Michael D Roth

University of California, Los Angeles, Los Angeles, CA, United States

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Publications (67)342.84 Total impact

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    ABSTRACT: Extent of systemic sclerosis (SSc)-related interstitial lung disease (ILD) assessed from thoracic high-resolution CT (HRCT) predicts disease course, mortality and treatment response. While quantitative HRCT analyses of extent of lung fibrosis (QLFib) or total interstitial lung disease (QILD) are more sensitive and reproducible than visual HRCT assessments of SSc-ILD, these analyses are not widely available. This study evaluates the relationship between clinical disease parameters and QLFib and QILD scores to identify potential surrogate measures of radiographic extent of ILD. Using baseline data from the Scleroderma Lung Study I (SLS I; N=158), multivariate regression analyses were performed using the best subset selection method to identify one to five variable models that best correlated with QLFib and QILD scores in both whole lung (WL) and the zone of maximal involvement (ZM). These models were subsequently validated using baseline data from SLS II (N=142). Bivariate analyses of the radiographic and clinical variables were also performed using pooled data. SLS I and II did not include patients with clinically significant pulmonary hypertension (PH). Diffusing capacity for carbon monoxide (DLCO) was the single best predictor of both QLF and QILD in the WL and ZM in all of the best subset models. Adding other disease parameters to the models did not substantially improve model performance. Forced vital capacity (FVC) did not predict QLF or QILD scores in any of the models. In the absence of PH, DLCO provides the best overall estimate of HRCT-measured lung disease in patients from two large SSc cohorts. FVC, although commonly used, may not be the best surrogate measure of extent of SSc-ILD at any point in time. www.clinicaltrials.gov NCT 00000-4563; SLS II: www.clinicaltrials.gov NCT 00883129. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Annals of the rheumatic diseases. 12/2014;
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    ABSTRACT: mRNA encoding for the CB(2) cannabinoid receptor is expressed by many subsets of human peripheral blood leukocytes (PBL), but little is known about the resulting protein expression and function. Employing clones from the A549 and 293T cell lines that were constructed to express both full-length human CB(2) and GFP, we developed a flow cytometry assay for characterizing CB(2) protein expression. A monoclonal antibody directed against human CB(2) selectively stained the surface of transduced but not parental cell lines. When cells were fixed and permeabilized, imaging flow cytometry identified large stores of intracellular protein. Total cellular staining for CB(2) corresponded closely with the level of GFP expression. When exposed to Δ(9)-tetrahydrocannabinol, CB(2)-expressing cells internalized cell surface CB(2) receptors in a time- and dose-dependent manner. Applying these approaches to human PBL, CB(2) protein was identified on the surface of human B cells but not on T cells or monocytes. In contrast, when PBL were fixed and permeabilized, intracellular CB(2) expression was readily detected in all three subsets by both conventional and imaging flow cytometry. Similar to the protein expression pattern observed in fixed and permeabilized PBL, purified B cells, T cells, and monocytes expressed relatively equal levels of CB(2) mRNA by quantitative real-time RT-PCR. Our findings confirm that human PBL express CB(2) protein but that its distribution is predominantly intracellular with only B cells expressing CB(2) protein at the extracellular membrane. The differential role of intracellular and extracellular CB(2) receptors in mediating ligand signaling and immune function remains to be determined.
    Journal of Neuroimmune Pharmacology 01/2013; · 3.80 Impact Factor
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    ABSTRACT: Though matrix metalloproteinases (MMPs) are critical in the pathogenesis of COPD, their utility as a disease biomarker remains uncertain. This study aimed to determine whether bronchoalveolar lavage (BALF) or plasma MMP measurements correlated with disease severity or functional decline in emphysema. Enzyme-linked immunosorbent assay and luminex assays measured MMP-1, -9, -12 and tissue inhibitor of matrix metalloproteinase-1 in the BALF and plasma of non-smokers, smokers with normal lung function and moderate-to-severe emphysema subjects. In the cohort of 101 emphysema subjects correlative analyses were done to determine if MMP or TIMP-1 levels were associated with key disease parameters or change in lung function over an 18-month time period. Compared to non-smoking controls, MMP and TIMP-1 BALF levels were significantly elevated in the emphysema cohort. Though MMP-1 was elevated in both the normal smoker and emphysema groups, collagenase activity was only increased in the emphysema subjects. In contrast to BALF, plasma MMP-9 and TIMP-1 levels were actually decreased in the emphysema cohort compared to the control groups. Both in the BALF and plasma, MMP and TIMP-1 measurements in the emphysema subjects did not correlate with important disease parameters and were not predictive of subsequent functional decline. MMPs are altered in the BALF and plasma of emphysema; however, the changes in MMPs correlate poorly with parameters of disease intensity or progression. Though MMPs are pivotal in the pathogenesis of COPD, these findings suggest that measuring MMPs will have limited utility as a prognostic marker in this disease.
