Synergistic effect of gefitinib and rofecoxib in mesothelioma cells

<p>Abstract</p> <p>Background</p> <p>Malignant mesothelioma (MM) is an aggressive tumor that is resistant to conventional modes of treatment with chemotherapy, surgery or radiation. Research into the molecular pathways involved in the development of MM should yield information that will guide therapeutic decisions. Epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) are involved in the carcinogenesis of MM. Combination of COX-2 and EGFR inhibitors, therefore, could be an effective strategy for reducing cell growth in those lines expressing the two molecular markers.</p> <p>Results</p> <p>In order to verify the effect of COX-2 and EGFR inhibitors, five MM cell lines NCI-2452, MPP89, Ist-Mes-1, Ist-Mes-2 and MSTO-211 were characterized for COX-2 and EGFR and then treated with respective inhibitors (rofecoxib and gefitinib) alone and in combination. Only MPP89, Ist-Mes-1 and Ist-Mes-2 were sensitive to rofecoxib and showed growth-inhibition upon gefitinib treatment. The combination of two drugs demonstrated synergistic effects on cell killing only in Ist-Mes-2, the cell line that was more sensitive to gefitinib and rofecoxib alone. Down-regulation of COX-2, EGFR, p-EGFR and up-regulation of p21 and p27 were found in Ist-Mes-2, after treatment with single agents and in combination. In contrast, association of two drugs resulted in antagonistic effect in Ist-Mes-1 and MPP89. In these cell lines after rofecoxib exposition, only an evident reduction of p-AKT was observed. No change in p-AKT in Ist-Mes-1 and MPP89 was observed after treatment with gefitinib alone and in combination with rofecoxib.</p> <p>Conclusions</p> <p>Gefitinib and rofecoxib exert cell type-specific effects that vary between different MM cells. Total EGFR expression and downstream signalling does not correlate with gefitinib sensitivity. These data suggest that the effect of gefitinib can be potentiated by rofecoxib in MM cell lines where AKT is not activated.</p

Inequities in Organ Donation and Transplantation Among Immigrant Populations in Italy: A Narrative Review of Evidence, Gaps in Research and Potential Areas for Intervention

Immigrants from outside Europe have increased over the past two decades, especially in Southern European countries including Italy. This influx coincided with an increased number of immigrants with end-stage organ diseases. In this narrative review, we reviewed evidence of the gaps between native-born and immigrant populations in the Organ Donation and Transplantation (ODT) process in Italy. Consistent with prior studies, despite the availability of a publicly funded health system with universal healthcare coverage, non-European-born individuals living in Italy are less likely to receive living donor kidney transplantation and more likely to have inferior long-term kidney graft function compared with EU-born and Eastern European-born individuals. While these patients are increasingly represented among transplant recipients (especially kidney and liver transplants), refusal rates for organ donation are higher in some ethnic groups compared with native-born and other foreign-born referents, with the potential downstream effects of prolonged waiting times and inferior transplant outcomes. In the process, we identified gaps in relevant research and biases in existing studies. Given the Italian National Transplant Center’s (CNT) commitment to fighting inequities in ODT, we illustrated actions taken by CNT to tackle inequities in ODT among immigrant communities in Italy

Molecular analysis of the effects of Piroxicam and Cisplatin on mesothelioma cells growth and viability

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been proposed for prevention and treatment of a variety of human cancers. Piroxicam, in particular, has been recently shown to exert significant anti-tumoral activity in combination with cisplatin (CDDP) on mesothelioma cells. However, the mechanisms through which NSAIDs regulate the cell cycle as well as the signal pathways involved in the growth inhibition, remain unclear. In the present study, using two mesothelioma cell lines, MSTO-211H and NCI-H2452, we have investigated the influence of piroxicam alone and in association with CDDP on proliferation, cell cycle regulation and apoptosis. In both cell lines a significant effect on cell growth inhibition, respect to the control, was observed with all the drugs tested. Moreover, treatment with piroxicam or CDDP alone altered the cell cycle phase distribution as well as the expression of some cell cycle regulatory proteins in both cell lines. These effects were increased, even if in a not completely overlapping manner, after treatment with the association of piroxicam and CDDP. In particular, the two drugs in NCI cell line had a synergistic effect on apoptosis, probably through activation of caspase 8 and caspase 9, while the most evident targets among the cell cycle regulators were cyclin D1 and p21waf1. These results suggest that the association of piroxicam and CDDP specifically triggers cell cycle regulation and apoptosis in different mesothelioma cell lines and may hold promise in the treatment of mesothelioma

