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S Jothy

Publications and source records attributed to S Jothy.

At least 37 records · Page 2Linked to original sources
PubMed1997

Impaired bone marrow microenvironment and immune function in T cell protein tyrosine phosphatase-deficient mice.

The T cell protein tyrosine phosphatase (TC-PTP) is one of the most abundant mammalian tyrosine phosphatases in hematopoietic cells; however, its role in hematopoietic cell function remains unknown. In this report, we investigated the physiological function(s) of TC-PTP by generating TC-PTP-deficient mutant mice. The three genotypes (+/+, +/-, -/-) showed mendelian segregation at birth (1:2:1) demonstrating that the absence of TC-PTP was not lethal in utero, but all homozygous mutant mice died by 3-5 wk of age, displaying runting, splenomegaly, and lymphadenopathy. Homozygous mice exhibited specific defects in bone marrow (BM), B cell lymphopoiesis, and erythropoiesis, as well as impaired T and B cell functions. However, myeloid and macrophage development in the BM and T cell development in the thymus were not significantly affected. BM transplantation experiments showed that hematopoietic failure in TC-PTP -/- animals was not due to a stem cell defect, but rather to a stromal cell deficiency. This study demonstrates that TC-PTP plays a significant role in both hematopoiesis and immune function.

Animals↗
PubMed1997

Changes in CD44 expression during carcinogenesis of the mouse colon.

CD44 glycoprotein is the main extracellular receptor for hyaluronic acid. The CD44 gene is composed of 20 exons and encodes a variety of isoforms generated by alternative splicing of 10 variant exons. Overexpression of discrete CD44 isoforms containing products of variant exons have been implicated in the progression of cancer, including human colon carcinoma. The pattern of CD44 transcripts changes during early colorectal carcinogenesis, and their relation to CD44 protein expression remains to be defined under experimental conditions. In the current study we investigated CD44 expression in a murine model of human colon adenoma/carcinoma. Colon tumors were induced in 19 ICR/Ha mice by 1,2-dimethylhydrazine injections and CD44 expression was studied by RT-PCR/ Southern blot analysis as well as immunohistochemistry. CD44 transcripts were strongly overexpressed in tumors compared to normal colon. Both neoplastic and normal colon samples exhibited the same species of CD44 transcript representing standard and variant isoforms. Seventy-five percent of neoplasms contained foci of CD44-positive tumor cells, whereas in normal colon the epithelial immunoreactivity was confined to the crypt base. Immunostaining of neoplastic cells was heterogeneous and there was a significant tendency toward the progressive loss of CD44 immunoreactivity in large invading tumors. It is concluded that early events in murine colorectal carcinogenesis are characterized by a marked global overexpression of standard and variant CD44 transcripts.

1,2-Dimethylhydrazine↗
PubMed1997

CD44 and the adhesion of neoplastic cells.

CD44 is a family of transmembrane glycoproteins that act mainly as a receptor for hyaluronan. It can also bind some other extracellular matrix ligands (chondroitin sulphate, heparan sulphate, fibronectin, serglycin, osteopontin) with lower affinity. CD44 is encoded by a single gene containing 20 exons, 10 of which (v1-v10) are variant exons inserted by alternative splicing. The standard, ubiquitously expressed isoform of CD44, does not contain sequences encoded by these variant exons. Numerous variant isoforms of CD44 containing different combinations of exons v1-v10 inserted into the extracellular domain can be expressed in proliferating epithelial cells and activated lymphocytes. CD44 plays a significant role in lymphocyte homing. Both alternative splicing and glycosylation influence receptor function of the molecule, usually reducing its affinity to hyaluronan. The cytoplasmic domain of CD44 communicates with the cytoskeleton via ankyrin and proteins belonging to the ezrin-moesin-radixin family. Relatively little is known about the intracellular events following interactions of CD44 with its ligands. Some variant isoforms, especially those containing sequences encoded by v6-v10, are overexpressed in both human and animal neoplasms. In a rat pancreatic adenocarcinoma model one of the variant CD44 isoforms was proved to be determinant in the metastatic process. For some human neoplasms (carcinomas of the digestive tract, non-Hodgkin's lymphomas, thyroid carcinomas, and others) correlations have been made between the particular pattern of CD44 variants produced by neoplastic cells and clinicopathological parameters of tumours, such as grade, stage, presence of metastases, and survival. In vitro studies indicate that modifications of CD44 expression result in different ligand recognition and influence cell motility, invasive properties, and metastatic potential of experimental tumours. Investigation of CD44 neoexpression can be useful both in early cancer diagnosis and in predicting tumour behaviour. It can also contribute to better understanding of molecular mechanisms leading to neoplastic transformation.

