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Diarrhea continues to be a global health problem as acute diarrhea carries the risk of dehydration, while both acute and chronic diarrhea can significantly affect patients’ quality of life and reduce productivity. The innovative medical device Actitan, which consists of a complex of natural molecules, could be an effective option for the treatment of diarrhea from various causes. The aim of this post-market cross-sectional study was to evaluate the perceived efficacy, safety and usage pattern of the two formulations for adults (Actitan-P) and children (Actitan-F) among patients/child caregivers, physicians and pharmacists. Participants completed online questionnaires with closed multiple-choice questions that were rated on a verbal 5-point Likert scale. These surveys were conducted via the online platform Real World Data, which provides digital questionnaires for patients, doctors and pharmacists. Two separate surveys were conducted for the two formulations, with a total of 2630 participants (1488 participants for Actitan-P and 1142 participants for Actitan-F). Overall, the results indicate a high level of efficacy and safety of the product. In the case of Actitan-F, more than 96% of caregivers rated safety as good or excellent, and over 92% rated efficacy as good or excellent. Actitan-P also received positive feedback: nearly 86% of patients reported good/excellent efficacy, and more than 93% rated safety as good or excellent. These positive evaluations were confirmed by physicians and pharmacists, who also did not report adverse effects. In summary, this study confirms the role of Actitan as a safe and effective option for the treatment of diarrhea of different causes and in different patient groups, including young children.

Abstract Locoregional recurrences represent a frequently unexpected problem in head and neck squamous cell carcinoma (HNSCC). Relapse often (10–30%) occurs in patients with histologically negative resection margins (RMs), probably due to residual tumor cells or hidden pre-cancerous lesions in normal mucosa, both missed by histopathological examination. Therefore, definition of a ‘clean’ or tumor-negative RM is controversial, demanding for novel approaches to be accurately explored. Here, we evaluated next generation sequencing (NGS) and digital PCR (dPCR) as tools to profile TP53 mutational status and circulating microRNA expression aiming at scoring the locoregional risk of recurrence by means of molecular analyses. Serial monitoring of these biomarkers allowed identifying patients at high risk, laying the ground for accurate tracking of disease evolution and potential intensification of post-operative treatments. Additionally, our pipeline demonstrated its applicability into the clinical routine, being cost-effective and feasible in terms of patient sampling, holding promise to accurately (re)-stage RMs in the era of precision medicine.

Background: Gestational diabetes mellitus (GDM) is the most common complication in pregnancy, representing a serious risk for the mother and fetus. Identifying new biomarkers to ameliorate the screening and improving GDM diagnosis and treatment is crucial. During the last decade, a few studies have used speckle tracking echocardiography (STE) for assessing the myocardial deformation properties of fetuses (FGDM) and infants (IGDM) of GDM women, providing not univocal results. Accordingly, we performed a meta-analysis to examine the overall influence of GDM on left ventricular (LV) and right ventricular (RV) global longitudinal strain (GLS) in both FGDM and IGDM. Methods: All echocardiographic studies assessing conventional echoDoppler parameters and biventricular strain indices in FGDM and IGDM vs. infants born to healthy pregnant women, selected from PubMed and EMBASE databases, were included. The studies performed on FGDM and IGDM were separately analyzed. The subtotal and overall standardized mean differences (SMDs) in LV-GLS and RV-GLS in FGDM and IGDM studies were calculated using the random-effect model. Results: The full texts of 18 studies with 1046 babies (72.5% fetuses) born to GDM women and 1573 babies of women with uncomplicated pregnancy (84.5% fetuses) were analyzed. Compared to controls, FGDM/IGDM were found with a significant reduction in both LV-GLS [average value −18.8% (range −11.6, −24.2%) vs. −21.5% (range −11.8, −28%), p < 0.05)] and RV-GLS [average value −19.7% (range −13.7, −26.6%) vs. −22.4% (range −15.5, −32.6%), p p < 0.001) and −0.82 (95%CI −1.13, −0.51, p < 0.001), respectively. Substantial heterogeneity was detected for both LV-GLS and RV-GLS studies, with an overall I2 statistic value of 92.0% and 89.3%, respectively (both p < 0.001). Egger’s test gave a p-value of 0.10 for LV-GLS studies and 0.78 for RV-GLS studies, indicating no publication bias. In the meta-regression analysis, none of the moderators (gestational age, maternal age, maternal body mass index, maternal glycosylated hemoglobin, white ethnicity, GDM criteria, ultrasound system, frame rate, FGDM/IGDM heart rate, and anti-diabetic treatment) were significantly associated with effect modification in both groups of studies (all p > 0.05). The sensitivity analysis supported the robustness of the results. Conclusions: GDM is independently associated with biventricular strain impairment in fetuses and infants of gestational diabetic mothers. STE analysis may allow for the early detection of subclinical myocardial dysfunction in FGDM/IGDM.

