Role of the Microbiota in Skin Neoplasms: New Therapeutic Horizons

The skin and the gut are regularly colonized by a variety of microorganisms capable of interacting with the immune system through their metabolites and influencing the balance between immune tolerance and inflammation. Alterations in the composition and diversity of the skin microbiota have been described in various cutaneous diseases, including skin cancer, and the actual function of the human microbiota in skin carcinogenesis, such as in progression and metastasis, is currently an active area of research. The role of Human Papilloma Virus (HPV) in the pathogenesis of squamous cell carcinoma is well consolidated, especially in chronically immunosuppressed patients. Furthermore, an imbalance between Staphylococcus spp., such as Staphylococcus epidermidis and aureus, has been found to be strongly related to the progression from actinic keratosis to squamous cell carcinoma and differently associated with various stages of the diseases in cutaneous T-cell lymphoma patients. Also, in melanoma patients, differences in microbiota have been related to dissimilar disease course and prognosis and may affect the effectiveness and tolerability of immune checkpoint inhibitors, which currently represent one of the best chances of a cure. From this point of view, acting on microbiota can be considered a possible therapeutic option for patients with advanced skin cancers, even if several issues are still open

Probiotics-addicted low-protein diet for microbiota modulation in patients with advanced chronic kidney disease (ProLowCKD): A protocol of placebo-controlled randomized trial

Abstract Microbiota is a term coined to describe the population of bacteria, viruses and fungi that inhabit in symbiosis within a living host. A connection between unbalanced microbiota and chronic kidney disease has been established. In these patients, high levels of urea reach the intestine promoting the overgrowth of bacterial species that are prone to generate uremic toxins. Due to the high morbidity and mortality of this condition, a large number of therapeutic approaches to reduce inflammation and microbial uremic toxins have been proposed, with controversial results. A low protein diet, with a protein intake of 0.6–0.8 g/kg of body weight, is a useful and historically pursued option with this regard. The aim of our study is to evaluate, among patients with advanced renal failure not on dialysis, the synergic beneficial effects of this diet and the selected probiotics Bifidobacterium longum (mix DLBL) and Lactobacillus reuteri LRE02 (DSM 23878)

In Vitro Selection of Lactobacillus and Bifidobacterium Probiotic Strains for the Management of Oral Pathobiont Infections Associated to Systemic Diseases

: The human oral pathobionts Aggregatibacter actinomycetemcomitans, Streptococcus mitis and Streptococcus mutans, in dysbiosis-promoting conditions, lead to oral infections, which also represent a threat to human systemic health. This scenario may be worsened by antibiotic misuse, which favours multi-drug resistance, making the research on pathogen containment strategies more than crucial. Therefore, we aimed to in vitro select the most promising probiotic strains against oral pathogen growth, viability, biofilm formation, and co-aggregation capacity, employing both the viable probiotics and their cell-free supernatants (CFSs). Interestingly, we also assessed probiotic efficacy against the three-pathogen co-culture, mimicking an environment similar to that in vivo. Overall, the results showed that Lactobacillus CFSs performed better than the Bifidobacterium, highlighting Limosilactobacillus reuteri LRE11, Lacticaseibacillus rhamnosus LR04, Lacticaseibacillus casei LC04, and Limosilactobacillus fermentum LF26 as the most effective strains, opening the chance to deeper investigation of their action and CFS composition. Altogether, the methodologies presented in this study can be used for probiotic efficacy screenings, in order to better focus the research on a viable probiotic, or on its postbiotics, suitable in case of infections

Effects of Probiotics Administration on Human Metabolic Phenotype

The establishment of the beneficial interactions between the host and its microbiota is essential for the correct functioning of the organism, since microflora alterations can lead to many diseases. Probiotics improve balanced microbial communities, exerting substantial healthpromoting effects. Here we monitored the molecular outcomes, obtained by gut microflora modulation through probiotic treatment, on human urine and serum metabolic profiles, with a metabolomic approach. Twenty-two subjects were enrolled in the study and administered with two different probiotic types, both singularly and in combination, for 8 weeks. Urine and serum samples were collected before and during the supplementation and were analyzed by nuclear magnetic resonance (NMR) spectroscopy and statistical analyses. After eight weeks of treatment, probiotics deeply influence the urinary metabolic profiles of the volunteers, without significantly altering their single phenotypes. Anyway, bacteria supplementation tends to reduce the differences in metabolic phenotypes among individuals. Overall, the effects are recipient-dependent, and in some individuals, robust effects are already well visible after four weeks. Modifications in metabolite levels, attributable to each type of probiotic administration, were also monitored. Metabolomic analysis of biofluids turns out to be a powerful technique to monitor the dynamic interactions between the microflora and the host, and the individual response to probiotic assumption

