[Formaldehyde in electronic cigarettes and in heat-not-burn products: let's make the point]. / La formaldeide nelle sigarette elettroniche e nei riscaldatori di tabacco (HnB): facciamo il punto.

The spread of electronic cigarettes (e-cigs) and of the so-called heat-not-burn (HnB), also known as heated tobacco products, presented as a less harmful alternative to traditional cigarettes, required further in-depth studies to demonstrate the real benefits or possible risks linked to this type of habit among smokers and possible new smokers. There are numerous harmful substances produced by these devices, such as metals, organic compounds, and aldehydes. The presence of formaldehyde is particularly worrying: its indoor concentration is 2.7, 1.2, and 40 µg/m3 for HnB, e-cigs, and traditional cigarettes, respectively. The evidence of this substance, which numerous epidemiological studies have already shown to be harmful to health (in particular, the International Agency for Research on Cancer classified it as a group 1 carcinogen), would lead to the need to modify the legislation with more restrictive rules on the use of these devices in public environment and in particular in the presence of more susceptible subjects, such as minors and pregnant women.

CpG-oligodeoxynucleotides exert remarkable antitumor activity against diffuse malignant peritoneal mesothelioma orthotopic xenografts.

BACKGROUND: Diffuse malignant peritoneal mesothelioma (DMPM) is a rare and locally aggressive disease. DMPM prognosis is dismal, mainly due to the lack of effective treatment options and the development of new therapeutic strategies is urgently needed. In this context, novel immunotherapy approaches can be explored in an attempt to improve DMPM patients' survival. METHODS: We tested the efficacy of CpG-oligodeoxynucleotides (CpG-ODN), synthetic DNA sequences recognized by Toll-like receptor 9 and able to induce innate/adaptive immune response, in two DMPM orthotopic xenografts (MesoII and STO), which properly recapitulate the dissemination pattern of the disease in the peritoneal cavity. Severe combined immunodeficiency mice carrying DMPM xenografts were treated at different stages of tumor development with i.p. delivered CpG-ODN1826 for 4 weeks. CpG-ODN1826-induced modulation in the composition of peritoneal immune infiltrate was assessed by flow cytometry. RESULTS: When administered to early-stage tumors (i.e., 4 days after i.p. DMPM cell injection in mice), the agent exhibited impressive efficacy against MesoII by completely inhibiting tumor take and ascites development (no evidence of tumor masses and ascites in 6/6 mice at necropsy), and also impaired STO tumor take and growth (4/6 tumor-free mice; i.p. tumor masses reduced by 94 % in the 2 remaining mice, P = 0.00005). Interestingly, when tested against late-stage STO tumors (i.e., 11 days after i.p. DMPM cell injection in mice), CpG-ODN1826 was still able to reduce the growth of i.p. tumor masses by 66 % (P = 0.0009). Peritoneal washings of tumor-bearing mice revealed a strong increase of macrophage infiltration together with a decrease in the presence of B-1 cells and a reduced IgM concentration after CpG-ODN1826 treatment. CONCLUSIONS: Our results indicate that locally administered CpG-ODN1826 is able to markedly affect the growth of both early- and late-stage DMPM orthotopic xenografts in the absence of severe side effects, and suggest a possible clinical role for the agent in the therapy of DMPM.

A gene expression-based classifier for HER2-low breast cancer.

