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Biomedical subjects

A Seth

Publications and source records attributed to A Seth.

At least 19 recordsLinked to original sources
PubMed2001

Downregulation of the potential suppressor gene IGFBP-rP1 in human breast cancer is associated with inactivation of the retinoblastoma protein, cyclin E overexpression and increased proliferation in estrogen receptor negative tumors.

The complex insulin-like growth factor network of ligands, receptors and binding proteins has been shown to be disturbed in breast cancer. In addition to defects in proteins controlling cell cycle checkpoints, this type of aberrations could affect tumor growth and survival thereby influencing both tumor aggressiveness and potential response to treatments. We have previously identified the T1A12/mac25 protein, which is identical to the IGFBP-rP1, as a differentially expressed gene product in breast cancer cells compared with normal cells. Here we compare the expression of IGFBP-rP1 in 106 tumor samples with known status of cell cycle aberrations and other clinicopathological data. This was done using a tumor tissue section array system that allows for simultaneous immunohistochemical staining of all samples in parallel. Cytoplasmic staining of variable intensity was observed in most tumors, 15% lacked IGFBP-rP1 staining completely, 20% had weak staining, 32% intermediate and 33% showed strong staining. Low IGFBP-rP1 was associated with high cyclin E protein content, retinoblastoma protein (pRb) inactivation, low bcl-2 protein, poorly differentiated tumors and higher stage. There was a significantly impaired prognosis for patients with low IGFBP-rP1 protein tumors. Interestingly, IGFBP-rP1 showed an inverse association with proliferation (Ki-67%) in estrogen receptor negative tumors as well as in cyclin E high tumors suggesting a separate cell cycle regulatory function for IGFBP-rP1 independent of interaction with the estrogen receptor or the pRb pathway.

Aneuploidy↗
PubMed2001

Alterations in T cell phenotype and human immunodeficiency virus type 1-specific cytotoxicity after potent antiretroviral therapy.

Cytotoxic T lymphocytes (CTLs) are an important defense against human immunodeficiency virus (HIV) type 1 but ultimately fail to control infection. To determine whether more efficient sustained immunity is induced by suppressing replication, the evolution of T cell phenotypes and HIV-specific CD8+ lymphocytes was prospectively investigated in 41 patients initiating combination therapy. Suppression of viremia to <200 copies/mL was associated with increases in naive cells (CD45RA+62L+) and declines in activated T cells (CD95+ cell counts and CD38+ HLA-DR+). HIV-specific tetramer-staining CD8+ T cells were detected in 6 of 10 HLA-A*0201-positive persons, which declined in 5 with treatment. CTL precursor frequencies were markedly consistent before and after treatment. Eight (72%) of 11 recognized > or =1 immunodominant epitope, representing either a new or an increased CTL response after treatment. Thus, activated CD8+ T cells, including those recognizing immunodominant epitopes, decline with combination therapy. However, the overall level of antigen-specific cells that are capable of differentiating into effectors remains stable, and the recognition of new epitopes may occur.

Anti-HIV Agents↗
PubMed2001

Deep intubation of 8 Fr guiding catheter to deliver coronary stent graft to seal coronary perforation: a case report.

Coronary perforation is an uncommon complication of angioplasty and is a challenging situation to manage. We describe a case of complex multivessel coronary angioplasty complicated by coronary perforation following balloon rupture that was successfully managed with a coronary stent graft. Delivery of the stent graft to the site of vessel rupture required deep intubation of an 8 Fr guiding catheter over the shaft of an inflated balloon. In addition to the availability of covered stents, it is essential to be familiar with various skills necessary to deploy these stents. Cathet Cardiovasc Intervent 2001;54:59-62.

Angioplasty, Balloon, Coronary↗
PubMed2001

Impact of power index, hydroureteronephrosis, stone size, and composition on the efficacy of in situ boosted ESWL for primary proximal ureteral calculi.

