tbuckley/cabot-search huggingface dataset:
Abstract 91: Alteration of Myocardial GRK2 Produces a Global Metabolic Phenotype.
Authors: Benjamin P Woodall, Meryl A Castellini, Alessandro Cannavo, Walter J Koch
Journal: Circulation Research (2014)

A vast body of literature has established GRK2 as a key player in the development and progression of heart failure. GRK2 levels increase in the heart post injury in an attempt to normalize sympathetic overdrive. While initially beneficial, this response becomes maladaptive. Inhibition of GRK2 improves cardiac function post injury in numerous animal models. Recently, discovery of several non-canonical GRK2 targets has expanded our view of this kinase. Amongst these, our lab has identified GRK2 as a negative regulator of cardiac insulin signaling and this is through direct interaction and phosphorylation of the insulin receptor substrate-1 (IRS1). While continuing to study cardiac metabolic aspects of GRK2 manipulation we have uncovered the novel and exciting finding that cardiac GRK2 activity can regulate whole body metabolism. We found that transgenic mice with cardiac-specific overexpression of GRK2 (Tg-GRK2) show resistance to high fat diet (HFD) induced obesity. In contrast, Tg-βARKct mice with cardiac-specific expression of a peptide inhibitor of GRK2, known as the βARKct display an enhanced obesogenic phenotype when fed a HFD. We placed transgenic mice (and their non-transgenic littermate controls) on a high fat diet (60% kcal% fat) or a control diet (10% kcal% fat) for up to 16 weeks. Mice were housed in grouped cages at room temperature (18-22°C). HFD feeding increased white adipose mass in Tg-BARKct mice vs. NLC, whereas adipose mass in Tg-GRK2 mice is lower than NLC animals. Moreover, HFD Tg-βARKct mice exhibit elevated serum leptin levels relative to NLC, indicating development of leptin resistance. The novelty of this finding could bear great clinical significance, not least because these cardiac specific transgenes elicit a global metabolic phenotype implicating the heart as an endocrine organ and GRK2 activity is essential for this new and unexpected finding.
Abstract 13593: Lower Plasma Omega-6 Polyunsaturated Fatty Acid Level and Malnutrition in Acute Heart Failure Patients and Its Association With Worse Clinical Outcome
Authors: Toshiyuki Nagai, Yoshiya Yamamoto, Yasuo Sugano, Takafumi Yamane, Tatsuhiro Shibata, Kenji Nakamura, Naotsugu Iwakami, Daigo Chinen, Yasuhide Asaumi, Takeshi Aiba, Teruo Noguchi, Masaharu Ishihara, Kengo Kusano, Hisao Ogawa, Satoshi Yasuda, Toshihisa Anzai
Journal: Circulation (2014)

