tbuckley/cabot-search huggingface dataset:
Phorbol ester- and diacylglycerol-mediated desensitization of cardiac beta-adrenergic receptors.
Authors: C J Limas, C Limas
Journal: Circulation Research (1985)

There are specific phorbol ester receptors on cardiac myocytes which may be identical with the calcium/phospholipid-dependent protein kinase (protein kinase C). Incubation of enzymatically dissociated rat cardiac myocytes with biologically active phorbol esters (such as 4 beta-phorbol-12, 13-dibutyrate and 12-O-tetradecanoyl phorbol-13-acetate) leads to a time- and concentration-dependent loss of beta-adrenergic receptors detectable with the hydrophilic ligand [3H]-CGP-12177. This loss is attributable to a reduction in both maximal beta-receptor numbers and their affinities. The synthetic diacylglycerol, 1-oleyl-2-acetyldiglycerol, which is known to activate protein kinase C, also induces desensitization of beta-receptors. Both phorbol dibutyrate and 1-oleyl-2-acetyldiglycerol have additive effects to isoproterenol, suggesting a separate site of action in promoting beta-receptor desensitization. The effects of phorbol dibutyrate and 1-oleyl-2-acetyldiglycerol are prevented by colchicine (but not its inactive analog, trimethylcolchicinic acid), indicating a microtubule dependence. The loss of membrane-bound beta-receptors after phorbol dibutyrate- or 1-oleyl-2-acetyldiglycerol preincubation is accompanied by an increase in beta-receptors associated with a cytosol-derived vesicular fraction devoid of plasma membrane markers, a finding consistent with an internalization process. These results suggest that protein kinase C activation by diacylglycerols derived from receptor-linked phosphoinositide hydrolysis may be a novel mechanism of cardiac beta-receptor desensitization.
Burden of Changes in Pill Appearance for Patients Receiving Generic Cardiovascular Medications After Myocardial Infarction
Authors: Aaron S. Kesselheim, Katsiaryna Bykov, Jerry Avorn, Angela Tong, Michael Doherty, Niteesh K. Choudhry
Journal: Annals of Internal Medicine (2014)

Generic prescription drugs made by different manufacturers may vary in color or shape, and switching among these drug products may interrupt medication use.To determine whether nonpersistent use of generic drugs among patients with cardiovascular disease after myocardial infarction (MI) is associated with inconsistent appearance of their medications.Cohort and nested case-control studies.Claims from a commercial health insurance database in the United States.Patients discharged after hospitalization for MI between 2006 and 2011 who initiated treatment with a generic β-blocker, angiotensin-converting enzyme inhibitor, angiotensin II-receptor blocker, or statin. Case patients discontinued their index medication for at least 1 month; control patients continued treatment. Control patients were matched to case patients on therapeutic class, number of dispensings before nonpersistence, sex, and age.Rates of changes in pill color and shape during the year after MI were calculated. Next, 2 refills preceding nonpersistence were evaluated to determine whether pill color or shape had changed. Odds of discordance among case and control patients were compared using conditional logistic regression.A total of 29% of patients (3286 of 11,513) had a change in pill shape or color during the study. Statins had the most changes in appearance, whereas β-blockers had the fewest. A total of 4573 episodes of nonpersistence was matched to 19,881 control episodes. The odds of nonpersistence in case patients increased by 34% after a change in pill color (adjusted odds ratio, 1.34 [95% CI, 1.12 to 1.59]) and 66% after a change in pill shape (adjusted odds ratio, 1.66 [CI, 1.43 to 1.94]).Only 3 categories of drugs indicated after MI were evaluated, and clinical outcomes were not addressed.Variation in the appearance of generic pills is associated with nonpersistent use of these essential drugs after MI among patients with cardiovascular disease.Agency for Healthcare Research and Quality and the Harvard Program in Therapeutic Science.
<i>PGC-1</i> α, A Potential Therapeutic Target for Early Intervention in Parkinson’s Disease
Authors: Bin Zheng, Zhixiang Liao, Joseph J. Locascio, Kristen A. Lesniak, Sarah S. Roderick, Marla L. Watt, Aron C. Eklund, Yanli Zhang-James, Peter D. Kim, Michael A. Hauser, Edna Grünblatt, Linda B. Moran, Silvia A. Mandel, Peter Riederer, Renee M. Miller, Howard J. Federoff, Ullrich Wüllner, Spyridon Papapetropoulos, Moussa B. Youdim, Ippolita Cantuti-Castelvetri, Anne B. Young, Jeffery M. Vance, Richard L. Davis, John C. Hedreen, Charles H. Adler, Thomas G. Beach, Manuel B. Graeber, Frank A. Middleton, Jean-Christophe Rochet, Clemens R. Scherzer
Journal: Science Translational Medicine (2010)

