Interferons have significant antiviral, antiproliferative and immunoregulatory activities. Interferons have been used for the treatment of many viral and non-viral malignancies. However, the response to treatment with interferons has been variable. Some patients respond favorably, while others fail to respond. We have shown that this variable response is partially due to the presence of interferon inhibitory activity in their blood circulation. Our laboratory is involved in the isolation and molecular characterization of this interferon inhibitory factor(s).
Interferon inhibitory activity in the blood circulation of late stage cancer HIV‑1 infected patients and in MS patients is due to: a) interferon inhibitory protein; b) high levels of PGE2; c) high levels of soluble interferon receptor; or d) any combination of these factors.
C57BL/6 mice maintained on alcohol containing diet had lower levels of T‑cells including CD4+. Splenocytes from these animals produced significantly low levels of IFN‑alpha and IFN‑gamma but did not differ in their NKC activity. Mice infected with LP‑BM5MuLV virus showed progressive splenomegaly, leukopenia, lymphadenopathy, and suppression in vitro of anti-SRBC response. IL‑2-mediated response of splenocytes did not differ significantly from uninfected controls. Spleen cell proliferation elicited by mixture of phorbol and IL‑2 or phorbol and ionomycin was significantly inhibited. We have observed that cocaine is a significant cofactor in the pathogenesis of HIV infection primarily because it increases susceptibility to and progression of HIV‑1 infection by inhibiting the synthesis of HIV‑1 protective chemokines and/or upregulating the HIV‑1 entry co-receptor, CCR5.
Prostate Cancer: Relevance of PSA and PSMA in Early Diagnosis. Role of PSA in prostate tumor tissue and its relevance to prostate tumor growth and metatasis. Prostate cancer has the highest incidence of any non-cutaneous malignancy in the Western world and is the second leading cause of cancer related deaths in men. PSA is a well-recognized marker for the early diagnosis and management of prostate cancer. However, it is not disease specific and results in many false positives. Our objective is to develop new methodology that will be more sensitive and will eliminate the risk of false positives. The physiological reasoning for the rise in PSA level in prostate cancer patients is not well understood. PSA seems to have a role in angiogenesis.
We have shown that PSA and its molecular complexes have an affinity for thiophilic gels (T‑gel). T‑gel affinity can be exploited for PSA purification as well as for obtaining serum-based PSA standard that will have both free PSA and its complexes.
We have developed methodology that permits measurement of PSMA in the sera of prostate cancer patients. Such a task has never been accomplished before. Our test will effectively eliminate false positives and therefore will eliminate unnecessary biopsies. We are currently testing additional samples to validate our test procedures.
In our primary studies, we have shown that treatment of human prostate cancer cells with PSA modulates factors, su. Prostate cancer has the highest incidence of any non-cutaneous malignancy in the western world and is the second leading cause of cancer related deaths in men. Prostate-Specific Antigen (PSA) is a well-recognized biomarker for the early diagnosis and management of prostate cancer. However, PSA test is neither disease specific nor tissue specific and results in >70% false positive. There are two major areas of research in my laboratory: one involves development of new biomarkers that will be more selective and specific and includes PSMA, IL-8, TGF-beta, etc., and the second area involves in determining if PSA has a physiological role as an anti-angiogenic molecule. In our preliminary studies, we have shown that human prostate cells that are highly malignant have higher levels of expression of pro-angiogenic growth factors such as VEGF, IL-8, TGF-beta, bFGF, etc. and low levels of anti-angiogenic factors such as interferons and angiostatin. The treatment of these cells with PSA results in down regulation of pro-angiogenic factors and up regulation of anti-angiogenic factors. We have now shown in a xenograft model that exogenously administered PSA can significantly reduce tumor growth. This suggests that PSA has a potential to be used as therapeutic modality to treat prostate cancer.
Biology of Interferon System
Biomarkers for Early Detection and Management of Prostate Cancer and Role of PSA in prostate tumor progression & Metastasis
Prostate Cancer: Relevance of PSA and PSMA in Early Diagnosis.
