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Mesothelioma: HELP
Articles by Pamela M. Vacek
Based on 5 articles published since 2008
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Between 2008 and 2019, Pamela Vacek wrote the following 5 articles about Mesothelioma.
 
+ Citations + Abstracts
1 Article Inflammasome Modulation by Chemotherapeutics in Malignant Mesothelioma. 2015

Westbom, Catherine / Thompson, Joyce K / Leggett, Alan / MacPherson, Maximilian / Beuschel, Stacie / Pass, Harvey / Vacek, Pamela / Shukla, Arti. ·Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, United States of America. · Department of Cardiothoracic Surgery, New York University School of Medicine, New York, New York, United States of America. · Department of Medical Biostatistics, University of Vermont College of Medicine, Burlington, VT, United States of America. ·PLoS One · Pubmed #26689911.

ABSTRACT: Malignant mesothelioma (MM) is a fatal disease in dire need of therapy. The role of inflammasomes in cancer is not very well studied, however, literature supports both pro-and anti-tumorigenic effects of inflammasomes on cancer depending upon the type of cancer. Asbestos is a causative agent for MM and we have shown before that it causes inflammasome priming and activation in mesothelial cells. MM tumor cells/tissues showed decreased levels of inflammasome components like NLRP3 and caspase-1 as compared to human mesothelial cells or normal tissue counterpart of tumor. Based on our preliminary findings we hypothesized that treatment of MMs with chemotherapeutic drugs may elevate the levels of NLRP3 and caspase-1 resulting in increased cell death by pyroptosis while increasing the levels of IL-1β and other pro-inflammatory molecules. Therefore, a combined strategy of chemotherapeutic drug and IL-1R antagonist may play a beneficial role in MM therapy. To test our hypothesis we used two human MM tumor cell lines (Hmeso, H2373) and two chemotherapeutic drugs (doxorubicin, cisplatin). Through a series of experiments we showed that both chemotherapeutic drugs caused increases in NLRP3 levels, caspase-1 activation, pyroptosis and pro-inflammatory molecules released from MM cells. In vivo studies using SCID mice and Hmeso cells showed that tumors were smaller in combined treatment group of cisplatin and IL-1R antagonist (Anakinra) as compared to cisplatin alone or untreated control groups. Taken together our study suggests that chemotherapeutic drugs in combination with IL-1R antagonist may have a beneficial role in MM treatment.

2 Article CREB-induced inflammation is important for malignant mesothelioma growth. 2014

Westbom, Catherine M / Shukla, Anurag / MacPherson, Maximilian B / Yasewicz, Elizabeth C / Miller, Jill M / Beuschel, Stacie L / Steele, Chad / Pass, Harvey I / Vacek, Pamela M / Shukla, Arti. ·Department of Pathology, College of Medicine, University of Vermont, Burlington, Vermont. · Department of Medicine, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama. · Langone Medical Center, NYU School of Medicine, New York, New York. · Department of Medical Biostatistics, College of Medicine, University of Vermont, Burlington, Vermont. · Department of Pathology, College of Medicine, University of Vermont, Burlington, Vermont. Electronic address: arti.shukla@uvm.edu. ·Am J Pathol · Pubmed #25111229.

ABSTRACT: Malignant mesothelioma (MM) is an aggressive tumor with no treatment regimen. Previously we have demonstrated that cyclic AMP response element binding protein (CREB) is constitutively activated in MM tumor cells and tissues and plays an important role in MM pathogenesis. To understand the role of CREB in MM tumor growth, we generated CREB-inhibited MM cell lines and performed in vitro and in vivo experiments. In vitro experiments demonstrated that CREB inhibition results in significant attenuation of proliferation and drug resistance of MM cells. CREB-silenced MM cells were then injected into severe combined immunodeficiency mice, and tumor growth in s.c. and i.p. models of MM was followed. We observed significant inhibition in MM tumor growth in both s.c. and i.p. models and the presence of a chemotherapeutic drug, doxorubicin, further inhibited MM tumor growth in the i.p. model. Peritoneal lavage fluids from CREB-inhibited tumor-bearing mice showed a significantly reduced total cell number, differential cell counts, and pro-inflammatory cytokines and chemokines (IL-6, IL-8, regulated on activation normal T cell expressed and secreted, monocyte chemotactic protein-1, and vascular endothelial growth factor). In vitro studies showed that asbestos-induced inflammasome/inflammation activation in mesothelial cells was CREB dependent, further supporting the role of CREB in inflammation-induced MM pathogenesis. In conclusion, our data demonstrate the involvement of CREB in the regulation of MM pathogenesis by regulation of inflammation.

