tbuckley/cabot-search huggingface dataset:
Senate Committee Investigates Price Hikes for Off-Patent Drugs
Authors: Rita Rubin
Journal: JAMA (2016)

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Phase IB study of primary chemotherapy with paclitaxel, gemcitabine, and sunitinib in patients with HER2-negative stage II/III breast cancer.
Authors: K. S. Lee, I. Park, J. Ro, H. S. Kang, S. W. Kim, S. Lee, S. Y. Jung, Y. Kwon
Journal: Journal of Clinical Oncology (2010)

685 Background: The combination of paclitaxel (P) and gemcitabine (G) was previously evaluated in the neoadjuvant setting and showed high efficacy with relatively mild toxicities (Inv New Drugs 2010). For HER2-negative early breast cancer (EBC), a phase IB trial was undertaken to evaluate sunitinib, an oral multi-targeted tyrosine kinase inhibitor, in combination with PG. The primary endpoint was to determine the recommended dose (RD) and maximum tolerable dose (MTD). Secondary endpoints included toxicity, pCR rate, progression-free survival (PFS), and overall survival. Methods: Eligible pts had potentially operable EBC and ECOG PS 0 or 1. Pts enrolled into sequential cohorts of “3 + 3” design. Dose level 1 cohort received paclitaxel 80 mg/m2 and gemcitabine 1,000 mg/m2 IV D1 and D8 with sunitinib 25 mg/day D2-D15 every 3 weeks preoperatively for 6 cycles. The doses of paclitaxel, gemcitabine, and sunitinib were 80/1,200/25 and 80/1,200/37.5 for dose level 2 and dose level 3 cohorts, respectively. We are going to present the outcomes of the primary endpoint. To determine the MTD, only dose limiting toxicity (DLT) occurring during the first cycle of treatment was considered. Results: 15 pts (6-dose level 1, 6-dose level 2, and 3-dose level 3 cohorts) were enrolled between Mar to Nov 2009. Pt characteristics included median age 48 (range 31-67); stage (1-IIB, 8-IIIA and 6-IIIC); ER and/or PR (9-positive and 6-negative); HER2 (1- positive and 14- negative). One HER2+ pt was enrolled based on HER2 immunohistochemistry 1+ positivity which later showed HER2 FISH-positivity. This pt was included in the analysis for the primary endpoint since she completed the first cycle. DLTs were: 1-delayed recovery of G3 neutropenia and 1-G3 febrile neutropenia of 3 pts assigned to dose level 3 cohort; 1-G3 skin rash and 1-G3 febrile neutropenia of 6 pts with dose level 2 cohort; no DLTs observed in 6 pts with dose level 1 cohort. Conclusions: MTD was determined at dose level 2. Based on this phase IB trial, the RD for phase II trials is paclitaxel 80 mg/m2 and gemcitabine 1,000 mg/m2 IV D1 and D8 with sunitinib 25 mg/day D2-D15 every 3 weeks. Supported by NCC Grant No 0910320-1. No significant financial relationships to disclose.
Abstract MP042: Overall AHA Cardiovascular Health Score In Latino Men And Women In Zulia State, Venezuela.
Authors: Hermes J Florez, Egle Silva, Sumaya Castillo-Florez, Tulio Sulvaran, Elena Ryder, Gladys Maestre, Lisset Oropesa
Journal: Circulation (2012)

