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Biomedical subjects

L Braun

Publications and source records attributed to L Braun.

At least 19 recordsLinked to original sources
PubMed1992

Regulation of growth and gene expression in human papillomavirus-transformed keratinocytes by transforming growth factor-beta: implications for the control of papillomavirus infection.

Cervical carcinogenesis is a multistep process that appears to be initiated by infection of squamous epithelial cells in the cervix with one of a limited number of human papillomavirus (HPV) types. However, the mechanisms involved in the evolution of benign, HPV-induced lesions to malignancy have not yet been fully elucidated. Transforming growth factor-beta (TGF-beta), a multifunctional growth factor produced by cells in the skin, inhibits the proliferation of foreskin and cervical keratinocytes in vitro. We examined the effects of TGF-beta on growth and virus early-gene expression in cell lines immortalized by two HPV types associated with cervical carcinogenesis as well as the expression of TGF-beta 1 mRNA transcripts in normal and HPV-positive cells in vivo and in vitro. We found that normal and HPV-positive cells expressed similar levels of TGF-beta 1 mRNAs and exhibited similar patterns of responsiveness to three isoforms of TGF-beta in both monolayer and modified organotypic cultures. Of particular interest is our finding that the expression of the E6 and E7 early viral transforming regions of both HPV16 and HPV18 was reversibly and rapidly inhibited by TGF-beta. In one HPV16-positive cell line examined in detail, inhibition of HPV expression required protein synthesis and occurred at the level of transcription. HPV-immortalized cells selected for resistance to in vitro differentiation signals remained sensitive to TGF-beta-mediated growth inhibition. These results, showing that both growth and virus gene expression in HPV-transformed cells were responsive to TGF-beta, suggest that endogenous growth factors produced by different cell types in squamous epithelium may play a role in the progression of cervical neoplasia.

Blotting, Northern↗
PubMed1991

A role for transforming growth factor-beta 1 in regulating natural killer cell and T lymphocyte proliferative responses during acute infection with lymphocytic choriomeningitis virus.

The role of transforming growth factor beta 1 (TGF-beta 1) in regulating NK and T cell proliferation during acute viral infections was investigated. After infection of mice with lymphocytic choriomeningitis virus, NK cell proliferation peaks on day 3 and subsides by days 5 to 7 postinfection, whereas T cell proliferation peaks on day 7 and declines by days 9 to 14 postinfection. As TGF-beta 1 has been shown to inhibit lymphocyte proliferation in culture, the production and function of TGF-beta 1 during infection was evaluated in this model. Northern blot analysis demonstrated that the accumulation of TGF-beta 1 transcripts remained relatively constant in total splenic leukocytes during infection. The Mv 1 Lu mink lung cell bioassay was modified and used to evaluate the production of biologically active TGF-beta 1 during infection. Media conditioned with splenic leukocytes isolated from infected mice contained factors that inhibited DNA synthesis by the Mv 1 Lu cells. Low levels of inhibition were observed with conditioned media prepared on day 3 postinfection and high levels of inhibition were observed with conditioned media prepared on days 5 through 14 postinfection. Neutralization with antibodies specific for TGF-beta 1 demonstrated that TGF-beta 1 contributed to the inhibitory activity. As TGF-beta 1 was produced at times coinciding with the decline in NK cell proliferation, the TGF-beta 1 sensitivity of in vivo-elicited NK cells was evaluated. In vitro and in vivo studies demonstrated that NK cell proliferation was extremely sensitive to inhibition by TGF-beta 1. In culture, TGF-beta 1 had an ID50 of 8 pg/ml for inhibiting DNA synthesis by blast NK cells. In vivo, administration of a total of 0.18 micrograms of TGF-beta 1 resulted in a 93% inhibition of NK cell-mediated lytic units per spleen on day 3 postinfection. The inhibition was a result of a block in NK cell proliferation, as administration of TGF-beta 1 profoundly suppressed the appearance of blast size NK cells and the incorporation of [3H] thymidine by NK cell-enriched, blast lymphocyte populations on day 3 postinfection. In contrast to NK cell proliferation, T cell proliferation was not inhibited by up to 100-fold higher concentrations of the factor in vitro or in vivo. Taken together, these data demonstrate that TGF-beta 1 is an important regulator of NK cell proliferation in vivo. Furthermore, the results indicate that differential sensitivity to TGF-beta 1 may contribute to the coordination of NK and T cell responses during viral infections.

