Bio

Professional Education


  • Doctor of Medicine, Shahid Beheshti University (2009)

Stanford Advisors


Publications

Journal Articles


  • Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition. Nature medicine Tang, Y., Gholamin, S., Schubert, S., Willardson, M. I., Lee, A., Bandopadhayay, P., Bergthold, G., Masoud, S., Nguyen, B., Vue, N., Balansay, B., Yu, F., Oh, S., Woo, P., Chen, S., Ponnuswami, A., Monje, M., Atwood, S. X., Whitson, R. J., Mitra, S., Cheshier, S. H., Qi, J., Beroukhim, R., Tang, J. Y., Wechsler-Reya, R., Oro, A. E., Link, B. A., Bradner, J. E., Cho, Y. 2014; 20 (7): 732-740

    Abstract

    Hedgehog signaling drives oncogenesis in several cancers, and strategies targeting this pathway have been developed, most notably through inhibition of Smoothened (SMO). However, resistance to Smoothened inhibitors occurs by genetic changes of Smoothened or other downstream Hedgehog components. Here we overcome these resistance mechanisms by modulating GLI transcription through inhibition of bromo and extra C-terminal (BET) bromodomain proteins. We show that BRD4 and other BET bromodomain proteins regulate GLI transcription downstream of SMO and suppressor of fused (SUFU), and chromatin immunoprecipitation studies reveal that BRD4 directly occupies GLI1 and GLI2 promoters, with a substantial decrease in engagement of these sites after treatment with JQ1, a small-molecule inhibitor targeting BRD4. Globally, genes associated with medulloblastoma-specific GLI1 binding sites are downregulated in response to JQ1 treatment, supporting direct regulation of GLI activity by BRD4. Notably, patient- and GEMM (genetically engineered mouse model)-derived Hedgehog-driven tumors (basal cell carcinoma, medulloblastoma and atypical teratoid rhabdoid tumor) respond to JQ1 even when harboring genetic lesions rendering them resistant to Smoothened antagonists. Altogether, our results reveal BET proteins as critical regulators of Hedgehog pathway transcriptional output and nominate BET bromodomain inhibitors as a strategy for treating Hedgehog-driven tumors with emerged or a priori resistance to Smoothened antagonists.

    View details for DOI 10.1038/nm.3613

    View details for PubMedID 24973920

  • Casein kinase 2α regulates glioblastoma brain tumor-initiating cell growth through the β-catenin pathway. Oncogene Nitta, R. T., Gholamin, S., Feroze, A. H., Agarwal, M., Cheshier, S. H., Mitra, S. S., Li, G. 2014

    Abstract

    Glioblastoma (GBM) is the most common and fatal primary brain tumor in humans, and it is essential that new and better therapies are developed to treat this disease. Previous research suggests that casein kinase 2 (CK2) may be a promising therapeutic target for GBMs. CK2 has enhanced expression or activity in numerous cancers, including GBM, and it has been demonstrated that inhibitors of CK2 regressed tumor growth in GBM xenograft mouse models. Our studies demonstrate that the CK2 subunit, CK2α, is overexpressed in and has an important role in regulating brain tumor-initiating cells (BTIC) in GBM. Initial studies showed that two GBM cell lines (U87-MG and U138) transduced with CK2α had enhanced proliferation and anchorage-independent growth. Inhibition of CKα using siRNA or small-molecule inhibitors (TBBz, CX-4945) reduced cell growth, decreased tumor size, and increased survival rates in GBM xenograft mouse models. We also verified that inhibition of CK2α decreased the activity of a well-known GBM-initiating cell regulator, β-catenin. Loss of CK2α decreased two β-catenin-regulated genes that are involved in GBM-initiating cell growth, OCT4 and NANOG. To determine the importance of CK2α in GBM stem cell maintenance, we reduced CK2α activity in primary GBM samples and tumor spheres derived from GBM patients. We discovered that loss of CK2α activity reduced the sphere-forming capacity of BTIC and decreased numerous GBM stem cell markers, including CD133, CD90, CD49f and A2B5. Our study suggests that CK2α is involved in GBM tumorigenesis by maintaining BTIC through the regulation of β-catenin.Oncogene advance online publication, 22 September 2014; doi:10.1038/onc.2014.299.

