tbuckley/cabot-search huggingface dataset:
Tumor regression and angiogenesis inhibition by phenyl-tert-butyl nitrone and its main metabolite in C6 rat glioma model
Authors: Sabrina Doblas, Yasvir Tesiram, Debbie Saunders, Preeti Kshirsagar, Quentin Pye, Jamie Pearson, Jenny Oblander, Brian Gordon, Stanley Kosanke, Robert Floyd, Rheal Towner
Journal: Cancer Research (2007)

5480   Prognosis of patients who are diagnosed with Glioblastoma multiforme, the most common type of primary brain tumors, is still very poor, because of the difficulty of an early and accurate diagnosis and of the lack of efficient therapeutic drugs. Magnetic resonance imaging (MRI) and angiography (MRA) can be used as non-invasive in vivo imaging modalities that can assess morphology and growth characteristics as well as angiogenic behavior of gliomas, and perhaps provide better diagnosis. New treatments are also sought, that would have an effect on well-established and vascularized tumors. MRI and MRA were used to evaluate the morphological and angiogenic properties of C6 rat glioma model, and to assess the efficiency of an antioxidant treatment, phenyl-tert-butyl nitrone (PBN), and of its main metabolite, 4-hydroxy-PBN (4OH-PBN), on this glioma model.  C6 cells (10,000 cells) were injected intracranially into the cortex (2mm from midline, 2mm anterior to bregma, at a depth of 3mm) of male Fischer 344 rats fed a choline-deficient diet. PBN or 4OH-PBN (75mg/kg/day in drinking water) treatment was started at different time points before and after cell implantation. MRI and MRA (time-of-flight technique) data was acquired at 7 Tesla at day 7 and then every third day until day 40 or death of the rat. Glioma morphologies and volumes were assessed by T1/T2-weighted images, and doubling time was calculated for each treatment group. Blood volume and vasculature projections were obtained in the tumor region of interest using MRA data and a Mathematica-based program. Finally, histology (H&E) and immunostaining assays (von Willebrand factor, synaptophysin and VEGF) were conducted for each animal.  MR results showed the diffusive invasiveness of C6 gliomas, which preferentially used pre-existing blood vessels for their nutrient sources. These results rival those from histology and immunostaining evaluations. PBN has also been found to clearly induce a decrease of the growth rate and tumor regression, while inhibiting neovascularization. It even had a 40% efficiency in reducing well-established tumors. 4OH-PBN efficiency was less pronounced, as only one third of the gliomas responded to a pre-treatment.  MRI and MRA are useful in vivo imaging tools to diagnose gliomas and evaluate therapeutic agents, such as PBN, which clearly inhibits glioma growth and angiogenesis in C6 rat glioma model.  Funds were appreciated from NIH P20RR016478 grant.
Use of Molecular Tools to Identify Patients With Indolent Breast Cancers With Ultralow Risk Over 2 Decades
Authors: Laura J. Esserman, Christina Yau, Carlie K. Thompson, Laura J. van 't Veer, Alexander D. Borowsky, Katherine A. Hoadley, Nicholas P. Tobin, Bo Nordenskjöld, Tommy Fornander, Olle Stål, Christopher C. Benz, Linda S. Lindström
Journal: JAMA Oncology (2017)

