Biomedical subjects

H Ben-Hur

Publications and source records attributed to H Ben-Hur.

At least 19 recordsLinked to original sources

PubMed1999

Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4.

Stem cell homing and repopulation are not well understood. The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 were found to be critical for murine bone marrow engraftment by human severe combined immunodeficient (SCID) repopulating stem cells. Treatment of human cells with antibodies to CXCR4 prevented engraftment. In vitro CXCR4-dependent migration to SDF-1 of CD34+CD38-/low cells correlated with in vivo engraftment and stem cell function. Stem cell factor and interleukin-6 induced CXCR4 expression on CD34+ cells, which potentiated migration to SDF-1 and engraftment in primary and secondary transplanted mice. Thus, up-regulation of CXCR4 expression may be useful for improving engraftment of repopulating stem cells in clinical transplantation.

ADP-ribosyl Cyclase↗

PubMed1999

Elevated serum alkaline phosphatase may enable early diagnosis of ovarian cancer.

A case of endometrioid ovarian carcinoma associated with elevated levels of serum placental-like alkaline phosphatase (PLAP) is presented. Two and a half years before a final diagnosis was made following explorative laparotomy, an incidental blood test revealed elevated alkaline phosphatase in the patient's serum. A thorough investigation for the source of this elevation was negative. Postoperative immunohistochemical staining of the tumor, showed diffuse stain with PLAP, along with gradual decline to normal values of serum total alkaline phosphatase. It is suggested, that whenever serum alkaline phosphatase is elevated due to unknown reason, an investigation including alkaline phosphatase isoenzymes, serum Ca-125, trans-vaginal pelvic sonogram and even diagnostic laparoscopy, should be considered in a search for early preclinical ovarian cancer.

Adenocarcinoma↗

PubMed1999

Estrogen and progesterone receptors in normal and varicose saphenous veins.

The presence of estrogen and progesterone receptors was investigated in the walls of normal and varicose veins. Cryostat sections from the saphenous veins of 29 normal individuals, and varicose and normal vein segments of 32 patients with varicose veins, were stained with anti-estrogen or anti-progesterone receptor antibodies. Nuclear stain intensity was scored by three independent observers. Receptors to both hormones were detected in the nuclear regions of the intima and media in females and males. In the adventitia, estrogen and the progesterone receptors were found only in nuclei of the vasa vasorum. Estrogen receptor levels were lower in non-varicose segments of varicose veins compared with normal veins. In varicose segments, estrogen receptors were more abundant than in the non-varicose parts of the same vein, especially in females. Similarly, progesterone receptor levels in the non-varicose portions were higher in females. These gender differences may be related to hormonal action. However, these differences may also be age related. These findings may be related to the involvement of sex-hormones in varicosis, by mechanisms as yet unknown.

Adult↗

PubMed1999

The chemokine SDF-1 stimulates integrin-mediated arrest of CD34(+) cells on vascular endothelium under shear flow.

The chemokine SDF-1 plays a central role in the repopulation of the bone marrow (BM) by circulating CD34(+) progenitors, but the mechanisms of its action remain obscure. To extravasate to target tissue, a blood-borne cell must arrest firmly on vascular endothelium. Murine hematopoietic progenitors were recently shown in vivo to roll along BM microvessels that display selectins and integrins. We now show that SDF-1 is constitutively expressed by human BM endothelium. In vitro, human CD34(+) cells establish efficient rolling on P-selectin, E-selectin, and the CD44 ligand hyaluronic acid under physiological shear flow. ICAM-1 alone did not tether CD34(+) cells under flow, but, in the presence of surface-bound SDF-1, CD34(+) progenitors rolling on endothelial selectin rapidly developed firm adhesion to the endothelial surface, mediated by an interaction between ICAM-1 and its integrin ligand, which coimmobilized with SDF-1. Human CD34(+) cells accumulated efficiently on TNF-activated human umbilical cord endothelial cells in the absence of SDF-1, but they required immobilized SDF-1 to develop firm integrin-mediated adhesion and spreading. In the absence of selectins, SDF-1 also promoted VLA-4-mediated, Gi protein-dependent tethering and firm adhesion to VCAM-1 under shear flow. To our knowledge, this is the first demonstration that SDF-1 expressed on vascular endothelium is crucial for translating rolling adhesion of CD34(+) progenitors into firm adhesion by increasing the adhesiveness of the integrins VLA-4 and LFA-1 to their respective endothelial ligands, VCAM-1 and ICAM-1.

