tbuckley/cabot-search huggingface dataset:
A pharmacogenetic study of irinotecan: Genetic polymorphisms in the coding region of <i>UGT1A1</i> gene and SN-38 glucuronidation in the body
Authors: K. Araki, K. Fujita, Y. Ando, F. Nagashima, W. Yamamoto, H. Endou, T. Miya, K. Kodama, M. Narabayashi, Y. Sasaki
Journal: Journal of Clinical Oncology (2006)

13078 Background: Pharmacogenetic testing of UGT1A1*28, a promoter variant of UGT1A1 gene, for estimating a risk of irinotecan toxicity has been introduced into clinical practice. Purpose: To elucidate clinical significance of UGT1A1*6 and UGT1A1*27, the variants in exon 1 that are found mostly in Asians. Methods: Pharmacogenetic relationships were explored between the genotyping results and ratio of area under the concentration-time curve (AUC) of SN-38 and its glucuronide (SN-38G) as a surrogate for a UGT1A1 activity (AUC SN-38 /AUC SN-38G ) in 36 Japanese patients who received various regimens of irinotecan chemotherapy at doses from 50 to 180 mg/m 2 . Results: No patients were homozygous for UGT1A1*28 and none had UGT1A1*27. One was heterozygous for UGT1A1*28. Two were homozygous and ten heterozygous for UGT1A1*6, all of whom were wild type with respect to UGT1A1*28. Two patients were simultaneously heterozygous for UGT1A1*28 and UGT1A1*6 that existed on the different chromosomes. The remaining 21 patients did not have any variants studied. The 2 patients who was simultaneously heterozygous for UGT1A1*28 and UGT1A1*6 and the 2 patients who were homozygous for UGT1A1*6 had significantly higher AUC SN-38 /AUC SN-38G than the others (P = 0.004). Conclusions: Concurrence of the two UGT1A1 variants, UGT1A1*28 and UGT1A1*6 even in their heterozygous statuses, remarkably altered drug disposition of irinotecan and could enhance susceptibility to the drug. Patients who are homozygous for UGT1A1*6 should also be monitored cautiously. Genotyping of UGT1A1 polymorphisms in the coding region together with UGT1A1*28 is necessary for predicting irinotecan toxicity at least for Asian patient population. [Table: see text] [Table: see text]
Chemotherapy-Dependent ATP Release from Leukemia Dying Cells Induces Indoleamine 2,3-Dioxygenase 1 in Dendritic Cells
Authors: Mariangela Lecciso, Darina Ocadlikova, Elena De Marchi, Elisa Orioli, Sabina Sangaletti, Sara Trabanelli, Camilla Jandus, Andrea Bontadini, Annarita Redavid, Pedro Romero, Mario Paolo Colombo, Francesco Di Virgilio, Giovanni Martinelli, Michele Cavo, Elena Adinolfi, Antonio Curti
Journal: Blood (2016)
METIS: A phase 3 study of radiosurgery with TTFields for 1-10 brain metastases from NSCLC.
Authors: Minesh P. Mehta, Vinai Gondi, Paul D. Brown
Journal: Journal of Clinical Oncology (2017)

TPS9106 Background: Tumor Treating Fields (TTFields) are non-invasive regional anti-mitotic treatment modality, based on low intensity alternating electric fields. Efficacy of TTFields in non-small cell lung cancer (NSCLC) has been demonstrated in multiple in vitro and in vivo models, and in a phase I/II clinical study. TTFields treatment to the brain was shown to be safe and to extend overall survival in newly-diagnosed glioblastoma patients. Methods: 270 patients with 1-10 brain metastases (BM) from NSCLC will be randomized in a ratio of 1:1 to receive stereotactic radio surgery (SRS) followed by either TTFields or supportive care alone. Patients are followed-up every two months until 2 nd cerebral progression. Patients in the control arm may cross over to receive TTFields at the time of 2 st cerebral progression. Objectives: To test the efficacy, safety and neurocognitive outcomes of TTFields in this patient population. Endpoints: Time to 1 st cerebral progression based on the RANO-BM Criteria or neurological death (primary); time to neurocognitive failure based on the following tests: HVLT, COWAT and TMT; overall survival; radiological response rate; quality of life; adverse events severity and frequency (secondary). Main eligibility criteria: Karnofsky performance status (KPS) of 70 or above, 1 inoperable or 2-10 brain lesions amenable to SRS, optimal standard therapy for the extracranial disease, no brain-directed therapy, no signs of significantly increased intracranial pressure, no electronic implantable devices in the brain. Treatment: Continuous TTFields at 150 kHz for at least 18 hours per day will be applied to the brain within 7 days of SRS. The treatment system is a portable medical device allowing normal daily activities. The device delivers TTFields to the brain using 4 Transducer Arrays, which may be covered by a wig or a hat for cosmetic reasons. Patients will receive the best standard of care for their systemic disease. Statistical Considerations: This is a prospective, randomized, multicenter study for 270 patients. The sample size was calculated using a log-rank test (based on Lakatos 1988 and 2002) and has 80% power at a two sided alpha of 0.05 to detect a hazard ratio of 0.57. Clinical trial information: NCT02831959.
In adults at risk for contrast-induced nephropathy, no prophylactic hydration was noninferior to hydration
Authors: Brent Wagner
Journal: Annals of Internal Medicine (2017)