OBJECTIVES: The efficacy, safety, feasibility, and outcome of in situ treatment applied to select proximal ureteral calculi was assessed and analyzed with a view to avoiding auxiliary interventions and providing high clearance rates in the shortest possible time. We studied the impact of several clinically important variables, including power index, degree of hydroureteronephrosis (HDUN), stone size, and composition on the efficacy of sequential in situ boosted extracorporeal shock wave lithotripsy (ESWL) in a select group. The power index requirement for the in situ boosted protocol and the impact of the stone size/composition, degree of HDUN, and clearance rates were also analyzed. METHODS: An in situ (no instrumentation) boosted protocol was applied to 130 primary unimpacted proximal ureteral calculi with no prior intervention. A typical session with the Siemens Lithostar Plus comprised 3000 shock waves, in installments of 500, deployed at a power setting of 1 to 4 kV with a gradual stepwise escalation. Sequential boosted additional sessions of ESWL were administered on days 2, 7, and 14, tailored to the degree of fragmentation, clearance status, and amount of residual stone bulk. Several parameters (shock waves, kilovolts used, fluoroscopy time, number of sessions, stone size, composition, fragmentation, clearance, and HDUN) were recorded and the results analyzed statistically. RESULTS: The results were excellent in 83.8%, with a mean duration to complete clearance of 11.3 days. In situ ESWL failed in 7.69%, and the auxiliary intervention rate was 10.7%. Pre-ESWL HDUN was present in 78.3%, the mean power index was 184.6/session/case, and the average stone burden was 8.9 mm(2). Calcium oxalate monohydrate was the most common stone (56%). Renal colic was the most common side effect observed. The power index, fragmentation at the first session, and stone size were found to be the most favorable significant variables affecting stone clearance. The degree of HDUN, number of sessions, and stone composition did not significantly impact the clearance rates. CONCLUSIONS: In situ boosted ESWL should be the first-line therapeutic modality in select unimpacted primary proximal ureteral stones.

Adolescent↗
PubMed2001

Wasp recruitment to the T cell:APC contact site occurs independently of Cdc42 activation.

Cdc42 and WASP are critical regulators of actin polymerization whose function during T cell signaling is poorly understood. Using a novel reagent that specifically detects Cdc42-GTP in fixed cells, we found that activated Cdc42 localizes to the T cell:APC contact site in an antigen-dependent manner. TCR signaling alone was sufficient to induce localization of Cdc42-GTP, and functional Lck and Zap-70 kinases were required. WASP also localized to the T cell:APC contact site in an antigen-dependent manner. Surprisingly, WASP localization was independent of the Cdc42 binding domain but required the proline-rich domain. Our results indicate that localized WASP activation requires the integration of multiple signals: WASP is recruited via interaction with SH3 domain-containing proteins and is activated by Cdc42-GTP concentrated at the same site.

Antigen-Presenting Cells↗
PubMed2001

Defining a test for HER-2/neu evaluation in breast cancer in the diagnostic setting.

In breast cancer amplification of the HER-2/neu oncogene and over-expression of the protein product is associated with poor prognosis, predicts response to some chemotherapeutic regimens and is the target for Herceptin treatment. To date there are several methods to assess the amplification/over-expression of HER-2/neu with each having advantages and disadvantages. We have studied amplification and over-expression of HER-2/neu in 250 consecutive cases of breast cancer (220 invasive and 30 in situ carcinomas) presenting to the Department of Pathology at Women's College Campus of Sunnybrook and Women's College Health Sciences Center. Thirty percent of the invasive carcinomas were node positive. HER-2/neu protein over-expression was assessed by immunohistochemistry (IH) using antibody CB11 and amplification of the gene by differential PCR. The percentage of tumor cells showing CB11 staining was determined and the most significant cut off point for positivity was > or =10% moderate or strong complete membranous staining. The gene was considered amplified if the density score of the product was > or =2. There was 94% concordance between the two methods (P value.0001). Both methods were positive in 16% of cases and negative in 78% of cases. Discrepant cases were examined by FISH which confirmed the IH results in 9/11 invasive carcinomas. These results show that there is excellent concordance between IH and PCR. However, immunohistochemistry is easier to perform and cheaper than PCR and could be used in routine assessment of HER-2/neu in breast cancer patients.