Chadha KS, Chadha KS, Schiff M , Sitrin MD , Wilding GE , Nava H. Clinical outcomes of using a conservative approach of late esophageal stent placement in palliation of malignant dysphagia. Journal of gastrointestinal cancer 2010; 41(3):173-178
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Sternberg Z, Chadha K, Lieberman A, Drake A, Hojnacki D, Weinstock-Guttman B, Munschauer F. Immunomodulatory responses of peripheral blood mononuclear cells from multiple sclerosis patients upon in vitro incubation with the flavonoid luteolin: additive effects of IFN-beta. Journal of neuroinflammation 2009; 6:28
Sternberg Z, Weinstock-Guttman B, Leung C, Chadha K, Benedict RHB, Kazim L, Bistulfi GL, Sternberg D, Hennies C, Munschauer F. Plasma pentosidine: a potential biomarker in the management of multiple sclerosis. Multiple sclerosis (Houndmills, Basingstoke, England) 2011; 17(2):157-163
Aalinkeel R, Nair BB, Reynolds JL, Sykes DE, Mahajan SD, Chadha KC, Schwartz SA. Overexpression of MMP-9 Contributes to Invasiveness of Prostate Cancer Cell Line LNCaP. Immunological investigations 2011;40(5):447-464
Aalinkeel R, Bindukumar B, Reynolds JL, Sykes DE, Mahajan SD, Chadha KC, Schwartz SA. The dietary bioflavonoid, quercetin, selectively induces apoptosis of prostate cancer cells by down-regulating the expression of heat shock protein 90. Prostate 2008; 68(16):1773-1789
Bindukumar B, Schwartz S, Aalinkeel R, Mahajan S, Lieberman A, Chadha K.Proteomic profiling of the effect of prostate-specific antigen on prostate cancer cells. Prostate 2008; 68(14):1531-1545
Satheesh Babu AK, Vijayalakshmi MA, Smith GJ, Chadha KC. Thiophilic-interaction chromatography of enzymatically active tissue prostate-specific antigen (T-PSA) and its modulation by zinc ions. Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 2008; 861(2):227-235
Sternberg Z, Weinstock-Guttman B, Grazioli E, Rocco P, Zamboni P, Drake A, Hojnacki D, Lieberman A, Chadha K, Munschauer F. Quercetin and interferon-beta modulate immune response(s) in peripheral blood mononuclear cells isolated from multiple sclerosis patients. Journal of neuroimmunology 2008;205(1-2):142-147
Sternberg Z, Grazioli E, Rocco P, Drake A, Kazim L, Lieberman A, Chadha K, Zivadinov R, Zamboni P, Hojnacki D, Weinstock-Guttman B, Munschauer F.Soluble receptor for advanced glycation end products in multiple sclerosis: a potential marker of disease severity. Multiple sclerosis (Houndmills, Basingstoke, England) 2008; 14(6):759-763
Chadha KC, Nair BB, Chakravarthi S, Zhou R, Godoy A, Mohler JL, Aalinkeel R, Schwartz SA, Smith GJ. Enzymatic activity of free-prostate-specific antigen (f-PSA) is not required for some of its physiological activities. Prostate 2011;71(15):1680-1690
Chadha K, Mashtare T, Iyer R. Clinical Outcomes in Metastatic Gastroenteropancreatic Neuro-endocrine Tumors (NETs) with Temozolomide and Thalidomide Combination Therapy. American journal of gastroenterology2009; 104(Suppl. 3):Abstract #1102
Chadha K, Sternberg Z, Lieberman A, Drake A, Weinstock-Guttman B, Munschauer F. Immmunomodulation by quercetin and interferon-beta in multiple sclerosis patients. Cytokine 2009; 48(1-2):108
Nair BB, Schwartz SA, Chadha KC. Proteomic profiling of effect of prostate specific antigen (PSA) in prostate cancer cells. BJU international 2007;100(Suppl. 3):19-20
Nicotera TM, Bourhim M, Schuster DS, Chadha K. Autocrine signaling by PSA in prostate cancer cells. Proceedings of the American Association for Cancer Research Annual Meeting 2007; 48:1042-1043