tbuckley/cabot-search huggingface dataset:
Efficacy and Safety of Adalimumab as the First and Second Biologic Agent in Juvenile Idiopathic Arthritis: The German Biologics JIA Registry
Authors: Heinrike Schmeling, Kirsten Minden, Ivan Foeldvari, Gerd Ganser, Tony Hospach, Gerd Horneff
Journal: Arthritis & Rheumatology (2014)

To evaluate the efficacy and safety of adalimumab in patients with juvenile idiopathic arthritis (JIA).Baseline demographic and clinical characteristics and disease activity parameters were prospectively documented in the German Biologics JIA Registry. Efficacy was determined using the American College of Rheumatology (ACR) Pediatric (Pedi) response criteria and the Juvenile Arthritis Disease Activity Score based on a 10-joint count (JADAS-10). Safety assessments were based on adverse event reports from the responsible physician.Two hundred eighty-nine patients with a total of 1,046 visits were identified (435.7 patient-years). A high proportion of patients demonstrated a significant response to treatment, with a marked decrease in the JADAS-10 score in both the biologics-naive group (which consisted of patients who had not received therapy with a biologic agent prior to initiation of adalimumab) and the biologic-switcher group (which consisted of patients who had been treated with a different biologic agent prior to initiation of adalimumab). The median JADAS-10 score at treatment start was significantly higher in the biologics-naive group than in the biologic-switcher group (12.9 versus 8.5; P = 0.00044), although the score in the biologics-naive group was lower over the course of adalimumab treatment. ACR Pedi 30, 50, 70, and 90 scores were achieved in 63.4%, 61.0%, 48.8%, and 34.2% of biologics-naive patients, respectively, at 6 months of treatment, while ACR Pedi 30, 50, 70, and 90 scores were achieved in 47.6%, 38.1%, 21.9%, and 15.2% of biologic-switcher patients, respectively. Forty-eight patients experienced 222 adverse events (50.9 per 100 patient-years). Eleven were reported as serious (2.5 per 100 patient-years). No malignancies were observed during adalimumab exposure. There were 16 uveitis flares in 11 patients. Treatment was discontinued in 58 patients for the following reasons: inefficacy 11.1%, adverse events 5.2%, remission 4.5%, patient request 11.8%, and other reasons 7.9%.Adalimumab appears to be highly effective in children and adolescents with JIA who have been previously treated with biologic agents and in children and adolescents who switched biologic agents. The treatment is safe and its efficacy is similar to that of other biologic agents used to treat JIA. Few patients discontinued therapy due to intolerance or inefficacy.
Severe metabolic acidosis in chronically ventilated Duchenne muscular dystrophy patients
Authors: Christian M. Lo Cascio, Tsogyal D. Latshang, Malcolm Kohler, Thomas Feher, Konrad E. Bloch
Journal: European Respiratory Journal (2011)

Background:  Duchenne muscular dystrophy (DMD) leads to progressive paresis, respiratory failure and premature death. Long-term positive pressure ventilation (ltPPV) improves quality of life and life expectancy while previously unrecognized DMD complications like metabolic acidosis (MA) arise. We analyzed characteristics and causes of MA.   Methods:  8 DMD patients (26±4 y) admitted to our institution with severe MA during the last 5 years were studied. History, physical exam, chemistry and arterial blood gases (ABG) were evaluated.   Results:  All 8 patients were on ltPPV, 6 for 24h/day. All were treated for chronic constipation and had reduced food/fluid intake in the last few days; 2 had respiratory infection. Despite ltPPV they suffered from dyspnea and abdominal discomfort and were in severely reduced condition with tachycardia (96-156/min) but normal blood pressure. Temperature was 36.5-40.0 °C. The table shows ABG at admission on ltPPV; O2 titrated to SpO2 >90%. Urinary ketones were positive in all. Rehydration, nutrition, regulation of intestinal motility and antibiotics lead to recovery in all.   Conclusions:  In older DMD patients on ltPPV we observed that severe, metabolic acidosis related to chronic constipation and its treatment, reduced fluid and food intake and associated respiratory infection resulted in a life-threatening condition. Adequate regulation of bowel movements, hydration and nutrition seem to be crucial in prevention of this life-threatening complication.  Grant support: Lunge Zurich.
Consensus clustering and functional interpretation of gene-expression data.
Authors: Stephen Swift, Allan Tucker, Veronica Vinciotti, Nigel Martin, Christine Orengo, Xiaohui Liu, Paul Kellam
Journal: Genome biology (2004)