Antigens, CD34↗

PubMed1999

Morphological and morphometric studies of the splenic antitumor immune response, elicited by liposome-covered soluble p53 kDa antigen, in chemically-induced rat colon cancer.

We evaluated the splenic morphometric changes in rats treated with carcinogen to study development of anti-cancer immune response. When liposome-covered soluble 53 kDa antigen (s53) was injected into these rats, significant tumor-suppression was seen and the percentage of tumor-free animals rose from 15.4% in non-vaccinated rats to 53.8%. In the spleens of carcinogen treated rats that did not develop tumors, activity of B lymphocytes increased significantly. This was manifested by the expansion of the germinal centers to 50.9% of the follicular area reflecting depletion of B cells, and the decrease of the mantle layer to 48.9% of the follicles. A similar picture was seen with T lymphocytes: the area of the marginal zone decreased to 55.2% of the T zone of the white pulp, and that of the periarterial lymph sheaths (PALS) to 33.6%. In tumor-bearing rats features of the immune decompensation were seen: the germinal centers increased to 96.5% of the follicular area, and the mantle layer and PALS decreased significantly. Vaccination prevented these effects, especially in tumor-bearing rats: the PALS occupies 30.4% of the white pulp and the marginal zone 56.1%, and the mantle layer occupied 58.1% of the follicular zone. Similar changes were found in vaccinated rats without tumors reflecting the compensatory character of the immune reaction in vaccinated rats. In conclusion, we found that treatment with carcinogen followed by vaccination with the s53-liposomes complex stimulated the activity of the splenic B, and to a lesser degree the T systems.

Animals↗

PubMed1999

Effects of low doses of carcinogen and different antibodies on the splenic lymphoid system of p53 transgenic mice: morphometric and immunohistochemical studies.

The role of the splenic immune system in the development of high sensitivity of p53 transgenic mice to low doses of carcinogen and vaccination was investigated immunohistochemically and morphometrically. Spleens were obtained from human p53 promoter-chloramphenicol acetyl transferase transgenic mice, grouped as follows: 1, untreated controls; 2, exposed to dimethylhydrazine (DMH); 3, and 4, vaccinated with polyclonal antibodies to soluble-53 kDa protein (s53); 5, vaccinated with monoclonal PAb DO1; 6, vaccinated with monoclonal PAb 421; 7, vaccinated with polyclonal alphaH-p53 antibody. Mice in groups 4-7 were treated with DMH after the course of vaccination. Six months later all the mice were tumor-free, but effects of the low dose carcinogen were distinct in the splenic immune system. They were mainly manifested in blast transformation: the total number of lymphocytes and lymphoblasts decreased to 56.5% of the controls. The total of lymphoid cells in the follicles (B zone) and periarterial lymph sheath (T zone) declined, reflecting moderate insufficiency of the spleen's lymphoid system. Vaccination of transgenic mice with antibodies to soluble-p53 elicited mainly a B system response, with lesser T system involvement. Only few signs of B system insufficiency were found in these mice. Vaccination of mice with different antibodies, with subsequent carcinogen treatment, caused changes in the spleen that were similar to those described for DMH alone, but varied with different anti-p53 antibodies. Vaccination with polyclonal antibodies to soluble-p53, or with monoclonal antibodies PAb DO1 or PAb 421, stimulated the splenic activity of T system, and therefore can decrease the tumorigenic effect of carcinogens.

1,2-Dimethylhydrazine↗

PubMed1999

Diagnostic dilemmas and current therapy of Fallopian tube cancer.

Primary tubal cancer, unlike ovarian cancer, is not routinely suspected preoperatively, and thus diagnosis and therapy are delayed. We have recently encountered two cases in which primary Fallopian tube cancer masqueraded as other lesions. One presented as a pelvic inflammatory process, the second as cervical cancer. Primary Fallopian cancer should be suspected by the clinician, even if the presenting symptoms are atypical. Chemotherapy with taxol and cisplatin was instituted following debulking surgery.

Adenocarcinoma↗

PubMed1999

Apoptosis and apoptosis-related proteins in the epithelium of human ovarian tumors: immunohistochemical and morphometric studies.

