tbuckley/cabot-search huggingface dataset:
Human immunodeficiency virus and lung cancer: differences in presentation and clinical course.
Authors: Craig M. Hooker, Eric A. Engels, Richard D. Moore, Maura L. Gillison, Julie R. Brahmer, Stephen Ames, Anthony J. Alberg, Rex C. Yung, Stephen C. Yang, James G. Herman, Stephen B. Baylin, Malcolm V. Brock
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

480 

Background: As HIV-infected patients are surviving longer on antiretroviral medication, case reports of lung cancer developing in HIV patients are emerging. We conducted the present study to characterize the differences between lung cancer patients with and without HIV infection. Methods: Patients with lung carcinoma and HIV were identified at an urban hospital, Johns Hopkins, between 1985-2004 by linking the institution’s Lung Cancer SPORE and outpatient HIV clinic databases. HIV + patients with lung cancer were compared to 7,428 patients in the Lung Cancer SPORE database with unknown HIV status (mostly HIV uninfected). Results: We identified 90 HIV+ patients with lung cancer. No patient developed lung cancer before HIV diagnosis. The median interval between HIV diagnosis and lung cancer was 6 years. HIV+ lung cancer patients were younger than others with lung cancer (median age 46 vs. 63 years, p=0.001). The younger age at onset is a likely explanation for lower average pack-years of smoking observed in the HIV-infected lung cancer patients (35 versus 53 pack-years, p=0.001), despite the fact that the prevalence of smoking was higher in the HIV-infected (99%) compared to other (88%) lung cancer patients. Both groups were majority male, but differed by race with the HIV cohort being more likely to be African-American (p=0.001). HIV+ patients more frequently presented with adenocarcinoma than other patients (53% vs. 32%, respectively, p=0.02). The median CD4 count for the HIV+ patients at lung cancer diagnosis was 298 cells/ml (range 0 - 1,091 cells/ml). The median viral load was 613 copies/ml (range 0 - 750,000 copies/ml). The survival of the HIV+ group was significantly shorter than that of the non-HIV lung cancer group (median 6 vs. 9 months; p=0.002; univariate RR 1.50, 95% CI, 1.19-1.87). Late stage of disease appeared to explain the poorer prognosis among HIV-infected lung cancer patients, since after adjusting for lung cancer stage at presentation in a multivariate analysis, HIV+ and other lung cancer patients had a similar death rate (RR 1.06, 95% CI 0.85-1.34). Conclusion: We report a clinical observation of a large number of patients with HIV and lung carcinoma in a single institution. HIV+ patients with lung cancer present at a younger age and are more likely than other patients to have adenocarcinomas and more advanced cancer at diagnosis. Extensive smoking histories are ubiquitous. Survival of HIV+ patients is poor primarily due to late stage of presentation. This study adds additional evidence concerning the potential link between HIV and lung cancer.
Interventions for treating oral lichen planus: a systematic review
Authors: G. Lodi, M. Carrozzo, S. Furness, K. Thongprasom
Journal: British Journal of Dermatology (2012)

Oral lichen planus (OLP) is a common chronic inflammatory disease associated with cell-mediated immunological dysfunction. Symptomatic OLP is painful and complete healing is rare. The aim of this review was to assess the evidence for the efficacy and safety of treatments for symptomatic OLP. The Cochrane Oral Health Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE were searched in January 2011 to identify all randomized controlled trials (RCTs) evaluating any intervention for the treatment of symptomatic OLP. A total of 28 trials were included in this Cochrane review. There was no evidence from three RCTs that topical pimecrolimus is better than placebo in reducing pain from OLP. There was weak evidence from two RCTs that topical aloe vera may be associated with a reduction in pain compared with placebo. There was weak and unreliable evidence from two small trials, at high risk of bias, that topical ciclosporin may reduce pain and clinical signs of OLP. There was no evidence (from five trials each evaluating a different steroid and/or calcineurin inhibitor) that there is a difference between treatment with topical corticosteroids (TCSs) compared with topical calcineurin inhibitors with regard to reducing pain associated with OLP or that any specific steroid therapy is more or less effective at reducing pain. Although TCSs are considered to be the first-line treatment, we did not identify any RCTs that compared TCSs with placebo in patients with symptomatic OLP. From the 28 trials included in this systematic review, the wide range of interventions compared means there is insufficient evidence to support the superior effectiveness of any specific treatment.
Abstract 5474: PD-L1 regulates cisplatin chemoresistance in head and neck squamous cell carcinoma
Authors: Randall S. Ruffner, Andrew Ramsey, Bert W. O'Malley, Daqing Li
Journal: Cancer Research (2015)

