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Following viral infection, antigen-restricted T lymphocytes are activated and recognize infected cells to eliminate them. A subset of T cells differentiates into memory lymphocytes able to counteract viral rechallenge in a faster and enhanced way. SARS-CoV-2 can escape immune responses leading to a poor clinical outcome. Immune escape can be associated with the failure of the development of T cell memory compartments. The aim of this study is to characterize the T memory subsets and to test the immune response against class I- and II-restricted immunodominant epitopes shared by ancestral and SARS-CoV-2 variants strains. T memory subsets and recognition of SARS-CoV-2S Spike-specific epitopes were analyzed by flow cytometry on 14 fully vaccinated healthy donors (HDV) and 18 COVID-19 recovered patients (CD). The results obtained showed that CD8+ T naïve subset numbers decreased in association with a significant increase of the effector memory T cell subset whereas there was a small increase in the percentage of SARS-CoV-2 antigen-restricted T clones in both CD4 + and CD8+ subset in the CD compared to HDV sample. Collectively, these features may reflect a broader cytotoxic T cell repertoire stimulated by the virus during the natural infection compared to the spike-restricted response activated during vaccination.

Background: CD20 + T cells represent up to 5% of circulating T lymphocytes. These cells have been shown to produce higher levels of IL-17A and IFN-γ than those of CD20 -  T lymphocytes. Some reports described the role of CD20 + T cells in autoimmune disorders such as multiple sclerosis and rheumatoid arthritis possibly due to their ability to produce these inflammatory cytokines. This study is aimed at describing the behavior of CD20 + T lymphocytes in the most frequent autoimmune disorder, i.e., Hashimoto's thyroiditis (HT), presenting isolated or associated to further autoaggressive disorders in a frame of poly-autoimmunity., Methods: The study group encompasses 65 HT patients: 23 presenting in isolated form (IT) and 42 with an associated non-endocrine autoimmune disorder [16 with chronic atrophic gastritis (CAG), 15 with nonsegmental vitiligo (VIT), and 11 with celiac disease (CD)]. Twenty healthy donors act as control group (HD). Chronic use of interfering drugs, severe or chronic disorders, and pregnancy and lactation were used as exclusion criteria. Whole blood samples (100 µl) were stained with fluorescent-labeled antibodies (anti-CD45, anti-CD3, anti-CD19, anti-CD16, anti-CD56, anti-CD4, anti-CD8, anti-CD20). Red blood cells were then lysed by adding 1 ml of hypotonic buffer, and samples were acquired on a Flow Cytometer., Results: CD3 + CD8 + CD20 + T lymphocytes' percentages, were significantly higher in the whole group of autoimmune patients compared to healthy donors (p = 0.0145). Dividing HT patients based on the type of presentation of autoimmune thyroiditis, CAG group showed the highest percentage of these cells as compared to HD and CD (p = 0.0058). IT patients showed higher percentages of CD3 + CD8 + CD20 + cells than those of HD patients although not reaching statistical significance. However, dividing IT group based on thyroid function, hypothyroid patients showed higher CD8 + CD20 + cell percentages than those of HD and euthyroid patients (p = 0.0111). Moreover, in IT patients, these cells were negatively correlated with FT4 levels (p = 0.0171; r = -0.4921)., Conclusions: These preliminary findings indicate that CD8 + CD20 + T cells are activated in patients with autoimmune thyroiditis and may behave differently according to the presence of poly-autoimmunity and hypothyroidism., (© 2024. The Author(s).)

The number of total hip and total knee replacements has increased steadily each year. Today, they are routinely performed all over the world. The increasing prevalence of obesity has led to an increase in the number of total knee arthroplasties (TKAs) performed in patients with a higher body mass index (BMI) and also has a higher rate of complications. Possible complications are infection, instability, misalignment, osteolysis, or fracture. Revision arthroplasty can be challenging due to bone defects, ligament instability, and difficulty in fixation. We present the case of a 66-year-old morbidly obese patient who underwent TKA. After the operation, infection and a mechanical complication of periprosthetic fracture of the tibial component occurred. The infection made the treatment more difficult. The patient had to undergo several surgeries in several stages to address the post-surgical complications. TKA in obese patients leads to a higher risk of postoperative complications., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Bocea et al.)

A new generation of an FFP2 (Filtering Face Piece of type 2) smart face mask is achieved by integrating broadband hybrid nanomaterials and a self-assembled optical metasurface. The multifunctional FFP2 face mask shows simultaneously white light-assisted on-demand disinfection properties and versatile biosensing capabilities. These properties are achieved by a powerful combination of white light thermoplasmonic responsive hybrid nanomaterials, which provide excellent photo-thermal disinfection properties, and optical metasurface-based colorimetric biosensors, with a very low limit of pathogens detection. The realized system is studied in optical, morphological, spectroscopic, and cell viability assay experiments and environmental monitoring of harmful pathogens, thus highlighting the extraordinary properties in reusability and pathogens detection of the innovative face mask., (© 2024 Wiley‐VCH GmbH.)

Coronavirus disease 2019 (COVID-19) is an infection characterized by the dysregulation of systemic cytokine levels. The measurement of serum levels of inflammatory cyto-/chemokines has been suggested as a tool in the management of COVID-19. The aim of this study is to highlight the significance of measured levels of interleukin (IL)-1α, IL-1β, IL-6, IL-8, IL-10, IL-12(p70), IL-27, interferon (IFN)γ, interferon gamma-induced protein (IP)-10, monocyte chemoattractant protein (MCP)-1, and tumor necrosis factor (TNF)-α in serum samples from infected and recovered subjects, possibly predictive of severity and/or duration of the disease. Serum samples from healthy (HD), positive at hospital admittance (T0), and recovered subjects (T1, 31-60, or 70-200 days post-negativization) were collected and tested through a bead-based cytometric assay and confirmed through ELISA. IL-10 levels were increased in the T0 group compared to both HD and T1. IL-27 significantly decreased in the 31-60 group. IL-1β significantly increased in the 70-200 day group. TNF-α significantly decreased in T0 compared to HD and in the 31-60 group versus HD. IP-10 significantly increased in T0 compared to HD. These results suggest that IP-10 could represent an early marker of clinical worsening, whereas IL-10 might be indicative of the possible onset of post-COVID-19 long syndrome.

Coxiella burnetii is the causative agent of Q fever. The main reservoirs for this bacterium, which can lead to human infection, in our region are typically cattle, goats, and sheep. In animals, C. burnetii infection is often detected due to reproductive problems. European Member States are required to report confirmed cases annually, but the lack of uniform reporting methods makes the data rather inconsistent. The Istituto Zooprofilattico Sperimentale dell'Abruzzo e del Molise is involved in official controls to identify the causes of abortions, monitor suspected or positive herds, evaluate suspected infections in pets and humans, monitor the spread in wildlife, etc. In this paper, we summarize the presence of C. burnetii over the last five years (2019-2023). Additionally, a detailed overview of C. burnetii infection in wild and domestic animals is provided. Five hundred sixty animals-including cattle; goats; sheep; wild animals, such as deer, boars, wolves, roe deer, owls, and otters; buffalo; dogs; horses; cats; and a donkey-and six human samples were tested by real-time PCR on the transposase gene IS1111 to detect C. burnetii . The MST profile was identified in some of the samples. Outbreaks of C. burnetii occurred in four herds. In one of them, it was possible to follow the outbreak from inception to eradication by evaluating the effect of vaccination on real-time PCR Ct values. A total of 116 animals tested positive for C. burnetii , including 73 goats, 42 sheep, and one bovine. None of the other samples tested positive. The strains for which the ST was performed were identified as ST79, a strain that has been present in the area for more than ten years. The effect of vaccination on the reduction of positive samples and the variation of real-time PCR Ct values was evaluated in strict correlation.

