tbuckley/cabot-search huggingface dataset:
Akt-Mediated Cisplatin Resistance in Ovarian Cancer: Modulation of p53 Action on Caspase-Dependent Mitochondrial Death Pathway
Authors: Xiaokui Yang, Michael Fraser, Ute M. Moll, Ajoy Basak, Benjamin K. Tsang
Journal: Cancer Research (2006)

Abstract Akt is a determinant of cisplatin [cis-diammine-dichloroplatinum (CDDP)] resistance in ovarian cancer cells, and this may be related to the regulation of p53. Precisely how Akt facilitates CDDP resistance and interacts with p53 is unclear. Apoptotic stimuli induce second mitochondria-derived activator of caspase (Smac) release from mitochondria into the cytosol, where it attenuates inhibitor of apoptosis protein–mediated caspase inhibition. Whereas Smac release is regulated by p53 via the transactivation of proapoptotic Bcl-2 family members, it is unclear whether p53 also facilitates Smac release via its direct mitochondrial activity. Here we show that CDDP induces mitochondrial p53 accumulation, the mitochondrial release of Smac, cytochrome c, and HTR/Omi, and apoptosis in chemosensitive but not in resistant ovarian cancer cells. Smac release was p53 dependent and was required for CDDP-induced apoptosis. Mitochondrial p53 directly induced Smac release. Akt attenuated mitochondrial p53 accumulation and Smac/cytochrome c/Omi release and conferred resistance. Inhibition of Akt facilitated Smac release and sensitized chemoresistant cells to CDDP in a p53-dependent manner. These results suggest that Akt confers resistance, in part, by modulating the direction action of p53 on the caspase-dependent mitochondrial death pathway. Understanding the precise etiology of chemoresistance may improve treatment for ovarian cancer. (Cancer Res 2006; 66(6): 3126-36)
Quantitative measurement of syndesmophyte volume and height in ankylosing spondylitis using CT
Authors: Sovira Tan, Jianhua Yao, John A Flynn, Lawrence Yao, Michael M Ward
Journal: Annals of the Rheumatic Diseases (2013)

Objective Syndesmophyte growth in ankylosing spondylitis can be difficult to measure using radiographs because of poor visualisation and semiquantitative scoring methods. We developed and tested the reliability and validity of a new computer-based method that fully quantifies syndesmophyte volumes and heights on CT scans. Methods In this developmental study, we performed lumbar spine CT scans on 38 patients and used our algorithm to compute syndesmophyte volume and height in four intervertebral disk spaces. To assess reliability, we compared results between two scans performed on the same day in nine patients. To assess validity, we compared computed measures to visual ratings of syndesmophyte volume and height on both CT scans and radiographs by two physician readers. Results Coefficients of variation for syndesmophyte volume and height, based on repeat scans, were 2.05% and 2.40%, respectively. Based on Bland–Altman analysis, an increase in syndesmophyte volume of more than 4% or in height of more than 0.20 mm represented a change greater than measurement error. Computed volumes and heights were strongly associated with physician ratings of syndesmophyte volume and height on visual examination of both the CT scans (p&lt;0.0001) and plain radiographs (p&lt;0.002). Syndesmophyte volumes correlated with the Schober test (r=−0.48) and lateral thoracolumbar flexion (r=−0.60). Conclusions This new CT-based method that fully quantifies syndesmophytes in three-dimensional space had excellent reliability and face and construct validity. Given its high precision, this method shows promise for longitudinal clinical studies of syndesmophyte development and growth.
Management of sharps injuries in the healthcare setting
Authors: Anna Riddell, Ioana Kennedy, C Y William Tong
Journal: BMJ (2015)

The function of the heart is essential hypertension and its response to sympathetic stimulation remain to be clarified. The effects of activation of the adrenergic system in isolated rat atria as well as the contractility of the tissue were examined in the present study. Contractile force exerted at various lengths and at equivalent resting tensions by preparations from hypertensive animals was either comparable to controls or only slightly reduced. Furthermore, increases in contractility initiated by paired stimulation were not significantly different in the two groups. Sympathetic activation by field stimulation and administration of tyramine caused comparable increases in contractile force in both groups, attesting to the integrity of the peripheral sympathetic nervous system. Norepinephrine also produced similar responses in both types of preparations. It is concluded that sensitivity to peripheral sympathetic activation is normal in atria derived from hypertensive animals.
Influenza virus-induced lung injury: pathogenesis and implications for treatment
Authors: Susanne Herold, Christin Becker, Karen M. Ridge, G.R. Scott Budinger
Journal: European Respiratory Journal (2015)