Acute Disease↗
PubMed1991

Growth arrest induced by transforming growth factor beta 1 is accompanied by protein phosphatase activation in human keratinocytes.

Protein phosphorylation and dephosphorylation are involved in regulation of cell growth. We tested the hypothesis that the growth inhibitory effect of transforming growth factor beta 1 (TGF-beta 1) involves activation of protein phosphatases. Exposure of human keratinocytes in culture to 400 pM TGF-beta 1 for 48 h led to 80% inhibition of DNA synthesis as measured by nuclear labeling. Incubation of cultured keratinocytes with 400 pM TGF-beta 1 rapidly activated (within 30 min) protein serine/threonine phosphatase, measured using phosphorylase as a substrate. Based on several criteria, including neutralization of activity with specific antibodies and inhibitor-2, TGF-beta 1-activated phosphorylase phosphatase was identified as protein phosphatase 1. TGF-beta 1 did not have rapid effects on protein serine/threonine phosphatase activity (type 2A) measured with histone phosphorylated by protein kinase C or on protein tyrosine phosphatase activity. However, protein tyrosine phosphatase was activated at 48 h, coincident with growth arrest. Differentiation, induced by the combination of TGF-beta 1 plus calcium or by serum, was not accompanied by further serine/threonine or tyrosine phosphatase activation. We conclude that induction of growth arrest in keratinocytes by TGF-beta 1 involves acute activation of protein phosphatase 1, while activation of protein tyrosine phosphatase may represent an additional mechanism for maintaining cells in a growth-arrested state.

Cell Differentiation↗
PubMed1991

[Rectal carcinoma. Analysis of 10-year results].

Between 1974 and 1979 139 patients with rectal cancer have been operated. Operative mortality was 14.4%. The fate of all patients was followed during 10 to 16 years. 46.8% of of patients died from recurrencies and metastases after a medium of 27.5 months. 3.6% died from another malignancy, 15.8% from other unrelated diseases. The 10-year survival rate is 22.3%; 19.4% of all patients are still alive with a mean survival time of 155 months. Prognosis depends mainly on tumour stage. No patient with recurrencies or metastases survived 10 years or longer.

Adult↗
PubMed1991

[Surgical therapy of ulcer disease. Early and late results of elective and emergency interventions].

Between 6/1974 and 12/1988 910 patients with peptic ulcer disease have been treated operatively. In 523 cases a resection, gastroenterostomy resp. ligation of a bleeding ulcer, in 160 cases with duodenal ulcers a vagotomy, and in 227 cases with perforated ulcers simple closure or primary resection have been performed. During this study the percentage of female patients rose from 32.0 to 39.7. There was also an increase of the mean age of the patients. Operative mortality rate was 7.3% for resection, GE resp. ligation of a bleeding vessel, 0.6% for vagotomies, and 16.3% for perforated ulcers. The fate of all patients was followed regularly. In patients operated before 1985--with a follow-up of 5-16 years--reoperations were necessary in 6.0% following resection, gastroenterostomy resp. ligation, in 7.7% following vagotomy, and in 21.3% following simple closure or primary resection of a perforated ulcer.

Adult↗
PubMed1991

[Preventive operations in hernia].

