tbuckley/cabot-search huggingface dataset:
Abstract 2896: Nanoparticle co-delivery of RNAi and chemotherapy for the treatment of drug-resistant cancers
Authors: Jinjun Shi, Alexander R. Votruba, Xiaoyang Xu, Robert Langer, Bruce R. Zetter, Omid C. Farokhzad
Journal: Cancer Research (2012)

Abstract The emergence of drug resistance has been a critical barrier for effective cancer chemotherapy. Recently, RNA interference (RNAi) has shown promise in suppressing the over-expression of drug resistance-associated proteins such as P-glycoprotein and Prohibitin1, and in treating multidrug resistant cancers through combination with chemotherapy. Nevertheless, the safe and effective delivery of RNAi therapeutics (e.g., siRNA and miRNA) to target cells remains a major hurdle for their clinical applications, and the co-delivery of RNAi and chemotherapeutic agents in a controlled fashion requires specific delivery vehicles. Herein, we present a novel nanoparticle (NP) platform to tackle the challenges associated with the delivery of siRNA and chemotherapeutic drugs, using biodegradable and biocompatible polymers and lipids. The hybrid lipid-polymer NP has a differentially charged hollow core/shell nanostructure which provides the delivery system with three distinct functional features: (i) a positively charged inner hollow core for dense loading of siRNA; (ii) a middle hydrophobic polymer layer for the encapsulation of anti-cancer drugs (e.g., taxanes) and for the controlled release of both siRNA and drug; and (iii) a relatively neutral lipid-polyethylene glycol (PEG) surface to keep the NP stable and prolong its systematic circulation. Moreover, such hybrid NPs can be formulated in a simple and robust way that could facilitate future scale-up. By screening various factors, such as inner cationic lipids, outer PEG chain length, and formulation parameters, the hybrid lipid-polymer NPs show excellent in vitro knockdown efficacy at low doses of siRNA, with greater than 80% luciferase silencing at an siRNA dose of 0.4 pmol (4.0 nM) and ∼ 95% silencing at a dose of 2.0 pmol (20 nM). These NPs can also efficiently reduce the expression of drug resistance-associated proteins (e.g., MDR1 and Prohibitin1), as evidenced by qPCR. Cellular cytotoxicity experiments further confirm that this NP co-delivery strategy can drastically improve the sensitivity of drug-resistant cells to chemotherapy. In addition, these hybrid NPs demonstrate promising in vivo results for co-delivering siRNA and chemotherapeutic drugs to treat drug-resistant cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2896. doi:1538-7445.AM2012-2896
Silencing of microRNA-132 reduces renal fibrosis by selectively inhibiting myofibroblast proliferation
Authors: Roel Bijkerk, Ruben G. de Bruin, Coen van Solingen, Janine M. van Gils, Jacques M.G.J. Duijs, Eric P. van der Veer, Ton J. Rabelink, Benjamin D. Humphreys, Anton Jan van Zonneveld
Journal: Kidney International (2016)
THU0432 Impact of Comorbidities on Measuring Indirect Utility by the SF-6D or the EQ-5D in Rheumatoid Arthritis: an Analysis of 962 Patients Enrolled in Comedra
Authors: C. Gaujoux-Viala, K. Hosseini, A.-C. Rat, F. Guillemin, A. Etcheto, M. Soubrier, B. Fautrel, M. Dougados
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Many patients with rheumatoid arthritis (RA) have several chronic co-occuring disorders (comorbidities). There is an inverse relationship between comorbidy and health-related quality of life (HRQoL). Because indirect utility measurement involves HRQoL, comorbidities probably affect utility assessment. <h3>Objectives</h3> We investigated the impact of comorbidities on the measure of utility with 2 indirect utility measures widely used to calculate quality-adjusted life-years (QALYs), SF-6D and EQ-5D, in patients with rheumatoid arthritis (RA). <h3>Methods</h3> 962 patients of COMEDRA, a French multicentric clinical trial involving patients with stable RA, were included in the study. Comorbidities assessed were chronic obstructive pulmonary disease, diabetes, hypertension, obesity, cardio-vascular diseases, stroke, hypercholesterolemia, renal insufficiency and osteoporosis. Bio-clinical variables were also recorded (activity by DAS28, function by HAQ score, Rheumatoid Arthritis Impact of Disease score ...). Two separate linear regression models, using the number of comorbidities and the different categories of comorbidities, were fitted to determine predictors of utility scores. <h3>Results</h3> For the 962 patients included (mean age ± SD =57.7±11.1 years, 79% women), the mean SF-6D utility score was 0.67±0.12 (range: 0.357, 1), and the mean EQ-5D utility score was 0.64±0.27 (range: -0.416, 1). The mean number of comorbidities was 1.02±0.95 and 40.6% of patients have 1 comorbidity, 19.3%, 2 comorbidities and 7%, ≥3 comorbidities. In the first multivariate model, for each additional comorbidity (range 0–5) the mean SF-6D utility score decreased of 0.007 point (p&lt;0.0001) and the mean EQ-5D utility score decreased of 0.028 point (p&lt;0.0001). In the second model, including comorbidities by categories, no comorbidity predicted significantly low utility score. In both regression models a worsened function (increased HAQ score) significantly decreased the EQ-5D utility score and a worsened mental state (increased mental component of RAID score) significantly decreased the SF-6D utility score. The number of comorbidities explained &lt;1% of the variance in utility scores (partial R-square=0.0097 for EQ-5D and 0.003 for SF-6D), whereas the HAQ score explained 51.2% of the variance in EQ-5D utility score in both models and the mental state explained 38,2% of the variance in SF-6D utility score. <h3>Conclusions</h3> Compared to greater negative effect of functional impairment for EQ-5D and mental state for SF-6D, the number of comorbidities has a negative but relatively marginal impact on indirect utility scores in RA. <h3>Disclosure of Interest</h3> : None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.5794
The Sympathetic-Nervous-System Defect in Primary Orthostatic Hypotension
Authors: Michael G. Ziegler, C. Raymond Lake, Irwin J. Kopin
Journal: New England Journal of Medicine (1977)