Abnormal expression of genes for energy regulation in Parkinson’s disease patients identifies a master regulator as a possible therapeutic target for early intervention.
Prevalence of human T-cell leukemia/lymphoma virus (HTLV) type II infection among high-risk individuals: type-specific identification of HTLVs by polymerase chain reaction
Authors: GD Ehrlich, JB Glaser, K LaVigne, D Quan, D Mildvan, JJ Sninsky, S Kwok, L Papsidero, BJ Poiesz
Journal: Blood (1989)
Endothelial lipase enhances low density lipoprotein binding and cell association in THP-1 macrophages
Authors: G QIU, J HILL
Journal: Cardiovascular Research (2007)

Endothelial lipase (EL) is expressed in macrophages in human atherosclerotic lesions. However, its specific metabolic role in human macrophages has not been fully explored.The present study used lentivirus containing either shRNA or cDNA for EL to decrease or increase EL expression, respectively in THP-1 macrophages to investigate the consequence on LDL binding and cell association.EL suppression significantly decreased the binding and cell association of native LDL (52% and 33%) and mildly oxLDL (43% and 36%) as well as extensively oxLDL binding (36%) in THP-1 macrophages. EL overexpression markedly increased the binding and cell association of native LDL (3.1- and 2.2-fold), mildly oxLDL (1.9- and 1.4-fold), and extensively oxLDL (1.5- and 1.5-fold). An inactive mutant EL compromised EL-mediated cell association of native and mildly oxLDL but not extensively oxLDL. Heparinase treatment almost completely eliminated EL-mediated native and oxLDL binding and cell association in THP-1 macrophages. LDL receptor blocking by antibodies decreased EL-mediated native LDL binding and cell association by 24% and 54%, respectively. Neither receptor associated protein or CD36 antibody treatment led to changes in EL-mediated lipoprotein binding and cell association. Furthermore, wild-type and the catalytically inactive mutant EL increased lipid accumulation in THP-1 macrophages.EL expression promotes the binding and uptake of native and oxidized LDL in THP-1 macrophages in a heparan sulfate proteoglycan-dependent manner, and the LDL receptor was partly responsible for the EL-enhanced uptake of native LDL.
The Fire Within: Cardiac Inflammatory Signaling in Health and Disease
Authors: Matthew Coggins, Anthony Rosenzweig
Journal: Circulation Research (2012)

Inflammatory mediators are operative in the pathogenesis of the most common forms of heart disease. Although in most cases the induction of these pathways is maladaptive and deleterious, there are notable exceptions when inflammatory pathways participate in healing or limiting the extent of injury. The appreciation of the role of these mechanisms in myocardial homeostasis and pathophysiology has led to increased efforts to elucidate the specific signaling pathways most relevant to the heart. Our goal in this introductory overview is to provide context for the five detailed reviews that follow by introducing the major relevant stimuli, the receptors, and pathways that mediate inflammatory signaling in the heart. We try to impart a sense of the scope and complexity of these pathways, as well as their interactions with signaling pathways regulating cell survival and metabolism. These complexities underscore the potential challenges of therapeutically targeting inflammatory mechanisms in heart disease and may help explain the mostly disappointing results of this approach to date.
Decreased motor inhibition in Tourette's disorder: evidence from transcranial magnetic stimulation
Authors: U Ziemann, W Paulus, A Rothenberger
Journal: American Journal of Psychiatry (1997)

