tbuckley/cabot-search huggingface dataset:
Targeting Antioxidants to Mitochondria by Conjugation to Lipophilic Cations
Authors: Michael P. Murphy, Robin A.J. Smith
Journal: The Annual Review of Pharmacology and Toxicology (2006)

Mitochondrial oxidative damage contributes to a range of degenerative diseases. Consequently, the selective inhibition of mitochondrial oxidative damage is a promising therapeutic strategy. One way to do this is to invent antioxidants that are selectively accumulated into mitochondria within patients. Such mitochondria-targeted antioxidants have been developed by conjugating the lipophilic triphenylphosphonium cation to an antioxidant moiety, such as ubiquinol or α-tocopherol. These compounds pass easily through all biological membranes, including the blood-brain barrier, and into muscle cells and thus reach those tissues most affected by mitochondrial oxidative damage. Furthermore, because of their positive charge they are accumulated several-hundredfold within mitochondria driven by the membrane potential, enhancing the protection of mitochondria from oxidative damage. These compounds protect mitochondria from damage following oral delivery and may therefore form the basis for mitochondria-protective therapies. Here we review the background and work to date on this class of mitochondria-targeted antioxidants.
The IP <sub>3</sub> Receptor Regulates Cardiac Hypertrophy in Response to Select Stimuli
Authors: Hiroyuki Nakayama, Ilona Bodi, Marjorie Maillet, Jaime DeSantiago, Timothy L. Domeier, Katsuhiko Mikoshiba, John N. Lorenz, Lothar A. Blatter, Donald M. Bers, Jeffery D. Molkentin
Journal: Circulation Research (2010)

Rationale: Inositol 1,4,5-trisphosphate (IP 3 ) is a second messenger that regulates intracellular Ca 2+ release through IP 3 receptors located in the sarco(endo)plasmic reticulum of cardiac myocytes. Many prohypertrophic G protein–coupled receptor (GPCR) signaling events lead to IP 3 liberation, although its importance in transducing the hypertrophic response has not been established in vivo. Objective: Here, we generated conditional, heart-specific transgenic mice with both gain- and loss-of-function for IP 3 receptor signaling to examine its hypertrophic growth effects following pathological and physiological stimulation. Methods and Results: Overexpression of the mouse type-2 IP 3 receptor (IP 3 R2) in the heart generated mild baseline cardiac hypertrophy at 3 months of age. Isolated myocytes from overexpressing lines showed increased Ca 2+ transients and arrhythmias in response to endothelin-1 stimulation. Although low levels of IP 3 R2 overexpression failed to augment/synergize cardiac hypertrophy following 2 weeks of pressure-overload stimulation, such levels did enhance hypertrophy following 2 weeks of isoproterenol infusion, in response to Gαq overexpression, and/or in response to exercise stimulation. To inhibit IP 3 signaling in vivo, we generated transgenic mice expressing an IP 3 chelating protein (IP 3 -sponge). IP 3 -sponge transgenic mice abrogated cardiac hypertrophy in response to isoproterenol and angiotensin II infusion but not pressure-overload stimulation. Mechanistically, IP 3 R2-enhanced cardiac hypertrophy following isoproterenol infusion was significantly reduced in the calcineurin-Aβ–null background. Conclusion: These results indicate that IP 3 -mediated Ca 2+ release plays a central role in regulating cardiac hypertrophy downstream of GPCR signaling, in part, through a calcineurin-dependent mechanism.
Serial levels of CA 19-9 and CEA in colonic cancer.
Authors: B H Novis, E Gluck, P Thomas, G D Steele, V R Zurawski, R Stewart, P T Lavin, N Zamcheck
Journal: Journal of Clinical Oncology (1986)

The use of serial carbohydrate antigen (CA) 19-9 assays was assessed by comparison with serial carcino-embryonic antigen (CEA) levels on the plasmas of 53 patients with colorectal carcinoma. The patients had all undergone resection for their primary tumors and in six instances subsequent resections for hepatic metastases. Initial CA 19-9 levels were greater than or equal to 37 U/mL in 22 of the 53 patients (41%) and in 68% of the patients with metastatic disease. Similar trends of serial CA 19-9 and CEA levels were found in 79% of the 53 patients. One patient with initially normal CEA levels had elevated CA 19-9 levels from the start. In ten of the 53 patients (19%), serial CA 19-9 levels remained low despite tumor recurrence or progression, and despite increasing CEA levels above 5 ng/mL. The increasing serial CEA trends predicted recurrence in 88% and increasing CA 19-9 trends in 50% of cases, which was increased to 70% by including trends of CA 19-9 levels below 37 U/mL. Following hepatic lobectomy, both serial CEA and CA 19-9 levels decreased rapidly. Used alone, serial CA 19-9 levels did not appear to be as sensitive as standard CEA in this retrospective study of selected patients.
Evolution of the WANCY region in amniote mitochondrial DNA.
Authors: G Seutin, B F Lang, D P Mindell, R Morais
Journal: Molecular Biology and Evolution (1994)