Backgrounds: Malnutrition was reported to be associated with poor clinical outcome in acute heart failure (AHF) patients. Plasma omega-6 (n-6) polyunsaturated fatty acids (PUFA) were parts of the essential fatty acids absorbed with intestine, and its absorption impairment could occur in right side of heart failure (HF). Thus, we aim to investigate whether the n-6 PUFA level could be a marker for malnutrition and a determinant of prognosis in patients with AHF. Methods: We examined 320 consecutive AHF patients who admitted to our institution between January 2013 and January 2014 from prospective registry. Patients with acute coronary syndrome and without complete data-set at admission were excluded. Finally, 284 patients were divided into two groups according to the plasma n-6 PUFA level as follows; Group A [lower plasma n-6 PUFA (dihomo-gamma-linolenic acid plus arachidonic acid) (below 163 μg/ml, the median), Group B [higher plasma n-6 PUFA (above 163 μg/ml) level] at admission. Adverse events were defined as worsening HF and death. Results: During a mean period of 231 days, adverse events were occurred in 78 patients (27 %). Group A had higher incidence of adverse events compared with group B (35% vs 20%, P&lt;0.01). Group A had lower blood pressure, hemoglobin, plasma omega-3 (n-3) PUFA levels, higher age and serum creatinine level on admission than group B. Regarding right HF sign, group A had higher prevalence of jugular vein distention (P=0.04), hepatomegaly (P&lt;0.01) and higher bilirubin level (P&lt;0.01) than group B. Furthermore, group A had lower serum total cholesterol (P&lt;0.01), triglyceride (P=0.02), and albumin (P&lt;0.01) levels as malnutrition than group B. In multivariate Cox proportional hazards model, lower plasma n-6 PUFA level (HR 1.62, 95% CI 1.01-2.65), higher serum creatinine (HR 1.83, 95% CI 1.02-3.59), and higher plasma BNP levels (HR 1.60, 95% CI 1.02-2.57) were independent determinants for adverse events, among variables including age, blood pressure, hemoglobin, plasma n-3 PUFA, serum albumin levels. Conclusions: Lower plasma n-6 PUFA level was an independent determinant for adverse events in association with right HF sign and malnutrition, suggesting plasma n-6 PUFA could be a potential surrogate marker for clinical outcome in AHF patients.
Defensin Stimulates the Binding of Lipoprotein (a) to Human Vascular Endothelial and Smooth Muscle Cells
Authors: Abd Al-Roof Higazi, Ehud Lavi, Khalil Bdeir, Anthony M. Ulrich, Dara G. Jamieson, Daniel J. Rader, David C. Usher, William Kane, Tomas Ganz, Douglas B. Cines
Journal: Blood (1997)
The influence of the polar head-group of synthetic cationic lipids on the transfection efficiency mediated by niosomes in rat retina and brain
Authors: E. Ojeda, G. Puras, M. Agirre, J. Zarate, S. Grijalvo, R. Eritja, G. Martinez-Navarrete, C. Soto-Sánchez, A. Diaz-Tahoces, M. Aviles-Trigueros, E. Fernández, J.L. Pedraz
Journal: Biomaterials (2015)
Endoscopic ultrasound (EUS)-guided duodenogastroenterostomy: why not do it from the other side?
Authors: Eduardo Rodrigues-Pinto, Ian Grimm, Todd Baron
Journal: Endoscopy (2015)

A 76-year-old woman, with previous resection of a metastatic mixed adenocarcinoma-neuroendocrine tumor of small-bowel origin presented with gastric outlet obstruction. Abdominal computed tomography revealed a submucosal mass in the third portion of the duodenum, with upstream gastroduodenal dilatation. There was intimate contact between the wall of the fourth duodenal portion and the stomach ([Fig. 1]).
Abstract 3319: Identification of cervical cancer stem cells by using an imaging system for proteasome activity
Authors: Keisuke Tamari, Hideshi Ishii, Kazuhiko Hayashi, Masamitsu Konno, Koichi Kawamoto, Naohiro Nishida, Jun Kozeki, Takahito Fukusumi, Yuichiro Doki, Masaki Mori, Kazuhiko Ogawa
Journal: Cancer Research (2015)

Abstract Cervical cancer is one of the most common cancers among women worldwide and the fourth most common cause of cancer death in women worldwide (275,100 deaths in 2008). For advanced cervical cancer, concurrent radiotherapy and chemotherapy are commonly administered. However, the 5-year survival rate remains at only ∼60%, indicating the need for significant improvements in clinical outcomes. Recurrence and metastatic potential can be due to a specific radioresistant subpopulation of cells with stem-like characteristics, cancer stem cells (CSCs) which maintain the capacity to regenerate entire tumors. Targeting of the CSCs is a promising avenue to explore to develop new therapies for this devastating cancer. Recently, cancer cells with low proteasome activity have been identified as CSCs in breast cancer, glioma, and pancreatic cancer with a fluorescence marker system for level of proteasome activity. We stably infected two cervical cancer cell lines, HeLa and CaSki, with an expression vector for a fusion protein between the green fluorescent protein, ZsGreen, and the C-terminal degron of murine ornithine decarboxylase to monitor 26S proteasome activity in living cells. we divided these cells into ZsGreen-high (low proteasome activity) and ZsGreen-low (high proteasome activity) groups according to their fluorescence intensity. Sphere forming assay revealed that the self-renewal ability of the ZsGreen-high population was significantly higher than that of the ZsGreen-low population. Tumorigenicity assay confirmed that the ZsGreen-high population exhibited higher tumorigenic potential than the ZsGreen-low population. The radioresistance of the ZsGreen-high population of both HeLa and CaSki cells and the chemoresistance of the ZsGreen-high population of CaSki cells were confirmed by clonogenic survival assay and the MTT assay, respectively. These results indicated that ZsGreen-high populations of both the HeLa and CaSki cell lines possess CSC-like properties and therapeutic resistance. We conclude that established cervical cancer cell lines are heterogeneous with regard to their intrinsic proteasome activity and that they contain CSCs-enriched subpopulations that can be identified by low proteasome activity. Citation Format: Keisuke Tamari, Hideshi Ishii, Kazuhiko Hayashi, Masamitsu Konno, Koichi Kawamoto, Naohiro Nishida, Jun Kozeki, Takahito Fukusumi, Yuichiro Doki, Masaki Mori, Kazuhiko Ogawa. Identification of cervical cancer stem cells by using an imaging system for proteasome activity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3319. doi:10.1158/1538-7445.AM2015-3319
Results of BFM 90 protocol at a single institute in a developing country: Three years experience
Authors: S. Shah, K. M. Patel, A. A. Patel, P. M. Shah, S. N. Shukla, B. J. Parikh, A. S. Anand, S. S. Talati, R. K. Srivastav, R. I. Dave
Journal: Journal of Clinical Oncology (2007)

