tbuckley/cabot-search huggingface dataset:
Resting energy expenditure and adipose tissue leptin expression in patients with COPD
Authors: Miroslav Brusik, Peter Skyba, Pavol Pobeha, Jozef Ukropec, Barbara Ukropcova, Daniela Gasperikova, Ruzena Tkacova, Pavol Joppa
Journal: European Respiratory Journal (2011)

Aim:  Increases in resting energy expenditure (REE) have been previously shown in wasting COPD patients. Decreased leptin levels have been associated with weight loss in patients with emphysema, however, adipose tissue (AT) leptin expression has not been studied previously in COPD. Our scope was to investigate the REE, leptin AT expression and serum levels in patients with COPD and different BMI.   Methods:  44 patients with stable COPD were divided into 3 groups: Group 1 with BMI ≤20kg/m 2  (n=9, 9 males, 61.4±8.2 years, FEV 1  33.8±19.8%), Group 2 with BMI 20-30kg/m 2  (n=24, 20 males, 62.8±5.9 years, FEV 1  59.4±22.7%) and Group 3 with BMI >30kg/m 2  (n=11, 9 males, 60.2±8.0 years, FEV 1  60.5±19.0%). REE was measured by indirect calorimetry using a ventilated hood system. Samples of subcutaneous AT were obtained by percutaneous biopsy. AT gene expression was measured in duplicates with aid of the real-time PCR using the TaqMan gene expression assays.   Results:  REE per kg of body weight (REE/kg) decreased from Group 1 to Group 2 and 3 (32.9±6.1 vs 26.2±5.8 vs 23.9±6.6 kcal/kg/24 h, p=0.006), whereas leptin AT expression (ΔΔCt) and serum leptin levels increased (8.8±9.4 vs 44.1±20.9 vs 58.1±15.8, p   Conclusion:  In patients with stable COPD resting metabolic rate increased with decreasing BMI, in association with reductions in AT leptin expression. Low leptin AT production is associated with hypermetabolism in lean COPD patients.  Support: VEGA 1/0227/11 and VVGS 36/10-11.
A novel splice site mutation in<i>NCSTN</i>underlies a Japanese family with hidradenitis suppurativa
Authors: Y. Nomura, T. Nomura, K. Sakai, K. Sasaki, Y. Ohguchi, O. Mizuno, H. Hata, S. Aoyagi, R. Abe, Y. Itaya, M. Akiyama, H. Shimizu
Journal: British Journal of Dermatology (2012)

Hidradenitis suppurativa (HS) is a chronic follicular occlusive disease with characteristic recurrent draining sinuses, skin abscesses and disfiguring scars, mainly involving the axilla, groin, perianal and perineal regions. While most HS cases are nonfamilial, familial cases showing autosomal dominant inheritance have been reported. Recently, loss-of-function mutations in the genes encoding γ-secretase have been identified as a cause of familial HS in the Chinese and British populations. To identify mutations in the genes encoding γ-secretase in Japanese patients with familial and nonfamilial HS. Two affected and three unaffected individuals from a Japanese family with familial HS and nine patients with nonfamilial HS were recruited. We conducted mutation analysis of the γ-secretase genes in Japanese patients with familial and nonfamilial HS. A novel splice site mutation in the nicastrin gene NCSTN, one of the six key component genes encoding γ-secretase, was identified in the patients with familial HS. Neither unaffected individuals in the family nor 100 ethnically matched control alleles carry this mutation. None of the nine patients with nonfamilial HS carry nonsense, frameshift or splice site mutations in this gene. A novel splice site mutation, c.582+1delG, in NCSTN was identified in the familial patients with HS. We also reveal for the first time that a γ-secretase gene mutation is not linked to the development of nonfamilial HS. These results would further pave the way to a better understanding of the contribution of γ-secretase and other genes to the pathogenesis of HS and to the development of a new therapeutic strategy for HS.
Specific Antigens of a Chemically Induced Tumor; Detection by Complement Fixation
Authors: Nile L. Albright, George H. Myers
Journal: JNCI Journal of the National Cancer Institute (1972)