Cost-Effectiveness of Dimethyl Fumarate Compared to Teriflunomide for Relapsing Remitting Multiple Sclerosis Patients in Italy

BACKGROUND: The objective of this economic analysis was to compare the cost-effectiveness of dimethyl fumarate vs teriflunomide for the treatment of adult patients with relapsing-remitting multiple sclerosis (RRMS) in the Italian setting. Additionally, the cost-effectiveness analysis was used to predict some patient-relevant outcomes such as burden of relapses and survival with disability over time.METHODS: A Markov model was used to conduct the cost-effectiveness analysis. The model measured health outcomes and costs of RRMS patients treated with either dimethyl fumarate or teriflunomide. Data from a published mixed treatment comparison were used for efficacy and safety input. Local economic data were used to calculate costs. A supplementary analysis was carried out to assess ICER variability over time from the Italian National Healthcare Service (NHS) and societal perspectives. Further analyses were conducted to compare clinical effectiveness of the alternatives over time, in terms of incidence of relapses, proportion of patients with EDSS (Expanded Disability Status Scale) score ≤3 and EDSS score ≥6.RESULTS: In the base-case analysis (lifetime horizon; societal perspective) dimethyl fumarate was dominant over teriflunomide (6.526 vs 5.953 QALYs – quality-adjusted life-years; € 1.01 M vs € 1.03 M). The most relevant cost savings (per-patient) with dimethyl fumarate were related to relapses (-€ 5,096), inpatient care (-€ 5,767), informal care (-€ 9,603), long-term absence/early retirement (-€ 14,187). The additional analysis of ICER by time horizon shows that dimethyl fumarate is cost-effective vs teriflunomide (i.e., ICER <€ 50,000 per QALY gained) at already 6 years and at 15 years in societal or NHS perspectives, respectively. Results favoured dimethyl fumarate vs teriflunomide also for: cumulative burden of relapses (-0.23 and -1.37 relapses saved per patient already at 1 year and 10 years, respectively), proportion of patients with mild disability (+4.0% at 10 years), proportion of patients with severe disability (-4.0% at 10 years).CONCLUSIONS: Dimethyl fumarate is dominant (societal perspective), or cost-effective (NHS perspective), referring to a threshold of € 50,000 per QALY gained, vs teriflunomide for the first-line treatment of RRMS, in the Italian setting

First serological evidence of SARS-CoV-2 natural infection in small ruminants : Brief report

: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) emerged in late December 2019 and spread worldwide, quickly becoming a pandemic. This zoonotic coronavirus shows a broad host range, including wildlife and domestic animals. Small ruminants are shown to be susceptible to SARS-CoV-2 but, to date, no natural infection has been reported. Herein, we performed a survey for SARS-CoV-2 among sheep and goats in the Campania region of Italy using an indirect multispecies ELISA. Next, positive sera were submitted to virus serum neutralization for the quantification of specific neutralizing antibodies. Out of 612 sheep and goats, 23 were found ELISA positive (3.75%) and 1 of them showed 1:20 neutralizing antibodies titer. No significant difference was found between the two species, as well as between male and female, geographical location and age. Our findings demonstrate that natural infection can occur in flocks in a field situation. Moreover, low susceptibility to SARS-CoV-2 is reported for sheep and goats, nevertheless, the continuous mutations of this virus open new scenarios on viral host range and tropism, highlighting the importance of investigating animal species that could represent ongoing or future possible hosts

preoperative therapy with trastuzumab and oral vinorelbine endocrine therapy in patients with her2 positive breast cancer

