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Purpose Two chimeric antigen receptor T-cell (CAR-T) therapies have been approved in the United States (USA) in 2017 and Europe (EU) in 2018: axicabtagene ciloleucel and tisagenlecleucel. They contain the patient’s own T cells, which are extracted, genetically modified, and reinfused. Alongside the good efficacy results, the assessment of safety profile of these new therapies represents a great challenge. Our aim was to analyze the reports of the adverse drug reactions (ADR) after CAR-T administration as occurred in the real clinical setting. Methods We performed a retrospective observational study, collecting all the reports in EU (EudraVigilance, EV) and US (FAERS) databases of ADRs regarding axicabtagene ciloleucel and tisagenlecleucel. Both descriptive and statistical analyses were performed, the latter by using Reporting Odds Ratio (ROR). Results A total number of 1426 reports of suspected ADRs were retrieved in EudraVigilance and FAERS. Patients’ reported age reflected the age range for which the drugs are approved (18–64 years for axicabtagene ciloleucel and patients aged under 25 years for tisagenlecleucel). The most reported event was cytokine release syndrome (CRS), 185 events for tisagenlecleucel and 462 for axicabtagene ciloleucel in FAERS and 137 and 498, respectively, in EudraVigilance. A disproportionality was found comparing axicabtagene ciloleucel with tisagenlecleucel for the above-mentioned event: EV ROR 2.47, 95% CI 2.22–2.74, FAERS 1.89, 1.70–2.10. Conclusion CRS represents the major problem with the administration of CAR-T therapies. Our analysis has not revealed new ADRs; however, it supports the safety profile of CAR-T with new data from real clinical setting.

Objective Serous tubal intraepithelial carcinoma (STIC) is currently considered the precursor lesion of pelvic high-grade serous carcinoma. The management of STIC diagnosed after risk-reducing salpingo-oophorectomy (RRSO) in women with BRCA1–2 variants remains unclear. The aim of our study was to evaluate the incidence of STIC, serous tubal intraepithelial lesions (STIL) and occult invasive cancer (OC) and to determine the long-term outcomes of these patients. Methods We conducted a retrospective study of patients with BRCA 1–2 variants who underwent RRSO between January-2010 and Dicember-2020 at the Clinic of Gynaecology of University of Padova. Inclusion criteria: women with a negative pelvic examination at the last screening prior to RRSO, patients with fallopian tubes analysed using the SEE-FIM protocol. Exclusion criteria: patients with a positive gynaecologic screening or with ovarian/tubal cancer prior to RRSO. Results We included 153 patients. STICs were diagnosed in 4 patients (2.6%) and STILs in 6 patients (3.9%). None of the patients with STIC underwent restaging surgery or adjuvant chemotherapy; all patients were followed closely every 6 months. None of the patients developed primary peritoneal carcinomas (PPCs) with a median FUP of 54.5 months (15–106). OC was diagnosed in 3 patients (2%). All patients with OC underwent staging surgery, and one patient developed a peritoneal carcinoma (PC) after 18 months by staging surgery. Conclusion(s) The incidence of STIC, STIL and OC after RRSO in BRCA1–2 variants was low. Our results demonstrated that long-term close surveillance in patients diagnosed with STIC should be considered a possible management strategy.

Aims: Human papilloma virus (HPV) is 1 of the most common sexually transmitted infection responsible for different types of cancer: cervical, penile, vulvar, anal and oropharyngeal. It can affect both males and females. Our aim was to enrich the knowledge on the safety profiles of HPV vaccines in the male population. Methods: We reviewed all the reports of adverse events following immunization (AEFI) present in the US Vaccine Adverse Event Reporting System from 1 January 2006 to 30 September 2018. Statistical data mining was performed using the reporting odds ratio with 95% confidence interval in order to detect disproportionality in reporting. Results: A total of 5493 reports of AEFI were retrieved. The events most reported and that proportionally occurred more frequently with HPV vaccines than with others in males were: syncope (n = 701, reporting odds ratio = 2.85, 95% confidence interval [1.41–5.76p), loss of consciousness (n = 425, 2.79 [1.36–5.72]) and fall (n = 272, 3.54 [2.00–6.26]). Conclusion: Most of the AEFIs were already reported in premarketing clinical trials and acknowledged for the corresponding vaccines. A disproportionate reporting was found for some of these events including syncope. The HPV vaccines are generally well tolerated in males, although limitations own of spontaneous reporting should be considered.

Little is known about the administration of direct-acting oral anticoagulants (DOACs) and the occurrence of alopecia. Our aim was to analyse the reports of alopecia following DOAC administration received until 2 May 2018 from VigiBase, the World Health Organization database. A descriptive analysis of age, sex, seriousness and dechallenge/rechallenge outcome was carried out. For each report, the time-to-onset was evaluated and the causality was assessed by using Naranjo algorithm. Overall, 1316 reports were retrieved, most concerning rivaroxaban (58.8%); 80% of the reports were related to females, in particular to those aged ≥65 years (23.1%). The median value of the time-to-onset was 28 days, with an interquartile range of 63 days. In 54.3% of the reports the causality was assessed as possible. In conclusion, a possible association could exist between DOACs administration and alopecia, but further observational studies are needed to confirm these findings.

Simple Summary Nutritional strategies focused on the use of botanicals as modulators of several physiological responses and health promoters of the gastrointestinal tract have attracted interest in animal production. Previous research indicates the positive results of using essential oils (EOs) as natural feed additives for several farmed animals. In the last decades, these nutritional alternatives have been evaluated and reported in fish production in order to increase fish growth and feed utilization and to promote animal welfare. Therefore, the present study was designed to compare the effects of feed EO supplementation in two different forms (natural and composed of active ingredients obtained by synthesis) on the gastric mucosa in European sea bass. EOs decrease oxyntopeptic cells and increase somatostatin and ghrelin enteroendocrine cells. In addition, we showed that Na+K+-ATPase was expressed in oxyntopeptic cells (OPs) in the same way as H+K+-ATPase (typical marker for mammalian parietal cells) and, for this reason, consider Na+K+-ATPase a valid marker for OPs. Abstract The current work was designed to assess the effect of feed supplemented with essential oils (EOs) on the histological features in sea bass’s gastric mucosa. Fish were fed three diets: control diet (CTR), HERBAL MIX® made with natural EOs (N-EOs), or HERBAL MIX® made with artificial EOs obtained by synthesis (S-EOs) during a 117-day feeding trial. Thereafter, the oxyntopeptic cells (OPs) and the ghrelin (GHR) and somatostatin (SOM) enteroendocrine cells (EECs) in the gastric mucosa were evaluated. The Na+K+-ATPase antibody was used to label OPs, while, for the EECs, anti-SOM and anti-GHR antibody were used. The highest density of OP immunoreactive (IR) area was in the CTR group (0.66 mm2 ± 0.1). The OP-IR area was reduced in the N-EO diet group (0.22 mm2 ± 1; CTR vs. N-EOs, p < 0.005), while in the S-EO diet group (0.39 mm2 ± 1) a trend was observed. We observed an increase of the number of SOM-IR cells in the N-EO diet (15.6 ± 4.2) compared to that in the CTR (11.8 ± 3.7) (N-EOs vs. CTR; p < 0.05), but not in the S-EOs diet. These observations will provide a basis to advance current knowledge on the anatomy and digestive physiology of this species in relation to pro-heath feeds.