Source Citation Nijssen EC, Rennenberg RJ, Nelemans PJ, et al. Prophylactic hydration to protect renal function from intravascular iodinated contrast material in patients at high risk of contrast-induced nephropathy (AMACING): a prospective, randomised, phase 3, controlled, open-label, non-inferiority trial. Lancet. 2017;389:1312-22. 28233565
Correlation of loss of ataxia-telangiectasia-mutated protein expression with poor prognosis and benefit from anthracycline containing adjuvant chemotherapy in breast cancer.
Authors: Koung Jin Suh, Han Suk Ryu, Kyung-Hun Lee, Hyojin Kim, Ahrum Min, Tae-Yong Kim, Yaewon Yang, Hyeong-Gon Moon, Sae-Won Han, Do-Youn Oh, Wonshik Han, In Ae Park, Dong-Young Noh, Seock-Ah Im
Journal: Journal of Clinical Oncology (2016)

e23268 Background: We aim to investigate the correlation of ataxia-telangiectasia-mutated (ATM) protein expression with clinicopathological features and prognosis in patients with breast cancer. Methods: ATM expression was determined by immunohistochemistry in 420 surgically resected breast tumors (1:100, ab32520; Abcam, UK). “ATM loss” was defined as less than 10% of cells with weakly positive (+/3) or higher intensity, that is, more than 90% of cells showing negative (0) or equivocal staining (±). Results: Of the 420 patients (median age 47), 149 (35.5%) had stage I disease; 231 (55%) and 40 (9.5%) had stage II and III disease, respectively; 326 (77.6%) were treated with adjuvant chemotherapy, 276 (65.7%) with radiotherapy, and 301 (71.7%) with hormone therapy. ATM loss was observed in 126/407 evaluable cases (31.0%), and was significantly associated with larger tumor size, lymph node metastasis, higher tumor grade, and ER- and/or PR-negative status. ATM loss was also associated with significantly lower disease-free survival (DFS) rates than those in patients with intact ATM (5-year DFS 81.2% vs. 90.5%, p = 0.015). In multivariate analysis, ATM loss combined with abnormal p53 expression was an independent predictor of shorter DFS (HR 3.481; 95% CI, 1.484 - 8.166, p = 0.004). A tendency towards a poorer prognosis was observed for tumoral ATM loss alone, although statistical significance was not reached by a narrow margin (hazard ratio [HR] 1.740; 95% CI 0.946 - 3.200; p = 0.075). In subgroup analysis, ATM loss was associated with poor DFS in patients who did not receive adjuvant anthracycline chemotherapy (5-year DFS 93.4% in intact ATM group vs. 68.1% in ATM loss group, p = 0.002), but this poor prognosis was overcome in patients who did (5-year DFS 89.8% vs. 84.4%, p = 0.243), suggesting more benefit from the chemotherapy. Conclusions: Tumors with loss of ATM expression have a poor prognosis and their prognoses are dependent on the use of adjuvant anthracycline. ATM loss might be a practical tool for predicting benefits from anthracycline-based adjuvant therapy.
Role of epigenetics-microRNA axis in drug resistance of multiple myeloma
Authors: Nasrin Rastgoo, Jahangir Abdi, Jian Hou, Hong Chang
Journal: Journal of Hematology & Oncology (2017)