Between 1986 and 1990 1311 inguinal or femoral, 215 abdominal-wall, and 20 hiatal hernias were treated operatively at the Department of Surgery in Detmold. The operations were classified as follows: elective in 87.1%, in conjunction with other operations in 6.1%, and as emergency in 6.9%. Postoperative mortality was 0.1% in elective surgery, but rose 85-fold to 8.5% in emergencies. Hernias therefore should nearly always be treated by elective surgery.

Adolescent↗
PubMed1991

[Incidence of ulcer disease among patients of the Detmold Surgical Clinic 1949-1989].

Between 1949 and 1989 2,042 patients with peptic ulcer disease were treated operatively. The incidence of operations increased markedly after 1949, reached a summit from 1964 to 1978, and decreased thereafter steadily. Different from this trend there was a continuous rise in operations for peptic ulcers in women since 1949 in particular in ulcus perforations. Moreover it could be demonstrated that the need for surgery because of severe complications of ulcus disease effects mainly elderly patients.

Aged↗
PubMed1990

Differential response of nontumorigenic and tumorigenic human papillomavirus type 16-positive epithelial cells to transforming growth factor beta 1.

The transforming growth factor (TGF) beta s are multifunctional polypeptide growth factors with diverse biological effects, including inhibition of epithelial cell proliferation both in vitro and in vivo. To investigate the possible role of TGF beta 1 in the regulation of papillomavirus infection and papillomavirus-associated transformation, we compared the response to TGF beta 1 of normal keratinocytes, human papillomavirus, type 16 (HPV 16)-positive-immortalized keratinocytes (nontumorigenic), and HPV 16-positive cervical carcinoma cells (tumorigenic) with respect to DNA synthesis and protooncogene expression. All HPV 16-immortalized cell lines were nearly as inhibited by TGF beta 1 as normal keratinocytes, whereas two cervical carcinoma cell lines (Caski and Siha) were refractory to growth inhibition by TGF beta 1. Cell surface receptors for TGF beta 1 were present on both normal and carcinoma cell lines. In all cases, growth inhibition by TGF beta 1 was accompanied by suppression of Steady-state levels of c-myc mRNA. In contrast, TGF beta 1 induced the expression of c-jun mRNA transcripts in normal, immortalized, and tumorigenic cells. We also studied the effect of TGF beta 1 on HPV 16 mRNA expression. Steady-state levels of HPV 16 mRNA transcripts were suppressed by TGF beta 1 in the nontumorigenic HPK cells but were unaffected in the tumorigenic lines. These findings suggest that TGF beta 1 may be an in vivo modulator of HPV infection and that loss of responsiveness to this growth inhibitory signal may be involved in HPV-associated malignant transformation.

Cell Division↗
PubMed1990

Induction of replicative competence ("priming") in normal liver.

We have used a system of nutritional manipulation to investigate whether hepatocytes of the normal liver can be primed for replication in vivo. In this system, rats that are denied protein for 3 days undergo a burst of hepatic DNA synthesis and mitosis when they are refed amino acids, while normally fed or starved rats do not respond. To determine if hepatocytes of protein deprived (PD) rats have been "primed" for replication, we examined changes in protooncogene expression in livers of PD rats to see if they would mimic the pattern of gene expression that is induced early after partial hepatectomy. c-jun, c-myc, and p53 mRNAs were elevated in livers of PD rats, while c-fos and c-ras genes were not expressed. The administration of amino acids to PD rats stimulated hepatic DNA synthesis in a shorter period than is required after partial hepatectomy and induced p53 and c-ras expression. In culture, hepatocytes from PD rats had higher levels of c-myc mRNA, underwent morphological changes more rapidly, and reached maximum rates of DNA synthesis earlier than normal hepatocytes. In both normal and primed hepatocyte cultures, transforming growth factor alpha stimulated DNA synthesis more effectively than epidermal growth factor. We conclude that hepatocytes pass through a priming stage before they proliferate and that replicative competence without DNA synthesis can be induced in hepatocytes in the normal liver.