The influenza viruses are some of the most important human pathogens, causing substantial seasonal and pandemic morbidity and mortality. In humans, infection of the lower respiratory tract of can result in flooding of the alveolar compartment, development of acute respiratory distress syndrome and death from respiratory failure. Influenza-mediated damage of the airway, alveolar epithelium and alveolar endothelium results from a combination of: 1) intrinsic viral pathogenicity, attributable to its tropism for host airway and alveolar epithelial cells; and 2) a robust host innate immune response, which, while contributing to viral clearance, can worsen the severity of lung injury. In this review, we summarise the molecular events at the virus–host interface during influenza virus infection, highlighting some of the important cellular responses. We discuss immune-mediated viral clearance, the mechanisms promoting or perpetuating lung injury, lung regeneration after influenza-induced injury, and recent advances in influenza prevention and therapy.
The Use of Chelated Radionuclide (Samarium-153-Ethylenediaminetetramethylenephosphonate) to Modulate Phenotype of Tumor Cells and Enhance T Cell–Mediated Killing
Authors: Mala Chakraborty, Elizabeth K. Wansley, Jorge A. Carrasquillo, Sarah Yu, Chang H. Paik, Kevin Camphausen, Michael D. Becker, William F. Goeckeler, Jeffrey Schlom, James W. Hodge
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Exposing human tumor cells to sublethal doses of external beam radiation up-regulates expression of tumor antigen and accessory molecules, rendering tumor cells more susceptible to killing by antigen-specific CTLs. This study explored the possibility that exposure to palliative doses of a radiopharmaceutical agent could alter the phenotype of tumor cells to render them more susceptible to T cell–mediated killing. Experimental Design: Here, 10 human tumor cell lines (4 prostate, 2 breast, and 4 lung) were exposed to increasing doses of the radiopharmaceutical samarium-153-ethylenediaminetetramethylenephosphonate (153Sm-EDTMP) used in cancer patients to treat pain due to bone metastasis. Fluorescence-activated cell sorting analysis and quantitative real-time PCR analysis for expression of five surface molecules and several tumor-associated antigens involved in prostate cancer were done. LNCaP human prostate cancer cells were exposed to 153Sm-EDTMP and incubated with tumor-associated antigen-specific CTL in a CTL killing assay to determine whether exposure to 153Sm-EDTMP rendered LNCaP cells more susceptible to T cell–mediated killing. Results: Tumor cells up-regulated the surface molecules Fas (100% of cell lines up-regulated Fas), carcinoembryonic antigen (90%), mucin-1 (60%), MHC class I (50%), and intercellular adhesion molecule-1 (40%) in response to 153Sm-EDTMP. Quantitative real-time PCR analysis revealed additional up-regulated tumor antigens. Exposure to 153Sm-EDTMP rendered LNCaP cells more susceptible to killing by CTLs specific for prostate-specific antigen, carcinoembryonic antigen, and mucin-1. Conclusions: Doses of 153Sm-EDTMP equivalent to palliative doses delivered to bone alter the phenotype of tumor cells, suggesting that 153Sm-EDTMP may work synergistically with immunotherapy to increase the susceptibility of tumor cells to CTL killing.
In Vitro Evidence for Homologous Recombinational Repair in Resistance to Melphalan
Authors: Z.-M. Wang, Z.-P. Chen, Z.-Y. Xu, G. Christodoulopoulos, V. Bello, G. Mohr, R. Aloyz, L. C. Panasci
Journal: JNCI Journal of the National Cancer Institute (2001)