In most vertebrate mitochondrial genomes, the site for initiation of light-strand replication, OL, is found within a cluster of five transfer RNA (tRNA) genes (tRNA(Trp), tRNA(Ala), tRNA(Asn), tRNA(Cys), and tRNA(Tyr)). This region and part of the adjacent cytochrome c oxydase subunit I (COI) gene were sequenced for two crocodilian, two turtle, and one snake species and for Sphenodon punctatus; part of the adjacent nicotinamide adenine dinucleotide dehydrogenase subunit 2 (ND2) gene was also sequenced for the crocodilian and turtle species. All had the typical vertebrate gene order. The turtles and the snake have a lengthy noncoding sequence between the tRNA(Asn) and tRNA(Cys) genes that we assumed to be homologous to the mammalian OL. The crocodilians and Sphenodon lack such a sequence, a condition they share with birds. Most proposed phylogenies for the amniotes require that OL at this position was lost at least twice during their diversification or was evolved independently more than once. Within the five tRNA genes, frequencies of substitutions are much higher in loops than in stems. Many loops vary dramatically in size among the species; in the most extreme case, the D-arm of the Sphenodon tRNA(Cys) is a "D-arm replacement" loop of seven nucleotides. Frequency of transitions in stems is relatively uniform across tRNAs, but frequency of transversions varies greatly. Mismatches in stems are infrequent, and their relative frequency in a specific tRNA is unrelated to the frequency of substitution in the corresponding gene. Several features of mammalian mitochondrial tRNAs are conserved in WANCY tRNAs throughout amniotes. The inferred initiation codon for COI is GTG in crocodilians, turtles, and the snake, a condition they share with fishes, certain amphibians, and birds. TTG appears to be the initiation codon for COI in Sphenodon; if correct, this would be a novel initiation codon for vertebrate mitochondrial DNA. Phylogenetic analyses of the inferred amino acid sequences of ND2 and COI support the sister-group relationship of birds and crocodilians and suggest that mammals are an early derived lineage within the amniotes.
A sum greater than its parts
Authors: Janice M. Leung, S.F. Paul Man
Journal: European Respiratory Journal (2014)

The pursuit of the perfect biomarker in chronic obstructive pulmonary disease (COPD) has been fraught with peril. The dream, of course, is of a single, accessible and inexpensive laboratory test that can more accurately diagnose COPD, define its severity, or fluctuate in accordance with disease progression and remission. In its ideal form, it would allow for earlier diagnosis of disease or earlier identification of the most severely affected patients, all with high sensitivity and specificity. Or it would properly indicate to a physician whether a particular COPD treatment has worked or failed. One only has to look to cardiology and its use of the troponin assay for the diagnosis of a myocardial infarction or to nephrology and its reliance on creatinine as a measure of renal function for such examples. If a similar biomarker is realised in COPD, it would significantly bolster what we can now predict through spirometry alone [1]. However, 20 years of painstaking research has led us no closer to this Holy Grail of biomarkers. To date, not one blood-based biomarker has reached meaningful clinical significance in COPD. Even the most promising candidates like C-reactive protein and fibrinogen, both of which have been shown to at least predict mortality in COPD, are nonspecific and lack the ability to distinguish manifestations of COPD from other inflammatory disorders [2, 3]. Pneumoproteins like surfactant protein D and club cell secretory protein, which are primarily produced in the lung, could theoretically circumvent these limitations. However, only weak associations have been found between …
Adjuvant Tamoxifen Prescription in Women 65 Years and Older With Primary Breast Cancer
Authors: Rebecca A. Silliman, Edward Guadagnoli, William Rakowski, Mary Beth Landrum, Timothy L. Lash, Robert Wolf, Aliza Fink, Patricia A. Ganz, Jerry Gurwitz, Catherine Borbas, Vincent Mor
Journal: Journal of Clinical Oncology (2002)

