M.D., Ph.D., D.Sc.
Cullen Eye Institute
Houston, Texas | United States
Additional Specialties: Immunology - Oncology - Pathology
Primary Affiliation: Cullen Eye Institute - Houston, Texas , United States
PubMed Central Citations
266PubMed Central Citations
Arthritis Res Ther 2015 Mar 10;17:53. Epub 2015 Mar 10.
Ocular Surface Center, Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, 6565 Fannin Street, NC505G, Houston, TX 77030, Texas, USA.
Exp Eye Res 2014 Jan 4;118:117-24. Epub 2013 Dec 4.
Ocular Surface Center, Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, 6565 Fannin Street, NC505, Houston, TX 77030, USA. Electronic address:
Mucosal Immunology; 4(4): 397-408.
Although the effects of the interleukin 13 (IL-13) on goblet cell (GC) hyperplasia have been studied in the gut and respiratory tracts, its effect on regulating conjunctival GC has not been explored. The purpose of this study was to determine the major IL-13-producing cell type and the role of IL-13 in GC homeostasis in normal murine conjunctiva. Using isolating techniques, we identified natural killer (NK) / natural killer T (NKT) cells as the main producers of IL-13. We also observed that IL-13 knockout (KO) and signal transducer and activator of transcription 6 knockout (STAT6KO) mice had a lower number of periodic acid Schiff (PAS)+ GCs. We observed that desiccating stress (DS) decreases NK population, GCs, and IL-13, whereas it increases interferon-γ (IFN γ) mRNA in conjunctiva. Cyclosporine A treatment during DS maintained the number of NK / NKT cells in the conjunctiva, increased IL-13 mRNA in NK+ cells, and decreased IFN-γ and IL-17A mRNA transcripts in NK+ and NK− populations. C57BL/6 mice chronically depleted of NK / NKT cells, as well as NKT cell-deficient RAG1KO and CD1dKO mice, had fewer filled GCs than their wild-type counterparts. NK depletion in CD1dKO mice had no further effect on the number of PAS+ cells. Taken together, these findings indicate that NKT cells are major sources of IL-13 in the conjunctival mucosa that regulates GC homeostasis. Received 23 March 2010; accepted 23 November 2010; published online 22 December 2010. doi:10.1038/mi.2010.82
Oncogene; 26(50): 7103-7110.
Transforming growth factor-β (TGF-β) signaling members, TGF-β receptor type II (TBRII), Smad2, Smad4 and Smad adaptor, embryonic liver fodrin (ELF), are prominent tumor suppressors in gastrointestinal cancers. Here, we show that 40% of elf+/- mice spontaneously develop hepatocellular cancer (HCC) with markedly increased cyclin D1, cyclin-dependent kinase 4 (Cdk4), c-Myc and MDM2 expression. Reduced ELF but not TBRII, or Smad4 was observed in 8 of 9 human HCCs (P˂0.017). ELF and TBRII are also markedly decreased in human HCC cell lines SNU-398 and SNU-475. Restoration of ELF and TBRII in SNU-398 cells markedly decreases cyclin D1 as well as hyperphosphorylated-retinoblastoma (hyperphosphorylated-pRb). Thus, we show that TGF-β signaling and Smad adaptor ELF suppress human hepatocarcinogenesis, potentially through cyclin D1 deregulation. Loss of ELF could serve as a primary event in progression toward a fully transformed phenotype and could hold promise for new therapeutic approaches in human HCCs. Keywords: hepatocellular carcinoma; ELF; cyclin D1; transforming growth factor-β; cell cycle Oncogene (2007) 26, #50, 7103–7110; doi:10.1038/sj.onc.1210513; published online 4 June 2007
Biochem Biophys Res Commun 2006 Aug 9;346(4):1150-7. Epub 2006 Jun 9.
Department of Surgery, Laboratory of Cancer Genetics, Digestive Diseases, and Developmental Molecular Biology, Lombardi Cancer Center, Georgetown University, Washington, DC, USA.
Oncogene, 2006; 25(5):693-705.