Background Zika virus (ZIKV) is associated with severe congenital abnormalities and laboratory diagnosis of antenatal infection is difficult. Here we evaluated ZIKV neutralizing antibody (nAb) kinetics in infants born to mothers with PCR-confirmed ZIKV infection during pregnancy. Methods Neonates (n = 98) had serum specimens tested repeatedly for ZIKV nAb over the first 2 years of life using virus neutralization test (VNT). ZIKV neonatal infection was confirmed by RT-PCR in blood or urine and/or presence of ZIKV IgM antibodies, and results were correlated with infant clinical features. Results Postnatal laboratory evidence of ZIKV vertical transmission was obtained for 60.2% of children, while 32.7% exhibited clinical abnormalities. Congenital abnormalities were found in 37.3% of children with confirmed ZIKV infection and 31.0% of children without confirmed infection (P = .734). All but 1 child displayed a physiologic decline in ZIKV nAb, reflecting maternal antibody decay, despite an early ZIKV-IgM response in one-third of infants. Conclusions Infants with antenatal ZIKV exposure do not develop ZIKV nAb despite an early IgM response. Therefore, ZIKV VNT in children is not useful for diagnosis of congenital infection. In light of these findings, it remains to be determined if children infected in utero are potentially susceptible to reinfection.

Purpose In Italy, the non-commercial trials on medicines are regulated by the Ministry Decree 17 December, 2004. Its intent is of encouraging the independent research for the improvement of clinical practice. We aimed to analyze the main features of the proposals of non-commercial clinical trials on medicines submitted to the Independent Ethics Committee (IEC) of the University Hospital of Bologna in the period 2010-2017. Methods Data were extracted from IEC registry and were organized with an ad hoc database. The relationships between the variables were examined using contingency tables. When appropriate, we applied the chi-square statistical test for the comparison of the categorical variables. Results Over the 8-year period, the IEC evaluated 2931 studies, of which 1156 (39.4%) related to clinical trials on medicines; 245 (21.2%) out of the latter were non-commercial ones. A percentage of 49.8 of the trials were of phase II; 137 trials (55.9%) were promoted by hospitals, medical schools or institutes for research, hospitalization and health care. Non-profit organizations and scientific societies were promoters of 88 trials (35.9%). Most phase I and phase II trials received additional support from pharmaceutical companies. Conclusions Our results show a not negligible industrial influence on non-commercial trials through additional support, mostly to those of phase II. An update of the present legislation on this matter is desirable, adopting clearer rules on the relations sponsor-industry.

Multiple Sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) in which inflammation plays a key pathological role. Recent evidences showed that systemic inflammation induces increasing cell infiltration within meninges and perivascular spaces in the brain parenchyma, triggering resident microglial and astrocytic activation. The anti‐inflammatory enzyme A20, also named TNF associated protein 3 (TNFAIP3), is considered a central gatekeeper in inflammation and peripheral immune system regulation through the inhibition of NF‐kB. The TNFAIP3 locus is genetically associated to MS and its transcripts is downregulated in blood cells in treatment‐naïve MS patients. Recently, several evidences in mouse models have led to hypothesize a function of A20 also in the CNS. Thus, here we aimed to unveil a possible contribution of A20 to the CNS human MS pathology. By immunohistochemistry/immunofluorescence and biomolecular techniques on post‐mortem brain tissue blocks obtained from control cases (CC) and progressive MS cases, we demonstrated that A20 is present in CC brain tissues in both white matter (WM) regions, mainly in few parenchymal astrocytes, and in grey matter (GM) areas, in some neuronal populations. Conversely, in MS brain tissues, we observed increased expression of A20 by perivascular infiltrating macrophages, resident‐activated astrocytes, and microglia in all the active and chronic active WM lesions. A20 was highly expressed also in the majority of active cortical lesions compared to the neighboring areas of normal‐appearing grey matter (NAGM) and control GM, particularly by activated astrocytes. We demonstrated increased A20 expression in the active MS plaques, particularly in macrophages and resident astrocytes, suggesting a key role of this molecule in chronic inflammation., The anti‐inflammatory enzyme A20, codified by the TNFAIP3 gene, is genetically associated to MS and its transcripts is down‐regulated in blood cells of treatment‐naïve MS patients. By immunohistochemistry/immunofluorescence and biomolecular techniques on post‐mortem brain tissues of progressive MS cases, we observed an increased expression of A20 in the active and chronic active white matter lesions and in the active cortical lesions, particularly in activated astrocytes. Our results suggest a key role of A20 also in chronic inflammation of the central nervous system.

We describe a case of prolonged COVID-19 caused by the SARS-CoV-2 Gamma variant in a fully vaccinated healthcare worker, 387 days after an infection caused by lineage B.1.1.33. Infections were confirmed by whole-genome sequencing and corroborated by the detection of neutralizing antibodies in convalescent serum samples. Considering the permanent exposure of this healthcare worker to SARS-CoV-2, the waning immunity after the first infection, the low efficacy of the inactivated vaccine at preventing COVID-19, the immune escape of the Gamma variant (VOC), and the burden of post-COVID syndrome, this individual would have benefited from an additional dose of a heterologous vaccine.

Older patients represent a subpopulation of concern for immune checkpoint inhibitor (ICI) toxicity because of changes in the aging immune system and the potentially relevant clinical implications for their quality of life. Current evidence on ICI safety in older patients is conflicting. This study aimed to assess whether older patient age was a risk factor for increased reporting with ICIs as compared to other antineoplastic drugs in VigiBase, the World Health Organization database of suspected adverse drug reactions. Disproportionality analyses computing the reporting odds ratios (RORs) were performed by age subgroups (&lt, 18 years, 18–64 years, 65–74 years, 75–84 years and ≥85 years). There were not signals of disproportionate reporting with ICIs specifically detected in older patient age subgroups (≥65 years), which were not present in the disproportionality analysis over the entire dataset. A signal of disproportionate reporting with ICIs emerged for eye disorders only in the age subgroup 18–64 years (ROR 1.13, 95% confidence interval 1.05–1.23). These findings showed that adverse event reporting with ICIs in older patients was comparable to that in the overall patient cohort and prompt for the further investigation of eye disorders with ICIs to elucidating risk factors and defining management strategies.

