tbuckley/cabot-search huggingface dataset:
Mitochondrial Retrograde Signaling Mediated by UCP2 Inhibits Cancer Cell Proliferation and Tumorigenesis
Authors: Pauline Esteves, Claire Pecqueur, Céline Ransy, Catherine Esnous, Véronique Lenoir, Frédéric Bouillaud, Anne-Laure Bulteau, Anne Lombès, Carina Prip-Buus, Daniel Ricquier, Marie-Clotilde Alves-Guerra
Journal: Cancer Research (2014)

Cancer cells tilt their energy production away from oxidative phosphorylation (OXPHOS) toward glycolysis during malignant progression, even when aerobic metabolism is available. Reversing this phenomenon, known as the Warburg effect, may offer a generalized anticancer strategy. In this study, we show that overexpression of the mitochondrial membrane transport protein UCP2 in cancer cells is sufficient to restore a balance toward oxidative phosphorylation and to repress malignant phenotypes. Altered expression of glycolytic and oxidative enzymes mediated the effects of this metabolic shift. Notably, UCP2 overexpression increased signaling from the master energy-regulating kinase, adenosine monophosphate-activated protein kinase, while downregulating expression of hypoxia-induced factor. In support of recent new evidence about UCP2 function, we found that UCP2 did not function in this setting as a membrane potential uncoupling protein, but instead acted to control routing of mitochondria substrates. Taken together, our results define a strategy to reorient mitochondrial function in cancer cells toward OXPHOS that restricts their malignant phenotype.
Survival of the Fittest: Cancer Stem Cells in Therapeutic Resistance and Angiogenesis
Authors: Christine E. Eyler, Jeremy N. Rich
Journal: Journal of Clinical Oncology (2008)

In an increasing number of cancers, tumor populations called cancer stem cells (CSCs), or tumor-initiating cells, have been defined in functional assays of self-renewal and tumor initiation. Moreover, recent work in several different cancers has suggested the CSC population as a source of chemotherapy and radiation-therapy resistance within tumors. Work in glioblastoma and breast cancers supports the idea that CSCs may possess innate resistance mechanisms against radiation- and chemotherapy-induced cancer cell death, allowing them to survive and initiate tumor recurrence. Several resistance mechanisms have been proposed, including amplified checkpoint activation and DNA damage repair as well as increased Wnt/β-catenin and Notch signaling. Novel targeted therapies against the DNA damage checkpoint or stem-cell maintenance pathways may sensitize CSCs to radiation or other therapies. Another important category of cancer therapies are antiangiogenic and vascular targeting agents, which are also becoming integrated in the treatment paradigm of an increasing number of cancers. Recent results from our laboratory and others support a role for CSCs in the angiogenic drive as well as the mechanism of antiangiogenic agents. Identifying and targeting the molecular mechanisms responsible for CSC therapeutic resistance may improve the efficacy of current cancer therapies.
Abstract 164: High-throughput epigenetic analysis of susceptibility loci identified by GWAS in pancreatic cancer
Authors: Ken C. Lo, Heather Holster, Jinping Jia, Hemang Parikh, Irene Collins, Robert Brazas, Rebecca Selzer, Laufey Amundadottir
Journal: Cancer Research (2010)

Abstract Pancreatic cancer is a highly lethal cancer with few well established risk factors. A genome wide association study (GWAS) of pancreatic cancer (PanScan) is being conducted within the framework of the NCI-sponsored Cohort Consortium and the Pancreatic Cancer Case-Control Consortium (PANC4). Susceptibility loci discovered to date in PanScan are non-coding variants that lie in intronic or intergenic regions, suggesting that the underlying signals may function through regulatory mechanisms that influence gene expression or splicing. Alternatively, these may lie in unannotated transcripts and directly affect their function. Epigenetic mechanisms, such as DNA methylation, can affect the regulation of gene expression and plays a critical role in the development of many human diseases including cancer. Powerful methods exist to analyze DNA methylation patterns in higher eukaryotes including methylated DNA immunoprecipitation (MeDIP), an affinity based approach to enrich methylated DNA regions from genomic DNA, which can be combined with microarrays to profile genomic DNA methylation patterns. We created a new semi-custom MeDIP-optimized array design based on our Human DNA Methylation 3×720K CpG Island Plus RefSeq Promoter array by tiling additional regions associated with pancreatic cancer that were identified in the PanScan study. To complement DNA methylation data a genome-wide transcriptome analysis was performed with RNA-sequencing (RNA-seq). Here we describe a comprehensive genome wide analysis of 8 pancreatic cancer cell lines to examine methylation patterns of Refseq promoters and annotated CpG islands as well as transcribed sequences. One of the susceptibility loci from PanScan is in the vicinity of the ABO gene on Chr9q34 where four SNPs (rs505922, rs495828, rs657152 and rs630014) are associated with a significantly increased risk of pancreatic cancer. As a pilot study, DNA methylation patterns and expressed sequences in this locus were investigated in cell lines derived from pancreatic tumors and normal pancreatic tissues. Our genome wide DNA methylation and RNA-seq analysis aims at establishing a comprehensive catalog of epigenetic patterns in pancreatic cell lines that could provide plausibility for the association signal in the ABO gene and other GWAS regions and thereby, initiate the characterization of the molecular phenotype of the susceptibility alleles for pancreatic cancer risk. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 164.
Cardiac Allograft Vasculopathy
Authors: Michael Weis, Wolfgang von Scheidt
Journal: Circulation (1997)