Fluctuating motor and vocal tics are the diagnostic feature of Tourette's disorder. The pathophysiology of tics is still unclear. One major hypothesis is a deficient inhibitory control through the cortical-striatal-thalamic-cortical motor loop. The authors tested this hypothesis by investigating motor cortex excitability through use of the technique of transcranial magnetic stimulation.Twenty patients with Tourette's disorder and a comparison group of 21 healthy subjects were studied. Focal transcranial magnetic stimulation was applied to the left motor cortex, and surface electromyography (EMG) was recorded from the right abductor digiti minimi muscle. As measures of motor cortex excitability, motor threshold, cortical silent period, and intracortical inhibition and facilitation were studied. The peripheral silent period and the maximum M wave after supramaximal electrical stimulation of the ulnar nerve at the wrist were also determined.Motor threshold and peripheral motor excitability were normal in the Tourette's disorder group, but the cortical silent period was shortened and the intracortical inhibition reduced. A subgroup analysis of the patients with Tourette's disorder revealed that these abnormalities were seen mainly when tics were present in the EMG target muscle or in patients without neuroleptic treatment. Age, sex, attention deficit hyperactivity disorder, obsessive-compulsive disorder, and sensory urges had no significant effect on motor excitability.Findings are consistent with the hypothesis that tics in Tourette's disorder originate either from a primarily subcortical disorder affecting the motor cortex through disinhibited afferent signals or from impaired inhibition directly at the level of the motor cortex or both.
Primary Colorectal Cancers and Their Subsequent Hepatic Metastases Are Genetically Different: Implications for Selection of Patients for Targeted Treatment
Authors: Joost S. Vermaat, Isaac J. Nijman, Marco J. Koudijs, Frank L. Gerritse, Stefan J. Scherer, Michal Mokry, Wijnand M. Roessingh, Nico Lansu, Ewart de Bruijn, Richard van Hillegersberg, Paul J. van Diest, Edwin Cuppen, Emile E. Voest
Journal: Clinical Cancer Research (2011)

In the era of DNA-guided personalized cancer treatment, it is essential to conduct predictive analysis on the tissue that matters. Here, we analyzed genetic differences between primary colorectal adenocarcinomas (CRC) and their respective hepatic metastasis.The primary CRC and the subsequent hepatic metastasis of 21 patients with CRC were analyzed using targeted deep-sequencing of DNA isolated from formalin-fixed, paraffin-embedded archived material.We have interrogated the genetic constitution of a designed "Cancer Mini-Genome" consisting of all exons of 1,264 genes associated with pathways relevant to cancer. In total, 6,696 known and 1,305 novel variations were identified in 1,174 and 667 genes, respectively, including 817 variants that potentially altered protein function. On average, 83 (SD = 69) potentially function-impairing variations were gained in the metastasis and 70 (SD = 48) variations were lost, showing that the primary tumor and hepatic metastasis are genetically significantly different. Besides novel and known variations in genes such as KRAS, BRAF, KDR, FLT1, PTEN, and PI3KCA, aberrations in the up/downstream genes of EGFR/PI3K/VEGF-pathways and other pathways (mTOR, TGFβ, etc.) were also detected, potentially influencing therapeutic responsiveness. Chemotherapy between removal of the primary tumor and the metastasis (N = 11) did not further increase the amount of genetic variation.Our study indicates that the genetic characteristics of the hepatic metastases are different from those of the primary CRC tumor. As a consequence, the choice of treatment in studies investigating targeted therapies should ideally be based on the genetic properties of the metastasis rather than on those of the primary tumor.
Complete differentiation of CD8+ T cells activated locally within the transplanted liver
Authors: Ingo Klein, Ian Nicholas Crispe
Journal: The Journal of Experimental Medicine (2006)

The transplanted liver elicits systemic tolerance, and the underlying mechanism may also account for the persistence of liver infections, such as malaria and viral hepatitis. These phenomena have led to the hypothesis that antigen presentation within the liver is abortive, leading to T cell tolerance or apoptosis. Here we test this hypothesis in an optimized orthotopic liver transplantation model. In direct contradiction to this model, the liver itself induces full CD8+ T cell activation and differentiation. The effects of microchimerism were neutralized by bone marrow transplantation in the liver donor, and the lack of liver-derived antigen-presenting cells was documented by eight-color flow cytometry and by sensitive functional assays. We conclude that local antigen presentation cannot explain liver tolerance. On the contrary, the liver may be an excellent priming site for naive CD8+ T cells.
S86 Quality of life in advanced non-small cell lung cancer, effects of cisplatin dose and carboplatin in combination with gemcitabine: results from BTOG2, a British Thoracic Oncology Group phase III trial in 1363 patients
Authors: L. J. Billingham, P. Gaunt, H. W. Jarrett, D. Dunlop, J. Thompson, K. J. O'Byrne, M. Kumar, G. Skailes, M. Nicolson, R. Shah, P. Leonard, A. Chetiyawardana, P. Wells, C. Lewanski, P. Woll, B. Crosse, M. Hill, D. Ferry
Journal: Thorax (2011)

