tbuckley/cabot-search huggingface dataset:
Inhibitors of poly (ADP-ribose) synthetase protect rat cardiomyocytes against oxidant stress
Authors: J Bowes
Journal: Cardiovascular Research (1999)

Objective: Inhibitors of poly (ADP-ribose) synthetase (PARS) activity reduce the infarct size caused by regional myocardial ischaemia and reperfusion in the rabbit and rat in vivo. The mechanism of action of these inhibitors is unclear. Here we investigate the effects of the PARS inhibitor 3-aminobenzamide (3-AB) on infarct size caused by ischaemia and reperfusion of the isolated, perfused heart of the rat. We also investigate the role of PARS in the hydrogen peroxide-mediated cell injury/necrosis in rat cardiac myoblasts. Methods: Rat isolated hearts perfused at constant pressure (80 mmHg) were subjected to 35 min of regional ischaemia and 2 h of reperfusion. Infarct size was determined at the end of the experiment using nitro-blue tetrazolium. 3-AB (300 μM) or 3-aminobenzoic acid (3-ABA, 300 μM) were infused during the reperfusion period. Rat cardiac myoblasts (H9c2 cells) were preincubated with the PARS inhibitors, 3-AB, nicotinamide (Nic) or 1,5-dihydroxyisoquinoline (ISO) or the inactive analogues 3-ABA or nicotinic acid (NicA) prior to exposure with hydrogen peroxide (1 mM). Cell injury was assessed by measuring mitochondrial respiration and cell necrosis by measuring the release of LDH. PARS activity was determined by measuring the incorporation of NAD into nuclear proteins. Results: Regional ischaemia and reperfusion of the isolated rat heart resulted in an infarct size of 54% which was reduced by 3-AB, but not by 3-ABA. Exposure of rat cardiac myoblasts to hydrogen peroxide caused an increase in PARS activity and cell injury/necrosis which was attenuated by pretreatment with the PARS inhibitors. Conclusion: Inhibition of the activity of PARS attenuates the cell death associated with oxidant stress in rat cardiac myoblasts and heart.
The World Bank: false financial and statistical accounts and medical malpractice in malaria treatment
Authors: Amir Attaran, Karen I Barnes, Roger Bate, Fred Binka, Umberto d'Alessandro, Caterina I Fanello, Laurie Garrett, Theonest K Mutabingwa, Donald Roberts, Carol Hopkins Sibley, Ambrose Talisuna, Jean-Pierre Van geertruyden, William M Watkins
Journal: The Lancet (2006)
The Microcirculation: Introduction to the Spotlight Issue
Authors: A. M. Lefer, G. W. Schmid-Schonbein
Journal: Cardiovascular Research (1996)

The last decade has witnessed an unparalleled increase in interest in the investigation of the microcirculation.The microcirculation is known as the 'business end of the circulatory system' and is the location where early manifestations of disease are encountered.Nevertheless, it is only in recent years with the advent of new techniques applied to the microcirculation including intravital microscopy, specific fluorescent cell markers, monoclonal antibodies, immunohistochemistry, imaging systems, and molecular genetics that this explosion in knowledge was able to occur.It is in light of these methodological advances that a new wave of interest in the biochemistry, biophysics, physiology, and pathophysiology of the microcirculation has occurred.This was the setting in which Professor David J. Hearse, previous editor of' Cardiovascular Research, proposed that we edit a Spotlight Issue on MICROCIRCULATION for Cardiocasculur Research in 1996.We have therefore set out to invite many of the leading scholars in this field to draft a recent updated review of selected topics representing
Targeted Therapies for Renal Cell Carcinoma: Review of Adverse Event Management Strategies
Authors: T. Eisen, C. N. Sternberg, C. Robert, P. Mulders, L. Pyle, S. Zbinden, H. Izzedine, B. Escudier
Journal: JNCI Journal of the National Cancer Institute (2012)

