tbuckley/cabot-search huggingface dataset:
Clinician change detection viewing longitudinal stereophotographs compared to confocal scanning laser tomography in the LSU Experimental Glaucoma (LEG) Study 1 1None of the authors has any proprietary interests in this paper.
Authors: John C. Ervin, Hans G. Lemij, Richard P. Mills, Harry A. Quigley, Hilary W. Thompson, Claude F. Burgoyne
Journal: Ophthalmology (2002)
Abstract 11655: Long Term Cardiovascular Mortality After Radiotherapy for Breast Cancer: A Meta-Analysis
Authors: Partha Sardar, Saurav Chatterjee, Anju Nohria, Ramez Nairooz, Pascal Meier, Sripal Bangalore, Debabrata Mukherjee, Carl J Lavie
Journal: Circulation (2014)

Introduction: Cardiovascular disease (CVD) is a late complication of radiotherapy (RT); the mean cardiac dose from irradiation of a left-sided breast cancer is much higher than that for a right-sided breast cancer. However, there is limited knowledge regarding the long-term risk of RT on CVD mortality. This study sought to investigate the use of RT for breast cancer and its association with CVD mortality, in the context of the laterality of breast cancer. Hypothesis: Long term cardiac mortalty with left-sided breast cancer radiotherapy is much higher than that for a right-sided breast cancer. Methods: Databases were searched from their inception through December 2013. Studies reporting CVD mortality with left versus right sided breast RT were included. Two authors reviewed the studies, abstracted the data and checked for accuracy, quality and strength of evidence. The outcome of interest was CVD mortality. We calculated summary risk ratio (RR) and 95% confidence intervals (CI) with the random effects model. Results: The analysis included 289,109 patients from 13 observational studies. Women, who had received RT for left-sided breast cancer, had a higher risk of CVD death than those who received RT for a right-sided breast cancer (RR 1.12, 95% CI: 1.07 to 1.18). Difference in CVD mortality between left versus right breast RT was more apparent after 15 years of follow up (RR 1.23, 95% CI: 1.08 to 1.41). Conclusions: Mortality from CVD with left sided RT was significantly higher compared to right sided RT for breast cancer; this difference was more apparent after at least 15 years of follow up.
Assessing operative skill
Authors: A. Darzi, S. Smith, N. Taffinder
Journal: BMJ (1999)

Pressure is mounting for surgeons to demonstrate that they can operate well, maintain their performance, and deliver acceptable results. Improved data collection after the Bristol affair may provide more information on the performance of individual surgeons, but a large number of failures are needed before statistical significance is reached,1 and, for patients, this will be a case of shutting the stable door after the horse has bolted. We need to be able to measure operative skill, set standards, and assess surgeons before any damage is done.

Although many factors influence surgical outcome, the skill of the surgeon in the operating theatre is very important. A skilfully performed operation is 75% decision making and 25% dexterity2; in some specialties, such as minimally invasive surgery, dexterity becomes more important. Though surgeons have formal examinations in surgical knowledge, there is no such requirement to show operative dexterity. …
Abstract 1457: Development of miRNA-loaded polymeric nanoformulation for pancreatic cancer therapy
Authors: Sumit Arora, Suresh K. Swaminathan, Sanjeev K. Srivastava, Seema Singh, Jayanth Panyam, Ajay P. Singh
Journal: Cancer Research (2014)

