tbuckley/cabot-search huggingface dataset:
A CD8 T cell gene expression signature predicts disease behaviour in inflammatory bowel disease
Authors: J. C. Lee, P. Lyons, M. Parkes, K. G. Smith
Journal: Gut (2011)

<h3>Introduction</h3> The natural history of Crohn9s disease (CD) and ulcerative colitis (UC) is variable. In patients with a frequently-relapsing/steroid-refractory disease course, sustained remission is more likely if immunomodulators/biologics are introduced earlier. However, many patients experience a quiescent course even without immunomodulators, and should not be exposed to the risks of unnecessary immunosuppression. Previous attempts to personalize treatment from diagnosis have been limited by our inability to reliably predict disease behaviour. Using microarray-based whole genome expression profiling, we have recently identified a common gene expression signature in CD8 T cells in two different autoimmune diseases (ANCA-associated vasculitis and SLE) that correlates with disease course. We attempted to determine if a similar signature existed in CD or UC. <h3>Methods</h3> We performed whole genome expression analysis of CD8 T cells isolated from the blood of 60 patients with active CD or UC before commencing treatment. Prospective follow-up was performed for up to 700 days. Patients were managed using a conventional ‘step-up’ approach by clinicians blinded to the microarray results. <h3>Results</h3> Microarray analysis of CD8 T cell gene expression data revealed the presence of two distinct subgroups within each disease cohort. Comparison of the genes that were differentially expressed between the subgroups in CD and UC demonstrated highly significant overlap (p&lt;1×10<sup>−300</sup>). Patients belonging to the equivalent subgroup in both diseases (termed IBD1) experienced a more aggressive disease course than those in the other subgroup (termed IBD2). This was characterised by a greater requirement to introduce immunomodulators or perform surgery (p=0.0025 (CD), p=0.0006 (UC)) and the necessity for more such escalations over the follow-up period (p=0.022 (CD), p=0.006 (UC)). Patients could not be assigned to these subgroups using other contemporaneous clinical or laboratory parameters. In both diseases, this stratification was superior to previously described methods of predicting outcomes. <h3>Conclusion</h3> Gene-expression profiling of CD8 T-cells isolated from blood can stratify patients with both UC and CD at diagnosis according to subsequent disease behaviour and represents a significant step towards personalised therapy.
The Richmond Agitation–Sedation Scale
Authors: Curtis N. Sessler, Mark S. Gosnell, Mary Jo Grap, Gretchen M. Brophy, Pam V. O'Neal, Kimberly A. Keane, Eljim P. Tesoro, R. K. Elswick
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Sedative medications are widely used in intensive care unit (ICU) patients. Structured assessment of sedation and agitation is useful to titrate sedative medications and to evaluate agitated behavior, yet existing sedation scales have limitations. We measured inter-rater reliability and validity of a new 10-level (+4 “combative” to −5 “unarousable”) scale, the Richmond Agitation–Sedation Scale (RASS), in two phases. In phase 1, we demonstrated excellent (r = 0.956, lower 90% confidence limit = 0.948; κ = 0.73, 95% confidence interval = 0.71, 0.75) inter-rater reliability among five investigators (two physicians, two nurses, and one pharmacist) in adult ICU patient encounters (n = 192). Robust inter-rater reliability (r = 0.922–0.983) (κ = 0.64–0.82) was demonstrated for patients from medical, surgical, cardiac surgery, coronary, and neuroscience ICUs, patients with and without mechanical ventilation, and patients with and without sedative medications. In validity testing, RASS correlated highly (r = 0.93) with a visual analog scale anchored by “combative” and “unresponsive,” including all patient subgroups (r = 0.84–0.98). In the second phase, after implementation of RASS in our medical ICU, inter-rater reliability between a nurse educator and 27 RASS-trained bedside nurses in 101 patient encounters was high (r = 0.964, lower 90% confidence limit = 0.950; κ = 0.80, 95% confidence interval = 0.69, 0.90) and very good for all subgroups (r = 0.773–0.970, κ = 0.66–0.89). Correlations between RASS and the Ramsay sedation scale (r = −0.78) and the Sedation Agitation Scale (r = 0.78) confirmed validity. Our nurses described RASS as logical, easy to administer, and readily recalled. RASS has high reliability and validity in medical and surgical, ventilated and nonventilated, and sedated and nonsedated adult ICU patients.
High Cyclooxygenase-2 Expression Following Neoadjuvant Radiochemotherapy Is Associated with Minor Histopathologic Response and Poor Prognosis in Esophageal Cancer
Authors: Huan Xi, Stephan E. Baldus, Ute Warnecke-Eberz, Jan Brabender, Susanne Neiss, Ralf Metzger, Frederike C. Ling, Hans P. Dienes, Elfriede Bollschweiler, Stefan Moenig, Rolf P. Mueller, Arnulf H. Hoelscher, Paul M. Schneider
Journal: Clinical Cancer Research (2005)

