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Biomedical subjects

N Arber

Publications and source records attributed to N Arber.

At least 73 records · Page 4Linked to original sources
PubMed1998

Inhibition of basal and mitogen-stimulated pancreatic cancer cell growth by cyclin D1 antisense is associated with loss of tumorigenicity and potentiation of cytotoxicity to cisplatinum.

Cyclin D1 belongs to a family of protein kinases that have been implicated in cell cycle regulation. Recent studies have demonstrated that elevated cyclin D1 levels correlate with decreased survival in human pancreatic cancer. In this study we expressed in a stable manner a cyclin D1 antisense cDNA construct in PANC-1 human pancreatic cancer cells. Expression of the antisense construct caused a decrease in cyclin D1 mRNA and protein levels and in cyclin D1-associated kinase activity. Antisense expressing clones displayed significantly increased doubling times, decreased anchorage-dependent and -independent basal growth, and complete loss of tumorigenicity in nude mice. EGF, FGF-2, and IGF-I enhanced mitogen-activated protein kinase activity in antisense expressing clones, but failed to stimulate their proliferation. In contrast, all three growth factors were mitogenic in parental cells. Furthermore, the inhibitory effect of cisplatinum on cell proliferation was enhanced markedly in the antisense expressing clones. These findings indicate that cyclin D1 overexpression contributes to abnormal growth and tumorigenicity in human pancreatic cancer and to the resistance of pancreatic cancer to chemotherapeutic agents.

Animals↗
PubMed1998

Induction of hydrogen peroxide production and Bax expression by caspase-3(-like) proteases in tyrosine kinase inhibitor-induced apoptosis in human small cell lung carcinoma cells.

In our previous studies (S. Simizu, et al., 1996, Cancer Res. 56, 4978-4982), we reported that apoptosis of human small cell lung carcinoma (SCLC) cells induced by protein tyrosine kinase inhibitors, such as erbstatin and herbimycin A, was mediated by H2O2 via a newly synthesized protein(s). In the present study, we demonstrated that induction of apoptosis by erbstatin resulted in activation of caspase-3(-like) proteases, which are interleukin-1 beta-converting enzyme family proteases (caspases) and that inhibition of these protease activities reduced the extent of cell death and H2O2 generation. We also demonstrated that expression of apoptotic protein Bax was induced by erbstatin. Erbstatin-induced Bax expression was inhibited by the inhibitor of caspase-3(-like) proteases. These results indicate that generation of intracellular H2O2 and Bax expression in tyrosine kinase inhibitor-induced apoptosis were modulated by the activation of caspase-3(-like) proteases in SCLC cells.

Apoptosis↗
PubMed1998

Cyclin D1 expression in human prostate carcinoma cell lines and primary tumors.

BACKGROUND: The cyclin D1 gene is amplified and/or overexpressed in several types of human cancer, including cancers of the breast, esophagus, head, and neck. However, the role of cyclin D1 in prostate cancer has not been previously studied in detail. METHODS: Six human prostate cancer cell lines and cultures of normal human prostate cells were examined by Western and Northern blot analyses for levels of expression of the cyclin D1 protein and mRNA, respectively. Southern blot analyses were performed to examine possible amplification of this gene. Immunostaining for cyclin D1 was performed on 50 primary prostate cancer samples. RESULTS: Cyclin D1 protein was expressed at relatively high levels in all of the six human prostate cancer cell lines examined, but was not detected in the cultures of normal human prostate cells. The ALVA 41 cell line expressed the highest level of this protein. Relatively high levels of cyclin D1 mRNA were also found in all of the prostate cancer cell lines. Nevertheless, none of these cell lines revealed amplification of the cyclin D1 gene. Twelve of the 50 primary prostate cancer samples (24%) revealed regions of moderate to strongly positive staining for cyclin D1. CONCLUSIONS: The increased expression of cyclin D1 in several prostate cancer cell lines and in a subset of primary prostate cancer samples suggests that further studies on the expression of this gene and related genes may be of interest in understanding the pathogenesis of prostate cancer.