Tumor antigens of a methylcholanthrene-induced sarcoma (MCA-A) were detected with the microcomplement fixation technique. Sera from strain-2 guinea pigs given repeated intradermal inoculations of viable MCA-A tumor cells contained a complement-fixing antibody that reacted specifically with antigens prepared from the immunizing tumor, but not with antigens from another methylcholanthreneinduced sarcoma (MCA-25) or with antigens prepared from normal tissues. A significant complementfixation titer could be detected with antigens prepared both from freshly excised tumor or a tissue culture cell line of the MCA-A tumor.
Directed Neural Stem Cell Differentiation with a Functionalized Graphene Oxide Nanocomposite
Authors: Cassandra L. Weaver, Xinyan Tracy Cui
Journal: Advanced Healthcare Materials (2015)

Neural stem cell (NSC) transplantation has the potential to restore function to diseased or damaged nervous tissue, but poor control over cell survival, differentiation, and maturation limits therapeutic prospects. Engineered scaffolds that have the ability to drive neural stem cell behavior can address these limitations facing cell transplantation. Conducting polymers, which have the ability to electrically interface with cells, are attractive scaffolding candidates, but they lack the capacity for simple covalent modification, which would enable surface patterning of biomolecules. In this work, the NSC scaffolding performance of a nanocomposite composed of conducting polymer poly(3,4‐ethylenedioxythiophene) (PEDOT) and graphene oxide (GO) nanosheets (GO/PEDOT) is investigated. The GO/PEDOT material is nontoxic and improves NSC differentiation toward the neuronal lineage. Biomolecules interferon‐γ (IFNγ) and platelet‐derived growth factor (PDGF) that selectively promote neuronal or oligodendrocyte lineage differentiation, respectively, are covalently cross‐linked to the surface of the GO/PEDOT nanocomposite via carboxylic acid functional groups provided by GO using carbodiimide chemistry. The surfaces support a larger population of neurons when modified with IFNγ and a larger population of oligodendrocytes when modified by PDGF. This work demonstrates the customizability of GO/PEDOT for cell scaffolding applications and underlines its potential for controlling NSC behavior to improve therapeutic potential.
Immunoregulatory effects of isotretinoin in patients with acne
Authors: A.S. Karadag, D.T. Ertugrul, S.G. Bilgili, Z. Takci, K.O. Akin, O. Calka
Journal: British Journal of Dermatology (2012)

In vitro studies have shown that retinoids influence T-cell differentiation.To study the effect of isotretinoin on T-cell differentiation markers in patients with acne.A total of 37 patients with acne vulgaris (25 female, 12 male, age 19.6 ± 3.7 years) and 30 age- and sex-matched healthy controls (19 female, 11 male, age 20.5 ± 4.4 years) were included in the study. Screening for biochemical parameters in serum samples were done just before initiation (pretreatment) and after 3 months of isotretinoin treatment (post-treatment) in the acne group.Baseline levels of tumour necrosis factor (TNF)-α (P<0.0001), interleukin (IL)-4 (P<0.0001), IL-17 (P<0.0001) and interferon (IFN)-γ (P=0.002) were significantly higher in the acne group compared with the control group. TNF-α (P<0.0001), IL-4 (P<0.0001), IL-17 (P<0.0001) and IFN-γ (P<0.0001) levels decreased after isotretinoin treatment. TNF-α and IL-4 values after isotretinoin treatment were similar to those of the control group. However, levels of IL-17 (P<0.0001) after isotretinoin treatment were higher than those of the control group, despite a significant decline after treatment. Levels of IFN-γ (P<0.0001) after isotretinoin treatment were lower than those of the control group.This study shows that isotretinoin treatment significantly decreases TNF, IL-4, IL-17 and IFN-γ levels in patients with acne. We failed to show that isotretinoin redirects naive T helper (Th) differentiation preferentially towards the Th2 cell lineage.
Health state and the quality of life in patients with chronic obstructive pulmonary disease (COPD) in Poland: A study using the EuroQoL-5D questionnaire
Authors: Piotr Boros, Wojciech Lubinski
Journal: European Respiratory Journal (2012)

