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Biomedical subjects

Alexander Marks

Publications and source records attributed to Alexander Marks.

25 records · Page 2Linked to original sources
PubMed2002

Enhanced epileptogenesis in S100B knockout mice.

S100B is a small calcium- and zinc-binding protein expressed by astrocytes in the central nervous system. Here, we examined the role of S100B in epileptogenesis using an amygdala kindling paradigm comparing S100B knockout mice with their wild-type counterparts. Astrocyte activation following kindling, assessed by glial fibrillary acidic protein expression in the hippocampus and amygdala, was similar in wild-type and knockout mice. In addition, wild-type and knockout mice did not have substantially different afterdischarge thresholds. However, knockout mice kindled more rapidly and exhibited more severe seizures. These results implicate normal levels of S100B in the attenuation of epileptogenesis.

Amygdala↗
PubMed2002

Regulation of the S100B gene by alpha 1-adrenergic stimulation in cardiac myocytes.

We previously reported that S100B, a 20-kDa Ca(2+)-binding homodimer, inhibited the postinfarct myocardial hypertrophic response mediated by alpha(1)-adrenergic stimulation through the protein kinase C (PKC) signaling pathway. In the present study, we examined whether the same pathway induced the S100B gene, supporting the hypothesis that S100B is a feedback negative regulator of this pathway. We transfected cultured neonatal rat cardiac myocytes with a luciferase reporter gene driven by the maximal human S100B promoter and progressively shorter segments of this promoter sequentially deleted from the 5' end. We identified a basic promoter essential for transcription spanning 162 bp upstream of the transcription initiation site and positive (at -782/-162 and -6,689/-4,463) and negative (at -4,463/-782) myocyte-selective regulatory elements. We showed that the basic and maximal S100B promoters were activated specifically by alpha(1)-adrenergic agonists through the alpha(1A)-adrenergic receptor, but not by any other trophic hormonal stimuli. The activation of the S100B promoter was mediated through the PKC signaling pathway. Transcription enhancer factor-1 (TEF-1) and related to TEF-1 (RTEF-1) influenced transcription from the maximal, but not the basic, promoter implicating active MCAT elements upstream from the basic promoter. Acting in opposing fashions, TEF-1 transrepressed the S100B promoter and RTEF-1 transactivated the promoter. Our results suggest that alpha(1)-adrenergic stimulation induces the S100B gene after myocardial infarction through the PKC signaling pathway and that this induction is modulated by TEF-1 and RTEF-1.

Adrenergic alpha-Agonists↗
PubMed2002

Altered expression of connexins 26 and 43 in Sertoli cells in seminiferous tubules infiltrated with carcinoma-in-situ or seminoma.

The expression of connexins (cx) 26 and 43 in testis infiltrated with carcinoma-in-situ (CIS) or seminoma was examined to gain insight into the relationship between aberrant gap junctional communication and spermatogenic impairment in the neoplastic testis. In uninvolved tubules with normal spermatogenesis, cx43 immunostaining was localized to the Sertoli-Sertoli junctional complex and cx26 was absent. In contrast, infiltrated tubules with spermatogonial arrest or CIS-only were negative for cx43, but displayed strong intracytoplasmic Sertoli cell staining for cx26. The Sertoli cells in these tubules re-expressed cytokeratin 18 (ck18), signifying a reversion to a less differentiated state. Western blot analysis for cx43 revealed a single immunoreactive band at 43 kD (normal spermatogenesis) and three bands at 43, 41, and 39 kD (impaired spermatogenesis with CIS or seminoma). For cx26, a doublet band at 26/28 kD (normal spermatogenesis) and an additional doublet band at 52/54 kD (impaired spermatogenesis with CIS or seminoma) were observed. The altered expression of cx26 and cx43 in Sertoli cells in testes infiltrated with CIS or seminoma suggests that a derangement in intercellular communication between Sertoli cells and between Sertoli cells and germ cells may play a role in the resulting spermatogenic impairment and possibly in the proliferation and neoplastic progression of CIS cells.

Adult↗
PubMed2002

Monoclonal antibody D2-40, a new marker of lymphatic endothelium, reacts with Kaposi's sarcoma and a subset of angiosarcomas.