BACKGROUND: The origin of malignant ovarian tumors is the subject of considerable controversy, which may be resolved by elucidation of molecular mechanisms of tumorigenesis. Therefore we have undertaken the study of apoptosis in these tumors. METHODS: Apoptosis and the expression of its related proteins, Fas, Fas ligand (FasL), bcl-2 and p53, in epithelial cells of human ovarian tumors of different histological grades, were determined immunohistochemically and morphometrically. RESULTS: Apoptosis-related proteins were absent from ovarian epithelia of patients afflicted with non-cancerous diseases. In ovarian tumors, the distribution of individual proteins varied, and depended on the grade and type of tumor. Fas and FasL were highly expressed in all tumors, while epithelial cells expressing bcl-2 were abundant in benign tumors, but their numbers significantly dwindled with the progression of malignancy. Cells expressing p53 were found in borderline tumors, and their numbers increased with malignancy, inverse of bcl-2 expression. Apoptotic tumor cells were scarce in borderline tumors and abundant in carcinomas. Grouping apoptosis was found in approximately 60% of the carcinomas. CONCLUSIONS: The initial development of ovarian tumors is accompanied by high epithelial expression of Fas, FasL and bcl-2 proteins, while apoptosis and p53 proteins are detected only at later stages of tumorigenesis.

Apoptosis↗

PubMed1999

Transplacental effects of IgG generated against soluble 53 kDa protein on the splenic lymph system of rat progeny exposed to carcinogen: rate of apoptosis, proliferation of lymphocytes and expression of Fas and Fas ligand proteins.

BACKGROUND: We have previously shown that vaccination with IgG generated against the soluble 53 kDa (s53) protein modified the splenic response to carcinogens. Here we studied whether such immunization could affect the splenic lymphatic system of the offspring. METHODS: Offspring of normal female rats or of rats immunized with anti-s53 IgG were exposed to a carcinogen (dimethyl-benz(a)antracene). After 4 months, their spleens were resected and evaluated immunohistochemically for lymphocyte proliferation, apoptosis and apoptosis-related proteins (Fas and Fas ligand), in tumor-free and tumor-bearing animals. RESULTS: Spleens of progeny of unvaccinated rats had a significant decrease in the areas of follicles, germinal centers and the mantle layer after exposure to carcinogens, while maternal vaccination resulted in a significant expansion of the progeny's splenic follicles and germinal centers, the zones of B cell proliferation. The area of periarterial lymph sheaths (PALS) expanded in these offspring, reflecting activation of the T-zone. Maternal vaccination also resulted in a significant rise of Fas ligand-positive lymphocytes in the follicles and PALS of their tumor-free offspring. Tumorigenesis stimulated the Fas activity of B and T cells in the spleens, and this was much enhanced by maternal vaccination. CONCLUSIONS: Maternal vaccination before pregnancy results in altered morphological and functional attributes of the splenic immune system of the offspring. This increased immunoreactivity could reduce the risk of tumors in progeny of vaccinated mothers.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1997

Engraftment of human kidney tissue in rat radiation chimera: II. Human fetal kidneys display reduced immunogenicity to adoptively transferred human peripheral blood mononuclear cells and exhibit rapid growth and development.

BACKGROUND: Transplantation of human kidney tissue under the kidney capsule of immunodeficient animals (severe combined immunodeficiency [SCID]/Lewis and SCID/nude chimeric rats), and the subsequent intraperitoneal infusion of allogeneic human peripheral blood mononuclear cells (PBMC), results in a rapid and consistent human renal allograft rejection. We investigated the consequences of grafting human fetal kidney fragments instead of the adult tissue. METHODS: The development of human fetal kidney tissue and its interaction with allogeneic human PBMC in chimeric rats were analyzed by histology, immunohistochemistry, and in situ hybridization. RESULTS: We report successful establishment of human fetal kidney to SCID/Lewis and SCID/nude chimeric rats. The intrarenal human fetal renal implants displayed rapid growth and maintained numerous developing glomeruli and tubular structures up to 4 months after transplantation. In contrast to the adult human kidney, infusion of allogeneic human PBMC resulted in either minimal human T-cell infiltration or abundant nonrejecting T-cell infiltrates, characterized by a reduced number of T cells of the CD45RO+ or HLA-DR+ subsets, both leading to less tissue destruction as well as to continued growth of the human fetal renal tissue. This observation was found to be related to the reduced protein expression of tissue HLA class I and II, intercellular adhesion molecule 1, and vascular adhesion molecule 1 in the fetal grafts compared with the adult grafts. Lack of tissue expression of Fas ligand in the fetal grafts suggests that the latter does not contribute to the delayed rejection of human fetal kidneys. CONCLUSIONS: Our model should be useful for the study of human fetal renal development and the human alloresponse against fetal tissue.

Adoptive Transfer↗

PubMed1997

Subcutaneous, omentum and tumor fatty acid composition, and serum insulin status in patients with benign or cancerous ovarian or endometrial tumors. Do tumors preferentially utilize polyunsaturated fatty acids?