Bisphenol A (BPA), an organic synthetic compound found in some plastics and epoxy resins, is classified as an endocrine disrupting chemical. Exposure to BPA is especially dangerous if it occurs during specific “critical periods” of life, when organisms are more sensitive to hormonal changes (i.e., intrauterine, perinatal, juvenile or puberty periods). In this study, we focused on the effects of chronic exposure to BPA in adult female mice starting during pregnancy. Three months old C57BL/6J females were orally exposed to BPA or to vehicle (corn oil). The treatment (4 µg/kg body weight/day) started the day 0 of pregnancy and continued throughout pregnancy, lactation, and lasted for a total of 20 weeks. BPA-treated dams did not show differences in body weight or food intake, but they showed an altered estrous cycle compared to the controls. In order to evidence alterations in social and sociosexual behaviors, we performed the Three-Chamber test for sociability, and analyzed two hypothalamic circuits (well-known targets of endocrine disruption) particularly involved in the control of social behavior: the vasopressin and the oxytocin systems. The test revealed some alterations in the displaying of social behavior: BPA-treated dams have higher locomotor activity compared to the control dams, probably a signal of high level of anxiety. In addition, BPA-treated dams spent more time interacting with no-tester females than with no-tester males. In brain sections, we observed a decrease of vasopressin immunoreactivity (only in the paraventricular and suprachiasmatic nuclei) of BPA-treated females, while we did not find any alteration of the oxytocin system. In parallel, we have also observed, in the same hypothalamic nuclei, a significant reduction of the membrane estrogen receptor GPER1 expression.

O Hemocentro de Ribeirao Preto possui longa experiencia na manufatura de celulas em Terapia Celular, atraves de uma infraestrutura com padrao de boas praticas que segue os criterios exigidos pela regulamentacao brasileira. Recentemente, o Hemocentro expandiu seu foco para a producao de celulas T geneticamente modificadas (celulas CAR-T), atraves da validacao do processo de manufatura de celulas CAR-T anti-CD19. Objetivo Demonstrar a estruturacao e validacao de uma plataforma brasileira para a manufatura de celulas CAR-T anti-CD19 no cenario brasileiro. Material e metodos Para a estruturacao da plataforma, uma linha de cuidados foi estabelecida em 04 etapas de acordo com o processo de manufatura. A etapa um, consistiu na coleta de leucocitos totais em sangue periferico por procedimento de aferese seguida de isolamento das celulas mononucleares (CMN) por meio de Ficoll Hypaque e, posteriormente, congeladas para permanencia em estoque ate o momento do processamento. Na etapa dois, as CMN foram descongeladas para a deplecao de monocitos apos o qual, as celulas-T foram ativadas por meio de Dynabeads CD3/CD28. Na etapa tres (24 horas apos a etapa dois), as celulas-T foram transduzidas com vetor lentiviral e expandidas em meio AIMV (com 5% de soro humano AB e IL-2) por aproximadamente 8 a 11 dias. A ultima etapa, consistiu na execucao dos seguintes testes de liberacao e controle de qualidade: identidade/pureza, teste funcional/potencia, analise microbiologica, analise do nivel de endotoxinas bacterianas, teste para deteccao de Mycoplasma, analise citogenetica, viabilidade e contagem de beads residuais. Resultados Ate o momento, foram produzidos 11 lotes de celulas CAR-T que foram expandidas ate atingir a dose minima de 1,0 x 106 CAR-T/kg de peso do paciente e, apos criopreservadas em bolsas. A mediana do perfil imunofenotipico dos 11 lotes de celulas CAR-T produzidos foi CD3 94,25%, CD4 38,1%, CD8 56,82%, CD16/56 2%, CD45/14 0,2%, CD19 0,2% e a % de CAR-CD19+ 35,8%. Em todos os lotes de celulas CAR-T produzidas houve lise das celulas alvos CD19+ evidenciado atraves de teste de potencia. Os ensaios de liberacao e do controle de qualidade da etapa 04 mostraram-se todos adequados para qualificar o produto final como apto para o uso clinico. Os lotes de celulas CAR-T apresentaram uma mediana de viabilidade de 91,81%. A contagem de beads residuais em todos os lotes foi inferior a 100 beads para cada 3x106 celulas. Discussao Todos os lotes de celulas CAR-T CD19+ apresentaram-se com perfil imunofenotipico, atividade funcional, ensaios de controle de qualidade e com criterios de aceitacao adequados dentro dos padroes GMP e da RDC ANVISA 508 de 2021. Dentre os 11 lotes produzidos, tres foram utilizados em cenario clinico em tratamento compassivo de pacientes portadores de linfoma nao-hodgkin de celulas B com niveis aceitaveis de toxicidade pos-infusao. Conclusao A plataforma de manufatura de celulas CAR-T desenvolvida em Ribeirao Preto mostrou-se viavel, segura e adequada para uso clinico em cenario brasileiro. O desenvolvimento de uma estrutura nacional tem o potencial de impactar o avanco cientifico da terapia celular avancada brasileira e, alem disso, permitir maior acesso dos pacientes a esta terapia que e reconhecidamente de altissimo custo.

Introduction/Background* Serous Tubal Intraepithelial Carcinoma (STIC) is a non-invasive subtype of high-grade serous carcinoma (HGSC), usually located at the tubo-peritoneal junction and currently considered the precursor lesion of HGSC. The management of STIC diagnosed after Risk-Reducing Salpingo-Oophorectomy (RRSO) in women with BRCA-carriers remains unclear. The aim of our study was to evaluate the incidence of STIC, serous tubal intraepithelial lesions (STIL) and Occult-Cancer (OC) in patients submitted to RRSO and determine the long-term outcomes of these patients. Methodology We conducted an observational retrospective study on patients with BRCA 1-2 mutation who undergone RRSO between January-2010 to Dicember-2020 at the Gynaecology Clinic of Padua. Inclusion criteria: (i) women with a negative pelvic examination prior to RRSO (ii) fallopian tubes analyzed using the Sectioning and Extensively Examining the Fimbriated (SEE-FIM) protocol. Exclusion criteria: patients with a positive gynecologic screening or with ovarian/tubal cancer prior to RRSO. We collected data about age, menopausal status, history of breast carcinoma, pre-operative CA-125 levels, transvaginal-ultrasound features before surgery, and follow up (FUP) information after RRSO, specifically with CA-125 and gynecologic examination. Result(s)* We included 153 patients: baseline characteristics (table 1). STICs was diagnosed in 4 (2.6%) and STILs in 6 (3.9%) patients. None patients with STIC and STIL underwent a restaging surgery or adjuvant chemotherapy; all patients were followed closely every 6 months with transvaginal-ultrasound and CA-125. None of them developed peritoneal carcinoma (PC) or primary peritoneal carcinomas (PPC) with a median FUP of 54.5 months (15-106) and 57,5 months (12-82) in patients with STIC and STIL, respectively. OC was diagnosed in 3 patients (2%) and they underwent a staging-surgery; one patient developed a recurrence with PC after 18 months by staging surgery. Conclusion* Considering the low incidence of OC-STIC-STIL, our data support the importance of RRSO in patients with BRCA 1-2 mutations for reducing the risk of ovarian cancer and for detecting the lesions in early stage. The management of patients with isolated STIC that is aimed to decreases the rates of subsequent PPC and PC. Our results demonstrated that a long-term close surveillance in patients with STIC should be considered a possible management strategy.