Psoriasis is a chronic inflammatory disease affecting skin and joints characterized by a chronically altered immune and inflammatory response. Several factors occur from the onset to the development of this disease due to different types of cells spatially and temporally localized in the affected area, such as, keratinocytes, macrophages, neutrophils and T helper lymphocytes. This scenario leads to the chronic release of high levels of inflammatory mediators ( i.e. , IL-17, IL-23, IL-22, TNF-α, S100 proteins, Defensins) and lastly parakeratosis and thickening of the stratum spinosum. Extracellular vesicles (EVs) are small double membraned biological nanoparticles that are secreted by all cell types and classified, based on dimension and biogenesis, into exosomes, microvesicles and apoptotic bodies. Their role as vessels for long range molecular signals renders them key elements in the pathogenesis of psoriasis, as well as innovative platforms for potential biomarker discovery and delivery of fine-tuned anti-inflammatory therapies. In this review, the role of EVs in the pathogenesis of psoriasis and the modulation of cellular microenvironment has been summarized. The biotechnological implementation of EVs for therapy and research for new biomarkers has been also discussed., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Iuliano, Grimaldi, Rosa, Scibetta, Bernardini, Proietti, Tolino, Skroza, Potenza, Mangino and Romeo.)

Inborn errors of metabolism are related to mitochondrial disorders caused by dysfunction of the oxidative phosphorylation (OXPHOS) system. Congenital hypermetabolism in the infant is a rare disease belonging to Luft syndrome, nonthyroidal hypermetabolism, arising from a singular example of a defect in OXPHOS. The mitochondria lose coupling of mitochondrial substrates oxidation from the ADP phosphorylation. Since Luft syndrome is due to uncoupled cell respiration responsible for deficient in ATP production that originates in the respiratory complexes, a de novo heterozygous variant in the catalytic subunit of mitochondrial F 1 F O -ATPase arises as the main cause of an autosomal dominant syndrome of hypermetabolism associated with dysfunction in ATP production, which does not involve the respiratory complexes. The F 1 F O -ATPase works as an embedded molecular machine with a rotary action using two different motor engines. The F O , which is an integral domain in the membrane, dissipates the chemical potential difference for H + , a proton motive force (Δp), across the inner membrane to generate a torsion. The F 1 domain-the hydrophilic portion responsible for ATP turnover-is powered by the molecular rotary action to synthesize ATP. The structural and functional coupling of F 1 and F O domains support the energy transduction for ATP synthesis. The dissipation of Δp by means of an H + slip correlated to rotor free-wheeling of the F 1 F O -ATPase has been discovered to cause enzyme dysfunction in primary mitochondrial disorders. In this insight, we try to offer commentary and analysis of the molecular mechanism in these impaired mitochondria., (© 2024 The Authors. Medicinal Research Reviews published by Wiley Periodicals LLC.)

Recently, the development of nonalcoholic steatohepatitis (NASH) in common strains of pigs has been achieved using a diet high in saturated fat, fructose, cholesterol, and cholate and deficient in choline and methionine. The aim of the present work was to characterize the hepatic and plasma lipidomic changes that accompany the progression of NASH and its reversal by switching pigs back to a chow diet. One month of this extreme steatotic diet was sufficient to induce porcine NASH. The lipidomic platform using liquid chromatography-mass spectrometry analyzed 467 lipid species. Seven hepatic phospholipids [PC(30:0), PC(32:0), PC(33:0), PC(33:1), PC(34:0), PC(34:3) and PC(36:2)] significantly discriminated the time of dietary exposure, and PC(30:0), PC(33:0), PC(33:1) and PC(34:0) showed rapid adaptation in the reversion period. Three transcripts ( CS , MAT1A , and SPP1 ) showed significant changes associated with hepatic triglycerides and PC(33:0). Plasma lipidomics revealed that these species [FA 16:0, FA 18:0, LPC(17:1), PA(40:5), PC(37:1), TG(45:0), TG(47:2) and TG(51:0)] were able to discriminate the time of dietary exposure. Among them, FA 16:0, FA 18:0, LPC(17:1) and PA(40:5) changed the trend in the reversion phase. Plasma LDL-cholesterol and IL12P40 were good parameters to study the progression of NASH, but their capacity was surpassed by hepatic [PC(33:0), PC(33:1), and PC(34:0)] or plasma lipid [FA 16:0, FA 18:0, and LPC(17:1)] species. Taken together, these lipid species can be used as biomarkers of metabolic changes in the progression and regression of NASH in this model. The lipid changes suggest that the development of NASH also affects peripheral lipid metabolism. NEW & NOTEWORTHY A NASH stage was obtained in crossbred pigs. Hepatic [PC(33:0), PC(33:1) and PC(34:0)] or plasma [FA 16:0, FA 18:0 and LPC(17:1)] species were sensitive parameters to detect subtle changes in development and regression of nonalcoholic steatohepatitis (NASH). These findings may delineate the liquid biopsy to detect subtle changes in progression or in treatments. Furthermore, phospholipid changes according to the insult-inducing NASH may play an important role in accepting or rejecting fatty livers in transplantation.

Oxidative stress represents a hallmark for many degenerative pathologies of the Central Nervous System. Throughout life, the constant pressure of noxious stimuli and/or episodes of traumatic events may expose the brain to a microenvironment where the non-balanced reactive oxygen species inevitably lead to neuronal loss and cognitive decline. HO-1, a 32 kDa heat-shock protein catalyzing the degradation of heme into carbon monoxide (CO), iron and biliverdin/bilirubin is considered one of the main antioxidant defense mechanisms playing pivotal roles in neuroprotection. Restoring the redox homeostasis is the goal of many natural or synthetic antioxidant molecules pursuing beneficial effects on brain functions. Here, we investigated the antioxidant capacity of four selected benzofuran-2-one derivatives in a cellular model of neurodegeneration represented by differentiated SH-SY5Y cells exposed to catechol-induced oxidative stress. Our main results highlight how all the molecules have antioxidant properties, especially compound 9 , showing great abilities in reducing intracellular ROS levels and protecting differentiated SH-SY5Y cells from catechol-induced death. This compound above all seems to boost HO-1 mRNA and perinuclear HO-1 protein isoform expression when cells are exposed to the oxidative insult. Our findings open the way to consider benzofuran-2-ones as a novel and promising adjuvant antioxidant strategy for many neurodegenerative disorders.