Breast Neoplasms↗
PubMed2001

Use of conditionally immortalized mouse cardiac fibroblasts to examine the effect of mechanical stretch on alpha-smooth muscle actin.

Mechanical stretch regulates alpha-smooth muscle actin (SMA) expression in myofibroblasts but limited replication and cellular heterogeneity have hampered definitive studies in vitro. We examined the role of applied force in regulating SMA expression in conditionally immortalized cardiac fibroblast lines derived from H-2Kb-tsA58 transgenic mice. When plated in differentiating conditions (37 degrees C without interferon-gamma), transgenic myofibroblasts exhibited vimentin staining, no desmin staining and abundant SMA in well-developed stress fibers that were indistinguishable from controls. Magnetically-generated tensile forces (approximately 500 pN/cell) applied through collagen-coated magnetite beads selectively reduced SMA but not beta-actin mRNA and protein content in both cell types. The early loss of SMA was due in part to selective leakage into the cell culture medium. Depolymerization of actin filaments with cytochalasin D blocked the force-induced reduction of SMA. Cardiac fibroblast lines established from H-2Kb-tsA58 transgenic mice provide a phenotypically stable source of cells for studying the role of physical forces in regulating SMA.

Actins↗
PubMed2001

Transitional cell carcinoma of the urinary bladder following exposure to cyclophosphamide in childhood.

With the increasing survival of children with malignancies, the long-term effects of chemotherapies are now becoming important and one of these dreadful long-term complications is the development of a second malignancy. Described here is a case of transitional cell carcinoma of the bladder developing 8 years following exposure to cyclophosphamide for the treatment of embryonal rhabdomyosarcoma.

Adolescent↗
PubMed2001

Management of renal angiomyolipoma in complex clinical situations.

Renal angiomyolipoma (AML) is associated with complex clinical situations such as tumour in a solitary kidney, bilateral, large or multicentric tumours or those associated with tuberous sclerosis (TS) or pregnancy. Management in these situations may be challenging. Fifteen patients (20 kidneys) were admitted with symptomatic AML over last 10 years. Eleven patients had one or the other complicating factor. Ten patients had a tumour of >10 cm, 4 had TS, 5 had multiple and bilateral tumours, 1 patient was pregnant and 1 had a solitary functioning kidney. With the newer imaging modalities correct diagnosis was possible in 12 cases and renal cell carcinoma (RCC) was suspected in 3 cases. Selective angioembolization (SAE) was done in 3 patients, which successfully controlled bleeding in all. Nephron-sparing surgery (NSS) was performed in 5 patients. Total nephrectomy was done in 4 cases, in 3 due to suspicion of RCC and in 1 due to extensive involvement of the kidney. Three patients with multiple and bilateral tumours were chosen for conservative treatment and none developed recurrence of bleeding on strict follow-up. In a pregnant patient, bleeding was successfully controlled with angioembolization. However, 1 patient with a solitary functioning kidney with large-sized tumour (20 x 18 cm) underwent NSS. In conclusion, the basis of management of AML is preservation of renal tissue, which can be effectively achieved with SAE or NSS. In a solitary functioning kidney, NSS or SAE is the ideal treatment, if feasible. The patients in the TS group are usually more complicated and require life-long follow-up after initial management with NSS or SAE. Pregnant AML patients can be safely managed with SAE. Conservative treatment without any intervention and regular follow-up may be more helpful in some patients with multiple, bilateral extensive tumours.

Adolescent↗
PubMed2001

Pelvic lipomatosis presenting as uraemic encephalopathy.

Pelvic lipomatosis is a benign disorder of unknown aetiology, characterised by deposition of mature fat in the pelvis. It has a variable natural history, manifesting either with symptoms attributable to the lower urinary tract or varying degrees of renal failure. Owing to the mild, non-specific initial symptoms and slow progression, presentation is delayed and patients are often lost to follow-up, only to present with advanced renal failure later on. We report a case of a young patient with pelvic lipomatosis who, after an initial diagnosis, was lost to follow-up for several years and then presented with uraemic encephalopathy. The case highlights the importance of regular follow-up and an early intervention before irreversible changes occur.

