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Biomedical subjects

R Lotan

Publications and source records attributed to R Lotan.

278 records · Page 16Linked to original sources
PubMedDate not supplied

Retinoids and chemoprevention of aerodigestive tract cancers.

Natural and synthetic vitamin A metabolites and analogs (retinoids) were found to suppress head and neck and lung carcinogenesis in animal models and inhibit carcinogenesis in individuals with premalignant lesions and a high risk to develop cancer of the aerodigestive tract. Likewise, retinoids prevent the development of second primary cancers in head and neck and lung cancer patients who had been treated for the first primary. These effects are thought to result from changes in the expression of genes that regulate cell growth and differentiation. Most of the effects of retinoids on gene expression are mediated by nuclear retinoic acid receptors RARs (alpha, beta, and gamma) and retinoid X receptors (RXR alpha, beta, and gamma), which function as retinoid-activated transcription factors. Like vitamin A deficiency, alterations in receptor expression or function could interfere with the retinoid signaling pathway and thereby enhance cancer development even in vitamin A sufficient individuals. We found that the expression of RAR beta was suppressed in more than 50% of oral and lung premalignant lesions in individuals without cancer (e.g., oral leukoplakia and squamous metaplasia), in dysplastic lesions adjacent to cancer, and in malignant oral and lung carcinomas. The expression of the other receptors was not different among normal, dysplastic, and malignant oral tissues. However, the expression of RAR gamma and RXR beta was somewhat decreased in lung cancers. These results show that RAR beta expression is lost at early stages of carcinogenesis in the aerodigestive tract and support the hypothesis that the loss of RAR beta expression may facilitate the development of some of these cancers.

Anticarcinogenic Agents↗
PubMedDate not supplied

Bacteriological profile of ophthalmic infections in an Israeli hospital.

AIM: To find the optimal antibiotic treatment for ophthalmic infections in an Israeli hospital. METHODS: In a retrospective study from our laboratory, which serves as both a primary and secondary referral center, we analyzed the bacteriological profile and the antibiotic sensitivity of ophthalmic infections using the computerized laboratory reports of 331 consecutive ophthlamic bacteriological cultures from patients with various ophthalmic infections. RESULTS: Microbiological growth was obtained in 113 samples (34.1%). The most commonly isolated organism was coagulase-negative staphylococcus (19.5%), followed by coagulase-positive staphylococcus (16.8%), Enterobacteriaceae (14.2%), Pseudomonas aeruginosa (13.3%), and streptococcal species (8.9%). Pseudomonas species were the most common isolates from the lacrimal pathways (20.0%). Streptococci were the most common isolates cultured from the conjunctiva (27.3%). Coagulase-positive staphylococcus was the most common isolate from corneal ulcers (33.3%), and coagulase-negative staphylococcus from the vitreous (30.8%). The overall antibiotic sensitivity of common ophthalmic pathogens was similar to that reported from other parts of the world. CONCLUSIONS: Although essentially similar to previous series, this report from the Middle East differs as follows. Firstly, Pseudomonas species were the most common isolates from the lacrimal pathways. Secondly, the overall rate of streptococcal isolates was lower than in previous reports. Thirdly, streptococcal species were rarely isolated from corneal samples. Although other studies from the region have described the causative organisms of ocular infections in specific ocular sites, this is the first study from the Middle East to summarize the full bacteriological profile of ocular infections in one medical center.

Anti-Bacterial Agents↗
PubMedDate not supplied

Expression of E-cadherin is associated with squamous differentiation in squamous cell carcinomas.

E-cadherin is a cell surface molecule that mediates cell-cell adhesion in normal epithelium. Disabled or aberrant E-cadherin expression increases cell motility and promotes the transition of well-differentiated adenoma to invasive carcinoma. To evaluate whether E-cadherin could serve as a biomarker of squamous cell differentiation, we analyzed its expression by immunohistochemistry in formalin-fixed, paraffin-embedded tissue sections of 7 head and neck cancer patients, 19 lung cancer patients, 73 esophageal cancer patients, 19 skin cancer patients, and 18 cervical cancer patients. E-cadherin was expressed at very high levels (93%-100%) in adjacent or distant normal squamous epithelia. Likewise, most (75-100%) well-differentiated squamous cell carcinomas (SCCs) also expressed E-cadherin. In contrast, poorly differentiated SCCs expressed less than 40% of E-cadherin. Furthermore, immunohistochemical analysis showed that the differentiation-inducing agent, all-trans retinoic acid, can up-regulate E-cadherin expression in esophageal SCC cells in vitro. Our data demonstrated that E-cadherin expression is associated with SCC differentiation and that may serve as a squamous cell differentiation marker.

Biomarkers, Tumor↗
PubMedDate not supplied

Receptor-independent induction of apoptosis by synthetic retinoids.

Retinoids modulate cell proliferation, differentiation and apoptosis. Many of these effects are mediated by nuclear retinoid receptors. However, studies with certain synthetic retinoids, including some that can activate retinoid receptors, revealed that they affect cell growth and especially apoptosis by mechanisms that are independent of nuclear receptors. This chapter describes the pro-apoptotic effects of the synthetic retinoid CD437 [6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid], and structurally-related retinoids and summarizes the mechanisms by which they induce apoptosis.