Abstract Purpose: High expression of cyclooxygenase-2 (COX-2) was shown to inhibit chemotherapy- and radiotherapy-induced apoptosis. We analyzed the association of COX-2 mRNA and protein expression with histomorphologic response to neoadjuvant radiochemotherapy in esophageal cancer. Experimental Design: Fifty-two patients with resectable esophageal cancers (cT2-4, Nx, and M0) received neoadjuvant radiochemotherapy (cisplatin, 5-5-fluorouracil, 36 Gy) followed by transthoracic en bloc esophagectomy. Histomorphologic regression was defined as major response when resected specimens contained less than 10% of residual vital tumor cells. RNA was isolated from endoscopic biopsies (paired tumor and normal tissue) before neoadjuvant treatment and quantitative real-time reverse transcriptase-PCR (Taqman) assays were done to determine COX-2 mRNA expression levels standardized for β-actin. COX-2 protein expression in pretreatment biopsies and post-therapeutic resection specimens was analyzed by immunostaining of tumor cells. Results: Median COX-2 mRNA expression levels were significantly (P &amp;lt; 0.0001) different between paired tumor (median, 2.2) and normal tissues (median, 0.159). Comparison of pre-therapeutic and posttherapeutic specimens showed a significant difference (P &amp;lt; 0.006) in COX-2 protein expression. Twelve of 52 tumors showed down-regulation and 3 of 52 showed up-regulation of COX-2 protein expression during neoadjuvant radiochemotherapy. High COX-2 protein expression in post-therapeutic resection specimens was significantly associated with minor histopathologic response (P &amp;lt; 0.04) and poor prognosis (5-year survival probabilities: 26.3 ± 8.2% for minor and 58.6% ± 12.9% for major histopathologic response; P &amp;lt; 0.01). Conclusion: High COX-2 protein expression following neoadjuvant radiochemotherapy in resection specimens is significantly associated with minor histopathologic response to neoadjuvant therapy and very poor prognosis.
mRNA/microRNA gene expression profile in microsatellite unstable colorectal cancer
Authors: Giovanni Lanza, Manuela Ferracin, Roberta Gafà, Angelo Veronese, Riccardo Spizzo, Flavia Pichiorri, Chang-gong Liu, George A Calin, Carlo M Croce, Massimo Negrini
Journal: Molecular Cancer (2007)

Abstract Background Colorectal cancer develops through two main genetic instability pathways characterized by distinct pathologic features and clinical outcome. Results We investigated colon cancer samples (23 characterized by microsatellite stability, MSS, and 16 by high microsatellite instability, MSI-H) for genome-wide expression of microRNA (miRNA) and mRNA. Based on combined miRNA and mRNA gene expression, a molecular signature consisting of twenty seven differentially expressed genes, inclusive of 8 miRNAs, could correctly distinguish MSI-H versus MSS colon cancer samples. Among the differentially expressed miRNAs, various members of the oncogenic miR-17-92 family were significantly up-regulated in MSS cancers. The majority of protein coding genes were also up-regulated in MSS cancers. Their functional classification revealed that they were most frequently associated with cell cycle, DNA replication, recombination, repair, gastrointestinal disease and immune response. Conclusion This is the first report that indicates the existence of differences in miRNA expression between MSS versus MSI-H colorectal cancers. In addition, the work suggests that the combination of mRNA/miRNA expression signatures may represent a general approach for improving bio-molecular classification of human cancer.
Effect of Hydrocortisone on Acidotic Failure of the Isolated Heart
Authors: GABRIEL G. NAHAS
Journal: Circulation Research (1957)

Acute myocardial failure observed when the denervated heart-lung preparation is rendered acidotic is mitigated if 5 to 10 mg. of hydrocortisone are administered to the preparation 12 to 15 min. before the onset of ventilation with high CO 2 .
Efficacy of two intervals and two routes of administration of misoprostol for termination of early pregnancy: a randomised controlled equivalence trial
Authors: Helena von Hertzen, Gilda Piaggio, Nguyen Thi My Huong, Karine Arustamyan, Evelio Cabezas, Manuel Gomez, Archil Khomassuridze, Rashmi Shah, Suneeta Mittal, Rajasekharan Nair, Radnaabazar Erdenetungalag, To Minh Huong, Nguyen Duc Vy, Nguyen Thi Ngoc Phuong, Hoang Thi Diem Tuyet, Alexandre Peregoudov
Journal: The Lancet (2007)
Hyaluronan digestion controls DC migration from the skin
Authors: Jun Muto, Yasuhide Morioka, Kenshi Yamasaki, Margaret Kim, Andrea Garcia, Aaron F. Carlin, Ajit Varki, Richard L. Gallo
Journal: Journal of Clinical Investigation (2014)