Background: The generation of DNA interstrand cross-links is thought to be important in the cytotoxicity of nitrogen mustard alkylating agents, such as melphalan, which have antitumor activity. Cell lines with mutations in recombinational repair pathways are hypersensitive to nitrogen mustards. Thus, resistance to melphalan may require accelerated DNA repair by either recombinational repair mechanisms involving Rad51-related proteins (including x-ray repair cross-complementing proteins Xrcc2, Xrcc3, and Rad52) or by nonhomologous endjoining involving DNA-dependent protein kinase (DNA-PK) and Ku proteins. We investigated the role of DNA repair in melphalan resistance in epithelial tumor cell lines. Methods: Melphalan cytotoxicity was determined in 14 epithelial tumor cell lines by use of the sulforhodamine assay. Homologous recombinational repair involving Rad51-related proteins was investigated by determining the levels of Rad51, Rad52, and Xrcc3 proteins and the density of nuclear melphalan-induced Rad51 foci, which represent sites of homologous recombinational repair. Nonhomologous endjoining was investigated by determining the levels of Ku70 and Ku86 proteins and DNA-PK activity. Linear regression analysis was used to analyze correlations between the various protein levels, DNA-PK activity, or Rad51 foci formation and melphalan cytotoxicity. All statistical tests were two-sided. Results: Melphalan resistance was correlated with Xrcc3 levels (r = .587; P = .027) and the density of melphalan-induced Rad51 foci (r = .848; P = .008). We found no correlation between melphalan resistance and Rad51, Rad52, or Ku protein levels or DNA-PK activity. Conclusion: Correlations of melphalan resistance in epithelial tumor cell lines with Xrcc3 protein levels and melphalan-induced Rad51 foci density suggest that homologous recombinational repair is involved in resistance to this nitrogen mustard.
Genetic aspects of female reproduction
Authors: J. Collins, K. Diedrich, S. Franks, J. P. M. Geraedts, P. A. Jacobs, B. Karges, S. Kennedy, A. Marozzi, L. Regan, D. T. Baird, P. G. Crosignani, P. Devroey, E. Diczfalusy, J. L. H. Evers, B. C. J. M. Fauser, L. Fraser, L. Gianaroli, A. Glasier, I. Liebaers, G. Ragni, A. Sunde, B. Tarlatzis, A. Van Steirteghem
Journal: Human Reproduction Update (2008)

BACKGROUNDSexual reproduction provides the means for preserving genetic identity and in turn, genetic variability may affect the ability to reproduce. This review aims to summarize current research on genetic diagnosis and genetic causes of reproductive disorders.
Exhaled nitric oxide is reduced in infants with cystic fibrosis
Authors: H E Elphick, E A G Demoncheaux, S Ritson, T W Higenbottam, M L Everard
Journal: Thorax (2001)

<h3>BACKGROUND</h3> Exhaled nitric oxide levels are low in patients with cystic fibrosis (CF), despite the chronic inflammation present in the airways. This study aimed to determine whether levels of exhaled nitric oxide were reduced prior to the onset of respiratory symptoms in infants with CF. <h3>METHODS</h3> The levels of exhaled nitric oxide were measured using a chemiluminescence analyser in five infants with CF and 11 healthy control subjects, both groups having a mean age of 48.6 days. <h3>RESULTS</h3> Mean levels of exhaled nitric oxide were significantly lower in infants with CF than in the control group (4.9 ppb <i>v</i> 12.1 ppb; p=0.01). <h3>CONCLUSIONS</h3> This finding may be the key to understanding the inflammatory processes in early cystic fibrosis and may lead to novel treatment approaches.
Crohn's disease and colorectal cancer.
Authors: C D Gillen, H A Andrews, P Prior, R N Allan
Journal: Gut (1994)

The colorectal cancer risk in Crohn9s disease eliminating all known biases was assessed in a cohort of 281 patients with Crohn9s disease who resided in the West Midlands at the time of diagnosis, and were first seen within five years of onset of symptoms between 1945-1975. All patients were 15 years of age or more at onset and were followed up from 12-35 years (total 5213 person years at risk (PYR)). The colorectal cancer risk in the series compared with the risk in the general population was computed by applying sex and age specific PYRs to the date of death or end of the study period 31 December 1991. There were six colonic and two rectal cancers. Six of the eight colorectal cancers were diagnosed 20 or more years after the onset of Crohn9s disease. The relative risk (RR) of colorectal cancer for the series as a whole was 3.4 (p &lt; 0.001), with a fivefold excess in the colon, but no significant excess in the rectum. Patients with extensive colitis showed an 18-fold increase in risk (RR = 18.2, p &lt; 0.001), which decreased with increasing age at onset. This study shows that there is a statistical excess risk of developing colorectal cancer in patients who develop their Crohn9s disease at a young age of onset (less than 30 years of age).
Process-Based Measures of Quality: The Need for Detailed Clinical Data in Large Health Care Databases
Authors: R. Heather Palmer
Journal: Annals of Internal Medicine (1997)