<h3>Background</h3> The standard of care for advanced NSCLC is platinum-based chemotherapy but the optimal dose of cisplatin and comparison with carboplatin is uncertain. With median survival at 8–12 months, the impact of such treatment choices on patients9 quality of life (QoL) is important. The BTOG2 trial is a large phase III randomised trial comparing three treatment arms: gemcitabine (1250 mg/m<sup>2</sup> day 1 and day 8) with either cisplatin 80 mg/m<sup>2</sup> (GC80), cisplatin 50 mg/m<sup>2</sup> (GC50) or carboplatin AUC6 (GCb6). The trial was innovative in aiming to collect QoL data on all trial patients and is the largest study to date addressing this issue in NSCLC. <h3>Methods</h3> QoL was measured at each cycle of chemotherapy and each follow-up visit using standard, validated questionnaires: EORTC QLQ-C30, LC13 and EQ-5D. <h3>Results</h3> More than 8000 questionnaires were returned from 1363 randomised patients with compliance around 90% during the treatment period. At pre-randomisation, the mean global heath status score and EQ-5D utility score were 62% and 0.66. On initiation of treatment, patients in all three treatment arms had improved pain, cough, haemoptysis, insomnia, appetite loss and emotional functioning with associated improvements in global measures of QoL but these benefits generally fell away after completion of chemotherapy (12+ weeks). GC50 performed better in terms of the functioning scores and in terms of fatigue, nausea and vomiting while GCb6 performed worst for dyspnoea. All treatments had a deleterious effect on peripheral neuropathy with the post-treatment toxicity momentum markedly worse for GC80. Mean quality-adjusted life months were 6.1 on GC80, 5.6 on GC50 and 6.1 on GCb6. <h3>Conclusion</h3> Although higher doses of cisplatin (80 mg/m<sup>2</sup>) are thought detrimental to QoL compared to 50 mg/m<sup>2</sup> we found minimal differences but a noteworthy problem in delayed neuropathy. Also, the belief that carboplatin produces superior QoL compared to cisplatin at either dose is not obvious. Importantly carboplatin treatment may not palliate dysponea as well as cisplatin. Adjusting for QoL does not change the conclusions from the primary survival analysis.
Somatic gene therapy to treat heart failure is one step closer to reality
Authors: M. Periasamy, J. A. Rafael-Fortney
Journal: Cardiovascular Research (2009)

Despite recent advances in heart failure therapy, patients with end-stage cardiac failure have a poor prognosis and die within 5 years. Diagnosis of the hereditary form of heart failure is becoming increasingly prevalent due to the identification of causative mutations in many structural genes encoding contractile and cytoskeletal proteins. The majority of muscular dystrophies including Duchenne muscular dystrophy (DMD) cause functional deficits not only in skeletal muscle but also in cardiac muscle since the proteins affected are normally present in all striated muscle. DMD is caused by mutations in the very large dystrophin gene. Dystrophin binds the submembranous cytoskeleton at one end and at the other end to a complex of membrane glycoproteins ( Figure 1 ) called the dystrophin-associated glycoprotein complex (DGC). The DGC plays an essential role in maintaining the integrity of the cell membrane by forming a structural link between the extracellular matrix and the cytoskeleton, and in this way, the entire complex transduces the force of contraction and thereby protects the cell membrane from damage. Mutations in dystrophin and several other members of this complex, known as the sarcoglycans, destabilize the entire complex from the membrane and cause both skeletal and cardiac myopathies characterizing DMD and limb-girdle muscular dystrophies. In addition to causing muscular dystrophies, certain mutations in dystrophin and DGC lead primarily to … 

*Corresponding author. Tel: +1 614 292 2310; fax: +1 614 292 4888. E-mail address : periasamy.1{at}osu.edu
Predicting time to ovarian carcinoma recurrence using protein markers
Authors: Ji-Yeon Yang, Kosuke Yoshihara, Kenichi Tanaka, Masayuki Hatae, Hideaki Masuzaki, Hiroaki Itamochi, Masashi Takano, Kimio Ushijima, Janos L. Tanyi, George Coukos, Yiling Lu, Gordon B. Mills, Roel G.W. Verhaak
Journal: Journal of Clinical Investigation (2013)