Background: During the last decades, a small number of studies reported a wide range of variability in the estimated prevalence of mitral valve prolapse (MVP) among individuals with pectus excavatum (PE). The present systematic review and meta-analysis has been primarily designed to summarize the main findings of these studies and to estimate the overall prevalence of MVP among PE individuals. Methods: All imaging studies assessing the prevalence of MVP in PE individuals vs. healthy controls, selected from PubMed and EMBASE databases, were included. The risk of bias was assessed by using the National Institutes of Health (NIH) Quality Assessment of Case–Control Studies. Events (presence of MVP) and nonevents (absence of MVP) in PE individuals and control groups were recorded. The main outcome was the measure of odds ratio (OR) for MVP presence pooled with 95% confidence intervals, using a fixed-effects model. Results: The full texts of eight studies with 303 PE patients (mean age 25.7 yrs) and 498 healthy controls (mean age 31 yrs) were analyzed. Three studies assessed MVP prevalence in children and early adolescents, whereas the remaining five studies examined PE adults. The prevalence of MVP in PE individuals and healthy controls was 40.6% and 12.8%, respectively. In the pooled sample, the OR for MVP presence was significantly higher in PE individuals compared to controls (OR = 5.80, 95%CI = 3.83–8.78, Z = 8.30, p < 0.001). Subgroup analysis revealed that MVP prevalence was approximately three-fold higher among PE children and early adolescents compared with PE adults. Overall, high consistency was observed in the pooled effect sizes, due to the low statistical heterogeneity among the included studies (I2 = 22.7%, p = 0.25). Egger’s test for a regression intercept gave a p-value of 0.07, indicating no publication bias. The sensitivity analysis supported the robustness of the results. Conclusions: PE individuals are nearly six times more likely to have MVP than controls. MVP prevalence is three-fold higher in PE individuals during childhood and early adolescence, compared to PE adults. Given the strong association between MVP and PE, MVP should be suspected in all individuals with anterior chest wall deformity.

Non‐small cell lung cancer (NSCLC) has a poor prognosis, and effective therapeutic strategies are lacking. The diabetes drug canagliflozin inhibits NSCLC cell proliferation and the mammalian target of rapamycin (mTOR) pathway, which mediates cell growth and survival, but it is unclear whether this drug can enhance response rates when combined with cytotoxic therapy. Here, we evaluated the effects of canagliflozin on human NSCLC response to cytotoxic therapy in tissue cultures and xenografts. Ribonucleic acid sequencing (RNA‐seq), real‐time quantitative PCR (RT‐qPCR), metabolic function, small interfering ribonucleic acid (siRNA) knockdown, and protein expression assays were used in mechanistic analyses. We found that canagliflozin inhibited proliferation and clonogenic survival of NSCLC cells and augmented the efficacy of radiotherapy to mediate these effects and inhibit NSCLC xenograft growth. Canagliflozin treatment alone moderately inhibited mitochondrial oxidative phosphorylation and exhibited greater antiproliferative capacity than specific mitochondrial complex‐I inhibitors. The treatment downregulated genes mediating hypoxia‐inducible factor (HIF)‐1α stability, metabolism and survival, activated adenosine monophosphate‐activated protein kinase (AMPK) and inhibited mTOR, a critical activator of hypoxia‐inducible factor‐1α (HIF‐1α) signaling. HIF‐1α knockdown and stabilization experiments suggested that canagliflozin mediates antiproliferative effects, in part, through suppression of HIF‐1α. Transcriptional regulatory network analysis pinpointed histone deacetylase 2 (HDAC2), a gene suppressed by canagliflozin, as a key mediator of canagliflozin's transcriptional reprogramming. HDAC2 knockdown eliminated HIF‐1α levels and enhanced the antiproliferative effects of canagliflozin. HDAC2‐regulated genes suppressed by canagliflozin are associated with poor prognosis in several clinical NSCLC datasets. In addition, we include evidence that canagliflozin also improves NSCLC response to chemotherapy. In summary, canagliflozin may be a promising therapy to develop in combination with cytotoxic therapy in NSCLC.

Abstract Background Immune checkpoint inhibitors (ICIs) are a therapeutic strategy for various cancers although only a subset of patients respond to the therapy. Identifying patients more prone to respond to ICIs may increase the therapeutic benefit and allow studying new approaches for resistant patients. Methods We analyzed the TCGA cohort of HNSCC patients in relation to their activation of 26 immune gene expression signatures, as well as their cell type composition, in order to define signaling pathways associated with resistance to ICIs. Results were validated on two cohorts of 102 HNSCC patients and 139 HNSCC patients under treatment with PD-L1 inhibitors, respectively, and a cohort of 108 HNSCC HPV negative patients and by in vitro experiments in HNSCC cell lines. Results We observed a significant association between the gene set and TP53 gene status and OS and PFS of HNSCC patients. Surprisingly, the presence of a TP53 mutation together with another co-driver mutation was associated with significantly higher levels of the immune gene expression, in comparison to tumors in which the TP53 gene was mutated alone. In addition, the higher level of TP53 mutated-dependent MYC signature was associated with lower levels of the immune gene expression signature. In vitro and three different patient cohorts validation analyses corroborated these findings. Conclusions Immune gene signature sets associated with TP53 status and co-mutations classify with more accuracy HNSCC patients. These biomarkers may be easily implemented in clinical setting.