    View details for DOI 10.1038/onc.2014.299

    View details for PubMedID 25241897

  • Targeting c-MET/HGF Signaling Pathway in Upper Gastrointestinal Cancers: Rationale and Progress CURRENT DRUG TARGETS Gholamin, S., Fiuji, H., Maftouh, M., Mirhafez, R., Shandiz, F. H., Avan, A. 2014; 15 (14): 1302-1311

    Abstract

    Aberrant activation of receptor-tyrosine kinase c-Met/HGF pathway is shown to be associated with cell proliferation, invasion, metastasis and poor-prognosis in several tumor types, including upper gastrointestinal-malignancies. The interaction of c-Met with multiple signalling-pathways involved in tumorigenic-properties and invasive-phenotype has gained substantial attention, suggesting its role as an intriguing-target for cancer-therapy. In recent years, there have been considerable efforts in development of effective c-Met inhibitors with potential clinical-applications and one of them, crizotinib (dual c-Met/ALK inhibitor), has recently been approved for lung-cancers with ALK-rearrangement. However several important questions remain to be unanswered on the molecular mechanisms underlying the antitumor effects of crizotinib, as well as on its possible role in the treatment of different tumor types, including upper-gastrointestinal-cancers. The aim of this review is to give an overview on critical role of the c-Met/HGF pathway in cancer, as well as the preclinical/clinical studies on c-Met inhibitors. There are accumulating evidences on therapeutic potential of c-Met inhibitors for the treatment of other malignancies, such as gastric and pancreatic cancers. However, further investigations are needed to identify determinants of the activity of c-Met inhibitors, through the analysis of genetic/environmental alterations affecting c-Met and parallel pro-cancer pathways; mechanisms result in developing resistance to anti-c-Met agents; and selection of patients that might benefit from therapy. These studies will be essential to improve the selectivity/efficacy of future anticancer strategies of c-Met targeted-therapies in treatment of upper gastrointestinal-cancers.

    View details for Web of Science ID 000346421300006

    View details for PubMedID 25382190

  • Antibody response to influenza immunization in coronary artery disease patients: A controlled trial VACCINE Keshtkar-Jahromi, M., Vakili, H., Rahnavardi, M., Gholamin, S., Razavi, S., Eskandari, A., Sadeghi, R., Vatan-Pour, H., Keshtkar-Jahromi, M., Haghighat, B., Ghaffaripour, M., Mokhtari-Azad, T. 2009; 28 (1): 110-113

    Abstract

    Safety of and humoral immune response to the anti-influenza vaccine in coronary artery disease (CAD) patients were evaluated. The trivalent vaccine was administered to 137 eligible CAD patients and 67 age- and sex-matched healthy individuals. Antibody (Ab) titers were measured before and 1 month after vaccination. CAD and HC groups were not significantly different in serologic response and magnitude of change in antibody titers against each of the vaccine antigens. In multivariate analyses, regular exercise and using multivitamin supplements were independently associated with better antibody response among CAD patients. There were no major cardiac or general adverse effects. Influenza vaccine was found safe in CAD patients and antibody responses were similar to HCs.