Alternative Splicing↗
PubMed1997

D-penicillamine-induced crescentic glomerulonephritis and antimyeloperoxidase antibodies in a patient with scleroderma. Case report and review of the literature.

Therapeutic use of D-penicillamine has been associated with a range of adverse effects. We present a patient with scleroderma, treated with D-penicillamine for 5 years, who developed severe renal failure due to rapidly progressive glomerulonephritis with both crescents and subepithelial immune deposits on renal biopsy. Serological findings included perinuclear antineutrophil cytoplasmic antibodies and antihistone antibodies. She was treated with cyclophosphamide, prednisone, discontinuation of D-penicillamine, and hemodialysis. Therapy resulted in partial recovery of renal function. The clinical course of our patient is in keeping with D-penicillamine-induced chronic membranous nephropathy, followed by rapidly progressive crescentic glomerulonephritis. We discuss the effects of D-penicillamine in our patient, and review the literature on immune-mediated renal disease associated with the use of this drug.

Aged↗
PubMed1997

Brain tumor-polyposis syndrome: two genetic diseases?

PURPOSE AND DESIGN: This report presents a comprehensive and statistical analysis of the brain tumor-polyposis (BTP) cases referred to as Turcot's syndrome in the literature. RESULTS: BTP patients encompass a heterogeneous group that can be classified into two statistically distinct clinical entities based on phenotype of the polyps (P = .0001), presence of colorectal cancer (P = .0001), type of brain neoplasm, ie, glioma or medulloblastoma (P = .0001), presence of skin lesions (P = .0004) and cafe-au-lait spots (P = .0008), as well as consanguinity (P = .0135). CONCLUSION: The first entity (BTP syndrome type 1) consists of patients who have glioma and colorectal adenomas without polyposis (non-FAP cases), and their siblings with glioma and/or colorectal adenomas. For these patients, we show that the patient's age at malignant glioma occurrence is less than 20 years (50 to 80 years in the general population), which strongly supports the existence of an underlying genetic cause. The neoplasms of these patients show DNA replication errors, which suggests a relationship with hereditary nonpolyposis colorectal cancer (HNPCC), a disease characterized by germline alterations in DNA mismatch repair genes. The second entity (BTP syndrome type 2) consists of patients with a CNS tumor that occurs in a familial adenomatous polyposis kindred (FAP cases). These patients carry germline mutations in the APC gene, which suggests that mutations in this gene might predispose to brain tumors. Risk analysis shows increased incidence of medulloblastoma in FAP patients, but APC mutations are not found in sporadic glioma or medulloblastoma. Therefore, further investigations should establish whether the occurrence of medulloblastoma in an FAP family represents a variant of FAP.

Adenomatous Polyposis Coli↗
PubMed1997

Cell-surface levels of human carcinoembryonic antigen are inversely correlated with colonocyte differentiation in colon carcinogenesis.