In clinical trials evaluating antibody-conjugated drugs (ADCs), HER2-low breast cancer is defined through protein immunohistochemistry scoring (IHC) 1+ or 2+ without gene amplification. However, in daily practice, the accuracy of IHC is compromised by inter-observer variability. Herein, we aimed to identify HER2-low breast cancer primary tumors by leveraging gene expression profiling. A discovery approach was applied to gene expression profile of institutional INT1 (n = 125) and INT2 (n = 84) datasets. We identified differentially expressed genes (DEGs) in each specific HER2 IHC category 0, 1+, 2+ and 3+. Principal Component Analysis was used to generate a HER2-low signature whose performance was evaluated in the independent INT3 (n = 95), and in the publicly available TCGA and GSE81538 datasets. The association between the HER2-low signature and HER2 IHC categories was evaluated by Kruskal-Wallis test with post hoc pair-wise comparisons. The HER2-low signature discriminatory capability was assessed by estimating the area under the receiver operating characteristic curve (AUC). Gene Ontology and KEGG analyses were performed to evaluate the HER2-low signature genes functional enrichment. A HER2-low signature was computed based on HER2 IHC category-specific DEGs. The twenty genes included in the signature were significantly enriched with lipid and steroid metabolism pathways, peptidase regulation, and humoral immune response. The HER2-low signature values showed a bell-shaped distribution across IHC categories (low values in 0 and 3+; high values in 1+ and 2+), effectively distinguishing HER2-low from 0 (p < 0.001) to 3+ (p < 0.001). Notably, the signature values were higher in tumors scored with 1+ as compared to 0. The HER2-low signature association with IHC categories and its bell-shaped distribution was confirmed in the independent INT3, TCGA and GSE81538 datasets. In the combined INT1 and INT3 datasets, the HER2-low signature achieved an AUC value of 0.74 (95% confidence interval, CI 0.67-0.81) in distinguishing HER2-low vs. the other categories, outperforming the individual ERBB2 mRNA AUC value of 0.52 (95% CI 0.43-0.60). These results represent a proof-of-concept for an observer-independent gene-expression-based classifier of HER2-low status. The herein identified 20-gene signature shows promise in distinguishing between HER2 0 and HER2-low expressing tumors, including those scored as 1+ at IHC, and in developing a selection approach for ADCs candidates.

The Impact of Russia-Ukraine geopolitical conflict on the air quality and toxicological properties of ambient PM2.5 in Milan, Italy.

The geopolitical conflict between Russia and Ukraine has disrupted Europe's natural gas supplies, driving up gas prices and leading to a shift towards biomass for residential heating during colder months. This study assessed the consequent air quality and toxicological impacts in Milan, Italy, focusing on fine particulate matter (PM2.5, dp < 2.5 µm) emissions. PM2.5 samples were analyzed for their chemical composition and assessed for their oxidative potential using the dithiothreitol (DTT) assay across three periods reflecting residential heating deployment (RHD): pre-RHD, intra-RHD, and post-RHD periods. During the intra-RHD period, PM2.5 levels were significantly higher than those in other periods, with concentrations reaching 57.94 ± 7.57 µg/m3, indicating a deterioration in air quality. Moreover, levoglucosan was 9.2 times higher during the intra-RHD period compared to the pre-RHD period, correlating with elevated levels of elemental carbon (EC) and polycyclic aromatic hydrocarbons (PAHs). These findings were compared with previous local studies before the conflict, underscoring a significant rise in biomass-related emissions. DTT assay levels during the intra-RHD were 2.1 times higher than those observed during the same period in 2022, strongly correlating with biomass burning emissions. Our findings highlight the necessity for policies to mitigate the indirect health effects of increased biomass burning emissions due to the energy crisis triggered by the geopolitical conflict.

A phase II study evaluating the efficacy of enzalutamide and the role of liquid biopsy for evaluation of ARv7 in mCRPC patients with measurable metastases including visceral disease (Excalibur study).

Background: Up to 30% of patients with metastatic castration-resistant prostate cancer (mCRPC) develop visceral metastases, which are associated with a poor prognosis. Objectives: Efficacy of enzalutamide in mCRPC patients with measurable metastases, including visceral and/or extra-regional lymph nodes. Methods: In this phase II multicenter study, patients with mCRPC and measurable metastases received enzalutamide as the first line. Primary endpoint: 3-month (mo) disease control rate (DCR) defined as the proportion of patients with complete (CR) or partial response (PR) or stable disease (SD) as per Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoint: safety. Exploratory endpoint: the association between ARv7 splicing variants in basal circulating tumor cell (CTC)-enriched blood samples and treatment response/resistance using the AdnaTest ProstateCancerSelect kit and the AdnaTest ProstateCancer Panel AR-V7. Results: From March 2017 to January 2021, 68 patients were enrolled. One patient never started treatment. Median age: 72 years. A total of 52 patients (78%) received enzalutamide as a first line for mCRPC. The median follow-up was 32 months. At the 3-month assessment, 24 patients presented an SD, 1 patient achieved a CR, and 23 patients had a PR (3-mo-DCR of 72%). Discontinuations due to adverse events (AEs), disease-related death, or disease progression occurred in 9%, 6%, and 48% of patients. All patients reported at least one grade (G) 1-2 AE: the most common were fatigue (49%) and hypertension (33%). Six G3 AEs were reported: two hypertension, one seizure, one fatigue, one diarrhea, and one headache. Basal detection of ARv7 was significantly associated with poor treatment response (p = 0.034) and a nonsignificant association (p = 0.15) was observed between ARv7 detection and response assessments. At month 3, ARv7 was detected in 57%, 25%, and 15% of patients undergoing progressive disease, SD, and PR, respectively. Conclusion: The study met its primary endpoint, showing the efficacy of enzalutamide in men with mCRPC and measurable metastatic lesions in visceral and/or lymph node sites. Trial registration: ClinicalTrials.gov Identifier: NCT03103724. First Posted: 6 April 2017. First patient enrollment: 19 April 2017.

