tbuckley/cabot-search huggingface dataset:
CYP3A5*3 and CYP3A4*1B polymorphisms are associated and more frequent in NSCLC tumors than in normal volunteers
Authors: J. M. Kolesar, A. Breunig, J. Miller, P. Stephenson, H. McLeod, S. Marsh, S. Keller, D. Johnson, J. H. Schiller
Journal: Journal of Clinical Oncology (2004)

2016 Background:. CYP3A4 and CYP3A5 are monooxygenases that metabolize tobacco, endogenous steroids, and numerous anti-cancer agents. The CYP3A4*1B polymorphism leads to increased promotor activity and is associated with small cell lung cancer. The CYP3A5*3 polymorphism causes decreased protein levels and is associated with an increased risk for non small cell lung cancer (NSCLC). Methods: Genomic DNA isolated from primary lung tumor and matched normal nodes from subjects with NSCLC enrolled in E3590 and from peripheral blood mononuclear cells from normal volunteers was evaluated for six CYP3A4/5 polymorphisms by pyrosequencing. Samples were designated as wild-type (WT), heterozygote or homozygous variant for each of the polymorphisms, and differences were evaluated by Chi square analysis and exact binomial confidence intervals were computed for proportions. Results: There were 187 primary tumors with 51 matched nodes and 95 normal volunteers analyzed. Homozygous polymorphisms in CYP3A4/*1B were identified in 2.9% of the tumors, 0.2% of the matched normal nodes and 0% of the normal volunteers. Homozygous polymorphisms in CYP3A5/*3 were identified in 5% of the tumors, 2% of the matched normal nodes and 0% of the normal volunteers. Polymorphisms in CYP3A4/*1B and CYP3A5/*3 were significantly associated (p=0.0001) and both polymorphisms were more common in tumors than in normal volunteers (CI 0.01–0.067 for CYP3A4/*1B, and 0.021–0.105 for CYP3A5/*3). Conclusions: The CYP3A5*3 and 4*1B polymorphisms are associated and occur more frequently in tumors from individuals with NSCLC than in the normal population. Individuals with the CYP3A5*3/4*1B genotype are expected to have high levels of CYP3A4 activity and very little CYP3A5 activity, which may be important in the metabolism of carcinogens such as tobacco smoke and the biotransformation of numerous anti-cancer agents. No significant financial relationships to disclose.
The impact of MRC classification on daily physical activity and physical health-related quality of life in mild to moderate COPD
Authors: Hans Van Remoortel, Miek Hornikx, Heleen Demeyer, Kristien De Bent, Erica Balligand, Laurence Vrancken, Chris Burtin, Daniel Langer, Marc Decramer, Rik Gosselink, Wim Janssens, Thierry Troosters
Journal: European Respiratory Journal (2012)

Dyspnea, reduced physical activity (PA) and impaired health-related quality of life (HRQL) are common features in COPD. This study aimed to investigate the impact of dyspnea on PA and HRQL in mild/moderate COPD.  Fifty-three subjects with COPD and 60 smoking controls were recruited. Medical Research Council (MRC) classified patients by symptoms of dyspnea. The SenseWear Armband was worn for 7 days and time spent in at least moderate intense PA and amount of steps served as PA estimates. HRQL was assessed by the SF-36 physical functioning score and the EQ5D general health VAS score.  Moderate intense PA was significantly reduced in MRC1 COPD compared to MRC1 smokers and tended to be lower versus MRC0 COPD (p=0.10). A trend for reduced daily steps in MRC1 COPD was observed versus MRC1 smokers and MRC0 COPD, p=0.09. MRC1 COPD reported reduced physical functioning and VAS scores versus MRC1 smokers and MRC0 COPD (70±19 vs 81±13 vs 91±7 for physical functioning, p  PA levels are reduced in symptomatic patients with mild to moderate COPD. MRC classification, as proposed by the new GOLD guidelines, is useful in identifying reductions in PA and (physical) HRQL, even in the early stages of COPD.
Gravity dependence of specific ventilation (SV), Hounsfield unit (ΔHU) and specific gas volume (ΔSVg) variations assessed by high resolution (HR) CT
Authors: Francesca Pennati, Caterina Salito, Guido Baroni, Jason Woods, Andrea Aliverti
Journal: European Respiratory Journal (2013)