Human carcinoembryonic antigen (CEA) is overexpressed in a wide variety of epithelial malignancies including colon cancer. CEA can function in vitro as a homotypic intercellular adhesion molecule and can block the terminal differentiation of rodent myoblasts, thus raising the possibility that deregulated expression of CEA might directly contribute to malignant progression. To address this question, the expression pattern and cell-surface levels of CEA were studied during malignant transformation of the colonic epithelium in sporadic and familial adenomatous polyposis-related neoplasms. The level of immunohistochemically detected CEA was higher in 30% to 62% of microadenomas and small adenomas from familial adenomatous polyposis patients compared with adjacent normal mucosa, and this proportion was positively correlated with lesion size and degree of dysplasia. Cytofluorometric analysis of highly purified single epithelial cell suspensions from freshly excised carcinomas versus adjacent normal tissue demonstrated up to a 20-fold increase of mean cell-surface CEA in a group of colon carcinomas representative of the overall majority of such tumors--from Dukes' stages A to D and ranging mainly from well to moderately differentiated, the degree of overproduction was inversely correlated with tumor differentiation and directly correlated with stage. A marked tendency toward nonpolarized versus apical cell-surface expression with progression was also noted. Nonspecific cross-reacting antigen (NCA), a CEA family member, is also a homotypic adhesion molecule and blocks terminal myogenic differentiation, whereas biliary glycoprotein is a CEA family adhesion molecule that does not. Cell-surface NCA showed even greater overexpression (up to 70-told) in dedifferentiated tumors, whereas total-cell biliary glycoprotein showed approximately 2-fold lower levels than was normal in more differentiated tumors and approximately 2-fold higher levels than in further progressed tumors. These results therefore support the suggestion that CEA and NCA can directly contribute to colon carcinogenesis by inhibiting colonocyte differentiation.

Adenoma↗
PubMed1996

Detailed deletion mapping with a refined physical map of 7q31 localizes a putative tumor suppressor gene for breast cancer in the region of MET.

In breast cancer, loss of heterozygosity (LOH) has been described on the long arm of chromosome 7 at band q31, suggesting the presence of a tumor suppressor gene in this region. To define the deleted region, we analysed 73 cases of breast cancer and matched normal DNAs with 17 polymorphic markers. A minimal area of LOH was identified as the chromosomal interval flanked by markers D7S687 and metH, spanning a segment of 2 Mb on chromosome 7q31. Of the 73 breast cancer patients studied, all were informative for at least one marker in this region and nine patients showed LOH at one or more loci (12.3%). To define the physical size of the deletion and to ensure the correct interpretation of the LOH deletion studies, we redefined the physical map of markers within this region of 7q31. We present a new physical order for markers at 7q31. More significantly, we have mapped the minimum deletion of 7q31 in the breast cancers studied to date to a physical distance of 1000 kb, contained on a single YAC clone, which includes the MET receptor tyrosine kinase but no other known genes.

Breast Neoplasms↗
PubMed1996

Field effect of human colon carcinoma on normal mucosa: relevance of carcinoembryonic antigen expression.

Human colon cancer usually develops on a mucosa which has already undergone multiple steps of genetic change. These multiple steps create a field effect characterized by the presence of morphologically normal, but biologically altered epithelial cells. This aims of this study were to evaluate whether the expression of carcinoembryonic antigen (CEA) can act as a phenotypic marker of the field effect, and to map its topography in relation to the presence of colorectal adenocarcinoma. The expression of CEA was tested by immunohistochemistry on morphologically normal mucosa at 4 increasing distances from 14 autologous cases of colorectal adenocarcinoma. CEA expression in the normal mucosa was compared to the tumor. The results show that in the mucosa adjacent to the edge of the autologous tumor, CEA is expressed to the same level as displayed in the carcinoma; there is a decrease in CEA expression in normal mucosa located at 1 cm or more from the edge of carcinoma. Mucosa sampled at 5 and 10 cm from the tumor expresses CEA at the same low level as in mucosa of control subjects with no colorectal neoplasm. In conclusion, this study demonstrates a gradient of CEA expression in the peritumoral area, supporting the concept of field effect, and maps its extent. These data are relevant to the biology of human colorectal cancer, and more practically, to the optimal location of surgical resection.