Adult↗
PubMed2000

Ets transcription factors and targets in osteogenesis.

Bone formation in vivo is a complex phenomenon whereby recruitment and replication of mesenchymal precursors of osteoblasts, differentiation into preosteoblasts, osteoblasts, and mature osteoblasts ultimately result in the accumulation and mineralization of the extracellular matrix. MC3T3-E1, a clonal osteoblastic cell line, was derived from mouse calvaria and undergoes an ordered and time dependent developmental sequence leading to formation of multilayered bone nodules over a 30 - 35 day period. This developmental pattern is characterized by the replication of preosteoblasts followed by growth arrest and expression of mature osteoblastic characteristics such as matrix maturation and eventual formation of multilayered nodules with a mineralized extracellular matrix. We have found that Ets1 is expressed in proliferating preosteoblastic cells whereas Ets2 is expressed by differentiating and mature osteoblasts. In addition, the expression of Ets1 can be induced in MC3T3-E1 and fetal rat calvaria cells by retinoic acid (RA) which is known to exert profound effects on skeletal growth and development, bone turnover, and induce specific cellular responses in bone cells. Thus the multiple functions of RA in bone cells are likely to be mediated in part by Ets1. Also, Ets2 transgenic mice develop multiple neurocranial, viserocranial, and cervical skeletal abnormalities. Significantly, these abnormalities are similar to the skeletal anomalies found in trisomy-16 mice and in humans with Down's syndrome, wherein the dosage of Ets2 is known to be increased. These results indicate that Ets2 has an important role in skeletal development and that Ets2 overexpression in transgenics is responsible for the genesis of the same type of skeletal abnormalities that are seen in Down's syndrome. Thus the genetic programs regulated by Ets1 and Ets2 may significantly affect the development and differentiation of osteoblasts, and in fact, Ets1 has been shown to interact with the 'quintessential' osteoblast transcription factor CbfA1. This review will examine in detail the role and possible targets of Ets1 and Ets2 in osteoblast differentiation and bone formation.

Animals↗
PubMed2000

Simian immunodeficiency virus-specific cytotoxic T lymphocytes and cell-associated viral RNA levels in distinct lymphoid compartments of SIVmac-infected rhesus monkeys.

Major histocompatibility class I-peptide tetramer technology and simian immunodeficiency virus of macaques (SIVmac)-infected rhesus monkeys were used to clarify the distribution of acquired immunodeficiency syndrome virus-specific cytotoxic T lymphocytes (CTL) in secondary lymphoid organs and to assess the relationship between these CTL and the extent of viral replication in the various anatomic compartments. SIVmac Gag epitope-specific CD8(+) T cells were evaluated in the spleen, bone marrow, tonsils, thymus, and 5 different lymph node compartments of 4 SIVmac-infected rhesus monkeys. The average percentage of CD8(+) T lymphocytes that bound this tetramer in all the different lymph node compartments was similar to that in peripheral blood lymphocytes in individual monkeys. The percentage of CD8(+) T cells that bound the tetramer in the thymus was uniformly low in the monkeys. However, the percentage of CD8(+) T cells that bound the tetramer in bone marrow and spleen was consistently higher than that seen in lymph nodes and peripheral blood. The phenotypic profile of the tetramer-binding CD8(+) T lymphocytes in the different lymphoid compartments was similar, showing a high expression of activation-associated adhesion molecules and a low level expression of naive T-cell-associated molecules. Surprisingly, no correlation was evident between the percentage of tetramer-binding CD8(+) T lymphocytes and the magnitude of the cell-associated SIV RNA level in each lymphoid compartment of individual monkeys. These studies suggest that a dynamic process of trafficking may obscure the tendency of CTL to localize in particular regional lymph nodes or that some lymphoid organs may provide milieus that are particularly conducive to CTL expansion. (Blood. 2000;96:1474-1479)

Animals↗
PubMed2000

Simian immunodeficiency virus (SIV)-specific CTL are present in large numbers in livers of SIV-infected rhesus monkeys.