    View details for DOI 10.1016/j.vaccine.2009.09.108

    View details for Web of Science ID 000274869200014

    View details for PubMedID 19819210

  • Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition NATURE MEDICINE Tang, Y., Gholamin, S., Schubert, S., Willardson, M. I., Lee, A., Bandopadhayay, P., Bergthold, G., Masoud, S., Nguyen, B., Vue, N., Balansay, B., Yu, F., Oh, S., Woo, P., Chen, S., Ponnuswami, A., Monje, M., Atwood, S. X., Whitson, R. J., Mitra, S., Cheshier, S. H., Qi, J., Beroukhim, R., Tang, J. Y., Wechsler-Reya, R., Oro, A. E., Link, B. A., Bradner, J. E., Cho, Y. 2014; 20 (7): 732-740

    Abstract

    Hedgehog signaling drives oncogenesis in several cancers, and strategies targeting this pathway have been developed, most notably through inhibition of Smoothened (SMO). However, resistance to Smoothened inhibitors occurs by genetic changes of Smoothened or other downstream Hedgehog components. Here we overcome these resistance mechanisms by modulating GLI transcription through inhibition of bromo and extra C-terminal (BET) bromodomain proteins. We show that BRD4 and other BET bromodomain proteins regulate GLI transcription downstream of SMO and suppressor of fused (SUFU), and chromatin immunoprecipitation studies reveal that BRD4 directly occupies GLI1 and GLI2 promoters, with a substantial decrease in engagement of these sites after treatment with JQ1, a small-molecule inhibitor targeting BRD4. Globally, genes associated with medulloblastoma-specific GLI1 binding sites are downregulated in response to JQ1 treatment, supporting direct regulation of GLI activity by BRD4. Notably, patient- and GEMM (genetically engineered mouse model)-derived Hedgehog-driven tumors (basal cell carcinoma, medulloblastoma and atypical teratoid rhabdoid tumor) respond to JQ1 even when harboring genetic lesions rendering them resistant to Smoothened antagonists. Altogether, our results reveal BET proteins as critical regulators of Hedgehog pathway transcriptional output and nominate BET bromodomain inhibitors as a strategy for treating Hedgehog-driven tumors with emerged or a priori resistance to Smoothened antagonists.

    View details for Web of Science ID 000338689500015

  • Lovastatin for Reduction of Leptin in Nondialysis Patients With Type 2 Diabetic Nephropathy IRANIAN JOURNAL OF KIDNEY DISEASES Gholamin, S., Razavi, S., Taghavi-Garmestani, S., Ghorbanihaghjo, A., Rashtchizadeh, N., Safa, J., Vatankhah, A. M., Azizi, T., Argani, H. 2014; 8 (3): 201-206

    Abstract

    Introduction: Diabetic Nephropathy (DN) is one of the main complications of diabetes mellitus, mostly ending to end-stage renal disease. Leptin and C-reactive protein (CRP), as inflammatory markers implicated in the progression of DN, increase in diabetes mellitus, while transferrin and albumin, as members of anti-oxidant defense mechanism, are found to decline.In a controlled clinical trial, 65 patients with type 2 DN were assigned to receive lovastatin or placebo, for 3 months, to assess statins' impact on serum levels of leptin, CRP, transferrin, albumin, and lipid profile.Serum levels of CRP (3.52 +/- 4.16 mg/dL to 2.84 +/- 3.06 mg/dL, P = .02), leptin (10.78 +/- 8.30 mg/dL to 7.80 +/- 5.41 mg/dL, P = .006), low-density lipoprotein cholesterol (116.16 +/- 46.54 mg/dL to 85.46 +/- 29.22 mg/dL, P = .001), and total cholesterol (199.00 +/- 43.33 mg/dL to 164.67 +/- 35.19 mg/dL, P = .001) were lowered after lovastatin therapy. Mean serum level of high-density lipoprotein cholesterol increased (40.00 mg/dL to 42.80 mg/dL, P = .005) after the treatment. Lovastatin had no significant effect on albumin and transferrin. Placebo did not change any of the parameters after 3 months.The effect of statins on the inflammatory markers involved in the development of DN is a new approach to evidence supporting the pleiotropic effect of this drug group.