Introduction: Chronic obstructive pulmonary disease (COPD) is a severe disease that leads to respiratory disability and a considerably reduced comfort of living that affects all the aspects of patient activity.  Objectives: The aim of our study was to assess the quality of life (QoL) in patients with diagnosed COPD using, as the research tool, EuroQoL-5D, a health-related QoL questionnaire.  Patients and methods: The data were obtained using designed questionnaire by conducting a cross-sectional survey in a large (N=9310) group of patients with COPD.  Results: Mild and moderate COPD patients (GOLD stage 1 and 2) constituted the majority of the study population (16% and 54%, respectively). A perceptible COPD-related low health state was shown for each stage of the disease, including patients with mild to moderate COPD. Significant differences were observed between the groups of patients stratified by spirometry results in perceived health state assessed with the questionnaire and on a visual analogue scale (VAS). Using linear regression models the association between the health status measured using VAS scale and comorbidities (especially heart failure), and severe (or very severe) COPD status were found (p  Conclusions: EQ-5D along with VAS seems to be a useful tool to characterise health state of patients with COPD. It is noteworthy that also in the milder stages of the disease there are limitations in various life aspects that are important to the patients.
Revised guideline for prescribing vigabatrin in children
Authors: A. L Lux
Journal: BMJ (2001)

Editor—The Vigabatrin Paediatric Advisory Group, which in 1998 produced a guideline to “help clinicians when prescribing vigabatrin in children,” has now revised it.1,2 We, the steering committee of the United Kingdom infantile spasm study (UKISS), responded to the original guideline.3 Our opinion was that there is no evidence that vigabatrin is a better treatment of infantile spasms than hormonal treatments, such as prednisolone and synthetic adrenocorticotrophic hormone preparations.

When we challenged the claim that vigabatrin is the drug of choice, the advisory group offered no rebuttal. Now the claim is stated again, without any appropriate new evidence being produced. Indeed, the finding that visual field losses attributable to vigabatrin occur in children as well as adults strengthens any challenge to the guideline's claim.

We stand by our argument that no one has yet determined the best first line treatment for infantile spasms. To back our challenge we cited the one randomised trial that has compared vigabatrin and adrenocorticotrophic hormone; confidence intervals for this suggest that vigabatrin is unlikely to have a superior treatment effect.4 Also, we pointed to a lack of studies using neurodevelopmental outcome measures and to new and emerging information about the safety of vigabatrin.

Our desire to gather reliable data is shared by many paediatricians and paediatric neurologists: consultants in over 140 health districts are helping our study to collect evidence about these treatments. Before clinicians can decide if any of the first line treatments for infantile spasms might reasonably be described as the drug of choice they will need to examine (when they become available) the results of studies such as the United Kingdom infantile spasm study.
A Randomized, Placebo-controlled Trial of Roflumilast. Effect on Proline-Glycine-Proline and Neutrophilic Inflammation in Chronic Obstructive Pulmonary Disease
Authors: J. Michael Wells, Patricia L. Jackson, Liliana Viera, Surya P. Bhatt, Joshua Gautney, Guy Handley, R. Wilson King, Xin Xu, Amit Gaggar, William C. Bailey, Mark T. Dransfield, J. Edwin Blalock
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Rationale: Roflumilast is a therapeutic agent in the treatment of chronic obstructive pulmonary disease (COPD). It has antiinflammatory effects; however, it is not known whether it can affect a biologic pathway implicated in COPD pathogenesis and progression. The self-propagating acetyl-proline-glycine-proline (AcPGP) pathway is a novel means of neutrophilic inflammation that is pathologic in the development of COPD. AcPGP is produced by extracellular matrix collagen breakdown with prolyl endopeptidase and leukotriene A4 hydrolase serving as the enzymes responsible for its production and degradation, respectively.Objectives: We hypothesized that roflumilast would decrease AcPGP, halting the feed-forward cycle of inflammation.Methods: We conducted a single-center, placebo-controlled, randomized study investigating 12 weeks of roflumilast treatment added to current therapy in moderate-to-severe COPD with chronic bronchitis. Subjects underwent sputum and blood analyses, pulmonary function testing, exercise tolerance, and quality-of-life assessment at 0, 4, and 12 weeks.Measurements and Main Results: Twenty-seven patients were enrolled in the intention-to-treat analysis. Roflumilast treatment decreased sputum AcPGP by more than 50% (P < 0.01) and prolyl endopeptidase by 46% (P = 0.02), without significant improvement in leukotriene A4 hydrolase activity compared with placebo. Roflumilast also reduces other inflammatory markers. There were no significant changes in lung function, quality of life, or exercise tolerance between roflumilast- and placebo-treated groups.Conclusions: Roflumilast reduces pulmonary inflammation through decreasing prolyl endopeptidase activity and AcPGP. As expected for lower AcPGP levels, markers of neutrophilic inflammation are blunted. Inhibiting this self-propagating pathway lessens the overall inflammatory burden, which may alter the natural history of COPD, including the risk of exacerbation.Clinical trial registered with www.clinicaltrials.gov (NCT 01572948).
PD-L1 and HLA Class I Antigen Expression and Clinical Course of the Disease in Intrahepatic Cholangiocarcinoma
Authors: Francesco Sabbatino, Vincenzo Villani, Jennifer H. Yearley, Vikram Deshpande, Lei Cai, Ioannis T. Konstantinidis, Christina Moon, Sjoerd Nota, Yangyang Wang, Ahmad Al-Sukaini, Andrew X. Zhu, Lipika Goyal, David T. Ting, Nabeel Bardeesy, Theodore S. Hong, Carlos Fernandez-del Castillo, Kenneth K. Tanabe, Keith D. Lillemoe, Soldano Ferrone, Cristina R. Ferrone
Journal: Clinical Cancer Research (2015)

