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Biomedical subjects

Subramanian Krishnakumar

Publications and source records attributed to Subramanian Krishnakumar.

At least 19 recordsLinked to original sources
PubMed2008

SRPK1: a cisplatin sensitive protein expressed in retinoblastoma.

Chemotherapy is an essential modality in the treatment of retinoblastoma (RB). Mammalian serine/arginine-rich protein-specific kinase 1 (SRPK1) is a cisplatin-sensitivity-related protein and its downregulation is known to be associated with decreased response to cisplatin and carboplatin. We investigated the expression of SRPK1 in 63 archival RB and correlated its expression with pathologic staging and exposure to chemotherapy. The majority of the RB (62/63) were advanced stage (Groups D and E) with intermediate to high risk of treatment failure according to the new international classification for intraocular RB and SRPK1 was reduced in 32/62 (51%) tumors. SRPK1 protein expression was reduced in (100%) 8/8 RB that had recurred in the orbit or had metastasized. SRPK1 protein expression is reduced in RB with advanced stage of presentation and this may add to drug resistance mechanisms in RB.

Adolescent↗
PubMed2006

Expressions of Rac1, Tiam1 and Cdc42 in retinoblastoma.

The Rho GTPases are the molecular regulators of the cell motility processes and are involved in cell cycle progression and gene transcription. We studied the expression of Rho-like GTPases molecules, particularly Rac, Tiam1 and cdc42, in retinoblastoma and correlated these with clinicopathological parameters of the tumors. Sixty-seven tumors were included which were divided in to two groups; group A: tumors with optic nerve/choroidal/orbital invasion (n=35) and group B: tumors with no invasion (n=32). Immunohistochemistry was done on paraffin sections for all the proteins and were confirmed by Western blot on fresh tumor samples. In group A tumors, Rac was positive in 10/35 (28%), cdc42 was positive in 12/35 (34%) and Tiam1 was positive in 30/35 (85%) tumors. In group 2 tumors, Rac was positive in 5/32 (15%), cdc42 was positive in 4/32 (12%) and Tiam1 was positive in 30/32 (93%) tumors. Two groups (both invasive and non-invasive tumors) showed decreased expression of Rac1 and cdc42 whereas Tiam1 was significantly expressed in invasive tumors compared to non-invasive tumors (P<0.0001). We observed a 70K cleavage product of Tiam1 along with an 110K product by blotting in RB samples. Caspase-3 was also demonstrated in RB samples, which showed Tiam1 cleavage products. This is the first study that showed the expression patterns of Rac, cdc42 and Tiam1 in retinoblastoma tumors. Thus, further studies are required to prove the involvement of caspase-3 in the cleavage of Tiam1 in vitro in RB cells and to trace out alternative pathways involved in tumor progression.

Adolescent↗
PubMed2006

The study of c-Src kinase and pStat3 protein expression in retinoblastoma.

We examine the immunoreactivity of the non-receptor tyrosine kinase, c-Src kinase and its downstream molecule, signal transducer and activator of transcription 3 (pStat3) in retinoblastoma (RB), and correlation with invasiveness and differentiation. Tumor samples from 40 patients with RB were available for the study. There were 18 tumors in group 1 (non-invasive) and 22 tumors in group 2 (invasive). The immunoreactivity of c-Src kinase and pStat3 was compared in the two groups of tumors. Group 1 (non-invasive) RB showed intermediate c-Src kinase immunoreactivity (Allred score 4-5) in 14/18 tumors and low immunoreactivity (Allred score 2-3) in 4/18 tumors. pStat3 was intermediate (Allred score 4-5) in 6/18 tumors and negative (Allred score 0) in 12/18 tumors. Group 2 (invasive) RB showed high c-Src kinase immunoreactivity (Allred score 6-8) in 22/22 tumors and high pStat3 (Allred score 6-8) in 19/22 tumors. The expression of c-Src kinase (P<0.001) and pStat3 (P<0.001) was significantly higher in group 2 RB. Src kinase expression (P<0.05) and pStat3 expression (P<0.05) was higher in the poorly differentiated tumors compared to moderately- and well-differentiated tumors. The increased expression of c-Src kinase and pStat3 expression could play a role in the invasiveness of group 2 tumors. Further characterization of the pathways involved in the pathogenesis of RB will shed light on fundamental mechanisms of tumorigenesis.