The relationships between the fatty acid composition of cancerous endometrium and ovary, and peripheral adipose tissues were studied in Israeli Jewish women, and are presented together since no differences were shown between them. The results suggest a mobilization of linoleic acid from subcutaneous and omental depots and its incorporation into tumors accompanied by a high degree of desaturation. High blood insulin concentrations characterized patients with stage I and II disease, and low concentrations characterized patients with advanced degrees of malignancy.

Adipose Tissue↗

PubMed1997

Metastasizing placental site trophoblastic tumor: immunohistochemical and DNA analysis. 2 case reports and a review of the literature.

Placental-site trophoblastic tumor (PSTT) is a rare form of gestational trophoblastic neoplasia. The clinical behaviour of PSTT is usually benign, but sometimes it can be highly malignant with late recurrence and metastasis. We describe two cases of PSTT with pulmonary metastasis in patients aged 35 and 29 years respectively. The mitotic rate was elevated to 9 and 13 mitotic figures per 10 high-power fields respectively. Immunohistochemical staining showed a predominance of human placental lactogen (hPL) positive cells when compared with human chorionic gonadotropin (hCG) reactive cells in one case, and a reverse pattern in the other one. DNA measurement in one case showed an aneuploid tumor with a tetraploid DNA peak. The clinical behaviour of PSTT remains unpredictable, and there are no reliable means of predicting clinical outcome.

Adult↗

PubMed1997

Estrogen, progesterone and testosterone receptors in human fetal cartilaginous tissue: immunohistochemical studies.

Computerized image analysis was used to study the distribution in cartilage of receptors to estrogen, progesterone, and testosterone during human fetal development. We have examined three histologically distinct cell groups (hypertrophic, proliferating, and reserve zones) in long bones, vertebrae, and trachea from 19 fetuses. Comparisons were made across gender and gestational age. Contrasting with controls, we examined the density of receptors, the size of the nuclear area in which the receptors were detected, the number of hormone receptor-bearing cells, and the total receptor quantity per sample. We found that estrogen, progesterone, and testosterone receptors were detected in the nuclei of all cell types, in both female and male embryonic cartilaginous tissue. Gender differences were small and inconsistent. Changes associated with gestational age depicted a pattern of hormone receptor manifestation, shifting from the immature cell types to more differentiated cells. This was evident from the receptor densities and from the cellular area in which receptors were sighted. These dynamics are accompanied by a general increase in receptor content per sample, brought about by the concomitant increase in receptor containing area size and cell number. The increase in receptor levels seems to reflect the maturation and growth of the fetal skeleton.

Cartilage↗

PubMed1997

Distribution of glutamate transporter subtypes during human brain development.

In the mature brain, removal of glutamate from the synaptic cleft plays an important role in the maintenance of subtoxic levels of glutamate. This requirement is handled by a family of glutamate transporters, EAAT1, EAAT2, EAAT3, and EAAT4. Due to the involvement of glutamate also in neuronal development, it is believed that glutamate transport plays a role in developmental processes as well. Therefore, we have used immunohistochemical and immunoblot analysis to determine the distribution of the four glutamate transporters during human brain development using human pre- and postnatal brain tissue. Regional analysis showed that each transporter subtype has a unique distribution during development. EAAT2 was the most prominent glutamate transporter subtype and was highly enriched in cortex, basal ganglia, cerebellum, and thalamus in all ages examined. EAAT1 immunoreactivity was lower than that of EAAT2, with predominant localization in cortex, basal ganglia, hippocampus, and periventricular region. EAAT3 was located mainly in cortex, basal ganglia, and hippocampus, and EAAT4 was found only in cortex, hippocampus, and cerebellar cortex. The distinct regional distribution of various EAAT subtypes and also the transient expression of specific EAAT subtypes during development suggest multiple functional roles for glutamate transporters in the developing brain.

ATP-Binding Cassette Transporters↗

PubMed1997

Immunoglobulin A in the epithelium of the respiratory tract and intrahepatic bile ducts of fetuses and newborns with pneumonia and sepsis.