With the advent of targeted agents for the treatment of renal cell carcinoma (RCC), overall survival has improved, and patients are being treated continuously for increasingly long periods of time. This has raised challenges in the management of adverse events (AEs) associated with the six targeted agents approved in RCC—sorafenib, sunitinib, pazopanib, bevacizumab (in combination with interferon alpha), temsirolimus, and everolimus. Suggestions for monitoring and managing AEs have been published, but there are few consensus recommendations. In addition, there is a risk that patients will be subjected to multiple unnecessary investigations. In this review, we aimed to identify the level of supporting evidence for suggested AE management strategies to provide practical guidance on essential monitoring and management that should be undertaken when using targeted agents. Five databases were systematically searched for relevant English language articles (including American Society of Clinical Oncology abstracts) published between January 2007 and March 2011; European Society of Medical Oncology congress abstracts were hand searched. Strategies for AE management were summarized and categorized according to the level of recommendation. A total of 107 articles were identified that describe a large number of different investigations for monitoring AEs and interventions for AE management. We identify and summarize clear recommendations for the management of dermatologic, gastrointestinal, thyroid, cardiovascular, and other AEs, based predominantly on expert opinion. However, because the evidence for the suggested management strategies is largely anecdotal, there is a need for further systematic investigation of management strategies for AEs related to targeted therapies for RCC.
Evidence for somatic selection of natural autoantibodies.
Authors: T Martin, S F Duffy, D A Carson, T J Kipps
Journal: The Journal of Experimental Medicine (1992)

Natural autoantibodies are primarily immunoglobulin M (IgM) antibodies that bind to a variety of self-antigens, including self-IgG. Accounting for a large proportion of the early B cell repertoire, such polyspecific autoantibodies are speculated to contribute to the homeostasis and/or competence of the primary humoral immune system. Recent studies indicate that the leukemia cells from most patients with chronic lymphocytic leukemia (CLL) also express such IgM autoantibodies. Similarly, the leukemia cells from many CLL patients react with murine monoclonal antibodies (mAbs) specific for crossreactive idiotypes (CRIs) associated with human IgM autoantibodies. In particular, leukemic cells frequently react with G6, a mAb specific for an Ig heavy chain (H chain)-associated CRI, and/or with 17.109, a mAb that defines a kappa light chain (L chain)-associated CRI. Generated against IgM rheumatoid factor (RF) paraproteins, G6 and 17.109 each recognize a major CRI that is present in many IgM RF paraproteins. Furthermore, over 90% of the IgM paraproteins found to bear both H and L chain-associated CRIs also are found to have RF activity. Molecular characterization of these CRIs demonstrates that each is a serologic marker for expression of a highly conserved Ig V gene. As such, the frequent production of IgM polyspecific autoantibodies in CLL simply may reflect the frequent use of such highly conserved autoantibody-encoding Ig V genes with little or no somatic mutation. To test this hypothesis, we generated murine transfectomas to pair the 17.109-reactive kappa L chain of SMI, a 17.109/G6-reactive CLL population, with the Ig H chain of SMI or other G6-reactive leukemia cells or tonsillar lymphocytes. Cotransfection of vectors encoding the Ig H and L chains of SMI generated transfectomas that produce IgM kappa RF autoantibodies reactive with human IgG1 and IgG4. In contrast to G6/17.109-reactive IgM kappa RF Waldenstrom's paraproteins, the SMI IgM kappa also reacts with several other self-antigens, including myoglobin, actin, and ssDNA. However, cotransfection of the SMI L chain with a vector encoding any one of 10 different G6-reactive Ig H chains generated transfectomas that produce IgM kappa antibodies without detectable polyspecific autoantibody activity. These results indicate that polyspecific antiself-reactivity of G6/17.019-reactive Ig is dependent on the somatically generated Ig third complementarity determining region. Collectively, these studies imply that selection may be responsible for the frequent expression of polyspecific autoantibodies in CLL and early B cell ontogeny.
MicroRNA-9 induces defective trafficking of Nav1.1 and Nav1.2 by targeting Navβ2 protein coding region in rat with chronic brain hypoperfusion
Authors: Li-Hua Sun, Mei-Ling Yan, Xue-Ling Hu, Li-Wei Peng, Hui Che, Ya-Nan Bao, Fei Guo, Tong Liu, Xin Chen, Rong Zhang, Tao Ban, Ning Wang, Huai-Lei Liu, Xu Hou, Jing Ai
Journal: Molecular Neurodegeneration (2015)