Biomarkers, Tumor↗
PubMed2006

Expression of insulin-like growth factor receptor (IGF-1R), c-Fos, and c-Jun in uveal melanoma: an immunohistochemical study.

The immunoreactivity of insulin-like growth factor receptor type 1 (IGF-1R), c-Fos, and c-Jun by immunohistochemistry was studied in three groups of uveal melanomas and was correlated clinicopathologically. Immunoanalysis was correlated with cell types, largest tumor diameter, tumor-infiltrating lymphocytes, mitosis, nuclear grade, and extrascleral extension/liver metastasis. In group C (n = 6), tumors with liver metastasis showed higher expressions of IGF-1R (p = 0.0001), c-Fos (p = 0.004), and c-Jun (p = 0.018) compared with the tumors with no extension/extrascleral extension without liver metastasis (groups A-45 and B-9). Further studies are required to elucidate the role of sequential upregulation of these proteins and the transcriptional activity of c-Fos and c-Jun in uveal melanomas with liver metastasis

Adolescent↗
PubMed2006

Retinoblastoma: expression of HLA-G.

PURPOSE: Human leukocyte antigen (HLA) mediates interactions of tumor cells with cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Retinoblastoma (RB) is the most common intraocular malignant tumor in childhood and is characterized by direct spread to the optic nerve and orbit as well as hematogenous and lymphatic spread. Earlier, we observed that invasive RB showed reduced HLA, which could contribute to its escape from the immune system. Little is known about the role of the nonclassical HLA molecule, HLA-G, in RB and its role in tumor escape mechanisms in RB. METHODS: Forty archival paraffin-embedded RB tumors were analyzed for the expression of HLA-G by immunohistochemistry using a monoclonal antibody; fresh tumor samples were also subjected to Western blot analysis. There were 22 tumors with no invasion and 18 with invasion of the choroid/optic nerve. Immunoanalysis was performed based on the International Histocompatibility Working Group Project Description. RESULTS: HLA-G was negative in the non-neoplastic retina, reduced in 22/22 tumors with no invasion, and positive in 15/18 with invasion. The immunohistochemistry results were confirmed by Western blot analysis. The difference in expression between the two groups was significant ( p < 0.001). There was no correlation of HLA-G expression with differentiation of the tumors. CONCLUSION: Increased expression of HLA-G was observed in invasive RB. This preliminary observation deserves further investigation and may shed more light on the immune escape mechanisms of this tumor and thus enable novel therapeutic strategies.

Antibodies, Monoclonal↗
PubMed2005

The role of nitric oxide synthases and nitrotyrosine in retinoblastoma.

BACKGROUND: To investigate the potential involvement of the nitric oxide (NO) pathway in retinoblastoma, the authors correlated immunoreactivity for endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), and nitrotyrosine (NT) with the degree of tumor invasiveness in retinoblastoma. METHODS: eNOS, iNOS, and NT reactivity was evaluated by immunohistochemistry in 34 archival retinoblastoma specimens and in a human Y79 retinoblastoma cell line. The tumors were divided into 2 groups: Group A tumors (n = 17 tumors) with no invasion and Group B tumors (n = 17 tumors) with invasion of the choroid, optic nerve, and/or orbit. The expression levels of eNOS, iNOS, and NT were correlated with invasiveness of the tumors. RESULTS: In Group A tumors (n = 17 tumors) without invasion, eNOS was positive in 17 of 17 tumors (100%), iNOS was positive in 14 of 17 tumors (82%), and NT was positive in 17 of 17 tumors (100%). In Group B tumors (n = 17 tumors) with invasion, eNOS was positive in 17 of 17 tumors (100%), iNOS was positive in 16 of 17 tumors (94%), and NT was positive in 17 of 17 tumors (100%). The invasive cohort showed significantly higher expression of iNOS (P < 0.0001) and NT (P < 0.020) compared with the noninvasive cohort. Y79 cells also expressed eNOS, iNOS, and NT; and nonneoplastic retina was positive for eNOS, iNOS, and NT. CONCLUSIONS: Taken together, the results suggested that retinoblastomas can produce NO. The roles of NO in the biology of retinoblastoma and in the prognosis for patients with retinoblastoma remain to be established.