Blotting, Northern↗
PubMed1998

Effects of sulindac and its metabolites on growth and apoptosis in human mammary epithelial and breast carcinoma cell lines.

Nonsteriodal anti-inflammatory drugs (NSAIDs) are among the most commonly used medications in the United States and elsewhere, mainly for the treatment of arthritis. The NSAID sulindac causes regression and prevents the recurrence of premalignant colonic polyps in patients with familial adenomatous polyposis and inhibits colon carcinogenesis in rodents. Sulindac and sulindac sulfone, a metabolite of sulindac that lacks cyclooxygenase (cox) inhibitory activity, also inhibit mammary carcinogenesis in rats. To obtain insights into the relevance of these findings to human breast cancer, we examined the mechanism of action of sulindac and its sulfide and sulfone metabolites on the normal human mammary epithelial cell line MCF-10F and the human breast cancer cell line MCF-7. Of the three compounds, the sulfide was the most potent inhibitor of cell growth, although the sulfone and sulfoxide were also active at higher concentrations. Treatment of MCF-10F and MCF-7 cells with 100 microM sulindac sulfide resulted in accumulation of cells in the G1 phase of the cell cycle and induction of apoptosis. Apoptosis occurred within 24 h as determined by the TUNEL assay and DNA laddering was observed at 72 h. The accumulation of cells in G1 was associated with decreased levels of expression of cyclin D1 but no effect was seen on the expression of CDK4 or the immediate early response gene c-jun. Treatment with sulindac sulfide caused a striking induction of the CDK inhibitor p21WAF1 in MCF-10F cells. The MCF-7 cell line expressed a high basal level of p21WAF1 which did not change significantly after drug treatment. The pro-apoptotic gene BAX was not induced in either MCF-10F or MCF-7 cells by sulindac sulfide. Stable overexpression of cyclin D1, which frequently occurs in breast cancers, did not protect mammary epithelial cells from inhibition by the sulfide. These studies suggest that this class of compounds warrants further study with respect to breast cancer prevention and treatment.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1998

Down-regulation of the CD62L antigen as a possible mechanism for neutrophilia during inflammation.

The expressions of both the CD11b/CD18 and CD62L (L-selectin) antigens as well as the absolute number of white blood cells in the peripheral circulating pool of blood in 116 patients with various inflammatory conditions were determined. A highly significant (P<0.0001) negative correlation (r = -0.57) was noted between the absolute number of peripheral blood polymorphonuclear leucocytes and the expression of the CD62L antigen on their surface. In view of the role of CD62L antigen in the rolling of leucocytes along endothelial cells in the microvasculature, its down-regulation might explain, at least in part, the demargination and appearance of neutrophilia during inflammation.

CD18 Antigens↗
PubMed1998

The leukocyte adhesiveness/aggregation test as an inflammation-related, plasma-dependent agglutination phenomenon.

The leukocyte adhesiveness/aggregation test (LAAT) is a non-specific marker of inflammation. In the present study, we examined the expression of the CD11b/CD18 as well as the CD62L antigens on the surface of peripheral blood leukocytes in 84 patients with various inflammatory conditions and 60 controls by using whole blood flow cytometry. We also conducted several in vitro experiments in order to explain the mechanism of the leukocyte adhesiveness/aggregation. A significant (r= -0.36, p<0.001) negative correlation was found between the expression of CD62L on the surface of peripheral blood polymorphonuclears and the state of LAA. There was no correlation between the availability of the CD11b/CD18 antigen and the adhesive state of these cells. In a series of in vitro experiments, we could show that it is possible to significantly reduce the number of aggregated leukocytes in the peripheral blood by using dilutions with buffer but not with plasma. There is no change in the degree of aggregation following incubation at low temperature in the presence of an aerobic metabolism blocker or following incubation with a divalent ion chelator. Additionally, white blood cells could be seen to adhere to protein-rich areas in the peripheral slides. We assume that the state of LAA in the peripheral blood as revealed by the LAA test is more a plasma factor-dependent agglutination than a firm aggregation phenomenon. Factors other than the leukocyte integrins or selectins should be sought as being responsible for this LAA phenomenon.