Can we define breast cancer HER2 status by liquid biopsy?

Human Epidermal growth factor Receptor 2 (HER2) assessment is crucial for breast cancer treatment. Therapeutic decisions for recurrent cases often rely on primary tumor status. However, mounting evidence suggests that tumors show dynamic changes and up to 10% of breast cancer modify their initial status during progression. It is still debated whether these changes reflect a biological evolution of the disease or are secondary to primary tumor heterogeneity. Certainly, repeating HER2 assessment during breast cancer trajectory is important for the increasing availability of effective anti-HER2 drugs. In response to this need, circulating biomarkers such as circulating tumor cells (CTCs) and cell-free circulating tumor DNA (ctDNA) offer the potential to safely and repeatedly assess HER2 status over time. This chapter outlines current methods for testing HER2 in CTCs and ctDNA, and reviews clinical trials evaluating its prognostic and predictive value in patients with breast cancer, as well as recent advances in the field.

The indole-3-carbinol cyclic tetrameric derivative CTet inhibits cell proliferation via overexpression of p21/CDKN1A in both estrogen receptor-positive and triple-negative breast cancer cell lines.

INTRODUCTION: Indole-3-carbinol (I3C), an autolysis product of glucosinolates present in cruciferous vegetables, and its dimeric derivative (3,3'-DIM) have been indicated as promising agents in preventing the development and progression of breast cancer. We have recently shown that I3C cyclic tetrameric derivative CTet formulated in γ-cyclodextrin (γ-CD) efficiently inhibited cellular proliferation in breast cancer cell lines. This study aims to analyze the mechanisms involved in the in vitro inhibition of cell proliferation and to evaluate the in vivo antitumor activity of CTet in a xenograft study. METHODS: Estrogen receptor-positive MCF-7 and triple-negative MDA-MB-231 breast cancer cell lines were exposed to CTet to evaluate cell cycle perturbation (propidium iodide staining and cytofluorimetric acquisition), induction of autophagic morphological features (co-localization of LC3b autophagosome marker and LAMP2a lysosome marker by immunofluorescence) and changes in protein expression (immunoblot and microarray-based gene expression analyses). To test the in vivo efficacy of CTet, female athymic nude mice inoculated with MCF-7 cells were i.p. treated with 5 mg/kg/day of CTet for five days/week for two weeks and the tumor mass was externally monitored. RESULTS: CTet induced accumulation in G2/M phase without evidence of apoptotic response induction in both cell lines tested. In triple-negative MDA-MB-231 the autophagic lysosomal activity was significantly up-regulated after exposure to 4 µM of CTet for 8 hours, while the highest CTet concentration was necessary to observe autophagic features in MCF-7 cells. The inhibition of Akt activity and p53-independent p21/CDKN1A and GADD45A overexpression were identified as the main molecular events responsible for CTet activity in MCF-7 and p53-mutant MDA-MB-231 cells. In vivo, CTet administration was able to significantly inhibit the growth of MCF-7 xenotransplanted into nude mice, without adverse effect on body weight or on haematological parameters. CONCLUSIONS: Our data support CTet formulated with γ-CD as a promising and injectable anticancer agent for both hormone-responsive and triple-negative breast tumors.

