Try a new search

Format these results:

Searched for:

in-biosketch:true

person:passh01

Total Results:

757


Withaferin A inhibits the proteasome activity in mesothelioma in vitro and in vivo

Yang, Huanjie; Wang, Ying; Cheryan, Vino T; Wu, Wenjuan; Cui, Cindy Qiuzhi; Polin, Lisa A; Pass, Harvey I; Dou, Q Ping; Rishi, Arun K; Wali, Anil
The medicinal plant Withania somnifera has been used for over centuries in Indian Ayurvedic Medicine to treat a wide spectrum of disorders. Withaferin A (WA), a bioactive compound that is isolated from this plant, has anti-inflammatory, immuno-modulatory, anti-angiogenic, and anti-cancer properties. Here we investigated malignant pleural mesothelioma (MPM) suppressive effects of WA and the molecular mechanisms involved. WA inhibited growth of the murine as well as patient-derived MPM cells in part by decreasing the chymotryptic activity of the proteasome that resulted in increased levels of ubiquitinated proteins and pro-apoptotic proteasome target proteins (p21, Bax, IkappaBalpha). WA suppression of MPM growth also involved elevated apoptosis as evidenced by activation of pro-apoptotic p38 stress activated protein kinase (SAPK) and caspase-3, elevated levels of pro-apoptotic Bax protein and cleavage of poly-(ADP-ribose)-polymerase (PARP). Our studies including gene-array based analyses further revealed that WA suppressed a number of cell growth and metastasis-promoting genes including c-myc. WA treatments also stimulated expression of the cell cycle and apoptosis regulatory protein (CARP)-1/CCAR1, a novel transducer of cell growth signaling. Knock-down of CARP-1, on the other hand, interfered with MPM growth inhibitory effects of WA. Intra-peritoneal administration of 5 mg/kg WA daily inhibited growth of murine MPM cell-derived tumors in vivo in part by inhibiting proteasome activity and stimulating apoptosis. Together our in vitro and in vivo studies suggest that WA suppresses MPM growth by targeting multiple pathways that include blockage of proteasome activity and stimulation of apoptosis, and thus holds promise as an anti-MPM agent.
PMCID:3422308
PMID: 22912669
ISSN: 1932-6203
CID: 753382

Early detection of malignant pleural mesothelioma in asbestos-exposed individuals with a noninvasive proteomics-based surveillance tool

Ostroff, Rachel M; Mehan, Michael R; Stewart, Alex; Ayers, Deborah; Brody, Edward N; Williams, Stephen A; Levin, Stephen; Black, Brad; Harbut, Michael; Carbone, Michele; Goparaju, Chandra; Pass, Harvey I
BACKGROUND: Malignant pleural mesothelioma (MM) is an aggressive, asbestos-related pulmonary cancer that is increasing in incidence. Because diagnosis is difficult and the disease is relatively rare, most patients present at a clinically advanced stage where possibility of cure is minimal. To improve surveillance and detection of MM in the high-risk population, we completed a series of clinical studies to develop a noninvasive test for early detection. METHODOLOGY/PRINCIPAL FINDINGS: We conducted multi-center case-control studies in serum from 117 MM cases and 142 asbestos-exposed control individuals. Biomarker discovery, verification, and validation were performed using SOMAmer proteomic technology, which simultaneously measures over 1000 proteins in unfractionated biologic samples. Using univariate and multivariate approaches we discovered 64 candidate protein biomarkers and derived a 13-marker random forest classifier with an AUC of 0.99+/-0.01 in training, 0.98+/-0.04 in independent blinded verification and 0.95+/-0.04 in blinded validation studies. Sensitivity and specificity at our pre-specified decision threshold were 97%/92% in training and 90%/95% in blinded verification. This classifier accuracy was maintained in a second blinded validation set with a sensitivity/specificity of 90%/89% and combined accuracy of 92%. Sensitivity correlated with pathologic stage; 77% of Stage I, 93% of Stage II, 96% of Stage III and 96% of Stage IV cases were detected. An alternative decision threshold in the validation study yielding 98% specificity would still detect 60% of MM cases. In a paired sample set the classifier AUC of 0.99 and 91%/94% sensitivity/specificity was superior to that of mesothelin with an AUC of 0.82 and 66%/88% sensitivity/specificity. The candidate biomarker panel consists of both inflammatory and proliferative proteins, processes strongly associated with asbestos-induced malignancy. SIGNIFICANCE: The SOMAmer biomarker panel discovered and validated in these studies provides a solid foundation for surveillance and diagnosis of MM in those at highest risk for this disease.
PMCID:3463527
PMID: 23056237
ISSN: 1932-6203
CID: 753352

