tbuckley/cabot-search huggingface dataset:
Information Technology and Manpower Productivity
Authors: G. Octo Barnett
Journal: JAMA (1969)

Technology as an aid to medical care productivity cannot be treated as an isolated phenomenon, apart from its effect on all phases of our society. Thus, the major impact of technology on the health care system has not come from modifications in medical care activities, per se, but rather from the urbanization and industrialization of America, each a result of technological innovations. For example, changes in society's travel and communication habits have placed greater emphasis on central facilities and efforts to coordinate health care delivery. Major referral centers are clearly a product of the revolution in transportation and communication. In the near future, however, technology should begin to be a truly integral part of clinical practice, and its impact probably will be at least as significant as that of the highway and telephone. In this discussion we would like to suggest that radical changes in the use of health manpower
Antitumor Activity of a Monoclonal Antibody Targeting Major Histocompatibility Complex Class I–Her2 Peptide Complexes
Authors: Rinki Jain, Amit Rawat, Bhavna Verma, Maciej M. Markiewski, Jon A. Weidanz
Journal: JNCI Journal of the National Cancer Institute (2013)

Applications of trastuzumab are limited to breast cancer patients with high Her2-expressing tumors. We developed a T-cell receptor mimic (TCRm) monoclonal antibody (hereafter called RL1B) that targets the Her2-E75 peptide (residues 369-377)-HLA-A2 complex and examined its effects in Her2-expressing cancer cells.RL1B binding affinity was determined by surface plasmon resonance and specificity was demonstrated using Her2 antigen-positive and negative tumor cell lines. Immunohistochemistry was used to assess binding to frozen sections of human carcinomas (n = 3). Antitumor activity mediated by RL1B and trastuzumab against Her2(+) tumor cell lines was evaluated using the WST-1 cell viability assay and caspase-3 and poly(ADP-ribose) polymerase cleavage assays. A xenograft mouse model (n = 6 per group) was used to assess RL1B antitumor activity. Mechanisms of RL1B-mediated cytotoxicity were evaluated with confocal microscopy, flow cytometry, and histology. All statistical tests were two-sided.RL1B bound with high specificity and affinity to the E75 peptide-HLA-A2 complex in all Her2(+) and HLA-A2(+) cancer cell lines and human carcinomas. Compared with control antibody, RL1B suppressed growth of low Her2-expressing breast tumors in mice (mean volume, RL1B vs control = 241 mm(3) vs 1531 mm(3); P = .0109) and statistically significantly increased mouse survival (P = .0098). It reduced viability compared to control monoclonal antibody-treated cells and statistically significantly increased caspase 3 activation of all Her2(+) carcinoma cell lines tested, whereas trastuzumab induced apoptosis only in high Her2-expressing cancer cells. Mechanisms of RL1B cytotoxicity were associated with antibody internalization and intracellular signaling.The TCRm RL1B could be a new approach to immunotherapy of Her2-expressing malignancies.
Global and Site-Specific Quantitative Phosphoproteomics: Principles and Applications
Authors: Boris Macek, Matthias Mann, Jesper V. Olsen
Journal: The Annual Review of Pharmacology and Toxicology (2008)

Protein phosphorylation is a key posttranslational modification, which reversibly regulates almost all processes in the living cell. Deregulated signaling is a hallmark of cancer and other diseases, and protein kinases are prominent drug targets. Phosphorylation events are commonly probed in a targeted manner by phosphorylation-specific antibodies. In contrast, advances in proteomics technology, including phosphopeptide enrichment, high-accuracy mass spectrometry, and associated bioinformatics now make it possible to analyze entire phosphoproteomes. Quantitative methods can assess the relative change in phosphorylation for several thousand sites in a single experiment. Here we review enrichment strategies and methods for mass spectrometric fragmentation and analysis of phosphopeptides. We also describe different quantitative methods and their application to problems in cell signaling and drug target discovery. Emerging phosphoproteomics technologies are becoming more comprehensive, robust, and generically applicable to a wide range of questions, including areas outside traditional eukaryotic cell signaling such as Ser/Thr/Tyr signaling in bacteria.
Selective Preservation of Pemetrexed Pharmacological Activity in HeLa Cells Lacking the Reduced Folate Carrier
Authors: Rongbao Zhao, Marie Hanscom, Shrikanta Chattopadhyay, I. David Goldman
Journal: Cancer Research (2004)