Amino Acids↗
PubMed1990

Expression of hepatocyte and oval cell antigens in hepatocellular carcinomas produced by oncogene-transfected liver epithelial cells.

We have established an in vivo/in vitro system in which epithelial cells ("oval cells") isolated from livers of rats fed a carcinogenic diet for a very brief period are placed in culture and transfected with an oncogene. Injection s.c. into nude mice of oval cells transfected with the activated c-Ha-ras (EJ oncogene) produces tumors with morphological features of differentiated hepatocellular carcinomas. Using monoclonal antibodies that can recognize hepatocyte, oval cell, and tumor antigens, we investigated the expression of these antigens in oval cells in culture, transfected with either the EJ oncogene or the normal c-Ha-ras allele and in tumors derived from the oncogene-transfected cells. We show that EJ-transfected cells and most particularly the tumors they produce expressed hepatocyte and oval cell antigens not detectable in untransfected cells or cells transfected with the normal c-Ha-ras gene. Furthermore, we found that in cloned tumor cells, the expression of hepatocyte antigens could be induced by changes in culture conditions and was accompanied by a decrease in the expression of oval cell markers. Trabecular hepatocellular carcinomas had higher reactivity toward monoclonal antibodies recognizing hepatocyte antigens while tumors with glandular architecture reacted predominantly with monoclonal antibodies against oval cells. We conclude that, in addition to its tumorigenic effect, the EJ oncogene induced the differentiation of tumor cells toward the hepatocyte lineage. In addition, the data provide further confirmation that oval cells can serve as progenitors of differentiated hepatocellular carcinomas.

Animals↗
PubMed1990

Null alleles of human complement C4. Evidence for pseudogenes at the C4A locus and for gene conversion at the C4B locus.

The two genes for the C4A and C4B isotypes of the fourth component of human complement are located in the MHC class III region. Previous studies have demonstrated the unusual expression of C4 genes in the form of aberrant or duplicated haplotypes. Null alleles of C4A or C4B (AQ0 or BQ0) have been defined by the absence of gene products and occur at frequencies of 0.1-0.3. However, only some C4 null alleles are due to gene deletions, the remainder were thought to be nonexpressed genes. We have analyzed the C4 gene structure of 26 individuals lacking either C4A or C4B protein. The DNA of individuals with apparently nonexpressed C4 genes was tested for the presence of C4A- and C4B-specific sequences using restriction fragment analysis and isotype-specific oligonucleotide hybridization of DNA amplified by polymerase chain reaction. All nondeleted AQ0 allels had C4A-specific sequences and may thus be described as pseudogenes, whereas the nondeleted BQ0 alleles had C4A-instead of C4B-specific sequences. Gene conversion is the probable mechanism by which a C4A gene is found at the second C4 locus normally occupied by C4B genes.

Alleles↗
PubMed1990

[Surgical treatment of gastric carcinoma: complications and results].

Between 1974 and 1989 468 patients with gastric cancer were operated upon. The correlations between age, tumour staging, operability, postoperative complications, and perioperative mortality are analyzed. The further course of the disease was followed carefully in all patients. Therefore it is possible to correlated survival with tumour stage and operability.

Adult↗
PubMed1990

Transforming growth factor beta 1 in liver carcinogenesis: messenger RNA expression and growth effects.