The breakdown and release of hyaluronan (HA) from the extracellular matrix has been hypothesized to act as an endogenous signal of injury. To test this hypothesis, we generated mice that conditionally overexpressed human hyaluronidase 1 (HYAL1). Mice expressing HYAL1 in skin either during early development or by inducible transient expression exhibited extensive HA degradation, yet displayed no evidence of spontaneous inflammation. Further, HYAL1 expression activated migration and promoted loss of DCs from the skin. We subsequently determined that induction of HYAL1 expression prior to topical antigen application resulted in a lack of an antigenic response due to the depletion of DCs from the skin. In contrast, induction of HYAL1 expression concurrent with antigen exposure accelerated allergic sensitization. Administration of HA tetrasaccharides, before or simultaneously with antigen application, recapitulated phenotypes observed in HYAL1-expressing animals, suggesting that the generation of small HA fragments, rather than the loss of large HA molecules, promotes DC migration and subsequent modification of allergic responses. Furthermore, mice lacking TLR4 did not exhibit HA-associated phenotypes, indicating that TLR4 mediates these responses. This study provides direct evidence that HA breakdown controls the capacity of the skin to present antigen. These events may influence DC function in injury or disease and have potential to be exploited therapeutically for modification of allergic responses.
Down-Regulated Xanthine Oxidoreductase Is a Feature of Aggressive Breast Cancer
Authors: Nina Linder, Johan Lundin, Jorma Isola, Mikael Lundin, Kari O. Raivio, Heikki Joensuu
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Xanthine oxidoreductase (XOR) is a key enzyme in the degradation of DNA, RNA, and high-energy phosphates and also plays a role in milk lipid globule secretion. Given the strong and regulated expression of XOR in normal breast epithelium, and the previously shown alterations of its expression in experimental tumorigenesis, we hypothesized that XOR may be differentially expressed in breast cancer. Experimental Design: XOR expression was analyzed by immunohistochemistry in tissue microarray specimens of 1,262 breast cancer patients with a median follow-up of 9.5 years. Results: Expression of XOR was moderately decreased in 50% and undetectable in another 7% of the tumors. Decreased XOR expression was associated with poor histologic grade of differentiation, ductal and lobular histologic types, large tumor size, high number of positive axillary lymph nodes, and high cyclooxygenase-2 expression, but not with estrogen or progesterone receptor status, Ki-67, p53, or ERBB2 amplification. Absence of XOR expression was associated with unfavorable outcome, and patients with no XOR expression had more than twice the risk of distant recurrence as compared with those with a moderately decreased or normal expression (hazard ratio, 2.21; P &amp;lt; 0.0001). This was also true in patients with node-negative disease (hazard ratio, 2.75; P &amp;lt; 0.0001) as well as in patients with small (≤1 cm) tumors (hazard ratio, 3.09; P = 0.027). In a multivariate survival analysis, negative XOR emerged as an independent prognostic factor both in the entire series (P = 0.01) and among patients with node-negative disease (P = 0.0009). Conclusion: Loss of XOR identifies breast cancer patients with unfavorable prognosis.
A Particle-Receptor Model for the Insulin-Induced Closure of Connexin43 Channels
Authors: Nobuo Homma, José Luis Alvarado, Wanda Coombs, Kathleen Stergiopoulos, Steven M. Taffet, Alan F. Lau, Mario Delmar
Journal: Circulation Research (1998)

