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Dopaminergic neurons express a heteromer composed of the dopamine D3 receptor and the α4β2 nicotinic acetylcholine receptor, the D3R-nAChR heteromer, activated by both nicotine and dopamine D2 and D3 receptors agonists, such as quinpirole, and crucial for dopaminergic neuron homeostasis. We now report that D3R-nAChR heteromer activity is potentiated by 17-β-estradiol which acts as a positive allosteric modulator by binding a specific domain on the α4 subunit of the nicotinic receptor protomer. In mouse dopaminergic neurons, in fact, 17-β-estradiol significantly increased the ability of nicotine and quinpirole in promoting neuron dendritic remodeling and in protecting neurons against the accumulation of α-synuclein induced by deprivation of glucose, with a mechanism that does not involve the classical estrogen receptors. The potentiation induced by 17-β-estradiol required the D3R-nAChR heteromer since either nicotinic receptor or dopamine D3 receptor antagonists and interfering TAT-peptides, but not the estrogen receptor antagonist fulvestrant, specifically prevented 17-β-estradiol effects. Evidence of estrogens neuroprotection, mainly mediated by genomic mechanisms, have been provided, which is in line with epidemiological data reporting that females are less likely to develop Parkinson's Disease than males. Therefore, potentiation of D3R-nAChR heteromer activity may represent a further mechanism by which 17-β-estradiol reduces dopaminergic neuron vulnerability., Competing Interests: Declaration of competing interest The authors declare no conflict of interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Toscana Virus (TosV) was firstly isolated from phlebotomine in our Institute about fifty years ago. Later, in 1984-1985, TosV infection, although asymptomatic in most cases, was shown to cause disease in humans, mainly fever and meningitis. By means of genetic analysis of part of M segment, we describe 3 new viral isolates obtained directly from cerebrospinal fluid or sera samples of patients diagnosed with TosV infection in July 2020 in Tuscany region. Phylogenesis was used to propose the clustering of TosV lineage A strains in 3 main groups, whereas deep mutational analysis based on 12 amino acid positions, allowed the identification of 9 putative strains. We discuss deep mutational analysis as a method to identify molecular signature of host adaptation and/or pathogenesis., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Claudio argentini reports a relationship with istituto superiore di sanità that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

A commercial olive leaf extract (OL), effective against Salmonella enterica , Escherichia coli , Listeria monocytogenes , and Staphylococcus aureus , was added to three different coating formulations (methylcellulose, MC; chitosan, CT; and alginate, ALG) to produce active polylactic acid (PLA) coated films. Evaluation of these coated PLA films revealed significant inhibition of S. aureus growth, particularly with the MC and CT formulations exhibiting the highest inhibition rates (99.7%). The coated films were then tested for food contact compatibility with three food simulants (A: 10% ethanol; B: 3% acetic acid; D2: olive oil), selected to assess their suitability for pre-cut hams and ready-to-eat vegetables in relation to overall migration. However, coated films with active functions exhibited migration values in simulants A and B above legal limits, while promising results were obtained for simulant D2, highlighting the need to deeply investigate these coatings' impact on a real food system. Untargeted metabolomics revealed that the type of coating influenced the selective release of certain phenolic classes based on the food simulant tested. The Oxitest analysis of simulant D2 demonstrated that the MC and ALG-coated PLA films slightly slowed down the oxidation of this food simulant, which is an edible vegetable oil.

Our recent study revealed that fluorescent lamp light can penetrate deep into the brain of mice and rats leading to the development of typical histological characteristics associated with Parkinson's disease such as the loss of dopamine neurons in the substantia nigra. Monochromatic LED lights were thus used in this work to deepen our knowledge on the effects of the major wavelength peaks of fluorescent light on mouse and human dopaminergic cells. In particular, we exposed immortalized dopaminergic MN9D neuronal cells, primary cultures of mouse mesencephalic dopaminergic cells and human dopaminergic neurons differentiated from induced pluripotent stem cells (hiPSC) to different LED light wavelengths. We found that chronic exposure to LED light reduced overall undifferentiated MN9D cell number, with the most significant effects observed at wavelengths of 485 nm and 610 nm. Moreover, LED light especially at 610 nm was able to negatively impact on the survival of mouse mesencephalic dopaminergic cells and of human dopaminergic neurons derived from hiPSC. Notably, differentiated MN9D dopaminergic cells, which closely resemble mature dopamine neuronal phenotype, acutely exposed for 3 h at 610 nm, showed a clear increase in ROS production and cytotoxicity compared to controls undifferentiated MN9D cells. These increases were even more pronounced by the co-treatment with the oxidative agent H 2 O 2 . Collectively, these findings suggest that specific wavelengths, particularly those capable of penetrating deep into the brain, could potentially pose an environmental hazard in relation to Parkinson's disease., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The delayed diagnosis of skin tumors is associated with a worsened prognosis. The impact of the interruption of clinical and surgical health services during the COVID-19 pandemic lockdowns has been documented among many pathologies. The impact of delayed diagnoses on patients with cutaneous squamous cell carcinomas (cSCCs) is poorly defined., Objective: To compare patient and lesion characteristics and the surgical management of excised cSCCs prior to the pandemic shutdown of services (2018-2019) with the phase following the pandemic's second wave (2021-2022)., Methods: An observational, single-center, cross-sectional study of 416 surgically excised cSCCs over the course of two years was performed. Only patients with histologically confirmed cSCC were enrolled. Data collection included patient demographics and lesion characteristics, time to surgery, surgical approach, and histological data., Results: More cSCC lesions were excised prior to the interruption of services ( n = 312 vs. n = 186). Lesions were significantly larger (1.7 ± 1.2 vs. 2.1 ± 1.5 cm; p = 0.006) and more invasive (52% vs. 89%; p < 0.001), in the period 2021-2022. Surgical reconstructive techniques were significantly different ( p = 0.001). Metastatic involvement was confirmed in three subjects (one in 2018-2019 and two in 2021-2022). There were no significant differences in the time to surgery or patient characteristics. Multivariable regression analysis identified a 4.7-times higher risk of tumor invasion (OR 4.69, 95%CI 2.55-8.16, p < 0.001), a two-times higher chance of dermo-epidermal grafts (OR 2.06, 95%CI 1.09-3.88, p = 0.025), and a 3.2-times higher risk of positive surgical margins (OR 3.21, 95%CI 1.44-7.17, p = 0.004)., Conclusions: Diagnostic delays of cutaneous SCCs associated with reduced patient access to clinical and diagnostic services are associated with a 4.7-times increased risk of more severe invasion, a three-times increased risk of positive surgical margins, and a significant impact on surgical management, compared to the pre-pandemic period. Comparable patient cohort characteristics and time to surgery remained unchanged.