Abstract Hyperthermic intraperitoneal administration of chemotherapy (HIPEC) increases local drug concentrations and reduces systemic side effects associated with prolonged adjuvant intraperitoneal exposure in patients affected by either peritoneal malignancies or metastatic diseases originating from gastric, colon, kidney, and ovarian primary tumors. Mechanistically, the anticancer effects of HIPEC have been poorly explored. Herein we documented that HIPEC treatment promoted miR-145-5p expression paired with a significant downregulation of its oncogenic target genes c-MYC, EGFR, OCT4, and MUC1 in a pilot cohort of patients with ovarian peritoneal metastatic lesions. RNA sequencing analyses of ovarian peritoneal metastatic nodules from HIPEC treated patients unveils HSF-1 as a transcriptional regulator factor of miR-145-5p expression. Notably, either depletion of HSF-1 expression or chemical inhibition of its transcriptional activity impaired miR-145-5p tumor suppressor activity and the response to cisplatin in ovarian cancer cell lines incubated at 42 °C. In aggregate, our findings highlight a novel transcriptional network involving HSF-1, miR145-5p, MYC, EGFR, MUC1, and OCT4 whose proper activity contributes to HIPEC anticancer efficacy in the treatment of ovarian metastatic peritoneal lesions.

Abstract Background Malignant pleural mesothelioma is a highly aggressive tumor associated with asbestos exposure. There are few effective treatment options for mesothelioma, and patients have a very poor prognosis. Mesothelioma has the potential to represent an appropriate disease to prevent because of its strong association with asbestos exposure and the long latency from exposure to the disease on-set. Methods In the present study, we tested biological activity and toxicity of an artichoke freeze-dried extract (AWPC) as potential complementary preventive/early stage treatment agent for mesothelioma. This phase II clinical study then was conducted in 18 male-patients with evidence of radiographic characteristics related to asbestos exposure such as asbestosis or benign pleural disease as surrogate disease for mesothelioma clinical model. Results We investigate AWPC biological activity assessing its effect on mesothelin serum level, a glycoprotein with low expression in normal mesothelial cells and high expression in mesothelioma and asbestos related diseases. We also assess the AWPC effect on circulating miRNAs, as novel biomarkers of both cancer risk and response to therapeutic targets. While we found a small and not significant effect of AWPC on mesothelin serum levels, we observed that AWPC intake modulated 11 serum miRNAs related to gene-pathways connected to mesothelioma etiology and development. In terms of toxicity, we also did not observe any severe adverse effects associated to AWPC treatment, only gastro-intestinal symptoms were reported by five study participants. Conclusions We observed an interesting AWPC effect on miRNAs which targets modulate mesothelioma development. New and much larger clinical studies based on follow-up of workers exposed to asbestos are needed to corroborate the role of AWPC in prevention and early treatment of mesothelioma. Trial registration ClinicalTrials.gov, NCT02076672 . Registered 03/03/2014.

The circular isoform of VEGFA mRNA (circ_0076611), associated with size and pathogenesis of triple-negative breast tumors, is produced via back splicing of exon-7 by a RNP complex comprising lncRNA-MALAT1, ID4 and SRSF1, and secreted through exosomes.

Objective: Dentists must be prepared to manage medical emergencies, which are arisen during dental practice together with the increase of age population and medically compromised patients. This study aims at assessing the occurrence of medical emergencies in a cohort of Italian dentists, to ascertain their level of confidence in the management of these conditions, also based on their educational training and type of medical graduation, and, finally, to know their educational needs, in order to plan appropriate institutional interventions for specific training. Methods: A national-based cross-sectional study was carried out by means of an online survey sent to all dentists working in Italy. Results: The survey included 6818 questionnaires. Most of the respondents (n = 4443; 65.2%) reported the occurrence of at least one medical emergency during their professional life. The events rarely resulted in death as declared by only 62 (0.9%) of respondents. The commonest medical emergency was the vasovagal syndrome. Most medical emergencies occurred during the dental procedure (n = 4883; 71.6%). An average degree of satisfaction about the ability to diagnose and manage medical emergencies was reported by most of respondents, with high level of confidence in treating vasovagal syndrome, while a lack in preparedness about the management of myocardial infarction or transient ischemic attack (TIA) and stroke. Medical doctors were more confident in managing the emergencies than dentistry graduates (p

Objectives: Despite extensive efforts to monitor the diffusion of COVID-19, the actual wave of infection is worldwide characterized by the presence of emerging SARS-CoV-2 variants. The present study aims to describe the presence of yet undiscovered SARS-CoV-2 variants in Italy. Methods: Next Generation Sequencing was performed on 16 respiratory samples from occasionally employed within the Bangladeshi community present in Ostia and Fiumicino towns. Computational strategy was used to identify all potential epitopes for reference and mutated Spike proteins. A simulation of proteasome activity and the identification of possible cleavage sites along the protein guided to a combined score involving binding affinity, peptide stability and T-cell propensity. Results: Retrospective sequencing analysis revealed a double Spike D614G/S939F mutation in COVID-19 positive subjects present in Ostia while D614G mutation was evidenced in those based in Fiumicino. Unlike D614G, S939F mutation affects immune response by the slight but significant modulation of T-cell propensity and the selective enrichment of potential binding epitopes for some HLA alleles. Conclusion: Collectively, our findings mirror further the importance of deep sequencing of SARS-CoV-2 genome as a unique approach to monitor the appearance of specific mutations as for those herein reported for Spike protein. This might have implications on both the type of immune response triggered by the viral infection and the severity of the related illness.