Abstract A methotrexate (MTX)-resistant HeLa subline (R5), developed in this laboratory, with impaired transport due to a genomic deletion of the reduced folate carrier (RFC) was only 2-fold resistant to pemetrexed (PMX), but 200- and 400-fold resistant to raltitrexed (ZD1694) and Nα-(-4-amino-4-deoxypteroyl)-Nδ-hemiphthaloyl-1-ornithine (PT523), respectively, compared with parental HeLa cells when grown with 2 μm folic acid. When folic acid was replaced with the more physiological 25 nm 5-formyltetrahydrofolate, R5 cells were 2-fold collaterally sensitive to PMX but still 40- and 200-fold resistant to ZD1694 and PT523, respectively. Sensitivity to PT523 and PMX could be completely restored, and sensitivity to ZD1694 nearly restored, by transfection of RFC cDNA into R5 cells, indicating that the defect in drug transport was the only, or major, factor in resistance. The preserved PMX activity in R5 cells could not be related to the very low expression of folate receptors. Rather, retained PMX activity in R5 cells was associated with residual transport by another process that exhibits good affinity for PMX (Kt = 12 μm) with much lower affinities for ZD1694, MTX, and PT523 (Kis of ∼ 90, 100, and 250 μm, respectively). PMX transported by this route was rapidly converted to higher polyglutamates and, when grown with 25 nm 5-formyl-tetrahydrofolate, the rate of formation of these derivatives and their net accumulation in R5 cells was comparable to that of wild-type cells. These data suggest that selective preservation of PMX pharmacological activity in RFC-null R5 cells is due, in part, to partial preservation of transport by secondary process with a higher affinity for PMX than the other antifolates evaluated.
Further arguments in support of localist coding in connectionist networks
Authors: Jeffrey S. Bowers
Journal: Behavioral and Brain Sciences (2000)

Two additional sources of evidence are provided in support of localist coding within connectionist networks. First, only models with localist codes can currently represent multiple pieces of information simultaneously or represent order among a set of items on-line. Second, recent priming data appear problematic for theories that rely on distributed representations. However, a faulty argument advanced by Page is also pointed out.
Is heart rate a convenient tool to monitor over-reaching? A systematic review of the literature
Authors: L Bosquet, S Merkari, D Arvisais, A E Aubert
Journal: British Journal of Sports Medicine (2008)

Objective: A meta-analysis was conducted on the effect of overload training on resting HR, submaximal and maximal exercise HR (HR), and heart rate variability (HRV), to determine whether these measures can be used as valid markers of over-reaching. Methods: Six databases were searched using relevant terms and strategies. Criteria for study inclusion were: participants had to be competitive athletes, an increased training load intervention had to be used, and all necessary data to calculate effect sizes had to be available. An arbitrary limit of 2 weeks was chosen to make the distinction between short-term and long-term interventions. Dependent variables were HR and HRV (during supine rest). Standardised mean differences (SMD) in HR or HRV before and after interventions were calculated, and weighted according to the within-group heterogeneity to develop an overall effect. Results: In these competitive athletes, short-term interventions resulted in a moderate increase in both resting HR (SMD = 0.55; p = 0.01) and low frequency/high frequency ratio (SMD = 0.52; p = 0.02), and a moderate decrease in maximal HR (SMD = −0.75; p = 0.01). Long-term interventions resulted in a small decrease in HR during submaximal (SMD = −0.38; p = 0.006) and maximal exercise (SMD = −0.33; p = 0.007), without alteration of resting values. Conclusion: The small to moderate amplitude of these alterations limits their clinical usefulness, as expected differences may fall within the day-to-day variability of these markers. Consequently, correct interpretation of HR or HRV fluctuations during the training process requires the comparison with other signs and symptoms of over-reaching to be meaningful.
Two Distinct Local Relapse Subtypes in Invasive Breast Cancer: Effect on their Prognostic Impact
Authors: Patrizia Casalini, Maria Luisa Carcangiu, Raija Tammi, Päivi Auvinen, Veli-Matti Kosma, Pinuccia Valagussa, Marco Greco, Andrea Balsari, Sylvie Ménard, Elda Tagliabue
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Local relapse (LR) remains an important concern in breast cancer surveillance. Given the unique opportunity to study local recurrences in the breast in the absence of irradiation, we tested the possibility of identifying a particular tumor feature that might account for LR. Experimental Design: Archival specimens from 235 patients belonging to the control arm (no radiotherapy) of the Milan 3 Trial were retrieved and included in this study. H&amp;E-stained histologic slides were reviewed for diagnostic reassessment. A panel of biological variables was assessed by immunohistochemical/cytochemical staining. Results: Onset of LR was significantly linked only to patient's age, with a hazard ratio (HR) to relapse reduced by 60% in patients &amp;gt;50 years of age (P = 0.002). Univariate and multivariate Cox analyses in women ≤50 years of age indicated that only expression of hyaluronan in tumor cells was associated with LR risk (HR, 2.48; P = 0.0364 and HR, 2.34; P = 0.0580, respectively). In patients &amp;gt;50 years of age, lymph node and estrogen receptor status were significantly predictive of LR (HR, 3.34; P = 0.0113 and HR, 0.39; P = 0.0424, respectively). Multivariate analysis indicated that apart from lymph node positivity (HR, 3.48; P = 0.0120), none of the variables associated with LR in univariate analysis displayed an independent LR-predictive power. LR had a strong prognostic impact on distant metastasis in patients &amp;gt;50 years of age, whereas in younger women, LR did not affect the risk of metastasis. Conclusions: These results support the notion that LR arises from two distinct mechanisms, one that is more frequent in young patients, associated with host characteristics, and is not linked with prognosis, and another that is less frequent, but is associated with tumor aggressiveness which represents a peculiar and distinct marker of breast tumor malignancy.
Human hepatocellular carcinomas with “Stemness”-related marker expression: keratin 19 expression and a poor prognosis
Authors: Haeryoung Kim, Gi Hong Choi, Deuk Chae Na, Ei Young Ahn, Gwang Il Kim, Jae Eun Lee, Jai Young Cho, Jeong Eun Yoo, Jin Sub Choi, Young Nyun Park
Journal: Hepatology (2011)