Introduction/Background* Hereditary BRCA 1-2 mutations are known risk factors for the development of breast and ovarian cancer. Risk-Reducing Salpingo-Oophorectomy (RRSO) and bilateral mastectomy are the only effective risk-reducing strategies for these patients. Commonly these are two step surgical procedures performed separately. The aim of this study was to evaluate the feasibility and the efficacy of RRSO, combined with simultaneous mastectomy and breast reconstruction in BRCA 1-2 mutation carriers. Methodology We conducted an observational retrospective study on patients with BRCA 1-2 mutation who undergone combined and simultaneous laparoscopic RRSO and mastectomy with breast reconstruction at the Gynaecology Clinic of Padua and Breast Unit of Veneto Institute of Oncology (IOV). Inclusion criteria: patients with BRCA 1-2 mutation, consent to simultaneous surgery. We collected data about age, menopausal status, history of breast carcinoma, pre-operative CA-125 levels, transvaginal-ultrasound features before surgery, operative times, intra and post-operative complications, follow up (FUP) information after RRSO and satisfaction about the simultaneous procedure. Result(s)* We included 40 patients: baseline characteristics are reported in table 1. RRSO was performed in all patients. 37 women underwent to bilateral mastectomy and 3 to monolateral mastectomy (all with breast reconstruction). The mean operative time was 229.6 ± 50.7 minutes (48 ± 16.9 minutes for the RRSO, 147.1 ± 43.6 for mastectomy and reconstruction with a mean surgical team changing time of 34.4 ± 19.6 minutes). No operative complications were reported for RRSO; concerning breast surgery we reported 4 cases of prosthesis loss and one of breast hematoma with a median FUP of 20 months (6-95). The mean hospitalization days was 3.4 ± 2.3. After one months after surgical procedure all patients expressed high satisfaction about the simultaneous surgery. Conclusion* RRSO combined with simultaneous mastectomy and breast reconstruction is feasible, effective and provides an intriguing option for BRCA 1-2 mutation carriers. A single time for anaesthesia, hospitalization and a not increased complication rate lead to high satisfaction of the patients. Nevertheless, patient’s selection should be carefully performed and surgical teams have to be properly instructed and coordinated.

Rotaviruses (RVs) are the most common cause of severe diarrheal disease. To date two rotavirus oral vaccines are licensed: Rotarix and Rotateq. Our aim was to contribute to the post-marketing evaluation of these vaccines safety profile. We collected all RV vaccines-related reports of Adverse Events Following Immunization (AEFI) in US Vaccine Adverse Events Reporting System (VAERS) and VigiBase between January 2007 and December 2017. A disproportionality analysis using Reporting Odds Ratio (ROR) was performed. A total of 17,750 reports in VAERS and 6,358 in VigiBase were retrieved. In VAERS, 86.2% of the reports concerned RotaTeq, whereas in VigiBase 67.7% of them involved Rotarix. Across the databases, diarrhea (1,672 events in VAERS, 1,961 in VigiBase) and vomiting (1,746 in VAERS, 1,508 in VigiBase) were the most reported AEFIs. Noteworthy, the RV vaccines-intussusception pair showed a ROR greater than 20 in both databases. Some new potential safety signals emerged such as fontanelle bulging, hypotonic-hyporesponsive episode, livedo reticularis, and opisthotonus. Overall, our data show that most of the reported AEFIs are listed in the Summary of Product Characteristics (SPCs). However, there remains the need to investigate the potential safety signals arose from this analysis, in order to complete the description of the AEFIs.

Background: Disseminated intravascular coagulation (DIC) occurs in several clinical conditions, including drug therapy. We aim to investigate the association between the administration of several drug classes and the onset of DIC by using the reports of Adverse Drug Reactions (ADR) collected in Vigibase, the World Health Organization (WHO) database of ADR. Methods: We collected reports of drug-related DIC from 1968 to September 2015, classified in Vigibase according to the MedDRA (Medical Dictionary for Regulatory Activities) term “Disseminated intravascular coagulation”. A disproportionality analysis using Reporting Odds Ratio (ROR) with 95% Confidence Interval (CI95%) was performed. Results: Overall, 4653 reports of drug-associated DIC were retrieved and the 75.9% of them was serious according to WHO seriousness criteria. DIC was significantly (ROR > 1, lower limit of CI95% > 1) associated with 88 drugs, mainly antineoplastic agents, antithrombotic agents and antibacterials for systemic use. Among of the most frequently reported individual drugs we found dabigatran (94 reports) ROR = 1.34 (CI95% 1.08–1.67), oxaliplatin and bevacizumab both with 75 reports and ROR = 1.77 (1.38–2.27) and 2.02 (1.57–2.61), respectively. Conclusion: A substantial number of drugs, widely used in the clinical practice, may be associated with the potential occurrence of DIC. For many of these drugs, the ADR is not acknowledged in the corresponding Summary of Product Characteristics. The high number of drugs involved underlines the importance of evaluate this condition such as an ADR that might occur during drug therapy.

A 71-day study was conducted to explore the effect of increasing dietary levels (0, 250, 500, 1000 mg kg feed−1; D0, D250, D500 and D1000, respectively) of a blend of microencapsulated organic acids (OA, specifically citric and sorbic acid) and nature identical compounds (NIC, specifically thymol and vanillin), on growth, intestinal immune parameters and gut microbiota (GM) of European sea bass juveniles reared under normal and subsequently suboptimal environmental conditions (high temperature, 30.0 ± 0.4 °C and low oxygen, 4.6 ± 0.6 mg L−1). OA and NIC did not promote growth, feed utilisation and feed intake at the inclusion tested but induced a significantly upregulation of IL-8, IL-10 and TGFβ. GM analyzed by next-generation sequencing showed that OA and NIC were able to exert prebiotic properties stimulating the development of beneficial bacteria taxa such as Lactobacillus, Leuconostoc, and Bacillus sp. Picrust analyses displayed a significant potential functional reconfiguration of GM promoting a decrease in inflammation-promoting and homeostatic functions at increasing OA and NIC administration. For the first time on this species the exposure to suboptimal rearing conditions was able to modify GM structure reducing LAB and increasing Proteobacteria, findings which were consistent with the inflammatory process observed at mRNA level.