Abstract Microarray analysis using clustering algorithms can suffer from lack of inter-method consistency in assigning related gene-expression profiles to clusters. Obtaining a consensus set of clusters from a number of clustering methods should improve confidence in gene-expression analysis. Here we introduce consensus clustering, which provides such an advantage. When coupled with a statistically based gene functional analysis, our method allowed the identification of novel genes regulated by NFκB and the unfolded protein response in certain B-cell lymphomas.
Late-breaking abstract: Comparison of respiratory symptoms in chronic pulmonary obstructive disease and restrictive ventilatory impairment according to disease stage: The PLATINO study in Latin America
Authors: Josiane Marchioro, Nivia Nonato, Oliver Nascimento, Fernanda Rosa, Jose R. Jardim, Aquiles Camilier, Rogelio Padilla, Juan Carlos Garcia, Maria Montes de Oca, Carlos Talamo, Carmen Lisboa, Maria Victorina Lopez, Bartolomei Celli
Journal: European Respiratory Journal (2011)

Introduction:  Obstructive pulmonary disease presents defined symptoms such as cough, dyspnea, sputum and wheezing. Symptoms of restrictive ventilatory impairment are less well defined.   Objective:  Compare the occurrence of respiratory symptoms in chronic obstructive pulmonary disease with the ones presented by individuals with restrictive impairment in the different stages of the disease.   Methods:  Between 2002 and 2004, individuals over 40 years of age from five cities in Latin America were analyzed and had a pre post-bronchodilator spirometry done and reported their respiratory symptoms.   Results:  N= 5315: 260 (4.9%) - restriction impairment and 759 (14.4%) - COPD diagnoses. Patients with COPD coughed more (31.4% vs 23.5%; OR 1.36: 1.05, 1.74) and had more sputum (28.3% vs 21.9%; OR 1.30: 1.0, 1.68). No difference was seen in dyspnea (OR:0.86 (0.69,1,06) between the two groups. Comparing the different stages of disease, at moderate stage: COPD patients presented more cough than those with restrictive impairment (40,5% vs 27,3%; OR 1,53: 1,07-2,20) and more sputum (36,6%) vs 23,6%; OR 1,57: 1,07- 2,30); moderate, severe and very severe stages: COPD had more wheezing episodes than those with restrictive disease. Regarding dyspnea, it was more intense in patients with mild restriction than in those with mild COPD (43% vs56%; OR 1,11: 1,02,1,21).   Conclusions:  Cough and sputum are more frequent in patients with COPD than those with restrictive ventilatory impairment. Dyspnea is a symptom more pronunced in patients with restrictive impairment compared with individuals with COPD in early stages of the disease.
Splenectomy inhibits tumor development and metastases in murine lung cancer models
Authors: Liran Levy, Inbal Mishalian, Zolotarob Lida, Rachel Bayuh, Zvi G. Fridlender
Journal: European Respiratory Journal (2012)

Introduction & Aims:  It has been shown that inhibitors of the immune system (e.g. myeloid derived suppressor cells) reside in the spleen and inhibit the endogenous anti-tumor effects of the immune system. We hypothesized that excision of the spleen (splenectomy) can inhibit growth of relatively big tumors, and reduce metastases by modulating systemic inhibition of the immune system. Our long-term goal is to implement mechanisms elucidated in these studies into future clinical trials.   Methods:  The clinical effect of splenectomy was evaluated in several murine lung cancer models. We compared immunological properties of blood and tumor after splenectomy or sham operation in tumor-bearing mice, using FACS analysis, RT-PCR and specific depletion studies.   Results:  We found that splenectomy reduces tumor growth, can induce their regression, and decreases metastases. These effects disappeared in NOD/SCID mice. No significant changes in cell types were found in the blood. Splenectomy increased the percentage out of total tumor cells of neutrophils (2.4% vs. 4.9%, p=0.012), and macrophages (10.9% vs. 14.4%, p=0.014), which tended to be less immune-inhibitory (non-M2/M2 macrophages ratio increased from 3.4 to 12.1, p=0.04). We further noted a tendency to increased activation of CD8 +  CTL (19.2% vs. 30%, p=0.09). Tumor microenvironment was found to be more pro-inflammatory following splenectomy (e.g. upregulation of MIG, TNF-α and IFN-γ). Using specific depletion of cells we evaluated the role of each cell in the effect of splenectomy.   Conclusions:  Splenectomy inhibits the development of tumors and metastases in murine models of lung cancer, by changing the amount and characteristics of myeloid cells.
Myocardial perfusion and oxygen consumption in reperfused noninfarcted dysfunctional myocardium after unstable angina
Authors: Bernhard L. Gerber, William Wijns, Jean-Louis J. Vanoverschelde, Guy R. Heyndrickx, Bernard De Bruyne, Jozef Bartunek, Jacques A. Melin
Journal: Journal of the American College of Cardiology (1999)
The new long-term patient in the public mental hospital: a follow-up
Authors: S R Platman, T C Booker
Journal: American Journal of Psychiatry (1984)