Abstract PD-L1 has been known to play a major role in suppressing the immune system. The effect of PD-L1 has been clinically studied by inhibiting PD-L1 in tumor and tumor-infiltrating immune cells, thereby activating anti-tumor T cells and re-establishing anti-tumor immune responses. Little is known about a unique role of PD-L1 in cisplatin chemoresistance of head and neck squamous cell carcinoma (HNSCC). The aim of the current study is to investigate a novel finding that PD-L1 regulates DNA double strand break (DSB) repairs via the MRE11-RAD50-NBS1 (MRN) complex and contributes to cisplatin chemoresistance in HNSCC. Well-characterized HNSCC tumor cell lines were used for this study. JHU 006 tumor cell line has a cisplatin resistant phenotype whereas JHU 020 is cisplatin sensitive. PD-L1 expression was determined by quantitative polymerase chain reaction (qPCR) and western blot before and after cisplatin treatment. The interactions between PD-L1 and MRN in DNA DSB mediated chemoresistant pathway were studied. PD-L1 siRNA was used to induce chemosensitization of HNSCC cells to cisplatin. Our study demonstrates that treatment of HNSCC cells with cisplatin resulted in increased expression of PD-L1 in cisplatin resistant tumor cells, whereas chemosensitive tumor cells showed no change in PD-L1 expression. Additionally, knockdown of PD-L1 using siRNA resulted in downregulation of NBS1, a key protein of the MRN DNA DSB repair complex. However, NBS1 was able to modulate the levels of PD-L1 expression as the use of either NBS1 siRNA or cells that had been transfected with a dominant negative NBS1 mutant resulted in increased PD-L1 expression. The experimental data suggest that PD-L1 may act as an upstream regulator of NBS1 and may facilitate formation of the MRN complex, enhancing repair of cisplatin induced DNA damage, thereby increasing the cell's resistance to chemotherapeutics. Decreasing expression of PD-L1 via siRNA leads to increased sensitivity of HNSCC cells to cisplatin. This highlights the importance of PD-L1 in the development of chemoresitance and suggests a potential therapeutic strategy for patients with cisplatin-resistant HNSCC. In conclusion, we have identified a novel role for PD-L1 in the development of chemoresistance through its interaction with the MRN complex, which plays a major role in the repair of chemo-induced DNA DSB. Therapies aimed at blocking PD-L1 show great promise because of their ability to enhance both chemotherapeutics and the anti-tumor immune response. Citation Format: Randall S. Ruffner, Andrew Ramsey, Bert W. O'Malley, Daqing Li. PD-L1 regulates cisplatin chemoresistance in head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5474. doi:10.1158/1538-7445.AM2015-5474
Abstract 12676: C-Terminal Residues of Phospholamban are Critical Determinants of the Quaternary Structure and Function of the Calcium ATPase Regulatory Complex
Authors: Neha Abrol, Nikolai Smolin, Delaine K Ceholski, Howard S Young, Seth L Robia
Journal: Circulation (2014)