We sought to elucidate further the neurologic defect of idiopathic orthostatic hypotension, which appears to represent two distinct clinical entities. While recumbent, patients with multiple central-nervous-system defects, as well as peripheral autonomic nervous dysfunction, have normal plasma levels of norepinephrine that fail to increase normally after standing or exertion (P less than 0.001 by t-test as compared to controls). While recumbent, patients with peripheral autonomic insufficiency without signs of central-nervous-system defects have low levels of plasma norepinephrine (P less than 0.001) that also fail to increase normally after standing or exercising (P less than 0.001). Both groups have low levels of plasma dopamine-beta-hydroxylase (P less than 0.02). These findings are consistent with other pathological and pharmacologic observations suggesting that patients with central-nervous-system disease are unable to activate appropriately an otherwise intact sympathetic nervous system, whereas in patients without signs of central-nervous-system disease the deficit affects peripheral sympathetic nerves.
Implicit learning from a computer-science perspective
Authors: Peter Kugel
Journal: Behavioral and Brain Sciences (1996)

Shanks and St. John (1994a) suggest that “human learning is almost invariably accompanied by conscious awareness (of what is being learned).” From the viewpoint of a computer scientist who tries to construct learning systems, that claim seems rather implausible. In this commentary I wish to suggest why, in the hopes of shedding light on the relationship between consciousness and learning.
Abstract 3002: Identification of frequently altered protein networks in ependymomas
Authors: Jared M. Bischof, Denise Scholtens, Kelly Arndt, Min Wang, Deli Wang, Chiang-Ching Huang, Maria de Fatima Bonaldo, Richard J. Gilbertson, Marcelo Bento Soares
Journal: Cancer Research (2012)

