tbuckley/cabot-search huggingface dataset:
The Poly(ADP-ribose) Polymerase-1-regulated Endonuclease DNAS1L3 Is Required for Etoposide-induced Internucleosomal DNA Fragmentation and Increases Etoposide Cytotoxicity in Transfected Osteosarcoma Cells
Authors: A. Hamid Boulares, Anna J. Zoltoski, Zaki A. Sherif, Alexander G. Yakovlev, Mark E. Smulson
Journal: Cancer Research (2002)

The cytotoxic effect of the chemotherapeutic drug etoposide (VP-16) is thought to result from its ability to induce DNA damage and thereby to trigger apoptosis. Internucleosomal DNA fragmentation occurs late during apoptosis in many cell types. However, whereas human osteosarcoma cells undergo internucleosomal DNA fragmentation during staurosporine-induced apoptosis, they fail to do so in response to VP-16. Recently, we showed that these cells also do not express the poly(ADP-ribosyl)ation-regulated Ca(2+)- and Mg(2+)-dependent endonuclease DNAS1L3. The possibility that this deficiency underlies the failure of these cells to undergo internucleosomal DNA fragmentation in response to VP-16 was investigated. The proteolytic processing and consequent activation of procaspase-3, cleavage of the inhibitory subunit of DNA fragmentation factor, and the degradation of DNA into 50-kb fragments occurred similarly in osteosarcoma cells exposed to either staurosporine or VP-16. However, the additional processing of the 50-kb DNA fragments to oligonucleosomal fragments was not apparent in the VP-16-treated cells. Ectopic expression of DNAS1L3 conferred on osteosarcoma cells the ability to undergo VP-16-induced internucleosomal DNA fragmentation. Furthermore, expression of DNAS1L3 markedly potentiated the cytotoxic effect of VP-16 in these cells. Both DNAS1L3-mediated and staurosporine-induced internucleosomal DNA fragmentation were Ca(2+) dependent, but only the DNAS1L3-mediated DNA cleavage was blocked by expression of a caspase-3-resistant mutant of poly(ADP-ribose) polymerase-1. The present work results suggest a direct relation between the activity of a chemotherapeutic drug (VP-16) and a specific endonuclease (DNAS1L3). They also indicate that internucleosomal DNA fragmentation plays an active role in apoptosis and that the failure of cancer cells to undergo such DNA degradation may contribute to the development of resistance to chemotherapeutic drugs.
PRECURSOR NAEVI IN CUTANEOUS MALIGNANT MELANOMA: A PROPOSED NOMENCLATURE
Authors: MarkH Greene, WallaceH Clark, MargaretA Tucker, DavidE Elder, KennethH Kraemer, MaryC Fraser, EdwardE Bondi, Dupont Guerry, Ralph Tuthill, Ralph Hamilton, Donato Larossa
Journal: The Lancet (1980)
Cd47 (Integrin-Associated Protein) Engagement of Dendritic Cell and Macrophage Counterreceptors Is Required to Prevent the Clearance of Donor Lymphohematopoietic Cells
Authors: Bruce R. Blazar, Frederik P. Lindberg, Elizabeth Ingulli, Angela Panoskaltsis-Mortari, Per-Arne Oldenborg, Koho Iizuka, Wayne M. Yokoyama, Patricia A. Taylor
Journal: The Journal of Experimental Medicine (2001)

Integrin-associated protein (CD47) is a broadly expressed protein that costimulates T cells, facilitates leukocyte migration, and inhibits macrophage scavenger function. To determine the role of CD47 in regulating alloresponses, CD47(+/+) or CD47(-/-) T cells were infused into irradiated or nonconditioned major histocompatibility complex disparate recipients. Graft-versus-host disease lethality was markedly reduced with CD47(-/-) T cells. Donor CD47(-/-) T cells failed to engraft in immunodeficient allogeneic recipients. CD47(-/-) marrow was unable to reconstitute heavily irradiated allogeneic or congenic immune-deficient CD47(+/+) recipients. These data suggested that CD47(-/-) T cells and marrow cells were cleared by the innate immune system. To address this hypothesis, dye-labeled CD47(-/-) and CD47(+/+) lymphocytes or marrow cells were infused in vivo and clearance was followed. Dye-labeled CD47(-/-) cells were engulfed by splenic dendritic cells and macrophages resulting in the clearance of virtually all CD47(-/-) lymphohematopoietic cells within 1 day after infusion. Host phagocyte-depleted CD47(+/+) recipients partially accepted allogeneic CD47(-/-) T cells. Thus, dendritic cells and macrophages clear lymphohematopoietic cells that have downregulated CD47 density. CD47 expression may be a critical indicator for determining whether lymphohematopoietic cells will survive or be cleared.
Surveillance for Hospital Outbreaks of Invasive Group A Streptococcal Infections in Ontario, Canada, 1992 to 2000
Authors: Nick Daneman, Karen A. Green, Donald E. Low, Andrew E. Simor, Barbara Willey, Benjamin Schwartz, Baldwin Toye, Peter Jessamine, Gregory J. Tyrrell, Sigmund Krajden, Lee Ramage, David Rose, Ruth Schertzberg, Delena Bragg, Allison McGeer
Journal: Annals of Internal Medicine (2007)