The frequency of cancers with indolent behavior has increased with screening. Better tools to identify indolent tumors are needed to avoid overtreatment.To determine if a multigene classifier is associated with indolent behavior of invasive breast cancers in women followed for 2 decades.This is a secondary analysis of a randomized clinical trial of tamoxifen vs no systemic therapy, with more than 20-year follow-up. An indolent threshold (ultralow risk) of the US Food and Drug Administration-cleared MammaPrint 70-gene expression score was established above which no breast cancer deaths occurred after 15 years in the absence of systemic therapy. Immunohistochemical markers (n = 727 women) and Agilent microarrays, for MammaPrint risk scoring (n = 652 women), were performed from formalin-fixed paraffin-embedded primary tumor blocks. Participants were postmenopausal women with clinically detected node-negative breast cancers treated with mastectomy or lumpectomy and radiation enrolled in the Stockholm tamoxifen (STO-3) trial, 1976 to 1990.After 2 years of tamoxifen vs no systemic therapy, regardless of hormone receptor status, patients without relapse who reconsented were further randomized to 3 additional years or none.Breast cancer-specific survival assessed by Kaplan-Meier analyses and multivariate Cox proportional hazard modeling, adjusted for treatment, patient age, year of diagnosis, tumor size, grade, hormone receptors, and ERBB2/HER2 and Ki67 status.In this secondary analysis of node-negative postmenopausal women, conducted in the era before mammography screening, among the 652 women with MammaPrint scoring available (median age, 62.8 years of age), 377 (58%) and 275 (42%) were MammaPrint low and high risk, respectively, while 98 (15%) were ultralow risk. At 20 years, women with 70-gene high and low tumors but not ultralow tumors had a significantly higher risk of disease-specific death compared with ultralow-risk patients by Cox analysis (hazard ratios, 4.73 [95% CI, 1.38-16.22] and 4.54 [95% CI, 1.40-14.80], respectively). There were no deaths in the ultralow-risk tamoxifen-treated arm at 15 years, and these patients had a 20-year disease-specific survival rate of 97%, whereas for untreated patients the survival rate was 94%. Recursive partitioning identified ultralow risk as the most significant predictor of good outcome. In tumors "not ultralow risk," tumor size greater than 2 cm was the most predictive of outcome.The ultralow-risk threshold of the 70-gene MammaPrint assay can identify patients whose long-term systemic risk of death from breast cancer after surgery alone is exceedingly low.
Circulating PD-L1 (programmed death-ligand 1) and outcomes in a HER2-positive metastatic breast cancer cohort treated with first-line trastuzumab.
Authors: Ayesha Ali, Laura Krecko, Kim Leitzel, Suhail M. Ali, Joseph J. Drabick, E Scott Halstead, Vinod Nagabhairu, Eric Marks, Hyma Vani Polimera, Angelique Ellerbee Richardson, Robert Evans, Howard Spiegel, Wolfgang Köstler, Francisco J. Esteva, Allan Lipton
Journal: Journal of Clinical Oncology (2017)

1024 Background: Recently the immune checkpoint inhibitors (ICIs) have demonstrated efficacy across a wide variety of cancers, but have been less effective in breast cancer. PD-L1 (B7-H1, CD274) is a ligand produced by many tumor cells and some immune cells, and suppresses the T cell immune response. This allows tumor cells to escape immune detection. PD-L1 is used as a companion tumor tissue IHC biomarker for patient selection for some of the FDA-approved ICIs (pembrolizumab), but not for others (nivolumab, atezolizumab). Circulating PD-L1 has been detected in multiple myeloma, renal, lung, and gastric cancer, but not in breast cancer. Here we correlated serum PD-L1 levels with outcome in a HER2-positive metastatic breast cancer cohort treated with trastuzumab. Methods: Pretreatment serum was obtained from 63 metastatic breast cancer patients before starting first-line trastuzumab-containing therapy. A novel ELLA microfluidic channel immunoassay platform (ProteinSimple, San Jose, CA) was employed to quantitate serum PD-L1. Serum PD-L1 levels were analyzed using continuous, quartile, and dichotomous (25%, median, and 75%) cutpoints. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. Results: On a continuous basis, patients with higher serum PD-L1 had a significantly reduced PFS (p = 0.045) and overall survival OS (p = 0.004) compared to patients with lower serum PD-L1 levels. Patients with the higher quartiles of serum PD-L1 also trended to have reduced PFS (0.11) and significantly reduced OS (p = 0.015) compared to the lower quartiles of serum PD-L1. Finally, using either the 25 th or 75 th percentile of serum PD-L1 as dichotomous cutpoint, patients with higher serum PD-L1 had significantly reduced OS (p = 0.04). Conclusions: Higher circulating PD-L1 levels were prognostic for reduced PFS and OS in HER2-positive metastatic breast cancer patients treated with first-line trastuzumab. Circulating PD-L1 deserves further study for prognostic and predictive biomarker utility in larger trials of immune checkpoint inhibitors and other immunotherapies in breast and other cancers. AA, LK contributed equally.
Abstract 231: Cardiac Myosin Binding Protein C Couples Cross-Bridge Cycling to Calcium Transients to Provide Normal Cardiac Function
Authors: Yang Liu, Mahamed Abdalla, Himakarnika Alluri, Daniel Jupiter, Shannon Glaser, David Dostal, Richard Moss, Carl Tong
Journal: Circulation Research (2012)