To compare the gravity dependence of the CT-based parameters proposed as lung function descriptors, namely ΔHU, SV (Simon et al, JClinMonitComput 2000) and ΔSVg (Salito et al, Radiology 2009),we quantified their vertical gradient in six supine healthy volunteers, scanned at TLC and RV by HRCT. ΔHU (HU RV -HU TLC ), SV and ΔSVg (SVg, TLC -SVg, RV ) were mapped voxel-by-voxel after registering TLC onto RV (Fig.1). The gravitationally-dependent gradients of ΔHU, SV and ΔSVg were significantly different, respectively 54.6±9.8%, 53.1±11.3%, 19.7±9.7% (p  Results show that ΔHU and SV percent vertical gradient is more than twice ΔSVg increase. The lower gravity-dependence of ΔSVg suggests this parameter as more reliable to discriminate healthy from pathological regions.
Human Alveolar Macrophage-derived Chemotactic Factor for Neutrophils
Authors: Gary W. Hunninghake, James E. Gadek, Henry M. Fales, Ronald G. Crystal
Journal: Journal of Clinical Investigation (1980)

The presence of neutrophils within the lung is a characteristic feature of a variety of lung diseases. To evaluate the potential role of alveolar macrophages in modulating the migration of neutrophils to the lung, normal human alveolar macrophages obtained from volunteers by bronchopulmonary lavage, were exposed for various periods of time in vitro to heat-killed microorganisms, and noninfectious particulates, immune complexes, and the macrophage supernates were evaluated for chemotactic activity. The microorganisms, noninfectious particulates, and immune complexes were chosen as stimuli for alveolar macrophages because these stimuli are representative of a spectrum of pathogenic agents that cause neutrophil accumulation in the lower respiratory tract. After incubation with each of these stimuli, alveolar macrophages released low molecular weight (400-600) chemotactic factor(s) (alveolar macrophage-derived chemotactic factor[s] [AMCF]) with relatively more activity for neutrophils than monocytes or eosinophils. Checker-board analysis of the AMCF revealed that the factor was primarily chemotactic and not chemokinetic for neutrophils. The selectivity for neutrophils vs. monocytes could not be explained by a selective deactivation of monocytes, because the AMCF was more potent in deactivating neutrophils than monocytes. Partial characterization of AMCF demonstrated it was heterogeneous with the following features: (a) stable to heating at 56 and 100 degrees C for 30 min; (b) stable over a pH range of 1.0 to 12.0 for 60 min; (c) stable after exposure to trypsin, papain, chymotrypsin, collagenase, and elastase; (d) partially inhibited by serum chemotactic factor inhibitor(s); (e) two major isoelectric points (pI 7.6 and 5.2); and (f) partially extractable into ethyl acetate, ether, and hexane. Although AMCF was, at least, partially lipid in nature, it did not appear to be similar to previously described lipid chemotactic factors (e.g., hydroxy-derivatives of 5,8,10,14-eicosatetraenoic acid); analysis by gas chromatography-mass spectrophotometry of AMCF extracted into ethyl acetate did not reveal the presence of 5,8,10,14-eicosatetraenoic acid. The macrophage supernates containing the AMCF also stimulated normal human neutrophils to release lysozyme and lactoferrin but not lactate dehydrogenase. These studies suggest that a wide variety of potentially pathogenic stimuli induce normal alveolar macrophages to generate a low molecular weight chemotactic factor(s) that preferentially attracts neutrophils. Because alveolar macrophages are normal residents of alveoli, it is likely that by releasing this factor(s) macrophages play a significant role in amplifying the inflammatory processes seen in many acute and chronic lung diseases.
The lysophosphatidylserine receptor GPR174 constrains regulatory T cell development and function
Authors: Michael J. Barnes, Chien-Ming Li, Ying Xu, Jinping An, Yong Huang, Jason G. Cyster
Journal: The Journal of Experimental Medicine (2015)

Regulatory T cell (T reg cell) numbers and activities are tightly calibrated to maintain immune homeostasis, but the mechanisms involved are incompletely defined. Here, we report that the lysophosphatidylserine (LysoPS) receptor GPR174 is abundantly expressed in developing and mature T reg cells. In mice that lacked this X-linked gene, T reg cell generation in the thymus was intrinsically favored, and a higher fraction of peripheral T reg cells expressed CD103. LysoPS could act in vitro via GPR174 to suppress T cell proliferation and T reg cell generation. In vivo, LysoPS was detected in lymphoid organ and spinal cord tissues and was abundant in the colon. Gpr174−/Y mice were less susceptible to experimental autoimmune encephalomyelitis than wild-type mice, and GPR174 deficiency in T reg cells contributed to this phenotype. This study provides evidence that a bioactive lipid, LysoPS, negatively influences T reg cell accumulation and activity through GPR174. As such, GPR174 antagonists might have therapeutic potential for promoting immune regulation in the context of autoimmune disease.
Variability in AHI and mean pressure over time in OSA patients treated with APAP
Authors: Sriram Chandramouli, Dorothy Price, Jennifer Furlong, Syed Huq, Justine Hadcroft
Journal: European Respiratory Journal (2011)