The recent passage of European Union (EU) Regulation 2017/745 on medical devices (MDs) has improved the classification of MDs and revised their approval process and the post-marketing evaluation of their safety and effectiveness, promoting transparency and post-marketing oversight in Europe. This new regulation can better ensure patient safety and provide new opportunities for therapeutic innovation. In addition, the new regulations include and define MDs made of substances or of combinations of substances (substance-based MDs: SBMDs). The impressive growth of the MD, including SBMDs, that have been marketed over the recent years has likely been a relevant factor fueling this change. MD regulation requires a major effort from both industry and regulatory bodies to comply with its provisions. Manufacturers should produce sufficient clinical evidence that an MD, under normal conditions of use, provides adequate performance and that the foreseeable risks and frequency of adverse events (AEs) have an acceptable minimum rate, taking into account the benefits provided. We describe how we implemented the post-marketing surveillance (PMS) system of SBMDs to properly deal with post-market monitoring and confirmation of safety and performance, including AEs and the benefit–risk evaluation, as required by the 2017/745 Regulation. The two pillars of this novel system are: 1) passive vigilance, i.e., spontaneous reporting and 2) active post-marketing clinical follow-up (PMCF) activities, which systematically gather, record, and analyze real-world data (RWD) on performance, quality, function, use, tolerability, and safety of an MD, collected through a dedicated, structured web platform. Active PMCF is achieved through a process of generation, validation, and administration of digital questionnaires to all stakeholders, i.e., patients, physicians, both general practitioners and specialists, and pharmacists. The technology, potential use, advantages, and limitations of this large source of RWD are also discussed.

Background: Gastroesophageal reflux disease (GERD) and functional dyspepsia (FD) are very common in the general population. GERD prevalence is considerably high in pregnant women, and it increases at a young age, alongside obesity. Mucosal protective agents (MPAs) are over-the-counter (OTC) treatments for FD and GERD commonly used alone or as add-on therapy to proton pump inhibitors (PPIs). Real-world data through surveys allow a clinical evaluation of marketed products that also complies with the new regulation on substance-based medical devices (SBMDs).Aim: The study aimed to evaluate perceived effectiveness, safety, and pattern of usage among patients, physicians, and pharmacists of the natural MPA Poliprotect, as assessed by a validated survey methodology.Methods: Questionnaire repeatability was first assessed, resulting in the intraclass correlation coefficient agreement level >0.9 in the three validation cohorts of physicians, pharmacists, and patients. All questions were closed multiple-choice, allowing measuring variations in frequency, quality, or magnitude of effect on a 5-point Likert-like verbal scale.Results: Three different surveys were performed in Italy and Spain on a total of 3,471 physicians, including 77 gastroenterologists, 848 patients, and 146 pharmacists who had an experience with Poliprotect in the previous year. Over 90% of general practitioners (GPs) rated Poliprotect effectiveness as good/excellent in controlling pyrosis, 80% for epigastric pain, and approximately 70% for digestion difficulties. GPs reported Poliprotect as very or extremely useful as an alternative to PPIs (73%) and for pregnancy-associated GERD symptoms (61%), almost unanimously (99.5%) reporting an excellent to good tolerability; 79% of the gastroenterologists answered to be extremely or very satisfied with the improvement of typical GERD symptoms, whereas improvement of dyspepsia and pregnancy- and breast-feeding-associated GERD symptoms was rated as highly satisfactory for 69, 52, and 62%, respectively, among GI specialists. Its use because of painful dyspeptic symptoms was reported by over 80% of patients, who rated symptom relief as excellent/good, and reported a marked quality-of-life improvement in 73% and in 65% of their answers, respectively. The product was used as monotherapy by 63% of patients. Conclusion: Large-scale, validated surveys support the safety and effectiveness of Poliprotect in the treatment of common functional upper GI disorders.

Multiple sclerosis (MS) is the most prevalent demyelinating disease of the central nervous system (CNS) with an autoimmune component affecting young adults in their third decade of life. The etiology is still undefined, but myelin damage is mainly due to an aberrant immune response of lymphocyte cells against myelin components. Therefore, inflammation, demyelination, and axonal degeneration represent the major pathologic hallmarks of the disease. There are many risk factors associated with MS, and probably the most relevant is gender-related. Women are up to four times more affected than men are. Although the female prevalence in MS is epidemiologically evident, the identification of key factors involved in this difference is under investigation. On the other side, if women are more affected, men show late onset and worse prognosis. This sexual dimorphism derives from many sources, including sex hormones, different genes on female sex chromosomes, and differences in bacterial species. Indeed, accumulating evidence proves a link among MS and gut microbiota where its dysbiosis could help the immune system to trigger neuroinflammation. In this context, oral biology alteration should be considered, too. This work is intended to explore current knowledge inside MS gender differences with a look towards oral–gut–brain axis involvement.