Of the 270 patients who had been hospitalized at least 1 year in Maryland public psychiatric facilities in 1976, 15% remained 7 years later. The authors' data provide evidence that a new long-term population is not accumulating in Maryland.
Inducible Gata1 suppression expands megakaryocyte-erythroid progenitors from embryonic stem cells
Authors: Ji-Yoon Noh, Shilpa Gandre-Babbe, Yuhuan Wang, Vincent Hayes, Yu Yao, Paul Gadue, Spencer K. Sullivan, Stella T. Chou, Kellie R. Machlus, Joseph E. Italiano, Michael Kyba, David Finkelstein, Jacob C. Ulirsch, Vijay G. Sankaran, Deborah L. French, Mortimer Poncz, Mitchell J. Weiss
Journal: Journal of Clinical Investigation (2015)

Transfusion of donor-derived platelets is commonly used for thrombocytopenia, which results from a variety of clinical conditions and relies on a constant donor supply due to the limited shelf life of these cells. Embryonic stem (ES) and induced pluripotent stem (iPS) cells represent a potential source of megakaryocytes and platelets for transfusion therapies; however, the majority of current ES/iPS cell differentiation protocols are limited by low yields of hematopoietic progeny. In both mice and humans, mutations in the gene-encoding transcription factor GATA1 cause an accumulation of proliferating, developmentally arrested megakaryocytes, suggesting that GATA1 suppression in ES and iPS cell–derived hematopoietic progenitors may enhance megakaryocyte production. Here, we engineered ES cells from WT mice to express a doxycycline-regulated (dox-regulated) shRNA that targets Gata1 transcripts for degradation. Differentiation of these cells in the presence of dox and thrombopoietin (TPO) resulted in an exponential (at least 1013-fold) expansion of immature hematopoietic progenitors. Dox withdrawal in combination with multilineage cytokines restored GATA1 expression, resulting in differentiation into erythroblasts and megakaryocytes. Following transfusion into recipient animals, these dox-deprived mature megakaryocytes generated functional platelets. Our findings provide a readily reproducible strategy to exponentially expand ES cell–derived megakaryocyte-erythroid progenitors that have the capacity to differentiate into functional platelet-producing megakaryocytes.
Osteoclastic giant cell tumor of the pancreas: A distinct clinical and pathologic entity.
Authors: N. A. Bhadkamkar, M. M. Javle, R. A. Wolff, W. D. Payne, D. Tan
Journal: Journal of Clinical Oncology (2010)

e14648 Background: Osteoclastic giant cell tumor of the pancreas (OGCTP) is a rare subtype of pancreatic cancer. It has been variably described in case reports as pancreatic cancer with pleomorphic, anaplastic, spindle cell, undifferentiated or mixed histology. Clinical and pathologic data regarding this tumor are very limited. Methods: We conducted a retrospective review of patient records with the above histologies at a single institution from 1994 to 2008. Archival pathology specimens were independently reviewed by two surgical pathologists (WP, DT). Results: Eleven patients with OGCTP were identified. Demographics: 9 males, median age = 66 (range 49-78), 10 Caucasian, 6 smokers. Median CA 19-9 was 70 IU/mL (range = 1.0-28,373). Site: 6 located in the body or tail, 5 locally advanced, 6 metastatic. A large, locally infiltrative mass was frequently seen on imaging studies. Pathologic examination revealed a histologically distinct entity consisting of a heterogeneous but characteristic mixture of bland osteoclast-like giant cells, mononuclear ovoid to spindle cells, large pleomorphic cells with bizarre nuclei, and a more typical adenocarcinoma component. This pattern was seen in all of the examined specimens. Treatment: 2 underwent surgical resection, 7 received gemcitabine or fluoropyrimidine chemotherapy, 3 received radiation. Response: Stable disease or partial response in 4 patients, 1 with long-term response to capecitabine. Median survival of 16.5 months (range = 2-58) was higher than usually noted historically with adenocarcinoma. Conclusions: This is the largest reported series of OGCTP and identifies this tumor as a distinct clinical and pathological entity. We are conducting additional pathologic studies to further characterize OGCTP. No significant financial relationships to disclose.
Abstract 3825: High DAPK expression is correlated with worse prognosis in colorectal cancer patients
Authors: Jelena Ivanovska, Inti Zlobec, Eva Diamantis-Karamitopoulou, Heather Dawson, Viktor Hendrik Koelzer, Abbas Agaimy, Fabian Garreis, William Laqua, Alessandro Lugli, Arndt Hartmann, Regine Schneider-Stock
Journal: Cancer Research (2014)