The World Health Organization recently presented the priorities for tackling abuse of older people in a coordinated and strategic way. However, data on the forensic scenario is still lacking. In this context, the aim of the present work was to provide a comprehensive literature review of this inherently complex phenomenon in the post-mortem setting, in order to better characterize it from a forensic point of view. A comprehensive literature search was performed in three electronic databases following the PRISMA guidelines. Sociodemographic and medical data of victims and perpetrators, post-mortem data, types of abuse and risk factors were extracted from non-aggregated data. Forty-eight papers dealing with abuse in the post-mortem setting were included, with a predominance of case reports and case series. The review showed that neglect was the most common type of abuse and victims are predominantly older women who are abused in a domestic setting by trusted family member. To generate more and better data, expanded research in the forensic field requires standardized methods and the raise of professional awareness about abuse of older people., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Food allergy (FA) affects approximately 6-8% of children worldwide causing a significant impact on the quality of life of children and their families. In past years, the possible role of weaning in the development of FA has been studied. According to recent studies, this is still controversial and influenced by several factors, such as the type of food, the age at food introduction and family history. In this narrative review, we aimed to collect the most recent evidence about weaning and its role in FA development, organizing the gathered data based on both the type of study and the food. As shown in most of the studies included in this review, early food introduction did not show a potential protective role against FA development, and we conclude that further evidence is needed from future clinical trials.

Acellular dermal matrices currently represent a useful reconstructive method in onco-dermatologic surgery. Nevertheless, they have some limitations, especially in terms of costs and outpatient post-operative wound care. While some studies on their cost-to-benefit ratio in breast surgery have already been issued, evidence is currently lacking in onco-dermatological surgery. The aim of this study was to evaluate the clinical outcomes perceived by patients who had undergone onco-dermatologic surgery in which either acellular dermal matrices or skin grafts had been used as reconstructive methods. A study population of 150 patients was identified retrospectively and patients' degree of satisfaction was assessed through the Global Aesthetic Improvement Scale and the Patient Scar Scale Questionnaire. Despite similar scores among the study groups, slightly better results were appreciable after single-stage grafting. However, to what extent these variations really represent a significant difference from a clinical point of view remains to be determined. Moreover, other potential bias in the interpretation of our results may reside in differences in terms of age, body location and baseline tumor size among the study groups. Therefore, further research is needed., Competing Interests: Conflict of interest: the authors declare no potential conflict of interest., (Copyright © 2024, the Author(s).)

Epidermolysis bullosa simplex (EBS) is a rare skin disease inherited mostly in an autosomal dominant manner. Patients display a skin fragility that leads to blisters and erosions caused by minor mechanical trauma. EBS phenotypic and genotypic variants are caused by genetic defects in intracellular proteins whose function is to provide the attachment of basal keratinocytes to the basement membrane zone and most EBS cases display mutations in keratin 5 (KRT5) and keratin 14 (KRT14) genes. Besides palliative treatments, there is still no long-lasting effective cure to correct the mutant gene and abolish the dominant negative effect of the pathogenic protein over its wild-type counterpart. Here, we propose a molecular strategy for EBS01 patient's keratinocytes carrying a monoallelic c.475/495del21 mutation in KRT14 exon 1. Through the CRISPR-Cas9 system, we perform a specific cleavage only on the mutant allele and restore a normal cellular phenotype and a correct intermediate filament network, without affecting the epidermal stem cell, referred to as holoclones, which play a crucial role in epidermal regeneration., Competing Interests: Declaration of interests M.D.L. is co-founder and member of the Board of Directors of Holostem Terapie Avanzate (HTA) s.r.l in liquidation, Modena, Italy, as well as consultants for J-TEC-Japan Tissue Engineering, Ltd., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

We have established Noonan syndrome (NS)-derived induced pluripotent stem cell (iPSC) lines derived from peripheral blood mononuclear cells (PBMCs) of a family cohort carrying the heterozygous PTPN11 c.188 A > G (p.Y63C) mutation. The new iPSC lines were validated by confirming the normal karyotype and targeted mutation, the pluripotent gene expression, and the differentiation capacity into three germ layers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

The frequency of locally transmitted dengue virus (DENV) infections has increased in Europe in recent years, facilitated by the invasive mosquito species Aedes albopictus , which is well established in a large area of Europe. In Italy, the first indigenous dengue outbreak was reported in August 2020 with 11 locally acquired cases in the Veneto region (northeast Italy), caused by a DENV-1 viral strain closely related to a previously described strain circulating in Singapore and China. In this study, we evaluated the vector competence of two Italian populations of Ae. albopictus compared to an Ae. aegypti lab colony. We performed experimental infections using a DENV-1 strain that is phylogenetically close to the strain responsible for the 2020 Italian autochthonous outbreak. Our results showed that local Ae. albopictus is susceptible to infection and is able to transmit the virus, confirming the relevant risk of possible outbreaks starting from an imported case.

Pancreatic cancer has a dismal prognosis, as it is often diagnosed at stage IV of the disease and is characterized by metastatic spread. Gut microbiota and its metabolites have been suggested to influence the metastatic spread by modulating the host immune system or by promoting angiogenesis. To date, the gut microbial profiles of metastatic and non-metastatic patients need to be explored. Taking advantage of the 16S metagenomic sequencing and the PEnalized LOgistic Regression Analysis (PELORA) we identified clusters of bacteria with differential abundances between metastatic and non-metastatic patients. An overall increase in Gram-negative bacteria in metastatic patients compared to non-metastatic ones was identified using this method. Furthermore, to gain more insight into how gut microbes can predict metastases, a machine learning approach (iterative Random Forest) was performed. Iterative Random Forest analysis revealed which microorganisms were characterized by a different level of relative abundance between metastatic and non-metastatic patients and established a functional relationship between the relative abundance and the probability of having metastases. At the species level, the following bacteria were found to have the highest discriminatory power: Anaerostipes hadrus , Coprobacter secundus , Clostridium sp. 619, Roseburia inulinivorans , Porphyromonas and Odoribacter at the genus level, and Rhodospirillaceae , Clostridiaceae and Peptococcaceae at the family level. Finally, these data were intertwined with those from a metabolomics analysis on fecal samples of patients with or without metastasis to better understand the role of gut microbiota in the metastatic process. Artificial intelligence has been applied in different areas of the medical field. Translating its application in the field of gut microbiota analysis may help fully exploit the potential information contained in such a large amount of data aiming to open up new supportive areas of intervention in the management of cancer.

Dengue (DENV) and Zika (ZIKV) viruses are mosquito-borne human pathogens. In Italy, the presence of the competent vector Aedes albopictus increases the risk of autochthonous transmission, and a national plan for arboviruses prevention, surveillance, and response (PNA 2020-2025) is in place. The results of laboratory diagnosis of both viruses by the National Reference Laboratory for arboviruses (NRLA) from November 2015 to November 2022 are presented. Samples from 655 suspected cases were tested by both molecular and serological assays. Virus and antibody kinetics, cross-reactivity, and diagnostic performance of IgM ELISA systems were analysed. Of 524 cases tested for DENV, 146 were classified as confirmed, 7 as probable, while 371 were excluded. Of 619 cases tested for ZIKV, 44 were classified as confirmed, while 492 were excluded. All cases were imported. Overall, 75.3% (110/146) of DENV and 50% (22/44) of ZIKV cases were confirmed through direct virus detection methods. High percentages of cross reactivity were observed between the two viruses. The median lag time from symptoms onset to sample collection was 7 days for both DENV molecular (range 0-20) and NS1 ELISA (range 0-48) tests, with high percentages of positivity also after 7 days (39% and 67%, respectively). For ZIKV, the median lag time was 5 days (range 0-22), with 16% positivity after 7 days. Diagnostic performance was assessed with negative predictive values ranging from 92% to 95% for the anti-DENV systems, and of 97% for the ZIKV one. Lower positive predictive values were seen in the tested population (DENV: 55% to 91%, ZIKV: 50%). DENV and ZIKV diagnosis by molecular test is the gold standard, but sample collection time is a limitation. Serological tests, including Plaque Reduction Neutralization Test, are thus necessary. Co-circulation and cross-reactivity between the two viruses increase diagnostic difficulty. Continuous evaluation of diagnostic strategies is essential to improve laboratory testing.