Background: Antimicrobials resistance (AMR) is an increasingly serious global health problem, both in terms of clinical implications and economic expenditure. In Italy, there are differences in prescribing rates between regions. We aimed to compare these differences in two Italian provinces: one of Emilia Romagna (north region) and one of Puglia (south region). Methods: The number of antibiotics prescribed packages and the relative expenditure data (year 2015) were obtained. We applied the prescription quality indicators proposed by the European Surveillance of Antimicrobial Consumption for an in-depth analysis. Results: Both consumption and expenditure were higher in the south province. In the Apulian province also the use of parenteral antibiotics was more frequent. The most prescribed antibiotics in both the provinces were: penicillins (combined or not), macrolides, and fluoroquinolones. Conclusion: We observed variability between the north and south province in terms of antibiotics prescription. Overall, our study indicates that antibacterials could be overprescribed. The choice of the right antibiotic continues to be a demanding task for practitioners and much still needs to be done in the fight against AMR, starting from a more appropriate use and interventions aimed at raising awareness of antibiotic resistance.

The effect of increasing dietary doses of lactose on canine faecal microbiota and apparent digestibility was evaluated. Fourteen adult healthy dogs [1–5 years of age, mean body weight (BW) of 19.0 kg] were fed with an extruded diet containing silica (5 g/kg) as a digestion marker. After a 20 d adaptation period, increasing doses of lactose were added to the dogs’ diet (0.5, 1 and 2 g/kg BW0.75/d) during three consecutive 20-d supplementation periods. Faeces were collected at the end of each period for analyses. Four dogs refused the diet added with lactose at 0.5 g/kg BW0.75/d and were excluded from the trial, as well as two dogs, which developed acute diarrhoea when lactose was fed at 1 g/kg BW0.75/d. Conversely, eight dogs remained healthy throughout the study. Faecal moisture was influenced by lactose (quadratic, p = .001), while faecal pH and ammonia were not affected by treatments. Lactose supplementations tended to linearly decrease isovalerate (p = .051) and quadratically influence n-valerate (p = .056) in canine faeces. No changes in faecal microbial populations were observed. Apparent digestibility of dry matter, Ca, K, Mn and Fe was influenced by lactose supplementation (quadratic, p

In approximately 15% of patients with acute myeloid leukemia (AML), total and phosphorylated EGFR proteins have been reported to be increased compared to healthy CD34+samples. However, it is unclear if this subset of patients would benefit from EGFR signaling pharmacological inhibition. Pre-clinical studies on AML cells provided evidence on the pro-differentiation benefits of EGFR inhibitors when combined with ATRA or ATOin vitro. Despite the success of ATRA and ATO in the treatment of patients with acute promyelocytic leukemia (APL), therapy-associated resistance is observed in 5-10% of the cases, pointing to a clear need for new therapeutic strategies for those patients. In this context, the functional role of EGFR tyrosine-kinase inhibitors has never been evaluated in APL. Here, we investigated the EGFR pathway in primary samples along with functionalin vitroandin vivostudies using several APL models. We observed that total and phosphorylated EGFR (Tyr992) was expressed in 28% and 19% of blast cells from APL patients, respectively, but not in healthy CD34+samples. Interestingly, the expression of the EGF was lower in APL plasma samples than in healthy controls. The EGFR ligand AREG was detected in 29% of APL patients at diagnosis, but not in control samples.In vitro, treatment with the EGFR inhibitor gefitinib (ZD1839) reduced cell proliferation and survival of NB4 (ATRA-sensitive) and NB4-R2 (ATRA-resistant) cells. Moreover, the combination of gefitinib with ATRA and ATO promoted myeloid cell differentiation in ATRA- and ATO-resistant APL cells.In vivo, the combination of gefitinib and ATRA prolonged survival compared to gefitinib- or vehicle-treated leukemic mice in a syngeneic transplantation model, while the gain in survival did not reach statistical difference compared to treatment with ATRA alone. Our results suggest that gefitinib is a potential adjuvant agent that can mitigate ATRA and ATO resistance in APL cells. Therefore, our data indicate that repurposing FDA-approved tyrosine-kinase inhibitors could provide new perspectives into combination therapy to overcome drug resistance in APL patients.

SummaryThe resurgence of yellow fever in South America has prompted mitigation through vaccination against the etiologic agent, yellow fever virus (YFV). Current vaccines are based on a virulent African isolate, and their capacity to induce neutralizing antibodies against the vaccine strain is widely used as a surrogate for protection. However, the sensitivity of genetically distinct South American strains to vaccine-induced antibodies is unknown. Here, we show that antiviral potency of the polyclonal antibody response in both U.S. and Brazilian vaccinees is attenuated against an emergent Brazilian strain. This reduction was attributable to genetic changes at two sites in the central domain II of the glycoprotein E, including the acquisition of an N–linked glycosylation site, which are unique to and shared among most South American YFV strains. Our findings call for a reevaluation of current approaches to YFV immunological surveillance in South America and suggest approaches for designing updated vaccines.