Antibodies, Monoclonal↗
PubMed1996

The prognostic significance of previous benign breast disease for women with carcinoma of the breast.

BACKGROUND: Risk factors for carcinoma of the breast may also have prognostic influence. Because benign breast disease is a risk factor for carcinoma of the breast, we compared the outcomes of patients with carcinoma of the breast with a history of benign breast disease to patients with carcinoma of the breast without a history of benign breast disease. STUDY DESIGN: Patients with benign breast disease and subsequent carcinoma of the breast were matched by age and ethnicity to patients with carcinoma of the breast with no prior history of benign breast disease. Risk factors, pathologic findings, and disease-free survival rates were compared. RESULTS: Patients with previous benign breast disease had a significantly greater family history of carcinoma of the breast (35 percent compared with 22 percent, p = 0.015) and used postmenopausal hormones significantly more frequently (16 percent compared with 5 percent; p < 0.001) than women without benign breast disease. In patients with benign breast disease, their subsequent carcinomas were smaller (T1, 53 percent compared with 43 percent), with significantly fewer nodes involved (1.8 compared with 2.7, p = 0.031), and were significantly more likely to contain an infiltrating lobular component (9 percent compared with 3 percent, p = 0.023). Significantly fewer patients with previous benign breast disease had metastatic disease (18 percent compared with 31 percent; p = 0.001). The ten-year cumulative disease-free survival rate for patients with benign breast disease was 68 percent compared with 59 percent for women without a history of benign breast disease. CONCLUSIONS: This study indicates that women with benign breast disease who have carcinoma of the breast develop may have a better outcome than women without a history of benign breast disease.

Adult↗
PubMed1996

Human breast cancer: genetic alterations in the MET gene region.

OBJECTIVE: to test whether the MET gene at chromosome 7q31, which encodes a receptor protein (tyrosine kinase) related to normal histological differentiation, undergoes structural changes in breast cancer. A previous study reported somatic alterations detected as loss of heterozygosity (LOH) at this locus in breast cancer. DESIGN: Analysis of DNA from tumours and matched normal tissue by Southern blot hybridization with the metH probe; the tumours were also analysed for estrogen and progesterone receptors, ploidy and S phase, and protein expression of the MET and c-erbB-2 protooncogenes. PARTICIPANTS: Eighty-two patients with breast cancer. RESULTS: Fifty-three percent of the patients were informative for polymorphism with the metH marker. Somatic alterations of MET, consisting of LOH, were demonstrated in 22% of women who were informative and had breast cancer. No correlation was found between LOH of MET and conventional prognostic factors, or status for c-erbB-2 proto-oncogene expression. Estrogen-receptor status correlated with progesterone-receptor status, and S phase correlated with ploidy and size of the tumour. CONCLUSIONS: Somatic alterations of MET, detected as LOH with the metH probe, occur in 22% of informative patients. These alterations do not correlate with the prognostic factors established when the mastectomy is performed. It remains to be determined whether the patients' overall survival and disease-free survival rates are correlated with genetic alteration of MET.

Breast Neoplasms↗
PubMed1995

The Ity/Lsh/Bcg locus: natural resistance to infection with intracellular parasites is abrogated by disruption of the Nramp1 gene.