Apigenin is one of the most widespread flavonoids in the plant kingdom. For centuries, apigenin-containing plant preparations have been used in traditional medicines to treat diseases that have an inflammatory and/or degenerative component. In the 1980s, apigenin was proposed to interfere with the process of carcinogenesis. Since then, more and more evidence has demonstrated its anticancer efficacy, both in vitro and in vivo. Apigenin has been shown to target signaling pathways involved in the development and progression of cancer, such as PI3K/Akt/mTOR, MAPK/ERK, JAK/STAT, NF-κB, and Wnt/β-catenin pathways, and to modulate different hallmarks of cancer, such as cell proliferation, metastasis, apoptosis, invasion, and cell migration. Furthermore, apigenin modulates PD1/PD-L1 expression in cancer/T killer cells and regulates the percentage of T killer and T regulatory cells. Recently, apigenin has been studied for its synergic and additive effects when combined with chemotherapy, minimizing the side effects. Unfortunately, its low bioavailability and high permeability limit its therapeutic applications. Based on micro- and nanoformulations that enhance the physical stability and drug-loading capacity of apigenin and increase the bioavailability of apigenin, novel drug-delivery systems have been investigated to improve its solubility.

A 64-year-old man diagnosed with chronic coronary syndrome (CCS) underwent elective percutaneous coronary intervention (PCI) to place a stent in a branch of the first diagonal artery. Fifteen minutes after the procedure, the patient suffered a cardiac arrest, which was subsequently determined to be caused by cardiac tamponade identified through ultrasound examination. Despite an hour of cardiopulmonary resuscitation, the patient died and a forensic investigation was requested by the public prosecutor. On review of the coronary angiography images, an extravasation of contrast was noted, which was classified as a type II perforation according to the Ellis classification. Autopsy revealed a hemorrhagic suffusion area on the anterior surface of the left ventricle with suspected epicardial discontinuity. Histopathological examination confirmed a complete rupture of the vessel wall in the distal section of the branch where the stent was placed, accompanied by adjacent hemorrhagic and fibrin-platelet material. The diagnosis of coronary perforation is typically made through imaging and histological confirmation is rarely obtained. In the present case, the correlation between in vivo imaging and post-mortem histopathology not only facilitated the precise localization of the coronary perforation but also had significant medico-legal implications in the assessment of presumed medical liability., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Establishing a common language that allows univocal and objective communication in describing wounds and their healing is of utmost importance in defining the diagnostic hypothesis and proper wound management. To measure the level of agreement on the description of wounds, an international study was performed among experts of different professional backgrounds on several common terms used to describe ulcerative lesions. A panel of 27 wound care experts anonymously completed a multiple-choice questionnaire on 100 images of 50 ulcerative lesions. The participants were asked to describe each image using a set of pre-defined terms. An expert data analyst interpreted the questionnaires to map the level of agreement on the used terminology. Our findings show a very low level of agreement among experts in using the proposed terminology to describe the wound bed, the wound edge, and the surrounding skin conditions. Efforts should be planned to find a consensus on the correct use of terminology for wound description. To this aim, partnership, consensus, and agreement with educators in medicine and nursing are necessary., (© 2023 The Authors. International Wound Journal published by Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

Background: Several studies report the useful therapeutic results of regional hyperthermia in association with chemotherapy (CHT) and radiotherapy for the treatment of pancreatic cancer. Modulated electro-hyperthermia (mEHT) is a new hyperthermia technique that induces immunogenic death or apoptosis of pancreatic cancer cells in laboratory experiments and increases tumor response rate and survival in pancreatic cancer patients, offering beneficial therapeutic effects against this severe type of cancer., Aim: To assess survival, tumor response and toxicity of mEHT alone or combined with CHT compared with CHT for the treatment of locally advanced or metastatic pancreatic cancer., Methods: This was a retrospective data collection on patients affected by locally advanced or metastatic pancreatic cancer (stage III and IV) performed in 9 Italian centers, members of International Clinical Hyperthermia Society-Italian Network. This study included 217 patients, 128 (59%) of them were treated with CHT (no-mEHT) and 89 (41%) patients received mEHT alone or in association with CHT. mEHT treatments were performed applying a power of 60-150 watts for 40-90 min, simultaneously or within 72 h of administration of CHT., Results: Median patients' age was 67 years (range 31-92 years). mEHT group had a median overall survival greater than non-mEHT group (20 mo, range 1.6-24, vs 9 mo, range 0.4-56.25, P < 0.001). mEHT group showed a higher number of partial responses (45% vs 24%, P = 0.0018) and a lower number of progressions (4% vs 31%, P < 0.001) than the no-mEHT group, at the three months follow-up. Adverse events were observed as mild skin burns in 2.6% of mEHT sessions., Conclusion: mEHT seems safe and has beneficial effects on survival and tumor response of stage III-IV pancreatic tumor treatment. Further randomized studies are warranted to confirm or not these results., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflict of interest., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