17524 Background: In a developing country the affordability status of a patient is the main factor in deciding the type of treatment a patient will receive. Majority of patients [&gt;95%] at our institute have received MCP 841 protocol for acute lymphoblastic lymphoma .We have reviewed the treatment results of patients who had received chemotherapy as per the BFM 90 protocol over last 3 years. Methods: 18 patients (15 males and 3 females) with ALL who had received BFM 90 protocol as therapy during the period between January 2003 to January 2006 were analysed. 15 were of the pediatric age group (2–13 years) and 3 were adult patients (31 &amp; 42 years). Median follow up period was 1 year 9 months. 5 patients were considered as high risk, 4 medium risk and the rest as standard risk. All patients were ph chromosome negative. Results: All paediatric patients are in CR. One patient had CNS relapse but he responded well to reinduction and is in CR. Three patients developed grade 4 toxicity after high dose methotrexate. The rest tolerated it well, however, leucoverin rescue had to be given empirically as methotrxeate level measurement was not available at that time. Two patients turned HCV positive during the course of treatment and had altered liver enzymes due to which maintenance treatment was interrupted. There were three instances of catheter removal and one port had to be removed due to infection. Both the adult patients had bone marrow relapse during treatment [one during maintenance and the other during reinduction] and could not be salvaged. Conclusions: BFM 90 protocol is a viable alternative to MCP 841 in developing countries where high dose methotrexate is given with empirical leucoverin rescue. High rates of catheter infection is of concern. Better patient education and improved techniques will probably improve the situation. No significant financial relationships to disclose.
Missed pill conception: fact or fiction? [letter]
Authors: Killick, Eyong E, Elstein M
Journal: BMJ (1985)

The authors assert that follicular development is not the only factor of relevance to the mechanism of missed pill failure; also relevant are concurrent endocrine variables ultrasonographic measurements and assessments of cervical mucus.  Although suppression of gonadotropin induced ovarian folliculogenesis is an important mode of action of combined oral contraceptives (OCs) ancillary contraceptive action is provided by impenetrable cervical mucus and the rendering of the endometrium unfavorable for implantation.  If a missed OC has served potentially to extend the pill free period and thus the time available for folliculogenesis and effective sperm transport patients should be advised to begin the next packet of pills without any break.  There appears to be no scientific basis for recommending the prolonged use of barrier contraception in cases where a pill is occasionally missed.  The cervical mucus barrier effect has been noted to persist even when 1-2 pills are omitted.
Advancing Clinical Trials to Streamline Drug Development
Authors: Susan E. Bates, Donald A. Berry, Sanjeeve Balasubramaniam, Stuart Bailey, Patricia M. LoRusso, Eric H. Rubin
Journal: Clinical Cancer Research (2015)