    View details for Web of Science ID 000337073100010

    View details for PubMedID 24878942

  • BET Bromodomain Inhibition of MYC-Amplified Medulloblastoma CLINICAL CANCER RESEARCH Bandopadhayay, P., Bergthold, G., Nguyen, B., Schubert, S., Gholamin, S., Tang, Y., Bolin, S., Schumacher, S. E., Zeid, R., Masoud, S., Yu, F., Vue, N., Gibson, W. J., Paolella, B. R., Mitra, S. S., Cheshier, S. H., Qi, J., Liu, K., Wechsler-Reya, R., Weiss, W. A., Swartling, F. J., Kieran, M. W., Bradner, J. E., Beroukhim, R., Cho, Y. 2014; 20 (4): 912-925

    Abstract

    MYC-amplified medulloblastomas are highly lethal tumors. BET bromodomain inhibition has recently been shown to suppress MYC-associated transcriptional activity in other cancers. The compound JQ1 inhibits BET bromodomain-containing proteins, including BRD4. Here we investigate BET bromodomain targeting for the treatment of MYC-amplified medulloblastoma.We evaluated the effects of genetic and pharmacological inhibition of BET bromodomains on proliferation, cell cycle, and apoptosis in established and newly generated patient- and GEMM-derived medulloblastoma cell lines and xenografts that harbored amplifications of MYC or MYCN. We also assessed the effect of JQ1 on MYC expression and global MYC-associated transcriptional activity. We assessed in vivo efficacy of JQ1 in orthotopic xenografts established in immunocompromised mice.Treatment of MYC-amplified medulloblastoma cells with JQ1 decreased cell viability associated with arrest at G1 and apoptosis. We observed down-regulation of MYC expression and confirmed inhibition of MYC-associated transcriptional targets. Exogenous expression of MYC from a retroviral promoter reduced the effect of JQ1 on cell viability, suggesting that attenuated levels of MYC contribute to the functional effects of JQ1. JQ1 significantly prolonged survival of orthotopic xenograft models of MYC-amplified medulloblastoma (p<0.001). Xenografts harvested from mice after five doses of JQ1 had reduced expression of MYC mRNA and a reduced proliferative index.JQ1 suppresses MYC expression and MYC-associated transcriptional activity in medulloblastomas, resulting in an overall decrease in medulloblastoma cell viability. These preclinical findings highlight the promise of BET bromodomain inhibitors as novel agents for MYC-amplified medulloblastoma.

    View details for DOI 10.1158/1078-0432.CCR-13-2281

    View details for Web of Science ID 000331875500015

    View details for PubMedID 24297863

  • Red Grape Seed Extract Improves Lipid Profiles and Decreases Oxidized Low-Density Lipoprotein in Patients with Mild Hyperlipidemia JOURNAL OF MEDICINAL FOOD Razavi, S., Gholamin, S., Eskandari, A., Mohsenian, N., Ghorbanihaghjo, A., Delazar, A., Rashtchizadeh, N., Keshtkar-Jahromi, M., Argani, H. 2013; 16 (3): 255-258

    Abstract

    Hyperlipidemia can lead to atherosclerosis by lipoprotein deposition inside the vessel wall and oxidative stress induction that leads to the formation of atherosclerotic plaque. Oxidized low-density lipoprotein particles (Ox-LDL) have a key role in the pathogenesis of atherosclerosis. The lipid-lowering properties and antioxidants of the grape seed can be beneficial in atherosclerosis prevention. We conducted a randomized double-blind placebo-controlled crossover clinical trial. Fifty-two mildly hyperlipidemic individuals were divided into two groups that received either 200 mg/day of the red grape seed extract (RGSE) or placebo for 8 weeks. After an 8-week washout period, the groups were crossed over for another 8 weeks. Lipid profiles and Ox-LDL were measured at the beginning and the end of each phase. RGSE consumption reduced total cholesterol (-10.68±26.76 mg/dL, P=.015), LDL cholesterol (-9.66±23.92 mg/dL, P=.014), and Ox-LDL (-5.47±12.12 mg/dL, P=.008). While triglyceride and very low-density lipoprotein cholesterol were decreased and high-density lipoprotein cholesterol was increased by RGSE, the changes were not statistically significant. RGSE consumption decreases Ox-LDL and has beneficial effects on lipid profile-consequently decreasing the risk of atherosclerosis and cardiovascular disorders-in mild hyperlipidemic individuals.