Abstract Cardiac allograft vasculopathy (CAV) remains a troublesome long-term complication of heart transplantation. It is manifested by a unique and unusually accelerated form of coronary disease affecting both intramural and epicardial coronary arteries and veins. CAV is characterized by vascular injury induced by a variety of noxious stimuli, including the immune system response to the allograft, ischemia-reperfusion injury, viral infection, immunosuppressive drugs, and classic risk factors such as hyperlipidemia, insulin resistance, and hypertension. The obstructive vascular lesions are thought to progress through repetitive endothelial injury followed by repair response. The role of major histocompatibility complex donor-recipient differences in the pathogenesis of CAV has not yet been completely elucidated. Intracoronary ultrasound studies reveal a dual morphology with donor-transmitted or de novo focal, noncircumferential plaques in proximal segments and/or a diffuse, concentric pattern observed in distal segments. A lack of correlation between microvascular and epicardial vessel disease suggests discordant manifestations and progression of CAV. Apoptosis and loss of functional vascular remodeling have to be considered as important mediators of clinically relevant CAV. Strategies for blocking T-cell costimulation and expression of adhesion molecules may help prevent chronic rejection in clinical transplantation. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and antiproliferative drugs may slow progression of CAV by various effects. Methods to augment endogenous nitric oxide bioavailability as well as newer immunosuppressive regimens may be protective. Balloon angioplasty has a limited role in the treatment of focal lesions. Experiences with coronary stenting, coronary artery bypass grafting, and transmyocardial laser revascularization are limited. Retransplantation has a worse outcome than initial transplantation.
Immunologic Studies in Cimetidine-Induced Nephropathy and Polymyositis
Authors: Alan J. S. Watson, Milton H. Dalbow, Irene Stachura, Jorge A. Fragola, Mario F. Rubin, Rosemarie M. Watson, Edmund Bourke
Journal: New England Journal of Medicine (1983)

CIMETIDINE is a histamine H2-receptor antagonist that is among the most widely prescribed drugs in the United States. In addition to its inhibitory action on gastric acid secretion, a possible role as an immunomodulator has been suggested.1 , 2 Isolated reports have also suggested an occasional association between cimetidine administration and polymyositis3 or interstitial nephritis,4 5 6 7 8 9 10 11 both of which appear to represent disorders of immunoregulation.12 13 14 We report on a patient in whom polymyositis and acute interstitial nephritis followed the institution of cimetidine therapy. Using monoclonal antibodies, we found a marked increase in the proportion of cytotoxic/suppressor T lymphocytes in the peripheral . . .
CUTIS VERTICIS GYRATA WITH FOREIGN BODY GRANULOMATA
Authors: J. THOMSON, R. C. MACGILLIVRAY
Journal: British Journal of Dermatology (1969)

SUMMARY.— A case report of a patient with cutis verticis gyrata, in whom an additional scalp abnormality had supervened, is presented. Histologically, the latter was composed of fibrous tissue in which there were foreign body granulomata around embedded hair shafts.
Electrophysiologic testing in patients with the long QT syndrome.
Authors: A K Bhandari, W A Shapiro, F Morady, E N Shen, J Mason, M M Scheinman
Journal: Circulation (1985)