The last decade in oncology has been marked by the identification of numerous new potential cancer targets and even more agents designed to inhibit them. The matrix of new targets, new agents, and the companion diagnostics required to identify the right patient for the right drug has created a major challenge for the clinical trial process. This has been compounded by the addition of new immunomodulators targeting the host immune system rather than the tumor. Recognizing the need for new approaches, industry, investigators, and regulators have responded to this challenge. New clinical trial designs are being evaluated to incorporate the genomic sequence data being obtained almost routinely after cancer diagnosis. New dose-finding approaches are being proposed to identify the maximum effective dose rather than the maximum tolerated dose. The FDA is involved in the drug approval process from points early in development and has accepted registration quality data from expansion cohorts in support of drug approval. Despite progress on several fronts, many challenges remain, including the lack of predictability of preclinical data for clinical results and phase II data for phase III results, an infrastructure that can be an obstacle to clinical trial development and implementation, and the increasing use of contracted clinical research organizations that limit a fit-for-purpose approach to clinical trial execution. Perhaps most challenging and important of all are the difficulties with clinical trial accrual that can prevent study completion. Both the innovations and the challenges highlight the important role of process in progress in clinical oncology.
Abstract P206: Estimation of Directly Quantified Visceral Adipose Tissue Using Cardiometabolic Biomarkers
Authors: Tiffany M Powell-Wiley, Josh Hasan, Parasuram Krishnamoorthy, Elizabeth Weiner, Jenny Dave, Julia Doveikis, Shawn Rose, Martin Playford, Jack Yao, Nehal Mehta
Journal: Circulation (2014)

Background: Visceral adipose tissue (VAT) has been linked to increased cardiovascular (CV) risk. Furthermore, there is limited data on how anthropometric measures and known markers of cardiometabolic disease (CMD) relate to the presence of VAT. Therefore, the aim of this study was to define how CMD biomarkers relate to directly-quantified volume-based measures of VAT using computed tomography (CT) scan measurements in a well-phenotyped sample of patients from an ongoing cohort study of inflammation and CMD. Methods and Results: We evaluated the relationship between directly measured VAT, anthropometric measures [body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR)] and CMD biomarkers [lipoproteins, lipoprotein particle size, high sensitivity C-reactive protein (hsCRP), insulin resistance markers] in a longitudinal study of CV risk predictors in chronic inflammation (NCT: NCT01778569). Patients underwent blood testing and CT to measure the sum of visceral adipose tissue between the diaphragm and the inferior border of the urinary bladder (slice 50-150 SumVAT) during a single baseline visit in 2012-2013 (N=42), resulting in a validated, volume-based measurement of VAT. Linear regression modeling was used to understand the relationship between VAT, anthropometric measures and CMD biomarkers. Those with higher levels of visceral adiposity were more likely to be male (p=0.05) and have higher BMI. Adjusting for age, sex, race, physical activity, smoking, and CV risk factors, HDL, hsCRP, insulin, and HOMA-IR were independent predictors of 50-150 SumVAT (Table). Conclusions: Markers of lipid metabolism, inflammation, and insulin resistance serve as independent predictors of visceral adiposity and may be useful surrogates to estimate VAT when volume-based CT measures are not possible. Therefore, these biomarkers may be used to evaluate cardio-metabolic risk in areas with limited access to imaging for defining visceral adiposity, particularly community-based settings.
Capturing Maximal Coronary Vasodilation for Myocardial Perfusion Imaging
Authors: Vasken Dilsizian, Jagat Narula
Journal: JACC. Cardiovascular imaging (2015)

Positron emission tomography (PET)–derived noninvasive quantification of hyperemic myocardial blood flow and flow reserve in absolute terms extends the scope of conventional single-photon emission computed tomography (SPECT) myocardial perfusion imaging from the detection of advanced and flow-
A randomized phase 2 trial of amrubicin compared to topotecan as second-line treatments in extensive disease small cell lung cancer (SCLC) sensitive to platinum-based first-line chemotherapy
Authors: R. M. Jotte, C. H. Reynolds, P. Conkling, J. W. Oliver, A. Allen
Journal: Journal of Clinical Oncology (2007)

