tbuckley/cabot-search huggingface dataset:
Abstract 815: CBL0137 demonstrates significant antitumor activity against hepatocellular carcinoma alone and in combination with sorafenib
Authors: Catherine Burkhart, Rachael Kohrn, Brittany Walker, Katerina Gurova, Andrei Purmal, Andrei Gudkov
Journal: Cancer Research (2014)

Abstract Primary hepatocellular carcinoma (HCC) is the 6th most common malignancy diagnosed worldwide with an incidence that continues to rise. Even with the use of the current standard of care drug sorafenib, survival of patients remains at ∼10-11 months and sorafenib toxicity results in dose interruptions and delays. Therefore, tolerable, effective therapies against HCC are greatly needed. CBL0137 represents a novel class of small molecules that simultaneously activate p53 and inhibit cancer-associated stress response pathways, such as NF-κB and HSF-1, and has demonstrated broad range antitumor activity against pre-clinical tumor models. The effects of CBL0137 are mediated by the inhibition of the chromatin remodelling factor FACT (FAcilitates Chromatin Transcription) comprised of SSRP1 and SPT16 subunits. FACT is expressed in undifferentiated progenitors and stem cells of adult tissues, but is almost undetectable in differentiated cells. It is expressed in many tumor types, including HCC, and is correlated with high grade and worse overall survival. Thus, FACT represents a potentially important target for cancer therapy. We investigated the effect of CBL0137 on HCC using HepG2 and Hep3B xenograft models. Treatment of tumor bearing mice intravenously with 60-70 mg/kg CBL0137 every 4th day resulted in ∼88-94% tumor growth inhibition in both models, including tumor regression in 60-80% of tumors during the course of treatment. Furthermore, combination of suboptimal doses of CBL0137 with sorafenib had greater efficacy compared to either drug alone (tumor growth inhibition: HepG2- 87.9% combination vs 73.6% CBL0137 only (P=0.0014), 75.7% sorafenib only (P=0.0006); Hep3B- 79.6% combination vs 38.2% CBL0137 only (P=0.003), 51.4% sorafenib only (P=0.032)). Although the mechanism resulting in the combination effect is unknown, in vitro analysis of markers of CBL0137 and sorafenib activity revealed that both drugs caused a marked decrease in the basal and induced expression of NF-κB target genes (IL-8 and TNF). Furthermore, the combination of CBL0137 and sorafenib almost completely abolished the expression of these genes in both HCC cell lines, suggesting that the combination effect may be in part mediated through inhibition of the NF-κB pathway. Together, these data indicate that CBL0137 may provide a clinical benefit for the treatment of HCC both alone and in combination with sorafenib. Citation Format: Catherine Burkhart, Rachael Kohrn, Brittany Walker, Katerina Gurova, Andrei Purmal, Andrei Gudkov. CBL0137 demonstrates significant antitumor activity against hepatocellular carcinoma alone and in combination with sorafenib. [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 815. doi:10.1158/1538-7445.AM2014-815
Overcoming tumor multidrug resistance using drugs able to evade P‐glycoprotein or to exploit its expression
Authors: Stefania Nobili, Ida Landini, Teresita Mazzei, Enrico Mini
Journal: Medicinal Research Reviews (2011)

Abstract Multidrug resistance (MDR) is a major obstacle to the effective treatment of cancer. Cellular overproduction of P‐glycoprotein (P‐gp), which acts as an efflux pump for various anticancer drugs (e.g. anthracyclines, Vinca alkaloids, taxanes, epipodophyllotoxins, and some of the newer antitumor drugs) is one of the more relevant mechanisms underlying MDR. P‐gp belongs to the superfamily of ATP‐binding cassette transporters and is encoded by the ABCB1 gene. Its overexpression in cancer cells has become a therapeutic target for circumventing MDR. As an alternative to the classical pharmacological strategy of the coadministration of pump inhibitors and cytotoxic substrates of P‐gp and to other approaches applied in experimental tumor models (e.g. P‐gp‐targeting antibodies, ABCB1 gene silencing strategies, and transcriptional modulators) and in the clinical setting (e.g. incapsulation of P‐gp substrate anticancer drugs into liposomes or nanoparticles), a more intriguing strategy for circumventing MDR is represented by the development of new anticancer drugs which are not substrates of P‐gp (e.g. epothilones, second‐ and third‐generation taxanes and other microtubule modulators, topoisomerase inhibitors). Some of these drugs have already been tested in clinical trials and, in most of cases, show relevant activity in patients previously treated with anticancer agents which are substrates of P‐gp. Of these drugs, ixabepilone, an epothilone, was approved in the United States for the treatment of breast cancer patients pretreated with an anthracycline and a taxane. Another innovative approach is the use of molecules whose activity takes advantage of the overexpression of P‐gp. The possibility of overcoming MDR using the latter two approaches is reviewed herein. © 2011 Wiley Periodicals, Inc. Med Res Rev
Abstract 4498: Role of Self-Expanding Drug-Eluting Axxess Stent in Bifurcation Lesions: Intravascular Ultrasound Findings of AXXESS, AXXENT and DIVERGE Trials
Authors: Bon-Kwon Koo, Takao Hasegawa, Akiyoshi Miyazawa, Hyeonsoo Chang, Junya Ako, Josef Dens, Stefan Verheye, Eberhard Grube, Yasuhiro Honda, Peter J Fitzgerald
Journal: Circulation (2008)

