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Biomedical subjects

N Arber

Publications and source records attributed to N Arber.

At least 55 records · Page 3Linked to original sources
PubMed2000

The inflammation meter: novel technology to detect the presence of infection/inflammation in patients without leukocytosis but with increased leukocyte adhesiveness/aggregation.

OBJECTIVES: To reveal the presence of infection/inflammation in patients with relatively normal white blood cell count (WBCC) by using the leukocyte adhesiveness/aggregation test (LAAT). METHODS: The LAAT was performed by using a simple slide test and image analysis (Inflamet), the WBCC, by an electronic cell analyzer, C-reactive protein, by Laser nephelometry and CD11b/CD18 by whole blood flow cytometry. RESULTS: Forty out of a cohort of 121 patients with nonviral acute febrile illness had a WBCC within normal limits. The intensity of the inflammatory response in these individuals as judged by either C-reactive protein, or fibrinogen concentrations, erythrocyte sedimentation or polymorphonuclear leukocyte CD11b/CD18 expression was similar to that observed in patients with a leukocytic response. Our present finding that 63% out of the group with documented infection/inflammation and no leukocytosis had a significantly increased LAAT suggest that the lack of leukocytosis is in part a pseudoleukopenia, or is associated with some degree of uncompensated tissue leukostasis. CONCLUSIONS: The lack of a leukocytic response in a patient with nonviral infection/inflammation is by no means a sign of a less inflammatory response. The increased state of leukocyte adhesiveness/aggregation might help to disclose the presence of inflammation in these individuals.

Adult↗
PubMed2000

Non-steroidal anti-inflammatory drugs and selective apoptotic anti-neoplastic drugs in the prevention of colorectal cancer: the role of super aspirins.

There is increasing evidence to suggest that aspirin and other non-steroidal anti-inflammatory drugs reduce the risk of colorectal cancer. This observation is supported by animal studies that show fewer tumors per animal and fewer animals with tumors after administration of several different NSAIDs. Intervention data in familial adenomatous polyposis have established that the effect is exerted on the process of human colonic adenoma formation. Supportive evidence in sporadic colorectal neoplasia, derived from 22 of 24 studies (both case-control and cohort), found a reduced risk in men and women for cancers of the colon and the rectum and for both aspirin and the other NSAIDs. Earlier detection of lesions as a result of drug-induced bleeding does not seem to account for these findings. Although the molecular mechanism responsible for the chemopreventive action of this class of drugs is not yet completely understood, the protection may affect several pathways including both cell cycle arrest and induction of apoptosis. In the third millennium the question is not if but how. Based on the consistency of epidemiological, clinical and experimental data, the association between regular long-term aspirin or NSAIDs intake and a decreased death rate from colorectal cancer is sound and there is no need for further placebo trials. At the same time, despite this consistency there is no clear data on the dose, duration or frequency of use for cancer-preventive activity.

Adenomatous Polyposis Coli↗
PubMed2000

Correlated expression of adhesive properties for both white and red blood cells during inflammation.

The state of leukocyte and erythrocyte adhesiveness/aggregation was determined in the peripheral blood of 382 patients with infection/inflammation as well as in 72 controls by using a simple slide test and image analysis. A highly significant correlation (r = 0.4, n = 455, p < 0.001) was found between the state of leukocyte and erythrocyte adhesiveness/aggregation. The extent of both leukocyte and erythrocyte aggregation correlated with the concentration of fibrinogen. Significant aggregation of leukocytes with erythrocytes was noted as well. We conclude that both leukocyte and erythrocyte aggregation occur in the peripheral blood of patients with infection/inflammation. Such cell aggregation, which might have detrimental rheological consequences, can be detected by using our novel technique.

Acute-Phase Reaction↗
PubMed2000

Additive deleterious effect of smoking on gastroduodenal pathology and clinical course in Helicobacter pylori-positive dyspeptic patients.