Adult↗
PubMed1998

Septic arthritis of the glenohumeral joint. A report of 11 cases and review of the literature.

Eleven cases (6 adults and 5 pediatrics) of shoulder septic arthritis are described, and the English literature from 1960 to 1997 reviewed, for a total of 168 cases. Shoulder septic arthritis is an uncommon and difficult diagnosis requiring a high index of suspicion and early evaluation of the affected shoulder by the clinician. The disease usually involves very young infants or elderly patients (65-75 years old). Associated medical conditions were identified in 60% of the patients and include systemic disorders such as liver diseases, alcoholism, and malignancies in 46%; preceding chronic arthritic disorders in 24%; and associated infectious focus in 13% of the patients. Associated infections were more prevalent in the pediatric population. Intravenous drug abuse appears not to constitute a major risk factor; it was identified in less than 5% of patients. All patients presented with acute shoulder ache or with exacerbation of existing chronic pain in joints previously damaged. Elevated body temperature (over 38 degrees C) appeared in 67% of the adult patients and in over 90% of the pediatric patients. Shoulder arthritis was frequently accompanied by an accelerated erythrocyte sedimentation rate that may rise above 100 mm/hr. Increased white blood cell count was found in approximately 40% of patients. The initial X-rays were frequently normal, while ultrasonography supported the diagnosis in some cases by demonstrating accumulation of fluid inside the joint space. Aspiration of synovial fluid from the affected glenohumeral joint was necessary to evaluate the offending pathogen. False-negative Gram stain appeared in approximately 90% of the patients, whereas synovial fluid cultures demonstrated the pathogen in 88% of patients. Blood cultures were positive in 50% of adult patients and 90% of pediatric patients. The most common isolated pathogen was Staphylococcus aureus, which accounted for 41% of infections. Gram-negative bacilli, which accounted for about 20% of infections, are more prevalent in the pediatric population, especially the neonates. Pyogenic shoulder arthritis should first be treated with intravenous antibiotics, effective at least against staphylococcal infections, until the organisms and sensitivities are identified. Duration of antibiotic therapy should be 3-6 weeks. Unfortunately, our experience in addition to the literature summary does not allow statistical analysis and firm conclusions concerning the best therapeutic approach. However, it appears that in the adult population an operative draining procedure is preferred, whereas in the pediatric population, a closed needle aspiration, if needed at all, is the optimal treatment. With prompt antibiotic therapy and drainage of the shoulder, the patient can be expected to improve clinically, with no serious long-term debilitating effects from the disease.

Aged↗
PubMed1998

Increased cyclin D1 expression in chronic pancreatitis.

Cyclin D1 is an important regulator of the G1 phase of the cell cycle. In this study we examined the expression and localization of cyclin D1 in chronic pancreatitis (CP), a condition associated with fibrosis, acinar cell degeneration, and foci of duct cell proliferation. Northern blotting of total RNA from the normal pancreas and from the pancreas of patients with CP revealed the presence of a 4.4-kb cyclin D1 mRNA transcript in all samples. Densitometric analysis indicated that pancreatic cyclin D1 mRNA levels were 2.0-fold increased in CP compared to normal controls (p = 0.0046). In the normal pancreas, faint cyclin D1 immunoreactivity was present in the nuclei and cytoplasm of some ductal cells and islet cells. In contrast, in CP, moderate to strong cyclin D1 immunoreactivity was present in many ductal and islet cells, as well as in some acinar cells and fibroblasts. These findings raise the possibility that enhanced cyclin D1 expression may contribute to a hyperproliferative state in CP.

Adult↗
PubMed1998

One-week triple therapy with omeprazole, clarithromycin, and nitroimidazole for Helicobacter pylori infection in children and adolescents.