Backgrounds Bifurcation location remains one of the most challenging lesion subsets even in the era of drug-eluting stents. AXXESS stent is a self-expanding drug-eluting stent designed to be placed in the proximal part of the main vessel, at the level of the carina. This stent has flared configuration so as to properly expand into the bifurcation anatomy. This study was performed to assess the efficacy of the AXXESS stent on the treatment of left main and non-left main bifurcation lesions using intravascular ultrasound (IVUS). Methods Volumetric IVUS data from 3 multi-center trials using AXXESS stent in bifurcation lesions (AXXESS trial: non-left main bifurcation, N=37, AXXENT trial: left main bifurcation, N=21 and DIVERGE trial: non-left main bifurcation, N=56) were analyzed. All IVUS analyses were performed at an independent core laboratory. To adjust the difference in length of measured segments, the parameter of volume index was derived from each volume parameter using the formula of volume/measured length (mm 3 /mm). Percent neointimal volume was defined as neointimal volume divided by stent volume. Results During follow-up, AXXESS stent volume index was increased by 27.6±20.2% (from 8.5±2.8 to 10.6±3.3mm 3 /mm). Percent neointimal volume obstruction was 3.4±4.2%. Lumen volume index was increased by 22.4±19.9% (from 8.5±2.8 to 10.3±3.2mm 3 /mm). Patients with 9 month follow-up IVUS had more NIV obstruction than with 6 month follow up (4.3±5.0 vs. 2.5±3.0%, p=0.03). There was a trend toward more stent expansion in non-left main bifurcation lesions than in left main bifurcation lesions (30±16% vs. 19±29%, P=0.1). However, percent neointimal volume obstruction was not different according to the location of lesions (P=0.5). Late acquired incomplete stent apposition was occurred in only 1 case. Conclusion This combined IVUS analysis suggests that AXXESS stent seems to be an effective treatment option for wide range of bifurcation lesion morphologies.
THE TREATMENT OF PNEUMOCOCCIC PNEUMONIA WITH SULFAPYRIDINE
Authors: K. G. Kohlstaedt, Irvine H. Page
Journal: Annals of Internal Medicine (1940)

Excerpt Several communications dealing with the clinical applications of sulfapyridine (2 sulfanyl-amino-pyridine) have appeared since Whitby's (1938) report of its value in the control of pneumococcic infections in mice. Among the first of these and one of great importance, is that of Evans and Gaisford (1938), which gave hope that a drug of value had been discovered. Subsequent work is confirming this belief. The purpose of this communication is to describe our experience in the treatment of pneumococcic pneumonia in the Indianapolis City Hospital and in the private pavillion of the Methodist Hospital during the fall and winter of 1938-1939. METHODS
The Clinical Significance of So-Called Chronic Appendicitis
Authors: Julius Friedenwald, Theodore H. Morrison
Journal: Annals of Internal Medicine (1931)