A 40-year old American has a 20% chance of developing heart failure (HF) in his/her lifetime. Although cross-bridge cycling forms the basis for contraction and relaxation of the heart, mechanisms that modulate cross-bridge cycling are not completely understood, nor are the alterations in these processes in HF. Cardiac myosin binding protein-C (MyBPC3) is a component of heart muscle that is believed to regulate cross-bridge cycling kinetics. We hypothesize that MyBPC3 tunes cross-bridge cycling to the [Ca2+]i transient to produce normal cardiac function, which we tested using our MyBPC3 knockout (KO) mouse. Echocardiography showed that MyBPC3(KO) hearts exhibited abbreviated aortic ejection durations (AED) and AED/(period between heart beats) ratio compared to WT. MyBPC3(KO) hearts also had smaller velocity-time integrals which indicate smaller stroke volumes as a result of abbreviated ejection. Brain natriuretic peptide expression level, heart weight/body weight, and lung weight/body weight were all increased in MyBPC3(KO) mice, consistent with HF. MyBPC3(KO) mice also exhibit increased 1-year mortality. We used simultaneous twitch force and intracellular calcium [Ca2+]i measurements on intact papillary muscles to evaluate the consequences of losing cross-bridge cycling regulation on force response to changing [Ca2+]i transients. MyBPC3 (KO) myocardium exhibited abbreviated contractions despite slower calcium transients and an inability to accelerate relaxation with respect to peak contraction. Therefore, loss of MyBPC3-mediated coupling of cross-bridge cycling to the [Ca2+]i transient was associated with contractile dysfunction and HF.
Prospective study of vaginal dilator use adherence and efficacy following pelvic and intravaginal radiotherapy.
Authors: Ethel Law, Joanne Frankel Kelvin, Bridgette Thom, Elyn Riedel, Ashlyn Tom, Karyn A. Goodman
Journal: Journal of Clinical Oncology (2013)

9524 Background: Vaginal stenosis (VS) as a late effect of pelvic radiotherapy (RT) and intravaginal brachytherapy (IVB) can impair long-term quality of life. The best care guideline for post-treatment 3x/week vaginal dilator (VD) use is based on limited research. This prospective study aimed to determine adherence and efficacy of VD use as measured by ability to return to pre-RT VD size at 12 months (mos). Methods: From 2009-2011, women with rectal (n=28), anal (n=35), endometrial (n= 45) and cervical (n=1) cancers were followed for one-year post-radiation therapy (RT). Clinicians provided structured teaching to use dilators 3x/week, regardless of frequency of sexual intercourse. For 12 mos, patients self-reported dilator size and vaginal symptoms in monthly diaries. At pre-RT, 1, 6 and 12 mos post-RT, clinicians graded VS using CTCAE v3. Adherence was measured as the percentage of times patients used the dilator out of the number of times they were instructed (3x/week X 52 weeks=156). Fisher’s exact and Kruskal-Wallis tests were used to assess differences among groups. Results: Among 109 participants, aged 28-81 years (median = 58), mean adherence with VD use over a 12 mos period was 42% (sd 34%, 95% Cl:36%- 49%). Adherence was highest in the first quarter (58%), but fell to 25% by the fourth quarter. Disease type, treatment sequence and chemotherapy were predictors of adherence (all p&lt;0.05). Rectal cancer patients were less likely to adhere to dilator use than anal and endometrial patients. 82% of all patients returned to pre-RT size at 12 mos; of the 49% who reported a decrease in dilator size from pre-RT to 1 month post-RT, 71% were able to return to pre-RT size at 12 mos. Anal cancer patients were most likely to report a decrease in VD size at 1 mo post-RT (77%), but 68% of these patients were able to return to baseline at 12 mos. Disease type and greater adherence to VD use at 6 months were associated with returning to pre-RT size at 12mos (both p &lt;0.05). Conclusions: Based on this prospective study, VD use is an effective strategy in minimizing VS, but adherence at 12 mos was poor. Future studies are needed to evaluate methods of improving adherence with VD use and to determine the optimal frequency and duration of VD use.
A Dose-Escalation (DE) Study with Expansion Evaluating Safety, Pharmacokinetics and Efficacy of the Novel, Balanced PI3K/mTOR Inhibitor PQR309 in Patients with Relapsed or Refractory Lymphoma
Authors: Graham P. Collins, Rakesh Popat, Anastasios Stathis, Fatime Krasniqi, Toby A. Eyre, Chin Hin Ng, Dima El-Sharkawi, Christian Schmidt, Andreas Wicki, Elena Ivanova, Debora Schmitz, Sasa Dimitrijevic, Martin H. Dreyling
Journal: Blood (2016)
Peg-Interferon Therapy in Patients with Haemophilia: Comparison of HCV Mono-Infected versus HCV / HIV Co-Infected Groups
Authors: D Kevans, A Grogan, B Hynes, G Farrell, M Hanlon, N Mammoud, B White, C Bergin, S Norris
Journal: Endoscopy (2006)