In gastrointestinal cells, biological signals for transforming growth factor-beta (TGF-β) are transduced through transmembrane serine/threonine kinase receptors that signal to Smad proteins. Smad4, a tumor suppressor, is often mutated in human gastrointestinal cancers. The mechanism of Smad4 inactivation, however, remains uncertain and could be through E3-mediated ubiquitination of Smad4/adaptor protein complexes. Disruption of ELF (embryonic liver fodrin), a Smad4 adaptor protein, modulates TGF-β signaling. We have found that PRAJA, a RING-H2 protein, interacts with ELF in a TGF-β-dependent manner, with a fivefold increase of PRAJA expression and a subsequent decrease in ELF and Smad4 expression, in gastrointestinal cancer cell lines (P˂0.05). Strikingly, PRAJA manifests substantial E3-dependent ubiquitination of ELF and Smad3, but not Smad4. Δ-PRAJA, which has a deleted RING finger domain at the C terminus, abolishes ubiquitination of ELF. A stable cell line that overexpresses PRAJA exhibits low levels of ELF in comparison to a Δ-PRAJA stable cell line, where ELF expression is high compared to normal controls. The alteration of ELF and/or Smad4 expression and/or function in the TGF-β signaling pathway may be induced by enhancement of ELF degradation, which is mediated by a high-level expression of PRAJA in gastrointestinal cancers. In hepatocytes, half-life (t1/2) and rate constant for degradation (kD) of ELF is 1.91 hand 21.72 min-1 when coupled with ectopic expression of PRAJA in cells stimulated by TGF-β, compared to PRAJA-transfected\ unstimulated cells (t1/2¼4.33hand kD¼9.6 min-1). These studies reveal a mechanism for tumorigenesis whereby defects in adaptor proteins for Smads, such as ELF, can undergo degradation by PRAJA, through the ubiquitin-mediated pathway. Keywords: ELF; PRAJA; TGF-β; ubiquitination; half-life Oncogene (2006) 25, #5, 693–705. doi:10.1038/sj.onc.1209123; published online 10 October 2005
Cancer Detect. Prev. 1998; 22(2): 176-184.
Cancer Detection and Prevention
ABSTRACT: To study the possible role of the host macrophages in the selection of tumor cells and tumor progression, a series of Syrian hamster tumor cell lines all originating from a single spontaneously transformed Syrian hamster embryo cell line (STHE strain) have been established. These STHE tumor cell variants, selected either in vitro with resident and lipopolysaccharide-activated macrophages or in vivo, differ in tumorigenic and metastatic activity. The selected malignant STHE cells become resistant to cytotoxic activity of activated peritoneal macrophages and of exogenous hydrogen peroxide (H2O2). Since activated macrophages are a known source for both cytotoxic agents H2O2 and tumor necrosis factor (TNF), the purpose of the present study was to define the sensitivity of the STHE tumor cell lines to a direct cytotoxic activity mediated by recombinant TNF-alpha in an attempt to understand the role of the cytokine in in vitro selection of a malignant STHE cells by activated macrophages. The spontaneously transformed STHE cells (selected in vivo and in vitro) as well as the hamster embryo cells transformed in vitro by a tumorigenic Rous sarcoma virus (Schmidt-Ruppin strain) were used as targets. TNF-alpha-sensitive mouse L929 cells were included in the study as a positive control. Sensitivity of actinomycin D-pretreated target cells studied for cytotoxic activity of a recombinant TNF-alpha was examined over 21 h with a crystal violet dye assay. It was found that, in contrast to L929 cells, the spontaneously transformed STHE cells as well as tumorigenic Rous sarcoma virus hamster embryo transformants, were all significantly resistant to the TNF-alpha-mediated cytolysis. This indicates that TNF-alpha is not the single factor responsible in in vitro selection of malignant STHE cell variants by activated macrophages. It appears that H2O2 is involved in the selection of the hamster macrophage-resistant STHE tumor cells. Cancer Detection and Prevention (Impact Factor: 2.52). 02/1998; 22(2):176-184. DOI:10.1046/j.1525-1500.1998.00640.x
Cancer Lett. 1995; 89(2): 169-176.
Abstract: We confirmed with the use of crystal violet bioassay the high susceptibility of mouse L929 cells to the cytotoxic action of recombinant tumor necrosis factor-alpha (TNF). However, when a [3H]thymidine release assay was used for the same purpose, we found that [3H]lthymidine uptake by the L929 cells, in contrast to low-malignant TNF-resistant spontaneously transformed Syrian hamster embryo cells of the STHE strain, was significantly reduced (P < 0.001). To investigate the mechanism of the low incorporation of [3H]thymidine in L929 cells the culture media from intact L929 cells was used for competition experiments with [3H]thymidine incorporation in the STHE target cells. The undiluted supematant from L929 cells significantly (up to 83-97%) reduced [3H]thymidine uptake by the STHE cells. Fifty percent inhibition of [3H]thymidine uptake was achieved at L929 supernatant dilutions up to 1:8 (in 4 h incubation), up to I:16 (in 20-42 h incubation) and even up to 1:32 (in 42 h incubation). The same high level of inhibition of [3H]thymidine uptake by STHE cells was seen with a commercial specimen of a thymidine (Sigma) at a concentration near 500 ng/ml. Thus, we conclude that a resistance of L929 cells to [3H]thymidine uptake is related to their unusually high production of cold thymidine. Keywords: Methylcholanthrene-induced L929 cells; Spontaneously transformed STHE cells; Recombinant TNF-alpha; Cytotoxicity; Peritoneal macrophages; Thymidine production; Tritiated thymidine uptake. Cancer Letters 1995; 89(2): 169-176. Received 23 November 1994; accepted I5 December 1994; published 2 March 1995.