Chemical characterization and source apportionment of fine and coarse particulate matter inside the refectory of Santa Maria Delle Grazie Church, home of Leonardo Da Vinci's "Last Supper".

The association between exposure to indoor particulate matter (PM) and damage to cultural assets has been of primary relevance to museum conservators. PM-induced damage to the "Last Supper" painting, one of Leonardo da Vinci's most famous artworks, has been a major concern, given the location of this masterpiece inside a refectory in the city center of Milan, one of Europe's most polluted cities. To assess this risk, a one-year sampling campaign was conducted at indoor and outdoor sites of the painting's location, where time-integrated fine and coarse PM (PM(2.5) and PM(2.5-10)) samples were simultaneously collected. Findings showed that PM(2.5) and PM(2.5-10) concentrations were reduced indoors by 88 and 94% on a yearly average basis, respectively. This large reduction is mainly attributed to the efficacy of the deployed ventilation system in removing particles. Furthermore, PM(2.5) dominated indoor particle levels, with organic matter as the most abundant species. Next, the chemical mass balance model was applied to apportion primary and secondary sources to monthly indoor fine organic carbon (OC) and PM mass. Results revealed that gasoline vehicles, urban soil, and wood-smoke only contributed to an annual average of 11.2 ± 3.7% of OC mass. Tracers for these major sources had minimal infiltration factors. On the other hand, fatty acids and squalane had high indoor-to-outdoor concentration ratios with fatty acids showing a good correlation with indoor OC, implying a common indoor source.

The impact of stay-home policies during Coronavirus-19 pandemic on the chemical and toxicological characteristics of ambient PM2.5 in the metropolitan area of Milan, Italy.

The goal of this study was to characterize changes in components and toxicological properties of PM2.5 during the nationwide 2019-Coronavirus (COVID-19) lockdown restrictions in Milan, Italy. Time-integrated PM2.5 filters were collected at a residential site in Milan metropolitan area from April 11th to June 3rd at 2020, encompassing full-lockdown (FL), the followed partial-lockdown (PL2), and full-relaxation (FR) periods of COVID-19 restrictions. The collected filters were analyzed for elemental and organic carbon (EC/OC), water-soluble organic carbon (WSOC), individual organic species (e.g., polycyclic aromatic hydrocarbons (PAHs), and levoglucosan), and metals. According to online data, nitrogen dioxide (NO2) and benzene (C6H6) levels significantly decreased during the entire COVID-19 period compared to the same time span in 2019, mainly due to the government-backed shutdowns and curtailed road traffic. Similarly, with a few exceptions, surrogates of tailpipe emissions (e.g., traffic-associated PAHs) as well as re-suspended road dust (e.g., Fe, Mn, Cu, Cr, and Ti) were relatively lower during FL and PL2 periods in comparison with year 2019, whereas an increasing trend in mass concentration of mentioned species was observed from FL to PL2 and FR phases due to the gradual lifting of lockdown restrictions. In contrast, comparable concentrations of ambient PM2.5 and black carbon (BC) between lockdown period and the same time span in 2019 were attributed to the interplay between decreased road traffic and elevated domestic biomass burning as a result of adopted stay-home strategies. Finally, the curtailed road traffic during FL and PL2 periods led to ~25% drop in the PM2.5 oxidative potential (measured via 2',7'-dichlorodihydrofluorescein (DCFH) and dithiothreitol (DTT) assays) with respect to the FR period as well as the same time span in 2019. The results of this study provide insights into the changes in components and oxidative potential of PM2.5 in the absence of road traffic during COVID-19 restrictions.

[Smoking in car: monitoring pollution of particulate matter, of organic volatile compounds and of carbon monoxide. The effect of opening the driver's window]. / Fumare in macchina: l'inquinamento da polveri, da composti organici volatili e da monossido di carbonio. L'effetto dell'apertura del finestrino.