Abstract Ependymomas are glial tumors that originate from the walls of the cerebral ventricles or from the spinal canal. The five-year survival for intracranial ependymomas in children is approximately 65%. Ependymomas exhibit a wide range of DNA copy number alterations that vary greatly in size and location. We hypothesize that an underlying protein network exists that is consistently compromised by such DNA copy number alterations in ependymomas. In this study, we analyzed an array-comparative genomic hybridization dataset generated by Johnson and colleagues [Nature 466(7306):632-6, 2010] to determine whether a protein interaction network could be identified that might be consistently functionally compromised in pediatric ependymomas. This cohort of 203 primary ependymomas consisted of 106 posterior fossa, 56 supratentorial, and 41 spinal ependymomas. The genes within each altered region were used to perform network analyses with GeneGo and Ingenuity to uncover protein networks that were altered in a significant number of tumors. For calculation of statistical significance, 100,000 samplings of randomly selected regions - equal in gene number to the regions of gain or loss - were performed. Indeed, some protein networks were found to be over-represented in the structural alterations exhibited by this cohort (p&amp;lt;0.05). These results warrant future investigations to demonstrate the role of the identified networks in the development and progression of ependymomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3002. doi:1538-7445.AM2012-3002
RISK STRATIFICATION SCORING PREDICTS MORTALITY IN DIALYSIS PATIENTS WITH ATRIAL FIBRILLATION
Authors: Michele A. Murphy, Jose Cuellar-Silva, Avirup Guha, Matthew Diamond, William Maddox, Robert Sorrentino, Sheldon Litwin, Stan Nahman, Jennifer Waller, M. Kheda
Journal: Journal of the American College of Cardiology (2014)
PROLONGED WITHDRAWAL OF FOOD IN CERTAIN CASES OF INTESTINAL DISORDER.
Authors: THOMAS D. PARKE
Journal: JAMA (1903)

It may safely be stated, as a general principle, that the less we rely on drugs in the management of any given diseased condition the more do we fall back on accessory management in the way of hygiene, diet, and hydrotherapy. The man who thinks he has found a specific for typhoid fever in his tablets given at prescribed intervals, loses interest in baths. The man who imagines he can digest food in a patient's stomach by means of artificial digestants, places less stress on diet.  So in disorders of the intestinal tract of childhood, when one comes to realize that drugs may not be depended on for cure, he falls back on management by other means.  All authorities agree that diet is the great desideratum in, as well as the great barrier to, the successful management of this class of cases. All authorities recommend that food be withdrawn in the beginning of such disorders, but in no text-book has been encountered a recommendation that the period of withdrawal
Abstract 4882: Downregulation of core component of miRNA machinery, Tudor-SN, impedes NSCLC resistance to chemotherapy
Authors: Nadeem S. Akbar, Olga Surova, Boris Zhivotovsky
Journal: Cancer Research (2012)