Background: Low-dose-medicine is based on the administration of low doses of biological regulators to restore the immunologic balance altered in the disease. Cytokines are pivotal regulators of cellular and tissue functions and impaired crosstalk, due to an imbalance between specific cytokines, it is fundamental in acute inflammation and diseases correlated to low-grade chronic inflammation. Osteoarthritis is the most prevalent arthritic disease and a leading cause of disability. In the treatment of muscle- skeletal pathologies, the therapeutic integration of conventional medicine with homotoxicology, or low-dose-medicine appears to be beneficial., Objective: This study aims to get more insights into the role of inflammatory cytokines and chemokines during the development of osteoarthritis and to evaluate a possible blocking strategy using anti-inflammatory molecules, we resort to an in vitro experimental model using an established human chondrosarcoma cell line that underwent to a well known pro-inflammatory stimulus as bacterial lipopolysaccharide., Methods: We tested the production of inflammatory-related cytokines and chemokines, and the efficacy of low-dose (LD) administration of anti-inflammatory compounds, namely IL-10 and anti-IL-1, to block inflammatory cellular pathways., Results: Following an inflammatory insult, chondrocytes upregulated the expression of several pro-inflammatory cyto-/chemokines and this induction could be counteracted by LD IL-10 and anti-IL-1. We reported that these effects could be ascribed to an interfering effect of LD drugs with the NF-κB signaling., Conclusion: Our results provided a good indication that LD drugs can be effective in inhibiting the inflammatory response in chondrocytes opening the way to new therapies for the treatment of diseases such as osteoarthritis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The ASTRI Mini-Array is an international collaboration led by the Italian National Institute for Astrophysics (INAF) that will operate nine telescopes to perform Cherenkov and optical stellar intensity interferometry (SII) observations. At the focal plane of these telescopes, we are planning to install a stellar intensity interferometry instrument. Here we present the selected design, based on Silicon Photomultiplier (SiPM) detectors matching the telescope point spread function together with dedicated front-end electronics.

Renewed interest towards natural substances has been pushed by the widespread diffusion of antibiotic resistance. Curcumin I is the most active and effective constituent of curcuminoids extracted from Curcuma longa and, among other beneficial effects, attracted attention for its antimicrobial potential. Since the poor pharmacokinetic profile hinders its efficient utilization, in the present paper, we report encapsulation of curcumin I in poly(styrene-co-maleic acid) (SMA-CUR) providing a nanomicellar system with improved aqueous solubility and bioavailability. SMA-CUR was characterized by means of size, zeta potential, polydispersity index, atomic force microscopy (AFM), drug release studies, spectroscopic properties and stability. SMA-CUR nanoformulation displayed exciting antimicrobial properties compared to free curcumin I towards Gram-positive and Gram-negative clinical isolates., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Helminth infection was analysed at necropsy and coprology in a total of 54 roe deer from the province of Grosseto (central Italy) between 2018 - 2020. Age and sex data were recorded for each deer for a total of 31 adults (23 females, 8 males) and 23 juveniles (11 females, 12 males). The results on the small intestine (51 samples) highlighted that nematodes belonging to the species Trichostrongylus colubriformis were the most prevalent parasite (41.2 %), followed by the cestode Moniezia expansa (7.8 %). The large intestine results (52 samples) showed Trichuris spp. (53.8 %), Oesophagostomum venulosum (50 %) and Chabertia ovina (26.9 %). In the abomasum, only Ostertagia ostertagi (17.9 %) was found. Of the 34 samples analysed by bronchopulmonary, only the lung of an adult female was positive for Dictyocaulus spp. In two livers out of 33 samples analysed, nematodes of the species Setaria tundra were found on the surface. Copropositivity was observed in 45 of the 52 faecal samples analysed. The results of the present study indicate that the roe deer is host to several species of parasites, which are also common in other cervids and domestic ruminants. Statistical testing highlighted a significant difference between mean intensities in males and females., Competing Interests: Conflict of Interest The authors declare no competing interest., (© 2023 F. Macchioni et al., published by Sciendo.)

Actinic keratosis (AK) is a carcinoma in situ precursor of cutaneous squamous cell carcinoma (cSCC), the second most common cancer affecting the Caucasian population. AK is frequently present in the sun-exposed skin of the elderly population, UV radiation being the main cause of this cancer, and other risk factors contributing to AK incidence. The dysregulation of microRNAs (miRNAs) observed in different cancers leads to an improper expression of miRNA targets involved in several cellular pathways. The TaqMan Array Human MicroRNA Card assay for miRNA expression profiling was performed in pooled AK compared to healthy skin scraping samples from the same patients. Forty-three miRNAs were modulated in the AK samples. The expression of miR-19b ( p < 0.05), -31, -34a ( p < 0.001), -126, -146a ( p < 0.01), -193b, and -222 ( p < 0.05) was validated by RT-qPCR. The MirPath tool was used for MiRNA target prediction and enriched pathways. The top DIANA-mirPath pathways regulated by the targets of the 43 miRNAs are TGF-beta signaling, Proteoglycans in cancer, Pathways in cancer, and Adherens junction (7.30 × 10 -10 < p < 1.84 × 10 -8 ). Selected genes regulating the KEGG pathways, i.e., TP53 , MDM2 , CDKN1A , CDK6 , and CCND1 , were analyzed. MiRNAs modulated in AK regulate different pathways involved in tumorigenesis, indicating miRNA regulation as a critical step in keratinocyte cancer.

In this work, we extend the concept of 5-fluorouracil/heme oxygenase 1 (5-FU/HO-1) inhibitor hybrid as an effective strategy for enhancing 5-FU-based anticancer therapies. For this purpose, we designed and synthesized new mutual prodrugs, named SI 1/20 and SI 1/22, in which the two active parent drugs (i. e., 5-FU and an imidazole-based HO-1 inhibitor) were connected through an easily cleavable succinic linker. Experimental hydrolysis rate, and in silico ADMET predictions were indicative of good drug-likeness and pharmacokinetic properties. Novel hybrids significantly reduced the viability of prostate DU145 cancer cells compared to the parent compounds 5-FU and HO-1 inhibitor administered alone or in combination. Interestingly, both compounds showed statistically significant lower toxicity, than 5-FU at the same dose, against non-tumorigenic human benign prostatic hyperplasia (BPH-1) cell line. Moreover, the newly synthesized mutual prodrugs inhibited the HO-1 activity both in a cell-free model and in vitro, as well as downregulated the HO-1 expression and increased the reactive oxygen species (ROS) levels., (© 2023 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

The number of newly described sandfly-borne phleboviruses has been steadily growing in recent years. Some phleboviruses are human pathogens, but their health relevance is largely uncharacterized. We aimed to investigate the circulation of these viruses in the Emilia-Romagna region where several have already been described. A total of 482 sandflies were collected in a site in Reggio Emilia in 2019 and 2020. Sandflies collected in 2020 were grouped in 21 pools with a maximum of 25 sandflies per pool, submitted to real time PCR, and isolated in Vero cell culture. Complete genome sequencing showed the isolation of a strain of a Ponticelli III virus. This virus, which belongs to the species Adana phlebovirus , differed in the M segment from the Ponticelli I and Ponticelli II viruses. Analysis performed on the genomic segments of the newly isolated virus compared with other phleboviruses highlighted a strong purifying selection in the L segments, and different substitution saturation, highest in the M segments. Future research should address the ecological processes driving the occurrence of these novel phleboviruses and their possible impact on public health.