BACKGROUND: Resolution of Helicobacter pylori infection is important in the management of peptic ulcer disease and reduces peptic ulcer recurrence in both adults and children. Various anti-H pylori treatment regimens have been proposed, reflecting the incomplete clinical success of each. A combination of omeprazole, clarithromycin, and tinidazole, given for 1 week, has been shown to be highly tolerable and effective, achieving a success rate of >90% in the adult population. OBJECTIVE: The aim of this study was to evaluate this short-term regimen in pediatric and adolescent populations. METHODS: The study group consisted of 35 children referred for evaluation of dyspeptic symptoms. They all underwent upper gastrointestinal endoscopy, in which H pylori infection was confirmed by rapid urease test and/or histologic staining. They were given omeprazole (20 mg twice daily), clarithromycin (250 mg twice daily), and tinidazole or metronidazole (500 mg twice daily) for 1 week. The patients were divided into two groups: those who received the first course of anti-H pylori therapy during this study (group 1) and those who had previously received standard metronidazole and bismuth combination therapies that failed to eradicate H pylori (group 2). Therapeutic efficacy was assessed by a 13C-urea breath test performed 4 weeks after completion of treatment. Results. The 35 study patients had a mean age of 15.9 years (range, 10 to 19) and included 19 males and 16 females, of whom 22 were born in Israel and 13 were immigrants from the former USSR. There were 27 patients (77. 1%) in group 1 and 8 patients (22.9%) in group 2. Endoscopic findings were nodular gastritis (14), gastritis (11), gastric ulcer (1), duodenal ulcer (5), and duodenitis (4). H pylori resolution was significantly higher in group 1 patients (24/27, 88.9%) than in group 2 patients (1/8, 12.5%). There was no difference between patients with nodular gastritis and those with nonnodular gastritis, and between Israeli-born patients and patients born in the former USSR. Compliance in both groups was equally good, and no major side effects were recorded. CONCLUSIONS: One-week omeprazole/clarithromycin/tinidazole triple therapy is highly tolerable and effective for treating H pylori in the pediatric age group, but previous treatment failure diminishes the likelihood of success with this regimen.

Adolescent↗
PubMed1998

Dissociation between the state of leukocyte adhesiveness/aggregation in the peripheral blood and the availability of the CD11B/CD18 and CD62L antigens on the surface of the cells in patients with stress.

We adopted whole blood flow cytometry and direct labeling of the CD11b/CD18 and the CD62L antigens to study the relationship between their expression on the surface of peripheral leukocytes and the state of leukocyte adhesiveness/aggregation (LAA) as revealed by the leukergy test. We examined patients with infection/inflammation, acute stress and controls. The mean +/- S.D. channel fluorescence intensity of CD11b/CD18 antigen did not differ between patients with infection/inflammation (173 +/- 78) and controls (167 +/- 72). However, a significant (p < 0.0001) difference between these groups was noted regarding LAA state. There was a significant (p = 0.04) reduction in CD11b/CD18 in stress (135 +/- 60) and a significant (p < 0.001) increment in LAA. In both study groups, there was a significant reduction in CD62L. Patients were divided into those with CD11b/CD18 above and below the control's average. No correlation was found between the antigens and LAA. We assume that LAA in patients with stress state is CD11b/CD18 and CD62L independent.

Adult↗
PubMed1998

The epidemiology of cancer of the small bowel.

Despite its anatomical location between two regions of high cancer risk, the small bowel rarely develops a malignant tumor. However, in recent years, small bowel cancer incidence rates have begun to rise. The purpose of this review is to explore the descriptive and analytic epidemiology of small bowel cancer for those factors that protect this organ and those factors associated with loss of this protection. Within the small intestine, the sites at the highest risk are the duodenum, for adenocarcinomas, and the ileum, for carcinoids and lymphomas. In industrialized countries, small bowel cancers are predominantly adenocarcinomas; in developing countries, lymphomas are much more common. The incidence of small bowel cancer rises with age and has generally been higher among males than among females. The risk factors for small bowel cancer include dietary factors similar to those implicated in large bowel cancer, cigarette smoking, alcohol intake, and other medical conditions, including Crohn's disease, familial adenomatous polyposis, cholecystectomy, peptic ulcer disease, and cystic fibrosis. The protective factors may include rapid cell turnover, a general absence of bacteria, an alkaline environment, and low levels of activating enzymes of precarcinogens. Adenocarcinomas of the small and large bowel are similar in risk factors and geographic distribution but not in recent time trends; colorectal cancer incidence rates in the United States have been falling since the mid-1980s. Small bowel lymphoma may be associated with infectious agents, such as HIV. Given the differences in anatomic and geographic location among histological subtypes, much may be learned from well-designed, histology-specific epidemiological and genetic studies of cancer of the small bowel.