BACKGROUND: Cigarette smoking has long been regarded as an important factor in the pathogenesis of peptic ulcer disease. OBJECTIVE: To investigate whether cigarette smoking has an additive effect on the clinical presentation and course of disease in Helicobacter pylori-positive dyspeptic patients. PATIENTS AND METHODS: The study group comprised 596 consecutive H. pylori-positive dyspeptic patients (334 males and 262 females, mean age 50.6, range 12-81 years). Following upper gastrointestinal endoscopy, patients were subdivided by diagnosis as follows: Non-ulcer patient group (n = 312: gastritis 193, duodenitis 119), gastric ulcer (n = 19), and duodenal ulcer (n = 265). H. pylori infection was confirmed by histology and/or rapid urease test. In addition, 244 patients had a positive 14C-urea breath test prior to antimicrobial treatment. The patients' medical history and smoking habits were obtained using a detailed questionnaire completed by the patients and their referring physicians. RESULTS: There were 337 non-smoking patients, 148 current smokers and 111 past smokers. Gastric and duodenal ulcers were significantly less prevalent in non-smokers than in current or past smokers (gastric 1.8%, 4.1%, 6.3%; duodenal 39.8%, 50%, 51.4%, respectively) (P < 0.05). The incidence of gastrointestinal bleeding was significantly lower in non-smokers than in current or past smokers (7.1%, 8.1% and 20.7%, respectively) (P < 0.05). Bacterial density, as assessed by the UBT value in 244 patients, was higher in non-smokers (mean 352.3 +/- 273 units) than in past smokers (mean 320.8 +/- 199) or current-smokers (mean 229.9 +/- 162) (P < 0.05). Logistic regression analysis revealed that male gender, current smoking, and immigration from developing countries were all significant independent risks for developing duodenal ulcer, while only past smoking was associated with a higher rate of upper gastrointestinal bleeding in the past. CONCLUSIONS: In H. pylori-positive dyspeptic patients, current smoking as well as male gender and immigration from developing countries are associated with an increased risk for duodenal ulcer. This effect does not seem to be related to the bacterial density or increased urease activity of H. pylori organisms.

Adolescent↗
PubMed1999

Inhibition of cyclin D1 expression in human pancreatic cancer cells is associated with increased chemosensitivity and decreased expression of multiple chemoresistance genes.

Cyclin D1 belongs to a family of protein kinases that have been implicated in cell cycle regulation. Inhibition of cyclin D1 expression has been recently shown (M. Kornmann, et al., J. Clin. Invest, 101: 344-352, 1998) to suppress pancreatic cancer cell growth and increase cytotoxic actions of cisplatinum. The aim of the present study was to determine whether inhibition of cyclin D1 expression also modulates the effects of other antineoplastic drugs and whether it is associated with alterations in the level of expression of drug resistance genes. The suppression of cyclin D1 expression after the stable transfection of a cyclin D1 antisense construct in PANC-1 and COLO-357 human pancreatic cancer cells resulted in a significant increase in sensitivity to the fluoropyrimidines 5-fluorouracil and 5-fluoro-2'-deoxyuridine and to mitoxantrone. All of the antisense-expressing dones exhibited a decrease in thymidylate synthase and an increase in thymidine phosphorylase mRNA expression as determined by reverse transcription-PCR analysis and decreased levels of MDR-1 and MRP mRNA as determined by Northern blotting. These findings demonstrate that the inhibition of cyclin D1, in addition to suppressing the growth of pancreatic cancer cells, enhances their responsiveness to multiple chemotherapeutic agents and suggest that this effect may be due to the altered expression of several chemoresistance genes.

Adenocarcinoma↗
PubMed1999

The appearance of L-selectin(low) polymorphonuclear leukocytes in the circulating pool of peripheral blood during myocardial infarction correlates with neutrophilia and with the size of the infarct.