A de novo heterozygous variant in the catalytic subunit of mitochondrial F 1 F O -ATPase has been recently discovered by Ganetzky et al. to be the main cause of an autosomal dominant syndrome of hypermetabolism associated with defective ATP production. We describe how the 'rotor free-wheeling' causes this F 1 F O -ATPase dysfunction in primary congenital hypothyroidism., Competing Interests: Declaration of interests All authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Squalene is a key minor component of virgin olive oil, the main source of fat in the Mediterranean diet, and had shown to improve the liver metabolism in rabbits and mice. The present research was carried out to find out whether this effect was conserved in a porcine model of hepatic steatohepatitis and to search for the lipidomic changes involved. The current study revealed that a 0.5% squalene supplementation to a steatotic diet for a month led to hepatic accumulation of squalene and decreased triglyceride content as well as area of hepatic lipid droplets without influencing cholesterol content or fiber areas. However, ballooning score was increased and associated with the hepatic squalene content. Of forty hepatic transcripts related to lipid metabolism and hepatic steatosis, only citrate synthase and a non-coding RNA showed decreased expressions. The hepatic lipidome, assessed by liquid chromatography-mass spectrometry in a platform able to analyze 467 lipids, revealed that squalene supplementation increased ceramide, Cer(36:2), and phosphatidylcholine (PC[32:0], PC[33:0] and PC[34:0]) species and decreased cardiolipin, CL(69:5), and triglyceride (TG[54:2], TG[55:0] and TG[55:2]) species. Plasma levels of interleukin 12p40 increased in pigs receiving the squalene diet. The latter also modified plasma lipidome by increasing TG(58:12) and decreasing non-esterified fatty acid (FA 14:0, FA 16:1 and FA 18:0) species without changes in total NEFA levels. Together this shows that squalene-induced changes in hepatic and plasma lipidomic profiles, non-coding RNA and anti-inflammatory interleukin are suggestive of an alleviation of the disease despite the increase in the ballooning score., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Substantial progress in the therapeutic arsenal used to treat acute myeloid leukemia became possible in the last decade, as a result of advances in gene editing and descriptive and functional genomics., Objective: The aim of this study is to analyze the efficacy and safety of venetoclax in the treatment of acute myeloid leukemia., Methods: A mini-review was achieved using the articles published in PubMed and Web of Science in the last year, prior to 05.05.2021, which were searched using the terms "acute myeloid leukemia" and "venetoclax" and the new patents published in this field., Results: BCL-2 inhibitors administered in monotherapy are active against acute myeloid leukemia cells, but their efficacy is partially limited because they do not target other antiapoptotic proteins and venetoclax induced overexpression of the other antiapoptotic molecules. Venetoclax-based combinations (including those with hypomethylating agents) were able to improve outcomes for older patients with acute myeloid leukemia, including both remission rates and overall survival. Other drugs used in combination with venetoclax include: FLT3 inhibitors, IDH2 inhibitors, chidamide, ibrutinib, lapatinib, mivebresib, triptolide, metabolic inhibitors, nucleoside analogs, and classical chemotherapeutics. Both the mechanisms of venetoclax resistance and the ways to overcome it, as well as the adverse effects of venetoclax are analyzed., Conclusion: The management of unfit and older patients with acute myeloid leukemia should be personalized and be the result of evaluating patient- and disease-specific factors that are essential to their care. Combinations that include venetoclax are an increasingly well-documented option for many of them., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Actinic keratosis (AK) is a precursor of cutaneous squamous cell carcinoma (cSCC). UV radiation is the major risk factor for AK, but certain human papillomaviruses (HPVs) of the beta genus are also involved in its development. Differently, the role of polyomaviruses (PyVs) in skin carcinogenesis is still debated. Fiftheen PyVs have been isolated from human tissues so far, including Merkel cell polyomavirus (MCPyV), the aetiological agent of Merkel cell carcinoma., Methods: The presence of 13 PyVs was assessed in skin samples from AK patients (n = 342). Matched fresh-frozen scrapings from healthy skin (HS) and AK lesions from 242 patients, and formalin-fixed paraffin-embedded AK biopsies from a different cohort of 100 patients were analyzed by multiplex PyVs genotyping assay., Results: The most frequent lesion site was the scalp in men (27.3%), and the cheek area in women (29.0%). Differences between men and women were significant for the scalp, the cheek area and the lips. Almost all the scrapings were PyV-positive (HS: 89.7%, AK: 94.6%; p = 0.04). The three most frequent PyVs were MCPyV, HPyV6 and JCPyV (HS: 87.2%, 58.7%, 6.6%, respectively; AK: 88.8%, 51.2%, 9.9%, respectively). HPyV9, TSPyV, BKPyV, HPyV7, LIPyV and SV40 were detected in < 2% of the scrapings. In most cases, matched HS and AK scrapings were both positive (MCPyV: 78.1%, HPyV6: 41.7%), or both negative for the individual genotypes (for the remaining PyVs). PyV prevalence in AK biopsies was 22.0%. Only MCPyV (21.0%) and HPyV6 (3.0%) were detected in these samples., Conclusions: PyV prevalence in HS and AK scrapings was high, but detection of PyVs exclusively in AK scrapings was rare. PyV positivity rate in AK biopsies was modest. Further research is need to reach firm conclusions regarding the role of these viruses in AK development., (© 2022. The Author(s).)

Objectives: Extracellular vesicles (EVs) are key biological mediators of several physiological functions within the cell microenvironment. Platelets are the most abundant source of EVs in the blood. Similarly, platelet lysate (PL), the best platelet derivative and angiogenic performer for regenerative purposes, is enriched of EVs, but their role is still too poorly discovered to be suitably exploited. Here, we explored the contribution of the EVs in PL, by investigating the angiogenic features extrapolated from that possessed by PL., Methods: We tested angiogenic ability and molecular cargo in 3D bioprinted models and by RNA sequencing analysis of PL-derived EVs., Results: A subset of small vesicles is highly represented in PL. The EVs do not retain aggregation ability, preserving a low redox state in human umbilical vein endothelial cells (HUVECs) and increasing the angiogenic tubularly-like structures in 3D endothelial bioprinted constructs. EVs resembled the miRNome profile of PL, mainly enriched with small RNAs and a high amount of miR-126, the most abundant angiogenic miRNA in platelets. The transfer of miR-126 by EVs in HUVEC after the in vitro inhibition of the endogenous form, restored angiogenesis, without involving VEGF as a downstream target in this system., Conclusion: PL is a biological source of available EVs with angiogenic effects involving a miRNAs-based cargo. These properties can be exploited for targeted molecular/biological manipulation of PL, by potentially developing a product exclusively manufactured of EVs., (© 2022 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

The overexpression of σ receptors (σRs) in various types of tumors has prompted a deep investigation of their role in cancer pathophysiology. Consequently, σR ligands have been widely studied in vitro and in vivo for their antiproliferative effects as a novel potential class of chemotherapeutic agents, both alone and in combination with other anticancer drugs. A growing body of evidence highlights that σR ligands can inhibit cancer cells' survival, migration, and proliferation, thanks to the modulation of a wide panel of tumorigenic pathways. In addition to their antitumor activity, σR ligands are gaining momentum as radiotracers for PET and SPECT imaging applications. The purpose of this review is to report on recent advances in the development of σR ligands. In particular, herein, we describe the structure-activity relationships of structurally diverse mixed σ 1 R/σ 2 R ligands that showed promising antitumor profiles towards a variety of cancer cell lines., 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 © 2022 Elsevier Ltd. All rights reserved.)

Benign prostatic hypertrophy (BPH) is a condition that appears with advancing age and affects 1/3 of men over 50 years, resulting in filling and emptying symptoms. One of the main limitations of endoscopic techniques for BPH is the occurrence of retrograde ejaculation. The purpose of this prospective observational study is to evaluate the efficacy and feasibility of ejaculation-sparing thulium laser enucleation of the prostate (ES-ThuLEP) in the treatment of BPH-related LUTS and the preservation of ejaculation. Sexually active patients with BPH were enrolled and followed up with at 3, 6, and 12 months after surgery. Personal and pharmacological histories were collected, while three standardized questionnaires—the International Index of Erectile Function short form (IIEF-5), the International Consultation on Incontinence Questionnaire for Male Sexual Matters Associated with Lower Urinary Tract Symptoms Module (ICIQ—MLUTSsex), and the International Prostatic Symptom Score (IPSS)—were administered. In addition, all patients underwent uroflowmetry and an assessment of post-void residual volume (PVR). A total of 53 patients were enrolled. A statistically significant improvement in the IPSS score, maximum flow (Qmax), and post-void volume (PVR) at 3 months, 6 months, and 12 months after surgery was found (p < 0.05), while no statistically significant differences were reported between IIEF-5 scores before and after surgery. A total of 48 patients (88.6%) had preserved ejaculation at 3 months, while 92.4% and 94.3% of patients reported preserved ejaculation at 6 and 12 months, respectively. Nevertheless, some degree of hypoposia was referred, at 3, 6, and 12 months, by 43.7%, 30.6%, and 13.2% of patients, respectively. The ES-ThuLEP technique successfully preserved ejaculation in over 90% of patients, representing an ejaculation-sparing alternative in the treatment of BPH.

