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Lactobacillus gasseri SF1183 belongs to a subpopulation of bacteria tightly associated to the human ileal epithelium. Cells of SF1183 survive and grow in simulated intestinal and gastric conditions, have a strong antimicrobial activity against Gram-positives and Gram-negatives and secrete molecule(s) sensed by human intestinal cells. We report that the oral administration of SF1183 cells had a protective effect in a murine model of DSS (Dextran-Sulfate-Sodium)-induced colitis. The analysis of the intestinal microbial composition indicated that several bacterial genera were differently represented in the intestine of DSS-treated animals. An overall similar alteration was observed in the microbiota of DSS-treated animals that received SF1183, suggesting that the beneficial role of the probiotic was not played through a reshuffling of the intestinal flora. Based on our in vivo data we propose the SF1183 strain of L. gasseri as a new anti-inflammatory probiotic, potentially useful as a therapeutic agent for the treatment of IBDs. more...

Objective: The link between metabolic derangement of the gut–2013liver–visceral white adipose tissue (v-WAT) axis and gut microbiota was investigated. Methods: Rats were fed a fructose-rich diet and treated with an antibiotic mix. Inflammation was measured in portal plasma, ileum, liver, and v-WAT, while insulin signalling was analysed by measuring levels of phosphorylated kinase Akt. The function and oxidative status of hepatic mitochondria and caecal microbiota composition were also evaluated. Results: Ileal inflammation, increase in plasma transaminases, plasma peroxidised lipids, portal concentrations of tumour necrosis factor alpha, lipopolysaccharide, and non-esterified fatty acids, were induced by fructose and were reversed by antibiotic. The increased hepatic ceramide content, inflammation and decreased insulin signaling in liver and v-WAT induced by fructose was reversed by antibiotic. Antibiotic also blunted the increase in hepatic mitochondrial efficiency and oxidative damage of rats fed fructose-rich diet. Three genera, Coprococcus, Ruminococcus, and Clostridium, significantly increased, while the Clostridiaceae family significantly decreased in rats fed a fructose-rich diet, and antibiotic abolished these variations Conclusions: When gut microbiota modulation by fructose is prevented by antibiotic, inflamma- tory flow from the gut to the liver and v-WAT are reversed. more...

The link between increased fructose intake and induction of gut and liver dysfunction has been established, while it remains to be understood whether this damage is reversible, particularly in the young population, in which the intake of fructose has reached dramatic levels. To this end, young (30 days old) rats were fed a fructose-rich or control diet for 3 weeks to highlight the early response of the gut and liver to increased fructose intake. After this period, fructose-fed rats were returned to a control diet for 3 weeks and compared to the rats that received the control diet for the entire period to identify whether fructose-induced changes in the gut-liver axis persist or not after switching back to a control diet. Glucose transporter 5 and the tight junction protein occludin were assessed in the ileum and colon. Markers of inflammation and redox homeostasis as well as fructose and uric acid levels were also evaluated in the ileum, colon and liver. From the whole data, it is seen that metabolic derangement elicited by a fructose-rich diet, even after a brief period of intake, is fully reversed in the liver by a period of fructose withdrawal, while the alterations persist in the gut, especially in the ileum. In conclusion, given the increasing consumption of fructose-rich foods in young populations, the present results highlight the risk arising from gut persistent alterations even after the end of a fructose-rich diet. Therefore, dietary recommendations of reducing the intake of this simple sugar is mandatory to avoid not only the related metabolic alterations but also the persistence of these detrimental changes. This journal is more...

Simple Summary NRP-1, a co-receptor of the EGFR, represented an interesting candidate to investigate in HNSCC, as Cetuximab, in combination with radio and chemotherapy, provided the first targeted therapy scheme approved by the FDA as a standard of care for patients with recurrent or metastatic HNSCC. High levels of NRP-1 expression significantly correlated with a shorter overall survival in both Oral Squamous Cell Carcinoma and Oropharyngeal Squamous Cell Carcinoma diagnosed patients, suggesting a prognostic role for this protein. In HNSCC cell lines in vitro experiments, NRP-1 sustained EGFR activation upon CDDP exposure, together with activation of downstream MAPK/AKT pathways. Furthermore, NRP-1 modulated the responsiveness to CDDP treatment. Abstract Head and neck squamous cell carcinoma (HNSCC) includes a group of aggressive malignancies characterized by the overexpression of the epidermal growth factor receptor (EGFR) in 90% of cases. Neuropilin-1 (NRP-1) acts as an EGFR co-receptor, enhancing, upon ligand stimulation, EGFR signaling in several cellular models. However, NRP-1 remains poorly characterized in HNSCC. By utilizing in vitro cellular models of HNSCC, we report that NRP-1 is involved in the regulation of EGFR signaling. In fact, NRP-1 can lead to cisplatin-induced EGFR phosphorylation, an escape mechanism activated by cancer cells upon cytotoxic stress. Furthermore, we evaluated Neuropilin-1 staining in tissue samples of an HNSCC case series (n = 218), unraveling a prognostic value for the Neuropilin-1 tissue expression. These data suggest a potential role for NRP-1 in HNSCC cancer progression, expanding the repertoire of signaling in which NRP-1 is involved and eliciting the need for further investigations on NRP-1 as a suitable target for HNSCC novel therapeutic approaches. more...

