Expression and potential role of the peptide orexin-A in prostate cancer

The peptides orexin-A and orexin-B and their G protein-coupled OX1 and OX2 receptors are involved in multiple physiological processes in the central nervous system and peripheral organs. Altered expression or signaling dysregulation of orexins and their receptors have been associated with a wide range of human diseases including narcolepsy, obesity, drug addiction, and cancer. Although orexin-A, its precursor molecule prepro-orexin and OX1 receptor have been detected in the human normal and hyperplastic prostate tissues, their expression and function in the prostate cancer (PCa) remains to be addressed. Here, we demonstrate for the first time the immunohistochemical localization of orexin-A in human PCa specimens, and the expression of prepro-orexin and OX1 receptor at both protein and mRNA levels in these tissues. Orexin-A administration to the human androgen-dependent prostate carcinoma cells LNCaP up-regulates OX1 receptor expression resulting in a decrease of cell survival. Noteworthy, nanomolar concentrations of the peptide counteract the testosterone-induced nuclear translocation of the androgen receptor in the cells: the orexin-A action is prevented by the addition of the OX1 receptor antagonist SB-408124 to the test system. These findings indicate that orexin-A/OX1 receptor interaction interferes with the activity of the androgen receptor which regulates PCa onset and progression, thus suggesting that orexin-A and its receptor might represent novel therapeutic targets to challenge this aggressive cancer

Tremelimumab and durvalumab combination for the non-operative management (Nom) of microsatellite instability (msi)-high resectable gastric or gastroesophageal junction cancer: The multicentre, single-arm, multi-cohort, phase ii infinity study

SIMPLE SUMMARY: The status of microsatellite instability (MSI-H) in gastric or gastroesophageal junction cancer (GC/GEJC) patients eligible for radical surgery proved to be prognostic for an improved survival outcome and predictive for poor/no benefit from the combination of adjuvant/peri-operative chemotherapy. MSI-H tumors display a high sensitivity to immunotherapy and exploratory studies showed that a pre-operative treatment with immune-checkpoint inhibitors may achieve elevated rates of pathological complete responses. The ongoing proof-of-concept INFINITY study is aimed at investigating the role of the combo-immunotherapy durvalumab plus tremelimumab as a neoadjuvant or potentially definitive treatment (avoiding surgery in case of complete clinical response) for MSI-H resectable GC/GEJC patients. ABSTRACT: In resectable gastric or gastroesophageal junction cancer (GC/GEJC), the powerful positive prognostic effect and the potential predictive value for a lack of benefit from the combination of adjuvant/peri-operative chemotherapy for the MSI-high status was demonstrated. Given the high sensitivity of MSI-high tumors for immunotherapy, exploratory trials showed that combination immunotherapy induces a high rate of complete pathological response (pCR), potentially achieving cancer cure without surgery. INFINITY is an ongoing phase II, multicentre, single-arm, multi-cohort trial investigating the activity and safety of tremelimumab and durvalumab as neoadjuvant (Cohort 1) or potentially definitive (Cohort 2) treatment for MSI-high/dMMR/EBV-negative, resectable GC/GEJC. About 310 patients will be pre-screened, to enroll a total of 31 patients, 18 and 13 in Cohort 1 and 2, at 25 Italian Centres. The primary endpoint of Cohort 1 is rate of pCR (ypT0N0) and negative ctDNA after neoadjuvant immunotherapy, of Cohort 2 is 2-year complete response rate, defined as absence of macroscopic or microscopic residual disease (locally/regionally/distantly) at radiological examinations, tissue and liquid biopsy, during non-operative management without salvage gastrectomy. The ongoing INFINITY proof-of-concept study may provide evidence on immunotherapy and the potential omission of surgery in localized/locally advanced GC/GEJC patients selected for dMMR/MSI-high status eligible for radical resection

Some chemical-physical properties of tricyclohexyltin hydroxide and its analytical determination

A gas-liq. chromatog. method is reported for detg. tricyclohexyltin hydroxide in powders marketed as insecticides, after its extn. with CHCl3. Different glass columns were tested using flame ionization or electron capture detectors. The linearity of the response was from 0.1 to 2.5 mg using the flame ionization detector and from 0.5 to 5.0 ng using the electron capture detector. Its recovery from the analyzed samples is satisfactory. Results of thermal anal., I.R. spectroscopy and mass spectrometry were also reporte