Article1 July 1931The Clinical Significance of So-Called Chronic AppendicitisJULIUS FRIEDENWALD, M.D., F.A.C.P., THEODORE H. MORRISON, M.D., F.A.C.P.JULIUS FRIEDENWALD, M.D., F.A.C.P.Search for more papers by this author, THEODORE H. MORRISON, M.D., F.A.C.P.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-5-1-1 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptMany conflicting views concerning the significance of chronic appendicitis have been held during the past 10 to 15 years. While some clinicians have attributed many disturbances occurring in the abdomen to this cause, others have held that it in itself has but slight clinical significance. According to the latter conception, so-called chronic appendicitis is not a disease in which the symptoms are due entirely to the appendix alone, but one in which many other abdominal as well as other factors play an important rôle.It is a well recognized fact, that since the advent of roentgenology numerous variations in the...References1 HEYDKILLIANMACNEAL : The Liver and Its Relation to Chronic Abdominal Infection—Beaumont Foundation Lecture Course, iii; 1924. Google Scholar2 DEAVER : A. J. M. Sciences, 177:749, 1929. Google Scholar3 ROHDENBERG : Arch. of Path. and Lab. Med., 3: 947, 1927. Google Scholar4 BROWNGAITHER : South. Med. Jour. 23: 591, 1930. CrossrefGoogle Scholar5 WHITE : Boston Med. and Surg. J., 188: 387, 1923; and Amer. J. Roent. and Rad. Therapy, 13: 18, 1925. CrossrefGoogle Scholar6 CASE : Northwest Medicine, 20:165, 1921. Google Scholar7 CARNETT : Surg. Gyn. and Obst., 42: 625, 1926. A. J. M. Sciences, 174: 579, 1927. A. J. M. Sciences, 174: 833, 1927. J. A. M. A., 91: 1679, 1928. Google Scholar8 BETTMAN : J. A. M. A., 83: 1216, 1924. Annals Int. Med. 2: 516, 1928. CrossrefGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Baltimore, Maryland*From the Gastro-Enterological Clinic of the Department of Medicine, University of Maryland.†Delivered at the Baltimore Meeting of the American College of Physicians, March 23, 1931. Nextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byPersistence of pain after appendectomyDie Krankheiten des HypophysenzwischenhirnsystemsDie Krankheiten des HypophysenzwischenhirnsystemsXVI. The Fifth, Ninth and Tenth Nerves in Bronchial AsthmaReflex spasm of the stomach and duodenum caused by disease of the appendix 1 July 1931Volume 5, Issue 1Page: 1-8KeywordsAppendicitisGastroenterology and hepatology ePublished: 1 December 2008 Issue Published: 1 July 1931 PDF downloadLoading ...
Abstract MP10: Traditional Risk Factors for Atrial Fibrillation in Individuals with Normal Left Atrial Size: The Atherosclerosis Risk in Communities Study
Authors: Waqas Qureshi, Elsayed Soliman, Scott Solomon, Dan Arking, Amil Shah, Deepak Shah, Alvaro Alonso, Lynne Wagenknecht, David Herrington
Journal: Circulation (2014)

Background: Traditional risk factors for atrial fibrillation (AF) likely contribute to the pathogenesis of AF through their effects on left atrial (LA) enlargement. However, little is known about risk factors for AF in individuals with normal LA size. Hypothesis: We hypothesized that the risk factors for AF differ between individuals with normal and enlarged LA. Methods: LA diameter was measured by cardiac echocardiography in participants in the Atherosclerosis Risk in Communities (ARIC) study during 2011 - 13. AF was defined by ECGs and/or hospital discharge ICD-9 codes. Gender-specific cut points (3.9 cm for females and 4.1 cm for males were used to dichotomize the sample into normal and enlarged LA. Univariate and multivariate logistic regression models adjusting for age, gender, race, diabetes, hypertension, alcohol use (&gt;1 drink/day), height, weight, coronary artery disease, heart failure, and exercise (&gt;1 day per week) were used to evaluate risk factors for AF among ARIC participants with and without enlarged LA. Results: Of 5540 (mean age 75.6±5.2, women 58.6%) participants enlarged LA was present in 955 (16.2%). AF was prevalent in 3.9% of normal LA and 20% of enlarged LA participants. In multivariate analysis, alcohol use and exercise (&gt;1 per week) were independently associated with AF in participants with normal sized LA (p&lt;0.05)(table). Interaction terms of alcohol use, and exercise with LA size were statistically significant despite adjusting for age, gender, height, weight and race in the multivariate model. The population attributable risk of AF for alcohol use and lack of exercise were 5.5% and 6.4%, respectively. ` Conclusion: Many of the risk factors for AF are similar irrespective of the LA size. However, lack of exercise and alcohol drinking are associated with prevalent AF only in the normal sized LA group. More research is warranted to determine the potential benefits of interventions targeting these two modifiable risk factors in the setting of normal LA size.
Abstract 13189: Clinical Presentation, Long-Term Follow-Up, and Disease Penetrance of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy in 1001 Patients and Family Members
Authors: Judith A Groeneweg, Aditya Bhonsale, Cynthia A James, Anneline S te Riele, Jeroen F van der Heijden, Brittney Murray, Crystall Tichnell, Abhishek Sawant, Pieter A Doevendans, Harikrishna Tandri, J P van Tintelen, Daniel P Judge, Toon A van Veen, Dennis Dooijes, Arthur A Wilde, Richard N Hauer, Hugh Calkins
Journal: Circulation (2014)