Despite administration of novel therapies, multiple myeloma (MM) remains incurable with resistance to drugs leading to relapse in most patients. Thus, it is critical to understand the detailed mechanisms underlying the drug resistance of MM and develop more effective therapeutic strategies. Genetic abnormalities are well known to play a central role in MM pathogenesis and therapy resistance; however, epigenetic aberrations mainly affecting the patterns of DNA methylation/histone modifications of genes (especially tumor suppressors) and miRNAs have also been shown to be involved. Importantly, while epigenetic silencing of miRNAs in MM is well documented, some epigenetic markers are known to be direct targets of miRNAs particularly the recently described “epimiRNAs”. Drugs targeting epigenetic modifiers (e.g., HDACs, EZH2) can sensitize MM-resistant cells to anti-myeloma drugs and reversibility of epigenetic changes makes these drugs promising therapeutic agents. Therefore, combination of miRNA mimics with inhibitors of epigenetic modifiers would be a more potent therapeutic strategy in MM patients in relapse or refractory to treatments. In this review, we will discuss the findings of recent investigations on epigenetics/miRNA regulatory axis in development of drug resistance in MM and highlight possible approaches for therapeutic applications of such interaction.
Clinical Utility of Routine Screening for IGA Deficiency in Samples Tested for EMA
Authors: C O'Leary, F Donnellan, M Keoghan, SE Patchett, FE Murray
Journal: Endoscopy (2004)

Aims: The prevalence of coeliac disease in Ireland is approximately 1%. Serological screening is by either antiendomysial (immunofluoresence) or tissue transglutaminase (ELISA) antibody testing, both are IgA based and have a sensitivity and specificity of 97–98%. This creates a problem in IgA deficiency, the prevalence of which is approximately 2.5% in coeliac disease, which is 15–16 times greater than in the general population.
Cooking Methods for Red Meats and Risk of Type 2 Diabetes: A Prospective Study of U.S. Women
Authors: Gang Liu, Geng Zong, Frank B. Hu, Walter C. Willett, David M. Eisenberg, Qi Sun
Journal: Diabetes Care (2017)

OBJECTIVE This study examined different cooking methods for red meats in relation to type 2 diabetes (T2D) risk among U.S. women who consumed red meats regularly (≥2 servings/week). RESEARCH DESIGN AND METHODS We monitored 59,033 women (1986–2012) aged 30–55 years and free of diabetes, cardiovascular disease, and cancer at baseline when information on frequency of different cooking methods for red meats, including broiling, barbequing, roasting, pan-frying, and stewing/boiling, was collected. RESULTS During 1.24 million person-years of follow-up, we documented 6,206 incident cases of T2D. After multivariate adjustment including red meat cooking methods, total red meat and processed red meat intake were both associated with a monotonically increased T2D risk (both P trend &amp;lt;0.05). After multivariate adjustment including total red meat intake, a higher frequency of broiling, barbequing, and roasting red meats was each independently associated with a higher T2D risk. When comparing ≥2 times/week with &amp;lt;1 time/month, the hazard ratios (HRs) and 95% CI of T2D were 1.29 (1.19, 1.40; P trend &amp;lt;0.001) for broiling, 1.23 (1.11, 1.38; P trend &amp;lt;0.001) for barbequing, and 1.11 (1.01, 1.23; P trend = 0.14) for roasting. In contrast, the frequency of stewing/boiling red meats was not associated with T2D risk, and an inverse association was observed for pan-frying frequency and T2D risk. The results remained similar after cooking methods were further mutually adjusted. CONCLUSIONS Independent of total red meat consumption, high-temperature and/or open-flame cooking methods for red meats, especially broiling and barbequing, may further increase diabetes risk among regular meat eaters.
Evaluation of Tumor-Derived Exosomal miRNA as Potential Diagnostic Biomarkers for Early-Stage Non–Small Cell Lung Cancer Using Next-Generation Sequencing
Authors: Xiance Jin, Yanfan Chen, Hanbin Chen, Shaoran Fei, Didi Chen, Xiaona Cai, Linger Liu, Baochai Lin, Huafang Su, Lihao Zhao, Meng Su, Huanle Pan, Lanxiao Shen, Deyao Xie, Congying Xie
Journal: Clinical Cancer Research (2017)