Abstract MicroRNAs (miRNAs) are small (18-22 nucleotide long) non-coding RNAs that play important roles in biological processes through post-transcriptional regulation of gene expression. Their aberrant expression and functional significance are reported in several human malignancies, including pancreatic cancer (PC). Recently, we identified miR-150 as a novel tumor suppressor microRNA in PC and demonstrated that its overexpression inhibits growth and malignant behavior of PC cells suggesting that restoration of miR-150 could serve as an effective therapeutic approach for pancreatic cancer. In the present study, we have developed a nanoparticle-based miR-150 delivery system and tested its therapeutic efficacy by in vitro assays. Using double emulsion solvent evaporation method, we developed a poly (D, L-lactide-co-glycolide) (PLGA)-based nanformulation (NF) of miR-150 (miR-150-NF). Polyethyleneimine (a cationic polymer) was incorporated in PLGA matrix to increase the encapsulation of miR-150. Physical characterization of miR-150-NF demonstrated that miR-150-loaded nanoparticles were spherical in shape, had high encapsulation efficiency (&amp;gt;75%), were stable at room temperature and exhibited sustained release profile. miR-150-NF efficiently delivered miR-150 mimics to PC cells and led to the downregulation of its target gene (MUC4) expression. Downregulation of MUC4 correlated with a concomitant decrease in the expression of its interacting partner, HER2, and repression of its downstream signaling. Furthermore, treatment of PC cells with miR-NF suppressed their growth, clonogenicity, motility and invasion. Together, these findings suggest that PLGA-based nanovector platform could be a potential candidate for systemic delivery of miR-150 to the pancreatic tumor cells and can be a step forward in miRNA-based cancer therapeutics. Citation Format: Sumit Arora, Suresh K. Swaminathan, Sanjeev K. Srivastava, Seema Singh, Jayanth Panyam, Ajay P. Singh. Development of miRNA-loaded polymeric nanoformulation for pancreatic cancer therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1457. doi:10.1158/1538-7445.AM2014-1457
Abstract 15844: Plasma Parathyroid Hormone is Independently Related to 24-Hour Pulse Wave Velocity in Patients With Primary Hyperparathyroidism - Insights fFom The EPATH Study
Authors: Julia Wetzel, Nicolas Verheyen, Evgeny Belyavskiy, Albrecht Schmidt, Caterina Colantonio, Elisabeth Kraigher-Krainer, Martin Gaksch, Martin Grübler, Johannes Schmid, Astrid Fahrleitner-Pammer, Burkhard Pieske, Stefan Pilz, Andreas Tomaschitz
Journal: Circulation (2014)

Introduction: Accumulating evidence indicated that high parathyroid hormone (PTH) is associated with increased cardiovascular risk. The impact of PTH on vascular structure and function is, however, still unclear. We evaluated the relationship between pulse wave velocity (PWV) as a novel index of arterial stiffness and circulating levels of PTH in patients with PTH-excess (primary hyperparathyroidism (pHPT)). Methods and Results: We analyzed baseline data of the ongoing randomized, double-blind, placebo-controlled “Effect of Eplerenone on Parathyroid Hormone Levels in Patients with Primary Hyperparathyroidism” (EPATH) study. Inclusion criteria were age of at least 18 years and a diagnosis of pHPT according to international guidelines. Standardized blood sampling was performed after an overnight fast and 24h PWV was measured by a validated non-invasive device for ambulatory hemodynamic monitoring (Mobil O Graph, I.E.M., Stolberg, Germany). Our analysis comprised 92 pHPT patients with a mean age of 68.5 +/- 9.7 years (71 % females) and a median PTH of 102 (IQR 81 - 132) pg/ml. Mean 24h PWV was 9.8 +/- 1.8 m/s, mean daytime and mean nighttime PWV were 10.0 +/- 1.7 m/s and 9.6 +/- 1.8 m/s, respectively. In multivariate linear regression analyses adjusted for age, sex, body mass index, smoking status, mean systolic and mean diastolic 24h blood pressure, antihypertensive medication, type 2 diabetes, 25-hydroxyvitamin D, serum calcium, intake of cinacalcet and fasting serum cholesterol PTH emerged as a strong predictor of mean 24h PWV (ß=0.30, p=0.012), daytime PWV and nighttime PWV (ß=0.30, p=0.011 and ß=0.30, p=0.019, respectively). Conclusion: In a selective cohort of patients with pHPT plasma PTH was strongly related to 24h PWV. These data strengthen the notion that PTH may impact on vascular function. Interventional and mechanistic trials are needed to evaluate modulatory effects on vasculature in patients with high PTH.
Effect of the Antiarrhythmic Agent Moricizine on Survival after Myocardial Infarction
Journal: New England Journal of Medicine (1992)

The Cardiac Arrhythmia Suppression Trial (CAST) tested the hypothesis that the suppression of asymptomatic or mildly symptomatic ventricular premature depolarizations in survivors of myocardial infarction would decrease the number of deaths from ventricular arrhythmias and improve overall survival. The second CAST study (CAST-II) tested this hypothesis with a comparison of moricizine and placebo.
A series of novel 6-substituted 2-amino-4-oxopyrrolo[2,3-d]pyrimidine antifolates specifically transported by folate receptors and targeting the de novo purine biosynthesis pathway
Authors: Yijun Deng, Yiqiang Wang, Christina Cherian, Zhanjun Hou, Aleem Gangjee, Larry Matherly
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