    PLoS ONE 01/2013; 8(2):e56352. · 3.53 Impact Factor
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    ABSTRACT: Ample studies suggest that the cyclooxygenase-2 (COX-2)/prostaglandin E(2) (PGE(2)) pathway plays a pivotal role in carcinogenesis and that COX-2 inhibition may help prevent lung cancer. Therefore, we conducted a randomized, double-blind, placebo-controlled trial of the COX-2-selective inhibitor celecoxib (400 mg bid for 6 months) in former-smokers (age ≥ 45, ≥ 30 pack-years of smoking, ≥ 1 year of sustained abstinence from smoking). We assessed the impact of celecoxib on cellular and molecular events associated with lung cancer pathogenesis; the primary endpoint was bronchial Ki-67 labeling index (Ki-67 LI) after 6 months of treatment. Of 137 randomized subjects, 101 completed both baseline and 6-month bronchoscopies and were evaluable for the primary endpoint analysis. The beneficial effect on Ki-67 LI was greater in the celecoxib arm (versus placebo) in a mixed-effects analysis (P = 0.0006), and celecoxib significantly decreased Ki-67 LI by an average of 34%, whereas placebo increased Ki-67 LI by an average of 3.8% (P = 0.04; t test). In participants who crossed over to the other study arm at 6 months (all of whom had received 6 months of celecoxib at the end of a 12 months treatment period), the decreases in Ki-67 LI correlated with a reduction and/or resolution of lung nodules on computed tomography. Celecoxib significantly reduced plasma c-reactive protein and interleukin-6 mRNA and protein and increased 15(S)-hydroxy-eicosatetraenoic acid levels in bronchoalveolar lavage (BAL) samples. The baseline ratio of COX-2 to 15-hydroxyprostaglandin dehydrogenase mRNA in BAL cells was a significant predictive marker of Ki-67 response to celecoxib (P = 0.002). Our collective findings support the continued investigation of celecoxib for lung cancer chemoprevention in former smokers at a low risk of cardiovascular disease.
    Cancer Prevention Research 07/2011; 4(7):984-93. · 4.89 Impact Factor
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    ABSTRACT: Patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) are thought to have the greatest decline in lung function (forced vital capacity [FVC]% predicted) in the early years after disease onset. The aim of this study was to assess the natural history of the decline in FVC% predicted in patients receiving placebo in the Scleroderma Lung Study and to evaluate possible factors for cohort enrichment in future therapeutic trials. Patients randomized to receive placebo (n=79) were divided into 3 groups based on the duration of SSc (0-2 years, 2-4 years, and >4 years). Descriptive statistics and a mixed-effects model were used to analyze the rate of decline in the FVC% predicted over a 1-year period. Additional analyses stratified according to the severity of fibrosis on high-resolution computed tomography (HRCT) were performed, and interactions between disease severity and disease duration were explored. The mean±SD decline in the unadjusted FVC% predicted during the 1-year period was 4.2±12.8%. At baseline, 28.5%, 43.0%, and 28.5% of patients were in the groups with disease durations of 0-2 years, 2-4 years, and >4 years, respectively. The rate of decline in the FVC% predicted was not significantly different across the 3 disease groups (P=0.85). When stratified by baseline fibrosis on HRCT, the rate of decline in the FVC% predicted was statistically significantly greater in the group with severe fibrosis (mean annualized decline in the FVC% predicted 7.2% versus 2.7% in the groups with no or moderate fibrosis; P=0.008). The decline observed in the group with severe fibrosis was most pronounced in those with a relatively short disease duration (0-2 years; annualized decline 7.0%). Among patients with SSc-ILD in the Scleroderma Lung Study, the rates of progression of lung disease were similar irrespective of disease duration. The baseline HRCT fibrosis score is a predictor of a future decline in the FVC% predicted in the absence of effective treatment.