Adenocarcinoma↗
PubMed1998

Neutrophilia of infection/inflammation: are we really dealing with "inflamed" leukocytes?

We adopted whole blood flow cytometry and direct labeling of the CD11b/CD18 and CD62L antigens to study the relationship between their expression and leukocytosis in patients with infection/inflammation, acute stress and healthy volunteers. Mean +/- S.D. channel fluorescence intensity of CD11b/CD18 antigen on peripheral blood polymorphonuclears did not differ between patients with infection/ inflammation (173+/-78) and controls (167+/-72), but was significantly (p = 0.04) reduced in stress (135+/-60). No correlation was found between CD11b/CD18 antigen level and either polymorphonuclears absolute number or serum C-reactive protein. A significant negative correlation was noted between CD62L antigen expression on polymorphonuclears and their absolute number. We assume that cells with increased CD11b/CD18 surface concentrations are retained in the capillaries and that part of the leukocytes in the peripheral blood are stressed leukocytes with reduced CD11b/CD18. Thus, leukocytes detected in peripheral blood are not necessarily the most "inflamed" ones.

Adult↗
PubMed1997

Antisense to cyclin D1 inhibits the growth and tumorigenicity of human colon cancer cells.

Cyclin D1 plays an important role in regulating the progression of cells through the G1 phase of the cell cycle. This gene is frequently overexpressed in human colon cancer. To address the role of cyclin D1 in growth control and tumorigenesis in this disease, we have overexpressed an antisense cyclin D1 cDNA construct in the human colon cancer cell line SW480E8, which expresses high levels of cyclin D1. The integration and expression of the antisense construct was verified by Southern and Northern blot analyses, respectively, and resulted in decreased expression of the cyclin D1 protein. This was associated with decreased levels of the Rb and p27Kip1 proteins. In addition, the hypophosphorylated form of Rb was increased in these cells. The SW480E8 antisense cyclin D1 cells displayed an increased doubling time, a decrease in saturation density, decreased plating efficiency and anchorage-independent growth, and a loss of tumorigenicity in nude mice. These findings provide direct evidence that increased expression of cyclin D1 in colon tumor cells contributes to their abnormal growth and tumorigenicity. The ability to revert the transformed phenotype of these cells with antisense cyclin D1 suggests that cyclin D1 or its associated cyclin-dependent kinase 4 may be useful targets in the therapy of colon cancer.

Animals↗
PubMed1997

A K-ras oncogene increases resistance to sulindac-induced apoptosis in rat enterocytes.

BACKGROUND & AIMS: Mutations of c-K-ras occur commonly in colonic neoplasms. The aim of this study was to determine how c-K-ras mutations alter the responses to the chemopreventive agent sulindac. METHODS: The parental rat intestinal cell line IEC-18 and c-K-ras-transformed derivatives were treated with sulindac sulfide. Cell cycle distribution was determined by flow-cytometric analysis (fluorescence-activated cell sorter), apoptosis by DNA fragmentation (laddering), flow cytometry, and microscopy, and changes in gene expression by immunoblotting. RESULTS: Sulindac sulfide inhibited cell growth and induced apoptosis in a time- and dose-dependent manner more rapidly in and at lower concentrations in parental cells than ras-transformed cells. Expression of the sulindac sulfide arrested cells in G0/G1, but cells entered apoptosis throughout the cell cycle. Proapoptotic protein Bak was relatively high in untreated parental cells and increased markedly after sulindac sulfide but was low in untreated ras-transformed cells and did not increase after sulindac sulfide. Expression of other Bcl-2 family members was unchanged after sulindac sulfide. However, sulindac sulfide reduced levels of cyclin D1 protein and cyclin E- and cyclin D1-associated kinase activity. CONCLUSIONS: c-K-ras-transformed enterocytes are relatively resistant to sulindac sulfide-induced growth inhibition and apoptosis, which may result from specific reduction of bak expression.