Abstract Objectives: Death-associated protein kinase (DAPK) is a cytoskeleton-associated serine/threonine kinase. It functions as a potent inhibitor of cell polarization and migration. DAPK loss has been shown to be associated with advanced tumor stages and unfavorable prognosis in many tumor types. However, the prognostic relevance of DAPK in patients with colorectal cancer is only poorly understood. Thus, we aimed to investigate the impact of DAPK protein expression on clinical outcome in patients with colorectal cancer. Methods: Samples from 220 colorectal cancer patients with a median follow-up of 60 months were analyzed for immunohistochemical DAPK protein expression on tissue microarrays. The effect of endogenous DAPK protein expression on cell migration was analyzed applying the ECIS system (electric cell-substrate impedance sensing) with stable DAPK knockdown (shRNA) and DAPK overexpressing cell lines generated from HCT116 wild type colon cancer cells. Colony formation ability was analyzed using soft agar assay. Results: In Kaplan-Meier-curve analysis DAPK loss was associated with longer survival time (p&amp;lt; 0.001). The 5-year survival rates were 52.3% and 25.6% in patients with DAPK negative tumors and DAPK positive tumors, respectively. 76.1% of DAPK positive tumors showed evidence of tumor budding. After adjusting for TNM stage in multivariate Cox regression analysis, DAPK retained its strong independent prognostic value. Patients with DAPK overexpressing tumors had a 1.9 times increased risk of death from the tumor than those with DAPK negative tumors. DAPK expression in tumor center showed a loss of expression toward the front (p=0.0126). This was in agreement with ECIS migration results indicating higher migration rate for DAPK shRNA cells. DAPK wild type cells showed an increased number of colonies in soft agar assay in comparison to other cell types. Colony formation ability showed time-dependent effects for DAPK overexpression. Conclusion: In contrast to the well-known function of DAPK as a tumor suppressor, our data showed DAPK overexpression to be associated with aggressiveness of tumors and an unfavorable outcome. This interesting and new finding has to be further evaluated. Citation Format: Jelena Ivanovska, Inti Zlobec, Eva Diamantis-Karamitopoulou, Heather Dawson, Viktor Hendrik Koelzer, Abbas Agaimy, Fabian Garreis, William Laqua, Alessandro Lugli, Arndt Hartmann, Regine Schneider-Stock. High DAPK expression is correlated with worse prognosis in colorectal cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3825. doi:10.1158/1538-7445.AM2014-3825
Identification of new therapeutic targets in breast cancer using chromatin engineering
Authors: Hasmawati Yahaya, Harun Roslan
Journal: Clinical Cancer Research (2007)

AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore

C37 

Introduction : Estrogen plays a pivotal role in breast cancer development and estrogen receptors are major therapeutic targets in breast cancer treatment. Nonetheless, almost 30% of ERα-positive tumors fail to respond to anti-estrogen therapy and importantly a large proportion of patients presenting with primary breast cancer and all patients with metastatic disease at first presentation become resistant to anti-estrogen therapies. An alternative approach involves the use of inhibitors of the enzymes in the estrogen biosynthetic pathway, namely aromatase inhibitors. Despite the effectiveness of these inhibitors, many patients, however, develop resistance. Interestingly, a considerable proportion of patients who become resistant to tamoxifen often respond to alternative anti-estrogens or to aromatase inhibitors in the first instance, indicative of a continued role for ERα in disease progression. These observations suggest that inhibiting estrogen-regulated gene expression, as opposed to inhibiting ER activity, is likely to be of significant therapeutic value and may be useful in the treatment of breast disease that becomes refractory to endocrine therapies.    Methods : Using chromatin engineering, we have modified the estrogen-responsive MCF-7 breast cancer cell line, such that estrogen-regulated gene expression and growth can be conditionally inhibited. In nude mice, the modified cells no longer form tumors, showing that key estrogen-regulated genes are repressed. Proteomic analysis has been used to identify candidate proteins that are responsible for mediating estrogen-regulated growth in MCF-7 cells, by comparing profiles of estrogen-regulated protein expression between chromatin engineered and parental cell lines.    Results : The use of proteomic studies and have led to the identification of proteins involved in cell growth. The proteomic analysis was found to be of limited utility, but did result in the identification of two proteins which act in a novel complex recently found to be involved in mediating a caspase independent apoptosis pathway. Taken together, these studies highlight the potential for novel chromatin engineered cell lines used in this work for the identification of new targets for breast cancer.
MicroRNA-551b is highly expressed in hematopoietic stem cells and a biomarker for relapse and poor prognosis in acute myeloid leukemia
Authors: D C de Leeuw, H J M P Verhagen, F Denkers, F G Kavelaars, P J M Valk, G J Schuurhuis, G J Ossenkoppele, L Smit
Journal: Leukemia (2015)
High-dose inhaled steroids in asthmatics: moderate efficacy gain and suppression of the hypothalamic-pituitary-adrenal (HPA) axis. Research Council of the Norwegian Thoracic Society
Authors: J Boe, P Bakke, T Rodolen, E Skovlund, A Gulsvik
Journal: European Respiratory Journal (1994)

We wanted to evaluate the improvement in efficacy when increasing the daily dose of inhaled steroids and to compare the efficacy, safety, and tolerance of 1.6 mg beclomethasone dipropionate (BDP) with that of 2.0 mg fluticasone propionate (FP). The study was a randomized, double-blind, 3 month, multicentre study. One hundred and thirty four asthmatics currently using inhaled steroids (0.4-1.6 mg BDP or budesonide (BUD)) were stratified according to pretrial daily steroid use. Within each stratum they were randomized to either 1.6 mg BDP or 2.0 mg FP. A significant increase in the primary efficacy variables, i.e. mean morning and evening peak expiratory flow (PEF) (approximately 20 l.min-1) during the treatment period, was found for both treatments. No significant differences between the drugs were revealed for these primary or any other secondary efficacy variables (use of beta 2-agonists, symptom scores, and PEF, forced vital capacity (FVC), forced expiratory volume in one second (FEV1) recorded at the clinical visits). However, significant differences between treatments occurred regarding decrease of serum cortisol and adrenocorticotropic hormone. We conclude that, although both treatments gave statistically significant increases in efficacy parameters when compared with baseline, the increases were so small that they can be regarded as being clinically unimportant. Daily doses of BDP, 1.6 mg, and FP, 2.0 mg, had comparable effects on lung function. A suppression of the hypothalamic pituitary adrenal (HPA) axis was only found with a daily dose of 2 mg FP.
Perioperative Intravesical Chemotherapy in Non–Muscle-Invasive Bladder Cancer: A Systematic Review and Meta-Analysis
Authors: Michael R. Abern, Richmond A. Owusu, Mark R. Anderson, Edward N. Rampersaud, Brant A. Inman
Journal: Journal of the National Comprehensive Cancer Network (2013)

The role for a single dose of intravesical chemotherapy (IVC) after transurethral resection (TUR) remains unclear in patients with non–muscle-invasive bladder cancer (NMIBC). Several recent randomized clinical trials (RCTs) have evaluated its effect on recurrence, prompting this systematic review of RCTs comparing a single immediate postoperative dose of IVC versus placebo within 24 hours of TUR of NMIBC, and this meta-analysis using a random-effects model to predict the pooled relative risk (RR) of tumor recurrence. Subanalyses pooled studies by drug type and a meta-regression was performed to determine the effect of underlying patient risk factors on the efficacy of a single dose of IVC. A total of 3103 patients were randomized in the 18 RCTs that met inclusion criteria. The recurrence rate in patients receiving perioperative IVC and TUR was 37% versus 50% in the TUR-alone group. The pooled RR of recurrence for IVC and TUR was 0.67 (95% CI, 0.56–0.79), corresponding to a 13% absolute reduction and a number needed to treat of 7.2 patients to avoid 1 recurrence. The proportions of patients with tumor risk factors (T1, high-grade, multifocal, or recurrent) were not associated with IVC efficacy. A single dose of IVC administered within 24 hours of TUR of NMIBC was found to result in a reduction in tumor recurrence (RR, 0.67; 95% CI, 0.56–0.79). Patients with higher-risk tumor features seem to benefit at a similar rate.