Background: In patients with obstructive sleep apnoea (OSA), studies have shown that automatic positive airway pressure (APAP) treatment is comparable to continuous positive airway pressure (CPAP) in its cost effectiveness and efficacy. Patients with OSA are treated with APAP devices in our hospital.

Aims: Monitor changes in APAP and apnoea hypopnoea index (AHI) over a period of 3 months

Identify factors which affect changes in mean AHI and APAP

Methods: Symptomatic OSA patients [Epworth sleep score (ESS) >10, AHI>10) were offered APAP therapy and monitored prospectively for 3 months.Data was downloaded at 2 weeks and 3 months and analyzed using paired t test and multiple regression.

Results: APAP therapy was initiated in 26 patients (22 men) with a mean (SD) age of 51 (11.7) years. Mean AHI was 44.5 (25.5) and mean Epworth score was 12 (4.7).

Changes in mean AHI and APAP are shown in the table.

View this table:

Table 1





Multiple regression identified baseline AHI to be the only predictor of AHI change over 2 weeks and 3 months (p<0.0001) while a higher mean APAP at 3 months was also found to be significant (p<0.0003)

Age, sex or body mass index did not affect changes in mean AHI or APAP.

Conclusions: In our study,AHI was significantly reduced after 2 weeks' treatment with APAP and continued to fall at 3 months even though mean pressure did not change noticeably.AHI change is greatest in patients with a higher baseline AHI and is affected by mean pressure at 3 months.This implies the influence of other factors such as change in upper airway muscle dynamics.Larger studies are needed to elucidate this complex relationship.
Abstract 924: Aging Induces Titin Oxidation And Increases Passive Cardiomyocyte Stiffness
Authors: Chee Lim, Lin Zhong, Michiel Helmes, Douglas B Sawyer
Journal: Circulation (2007)

One of the hallmarks of aging is an increase in ventricular passive stiffness leading to diastolic heart failure, however, the molecular basis for this is unclear. The giant elastic protein titin, working as an entropic spring, is the major determinant of passive cardiomyocyte stiffness. We hypothesized that accumulation of oxidized titin in the aging heart results in increased cardiomyocyte passive stiffness and thereby contributes to diastolic dysfunction. We further hypothesized that an age-assocated disturbance in the ubiquitin/proteasome pathway plays a role in the accumulation of oxidized titin. Methods: Cardiomyocytes from adult (4 month) and aging (34 month) mouse hearts were isolated and chemically skinned and the passive force-sarcomere length relationship in single cells were obtained. Post-translational modification of titin was assessed in whole heart homogenates by determining the content of 1) titin carbonyls, a marker of irreversible protein oxidation, and 2) titin ubiquitinylation, a marker for proteasomal degradation. Results: Cardiomyocyte passive tension was significantly higher in the aging group (at SL=2.45 μm, 1008.4 ± 45.5 vs. 871.6 ± 48.3 μg; p&lt;0.05). While the total amount of titin was unchanged between both groups, the carbonyl content of titin was increased 3-fold with aging (p&lt;0.05). High molecular weight ubiquitin-conjugated proteins were increased with aging, which is consistent with a decrease in proteasomal activity with age. Surprisingly, titin ubiquitinylation was decreased with aging suggesting an impairment upstream of the proteasome, in titin-specific ubiquitin ligase activity. Furthermore, the muscle specific ubiquitin ligase MURF-2, which has been shown to interact with titin and play a role in muscle protein turnover, showed a significant shift from a high to low molecular weight isoform with aging. Conclusion: Our data suggests that an age-associated impairment in titin turnover contributes to accumulation of oxidatively modified titins with consequent impairment of cardiomyocyte stiffness. We speculate that the oxidation of titin will change the elastic properties of titin, directly accounting for the change in passive tension and contributing to diastolic dysfunction associated with aging.
Clinical significance of serum osteopontin levels in lung cancer
Authors: Aikaterini Kazakou, Theodora Kerenidi, Martha Lada, Irini Tsilioni, Eleftherios Dalaveris, Konstantinos Gourgoulianis
Journal: European Respiratory Journal (2012)