Background/Purpose: Type 2 diabetes and obesity increase the risk of developing colorectal cancer. Metformin may reduce colorectal cancer but the mechanisms mediating this effect remain unclear. In mice and humans, a high-fat diet (HFD), obesity and metformin are known to alter the gut microbiome but whether this is important for influencing tumor growth is not known. Methods: Mice with syngeneic MC38 colon adenocarcinomas were treated with metformin or feces obtained from control or metformin treated mice. Results: We find that compared to chow-fed controls, tumor growth is increased when mice are fed a HFD and that this acceleration of tumor growth can be partially recapitulated through transfer of the fecal microbiome or in vitro treatment of cells with fecal filtrates from HFD-fed animals. Treatment of HFD-fed mice with orally ingested, but not intraperitoneally injected, metformin suppresses tumor growth and increases the expression of short-chain fatty acid (SCFA)-producing microbes Alistipes, Lachnospiraceae and Ruminococcaceae. The transfer of the gut microbiome from mice treated orally with metformin to drug naïve, conventionalized HFD-fed mice increases circulating propionate and butyrate, reduces tumor proliferation, and suppresses the expression of sterol response element binding protein (SREBP) gene targets in the tumor. Conclusion: These data indicate that in obese mice fed a HFD, metformin reduces tumor burden through changes in the gut microbiome.

Objectives: Despite an extensive risk of exposure to COVID-19, the residents of Giglio Island, Italy, did not develop any symptom of SARS-CoV-2. The present study aims to characterize the nature of exposure and to describe the local population dynamics underlying its apparent resistance to COVID-19. Methods: Descriptive study of an islander partially-segregated population cohort based on a seroprevalence screening conducted from Aprile 29 to May 3, 2020 and including SARS-CoV-2 seroprevalence and viral prevalence in samples of saliva assessed through RT-qPCR. Serologic testing was performed using a COVID-19 IgG/IgM rapid test while molecular analyses were carried out by Allplex 2019-nCoV Assay (Seegene). Results: A total of 634 residents out of 748 (84.8%) present at the time, and 89 non-residents underwent serological testing. 364 males and 359 females with a median age of 58.5 years. The serological screening identified one positive, asymptomatic subject. The Nucleic Acid Amplification Tests (NAAT) did not yield any positive result. Conclusion: Despite extensive exposure to SARS-CoV-2, possibly only one new asymptomatic infection occurred in this population, as documented by IgM positivity not confirmed by RT-qPCR. This may be due to unknown protective factors or chance. On the basis of this baseline study, using its population as a reference model, further investigations will be conducted to test the advanced hypotheses, focusing on the evaluation of a possible cross-reactivity to SARS-CoV-2 from exposure to endemic viruses.

Abstract Background SARS-coronavirus-2 enters host cells through binding of the Spike protein to ACE2 receptor and subsequent S priming by the TMPRSS2 protease. We aim to assess differences in both ACE2 and TMPRSS2 expression in normal tissues from oral cavity, pharynx, larynx and lung tissues as well as neoplastic tissues from the same areas. Methods The study has been conducted using the TCGA and the Regina Elena Institute databases and validated by experimental model in HNSCC cells. We also included data from one COVID19 patient who went under surgery for HNSCC. Results TMPRSS2 expression in HNSCC was significantly reduced compared to the normal tissues. It was more evident in women than in men, in TP53 mutated versus wild TP53 tumors, in HPV negative patients compared to HPV positive counterparts. Functionally, we modeled the multivariate effect of TP53, HPV, and other inherent variables on TMPRSS2. All variables had a statistically significant independent effect on TMPRSS2. In particular, in tumor tissues, HPV negative, TP53 mutated status and elevated TP53-dependent Myc-target genes were associated with low TMPRSS2 expression. The further analysis of both TCGA and our institutional HNSCC datasets identified a signature anti-correlated to TMPRSS2. As proof-of-principle we also validated the anti-correlation between microRNAs and TMPRSS2 expression in a SARS-CoV-2 positive HNSCC patient tissues Finally, we did not find TMPRSS2 promoter methylation. Conclusions Collectively, these findings suggest that tumoral tissues, herein exemplified by HNSCC and lung cancers might be more resistant to SARS-CoV-2 infection due to reduced expression of TMPRSS2. These observations may help to better assess the frailty of SARS-CoV-2 positive cancer patients.

Abstract Background During healthcare guideline development, panel members often have implicit, different definitions of health outcomes that can lead to misunderstandings about how important these outcomes are and how to balance benefits and harms. McMaster GRADE Centre researchers developed ‘health outcome descriptors’ for standardizing descriptions of health outcomes and overcoming these problems to support the European Commission Initiative on Breast Cancer (ECIBC) Guideline Development Group (GDG). We aimed to determine which aspects of the development, content, and use of health outcome descriptors were valuable to guideline developers. Methods We developed 24 health outcome descriptors related to breast cancer screening and diagnosis for the European Commission Breast Guideline Development Group (GDG). Eighteen GDG members provided feedback in written format or in interviews. We then evaluated the process and conducted two health utility rating surveys. Results Feedback from GDG members revealed that health outcome descriptors are probably useful for developing recommendations and improving transparency of guideline methods. Time commitment, methodology training, and need for multidisciplinary expertise throughout development were considered important determinants of the process. Comparison of the two health utility surveys showed a decrease in standard deviation in the second survey across 21 (88%) of the outcomes. Conclusions Health outcome descriptors are feasible and should be developed prior to the outcome prioritization step in the guideline development process. Guideline developers should involve a subgroup of multidisciplinary experts in all stages of development and ensure all guideline panel members are trained in guideline methodology that includes understanding the importance of defining and understanding the outcomes of interest.