Animals↗
PubMedDate not supplied

Retinoic acid inhibits human melanoma tumor cell invasion.

The anticancer effects of retinoids have been recognized both in vivo and in vitro; however, little is known about their mechanism of action. Our study evaluated the effects of retinoic acid on the invasiveness of four human melanoma cell lines in vitro and showed a time-dependent inhibition of the ability of these cells to penetrate matrigel-coated filters. The possible mechanisms of action responsible for the anti-invasive effect were further investigated, and the data showed that retinoic acid-treated cells: (a) secreted lower levels of collagenolytic enzymes detected in type IV collagen-containing polyacrylamide gels compared with control cells, which was demonstrated by a decreased ability to degrade [3H]proline-labeled type IV collagen substrate; (b) showed a reduction in PA activity, primarily in the form of tPA, as demonstrated by chromogenic analysis; (c) showed a heterogeneous response with regard to c-myc, c-fos and c-jun mRNA expression, as determined by Northern blot analysis; and (d) demonstrated a decrease in B-actin levels and an increase in vimentin, as demonstrated by Northern blot analysis and SDS-PAGE transblot analysis. Collectively, these data suggest that RA causes an inhibitory effect on tumor cell invasion through a reconstituted basement basement membrane matrix by suppressing type IV collagenolytic activity and PA activity, which is probably triggered through a complex series of oncogene trans-acting factors, ultimately affecting cytoskeletal expression.

Actins↗
PubMedDate not supplied

The natural history of cervical intraepithelial neoplasia: an argument for intermediate endpoint biomarkers.

Cervical cancer is the second most common malignancy in women worldwide and remains a significant health problem for women, especially minority women in the United States. Despite morbid and costly treatment with whole pelvic radiotherapy, radical surgery, and chemotherapy, the overall survival remains 40%. While the epidemiological risk factors are well known, little is known of the pathobiology of cervical carcinogenesis. Prevention of cervical cancer and its precursors is an important objective. New strategies, both clinical and laboratory based, are desperately needed. Cellular and molecular characteristics of the pathobiology of cervical cancer and its precursors need to be quantified, thereby providing insights into the multistep process of cervical carcinogenesis, identifying those precancerous lesions at high risk for progression to invasion, providing potential targets for intervention, and providing intermediate end point biomarkers for chemopreventive therapies. The premise for this strategy in cervical cancer prevention is that squamous cancers of the female genital tract have a well defined preinvasive stage, and that carcinogenesis is a multistep genetic process which involves increasing dysregulation of proliferation and differentiation as lesions progress from normal to human papillomavirus infected tissue to cervical intraepithelial neoplasia to cancer.

Carcinoma, Squamous Cell↗
PubMedDate not supplied

Retinoids and their receptors in modulation of differentiation, development, and prevention of head and neck cancers.

Retinoids suppress oral premalignant lesions (OPLs) and decrease the incidence of second primary tumors in head and neck (HN) cancer patients. The optimal clinical use of retinoids depends on the understanding of the mechanism by which they suppress carcinogenesis. It is thought that retinoids restore normal cell growth and differentiation by means of nuclear retinoic acid (RA) receptors (RAR alpha, beta, and gamma) and retinoid X receptors (RXR alpha, beta, and gamma). We used cultured HNSCC cell lines and surgical specimens from normal oral mucosa and from premalignant oral lesions and HN squamous cell carcinomas (HNSCCs) to understand fundamental aspects of retinoids mode of action. RA inhibited the growth and suppressed the aberrant squamous cell differentiation in the majority of HNSCC cell lines examined. Four cell lines expressed mRNAs for RAR alpha, RAR beta, RAR gamma, and RXR alpha. RA treatment increased the levels of the three RAR mRNAs in most of the cell lines but had no effect on the RXR mRNAs. An inverse relationship has been established between the level of RAR beta and squamous differentiation markers. The expression of retrovirally transduced RAR beta in a HNSCC cell line, which did not express RAR beta constitutively, showed a 1,000-fold increase in sensitivity to the suppression of squamous cell differentiation by RA. The expression of retrovirally transduced RAR gamma sense rendered the cells more sensitive, and expression of retrovirally transduced RAR gamma anti-sense made them less sensitive to growth inhibition by RA than parental cells. These results indicate that RAR beta may mediate suppression of squamous differentiation, whereas RAR gamma may mediate the growth inhibition. RAR alpha, RAR beta, RAR gamma, RXR alpha, and RXR beta mRNAs were detected by in situ hybridization in specimens from normal oral mucosa, and all but RAR-beta were also expressed in most of the adjacent normal, hyperplastic, dysplastic, and malignant HN tissues. In contrast, RAR beta mRNA was detected in only 70% of adjacent normal and hyperplastic HN lesions, and its expression was decreased further to 56% of dysplastic lesions and to 35% of SCCs. Likewise, RAR beta was expressed in only 40% of OPLs. Treatment of OPLs with 13-cis-RA increased RAR beta expression from 40% to 90% of the cases. The increase in RAR beta level was associated with clinical response. These results show that selective loss of RAR beta mRNA expression occurs in the early stages of carcinogenesis and may be involved in HN cancer development; and demonstrate that RAR beta is induced by 13-cis-RA in humans.

Cell Differentiation↗