    Arthritis & Rheumatology 05/2011; 63(10):3078-85. · 7.48 Impact Factor
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    ABSTRACT: To identify baseline characteristics of patients with scleroderma-related interstitial lung disease (SSc-ILD) that could serve as predictors of the most favorable response to 12-month treatment with oral cyclophosphamide (CYC). Regression analyses were retrospectively applied to the Scleroderma Lung Study data in order to identify baseline characteristics that correlated with the absolute change in forced vital capacity (FVC) (% predicted values) and the placebo-adjusted change in % predicted FVC over time (the CYC treatment effect). Completion of the CYC arm of the Scleroderma Lung Study was associated with a placebo-adjusted improvement in the % predicted FVC of 2.11% at 12 months, which increased to 4.16% when patients were followed up for another 6 months (P=0.014). Multivariate regression analyses identified the maximal severity of reticular infiltrates (assessed as maximum fibrosis scores) on high-resolution computed tomography (HRCT) at baseline, the modified Rodnan skin thickness score (MRSS) at baseline, and the Mahler baseline dyspnea index as independent correlates of treatment response. When patients were stratified on the basis of whether 50% or more of any lung zone was involved by reticular infiltrates on HRCT and/or whether patients exhibited an MRSS of at least 23, a subgroup of patients emerged in whom there was an average CYC treatment effect of 9.81% at 18 months (P<0.001). Conversely, there was no treatment effect (a -0.58% difference) in patients with less severe HRCT findings and a lower MRSS at baseline. A retrospective analysis of the Scleroderma Lung Study data identified the severity of reticular infiltrates on baseline HRCT and the baseline MRSS as patient features that might be predictive of responsiveness to CYC therapy.
    Arthritis & Rheumatology 05/2011; 63(9):2797-808. · 7.48 Impact Factor
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    ABSTRACT: The Scleroderma Lung Study (SLS) was a 1-year, randomized, controlled trial of oral cyclophosphamide for scleroderma-related pulmonary alveolitis. It concluded that oral cyclophosphamide slowed the decline in the forced vital capacity (% predicted) and had a beneficial effect on dyspnea, skin changes, and several quality of life measures of systemic sclerosis. We now report an in-depth assessment of the toxicity of cyclophosphamide during the year of therapy and the year after therapy was completed, during which time the investigators were still masked to the treatment assignment. One-year, double-blind, randomized controlled trial of oral cyclophosphamide versus placebo with 1-year masked follow-up. Adverse events (AEs) were tabulated, described, and compared using descriptive statistics (eg, mean and median) and t, Wilcoxon rank sum, chi-squared, or Fisher's exact tests as appropriate. During year 1, treatment-related overall AEs occurred more frequently in cyclophosphamide (CYC)-treated patients (overall AEs for CYC=154 events vs placebo=60 events; P=0.002), and especially for mild to moderate leukopenia (CYC=19 subjects vs placebo=0 subjects; P < .0001). For cancer, we followed patients beyond 2 years. There were no differences in the occurrence of cancer (CYC=4 subjects vs placebo=2 subjects), serious related AEs (CYC=8 events vs placebo=13 events), or deaths (CYC=6 subjects vs placebo=6 subjects). Over 2 years, cyclophosphamide was associated with more AEs than placebo, including overall AEs and relative leukopenia. There were no differences in other AEs, including serious AEs, cancers, or deaths.