More effective therapy is needed for intrahepatic cholangiocarcinoma (ICC). The encouraging clinical results obtained with checkpoint molecule-specific monoclonal antibodies (mAb) have prompted us to investigate whether this type of immunotherapy may be applicable to ICC. The aims of this study were to determine whether (i) patients mount a T-cell immune response to their ICC, (ii) checkpoint molecules are expressed on both T cells and tumor cells, and (iii) tumor cells are susceptible to recognition by cognate T cells.Twenty-seven ICC tumors were analyzed for (i) lymphocyte infiltrate, (ii) HLA class I and HLA class II expression, and (iii) PD-1 and PD-L1 expression by T cells and ICC cells, respectively. The results of this analysis were correlated with the clinicopathologic characteristics of the patients investigated.Lymphocyte infiltrates were identified in all tumors. PD-L1 expression and HLA class I antigen expression by ICC cells was observed in 8 and 11, respectively, of the 27 tumors analyzed. HLA class I antigen expression correlated with CD8(+) T-cell infiltrate. Furthermore, positive HLA class I antigen expression in combination with negative/rare PD-L1 expression was associated with favorable clinical course of the disease.ICC patients are likely to mount a T-cell immune response against their own tumors. Defects in HLA class I antigen expression in combination with PD-L1 expression by ICC cells provide them with an immune escape mechanism. This mechanism justifies the implementation of immunotherapy with checkpoint molecule-specific mAbs in patients bearing ICC tumors without defects in HLA class I antigen expression.
Improved outcome with delayed intensification for children with acute lymphoblastic leukemia and intermediate presenting features: a Childrens Cancer Group phase III trial.
Authors: D G Tubergen, G S Gilchrist, R T O'Brien, P F Coccia, H N Sather, M J Waskerwitz, G D Hammond
Journal: Journal of Clinical Oncology (1993)

PURPOSE The Berlin-Frankfurt-Munster (BFM) 76/79 trial of acute lymphoblastic leukemia (ALL) in children produced impressive disease-free survival (DFS) rates with a protocol that began with 8 weeks of intensive therapy, followed by 8 weeks of maintenance therapy, and then another 6 weeks of intensive treatment. The current study was conducted to determine the relative contributions of each of these periods of intense therapy on the DFS rates of ALL patients with intermediate presenting features. In addition, due to concerns regarding the toxicity of CNS irradiation, we compared cranial irradiation (CXRT) with intrathecal methotrexate (IT MTX) administered during induction and consolidation to IT MTX during all phases of the treatment program. PATIENTS AND METHODS Between May 1983 and April 1989, more than 1,600 children with ALL and intermediate presenting features, as defined by the Childrens Cancer Group (CCG), were entered into a randomized trial that tested four systemic therapy regimens and two CNS programs. RESULTS The results with a median follow-up of 57 months show that systemic regimens with a delayed intensification (Delint) phase of therapy had a 5-year event-free survival (EFS) rate of 73% compared with the control regimen EFS rate of 61% (p = .006). For children less than 10 years of age, standard three-drug induction and Delint produced a 77% 5-year EFS. IT MTX during all phases of therapy provided CNS protection comparable to the CXRT regimen in children less than 10 years of age. Children 10 years of age or older appear to have a better EFS rate with intensive induction, Delint, and CXRT. CONCLUSION Delint improves the EFS rate of children with ALL and intermediate presenting features. Maintenance IT MTX can be safely substituted for CXRT for presymptomatic CNS therapy in children with intermediate-risk characteristics less than 10 years of age.
Population pharmacokinetic and pharmacodynamic (PK-PD) parameters of Erwinia Chrysanthemi (ERW) asparaginase (ASNase) using the fused first-order elimination and Michaelis-Menten (MM) limited physiological model
Authors: V. I. Avramis, C. Fu
Journal: Journal of Clinical Oncology (2007)