The pandemic caused by the SARS-CoV-2 has created the need of compounds able to interfere with the biological processes exploited by the virus. Doxycycline, with its pleiotropic effects, including anti-viral activity, has been proposed as a therapeutic candidate for COVID-19 and about twenty clinical trials have started since the beginning of the pandemic.To gain information on the activity of doxycycline against SARS-CoV-2 infection and clarify some of the conflicting clinical data published, we designed in vitro binding tests and infection studies with a pseudotyped virus expressing the spike protein, as well as a clinically isolated SARS-CoV-2 strain. Doxycycline inhibited the transduction of the pseudotyped virus in Vero E6 and HEK-293 T cells stably expressing human receptor angiotensin-converting enzyme 2 but did not affect the entry and replication of SARS-CoV-2.Although this conclusion is apparently disappointing, it is paradigmatic of an experimental approach aimed at developing an integrated multidisciplinary platform. To avoid wasting precious time and resources we believe very stringent experimental criteria are needed in the preclinical phase, including infectious studies with SARS-CoV-2 in the platform before moving on to [failed] clinical trials.Author SummaryThe pandemic caused by the SARS-CoV-2 virus has created a completely unusual situation in rapidly searching for compounds able to interfere with the biological processes exploited by the virus. This new scenario has substantially changed the timing of drug development which has also resulted in the generation of controversial results, proving that the transition from computational screening to the clinical application requires great caution and careful studies. It is therefore necessary to establish new paradigms for evaluating the efficacy of a potential active molecule.We set up a preclinical platform aimed at identifying molecules active against SARS-CoV-2 infection developing a multidisciplinary approach based on very stringent experimental criteria, comprising in-silico studies, in vitro binding tests and infection studies with pseudovirus expressing the spike protein as well as clinically isolated SARS-CoV-2 strains. We focused our attention on doxycycline which has been suggested as potential therapeutic candidate for treating COVID-19 and is currently employed in about twenty clinical trials. Doxycycline resulted effective in inhibiting the transduction of pseudovirus but it did not affect the entry and replication of SARS-CoV-2. The results obtained underline the need to define more stringent and controlled pharmacological approaches before wasting precious time and resources with clinical trials.

Study question How does the septate uterus and his metroplasty influence pregnancy rate (PR), live birth rate (LBR), spontaneous abortion rates (SA) and preterm labour rates (PL)? Summary answer Uterine septum is associated with a poor reproductive outcome. Metroplasty reduce the rate of SA but non-conclusive evidence can be extrapolated about PR and PL. What is known already Different studies evaluated the correlation between uterine septum and reproductive outcomes. On one hand, studies reported its association with poor obstetrics outcomes. On the other hand, recent studies raised doubts about the effectiveness of septum metroplasty to improve reproductive outcomes, although recent position papers continue to propose metroplasty in patients with a septate uterus and a history of infertility or miscarriages. Debate is still ongoing on reproductive outcomes of uterine septum on infertile patients and especially on patients with recurrent miscarriage, leading to an unanswered question whether or not these women should be treated. Study design, size, duration Systematic review and meta-analysis of published studies that evaluated the clinical impact of uterine septum and its metroplasty on reproductive and obstetrics outcomes. The meta-analysis included study with infertile patients or patients with a history of recurrent miscarriage. Searches were conducted using the following search terms: uterine septum, septate uterus, metroplasty, pregnancy rate, live birth rate, spontaneous miscarriage, infertility, preterm delivery. Primary outcomes were PR and LBR. Secondary outcomes were SA and PL. Participants/materials, setting, methods The meta-analysis was written following the PRISMA guidelines. Fifty-nine full-text articles were preselected based on title and abstract. Endpoints were evaluated in three subgroups: 1) infertile/recurrent miscarriage patients with septum versus no septum 2) infertile/recurrent miscarriage patients with treated versus untreated septum 3) infertile/recurrent miscarriage patients before-after septum removal. Odds-ratios (OR) with 95% confidence intervals (CI) were calculated for outcome measures. Random-effect meta-analysis was performed and a p-value less than 0.05 was considered statistically significant. Main results and the role of chance Data from 37 articles were extracted. In the first subgroup (10 studies), a lower PR and LBR were associated with septate uterus vs. controls, respectively (OR 0.39, 95% CI 0.26 to 0.58; p Limitations, reasons for caution The present meta-analysis is limited by the observational design of included studies because, in literature, there are no prospective randomized controlled trials (RCTs). In the second and third subgroup of analysis clinical heterogeneity within and between studies represents another limitation. Wider implications of the findings The results of this meta-analysis confirm the detrimental effect of uterine septum on PR, LBR, SA and PL. Its treatment seems to reduce the rate of SA. Metroplasty should still be considered as good clinical practice in patients with a history of infertility and recurrent abortion. Trial registration number Not applicable © The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.

Background Zika virus (ZIKV) infection gained public health concern after the 2015 outbreak in Brazil, when microcephaly rates increased in babies born from infected mothers. It was demonstrated that ZIKV causes a congenital Zika virus syndrome, including various alterations in the development of the central nervous system. Although the infection of cells from the nervous system has been well documented, less is known in respect of ZIKV ability to infect immune cells. Herein, we investigated if peripheral blood mononuclear cells (PBMCs), freshly-isolated from healthy donors, could be infected by ZIKV. Methods PBMCs from healthy donors were isolated and cultured in medium with ZIKV strain Rio-U1 (MOI = 0.1). Infection was analyzed by RT-qPCR and flow cytometry. Results We detected the ZIKV RNA in PBMCs from all donors by RT-qPCR analysis. The detection of viral antigens by flow cytometry revealed that PBMC from more than 50% the donors were infected by ZIKV, with CD3+CD4+ T cells, CD3−CD19+ B cells and CD3+CD8+ T cells being, respectively, the most frequently infected subpopulations, followed by CD14+ monocytes. Additionally, we observed high variability in PBMC infection rates among different donors, either by numbers or type infected cells. Conclusions These findings raise the hypothesis that PBMCs can act as a reservoir of the virus, which may facilitate viral dissemination to different organs, including immune-privileged sites.

Aims Arrhythmogenic cardiomyopathy (AC) is one of the most common inherited cardiomyopathies, characterized by progressive fibro-fatty replacement in the myocardium. Clinically, AC manifests itself with ventricular arrhythmias, syncope, and sudden death and shows wide inter- and intra-familial variability. Among the causative genes identified so far, those encoding for the desmosomal proteins plakophilin-2 (PKP2), desmoplakin (DSP), and desmoglein-2 (DSG2) are the most commonly mutated. So far, little is known about the molecular mechanism(s) behind such a varied spectrum of phenotypes, although it has been shown that the causative mutations not only lead to structural abnormalities but also affect the miRNA profiling of cardiac tissue. Here, we aimed at studying the pathogenic effects of a nonsense mutation of the desmoglein-2 gene, both at the structural level and in terms of miRNA expression pattern.Methods and results We generated transgenic mice with cardiomyocyte-specific overexpression of a FLAG-tagged human desmoglein-2 harbouring the Q558* nonsense mutation found in an AC patient. The hearts of these mice showed signs of fibrosis, decrease in desmosomal size and number, and reduction of the Wnt/beta-catenin signalling. Genome-wide RNA-Seq performed in Tg-hQ hearts and non-transgenic hearts revealed that 24 miRNAs were dysregulated in transgenic animals. Further bioinformatic analyses for selected miRNAs suggested that miR-217-5p, miR-499-5p, and miR-708-5p might be involved in the pathogenesis of the disease.Conclusion Down-regulation of the canonical Wnt/beta-catenin signalling might be considered a common key event in the AC pathogenesis. We identified the miRNA signature in AC hearts, with miR-708-5p and miR-217-5p being the most up-regulated and miR-499-5p the most down-regulated miRNAs. All of them were predicted to be involved in the regulation of the Wnt/beta-catenin pathway and might reveal the potential pathophysiology mechanisms of AC, as well as be useful as therapeutic targets for the disease.