Abstract Odontogenic tumors (OT) are considered rare events and their epidemiologic data are scarce and under-estimated in developing countries because there is no systematic collection of clinical features including histological analyses of the tissue samples. Furthermore, there is an underestimation of the disease relevance and affected people are often marginalized in spite of severe functional impairment of aero-digestive tract. Etiology of OT in humans is still unknown and it represents an important therapeutic and diagnostic challenge. Lassa fever is an acute viral haemorrhagic illness caused by Lassa virus, a member of the arenavirus family of viruses. The disease is endemic in the rodent population in West-East Africa. Humans usually become infected with Lassa virus through exposure to the food or household items contaminated with urine or feces of infected rats. It is also reported person-to-person infections. About 80% of people infected by Lassa virus have no symptoms but the virus establishes a life-long persistent infection. The present commentary significance is to start, for the first time ever, a systematic collection of clinical features and tissue sample collection at the St. Mary’s Hospital in Lacor (Gulu) North Uganda where the considered pathologies have an important frequency. The systematic collection will allow to corroborate the possible association between arenaviruses infection and pathogenesis of odontogenic tumors in humans.

ObjectivesThe COVID-19 pandemic represents a difficult challenge for the whole of humanity. Sports, in which contact between athletes is essential, became impossible to practice without the risk of viral spread. Athletes of the national teams are a particular subgroup of the population for whom there is an important need for protection and the implementation of targeted preventive measures. The present report describes the protocol that was developed to answer the urgent protection need for athletes during COVID-19 pandemic. The protocol aimed at demonstrating the feasibility of a rigid prevention intervention to prevent outbreaks and infections in terms of COVID-19 as well as in other potential future pandemics from pathogens with similar path of transmission.MethodsThe study was conducted in rowing para-thletes training of the Paralympic Games in Tokyo2020. It was designed to create an anti-COVID-19 “protection bubble” with the aim to isolate para-athletes and their technical support team during pre-Olympic retreats. The “bubble” development relied on a carefully conducted protocol of repeated antigen and molecular COVID-19 tests on nasal and oropharyngeal fluids among all participants carried out before, during and at the end of each retreat.ResultsDuring the 10 months of protocol implementation there were no COVID-19 outbreaks among the para-athletes and technical personnel during the retreats. In total, 552 PCR tests and 298 antigen-based tests were performed for an average number of 42 test per athlete. The number of retreat participants was larger (n = 23) in the beginning of the year due to the Paralympic selection rounds and smaller at the end of the study period (n = 12).ConclusionThe protocol has indicated that it is possible to implement an anti-COVID-19 protection protocol where athletes and technical staff can train and compete in safe conditions. The study showed that it is feasible to implement a rigid prevention protocol for athletes and technical staff based on repeated COVID-19 antigenic and molecular tests for a long period of training with excellent participation and compliance.

The impact of COVID-19 on socio-economical activities has changed everyday life. Dental hygienists, who perform aerosol generating procedures, have been strongly affected by changes in routine procedures. This cross-sectional study aimed at carrying out an online survey among dental hygienists in Lombardy. The survey was implemented after the first-wave lockdown focusing on the level of knowledge on COVID-19 and Sars-CoV-2, the virus-related changes in their attitude and working routine, and the socio-economic effects. In this report, we included 313 questionnaires of respondents (259 Females, and 54 Males; age = 33 ± 9 years). A significant percentage of respondents acknowledged the use of "word of mouth" among colleagues (n = 114, 36%) and social networks (n = 113, 36%) to be up to date on COVID-19. About half of respondents correctly identified the main COVID-19 symptoms/signs, just 13% (n = 41) identified the routes of transmission. Three quarters of respondents (n = 234, 75%) were afraid of being infected during the clinical practice, and about half of them would be afraid to treat patients having symptoms attributable to COVID-19. Twenty-one percent (n = 67) of participants also thought about changing job. Air-polishing was identified as the highest risk procedure, and 82% (n = 256) reported that they eliminated its use. Most claimed they never had a swab or a serological test, with two respondents positive to molecular test (0.6%), and 12 positives to serological test (3.8%). More than half of the participants (65%; n = 202) complained the dental hygienist is not protected, despite a loss of earnings due to lockdown between 2,000 and 10,000 euros. This study demonstrated that dental hygienists were emotionally and economically affected by the pandemic, significantly changing their work routine. Anti-epidemic protocols are pivotal to react promptly and to contain the virus in the dental setting.

