tbuckley/cabot-search huggingface dataset:
THE ROLE OF DEFINITIONS IN PSYCHIATRY
Authors: JOHN R. REID, JACOB E. FINESINGER
Journal: American Journal of Psychiatry (1952)

The function of definitions is to make clear and unambiguous the meanings of the terms we use. When precisely formulated and conscientiously followed, definitions in turn make our reasoning more exact and our communication more successful. Unless its meaning is clearly understood, no statement can be empirically verified nor logically validated by reference to any other statement. In all scientific fields, but particularly in psychiatry, such clarity of meaning can be achieved only through the most scrupulous efforts to specify these meanings in carefully formulated definitions. If such definitions are to satisfy the pragmatic criterion of "working successfully," the descriptive terms in them must, wherever possible, refer to public matters of fact that can be established by operational procedures that are feasible to carry out by suitably trained investigators. Furthermore, all implicit inferences to causal antecedents or to future consequences, to subjective processes that can be directly experienced by only one subject or to unconscious factors (in the dynamic Freudian sense) that can be directly experienced by no subject, but merely inferred—all such more or less dubious inferences must be brought out into the open and clearly so labeled, and not, as so often happens, be left concealed under the verbal cloak of the definition as formulated, where they create endless confusions. Definitions so conceived, so formulated, and so used do not limit our intellectual freedom to say anything we mean, but are, rather, the logical instruments by which alone what we mean can be said, and this intellectual freedom become, accordingly, a positive condition of self-expression and successful communication.
Development of Antidrug Antibodies Against Adalimumab and Association With Disease Activity and Treatment Failure During Long-term Follow-up
Authors: Geertje M. Bartelds
Journal: JAMA (2011)

<h3>Context</h3>Short-term data on the immunogenicity of monoclonal antibodies showed associations between the development of antidrug antibodies and diminished serum drug levels, and a diminished treatment response. Little is known about the clinical relevance of antidrug antibodies against these drugs during long-term follow-up.<h3>Objective</h3>To examine the course of antidrug antibody formation against fully human monoclonal antibody adalimumab and its clinical relevance during long-term (3-year) follow-up of patients with rheumatoid arthritis (RA).<h3>Design, Setting, and Patients</h3>Prospective cohort study February 2004-September 2008; end of follow-up was September 2010. All 272 patients were diagnosed with RA and started treatment with adalimumab in an outpatient clinic.<h3>Main Outcome Measures</h3>Disease activity was monitored and trough serum samples were obtained at baseline and 8 time points to 156 weeks. Serum adalimumab concentrations and antiadalimumab antibody titers were determined after follow-up. Treatment discontinuation, minimal disease activity, and clinical remission were compared for patients with and without antiadalimumab antibodies.<h3>Results</h3>After 3 years, 76 of 272 patients (28%) developed antiadalimumab antibodies—51 of these (67%) during the first 28 weeks of treatment. Patients without antiadalimumab antibodies had much higher adalimumab concentrations (median, 12 mg/L; IQR, 9-16 mg/L) compared with patients with antibody titers from 13 to 100 AU/mL (median, 5 mg/L; IQR, 3-9 mg/L; regression coefficient, −4.5; 95% CI, −6.0 to −2.9; P &lt; .001) and also those greater than 100 AU/mL (median, 0 mg/L; IQR, 0-3 mg/L; regression coefficient, −7.1; 95% CI, −8.4 to −5.8; P &lt; .001). Patients with antiadalimumab antibodies more often discontinued participation due to treatment failure (n = 29 [38%]; hazard ratio [HR], 3.0; 95% CI, 1.6-5.5; P &lt; .001) compared with antiadalimumab antibody–negative ones (n = 28 [14%]). Ninety-five of 196 patients (48%) without antiadalimumab antibodies had minimal disease activity vs 10 of 76 patients (13%) with antiadalimumab antibodies; patients with antiadalimumab antibodies less often had sustained minimal disease activity score in 28 joints (DAS28) (&lt; 3.2; HR, 3.6; 95% CI, 1.8-7.2; P &lt; .001) compared with antiadalimumab antibody–negative ones. Three of 76 patients (4%) with antiadalimumab antibodies achieved sustained remission compared with 67 of 196 (34%) antiadalimumab antibody–negative ones; patients with antiadalimumab antibodies less often achieved remission (DAS28 &lt; 2.6; HR, 7.1; 95% CI, 2.1-23.4; P &lt; .001) compared with antiadalimumab antibody–negative ones.<h3>Conclusion</h3>Among outpatients with RA in whom adalimumab was started over 3 years, the development of antidrug antibodies was associated with lower adalimumab concentration and lower likelihood of minimal disease activity or clinical remission.
Plasma Epstein-Barr Virus DNA and Residual Disease After Radiotherapy for Undifferentiated Nasopharyngeal Carcinoma
Authors: A. T. C. Chan
Journal: JNCI Journal of the National Cancer Institute (2002)

