Protection against malignant conversion in SENCAR mouse skin by all Trans retinoic acid: Inhibition of the ras p21-processing enzyme farnesyltransferase and Ha-ras p21 membrane localization

Many studies have shown that all trans retinoic acid (RA) exhibits significant protective effects against mouse skin tumor promotion and spontaneous as well as enhanced malignant conversion. In a recently completed study, we showed that under treatments in which papillomas on SENCAR mouse skin are induced at low and high probabilities to convert to malignant carcinomas, RA affords significant protection against both tumor promotion and subsequent malignant conversion. More than 95% of these mouse skin papillomas and carcinomas have been shown to contain point mutation at the 61 codon of Ha-ras oncogene. The ras oncogene encodes a p21 protein that, in its mutated form, transforms mammalian cells only when p21 is at the inner surface of the plasma membrane, by a series of enzymatic reactions in which the initial step is catalyzed by farnesyltransferase (FTase). In this study, we assessed whether the protective effect of RA against malignant conversion involves the inhibition of ras p21 processing in those tumors that contain the activated ras oncogene. The FTase activity and the levels of cytosolic and membrane-bound Ha-ras p21 were determined in all papillomas and carcinomas obtained from acetone- or RA-treated animals. No matter how the data were analyzed and what comparisons were considered, in all the protocols used, compared with controls, papillomas and carcinomas obtained from RA-treated groups showed significantly decreased (P < 0.01–0.001) FTase activity. Furthermore, the tissue samples from RA-treated groups in different protocols also showed significantly diminished membrane localization of Ha-ras p21, with a concomitant increase in cytosolic Ha-ras p21 levels. The analysis of these data also showed that in all the protocols used, the increased FTase activity and membrane localization of Ha-ras p21 were associated with the induction of papillomas and their subsequent malignant conversion to squamous cell carcinomas. Taken together, these results indicate a strong correlation between the inhibition of ras p21 farnesylation because of a decrease in FTase activity by RA and its protective effect against malignant conversion of papillomas to carcinomas. Based on the results of this study, it is tempting to suggest that clinical trials evaluating the preventive or therapeutic potential of retinoids may be directed more toward those clinical malignancies that are known to contain the activated ras oncogene. © 1996 Wiley-Liss, Inc.     

Development of rapid and selective epoxidation of α-pinene using single-step addition of H2O2 in an organic solvent-free process

This study reports substantial improvement in the process for oxidising α-pinene, using environmentally friendly H₂O₂ at high atom economy (∼93%) and selectivity to α-pinene oxide (100%). The epoxidation of α-pinene with H₂O₂ was catalysed by tungsten-based polyoxometalates without any solvent. The variables in the screening parameters were temperatures (30–70 °C), oxidant amount (100–200 mol%), acid concentrations (0.02–0.09 M) and solvent types (i.e., 1,2-dichloroethane, toluene, p-cymene and acetonitrile). Screening the process parameters revealed that almost 100% selective epoxidation of α-pinene to α-pinene oxide was possible with negligible side product formation within a short reaction time (∼20 min), using process conditions of a 50 °C temperature in the absence of solvent and α-pinene/H₂O₂/catalyst molar ratio of 5 : 1 : 0.01. A kinetic investigation showed that the reaction was first-order for α-pinene and catalyst concentration, and a fractional order (∼0.5) for H₂O₂ concentration. The activation energy (E_a) for the epoxidation of α-pinene was ∼35 kJ mol⁻¹. The advantages of the epoxidation reported here are that the reaction could be performed isothermally in an organic solvent-free environment to enhance the reaction rate, achieving nearly 100% selectivity to α-pinene oxide.

Products obtained from the oxidation of α-pinene with hydrogen peroxide (H₂O₂) in the presence of tungsten-based polyoxometalates (α-pinene 1, α-pinene oxide 2, pinanediol 3, campholenic aldehyde 4, sobrerol 5, verbenol 6 and verbenone 7).     