Introduction: HCV-infected haemophiliacs are traditionally underepresented in international treatment studies. There are no published studies assessing response to pegylated-interferon (peg-IFN) and ribavarin (RBV) in haemophiliacs who have HCV mono-infection or HCV/HIV co-infection.
DNA-Methyltransferase 1 Induces Dedifferentiation of Pancreatic Cancer Cells through Silencing of Krüppel-Like Factor 4 Expression
Authors: Victoria K. Xie, Zhiwei Li, Yongmin Yan, Zhiliang Jia, Xiangsheng Zuo, Zhenlin Ju, Jing Wang, Jiawei Du, Dacheng Xie, Keping Xie, Daoyan Wei
Journal: Clinical Cancer Research (2017)

Purpose: The dismal prognosis of pancreatic cancer has been linked to poor tumor differentiation. However, molecular basis of pancreatic cancer differentiation and potential therapeutic value of the underlying molecules remain unknown. We investigated the mechanistic underexpression of Krüppel-like factor 4 (KLF4) in pancreatic cancer and defined a novel epigenetic pathway of its activation for pancreatic cancer differentiation and treatment.Experimental Design: Expressions of KLF4 and DNMT1 in pancreatic cancer tissues were determined by IHC and the genetic and epigenetic alterations of KLF4 in and KLF4's impact on differentiation of pancreatic cancer were examined using molecular biology techniques. The function of dietary 3,3'-diindolylmethane (DIM) on miR-152/DNMT1/KLF4 signaling in pancreatic cancer was evaluated using both cell culture and animal models.Results: Overexpression of DNMT1 and promoter hypermethylation contributed to decreased KLF4 expression in and associated with poor differentiation of pancreatic cancer. Manipulation of KLF4 expression significantly affected differentiation marker expressions in pancreatic cancer cells. DIM treatment significantly induced miR-152 expression, which blocked DNMT1 protein expression and its binding to KLF4 promoter region, and consequently reduced promoter DNA methylation and activated KLF4 expression in pancreatic cancer cells. In addition, DIM treatment caused significant inhibition of cell growth in vitro and tumorigenesis in animal models of pancreatic cancer.Conclusions: This is the first demonstration that dysregulated KLF4 expression associates with poor differentiation of pancreatic cancer. Epigenetic activation of miR-152/DNMT1/KLF4 signaling pathway by dietary DIM causes differentiation and significant growth inhibition of pancreatic cancer cells, highlighting its translational implications for pancreatic and other cancers. Clin Cancer Res; 23(18); 5585-97. ©2017 AACR.
Nivolumab monotherapy in patients with advanced gastric or gastroesophageal junction (GEJ) cancer and 2 or more prior treatment regimens: Sub-analysis of the CheckMate 032 study
Authors: Patrick Ott, Emiliano Calvo, Padmanee Sharma, Dirk Jaeger, Paolo Ascierto, Ian Chau, Johanna Bendell, Katriina Peltola, Matthew Taylor, Marina Tschaika, Cecile Dorange, Yelena Janjigian, Dung Le
Journal: Annals of Oncology (2017)
The evaluation of endometrial thickness and bone mineral density based on CYP2D6 polymorphisims in Turkish breast cancer patients receiving tamoxifen treatment.
Authors: Meral Gunaldi, Melek Erkisi, Cigdem Usul Afsar, Vehbi Ercolak, Semra Paydas, Ismail Oguz Kara, Berksoy Sahin, Umran Gulec, Ata Secilmis
Journal: Journal of Clinical Oncology (2014)