Background: Epstein-Barr virus (EBV) DNA can be detected and quantified in the plasma of patients with EBV-related tumors, such as nasopharyngeal carcinoma (NPC). Although NPC at early stages can be cured by radical radiotherapy, there is a high recurrence rate in patients with advanced NPC. The pretreatment level of circulating EBV DNA is a prognostic factor for NPC, but the prognostic value of post-treatment EBV DNA has not been studied. We designed a prospective study in Hong Kong, China, to investigate the value of plasma EBV DNA as a prognostic factor for NPC. Methods: One hundred seventy NPC patients, without metastatic disease at presentation, were treated with a uniform radiotherapy protocol. Circulating EBV DNA was measured by real-time quantitative polymerase chain reaction before treatment and 6–8 weeks after radiotherapy was completed. Risk ratios (RRs) were determined with a Cox regression model, and associations of various factors with progression-free and overall survival and recurrence rates were determined with a stepwise Cox proportional hazards model. All statistical tests were two-sided. Results: Ninety-nine percent of patients achieved complete clinical remission. Levels of post-treatment EBV DNA dominated the effect of levels of pretreatment EBV DNA for progression-free survival. The RR for NPC recurrence was 11.9 (95% confidence interval [CI] = 5.53 to 25.43) for patients with higher post-treatment EBV DNA and 2.5 (95% CI = 1.14 to 5.70) for patients with higher pretreatment EBV DNA. Higher levels of post-treatment EBV DNA were statistically significantly associated with overall survival (P<.001; RR for NPC recurrence = 8.6, 95% CI = 3.69 to 19.97). The positive and negative predictive values for NPC recurrence for a higher level of post-treatment EBV DNA were 87% (95% CI = 58% to 98%) and 83% (95% CI = 76% to 89%), respectively. Conclusion: Levels of post-treatment plasma EBV DNA in patients with NPC appear to strongly predict progression-free and overall survival and to accurately reflect the post-treatment residual tumor load.
Long non-coding RNA TUG1 is up-regulated in hepatocellular carcinoma and promotes cell growth and apoptosis by epigenetically silencing of KLF2
Authors: Ming-De Huang, Wen-Ming Chen, Fu-Zhen Qi, Ming Sun, Tong-Peng Xu, Pei Ma, Yong-qian Shu
Journal: Molecular Cancer (2015)

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, and the biology of this cancer remains poorly understood. Recent evidence indicates that long non-coding RNAs (lncRNAs) are found to be dysregulated in a variety of cancers, including HCC. Taurine Up-regulated Gene 1 (TUG1), a 7.1-kb lncRNA, recruiting and binding to polycomb repressive complex 2 (PRC2), is found to be disregulated in non-small cell lung carcinoma (NSCLC) and esophageal squamous cell carcinoma (ESCC). However, its clinical significance and potential role in HCC remain unclear.In this study, expression of TUG1 was analyzed in 77 HCC tissues and matched normal tissues by using quantitative polymerase chain reaction (qPCR). TUG1 expression was up-regulated in HCC tissues and the higher expression of TUG1 was significantly correlated with tumor size and Barcelona Clinic Liver Cancer (BCLC) stage. Moreover, silencing of TUG1 expression inhibited HCC cell proliferation, colony formation, tumorigenicity and induced apoptosis in HCC cell lines. We also found that TUG1 overexpression was induced by nuclear transcription factor SP1 and TUG1 could epigeneticly repress Kruppel-like factor 2 (KLF2) transcription in HCC cells by binding with PRC2 and recruiting it to KLF2 promoter region.Our results suggest that lncRNA TUG1, as a growth regulator, may serve as a new diagnostic biomarker and therapy target for HCC.
Explaining the Adjustment of Adolescents With Type 1 Diabetes
Authors: Jamil A. Malik, Hans M. Koot
Journal: Diabetes Care (2009)