3288 

A major obstacle in the therapy of cancer involves an inability to selectively target tumor cells while inflicting minimal toxicity toward normal tissues. Cellular uptake of folates and antifolates by tissues and tumors is primarily by the ubiquitously expressed reduced folate carrier (RFC). The high affinity folate receptors (FRs), FRα and FRβ, are another mode of folate uptake and are considered potential targets for selective tumor targeting, since most normal tissues do not express FRs whereas tumors such as ovarian and endometrial carcinomas express high levels of FRα and acute myeloid leukemias express FRβ. We generated a series of isogenic Chinese hamster ovary (CHO) cell lines that expressed human RFC, or human FRα or FRβ. When assayed for drug activity with a series of 6-substituted 2-amino-4-oxopyrrolo[2,3- d ]pyrimidine antifolates with 3, 4, 5, or 6 carbon bridge substitutions (designated 2, 3, 4, or 5, respectively), there was negligible activity toward RFC-expressing CHO cells. However, we detected remarkably potent (i.e., nM) activities for the analogs toward CHO cells that expressed FRα and FRβ. Nearly identical results were obtained with FRα-expressing KB and IGROV1 human tumor cells. In proliferation assays, growth inhibition was maximal for compounds 2 and 3, and decreased for compounds 4 and 5. A dose-dependent inhibition of KB cell colony formation was also seen. The pyrrolopyrimidine antifolates were poor substrates for RFC, as reflected in competitive inhibition assays with 3H-methotrexate. Analogs 2-5 were all high affinity ligands for FRα and FRβ, whereas the 2 carbon bridge analog (compound 1) bound poorly. Adenosine and 4-amino-5-carboxyamide reversed growth inhibition, suggesting that glycinamide ribonucleotide (GAR) formyl transferase (GARFTase) was the primary intracellular target for the 6-substituted pyrrolopyrimidine series. This was confirmed by assays with recombinant murine GARFTase using 10-formyl-5,8-dideazafolic acid as formyl donor, and by in situ assays that measured 14C-formyl GAR accumulation from 14C-glycine. The combined properties of selective FR targeting and GARFTase inhibition are unprecedented and our results suggest a distinctive structure-activity profile for the 6-substituted pyrrolopyrimdine analogs involving the length of the methylene bridge between the pyrrolopyrimidine and p-aminobenzoate moieties, with 3 or 4 methylenes as optimal.
Sickle-Cell Transfusions
Authors: Tracy Hampton
Journal: JAMA (2005)

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Abstract 1737: Allosteric FGFR2 inhibitor RPT835 impacts on tumor growth and neovascularization
Authors: Ilya Tsimafeyeu, Evgenia Stepanova, Eliso Solomko, Dmitry Kochenkov, Nina Peretolchina, Oxana Ryabaya, Mikhail Byakhov, Sergey Tjulandin
Journal: Cancer Research (2014)

Abstract Encouraged by the clinical validation of fibroblast growth factor receptor 2 (FGFR2) as the target for the treatment of several tumors, we sought to identify pharmacological agents that could target this receptor by an allosteric mechanism. We report the efficacy of RPT835, novel highly potent inhibitor of the FGFR2 extracellular domain (RusPharmTech, LLC), in vitro and in vivo. Concordant with this activity, in human umbilical vein endothelial cells (HUVEC) and mouse endothelial cells (SVEC-4-10), RPT835 inhibited FGF-stimulated proliferation with IC50 values of 11 and 10 nmol/L, respectively. Inhibition of HUVEC cells proliferation by brivanib as positive control was significantly lower (IC50=289 nmol/L, P&amp;lt;0.001). Once-daily oral administration of RPT835 significantly ablated experimental FGF-induced angiogenesis in vivo and reduced endothelial cell migration, capillary-like tubular structure and mature vessel formation in comparison with bevacizumab (P&amp;lt;0.001). The growth of established human tumor xenograft of breast cancer (HS578T) in athymic mice was inhibited by RPT835 with chronic administration of 30 mg per kg per day. Differences with control group were significant on 34 day of study. There was no significant impact of RPT835 on colon (HCT-116, 10 mg/kg) and lung (NCI-H226, 30 mg/kg) cancer growth. Collectively, the data obtained with RPT835 are consistent with potent inhibition of FGF signaling, angiogenesis, and breast cancer growth. Citation Format: Ilya Tsimafeyeu, Evgenia Stepanova, Eliso Solomko, Dmitry Kochenkov, Nina Peretolchina, Oxana Ryabaya, Mikhail Byakhov, Sergey Tjulandin. Allosteric FGFR2 inhibitor RPT835 impacts on tumor growth and neovascularization. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1737. doi:10.1158/1538-7445.AM2014-1737
Abstract 12470: Aging Impairs Myocardium-induced Dilation in Coronary Arterioles: Role of Hydrogen Peroxide and Angiotensin
Authors: Hirofumi Machii, Shu-ichi Saitoh, Takashi Kaneshiro, Yasuchika Takeishi
Journal: Circulation (2010)