Gas-liquid chromatographic analysis of bioresmethrin

Bioresmethrin was detd. by gas chromatog. using flame ionization or electron capture detectors. The detection threshold for both detectors was 0.1 mg. In the presence of piperonyl butoxide, it was detd. as 2-benzyl-4-hydroxymethylfuran, an alk. hydrolysis product. Principal gas chromatog. parameters were: column packing (e.g. 3% OV-101 absorbed on 100-140 mesh Chromosorb G-HP); carrier gases (N2 for flame ionization and Ar-CH4 mixt. for electron capture); detector and injection port temps., 300

Valutazione dell’esposizione personale ad idrocarburi policiclici aromatici ed a benzene, toluene e xileni di lavoratori di una centrale termoelettrica che utilizza olio combustibile denso

Occupational exposure to polycyclic aromatic hydrocarbons (PAHs) has been demonstrated in many industrial sectors. However, up to date there are few studies in the literature on PAH exposure in thermoelectric power plants. The study was aimed at the evaluation of personal exposure to PAHs in workers or a power plant fuelled with heavy oil. Exposure to polycyclic aromatic hydrocarbons (PAHs) and to benzene, toluene and xylenes (BTX) was evaluated on powerplant workers exposed to heavy fuel oil; the control group consisted of office workers of the same power plant. Altogether 39 subjects were studied, for a total of 84 days of monitoring. Personal environmental exposure, cutaneous exposure and urinary concentrations of 1-hydroxypyrene (1-OHP), trans, trans-muconic acid (TTMA) and nicotine were measured. Personal environmental exposure to PAHs was very low; only maintenance workers showed exposure to total carcinogenic PAHs significantly higher than controls (median levels 3.05 and 0.88 ng/m3 respectively). All workers showed very low levels of dermal exposure to PAHs (less than 1 ng). The median 1-OHP urinary concentrations were 0.16, 0.11 and 0.08 \u3bcmol/mol creatinine in the groups of exposed workers and 0.08m \u3bcmol/mol creatinine in the control group. Neither the exposed workers nor the controls showed a significant increase in 1-OHP urinary concentrations across the shift. The regression analysis showed a significant effect of cigarette smoking on urinary 1-OHP, while no association was observed between occupational exposure and diet. Personal environmental exposure levels to BTX were very low. TTMA urinary concentrations of the exposed subjects were similar to those of the controls. No significant increase in the TTMA urinary concentrations was observed across the shift and, as expected, smokers showed higher values than non-smokers. The study did not show a measurable intake of PAHs and BTX in power plant workers that could be ascribed to occupational exposure, thus confirming the efficacy of the protective measures in force

Mortality among workers in the geothermal power plants at Larderello, Italy

Background Since the early 1990s, various European electricity companies have set up a research program, named EURELEX, devoted to the development of a comprehensive and validated title-occupation -job-exposure matrix (i.e., an instrument to assess exposures from occupations and jobs), in order to estimate and quantify, past exposure to a number of potentially carcinogenic agents plus a few selected other toxic substances. The EURELEX program was first applied in Italy to a cohort of geothermal workers in Larderello, Tuscany. Methods The cohort mortality study comprised 4,237 men who had worked at the geothermal power plant between 1950 and 1990. Vital status and death certificates were obtained from registration offices in the municipality of birth or death. Particular attention was paid to neoplastic effects of exposure to asbestos, largely used in the past for pipeline insulating purposes The matrix allowed the workers to be subdivided into several categories according to estimated asbestos exposure. Smoking information was not available. Results No excess mortality was found for all causes and total cancer mortality. A small excess of pleural cancer (2 obs. vs 1.4 exp.) was not statistically significant The effect of other agents included in the matrix was also examined: the small excess of leukemia among those exposed to solvents prior to 1963 (year of benzene ban in Italy) did not reach the level of statistical significance. No cases of leukemia were found among the workers presumed to have been exposed to important ELF electromagnetic fields. Conclusion The study provides reassuring information, on a large cohort of a unique geothermal power plant since no significant excess mortality for asbestos related cancers was observed Furthermore, it represents a useful application and validation of a comprehensive job-exposure matrix for the electric industry in Europe. Am. J. Ind. Med. 35:536-539, 1999, (C) 1999 Wiley-Liss, Inc