    The American journal of medicine 05/2011; 124(5):459-67. · 5.30 Impact Factor
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    Airi Harui, Sylvia M Kiertscher, Michael D Roth
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    ABSTRACT: Humanized mouse models provide a unique opportunity to study human immune cells in vivo, but traditional models have been limited to the evaluation of non-specific T-cell interactions due to the absence of antigen-presenting cells. In this study, immunodeficient NOD/SCID/IL2r-γ(null) (NSG) mice were engrafted with human peripheral blood lymphocytes alone or in combination with donor-matched monocyte-derived dendritic cells (DC) to determine whether antigen-specific T-cell activation could be reconstituted. Over a period of 3 weeks, transferred peripheral blood lymphocytes reconstituted the spleen and peripheral blood of recipient mice with predominantly human CD45-positive lymphocytes. Animals exhibited a relatively normal CD4/CD8 ratio (average 1.63:1) as well as reconstitution of CD3/CD56 (averaging 17.8%) and CD20 subsets (averaging 4.0%). Animals reconstituted with donor-matched CD11c+ DC also demonstrated a CD11c+ population within their spleen, representing 0.27% to 0.43% of the recovered human cells with concurrent expression of HLA-DR, CD40, and CD86. When immunized with adenovirus, either as free replication-incompetent vector (AdV) or as vector-transduced DC (DC/AdV), there was activation and expansion of AdV-specific T-cells, an increase in Th1 cytokines in serum, and skewing of T-cells toward an effector/memory phenotype. T-cells recovered from animals challenged with AdV in vivo proliferated and secreted a Th1-profile of cytokines in response to DC/AdV challenge in vitro. Our results suggest that engrafting NSG mice with a combination of lymphocytes and donor-matched DC can reconstitute antigen responsiveness and allow the in vivo assessment of human immune response to viruses, vaccines, and other immune challenges.
    Journal of Neuroimmune Pharmacology 03/2011; 6(1):148-57. · 3.80 Impact Factor
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    ABSTRACT: To evaluate changes in vascular and musculoskeletal involvement in subjects in the Scleroderma Lung Study, a multicenter, double-blind, randomized, controlled trial comparing placebo treatment with oral cyclophosphamide (CYC) for 1 year in systemic sclerosis patients with interstitial lung disease. Subjects were then followed off the study agent for an additional 12 months. The following parameters were noted at baseline and every 6 months for each patient: digital tip ulcers, other dermal ulcers, joint swelling, joint tenderness, large joint contractures, muscle tenderness, muscle weakness, oral aperture, hand extension, and fist closure. A total of 158 patients were enrolled from 13 centers in the US; 79 were randomized to the CYC group and 79 to the placebo group. There were no differences in dermal ulcer and musculoskeletal measures between the CYC and placebo groups at baseline and 12 and 24 months. Improvement in percent predicted forced vital capacity was associated with improvement in the Rodnan skin thickness score (P<0.05) at 12 and 24 months, and with increased mean oral aperture at 24 months (P=0.005). These data document the frequency and course of these vascular and musculoskeletal features over time, therefore providing essential information for sample size calculations and magnitude of effect in future clinical trials. There was no treatment effect of CYC on the vascular and musculoskeletal features described.
    Arthritis care & research. 12/2010; 62(12):1772-8.
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    ABSTRACT: Redirecting the tropism of viral vectors enables specific transduction of selected cells by direct administration of vectors. We previously developed targeting lentiviral vectors by pseudotyping with modified Sindbis virus envelope proteins. These modified Sindbis virus envelope proteins have mutations in their original receptor-binding regions to eliminate their natural tropisms, and they are conjugated with targeting proteins, including antibodies and peptides, to confer their tropisms on target cells. We investigated whether our targeting vectors interact with DC-SIGN, which traps many types of viruses and gene therapy vectors by binding to the N-glycans of their envelope proteins. We found that these vectors do not interact with DC-SIGN. When these vectors were produced in the presence of deoxymannojirimycin, which alters the structures of N-glycans from complex to high mannose, these vectors used DC-SIGN as their receptor. Genetic analysis demonstrated that the N-glycans at E2 amino acid (aa) 196 and E1 aa 139 mediate binding to DC-SIGN, which supports the results of a previous report of cryoelectron microscopy analysis. In addition, we investigated whether modification of the N-glycan structures could activate serum complement activity, possibly by the lectin pathway of complement activation. DC-SIGN-targeted transduction occurs in the presence of human serum complement, demonstrating that high-mannose structure N-glycans of the envelope proteins do not activate human serum complement. These results indicate that the strategy of redirecting viral vectors according to alterations of their N-glycan structures would enable the vectors to target specific cells types expressing particular types of lectins.
