Expression and Biological Functions of miRNAs in Chronic Pain: A Review on Human Studies

none10noChronic pain is a major public health problem and an economic burden worldwide. However, its underlying pathological mechanisms remain unclear. MicroRNAs (miRNAs) are a class of small noncoding RNAs that post-transcriptionally regulate gene expression and serve key roles in physiological and pathological processes. This review aims to synthesize the human studies examining miRNA expression in the pathogenesis of chronic primary pain and chronic secondary pain. Additionally, to understand the potential pathophysiological impact of miRNAs in these conditions, an in silico analysis was performed to reveal the target genes and pathways involved in primary and secondary pain and their differential regulation in the different types of chronic pain. The findings, methodological issues and challenges of miRNA research in the pathophysiology of chronic pain are discussed. The available evidence suggests the potential role of miRNA in disease pathogenesis and possibly the pain process, eventually enabling this role to be exploited for pain monitoring and management.Sabina S.; Panico A.; Mincarone P.; Leo C.G.; Garbarino S.; Grassi T.; Bagordo F.; De Donno A.; Scoditti E.; Tumolo M.R.Sabina, S.; Panico, A.; Mincarone, P.; Leo, C. G.; Garbarino, S.; Grassi, T.; Bagordo, F.; De Donno, A.; Scoditti, E.; Tumolo, M. R

Has VZV epidemiology changed in Italy? Results of a seroprevalence study

The aim of the study was to evaluate if and how varicella prevalence has changed in Italy. In particular a seroprevalence study was performed, comparing it to similar surveys conducted in pre-immunization era. During 2013–2014, sera obtained from blood samples taken for diagnostic purposes or routine investigations were collected in collaboration with at least one laboratory/center for each region, following the approval of the Ethics Committee. Data were stratified by sex and age. All samples were processed in a national reference laboratory by an immunoassay with high sensitivity and specificity. Statutory notifications, national hospital discharge database and mortality data related to VZV infection were analyzed as well. A total of 3707 sera were collected and tested. In the studied period both incidence and hospitalization rates decreased and about 5 deaths per year have been registered. The seroprevalence decreased in the first year of life in subjects passively protected by their mother, followed by an increase in the following age classes. The overall antibody prevalence was 84%. The comparison with surveys conducted with the same methodology in 1996–1997 and 2003–2004 showed significant differences in age groups 1–19 y. The study confirms that in Italy VZV infection typically occurs in children. The impact of varicella on Italian population is changing. The comparison between studies performed in different periods shows a significant increase of seropositivity in age class 1–4 years, expression of vaccine interventions already adopted in some regions

Thymidylate synthetase mRNA levels are increased in liver metastases of colorectal cancer patients resistant to fluoropyrimidine-based chemotherapy

BACKGROUND: Fluoropyrimidines such as 5-fluorouracil (5-FU) and 5-fluoro-2'deoxyuridine (FUDR) are among the most effective chemotherapeutic agents for treatment of metastatic colorectal cancer (CRC). Increased expression of thymidylate synthetase (TS) in CRC metastases has been proposed to be an important mechanism of resistance to fluoropyrimidine-based chemotherapy. METHODS: The present study investigated whether TS mRNA levels in liver metastases of 20 CRC patients before treatment with FUDR by hepatic arterial infusion (HAI) correlated with frequency of clinical response or survival duration. RESULTS: Median survival duration of patients with TS mRNA levels above and below the median was 15 and 18 months, respectively (p > 0.05). Clinical response was achieved in 40% of patients with low TS mRNA levels, but in only 20% of patients with high TS mRNA levels (p = 0.01). TS mRNA levels were also measured for liver metastases of 7 of the patients that did not achieve a clinical response. A statistically significant increase in expression of TS mRNA was observed for liver metastases resistant to chemotherapy (21 ± 14) in comparison to liver metastases of the same patients before chemotherapy (8 ± 4) (p = 0.03). CONCLUSION: This is the first report to demonstrate increased TS expression in liver metastases from CRC patients resistant to fluoropyrimidine based chemotherapy. These findings are consistent with previous studies indicating that increased TS expression is associated with resistance to fluoropyrimidine-based chemotherapy

Results from the European Union MAPEC_LIFE cohort study on air pollution and chromosomal damage in children: are public health policies sufficiently protective?