Child, Preschool↗
PubMed2005

Human leukocyte class I antigen and beta2-microglobulin expression in conjunctival dysplasia, carcinoma in situ, and squamous cell carcinoma.

PURPOSE: Malignant transformation of cells is frequently associated with abnormalities in HLA expression. These abnormalities may play a significant role in the clinical course of the disease because the cellular immune response to tumors relies on concomitant recognition of tumor antigens with self-HLA molecules. Since HLA molecules mediate interactions of tumor cells with specific receptors on T and natural killer (NK) cells, tight control of expression of HLA molecules is critical for initiation and implementation of an effective cellular immune response. There is not much information on HLA class I antigens in conjunctival carcinomas. We studied the immunoexpression of HLA class I antigen and beta2-microglobulin (beta2-m) in conjunctival dysplasias and conjunctival squamous cell carcinomas. METHODS: HLA class I antigen and beta2-m expression were analyzed in 10 conjunctival dysplasias, 6 carcinomas in situ, and in 11 conjunctival carcinomas by immunoperoxidase staining with monoclonal antibodies to HLA class I antigen and beta2-m on the archival clinical samples. Immunoanalysis was done according to the International Histocompatibility Working Group Project Description. RESULTS: HLA class I antigen and beta2-m were heterogeneous in 10 conjunctival dysplasias, negative in 6 carcinomas in situ, and 11 conjunctival squamous cell carcinomas. The difference of immunoexpression for HLA class I and beta2-m among the 3 groups was statistically significant (P <0.001). CONCLUSIONS: HLA class I antigens and beta2-m are decreased in conjunctival dysplasias and negative in carcinomas in situ, and carcinomas. The findings support the role of cytotoxic T lymphocyte-mediated control of tumor growth in the clinical course of conjunctival squamous cell carcinomas.

Antibodies, Monoclonal↗
PubMed2004

Expression of Fas ligand in retinoblastoma.

BACKGROUND: The importance of the Fas-Fas ligand (FasL) mechanism for the immune evasion by tumors provided a strong rationale for the examination of FasL expression in retinoblastoma. In an earlier publication, the authors reported that invasive retinoblastomas decreased Fas expression. Because to the authors' knowledge there is not much information regarding the effect of FasL expression on retinoblastoma, the authors studied the expression of FasL in retinoblastoma and correlated it with invasiveness. METHODS: Thirty-six archival retinoblastoma specimens were divided into 2 groups. Group A (n = 17) was comprised of specimens from tumors with no invasion and Group B (n = 19) was comprised of specimens from tumors with invasion of the choroid (focal, diffuse), optic nerve (laminar, postlaminar, surgical end), and orbit. Sections were immunostained with a monoclonal antibody to FasL and the immunoreactivity was assessed. RESULTS: In Group A, FasL was negative in 100% (17 of 17) of the tumor specimens. In Group B, FasL was expressed in 79% (15 of 19) of the tumor specimens (positive in 9 tumors and heterogeneous in 6 tumors). The difference in FasL expression between the two groups was significant (P < 0.001) CONCLUSIONS: Increased expression of FasL was observed in specimens taken from patients with aggressive tumors. Thus, Loss of Fas and gain of aberrant FasL expression were common features of malignant transformation. The data suggested that the Fas/FasL pathway is potentially immunosuppressive and may be involved in the escape of retinoblastoma cells from immune destruction.

Adolescent↗
PubMed2004

Major histocompatibility antigens and antigen-processing molecules in retinoblastoma.