Abstract Lung cancer (LC) is among the most common tumors liable for worldwide highest mortality rate. It has a poor prognosis and symptoms related to disease occur at an advanced stage where therapy response becomes less effective. Resistance to radio- and chemotherapy of all tumors in general and LC, in particular, is a complex phenomenon. Evasion of cell death is one of the key hallmarks of both tumorigenesis and resistance to treatment. Differential expression of microRNAs (miRNAs or miRs), a class of small non-coding RNAs, 19-25 nucleotides in length, and proteins involved in miRNAs maturation (Drosha, Exportin-5, Dicer1, PACT, Tudor-SN, Argonaute-2, and FXR1) have been linked to carcinogenesis and therapy resistance. Nevertheless, comprehensive information is needed to better understand their function in tumor formation and resistance/sensitization to therapy. Therefore, the aim of this study was to investigate the role of miRNA machinery in chemoresistance of a selected panel of non-small cell lung carcinoma (NSCLC) cell lines (U1810, H661 and A549) resistant to treatment. It was revealed that knockdown of Drosha, Dicer-1 and Ago-2 was not sufficient to sensitize them to subsequent treatment with either cisplatin, 5-FU, etoposide or camptothecin (CPT), while silencing of Staphylococcal nuclease domain containing 1(SND1/p100/TSN), a key component of RISC complex, led to increased sensitivity of NSCLC cells to the DNA-damaging agents. Besides its function as a component of the multiprotein complex involved in miRNA functioning, TSN is known to act as a transcriptional activator and oncogene in many cancers. Additionally, it is cleaved during apoptosis, losing its pro-carcinogenic function. Our results show that these NSCLC cells with TSN-knocked down exhibited much stronger response to treatment with CPT and cisplatin compared to wild-type cells, as monitored by enhanced cleavage of PARP, increase in percentage of subG1 cells and potentiation of caspase-3-like activity. Overall, obtained data suggest that this nuclease can play an important role in the resistance of NSCLC cells to chemotherapy and can be used as a potential target to increase sensitivity of lung tumors to this type of treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4882. doi:1538-7445.AM2012-4882
AB1013 Serious effects of alcohol on bone density and fracture incidence
Authors: C. Kelly, P. Bartholomew, A. Grapes, A. Reddy
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Alcoholic liver disease (ALD) has reached almost epidemic proportions over the last decade, and has become one of the most frequent causes for seeking medical admission. It often affects relatively young people and carries significant mortality and morbidity. Whilst the effects of alcohol on the liver are well recognised, patients and clinicians are less aware of its effects on bone. There are data to suggest that alcohol does play a major role in inducing osteoporostic fractures (1) and that these carry a significant cost for health services (2). <h3>Objectives</h3> We undertook a prospective study to assess the incidence of fractures and to measure bone density in patients with ALD. <h3>Methods</h3> We recruited all patients admitted to the Hospital over a three month period with a diagnosis of ALD. Patients were then divided into three groups, depending on the results of their investigations: high alcohol intake, alcoholic hepatitis or established cirrhosis. The presence of any low trauma fractures within the previous two years was recorded, and bone mineral density measurements were performed at hip and spine using a Hologic Discovery C scanner. We recorded absolute BMD and T/Z scores for each site, and compared results witrh those obtained from age and gender matched controls with no evidence of ALD. <h3>Results</h3> We identified 48 admissions with ALD over a 3 month period who were willing to be assessed. 34 were male and group median age was 47 years. Twenty patients had suffered a low trauma fracture within the previous 24 months (42%). These were widely distributed. Bone mineral density data showed no significant differences in values at either spine or hip between the three groups so data was amalgamated. Group mean Z scores at spine and hip were both significantly reduced at -0.91 (SD 1.52) [p&lt;0.01] and -0.55 (SD 0.97) [p&lt;0.01] respectively, when compared to controls. Men and women were equally affected and only 30% of ALD patients had normal bone density. <h3>Conclusions</h3> Alcohol excess is strongly related to a reduction in bone mineral density, independent of whether individuals have developed reversible or irreversible liver disease. This affects both axial and cortical bone and is strongly linked to an increased risk of low trauma fracture at sites including the spine and hip. Clinicians and patients need to be aware of this association which carries significant prognostic and therapeutic implications. <h3>References</h3> Kanis JA, Johansson H, Johnell O et al Alcohol intake as a risk factor for fracture. Osteoporosis Int 2005; 16:737–742 Lawrence T, White C, Wenn R et al. Total costs of hospital treatment for hip fractures. Injury 2005; 36: 88-91 <h3>Disclosure of Interest</h3> None Declared
Bias Analysis for Uncontrolled Confounding in the Health Sciences
Authors: Onyebuchi A. Arah
Journal: Annual Review of Public Health (2015)

Uncontrolled confounding due to unmeasured confounders biases causal inference in health science studies using observational and imperfect experimental designs. The adoption of methods for analysis of bias due to uncontrolled confounding has been slow, despite the increasing availability of such methods. Bias analysis for such uncontrolled confounding is most useful in big data studies and systematic reviews to gauge the extent to which extraneous preexposure variables that affect the exposure and the outcome can explain some or all of the reported exposure-outcome associations. We review methods that can be applied during or after data analysis to adjust for uncontrolled confounding for different outcomes, confounders, and study settings. We discuss relevant bias formulas and how to obtain the required information for applying them. Finally, we develop a new intuitive generalized bias analysis framework for simulating and adjusting for the amount of uncontrolled confounding due to not measuring and adjusting for one or more confounders.
Consequences of a network view for genetic association studies
Authors: Sophie van der Sluis, Kees-Jan Kan, Conor V. Dolan
Journal: Behavioral and Brain Sciences (2010)

Abstract Cramer et al's proposal to view mental disorders as the outcome of network dynamics among symptoms obviates the need to invoke latent traits to explain co-occurrence of symptoms and syndromes. This commentary considers the consequences of such a network view for genetic association studies.
Abstract 1414: Regulation of tumor cell trafficking by chromogranin A
Authors: Eleonora Dondossola, Luca Crippa, Barbara Colombo, Elisabetta Ferrero, Angelo Corti
Journal: Cancer Research (2012)