Introduction: Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) is a hereditary progressive cardiomyopathy. We aimed to define long-term outcome in a transatlantic ARVD/C cohort of 1001 individuals. Methods: Clinical/genetic characteristics and follow-up data of ARVD/C index patients (n=439, fulfillment of 2010 criteria in all) and family members (n=562) were assessed. Genetic screening of desmosomal and TMEM43 and PLN genes was performed in index patients. Results: Mutations, predominantly in PKP2, were identified in 276/439 (63%). Index patients presented mostly with sustained ventricular arrhythmias (VA) (268/439, 61%). Recurrent sustained VA (in 301/416 (72%) patients presenting alive) characterized follow-up (median 7 years) with 10/63 (16%) sudden cardiac deaths (SCD) in patients without implantable cardioverter-defibrillators (ICDs) versus 2/335 (0.6%) in those with ICDs. Overall, cardiac mortality during follow-up (6%) and cardiac transplantation rate (4%) were low. Although disease onset was significantly earlier in index patients with mutations (first presentation 34 vs.38 years old, p&lt;0.001), disease burden was similar in index patients with and without identified mutations. No phenotypic differences were found between index patients with familial and isolated ARVD/C. Of family members, 37% (207/562) had ARVD/C. Symptoms at presentation correlated with disease expression. Nonetheless, even 103/324 (32%) initially asymptomatic mutation-carrying family members, developed ARVD/C. Family members with mutations more often had ARVD/C (40 vs. 18%, p&lt;0.001), sustained VA (11 vs. 1.3%, p&lt;0.001), and cardiac death (2 vs. 0%) than those without. Conclusions: Long-term outcome in ARVD/C index patients was favorable when diagnosed and treated. Prognosis in family members was determined by symptoms and mutation status. One in three family members, including asymptomatic mutation carriers, developed ARVD/C.
Abstract 12433: Plasma Galectin-3 Levels in Patients with Structural and Clinical Manifestations of Hypertensive Heart Disease: Relationship to Determinants of Matrix Composition
Authors: Michael R Zile, Stacia M DeSantis, Catalin F Baicu, Corey B Prescott, Robert E Stroud, Sheila B Thompson, Catherine D McClure, Francis G Spinale
Journal: Circulation (2010)

Background:  The β-galactoside binding protein galectin-3 (Gal-3) has been demonstrated to regulate both cellular and extracellular structure and function in tissue remodeling processes such as inflammation and cancer. Gal-3 binds to a number of extracellular matrix (ECM) ligands including fibrillar collagens, basement membrane proteins and integrins. The development of LV hypertrophy (LVH) and progression to diastolic heart failure (DHF) are accompanied by significant changes in the ECM, but whether plasma Gal-3 levels are altered in these processes and related to other determinants of ECM remodeling is unknown.   Methods/Results:  Plasma profiles for Gal-3 and determinants of ECM remodeling such as matrix metalloproteinases (MMPs-2,-9,-3,-7,-8), tissue inhibitors of MMPs (TIMPs-1,-2,-3,-4), and collagen peptides (PIIINP, CITP) were measured by high sensitivity immunoassays in control subjects (n=19 CTL); patients with LVH but no DHF (n=21, LVH), and patients with LVH and DHF (n=21, DHF). Echocardiography and 6 minute hall walk (6MHW) showed that DHF patients had shorter 6MHW and increased pulmonary wedge pressures vs. CTL or LVH. Plasma MMP-2, TIMP-1, TIMP-4, NT-proBNP, and Gal-3 were increased in the DHF group vs. CTL and LVH, (Table). Gal-3 values were significantly correlated with changes in MMP-2, TIMP-1, TIMP-4, and NT-proBNP (all r ≥0.3, p   Conclusions:  Plasma profiles of the bioactive molecule Gal-3, which regulates ECM composition and structure, were significantly increased in patients with DHF; Gal-3 was associated with changes in other determinants of ECM remodeling. Thus, biomarker profiling of the ECM remodeling process holds potential diagnostic and prognostic utility in identifying patients transitioning from LVH to DHF.
Evaluating NHS Direct
Authors: D. Florin, R. Rosen
Journal: BMJ (1999)

The creation of NHS Direct reflects a number of different political and policy concerns. One is consumerism and the growth of the 24 hour society.1 2 Another is the need for demand management against a background of growing demand for primary and emergency care and problems in recruiting and retaining nurses and general practitioners. Is the recently announced expansion of NHS Direct supported by its preliminary evaluation?3 This has been reported as showing that it is a success,4 but a closer look at the detailed results reveals a more equivocal picture.