Previous studies have demonstrated that the trafficking defects of Nav1.1/Nav1.2 are involved in the dementia pathophysiology. However, the detailed mechanisms are not fully understood. Moreover, whether the impaired miRNAs regulation linked to dementia is a key player in sodium channel trafficking disturbance remains unclear. The cognitive impairment induced by chronic cerebral ischemia through chronic brain hypoperfusion (CBH) is likely reason to precede dementia. Therefore, our goal in the present study was to examine the role of microRNA-9 (miR-9) in regulating Nav1.1/Nav1.2 trafficking under CBH generated by bilateral common carotid artery occlusion (2VO). The impairment of Nav1.1/Nav1.2 trafficking and decreased expression of Navβ2 were found in the hippocampi and cortices of rats following CBH generated by bilateral 2VO. MiR-9 was increased in both the hippocampi and cortices of rats following CBH by qRT-PCR. Intriguingly, miR-9 suppressed, while AMO-miR-9 enhanced, the trafficking of Nav1.1/Nav1.2 from cytoplasm to cell membrane. Further study showed that overexpression of miR-9 inhibited the Navβ2 expression by targeting on its coding sequence (CDS) domain by dual luciferase assay. However, binding-site mutation or miR-masks failed to influence Navβ2 expression as well as Nav1.1/Nav1.2 trafficking process, indicating that Navβ2 is a potential target for miR-9. Lentivirus-mediated miR-9 overexpression also inhibited Navβ2 expression and elicited translocation deficits to cell membrane of Nav1.1/Nav1.2 in rats, whereas injection of lentivirus-mediated miR-9 knockdown could reverse the impaired trafficking of Nav1.1/Nav1.2 triggered by 2VO. We conclude that miR-9 may play a key role in regulating the process of Nav1.1/Nav1.2 trafficking via targeting on Navβ2 protein in 2VO rats at post-transcriptional level, and inhibition of miR-9 may be a potentially valuable approach to prevent Nav1.1/Nav1.2 trafficking disturbance induced by CBH.
Mutations in the cofilin partner Aip1/Wdr1 cause autoinflammatory disease and macrothrombocytopenia
Authors: Benjamin T. Kile, Athanasia D. Panopoulos, Roslynn A. Stirzaker, Douglas F. Hacking, Lubna H. Tahtamouni, Tracy A. Willson, Lisa A. Mielke, Katya J. Henley, Jian-Guo Zhang, Ian P. Wicks, William S. Stevenson, Paquita Nurden, Stephanie S. Watowich, Monica J. Justice
Journal: Blood (2007)
Comparison of diaphragm strength between healthy adult elderly and young men.
Authors: K Tolep, N Higgins, S Muza, G Criner, S G Kelsen
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

To test the hypothesis that aging is associated with a reduction in the diaphragm's force-generating capacity, we compared the maximum transdiaphragmatic pressure (Pdimax) obtained during voluntary maximal inspiratory efforts in nine young (19-28 yr) and ten elderly (65-75 yr) subjects. The relationship between Pdi and lung volume was compared in the two groups by having subjects make maximal inspiratory maneuvers at specified lung volumes (i.e., 20, 40, and 80% vital capacity). Subjects underwent symptom-limited exercise tests to characterize their aerobic capacities and evaluate the relationship between aerobic capacity and Pdimax. The average Pdimax of the elderly subjects (128 +/- 9 cm H2O) was significantly lower (p < 0.003) than the average Pdimax of the younger subjects (171 +/- 8 cm H2O). In the elderly, Pdi was lower across the range of lung volumes tested (p < 0.001), and Pdimax occurred at similar relative lung volumes (elderly, at 47% total lung capacity [TLC]; young, at 50% TLC) in both groups. The elderly subjects were quite fit based on their VO2max, and there was no significant relationship between Pdimax and VO2max. This study suggests that diaphragm strength is reduced in elderly individuals. This age-related decrease in diaphragm strength may predispose elderly patients to diaphragm fatigue in the presence of conditions that impair inspiratory muscle function or increase ventilatory load.
Recent advances in transthyretin amyloidosis therapy
Authors: Mitsuharu Ueda, Yukio Ando
Journal: Translational Neurodegeneration (2014)