In mice, natural resistance or susceptibility to infection with intracellular parasites is determined by a locus or group of loci on chromosome 1, designated Bcg, Lsh, and Ity, which controls early microbial replication in reticuloendothelial organs. We have identified by positional cloning a candidate gene for Bcg, Nramp1, which codes for a novel macrophage-specific membrane transport protein. We have created a mouse mutant bearing a null allele at Nramp1, and we have analyzed the effect of such a mutation on natural resistance to infection. Targeted disruption of Nramp1 has pleiotropic effects on natural resistance to infection with intracellular parasites, as it eliminated resistance to Mycobacterium bovis, Leishmania donovani, and lethal Salmonella typhimurium infection, establishing that Nramp1, Bcg, Lsh, and Ity are the same locus. Comparing the profiles of parasite replication in control and Nramp1-/- mice indicated that the Nramp1Asp169 allele of BcgS inbred strains is a null allele, pointing to a critical role of this residue in the mechanism of action of the protein. Despite their inability to control parasite growth in the early nonimmune phase of the infection, Nramp1-/- mutants can overcome the infection in the late immune phase, suggesting that Nramp1 plays a key role only in the early part of the macrophage-parasite interaction and may function by a cytocidal or cytostatic mechanism distinct from those expressed by activated macrophages.

Alleles↗
PubMed1995

Expression of prostaglandin G/H synthase-1 and -2 protein in human colon cancer.

Prostaglandin G/H synthase (PGHS), a key enzyme leading to the formation of prostaglandins, is the target of nonsteroidal antiinflammatory drugs. Two forms of the enzyme have been identified, PGHS-1 and PGHS-2. Epidemiological evidence has suggested that aspirin and other nonsteroidal antiinflammatory drugs may reduce the risk of colorectal cancer. We examined by immunoblot analyses the expression of human PGHS-1 and PGHS-2 protein in 25 matched colon cancer and nontumor tissues, 4 premalignant polyps, 5 control colon tissues from noncancer patients, and 3 matched normal and cancerous breast tissue samples. PGHS-1 was detected in all normal and tumor tissue. In contrast, PGHS-2 was not detected in 23 of 25 normal colon tissues but was detected in 19 of 25 colon tumors. PGHS-2 protein was not observed in four human premalignant polyp samples, control colon from noncancer patients, or matched normal or cancerous breast tissues. These results suggest that the beneficial effects of nonsteroidal antiinflammatory drugs in colon cancer may be mediated by inhibition of PGHS-2.

Adenomatous Polyps↗
PubMed1995

E-cadherin and OB-cadherin mRNA levels in normal human colon and colon carcinoma.

A polymerase chain reaction strategy was utilized to identify members of the cadherin family of cell adhesion molecules that are expressed in normal human colon and colon carcinoma. E-cadherin (an epithelial cadherin) and OB-cadherin (a mesenchymal cadherin) were found to be present in the colon specimens. Furthermore, a novel semiquantitative polymerase chain reaction (PCR) assay was developed for each of these two cadherins. These assays were used to determine the relative levels of E-cadherin and OB-cadherin in normal human colon and colon carcinoma specimens. E-cadherin levels were found to be reduced approximately twofold in the adenocarcinoma specimens in comparison to matched normal colon specimens. In contrast, OB-cadherin levels did not correlate with malignant transformation. We speculate that this novel PCR method will be widely applicable for assessing E-cadherin mRNA levels in carcinomas.

Adenocarcinoma↗
PubMed1995

Adhesion or anti-adhesion in cancer: what matters more?

The regulation of adhesion processes between normal epithelial cells is an essential condition for the maintenance of appropriate tissular architecture and differentiation. Quantitative and qualitative alterations in these homotypic adhesions occur during the transformation of normal into malignant epithelium. How these complex alterations in various homotypic adhesions modify the ability of tumor cells to detach from the original neoplastic site, to grow and move as single or clumped cells, and to invade the stroma are current issues in tumor biology. This review contrasts tumor cell adhesion mediated by E-cadherin which is consistently decreased in carcinomas, with adhesion mediated by CD44 and CEA which are increased in the tumors. A model proposing to resolve the apparent paradox of simultaneous adhesion and anti-adhesion mediated by the same protein is proposed.

Cadherins↗
PubMed1995

Clinicopathological relevance of the association between gastrointestinal and sebaceous neoplasms: the Muir-Torre syndrome.