Rationale: A naturally occurring missense Leu-39stop (L39X) mutation in phospholamban (PLB) results in truncation of the C-terminal transmembrane domain, leading to cardiomyopathy and premature death in humans. Objective: The goal of this study was to determine the structural and regulatory role of the C-terminal residues of PLB in the membranes of living cells. Methods and Results: We fused fluorescent protein tags to PLB and cardiac Ca 2+ ATPase (SERCA) to investigate the role of PLB C-terminal residues for membrane localization, PLB oligomerization and SERCA regulation. Alanine substitution of C-terminal residues significantly altered fluorescence resonance energy transfer (FRET) from PLB to PLB and SERCA to PLB. Notably, substitution mutation V49A had profound effects on pentamer structure and regulatory complex conformation, increasing and decreasing probe separation distance, respectively. Progressive deletion of only a few C-terminal residues resulted in significant loss of PLB membrane anchoring and mislocalization to the cytoplasm and nucleus. Selective permeabilization of the plasma membrane by saponin resulted in diffusion of fluorescently labeled PLB out of the cells, consistent with solubilization of truncated proteins. Molecular dynamics simulations recapitulated decreased bilayer anchoring for truncated PLB. C-terminal truncations resulted in progressive loss of PLB-PLB FRET, due to a decrease in the apparent affinity of PLB oligomerization. We quantified a similar decrease in the SERCA-PLB binding affinity, and loss of inhibitory potency as quantified by Ca 2+ -dependent ATPase activity. However, despite decreased SERCA-PLB binding, intermolecular FRET was paradoxically increased as a result of a 14.5 Å decrease in the distance between donor and acceptor fluorophores. Conclusions: We conclude that PLB C-terminal residues are critical for membrane anchoring and quaternary structure determination of PLB pentamer and PLB-SERCA regulatory complex. The loss of membrane registration restraint by C-terminal residues (especially V49) causes displacement of PLB to an alternative position on SERCA. The data are compatible with a model in which PLB binds to the canonical inhibitory binding site and an additional novel site.
LSC 2012 abstract - TGF-β1 regulates the epithelial supportive capacity of mesenchymal stromal cells
Authors: Jonathan McQualter, Rosa McCarty, Ivan Bertoncello
Journal: European Respiratory Journal (2012)

Despite recent advances in biomarker profiling, prospective isolation and clonogenic assay of putative lung stem cells their regenerative capacity remains ill-defined. On that account we have developed a clonogenic colony-forming assay that has enabled us to identify a population of multi-potent lung epithelial stem cells (EpCAMhi CD49fpos CD104pos CD24low) that are able to self-renew and give rise to airway and alveolar epithelial cell lineages. However,the intrinsic regenerative potential of stem cells is conditional upon their interaction with permissive and restrictive microenvironmental cues. On this note, we have shown that the proliferation and differentiation of lung epithelial stem cells in vitro is dependent on co-culture with endogenous lung mesenchymal stromal cells (EpCAMneg Sca-1pos), or mesenchyme-derived growth factors including FGF-10 and HGF. On the flip side, we have shown that more differentiated mesenchymal stromal cells (FGF-10low α- SMApos) are unable to support epithelial colony formation. Importantly, we have shown that the capacity of mesenchymal stromal cells to support epithelial stem cells is regulated by TGF- β1 and can be reversed by blockade of SMAD2/3 phosphorylation downstream of TGF-β activation. This data suggests that TGF-β mediated mesenchymal differentriation in chronic lung diseases may obstruct epithelial regeneration.
Abstract 2374: Whole Grain Intake in Relation to Lipids, Apolipoproteins, and Lipoprotein Subclasses in a Multi-ethnic Cohort: The Insulin Resistance Atherosclerosis Study
Authors: Philip Mellen, Angela Liese, Steven Haffner, David Goff
Journal: Circulation (2007)

Context: Whole grain intake is inversely associated with LDL-c and the metabolic syndrome, but the relationship of whole grains with other lipid parameters, such as small, dense LDL, is not established. We sought to evaluate the relationship of whole grain intake with lipids, apolipoproteins, and LDL lipoprotein subclasses in a large, multi-ethnic cohort. Methods: This cross-sectional study evaluated 975 non-diabetic participants in the Insulin Resistance Atherosclerosis Study. Baseline whole grain intake was estimated based on intake of dark breads, cooked cereals, and high-fiber cereals assessed in a validated food frequency questionnaire. Fasting lipid measurements included apolipoproteins and lipoprotein subclasses quantified by NMR spectroscopy. Linear regression models evaluated lipid parameters across quartile of whole grain intake after adjustment for demographics (age, sex, ethnicity, center), anthropometrics (BMI, waist circumference), lifestyle factors (smoking, alcohol intake), dietary factors (total kcal, fruits, vegetables, dietary fats) and lipid-lowering medication use. Additional models included directly measured insulin sensitivity (Si). Results: The cohort was 56% female, had a mean (SD) age of 54.8 (8.5) years, and was 60% non-white, with a median whole grain intake of .73 servings/day. In adjusted models, there was an inverse association between whole grain intake and LDL-c, Apo-B, Apo-B/Apo-A1 ratio, LDL particle concentration (LDL-p), and small LDL-p (Table ). These associations remained significant after adjustment for Si (LDL-c: p=.007; Apo-B: p=.04; Apo-B/Apo-A1: p=.03; LDL-p: p=.03; small LDL-p: p=.03). Conclusion: Whole grain intake is inversely associated with multiple lipid risk factors, including total and small LDL particle concentration, independent of insulin sensitivity and other confounders. This demonstrates additional mechanisms for the cardioprotective effects of whole grains.
Fatty acid synthase inhibition down-regulates HER2 expression and induces apoptosis in breast cancer cells via induction of Reactive Oxygen Species (ROS)
Authors: binghui Li, Hong Liu, Ingrid Espinoza, Ruth Lupu
Journal: Cancer Research (2007)