OBJECTIVE The aim of this study was to explain adjustment (diabetes-related quality of life, general well-being, and psychopathology) in adolescents with type 1 diabetes by testing the direct, mediating, and moderating effects of diabetes-specific and psychosocial factors, using an adapted version of the Disability-Stress-Coping model of Wallander and Varni. RESEARCH DESIGN AND METHODS A total of 437 adolescents (54.5% girls; age range 11–19 years) with type 1 diabetes (mean ± SD diabetes duration 6.13 ± 3.78 years) were recruited from 25 hospitals in the Netherlands. Questionnaires were completed by the adolescents and their family members. Metabolic control was assessed by measuring A1C in all participants in one laboratory. RESULTS Diabetes stress mediated between A1C and adjustment, after controlling for protective factors, and explained an additional 16% variance in quality of life and a 15% variance in general well-being, whereas a 19% additional variance in psychopathology was explained by both diabetes-related and general stress. No moderating effects were identified after controlling for the main effects of all risk and protective factors in the model. CONCLUSIONS Both diabetes-related and general stress are critical predictors of the adjustment of adolescents with type 1 diabetes. Protective factors such as self-worth and social support may mediate the effects of generic stress and thus should be encouraged. Diabetes-related stress has the potential to displace the effects of protective factors and thus may play a critical role in the development of maladjustment in adolescents with type 1 diabetes.
6-Shogaol inhibits cathepsin-K activity and has anticatabolic and anti-inflammatory properties in stimulated chondrocytes
Authors: Amanda Villalvilla, Jame's Almada, Paulo Cezar Vieira, Raquel Largo, Gabriel Herrero-Beaumont, Rodolfo Gómez
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Backgroundand objectives</h3> Ginger has been used in Asiatic traditional medicine, as an arthritis treatment. Supporting this therapeutic use, very recently it has been reported ginger derivatives (GDs) ability to control inflammation associated with different arthritis models. So the authors decided to study GDs toxicity, anti-catabolic and anti-inflammatory properties in cultured chondrocytes. <h3>Materials and methods</h3> GDs toxicity was tested by MTT assay in cultured ATDC5 chondrocytes. Supernatant nitrite accumulation was determined by Griess reaction. Inducible nitric oxide synthase (NOS2), MyD88 and ERK protein expression was examined by western-blot. MMPs activity was tested by gelatin zymography. Cathepsin-K activity was evaluated by biochemical and biological assays in cultured human chondrocytes. <h3>Results</h3> 6-shogaol and 10-gingerol, were isolated from ginger extracts. In addition, a new synthetic derivative was also designed, SSi6. MTT assay revealed that unlike 10-gingerol, 6-shogaol and SSi6 were not toxic at studied concentrations. All these compounds inhibited cathepsin-K activity, however, only 6-shogaol was able to inhibit nitrite accumulation in the culture medium of LPS stimulated chondrocytes. In contrast, neither 6-shogaol nor SSi6 were able to reduce significantly IL-1β induced nitrite accumulation. Moreover, 6-shogaol was able to inhibit LPS mediated ERK activation and NOS2 and MyD88 induced expression. In addition 6-shogaol inhibited MMP-2 and MMP-9 induction in the culture medium of LPS treated cells. <h3>Conclusions</h3> Data obtained reveal new potential avenues for OA treatment based in GDs properties to inhibit cathepsin-K activity and 6-shogaol ability to inhibit innate immune inflammatory responses through TLR4 blockade.
Anti-inflammatory Properties of the Novel Antitumor Agent Yondelis (Trabectedin): Inhibition of Macrophage Differentiation and Cytokine Production
Authors: Paola Allavena, Mauro Signorelli, Marcello Chieppa, Eugenio Erba, Giancarlo Bianchi, Federica Marchesi, Chiara Omero Olimpio, Claudia Bonardi, Annalisa Garbi, Andrea Lissoni, Filippo de Braud, José Jimeno, Maurizio D'Incalci
Journal: Cancer Research (2005)