The underlying mechanisms that drive age-related modification of coronary circulation by myocardium have not been fully defined. Recently, we have reported cardiac myocyte metabolites regulate coronary vascular tone. To elucidate the aging effect to coronary circulation derived by myocytes, we measured changes in diameter of isolated, pressurized coronary arterioles (56±6 μm, diameter) to supernatant collected from enzymatically isolated cardiac myocytes from young (2 mo) and old (24 mo) rats (unpaced or stimulated 20 min at 400 beats/min, n=10, each). Pacing increased superoxide and hydrogen peroxide in cardiac myocytes. The level of hydrogen peroxide in myocyte supernatant was greater in old rats compared to young rats (15.9±1.8 vs. 9.5±0.7 μM, P
Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta
Authors: Edwin M. Horwitz, Darwin J. Prockop, Lorraine A. Fitzpatrick, Winston W. K. Koo, Patricia L. Gordon, Michael Neel, Michael Sussman, Paul Orchard, Jeffrey C. Marx, Reed E. Pyeritz, Malcolm K. Brenner
Journal: Nature Medicine (1999)
Abstract 13272: High Density Lipoprotein Subclasses Predict Non-Cardiovascular Disease, Non-Cancer Chronic Inflammatory-Related Death and Hospitalization More Strongly than Cardiovascular Disease Events in the Multi-Ethnic Study of Atherosclerosis
Authors: Daniel Duprez, James Otvos, Kenneth Feingold, Philip Greenland, Myron D Gross, Jao Lima, James D Neaton, Otto A Sanchez, Russel Tracy, David Jacobs
Journal: Circulation (2014)

In vitro studies have demonstrated that high density lipoprotein particles (HDL-P) antagonize inflammatory processes. We studied the predictive value of HDL-P and inflammatory markers for incident cardiovascular disease (CVD) and non-CVD, non-cancer, chronic inflammatory-related events. Methods: In the Multi-Ethnic Study of Atherosclerosis, we studied 6475 men and women free of overt CVD, baseline age 45-84 years, who had fasting venous samples for lipid profile, lipoprotein particles, and inflammatory markers Interleukin-6 (IL-6), hs-CRP and D-dimer at baseline. Median follow-up was 10.1 years. Poisson regression models predicted non-CVD, non-cancer, chronic inflammatory-related events (death and hospitalization), based on diagnostic codes, n=1054) and CVD events due to coronary heart disease, myocardial infarction, coronary artery disease requiring revascularization, stroke, peripheral arterial disease, congestive heart failure and CVD or unwitnessed death (adjudicated, n=756). Adjustment was for age, race, gender, clinic, heart rate, smoking, body mass index, blood pressure, blood pressure and lipid lowering medication, diabetes mellitus, plus all lipid, lipoprotein particle and inflammatory variables. Results: Non-CVD, non-cancer, chronic inflammatory-related events were inversely associated with the sum of small+medium HDL-P independent of covariates (relative risk (RR) per standard deviation (95% confidence limits), RR: 0.85 (0.79-0.91, P &lt; 0.0001). Non-CVD, non-cancer, chronic inflammatory-related events were positively associated with IL-6, RR:1.19 (1.11-1.27, P &lt; 0.0001) and D-dimer, RR: 1.10 (1.05-1.16, P &lt; 0.0001). CVD was associated with small+medium HDL-P, RR: 0.90 (0.82-0.99, P &lt; 0.03) and IL-6, RR:1.15 (1.06-1.25 P &lt; 0.0001). hsCRP was unrelated to either outcome after adjustment for other inflammatory markers. Conclusion: The long-term inverse association of small+medium HDL-P with non-CVD, non-cancer, chronic inflammatory-related death and hospitalization was stronger than with fatal and non-fatal CVD in subjects initially free of overt CVD. These findings provide clinical evidence that small+medium HDL-P have anti-inflammatory properties and may rethink the importance of HDL-P beyond CVD.
Abstract 3946: Wnt/ß-catenin signaling mediates resistance of colorectal cancer cells to chemoradiotherapy
Authors: Georg Emons, Melanie Spitzner, Sebastian Reineke, Janneke Möller, Emil Kendziorra, Tim Beissbarth, Margret Rave-Fraenk, Jochen Gaedcke, Thomas Ried, Michael Ghadimi, Marian Grade
Journal: Cancer Research (2014)