PURPOSE: We examined patterns of adjuvant tamoxifen discussion and prescription among breast cancer patients age 65 years and older. METHODS: We selected from women diagnosed with primary breast cancer those with (1) stage I (tumor diameter ≥ 1 cm), stage II, or stage IIIa disease; (2) age 65 years or older on the date of diagnosis; and (3) permission from the attending physician to contact. Data were collected from consenting patients’ medical records, telephone interviews with patients, and mailed questionnaires completed by their physicians. RESULTS: We obtained medical record and interview data for 698 patients. The oldest patients (odds ratio [OR], 0.45; 95% confidence interval [CI], 0.23 to 0.87 for those aged 80+ relative to those aged 65 to 69 years old), those with more comorbid conditions (each additional comorbid condition reduced the odds of discussion by 0.84; 95% CI, 0.73 to 0.96), and those who were estrogen receptor–negative (OR, 0.56; 95% CI, 0.32 to 0.99) were less likely to report discussion of tamoxifen therapy with a physician. Older patients (OR, 2.17; 95% CI, 1.18 to 4.01 for 70- to 79-year-olds relative to 65- to 69-year-olds; OR, 2.44; 95% CI, 1.11 to 5.34 for those aged 80+ relative to those aged 65 to 69 years old), those who reported a greater influence of information about tamoxifen on decision-making (an increase in 1 SD increased the odds by 7.43; 95% CI, 4.36 to 12.65), and those whose physicians believed that the benefits of tamoxifen outweighed its risks (an increase in 1 SD increased the odds by 1.87; 95% CI, 1.34 to 2.62) were more likely to be prescribed tamoxifen. CONCLUSION: These findings highlight the key role of communication in the care of older women with breast cancer and its ultimate influence on the receipt of therapy.
Thalidomide derivative CC-4047 inhibits osteoclast formation by down-regulation of PU.1
Authors: Gülsüm Anderson, Margarete Gries, Noriyoshi Kurihara, Tadashi Honjo, Judy Anderson, Vera Donnenberg, Albert Donnenberg, Irene Ghobrial, Markus Y. Mapara, David Stirling, David Roodman, Suzanne Lentzsch
Journal: Blood (2005)
Total Systemic Autoregulation in the Dog and Its Inhibition by Baroreceptor Reflexes
Authors: A. James LIEDTKE, CHARLES W. URSCHEL, EDWARD S. KIRK
Journal: Circulation Research (1973)

Although many organs maintain constant blood flow despite changes in perfusion pressure, autoregulation in the total systemic circulation has only been reported in animals after destruction of the central nervous system. The present study examined the role of the baroreceptors in this autoregulatory response in open-chest dogs anesthetized with chloralose-urethane. Cardiac output was varied over nearly a twofold range by altering myocardial contractility with either inotropic agents or controlled myocardial ischemia. Cardiac output, determined by dye dilution, and mean aortic pressure stabilized within 3 minutes after the start of infusions of calcium (15-62 mg/min) into the cannulated left coronary artery or the reduction of coronary flow. With bilateral vagotomy and carotid sinus denervation, autoregulation of total peripheral flow was observed. Thus, changes in cardiac output evoked parallel changes in total peripheral resistance and wide variations in aortic pressure. However, with the baroreceptors intact, changes in cardiac output evoked inverse changes in total peripheral resistance which resulted in regulation of aortic pressure. We concluded that autoregulation in peripheral vascular beds could result in autoregulation of total peripheral flow after simple baroreceptor denervation. However, the baroreceptor reflexes normally achieved regulation of aortic pressure by inhibiting autoregulation in much of the peripheral circulation.
Perinatal mortality and neonatal survival in Avon: 1976-9.
Authors: L M Mutch, N J Brown, B D Speidel, P M Dunn
Journal: BMJ (1981)

A study of perinatal and neonatal mortality figures for all 36 810 infants born to Avon residents during 1976-9 reported by year of birth and in relation to birth weight, gestational age, and th presence of lethal malformation showed the need for reporting mortality data for normally formed infants weighing 1000 g or more at birth and for assessing perinatal morbidity as well as mortality when attempting to evaluate the standard of perinatal care and the resources required to provide for it.
Hsp27 Associates with Actin and Limits Injury in Energy Depleted Renal Epithelia
Authors: Scott K. Van Why, Andrea S. Mann, Thomas Ardito, Gunilla Thulin, Sarah Ferris, Megan A. Macleod, Michael Kashgarian, Norman J. Siegel
Journal: Journal of the American Society of Nephrology (2003)