Abstract Chromogranin A (CgA) is an acidic glycoprotein present within secretory vesicles of many normal and neoplastic endocrine and neuroendocrine cells. CgA is abnormally released in circulation in patients with neuroendocrine and non neuroendocrine tumors, as in a subpopulation of patients with non small cell lung cancer (NSCLC), with important prognostic implications. We have previously demonstrated that CgA can preserve the barrier function of the vascular endothelium. This prompted us to investigate the role of circulating CgA on metastasis development and tumor self-seeding, the ability of tumor cells to re-infiltrate their tumor of origin. Using mouse mammary adenocarcinoma models we observed that CgA inhibits both tumor self-seeding and organ colonization. Studies of the mechanism of action showed that CgA can inhibit the shedding of cancer cells in circulation from primary tumors, the re-infiltration of tumors and the colonization of lungs by circulating tumor cells. Pharmacological modulation of CgA further affected the development of lung colonies by tumor cells. We obtained evidences to suggest that CgA can inhibit the transendothelial migration of cancer cells, by preserving the VE-cadherin-dependent endothelial barrier function. These findings point to a role of circulating CgA as a regulator of tumor cell trafficking from tumor-to-blood and from blood-to-tumor/normal tissues. Inhibition of the multidirectional trafficking of cancer cells in normal and neoplastic tissues may represent a novel strategy to reduce cancer progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1414. doi:1538-7445.AM2012-1414
Abstract P4-06-22: Persistent Triple-Negative Phenotype Is Associated with Poorest Outcome among Patients with Metastatic Breast Cancer (BC) - Results of the Retrospective Multicenter <i>PriMet</i> Study Comparing Molecular BC Phenotypes in Primary Tumors and Corresponding Recurrences
Authors: C Liedtke, O Gluz, F Heitz, M Freudenberger, R Würstlein, D Hungermann, M Ortmann, RE Kates, U Nitz, A du Bois, TN Fehm, N. Harbeck
Journal: Cancer Research (2010)

Abstract Background: Patients with triple negative (TN) breast cancer (BC), defined by lack of both ER/PR expression and HER2 overexpression, have an unfavorable prognosis. Although phenotype changes between primary tumor (PT) and disease recurrence (DR) have been described, their clinical significance is still unclear. Methods: We conducted PriMet, a retrospective multicenter (n=11) study to compare BC phenotype in PT and corresponding DR. Inclusion criteria comprised (1) unilateral BC with subsequent/synchronous local/regional/distant DR and (2) immunohistochemical confirmation of DR. Our aim was to (a) evaluate discordance rates between PT/DR, (b) find predictors for discordance, and (c) analyze the impact of discordance on patient outcome. Results: 436 patients were entered into PriMet; 414 had no evidence of primary metastatic disease (M0). Median follow-up in patients alive at time of analysis was 73. 1 (4.4-293.6) months. Triple receptor status for PT and DR was available in 377 patients; 68 patients (18.0 %) showed TNBC in PT, 40 patients (10.6 %) had TNBC in both PT and DR (i.e. TNBC persistence); 28 patients (7.4 %) changed from TNBC to non-TNBC (15 became HER2 positive (4.0 %)). Status changes for ER and PR were significantly positively associated (P&amp;lt;0.001). Patients with either persistent TNBC or non-TNBC had a median age at diagnosis of 52.0 compared to 55.5 yrs for patients with discordant TN status (p=0.04). Compared to differing constellations, persistent TNBC was associated with higher tumor grade (p=0.018) as well as with both decreased disease-free survival (DFS) (see figure) and post-recurrence survival (PRS) in M0 patients. In multivariate analysis containing pT stage, nodal stage, tumor grade in PT, TNBC in PT and TNBC persistence, TNBC persistence remained significantly associated with decreased DFS and PRS. Conclusion: PriMet provides substantial evidence regarding potential phenotype changes in PT vs. DR and underlines the importance of immunohistochemical DR verification even in initially TN disease. TNBC persistence was significantly associated with adverse patient outcome. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-06-22.