    Journal of Virology 07/2010; 84(14):6923-34. · 5.08 Impact Factor
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    ABSTRACT: The Scleroderma Lung Study (SLS) demonstrated significant treatment-associated improvements in pulmonary function and symptoms when patients with scleroderma-related interstitial lung disease (SSc-ILD) were treated with a 1-year course of cyclophosphamide (CYC) in a randomized, double-blinded, placebo-controlled clinical trial. This study examined thoracic high-resolution CT (HRCT) scans obtained during the SLS for treatment-associated changes over time. Ninety-eight of the 158 subjects (CYC group, 49 subjects; placebo group, 49 subjects) participating in the SLS underwent thoracic HRCT scans both at baseline and after 12 months of treatment, which were available for analysis. Two independent radiologists visually scored the baseline HRCT scans for the presence of ground-glass opacities (GGOs), fibrosis (FIB), and honeycomb cysts (HCs) on a scale of 0 to 4. The treatment effect at 12 months was assessed by a blinded comparison of baseline and follow-up scans for evidence of stability and improvement (not worse) or deterioration (worse). At the end of treatment, FIB was significantly worse in the placebo treatment group than in the CYC treatment group (p = 0.014). Furthermore, differences in the 12-month change in FIB between the CYC and placebo groups correlated significantly with other outcome measures, including the 12-month changes in FVC (p < 0.05), total lung capacity (p < 0.05), and dyspnea (p < 0.001) scores. However, no differences were noted between the two groups with respect to changes in either GGOs or HCs. A 1-year course of treatment of SSc-ILD with CYC was associated with treatment-related changes in FIB scores on HRCT scans, which correlated with other measures of treatment response. ClinicalTrials.gov Identifier: NCT00004563.
    Chest 11/2009; 136(5):1333-40. · 7.13 Impact Factor
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    ABSTRACT: The major marker utilized to monitor COPD patients is forced expiratory volume in one second (FEV1). However, a single measurement of FEV1 cannot reliably predict subsequent decline. Recent studies indicate that T lymphocytes and eosinophils are important determinants of disease stability in COPD. We therefore measured cytokine levels in the lung lavage fluid and plasma of COPD patients in order to determine if the levels of T cell or eosinophil related cytokines were predictive of the future course of the disease. Baseline lung lavage and plasma samples were collected from COPD subjects with moderately severe airway obstruction and emphysematous changes on chest CT. The study participants were former smokers who had not had a disease exacerbation within the past six months or used steroids within the past two months. Those subjects who demonstrated stable disease over the following six months (DeltaFEV1 % predicted = 4.7 +/- 7.2; N = 34) were retrospectively compared with study participants who experienced a rapid decline in lung function (DeltaFEV1 % predicted = -16.0 +/- 6.0; N = 16) during the same time period and with normal controls (N = 11). Plasma and lung lavage cytokines were measured from clinical samples using the Luminex multiplex kit which enabled the simultaneous measurement of several T cell and eosinophil related cytokines. Stable COPD participants had significantly higher plasma IL-2 levels compared to participants with rapidly progressive COPD (p = 0.04). In contrast, plasma eotaxin-1 levels were significantly lower in stable COPD subjects compared to normal controls (p < 0.03). In addition, lung lavage eotaxin-1 levels were significantly higher in rapidly progressive COPD participants compared to both normal controls (p < 0.02) and stable COPD participants (p < 0.05). These findings indicate that IL-2 and eotaxin-1 levels may be important markers of disease stability in advanced emphysema patients. Prospective studies will need to confirm whether measuring IL-2 or eotaxin-1 can identify patients at risk for rapid disease progression.
    Respiratory research 11/2009; 10:113. · 3.64 Impact Factor
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    ABSTRACT: The ability to recruit qualified subjects who are willing to adhere to the study protocol in clinical trials is an essential component of translational research. Such tasks can be particularly challenging for chemoprevention studies when the targeted study population is healthy, at risk individuals who do not have signs or symptoms of the disease, and the study participation involves complex scheduling and invasive procedures such as bronchoscopy. In this report, we describe the recruitment process and evaluated the effectiveness of various recruitment strategies utilized in our National Cancer Institute sponsored lung cancer chemoprevention study with celecoxib. Heavy ex-smokers were recruited into the study through various methods such as radio advertisements, print media, mass mailings, flyers, internet postings and others. The number of inquiries, on-site screenees and randomization generated by each method determined the efficacy of that recruitment strategy. We prescreened 4470 individuals, invited 323 people for on-site screening and randomized 137 subjects. Radio advertisements (ads) generated the most inquiries (71.1%), followed by internet posting (11.8%), print media (6.0%), posted and racked flyers (4.4%), mass mailings (2.7%) and other strategies such as referrals from friends or family members or health care providers (2.3%). Radio ads, although costly, yielded the most subjects for on-site screening and randomization. Moreover, among the various types of radio stations, news radio stations were by far the most successful. Our results suggest that advertising on news radio is a highly effective recruitment method for successful accrual of ex-smokers into lung cancer chemoprevention trials.