The bacterial product CNF1, through its action on the Rho GTPases, is emerging as a modulator of crucial signalling pathways involved in selected neurological diseases characterized by mitochondrial dysfunctions. Mitochondrial impairment has been hypothesized to have a key role in paramount mechanisms underlying Rett syndrome (RTT), a severe neurologic rare disorder. CNF1 has been already reported to have beneficial effects in mouse models of RTT. Using human RTT fibroblasts from four patients carrying different mutations, as a reliable disease-in-a-dish model, we explored the cellular and molecular mechanisms, which can underlie the CNF1-induced amelioration of RTT deficits. We found that CNF1 treatment modulates the Rho GTPases activity of RTT fibroblasts and induces a considerable re-organization of the actin cytoskeleton, mainly in stress fibres. Mitochondria of RTT fibroblasts show a hyperfused morphology and CNF1 decreases the mitochondrial mass leaving substantially unaltered the mitochondrial dynamic. From a functional perspective, CNF1 induces mitochondrial membrane potential depolarization and activation of AKT in RTT fibroblasts. Given that mitochondrial quality control is altered in RTT, our results are suggestive of a reactivation of the damaged mitochondria removal via mitophagy restoration. These effects can be at the basis of the beneficial effects of CNF1 in RTT., (© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Neuronal nicotinic acetylcholine receptors (nAChRs) are widely distributed in both the peripheral and the central nervous systems. nAChRs exert a crucial modulatory influence on several brain biological processes; they are involved in a variety of neuronal diseases including Parkinson's disease, Alzheimer's disease, epilepsy, and nicotine addiction. The influence of nAChRs on brain function depends on the activity of other neurotransmitter receptors that co-exist with nAChRs on neurons. In fact, the crosstalk between receptors is an important mechanism of neurotransmission modulation and plasticity. This may be due to converging intracellular pathways but also occurs at the membrane level, because of direct physical interactions between receptors. In this line, this review is dedicated to summarizing how nAChRs and other ionotropic and metabotropic receptors interact and the relevance of nAChRs cross-talks in modulating various neuronal processes ranging from the classical modulation of neurotransmitter release to neuron plasticity and neuroprotection., Competing Interests: Conflict of Interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Chemotherapy- or inflammation-induced increase in intestinal permeability represents a severe element in disease evolution in patients suffering from colorectal cancer and gut inflammatory conditions. Emerging data strongly support the gut microbiota's role in preserving intestinal barrier integrity, whilst both chemotherapy and gut inflammation alter microbiota composition. Some probiotics might have a strong re-balancing effect on the gut microbiota, also positively affecting intestinal barrier integrity. In this study, we asked whether Limosilactobacillus fermentum ME-3 can prevent the intestinal paracellular permeability increase caused by the chemotherapeutic drug Irinotecan or by inflammatory stimuli, such as lipopolysaccharide (LPS). As an intestinal barrier model, we used a confluent and polarized Caco-2 cell monolayer and assessed the ME-3-induced effect on paracellular permeability by transepithelial electrical resistance (TEER) and fluorescent-dextran flux assays. The integrity of tight and adherens junctions was examined by confocal microscopy analysis. Transwell co-cultures of Caco-2 cells and U937-derived macrophages were used as models of LPS-induced intestinal inflammation to test the effect of ME-3 on release of the pro-inflammatory cytokines Tumor Necrosis Factor α, Interleukin-6, and Interleukin-8, was measured by ELISA. The results demonstrate that ME-3 prevents the IRI-induced increment in paracellular permeability, possibly by modulating the expression and localization of cell junction components. In addition, ME-3 inhibited both the increase in paracellular permeability and the release of pro-inflammatory cytokines in the co-culture model of LPS-induced inflammation. Our findings sustain the validity of L. fermentum ME-3 as a valuable therapeutic tool for preventing leaky gut syndrome, still currently without an available specific treatment.

The heteromer composed of dopamine D1 and D3 receptors (D1R-D3R) has been defined as a structure able to trigger Erk1/2 and Akt signaling in a G protein-independent, beta-arrestin 1-dependent way that is physiologically expressed in the ventral striatum and is likely involved in the control of locomotor activity. Indeed, abnormal levels of D1R-D3R heteromer in the dorsal striatum have been correlated with the development of L-DOPA-induced dyskinesia (LID) in Parkinson's disease patients, a motor complication associated with striatal D1R signaling, thus requiring Gs protein and PKA activity to activate Erk1/2. Therefore, to clarify the role of the D1R/D3R heteromer in LID, we investigated the signaling pathway induced by the heteromer using transfected cells and primary mouse striatal neurons. Collectively, we found that in both the cell models, D1R/D3R heteromer-induced activation of Erk1/2 exclusively required the D1R molecular effectors, such as Gs protein and PKA, with the contribution of the phosphatase Shp-2 and beta-arrestins, indicating that heterodimerization with the D3R abolishes the specific D3R-mediated signaling but strongly allows D1R signals. Therefore, while in physiological conditions the D1R/D3R heteromer could represent a mechanism that strengthens the D1R activity, its pathological expression may contribute to the abnormal PKA-Shp-2-Erk1/2 pathway connected with LID.

Background: MatriDerm and Integra are both widely used collagenic acellular dermal matrices (ADMs) in the surgical setting, with similar characteristics in terms of healing time and clinical indication. The aim of the present study is to compare the two ADMs in terms of clinical and histological results in the setting of dermato-oncological surgery., Methods: Ten consecutive patients with medical indications to undergo surgical excision of skin cancers were treated with a 2-step procedure at our Dermatologic Surgery Unit. Immediately after tumor removal, both ADMs were positioned on the wound bed, one adjacent to the other. Closure through split-thickness skin grafting was performed after approximately 3 weeks. Conventional histology, immunostaining and ELISA assay were performed on cutaneous samples at different timepoints., Results: No significant differences were detected in terms of either final clinical outcomes or in extracellular matrix content of the neoformed dermis. However, Matriderm was observed to induce scar retraction more frequently. In contrast, Integra was shown to carry higher infectious risk and to be more slowly reabsorbed into the wound bed. Sometimes foreign body-like granulomatous reactions were also observed, especially in Integra samples., Conclusions: Even in the presence of subtle differences between the ADMs, comparable global outcomes were demonstrated after dermato-oncological surgery.

G protein-coupled receptors (GPCR) heterodimers represent new entities with unique pharmacological, signalling, and trafficking properties, with specific distribution restricted to those cells where the two interacting receptors are co-expressed. Like other GPCR, dopamine D3 receptors (D3R) directly interact with various receptors to form heterodimers: data showing the D3R physical interaction with both GPCR and non-GPCR receptors have been provided including D3R interaction with other dopamine receptors. The aim of this chapter is to summarize current knowledge of the distinct roles of heterodimers involving D3R, focusing on the D3R interaction with the dopamine D1 receptor (D1R): the D1R-D3R heteromer, in fact, has been postulated in both ventral and motor striatum. Interestingly, since both D1R and D3R have been implicated in several pathological conditions, including schizophrenia, motor dysfunctions, and substance use disorders, the D1R-D3R heteromer may represent a potential drug target for the treatment of these diseases., (© 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Background: Very few studies have examined predictors of Driving Under the Influence (DUI) as a function of gender. This oversight is relevant, because analyzing gender differences prevents generalization of results observed in men, who still currently account for the majority of drivers worldwide, to women. The aim of this study is to analyze the prevalence of DUI of drugs in men and women reported in real case studies published in the last two decades, and to assess gender differences in risky DUI behaviour., Methods: PubMed, Scopus, Web of Science were searched for eligible studies in May 2021; a follow-up literature search was conducted in August 2021. Real-case studies of drivers convicted for DUI of psychoactive drugs with positive toxicological confirmatory analysis were included. The extracted outcome was the prevalence of positive findings of men and women for cocaine, cannabinoids, amphetamine-like drugs, opioids, and psychoactive prescription drugs. A meta-analysis of random effects estimates was performed to investigate the change in the size of the overall effect (by Cohen d standardized mean difference test). A Mann Whitney U test was performed to test for differences between genders., Results: Of the 2877 studies screened, 439 were retrieved in full-text and 26 were included. The meta-analysis showed a significant higher prevalence among men for cocaine (1.8% vs 0.9%; p < 0.001), cannabinoids (3.5% vs 1.6%; p = <0.01) and amphetamine-like drugs (1.2% vs 0.6%; p < 0.01). Surprisingly, no differences were observed in the use of opioids (2.3% vs 2.2%; p = 0.45) and benzodiazepines/Z-drugs (2.9% vs 3.7%; p = 0.52)., Conclusion: Contrary to the extraordinary number of real-case studies reported in literature, only a few papers differentiate the prevalence of DUI between men and women. This can lead to an underestimation of the influence of gender in DUI phenomenon or complicate the evaluation of the results for some classes of substances, as observed for medications and opioids. The primary goal in the future will be to collect the data concerning DUI drivers following shared and homogeneous methodologies, in order to allow the analysis of data disaggregated by gender, which can be used for monitoring evolving trends and developing gender-specific targeted prevention and enforcement efforts., Competing Interests: Conflict of interest The authors declare that there is no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Parapoxvirus (PPV) infections are considered neglected zoonoses because their incidence is often unknown or greatly underestimated despite being endemic globally. Here, we report the comprehensive diagnostic workflow that led to the identification of two cases of persistent PPV infections. The results obtained underline the importance of adopting a "One Health" approach and cross-sectoral collaboration between human and veterinary medicine for precise aetiological diagnosis and correct management of patients affected by zoonotic diseases.