The purpose of the study was to determine whether Hsp27 interacts with actin and could protect against selected manifestations of injury from energy depletion in renal epithelia. LLC-PK1 cells were stably transfected to overexpress human Hsp27 tagged with green fluorescence protein (GFP). Transfected expression of the labeled Hsp27 did not reduce endogenous Hsp25 levels in the cells compared with either nontransfected cells or cells transfected with GFP alone used as the transfectant control (G). By fluorescence energy transfer (FRET) between GFP-tagged Hsp27 and rhodamine phalloidin-decorated actin, minimal interaction was found in uninjured control cells. In ATP-depleted cells, Hsp27 was associated closely with F-actin at lateral cell boundaries and with aggregated actin within the cell body. Less Hsp27 interaction with actin was found during recovery; but when adjusted for total phalloidin fluorescence, FRET between Hsp27 and F-actin did not change between 2-h ATP depletion and 4-h recovery. Where Hsp27 association with actin persisted during recovery, it was principally with the residual aggregates of actin in the cell body. Detachment of Na,K-ATPase from the cytoskeleton at 2-h ATP depletion was significantly less in Hsp27 cells compared with transfectant control G cells but not at 4-h ATP depletion. Detachment of ezrin from the cytoskeleton during ATP depletion was nearly complete and was not prevented in the Hsp27 cells. Protection of the Hsp27 cells was not attributable to preservation of cellular ATP levels. Hsp27 appears to have specific actions in renal epithelia subjected to energy depletion, including interacting with actin to preserve architecture in specific intracellular domains.
Where Is the Patient in Diabetes Performance Measures?
Authors: Russell E. Glasgow, Malinda Peeples, Soren E. Skovlund
Journal: Diabetes Care (2008)

Health policies are important determinants of clinician and patient behavior, and an important policy issue is what items are included in healthcare quality and performance measures. There is consensus that patient-centered care and self-management support are essential evidence-based components of good diabetes care. However, most major diabetes performance measures such as the National Committee for Quality Assurance (NCQA)/American Diabetes Association (ADA) Provider Recognition Program indexes have not included self-management or psychosocial items.We review the case for and propose a set of patient-centered, self-management indicators to be included as a standard part of diabetes quality indicators. The proposed indicators include: patient self-management goal(s), measures of health behaviors (e.g., healthy eating, medication taking, physical activity, and smoking status), quality of life, and patient-centered collaborative care. We discuss the evidence and the concerns about patient-report measures and summarize successful incorporation of such patient-centered measures in other countries and by the American Association of Diabetes Educators (AADE).The adage that "what gets measured, gets done" applies to diabetes management and many other areas of healthcare. Inclusion of the proposed indicators in national diabetes performance measures would be consistent with Institute of Medicine (IOM), ADA, Centers for Disease Control (CDC), Diabetes Attitudes, Wishes, and Needs (DAWN), AADE, and Society of Behavioral Medicine (SBM) recommendations. Such action would enhance both the priority and delivery of quality, patient-centered care, and diabetes self-management support.
THE IN VITRO DIFFERENTIATION OF MONONUCLEAR PHAGOCYTES
Authors: Zanvil A. Cohn, James G. Hirsch, Martha E. Fedorko
Journal: The Journal of Experimental Medicine (1966)

The structure of unstimulated mouse peritoneal phagocytes has been examined by electron microscopy and compared to cells obtained from the inflamed peritoneum and from cultures maintained in vitro. The unstimulated cell resembles the blood monocyte and contains a moderate amount of rough surfaced endoplasmic reticulum, a small but well defined Golgi apparatus and a few, small, electron-opaque granules in the cytoplasm. During in vitro cultivation there are marked changes in cell ultrastructure. Most prominent is the formation of large electron-opaque granules, some of which have a complex matrix containing both electron-opaque and lucent vesicles. In addition, there is an increase in size of the Golgi apparatus with the appearance of new lamellae and tiny, smooth surfaced vesicles. With continued cultivation, large lipid droplets are found in apposition to the rough endoplasmic reticulum. The formation and size of electron-opaque granules as well as the enlargement of the Golgi region is stimulated by high concentrations of serum in the medium. Cells obtained from the peritoneal cavity of lipopolysaccharide stimulated animals demonstrated changes in ultrastructure similar to those seen in cells cultured in vitro.
Efficacy and Safety of TachoSil ® as Haemostatic Treatment versus Standard Suturing in Kidney Tumour Resection: A Randomised Prospective Study
Authors: Stefan Siemer, Sven Lahme, Stefan Altziebler, Stefan Machtens, Walter Strohmaier, Hans-W. Wechsel, Peter Goebell, Nicolaus Schmeller, Ralph Oberneder, Jens-Uwe Stolzenburg, Hermann Becker, Werner Lüftenegger, Vilhelm Tetens, Hein Van Poppel
Journal: European Urology (2007)
Early transduction produces highly functional chimeric antigen receptor-modified virus-specific T-cells with central memory markers: a Production Assistant for Cell Therapy (PACT) translational application
Authors: Jiali Sun, Leslie E Huye, Natalia Lapteva, Maksim Mamonkin, Manasa Hiregange, Brandon Ballard, Olga Dakhova, Darshana Raghavan, April G Durett, Serena K Perna, Bilal Omer, Lisa A Rollins, Ann M Leen, Juan F Vera, Gianpietro Dotti, Adrian P Gee, Malcolm K Brenner, Douglas G Myers, Cliona M Rooney
Journal: Journal for ImmunoTherapy of Cancer (2015)