Proceedings of the Latvian Academy of Sciences, B. 1993; 47(5-550), 59-64.
Proceedings of the Latvian Academy of Sciences, B.
Proceedings of the Latvian Academy of Sciences, B. - 1993 - 47: 5 (550), 59-64. Levan prolongs the life-span of tumor-bearing or irradiated mice, and enhances the antitumor activity of leukocytes. Vija Liepa*, Gunars Zakenfelds*, Eugene Volpe*, Zhanna Koronova*, Roalds Lapsa*, Maris Laivenieks**, Martins Bekers**, Jiři Pospíšil*** * Institute of Experimental and Clinical Medicine, Riga, Latvia ** Institute of Microbiology and Biotechnology, Riga, Latvia *** Institute of Biophysics and Nuclear Medicine, Charles University, Prague, Czech Republic Levan stimulates both leukopoiesis and antibody production by splenocytes, activates reactive oxygen intermediates formation by phagocytes, promotes tumoricidal activity of phagocytes. The antitumor action of levan is realized via the immune system of the organism. Levan prolongs the life-span of tumor-bearing mice. Levan also has radioprotective properties. Key words: polyfructoside levan, peripheral blood leukocyte count, splenocytes, peritoneal phagocytes, antibody production, antitumor activity, life-span, tumor-bearing and irradiated mice. Received April 14, 1993 Special Issue: To the Second World Congress of Latvian Physicians ISSN 0868-6556 Academia Scientarum Latviensis
Herald of N.N. Blokhin Cancer Research Center RAMS 1993 Mar; 4(1):15-19.
Herald of N.N. Blokhin Cancer Research Center RAMS
Abstract. Low-malignant STHE cells (never selected in vivo) and their variants with various biological features selected in vivo and in vitro are a good model for study of mechanisms responsible for expression of malignant phenotype in carcinogenesis and tumor progression. - www.elibrary.ru
J. Exp. Clin. Cancer Res.1992 Jul; 11(2): 109-122.
Journal of Experimental & Clinical Cancer Research
Laboratory of Anti-tumor Immunity, Institute of Carcinogenesis, Cancer Research Center, Academy of Medical Sciences, Moscow, Russia. In order to determine the possible role of the host macrophages (MP) in the selection of tumor cells and tumor progression, we studied the ability of normal (resident) and LPS-activated peritoneal MP of Syrian hamsters to select low-malignant spontaneously transformed hamster embryo cells (STHE strain) in vitro. Ten cycles of in vitro selected STHE cell variants as well as parental ones were studied either in vitro (on the susceptibility to MP- and hydrogen peroxide (H2O2)- mediated cytotoxic activity (CTA) with the use of 3H-TdR assays) or in vivo (on tumorigenic and metastasizing activity in spontaneous and experimental metastasis assays). The results show that all the five STHE cell variants obtained after different number of cycles of the in vitro selection with LPS-activated MP (beginning from the first cycle), in contrast to the parental cells and STHE cells selected with resident MP, were significantly more resistant to CTA of both, activated MP and H2O2, and simultaneously they were more malignant, i.e. more tumorigenic and more metastatic (in experimental metastasis assay). The resistance to MP and H2O2, seems to be necessary, but not sufficient for spontaneous metastasis formation. It can be concluded that activated MP (and possibly polymorphonuclear neutrophils) are capable of selecting malignant tumor cells in vitro and in vivo. Key words: Natural resistance, Transformed cells, In vitro selection, Macrophages, Syrian hamsters, Tumor progression.
Experientia – CMLS 1992 May 15; 48(5): 500-503.