There is a recently proposed subtype of hepatocellular carcinoma (HCC) that is histologically similar to usual HCC, but characterized by the expression of "stemness"-related markers. A large-scale study on two different cohorts of HCCs was performed to investigate the clinicopathologic features and epithelial-mesenchymal transition (EMT)-related protein expression status of this subtype of HCCs. The expression status of stemness-related (e.g., keratin 19 [K19], cluster of differentiation [CD]133, epithelial cell adhesion molecule [EpCAM], and c-kit) and EMT-related markers (e.g., snail, S100A4, urokinase plasminogen activator receptor [uPAR], ezrin, vimentin, E-cadherin, and matrix metalloproteinase [MMP]2) were examined using tissue microarrays from cohort 1 HCCs (n = 137). K19 protein expression in cohort 2 HCCs (n = 237) was correlated with the clinicopathologic parameters and messenger RNA (mRNA) levels of K19, uPAR, VIL2, Snail, Slug, and Twist. K19, EpCAM, c-kit, and CD133 positivity were observed in 18.2%, 35.0%, 34.3%, and 24.8%, respectively. K19 was most frequently expressed in combination with at least one other stemness-related marker (92.0%). K19-positive HCCs demonstrated more frequent major vessel invasion and increased tumor size, compared to K19-negative HCCs (P < 0.05). K19 was most significantly associated with EMT-related protein expression (e.g., vimentin, S100A4, uPAR, and ezrin) (P < 0.05) and a poor prognosis (overall survival: P = 0.018; disease-free survival: P = 0.007) in cohort 1. In cohort 2, HCCs with high K19 mRNA levels demonstrated higher mRNA levels of Snail, uPAR, and MMP2 (P < 0.05). K19-positive HCCs demonstrated more frequent microvascular invasion, fibrous stroma, and less tumor-capsule formation, compared to K19-negative HCCs (P < 0.05). K19 expression was a significant independent predictive factor of poor disease-free survival (P = 0.032).K19 was well correlated with clinicopathologic features of tumor aggressiveness, compared to other stemness-related proteins. K19-positive HCCs showed significantly increased EMT-related protein and mRNA expression, suggesting that they may acquire more invasive characteristics, compared to K19-negative HCCs through the up-regulation of EMT-associated genes.
Action of caffeine on calcium transport by isolated fractions of myofibrils, mitochondria, and sarcoplasmic reticulum from rabbit heart.
Authors: L Blayney, H Thomas, J Muir, A Henderson
Journal: Circulation Research (1978)