Outcomes of music therapy interventions in cancer patients. A review of the literature

Background: Effectiveness of music-based interventions (MI) on cancer patients\u2019 anxiety, depression, pain and quality of life (QoL) is a current research theme. MI are highly variable, making it challenging to compare studies. Objective and methods: To summarize the evidence on MI in cancer patients, 40 studies were reviewed following the PRISMA statement. Studies were included if assessing at least one outcome among anxiety, depression, QoL and pain in patients aged 65 18, with an active oncological/onco-haematological diagnosis, participating to any kind of MT, during/after surgery, chemotherapy or radiotherapy. Results: A positive effect of MI on the outcomes measured was supported. Greater reductions of anxiety and depression were observed in breast cancer patients. MI involving patients admitted to a hospital ward were less effective on QoL. Conclusion: The increasing evidence about MI effectiveness, tolerability, feasibility and appreciation, supports the need of MI implementation in Oncology, Radiotherapy and Surgery wards, and promotion of knowledge among health operators

Role of the co-stimulatory molecule inducible T-cell co-stimulator ligand (ICOSL) in the progression of experimental metabolic dysfunction-associated steatohepatitis

Background and aimsInducible T-cell Co-Stimulator (ICOS) present on T-lymphocytes and its ligand ICOSL expressed by myeloid cells play multiple roles in regulating T-cell functions. However, recent evidence indicates that reverse signalling involving ICOSL is also important in directing the differentiation of monocyte-derived cells. In this study, we investigated the involvement of ICOS/ICOSL dyad in modulating macrophage functions during the evolution of metabolic dysfunction-associated steatohepatitis (MASH).ResultsIn animal models of MASH, ICOS was selectively up-regulated on CD8+ T-cells in parallel with an expansion of ICOSL-expressing macrophages. An increase in circulating soluble ICOSL was also evident in patients with MASH as compared to healthy individuals. ICOSL knockout (ICOSL-/-) mice receiving choline/methionine deficient (MCD) diet for 6 weeks had milder steatohepatitis than wild type mice. MASH improvement was confirmed in mice fed with cholesterol-enriched Western diet for 24 weeks in which ICOSL deficiency greatly reduced liver fibrosis along with the formation of crown-like macrophage aggregates producing the pro-fibrogenic mediators osteopontin (OPN) and galectin-3 (Gal-3). These effects associated with a selective shewing of F4-80+/CD11bhigh monocyte-derived macrophages (MoMFs) expressing the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) to CD11blow/F4-80+ cells positive for the Kupffer cell marker C-type lectin-like type 2 receptor (CLEC-2), thus indicating an increased MoMF maturation toward monocyte-derived Kupffer cells.ConclusionsThese results suggest that CD8+ T-cells interaction with monocyte-derived macrophages through ICOS/ICOSL critically supports a specific subset of TREM2+-expressing cells contributing to the evolution of steatohepatitis. The data also point ICOS/ICOSL dyad as a possible target for therapeutic interventions in MASH

Extracellular vesicles from human plasma for biomarkers discovery: Impact of anticoagulants and isolation techniques