Experientia – Cellular and Molecular Life Sciences (CMLS)
Laboratory of Anti-tumor Immunity, Institute of Carcinogenesis, Cancer Research Center, Academy of Medical Sciences, 24 Kashirskoye chaussee, 115478 Moscow, Russia. Abstract. The cytotoxic activity (CTA) of activated peritoneal macrophages (MP) on variant lines of Syrian hamster embryo (HE) cells of differing malignant characteristics was studied. The target cells were a line of low-malignant cells resulting from spontaneous transformation of HE cells in vitro (STHE strain), and malignant variants selected from them in vivo (STHE-LM-4, STHE-LM-8, and STHE-75/18 strains). In addition, we used cells of the HET-SR-1 strain; these are HE cells transformed in vitro by a tumorigenic Rous sarcoma virus (Schmidt-Ruppin strain, RSV-SR), or the TU-ST strain induced by RSV-SR in vivo. Thioglycollate-elicited peritoneal MP from Syrian hamsters were activated in vitro with bacterial levan, LPS or MDP and used as effector cells. MP-mediated cytolysis was determined by means of a 42-h radioactivity release assay with 3H-thymidine-labeled target cells. We found that only the parental STHE cells were susceptible towards fully-activated MP-mediated CTA. All three of the in vivo-selected malignant variants of the STHE cell sublines, as well as the tumorigenic RSV-SR transformants, were resistant to cytolysis by activated MP. Non-activated thyoglycollate-elicited MP did not lyse any of the tumor cells studied. Key words. Natural resistance; tumors; spontaneously- and Rous sarcoma virus-transformed cells; Syrian hamsters; peritoneal exudate cells; macrophages; activation; cytotoxicity. Received 22 April 1991; accepted 30 September 1991
Bull. Exp. Biol. Med. 1991 Nov; 112(11): 1637-1641.
Bulletin of Experimental Biology and Medicine
Laboratory of Antitumor Immunity, Research Institute of Carcinogenesis, All-Union Oncologic Scientific Center, Academy of Medical Sciences of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR N. N. Trapeznikov) Translated from Byulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 112, No. 11, pp. 525-529, November, 1991. Original article submitted March 19, 1991. 0007-4888/91/0011-1637 $12.50 ©1992 Plenum Publishing Corporation Key words: natural resistance; peritoneal exudate cells; in vitro selection; transformed cells; tumor progression; tumorigenicity; metastasization.
Bull. Exp. Biol. Med. 1991 Aug; 112(8): 1169-1172.
Bulletin of Experimental Biology and Medicine
Laboratory of Antitumor Immunity, Research Institute of Carcinogenesis, All-Union Oncologic Scientific Center, Academy of Medical Sciences of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR N. N. Trapeznikov) Translated from Byulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 112, No. 8, pp. 192-195, August, 1991. Original article submitted December 29, 1990. 0007-4888/91/0008-1169 $12.50 ©1992 Plenum Publishing Corporation Key words: transformed cells; natural resistance; resident and activated peritoneal exudate cells; macrophages; hydrogen peroxide; in vitro selection.
Bull. Exp. Biol. Med. 1991 Feb; 111(2): 213-215.
Bulletin of Experimental Biology and Medicine
Laboratory of Antitumor Immunity, Research Institute of Carcinogenesis, All-Union Oncologic Scientific Center, Academy of Medical Sciences of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR N. N. Trapeznikov) Translated from Byulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 111, No. 2, pp. 177-179, February, 1991. Original article submitted June 5, 1990. 0007-4888/91/0002-0213 $12.50 ©1991 Plenum Publishing Corporation Key words: transformed cells, tumors, activated macrophages, natural resistance, immunomodulators.
Bull. Exp. Biol. Med. 1991 Jan; 111(1): 80-82.
Bulletin of Experimental Biology and Medicine
Laboratory of Antitumor Immunity, Research Institute of Carcinogenesis, All-Union Oncologic Scientific Center, Academy of Medical Sciences of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR N. N. Trapeznikov) Translated from Byulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 111, No. 1, pp. 59-62, January, 1991. Original article submitted June 5, 1990. 0007-4888/91/0001-0080 $12.50 ©1991 Plenum Publishing Corporation Key words: transformed cells, macrophages, natural resistance, immunomodulators, actinomycin D.
Eksp. Onkol. 1989 Aug; 11(4): 1-5, 82. Russian.
Research Institute for Experimental and Clinical Medicine, Riga It has been shown in the cytolytic test in vitro that casein-elicited neutrophils from peritoneal exudates are cytotoxic in 42-h assay with 3H-thymidine labeled tumor target cells (TC) at 37oC with 5% CO2. Examined tumor TC are differing on malignant phenotype (low-malignant STHE strain, highly-malignant TU-SR, HET-SR strains, and highly-metastatic HET-SR-2SC-MLN one). We showed that neutrophils-mediated cytolysis depends on neutrophils amount and the TC/neutrophils ratio, and the cytolysis was increased with augmentation of TC examined. This phenomenon appears to be determined on activating natural antitumor resistance factor(s) production by tumor cells. There was no difference between the cytolysis and malignant characteristics of tumor TC tested.