3 Article Extracellular signal-regulated kinase 5: a potential therapeutic target for malignant mesotheliomas. 2013

Shukla, Arti / Miller, Jill M / Cason, Christopher / Sayan, Mutlay / MacPherson, Maximilian B / Beuschel, Stacie L / Hillegass, Jedd / Vacek, Pamela M / Pass, Harvey I / Mossman, Brooke T. ·Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont 05405, USA. Arti.Shukla@med.uvm.edu ·Clin Cancer Res · Pubmed #23446998.

ABSTRACT: PURPOSE: Malignant mesothelioma is a devastating disease with a need for new treatment strategies. In the present study, we showed the importance of extracellular signal-regulated kinase 5 (ERK5) in malignant mesothelioma tumor growth and treatment. EXPERIMENTAL DESIGN: ERK5 as a target for malignant mesothelioma therapy was verified using mesothelial and mesothelioma cell lines as well as by xenograft severe combined immunodeficient (SCID) mouse models. RESULTS: We first showed that crocidolite asbestos activated ERK5 in LP9 cells and mesothelioma cell lines exhibit constitutive activation of ERK5. Addition of doxorubicin resulted in further activation of ERK5 in malignant mesothelioma cells. ERK5 silencing increased doxorubicin-induced cell death and doxorubicin retention in malignant mesothelioma cells. In addition, shERK5 malignant mesothelioma lines exhibited both attenuated colony formation on soft agar and invasion of malignant mesothelioma cells in vitro that could be related to modulation of gene expression linked to cell proliferation, apoptosis, migration/invasion, and drug resistance as shown by microarray analysis. Most importantly, injection of shERK5 malignant mesothelioma cell lines into SCID mice showed significant reduction in tumor growth using both subcutaneous and intraperitoneal models. Assessment of selected human cytokine profiles in peritoneal lavage fluid from intraperitoneal shERK5 and control tumor-bearing mice showed that ERK5 was critical in regulation of various proinflammatory (RANTES/CCL5, MCP-1) and angiogenesis-related (interleukin-8, VEGF) cytokines. Finally, use of doxorubicin and cisplatin in combination with ERK5 inhibition showed further reduction in tumor weight and volume in the intraperitoneal model of tumor growth. CONCLUSION: ERK5 inhibition in combination with chemotherapeutic drugs is a beneficial strategy for combination therapy in patients with malignant mesothelioma.

4 Article ERK2 is essential for the growth of human epithelioid malignant mesotheliomas. 2011

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. ·Department of Pathology, University of Vermont College of Medicine, Burlington, VT 05405-0068, USA. arti.shukla@uvm.edu ·Int J Cancer · Pubmed #21710492.

ABSTRACT: 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.

5 Article Blocking of ERK1 and ERK2 sensitizes human mesothelioma cells to doxorubicin. 2010

Shukla, Arti / Hillegass, Jedd M / MacPherson, Maximilian B / Beuschel, Stacie L / Vacek, Pamela M / Pass, Harvey I / Carbone, Michele / Testa, Joseph R / Mossman, Brooke T. ·Department of Pathology, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT 05405, USA. Arti.Shukla@uvm.edu ·Mol Cancer · Pubmed #21159167.

ABSTRACT: BACKGROUND: Malignant mesotheliomas (MM) have a poor prognosis, largely because of their chemoresistance to anti-cancer drugs such as doxorubicin (Dox). Here we show using human MM lines that Dox activates extracellular signal-regulated kinases (ERK1 and 2), causally linked to increased expression of ABC transporter genes, decreased accumulation of Dox, and enhanced MM growth. Using the MEK1/2 inhibitor, U0126 and stably transfected shERK1 and shERK2 MM cell lines, we show that inhibition of both ERK1 and 2 sensitizes MM cells to Dox. RESULTS: U0126 significantly modulated endogenous expression of several important drug resistance (BCL2, ABCB1, ABCC3), prosurvival (BCL2), DNA repair (BRCA1, BRCA2), hormone receptor (AR, ESR2, PPARγ) and drug metabolism (CYP3A4) genes newly identified in MM cells. In comparison to shControl lines, MM cell lines stably transfected with shERK1 or shERK2 exhibited significant increases in intracellular accumulation of Dox and decreases in cell viability. Affymetrix microarray analysis on stable shERK1 and shERK2 MM lines showed more than 2-fold inhibition (p ≤ 0.05) of expression of ATP binding cassette genes (ABCG1, ABCA5, ABCA2, MDR/TAP, ABCA1, ABCA8, ABCC2) in comparison to shControl lines. Moreover, injection of human MM lines into SCID mice showed that stable shERK1 or shERK2 lines had significantly slower tumor growth rates in comparison to shControl lines after Dox treatment. CONCLUSIONS: These studies suggest that blocking ERK1 and 2, which play critical roles in multi-drug resistance and survival, may be beneficial in combination with chemotherapeutic drugs in the treatment of MMs and other tumors.