Introduction: Cardiovascular (CV) disease has remained the leading cause of morbidity and mortality worldwide. The American Heart Association (AHA) recently set goals for CV health promotion and disease reduction. There are limited CVD data available to plan prevention strategies in developing countries. Aim: To assess the effect age and gender on the AHA overall CV health score in the Venezuelan population. Methods: In a population-based study in Zulia State, Venezuela, we evaluated 3108 Latino adult men and women on the prevalence of ideal CV health behaviors (nonsmoking, achieving normal weight, enough physical activity, and a healthy diet) and ideal CV health factors (total cholesterol&lt;200 mg/dl, blood pressure&lt; 120/80 mmHg, and fasting blood glucose&lt;100 mg/dl). We calculated AHA global CV health score assigning 1 to each ideal behavior and factor (for a maximum of 7) and 0 for poor status to each one. Results: Most (75.7%) of the population had intermediate CV scores (between 3 and 5) while in 10.8% had poor scores (&lt;3) and only 13.5% had ideal scores (&gt;5). Large portions of the population need improvements on diet (97.9%), physical activity (80.9%), weight management (60.2%) and blood pressure (59.6%), while some need interventions to reduce hypercholesterolemia (26.9%), hyperglycemia (23.8%), and smoking (20.8%). The global cardiovascular score significantly decreases with age (p&lt;0.001) but this reduction was steeper in women than in men after age 50 (p&lt;0.001for gender*age interaction). Conclusions: CV health promotion strategies are needed in the majority (∼86%) of the Latino population in Zulia, Venezuela. Prevention strategies focusing on weight reduction through healthy diet and increased physical activity may have significant impact improving overall CV health and reducing obesity related comorbidities, such as hypertension and diabetes, in this population.
Validation of RRM1 and PTEN as prognostic parameters of outcome in non-small cell lung cancer
Authors: G. Bepler, S. Sharma, A. Cantor, A. Gautam, E. Haura, G. Simon, A. Sharma, E. Sommers, L. Robinson
Journal: Journal of Clinical Oncology (2004)

7154 Background: RRM1 has important functions in determination of the malignant phenotype. It controls cell proliferation through deoxynucleotide production and metastatic propensity through PTEN induction. It is located in a region of loss of heterozygosity in non-small cell lung cancer (NSCLC), which is a predictor of poor survival. We hypothesized that RRM1 expression would be a significant predictor of outcome in NSCLC. Methods: A retrospective dataset of 49 patients and a prospective dataset of 77 patients with resectable NSCLC were studied. RNA was extracted from tumor and normal lung tissue, and expression of the genes RRM1, PTEN, and RRM2 was determined by real-time quantitative polymerase chain reaction. Results: RRM1 expression was significantly correlated with PTEN and RRM2 expression in both tumor and normal lung tissue. RRM1 and PTEN expression in tumor tissue were highly predictive of overall (p=0.011 and 0.018) and disease-free survival (p=0.002 and 0.026). Patients with high levels of expression lived longer and had disease recurrence later than patients with low levels of RRM1 and PTEN. In a multivariate analysis, high RRM1 expression was predictive of long survival independent of tumor stage, performance status, and weight loss. Conclusion:: RRM1 is a biologically and clinically important determinant of malignant behavior in NSCLC. Knowing the level of expression of this gene adds significant information to management decisions independent of the currently used outcome predictors tumor stage, performance status, and weight loss. Future clinical trials should stratify patients based on expression of this gene to avoid unwanted biases. No significant financial relationships to disclose.
Spatial heterogeneity in regional pulmonary function in COPD patients and healthy young and elderly subjects
Authors: Barbara Gawelczyk, Sven Pulletz, Hans-Peter Hauber, Peter Zabel, Norbert Weiler, Inéz Frerichs
Journal: European Respiratory Journal (2011)

Introduction:  Electrical impedance tomography (EIT) can determine regional dynamic gas volume changes in the lungs. The aim of our study was to examine the regional differences in lung function in COPD patients and healthy adults using EIT.   Patients and methods:  33 COPD patients (GOLD II-IV) and 25 healthy young and elderly adults were studied. EIT data were collected at up to 44 images/s (Goe-MF II, CareFusion, Hoechberg, Germany) in parallel with spirometry. Regional inspiratory (IVC) and forced vital capacities (FVC), forced expired volume in 1s (FEV 1 ) and tidal volume (V T ) were determined in 912 EIT image pixels in the chest cross-section. Coefficient of variation (CV) was calculated from all pixel values to characterize the heterogeneity of lung function. The average value reflecting the volumetric changes in the cross-section was also determined. Statistical analysis was carried out by one-way ANOVA with Bonferroni post test.   Results:  The CV values of regional IVC, FVC, FEV 1  and V T  were significantly different between healthy adults and COPD patients (p values: 0.0102, 0.0050, 0.0022 and 0.0047). No differences existed between the young and elderly subjects. The average IVC, FVC, FEV 1  and V T  in the chest cross-section were significantly different among the groups (p values: 1 .   Conclusion:  EIT is able to detect disease and age related differences in regional lung function. The heterogeneity of lung function is similar in the young and elderly healthy subjects but lower than in COPD patients.
Effect of introduction of paclitaxel on survival among women with stage III and IV ovarian cancer
Authors: S. S. Dawood, C. Albaracin, A. Gonzalez-Angulo, M. Markman, B. Hennessy
Journal: Journal of Clinical Oncology (2009)