Background: Children are at high risk of suffering health consequences of air pollution and childhood exposure can increase the risk of developing chronic diseases in adulthood. This study, part of the MAPEC_LIFE project (LIFE12 ENV/IT/000614), aimed to investigate the associations between exposure to urban air pollutants and micronucleus (MN) frequency, as a biomarker of chromosomal damage, in buccal cells of children for supporting implementation and updating of environmental policy and legislation. Methods: This prospective epidemiological cohort study was carried out on 6- to 8-year-old children living in five Italian towns with different levels and features of air pollution. Exfoliated buccal cells of the children were sampled twice, in winter and spring, obtaining 2139 biological samples for genotoxicological investigation. Micronucleus (MN) frequency was investigated in buccal cells of children and its association with air pollution exposure was assessed applying multiple Poisson regression mixed models, including socio-demographic and lifestyle factors as confounders. We also dichotomize air pollutants\u2019 concentration according to the EU Ambient Air Quality Directives and WHO Air Quality Guidelines in all Poisson regression models to assess their risk predictive capacity. Results: Positive and statistically significant associations were found between MN frequency and PM10, PM2.5, benzene, SO2 and ozone. The increment of the risk of having MN in buccal cells for each \u3bcg/m3 increase of pollutant concentration was maximum for benzene (18.9%, 95% CIs 2.2\u201338.4%) and modest for the other pollutants (between 0.2 and 1.4%). An increased risk (between 17.9% and 59.8%) was found also for exposure to PM10, benzene and benzo(a)pyrene levels higher than the threshold limits. Conclusions: Some air pollutants are able to induce chromosomal damage in buccal cells of children even at concentrations below present EU/WHO limits. This type of biological effects may be indicative of the environmental pressure which populations are exposed to in urban areas

Doxorubicin versus doxorubicin and cisplatin in endometrial carcinoma: definitive results of a randomised study (55872) by the EORTC Gynaecological Cancer Group

Background: Combination chemotherapy yields better response rates which do not always lead to a survival advantage. The aim of this study was to investigate whether the reported differences in the efficacy and toxicity of monotherapy with doxorubicin (DOX) versus combination therapy with cisplatin (CDDP) in endometrial adenocarcinoma lead to significant advantage in favour of the combination. Patients and methods: Eligible patients had histologically-proven advanced and/or recurrent endometrial adenocarcinoma and were chemo-naïve. Treatment consisted of either DOX 60 mg/m2 alone or CDDP 50 mg/m2 added to DOX 60 mg/m2, every 4 weeks. Results: A total of 177 patients were entered and median follow-up is 7.1 years. The combination DOX-CDDP was more toxic than DOX alone. Haematological toxicity consisted mainly of white blood cell toxicity grade 3 and 4 (55% versus 30%). Non-haematological toxicity consisted mainly of grade 3 and 4 alopecia (72% versus 65%) and nausea/vomiting (36 % versus 12%). The combination DOX-CDDP provided a significantly higher response rate than single agent DOX (P <0.001). Thirty-nine patients (43%) responded on DOX-CDDP [13 complete responses (CRs) and 26 partial responses (PRs)], versus 15 patients (17%) on DOX alone (8 CR and 7 PR). The median overall survival (OS) was 9 months in the DOX-CDDP arm versus 7 months in the DOX alone arm (Wilcoxon P = 0.0654). Regression analysis showed that WHO performance status was statistically significant as a prognostic factor for survival, and stratifying for this factor, treatment effect reaches significance (hazard ratio = 1.46, 95% confidence interval 1.05-2.03, P = 0.024). Conclusions: In comparison to single agent DOX, the combination of DOX-CDDP results in higher but acceptable toxicity. The response rate produced is significantly higher, and a modest survival benefit is achieved with this combination regimen, especially in patients with a good performance statu