Background: Hereditary epidermolysis bullosa (EB) is a rare genodermatosis characterized by skin fragility and blistering of the skin and mucous membranes in reaction to minimal traumas. The development of cutaneous squamous cell carcinomas (cSCCs) is one of the most common medical complications in junctional and dystrophic forms of the disease. Complete surgical excision of cutaneous tumors represents the gold standard of treatment. However, not only recognition of cSCCs can be challenging in the affected skin but also wound closure after surgical excision poses a great therapeutic challenge in EB patients. The aim of our study was to analyze the postoperative outcomes of such patients in order to have a better knowledge of the main critical issues in their surgical management and oncological follow-up., Methods: We retrospectively identified a cohort of five EB patients treated at Modena University Hospital. Collected data included patient age and sex, date of cSCC diagnosis, relapses/recurrences, site of the neoplasm, number of surgical interventions, use of dermal substitutes, and postoperative infections., Results: A total of 26 cSCCs were detected in our cohort. Forty-one surgical interventions were necessary to achieve excision of cSCCs with clear margins, varying from 1 to 4 surgical sessions per cSCC. Dermal substitutes were used in most cases but carried a higher infectious risk., Conclusions: EB patients tend to develop numerous cSCCs that often relapse even after complete excision with clear margins. These results stress the importance of early cSCC diagnosis and strict postsurgical follow-up., (© 2022 The Authors. International Journal of Dermatology published by Wiley Periodicals LLC on behalf of the International Society of Dermatology.)

Background: Patients with unresectable recurrent rectal cancer (RRC) or colorectal cancer (CRC) with liver metastases, refractory to at least two lines of traditional systemic therapy, may receive third line intraarterial chemotherapy (IC) and targeted therapy (TT) using drugs selected by chemosensitivity and tumor gene expression analyses of liquid biopsy-derived circulating tumor cells (CTCs)., Methods: In this retrospective study, 36 patients with refractory unresectable RRC or refractory unresectable CRC liver metastases were submitted for IC and TT with agents selected by precision oncotherapy chemosensitivity assays performed on liquid biopsy-derived CTCs, transiently cultured in vitro, and by tumor gene expression in the same CTC population, as a ratio to tumor gene expression in peripheral mononuclear blood cells (PMBCs) from the same individual. The endpoint was to evaluate the predictive accuracy of a specific liquid biopsy precision oncotherapy CTC purification and in vitro culture methodology for a positive RECIST 1.1 response to the therapy selected., Results: Our analyses resulted in evaluations of 94.12% (95% CI 0.71-0.99) for sensitivity, 5.26% (95% CI 0.01-0.26) for specificity, a predictive value of 47.06% (95% CI 0.29-0.65) for a positive response, a predictive value of 50% (95% CI 0.01-0.98) for a negative response, with an overall calculated predictive accuracy of 47.22% (95% CI 0.30-0.64)., Conclusions: This is the first reported estimation of predictive accuracy derived from combining chemosensitivity and tumor gene expression analyses on liquid biopsy-derived CTCs, transiently cultured in vitro which, despite limitations, represents a baseline and benchmark which we envisage will be improve upon by methodological and technological advances and future clinical trials., (© 2022. The Author(s).)

The microbiota is increasingly recognized as a critical player in cancer onset and progression and response to cancer chemotherapy treatment. In recent years, several preclinical and clinical studies have evidenced the involvement of microbiota in lung cancer, one of the world's deadliest cancers. However, the mechanisms by which the microbiota can impact this type of cancer and patient survival and response to treatments remain poorly investigated. In this review, the peculiarities of the gut and lung microbial ecosystems have been highlighted, and recent findings illustrating the possible mechanisms underlying the microbiota-lung cancer interaction and the host immune response have been discussed. In addition, the mucosal immune system has been identified as a crucial communication frame to ease interactive dynamics between the immune system and the microbiota. Finally, the use of specific next-generation intestinal probiotic strains in counteracting airway diseases has been evaluated. We believe that restoring homeostasis and the balance of bacterial microflora should become part of the routine of integrated cancer interventions, using probiotics, prebiotics, and postbiotics, and promoting a healthy diet and lifestyle.

Competing Interests: None

We have previously shown that the heteromer composed by the dopamine D3 receptor (D3R) and the nicotinic acetylcholine receptor (nAChR) (D3R-nAChR heteromer) is expressed in dopaminergic neurons, activated by nicotine and represents the molecular unit that, in these neurons, contributes to the modulation of critical events such as structural plasticity and neuroprotection. We now extended this study by investigating the D3R-nAChR heteromer properties using various cell models such as transfected HEK293 cells, primary cultures of mouse dopaminergic neurons and human dopaminergic neurons derived from induced pluripotent stem cells.We found that the D3R-nAChR heteromer is the molecular effector that transduces the remodeling properties not only associated with nicotine but also with D3R agonist stimulation: neither nAChR nor D3R, in fact, when express as monomers, are able to elicit these effects. Moreover, strong and sustained activation of the PI3K-ERK1/2/Akt pathways is coupled with D3R-nAChR heteromer stimulation, leading to the expression of the immediate-early gene c-Fos and to sustained phosphorylation of cytosolic p70 ribosomal S6 kinase (p70S6K), critical for dendritic remodeling. By contrast, while D3R stimulation results in rapid and transient activation of both Erk1/2 and Akt, that is PI3K-dependent, stimulation of nAChR is associated with persistent activation of Erk1/2 and Akt, in a PI3K-independent way. Thus, the D3R-nAChR heteromer and its ability to trigger the PI3K-ERK1/2/Akt signaling pathways may represent a novel target for preserving dopaminergic neurons healthy and for conferring neuronal protection against injuries., (© 2022. The Author(s).)