Impact of COVID-19 on cancer management in military hospitals of Saudi Arabia

Objectives:To evaluate the impact of COVID-19 on cancer management in Saudi Arabia’s military hospitals.Methods:This multi-centric, retrospective study compared cancer patients diagnosed from February-July 2019 and 2020, focusing on the time duration for acceptance and time for oncologic treatment initiation. Eligibility and referral status were recorded. Clinical data of COVID-19-positive cancer patients were collected and evaluated their outcomes and survival.Results:Data of 1574 cancer patients (mean age, 57.1 years) were collected. Mean time for acceptance was 7.3 days in 2019 and 8 days in 2020, with no statistically significant difference. Mean time for oncology treatment initiation was 38.4 days in 2019 and 44.3 days in 2020, with no statistically significant difference. The number of new cancer patients decreased in 2020 but increased in peripheral hospitals. It decreased in Riyadh and Jeddah hospitals. Concerning referral status, a statistically significant modification was recorded only in Riyadh and Tabuk hospitals. No significant changes observed in time duration for acceptance of new patients and oncology treatment initiation from 2019-2020. A total of 76 COVID-19-positive cancer patients recorded; 72% were symptomatic, 73.6% recovered, 22.3% died due to COVID-19 complications, and 8% died due to cancer; cancer progressed in 7 patients.Conclusion:COVID-19 did not affect oncology service in Saudi Arabia’s military hospitals. New cancer cases reduced during the pandemic. Cancer patients are at increased risk for COVID-19 complications, including death.     

Delphinidin,a dietary antioxidant,induces human epidermal keratinocyte differentiation but not apoptosis: studies in submerged and three‐dimensional epidermal equivalent models

Delphinidin (Del), [3,5,7,3'‐,4'‐,5'‐hexahydroxyflavylium], an anthocyanidin and a potent antioxidant abundantly found in pigmented fruits and vegetables exhibits proapoptotic effects in many cancer cells. Here, we determined the effect of Del on growth, apoptosis and differentiation of normal human epidermal keratinocytes (NHEKs) in vitro in submerged cultures and examined its effects in a three‐dimensional (3D) epidermal equivalent (EE) model that permits complete differentiation reminiscent of in vivo skin. Treatment of NHEKs with Del (10–40 μm ; 24–48 h) significantly enhanced keratinocyte differentiation. In Del‐treated cells, there was marked increase in human involucrin (hINV) promoter activity with simultaneous increase in the mRNA and protein expressions of involucrin and other epidermal differentiation markers including procaspase‐14 and transglutaminase‐1 (TGM1), but without any effect on TGM2. Del treatment of NHEKs was associated with minimal decrease in cell viability, which was not associated with apoptosis as evident by lack of modulation of caspases, apoptosis‐related proteins including Bcl‐2 family of proteins and poly(ADP‐ribose) polymerase cleavage. To establish the in vivo relevance of our observations in submerged cultures, we then validated these effects in a 3D EE model, where Del was found to significantly enhance cornification and increase the protein expression of cornification markers including caspase‐14 and keratin 1. For the first time, we show that Del induces epidermal differentiation using an experimental system that closely mimics in vivo human skin. These observations suggest that Del could be a useful agent for dermatoses associated with epidermal barrier defects including aberrant keratinization, hyperproliferation or inflammation observed in skin diseases like psoriasis and ichthyoses.     

Ptosis postcardiac surgery: a case of pituitary apoplexy

We present a patient in whom ptosis and third cranial nerve palsy developed postcoronary artery bypass grafting, and discuss the management of pituitary apoplexy postcardiac surgery.     