Background: There is need for well-tolerated therapies for prostate cancer (PrCa) secondary prevention and to improve response to radiotherapy (RT). The anti-diabetic agent metformin (MET) and the aspirin metabolite salicylate (SAL) are shown to activate AMP-activated protein kinase (AMPK), suppress de novo lipogenesis (DNL), the mammalian target of rapamycin (mTOR) pathway and reduce PrCa proliferation in-vitro. The purpose of this study was to examine whether combined MET+SAL treatment could provide enhanced PrCa tumor suppression and improve response to RT. Methods: Androgen-sensitive (22RV1) and resistant (PC3, DU-145) PrCa cells and PC3 xenografts were used to examine whether combined treatment with MET+SAL can provide improved anti-tumor activity compared to each agent alone in non-irradiated and irradiated PrCa cells and tumors. Mechanisms of action were investigated with analysis of signaling events, mitochondria respiration and DNL activity assays. Results: We observed that PrCa cells are resistant to clinically relevant doses of MET. Combined MET + SAL treatment provides synergistic anti-proliferative activity at clinically relevant doses and enhances the anti-proliferative effects of RT. This was associated with suppression of oxygen consumption rate (OCR), activation of AMPK, suppression of acetyl-CoA carboxylase (ACC)-DNL and mTOR-p70s6k/4EBP1 and HIF1α pathways. MET + SAL reduced tumor growth in non-irradiated tumors and enhanced the effects of RT. Conclusion: MET+SAL treatment suppresses PrCa cell proliferation and tumor growth and enhances responses to RT at clinically relevant doses. Since MET and SAL are safe, widely-used and inexpensive agents, these data support the investigation of MET+SAL in PrCa clinical trials alone and in combination with RT.

Abstract Background Over the past decade, newly designed cancer therapies have not significantly improved the survival of patients diagnosed with Malignant Pleural Mesothelioma (MPM). Among a limited number of genes that are frequently mutated in MPM several of them encode proteins that belong to the HIPPO tumor suppressor pathway. Methods The anticancer effects of the top flower standardized extract of Filipendula vulgaris (Dropwort) were characterized in “in vitro” and “in vivo” models of MPM. At the molecular level, two “omic” approaches were used to investigate Dropwort anticancer mechanism of action: a metabolomic profiling and a phosphoarray analysis. Results We found that Dropwort significantly reduced cell proliferation, viability, migration and in vivo tumor growth of MPM cell lines. Notably, Dropwort affected viability of tumor-initiating MPM cells and synergized with Cisplatin and Pemetrexed in vitro. Metabolomic profiling revealed that Dropwort treatment affected both glycolysis/tricarboxylic acid cycle as for the decreased consumption of glucose, pyruvate, succinate and acetate, and the lipid metabolism. We also document that Dropwort exerted its anticancer effects, at least partially, promoting YAP and TAZ protein ubiquitination. Conclusions Our findings reveal that Dropwort is a promising source of natural compound(s) for targeting the HIPPO pathway with chemo-preventive and anticancer implications for MPM management.

Abstract Background Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cancer worldwide. They are typically characterized by a high incidence of local recurrence, which is the most common cause of death in HNSCC patients. TP53 is the most frequently mutated gene in HNSCC and patients carrying TP53 mutations are associated with a higher probability to develop local recurrence. MiRNAs, which are among the mediators of the oncogenic activity of mt-p53 protein, emerge as an appealing tool for screening, diagnosis and prognosis of cancer. We previously identified a signature of 12 miRNAs whose aberrant expression associated with TP53 mutations and was prognostic for HNSCC. Among them miR-96-5p emerges as an oncogenic miRNAs with prognostic significance in HNSCC. Methods To evaluate the oncogenic role of miR-96-5p in a tumoral context, we performed colony formation, cell migration and cell viability assays in two HNSCC cell lines transfected for miR-96-5p mimic or inhibitor and treated with or without radio/chemo-therapy. In addition, to identify genes positively and negatively correlated to miR-96-5p expression in HNSCC, we analyzed the correlation between gene expression and miR-96-5p level in the subset of TCGA HNSCC tumors carrying missense TP53 mutations by Spearman and Pearson correlation. To finally identify targets of miR-96-5p, we used in silico analysis and the luciferase reporter assay to confirm PTEN as direct target. Results Our data showed that overexpression of miR-96-5p led to increased cell migration and radio-resistance, chemotherapy resistance in HNSCC cells. In agreement with these results, among the most statistically significant pathways in which miR-96-5p is involved, are focal Adhesion, extracellular matrix organization and PI3K-Akt-mTOR-signaling pathway. As a direct target of miR-96-5p, we identified PTEN, the main negative regulator of PI3K-Akt signalling pathway activation. Conclusions These results highlight a new mechanism of chemo/radio-resistance insurgence in HNSCC cells and support the possibility that miR-96-5p expression could be used as a novel promising biomarker to predict radiotherapy response and local recurrence development in HNSCC patients. In addition, the identification of pathways in which miR-96-5p is involved could contribute to develop new therapeutic strategies to overcome radio-resistance.