Background: The latest European Chikungunya virus (CHIKV) outbreak occurred in Italy in 2017, in the municipalities of Anzio and Rome (Lazio Region), with a secondary outbreak in the Calabrian Region. Most CHIKV infections are symptomatic but about 15% of people who acquire the infection may be asymptomatic. A retrospective study was conducted with the aim of assessing the prevalence of recent/ongoing CHIKV infections on the blood donor population in the Lazio Region, during the 2017 outbreak (including in the period before it was detected)., Methods: The study was conducted on 4595 plasma samples from donors who donated in 14 different Blood Establishments in the Lazio Region, in the period June-November 2017. A total of 389 of these samples were collected in provinces not affected by the outbreak and were used as negative controls. All samples were tested for IgM detection by the use of an ELISA test, and positive samples were tested for confirmation through the use of a PRNT. Molecular tests were performed on sera that were found to be IgM-positive or borderline., Results: A total of 41 (0.89%) blood donors tested positive for IgM. None of these positive IgM ELISA results was confirmed either by PRNT or by molecular tests., Conclusions: Our study has shown no evidence of recent/ongoing CHIKV infection in blood donors of the affected area.

Mitotane is the only approved drug for treating adrenocortical carcinoma (ACC). The regimen added to mitotane is chemotherapy with etoposide, doxorubicin, and cisplatin. This pharmacological approach, however, has a limited efficacy and significant toxicity. Target-therapy agents represent a new promising approach to cancer therapy. Among these, a preeminent role is played by agents that interfere with cell-cycle progression, such as CDK4/6-inhibitors. Here, we investigate whether ribociclib could induce a cytotoxic effect both in ACC cell line and patient-derived primary cell cultures, alone or in combined settings. Cell viability was determined by 3-(4,5-dimethyl-2-thiazol)-2,5-diphenyl-2H-tetrazolium bromide assay, whereas cell proliferation was evaluated by direct count. Binary combination experiments were performed using Chou and Talalay method. Gene expression was analyzed by quantitative RT-PCR, whereas protein expression was evaluated by immunofluorescence. A double staining assay revealed that ribociclib induced a prevalent apoptotic cell death. Cell-cycle analysis was performed to evaluate the effect of ribociclib treatment on cell-cycle progression in ACC cell models. Our results indicate that ribociclib was cytotoxic and reduced the cell proliferation rate. The effect on cell viability was enhanced when ribociclib was combined with progesterone and/or mitotane. The effect of ribociclib on cell-cycle progression revealed a drug-induced cell accumulation in G2 phase. The positive relationship underlined by our results between ribociclib, progesterone, and mitotane strengthen the clinical potential of this combination., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Ventricular arrhythmias (VAs) represent a critical issue with regard to sports eligibility assessment in athletes. The ideal diagnostic evaluation of competitive and leisure-time athletes with complex VAs has not been clearly defined., Objective: The purpose of this study was to assess the clinical implications of invasive electrophysiological assessments and endomyocardial biopsy (EMB) among athletes with VAs., Methods: We evaluated 227 consecutive athletes who presented to our institutions after being disqualified from participating in sports because of VAs. After noninvasive tests, electrophysiological study (EPS), electroanatomic mapping (EAM), and EAM- or cardiac magnetic resonance imaging-guided EMB was performed, following a prespecified protocol. Sports eligibility status was redefined at 6-month follow-up., Results: From our sample, 188 athletes (82.8%) underwent EAM and EPS, and 42 (15.2%) underwent EMB. A diagnosis of heart disease could be formulated in 30% of the study population (67/227; 95% confidence interval [CI] 0.24-0.36) after noninvasive tests; in 37% (83/227; 95% CI 31%-43%) after EPS and EAM; and in 45% (102/227; 95% CI 39%-51%) after EMB. In the subset of athletes undergoing EMB, invasive diagnostic workup allowed diagnostic reclassification of half of the athletes (n = 21 [50%]). Reclassification was particularly common among subjects without definitive findings after noninvasive evaluation (n = 23; 87% reclassified). History of syncope, abnormal echocardiogram, presence of late gadolinium enhancement, and abnormal EAM were linked to sports ineligibility at 6-month follow-up., Conclusion: A comprehensive invasive workup provided additional diagnostic elements and could improve the sports eligibility assessment of athletes presenting with VAs. The extensive invasive evaluation presented could be especially helpful when noninvasive tests show unclear findings., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Peritoneal Carcinomatosis (PC) is considered as a terminal disease with short survival. It is treated with palliative therapies, consisting of repeated drainages and sometimes instillation of chemotherapy. Since the nineties, surgery has been combined with more effective systemic chemotherapy, intraperitoneal chemotherapy and hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of PC. This combination therapy significantly increases the overall survival of selected PC patients. The understanding of how intraperitoneal chemotherapy and HIPEC can cure patients is still unclear. Experts hypothesized that the efficacy is obtained by the ability of high peritoneal drug exposure and hyperthermia to directly kill cancer cells. Several studies indicate that cancer cells death directly influences the response of the immune system. For this reason, the protective effect of intraperitoneal chemotherapy and HIPEC could be mediated by its ability to kill cancer cells in an immuno-genic way, causing an efficient anticancer immune response. In this review, we investigate the role of the innate peritoneal or locoregional therapy-induced immune response in PC therapy., Competing Interests: Conflict of interest The authors do not have any conflict of interest to declare. No funding was received., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The thermal stability of four different commercial citrus peel extracts was tested and improved by an encapsulation process with β-cyclodextrins in a spray-dryer. All extracts after the encapsulation process maintained a good antioxidant capacity, with an apparent loss in total phenolic compounds of around 20-25%. In addition, all samples showed good antimicrobial activity (MIC 5-0.625 mg/mL) against Staphylococcus aureus , which was maintained after the encapsulation process (MIC 5-1.25 mg/mL). Based on the antioxidant and antimicrobial activity results, the best-encapsulated citrus extract was selected for incorporation into a polylactic acid/polyhydroxy butyrate (PLA/PHB) film. The latter was then produced on an industrial scale by cast extrusion and was found to be suitable for food contact as it showed overall migration values in different food simulants lower than the legislative limit of 10 mg of non-volatile substances per 1 dm 2 of surface area. The UHPLC-HRMS analysis, performed to evaluate the migration of the active compounds, revealed about 13.41% release in food simulant A and 11.02% in food simulant B. Antimicrobial analysis conducted directly on the film showed a growth inhibition activity towards Escherichia coli and Staphylococcus aureus equal to 30 and 60%, respectively.

The AHCC standardized extract of cultured Lentinula edodes mycelia, and the standardized extract of Asparagus officinalis stem, trademarked as ETAS, are well known supplements with immunomodulatory and anticancer potential. Several reports have described their therapeutic effects, including antioxidant and anticancer activity and improvement of immune response. In this study we aimed at investigating the effects of a combination of AHCC and ETAS on colorectal cancer cells and biopsies from healthy donors to assess the possible use in patients with colorectal cancer. Our results showed that the combination of AHCC and ETAS was synergistic in inducing a significant decrease in cancer cell growth, compared with single agents. Moreover, the combined treatment induced a significant increase in apoptosis, sparing colonocytes from healthy donors, and was able to induce a strong reduction in migration potential, accompanied by a significant modulation of proteins involved in invasiveness. Finally, combined treatment was able to significantly downregulate LGR5 and Notch1 in SW620 cancer stem cell (CSC) colonospheres. Overall, these findings support the potential therapeutic benefits of the AHCC and ETAS combinatorial treatment for patients with colorectal cancer.