Mutant (MT) forms of transthyretin (TTR) cause the most common type of autosomal-dominant hereditary systemic amyloidosis—familial amyloidotic polyneuropathy (FAP). Until 20 years ago, FAP was thought to be an endemic disease, but FAP is known to occur worldwide. To date, more than 130 mutations in the TTR gene have been reported. Genotype-phenotype correlations are seen in FAP, and some variation in clinical presentation is often observed in individual kindreds with the same mutation and even among family members. Of the pathogenic TTR mutations, Val30Met was the first to be identified and is the most frequent known mutation found throughout the world. Studies of patients with FAP amyloidogenic TTR (ATTR) Val30Met documented sensorimotor polyneuropathy, autonomic dysfunction, heart and kidney failure, gastrointestinal tract (GI) disorders, and other symptoms leading to death, usually within 10 years of the onset of disease. Diagnosis is sometimes delayed, especially in patients without a clear family history and typical clinical manifestations, since diagnosis requires various studies and techniques such as histopathology, genetic testing, and mass spectrometry. For treatment of FAP, liver transplantation (LT) reportedly halts the progression of clinical manifestations. Exchange of an FAP patient’s diseased liver with a healthy liver causes MT TTR in the body to be replaced by wild-type (WT) TTR. Although clinical evaluations indicated that progression of other clinical symptoms such as peripheral neuropathy, GI symptoms, and renal involvement usually halted after LT in FAP ATTR Val30Met patients, recent studies suggested that LT failed to prevent progression of cardiac amyloidosis in FAP ATTR Val30Met patients after LT, with this failure reportedly being due to continued formation of amyloid that derived mainly from WT TTR secreted from the transplanted non-mutant liver graft. In recent years, many therapeutic strategies have been proposed, and several ongoing therapeutic trials involve, for example, stabilizers of TTR tetramers (tafamidis and diflunisal) and gene therapies to suppress TTR expression (antisense methods and use of small interfering RNAs). These novel therapies may prove to prevent progression of FAP.
RapidCaP, a Novel GEM Model for Metastatic Prostate Cancer Analysis and Therapy, Reveals Myc as a Driver of <i>Pten</i>-Mutant Metastasis
Authors: Hyejin Cho, Tali Herzka, Wu Zheng, Jun Qi, John E. Wilkinson, James E. Bradner, Brian D. Robinson, Mireia Castillo-Martin, Carlos Cordon-Cardo, Lloyd C. Trotman
Journal: Cancer Discovery (2014)

Genetically engineered mouse (GEM) models are a pillar of functional cancer research. Here, we developed RapidCaP, a GEM modeling system that uses surgical injection for viral gene delivery to the prostate. We show that in Pten deficiency, loss of p53 suffices to trigger metastasis to distant sites at greater than 50% penetrance by four months, consistent with results from human prostate cancer genome analysis. Live bioluminescence tracking showed that endogenous primary and metastatic disease responds to castration before developing lethal castration resistance. To our surprise, the resulting lesions showed no activation of Akt but activation of the Myc oncogene. Using RapidCaP, we find that Myc drives local prostate metastasis and is critical for maintenance of metastasis, as shown by using the Brd4 inhibitor JQ1. Taken together, our data suggest that a "MYC-switch" away from AKT forms a critical and druggable event in PTEN-mutant prostate cancer metastasis and castration resistance.
Civil Commitment for Addicts: The California Program
Authors: JOHN C. KRAMER, RICHARD A. BASS, JOHN E. BERECOCHEA
Journal: American Journal of Psychiatry (1968)

The California civil commitment program for addicts has achieved a modest degree of success. On parole, one out of three outpatients remains in good standing at the end of one year and one out of six at the end of three years. The value of even this degree of success is tempered by the problems posed by repeated incarceration and the fact that the program has been largely an alternative to jail or prison.
Dihydrotestosterone in prostatic hypertrophy
Authors: Pentti K. Siiteri, Jean D. Wilson
Journal: Journal of Clinical Investigation (1970)

To explore the relation between androgens and prostatic hypertrophy in man, the concentrations of testosterone, dihydrotestosterone, and androstenedione and the rate of conversion of testosterone to dihydrotestosterone have been measured in normal and hypertrophic prostate tissue. First, a double isotope derivative technique was adapted for the measurement of tissue androgen content in 15 normal and 10 hypertrophic prostates. Although there was no significant difference in the content of androstenedione and testosterone between the two types of tissue, the content of dihydrotestosterone was significantly greater in the hypertrophic tissue (0.60 +/-0.10 mug/100 g) than in the normal glands (0.13 +/-0.05 mug/100 g). Second, a regional study was performed in three normal prostates and four glands with early hypertrophy, and it was demonstrated that the dihydrotestosterone content was two and three fold greater in the periurethral area where prostatic hypertrophy usually commences than in the outer regions of the gland. Finally, the rate of conversion of testosterone to dihydrotestosterone has been measured under standardized conditions in tissue slices from 4 normal and 20 hypertrophic prostates. There was no significant difference in the rate of dihydrotestosterone formation between the two types of gland (6.0 +/-0.8 and 7.8 +/-0.5 mumumoles/15 mg of tissue per hr). While the mechanism by which dihydrotestosterone accumulation occurs remains unexplained, it is possible that the local accumulation of dihydrotestosterone may be involved in the pathogenesis of prostatic hypertrophy in man.
Second cancers after adjuvant tamoxifen therapy for breast cancer in Japan
Authors: Y. Matsuyama, T. Tominaga, Y. Nomura, H. Koyama, M. Kimura, M. Sano, S. Miura, S. Takashima, S. Mitsuyama, H. Ueo, Y. Ohashi
Journal: Annals of Oncology (2000)
Are Deaths Within 1 Month of Cancer-Directed Surgery Attributed to Cancer?
Authors: H. G. Welch
Journal: JNCI Journal of the National Cancer Institute (2002)