    View details for DOI 10.1089/jmf.2012.2408

    View details for Web of Science ID 000316051800010

    View details for PubMedID 23437789

  • Medical Versus Medical and Surgical Treatment for Brucella Endocarditis ANNALS OF THORACIC SURGERY Keshtkar-Jahromi, M., Razavi, S., Gholamin, S., Keshtkar-Jahromi, M., Hossain, M., Sajadi, M. M. 2012; 94 (6): 2141-2146

    Abstract

    This review was undertaken to determine the role of surgery in the treatment of brucella endocarditis. All English and French articles reporting brucella endocarditis (1966 to 2011) in PubMed, Google, and Scopus were reviewed. In all, 308 cases were identified, and linear and logistic regression was performed. Surgery improved outcomes by decreasing mortality from 32.7% in the medical treatment only group to 6.7% in the combined surgical and medical treatment group (p<0.001). This association was still significant while controlling for other contributing factors. In the absence of a controlled trial, we recommend the utmost vigilance and consideration of surgical management in treating such patients.

    View details for DOI 10.1016/j.athoracsur.2012.07.006

    View details for Web of Science ID 000311436300076

    View details for PubMedID 23102495

  • Influenza vaccination in patients with pulmonary sarcoidosis: efficacy and safety INFLUENZA AND OTHER RESPIRATORY VIRUSES Tavana, S., Argani, H., Gholamin, S., Razavi, S., Keshtkar-Jahromi, M., Talebian, A. S., Moghaddam, K. G., Sepehri, Z., Azad, T. M., Keshtkar-Jahromi, M. 2012; 6 (2): 136-141

    Abstract

    Sarcoidosis is an inflammatory, granulomatous disorder of unknown etiology. The role of cellular and humoral immune systems in this disease is unclear, whereas dysregulation of the immune system is suggested. Patients with sarcoidosis show diverse responses while exposed to various antigens. Although influenza vaccination is recommended in pulmonary sarcoidosis, its efficacy and safety has not been investigated.? To evaluate safety and immunogenicity of influenza vaccine in patients with sarcoidosis.Influenza vaccination was performed in 23 eligible patients with sarcoidosis (SP) and 26 healthy controls (HC). Antibody titers against H1N1, H3N2, and B influenza virus antigens were evaluated just before and 1 month after vaccination. Patients were followed for 6 months to assess vaccine safety.Serological response and magnitude of changes in antibody titers against influenza vaccine antigens were comparable between SPs and HCs. Women showed a better serological response against B antigen (P = 0·034) than men. Twenty-four-hour urine calcium was associated with antibody response against H1N1 [correlation coefficient (CC) = 0·477, P = 0·003] and H3N2 (CC = 0·352, P = 0·028) antigens. Serum angiotensin-converting enzyme correlated negatively with antibody response against B antigen (CC = -0·331, P = 0·040). Higher residual volume was associated with fewer rises in antibody titer against H3N2 antigen (CC = -0·377, P = 0·035). No major adverse events or disease flare-up was observed during follow-up.In this study, influenza vaccination did not cause any major adverse event in SPs, and their serological response was equal to HCs. Studies with larger sample size and a broader selection of subjects could help validate the results of this study.