<h3>Background</h3> Virus-specific T-cells (VSTs) proliferate exponentially after adoptive transfer into hematopoietic stem cell transplant (HSCT) recipients, eliminate virus infections, then persist and provide long-term protection from viral disease. If VSTs behaved similarly when modified with tumor-specific chimeric antigen receptors (CARs), they should have potent anti-tumor activity. This theory was evaluated by Cruz et al. in a previous clinical trial with CD19.CAR-modified VSTs, but there was little apparent expansion of these cells in patients. In that study, VSTs were gene-modified on day 19 of culture and we hypothesized that by this time, sufficient T-cell differentiation may have occurred to limit the subsequent proliferative capacity of the transduced T-cells. To facilitate the clinical testing of this hypothesis in a project supported by the NHLBI-PACT mechanism, we developed and optimized a good manufacturing practices (GMP) compliant method for the early transduction of VSTs directed to Epstein-Barr virus (EBV), Adenovirus (AdV) and cytomegalovirus (CMV) using a CAR directed to the tumor-associated antigen disialoganglioside (GD2). <h3>Results</h3> Ad-CMVpp65-transduced EBV-LCLs effectively stimulated VSTs directed to all three viruses (triVSTs). Transduction efficiency on day three was increased in the presence of cytokines and high-speed centrifugation of retroviral supernatant onto retronectin-coated plates, so that under optimal conditions up to 88% of tetramer-positive VSTs expressed the GD2.CAR. The average transduction efficiency of early-and late transduced VSTs was 55 ± 4% and 22 ± 5% respectively, and early-transduced VSTs maintained higher frequencies of T cells with central memory or intermediate memory phenotypes. Early-transduced VSTs also had higher proliferative capacity and produced higher levels of T<sub>H</sub>1 cytokines IL-2, TNF-α, IFN-γ, MIP-1α, MIP-1β and other cytokines <i>in vitro</i>. <h3>Conclusions</h3> We developed a rapid and GMP compliant method for the early transduction of multivirus-specific T-cells that allowed stable expression of high levels of a tumor directed CAR. Since a proportion of early-transduced CAR-VSTs had a central memory phenotype, they should expand and persist <i>in vivo</i>, simultaneously protecting against infection and targeting residual malignancy. This manufacturing strategy is currently under clinical investigation in patients receiving allogeneic HSCT for relapsed neuroblastoma and B-cell malignancies (NCT01460901 using a GD2.CAR and NCT00840853 using a CD19.CAR).
Interventions to promote adherence to antiretroviral therapy in Africa: a network meta-analysis
Authors: Edward J Mills, Richard Lester, Kristian Thorlund, Maria Lorenzi, Katherine Muldoon, Steve Kanters, Sebastian Linnemayr, Robert Gross, Yvette Calderon, K Rivet Amico, Harsha Thirumurthy, Cynthia Pearson, Robert H Remien, Lawrence Mbuagbaw, Lehana Thabane, Michael H Chung, Ira B Wilson, Albert Liu, Olalekan A Uthman, Jane Simoni, David Bangsberg, Sanni Yaya, Till Bärnighausen, Nathan Ford, Jean B Nachega
Journal: The Lancet HIV (2014)
Pulmonary Toxicity Associated with Bischloroethylnitrosourea (BCNU)
Authors: JOHN R. DURANT
Journal: Annals of Internal Medicine (1979)

Ten patients developed pulmonary fibrosis after bischloroethylnitrosourea (BCNU) therapy for malignancy. This was lethal in seven patients, four of whom had no evidence of tumor at autopsy. Presenting symptoms were either the insidious onset of cough and dyspnea or the sudden onset of respiratory failure. Physical findings were unremarkable. Chest roentgenogram usually showed interstitial infiltrates. Pulmonary function studies showed resting hypoxia with diffusion and restrictive defects. This complication of therapy does not appear to be dose related and may be made more likely by the concomitant administration of cyclophosphamide. Prednisone therapy did not benefit most patients. The literature and the implications of the use of BCNU alone or in combination are reviewed.