The association between sebaceous neoplasms of the skin and visceral cancers, known as Muir-Torre syndrome, is described in three patients, including one with an extensive history of cancer in his family. The first patient, a 54-year-old man, developed multiple sebaceous adenomas, epitheliomas, and carcinomas in association with a colonic carcinoma 6 years after cardiac transplantation. Family history in this patient disclosed colon cancer in 17 relatives. The second patient was a 51-year-old man who had recurrent adenocarcinoma of the sigmoid colon, adenocarcinoma arising in Barrett's esophagus, and sebaceous epithelioma during a period of 15 years. The third patient was a 90-year-old man with a sebaceous adenoma followed 5 months later by adenocarcinoma of the sigmoid colon with liver metastases. Muir-Torre syndrome in 129 other patients published in the literature is reviewed. Although it is a rare disease, Muir-Torre syndrome requires recognition because skin lesions may be the first sign of the syndrome and this may lead to early diagnosis of associated visceral cancers. Moreover, because this syndrome appears to be inherited, family members should be screened for visceral cancer, especially colorectal adenocarcinoma.

Adenocarcinoma, Sebaceous↗
PubMed1995

Renal glomerular fibrosis in two pigs.

Massive deposition of collagen fibrils was found in the renal glomeruli of two pigs. The affected pigs were a 6-month-old female hybrid pig with systemic mycobacteriosis and a retired sow showing azotemia. Microscopically, various amounts of a homogeneous eosinophilic substance were deposited within the expanded mesangium of almost all renal glomeruli in both cases. The deposit was also seen occasionally on the glomerular capillary walls in the sow. Capillary lumens were occluded in the glomerular segments with heavy deposition. Obsolescent glomeruli were often surrounded by lymphoid cells. The deposited substance was Congo red negative and stained deep blue with Heidenhain's azan staining. Immunohistochemical evaluation revealed that the major component of the homogeneous substance was type-III collagen. Electron microscopic examination showed that the deposits were masses of fibrils of variable length, width, and shape. The fibrils had transverse bands with a periodicity of approximately 60 nm, consistent with collagen fibrils. These glomerular changes were identical to those of collagenofibrotic glomerulonephropathy that has recently been described as a new glomerular disease in humans. The glomerular lesion may be the result of unusual production of type-III collagen by mesangial cells.

Animals↗
PubMed1994

Expression of c-erbB-2 oncogene product in Barrett's adenocarcinoma: pathological and prognostic correlations.

AIMS: To establish the prevalence of c-erbB-2 protein expression in a surgical series of Barrett's adenocarcinomas; and to correlate this expression with clinicopathological data and prognosis. METHODS: Sixty six surgical specimens of Barrett's adenocarcinomas were included in this retrospective study. Blocks of the tumour and of non-dysplastic Barrett's mucosa were stained with a polyclonal antibody specific for the intracytoplasmic domain of the c-erbB-2 protein. RESULTS: Seven of 66 tumours showed membrane staining for the c-erbB-2 protein. The non-dysplastic Barrett's mucosa was negative in all cases. There was no difference between c-erbB-2 positive and negative tumours with regard to mean age, sex ratio, percentage of alcohol misusers, percentage of smokers, tumour differentiation, depth of invasion, lymph node response, and proliferative activity, assessed by the percentage of tumour cells positive with the MIB-1 antibody directed against the Ki-67 antigen. All c-erb B2 positive tumours were of Lauren's intestinal type compared with negative c-erbB-2 tumours. Patients with c-erbB-2 positive tumours had a significantly poorer prognosis than patients with negative tumours. CONCLUSIONS: The prevalence of Barrett's adenocarcinomas expressing c-erbB-2 found in this study (11%) was similar to that observed in published series of gastric adenocarcinomas. c-erbB-2 protein expression could be an important prognostic indicator in Barrett's adenocarcinoma.

Adenocarcinoma↗