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Hemostatic abnormalities and impaired platelet function have been described in patients affected by connective tissue disorders. We observed a moderate bleeding tendency in patients affected by collagen VI–related disorders and investigated the defects in platelet functionality, whose mechanisms are unknown. We demonstrated that megakaryocytes express collagen VI that is involved in the regulation of functional platelet production. By exploiting a collagen VI–null mouse model (Col6a1−/−), we found that collagen VI–null platelets display significantly increased susceptibility to activation and intracellular calcium signaling. Col6a1−/− megakaryocytes and platelets showed increased expression of stromal interaction molecule 1 (STIM1) and ORAI1, the components of store-operated calcium entry (SOCE), and activation of the mammalian target of rapamycin (mTOR) signaling pathway. In vivo mTOR inhibition by rapamycin reduced STIM1 and ORAI1 expression and calcium flows, resulting in a normalization of platelet susceptibility to activation. These defects were cell autonomous, because transplantation of lineage-negative bone marrow cells from Col6a1−/− mice into lethally irradiated wild-type animals showed the same alteration in SOCE and platelet activation seen in Col6a1−/− mice. Peripheral blood platelets of patients affected by collagen VI–related diseases, Bethlem myopathy and Ullrich congenital muscular dystrophy, displayed increased expression of STIM1 and ORAI1 and were more prone to activation. Altogether, these data demonstrate the importance of collagen VI in the production of functional platelets by megakaryocytes in mouse models and in collagen VI–related diseases.

Introduction: The membrane-associated G protein-coupled estrogen receptor 1 (GPER) mediates the regulation by estradiol of arginine-vasopressin immunoreactivity in the supraoptic and paraventricular hypothalamic nuclei of female rats and is involved in the estrogenic control of hypothalamic regulated functions, such as food intake, sexual receptivity, and lordosis behavior. Objective: To assess GPER distribution in the rat hypothalamus. Methods: GPER immunoreactivity was assessed in different anatomical subdivisions of five selected hypothalamic regions of young adult male and cycling female rats: the arcuate nucleus, the lateral hypothalamus, the paraventricular nucleus, the supraoptic nucleus, and the ventromedial hypothalamic nucleus. GPER immunoreactivity was colocalized with NeuN as a marker of mature neurons, GFAP as a marker of astrocytes, and CC1 as a marker of mature oligodendrocytes. Results: GPER immunoreactivity was detected in hypothalamic neurons, astrocytes, and oligodendrocytes. Sex and regional differences and changes during the estrous cycle were detected in the total number of GPER-immunoreactive cells and in the proportion of neurons, astrocytes, and oligodendrocytes that were GPER-immunoreactive. Conclusions: These findings suggest that estrogenic regulation of hypothalamic function through GPER may be different in males and females and may fluctuate during the estrous cycle in females., This study was supported by the Ministero dell’Istruzione, dell’Università e della Ricerca, Italy (MIUR project Dipartimenti di Eccellenza 2018–2022) to the Department of Neuroscience Rita Levi Montalcini, Agencia Estatal de Investigación, Spain (BFU201782754-R), Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable, Instituto de Salud Carlos III, Madrid and Fondos FEDER. The fellowship of M. Marraudino was generously granted by Prof. G.C. Bergui.

The Covid-19 emergency has determined an unpredictable increase in the number of patients with Covid-like symptoms in the Emergency Department (ED) of Italian hospitals.

The extracellular matrix is a three-dimensional network providing the proper microenvironment for muscle development and function. Different types of collagens play critical roles in skeletal muscle homeostasis, as revealed by the fact that mutations in distinct collagen genes are linked to inherited muscle disorders, including some forms of myopathies and congenital muscular dystrophies. The following chapter discusses the current knowledge of collagens and their roles in muscle disorders, mostly focusing on collagen VI since it is the collagen type with the major known impact in muscle physiology and whose deficiency is causative for a distinctive group of muscle diseases. Collagen VI is a unique member of the collagen superfamily, displaying distinctive protein domains, supramolecular assembly, and tissue distribution. Moreover, it exerts a broad range of essential functions in the skeletal muscle, and mutations of its genes are linked to congenital muscular dystrophies and congenital myopathies. Mutant and knockout animal models for collagen VI and other collagen types provided a tremendous tool for the mechanistic understanding of human muscle diseases linked to collagens’ defects and, thus, for translational studies. Indeed, the increasing knowledge on the underlying pathomolecular mechanisms and the identification of suitable targets represent invaluable benefits for proper clinical diagnosis and for developing treatments and therapeutic opportunities to counteract the onset and progression of clinical symptoms of such severe and often life-threatening muscle pathologies.

Objectives To describe antibacterial prescribing patterns in outpatients aged 0–5 years from 2007 to 2013 in the Emilia-Romagna region, assessing sex- and age-specific consumption over time. Methods All children aged 0–5 years resident in the Emilia-Romagna region who received at least one prescription of a systemic antibacterial in the period 2007–13 were enrolled. The prescriptions of systemic antibacterials to children were collected from the regional prescription database. Data were stratified by year, sex and age, and analysed in terms of periodic prevalence and of annual prescription rate per 1000 person-years. Results The prevalence of children receiving at least one prescription per year varied from 68.0% in 2007 to 59.0% in 2013, while the average prevalence of children receiving five or more prescriptions per year was 6.96%. The annual prescription rate varied from 1621.26 in 2007 to 1372.27 in 2013. Penicillins + β-lactamase inhibitors accounted for 35.3% of total prescriptions, followed by extended-spectrum penicillins (28.6%), macrolides (17.0%) and third-generation cephalosporins (13.9%). Conclusions Despite recommendations, a significant overprescription of antibacterials to children still exists, showing no satisfactory improvements over the years. In contrast to Northern European countries, adherence to evidence-based guidelines was poor, with frequent prescribing of broad-spectrum agents for the treatment of mostly viral childhood infectious disease.