    View details for DOI 10.1111/j.1750-2659.2011.00290.x

    View details for Web of Science ID 000300689300009

    View details for PubMedID 21955954

  • Comparing Peripheral Blood Mononuclear Cell DNA and Circulating Plasma viral RNA pol Genotypes of Subtype C HIV-1. Journal of AIDS & clinical research Banks, L., Gholamin, S., White, E., Zijenah, L., Katzenstein, D. A. 2012; 3 (2): 141-147

    Abstract

    INTRODUCTION: Drug resistance mutations (DRM) in viral RNA are important in defining to provide effective antiretroviral therapy (ART) in HIV-1 infected patients. Detection of DRM in peripheral blood mononuclear cell (PBMC) DNA is another source of information, although the clinical significance of DRMs in proviral DNA is less clear. MATERIALS AND METHODS: From 25 patients receiving ART at a center in Zimbabwe, 32 blood samples were collected. Dideoxy-sequencing of gag-pol identified subtype and resistance mutations from plasma viral RNA and proviral DNA. Drug resistance was estimated using the calibrated population resistance tool on www.hivdb.stanford.edu database. Numerical resistance scores were calculated for all antiretroviral drugs and for the subjects' reported regimen. Phylogenetic analysis as maximum likelihood was performed to determine the evolutionary distance between sequences. RESULTS: Of the 25 patients, 4 patients (2 of which had given 2 blood samples) were not known to be on ART (NA) and had exclusively wild-type virus, 17 had received Protease inhibitors (PI), 18, non-nucleoside reverse transcriptase inhibitors (NNRTI) and 19, two or more nucleoside reverse transcriptase inhibitors (NRTI). Of the 17 with history of PI, 10 had PI mutations, 5 had minor differences between mutations in RNA and DNA. Eighteen samples had NNRTI mutations, six of which demonstrated some discordance between DNA and RNA mutations. Although NRTI resistance mutations were frequently different between analyses, mutations resulted in very similar estimated phenotypes as measured by resistance scores. The numerical resistance scores from RNA and DNA for PIs differed between 2/10, for NNRTIs between 8/18, and for NRTIs between 17/32 pairs. When calculated resistance scores were collapsed, 3 pairs showed discordance between RNA and DNA for at least one PI, 6 were discordant for at least one NNRTI and 11 for at least one NRTI. Regarding phylogenetic evolutionary analysis, all RNA and DNA sequence pairs clustered closely in a maximum likelihood tree. CONCLUSION: PBMC DNA could be useful for testing drug resistance in conjunction with plasma RNA where the results of each yielded complementary information about drug resistance. Identification of DRM, archived in proviral DNA, could be used to provide for sustainable public health surveillance among subtype C infected patients.

    View details for PubMedID 23019537

  • Brucella endocarditis, a report of 14 cases (1991-2009) JOURNAL OF INFECTION Keshtkar-Jahromi, M., Boroumand, M., Razavi, S., Gholamin, S., Haghighat, B., Hashemi, M., Khani, M., Keshtkar-Jahromi, M., Naghili, B. 2010; 61 (1): 89-92

    View details for DOI 10.1016/j.jinf.2010.03.027

    View details for Web of Science ID 000278817900014

    View details for PubMedID 20362000

  • Cystic lymphangioma of the pancreas: diagnostic and therapeutic challenges. JOP : Journal of the pancreas Fahimi, H., Faridi, M., Gholamin, S., Molanaee, S., Khorsandi, M. 2010; 11 (6): 617-619

    Abstract

    Cystic lymphangiomas originate as benign masses which occur mostly in children especially in the head and neck region and/or the groin. Although abdominal lymphangiomas are rare, they are most commonly reported in adults. In addition, pancreatic involvement is rare. Lymphatic malformation with blockage of the lymphatic flow is the most common etiology leading to the formation of lymphangiomas. Cystic lymphangiomas should always be included in the differential diagnosis of abdominal masses which present with mass effect signs and symptoms. Due to its rarity, it forms a diagnostic and therapeutic challenge for the clinician.We herein report the case of a 43-year-old man with a cystic lymphangioma detected in the head of the pancreas and describe the surgical procedure utilized as the therapeutic medium.To remove this mass, we utilized a modified approach to a classic pancreaticoduodenectomy. This technique involved resection of the head of the pancreas while preserving the upper 2nd portion of the duodenum and the ampulla of Vater. The result of our 30-month follow-up of this patient has been very satisfactory with no complications.

    View details for PubMedID 21068498

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