5536 Background: The objective of this study was to evaluate survival over time in relation to FDA approval of paclitaxel (P) for second- and first-line treatment in a population-based cohort of women with stage III and de novo stage IV ovarian cancer. Methods: The Surveillance, Epidemiology, and End Results (SEER) program was searched to identify 8,267 and 10,746 women with stage III and stage IV epithelial ovarian cancer diagnosed between 1988–2004. Women were divided according to their year of diagnosis and year of FDA approval of P for second- (1992) and first-line(1998) treatment of ovarian cancer: Group1 (1988–1991; before P approval); Group2 (1992–1997; P approved for second-line); Group3 (1998–2003; P approved for first-line). Overall (OS) and ovarian-cancer-specific survival (OCS) were estimated using Kaplan-Meier product method and compared across groups with log rank statistic. Cox-proportional hazards models were fitted to determine the association of group year of diagnosis and survival after adjusting for patient/tumor characteristics. Results: Median age was 66 years. Median OCS was 44 and 18 months among women with stages III and IV disease, respectively. With stage III disease, 2-year OCS was 64%, 68%, and 70% for groups 1, 2, and 3, respectively (p &lt; 0.0001). With stage IV disease, 2-year OCS was 39%, 41%, and 42% for groups 1, 2, and 3, respectively (p = 0.19). In the multivariable model for stage III disease, women in group 1 (HR = 1.4, 95% CI 1.2–1.5, p &lt; 0.0001) and group 2 (HR = 1.2, 95% CI 1.1–1.3, p = 0.0003) had an increased hazard of ovarian-cancer-specific death vs. group 3. For stage IV disease, women in group 1 (HR = 1.2, 95% CI 1.12–1.3, p &lt; 0.0001) had a significantly increased hazard of ovarian cancer-specific death, but no significant difference in group 2 (HR = 1.0, 95% CI 0.9–1.1, p = 0.88) vs. group 3. Similar trends were observed for OS. Conclusions: The survival of women with stages III and IV ovarian cancer has significantly improved with the introduction of P over the last two decades. However, the incremental improvement in survival with stage IV disease is clinically minimal and indeed not significant in the univariable analysis in the SEER patient cohort analyzed, suggesting a desperate need for new and more active drugs in these patients. No significant financial relationships to disclose.
A fire-setting epidemic in a state mental health center
Authors: L Boling, C Brotman
Journal: American Journal of Psychiatry (1975)

The authors describe a period in which 13 fires were set by 4 patients on an inpatient service of a state mental health center. Unlike previous patients reported in the literature, these individuals had no history of fire setting, although they did display several previously reported characteristics (e.g., primitive and impulsive personalities and absent fathers). The influence of institutional changes and conflict upon such disruptive patient behavior is emphasized; the authors suggest that efforts to deal with fire setting should recognize the total situation and include clear limit setting by the hospital administration.
P30 Cytoplasmic expression of Toll-like receptor-9 is associated with increased cellular proliferation in hepatocellular carcinoma
Authors: F Mohamed, D Dhar, A Winstanley, N Shah, S Behboudi, R Mookerjee, S O Damink, N Davies, R Jalan
Journal: Gut (2010)