Purpose: To identify tumor-derived exosomal biomarkers that are able to discriminate between adenocarcinoma and squamous cell carcinoma (SCC) as a noninvasive method in the early diagnosis of non-small cell lung cancer (NSCLC).Experimental Design: Tumor-derived exosomes from the plasma of early-stage NSCLC patients were isolated. Exosomal miRNA profiling of 46 stage I NSCLC patients and 42 healthy individuals was performed using miRNA-seq to identify and validate adenocarcinoma- and SCC-specific miRNAs. The diagnostic accuracy of select miRNAs was tested further with an additional 60 individuals.Results: There were 11 and 6 miRNAs expressed at remarkably higher levels, 13 and 8 miRNAs expressed at lower levels in adenocarcinoma and SCC patients, respectively, compared with healthy volunteers. Distinct adenocarcinoma- and SCC-specific exosomal miRNAs were validated. The reliability of miRNA-seq data was verified with several demonstrated diagnostic potential miRNAs for NSCLC and other carcinomas, as reported in previous studies, such as let-7, miR-21, miR-24, and miR-486. The results indicated that miR-181-5p, miR-30a-3p, miR-30e-3p, and miR-361-5p were adenocarcinoma-specific, and miR-10b-5p, miR-15b-5p, and miR-320b were SCC-specific. The diagnostic accuracy of three combination miRNA panels was evaluated using an AUC value of 0.899, 0.936, and 0.911 for detecting NSCLC, adenocarcinoma, and SCC, respectively.Conclusions: Tumor-derived exosomal miRNAs, adenocarcinoma-specific miR-181-5p, miR-30a-3p, miR-30e-3p and miR-361-5p, and SCC-specific miR-10b-5p, miR-15b-5p, and miR-320b were observed by next-generation sequencing, and their diagnostic accuracy were verified. These miRNAs may be promising and effective candidates in the development of highly sensitive, noninvasive biomarkers for early NSCLC diagnosis. Clin Cancer Res; 23(17); 5311-9. ©2017 AACR.
Treatment of Pancreatic Cancer Patient–Derived Xenograft Panel with Metabolic Inhibitors Reveals Efficacy of Phenformin
Authors: N.V. Rajeshkumar, Shinichi Yabuuchi, Shweta G. Pai, Elizabeth De Oliveira, Jurre J. Kamphorst, Joshua D. Rabinowitz, Héctor Tejero, Fátima Al-Shahrour, Manuel Hidalgo, Anirban Maitra, Chi V. Dang
Journal: Clinical Cancer Research (2017)

Purpose: To identify effective metabolic inhibitors to suppress the aggressive growth of pancreatic ductal adenocarcinoma (PDAC), we explored the in vivo antitumor efficacy of metabolic inhibitors, as single agents, in a panel of patient-derived PDAC xenograft models (PDX) and investigated whether genomic alterations of tumors correlate with the sensitivity to metabolic inhibitors.Experimental Design: Mice with established PDAC tumors from 6 to 13 individual PDXs were randomized and treated, once daily for 4 weeks, with either sterile PBS (vehicle) or the glutaminase inhibitor bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES), transaminase inhibitor aminooxyacetate (AOA), pyruvate dehydrogenase kinase inhibitor dichloroacetate (DCA), autophagy inhibitor chloroquine (CQ), and mitochondrial complex I inhibitor phenformin/metformin.Results: Among the agents tested, phenformin showed significant tumor growth inhibition (>30% compared with vehicle) in 5 of 12 individual PDXs. Metformin, at a fivefold higher dose, displayed significant tumor growth inhibition in 3 of 12 PDXs similar to BPTES (2/8 PDXs) and DCA (2/6 PDXs). AOA and CQ had the lowest response rates. Gene set enrichment analysis conducted using the baseline gene expression profile of pancreatic tumors identified a gene expression signature that inversely correlated with phenformin sensitivity, which is in agreement with the phenformin gene expression signature of NIH Library of Integrated Network-based Cellular Signatures (LINCS). The PDXs that were more sensitive to phenformin showed a baseline reduction in amino acids and elevation in oxidized glutathione. There was no correlation between phenformin response and genetic alterations in KRAS, TP53, SMAD4, or PTENConclusions: Phenformin treatment showed relatively higher antitumor efficacy against established PDAC tumors, compared with the efficacy of other metabolic inhibitors and metformin. Phenformin treatment significantly diminished PDAC tumor progression and prolonged tumor doubling time. Overall, our results serve as a foundation for further evaluation of phenformin as a therapeutic agent in pancreatic cancer. Clin Cancer Res; 23(18); 5639-47. ©2017 AACR.
Effects of Dasatinib and Interferon-α Combination Treatment on the Immune System in CML
Authors: Mette Ilander, Hanna Lähteenmäki, Ulla Olsson-Stromberg, Jesper Stentoft, Johan Richter, Perttu Koskenvesa, Martin Höglund, Arta Dreimane, Kimmo Porkka, Tobias Gedde-Dahl, Björn T. Gjertsen, Franz X. Gruber, Leif Stenke, Kristina Myhr-Eriksson, Berit Markevärn, Anna Lubking, Hanne Vestergaard, Lene Udby, Ole Weis Bjerrum, Henrik Hjorth-Hansen, Satu Mustjoki
Journal: Blood (2016)
A Functional Polymorphism of the Stromelysin Gene (MMP3) May Influence Disease Progression in HCV Infection
Authors: CP O'Brien, M O'Brien, M Curry, C O'Farrelly, J Hegarty, PT Donaldson
Journal: Endoscopy (2004)