Fatigue and weight loss predict survival on circadian chemotherapy for metastatic colorectal cancer

BACKGROUND:Chemotherapy-induced neutropenia has been associated with prolonged survival selectively in patients on a conventional schedule (combined 5-fluorouracil, leucovorin, and oxaliplatin [FOLFOX2]) but not on a chronomodulated schedule of the same drugs administered at specific circadian times (chronoFLO4). The authors hypothesized that the early occurrence of chemotherapy-induced symptoms correlated with circadian disruption would selectively hinder the efficacy of chronotherapy. METHODS:Fatigue and weight loss (FWL) were considered to be associated with circadian disruption based on previous data. Patients with metastatic colorectal cancer (n = 543) from an international phase 3 trial comparing FOLFOX2 with chronoFLO4 were categorized into 4 subgroups according to the occurrence of FWL or other clinically relevant toxicities during the initial 2 courses of chemotherapy. Multivariate Cox models were used to assess the role of toxicity on the time to progression (TTP) and overall survival (OS). RESULTS:The proportions of patients in the 4 subgroups were comparable in both treatment arms (P = .77). No toxicity was associated with TTP or OS on FOLFOX2. The median OS on FOLFOX2 ranged from 16.4 (95% confidence limits [CL], 7.2-25.6 months) to 19.8 months (95% CL, 17.7-22.0 months) according to toxicity subgroup (P = .45). Conversely, FWL, but no other toxicity, independently predicted for significantly shorter TTP (P < .0001) and OS (P = .001) on chronoFLO4. The median OS on chronoFLO4 was 13.8 months (95% CL, 10.4-17.2 months) or 21.1 months (95% CL, 19.0-23.1 months) according to presence or absence of chemotherapy-induced FWL, respectively. CONCLUSIONS: Early onset chemotherapy-induced FWL was an independent predictor of poor TTP and OS only on chronotherapy. Dynamic monitoring to detect early chemotherapy-induced circadian disruption could allow the optimization of rapid chronotherapy and concomitant improvements in safety and efficacy

Primary chemotherapy with gemcitabine, epirubicin and taxol (GET) in operable breast cancer: a phase II study

This trial was conducted to assess the activity and tolerability of the gemcitabine, epirubicin, taxol triplet combination in patients with operable breast cancer. After core biopsy, 43 women with stage II–IIIA breast cancer were treated with gemcitabine 1000 mg m−2 over 30 min on days 1 and 4, epirubicin 90 mg m−2 as an intravenous bolus on day 1, and taxol 175 mg m−2 as a 3-h infusion on day 1, every 21 days for four cycles. The primary end point was the percentage of pathological complete responses (pCR) in the breast; secondary end points were tolerability, clinical response rates, overall and progression-free survival, tumour biomarkers before and after primary chemotherapy (PCT). All patients were included in safety and survival analyses; 41 eligible patients were evaluated for response. The overall clinical response rate was 87.8% (95% CI 77.8–97.8), with 26.8% complete responses (95% CI 13.3–40.3). A pCR in the breast was observed in six patients (14.6%; 95% CI 3.8–25.4); 15 patients (36.6%; 95% CI 21.9–51.3) had negative axillary lymph nodes. Grade 4 neutropenia was observed in 67.4% of the patients; febrile neutropenia occurred in 1.9% of cycles (granulocyte colony-stimulating factor was used in 3.2% of the cycles to shorten the duration of neutropenia). A statistically significant difference between Mib-1 at baseline (⩾20% in 71.4% of the patients) and at definitive surgery (28.6%, P<0.05) was observed. The gemcitabine, epirubicin, taxol regimen is active and well tolerated as PCT for operable breast cancer. This combination allows the administration of full doses of active agents with a low incidence of febrile neutropenia