Background: Osteopontin (OPN) is a multifunctional glycoprotein associated with lung cancer (LC) via several pathways including tumour angiogenesis.  Aims and objectives: The aim of our study was to investigate possible associations between serum levels of OPN in patients with LC and clinicopathological variables, VEGF and MMP-9 levels and overall survival.  Methods: We enrolled 51 patients (mean age 66±8.8 years) with primary LC and 30 healthy control subjects. 43 patients were ever smokers and 8 non-smokers, 12 patients had SCLC and 39 NSCLC (18 squamous, 16 adenocarcinoma and 5 NSCLC-NOS) with stage I-II/4, III/18, IV/29. Serum levels of OPN, VEGF and MMP-9 were measured by ELISA.  Results: Patients with LC had statistically significantly higher serum OPN levels than controls (45.9[10.5-266.8] vs 16[6.8-29.8] ng/ml, p 23.8 ng/ml, sensitivity for detection of LC was 80.4% and specificity was 86.7%. OPN levels were also found higher in smokers (p=0.019) and in older patients (p=0.026). Moreover, patients with squamous LC had statistically significantly higher OPN levels compared to patients with adenocarcinoma. Additionally, patients with serum OPN levels lower than median value (  Conclusions: OPN levels were increased in patients with LC, and higher levels were correlated with worse survival, therefore suggesting a possible diagnostic and prognostic value of OPN in patients with LC.
Why we need a broad perspective on meta-analysis
Authors: P. C Gotzsche
Journal: BMJ (2000)

In the world of clinical trials and meta-analyses there is an important debate between the “lumpers” and the “splitters.” This relates to whether the overall findings of clinical trials and meta-analyses are the appropriate outcome to apply to individuals (lumping) or whether it is better to try to match the characteristics of particular patients to characteristics of subgroups within trials or meta-analyses (splitting). Although the splitters' view seems intuitively correct, there are usually substantial clinical and methodological advantages to lumping.

The generalisability and usefulness of meta-analyses are increased considerably if the individual trials cover different patient populations, settings, and concomitant routine care. For example, when a meta-analysis showed that the use of human albumin increased mortality1 this result applied to all three groups of critically ill patients studied. For patients with hypovolaemia the difference was not conventionally significant (95% confidence interval for the odds ratio 0.99 to 3.15), but it would be wrong to interpret this result as meaning that clinicians should continue to give these patients albumin. Most significant results will disappear because of lack of power if trials in a meta-analysis are split up into a large enough number of subgroups. It is more relevant that the point estimates were similar …
Impact of Lowering BMI Cut Points as Recommended in the Revised American Diabetes Association's <i>Standards of Medical Care in Diabetes—2015</i> on Diabetes Screening in Asian Americans
Authors: Daniel S. Hsia, Sandra Larrivee, William T. Cefalu, William D. Johnson
Journal: Diabetes Care (2015)

OBJECTIVE This study estimated the screening prevalence of prediabetes and diabetes using a lower BMI cutoff of 23 kg/m2 in Asians in the U.S. using the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2012. RESEARCH DESIGN AND METHODS A cross-sectional analysis was conducted of non-Hispanic Asians, aged 45 years and older, with available BMI, HbA1c, and fasting glucose data. These overall criteria were met by 341 participants. RESULTS Lowering the screening BMI to 23 kg/m2 increased the sensitivity of screening for prediabetes and diabetes from 50.2 to 74.1% (P &amp;lt; 0.0001) but decreased the specificity from 62.9 to 38.7% (P &amp;lt; 0.0001). CONCLUSIONS Although this will add additional health care costs resulting from more widespread screening, early identification of these conditions may be beneficial for primary and secondary prevention in this unique population that develops prediabetes and diabetes at lower BMI levels.
Randomized Comparison of Cisplatin/Vincristine/Fluorouracil and Cisplatin/Continuous Infusion Doxorubicin for Treatment of Pediatric Hepatoblastoma: A Report From the Children’s Cancer Group and the Pediatric Oncology Group
Authors: Jorge A. Ortega, Edwin C. Douglass, James H. Feusner, Marleta Reynolds, John J. Quinn, Milton J. Finegold, Joel E. Haas, Denis R. King, Wen Liu-Mares, Martha G. Sensel, Mark D. Krailo
Journal: Journal of Clinical Oncology (2000)