4485  We have previously reported that tumor-associated fatty acid synthase (FAS) plays a critical role in breast cancers, especially those overexpressing HER2. A bi-directional cross-talk between FAS and HER2 has been suggested. We and other groups previously reported that the inhibition of HER2 can suppress FAS expression via Ras-MAPK and PI-3’K signaling pathways. However, the mechanism underlying the down-regulation of HER2 by FAS inhibition is still unclear and how FAS inhibition induces apoptosis remains to be determined. Up to date, there are two model theories for the apoptosis induced by FAS inhibition: 1) the accumulated substrate malonyl-CoA or 2) decreased product palmitate of FAS mediates FAS inhibition-induced apoptosis. An understudied area of research in this field is to explore the role of NADPH, another substrate of FAS, in FAS-induced apoptosis. It is known that FAS is a NADPH-dependent enzyme and synthesizes one mole of palmitate, concomitantly oxidizing fourteen moles of NADPH. Therefore, overexpression of FAS is critical to maintain the redox balance in cancer. It is plausible to postulate that while FAS is blocked, a large quantity of NADPH is accumulated to produce oxidative stress, promoting the activation of the reactive oxygen species (ROS)-generating enzymes. Here we determine whether ROS plays a role in down-regulation of HER2 and apoptosis induced by FAS inhibition. Two cell lines overexpressing HER2and FAS (SK-Br3 and BT474) were selected for the study. FAS activity was inhibited utilizing increasing concentrations of the pharmacological inhibitor cerulenin (0-10 μg/ml). The levels of ROS in cerulenin treated and untreated cells were measured by flow cytometry. The level o FAS and HER2protein expression were determine using western blotting analysis. Our results demonstrate that FAS inhibition rapidly induces ROS and specifically downregulates the expression of HER2 protein which in turn leads to apoptosis of SK-Br3 and BT474 cells. In order to assess the direct relationship between ROS, generated by the inhibition of FAS, and HER2 downregulation, we utilized an NADPH oxidase (NOX) inhibitor (diphenylene iodonium) that significantly suppresses ROS production. This demonstrates that NOX plays a critical role in ROS production induced by FAS inhibition. Moreover, we determined that treatment of HER2 overexpressing cells with N-acetyl-cysteine (NAC), a ROS scavenger, can restore the expression HER2 protein reduced by FAS inhibition and furthermore, rescue apoptosis induced by FAS inhibitors, suggesting a fundamental role of ROS in FAS inhibition-mediated apoptosis in HER2overexpressing cells. Our data indicate that the accumulated NADPH resulting from FAS inhibition activates NOX, a ROS-producing enzyme, to, in turn, promote ROS to repress the expression of oncoprotein HER2 and induce the apoptosis.
Abstract 14984: Left Ventricular Longitudinal Contraction Abnormality Reflects the Subendocardial Fibrosis in Heart Failure with Preserved Ejection Fraction Model Rat
Authors: Rumi Koshizuka, Tomoko Ishizu, Yuri Kameda, Yoshihiro Seo, Kazutaka Aonuma
Journal: Circulation (2011)

Background: Left ventricular (LV) longitudinal contraction has been reported to be the feature of early cardiac dysfunction in heart failure with preserved ejection fraction (HFpEF). However, the u...
Abstract 4066: Visceral and Subcutaneous Adipose Tissue Volumes are Related to Markers of Inflammation and Oxidative Stress: the Framingham Heart Study
Authors: Karla M Pou, Joseph M Massaro, Udo Hoffman, Ramachandran S Vasan, Pal Maurovich-Horvat, Martin G Larson, John F Keaney, James B Meigs, Izabella Lipinska, Joanne M Murabito, Christopher J O'Donnell, Emelia J Benjamin, Caroline S Fox
Journal: Circulation (2006)