The level of different immunoglobulins (IgA, IgG, IgM) in the tissues of 28 late fetuses and newborns was studied with peroxidase-labeled monoclonal antibodies. IgA+ and IgM+ lymphocytes were found in the spleen, lymph nodes and sometimes in the liver. IgG+ lymphocytes were not found. A high level of IgA+ material was found in the epithelium of the trachea, the epithelium and submucosal glands of the bronchi, but not the bronchioles, and in the epithelium of hepatic bile ducts and in their lumina. Such IgA is considered to be secretory--sIgA. Secretory IgA-containing epithelial cells appeared at 20 to 21 weeks of gestation; their number increased from 2.5 cells/10,000 microns2 in 23- to 26-week-old fetuses, to 8 cells/10,000 microns2 in 36- to 40-week-old fetuses. Secretory IgG and IgM were not detected. In fetuses with pneumonia or sepsis, the number of IgM+ and IgA+ lymphocytes increased significantly. IgM+ lymphocytes appeared not only in the spleen and lymph nodes, but also in the lungs. In such cases, the number of sIgA-containing epithelial cells in the trachea, bronchi and intrahepatic bile ducts decreased, sometimes completely disappearing. The amount of IgA+ material in the lumina of these organs increased, reflecting an intensification of sIgA secretion during infections. The presence of a marked amount of sIgA in fetuses from week 20 of gestation is considered to reflect the high importance of this immunoglobulin against normal contamination by microbes after birth, and to evidence the early maturation of the immune system.

B-Lymphocytes↗

PubMed1997

Serological and immunohistochemical determinations of p53 protein in diagnosis of endometrial cancer: a comparative study.

BACKGROUND: The role of different methods for the determination of p53 protein was evaluated for the detection of endometrial cancer in humans. METHODS: p53 antigen was detected immunohistochemically in the cell nuclei of endometrial tumors and serologically in the serum of the same patients. The high performance liquid chromatography (HPLC) technique was used to measure serum levels of p53 protein after its partial purification on gel fiberglass affinity chromatography columns. RESULTS: Image analysis of cellular concentrations of p53 protein revealed an increase from 12% in hyperplastic endometrium to 74% in adenocarcinomas. Image analysis has also revealed a strong correlation between cellular concentrations of p53 antigen and tumor grade (r = 0.54). Visual cell determination of p53 antigen was effective mainly among patients with benign lesions (r = 0.61). There was a positive correlation between cellular concentration of p53 protein in tumor tissue and its serum level in cancer patients (r = 0.44). The serum level of the cytoplasmic form of p53 antigen significantly increased in cancer patients (3 mg/ml) compared to the concentration in patients with benign disorders (0.7 mg/ml); a consequence of its higher concentration in tumor cells. Serum level of p53 antigen was highly active both in patients with non-cancerous lesions (r = 0.42) and in patients with cancer (r = 0.51). Diagnostic significance of tissue concentrations of estrogen and progesterone applies only to cancer patients: coefficients of correlation between these parameters and tumor gradation were 0.58 and 0.89, respectively. CONCLUSIONS: Serum determination of cytoplasmic p53 antigen can reveal this oncoprotein in the early stages of cancer, or even foretell its development.

Adenocarcinoma↗

PubMed1996

Cytogenetic analysis of fetal chondrocytes: a comparative study.

Progress in the prevention and prenatal detection of birth defects has led to a relative increase in the number of interruption of pregnancies associated with chromosomal abnormalities. There is an inverse relationship between the rate of success of fetal cell cultures and the interval between fetal demise and the initiation of culture. This report describes the cytogenetic analyses of cultured fetal chondrocytes compared with tissue cultures of fetal skin, fetal membranes, and placenta. The results show that cells obtained from the fetal chondrocostal junction and/or patella from missed abortions, intrauterine fetal deaths, or stillbirths can be cultured and successfully karyotyped. Since cartilage cells remain viable for some time after fetal demise, the culture of fetal chondrocytes is a complementary method for fetal chromosome analysis, especially in cases of tissue maceration after fetal demise. The success rate of chondrocyte cultures is similar to that of conventional fetal tissue cultures.

Biopsy↗

PubMed1996

Hyperestrogenemia and presence of estrogen receptors associated with an epithelial ovarian tumor of low malignant potential.

An 80-year-old woman presented with breast congestion, tenderness and pain. Mammography was normal. Circulating estradiol was markedly elevated, while LH and FSH were low. Pelvic examination and imaging revealed an ovarian mass which was extirpated during total abdominal hysterectomy and bilateral salpingo-oophorectomy. Histopathology revealed an ovarian mucinous cystadenocarcinoma of low malignant potential, stage 1. The tumor was positively stained for estrogen receptors. Estradiol levels returned to normal post-operatively, with a corresponding adjustment of LH/FSH. Possible autocrine steroid production is discussed.

Aged↗