The immunopathogenesis of AIDS-associated hepatitis was explored in the SIV/rhesus monkey model. The livers of SIV-infected monkeys showed a mild hepatitis, with a predominantly CD8+ T lymphocyte infiltration in the periportal fields and sinusoids. These liver-associated CD8+ T cells were comprised of a high percentage of SIV-specific CTL as defined by MHC class I/Gag peptide tetramer binding and Gag peptide epitope-specific lytic activity. There was insufficient viral replication in these livers to account for attracting this large number of functional virus-specific CTL to the liver. There was also no evidence that the predominant population of CTL were functionally end-stage cells trapped in the liver and destined to undergo apoptotic cell death in that organ. Interestingly, we noted that liver tetramer-binding cells showed an increased expression of CD62L, an adhesion molecule usually only rarely expressed on tetramer-binding cells. This observation suggests that the expression of specific adhesion molecules by CTL might facilitate the capture of these cells in the liver. These results demonstrate that functional SIV-specific CD8+ T cells are present in large numbers in the liver of chronically SIV-infected monkeys. Thus, the liver may be a trap for virus-specific cytotoxic T cells.

Animals↗
PubMed2000

Involvement of Ets transcription factors and targets in osteoblast differentiation and matrix mineralization.

The osteoblast-like MC3T3-E1 cell line provides an excellent in vitro model of bone development. This system undergoes three orderly time-dependent phases characterized by proliferating preosteoblasts, matrix accumulation by postmitotic differentiating osteoblasts, and mineralization of the matrix, which results in the formation of multilayered bone nodules. The Ets family transcription factors regulate genetic programs that affect the proliferation and differentiation of osteoblasts. Of the eight Ets family transcription factors examined by our laboratory, only Etsl and Ets2 were found to be expressed at significant levels in this osteogenic system. Etsl is expressed in proliferating preosteoblastic cells, whereas Ets2, silent during this phase, is expressed by differentiating and mature osteoblasts. In addition, the expression of Etsl can be induced in MC3T3-E1 and fetal rat calvaria cells by retinoic acid (RA) which is known to exert profound effects on skeletal growth and development and bone turnover and induce specific cellular responses in bone cells. Thus, the multiple functions of RA in bone cells are likely to be mediated in part by Etsl. We show that the expression of Ets2 precedes and then parallels osteopontin expression and that the OPN promoter contains Ets binding sites and is a transcriptional target of Ets2. In order to identify other potential Ets target genes, we analyzed promoter regions of genes revealed by serial analysis of gene expression as present in the differentiation stage. The functional analysis of these genes has the potential to provide much needed information as to their function in osteogenesis and mineralization of the extracellular matrix and in bone-related diseases.

Animals↗
PubMed2000

The Ets1 proto-oncogene is upregulated by retinoic acid: characterization of a functional retinoic acid response element in the Ets1 promoter.

The v-ets oncoprotein and its progenitor Ets1 belong to a family of transcription factors that are related by an 85 amino acid conserved DNA binding domain, the ets domain. Ets1 plays important role(s) in control of cell proliferation, differentiation and apoptosis. Abnormal expression of Ets1 could lead to disruption of these processes and contribute to development of malignancy. Retinoic acid (RA) inhibits proliferation, induces differentiation and regulates apoptosis in many different cell types. Here, we demonstrate that RA treatment increases the expression of Ets1 mRNA, but not that of Ets2, Elk1 or Fli1 in MC3T3-E1 cells. Ets1 induction is detectable after 4 h, can be maintained for at least 14 days, and is inhibited by Actinomycin D, which suggests that RA regulation of Ets1 occurs at the transcriptional level. The promoter region of Ets1 contains four retinoic acid response element (RARE) half sites located at -94, -152, -1765 and -2252 from the translation start site. We show that RARbeta is expressed by MC3T3-E1 cells in the presence of RA and demonstrate that it binds to the -94 RARE half site. Furthermore, RA induces transcription of Ets1 promoter-reporter constructs containing this RARE half site.

Cells, Cultured↗