BACKGROUND: Malignant transformation of cells is frequently associated with abnormalities in human leukocyte antigen (HLA) expression. These abnormalities may play a role in the clinical course of the disease, because HLAs mediate interactions of tumor cells with cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Retinoblastoma is the most common intraocular malignant tumor in childhood and is characterized by direct spread to the optic nerve and orbit as well as hematogeneous and lymphatic spread. Little is known about the role of HLA expression in the progression of this malignant disease. METHODS: HLA Class I antigen, beta2-microglobulin (beta2-m), HLA Class II antigens, and the antigen-processing molecules (APMs) of the HLA Class I pathway, including proteasomal subunits (low-molecular mass polypeptide 2 [LMP-2] and LMP-10), the transporter-associated protein (TAP-1) subunit, the binding protein tapasin, and the chaperone molecule calnexin, were studied in 30 archival retinoblastoma specimens by immunohistochemistry. Immunoanalysis was performed based on the International Histocompatibility Working Group Project Description. RESULTS: HLA Class I antigen, beta2-m, HLA Class II antigen, and APMs were positive in 12 tumors with no invasion and were decreased in 13 tumors with choroidal and optic nerve invasion. The difference in HLA and APM expression between the 2 groups was statistically significant (P < 0.001). CONCLUSIONS: Decreased expression of HLA was observed in aggressive tumors and in poorly differentiated tumors. The current findings support a role for both CTLs and NK cell-mediated control of tumor growth in the clinical course of retinoblastoma.

Biomarkers, Tumor↗
PubMed2004

Adult onset Langerhans cell histiocytosis of the orbit--a case report.

PURPOSE: To report an interesting case of adult onset Langerhans cell histiocytosis in a 41-year-old male with clinicopathological correlation. DESIGN: Interventional case report. MATERIALS AND METHODS: A 41-year-old male presented with an ill-defined mass occupying the temporal quadrant of the left orbit. Computerized tomography revealed an ill-defined extraconal mass involving the superolateral aspect of the left orbit with areas of osteolysis involving the lateral and superior orbital walls. The mass excised at orbitotomy showed microscopic features consistent with Langerhans cell histiocytosis. Immunohistochemistry with CD-68 macrophage marker and S-100 was positive, confirming the diagnosis. Treatment included oral steroids and radiotherapy. At 6 months follow-up, he developed a punched-out lytic lesion in the left parietal calvarium. He again received external beam radiotherapy. At 14 months follow-up, he is doing well with no recurrences. CONCLUSIONS: Adult onset Langerhans cell histiocytosis, though rare, should be included in the differential diagnosis of lytic lesions of the lateral orbital wall in an adult patient.

Adult↗
PubMed2004

HLA expression in choroidal melanomas: correlation with clinicopathological features.

PURPOSE: In this retrospective study, we analyzed the relevance of human leukocyte antigen (HLA) expression to clinical behavior of uveal melanoma and correlated it with conventional light microscopic parameters. METHODS: HLA class I antigen and Beta 2 microglobulin expression were analyzed in 45 primary choroidal melanoma lesions by immunoperoxidase staining with monoclonal antibodies to HLA class I antigen and beta 2 microglobulin and correlated with the known clinicopathological parameters. Immunoanalysis was done by a semi quantitative method. The tumors were divided into 3 groups. Group A: Tumors with no extrascleral extension/no liver metastases, group B: tumors with only extrascleral extension and group C: tumors with liver metastases. For statistical analysis we analyzed the negative, weak (heterogeneous) and the positive expression of HLA and beta 2 microglobulin with known clinicopathological parameters. RESULTS: In-group A (n = 35) tumors with no extrascleral extension and no liver metastases HLA class I antigen and beta 2 microglobulin are negative (absent staining) in 30 choroidal melanomas. In-group B (n = 4) they are weak (heterogeneous) in 3 tumors. In-group C (n = 6) all the 6 tumors have a positive (bright staining) immunoexpression. No statistical significance was obtained when HLA and beta 2 microglobulin immunoreactivity was compared against largest tumor diameter (LTD), tumor infiltrating lymphocytes (TIL), mitosis and nuclear grade. The difference of HLA class I and beta 2-microglobulin imunoreactivity among the various cell types spindle, mixed and epithelioid was statistically significant (p = 0.003), (p = 0.004). The difference in immunoreactivity between tumors with no liver metastases and tumors with liver metastases was statistically significant (p < 0.001). CONCLUSIONS: HLA class I antigen and beta 2 microglobulin are negative in melanomas with no extrascleral extension and liver metastases and weak in melanomas with extrascleral extension and are positive in melanomas with liver metastases. HLA expression is independent of the conventional markers in uveal melanoma.