Deficits in social cognition and communication, the processes associated with human social behavior and interaction, have been described in individuals with eating disorder psychopathology. The current study examined whether social communication characteristics present in middle childhood (ages 8-14) were associated with eating disorder behaviors, cognitions, and diagnoses across adolescence (ages 14-18) in a large, population-based sample. Participants (N = 4864) were children enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC), a population-based, prospective study of women and their children. Regression methods tested prospective associations between social functioning using a facial emotion recognition task and parentally reported social communication symptoms (or difficulties), measured by the Social Communication Disorder Checklist (SCDC), with eating disorder symptoms and diagnoses. Misattribution of faces as sad or angry at age 8.5 was associated with purging and anorexia nervosa diagnosis at age 14, respectively, among girls. Furthermore, autistic-like social communication difficulties during middle childhood were associated with bulimia nervosa symptoms during adolescence among both girls and boys. Results did not support global associations between measured social communication deficits and eating disorder risk in this sample, but specific difficulties with facial emotion recognition and social communication may enhance the risk for disordered eating behaviors., (© 2020. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: An increasing number of studies report the beneficial effects of regional hyperthermia in association with chemotherapy (CHT) and radiotherapy for the treatment of pancreatic cancer; in particular, the use of modulated electro-hyperthermia (mEHT) results in increased survival and tumor response., Aim: To compare outcomes of CHT alone or in association with mEHT for the treatment of stage III and IV pancreatic cancer., Methods: This was an observational retrospective study; data were collected for patients with stage III-IV pancreatic cancer that were treated with CHT alone or in combination with mEHT from 2003 to 2019. A total of 158 patients were included in the study out 270 patients screened in four Italian hospitals; 58 (37%) of these received CHT + mEHT and 100 (63%) CHT. CHT was mainly gemcitabine-based regimens in both groups., Results: Overall (19.5 mo vs 11.02 mo, P < 0.001) and progression-free (12 mo vs 3 mo, P < 0.001) survival were better for the CHT + mEHT group compared to the CHT group. The association of mEHT resulted also in an improvement of tumor response with disease control rate 95% vs 58% ( P < 0.001) at 3 mo. Toxicity was comparable in the two study groups, and mEHT related adverse events were limited in 8 patients presenting G1-2 skin burns., Conclusion: The addition of mEHT to systemic CHT improved overall and progression-free survival and local tumor control with comparable toxicity., Competing Interests: Conflict-of-interest statement: No conflict of interest., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Cytotoxic necrotizing factor 1 (CNF1) is a bacterial virulence factor, the target of which is represented by Rho GTPases, small proteins involved in a huge number of crucial cellular processes. CNF1, due to its ability to modulate the activity of Rho GTPases, represents a widely used tool to unravel the role played by these regulatory proteins in different biological processes. In this review, we summarized the data available in the scientific literature concerning the observed in vitro effects induced by CNF1. An article search was performed on electronic bibliographic resources. Screenings were performed of titles, abstracts, and full-texts according to PRISMA guidelines, whereas eligibility criteria were defined for in vitro studies. We identified a total of 299 records by electronic article search and included 76 original peer-reviewed scientific articles reporting morphological or biochemical modifications induced in vitro by soluble CNF1, either recombinant or from pathogenic Escherichia coli extracts highly purified with chromatographic methods. Most of the described CNF1-induced effects on cultured cells are ascribable to the modulating activity of the toxin on Rho GTPases and the consequent effects on actin cytoskeleton organization. All in all, the present review could be a prospectus about the CNF1-induced effects on cultured cells reported so far.

Frailty is an aging related condition, which has been defined as a state of enhanced vulnerability to stressors, leading to a limited capacity to meet homeostatic demands. Cognitive impairment is also frequent in older people, often accompanying frailty. Age is the main independent risk factor for both frailty and cognitive impairment, and compelling evidence suggests that similar age-associated mechanisms could underlie both clinical conditions. Accordingly, it has been suggested that frailty and cognitive impairment share common pathways, and some authors proposed "cognitive frailty" as a single complex phenotype. Nevertheless, so far, no clear common underlying pathways have been discovered for both conditions. microRNAs (miRNAs) have emerged as key fine-tuning regulators in most physiological processes, as well as pathological conditions. Importantly, miRNAs have been proposed as both peripheral biomarkers and potential molecular factors involved in physiological and pathological aging. In this review, we discuss the evidence linking changes of selected miRNAs expression with frailty and cognitive impairment. Overall, miR-92a-5p and miR-532-5p, as well as other miRNAs implicated in pathological aging, should be investigated as potential biomarkers (and putative molecular effectors) of cognitive frailty., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Carini, Musazzi, Bolzetta, Cester, Fiorentini, Ieraci, Maggi, Popoli, Veronese and Barbon.)

Athlete's heart is typically accompanied by a remodelling of the cardiac chambers induced by exercise. However, although competitive athletes are commonly considered healthy, they can be affected by cardiac disorders characterised by an increase in left ventricular mass and wall thickness, such as hypertension. Unfortunately, training-induced increase in left ventricular mass, wall thickness, and atrial and ventricular dilatation observed in competitive athletes may mimic the pathological remodelling of pathological hypertrophy. As a consequence, distinguishing between athlete's heart and hypertension can sometimes be challenging. The present review aimed to focus on the differential diagnosis between hypertensive heart disease and athlete's heart, providing clinical information useful to distinguish between physiological and pathological remodelling., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Colorectal cancer (CRC) is a leading cause of cancer death worldwide, and its incidence is correlated with infections, chronic inflammation, diet, and genetic factors. An emerging aspect is that microbial dysbiosis and chronic infections triggered by certain bacteria can be risk factors for tumor progression. Recent data suggest that certain bacterial toxins implicated in DNA attack or in proliferation, replication, and death can be risk factors for insurgence and progression of CRC. In this study, we recruited more than 300 biopsy specimens from people undergoing colonoscopy, and we analyzed to determine whether a correlation exists between the presence of bacterial genes coding for toxins possibly involved in CRC onset and progression and the different stages of CRC. We also analyzed to determine whether CRC-predisposing genetic factors could contribute to bacterial toxins response. Our results showed that CIF toxin is associated with polyps or adenomas, whereas pks+ seems to be a predisposing factor for CRC. Toxins from Escherichia coli as a whole have a higher incidence rate in adenocarcinoma patients compared to controls, whereas Bacteroides fragilis toxin does not seem to be associated with pre-cancerous nor with cancerous lesions. These results have been obtained irrespectively of the presence of CRC-risk loci.