We studied the effects of caffeine on calcium transport by subcellular organelles isolated from rabbit myocardium. Caffeine increased myofibrillar basic and calcium-activated ATPase activity at 20 mM but not at lower concentrations. Mitochondrial and sarcoplasmic reticulum (SR) calcium accumulation was measured both by dual wavelength spectrophotometry with the calcium-sensitive dye, murexide, and by Millipore filtration with 45Ca. In mitochondria, caffeine impaired phosphate-assisted calcium transport but did not alter the closely related parameters of oxygen uptake, P/O ratio (nmol adenosine diphosphate consumed/n ats oxygen consumed, state 3 respiration) or limited calcium loading. In SR, caffeine impaired calcium accumulation. New methods were used to characterize calcium accumulation in the absence of oxalate according to first order reaction kinetics. Caffeine increased the rate constant while decreasing the calcium accumulated. It also increased the associated calcium-activated ATPase activity at low (30 mM) but not high (240 micrometer) external calcium concentration. In the presence of oxalate, caffeine decreased the rate of calcium accumulation, more with low than high calcium concentration. Net efflux of 45Ca from preloaded SR also was increased by caffeine. The findings indicate that caffeine impairs active calcium accumulation by making SR vesicle membranes more permeable to calcium.
Longitudinal Cohort Study of Risk Factors in Cancer Patients of Bisphosphonate-Related Osteonecrosis of the Jaw
Authors: Konstantinos Vahtsevanos, Athanassios Kyrgidis, Evgenia Verrou, Eirini Katodritou, Stefanos Triaridis, Charalampos G. Andreadis, Ioannis Boukovinas, Georgios E. Koloutsos, Zisis Teleioudis, Kyriaki Kitikidou, Panagiotis Paraskevopoulos, Konstantinos Zervas, Konstantinos Antoniades
Journal: Journal of Clinical Oncology (2009)

The reported incidence of osteonecrosis of the jaw (ONJ) ranges from 0.94% to 18.6%. This cohort study aimed to calculate the incidence of and identify the risk factors for ONJ in patients with cancer treated with intravenous zoledronate, ibandronate, and pamidronate.Data analyzed included age, sex, smoking status, underlying disease, medical and dental history, bisphosphonates (BP) type, and doses administered. Relative risks, crude and adjusted odds ratios (aORs), and cumulative hazard ratios for ONJ development were calculated.We included 1,621 patients who received 29,006 intravenous doses of BP, given monthly. Crude ONJ incidence was 8.5%, 3.1%, and 4.9% in patients with multiple myeloma, breast cancer, and prostate cancer, respectively. Patients with breast cancer demonstrated a reduced risk for ONJ development, which turned out to be nonsignificant after adjustment for other variables. Multivariate analysis demonstrated that use of dentures (aOR = 2.02; 95% CI, 1.03 to 3.96), history of dental extraction (aOR = 32.97; 95% CI, 18.02 to 60.31), having ever received zoledronate (aOR = 28.09; 95% CI, 5.74 to 137.43), and each zoledronate dose (aOR = 2.02; 95% CI, 1.15 to 3.56) were associated with increased risk for ONJ development. Smoking, periodontitis, and root canal treatment did not increase risk for ONJ in patients receiving BP.The conclusions of this study validated dental extractions and use of dentures as risk factors for ONJ development. Ibandronate and pamidronate at the dosages and frequency used in this study seem to exhibit a safer drug profile concerning ONJ complication; however, randomized controlled trials are needed to validate these results. Before initiation of a bisphosphonate, patients should have a comprehensive dental examination. Patients with a challenging dental situation should have dental care attended to before initiation of these drugs.
Alternative Perspectives on the Biased Foundations of Medical Technology Assessment
Authors: George A. Diamond
Journal: Annals of Internal Medicine (1993)

Medical technology assessment seeks to improve the care of individual patients (the conventional unit of clinical practice) through evaluation studies conducted in groups of patients (the conventional unit of clinical investigation).This distinction between individuals and groups has practical relevance to the design, analysis, and clinical applicability of technology assessment studies. We define several biased perspectives about technology assessment that derive from the distinction between individuals and groups: a misguided emphasis on efficacy versus effectiveness, on statistical significance versus clinical importance, and on objective versus subjective outcomes. In each case, we contrast these alternative perspectives and speculate on their implications for health care policy.
Association of Expression Aberrances and Genetic Polymorphisms of <i>Lysyl Oxidase</i> with Areca-Associated Oral Tumorigenesis
Authors: Tzong-Ming Shieh, Shu-Chun Lin, Chung-Ji Liu, Shu-Shin Chang, Ti-Hsuan Ku, Kuo-Wei Chang
Journal: Clinical Cancer Research (2007)