    Contemporary clinical trials 07/2009; 30(5):464-72. · 1.51 Impact Factor
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    ABSTRACT: Experimental data suggested that exposure to recreational drugs might adversely affect antitumor immunity, which led us to examine the hypothesis that use of marijuana, cocaine, poppers, and amphetamines might increase the risk of Kaposi's sarcoma (KS) in HIV- and HHV-8-coinfected homosexual men. We analyzed data prospectively collected from the Multicenter AIDS Cohort Study (MACS) between 1984 and 2002. Among the 1335 HIV- and HHV-8-coinfected white men, 401 KS cases were identified. Multivariable Cox regression models were used to estimate the effects of time-varying recreational drug use on KS risk adjusting for potential confounders. The effects of both recent use (6 months prior) of recreational drugs and lagged exposure (i.e., use from 3 and 5 years prior) were examined. We did not observe any clear association with KS for recent use of any of the four drugs. In the analyses using lagged exposures, KS risk was associated with use of poppers 3-5 years prior [hazard ratio (HR)(3 years prior) = 1.27, 95% CI (0.97-1.67), HR(5 years prior) = 1.46 (1.01-2.13)]. However, no clear dose-response relationship was observed. These findings do not support a biological association between use of these substances and KS development in HIV- and HHV-8-coinfected homosexual men.
    AIDS research and human retroviruses 01/2009; 25(2):149-56. · 2.18 Impact Factor
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    ABSTRACT: The results of many laboratory studies suggest that amphetamine use may lead to altered immune function and cytokine expression, both of which are implicated in HIV-related lymphomagenesis. We examined the hypothesis that use of amphetamines modifies risk of non-Hodgkin lymphoma (NHL) in HIV-infected men in the Multicenter AIDS Cohort Study. Data on amphetamine use were collected every six months during the follow-up period between 1984 and 2002. A total of 171 NHL cases were diagnosed from the 19,250 person-years accrued. Multivariable Cox models were used to estimate the effects of baseline exposures, time-varying recent exposures, and three years lagged exposures on risk of NHL adjusting for potential confounders such as demographics, use of other substances, and risky sexual behaviors. We found that weekly or more frequent use of amphetamines was associated with an increased risk of NHL, with hazard ratios of 1.75 (95% CI = 0.81-3.77) for use at baseline, 4.73 (1.41-15.81) for recent use, and 3.05 (1.19-7.82) for three years prior use. Similar associations were observed when we separately examined systemic NHL and diffuse large B-cell lymphoma. Given these observations, the impact of amphetamines on lymphomagenesis among HIV-infected populations should be assessed more thoroughly.