Adolescent↗
PubMed2004

Nm23 expression in retinoblastoma.

PURPOSE: Nm23 is a metastasis-suppressor protein. Decreased nm23 protein contributes to aggressiveness in many tumors. Nm23 immunoreactivity was studied in retinoblastoma and correlated with differentiation and invasiveness. METHODS: Immunohistochemistry was performed on 73 formalin-fixed, paraffin-embedded specimens of retinoblastoma. Western blot was conducted to confirm the immunohistochemical study. Prognostic features such as differentiation, invasion of choroid, optic nerve, and orbit, and metastasis were analyzed. RESULTS: Intense nm23 immunoreactivity was seen in 61% of the retinoblastomas with no invasion and faint nm23 immunoreactivity was seen in 85% of the retinoblastomas with invasion (p < 0.001). Poorly differentiated retinoblastoma showed decreased nm23 immunoreactivity compared to well-differentiated retinoblastomas (p = 0.02). An inverse correlation was observed between invasion of choroid, optic nerve, orbit, and metastasis, and nm23 immunoreactivity. Western blot assays of fresh tumor extracts confirmed the immunohistochemical findings. CONCLUSIONS: Decreased nm23 immunoreactivity was seen in poorly differentiated retinoblastomas and in retinoblastomas with invasiveness. These findings may lay the groundwork for further studies to better understand the molecular mechanisms and provide a more accurate prediction of invasion and metastasis of retinoblastoma.

Blotting, Western↗
PubMed2004

EpCAM expression in retinoblastoma: a novel molecular target for therapy.

PURPOSE: This study was conducted to investigate the potential of targeting epithelial cell adhesion molecules (EpCAMs) in the treatment of retinoblastoma. It was first determined whether EpCAM is expressed in retinoblastoma and then whether EpCAM reactivity correlates with tumor aggressiveness. METHODS: EpCAM reactivity was evaluated by immunohistochemistry in 43 retinoblastoma specimens from 43 patients, by using the monoclonal antibody GA733.2. The tumors were divided into two groups. There were 20 tumors with no invasion of the choroid and optic nerve (group A) and 23 tumors with invasion of the choroid, optic nerve, and orbit (group B). EpCAM reactivity was correlated with invasion and differentiation of the tumors. RESULTS: Among the 43 tumors, EpCAM reactivity was observed in 100% (43/43) tumors. EpCAM reactivity was significantly higher in the invasive than the noninvasive tumors (P < 0.05) and in poorly differentiated than in well-differentiated tumors (P < 0.005). Non-neoplastic retina also expressed EpCAM. CONCLUSIONS: The results confirm that EpCAM is vastly expressed in retinoblastoma and point to its use as a target for therapy in the future.

Adult↗
PubMed2004

Recurrent mucinous carcinoma of the eyelid.

A case of recurrent mucinous carcinoma of the lid in a 40-year-old male is reported. Clinical differential diagnosis and histopathologic features are discussed.

Adenocarcinoma, Mucinous↗
PubMed2003

Major histocompatibility antigens and antigen-processing molecules in uveal melanoma.