Converging clinical and preclinical evidence demonstrates that depressive phenotypes are associated with synaptic dysfunction and dendritic simplification in cortico-limbic glutamatergic areas. On the other hand, the rapid antidepressant effect of acute ketamine is consistently reported to occur together with the rescue of dendritic atrophy and reduction of spine number induced by chronic stress in the hippocampus and prefrontal cortex of animal models of depression. Nevertheless, the molecular mechanisms underlying these morphological alterations remain largely unknown. Here, we found that miR-9-5p levels were selectively reduced in the hippocampus of rats vulnerable to Chronic Mild Stress (CMS), while acute subanesthetic ketamine restored its levels to basal condition in just 24h; miR-9-5p expression inversely correlated with the anhedonic phenotype. A decrease of miR-9-5p was reproduced in an in vitro model of stress, based on primary hippocampal neurons incubated with the stress hormone corticosterone. In both CMS animals and primary neurons, decreased miR-9-5p levels were associated with dendritic simplification, while treatment with ketamine completely rescued the changes. In vitro modulation of miR-9-5p expression showed a direct role of miR-9-5p in regulating dendritic length and spine density in mature primary hippocampal neurons. Among the putative target genes tested, Rest and Sirt1 were validated as biological targets in primary neuronal cultures. Moreover, in line with miR-9-5p changes, REST protein expression levels were remarkably increased in both CMS vulnerable animals and corticosterone-treated neurons, while ketamine completely abolished this alteration. Finally, the shortening of dendritic length in corticosterone-treated neurons was shown to be partly rescued by miR-9-5p overexpression and dependent on REST protein expression. Overall, our data unveiled the functional role of miR-9-5p in the remodeling of dendritic arbor induced by stress/corticosterone in vulnerable animals and its rescue by acute antidepressant treatment with ketamine., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 Published by Elsevier Inc.)

Aims: Bevacizumab (B) in association with systemic chemotherapy is commonly used for the treatment of colorectal cancer liver metastases. The aim of this study was to monitor tumor response, overall survival (OS) and progression-free survival (PFS) of patients with colorectal cancer liver metastases treated with transarterial chemoembolization (TACE) + B compared with TACE alone and to correlate the results with KRAS mutational status., Patients & Methods: This was an observational multicentric case-control study (NCT03732235) on the efficacy and safety of B administered after TACE., Results: The disease control rate was significantly higher for the TACE + B than the TACE alone group (p < 0.001). KRAS wild-type patients had a significantly better disease control rate than those with KRAS mutations in the TACE + B group. Median OS and PFS were similar for the TACE + B and TACE groups, whereas median time to progression was significantly higher for the TACE + B group (p < 0.01)., Conclusion: The combination of TACE with B may improve tumor response and delay disease progression., Competing Interests: Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript., (© 2021 Giammaria Fiorentini.)

Cancer and cardiovascular diseases are the leading causes of death in high-income countries. Cardiovascular complications can be found in cancer patients, being the result of so-called 'cardio-toxicity'. Therefore, it becomes essential to thoroughly investigate the origin of cardiac damage and the strategy to prevent it or to reverse the negative remodelling associated with cardiotoxicity. In this review the beneficial effects of physical exercise in cancer patients were analysed, particularly to prevent cardio-toxicity before its clinical manifestation. According to the relevance of exercise, we suggest strategies for exercise prescription with a tailored approach in these patients. In conclusion, physical exercise seems to be a promising and effective treatment for cancer patients during and after therapy and seems to counteract the negative effects induced by drugs on the cardiovascular system. Exercise prescription should be tailored according to patient's individual characteristics, to the drugs administered, to the personal history, and to his/her response to exercise, taking into account that different types of training can be prescribed according also to the patient's choice. A cardiological evaluation including exercise testing is essential for an appropriate prescription of exercise in these patients., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Rett syndrome (RTT) is a rare neurological disorder caused by mutations in the X-linked MECP2 gene and a major cause of intellectual disability in females. No cure exists for RTT. We previously reported that the behavioural phenotype and brain mitochondria dysfunction are widely rescued by a single intracerebroventricular injection of the bacterial toxin CNF1 in a RTT mouse model carrying a truncating mutation of the MeCP2 gene (MeCP2-308 mice). Given the heterogeneity of MECP2 mutations in RTT patients, we tested the CNF1 therapeutic efficacy in a mouse model carrying a null mutation (MeCP2-Bird mice). CNF1 selectively rescued cognitive defects, without improving other RTT-related behavioural alterations, and restored brain mitochondrial respiratory chain complex activity in MeCP2-Bird mice. To shed light on the molecular mechanisms underlying the differential CNF1 effects on the behavioural phenotype, we compared treatment effects on relevant signalling cascades in the brain of the two RTT models. CNF1 provided a significant boost of the mTOR activation in MeCP2-308 hippocampus, which was not observed in the MeCP2-Bird model, possibly explaining the differential effects of CNF1. These results demonstrate that CNF1 efficacy depends on the mutation beared by MeCP2-mutated mice, stressing the need of testing potential therapeutic approaches across RTT models.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) are the most common genetic determinants of Parkinson's disease (PD), with the G2019S accounting for about 3% of PD cases. LRRK2 regulates various cellular processes, including vesicle trafficking that is crucial for receptor localization at the plasma membrane. In this study, induced pluripotent stem cells derived from 2 PD patients bearing the G2019S LRRK2 kinase activating mutation were used to generate neuronal cultures enriched in dopaminergic neurons. The results show that mutant LRRK2 prevents the membrane localization of both the dopamine D3 receptors (D3R) and the nicotinic acetylcholine receptors (nAChR) and the formation of the D3R-nAChR heteromer, a molecular unit crucial for promoting neuronal homeostasis and preserving dopaminergic neuron health. Interestingly, D3R and nAChR as well as the corresponding heteromer membrane localization were rescued by inhibiting the abnormally increased kinase activity. Thus, the altered membrane localization of the D3R-nAChR heteromer associated with mutation in LRRK2 might represent a pre-degenerative feature of dopaminergic neurons contributing to the special vulnerability of this neuronal population., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The progressive neuropathological damage seen in Parkinson's disease (PD) is thought to be related to the spreading of aggregated forms of α-synuclein. Clearance of extracellular α-synuclein released by degenerating neurons may be therefore a key mechanism to control the concentration of α-synuclein in the extracellular space. Several molecular chaperones control misfolded protein accumulation in the extracellular compartment. Among these, clusterin, a glycoprotein associated with Alzheimer's disease, binds α-synuclein aggregated species and is present in Lewy bodies, intraneuronal aggregates mainly composed by fibrillary α-synuclein. In this study, using murine primary astrocytes with clusterin genetic deletion, human-induced pluripotent stem cell (iPSC)-derived astrocytes with clusterin silencing and two animal models relevant for PD we explore how clusterin affects the clearance of α-synuclein aggregates by astrocytes. Our findings showed that astrocytes take up α-synuclein preformed fibrils (pffs) through dynamin-dependent endocytosis and that clusterin levels are modulated in the culture media of cells upon α-synuclein pffs exposure. Specifically, we found that clusterin interacts with α-synuclein pffs in the extracellular compartment and the clusterin/α-synuclein complex can be internalized by astrocytes. Mechanistically, using clusterin knock-out primary astrocytes and clusterin knock-down hiPSC-derived astrocytes we observed that clusterin limits the uptake of α-synuclein pffs by cells. Interestingly, we detected increased levels of clusterin in the adeno-associated virus- and the α-synuclein pffs- injected mouse model, suggesting a crucial role of this chaperone in the pathogenesis of PD. Overall, our observations indicate that clusterin can limit the uptake of extracellular α-synuclein aggregates by astrocytes and, hence, contribute to the spreading of Parkinson pathology., (© 2020 The Authors. GLIA published by Wiley Periodicals LLC.)