Cases of sand fly-borne diseases in the Emilia-Romagna region, such as meningitis caused by Toscana virus and human leishmaniasis, are reported annually through dedicated surveillance systems. Sand flies are abundant in the hilly part of the region, while the lowland is unsuitable habitat for sand flies, which are found in lower numbers in this environment with respect to the hilly areas. In this study, we retrieved sand flies collected during entomological surveillance of the West Nile virus (from 2018 to 2021) to assess their abundance and screen them for the presence of pathogens. Over the four-year period, we collected 3022 sand flies, more than half in 2021. The most abundant sand fly species was Phlebotomus (Ph.) perfiliewi , followed by Ph. perniciosus ; while more rarely sampled species were Ph. papatasi , Ph. mascittii and Sergentomyia minuta . Sand flies were collected from the end of May to the end of September. The pattern of distribution of the species is characterized by an abundant number of Ph. perfiliewi in the eastern part of the region, which then falls to almost none in the western part of the region, while Ph. perniciosus seems more uniformly distributed throughout. We tested more than 1500 female sand flies in 54 pools to detect phleboviruses and Leishmania species using different PCR protocols. Toscana virus and Leishmania infantum , both human pathogens, were detected in 5 pools and 7 pools, respectively. We also detected Fermo virus, a phlebovirus uncharacterized in terms of relevance to public health, in 4 pools. We recorded different sand fly abundance in different seasons in Emilia-Romagna. During the season more favorable for sand flies, we also detected pathogens transmitted by these insects. This finding implies a health risk linked to sand fly-borne pathogens in the surveyed area in lowland, despite being considered a less suitable habitat for sand flies with respect to the hilly areas.

Lateral periodontal cyst (LPC) and odontogenic keratocystic (OK) are two osteolytic lesions of the jaw with different local invasiveness and percentage of recurrence. The aim of this study was to highlight the attention on the differential diagnosis of these lesions that sometimes can have unexpected location and can lead doubts on diagnosis, therapy, and follow-up. A 34-year-old man presented to our department with a complaint of soft pain in the vestibular aspect of left mandibular second premolar and left mandibular first molar. Vital teeth in the left mandible, no mucosal swelling, and no drainage were observed. The CBCT showed a well circumscribed hypodensity area, extending between 3.5 and the apex of mesial root of 3.6. No displacement and no resorption of the roots were notified. Upon clinical and radiographical examination, a provisional diagnosis of LPC was made and enucleation of the lesion and histological examination were planned. Histologically, a cystic wall partially lined by a keratinizing squamous epithelium was observed. Surrounding and within the lesion, there was a chronic inflammatory infiltrate also of granulomatous type and with cholesterol clefts. Based on these findings, the diagnosis of odontogenic keratocystic was done. Radiolucent lesions in the premolar and canine region are frequently clinically and radiographically misdiagnosed. The identification of keratocyst in a location preoperatively favoring a lateral periodontal cyst should be suspected and biopsy must be considered in all cases to establish the nature of the lesion, the best surgical treatment, and the follow-up appointments.

Purpose: Extracellular Vesicles (EVs) are a heterogeneous group of cell-derived membranous nanoparticles involved in several physiopathological processes. EVs play a crucial role in the definition of the extracellular microenvironment through the transfer of their cargo. Psoriasis is a prototypical chronic inflammatory disease characterized by several secreted mediators, among which antimicrobial peptides (AMPs) are considered pivotal in the development of the psoriatic inflammatory microenvironment. The role of EVs in the pathogenesis of psoriasis has not been elucidated yet, even if emerging evidence demonstrated that interleukin-17A (IL-17A), the psoriasis-related principal cytokine, modifies EVs release and cargo content. The aim of this work was to analyze whether, besides IL-17A, other psoriasis-related cytokines (ie, IFN-γ, TNF-α, IL-22 and IL-23) could affect EVs release and their AMPs mRNAs cargo as well as to analyze the potential biological effect due to EVs internalization by different acceptor cells., Methods: Nanoparticle tracking analysis (NTA) was performed on supernatants of HaCaT cells stimulated with IL-17A, IFN-γ, TNF-α, IL-22 or IL-23 to enumerate EVs. Real-Time RT-PCR was used for gene expression analysis in cells and EVs. Confocal microscopy and Flow cytometry were used to, respectively, study Netosis and EVs internalization., Results: IL-17A and IFN-γ increased EVs release by HaCaT cells. All the tested cytokines modulated AMPs mRNA expression in parental cells and in their respective EVs. S100A12 and hBD2 mRNAs were upregulated following IL-17A and IL-22 treatments. Interestingly, EVs derived from cytokine treated HaCaT cells induced Netosis in freshly isolated neutrophils. Upregulation of S100A12 and hBD2 mRNA was also detectable in acceptor cells incubated with EVs derived from cells treated with psoriasis-related cytokines., Conclusion: The obtained results highlighted the role of EVs in the composition of psoriasis-associated secretome and microenvironment also suggesting the EV involvement in the spreading of the disease mediators and in the possible associated comorbidities., Competing Interests: The authors report no conflicts of interest in this work., (© 2022 Capriotti et al.)

The beneficial effects of bergamot polyphenolic fraction (BPF) on the mitochondrial bioenergetics of porcine aortic endothelial cells (pAECs) were verified under the cardiotoxic action of doxorubicin (DOX). The cell viability of pAECs treated for 24 h with different concentrations of DOX was reduced by 50%, but the negative effect of DOX was reversed in the presence of increasing doses of BPF (100 µg/mL and 200 µg/mL BPF). An analysis of the protective effect of BPF on the toxic action of DOX was also carried out on cell respiration. We observed the inhibition of the mitochondrial activity at 10 µM DOX, which was not restored by 200 µg/mL BPF. Conversely, the decrease in basal respiration and ATP production caused by 0.5 or 1.0 µM DOX were improved in the presence of 100 or 200 µg/mL BPF, respectively. After 24 h of cell recovery with 100 µg/mL or 200 µg/mL BPF on pAECs treated with 0.5 µM or 1.0 µM DOX, respectively, the mitochondrial parameters of oxidative metabolism impaired by DOX were re-boosted.