Patients with ovarian cancer are at high risk of tumor recurrence. Prediction of therapy outcome may provide therapeutic avenues to improve patient outcomes. Using reverse-phase protein arrays, we generated ovarian carcinoma protein expression profiles on 412 cases from TCGA and constructed a PRotein-driven index of OVARian cancer (PROVAR). PROVAR significantly discriminated an independent cohort of 226 high-grade serous ovarian carcinomas into groups of high risk and low risk of tumor recurrence as well as short-term and long-term survivors. Comparison with gene expression–based outcome classification models showed a significantly improved capacity of the protein-based PROVAR to predict tumor progression. Identification of protein markers linked to disease recurrence may yield insights into tumor biology. When combined with features known to be associated with outcome, such as BRCA mutation, PROVAR may provide clinically useful predictions of time to tumor recurrence.
Proximal chiasma localization within an interstitial chromosome segment, a likely correlate of adjacent-2 segregation of translocation causing multivalents in the mouse.
Authors: P de Boer
Journal: Environmental Health Perspectives (1979)

Two T7OH/+ translocation-carrying male mice were used in an investigation into the relation between the segregation pattern of the translocation caused multivalent at anaphase I and the position of the only chiasma in a long interstitial segment. Moreover, the relation between meiotic stage (from early diakinesis to metaphase I) and chiasma movement was assessed. It appeared that pronounced movement of a chiasma within the multivalent was linked with chiasma terminalization in an adjacent segment, either on the same side of the translocation breakpoint or on the other side. On summing the CIV and CIII+I configurations (making up 97.9% of all configurations found) and focusing on the multivalents from late meiotic cells, 41.3% had a proximal chiasma in the long interstitial segment of the multivalent. In total, a percentage of 33.5% of all secondary spermatocytes were characteristic of adjacent-2 segregation (i.e., homologous centromeres move to the same pole at anaphase I). Results obtained with T7OH translocation trisomics, which are briefly discussed in this paper, confirm the tendency of proximal chiasma frequencies in late meiotic cells to coincide with the frequency of absence of homologous centromere separation within the T7OH translocation multivalent. The importance of this phenomenon for normal bivalent behavior during anaphase I is considered.
CD95-Mediated Apoptosis Is Impaired at Receptor Level by Cellular FLICE-Inhibitory Protein (Long Form) in Wild-Type p53 Human Ovarian Carcinoma
Authors: Delia Mezzanzanica, Emanuela Balladore, Fabio Turatti, Elena Luison, Paola Alberti, Marina Bagnoli, Mariangela Figini, Alessandra Mazzoni, Francesco Raspagliesi, Maria Oggionni, Silvana Pilotti, Silvana Canevari
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Ovarian carcinoma is a highly lethal malignancy that often becomes resistant to chemotherapy. Alterations in apoptotic signals and p53 status contribute to drug resistance, and CD95-mediated apoptosis is also deficient in resistant cells. We analyzed the mechanism of resistance to CD95-mediated apoptosis in ovarian carcinoma cell lines differing in p53 status. Experimental Design: CD95-mediated apoptosis was induced by agonistic anti-CD95 antibody, and the apoptotic cascade was monitored with biochemical and functional assays. Results: CD95-mediated apoptosis was blocked in human ovarian cancer cells. In cell lines with wild-type p53, treatment with the protein synthesis inhibitor cycloheximide (CHX) together with anti-CD95 overcame the resistance, suggesting the presence of a labile inhibiting protein. Indeed, the labile protein cellular FLICE-inhibitory protein long form (c-FLIPL) was found to block caspase-8 recruitment to the death-inducing signaling complex (DISC), and sensitization of cells by CHX was due to c-FLIPL down-modulation at the DISC level. Down-regulation of c-FLIPL with antisense oligonucleotides increased CD95-mediated apoptosis as in cells sensitized by CHX, demonstrating the direct involvement of c-FLIPL in apoptosis resistance. Removal of c-FLIPL block at DISC level allowed full activation of the mitochondrial pathway and, eventually, apoptosis in wild-type p53 cells, whereas in cells with mutated p53, c-FLIPL involvement in CD95-mediated apoptosis resistance appeared to be irrelevant. Immunohistochemical analysis of an ovarian tumor tissue array revealed c-FLIPL expression in samples with no p53 accumulation (P = 0.034), and a significant (P = 0.037) inverse relationship between c-FLIPL and p53 expression levels was also observed in 27 epithelial ovarian cancer specimens with known p53 status. Conclusion: The inhibitory protein c-FLIPL is involved in resistance to CD95-mediated apoptosis in ovarian carcinoma cells with wild-type p53.