OBJECTIVE: to identify the most suitable marker for monitoring ETS inside a moving car, and to verify the efficacy of window opening to reduce ETS pollution inside the car. DESIGN: experimental pilot study. SSETTING AND PARTICIPANTS: monitoring of ETS markers in a moving car. MAIN OUTCOMES MEASURES: we used real time analyzers to measure: n particulate matter as mass (mug/m3, PM1, PM2.5, PM10); n suspended particle number (total number of particles sized >0.3 e >0.4 mum; n the number of particles with aerodynamic size between 0.3-0.4 mum in diameter; n total volatile organic compounds (TVOC); n carbon monoxide (CO). The recordings were carried out inside a car moving on the road at the speed of 50 km/h, with controlled conditions of temperature and relative humidity. RESULTS: after lighting a cigarette, with driver's window closed, the levels of all the pollutants increased dramatically, with peaks of 700 mug/m3 for PM2.5 and PM10, and of over 600,000 particles/ liter, while TVOC reached values up to 6,000 mug/m3 and CO up to 6 ppm. When a cigarette was lit with the window 1/4 open, excess pollution was promptly recorded, although with less intensity. With the window completely open, PM, TVOC and CO concentrations were hardly measurable as compared to background levels. On the contrary, particle number increased dramatically up to over 300,000/liter, mostly due to the submicrometric particle fraction in the range 0.3-0.4 mum. CONCLUSION: smoking just a cigarette inside a car represents an extremely high exposure to ETS. Partially opening the window is useless to prevent the accumulation of pollutants. Complete window opening is helpful to remove coarse PM and volatile pollutants, but is ineffective against submicrometer particles. Measuring particle number seems to be the best way to assess ETS pollution inside a car.

[Observed smoking in car: results of a study of the Regional Health Prevention Service of Veneto, Northern Italy]. / La prevalenza dell'abitudine a fumare in automobile: i risultati dello studio osservazionale in Veneto.

OBJECTIVE: to estimate the prevalence of smokers inside cars or duty vehicles and the presence of children exposed to second hand smoke on board, in the NHS districts of Veneto Region. DESIGN: an observational study was carried out by the technicians of the Prevention department from October 1st to October 17th 2008. The observers had to record sex of the driver and of the passengers, their presumed ages, verify if drivers or passengers were smoking, and if there were any children on board. SETTING AND PARTICIPANTS: 19 Local Health Authorities (90,5%) out of 21 in the Veneto region. MAIN OUTCOMES MEASURES: percentage of crossings monitored out of the total scheduled. RESULTS: a total of 5,928 cars were examined at the crossings, males accounted for 61,4% of the drivers. Smoking overall by at least one person in the car was reported in 409 cases (6.9%, 12% among commercial vehicles), the driver alone was smoking in 87.3% of the cases, whereas only the passenger smoking represented 8.3% of the cases. Both the driver and passenger smoking were 4.4% of the observations. Children were present as passengers in 762 cars (12.9%); there were people smoking with children on board in 7 cars (0.9%). CONCLUSION: in spite of the efforts to limit the dangers of second hand smoke, smoking in car is still a common behaviour, and represents a serious risk both for both, adults and children. Focusing in research projects could help the Department of Prevention of the Local Health Authorities to increase their activities and involvement in the research field.

Selinexor Sensitizes TRAIL-R2-Positive TNBC Cells to the Activity of TRAIL-R2xCD3 Bispecific Antibody.

Triple-negative breast cancer (TNBC) is an aggressive disease with poor prognosis and limited therapeutic options. Recent advances in the immunotherapy field have enabled the development of new treatment strategies, among which the use of bispecific antibodies (BsAbs), able to redirect T cells against tumors, has shown promising results. In particular, a BsAb that uses TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) as a target was constructed and demonstrated good results in redirecting CD3+ T cells to kill TRAIL-R2-expressing TNBC cells. In the present study, we investigated whether treatment with selinexor, a selective inhibitor of nuclear export (SINE) targeting exportin-1/chromosome maintenance protein 1 (XPO1/CRM1), could potentiate the antitumor activity of this BsAb. In combination experiments, we found that selinexor-exposed TNBC cells exhibited greater growth inhibition when treated with the TRAIL-R2xCD3 BsAb than that expected by simple additivity. Similarly, the apoptosis rate in selinexor/TRAIL-R2xCD3 BsAb-treated TNBC cells was significantly higher than that observed after exposure to either single agent. Together, our results suggest that the combination of selinexor and TRAIL-R2xCD3 BsAb can be a viable anticancer strategy and indicate this treatment as a promising therapeutic option for TNBC patients.