BACKGROUND: It is assumed that not only leukocytosis, but also the activation of white blood cells (WBC) may play a role in the pathogenesis and prognosis of patients with myocardial infarction (MI). Activation of WBC includes upregulation of CD11b/CD18 and downregulation of CD62L (L-selectin) antigens. HYPOTHESIS: The activation of WBC is associated with the appearance of a larger MI. METHODS: CD11b/CD18 and CD62L were measured on the surface of WBC on Day 1 and Day 3 from the onset of MI. The size of the infarct with estimated by calculating the area under the curve of the creatine kinase enzyme, which was measured every 6 h. RESULTS: A negative correlation was noted between the absolute polymorphonuclear count and the availability of the CD62L on these cells during Day 1 (r = -0.46, p = 0.003) and Day 3 (r = -0.35, p = 0.05). There was a positive correlation between the size of MI and the WBC count (r = 0.46, p = 0.004) and a negative correlation with CD62L on polymorphonuclears (r = -0.35, p = 0.03). During Day 3, the CD11b/CD18 on the polymorphonuclears increased despite a decrement in the absolute number of these cells. CONCLUSION: The neutrophilia during the early phases of acute MI correspond to the appearance of the L-selectin(low) population of polymorphonuclear leukocytes. There is a correlation between the appearance of this population and the size of the infarct.

Aged↗
PubMed1999

Nonsteroidal anti-inflammatory drugs and prevention of colorectal cancer.

Increasing evidence suggests that aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of colorectal cancer. This observation is supported by results from animal studies that show fewer tumors per animal and fewer animals with tumors after administration of several different NSAIDs. Results from clinical studies with humans consistently support these findings as well. The intervention data in familial adenomatous polyposis patients establishes that the antineoplastic effect may target human adenoma formation. Supportive evidence comes with both aspirin and non-aspirin NSAIDs. Earlier detection of lesions as a result of drug-induced gastrointestinal bleeding does not seem to account for these findings. The molecular mechanism responsible for the chemopreventive action of this class of drugs is not clear. Protection may affect several pathways, with results including cell cycle arrest, induction of apoptosis, and angiogenesis. This review focuses primarily on the potential chemopreventive activity of NSAIDS in sporadic human colon cancer and adenomas and outlines current concepts for the biologic and biochemical mechanisms for this protective effect.

Animals↗
PubMed1999

Increased expression of the CD11b/CD18 antigen on the surface of peripheral white blood cells in patients with ischemic heart disease: further evidence for smoldering inflammation in patients with atherosclerosis.

BACKGROUND: This study examined the availability of the CD11b/CD18 and CD62L antigens on the surface of peripheral blood leukocytes in patients with ischemic heart disease. METHODS AND RESULTS: The study population included 45 patients with angiographically documented ischemic heart disease admitted to our department of internal medicine and the cardiology department during 1 month (December 1997). Sixty-six healthy members of the hospital medical staff served as control subjects. Another 39 post-trauma patients who were admitted to the emergency room were also evaluated. Patients with ischemic heart disease had significantly (P <.002) higher concentrations of CD11b/CD18 antigen on the surface of their polymorphonuclear leukocytes and monocytes (mean fluorescence intensity of 203 +/- 81 and 261 +/- 75, respectively) compared with the control group (mean fluorescence intensity 158 +/- 68 and 211 +/- 74, respectively) and to the group of patients with acute stress (mean fluorescence intensity of 146 +/- 70 and 200 +/- 22, respectively). CONCLUSIONS: The presence of increased concentration of CD11b/CD18 suggests that circulating leukocytes are activated in patients with ischemic heart disease. This activation probably reflects the presence of an inflammatory response involving the atherosclerotic lesion and is not merely a result of acute stress.

Aged↗
PubMed1999

Overexpression of cyclin D1 occurs in both squamous carcinomas and adenocarcinomas of the esophagus and in adenocarcinomas of the stomach.