Systemic sclerosis (SSc) is a systemic autoimmune disease in which gastrointestinal disorders represent a complication in up to 90% of patients. SSc may associate with thyroid autoimmune disorders, with Hashimoto's thyroiditis (HT) being the more prevalent worldwide. Previous studies have examined the behavior of Th17 lymphocytes and Breg cells in patients with HT and concomitant autoimmune organ-specific disorders. These immune phenotypes seem to play a significant role in the pathogenesis of both these autoimmune processes, but their behavior when these two disorders coexist has not been described. We analyzed Th17 and Breg (CD24hiCD38hi) cell subsets in 50 subjects (45F/5M; median age = 49 years): 18 were healthy donors (HD), 20 had isolated HT, and 12 had SSc, seven of whom had both HT and SSc. Breg cells' function was also evaluated by measuring their IL-10 production when stimulated by specific activators. An increased percentage of Th17 lymphocytes characterized HT patients as compared to both HD and the whole group of SSc patients (p = 0.0018). On the contrary, the percentage of unstimulated Breg cells in SSc patients was higher (p = 0.0260), either associated or not with HT, as compared to both HT patients and HD, which, instead, showed a similar percentage of Breg cells. Following a specific stimulation with CpG, the percentages of Breg cells were increased in the whole sample of SSc patients (p < 0.001) as well as in isolated SSc and in SSc+HT ones as compared to isolated HT. However, qualitative analysis, obtained through the detection of the IL-10-producing phenotype, revealed that the percentage of CpG-stimulated CD24hiCD38hi-IL10+cells was significantly decreased in SSc patients (p < 0.0001) with no difference between isolated SSc and SSc+HT patients. The IL-10-producing phenotype was instead slightly increased in HT patients as compared to HD (4.1% vs. 2.8%). The presence of SSc seems to be characterized by an enrichment of total Breg cells but by a reduced Breg IL-10-producing phenotype, representing functional Bregs. This last finding was entirely due to the presence of SSc independently from the association with HT. This behavior is different from the ones described about the association of HT with organ-specific autoimmune disorders., 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 © 2022 Capriello, Ferrari, Gatto, Santaguida, Fallahi, Antonelli, Mangino, Romeo, Virili and Centanni.)

Background: The β3 human papillomavirus (HPV)49 induces immortalization of primary keratinocytes through the action of E6 and E7 oncoproteins with an efficiency similar to alpha high risk (HR)-HPV16. Since HR-HPV oncoproteins are known to alter microRNA (miRNA) expression and extracellular vesicle (EV) production, we investigated the impact of HPV49 E6 and E7 proteins on miRNA profile and EV expression, and their involvement in the control of cell proliferation., Methods: The miRNA expression was evaluated by a miRNA array and validated by RT-qPCR in primary human keratinocytes immortalized by β3 HPV49 (K49) or α9 HR-HPV16 (K16), and in EVs from K49 and K16. The modulation of miRNA target proteins was investigated by immunoblotting analyses., Results: By comparing miRNA expression in K49 and K16 and the derived EVs, six miRNAs involved in HPV tumorigenesis were selected and validated. MiR-19a and -99a were found to be upregulated and miR-34a downregulated in both cell lines; miR-17 and -590-5p were upregulated in K49 and downmodulated in K16; miR-21 was downregulated only in K16. As for EV-carried miRNAs, the expression of miR-17, -19a, -21 and -99a was decreased and miR-34a was increased in K49 EVs. In K16 EVs, we revealed the same modulation of miR-19a, -34a, and -99a observed in producing cells, while miR-21 was upregulated. Cyclin D1, a common target of the selected miRNAs, was downmodulated in both cell lines, whereas cyclin-dependent kinase 4 was down-modulated in K49 but upregulated in K16., Conclusion: These data suggest that E6 and E7 proteins of β3 HPV49 and α9 HR-HPV16 affect key factors of cell cycle control by indirect mechanisms based on miRNA modulation., (© 2022. The Author(s).)

There is an ever-increasing patient demand for an esthetic and ultraconservative approach in the restoration of anterior teeth. No-prep veneers are one of the most conservative methods of rehabilitation in esthetic dentistry. To implement the no-prep veneer technique successfully, it is essential to adhere to an analytical treatment concept. In the present case report, despite the fact that some of the veneers were very thin, they could be designed in a nature-identical manner in terms of light dynamics and color. The laboratory technique presented in this article opens up the possibility of modifying and harmonizing tooth shapes and gingival margin contours, and makes it possible to position the prosthetic termination line at different levels without affecting the marginal and interproximal adaptation of the restoration.

The term ferroptosis refers to a peculiar type of programmed cell death (PCD) mainly characterized by extensive iron-dependent lipid peroxidation. Recently, ferroptosis has been suggested as a potential new strategy for the treatment of several cancers, including breast cancer (BC). In particular, among the BC subtypes, triple negative breast cancer (TNBC) is considered the most aggressive, and conventional drugs fail to provide long-term efficacy. In this context, our study's purpose was to investigate the mechanism of ferroptosis in breast cancer cell lines and reveal the significance of heme oxygenase (HO) modulation in the process, providing new biochemical approaches. HO's effect on BC was evaluated by MTT tests, gene silencing, Western blot analysis, and measurement of reactive oxygen species (ROS), glutathione (GSH) and lipid hydroperoxide (LOOH) levels. In order to assess HO's implication, different approaches were exploited, using two distinct HO-1 inducers (hemin and curcumin), a well-known HO inhibitor (SnMP) and a selective HO-2 inhibitor. The data obtained showed HO's contribution to the onset of ferroptosis; in particular, HO-1 induction seemed to accelerate the process. Moreover, our results suggest a potential role of HO-2 in erastin-induced ferroptosis. In view of the above, HO modulation in ferroptosis can offer a novel approach for breast cancer treatment.

This paper reports on a novel series of tyrosine kinase inhibitors (TKIs) potentially useful for the treatment of chronic myeloid leukemia (CML). The newly designed and synthesized compounds are structurally related to nilotinib (NIL), a second-generation oral TKI, and to a series of imatinib (IM)-based TKIs, previously reported by our research group, these latter characterized by a hybrid structure between TKIs and heme oxygenase-1 (HO-1) inhibitors. The enzyme HO-1 was selected as an additional target since it is overexpressed in many cases of drug resistance, including CML. The new derivatives 1a - j correctly tackle the chimeric protein BCR-ABL. Therefore, the inhibition of TK was comparable to or higher than NIL and IM for many novel compounds, while most of the new analogs showed only moderate potency against HO-1. Molecular docking studies revealed insights into the binding mode with BCR-ABL and HO-1, providing a structural explanation for the differential activity. Cytotoxicity on K562 CML cells, both NIL-sensitive and -resistant, was evaluated. Notably, some new compounds strongly reduced the viability of K562 sensitive cells.

The bergamot polyphenolic fraction (BPF) was evaluated in the F 1 F O -ATPase activity of swine heart mitochondria. In the presence of a concentration higher than 50 µg/mL BPF, the ATPase activity of F 1 F O -ATPase, dependent on the natural cofactor Mg 2+ , increased by 15%, whereas the enzyme activity in the presence of Ca 2+ was inhibited by 10%. By considering this opposite BPF effect, the F 1 F O -ATPase activity involved in providing ATP synthesis in oxidative phosphorylation and triggering mitochondrial permeability transition pore (mPTP) formation has been evaluated. The BPF improved the catalytic coupling of oxidative phosphorylation in the presence of a substrate at the first phosphorylation site, boosting the respiratory control ratios (state 3/state 4) by 25% and 85% with 50 µg/mL and 100 µg/mL BPF, respectively. Conversely, the substrate at the second phosphorylation site led to the improvement of the state 3/state 4 ratios by 15% only with 100 µg/mL BPF. Moreover, the BPF carried out its beneficial effect on the mPTP phenomenon by desensitizing the pore opening. The acute effect of the BPF on the metabolism of porcine aortica endothelial cells (pAECs) showed an ATP rate index greater than one, which points out a prevailing mitochondrial oxidative metabolism with respect to the glycolytic pathway, and this ratio rose by about three times with 100 µg/mL BPF. Consistently, the mitochondrial ATP turnover, in addition to the basal and maximal respiration, were higher in the presence of the BPF than in the controls, and the MTT test revealed an increase in cell viability with a BPF concentration above 200 µg/mL. Therefore, the molecule mixture of the BPF aims to ensure good performance of the mitochondrial bioenergetic parameters.