Background: Streptococcus pyogenes can cause severe disease in the individual patient and dramatic hospital outbreaks. Objective: To describe the epidemiology of hospital outbreaks of invasive group A streptococcal infection in order to understand the potential benefit of proposed outbreak investigation and management strategies. Design: Prospective, population-based surveillance. Setting: Short-term care hospitals in Ontario, Canada. Patients: Persons with a positive culture for group A streptococcus from a normally sterile site between 1 January 1992 and 31 December 2000. Measurements: Laboratory-based surveillance identified patients with nosocomial invasive group A streptococcal infection. Epidemiologic and microbiological investigations were used to detect transmission. Results: Of 2351 cases of invasive group A streptococcal disease, 291 (12%) were hospital acquired. Twenty-nine (10%) nosocomial cases occurred as part of 20 outbreaks. Seventy percent (14 of 20) of outbreaks involved nonsurgical, nonobstetric patients. Community-acquired cases initiated 25% of outbreaks; most were cases of necrotizing fasciitis in patients admitted to the intensive care unit. Outbreaks were small (median, 2 cases [range, 2 to 10 cases]) and short (median duration, 6 days [range, 0 to 30 days]). The median time between the first 2 cases was 4.5 days. The most common mode of propagation was patient-to-patient transmission. A staff carrier was the primary mode of transmission in 2 (10%) outbreaks, but 1 or more health care workers were colonized with the outbreak strain in 6 of 18 (33%) other outbreaks. Limitations: Some outbreaks with 1 case of invasive disease may have been missed; advice provided to participating hospitals may have reduced the number and size of outbreaks. Conclusions: Practices to prevent hospital transmission of group A streptococci should include isolation of patients admitted to the intensive care unit with necrotizing fasciitis, investigation after a single nosocomial case, and emphasis on identifying and treating health care worker carriers on surgical and obstetric services and patient reservoirs on other wards. *For members of the Ontario Group A Streptococcal Study Group, see the Appendix.
ABC of child abuse. Role of the child psychiatry team.
Authors: A. R. Nicol
Journal: BMJ (1989)

In summary, a child psychiatrist can make an important contribution to the management of child abuse. At least one child psychiatrist in each district should take an interest in this work and should be given the time to do so. As for other professionals, child abuse is an aspect of the work of child psychiatrists that is particularly harrowing and time consuming.
Early Expression of Negative/Disorganized Symptoms Predicting Psychotic Experiences and Subsequent Clinical Psychosis: A 10-Year Study
Authors: Maria-de-Gracia Dominguez, Meram Can Saka, Roselind Lieb, Hans-Ulrich Wittchen, Jim van Os
Journal: American Journal of Psychiatry (2010)

Objective: The cognitive and motivational impairments observed in psychotic disorders may reflect early developmental alterations that, when combined with later environmental exposures, may drive the onset of positive psychotic symptoms. The epidemiological predictions of this model were tested. Method: A longitudinal prospective cohort study (the Early Developmental Stages of Psychopathology Study) was conducted with a representative general population sample of adolescents and young adults from Munich (N=3,021), who were 14–24 years of age at baseline. Sociodemographic factors, environmental exposures, and measures of psychopathology and associated clinical relevance were assessed across three waves, covering a period of up to 10 years, by clinical psychologists using the Composite International Diagnostic Interview. Results: Both negative/disorganized and positive psychotic symptoms were frequent (5-year cumulative prevalence rates of around 12%) and occurred in combination more often than predicted by chance. Negative/disorganized symptoms revealed a pattern of sociodemographic associations indicative of developmental impairment, whereas the positive symptoms were associated with environmental exposures such as trauma, cannabis use, and urbanicity. Negative/disorganized symptoms predicted positive symptoms over time, and co-occurrence of positive and negative/disorganized symptoms was predictive of clinical relevance in terms of secondary functional impairment and help-seeking behavior. Conclusion: The results suggest that the negative/disorganized features associated with psychotic disorder are distributed at the population level and drive the ontogenesis of positive psychotic experiences after exposure to environmental risks, increasing the likelihood of impairment and need for care.
Using plasma topotecan pharmacokinetics to estimate topotecan exposure in cerebrospinal fluid of children with medulloblastoma1
Authors: Burgess B. Freeman, Lisa C. Iacono, John C. Panetta, Amar Gajjar, Clinton F. Stewart
Journal: Neuro-Oncology (2006)