Inhaled steroid/tobacco smoke particle interactions: a new light on steroid resistance.

BACKGROUND: Inhaled steroid resistance is an obstacle to asthma control in asthmatic smokers. The reasons of this phenomenon are not yet entirely understood. Interaction of drug particles with environmental tobacco smoke (ETS) could change the aerodynamic profile of the drug through the particle coagulation phenomenon. Aim of the present study was to examine whether steroid particles interact with smoke when delivered in the presence of ETS. METHODS: Beclomethasone-hydrofluoralkane (BDP-HFA) pMDI particle profile was studied after a single actuation delivered in ambient air or in the presence of ETS in an experimental chamber using a light scattering Optical Particle Counter capable of measuring the concentrations of particle sized 0.3-1.0, 1.1-2.0, 2.1-3.0, 3.1-4.0, 4.1-5.0, and > 5.1 microm in diameter with a sampling time of one second. The number of drug particles delivered after a single actuation was measured as the difference between total particle number after drug delivery and background particle number. Two groups of experiments were carried out at different ambient background particle concentrations. Two-tail Student's t-test was used for statistical analysis. RESULTS: When delivered in ambient air, over 90% of BDP-HFA particles were found in the 0.3-1.0 microm size class, while particles sized 1.1-2.0 microm and 2.1-3.0 represented less than 6.6% and 2.8% of total particles, respectively. However, when delivered in the presence of ETS, drug particle profile was modified, with an impressive decrease of 0.3-1.0 microm particles, the most represented particles resulting those sized 1.1-2.0 microm (over 66.6% of total particles), and 2.1-3.0 microm particles accounting up to 31% of total particles. CONCLUSION: Our data suggest that particle interaction between inhaled BDP-HFA pMDI and ETS takes place in the first few seconds after drug delivery, with a decrease in smaller particles and a concurrent increase of larger particles. The resulting changes in aerosol particle profile might modify regional drug deposition with potential detriment to drug efficacy, and represent a new element of steroid resistance in smokers. Although the present study does not provide any functional or clinical assessment, it might be useful to advise smokers and non smokers with obstructive lung disease such as asthma or COPD, to avoid to act inhaled drugs in the presence of ETS in order to obtain the best therapeutic effect.

Multiple mechanisms of telomere maintenance exist and differentially affect clinical outcome in diffuse malignant peritoneal mesothelioma.

PURPOSE: This study aims to investigate the prevalence of the two known telomere maintenance mechanisms, telomerase activity (TA) and alternative lengthening of telomeres (ALT), and to assess their prognostic relevance in diffuse malignant peritoneal mesothelioma (DMPM). EXPERIMENTAL DESIGN: In 44 DMPM specimens obtained from 38 patients, TA was determined using the telomeric repeat amplification protocol and ALT was detected by assaying ALT-associated promyelocytic leukemia nuclear bodies. The prognostic significance of telomere maintenance mechanisms was analyzed by Cox regression in the overall series and in a subset of 29 patients who underwent a uniform treatment regimen consisting of cytoreductive surgery and hyperthermic i.p. chemotherapy. RESULTS: Telomere maintenance mechanisms were detectable in 86.4% of DMPM: ALT or TA alone was found in 18.2% or 63.6% of lesions, respectively, whereas two cases (4.6%) were ALT+/TA+. TA and ALT proved to be inversely associated (P = 0.002). In the overall series, TA was prognostic for 4-year relapse (TA+ versus TA-, hazard ratio, 3.30; 95% confidence interval, 1.23-8.86; P = 0.018) and cancer-related death (TA+ versus TA-, hazard ratio, 3.56; 95% confidence interval, 1.03-12.51; P = 0.045), whereas ALT failed to significantly affect clinical outcome. These results held true also in the subset of patients submitted to uniform treatment with cytoreductive surgery and hyperthermic i.p. chemotherapy. CONCLUSIONS: Our results indicate that both known telomere maintenance mechanisms, TA and ALT, are present in DMPM and differentially affect patient prognosis.