Two independent trials were carried out to assess the effect of two enrichment tools on the prevalence of skin and tail lesions recorded prior of slaughtering, lesions of the pars oesophagea (OGL) of the stomach, and on carcase and meat quality traits in Italian heavy pigs (body weight range: 25–160 kg). Eighty undocked barrows (Landrace × Large White) were used in two trials (20 pigs/experimental group, 5 pigs/pen). In Trial 1, the control group received a hanging metal chain (C1), while the other group received wood logs (WL) placed inside a metal rack. In Trial 2, the control group was provided with hanging chain (C2), while the pen of the other group was enriched with a vegetal edible block (EB) placed inside the metal rack. In both trials, no differences were observed in the prevalence and severity of skin, tail and gastric lesions (p > .05). In Trial 1, WL pigs presented lower backfat (p = .01), higher lean meat percentage (p = .03) and higher drip loss in the loin muscle (p = .02) than C1 pigs. Tail score and gastric lesions showed a moderate correlation (r = 0.42; p = .01) in Trial 1. Treatments had no effect on carcase or meat quality traits in Trial 2 (p > .05). In conclusion, the two enrichments provided did not affect body and gastric lesions, carcase and meat quality of Italian heavy pigs, if compared to the metal chains.

Autophagy is a very versatile process through which the cell degrades damaged long-lived proteins, entire organelles, or pathogens, by engulfing them in characteristic double-membrane vesicles and conveying the cargo to lysosomes. It is a dynamic pathway tunable at multiple levels and responsive to nutrient and stress stimuli, also coming from the extracellular microenvironment and its remodeling. In the extracellular matrix, collagen type VI forms a distinctive set of beaded microfilaments that assemble into an intricate and multimodular meshwork of tightly linked proteins and surface receptors. When missing or defective, collagen VI triggers a series of pathological events in skeletal muscle and other tissues, with a remarkable impact on key cell processes, such as apoptosis and autophagy. In this review, we discuss the current knowledge about collagen VI regulation of autophagy in the different experimental models and human pathologies where it was studied, and provide some hints for future directions aimed at the fine dissection of this intriguing relationship, as well as its prospective translational impact for disease and therapy.

Background Congenital muscular dystrophies (CMD) are a clinically and genetically heterogeneous group of neuromuscular disorders characterized by muscle weakness. The two most prevalent forms of CMD, collagen VI-related myopathies (COL6RM) and laminin α2 deficient CMD type 1A (MDC1A), are both caused by deficiency or dysfunction of extracellular matrix proteins. Previously, we showed that an intramuscular transplantation of human adipose-derived stem cells (ADSC) into the muscle of the Col6a1−/− mice results in efficient stem cell engraftment, migration, long-term survival, and continuous production of the collagen VI protein, suggesting the feasibility of the systemic cellular therapy for COL6RM. In order for this therapeutic approach to work however, stem cells must be efficiently targeted to the entire body musculature. Thus, the main goal of this study is to test whether muscle homing of systemically transplanted ADSC can be enhanced by employing muscle-specific chemotactic signals originating from CMD-affected muscle tissue. Methods Proteomic screens of chemotactic molecules were conducted in the skeletal muscles of COL6RM- and MDC1A-affected patients and CMD mouse models to define the inflammatory and immune activities, thus, providing potential markers of disease activity or treatment effect. Also using a pre-clinical animal model, recapitulating mild Ullrich congenital muscular dystrophy (UCMD), the therapeutic relevance of identified chemotactic pathways was investigated in vivo, providing a basis for future clinical investigations. Results Comprehensive proteomic screens evaluating relevant human and mouse skeletal muscle biopsies offered chemotactic axes to enhance directional migration of systemically transplanted cells into CMD-affected muscles, including CCL5-CCR1/3/5, CCL2-CCR2, CXCL1/2-CXCR1,2, and CXCL7-CXCR2. Also, the specific populations of ADSC selected with an affinity for the chemokines being released by damaged muscle showed efficient migration to injured site and presented their therapeutic effect. Conclusions Collectively, identified molecules provided insight into the mechanisms governing directional migration and intramuscular trafficking of systemically infused stem cells, thus, permitting broad and effective application of the therapeutic adult stem cells for CMD treatment.

Purpose The Ubiquitin Proteasome System (UPS) is a selective degradation system mediating the removal of intracellular unfolded/misfolded proteins and is essential for cardiomyocyte (CM) health. Substrate specificity and ubiquitination rate are mediated by E3 ubiquitin-ligases, such as Atrogin1 and MuRF1, which are specifically expressed in muscle cells. Perturbation of protein quality control causes aggregation of misfolded proteins, leading to CM proteotoxicity. UPS dysfunction occurs in ageing, a risk factor for cardiac hypertrophy and HF. We recently demonstrated that Atrogin-1 is essential to maintain CM health, during ageing. Whether MuRF1 plays similar roles in heart adaptation to ageing is still unexplored, and different studies have yielded contrasting results. Methods To assess the role of MuRF1 in heart homeostasis, we combined echocardiography, histology, IF, TUNEL assay and EM on heart sections from MuRF1 knock-out (KO) mice, and littermate controls, at 3, 10 and 24 mo. RTqPCR and WB assessed markers of UPS and extracellular matrix. Langendorff procedure was used to separate CMs from cardiac fibroblasts. Molecular and IF analyses were performed in heart samples from patients affected by aortic stenosis. Results MuRF1 ablation leads to cardiac hypertrophy, progressing during ageing (LV CM areas: 3 mo., KO: 329.14±10.66 vs Ctrl: 296.25±5.43; 10 mo., KO: 399.73±7.64 vs Ctrl: 247.49±3.67; 24 mo., KO: 418.89±11.10 vs. Ctrl: 209.93±4.48, in μm2). The hypertrophic remodeling was accompanied by diastolic dysfunction in the adulthood and, during ageing, also by systolic dysfunction (EF, 24 mo., KO: 29.55±8.82 vs Ctrl: 51.23±6.56, in %). Loss of MuRF1 causes increased interstitial collagen -I and -VI deposition, even before the onset of contractile dysfunction, followed by activation of Matrix MetalloProteinases (MMPs), suggesting that such alterations may be responsible for decreased cardiac performance. Interestingly, collagen established rings enveloping MuRF1 KO CMs and such fibrotic remodeling was not accompanied by increased CM apoptosis, nor myofibroblast activation. Such peculiar remodelling, called peri-endomysial fibrosis, was detected in hearts from patients with aortic stenosis, a condition in which MuRF1 levels decrease. Our data supports that MuRF1 has a role in CM-dependent regulation of the extracellular matrix (ECM) dynamics. Consistently, MuRF1 downregulation in normal cultured CMs demonstrated that such ubiquitin ligase impacts on signaling pathways involved in the control of the ECM homeostasis. In addition, fibroblasts treated with culture medium conditioned by MuRF1 KO CM display increased collagen and MMP expression. Conclusions We identifieded a novel role of MuRF1 in the control of CM proteostasis, and unveiled that in addition to cardiac fibroblasts, CM may directly regulate ECM dynamics, indicating that the correct function of MuRF1 is essential for heart adaptation to aging. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): University of Padova