NHS Direct is a telephone triage system operated by nurses to advise callers on the most appropriate form of care. The evaluation has so far looked at three aspects of the service in the first three pilot sites: a descriptive account of the organisation and users of NHS Direct; caller satisfaction; and a “before and after” assessment of its effects on other services.3 This last aspect is important because at least part of the rationale for NHS Direct is to reduce unnecessary demand on other NHS services.

The results to date show lower call rates than expected, with only one third of the predicted total number of calls over the first eight months. This volume might, however, increase as the service becomes better known. Rates of calls …
Review of the 92nd Annual Meeting of the British Association of Dermatologists, 3-5 July 2012, Birmingham, U.K
Authors: M.L. Lam, A.N. Patel, A.D. Ferguson
Journal: British Journal of Dermatology (2012)

This is a synopsis of the main research and clinical findings presented at the 92nd Annual Meeting of the British Association of Dermatologists, held on 3-5 July 2012 in Birmingham, U.K. The conference highlighted the biological, epidemiological and therapeutic advances that have been made recently in the field of dermatology. This synopsis is a selection of the major findings from the meeting; it is not intended to be a substitute for reading the conference proceedings and related references quoted in this article.
Role of tissue microenvironment in determining prostate cancer cell phenotype
Authors: Gary J. Smith, Wendy J. Huss, Danny R. Gray, Wayne J. Glover, Eric S. Werdin
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

2785 

The tissue microenvironment in which prostate cancer arises contributes significantly to the differences in quiescence/progression, apoptotic death/survival and remission/recurrent growth of CaP. We have developed a model for characterizing the role of the tissue microenvironment in determining tumorigenic potential and tumor phenotype of transformed prostate stem cells. In vitro selection of spontaneous transformants of rat prostate stem cells employed a “fluctuation analysis” format where individual lineages initiated from four independent rat prostate stem cell lines were maintained independently for twelve cycles of in vitro selection comprised of maintenance at confluence for one month. At the conclusion of the sixth and twelfth cycles of in vitro selection the individual lineages were transplanted subcutaneously into young male syngeneic rat hosts. None of the parental stem cell lines produced tumors during one-year of in vivo incubation. Transplantation of syngeneic hosts with the lineages at the completion of six rounds of in vitro selection produced 8 tumors (12% of hosts transplanted) that developed with an average latency of 240 days. Transplantation of the syngeneic hosts with the lineages following 12 rounds of in vitro selection has produced 24 tumors (33% of hosts), to date, with an average latency of 130 days. Tumors produced by the lineages derived from two of the rat prostate stem cell lines predominantly form well-differentiated adenocarcinomas that express AR, often at high levels, but that are negative for expression of the basal cell marker p63 and the neuroendocrine cell marker synaptophysin. However, two of these tumors contained nests of basal-like cells that were strongly positive for both AR and p63, but with no synaptophysin positive cells. In contrast, tumors produced by lineages of another stem cell line were described as epithelial tumors (carcinomas). These tumors generally were comprised of basal-like cells that were p63 positive and AR negative, containing adjacent areas of cells that stained weakly for both p63 and AR with the morphology of poorly differentiated adenocarcinomas and focal areas of synaptophysin positive, NE-like cells that generally were localized at the interfaces between areas of p63 positive basal-like cells and the AR positive carcinoma cells. The mixed phenotypes exhibited by the tumor cells suggest the potential for commitment to multiple differentiation lineages and supports the hypothesis of the role of stem-like cells as the nidus of malignant neoplasms and the importance of the tissue microenvironment in determining the phenotype of the tumor.
Diagnostic Accuracy of Computed Tomography Angiography in Patients After Bypass Grafting
Authors: Annick C. Weustink, Koen Nieman, Fransesca Pugliese, Nico R. Mollet, Bob W. Meijboom, Carlos van Mieghem, Gert-Jan ten Kate, Filippo Cademartiri, Gabriel P. Krestin, Pim J. de Feyter
Journal: JACC. Cardiovascular imaging (2009)