Abstract Yondelis (Trabectedin) is a novel antitumor agent of marine origin extracted from the tunicate Ecteinascidia turbinata. This original compound is active against several human tumors including sarcoma and ovarian and breast adenocarcinoma, as evidenced in phase II clinical trials in advanced multitreated patients. Yondelis is a DNA minor groove binder that blocks cell cycle and interferes with inducible gene transcription in a selective manner. In this study, we investigated the immunomodulatory properties of Yondelis on leukocytes. Human blood monocytes were highly susceptible in vitro to its cytotoxic effect and underwent apoptosis at pharmacologically relevant concentrations (5 nmol/L), whereas lymphocytes were up to 5-fold less sensitive. Macrophages differentiated in vitro with macrophage colony-stimulating factor and tumor-associated macrophages (TAM), isolated from patients with ovarian cancer, were also susceptible. At subcytotoxic concentrations, Yondelis inhibited the in vitro differentiation of monocytes to macrophages. In tumor-treated patients, drug infusion caused a selective decrease of monocyte counts and of ex vivo macrophage differentiation. The in vitro production of two proinflammatory mediators, CCL2 and IL-6, was markedly reduced by Yondelis in monocytes, macrophages, TAM, and freshly isolated ovarian tumor cells. The chemokine CCL2 is the major determinant of monocyte recruitment at tumor sites, whereas IL-6 is a growth factor for ovarian tumors. In view of the protumor activity of TAM and of the strong association between chronic inflammation and cancer progression, the inhibitory effect of Yondelis on macrophage viability, differentiation, and cytokine production is likely to contribute to the antitumor activity of this agent in inflammation-associated human tumors.
Effects and side-effects of partial ileal by-pass surgery for familial hypercholesterolaemia.
Authors: O Faergeman, H Meinertz, E Hylander, K Fischerman, S Jarnum, O V Nielsen
Journal: Gut (1982)

Ten patients with familial hypercholesterolaemia were subjected to partial ileal by-pass surgery. Plasma cholesterol fell by 41 and 38% and low-density lipoprotein cholesterol by 51 and 46% after six and 18 months respectively. High-density and very low-density lipoprotein cholesterol and plasma triglycerides were unaffected. Alanine aminotransferase increased transiently in half of the patients. Diarrhoea and slight steatorrhoea troubled most of the patients for the duration of 18 months9 period of observation. Other long-term side effects were slight but significant increase in the renal excretion of oxalic acid and reduction in the intestinal absorption of calcium. The study shows that this operation has metabolic side-effects that warrant continued medical care of these patients.
Increased cardiac IL-18 mRNA, pro-IL-18 and plasma IL-18 after myocardial infarction in the mouse; a potential role in cardiac dysfunction
Authors: P Reidar Woldbaek
Journal: Cardiovascular Research (2003)

Interleukin (IL)-18 has been reported to be an important predictor for mortality in ischemic heart disease. IL-18 has proinflammatory properties, induces cell death and stimulates nitric oxide production. We hypothesized that following myocardial infarction (MI) an increased myocardial IL-18 production occurs, which may be involved in the pathogenesis of post-ischemic heart failure.Seven days after induction of MI in the mouse, myocardial hypertrophy and pulmonary edema were observed. RNase protection assay of tissue from the non-infarcted left ventricular myocardium revealed an increase in IL-18 (2.0-fold; P<0.001) and IL-1 beta (1.6-fold; P<0.001) mRNA after MI. Enhanced abundance of pro-IL-18 (1.4-fold; P<0.05), IL-18 receptor (3.5-fold; P<0.05) and IL-18 binding proteins (1.6-fold; P<0.05) was also demonstrated, whereas cardiac IL-18 protein decreased by 25% (P<0.05) following MI. However, the concentration of circulating IL-18 was significantly elevated (MI; 90.4+/-11.7 pg/ml, sham; 47.2+/-4.2 pg/ml; P<0.001). After MI, enhanced cardiac activity of the pro-IL-18 processing enzyme, caspase-1, was measured. Additionally, a 3.4-fold increase (P<0.001) in the activity of the IL-18 degrading enzyme, caspase-3, was found in cardiac tissue, which may explain the observed reduction of cardiac IL-18 protein abundance. Finally, IL-18 reduced shortening of electrically stimulated adult cardiomyocytes and left ventricular contractility in vivo.After MI in the mouse, increased production of cardiac IL-18 mRNA and pro-IL-18, as well as circulating IL-18 occurs. Since IL-18 also reduced myocardial contractility, we suggest that IL-18 may be involved in the pathogenesis of contractile dysfunction following MI.
Treatment of human pre-B acute lymphoblastic leukemia with the Aurora kinase inhibitor PHA-739358 (Danusertib)
Authors: Fei Fei, Min Lim, Sabine Schmidhuber, Jürgen Moll, John Groffen, Nora Heisterkamp
Journal: Molecular Cancer (2012)