Background: Cancer mortality should include not only deaths from cancer but also deaths from cancer treatment. By convention, deaths within 30 days of a surgical procedure are considered treatment-related deaths in the calculation of operative mortality—that is, the chance of dying from surgery. How cause of death is attributed in patients who die within 1 month of cancer-directed surgery is unknown. Methods: The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program data from 1994 through 1998 were used to examine the cause of death in patients diagnosed with one of 19 common solid tumors who had died within 1 month of diagnosis and had also received cancer-directed surgery. We determined the proportion of deaths not attributed to the cancer and the magnitude of the undercount in cancer-specific mortality. Results: Among 4135 patients with only one cancer who died within 1 month of diagnosis and cancer-directed surgery, the proportion of deaths not attributed to the coded cancer was 41% (1714/4135), ranging from 13% (1/8) for cervical cancer to 81% (13/16) for laryngeal cancer. Selected intermediate values include 25% (14/56) for esophageal cancer, 34% (177/525) for lung cancer, 42% (719/1695) for colorectal cancer, 59% (110/186) for breast cancer, and 75% (80/106) for prostate cancer. Restricting the analysis to deaths following specific major procedures (e.g., esophagectomy, pneumonectomy, colectomy) had little effect on the findings. If all deaths within 1 month of cancer-directed surgery were attributed to cancer, cancer mortality would rise about 1%. Conclusion: Some deaths that are conventionally attributed to surgery are not being attributed to the cancer for which the surgery was performed. Although the estimated effect of this misclassification on overall cancer mortality is modest, it may be indicative of more widespread confusion about how to code treatment-related deaths of patients with cancer.
The absorption of arsenic and its relation to carcinoma
Authors: F.RAY BETTLEY, J.A. O'SHEA
Journal: British Journal of Dermatology (2006)

A test dose of arsenic was given to four patients with arsenical carcinoma. Blood arsenic levels, urinary and faecal excretion were measured and compared with those of three normal control subjects. Blood levels and urinary excretion were lower in the carcinoma subjects, suggesting increased storage. Abnormally high retention of arsenic, either medicinal or environmental, may be an individual metabolic trait and may be an important factor in carcinogenesis.
THE MAMMALIAN CELL-VIRUS RELATIONSHIP
Authors: Leroy C. McLaren, John J. Holland, Jerome T. Syverton
Journal: The Journal of Experimental Medicine (1959)

Primary or established strain cultures of a variety of primate cells that were susceptible to cytopathic infection strongly adsorbed poliovirus. Insusceptible non-primate cells in primary or established-strain culture did not so adsorb virus (or propagate it), with exception of the ERK-1 embryo rabbit kidney strain. All tested cells, regardless of type or susceptibility, adsorbed about 1 per cent of input virus, which became cell-associated (CAV) without loss of infectivity. In combination with susceptible or insusceptible cells, CAV was only about 90 per cent neutralized by homotypic antiserum. CAV eluted continuously from non-susceptible cells with continued incubation; eluted virus gave rise to infection and new CAV to the same degree in susceptible cells as did original virus.
Early time-limited antiretroviral therapy versus deferred therapy in South African infants infected with HIV: results from the children with HIV early antiretroviral (CHER) randomised trial
Authors: Mark F Cotton, Avy Violari, Kennedy Otwombe, Ravindre Panchia, Els Dobbels, Helena Rabie, Deirdre Josipovic, Afaaf Liberty, Erica Lazarus, Steve Innes, Anita Janse van Rensburg, Wilma Pelser, Handre Truter, Shabir A Madhi, Edward Handelsman, Patrick Jean-Philippe, James A McIntyre, Diana M Gibb, Abdel G Babiker
Journal: The Lancet (2013)