PURPOSE: Previous studies demonstrated that chemotherapy with either cisplatin, vincristine, and fluorouracil (regimen A) or cisplatin and continuous infusion doxorubicin (regimen B) improved survival in children with hepatoblastoma. The current trial is a randomized comparison of these two regimens. PATIENTS AND METHODS: Patients (N = 182) were enrolled onto study between August 1989 and December 1992. After initial surgery, patients with stage I–unfavorable histology (UH; n = 43), stage II (n = 7), stage III (n = 83), and stage IV (n = 40) hepatoblastoma were randomized to receive regimen A (n = 92) or regimen B (n = 81). Patients with stage I–favorable histology (FH; n = 9) were treated with four cycles of doxorubicin alone. RESULTS: There were no events among patients with stage I-FH disease. Five-year event-free survival (EFS) estimates were 57% (SD = 5%) and 69% (SD = 5%) for patients on regimens A and B, respectively (P = .09) with a relative risk of 1.54 (95% confidence interval, 0.93 to 2.5) for regimen A versus B. Toxicities were more frequent on regimen B. Patients with stage I-UH, stage II, stage III, or stage IV disease had 5-year EFS estimates of 91% (SD = 4%), 100%, 64% (SD = 5%), and 25% (SD = 7%), respectively. Outcome was similar for either regimen within disease stages. At postinduction surgery I, patients with stage III or IV disease who were found to be tumor-free had no events; those who had complete resections achieved a 5-year EFS of 83% (SD = 6%); other patients with stage III or IV disease had worse outcome. CONCLUSION: Treatment outcome was not significantly different between regimen A and regimen B. Excellent outcome was achieved for patients with stage I-UH and stage II hepatoblastoma and for subsets of patients with stage III disease. New treatment strategies are needed for the majority of patients with advanced-stage hepatoblastoma.
Squamous cell carcinoma antigen as a marker for squamous cell carcinoma of the anal canal.
Authors: N J Petrelli, N Shaw, A Bhargava, J Daufeldt, L Herrera, J P Stulc, B Sischy, A Mittelman
Journal: Journal of Clinical Oncology (1988)

Twenty-one patients with documented squamous cell carcinoma (SCC) of the anal canal underwent prospective serial collection of 101 serum samples for radioimmunoassay of SCC antigen to evaluate regression or progression of disease. Eighteen presented with primary SCC of the anal canal, two with metastatic disease, and one with a recurrence in the perineum. Median follow-up was 18 months. Thirteen of 22 serum samples were true-positives, and nine of 22 were false-negatives. Four of 79 serum samples were false-positives and 75 of 79 were true-negatives. The sensitivity of this test is 59% and the specificity is 95%, with the accuracy of a positive test being 76%.
The relationship between obstructive sleep apnea syndrome and apolipoprotein E allels
Authors: Ebru Kucuk, Oner Balbay, Ali Nihat Annakkaya, Ege Gulec Balbay, Fatma Silan, Peri Arbak
Journal: European Respiratory Journal (2011)

Aim:  Clinical and epidemiological studies indicate that OSAS has a strong genetic basis. Apo E in humans is an important determinant of blood lipid levels. There are few studies investigating the possible relationship between OSAS and Apolipoprptein E. In this study, we aimed to investigate the apolipoprotein E allels as a genetic risk factor in OSAS.   Method:  62 adult patients (35 male, 27 female) with sleep apnea applying to Chest Diseases Clinic between October 2006 and May 2009 were included in this study. All patients underwent fullnight PSG and were evaluated for apolipoprotein E allels.   Results:  The mean age was 51±12. According to PSG results, 20 cases with negative PSG and 18 with mild, 10 with moderate, 14 with severe OSAS patients was diagnosed.  Clinically important patients were divided into 2 groups according to AHI 15 (n:24). No homozygote Apo E2 (22) and homozygote Apo E4 (44) were observed in study group. The cases with OSAS had almost statistically significant higher Apo E2 frequency than that of not OSAS (23.8%, respectively, 10/42 and 5%, 1/20, p = 0.080).  As AHI increases, frequency of Apo E3 allel detection will also increase in OSAS patients. But frequency of Apo E4 allel detection will decrease (respectively, p=0,717, and p=0,613). Apo E3 allel contrary to Apo E4 was frequently observed AHI above 15 whereas Apo E4 allel was frequently observed AHI below 15.   Conclusion:  It9s thought that APO E2 allel is a risk factor for OSAS. But more studies are needed to confirm this relation.