Electrophysiologic studies were performed in 15 patients with syncope and/or cardiac arrest who had the long QT syndrome and 11 control subjects who had normal QT intervals. The syndrome was familial in five patients and idiopathic in 10. All patients had a prolonged QT (546 +/- 68 msec, mean +/- SD) and corrected QT (550 +/- 51 msec). Incremental atrial pacing at cycle lengths of 600 to 400 msec resulted in shortening of the QT interval, but there was no significant difference in the magnitude or percent of shortening of the QT interval between patients with the long QT syndrome and control subjects. Intravenous propranolol did not influence the QT interval measured at fixed atrial-paced cycle lengths in patients with either the familial or idiopathic form of the syndrome. Programmed right and left ventricular stimulation with up to three extrastimuli before and during isoproterenol infusion did not induce sustained ventricular tachycardia or ventricular fibrillation in any of the patients. However, rapid polymorphic nonsustained ventricular tachycardia was induced in six of the 15 patients (40%). Neither the inducibility of nonsustained ventricular tachycardia nor the results of electropharmacologic testing with beta-blockers proved to be of any prognostic value during the mean follow-up period of 28 +/- 17 months. Electrophysiologic studies are of limited value in the diagnosis and treatment of patients with the long QT syndrome.
Kinetic Stabilization of Microtubule Dynamics by Estramustine Is Associated with Tubulin Acetylation, Spindle Abnormalities, and Mitotic Arrest
Authors: Renu Mohan, Dulal Panda
Journal: Cancer Research (2008)

Estramustine (EM) alone or in combination with other anticancer agents is clinically used for the treatment of hormone refractory prostate cancer. Furthermore, EM has been shown to potently inhibit the proliferation of different types of cancer cells in culture apparently by targeting microtubules; however, the antiproliferative mechanism of action of EM is not clear. In this work, we have shown that EM strongly suppressed the dynamic instability of individual microtubules in MCF-7 cells by reducing the rates of growing and shortening excursions and increasing the time microtubule spent in the pause state. At its half maximal proliferation inhibitory concentration (IC(50)), EM exerted strong suppressive effects on the dynamics of microtubules in MCF-7 cells without detectably affecting either the organization or the polymerized mass of microtubules. At relatively high concentrations (5 x IC(50)), EM significantly depolymerized microtubules in the cells. Furthermore, the microtubules were found highly acetylated, supporting the conclusion that they were stabilized by the drug. EM treatment induced spindle abnormalities in MCF-7 cells, and a major population of the arrested mitotic cells was multipolar. EM also perturbed the microtubule-kinetochore interaction, thereby activating the spindle assembly checkpoint and leading to apoptotic cell death.
Composite Outcomes in Randomized Trials
Authors: Nick Freemantle, Melanie Calvert, John Wood, Joanne Eastaugh, Carl Griffin
Journal: JAMA (2003)

Composite outcomes, in which multiple end points are combined, are frequently used as primary outcome measures in randomized trials and are often associated with increased statistical efficiency. However, such measures may prove challenging for the interpretation of results. In this article, we examine the use of composite outcomes in major clinical trials, assess the arguments for and against them, and provide guidance on their application and reporting. To assess incidence and quality of reporting, we systematically reviewed the use of composite end points in clinical trials in Annals of Internal Medicine, BMJ, Circulation, Clinical Infectious Diseases, Journal of the American College of Cardiology, JAMA, Lancet, New England Journal of Medicine, and Stroke from 1997 through 2001 using a sensitive search strategy. We selected for review 167 original reports of randomized trials (with a total of 300 276 patients) that included a composite primary outcome that incorporated all-cause mortality. Sixty-three trials (38%) were neutral both for the primary end point and the mortality component. Sixty trials (36%) reported significant results for the primary outcome measure but not for the mortality component. Only 6 trials (4%) were significant for the mortality component but not for the primary composite outcome, whereas 19 trials (11%) were significant for both. Twenty-two trials (13%) were inadequately reported. Our review suggests that reporting of composite outcomes is generally inadequate, implying that the results apply to the individual components of the composite outcome rather than only to the overall composite. Current guidelines for the undertaking and reporting of clinical trials could be revised to reflect the common use of composite outcomes in clinical trials.
Cancer-Testis Antigen Lymphocyte Antigen 6 Complex Locus K Is a Serologic Biomarker and a Therapeutic Target for Lung and Esophageal Carcinomas
Authors: Nobuhisa Ishikawa, Atsushi Takano, Wataru Yasui, Kouki Inai, Hitoshi Nishimura, Hiroyuki Ito, Yohei Miyagi, Haruhiko Nakayama, Masahiro Fujita, Masao Hosokawa, Eiju Tsuchiya, Nobuoki Kohno, Yusuke Nakamura, Yataro Daigo
Journal: Cancer Research (2007)