Introduction  Effective treatment of Hepatocellular carcinoma (HCC) still remains an unmet need. Inflammation plays a crucial role in the pathogenesis of HCC by causing repeated cell damage and creating a microenviroment rich in cytokines that can enhance cell replication, angiogenesis and invasion into the surrounding structures. Toll-like receptors (TLRs) are important pathogen recognition receptors. Stimulation of TLRs is followed by cascade of transcriptional and translational reactions resulting in activation of NF-kB which subsequently serves as a common- link between the chronic inflammation and tumour development.  Aim  The aim of this study was to characterise the expression of TLR-9 along the HCC tumour genesis pathway including the normal liver, viral hepatitis, cirrhosis and HCC and the results were collated with cell proliferation as determined by Ki-67 staining.  Method  We used a human tissue array platforms (Vbiolab, Cambridge, UK) which includes 102 cores of liver tissue including nine normal livers, 26 hepatitis (B, C and Non-b, Non-C hepatitis), 25 cirrhosis and 42 HCC. Immunohistochemistry was performed for the expression of TLR-9 and Ki-67. The scoring was performed in a blinded fashion by two individual pathologists. For the quantitation of Ki-67 expression, we counted the positively stained nuclei among 1000 hepatocytes in the highest expression area using a standardised grid.  Results  TLR-9 expression was noticed as membranous staining in 2/9 cases in normal liver. 12/26 cases of hepatitis and 13/25 of cirrhosis. Weak cytoplasmic staining was noticed in 4/26 cases of hepatitis and one case in cirrhosis whereas the staining was predominantly cytoplasmic in HCC; weak (+1) in 17/42 cases and moderate to strong (+2 and+3) in 17/42 cases, whilst in eight cases it was negative. In 13/42 cases, it was found in both cytoplasm and cell membrane. There was a close correlation between the proliferative index (Ki-67 staining) and TLR-9 staining; r=0.8, p 200 in TLR9 negative, weak and moderate-to-strong cases, respectively.  Conclusion  The results of our study show, for the first time, a strong correlation between the amount of cellular proliferation and TLR-9 expression in HCC. Also we found the shifting of TLR9 expression from the membranous type in hepatitis and cirrhosis into cytoplasmic in HCC. Our data suggest that TLR-9 might have a pivotal role in cellular proliferation in HCC and merits further studies to explore the possibility of exploiting it as a potential target for future therapy.
A New Approach to Cancer Chemotherapy: Selective Enhancement of Tumor Blood Flow With Angiotensin II&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="fn3"&gt;3&lt;/xref&gt;
Authors: M Suzuki, K Hori, I Abe, S Saito, H Sato
Journal: JNCI Journal of the National Cancer Institute (1981)

Elevation of the mean arterial blood pressure to approximately 150 mmHg by infusion of angiotensin II resulted in an approximate 5.7-fold selective increase in blood flow in tumor tissue without increasing blood flow in normal tissue. This finding of no autoregulation of blood flow in tumor tissue was made in an experiment on inbred DONRYU rats with sc transplanted AH109A solid tumors (Yoshida ascites hepatoma). Changes in tissue blood flow were measured by a thermoelectrical method. In another experiment in which DONRYU rats with sc transplanted AH272 solid tumors were used, the chemotherapeutic effect of mitomycin C on main tumors and lymph node metastatic foci was markedly enhanced in rats with angiotensin-induced hypertension, as compared to its effect in rats without angiotensin-induced hypertension. Thus a new approach to cancer chemotherapy has been demonstrated in which the delivery to tumor tissue of systemically administered anticancer drugs can be selectively enhanced.
Imaging tumor hypoxia with BOLD MRI in primary breast cancer.
Authors: S. P. Li, A. R. Padhani, N. J. Taylor, M. W. Ah-See, M. J. Beresford, J. J. Stirling, D. J. Collins, J. A. d'Arcy, A. Makris
Journal: Journal of Clinical Oncology (2010)