Animals↗
PubMed1997

Methimazole slows hepatocyte streaming in rats.

Hepatocytes are hypothesized to continually stream from the portal tract to the terminal hepatic vein. By this model, when a cell divides, one of its progeny replaces the dividing ancestor and the other is displaced into a more remote location. The present experiment aims to demonstrate that hypothyroidism affects liver cell turnover. Thirty male adult rats were divided into two groups. One received methimazole for two weeks and the other served as control. Each rat was injected intraperitoneally with 18.5 KBq [3H]thymidine/g body weight. Rats were killed after 1 hr and two and four weeks. Autoradiography was done. The distance of the labeled cells from the portal tract was measured. The mean TSH levels of the methimazole-treated group and controls were 1.45 and 0.25 mM/liter, respectively (P < 0.01). Hepatocyte streaming was lower in hypothyroid (1.8 microns/day) than in untreated rats (2.5 microns/day) (P < 0.01). The respective labeling indices 1 hr after labeling were 0.9% and 1.24% (P < 0.05). We conclude that hypothyroidism diminishes hepatocyte and littoral cell turnover and slows down their streaming.

Animals↗
PubMed1997

Disorders in cell circuitry associated with multistage carcinogenesis: exploitable targets for cancer prevention and therapy.

The development of a malignant tumor involves the progressive acquisition of mutations and epigenetic abnormalities in multiple genes that have highly diverse functions. Some of these genes code for pathways of signal transduction that mediate the action of growth factors. The enzyme protein kinase C plays an important role in these events and in the process of tumor promotion. Therefore, we examined the effects of three inhibitors of protein kinase C, CGP 41251, RO 31-8220, and calphostin C, on human glioblastoma cells. These compounds inhibited growth and induced apoptosis; these activities were associated with a decrease in the level of CDC2 and cyclin B1/CDC2-associated kinase activity. This may explain why the treated cells accumulated in G2-M. In a separate series of studies, we examined abnormalities in cell cycle control genes in human cancer. We have found that cyclin D1 is frequently overexpressed in a variety of human cancers. Mechanistic studies indicate that cyclin D1 can play a critical role in carcinogenesis because: overexpression enhances cell transformation and tumorigenesis; introduction of an antisense cyclin D1 cDNA into either human esophageal or colon cancer cells reverts their malignant phenotype; and overexpression of cyclin D1 can enhance the amplification of other genes. The latter finding suggests that cyclin D1 can enhance genomic instability and, thereby, the process of tumor progression. Therefore, inhibitors of the function of cyclin D1 may be useful in both cancer chemoprevention and therapy. We obtained evidence for the existence of homeostatic feedback loops between cyclins D1 or E and the cell cycle inhibitory protein p27Kip1. On the basis of these and other findings, we hypothesize that, because of their disordered circuitry, cancer cells suffer from "gene addiction" and "gene hypersensitivity," disorders that might be exploited in both cancer prevention and therapy.

Apoptosis↗
PubMed1997

Increased leukocyte adhesiveness/aggregation in patients with recurrent TIA.

OBJECTIVE: White blood cells might have a pathogenetic role in ischemic vascular conditions. Several studies have suggested that increased adhesiveness of these cells could contribute to such a damage. The present study was undertaken in order to examine the adhesive properties of leukocytes in the peripheral blood of patients with various degrees of ischemic neuro-vascular diseases. METHODS: The percentage of aggregated white blood cells was determined by using a direct slide test. RESULTS: The respective values of aggregated cells in 28 patients with major stroke, 11 with minor stroke, 17 with a single TIA, 11 with recurrent TIAs and 18 controls were 15.9 +/- 7.4%, 6.6 +/- 3.3%, 3.0 +/- 2.6%, 10.9 +/- 8.4% and 1.5 +/- 0.4%. The difference between patients with a single TIA and those with recurrent TIAs being significant at P < 0.05. CONCLUSION: Being a sensitive marker of inflammation, our test might reveal the presence of an underlying smoldering inflammation in patients with recurrent TIA. These results are in agreement with modern studies that show that inflammation is an important feature of atherosclerosis.

Aged↗