13010 Background: Using the linear PK first order (FO) compartmental approach, the methodical and computational uniformity in modeling various linear systems (ERW) is the dominant characteristic of the population PK analyses. However, saturation of the enzymatic reaction results in nonlinear kinetics based on the MM equation, i.e., the deamination of ASN by ERW, which complicates the PK-PD model. The PK with FO &amp; the MM PK-PD model is theoretically better when single dose of ERW is given. To simulate the PK-PD data and to project patient (pt) data using this model, we used simultaneous integration of the FO+MM equations. Methods: In the 1990’s, ERW was used in pediatric ALL pt (n=23, 1 st cohort evaluated for PK-PD). The current study was started to assess if the parallel MM+FO (MM+FO) PK-PD model fit the limited ERW (25K) data better than the MM model, and to validate the MM+FO model and its population parameter estimates. Results: The population PK-PD model best-fitted serum ERW &amp; ASN-time pairs obtained in 23 and from 5 pediatric pt with ALL, using nonlinear mixed-effects modeling (NONMEM). The validity of the MM+FO population PK-PD model and the estimated parameters were tested using the naive prediction method. Patients were administered ERW 6K or 25 K IU/m 2 when allergy to E. coli formulations appeared. High correlation between ERW peak serum levels calculated from limited individual pt’ KM (900 μM) &amp; Vmax values in 5 pediatric pt (2 nd cohort) and the observed ERW trough levels &amp; its substrate (ASN) were found. The T1/2 averaged 16 hr (25K ERW), and the trough level of 0.1–0.2 IU/ml was correlated with ASN &lt;3 μM. These PK-PD parameters validated those obtained from the 1 st cohort. When simulations on population parameters were conducted, the MM+FO predicted the multiple dose steady-state serum ERW &amp; ASN levels nicely. Therefore, the MM+FO model was clearly superior to either the FO or the MM PD models. Moreover, simulations compared favorably ERW 25K Q2 days x3 doses &amp; x2 weeks vs. Pegaspargase 2,5K Q2 weeks. Conclusions: The NONMEM PK-PD model for ERW fitted the simultaneous analyses of data from different doses and regimens better than either standard Two-stage or MM could. No significant financial relationships to disclose.
Double deletion of tetraspanins CD9 and CD81 in mice develops COPD-like phenotype with a syndrome resembling aging
Authors: Yoshito Takeda, Yingji Jin, Yasushi Kondo, Mari Ito, Isao Tachibana, Atsushi Kumanogoh
Journal: European Respiratory Journal (2013)

Tetraspanins are four membrane-spanning proteins that function as the organizers of membrane microdomains. Tetraspanins associate with other membrane-bound molecules such as integrins, and growth factor receptors, thereby regulating key cellular processes such as adhesion, migration, and differentiation. Among 33 tetraspanins, CD9 and CD81 are widely distributed, and are closely related tetraspanins. We previously showed that CD9/CD81 double-knockout (DKO) mice spontaneously developed pulmonary emphysema, weight loss, and osteoporosis. Moreover, expression of CD9 and CD81 in macrophages was down-regulated after cigarette smoke exposure. Recently, increasing attention has been paid to aging because the pahthogenesis of aging would underlie most of the diseases such as cardiovascular diseases, and lung diseases. Therefore, we sought to analyze the further phenotype and its underlying mechanism in DKO mice.

Here, we found that DKO mice leads to a syndrome resembling human aging, including a short lifespan, cataract, hair loss, skin atrophy, and muscle atrophy associated with augmented inflammation. In addition, these macroscopic phenotypes were further validated by histological analysis. Consistent with these phenotypes, we identified an enrichment of genes involved in ‘aging-related genes’ in the lungs of DKO mice by DNA Microarray. Among them, we found that CD9 and CD81 additively regulated SIRT-1 as well as cell cycle regulators such as p21, p53 and p16. Therefore, deletion of these tetraspanins affected cell proliferation and apoptosis. Collectively, CD9/CD81 DKO mice could be a novel mouse model for COPD, but also accerelated senescence.