Abstract Background Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemias (Ph-positive ALL) with clinically approved inhibitors of the Bcr/Abl tyrosine kinase frequently results in the emergence of a leukemic clone carrying the T315I mutation in Bcr/Abl, which confers resistance to these drugs. PHA-739358, an Aurora kinase inhibitor, was reported to inhibit the Bcr/Abl T315I mutant in CML cells but no preclinical studies have examined this in detail in human ALL. Results We compared the sensitivity of human Bcr/Abl T315I, Bcr/Abl wild type and non-Bcr/Abl ALL cells to this drug. PHA-739358 inhibited proliferation and induced apoptosis independently of Bcr/Abl, the T315I mutation, or presence of the tumor suppressor p53, but the degree of effectiveness varied between different ALL samples. Since short-term treatment with a single dose of drug only transiently inhibited proliferation, we tested combination treatments of PHA-739358 with the farnesyltransferase inhibitor Lonafarnib, with vincristine and with dasatinib. All combinations reduced viability and cell numbers compared to treatment with a single drug. Clonogenic assays showed that 25 nM PHA-739358 significantly reduced the colony growth potential of Ph-positive ALL cells, and combined treatment with a second drug abrogated colony growth in this assay. PHA-739358 further effectively blocked Bcr/Abl tyrosine kinase activity and Aurora kinase B in vivo, and mice transplanted with human Bcr/Abl T315I ALL cells treated with a 3x 7-day cycle of PHA-739358 as mono-treatment had significantly longer survival. Conclusions PHA-739358 represents an alternative drug for the treatment of both Ph-positive and negative ALL, although combined treatment with a second drug may be needed to eradicate the leukemic cells.
The role of H-2-linked genes in helper T-cell function. III. Expression of immune response genes for trinitrophenyl conjugates of poly-L(Tyr, Glu)-poly-D,L-Ala--poly-L-Lys in B cells and macrophages.
Authors: P Marrack, J W Kappler
Journal: The Journal of Experimental Medicine (1978)

Using lymph node T cells from poly-L(Tyr,Glu)-poly-D,L-Ala--poly-L-Lys[(TG)-A--L]-primed animals and B cells from animals primed with trinitrophenylated (TNP) protein or lipopolysaccharide, we have obtained anti-TNP-(TG)-A--L direct plaque-forming responses in vitro. Response to this antigen was shown to be controlled by the H-2 haplotype of the animal studied. The strain distribution of in vitro response was very similar to that previously reported by others for in vivo secondary IgG responses to (TG)-A--L. We investigated the cell types expressing the Ir gene(s) for (TG)-A--L in our cultures. F1, high responder x low responder mice were primed with (TG)-A--L. Their T cells were active in stimulating anti-TNP-(TG)-A--L responses of high responder but not low responder B cells and macrophages (MPHI), even though both preparations of B cells and Mphi were obtained from mice congenic at H-2 with one of the parents of the F1. For three low responder strains tested, of the H-2h2, H-2k, and H-2f haplotypes, the anti-TNP-(TG)-A--L response of low responder B cells and Mphis in the presence of high responder, F1 T cells could not be improved by the addition of high responder, antigen-bearing Mphis to the cultures. In one strain of the H-2a haplotype, it was shown that neither the B cells nor Mphis could be functional in anti-TNP-(TG)-A--L responses. Our results therefore suggested the Ir genes for anti-TNP-(TG)-A--L responses were expressed at least in B cells in all the low responder strains we studied, and, in mice of the H-2a haplotype, in Mphis too.
Lung cancer survival
Authors: H SATOH
Journal: Thorax (2001)

COPD exacerbationsWe read with interest the paper by Cotton and associates 1 on early discharge for patients with exacerbations of chronic obstructive pulmonary disease and the accompanying editorial by Killen and Ellis. 2 In both publications the 1991 study of our RespiCare home care programme was referenced, 3 and both asserted that our programme was not cost eVective.In fact, our study reached the opposite conclusion-namely, that the Respi-Care programme was shown to be cost eVective.Actual direct care charges in US dollars were used in our calculations of both pre-programme and on-programme costs.Additionally, administrative costs of operating RespiCare were added into the onprogramme costs.Our findings showed that, while hospitalisation costs substantially decreased during the programme, home care costs increased.However, the decrease in hospital costs more than oVset the subsequent increase in home care costs, with a total cost savings of $328 US dollars per patient per month or $3956 per year being realised for those on the RespiCare programme.Although the emphasis of the work was on improvements in clinical outcome, the cost savings were a significant and important aspect of our study.I hope this clarifies any misunderstanding created by the recent articles.