SeaConditions: a web and mobile service for safer professional and recreational activities in the Mediterranean Sea

Reliable and timely information on the environmental conditions at sea is key to the safety of professional and recreational users as well as to the optimal execution of their activities. The possibility of users obtaining environmental information in due time and with adequate accuracy in the marine and coastal environment is defined as sea situational awareness (SSA). Without adequate information on the environmental meteorological and oceanographic conditions, users have a limited capacity to respond, which has led to loss of lives and to large environmental disasters with enormous consequent damage to the economy, society and ecosystems. Within the framework of the TESSA project, new SSA services for the Mediterranean Sea have been developed. In this paper we present SeaConditions, which is a web and mobile application for the provision of meteorological and oceanographic observation and forecasting products. Model forecasts and satellite products from operational services, such as ECMWF and CMEMS, can be visualized in SeaConditions. In addition, layers of information related to bathymetry, sea level and ocean-colour data (chl a and water transparency) are displayed. Ocean forecasts at high spatial resolutions are included in the version of SeaConditions presented here. SeaConditions provides a user-friendly experience with a fluid zoom capability, facilitating the appropriate display of data with different levels of detail. SeaConditions is a single point of access to interactive maps from different geophysical fields, providing high-quality information based on advanced oceanographic models. The SeaConditions services are available through both web and mobile applications. The web application is available at www.sea-conditions.com and is accessible and compatible with present-day browsers. Interoperability with GIS software is implemented. User feedback has been collected and taken into account in order to improve the service. The SeaConditions iOS and Android apps have been downloaded by more than 105 000 users to date (May 2016), and more than 100 000 users have visited the web version

Colorectal Cancer Stage at Diagnosis Before vs During the COVID-19 Pandemic in Italy

IMPORTANCE Delays in screening programs and the reluctance of patients to seek medical attention because of the outbreak of SARS-CoV-2 could be associated with the risk of more advanced colorectal cancers at diagnosis. OBJECTIVE To evaluate whether the SARS-CoV-2 pandemic was associated with more advanced oncologic stage and change in clinical presentation for patients with colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study included all 17 938 adult patients who underwent surgery for colorectal cancer from March 1, 2020, to December 31, 2021 (pandemic period), and from January 1, 2018, to February 29, 2020 (prepandemic period), in 81 participating centers in Italy, including tertiary centers and community hospitals. Follow-up was 30 days from surgery. EXPOSURES Any type of surgical procedure for colorectal cancer, including explorative surgery, palliative procedures, and atypical or segmental resections. MAIN OUTCOMES AND MEASURES The primary outcome was advanced stage of colorectal cancer at diagnosis. Secondary outcomes were distant metastasis, T4 stage, aggressive biology (defined as cancer with at least 1 of the following characteristics: signet ring cells, mucinous tumor, budding, lymphovascular invasion, perineural invasion, and lymphangitis), stenotic lesion, emergency surgery, and palliative surgery. The independent association between the pandemic period and the outcomes was assessed using multivariate random-effects logistic regression, with hospital as the cluster variable. RESULTS A total of 17 938 patients (10 007 men [55.8%]; mean [SD] age, 70.6 [12.2] years) underwent surgery for colorectal cancer: 7796 (43.5%) during the pandemic period and 10 142 (56.5%) during the prepandemic period. Logistic regression indicated that the pandemic period was significantly associated with an increased rate of advanced-stage colorectal cancer (odds ratio [OR], 1.07; 95%CI, 1.01-1.13; P = .03), aggressive biology (OR, 1.32; 95%CI, 1.15-1.53; P &lt; .001), and stenotic lesions (OR, 1.15; 95%CI, 1.01-1.31; P = .03). CONCLUSIONS AND RELEVANCE This cohort study suggests a significant association between the SARS-CoV-2 pandemic and the risk of a more advanced oncologic stage at diagnosis among patients undergoing surgery for colorectal cancer and might indicate a potential reduction of survival for these patients