Oral cancer is among the deadliest types of malignancy due to the late stage at which it is usually diagnosed, leaving the patient with an average five-year survival rate of less than 50%. The booming field of biosensing and point of care diagnostics can, in this regard, play a major role in the early detection of oral cancer. Saliva is gaining interest as an alternative biofluid for non-invasive diagnostics, and many salivary biomarkers of oral cancer have been proposed. While these findings are promising for the application of salivaomics tools in routine practice, studies on larger cohorts are still needed for clinical validation. This review aims to summarize the most recent development in the field of biosensing related to the detection of salivary biomarkers commonly associated with oral cancer. An introduction to oral cancer diagnosis, prognosis and treatment is given to define the clinical problem clearly, then saliva as an alternative biofluid is presented, along with its advantages, disadvantages, and collection procedures. Finally, a brief paragraph on the most promising salivary biomarkers introduces the sensing technologies commonly exploited to detect oral cancer markers in saliva. Hence this review provides a comprehensive overview of both the clinical and technological advantages and challenges associated with oral cancer detection through salivary biomarkers.

The AMP‐activated protein kinase (AMPK) is a heterotrimeric protein complex that is an important sensor of cellular energy status. Reduced expression of the AMPK β1 isoform has been linked to reduced survival in different cancers, but whether this accelerates tumor progression and the potential mechanism mediating these effects are not known. Furthermore, it is unknown whether AMPK β1 is implicated in tumorigenesis, and if so, what tissues may be most sensitive. In the current study, we find that in the absence of the tumor suppressor p53, germline genetic deletion of AMPK β1 accelerates the appearance of a T‐cell lymphoma that reduces lifespan compared to p53 deficiency alone. This increased tumorigenesis is linked to increases in interleukin‐1β (IL1β), reductions in acetyl‐CoA carboxylase (ACC) phosphorylation, and elevated lipogenesis. Collectively, these data indicate that reductions in the AMPK β1 subunit accelerate the development of T‐cell lymphoma, suggesting that therapies targeting this AMPK subunit or inhibiting lipogenesis may be effective for limiting the proliferation of p53‐mutant tumors.

Objective: The sodium-glucose transporter 2 (SGLT2) inhibitors Canagliflozin and Dapagliflozin are recently approved medications for type 2 diabetes. Recent studies indicate that SGLT2 inhibitors may inhibit the growth of some cancer cells but the mechanism(s) remain unclear. Methods: Cellular proliferation and clonogenic survival were used to assess the sensitivity of prostate and lung cancer cell growth to the SGLT2 inhibitors. Oxygen consumption, extracellular acidification rate, cellular ATP, glucose uptake, lipogenesis, and phosphorylation of AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase, and the p70S6 kinase were assessed. Overexpression of a protein that maintains complex-I supported mitochondrial respiration (NDI1) was used to establish the importance of this pathway for mediating the anti-proliferative effects of Canagliflozin. Results: Clinically achievable concentrations of Canagliflozin, but not Dapagliflozin, inhibit cellular proliferation and clonogenic survival of prostate and lung cancer cells alone and in combination with ionizing radiation and the chemotherapy Docetaxel. Canagliflozin reduced glucose uptake, mitochondrial complex-I supported respiration, ATP, and lipogenesis while increasing the activating phosphorylation of AMPK. The overexpression of NDI1 blocked the anti-proliferative effects of Canagliflozin indicating reductions in mitochondrial respiration are critical for anti-proliferative actions. Conclusion: These data indicate that like the biguanide metformin, Canagliflozin not only lowers blood glucose but also inhibits complex-I supported respiration and cellular proliferation in prostate and lung cancer cells. These observations support the initiation of studies evaluating the clinical efficacy of Canagliflozin on limiting tumorigenesis in pre-clinical animal models as well epidemiological studies on cancer incidence relative to other glucose lowering therapies in clinical populations. Keywords: AMP-activated protein kinase AMPK, Lipogenesis, SGLT2, Prostate cancer, Lung cancer, Breast cancer, Colon cancer, mTOR, Cancer metabolism, Glucose uptake

Cancer metabolism is the focus of intense research, which witnesses its key role in human tumors. Diabetic patients treated with metformin exhibit a reduced incidence of cancer and cancer-related mortality. This highlights the possibility that the tackling of metabolic alterations might also hold promising value for treating cancer patients. Here, we review the emerging role of metformin as a paradigmatic example of an old drug used worldwide to treat patients with type II diabetes which to date is gaining strong in vitro and in vivo anticancer activities to be included in clinical trials. Metformin is also becoming the focus of intense basic and clinical research on chemoprevention, thus suggesting that metabolic alteration is an early lesion along cancer transformation. Metabolic reprogramming might be a very efficient prevention strategy with a profound impact on public health worldwide.

Abstract Deregulated proliferation is a hallmark of cancer cells. Here, we show that microRNA‐10b* is a master regulator of breast cancer cell proliferation and is downregulated in tumoural samples versus matched peritumoural counterparts. Two canonical CpG islands (5 kb) upstream from the precursor sequence are hypermethylated in the analysed breast cancer tissues. Ectopic delivery of synthetic microRNA‐10b* in breast cancer cell lines or into xenograft mouse breast tumours inhibits cell proliferation and impairs tumour growth in vivo, respectively. We identified and validated in vitro and in vivo three novel target mRNAs of miR‐10b* (BUB1, PLK1 and CCNA2), which play a remarkable role in cell cycle regulation and whose high expression in breast cancer patients is associated with reduced disease‐free survival, relapse‐free survival and metastasis‐free survival when compared to patients with low expression. This also suggests that restoration of microRNA‐10b* expression might have therapeutic promise.