Areca nut use is the major cause of oral squamous cell carcinoma (OSCC) in Southern Asians. Areca nut contains a high level of free copper ions. Lysyl oxidase (LOX) is a copper-activated enzyme critical for extracellular matrix organization. Contradictory evidence has been put forward to suggest that LOX may be either an oncogenic or a suppressive element. This study investigated the oncogenic significance of LOX in areca-associated OSCC.The expression assays and polymorphism analysis were done to know the clinicopathologic implications of LOX status in OSCC. Knockdown and overexpression experiments were conducted to know the phenotypic effects of LOX on OSCC cells.Up-regulation of LOX mRNA and LOX protein expression in OSCCs relative to adjacent oral mucosa was found. Precancerous lesions had the highest LOX mRNA expression. Areca nut extract up-regulated LOX expression in oral epithelial cells. Knockdown of LOX induced cellular migration and invasion, but it reduced the anchorage-independent growth and xenographic tumorigenesis of OSCC cells. The reduction of migration and invasion by LOX overexpression was partially rescued by blockage of LOX activity. The Arg158Gln polymorphism was associated with earlier clinical stage of OSCC. Wild-type LOX overexpression induced anchorage-independent growth in OSCC cells, but this was not for LOXArg158Gln overexpression.LOX exerts oncogenic roles in areca-associated OSCC. This potential could be affected by the existence of LOX propeptide domain or genetic polymorphism.
Azithromycin induces anti-viral responses in bronchial epithelial cells
Authors: V. Gielen, S.L. Johnston, M.R. Edwards
Journal: European Respiratory Journal (2010)

The majority of asthma exacerbations are caused by rhinovirus. Currently the treatment of asthma exacerbations is inadequate. Previous evidence suggests that macrolide antibiotics have anti-inflammatory and antiviral effects; however, the mechanism is unknown. We investigated the anti-rhinoviral potential of macrolides through the induction of antiviral gene mRNA and protein. Primary human bronchial epithelial cells were pre-treated with the macrolides azithromycin, erythromycin and telithromycin, and infected with minor-group rhinovirus 1B and major-group rhinovirus 16. The mRNA expression of the antiviral genes, type I interferon-β and type III interferon-λ1, interferon-λ2/3, and interferon-stimulated genes (retinoic acid inducible gene I, melanoma differentiation associated gene 5, oligoadenylate synthase, MxA and viperin) and pro-inflammatory cytokines (interleukin (IL)-6 and IL-8), and rhinovirus replication and release were measured. Azithromycin, but not erythromycin or telithromycin, significantly increased rhinovirus 1B- and rhinovirus 16-induced interferons and interferon-stimulated gene mRNA expression and protein production. Furthermore, azithromycin significantly reduced rhinovirus replication and release. Rhinovirus induced IL-6 and IL-8 protein and mRNA expression were not significantly reduced by azithromycin pre-treatment. In conclusion, the results demonstrate that azithromycin has anti-rhinoviral activity in bronchial epithelial cells and, during rhinovirus infection, increases the production of interferon-stimulated genes.
Effective variable-number tandem repeats loci for discrimination of Mycobacterium tuberculosis isolated from Korea
Authors: Young Kil Park, Hee Yoon Kang, Ji Hye Lee, Sa Rang Kim
Journal: European Respiratory Journal (2012)

Introduction   The variable-number tandem repeats (VNTR) typing is a promising method to discriminate  M. tuberculosis  isolates in molecular epidemiology.   Objectives   The purpose of this study was to evaluate already known VNTR loci and to select best combination of VNTR loci set for discrimination Korean TB strains.   Methods   The 307 clinical isolates collected from throughout Korea were genotyped using IS 6110  RFLP, and analyzed the number of VNTR copies for the 32 VNTR loci including Supply-15, Supply-24 and JATA-15(except QUB-18); MIRU-02, -04, -10, -16, -20, -23, -24, -26, -27, -31, -39,- 40, ETR-A, -B, -C, QUB-11a, -11b, -15, -26, Mtub-04, -21, -24, -29, -30, -34, -39, VNTR-2372, -3232, -3336, -3820, -4120, -4156. And then, allelic diversity ( h ) and the Hunter-Gaston discriminatory index (HGDI) were calculated to evaluate discriminatory power of locus and combination of VNTR loci.   Results   As a results of analysis of the 32 VNTR loci, we found that 12 loci (MIRU-26, -31, QUB-11a, -11b, -26, Mtub-04, -21, VNTR-3232, -3336, -3820, -4120, -4156) showed high discrimination power (each  h  values of them was over 0.6). This new 12-locus combination for Korea TB strains was designated as a KIT-12. The discriminatory index (HGDI) of IS 6110  RFLP and VNTRs of Supply-15, Supply-24, JATA-15, and  KIT-12  was 0.9992, 0.9980, 0.9987, 0.9992, and  0.9997  respectively. Also the percentage of clustered cases was 16.6%(51/307), 21.8%(67/307), 16.9%(52/307), 14.3%(44/307),  6.8%(21/307)  respectively.   Conclusions   The newly proposed VNTR typing system, KIT-12 loci can be effective tool for  M. tuberculosis  genotyping in Korea where the Beijing strains are predominant.