy on reproductive and endocrine gonadal function was studied in ten women and ten men with acute lymphoblastic leukemia (ALL) or acute undifferentiated leukemia (AUL) in complete remission. Hormone determinations, sperm analyses, measurements of basal body temperature, and interviews with a standardized questionnaire were used for diagnostic evaluation. Elevated serum follicle-stimulating hormone (FSH) levels and azoospermia were seen in all male patients after completion of induction and consolidation therapy as a result of germ cell and stem cell loss. Recovery of spermatogenesis, as indicated by normalization of serum FSH values and sperm density, occurred in the second year of maintenance therapy in all men. Serum testosterone and luteinizing hormone (LH) values remained within normal limits indicating resistance of Leydig cells to chemotherapy. All female patients showed normal serum levels of gonadal steroids and gonadotropins, as well as an adequate increase in basal body temperature after intensified chemotherapy, indicating intact follicle function and ovulation. Most patients reported normal sexual functions after induction and consolidation therapy. These results demonstrate that multidrug chemotherapy induced significant impairment of reproductive function in all male patients with early and complete recovery. In contrast, endocrine gonadal function was unaffected in men treated with ALL/AUL. In female patients, neither reproductive nor endocrine functions were influenced by aggressive chemotherapy.
Pharmacokinetic of inhaled low molecular weight heparin
Authors: G. Scheuch, S. Haeussermann, P. Brand, C. Herpich, T. Meyer
Journal: Journal of Clinical Oncology (2006)

7209 Background: Treatment with Heparin and low molecular weight (LMW) Heparin is frequently used in oncology settings. Usually, these drugs are delivered by subcutaneous (s.c.) administration. Since 1963, the clinical relevance of inhalation of unfractionated as well as LMW-Heparin has been investigated in various studies with over 500 subjects. In this study, a single inhalation of the LMW-Heparin Certoparin (Mono-Embolex, Novartis) was investigated in 10 healthy subjects. The goal was to assess the pharmacokinetic behavior. Inhalations were performed using a novel inhalation system, which allows an accurate dosing in the lungs by controlling patient’s breathing pattern (AKITA). Lung deposition is about 85% of the emitted dose. Methods: 10 non-smoking healthy subjects participated in this study. Inhalation of 9000 IU of LMW-Heparin was compared to 3000 IU s.c. administration to achieve factor-Xa-activity in the plasma of 0.2 to 0.3 U/ml. Intravenous blood samples were taken 0.25, 0.5, 1, 2, 4, 6, 24, 48 hrs after administration. Factor-Xa-activity in plasma was assessed using the Berichrom assay (Dade Behring, Marburg, Germany). Results: Inhalation of LMW-Heparin was well tolerated and did not result in any side effects or changes in lung function. The maximum anti-Xa-activity in the plasma was 0.3 U/ml for the s.c. administration of Certoparin and 0.32 U/ml after inhalation of 9000 IU. However, pharmacokinetics was considerably different. Inhaled LMW-Heparin resulted in a prolonged anti-Xa-activity. After 6 (24) hours, the anti-Xa-activity after s.c. administration was down at 0.16 U/ml (0.10) and after inhalation at 0.30 (0.18) U/ml. Even after 48 hrs, the anti-Xa-activity after inhalation was significantly higher than the baseline value. Comparing area under the curve (AUC), bioavailability for the inhalation was 9.4 U · h/ml ± 14% compared to 5.7 U · h/ml ± 27% after s.c. administration. Conclusions: These results suggest that with controlled inhalation, this administration route is an attractive alternative to s.c. administration, with the result of longer bioavailability and less variability. A once daily administration is possible. Inhalation therapy with these kind of systems might also be useful with different anticancer agents, which cannot be administered orally. [Table: see text]
The relationship between microRNA-126 and maintenance therapy with bevacizumab after bevacizumab plus chemotherapy as first-line treatment for patients with metastatic colorectal cancer: Results of the phase III Nordic ACT trial NCT00598156 translational study.
Authors: Torben Hansen, Rene dePont Christensen, Rikke Fredslund Andersen, Karen-Lise Garm Spindler, Flemming Brandt Soerensen, Anders Johnsson, Anders Kristian Moeller Jakobsen
Journal: Journal of Clinical Oncology (2012)

3573 Background: Maintenance therapy during chemotherapy free intervals is a debatable topic in metastatic colorectal cancer (mCRC). In the Nordic ACT trial patients benefitting from induction chemotherapy plus bevacizumab were randomized to bevacizumab with or without erlotinib. MicroRNA-126 (miRNA-126) is believed to influence angiogenesis in several ways, and we investigated the relationship between miRNA-126 and progression free survival (PFS) under maintenance therapy. Methods: The miRNA-126 was analysed by polymerase chain reaction on both genomic DNA (by the pri-miRNA-126 (A24G) single nucleotide polymorphism (SNP)) and paraffin embedded primary tumors, (which were classified as low or high miRNA-126 expressing tumours using the median value as cut-off). Diagnostic biopsies were not processed due to limited tumour tissue. Of the 159 randomized patients blood samples were available from 151 and primary tumours from 91. The PFS (from time of randomization) was compared using the Kaplan-Meier method and the log rank test. The Cox Regression analyses were used to test for independent contributions. Results: The A24G SNP was not related to PFS, but a significant association was seen between genotypes and miRNA-126 expression levels.Furthermore, the PFS was increased in patients with high tumor miRNA-126 expression compared to patients with low expression, hazard ratio (HR) 0.58 (95% confidence interval (CI) 0.38-0.90), p = 0.015. The median PFS was 6.2 months (95% CI 4.3-6.6 months) and 4.0 months (95% CI 2.6-4.5 months), respectively. Results did not differ between treatment arms, but the Cox Regression analysis confirmed an independent prognostic value of the tumor miRNA-126 expression, HR 0.61 (95% CI 0.39-0.95), p = 0.030. Conclusions: The miRNA-126 may be a potential marker for bevacizumab containing maintenance therapy. A similar relationship with PFS has recently been demonstrated in patients with mCRC treated with chemotherapy only. The results call for validation.