    Cancer Causes and Control 12/2008; 20(5):509-16. · 3.20 Impact Factor
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    ABSTRACT: Marijuana smoking is associated with a number of abnormal findings in the lungs of habitual smokers. Previous studies revealed that Δ9-tetrahydrocannabinol (THC) caused mitochondrial injury in primary lung epithelial cells and in the cell line, A549 [Sarafian, T. A., Kouyoumjian, S., Khoshaghideh, F., Tashkin, D. P., and Roth, M. D. (2003). Delta 9-tetrahydrocannabinol disrupts mitochondrial function and cell energetics. Am J Physiol Lung Cell Mol Physiol 284, L298–306; Sarafian, T., Habib, N., Mao, J. T., Tsu, I. H., Yamamoto, M. L., Hsu, E., Tashkin, D. P., and Roth, M. D. (2005). Gene expression changes in human small airway epithelial cells exposed to Delta9-tetrahydrocannabinol. Toxicol Lett 158, 95–107]. The role of cannabinoid receptors in this injury was unclear, as was the potential impact on cell function. In order to investigate these questions, A549 cells were engineered to over-express the type 2 cannabinoid receptor (CB2R) using a self-inactivating lentiviral vector. This transduction resulted in a 60-fold increase in CB2R mRNA relative to cells transduced with a control vector. Transduced cell lines were used to study the effects of THC on chemotactic activity and mitochondrial function. Chemotaxis in response to a 10% serum gradient was suppressed in a concentration-dependent manner by exposure to THC. CB2R-transduced cells exhibited less intrinsic chemotactic activity (p < 0.05) and were 80- to 100-fold more sensitive to the inhibitory effects of THC. Studies using SR144528, a selective CB2R antagonist, verified that these effects were mediated by the CB2R. Marijuana smoke extract, but not smoke extracts from tobacco or placebo marijuana cigarettes, reproduced these effects (p < 0.05). THC decreased ATP level and mitochondrial membrane potential (Ψm) in both control and CB2R-transduced cells. However, these decreases did not play a significant role in chemotaxis inhibition since cyclosporine A, which protected against ATP loss, did not increase cell migration. Moreover, CB2R-transduced cells displayed higher Ψm than did control cells. Since both Ψm and chemotaxis are regulated by intracellular signaling, we investigated the effects of THC on the activation of multiple signaling pathways. Serum exposure activated several signaling events of which phosphorylation of IκB-α and JNK was regulated in a CB2R- and THC-dependent manner. We conclude that airway epithelial cells are sensitive to both CB2R-dependent and independent effects mediated by THC.
    Toxicology and Applied Pharmacology 09/2008; · 3.98 Impact Factor
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    ABSTRACT: Lung disease has become the leading cause of mortality and morbidity in scleroderma (SSc) patients. The frequency, nature, and progression of interstitial lung disease seen on high-resolution CT (HRCT) scans in patients with diffuse SSc (dcSSc) compared with those with limited SSc (lcSSc) has not been well characterized. Baseline HRCT scan images of 162 participants randomized into a National Institutes of Health-funded clinical trial were compared to clinical features, pulmonary function test measures, and BAL fluid cellularity. The extent and distribution of interstitial lung disease HRCT findings, including pure ground-glass opacity (pGGO), pulmonary fibrosis (PF), and honeycomb cysts (HCs), were recorded in the upper, middle, and lower lung zones on baseline and follow-up CT scan studies. HRCT scan findings included 92.9% PF, 49.4% pGGO, and 37.2% HCs. There was a significantly higher incidence of HCs in the three zones in lcSSc patients compared to dcSSc patients (p = 0.034, p = 0.048, and p = 0.0007, respectively). The extent of PF seen on HRCT scans was significantly negatively correlated with FVC (r = - 0.22), diffusing capacity of the lung for carbon monoxide (r = - 0.44), and total lung capacity (r = - 0.36). A positive correlation was found between pGGO and the increased number of acute inflammatory cells found in BAL fluid (r = 0.28). In the placebo group, disease progression was assessed as 30% in the upper and middle lung zones, and 45% in the lower lung zones. No difference in the progression rate was seen between lcSSc and dcSSc patients. PF and GGO were the most common HRCT scan findings in symptomatic SSc patients. HCs were seen in more than one third of cases, being more common in lcSSc vs dcSSc. There was no relationship between progression and baseline PF extent or lcSSc vs dcSSc. Trial registration: Clinicaltrials.gov Identifier: NCT00004563.
    Chest 08/2008; 134(2):358-67. · 7.13 Impact Factor

Publication Stats

2k Citations
342.84 Total Impact Points

Institutions

  • 1970–2013
    • University of California, Los Angeles
      • • Department of Medicine
      • • Division of Pulmonary and Critical Care
      • • Jonsson Comprehensive Cancer Center
      Los Angeles, CA, United States
  • 2008
    • Medical University of South Carolina
      • Division of Pulmonary, Critical Care, Allergy & Sleep Medicine
      Charleston, SC, United States
    • Kaiser Permanente
      Oakland, California, United States
  • 2006
    • National Institute of Biomedical Innovation
      Ibaragi, Ōsaka, Japan
  • 1998–2003
    • Children's Hospital Los Angeles
      • • Division of Critical Care Medicine
      • • Division of Hospital Medicine
      Los Angeles, California, United States