Efficacy of pins and diplomas as a reward for long-term smoking cessation.

AIMS AND BACKGROUND: Since 2004, the Antismoking Center of the National Cancer Institute of Milan has rewarded those who have been ex-smokers for longer than a year with a "former smoker" pin and a diploma. We investigated firstly whether these rewards contributed to maintain smoking withdrawal, secondly, which one of these was more appreciated and why, and thirdly, how they may have influenced the ex-smokers' perception of smoking and how this was reflected on those surrounding them (i.e., ex-smokers' personal and/or interpersonal areas). METHODS: A multiple-choice questionnaire was developed to investigate how much the rewards were appreciated and their effectiveness in maintaining smoking cessation. Moreover, smokers and non-smokers were asked about the impact of the pin. The questionnaire was completed on the phone by the last 100 ex-smokers who entered the pin and diploma program. RESULTS: All subjects appreciated the rewards, but only a few of them considered them as an aid to maintain long-term smoking cessation. Those who preferred the diploma stated that it represented a contribution to their self-esteem, an official recognition of being an ex-smoker, besides being something to show with pride to others. Those who preferred the pin principally stated it allowed them to be an example to other smokers. Most of the subjects reported that they wore the pin in several circumstances, raising interest and admiration. CONCLUSIONS: Rewarding ex-smokers one year after smoking cessation with a small prize may be a useful practice to improve the doctor-patient relationship, which is vital to maintain smoking cessation, and to boost the awareness of the availability of aids to reach this objective.

Comparative evaluation of C1311 cytotoxic activity and interference with cell cycle progression in a panel of human solid tumour and leukaemia cell lines.

The cytotoxic activity of the imidazoacridinone C1311 was related to its effect on cell cycle progression in 16 human cell lines from different solid tumour types and leukaemias. A 72-h exposure to C1311 induced a wide range of growth inhibition (IC50 values ranging from 0.0094 to 0.8 microM; median, 0.279 microM), with the highest activity in the 2 gastric cancer cell lines (IC50, 0.0094 and 0.0098 microM). No significant association was found between in vitro sensitivtity to C1311 and doxorubicin or taxol. Moreover, the activity of C1311 was independent of the p53 gene status of the cell line. Twenty-four-hour exposure to C1311 led to a marked increase in the number of cells in the G2M phase in the majority of cell lines, although the extent of such accumulation was independent of the level of drug cytotoxic activity. C1311 did not generally affect the expression level of cyclin B1 or Cdk1 (p34cdc2) proteins. Conversely, when normalised on the basis of the number of cells arrested in the G2M compartment, Cdk1 kinase activity appeared lower than that of untreated cells in the 4 cell lines showing the most pronounced accumulation in G2M. Overall, such data show that C1311 is active against a variety of human tumour cell lines and strongly support further evaluation of the drug in clinical trials.

Survivin is highly expressed and promotes cell survival in malignant peritoneal mesothelioma.

BACKGROUND: The biology of malignant peritoneal mesothelioma (MPM) is largely unknown. In the present study, we assessed the expression of survivin and other members of the inhibitors of apoptosis proteins (IAP) family (IAP-1, IAP-2 and X-IAP) in a series of 32 MPM surgical specimens and investigated the effects of survivin knockdown in an established MPM cell line. METHODS: Expression of different IAPs was measured by immunohistochemistry. MPM cells were transfected with a small-interfering RNA (siRNA) targeting survivin mRNA and analyzed for survivin expression, growth rate, and ability to undergo spontaneous and drug (cisplatin, doxorubicin)-induced apoptosis. RESULTS: Survivin expression was observed in 29 (91%) surgical MPM specimens, whereas the positivity rate for the other IAPs ranged from 69% to 100%. Transfection of MPM cells with the survivin siRNA induced a marked inhibition of survivin protein expression, a time-dependent decline in cell growth and an enhanced rate of spontaneous and drug-induced apoptosis, with a concomitant increase in the catalytic activity of caspase-9. CONCLUSION: Our results show for the first time that survivin, as well as other IAPs, is largely expressed in clinical MPMs and suggest that strategies aimed at down-regulating survivin may provide a novel approach for the treatment of the malignancy.