Background: Phlebotomine sand flies are known as vectors of various pathogens such as Leishmania sp parasite and Toscana virus (TOSV). Leishmaniasis is endemic in Morocco, and TOSV is increasingly reported. Our objective is to analyze the specific composition of the natural population of sand flies in endemic and non endemic area of leishmaniasis in Morocco, thus evaluated their infection by Toscana virus., Methods: Sand flies were collected by CDC miniature light traps from seven different localities with an altitude range from 399 m to 1496 m. Synanthropic index was calculated for each sand fly species. The collected female sand flies were grouped in 73 pools, with a maximum of 50 specimens per pool, and submitted to real time PCR for TOSV detection., Results: 8 sand fly species were identified morphologically: 5 of the Phlebotomus genus and 3 of the Sergentomyia genus. Phlebotomus sergenti was the most abundant species comprising of 43,12% of identified sand flies, followed by P. papatasi (18,89%) and P. longicuspis (13,43%). Estimated synanthropic indices for these species were between + 1.1 and + 12.6 suggesting a high preference to anthropogenic environments. A total of 3558 sand fly females were grouped in 73 pools (up to 50 sand flies per pool) for TOSV detection. TOSV was detected in one pool (out of 6 tested) from Lalla Laaziza locality (Chichaoua Province) where P. sergenti was the most abundant sand fly species., Conclusion: We reported the TOSV for the first time in a central Morocco, where cutaneous leishmaniasis by L. tropica is endemic. This result has epidemiological importance for both researchers and health authorities to monitor circulation of TOSV and implement a surveillance plan of sand fly-borne phleboviruses in Morocco., Competing Interests: Conflicts of interest/Competing interests There are no conflicts to declare., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The host preference of hematophagous insects is important in determining the cycle of pathogens that they potentially transmit; for example, sand flies are competent vectors of Leishmania parasites. In this work, we evaluated the host preference of sand flies collected in the Emilia-Romagna region of Italy in 2018 and 2019 in an area in which Leishmania infantum circulates actively. Out of about 30,000 sampled sand flies, we obtained 252 engorged females, which were processed to identify the sources of blood meals. Sampling data collected confirmed a positive phototropism of Phlebotomus (Ph.) perfiliewi respect to Ph. perniciosus and the enhanced efficiency of light traps in collecting engorged females compared with traps baited with carbon dioxide. We identified blood source in 185 females (183 Ph. perfiliewi, two Ph. pernicious). The most bitten animal was the roe deer (49.5%), followed by humans (29.2%), hare (7.1%) and cow (4.7%). Other animals, including wild boar, horse, donkey, porcupine, chicken and red fox, were less represented (<2%), while the blood of dogs and rodents were not detected. In addition, we singly screened engorged females for Leishmania founding 5 positive specimens, fed on roe deer (4) and man (1), providing evidence of parasite circulation in a sylvatic environment, where presence of dogs was not common. These findings suggest the existence of an uncharacterized Leishmania reservoir in the surveyed area., (Copyright © 2021. Published by Elsevier B.V.)

Non-alcoholic fatty liver disease (NAFLD) is currently a growing epidemic disease that can lead to cirrhosis and hepatic cancer when it evolves into non-alcoholic steatohepatitis (NASH), a gap not well understood. To characterize this disease, pigs, considered to be one of the most similar to human experimental animal models, were used. To date, all swine-based settings have been carried out using rare predisposed breeds or long-term experiments. Herein, we fully describe a new experimental swine model for initial and reversible NASH using cross-bred animals fed on a high saturated fat, fructose, cholesterol, cholate, choline and methionine-deficient diet. To gain insight into the hepatic transcriptome that undergoes steatosis and steatohepatitis, we used RNA sequencing. This process significantly up-regulated 976 and down-regulated 209 genes mainly involved in cellular processes. Gene expression changes of 22 selected transcripts were verified by RT-qPCR. Lipid droplet area was positively associated with CD68, GPNMB, LGALS3, SLC51B and SPP1, and negatively with SQLE expressions. When these genes were tested in a second experiment of NASH reversion, LGALS3, SLC51B and SPP1 significantly decreased their expression. However, only LGALS3 was associated with lipid droplet areas. Our results suggest a role for LGALS3 in the transition of NAFLD to NASH., (© 2022. The Author(s).)

Neuropathic pain is a significant problem with few effective treatments lacking adverse effects. The sigma-1 receptor (S1R) is a potential therapeutic target for neuropathic pain, as antagonists for this receptor effectively ameliorate pain in both preclinical and clinical studies. The current research examines the antinociceptive and anti-allodynic efficacy of SI 1/28, a recently reported benzylpiperazine derivative and analog of the S1R antagonist SI 1/13, that was 423-fold more selective for S1R over the sigma-2 receptor (S2R). In addition, possible liabilities of respiration, sedation, and drug reinforcement caused by SI 1/28 have been evaluated. Inflammatory and chemical nociception, chronic nerve constriction injury (CCI) induced mechanical allodynia, and adverse effects of sedation in a rotarod assay, conditioned place preference (CPP), and changes in breath rate and locomotor activity were assessed after i.p. administration of SI 1/28. Pretreatment with SI 1/28 produced dose-dependent antinociception in the formalin test, with an ED 50 (and 95% C.I.) value of 13.2 (7.42-28.3) mg/kg, i.p. Likewise, SI 1/28 produced dose-dependent antinociception against visceral nociception and anti-allodynia against CCI-induced neuropathic pain. SI 1/28 demonstrated no impairment of locomotor activity, conditioned place preference, or respiratory depression. In summary, SI 1/28 proved efficacious in the treatment of acute inflammatory pain and chronic neuropathy without liabilities at therapeutic doses, supporting the development of S1R antagonists as therapeutics for chronic pain.

The Van Allen Probes mission operations materialized through a distributed model in which operational responsibility was divided between the Mission Operations Center (MOC) and separate instrument specific SOCs. The sole MOC handled all aspects of telemetering and receiving tasks as well as certain scientifically relevant ancillary tasks. Each instrument science team developed individual instrument specific SOCs proficient in unique capabilities in support of science data acquisition, data processing, instrument performance, and tools for the instrument team scientists. In parallel activities, project scientists took on the task of providing a significant modeling tool base usable by the instrument science teams and the larger scientific community. With a mission as complex as Van Allen Probes, scientific inquiry occurred due to constant and significant collaboration between the SOCs and in concert with the project science team. Planned cross-instrument coordinated observations resulted in critical discoveries during the seven-year mission. Instrument cross-calibration activities elucidated a more seamless set of data products. Specific topics include post-launch changes and enhancements to the SOCs, discussion of coordination activities between the SOCs, SOC specific analysis software, modeling software provided by the Van Allen Probes project, and a section on lessons learned. One of the most significant lessons learned was the importance of the original decision to implement individual team SOCs providing timely and well-documented instrument data for the NASA Van Allen Probes Mission scientists and the larger magnetospheric and radiation belt scientific community., (© The Author(s) 2022.)