PURPOSE: Malignant transformation of cells is frequently associated with abnormalities in the human leukocyte antigen (HLA) expression. These abnormalities may play a role in the clinical course of the disease, because HLA antigens mediate interactions of tumor cells with T cells and natural killer cells. Uveal melanoma is a highly malignant tumor of the eye and is characterized by hematogenic spread to liver. Antigen-processing molecules (APMs) are necessary for efficient expression of HLA class I antigens. We studied the expression of HLA antigens and the APM in uveal melanomas by immunohistochemistry and correlated clinicopathologically. EXPERIMENTAL DESIGN: HLA class I antigen, beta(2)-microglobulin (beta(2)-m), HLA class II antigens, and the APM comprising proteasomal subunits low molecular mass polypeptide (LMP) 2, beta-subunit of LMP2-Delta, LMP 10, transporter associated protein 1 subunit, and chaperone molecules tapasin and calnexin were studied in 41 primary uveal melanoma archival specimens by immunohistochemistry. Immunoanalysis was done by a semiquantitative method and correlated with extrascleral extension, cell types, and the largest tumor diameter. RESULTS: HLA class I antigen, beta(2)-m, HLA class II antigen, and the APM were decreased (negative staining in 29 tumors and dull staining in 3 tumors) in 100% (32 of 32) uveal melanomas with no extrascleral extension. (P = 0.01) and positive (bright staining) in 67% (4 of 9) tumors with liver metastasis. Decreased immunoexpression of HLA antigens and the APM was seen in nonepithelioid cell melanomas. There was no correlation with largest tumor diameter. CONCLUSIONS: Our data suggest decreased expression of HLA, and APM are seen in uveal melanomas with no extrascleral extension and in nonepithelioid cell melanomas. Decreased expression of APM may contribute to decreased HLA class I antigen expression.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

HLA class II antigen expression in uveal melanoma: correlation with clinicopathological features.

The authors examined the immunoexpression of human leukocyte (HLA) class II antigen in uveal melanomas and correlated with the cell types, largest tumour dimension and extrascleral invasion. HLA class II antigen expression was analysed in 45 primary uveal melanoma lesions by immunoperoxidase staining with monoclonal antibody. Immunoanalysis was done by a semi-quantitative method according to the International Histocompatibility Working Group, Project description. The results were correlated clinicopathologically. Among the 45-uveal melanomas, 17 were spindle cell types, 16 were mixed cell types and 12 were epithelioid cell types. Among the 35 tumours with no extrascleral extension, HLA class II antigen was decreased in (100%) 35/35 tumours. Among the 10 tumours with extrascleral extension, HLA class II antigen was positive in the 60% (6/10) tumours with liver metastasis and decreased in 40% (4/10) tumours with no liver metastasis. HLA class II antigen was negative in 94% (16/17) spindle cell melanomas. Decreased HLA class II immunoreactivity in tumours with no extrascleral extension was significant (P<0.001). Negative HLA class II immunoreactivity in the spindle cell melanoma was significant (P<0.001). There was no correlation with largest tumour diameter and immunoreactivity. HLA class II antigen is an independent prognostic marker in uveal melanoma. Thus, HLA class II antigen expression in uveal melanoma in relation to prognosis and cell types are similar to HLA class I antigen expression, where downregulation and presence of spindle cell melanoma correlates with favourable outcome. This may have important implications with respect to proposed T cell based immunotherapy.

Adolescent↗
PubMed2003

HLA class II antigen expression in conjunctival precancerous lesions and squamous cell carcinomas.

PURPOSE: The expression of human leukocyte antigen (HLA) class II molecules on the cell surface is necessary for the presentation of peptide antigens to helper CD4 T lymphocytes of the immune system. We studied the immunoexpression of HLA class II antigen in conjunctival precursor lesions and conjunctival squamous cell carcinomas. METHODS: HLA class II antigen expression was analyzed in 8 conjunctival dysplasias, 6 carcinomas in situ and in 7 conjunctival squamous cell carcinomas, by immunoperoxidase staining with monoclonal antibody to HLA class II antigen on the archival clinical samples. Immunoanalysis was done by a semi quantitative method based on the intensity of staining and the percentage of stained cells. RESULTS: HLA class II antigen immunoexpression was heterogeneous in 8 conjunctival dysplasias and in 6 carcinoma in situ and negative in 7 conjunctival squamous cell carcinomas. CONCLUSIONS: Human leukocyte class II antigen immunoexpression is decreased in conjunctival precancerous and squamous cell carcinomas.

Carcinoma, Squamous Cell↗