Increased expression of the cyclin D1 gene frequently occurs in human squamous carcinomas of the esophagus. However, the expression of cyclin D1 has not been previously examined in detail in adenocarcinomas of the esophagus or stomach. Therefore, we examined, in parallel, the expression of cyclin D1 in both squamous and adenocarcinomas of the esophagus and in adenocarcinomas of the stomach. The level of expression of the cyclin D1 protein was assessed by immunohistochemistry in 39 esophageal and 34 gastric carcinomas and correlated with clinical and pathology parameters. Within the esophagus, 71% of the squamous carcinomas and 64% of the adenocarcinomas were positive for increased cyclin D1 nuclear staining. For adenocarcinomas of the stomach, the overall positive rate was 47%; in the gastric cardia, the rate was 44%, and in other regions of the stomach, it was 50%. In esophageal and gastric adenocarcinomas of the intestinal type, increased expression of cyclin D1 was seen in 70% of the samples, whereas with the diffuse type only 13% were positive (P < .01). Tumors from patients older than the median age of 67 years were more frequently positive than tumors from patients younger than 67 years (74% v 42%, respectively) (P < .01). Positive staining was also seen more frequently in well and moderately differentiated tumors than in poorly differentiated tumors (74% v 49%, respectively) (P < .05). Cytoplasmic staining for cyclin D1 was noted in 22% of the tumors, of various types. Therefore, increased expression of cyclin D1 frequently occurs in both adenocarcinomas and squamous carcinomas of the esophagus, and in adenocarcinomas of the stomach. The increased expression in adenocarcinomas is especially frequent in the intestinal-type lesions.

Adenocarcinoma↗
PubMed1999

Roles of cyclin D1 and related genes in growth inhibition, senescence and apoptosis.

It is now apparent that apoptosis is closely linked to the control of cell cycle progression. During the G1 to S progression, cyclin D1, p53, and the cyclin dependent kinase inhibitors p21WAF1 and p27kip1 can play roles in induction of apoptosis. During the G2 and M phases, premature activation of Cdk1 can cause cells to enter mitotic catastrophe, which results in apoptosis. In this review we focus on factors acting during G1 and S, particularly cyclin D1, and their effects on cell growth, senescence and apoptosis. We emphasize that cyclin D1 can have diverse effects on cells depending on its level of expression, the specific cell type, the cell context and other factors. Possible mechanisms by which cyclin D1 exerts these diverse effects, via cyclin dependent kinase-dependent and -independent pathways, are discussed.

Journal Article↗
PubMed1999

Janus faces of ras: anti or pro-apoptotic?

Cell population homeostasis is a balance between cell proliferation on one hand and the rate of cell loss on the other hand. Normal tissue homeostasis requires the physiological deletion of cells by activation of apoptosis, a genetically determined program of autonomous cell death. ras is most probably the most important oncogene in human cancer. It is mutated in 30% of all tumors especially those of the gastrointestinal tract. In regulating apoptosis ras has many faces. it has both negative and positive effects depending on the stimulation and cell type. The responses of cells to ras signaling depends on the level of Ras expression, the activity of various pathways, and which of the cell cycle check points are functioning. New farnesyl transferase inhibitors and non-steroidal anti-inflammatory compounds may provide a new strategy for novel therapeutic modalities in the treatment of human cancer. The first clinical trials have been initiated, preliminary results are promising, although no firm results are yet available.

Journal Article↗
PubMed1999

The efficacy of omeprazole-based short-term triple therapy in Helicobacter pylori-positive older patients with dyspepsia.