The purpose of this study was to estimate ventricular cerebrospinal fluid (vCSF) topotecan lactone (TPT) exposures in pediatric medulloblastoma patients from plasma concentration-time data by using a pharmacokinetic (PK) model. We studied children with high–risk medulloblastoma who received pharmacokinetically guided TPT (target plasma area under the concentration-time curve [AUC], 120-160 ng/ml–h) and obtained serial vCSF samples to assess TPT exposure. Population pharmacokinetic parameters were determined by using linear mixed–effects modeling via the two–stage approach. We simulated TPT vCSF exposure duration at plasma TPT AUC values of 120 to 200 ng/ml–h and determined percentages of studies meeting or exceeding the vCSF exposure duration threshold (EDT) of 1 ng/ml for 8 h. We then used bootstrap methods to estimate variability in vCSF EDT. Eighteen PK studies were conducted in six patients (median age, 4.8 years). In these patients, seven of nine studies attaining target plasma TPT AUC achieved the vCSF EDT. Given a plasma TPT AUC of 120 ng/ml–h, the median percentage of results meeting or exceeding EDT was 78% (95% CI, 61%-100%). One patient (four studies) with tumor blockage of CSF flow, which can alter CSF pharmacokinetics, was removed, and the bootstrap analysis was repeated. In this subset, a median 93% (95% CI, 79%-100%) of studies achieved vCSF EDT. Increasing plasma TPT AUC values resulted in increased ability to achieve vCSF EDT. We demonstrated that a plasma PK model could estimate vCSF TPT concentrations. Further, our results indicate that the TPT vCSF EDT can be achieved in more than 80% of studies targeted to a plasma TPT AUC of 120 ng/ml–h.
Molecular Pathways: Targeting P21-Activated Kinase 1 Signaling in Cancer—Opportunities, Challenges, and Limitations
Authors: Jeyanthy Eswaran, Da-Qiang Li, Anil Shah, Rakesh Kumar
Journal: Clinical Cancer Research (2012)

Abstract The evolution of cancer cells involves deregulation of highly regulated fundamental pathways that are central to normal cellular architecture and functions. p21-activated kinase 1 (PAK1) was initially identified as a downstream effector of the GTPases Rac and Cdc42. Subsequent studies uncovered a variety of new functions for this kinase in growth factor and steroid receptor signaling, cytoskeleton remodeling, cell survival, oncogenic transformation, and gene transcription, largely through systematic discovery of its direct, physiologically relevant substrates. PAK1 is widely upregulated in several human cancers, such as hormone-dependent cancer, and is intimately linked to tumor progression and therapeutic resistance. These exciting developments combined with the kinase-independent role of PAK1-centered phenotypic signaling in cancer cells elevated PAK1 as an attractive drug target. Structural and biochemical studies revealed the precise mechanism of PAK1 activation, offering the possibility to develop PAK1-targeted cancer therapeutic approaches. In addition, emerging reports suggest the potential of PAK1 and its specific phosphorylated substrates as cancer prognostic markers. Here, we summarize recent findings about the PAK1 molecular pathways in human cancer and discuss the current status of PAK1-targeted anticancer therapies. Clin Cancer Res; 18(14); 3743–9. ©2012 AACR.
Clinical Pharmacodynamic Effects of the Growth Hormone Receptor Antagonist Pegvisomant: Implications for Cancer Therapy
Authors: Donghua Yin, Franzanne Vreeland, Larry J. Schaaf, Robert Millham, Barbara A. Duncan, Amarnath Sharma
Journal: Clinical Cancer Research (2007)