There is controversy over the histogenesis of Kaposi's sarcoma (KS) from lymphatic or blood vessel endothelium. D2-40 is a novel monoclonal antibody to an Mr 40,000 O-linked sialoglycoprotein that reacts with a fixation-resistant epitope on lymphatic endothelium. We sought to establish the selectivity of D2-40 for lymphatic endothelium in normal tissues and compare its reactivity with the expression of the widely used vascular endothelial marker CD31 in a series of 62 formalin-fixed and paraffin-embedded vascular lesions including KS. In normal tissues, D2-40 stained the endothelium of lymphatic channels but not of blood vessels, including arteries and capillaries defined by reactivity with the blood vessel endothelial marker PAL-E. In our series of vascular lesions, D2-40 stained lymphangiomas (10/10), benign tumors of undisputed lymphatic origin, but not benign neoplasms or tumorlike lesions of blood vessel origin, including hemangiomas (0/10), glomus tumors (0/3), angiolipomas (0/2), pyogenic granulomas (0/2), vascular malformations (0/2), hemangiopericytoma (0/1), or hemangioendothelioma (0/1). D2-40 stained all cases of cutaneous KS (24/24) at all stages of progression, including patch, plaque, and nodular stages, supporting the concept that this disease originates from a cell type capable of undergoing lymphatic differentiation. D2-40 also stained three of seven angiosarcomas, indicating that a subset of these tumors can undergo at least partial differentiation along the lymphatic endothelial lineage and could be classified as lymphangiosarcomas. In comparison, CD31 was expressed in all benign and malignant vascular lesions, except for glomus tumors (0/3) and 5/10 lymphangiomas, in which staining was absent. We conclude that D2-40 is a new selective marker of lymphatic endothelium in normal tissues and vascular lesions and is valuable for studying benign and malignant vascular disorders in routinely processed tissue specimens.

Antibodies, Monoclonal↗
PubMed2002

Androgen modulation of adhesion and antiadhesion molecules in PC-3 prostate cancer cells expressing androgen receptor.

The metastatic spread of cancer cells involves a complex process of detachment via antiadhesion molecules and attachment and migration through adhesion. In the prostate, androgens are generally thought to contribute to the development and progression of prostate cancer by promoting cell proliferation and survival through poorly defined mechanisms. We have reported previously that PC-3 prostate cancer cells, which are unresponsive to androgens, show androgen-dependent detachment and ultimately apoptosis when stably transfected with a full-length human androgen receptor (AR) cDNA. We now demonstrate that treatment of these cells with 5alpha-dihydrotestosterone (DHT) for 24 or 48 h increased the expression of antiadhesion mucin MUC-1 at the cell surface as detected by flow cytometry with two independent antibodies. This increase in protein was concordant with up-regulation of MUC-1 mRNA in the AR-transfected PC-3 sublines, as determined by quantitative RT-PCR. Treatment with DHT for 48 h also down-regulated the cell surface expression of alpha2beta1-integrin but having little effect on the levels of alpha3beta1- and alpha5beta1-integrins. Androgen also decreased, in a dose-dependent manner, the adhesion of AR-transfected PC-3 cells to collagen type I, which was shown to be specifically inhibited by blocking antibody to alpha2beta1-integrin. The present data demonstrate that DHT can modulate expression of adhesion and antiadhesion molecules and suggest that this effect of androgen might contribute to prostate cancer progression.

Cell Adhesion↗
PubMedDate not supplied

Biological significance of occult micrometastases in histologically negative axillary lymph nodes in breast cancer patients using the recent American Joint Committee on Cancer breast cancer staging system.

The biological significance of occult metastases in axillary lymph nodes of breast cancer patients is controversial. The purpose of the study was to determine the prognostic significance of occult micrometastases using the current American Joint Committee on Cancer (AJCC) staging system in a cohort of women with node-negative breast cancer, of whom 5% received adjuvant systemic therapy and who all had long-term follow-up. We studied a cohort of 214 consecutive histologically node-negative breast cancer patients with a median follow-up of 8 years. Blocks of the axillary lymph nodes were assessed for occult micrometastases by examination of an additional hematoxylin-eosin-stained slide and by immunohistochemical staining using an antibody to low molecular weight keratin. Occult metastases were classified according to the sixth edition of the AJCC cancer staging manual. We examined the prognostic effects of occult micrometastases and other clinicopathologic features on recurrence outside the breast with disease-free interval (DFI) and survival from breast cancer with disease-specific survival (DSS). Cytokeratin-positive tumor cells were identified in the lymph nodes in 29 of 214 cases (14%). Two cases had isolated tumor cells and no cluster larger than 0.2 mm [pN0(i+)], whereas 27 of 214 (13%) had micrometastases (larger than 0.2 mm and <or=2.0 mm] (pN1mi). None of the cases had macrometastases. With median 8 years follow-up, occult micrometastases were not significantly associated with any of the clinicopathologic features. In addition, occult micrometastases were not significantly associated with DFI or DSS and thus were not included in the multivariate analysis. On multivariate analysis, lymphovascular invasion was significantly associated with DFI (p < 0.001) and DSS (p = 0.02), whereas percentage S-phase was significantly associated with DSS (p = 0.02). This study, in which 95% of patients did not receive adjuvant systemic therapy, suggests that breast cancer patients with occult micrometastases in axillary lymph nodes have a similar prognosis to those with no micrometastases. This information is important with regard to the practice of sentinel node biopsy and subsequent axillary node dissection and to the decision to administer adjuvant therapy based on detection of micrometastases in lymph nodes.

Axilla↗