OBJECTIVE: To evaluate the efficacy of 1-week triple therapy with omeprazole, clarithromycin,and tinidazole (OCT) in Helicobacter pylori-positive older patients with dyspepsia. DESIGN: A prospective, nonrandomized therapeutic study. SETTING: The primary care and referral center of a gastroenterological outpatient clinic at a central university hospital serving an urban population (>1 million) in Israel. PARTICIPANTS: The study group consisted of 134 patients (71 men, and 63 women) more than 60 years old who were referred for evaluation of symptoms of dyspepsia and were endoscopically diagnosed as H. pylori positive. The patients were divided into two groups: those who received their 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 the H. pylori (Group 2). MEASUREMENTS: All the patients underwent upper gastrointestinal endoscopy, and H. pylori infection was confirmed by a rapid urease test (CUTest) and/or histological staining. Therapeutic efficacy was assessed by a 13C-urea breath test 4 weeks after completion of treatment. RESULTS: The mean age of the study population was 68.8 years (range 60-87). There were 112 patients in Group 1 and 22 patients in Group 2. Endoscopic findings were: gastritis (in 46), gastric ulcer (8), duodenal ulcer (52), and duodenitis (28). The H. pylori eradication rate was significantly higher in Group 1 patients (104/112, 92.9%) than in patients of Group 2 (15/22, 68.2%). There was no difference in the eradication rate in relation to gender, endoscopic diagnosis, more advanced age, place of birth, or smoking habits. The compliance in both groups was equally good, and no major side effects were recorded. CONCLUSIONS: A 1-week OCT triple therapy is well tolerated and effective as first line therapy for H. pylori among older people. It is less effective in patients previously treated.

Aged↗
PubMed1999

Paradoxical increase in retinoblastoma protein in colorectal carcinomas may protect cells from apoptosis.

The retinoblastoma (Rb) gene is inactivated in a variety of human cancers, but in colorectal carcinomas there is frequently increased expression of this gene. This is paradoxical in view of the known role of Rb as a tumor suppressor gene. In the present study, we compared the levels of expression of the Rb protein (pRb) in normal human colorectal mucosa, adenomatous polyps, and carcinomas by immunohistochemistry. In vitro studies were also done to examine the phenotypic effects of an antisense oligodeoxynucleotide (AS-Rb) targeted to Rb mRNA in the HCT116 colon carcinoma cell line that expresses a relatively high level of pRb. The incidence of pRb-positive cells was increased during multistage colorectal carcinogenesis. In vitro treatment of HCT116 cells with AS-Rb decreased the level of pRb by about 70% and also decreased the levels of the cyclin D1 protein and cyclin D1-associated kinase activity. AS-Rb inhibited growth of HCT116 cells and induced apoptosis. Reporter assays indicated about a 17-fold increase in E2F activity. These findings suggest that the increased expression of pRb in colorectal carcinoma cells may provide a homeostatic mechanism that protects them from growth inhibition and apoptosis, perhaps by counterbalancing potentially toxic effects of excessive E2F activity.

Apoptosis↗
PubMed1999

Abnormalities in the expression of cell cycle-related proteins in tumors of the small bowel.

Tumors of the small bowel are quite rare for unknown reasons, although they resemble colorectal tumors in many respects. The purpose of this study was to determine whether abnormalities in the expression of several cell cycle control genes are of importance in small bowel tumorigenesis by comparing a series of samples of normal mucosa, adenomatous polyps, and adenocarcinomas. The levels of cyclin D1, cyclin E, p16, p21, p27, and p53 proteins were determined by immunohistochemistry in samples of normal small bowel (n = 16), small bowel adenomas (n = 20), and small bowel adenocarcinomas (n = 24). Normal small bowel mucosa expressed p27 protein, but not the other cell cycle-related proteins. About 20% of the tumors displayed a decrease in the expression of this protein. The most frequent alteration in the tumors was an increase in the p16 protein. Increased expression of p53 was associated with tumor progression because it was overexpressed in 45% of the adenomas and 65% of the adenocarcinomas (P<0.05). Advanced age and increased detection of cyclin D1 and p53 were associated with a decreased 3-year survival (P<0.05). Cell cycle abnormalities are early and important events in the multistep process of small bowel tumorigenesis, thus resembling colorectal carcinogenesis. As in colon cancer, deregulated expression of G1 proteins may perturb cell cycle control in benign adenomas of the small bowel and thereby enhance tumor progression. Increased expression of cell cycle inhibitors in tumors may serve as a defense mechanism for tumor progression.

Adenocarcinoma↗