Extracellular vesicles (EVs) isolated from plasma are increasingly recognized as promising circulating biomarkers for disease discovery and progression, as well as for therapeutic drug delivery. The scientific community underlined the necessity of standard operative procedures for the isolation and storage of the EVs to ensure robust results. The understanding of the impact of the pre-analytical variables is still limited and some considerations about plasma anticoagulants and isolation methods are necessary. Therefore, we performed a comparison study between EVs isolated by ultracentrifugation and by affinity substrate separation from plasma EDTA and sodium citrate. The EVs were characterized by Nano Tracking Analysis, Western Blot, cytofluorimetric analysis of surface markers, and lipidomic analysis. While anticoagulants did not significantly alter any of the analyzed parameters, the isolation methods influenced EVs size, purity, surface markers expression and lipidomic profile. Compared to ultracentrifugation, affinity substrate separation yielded bigger particles highly enriched in tetraspanins (CD9, CD63, CD81), fatty acids and glycerolipids, with a predominant LDL- and vLDL-like contamination. Herein, we highlighted that the isolation method should be carefully evaluated prior to study design and the need of standardized operative procedures for EVs isolation and application to biomarkers discovery

Delay of neuropathic pain sensitization after application of dexamethasone-loaded implant in sciatic nerve-injured rats

Neuroimmune interactions underlying the development of pain sensitization in models of neuropathic pain have been widely studied. In this study, we evaluated the development of allodynia and its reduction associated with peripheral antineuroinflammatory effects induced by a dexamethasone-loaded biodegradable implant. Chronic constriction injury (CCI) of the sciatic nerve was performed in Wistar rats. The electronic von Frey test was applied to assess mechanical allodynia. The dexamethasone-loaded implant was placed perineurally at the moment of CCI or 12 days after surgery. Dorsal root ganglia (DRG; L4-L5) were harvested and nuclear extracts were assayed by Western blot for detection of nuclear factor (NF)-κB p65/RelA translocation. Dexamethasone delivered from the implant delayed the development of allodynia for approximately three weeks in CCI rats when the implantation was performed at day 0, but allodynia was not reversed when the implantation was performed at day 12. NF-κB was activated in CCI rat DRG compared with naïve or sham animals (day 15), and dexamethasone implant inhibited p65/ RelA translocation in CCI rats compared with control. This study demonstrated that the dexamethasoneloaded implant suppresses allodynia development and peripheral neuroinflammation. This device can reduce the potential side effects associated with oral anti-inflammatory drugs

Determinants of long COVID among adults hospitalized for SARS-CoV-2 infection: A prospective cohort study

Rationale: Factors associated with long-term sequelae emerging after the acute phase of COVID-19 (so called "long COVID") are unclear. Here, we aimed to identify risk factors for the development of COVID-19 sequelae in a prospective cohort of subjects hospitalized for SARS-CoV-2 infection and followed up one year after discharge. Methods: A total of 324 subjects underwent a comprehensive and multidisciplinary evaluation one year after hospital discharge for COVID-19. A subgroup of 247/324 who consented to donate a blood sample were tested for a panel of circulating cytokines. Results: In 122 patients (37.8%) there was evidence of at least one persisting physical symptom. After correcting for comorbidities and COVID-19 severity, the risk of developing long COVID was lower in the 109 subjects admitted to the hospital in the third wave of the pandemic than in the 215 admitted during the first wave, (OR 0.69, 95%CI 0.51-0.93, p=0.01). Univariable analysis revealed female sex, diffusing capacity of the lungs for carbon monoxide (DLCO) value, body mass index, anxiety and depressive symptoms to be positively associated with COVID-19 sequelae at 1 year. Following logistic regression analysis, DLCO was the only independent predictor of residual symptoms (OR 0.98 CI 95% (0.96-0.99), p=0.01). In the subgroup of subjects with normal DLCO (> 80%), for whom residual lung damage was an unlikely explanation for long COVID, the presence of anxiety and depressive symptoms was significantly associated to persistent symptoms, together with increased levels of a set of pro-inflammatory cytokines: interferon-gamma, tumor necrosis factor-alpha, interleukin (IL)-2, IL-12, IL-1β, IL-17. In logistic regression analysis, depressive symptoms (p=0.02, OR 4.57 [1.21-17.21]) and IL-12 levels (p=0.03, OR 1.06 [1.00-1.11]) 1-year after hospital discharge were independently associated with persistence of symptoms. Conclusions: Long COVID appears mainly related to respiratory sequelae, prevalently observed during the first pandemic wave. Among patients with little or no residual lung damage, a cytokine pattern consistent with systemic inflammation is in place