Accident prevention program in a glass factory in Shoubra El Khema district

BACKGROUND: An accident can be defined as an unplanned event that results in or suggests the possibility of personal injury, property damage production interruption diminished health or environmental damage. The accidents have a cost impact on the employees and the company itself. OBJECTIVE: This intervention study was carried out to decrease the accident rate in a glass factory in Shoubra El-Khema district. METHODS: A glass factory in Shoubra El-Khema was selected to implement an intervention program. The program was done through three phases. 1. A preliminary interview questionnaire. 2. Seminars of health education were done to all workers and managers with availability of health education posters, establishment of accident committee and a new reporting system, contract with a housekeeping company was done and also training of some leaders. 3. Concurrent and final evaluation of the program was done. RESULTS: The incidence rate, frequency and severity rate of accidents were decreased at the end of the year after the intervention program. The differences were statistically significant. The opinions of the workers and managers about the different causes of accidents were changed. The belief of the workers and managers about efficiency of health educatio program was changed. Some leaders were trained on skills of health education. Modification of reporting and notification system was done. CONCLUSION: This intervention study succeeded in decreasing accidents rates and increasing the awareness of the managers to decrease accident rates. The beliefs and thoughts o both workers and managers became near to each other. The production loss due to days lost by accidents was reduced. RECOMMENDATIONS: Upgrading process in the factory are recommended to eliminate the hazards at source. Sustaining and continuation of the established preventive program should be done. Trying to apply the program in similar factories is also recommended.     

A novel biomarker for staging human prostate adenocarcinoma: overexpression of matriptase with concomitant loss of its inhibitor, hepatocyte growth factor activator inhibitor-1.

BACKGROUND: Matriptase, a type II transmembrane serine protease is involved in angiogenesis, degradation of extracellular matrix, and in the progression of some epithelial cancers. Here, we establish the clinical significance of matriptase and its inhibitor, hepatocyte growth factor activator inhibitor-1 (HAI-1), during the progression of human prostate cancer (CaP). METHODS: The expression patterns of matriptase and HAI-1 were determined in primary cultures of normal human prostate epithelial (NHPE) cells, human CaP cells LNCaP, DU-145, CWR22Rnu1, and PC-3, and in tissue samples of 172 patients with normal prostate, benign prostatic hyperplasia (BPH), prostatic intraepithelial neoplasia (PIN), and adenocarcinoma of different tumor grades. RESULTS: The protein and mRNA levels of matriptase were significantly higher in all carcinoma cells as compared with NHPE cells. Conversely, all CaP cells exhibited a reduced expression of HAI-1 as compared with NHPE cells. A progressive increase in the protein levels of matriptase was observed with increasing tumor grade in CaP specimens as compared with normal and BPH tissue specimens. Tissue samples of normal prostate exhibited a high constitutive protein level of HAI-1 compared with BPH and low-grade cancer with a progressive loss with increasing tumor grade. CONCLUSION: The increased expression of matriptase and loss of HAI-1 may be an important event during the progression of CaP in humans. We suggest that the ratio of these two gene products may serve as a promising biomarker for CaP progression and a potential marker for establishing the efficacy of therapeutic and chemopreventive interventions.     

Ras protein p21 processing enzyme farnesyltransferase in chemical carcinogen—induced murine skin tumors

Farnesylation of ras protein p21 is crucial for the protein's membrane localization, which is essential for its cell-transforming activity, which in turn is thought to be critical for the ultimate induction of cancer. The cytosolic enzyme farnesyltransferase plays a major role in posttranslational modification of p21, but the level of farnesyltransferase activity in mammalian tumors and its relationship to the processing of cytosolic p21 that leads to tumorigenesis are unknown. We report here that farnesyltransferase activity was significantly higher in chemical carcinogen—induced benign skin papillomas in SENCAR mice than in the epidermises of control animals. The enzyme is primarily epidermal in origin, and kinetic studies with cytosol from epidermis and papillomas showed that the reaction was linear with respect to time, substrate concentration, and protein content. Skin papillomas showed significantly elevated levels of both cytosolic and membrane-bound Ha-ras p21, whereas far lesser cytosolic and almost negligible amounts of membrane-bound p21 were present in the epidermis of control mice. There was a positive correlation between increased enzyme activity in papilloma cytosol and the processing of overexpressed cytosolic Ha-ras p21 for its localization to membrane.