18064 Background: SCLC accounts for about 13% of lung cancers and presents as extensive disease (ED-SCLC) in 60%-70% of patients (pts). Treatment options have been limited for ED-SCLC and survival enhanced by a median of only 2–3 months over the past 20 years. Our trial assessed response rates with amrubicin, a fully synthetic anthracycline and inhibitor of DNA topoisomerase II, versus standard therapy topotecan, for second-line treatment of sensitive SCLC. Methods: This phase 2, open-label, multicenter trial compares second-line therapy with amrubicin versus topotecan in ED-SCLC pts (=18 years, ECOG performance status =2), sensitive to first-line platinum-based therapy but with recurrence or progression =90 days later. Pts are randomized to amrubicin (40 mg/m 2 via 5-minute bolus infusion daily x 3 days) or topotecan (1.5 mg/m 2 via 30-minute infusion daily x 5 days), both starting on Day 1 of a 21 day cycle. Treatment is continued until disease progression, unacceptable toxicity, or withdrawal. Response is assessed using RECIST criteria. In all, 75 evaluable pts (50 randomized to amrubicin and 25 to topotecan; 2:1 per the standard topotecan therapy reference group) are planned to be enrolled. Results: To date, 22 pts are enrolled with 15 evaluable for response: 10 on amrubicin; 5 on topotecan. After 1–6 cycles, 5/10 amrubicin pts have responded (1 CR, 4 PRs). One topotecan patient responded (PR) but had progressive disease at the next visit. Seventeen pts are evaluable for safety. Hematological adverse events (AEs, = Grade 3) were the most commonly reported and were similarly observed across treatments (Table). Tachycardia (&lt; Grade 3) was recorded for 1 amrubicin and 2 topotecan pts. No other cardiac AEs were observed. Conclusions: Amrubicin compares favorably with standard therapy topotecan as second-line treatment in sensitive ED-SCLC patients. No anthracycline- induced cardiomyopathy has been observed to date. [Table: see text] No significant financial relationships to disclose.
Value of Estrogenic Recruitment Before Chemotherapy: First Randomized Trial in Primary Breast Cancer
Authors: M. Bontenbal, W.L. J. van Putten, J. Th. M. Burghouts, M.G. A. Baggen, G.J. Ras, W.F. Stiegelis, M. Beudeker, J. Th. P. Janssen, J.J. Braun, G.H. M. van der Linden, P.C. van der Velden, A.N. van Geel, P. Helle, M. Leisink, J.A. Foekens, J.G. M. Klijn
Journal: Journal of Clinical Oncology (2000)

PURPOSE: Several preclinical studies showed that short-term pretreatment of breast cancer cells with estrogens can increase the antitumor efficacy of different cytotoxic drugs. Some early clinical studies in patients with advanced breast cancer did seem to support these findings. Therefore, the efficacy of estrogenic recruitment followed by chemotherapy was compared with that of chemotherapy alone in a randomized phase III study in women with lymph node–positive primary breast cancer. PATIENTS AND METHODS: Three hundred twenty-eight patients with stage II/IIIA breast cancer who were younger than 66 years of age were randomly allocated to chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide (FAC) or FAC plus pretreatment with ethinyl estradiol (EE 2 ). FAC (500, 50, and 500 mg/m 2 , respectively) was administered intravenously once every 4 weeks for four cycles. EE 2 (0.5 mg) was administered orally, both 24 hours and immediately preceding FAC chemotherapy. RESULTS: Patient and tumor characteristics and chemotherapy dosages were comparable in both treatment groups. Of 318 assessable patients, with a median follow-up of 6.8 years, 177 patients had a relapse and 127 died. No significant differences were observed between the two treatment groups with respect to relapse-free, local recurrence–free, and overall survival according to univariate and multivariate analyses adjusted for age, menopausal status, tumor size, grade, number of positive nodes, and steroid-receptor status. The power for the detection of an increase of 50% in the median relapse-free survival was 80%. CONCLUSION: Estrogenic recruitment of breast cancer cells before FAC chemotherapy did not influence the efficacy of adjuvant chemotherapy in stage II/IIIA breast cancer patients after a follow-up of 6.8 years.
Genome editing of tumor specific T cells for sustained functionality in a suppressive tumor microenvironment
Authors: Sara R Pedersen, Per Thor Straten
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Solid tumors are known to be infiltrated by cells of the immune system, and a positive prognostic value of tumor infiltrating CD8 T cells are found in most cancers. Such tumor infiltrating lymphocytes (TIL) can be expanded by in vitro culture and used for adoptive cell transfer (
Real Time Color Coded Imaging of Cell Cycle Phase Demonstrates Why Invasive Metastatic Cancer Cells are Drug Resistant
Authors: Robert M. Hoffman, Shuya Yano, Shinji Miwa, Sumiyuki Mii, Yukihiko Hiroshima, Fuminari Uehara, Mako Yamamoto, Hiroyuki Kishimoto, Hiroshi Tazawa, Toshiyoshi Fujiwara
Journal: Annals of Oncology (2014)
Familial Carcinoma of Unknown Primary
Authors: Henry T. Lynch, Brody Slostad, Peter Silberstein
Journal: JAMA Oncology (2015)

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