Aim: Considering ileocolic resection as a surgical standard for the treatment of ileocecal valve Crohn's disease, we propose a limited resection of the terminal ileum and ileocecal valve with ileocecal anastomosis., Material of Study: Three patiens between 20 and 37 years of age, diagnosed with Crohn's disease unresponsive to medical therapy, who have stenoses or fissures confined to the terminal ileum and ileocecal valve, seen during instrumental investigations., Results: The proposed procedure allowed us to perform a minimal resection and reconstruction of a new ileocecal valve. Once the symptoms have resolved, at endoscopic follow ups, at 6 and 12 months after surgery, there were no changes in the mucosa of the ileocecal neo-anastomosis., Discussion: Since Crohn's disease is a systemic disease with a chronic relapsing course complicated by a high rate of post-surgical relapses, it is essential to limit the extension of resections to the macroscopically involved tissues and reduce the anastomotic surfaces. The proposed surgical procedure allows to preserve the caecum and the colon with an optimal postoperative course., Conclusion: We believe that, with specific clinical and endoscopic conditions, the treatment we illustrated can be proposed to other patients as an alternative to the standard VL ileocolic resection., Key Words: Crohn's Disease, Ileocaecal Valve, Ileocaecal Anastomosis.

The development of potent antitumor agents with a low toxicological profile against healthy cells is still one of the greatest challenges facing medicinal chemistry. In this context, the "mutual prodrug" approach has emerged as a potential tool to overcome undesirable physicochemical features and mitigate the side effects of approved drugs. Among broad-spectrum chemotherapeutics available for clinical use today, 5-fluorouracil (5-FU) is one of the most representative, also included in the World Health Organization model list of essential medicines. Unfortunately, severe side effects and drug resistance phenomena are still the primary limits and drawbacks in its clinical use. This review describes the progress made over the last ten years in developing 5-FU-based mutual prodrugs to improve the therapeutic profile and achieve targeted delivery to cancer tissues., (© 2021 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

Between 1988 and 2007, during the courses of the European School of Genetic Medicine, many of us had the opportunity to appreciate the tolerant and open-minded personality of Victor McKusick. He was gifted with a unique foresight for the innovations introduced into medicine through the development of the Human Genome Project. The aim of our separate contributions in this article is to document how his insights had an important impact on the European medical training system., (© 2021 Wiley Periodicals LLC.)

Objectives: to assess the extent of the excess mortality from all causes in 2020 compared to 2015-2019 in Central Tuscany (Italy) as a proxy to estimate COVID-19-related excess mortality and to identify demographic and clinical differences between subjects who died from COVID-19 and those who died from other causes in 2020., Design: descriptive analysis of the temporal trend of general mortality., Setting and Participants: the study population is represented by the 1.6 million residents living in the territory of the Central Tuscany Healthcare Authority in Central Italy, i.e., little less than half of the population of Tuscany, in an area of just over one fifth of the entire region, where the provinces of Florence, Pistoia, and Prato are comprised. MAIN OUTCOME MEASURES: using the Italian National Resident Population Registry (ANPR) as a source of mortality data, standardized mortality ratios with 95% confidence intervals were calculated to compare the number of deaths in 2020 with the number of deaths expected on the basis of mortality data from 2015 to 2019. Furthermore, after record linkage with data from the integrated surveillance of cases of SARS-CoV-2 virus infection and with the MaCro dataset of comorbidities, the characteristics of subjects who died from COVID-19 were compared with those of patients who died from other causes using a multivariate logistic regression model; odds ratios with 95% confidence intervals were calculated., Results: a statistically significant excess mortality was observed during the first pandemic wave in March and April, and during the second wave in the fall; it ranged between +9% in March and +51% in November. On the contrary, in January, February, and May, all-cause mortality was significantly lower than in previous years. The male gender, dyslipidaemia, and dementia were positively associated with death from COVID-19 rather than from all other causes. On the contrary, heart failure and recent tumours were more represented among deaths from other causes. CONCLUSIONS: much of the over-mortality observed in spring is attributable to the harvesting effect COVID-19 exerted on a segment of population with serious underlying chronic conditions and who in the previous months had survived a mild winter and a flu season of medium intensity. In the second pandemic wave, in autumn, the impact of both direct and indirect effects of COVID-19 was substantially higher. Consistently with the available evidence, death from COVID-19 was related to the male gender and to clinical conditions such as dyslipidaemia and dementia.

Oncogenic viruses favor the development of tumors in mammals by persistent infection and specific cellular pathways modifications by deregulating cell proliferation and inhibiting apoptosis. They counteract the cellular antiviral defense through viral proteins as well as specific cellular effectors involved in virus-induced tumorigenesis. Type I interferons (IFNs) are a family of cytokines critical not only for viral interference but also for their broad range of properties that go beyond the antiviral action. In fact, they can inhibit cell proliferation and modulate differentiation, apoptosis, and migration. However, their principal role is to regulate the development and activity of most effector cells of the innate and adaptive immune responses. Various are the mechanisms by which IFNs exert their effects on immune cells. They can act directly, through IFN receptor triggering, or indirectly by the induction of chemokines, the secretion of further cytokines, or by the stimulation of cells useful for the activation of particular immune cells. All the properties of IFNs are crucial in the host defense against viruses and bacteria, as well as in the immune surveillance against tumors. IFNs may be affected by and, in turn, affect signaling pathways to mediate anti-proliferative and antiviral responses in virus-induced tumorigenic context. New data on cellular and viral microRNAs (miRNAs) machinery, as well as cellular communication and microenvironment modification via classical secretion mechanisms and extracellular vesicles-mediated delivery are reported. Recent research is reviewed on the tumorigenesis induced by specific viruses with RNA or DNA genome, belonging to different families (i.e., HPV, HTLV-1, MCPyV, JCPyV, Herpesviruses, HBV, HCV) and the IFN system involvement.

Background: Due to a substantial decline in pancreas transplantation (PT) across the United States over the past 15 years, we sought to understand the perceptions and practices of US PT programs., Methods: Surveys were sent to members of the American Society of Transplantation Surgeons and the American Society of Transplantation by email and professional society postings between August 2019 and November 2019., Results: One hundred twenty three responses were recorded from 56 unique programs. Program characteristics were obtained from the Scientific Registry of Transplant Recipients. Respondents were transplant surgeons (71%), transplant nephrologists (17%), trainees (9%), and allied professionals (3%). Programs were defined according to annual volume as: low (<5 PT/year), intermediate (6-20), or high (>20). High-volume programs reported that these factors were most important for increased PT: expansion of recipient selection, more aggressive donor utilization, and hiring of PT program-specific personnel. At both the program and national level, the vast majority (82% and 79%, respectively) felt the number of PTs currently performed are not in balance with patients' needs., Conclusions: Overall, programs reported that the option of PT is not offered adequately to diabetic patients and that strategies to maintain higher PT volume are most evident at intermediate, and especially, high-volume programs., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Heme oxygenase-1 (HO-1) promotes heme catabolism exercising cytoprotective roles in normal and cancer cells. Herein, we report the design, synthesis, molecular modeling, and biological evaluation of novel HO-1 inhibitors. Specifically, an amide linker in the central spacer and an imidazole were fixed, and the hydrophobic moiety required by the pharmacophore was largely modified. In many tumors, overexpression of HO-1 correlates with poor prognosis and chemoresistance, suggesting the inhibition of HO-1 as a possible antitumor strategy. Accordingly, compounds 7i and 7l - p emerged for their potency against HO-1 and were investigated for their anticancer activity against prostate (DU145), lung (A549), and glioblastoma (U87MG, A172) cancer cells. The selected compounds showed the best activity toward U87MG cells. Compound 7l was further investigated for its in-cell enzymatic HO-1 activity, expression levels, and effects on cell invasion and vascular endothelial growth factor (VEGF) extracellular release. The obtained data suggest that 7l can reduce cell invasivity acting through modulation of HO-1 expression.