Abstract —Connexin43(Cx43) channels can be regulated by a variety of factors, including low pH i . Structure/function studies from this laboratory have demonstrated that pH gating follows a particle-receptor mechanism, similar to the “ball-and-chain” model of voltage-dependent inactivation of ion channels. The question whether the particle-receptor model is applicable only to pH gating or to other forms of Cx43 regulation as well remains. To address this question, we looked at the uncoupling effects of insulin and of insulin-like growth factor-1 (IGF) on Cx43 channels expressed in Xenopus oocytes. These agonists do not induce changes in pH i . Junctional conductance (Gj) was measured by the dual 2-electrode voltage-clamp technique. Control studies showed that relative Gj did not change spontaneously as a function of time. Continuous exposure of Cx43-expressing oocytes to insulin (10 μ/L) led to a decrease in Gj. After 80 minutes, Gj was 54±5% from control (n=12). Exposure of oocytes to IGF (10 nmol/L) caused an even more pronounced change in Gj (37±4% of control, n=6). The time course of the IGF-induced uncoupling was similar to that observed after insulin exposure. The effect of insulin was abolished by truncation of the carboxyl-terminal domain of Cx43 at amino acid 257 (M257). Interestingly, as in the case of pH gating, coexpression of the carboxyl-terminal domain (amino acids 258 to 282) together with M257 rescued the ability of insulin to reduce coupling (Gj, 39±12% from control; n=6). Structure/function experiments using various deletion mutants of the carboxyl-terminal domain showed that insulin treatment does not modify Gj if amino acids 261 to 280 are missing from the Cx43 sequence. Our results suggest that a particle-receptor (or ball-and-chain) mechanism, similar to that described for pH gating, also applies to chemical regulation of Cx43 by other factors.
Primary Angioplasty in Acute Myocardial Infarction at Hospitals With No Surgery On-Site (the PAMI-No SOS study) versus transfer to surgical centers for primary angioplasty
Authors: Thomas P. Wharton, Lorelei L. Grines, Mark A. Turco, James D. Johnston, Jane Souther, David C. Lew, Ajazuddin Z. Shaikh, William Bilnoski, Sushil K. Singhi, A.Ersin Atay, Nancy Sinclair, Dawn E. Shaddinger, Mark Barsamian, Mariann Graham, Judith Boura, Cindy L. Grines
Journal: Journal of the American College of Cardiology (2004)
Compliance with drug treatment.
Authors: M O'Hanrahan, K O'Malley
Journal: BMJ (1981)

I asked the chief tonometrist at the Princess Alexandra Eye Pavilion in Edinburgh to approve this form for recording intra- ocular pressure before I had it duplicated.She told me that it would not do.I wondered why-it was simple, neat, and unambiguous.Or was it?The patient's right eye is, of course, on the tonometrist's left as she faces the patient and ought to be so on the form also. Therefore the form should be redesigned as shown. Time (hours) Right eyeLeft eye 09.00 11.00If experience is the sum of one's errors then I, for one, have learned a vast amount, and one of the most valuable lessons is always to check out form design with the person who will do the recording and, for all but the simplest forms, to pilot them before the trial proper begins.'Useful pointers on form design have been given by Wright and Haybittle.'References
Genetic polymorphisms of mannan binding lectin (MBL), serum levels of MBL, the MBL associated serine protease and H-ficolin in patients with Crohn's disease
Authors: R G Nielsen, I Vind, P Munkholm, J C Jensenius, S Thiel, S Husby
Journal: Gut (2007)

<h3>SUMMARY</h3> The pelagic longline fishery, in an effort to reduce bycatch of sea turtles, have developed and deployed fisheries bycatch mitigation techniques such as replacing J/tuna hooks and squid bait with circle hooks and whole fish bait. However, little emphasis has been placed on the side effects of bycatch mitigation measures on endangered species other than target bycatch species. Several previous studies of the side effects have been marred by lack of control for the covariates. Here, based on long-term data obtained from research cruises by a pelagic longline vessel, we examined the effects of using circle hooks and whole fish bait to replace squid bait on the fishing mortality of target and non-target fishes, and also bycatch species. A quantitative evaluation analysis of our results, based on a Bayesian approach, showed the use of circle hooks to increase mouth hooking in target and bycatch species, and their size to be proportional to the magnitude of the effect. Although deploying circle hooks increased catch per unit effort (CPUE) and fishing mortality per unit effort (MPUE), changing the bait species from squid to fish clearly had a far greater impact on shark mortality than the use of circle hooks. Because the impact of the introduction of bycatch mitigation measures on species other than the focused bycatch species is non-negligible, a quantitative assessment of bycatch mitigation-related fishing mortality is critical before introducing such measures.
Nevirapine, Zidovudine, and Didanosine Compared with Zidovudine and Didanosine in Patients with HIV-1 Infection
Authors: Richard T. D'Aquila
Journal: Annals of Internal Medicine (1996)