Abstract Background Combined trastuzumab and intravenous vinorelbine yielded high clinical activity as preoperative treatment in patients (pts) with HER 2/ neu positive breast cancer. Patients and methods We tested a preoperative combination of trastuzumab with oral vinorelbine (oV) in pts with locally advanced (T2-T4 N0-3 M0) HER2-positive breast cancer. Trastuzumab was administered i.v q 3 wks and oV was administered at the dose of 55 mg/sqm on days 1 and 3 q 3 wks, for 8 courses. Pts with ER ≥ 10% tumors received endocrine therapy with letrozole 2.5 mg/day, plus monthly triptorelin if premenopausal. Results Forty-five pts entered the study. The overall response rate (CR + PR) was 76% (95% CI: 60%–87%). pCR was observed in 4 pts (10%). Among ER-positive tumors 21/25 pts obtained a clinical response (84%) and two pts obtained a pCR (8%). Conclusions The combination of trastuzumab and oral vinorelbine demonstrated encouraging activity in patients with HER 2 positive ER-positive tumors. Alternative strategies should be investigated in patients with endocrine non responsive disease

topoisomerase iiα gene status and prediction of pathological complete remission after anthracycline based neoadjuvant chemotherapy in endocrine non responsive her2 neu positive breast cancer

Abstract Purpose Topoisomerase IIα (Topo II) is a potential marker of responsiveness to anthracycline-based therapy. We analyzed the role of Topo II gene status in the prediction of pathological complete remission (pCR) after primary anthracycline-based chemotherapy in non- endocrine responsive breast cancers overexpressing Her2/neu. Methods Twenty-three patients, with T2–T4, ER and PgR absent, overexpressing Her2/neu breast cancers treated with anthracycline-based chemotherapy were evaluated. Topo II gene status was assessed by FISH in pre-treatment tumor specimens and the results were correlated to pathological and clinical responses. Results Overall, six patients had a pCR (26%). Topo II was amplified in 5 (22%) of the tumors. In all patients with Topo II amplification, Her2/neu gene amplification was also detected. Among patients without amplification, one had polysomia of chromosome (Cr) 17 and four patients had deletion of the Topo II gene. A higher probability of pCR was observed when Topo II amplification and Cr 17 polysomy were present: pCR was reported in 3 of 5 amplified tumors (60%), in the polysomic tumor (amplified plus polysomic 67%) and in only 2 out of 13 tumors without alteration of Topo II status (15%). If we compare the frequency of pCR in tumors with amplification or polysomy versus the frequency of tumors with not amplification (deletion or no modification), a significant difference was detected ( p =0.02). One progressive disease (PD) was reported in one tumor with Topo II deletion (1/4, 25%) and one in tumor without any modification of Topo II gene status (1/13, 8%). Conclusions In patients with endocrine unresponsive and Her2 overexpressing tumors, Topo II amplification or the presence of chromosome 17 polysomy correlate with a significantly high probability of achieving pCR after neoadjuvant, anthracycline-based chemotherapy. Further prospective studies in order to more clearly define the predictive role of Topo II status in this subgroup of patients are warranted

Impact of treatment with dimethyl fumarate on sleep quality in patients with relapsing-remitting multiple sclerosis: A multicentre Italian wearable tracker study

BackgroundSleep disorders are common in patients with multiple sclerosis and have a bidirectional interplay with fatigue and depression. ObjectiveTo evaluate the effect of treatment with oral dimethyl fumarate on the quality of sleep in relapsing-remitting multiple sclerosis. MethodsThis was a multicentre observational study with 223 relapsing-remitting multiple sclerosis subjects starting treatment with dimethyl fumarate (n=177) or beta interferon (n=46). All patients underwent subjective (Pittsburgh Sleep Quality Index) and objective (wearable tracker) measurements of quality of sleep. Fatigue, depression, and quality of life were also investigated and physical activity was monitored. ResultsPatients treated with dimethyl fumarate had significant improvement in the quality of sleep as measured with the Pittsburgh Sleep Quality Index (p&lt;0.001). At all-time points, no significant changes in Pittsburgh Sleep Quality Index score were observed in the interferon group. Total and deep sleep measured by wearable tracker decreased at week 12 with both treatments, then remained stable for the total study duration. Depression significantly improved in patients treated with dimethyl fumarate. No significant changes were observed in mobility, fatigue and quality of life. ConclusionIn patients with relapsing-remitting multiple sclerosis, the treatment with dimethyl fumarate was associated with improvements in patient-reported quality of sleep. Further randomised clinical trials are needed to confirm the benefits of long-term treatment with dimethyl fumarate