Plasma osteopontin velocity differentiates lung cancers from controls in a CT screening population

Joseph, Sasha; Harrington, Ryan; Walter, Dawn; Goldberg, Judith D; Li, Xiaochun; Beck, Amanda; Litton, Tyler; Hirsch, Nathalie; Blasberg, Justin; Slomiany, Mark; Rom, William; Pass, Harvey; Donington, Jessica
INTRODUCTION: As CT screening is integrated into non-small cell lung cancer (NSCLC) care, additional parameters are needed to help distinguish cancers from benign nodules. Osteopontin (OPN), a secreted phosphoprotein, has elevated plasma levels in NSCLC. We hypothesize that changes in plasma OPN over time (i.e., OPN velocity [OPNV]) can differentiate NSCLC patients from those without cancer in a CT screening population. METHODS: A nested case-control study was conducted within a NSCLC CT screening trial. Incident cancers with serial plasma were matched to controls. OPN was measured by ELISA. Demographic, OPN, and OPNV were compared between cancers and controls using Wilcoxon Signed Rank tests. RESULTS: Ten incident cancers were identified. The pack years distributions were similar, but cancers were older (median of the paired difference: 5.35 years; p=0.002) and their surveillance intervals were shorter (median of the paired difference: -2 months; p=0. 03) than matched controls. Baseline OPN was similar (median of the paired difference: -5.15 ng/ml, p=0.50), but OPNV in the cancers was significantly greater than that of matched controls, (median of the paired difference: 1.06 ng/ml/month, p=0.01). Accuracy rate for prediction of disease status based on OPNV (adjusted for age and surveillance) was 83%. CONCLUSIONS: These are early evidence for utility of monitoring plasma OPN during CT screening to assist in identification of NSCLCs.
PMCID:3746829
PMID: 23568008
ISSN: 1574-0153
CID: 287312

CT Scan Screening for Lung Cancer: Risk Factors for Nodules and Malignancy in a High-Risk Urban Cohort

Greenberg, Alissa K; Lu, Feng; Goldberg, Judith D; Eylers, Ellen; Tsay, Jun-Chieh; Yie, Ting-An; Naidich, David; McGuinness, Georgeann; Pass, Harvey; Tchou-Wong, Kam-Meng; Addrizzo-Harris, Doreen; Chachoua, Abraham; Crawford, Bernard; Rom, William N
BACKGROUND: Low-dose computed tomography (CT) for lung cancer screening can reduce lung cancer mortality. The National Lung Screening Trial reported a 20% reduction in lung cancer mortality in high-risk smokers. However, CT scanning is extremely sensitive and detects non-calcified nodules (NCNs) in 24-50% of subjects, suggesting an unacceptably high false-positive rate. We hypothesized that by reviewing demographic, clinical and nodule characteristics, we could identify risk factors associated with the presence of nodules on screening CT, and with the probability that a NCN was malignant. METHODS: We performed a longitudinal lung cancer biomarker discovery trial (NYU LCBC) that included low-dose CT-screening of high-risk individuals over 50 years of age, with more than 20 pack-year smoking histories, living in an urban setting, and with a potential for asbestos exposure. We used case-control studies to identify risk factors associated with the presence of nodules (n = 625) versus no nodules (n = 557), and lung cancer patients (n = 30) versus benign nodules (n = 128). RESULTS: The NYU LCBC followed 1182 study subjects prospectively over a 10-year period. We found 52% to have NCNs >4 mm on their baseline screen. Most of the nodules were stable, and 9.7% of solid and 26.2% of sub-solid nodules resolved. We diagnosed 30 lung cancers, 26 stage I. Three patients had synchronous primary lung cancers or multifocal disease. Thus, there were 33 lung cancers: 10 incident, and 23 prevalent. A sub-group of the prevalent group were stable for a prolonged period prior to diagnosis. These were all stage I at diagnosis and 12/13 were adenocarcinomas. CONCLUSIONS: NCNs are common among CT-screened high-risk subjects and can often be managed conservatively. Risk factors for malignancy included increasing age, size and number of nodules, reduced FEV1 and FVC, and increased pack-years smoking. A sub-group of screen-detected cancers are slow-growing and may contribute to over-diagnosis and lead-time biases.
PMCID:3388074
PMID: 22768300
ISSN: 1932-6203
CID: 171565