e11559 Background: The drug efficacy and metabolism of tamoxifen on the treatment of breast cancer in the presence of gene polymorphisms CYP2D6, has been investigated in many studies. In the present study, different CYP2D6 genotypes were observed from various populations and were divided according to the discrepancies in the metabolizer groups. Methods: The CYP2D6 genotypes of 92 Turkish breast cancer patients treated with early-stage hormone receptor positive adjuvant tamoxifen (20 mg) were determined and classified according to metabolizer groups. The side effects of tamoxifen that include endometrial thickness, serum lipid levels, bone density measurements, and hepatosteatosis were evaluated according to the CYP2D6 polymorphism. Results: The CYP2D6 gene polymorphisms identified in the Turkish population were as follows: 77.1% normal metabolizer, 11.5% intermediate metabolizer, 5.2% ultra rapid metabolizer, and 2.1% poor metabolizer. The CYP2D6 genotypes of rapid metabolizer group were identified as CYP2D6 3X*1/*1 Duplication (DUP) and CYP2D6 2X*1/*2, while those of a poor metabolizer group were determined as CYP2D6*3/*4 and CYP2D6*6/*6. There was no significant relationship between metabolizer groups with bone density measurements and hepatosteatosis. In the lipid profile, total cholesterol and triglyceride levels were detected with statistical significance (p=0.003, p=0.02). The assessment of endometrial thickness showed hyperplasia in the poor metabolizer group and atrophy in ultra rapid metabolizer groups with statistical significance (p=0.01). Conclusions: The development of endometrial hyperplasia was determined to be significant in the poor metabolized group of patients taking adjuvant tamoxifen in this study. Therefore, we propose tamoxifen as a predictor of endometrial thickening in the poor metabolizer group.
Induction chemotherapy for patients with Locally advanced triple negative breast cancer.
Authors: Ekaterina Ignatova, Mona Frolova, Marina B. Stenina, Alexander Petrovsky, Sergei Tjulandin
Journal: Journal of Clinical Oncology (2016)

e12573 Background: Compared to other breast cancer subtypes, patients (pts) with triple-negative breast cancer (TNBC) have a lower recurrence-free and overall survival, regardless of disease stage at diagnosis. One of the ways to improve the results of treatment of locally advanced (LA) TNBC is intensification of induction chemotherapy regimens. We performed a prospective trial to evaluate efficacy of two consequent induction chemotherapy regimens: рaclitaxel, сarboplatinum weekly, then metronomic doxorubicin, cyclophosphamide and capecitabine (NCT01969032). Methods: Pts with LA TNBC (cТ2-4 N 2-3 M0) were treated with 2 consequent chemotherapy regimens: рaclitaxel 60 mg/m2 IV weekly plus сarboplatinum AUC2 IV weekly for 9 weeks, then doxorubicin 25 mg/m2 IV weekly plus cyclophosphamide 50 mg per os q.i.d. plus capecitabine 500 mg t.i.d for 9 weeks. Pathological response was evaluated according to the Chevallier classification. Results: Forty one pts were included in the study in 2011-2013. Median agewas 50 years (27-69), 33.3% of pts had tumor Grade 3, Ki67 was > 20% in 100% of cases. Forty pts completed chemotherapy. Overall response rate was 87.5% with 14.6% of complete responses and 73.2% of partial responses. Forty pts underwent surgery. Twenty-four pts (60%) achieved pCR. With median follow-up of 37,8 (10.2–55.8+) months, 12/14 (29%) pts had a disease progression: 5/12 (41.6%) with pCR, 6/12 (50%) with residual tumor. Оne pt had a disease progression during chemotherapy and was switched to 2nd-line chemotherapy. Death was registered in 7 (17%) pts.Three-year disease-free survival was 71% and overall survivalwas 82%. The dose-limiting toxicities were neutropenia (22.2% grade 3-4), mucositis (8.3% grade 3) and hand-foot syndrome (5.6% grade 3). In 11 pts treatment was discontinued early due to toxicity. Conclusions: Two consequent induction chemotherapy regimens: рaclitaxel, сarboplatinum weekly, then metronomic doxorubicin, cyclophosphamide and capecitabine shows promising activity in treatment of LA TNBC with acceptable toxicity. Clinical trial information: NCT01969032.
Salmonella newport infections associated with consumption of unpasteurized milk - Utah, April-June 2010.
Authors: J. M. Hall, R. K. Herlihy, M. P. S. Dimond, J. Holbrook, L. H. Smith, J. M. Wagner, R. W. Clark, W. A. Lanier
Journal: MMWR Morbidity and Mortality Weekly Report (2010)
Pharmacogenetic clinical randomized phase II trial to evaluate the efficacy and safety of FOLFIRI with high dose of irinotecan (FOLFIRI-HD) in metastatic colorectal cancer patients according to UGT1A 1 genotype
Authors: David Paez, Maria Tobeña, Ana Sebio, Julen Fernandez-Plana, Marta Martin, Anna Virgili, Pau Riera, Ivana Sullivan, Juliana Salazar
Journal: Annals of Oncology (2017)