The outcome following infection with HCV is highly variable and the determinants of disease progression are poorly defined. Stromelysin is a member of the Matrix Metalloproteinase (MMP) family of enzymes which regulate extracellular matrix degradation and fibrosis. Recent studies suggest that a functional polymorphism in the stromelysin gene (MMP3) is associated with both increased susceptibility (risk) and progression of the fibrotic liver disease, primary sclerosing cholangitis. The aim of the present study was to determine whether this polymorphism is indicative of prognosis and outcome following HCV infection. The MMP3–1171 5A/6A polymorphism was determined in a homogenous cohort of 212 Irish women infected with HCV genotype 1b after the administration of contaminated anti-D immunoglobulin in 1977/8. A standard ARMS-PCR technique was used throughout. The overall genotype distribution was similar to that of racially matched controls. There was no significant difference in genotype distribution between those with persistent viraemia (n=131, 5A/5A (24.4%), 5A/6A (50.4%), 6A/6A (25.2%) and those with spontaneous (untreated) viral clearance (n=81, 26%, 57.1%, 16.9%). Of the 131 HCV RNA + patients, 82 (62%) had established fibrosis on liver biopsy. Among patients with the 5A/5A homozygous genotype, 74.2% had fibrosis on biopsy compared with 61% of non 5A/5A genotypes, which just failed to reach statistical significance (p=0.06). These data suggest that the 5A/5A genotype may predispose to the development of hepatic fibrosis in HCV infection. Identification of a genetic marker predictive of fibrosis would enable therapy to be tailored towards those most likely to develop progressive disease.
Emergency response facilities including primary and secondary prevention strategies across 79 professional football clubs in England
Authors: Aneil Malhotra, Harshil Dhutia, Sabiha Gati, Tee-Joo Yeo, Gherardo Finnochiaro, Tracey Keteepe-Arachi, Thomas Richards, Mike Walker, Robin Birt, David Stuckey, Laurence Robinson, Maite Tome, Ian Beasley, Michael Papadakis, Sanjay Sharma
Journal: British Journal of Sports Medicine (2017)

To assess the emergency response planning and prevention strategies for sudden cardiac arrest (SCA) across a wide range of professional football clubs in England.A written survey was sent to all professional clubs in the English football league, namely the Premiership, Championship, League 1 and League 2. Outcomes included: (1) number of clubs performing cardiac screening and frequency of screening; (2) emergency planning and documentation; (3) automated external defibrillator (AED) training and availability; and (4) provision of emergency services at sporting venues.79 clubs (86%) responded to the survey. 100% clubs participated in cardiac screening. All clubs had AEDs available on match days and during training sessions. 100% Premiership clubs provided AED training to designated staff. In contrast, 30% of lower division clubs with AEDs available did not provide formal training. Most clubs (n=66; 83%) reported the existence of an emergency action plan for SCA but formal documentation was variable. All clubs in the Premiership and League 1 provided an ambulance equipped for medical emergencies on match days compared with 75% of clubs in the Championship and 66% in League 2.The majority of football clubs in England have satisfactory prevention strategies and emergency response planning in line with European recommendations. Additional improvements such as increasing awareness of European guidelines for emergency planning, AED training and mentorship with financial support to lower division clubs are necessary to further enhance cardiovascular safety of athletes and spectators and close the gap between the highest and lower divisions.
Immunotherapy for transplantation-associated viral infections
Authors: Claire Roddie, Karl S. Peggs
Journal: Journal of Clinical Investigation (2017)

Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections following allogeneic hematopoietic stem cell transplantation (HSCT) are a major cause of morbidity and mortality. Early clinical trials demonstrate that adoptive transfer of donor-derived virus-specific T cells to restore virus-specific immunity is an effective strategy to control CMV and EBV infection after HSCT, conferring protection in 70%-90% of patients. The field has evolved rapidly to develop solutions to some of the manufacturing challenges identified in early clinical studies, such as prolonged in vitro culture, optimization of the purity of the virus-specific T cell product, the potential limitations of targeting a single viral antigen, and how to manage the patient with a virus-naive donor. This Review both discusses the seminal early studies and explores cutting-edge novel technologies that broaden the feasibility of and the scope for delivering virus-specific T cells to patients after HSCT.