Transforming growth factor beta 1 (TGF-beta 1) is a potent inhibitor of hepatocyte proliferation. Since loss of sensitivity to growth inhibition is thought to contribute to the development of neoplasia, we analyzed the expression of TGF-beta 1 mRNA during hepatocarcinogenesis in vivo and in cultured liver epithelial cells (oval cells) obtained from carcinogen-treated animals. We found that TGF-beta 1 mRNA increases in the liver during carcinogenesis and that, at the early stages of the process, oval cells but not hepatocytes contain the growth factor mRNA. Moreover, immortalized, nontumorigenic oval cells (LE/6 cell line) continued to produce TGF-beta 1 mRNA in culture. TGF-beta 1 message markedly decreased upon cell transformation, but message levels, although generally low, were variable in various tumor cell clones. A consistent feature of the tumorigenic cell lines was a loss of sensitivity to TGF-beta 1 growth inhibition. Tumor cells could bind TGF-beta 1 with similar capacity as normal cells and had the same type of receptors (Mr 280,000, 85,000, and 65,000) capable of binding iodinated TGF-beta 1, suggesting that the loss of sensitivity to TGF-beta 1 in transformed liver epithelial cells involves postreceptor mechanisms. Further studies showed that c-myc is not a target for TGF-beta 1 in liver epithelial cells and that TGF-beta 1 no longer induces fibronectin mRNA in transformed cells. The data presented are consistent with the hypothesis that TGF-beta 1 secreted during liver carcinogenesis may inhibit the proliferation of normal cells while providing a selective advantage for the growth of cells that are "partially transformed" and are unresponsive to the factor.

Animals↗
PubMed1989

Production of hepatocellular carcinoma by oval cells: cell cycle expression of c-myc and p53 at different stages of oval cell transformation.

In rats maintained on a carcinogenic diet (choline deficient containing 0.1% ethionine), the levels of c-myc and p53 mRNAs increased by 4 wk after animals were placed on the diet. Cell isolation studies showed that the change in c-myc takes place in oval cells, while p53 increases predominantly in oval cells but also in hepatocytes. To determine whether this increase is a consequence of cell proliferation or is associated with transformation, we have developed an in vitro model of hepatocarcinogenesis using epithelial cells isolated from the livers of rats fed the carcinogenic diet. When maintained in vitro with infrequent subculture, this cell line (LE/6) undergoes spontaneous transformation. Inoculation s.c. of the transformed cells into nude mice yields tumors histologically identified as hepatocellular carcinoma. We have used these cell lines to compare the cell cycle expression of c-myc and p53 mRNAs in untransformed, partially transformed, and tumorigenic LE/6 cells. We find that the expression of both genes is under cell cycle control in untransformed and partially transformed cells. However, complete transformation of this cell line is associated with constitutive expression of myc but not p53 transcripts. On the basis of this work we suggest that constitutive expression of c-myc may be a late event in hepatocarcinogenesis.

Animals↗
PubMed1989

Possible association of sudden infant death with partial complement C4 deficiency revealed by post-mortem DNA typing of HLA class II and III genes.

Based on evidence of an increased rate of respiratory infections in sudden infant death (SID) infants as well as the observation of familial occurrence, we analysed in a retrospective study class II and class II genes of the major histocompatibility complex in 40 cases of SID by Southern blot analysis of DNA obtained post mortem from tissue samples. In 24 cases, the parents were interviewed and confirmatory human lymphocyte antigen (HLA) and DNA typing was carried out. Using HLA-DR beta and -DQ beta probes, no evidence of an abnormal HLA-DR frequency distribution in SID infants was detected (P = 0.97). Using DNA probes for the tandemly arranged complement C4 and steroid 21-hydroxylase genes, an increased number of C4B gene deletions in SID cases was found. The increase in C4 gene deletions was significant (P = 0.0125) in infants with recurrent infections. These data indicate a possible role of partial C4 deficiency as a genetically predisposing risk factor in SID.

Complement C4↗
PubMed1989

[The role of gastrectomy in the treatment of hemorrhaging stomach ulcers].

It is reported about 6 patients whose bleeding gastric ulcers required gastrectomy as ultima ratio. The operative technique depends on the individual case. Gastrectomy is indicated in patients with diffuse bleeding from erosions or multiple ulcers especially combined to coagulation disorders or in patients with recurrence bleeding after previous gastric resection. We saw no letal complication in spite of unfavourable initial conditions and major operating trauma. There were no essential postoperative complications except of one patient. The definite hemostasis seems to be most important for the prognosis of such critically ill patients.

Aged↗