Abstract Background: Preoperative chemoradiotherapy represents the standard treatment for patients with rectal cancer. However, the clinical response of individual tumors to multimodal treatment is not uniform, and ranges from complete response to complete resistance. Therefore, the identification of novel therapeutic targets whose modification could be harnessed to sensitize a priori resistant tumors is exceedingly important. In this context, we have previously demonstrated that the Wnt transcription factor TCF4 was over-expressed in rectal cancers that were resistant to chemoradiotherapy. The aim of this study was to explore the functional relevance of TCF4 and Wnt/β-catenin signaling for mediating treatment resistance. Methods: Colorectal cancer cell lines SW837, SW480, and HT-29 were transfected with shRNAs targeting TCF4. After establishing stable single-cell clone (SCC) populations, selected clones were irradiated at 0, 1, 2, 4, 6 and 8 Gy of X-rays. To assess the putative Wnt/β-catenin dependency, β-catenin was inhibited in cancer cell lines using siRNAs, the tankyrase inhibitors XAV939 / JW55 and the porcupine inhibitor LGK 974. Furthermore Wnt/β-catenin signaling activity was stimulated in normal retinal pigment epithelial (RPE) cells through incubation with Wnt3a. Results: RNAi-mediated silencing of TCF4 led to a significant radiosensitization in SW837 and SW480, two cell lines with a high basal TCF4-activity, whereas no effect was observed in HT-29 a cell line with low activity. Inhibition of β-catenin similarly caused a pronounced sensitization of CRC cells to clinically relevant doses of X-rays. Finally, exogenous stimulation of canonical Wnt signaling with Wnt3a resulted in a significantly decreased sensitivity of RPE cells to radiotherapy, i.e. induced radioresistance. Conclusion: We have uncovered a novel role of Wnt/β-catenin signaling in mediating resistance to chemoradiotherapy. Moreover, these data suggest that targeting key components of this pathway may represent a potential therapeutic strategy to increase the proportion of patients that respond to chemoradiotherapy, with considerable clinical implications. Citation Format: Georg Emons, Melanie Spitzner, Sebastian Reineke, Janneke Möller, Emil Kendziorra, Tim Beissbarth, Margret Rave-Fraenk, Jochen Gaedcke, Thomas Ried, Michael Ghadimi, Marian Grade. Wnt/ß-catenin signaling mediates resistance of colorectal cancer cells to chemoradiotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3946. doi:10.1158/1538-7445.AM2014-3946
A novel anti-inflammatory drug, SDZ ASM 981, for the treatment of skin diseases: in vitro pharmacology
Authors: None Grassberger, None Baumruker, None Enz, None Hiestand, None Hultsch, None Kalthoff, None Schuler, None Schulz, None Werner, None Winiski, None Wolff, None Zenke
Journal: British Journal of Dermatology (1999)

SDZ ASM 981, a novel ascomycin macrolactam derivative, has high anti-inflammatory activity in animal models of allergic contact dermatitis and shows clinical efficacy in atopic dermatitis, allergic contact dermatitis and psoriasis, after topical application. Here we report on the in vitro activities of this promising new drug. SDZ ASM 981 inhibits the proliferation of human T cells after antigen-specific or non-specific stimulation. It downregulates the production of Th1 [interleukin (IL)-2, interferon-gamma] and Th2 (IL-4, IL-10) type cytokines after antigen-specific stimulation of a human T-helper cell clone isolated from the skin of an atopic dermatitis patient. SDZ ASM 981 inhibits the phorbol myristate acetate/phytohaemagglutinin-stimulated transcription of a reporter gene coupled to the human IL-2 promoter in the human T-cell line Jurkat and the IgE/antigen-mediated transcription of a reporter gene coupled to the human tumour necrosis factor (TNF)-alpha promoter in the murine mast-cell line CPII. It does not, however, affect the human TNF-alpha promoter controlled transcription of a reporter gene in a murine dendritic cell line (DC18 RGA) after stimulation via the FcgammaRIII receptor. SDZ ASM 981 also prevents the release of preformed pro-inflammatory mediators from mast cells, as shown in the murine cell line CPII after stimulation with IgE/antigen. In summary, these results demonstrate that SDZ ASM 981 is a specific inhibitor of the production of pro-inflammatory cytokines from T cells and mast cells in vitro.
Predominance of staphylococcal cassette chromosome mec (SCCmec) type IV among methicillin-resistant Staphylococcus aureus (MRSA) in a Swedish county and presence of unknown SCCmec types with Panton-Valentine leukocidin genes
Authors: C. Berglund, P. Mölling, L. Sjöberg, B. Söderquist
Journal: Clinical Microbiology and Infection (2005)