Eksp. Onkol. 1985; 7(3): 43-47. Russian.
226004 Research Institute of Experimental and Clinical Medicine, Ministry of Public Health, Latvian SSR, Riga Zymosan and its combination with cyclophosphamide were tested for their effect on various immune responses. Zymosan alone had only minor effect on the cytotoxicity of lymphocytes to allogeneic and syngeneic tumour cells but significantly stimulated delayed-type hypersensitivity response, rosette formation and plaque forming cell response to sheep red blood cells in normal mice. Zymosan diminished immunosuppressive action of cyclophosphamide on the plaque and rosette formations and nonspecific allogeneic lysis of target cells by lymph node lymphocytes. Delayed-type hypersensitivity skin reaction and syngeneic T-killer cell activity increased significantly after the procedure of combination therapy. Lymphocyte stimulation action by the polysaccharide dependent on the injection schedule used. Preliminary injection of zymosan was an optimal condition for enhancement of the cellular immune response.
Experientia – CMLS 1978 Jan 15; 34(1): 113-116.
Experientia – Cellular and Molecular Life Sciences (CMLS)
Laboratory of Tumor Immunology, Cancer Research Center, USSR Academy of Medical Sciences, Kashirskoye shosse 6, Moscow 115 478, USSR Summary. Using the modified technique of transplantation test, ITR serum activity was found in most (14 out of 21) individual hamster sera obtained during the latent period of primary SV40 carcinogenesis (60 days after virus infection when newborn). On the other hand, as a rule, no ITR activity was observed in the sera of the same hamsters after tumor appearance and during their growth. ITR activity rapidly disappeared from sera of hamsters neonatally infected with SV40 after their successful immunization with the same virus during the latent period. There appears to be a correlation between the presence of ITR serum factor during the latent period and the subsequent primary SV40 tumor appearance in hamsters. Received 8 October 1976
Neoplasma 1976; 23(4): 345-353.
Institute of Experimental and Clinical Oncology USSR Academy of Medical Sciences, 115 418 Moscow, USSR. The blocking of specific SV40-incluced resistance of hamsters by the sera collected from 12 individual hamsters infected with SV40 when newborn was studied at different periods of primary virus-induced carcinogenesis. The serum samples were collected at the following periods of primary carcinogenesis: during the latent period (60 days after virus inoculation), at the day of primary tumor appearance, and 19—36 and 45—57 days after primary tumor appearance. For detection of the blocking activity of the collected sera the cells of transplantable SV40 test-tumor were pretreated in vitro with these sera and with control normal hamster sera, and then used for challenge in vivo in SV40-immunized and normal hamsters. With the use of such method, as a rule, no blocking activity of the serum samples collected at any time after the tumor appearance was observed. However, the sera obtained from 7 out of 12 of those hamsters during the latent period significantly decreased the resistance index of animals challenged in transplantation test with the serum pretreated tumor cells. Possible explanations of these findings are discussed. Key words: SV40 tumor immunity, in vivo serum blocking activity, transplantation test. Received May 27, 1975
Vestnik Akad. med. nauk SSSR 1976, 31(2): 26-31. Russian.
Herald of Academy of Medical Sciences USSR - Vestnik Akademii meditsinskikh nauk SSSR
Blocking effect of the blood serum of Syrian hamsters-carriers of SV40 virus-induced primary tumors upon specific antitumor immunity was studied. Individual samples of the hamster blood sera were taken at various periods of carcinogenesis (in the middle of the latent period, on the 1st day of the end of latent period, after 18-21 and 45-56 days of the primary tumor growth). In the course of the experiments cells of the test SV40 virus-induced tumor were treated in vitro with both the sera under study and control (normal) sera, then these cells were inoculated to immune and normal animals. The data obtained showed that the sera taken in the middle of the latent period exhibited a considerable activity in blocking the specific antitumor immunity. No blocking activity was noted in the sera obtained from the same animals at later stages of carcinogenesis after the appearance of primary SV40 tumors. A possible role of a humoral factor capable of blocking immunity in SV40 virus-induced carcinogenesis is discussed. Keywords: Animal; Hamsters; Immune Sera; Experimental Neoplasm; Immunology; Simian virus 40; Time Factors.