Abstract Purpose: The present study evaluated and compared the efficacy of pegvisomant and octreotide in blocking the growth hormone (GH) axis in humans based on pharmacodynamic biomarkers associated with the GH axis. The study also evaluated the safety of pegvisomant given at high s.c. doses for 14 days. Experimental Design: Eighty healthy subjects were enrolled in five cohorts: cohorts 1 to 3, s.c. pegvisomant at 40, 60, or 80 mg once daily × 14 days (n = 18 per cohort); cohort 4, s.c. octreotide at 200 μg thrice daily × 14 days (n = 18); and cohort 5, untreated control (n = 8). Serial blood samples were collected to measure plasma concentrations of total insulin-like growth factor type I (IGF-I), free IGF-I, IGF-II, IGF-binding protein 3 (IGFBP-3), and GH in all subjects and serum pegvisomant concentrations in subjects of cohorts 1 to 3. All subjects receiving treatment were monitored for adverse events (AE). Results: After s.c. dosing of pegvisomant once daily for 14 days, the mean maximum suppression values of total IGF-I were 57%, 60%, and 62%, at 40, 60, and 80 mg dose levels, respectively. The maximum suppression was achieved ∼7 days after the last dose and was sustained for ∼21 days. Pegvisomant also led to a sustained reduction in free IGF-I, IGFBP-3, and IGF-II concentrations by up to 33%, 46%, and 35%, respectively, and an increase in GH levels. In comparison, octreotide resulted in a considerably weaker inhibition of total IGF-I and IGFBP-3 for a much shorter duration, and no inhibition of IGF-II. AEs in pegvisomant-treated subjects were generally either grade 1 or 2. The most frequent treatment-related AEs included injection site reactions, headache, and fatigue. Conclusions: Pegvisomant at well-tolerated s.c. doses was considerably more efficacious than octreotide in suppressing the GH axis, resulting in substantial and sustained inhibition of circulating IGF-I, IGF-II, and IGFBP-3 concentrations. These results provide evidence in favor of further testing the hypothesis that pegvisomant, through blocking the GH receptor–mediated signal transduction pathways, could be effective in treating tumors that may be GH, IGF-I, and/or IGF-II dependent, such as breast and colorectal cancer.
Prostaglandin biosynthesis by rabbit renomedullary interstitial cells in tissue culture. Stimulation by angiotensin II, bradykinin, and arginine vasopressin.
Authors: R M Zusman, H R Keiser
Journal: Journal of Clinical Investigation (1977)

Rabbit renomedullary interstitial cells were isolated and grown in tissue culture. These cells synthesize 0.8 ng of prostaglandin E2 (PGE2) per microgram cellular protein per hour in monolayer tissue culture; prostaglandins A2 and F2alpha (PGA2 and PGF2alpha) biosynthesis was 10 and 5% of PGE2 biosynthesis, respectively. Arachidonic acid markedly stimulated the production of PGE2 and PGF2alpha, with conversion rates of 0.24 and 0.02%/h, respectively. Angiotensin II, hyperosmolality, bradykinin, and arginine vasopressin each stimulated PGE2 biosynthesis; maximum stimulation was 20, 3.7, 3.6, and 3.2 times basal production, respectively. PGE2 biosynthesis by the renomedullary interstitial cells was inhibited by isoproterenol, potassium, nonsteroidal anti-inflammatory agents (indomethacin, naproxen, ibuprofen, suprofen, meclofenamate, and acetylsalicylic acid), mepacrine (a phospholipase inhibitor), hydrocortisone, and cortisone. The rabbit renomedullary interstitial cell in tissue culture is a model system for the study of hormonal regulation of PGE2 biosynthesis.
Alarmins S100A8/S100A9 aggravate osteophyte formation in experimental osteoarthritis and predict osteophyte progression in early human symptomatic osteoarthritis
Authors: R F P Schelbergen, W de Munter, M H J van den Bosch, F P J G Lafeber, A Sloetjes, T Vogl, J Roth, W B van den Berg, P M van der Kraan, A B Blom, P L E M van Lent
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Introduction</h3> Extracorporeal cardiopulmonary resuscitation (eCPR) is increasingly applied in out-of-hospital cardiac arrest (OHCA) and in-hospital cardiac arrest (IHCA) patients. Treatment results are promising, but the efficacy and safety of the procedure are still unclear. Currently, there are no recommended target perfusion parameters during eCPR, the lack of which could result in inadequate (re)perfusion. We aim to perform a scoping review to explore the current literature addressing target perfusion parameters, target values, corresponding survival rates and neurologic outcomes in OHCA and IHCA patients treated with eCPR. <h3>Methods and analysis</h3> To identify relevant research, we will conduct searches in the electronic databases MEDLINE, EMBASE, Social Science Citation Index, Social Science Citation Index Expanded and the Cochrane library. We will also check references of relevant articles and perform a cited reference research (forward citation tracking). Two independent reviewers will screen titles and abstracts, check full texts for eligibility and perform data extraction. We will resolve dissent by consensus, moderated by a third reviewer. We will include observational and controlled studies addressing target perfusion parameters and outcomes such as survival rates and neurologic findings in OHCA and IHCA patients treated with eCPR. Data extraction tables will be set up, including study and patients' characteristics, aim of study, details on eCPR including target perfusion parameters and reported outcomes. We will summarise the data using tables and figures (ie, bubble plot) to present the research landscape and to describe potential clusters and/or gaps. <h3>Ethics and dissemination</h3> An ethical approval is not needed. We intend to publish the scoping review in a peer-reviewed journal and present results on a scientific meeting.
Prolonged remission in Caucasian patients with SLE: prevalence and outcomes
Authors: Margherita Zen, Luca Iaccarino, Mariele Gatto, Silvano Bettio, Linda Nalotto, Anna Ghirardello, Leonardo Punzi, Andrea Doria
Journal: Annals of the Rheumatic Diseases (2015)