e13526 Background: Blood oxygenation level dependent (BOLD) MRI provides a noninvasive means of assessing in vivo tumor oxygenation by relying on endogenous deoxyhemoglobin as a contrast agent. Higher apparent relaxation rates (R2*) represent a more hypoxic environment. However BOLD MRI is underexplored in breast cancer (BC) and histologic correlates and chemotherapy response in relation to R2* are unknown. Methods: 83 pts with primary BC were selected to undergo dynamic contrast enhanced (DCE) and BOLD MRI before and after 2 cycles of neoadjuvant chemotherapy (NAC). Pts with diffusely infiltrating, invasive lobular (ILC) or necrotic tumors were excluded due to confounding R2* values. DCE MRI T1 and T2w parameters (Ktrans, ve, kep, IAUGC60, relative blood flow (rBF) and volume (rBV), MTT) and R2* were derived. Relationships between baseline characteristics (grade, size, ER/PR/HER2), imaging parameters and R2* were examined; continuous variables using Spearman's rank correlation (ρ) and discrete variables with the Mann-Whitney U test. Baseline R2* and R2* changes with NAC were correlated with final pathologic response using paired t-testing. Results: 31 pts (median age 44; T2-4, N0-1, M0) were available for baseline and 27 for response assessment. 12 did not undergo both MRIs, 1 had only nodal disease visible, images for 2 were not analyzable and another 4 did not undergo second MRIs. 37 had either ILC, ill-defined and/or necrotic tumors. 15 pts received anthracycline based and 12 docetaxel NAC. Baseline R2* did not correlate with histologic parameters, size, or response. Inverse correlations were observed between rBF/rBV and R2* (p=−0.48, p=0.013; p=−0.44, p=0.024) which disappeared with NAC (p=−0.28, p=0.196; p=−0.31, p=0.155). R2* increases were observed with NAC (34.8 s-1 vs. -31.1 s-1, p=0.006) with larger increases correlating with final pathologic response (36.5 s-1 vs. 31.7 s-1, p=0.025). Conclusions: The relationship between R2* and rBV/BF confirms that R2* in treatment naÏve BC relates to blood rather than tumor oxygenation. However with the loss of this relationship after NAC, R2* becomes a marker of tumor hypoxia. The R2* increases seen with NAC suggest that tumors become hypoxic with NAC particularly in responders. BOLD MRI may help select pts suitable for hypoxia modifying agents. No significant financial relationships to disclose.
A phase II trial of dacarbazine, fluorouracil and epirubicin in patients with neuroendocrine tumours. A study by the Italian Trials in Medical Oncology (I.T.M.O.) Group
Authors: M. Di Bartolomeo, E. Bajetta, A.M. Bochicchio, C. Carnaghi, L. Somma, V. Mazzaferro, M. Visini, V. Gebbia, S. Tumolo, P. Ballatore
Journal: Annals of Oncology (1995)
Exacting Requirements for Development of the Egg
Authors: Jurrien Dean
Journal: New England Journal of Medicine (2016)

The hallmark of successful human reproduction is the fusion between a haploid spermatozoon and a metaphase II oocyte. The generation of such an oocyte involves a series of steps whereby germinal-vesicle oocytes (in which the nuclei are intact) at prophase I are stimulated to resume meiosis and mature to metaphase II, a sequence of events that prepares the oocyte for fertilization. Meiosis in mammalian females entails two reductive divisions of DNA to produce ovulated oocytes that can be fertilized in the oviduct (Figure 1). In the first meiotic division, replicated chromosomes condense and attach to kinetochores through their centromeres to . . .
Clinical Experience With High-Dosage Pramipexole in Patients With Treatment-Resistant Depressive Episodes in Unipolar and Bipolar Depression
Authors: Jan Fawcett, A. John Rush, John Vukelich, Shanna H. Diaz, Lucas Dunklee, Paul Romo, Brandon C. Yarns, Rodrigo Escalona
Journal: American Journal of Psychiatry (2016)
Pharmacokinetics (PK) Study Of Antithymocyte Globulins Fresenius (ATG-F) Prior To Allogeneic Stem Cell Transplantation: Implications For Timing Of Graft and Early Adoptive Immunotherapy Infusions
Authors: Sara Mastaglio, Alessandra Forcina, Isabell Seitz, Holger Martinius, Jacopo Peccatori, Massimo Bernardi, Daniela Clerici, Consuelo Corti, Alessandro Crotta, Maria Teresa Lupo Stanghellini, Carlo Messina, Chiara Bonini, Fabio Ciceri
Journal: Blood (2013)
Efficacy and safety of oral solithromycin versus oral moxifloxacin for treatment of community-acquired bacterial pneumonia: a global, double-blind, multicentre, randomised, active-controlled, non-inferiority trial (SOLITAIRE-ORAL)
Authors: Carlos M Barrera, Analia Mykietiuk, Hristo Metev, Mimi Floarea Nitu, Najumuddin Karimjee, Pablo Alexis Doreski, Ismail Mitha, Cristina Mihaela Tanaseanu, Joseph McDermott Molina, Yuri Antonovsky, Dirkie Johanna Van Rensburg, Brian H Rowe, Jose Flores-Figueroa, Barbara Rewerska, Kay Clark, Kara Keedy, Amanda Sheets, Drusilla Scott, Gary Horwith, Anita F Das, Brian Jamieson, Prabhavathi Fernandes, David Oldach
Journal: The Lancet Infectious Diseases (2016)