Abstract Gene expression profile analyses of non–small cell lung carcinomas (NSCLC) and esophageal squamous cell carcinomas (ESCC) revealed that lymphocyte antigen 6 complex locus K (LY6K) was specifically expressed in testis and transactivated in a majority of NSCLCs and ESCCs. Immunohistochemical staining using 406 NSCLC and 265 ESCC specimens confirmed that LY6K overexpression was associated with poor prognosis for patients with NSCLC (P = 0.0003), as well as ESCC (P = 0.0278), and multivariate analysis confirmed its independent prognostic value for NSCLC (P = 0.0035). We established an ELISA to measure serum LY6K and found that the proportion of the serum LY6K-positive cases was 38 of 112 (33.9%) NSCLC and 26 of 81 (32.1%) ESCC, whereas only 3 of 74 (4.1%) healthy volunteers were falsely diagnosed. In most cases, there was no correlation between serum LY6K and conventional tumor markers of carcinoembryonic antigen (CEA) and cytokeratin 19-fragment (CYFRA 21-1) values. A combined ELISA for both LY6K and CEA classified 64.7% of lung adenocarcinoma patients as positive, and the use of both LY6K and CYFRA 21-1 increased sensitivity in the detection of lung squamous cell carcinomas and ESCCs up to 70.4% and 52.5%, respectively, whereas the false positive rate was 6.8% to 9.5%. In addition, knocked down of LY6K expression with small interfering RNAs resulted in growth suppression of the lung and esophageal cancer cells. Our data imply that a cancer-testis antigen, LY6K, should be useful as a new type of tumor biomarker and probably as a target for the development of new molecular therapies for cancer treatment. [Cancer Res 2007;67(24):11536–46]
Prevalence of Diabetes in Patients With Multiple Sclerosis
Authors: Wiam I. Hussein, Sethu S. Reddy
Journal: Diabetes Care (2006)

Diabetes prevalence is unknown in patients with multiple sclerosis (MS). The objective of this study was to estimate the prevalence of both types of diabetes in MS patients. We reviewed the database from our MS center. A total of 1,206 patients were diagnosed and treated at the center for MS in a duration of 6 years (1991–1997). Of those patients, 92 were diagnosed as having diabetes. Health records were reviewed for sex, race, type of diabetes (type 1 versus type 2), age of onset of MS and diabetes, …
Geometry of tricuspid annulus determined by real-time 3-D echo in tricuspid regurgitant patients with intact leaflets
Authors: None Jian Xin Qin, Takahiro Shiota, None Yong Jin Kim, Deborah A. Agler, Xiyi Hang, Jun Kwan, Patrick M. McCarthy, James D. Thomas
Journal: Journal of the American College of Cardiology (2002)
Multimeric pattern of plasma and platelet von willebrand factor is normal in uremic patients
Authors: Giancarlo Castaman, Francesco Rodeghiero, Antonella Lattuada, Giuseppe La Greca, Pier Mannuccio Mannucci
Journal: American Journal of Hematology (1993)

Several studies have reported increased von Willebrand factor (vWF) levels in plasma of uremic patients, with a normal multimeric pattern. Two recent studies, however, have shown a reduction of the larger multimers of plasma vWF and one has also found low levels of platelet vWF in uremic patients with prolonged bleeding time (BT). We have measured plasma and platelet vWF and analyzed its multimeric pattern in 20 uremic patients, 11 with a prolonged BT and 9 with a normal BT. For Plasma vWF, no difference for vWF:Ag, RiCof, and ristocetin-induced platelet agglutination was found between the two groups with normal and prolonged BT. The multimeric pattern of plasma vWF, as evaluated by densitometric scanning of the electrophoretic gels, was normal in both groups. For platelet vWF, vWF:Ag and RiCof content was similar in the two groups. The multimeric pattern was indistinguishable from that of normal platelets. In conclusion, our study does not confirm the presence of a structural defect of plasma vWF and the reduction of platelet vWF content in uremia.
Puerperal Fat Embolism
Authors: Marvin Lillian, Russell H. Pope, Frank G. Elliott
Journal: New England Journal of Medicine (1955)