Pleurectomy and other surgical options for malignant mesothelioma

Chapter by: Pass, HI
in: Cardiothoracic Surgery Review by
pp. 1144-1145
ISBN: 9781451154153
CID: 2229002

An ERK2 Survival Pathway Mediates Resistance of Human Mesothelioma Cells to Asbestos-Induced Injury

Shukla A; Barrett TF; Macpherson MB; Hillegass JM; Fukagawa NK; Swain WA; O'Byrne KJ; Testa JR; Pass HI; Faux SP; Mossman BT
We hypothesized that normal human mesothelial cells acquire resistance to asbestos-induced toxicity via induction of one or more EGFR-linked survival pathways (PI3K/AKT/mTOR and ERK1/2) during SV40 transformation and carcinogenesis. Both isolated HKNM-2 mesothelial cells and a telomerase-immortalized mesothelial line (LP9/TERT-1) were more sensitive to crocidolite asbestos toxicity than an SV40 Tag-immortalized mesothelial line (MET5A) and mesothelioma (MM) cell lines (HMESO and PPM Mill). Whereas increases in phosphorylation of AKT (pAKT) were observed in MET5A cells in response to asbestos, LP9/TERT-1 cells exhibited dose-related decreases in pAKT levels. Pretreatment with an EGFR phosphorylation or MEK1/2 inhibitor abrogated asbestos-induced pERK1/2 levels in both LP9/TERT-1 and MET5A cells as well as increases in pAKT levels in MET5A cells. Transient transfection of siRNAs targeting ERK1, ERK2 or AKT revealed that ERK1/2 pathways were involved in cell death by asbestos in both cell lines. Asbestos-resistant HMESO or PPM Mill cells with high endogenous levels of ERKs or AKT did not show dose-responsive increases in pERK1/ERK1, pERK2/ERK2 or pAKT/AKT levels by asbestos. However, shERK2 stable cell lines created from both MM lines were more sensitive to asbestos toxicity than shERK1 and shControl lines, and exhibited unique, tumor-specific changes in endogenous cell-death-related gene expression. Our results suggest that EGFR phosphorylation is causally linked to pERK and pAKT activation by asbestos in normal and SV40 Tag-immortalized human mesothelial cells. They also indicate that ERK2 plays a role in modulating asbestos toxicity by regulating genes critical to cell injury and survival that are differentially expressed in human mesotheliomas
PMCID:3262687
PMID: 21454801
ISSN: 1535-4989
CID: 135522

The MARS feasibility trial: conclusions not supported by data [Letter]

Weder, Walter; Stahel, Rolf A; Baas, Paul; Dafni, Urania; de Perrot, Marc; McCaughan, Brian C; Nakano, Takashi; Pass, Harvey I; Robinson, Bruce W S; Rusch, Valerie W; Sugarbaker, David J; van Zandwijk, Nico
PMID: 22041539
ISSN: 1474-5488
CID: 149987

Curcumin suppresses growth of mesothelioma cells in vitro and in vivo, in part, by stimulating apoptosis

Wang Y; Rishi AK; Wu W; Polin L; Sharma S; Levi E; Albelda S; Pass HI; Wali A
Malignant pleural mesothelioma (MPM) is an aggressive, asbestos-related malignancy of the thoracic pleura. Although, platinum-based agents are the first line of therapy, there is an urgent need for second-line therapies to treat the drug-resistant MPM. Cell cycle as well as apoptosis pathways are frequently altered in MPM and thus remain attractive targets for intervention strategies. Curcumin, the major component in the spice turmeric, alone or in combination with other chemotherapeutics has been under investigation for a number of cancers. In this study, we investigated the biological and molecular responses of MPM cells to curcumin treatments and the mechanisms involved. Flow-cytometric analyses coupled with western immunoblotting and gene-array analyses were conducted to determine mechanisms of curcumin-dependent growth suppression of human (H2373, H2452, H2461, and H226) and murine (AB12) MPM cells. Curcumin inhibited MPM cell growth in a dose- and time-dependent manner while pretreatment of MPM cells with curcumin enhanced cisplatin efficacy. Curcumin activated the stress-activated p38 kinase, caspases 9 and 3, caused elevated levels of proapoptotic proteins Bax, stimulated PARP cleavage, and apoptosis. In addition, curcumin treatments stimulated expression of novel transducers of cell growth suppression such as CARP-1, XAF1, and SULF1 proteins. Oral administration of curcumin inhibited growth of murine MPM cell-derived tumors in vivo in part by stimulating apoptosis. Thus, curcumin targets cell cycle and promotes apoptosis to suppress MPM growth in vitro and in vivo. Our studies provide a proof-of-principle rationale for further in-depth analysis of MPM growth suppression mechanisms and their future exploitation in effective management of resistant MPM
PMCID:3809898
PMID: 21594647
ISSN: 1573-4919
CID: 135521