Objective: To study the addition of a third human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitor, nevirapine, to the combination of zidovudine and didanosine. Design: A 48-week, randomized, double-blind, placebo-controlled trial at 16 AIDS (acquired immunodeficiency syndrome) Clinical Trials Units. Patients: 398 adults who had HIV-1 infection, had 350 or fewer CD4+ T lymphocytes/mm3, and had had more than 6 months of previous nucleoside therapy. Intervention: 1) Either nevirapine or placebo [200 mg/d for 2 weeks, then 400 mg/d thereafter] and 2) open-label zidovudine (600 mg/d) and didanosine (400 mg/d for patients weighing more than equals to 60 kg). Measurements: CD4+ T lymphocyte counts, time to first HIV-1 disease progression event or death, adverse events, and nevirapine levels in plasma samples taken at random were measured in all patients. Plasma levels of HIV-1 RNA; HIV-1 infectivity titer in peripheral blood mononuclear cells; serum p24 antigen levels; and plasma levels of zidovudine and didanosine were measured in patients enrolled at half the study sites. Results: After 48 weeks of study treatment, the patients assigned to the triple-combination regimen (nevirapine, zidovudine, and didanosine) had an 18% higher mean absolute CD4 cell count (95% CI, 7% to 29%; P = 0.001), a 0.32 log10 lower mean infectious HIV-1 titer in peripheral blood mononuclear cells (CI, 0.05 to 0.59 log10 infectious units per million cells; P = 0.023), and a 0.25 log10 lower mean plasma HIV-1 RNA level (CI, 0.03 to 0.48 log10RNA copies/mL; P = 0.028) than did patients assigned to the double-combination regimen (zidovudine and didanosine). Severe rashes were more common among patients assigned to receive the triple combination (9% compared with 2%; P = 0.002). Risk for disease progression did not differ between the two groups (relative hazard of the triple-combination group, 1.24 [CI, 0.75 to 2.06]; P > 0.2), although the study had only moderate power to detect a major difference. Conclusions: Adding nevirapine to zidovudine and didanosine improved the long-term immunologic and virologic effects of therapy and was associated with severe rash among the patients studied, who had had extensive previous therapy. These results support 1) the continuing development of combinations of more than two antiretroviral drugs to increase and prolong HIV-1 suppression and 2) the potential utility of nevirapine in combination regimens.
Local response to cardiac overload on myosin heavy chain gene expression and isozyme transition.
Authors: S Imamura, R Matsuoka, E Hiratsuka, M Kimura, T Nishikawa, A Takao
Journal: Circulation Research (1990)

It is uncertain whether the shift of cardiac myosin heavy chain (MHC) during pressure overload can be induced by some intrinsic factors or by the stress imposed directly on the individual myocytes. To study whether the changes in cardiac MHC gene expression produced by one-sided overload are limited to the involved ventricle or extend to the other ventricle, we examined MHC gene expression and isozyme transition in the left and right ventricles in aortic coarctated and pulmonary artery-banded rats. It has been confirmed that the pressure overload is indeed limited to the loaded ventricle. The results showed that, compared with sham-operated rats, there was no significant induction of the beta-MHC messenger RNA and corresponding protein in the unloaded ventricle, whereas significant induction was observed in the overloaded ventricle. These results demonstrated that the changes in MHC gene expression and isozyme produced by one-sided ventricular overload are limited to the involved ventricle. We conclude that the MHC gene regulation during hemodynamic overload may not be induced by intrinsic factors, such as hormones, catecholamine, or atrial natriuretic peptide, but is induced by direct local response to increased load.
Surveillance Policy for Stage IA Malignant Ovarian Germ Cell Tumors in Children and Young Adults
Authors: Giorgia Mangili, Cristina Sigismondi, Domenica Lorusso, Sandro Pignata
Journal: Journal of Clinical Oncology (2014)

disease; the recurrence rate in these patients was 75%, and in confirmed stage IA tumors the relapse rate may be lower than the reported 48%. Moreover, as suggested in the article by Billmire et al, COG criteria for surgical staging could lead to understaging in patients with greater than stage I disease. Two patients experienced relapse within 1 month (probably, the disease had already spread at the time of diagnosis), three patients experienced a retroperitoneal recurrence, and lymphnodal relapse was found in 37% of patients with a detected mass, indicating a possible predilection for lymphatic spread. The authors emphasized that although it could be argued that a more systematic surgical approach would have detected occult disease, the salvage rate with chemotherapy would be eventually equivalent.Wesuggestthatsurgicalorradiologicstagingmaybeusefulto identify patients who may benefit from adjuvant chemotherapy, given that, at present, we cannot rule out the possibility that postponing chemotherapy in disease with an occult stage greater than 1A may worsen the prognosis. Given the dearth of high-quality prospective trials on rare tumors,Billmireetal 1 shouldbecongratulatedfortheirstudy.However,