To assess the prevalence of prolonged remission in Caucasian patients affected with systemic lupus erythematosus (SLE) and its relationship with damage accrual.Caucasian patients diagnosed with SLE between 1990 and 2009 and quarterly seen from 2009 to 2013 were included in the study. We defined remission as prolonged when lasting ≥5 consecutive years. Three levels of remission were defined using the SLE Disease Activity Index-2000 (SLEDAI-2K): complete remission: no disease activity in corticosteroid-free and immunosuppressant-free patients; clinical remission off corticosteroids: serologically active clinical quiescent (SACQ) disease in corticosteroid-free patients and clinical remission on corticosteroids: SACQ disease in patients taking prednisone 1-5 mg/day. Damage was measured by the SLICC/American College of Rheumatology Damage Index (SDI).224 patients fulfilled inclusion criteria: 196 (87.5%) were women, mean±SD disease duration 11.2±6.8 years. During the 5-year follow-up, 16 patients (7.1%) achieved prolonged complete remission, 33 (14.7%) prolonged clinical remission off corticosteroids and 35 (15.6%) prolonged clinical remission on corticosteroids. At the multivariate analysis, vasculitis (OR 4.95), glomerulonephritis (OR 2.38) and haematological manifestations (OR 2.19) over the patients' disease course were associated with an unremitted disease. SDI increased more frequently in unremitted (72/140, 51.4%) than in remitted patients (22/84, 26.2%; p=0.001); SDI median increase was higher in unremitted than in remitted patients: 1 (0-3) vs 0 (0-2), respectively (p<0.001). At multivariate analysis, unremitted disease (OR 2.52) and high-dose corticosteroid intake (OR 2.35) were risk factors for damage accrual.Thirty-seven percent of our Caucasian patients achieved a prolonged remission, which was associated with a better outcome in terms of damage accrual.
Baseline ventilatory function predicts the development of higher levels of fasting insulin and fasting insulin resistance index: the Normative Aging Study
Authors: R Lazarus, D Sparrow, ST Weiss
Journal: European Respiratory Journal (1998)

A consistent but as yet unexplained association between baseline ventilatory function and risk of coronary heart disease (CHD) has been reported from many prospective studies. Insulin-resistant states are associated with increased risk of CHD. Forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and maximal mid-expiratory flow rate (MMEF) at study entry were examined as predictors for indirect measures of insulin resistance after a mean follow-up interval of 20.9 yrs in 1050 nondiabetic male subjects in the Normative Aging Study. Males in the top quintile of insulin or fasting insulin resistance index (FIRI) levels at follow-up were defined as being relatively insulin resistant. FVC was negatively associated with risk of being relatively insulin resistant using the insulin (p=0.002) or FIRI (p=0.0001) criteria at follow-up in logistic regression models adjusting for baseline age, body mass index, fat distribution pattern and cigarette smoking. Similar associations were found for FEV1 and MMEF. Additional adjustment for baseline postcarbohydrate challenge glucose levels made little difference to the results, suggesting that baseline glucose intolerance was not a significant source of bias. These findings are consistent with the possibility that insulin resistance may be one of the factors mediating the previously unexplained prospective association between impairment of ventilatory function and risk of mortality from coronary heart disease.