The Institute of Medicine defines health care quality as increasing "the likelihood of desired health outcomes" using "services ... consistent with current professional knowledge." This definition implies that quality measures can be based on either achieving health care outcomes or completing processes that experts agree have been shown by scientific evidence to improve outcomes. Process-based measures are especially suitable when the user needs to know how to improve quality, when provider comparisons show equivalent outcomes but all providers should improve processes, when measures are needed to evaluate health care that is intended to improve long-term outcomes, or when the contribution of individual providers (especially providers who have a small number of cases) needs to be defined. However, many different process-based measures are needed to comprehensively assess quality, and many process-based measures require detailed clinical data currently found only in medical records. Therefore, the expense of abstracting records is a barrier to process-based measurement. Fortunately, large-scale process-based measures are becoming more feasible because the required clinical data are being included in large databases. The merging of existing inpatient and outpatient databases with pharmacy and laboratory databases is an important step toward obtaining data that link all patient admissions, appointments, diagnostic procedures, and prescriptions with diagnoses and test results. Other data that are valuable for process-based measures must still be obtained by abstracting data from records, including clinical findings, patient preferences, and medical and family history. In the future, such data may be added to large databases to create computerized medical records.
Animal models for arrhythmias
Authors: D MILAN, C MACRAE
Journal: Cardiovascular Research (2005)

The complex pathophysiology of human arrhythmias has proven difficult to model. Direct correlations between the traditional arrhythmia mechanisms, including abnormal excitability, conduction, or repolarization and underlying molecular or cellular biology are poorly defined, as the primary etiologies of many human arrhythmias remain unknown. Since the causes of several arrhythmic syndromes have been identified, genetic models reproducing the mechanisms of these arrhythmias have become feasible. Initial murine modeling has revealed that in many cases the pathophysiology of the respective human disease is more complex than had been suspected. Insights from human genetic studies and animal models strongly suggest that the primary molecular defects may contribute at many stages in the causal chain leading to arrhythmia. The comprehensive analysis of each arrhythmia will require knowledge not only of the membrane effects of the primary defects, but also downstream intracellular signals, the developmental results of these perturbations, and the integration of compensatory responses and environmental factors. Precise modeling will require not only the mutation of specific residues in known disease genes, but also the systematic study of each of the many steps in arrhythmogenesis. Ultimately, such models will enable unbiased screens for disease mechanisms and novel therapies.
Endothelial Progenitor Cells Are Decreased in Blood of Cardiac Allograft Patients With Vasculopathy and Endothelial Cells of Noncardiac Origin Are Enriched in Transplant Atherosclerosis
Authors: David Simper, Shaohua Wang, Arjun Deb, David Holmes, Christopher McGregor, Robert Frantz, Sudhir S. Kushwaha, Noel M. Caplice
Journal: Circulation (2003)

Recent studies in animals suggest that circulating recipient endothelial precursors may participate in the biology of transplant vasculopathy. It is currently unknown whether a similar interaction between recipient endothelial cells and the vessel wall occurs in human subjects undergoing allogeneic cardiac transplantation.Circulating endothelial cells and endothelial progenitor cells (EPCs) were quantified in 15 cardiac transplantation subjects with and without angiographic evidence of vasculopathy. In a separate series of experiments, the origin (donor or recipient) of transplant plaque endothelial cells was assessed in subjects who had undergone a gender-mismatched cardiac transplantation and had histological evidence of severe vasculopathy at the time of heart explantation. Circulating EPC outgrowth colonies in peripheral blood were significantly reduced in subjects with transplant vasculopathy compared with those without angiographic evidence of disease (EPC colony-forming units [CFUEPC]: 4.5+/-1.9 versus 15.1+/-3.7, P<0.05). There was no significant difference in circulating endothelial cell numbers as defined by day 4 culture acetylated LDL/lectin assay in either of these patient groups. In a separate group of 5 subjects who underwent gender-mismatched cardiac transplantation, there was a significant seeding of recipient endothelial cells (range: 1% to 24% of all luminal endothelial cells) in large-vessel lumen and adventitial microvessel lumen of arteriopathic vessels. No opposite-sex chimeric cells were observed in control gender-matched transplantation scenarios.These data suggest that the human cardiac transplant arteriopathy is associated with reduction in circulating endothelial precursors and with seeding of recipient-derived endothelial cells at the site of plaque development.
Reliability of home respiratory polygraphy monitoring for diagnosis of sleep apnea/hypopnea syndrome (SAHS) in children
Authors: María-Luz Alonso-Alvarez, Joaquin Teran-Santos, Jose-Aurelio Cordero-Guevara, Estrella Ordax-Carbajo, Ana-Isabel Navazo-Egüia
Journal: European Respiratory Journal (2013)

Polysomnography (PSG) performed in a sleep laboratory is the currently accepted technique for the diagnosis of sleep apnea/hipopnea syndrome (SAHS) in children. Respiratory Polygraphy (RP) in children has been validated in the sleep laboratory.