ERK2 is essential for the growth of human epithelioid malignant mesotheliomas

Shukla, Arti; Hillegass, Jedd M; Macpherson, Maximilian B; Beuschel, Stacie L; Vacek, Pamela M; Butnor, Kelly J; Pass, Harvey I; Carbone, Michele; Testa, Joseph R; Heintz, Nicholas H; Mossman, Brooke T
Members of the extracellular signal-regulated kinase (ERK) family may have distinct roles in the development of cell injury and repair, differentiation and carcinogenesis. Here, we show, using a synthetic small-molecule MEK1/2 inhibitor (U0126) and RNA silencing of ERK1 and 2, comparatively, that ERK2 is critical to transformation and homeostasis of human epithelioid malignant mesotheliomas (MMs), asbestos-induced tumors with a poor prognosis. Although MM cell (HMESO) lines stably transfected with shERK1 or shERK2 both exhibited significant decreases in cell proliferation in vitro, injection of shERK2 cells, and not shERK1 cells, into immunocompromised severe combined immunodeficiency (SCID) mice showed significant attenuated tumor growth in comparison to shControl (shCon) cells. Inhibition of migration, invasion and colony formation occurred in shERK2 MM cells in vitro, suggesting multiple roles of ERK2 in neoplasia. Microarray and quantitative real-time PCR analyses revealed gene expression that was significantly increased (CASP1, TRAF1 and FAS) or decreased (SEMA3E, RPS6KA2, EGF and BCL2L1) in shERK2-transfected MM cells in contrast to shCon-transfected MM cells. Most striking decreases were observed in mRNA levels of Semaphorin 3 (SEMA3E), a candidate tumor suppressor gene linked to inhibition of angiogenesis. These studies demonstrate a key role of ERK2 in novel gene expression critical to the development of epithelioid MMs. After injection of sarcomatoid human MM (PPMMill) cells into SCID mice, both shERK1 and shERK2 lines showed significant decreased tumor growth, suggesting heterogeneous effects of ERKs in individual MMs
PMCID:3071888
PMID: 21710492
ISSN: 1097-0215
CID: 135518

Telomerase activity in pleural malignant mesotheliomas

Au AY; Hackl T; Yeager TR; Cohen SB; Pass HI; Harris CC; Reddel RR
New treatments are needed for malignant pleural mesothelioma (MPM), which currently has a poor prognosis. Cellular immortalisation, one of the hallmarks of cancer, depends on the activity of a telomere length maintenance mechanism (TMM) - either telomerase or alternative lengthening of telomeres (ALT). The TMMs are widely regarded as potential targets for cancer therapies and telomerase inhibitors have entered clinical trials. The aim of this study was to determine what proportion of MPMs use ALT and/or telomerase. Forty-three MPMs from 42 patients were examined for telomerase and ALT activity. Telomerase activity was detected by immunoaffinity purification followed by the telomere repeat amplification protocol (TRAP), and ALT activity was determined by the C-circle assay and by assessing telomere lengths using terminal restriction fragment analyses. We found that 43 of 43 MPMs were telomerase-positive[+] and ALT-negative[-]. Therefore, to investigate whether pleural mesothelial cells are unusually susceptible to activation of telomerase, we examined activation of the TMMs in an in vitro model of cellular immortalisation, in which normal pleural mesothelial cells were transduced with simian virus 40 (SV40) oncogenes. We found that normal mesothelial cells were TMM-negative, and that expression of the SV40 oncogenes did not directly activate telomerase or ALT. Immortalisation, which in this experimental system results from additional genetic changes that have not yet been identified, was accompanied by activation of either TMM. Therefore, pleural mesothelial cells are capable of activating either TMM in vitro, and the observation that 100% of MPMs were telomerase[+] suggests that there are factors in vivo that select for telomerase activity during oncogenesis of this tumour type. We conclude that MPM is a tumour that could be considered for anti-telomerase therapy
PMCID:3135747
PMID: 21277646
ISSN: 1872-8332
CID: 135524