FAT embolism is usually related to the effects of trauma on the skeleton; it has also complicated surgery involving adipose tissues. Recently, a case was observed in the early puerperium. With the exception of Warthin's1 case, similar occurrences have not been described in medical publications. The rarity of this puerperal complication prompts its report.Case ReportA 39-year-old Negress, a gravida ii, was admitted to the Bridgeport Hospital on November 13, 1954, at 2:20 p.m., in the 40th week of pregnancy in early labor. She had been hospitalized 2 years previously for a normal, full-term spontaneous delivery of a living . . .
A bump on the head
Authors: P. J Shirley
Journal: BMJ (1998)

I was asked at my recent yearly training assessment interview what my greatest achievement over the previous year had been. My reply was returning to work and learning to intubate again. (The honest answer being the completion of my fifth, sub three hour London marathon despite missing six weeks' training.) “You should write a personal view,” was the response. Although initially sceptical I have relented.

Owing to the mild weather my 12 mile cycle to work had enjoyed a continuation well into winter. I had been proud of my non- car use and my mode of transport on these dark mornings from my rural location had been noted as a tolerable eccentricity.

On 1 December 1997 I remember setting off. My next thoughts were why had I been sleeping in the middle of the road in the village and why was this man standing over me? He kindly helped me to the side of the road: it was still dark. He then drove away. I had no idea what had happened and got back on the bike which was lying …
Homology of the NH2-terminal amino acid sequences of the heavy and light chains of human monoclonal lupus autoantibodies containing the dominant 16/6 idiotype.
Authors: P M Atkinson, G W Lampman, B C Furie, Y Naparstek, R S Schwartz, B D Stollar, B Furie
Journal: Journal of Clinical Investigation (1985)

The NH2-terminal amino acid sequences have been determined by automated Edman degradation for the heavy and light chains of five monoclonal IgM anti-DNA autoantibodies that were produced by human-human hybridomas derived from lymphocytes of two patients with systemic lupus erythematosus. Four of the antibodies were closely related to the idiotype system 16/6, whereas the fifth antibody was unrelated idiotypically. The light chains of the 16/6 idiotype-positive autoantibodies (HF2-1/13b, HF2-1/17, HF2-18/2, and HF3-16/6) had identical amino acid sequences from residues 1 to 40. Their framework structures were characteristic of VKI light chains. The light chain of the 16/6 idiotype-negative autoantibody HF6-21/28 was characteristic of the VKII subgroup. The heavy chains of the 16/6 idiotype-positive autoantibodies had nearly identical amino acid sequences from residues 1 to 40. The framework structures were characteristic of the VHIII subgroup. In contrast, the GM4672 fusion partner of the hybridoma produced small quantities of an IgG with a VHI heavy chain and a VKI light chain. The heavy chains of the lupus autoantibodies and the light chains of those autoantibodies that were idiotypically related to the 16/6 system had marked sequence homology with WEA, a Waldenstrom IgM that binds to Klebsiella polysaccharides and expresses the 16/6 idiotype. These results indicate a striking homology in the amino termini of the heavy and light chains of the lupus autoantibodies studied and suggest that the V regions of the heavy and light chains of the 16/6 idiotype-positive DNA-binding lupus auto-antibodies are each encoded by a single germ line gene.
Cardiac Cell Therapy — Mixed Results from Mixed Cells
Authors: Anthony Rosenzweig
Journal: New England Journal of Medicine (2006)

Despite substantial advances in treatment, ischemic cardiac injury and the ventricular dysfunction it can provoke remain major causes of morbidity and mortality throughout the world. The endogenous regenerative capacity of the heart appears inadequate to repair injured myocardium, leading to the cumulative loss of cardiomyocytes over the lifetime of a patient. This may contribute to the prevalence of heart failure as a diagnosis at hospital admission — particularly among the elderly.For these reasons, experiments in animals suggesting that the transfer of cells derived from bone marrow (BMC) could dramatically improve cardiac function after infarction through regeneration of the myocardium . . .
Ultrasound-enhanced drug delivery in prostate cancer xenografts by nanoparticles stabilizing microbubbles
Authors: Siv Eggen, Stein-Martin Fagerland, Ýrr Mørch, Rune Hansen, Kishia Søvik, Sigrid Berg, Håkon Furu, Audun Dybvik Bøhn, Magnus B. Lilledahl, Anders Angelsen, Bjørn Angelsen, Catharina de Lange Davies
Journal: Journal of Controlled Release (2014)