AIM:

To evaluate the reliability diagnostic of home respiratory Polygraph (HRP) in children with a clinical suspicion of SAHS.

Methods:

Cross-sectional study. We included children aged 2 to 14 years, of both sexes, with clinical suspicion of SAHS. The whole group underwent clinical history, physical examination, a first home respiratory polygraphy (HRP) and between 1 and 2 weeks later underwent a second RP and PSG in the same night in sleep laboratory.

We calculated Respiratory disturbance index (RDI), Obstructive respiratory disturbance index (oRDI) Obstructive Apnea-Hypopneas index (oAHI).

Intraclass correlation coefficients (ICC), Bland-Altman plots and receiver operator curves (ROC) were calculated for statistical analysis.

Results: We studied 27 boys and 23 girls with a mean age of 5.3 (SD: 2.55). 39 (78%), 33 (66%), 26 (52%) were diagnosed of SAHS, when RDI≥ 3, oRDI≥ 3 and OAHI≥3 were take as diagnosis of SAHS. The mean RDI was 13.92 (SD16, 57), 14.46 (SD: 13.23), 16.47 (SD: 15.32) in the PSG, Home RP, RP at laboratory respectively.

The area under ROC curve for RDI ≥ 3, oRDI≥ 3 and OAHI≥3 in the laboratory RP were 93.5 (85.5 - 1), 96.8 (92.1 - 1), 95. 5 (90.6 - 1) and in the HRP were 93.5 (86.8 - 1), 93.9 (87.0 - 1), 92.9 (85.9 - 1) respectively.

Conclusions:

Home Respiratory Poligraphy is a useful technique for diagnosis of SAHS in children.

Funded:Ministry of health Castilla – Leon and SEPAR.
Mesothelin-specific CD8+ T Cell Responses Provide Evidence of In Vivo Cross-Priming by Antigen-Presenting Cells in Vaccinated Pancreatic Cancer Patients
Authors: Amy Morck Thomas, Lynn M. Santarsiero, Eric R. Lutz, Todd D. Armstrong, Yi-Cheng Chen, Lan-Qing Huang, Daniel A. Laheru, Michael Goggins, Ralph H. Hruban, Elizabeth M. Jaffee
Journal: The Journal of Experimental Medicine (2004)

Tumor-specific CD8+ T cells can potentially be activated by two distinct mechanisms of major histocompatibility complex class I–restricted antigen presentation as follows: direct presentation by tumor cells themselves or indirect presentation by professional antigen-presenting cells (APCs). However, controversy still exists as to whether indirect presentation (the cross-priming mechanism) can contribute to effective in vivo priming of tumor-specific CD8+ T cells that are capable of eradicating cancer in patients. A clinical trial of vaccination with granulocyte macrophage–colony stimulating factor–transduced pancreatic cancer lines was designed to test whether cross-presentation by locally recruited APCs can activate pancreatic tumor-specific CD8+ T cells. Previously, we reported postvaccination delayed-type hypersensitivity (DTH) responses to autologous tumor in 3 out of 14 treated patients. Mesothelin is an antigen demonstrated previously by gene expression profiling to be up-regulated in most pancreatic cancers. We report here the consistent induction of CD8+ T cell responses to multiple HLA-A2, A3, and A24-restricted mesothelin epitopes exclusively in the three patients with vaccine-induced DTH responses. Importantly, neither of the vaccinating pancreatic cancer cell lines expressed HLA-A2, A3, or A24. These results provide the first direct evidence that CD8 T cell responses can be generated via cross-presentation by an immunotherapy approach designed to recruit APCs to the vaccination site.
Peer review: Agreement and disagreement
Authors: Domenic V. Cicchetti
Journal: Behavioral and Brain Sciences (1996)

Rl In response to Somit &amp; Peterson's call for multiple journal manuscript submissions, and consistent with Cicchetti (1991a and 1991b), counterarguments are presented. The policy for multiple submissions is difficult to defend scientifically ana would place an unwarranted burden on both reviewers and journal editors. As such the policy is again rejected. R2 As earlier hypothesized, referee agreement on manuscripts submitted to a major journal in chemistry was significantly higher for acceptance than for rejection. This is consistent with the high acceptance rate (&gt;70%) of this journal. There is significantly more referee agreement on rejection than on acceptance for manuscripts submitted to major journals, in behavioral science and medicine. These journals have high rejection rates (often &gt;70%).