Background  Abdominal adiposity is associated with systemic markers of inflammation. We investigated whether subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) determined by computed tomography contribute differentially to inflammation in a community-based cohort.   Methods  Participants from the Framingham Offspring Study (n=1250, 52% women, mean age 60±9 years) underwent computed tomography quantification of SAT and VAT. Using multivariable linear regression, SAT and VAT (predictor variables) were examined in relation to log-transformed markers of inflammation (CRP, CD40L, fibrinogen, ICAM-1, IL-6, MCP-1, osteoprotegerin, p-selectin, TNF-α, TNFR2) and oxidative stress (MPO, urinary isoprostanes). Models were adjusted for age, sex, smoking, physical activity, menopause, hormone replacement therapy, alcohol, and aspirin use; additional models included body mass index (BMI) and waist circumference (WC).   Results  Mean (±SD) SAT and VAT were 3023±1329 and 2126±1112 cm 3 , respectively. There were no significant differences in the strong positive associations of SAT or VAT (model R 2  ranges 0.06–0.24 and 0.07–0.24 respectively) with CRP, fibrinogen, ICAM-1, IL-6, p-selectin and TNFR2. We observed modest differences in the associations between the two fat compartments and MCP-1 and isoprostanes. Compared with SAT (R 2  0.07), VAT (R 2  0.08) was more highly correlated with MCP-1 (SAT vs VAT comparison p=0.04). Similarly for isoprostanes, compared with SAT (R 2  0.07), VAT (R 2  0.10) was more highly correlated (comparison p=0.002). Only SAT was associated with MPO (R 2  0.05). Neither compartment was associated with TNF-α, osteoprotegerin, and CD40L. Adding BMI and WC to the models, only VAT remained significantly associated with CRP (p=0.007), IL-6 (p=0.01), MCP-1 (p=0.008), and isoprostanes (p=0.0002).   Conclusions  Contrary to multiple small studies suggesting differential effects of abdominal fat compartments, SAT and VAT are similarly correlated with many markers of systemic inflammation. Adjusting for clinical measures of adiposity, only VAT remains associated with several markers. Our cross-sectional data are consistent with a potential unique role of VAT in the pathogenesis of inflammation and oxidative stress.
Comparison of inhaled beclomethasone and budesonide
Authors: C. Cates, P. Black, S. Edsbacker, M. Gerhardsson deVerdier, C. Hultquist, S. Suissa, P. Ernst, B D Pethica
Journal: BMJ (1999)

Editor—The conclusions reached by Pethica et al in their paper concerning the relative potency of inhaled beclomethasone and budesonide are not justified because the authors have not verified an important assumption in the paper.1 They have assumed that patients are regularly taking the dose recorded on their prescription; the data presented in their paper suggest that this is most unlikely. The total number of prescriptions issued to 5930 patients was only 16 725 (under three a year). Most formulations of inhaled steroid last 50 days at the usual prescribed dose, so patients taking regular treatment should have used around seven prescriptions in the 12 months of the study.

Analysis of computerised prescriptions in my practice over the 12 months July 1997 to June 1998 shows a similar pattern: 625 patients received 2424 prescriptions for inhaled steroids (around four a year on average). Analysis of individual data on 59 patients aged 30-35 shows that 36 of the 59 were prescribed fewer than four inhalers a year (table). These patients did not receive enough medication to have taken the prescribed dose of inhaled steroid regularly over the 12 months. 

The analysis carried out in Pethica et al’s paper is based on the mean prescribed dose, which may bear little relation to the dose actually taken over the whole period. The total inhaled dose for each patient would be better estimated by multiplying the contents of each inhaler by the number of inhalers prescribed over the 12 months studied. Analysis should be restricted to those patients who can be shown to be taking regular inhaled steroids.

Beclomethasone is available as a 100 μg metered dose inhaler, while budesonide is available for adults only as a 200 μg metered dose inhaler. Since a dose of two puffs twice daily is commonly used when patients start inhaled steroids, there is a possibility that budesonide in adults may be started at a higher dose than beclomethasone. This could distort the findings in Pethica et al’s analysis.

Before any guidelines are altered, further analysis is required of Pethica et al’s data as well as confirmatory evidence from patients in other countries.