Low-grade intraductal carcinoma is a rare neoplasia with an excellent prognosis, previously classified as low-grade cribriform cystadenocarcinoma and low-grade salivary duct carcinoma. The tumor mainly occurs in the parotid gland and presents a ductal phenotype and an intraductal/intracystic growth pattern. It resembles intraductal breast lesions such as atypical ductal hyperplasia, papillary and cribriform ductal carcinoma in situ. Despite its infrequency, discriminating low-grade intraductal carcinoma from other salivary gland tumors is crucial, especially because of its favorable prognosis. A 74-year-old woman with a history of neurofibromatosis underwent a superficial parotidectomy to remove a sharply demarcated multi-cystic mass, diagnosed as category 4 at FNAC. The histological examination revealed a demarcated but unencapsulated lesion composed of a bigger cyst surrounded by several smaller cysts, lined by a monolayer or bilayer epithelium alternated with a cribriform proliferation, characterized by “Roman-bridges”, with occasional micro-papillae. A myoepithelial component, with a basal disposition, was present, confirmed by intense staining for protein p63 and SMA. Immunohistochemical stains showed intense, strong uniform positivity for pan-cytokeratin, protein S100, and SOX10. The Ki67 proliferation index was low (< 10%). A diagnosis of Low-grade Intraductal Carcinoma (LGIC) of the parotid was made. We performed a literature search in PUBMED for “Intraductal carcinoma”, “Low-grade Intraductal Carcinoma”, “Cribriform Cystadenocarcinoma”, “Salivary Duct Carcinoma”, and “Low-Grade Salivary Duct Carcinoma”. We selected 17 papers published between 1983 and 2020; the most affected anatomical site was the parotid gland (77/90), followed by minor salivary glands (6/90), the intraparotid lymph nodes (3/90) and the submandibular gland (4/90). Their main histopathological features are reported in the paper. Here we present a case report and a review of scientific literature on this topic to provide some essential diagnostic tools to discriminate this rare entity. more...

Uveal melanoma (UM) is the most common intraocular tumor in adults. Despite sharing the name and similar morphological features with cutaneous melanoma (CM), it is an entirely different neoplasia with a particular genetic background and clinical behavior. CDKN2A is a gene located at chromosome 9p21, encoding for P16INK4a and P14(ARF) proteins, whose role as a tumor suppressor has been clearly defined in many malignant tumors. CDKN2A frequently presents germline mutations in familial CM and epigenetic downregulation in a considerable percentage of sporadic CM. It has been hypothesized that CDKN2A alterations are early events in CM development, playing a central role in the malignant transformation of melanocytes. Alterations of the CDKN2A gene reduce the expression of P16INK4a in most CM subtypes. Immunohistochemical evaluation of P16INK4a is currently used, in association with Ki67 and HMB45, in pathology practice to discriminate between dysplastic nevi and melanoma. On the other hand, CKDN2A is rarely mutated in UM, and the immunohistochemical expression of P16INK4a has only been reported in small case series. We tested P16INK4a expression on paraffin-embedded tissue sections from 9 tissue microarrays (TMAs), built with 2 mm cores derived from 133 uveal melanoma FFPE blocks, collected from 1990 to 2018, and from selected paraffin-blocks of 3 UM liver metastases. The immunohistochemical expression of P16INK4a was assessed with a visual evaluation by light microscopy and then with a digital approach. Both approaches, with an acceptable concordance rate, revealed P16INK4a expression in a large proportion of UM cases and all liver metastases, opening new possibilities of using it in the differential diagnosis between cutaneous and uveal melanoma metastases in cases of unknown primary tumor or patients with two different primary melanomas. more...

In this study we investigated the effects of snake venom Group IA secreted phospholipase A2 (svGIA) on the release of inflammatory and angiogenic mediators from human lung macrophages (HLMs). HLMs were incubated with lipopolysaccharide (LPS) or svGIA with or without macrophage-polarizing stimuli (IL-4, IL-10, IFN-γ or the adenosine analogue NECA). M2-polarizing cytokines (IL-4 and IL-10) inhibited TNF-α, IL-6, IL-12, IL-1β, CXCL8 and CCL1 release induced by both LPS and svGIA. IL-4 inhibited also the release of IL-10. IFN-γ reduced IL-10 and IL-12 and increased CCL1 release by both the LPS and svGIA-stimulated HLMs, conversely IFN-γ reduced IL-1β only by svGIA-stimulated HLMs. In addition, IFNγ promoted TNF-α and IL-6 release from svGIA-stimulated HLMs to a greater extent than LPS. NECA inhibited TNF-α and IL-12 but promoted IL-10 release from LPS-stimulated HLMs according to the well-known effect of adenosine in down-regulating M1 activation. By contrast NECA reduced TNF-α, IL-10, CCL1 and IL-1β release from svGIA-activated HLM. IL-10 and NECA increased both LPS- and svGIA-induced vascular endothelial growth factor A (VEGF-A) release. By contrast, IL-10 reduced angiopoietin-1 (ANGPT1) production from activated HLMs. IFN-γ and IL-4 reduced VEGF-A and ANGPT1 release from both LPS- and svGIA-activated HLMs. Moreover, IL-10 inhibited LPS-induced ANGPT2 production. In conclusion, we demonstrated a fine-tuning modulation of svGIA-activated HLMs differentially exerted by the classical macrophage-polarizing cytokines. more...

To assess the effect of 4 weeks of high fat-high fructose feeding on whole body composition, energy balance, specific markers of oxidative stress and inflammation, and insulin sensitivity in the liver of middle-aged rats, rats (1 year) were fed a diet rich in saturated fatty acids and fructose (HFF rats), mimicking the &ldquo, Western diet&rdquo, and compared with rats of the same age that were fed a low fat diet (LF rats). HFF rats exhibited a significant increase in the gain of body weight, energy, and lipids compared to LF rats. HFF rats also showed hepatic insulin resistance, together with an increase in plasma triglycerides, cholesterol, and tumor necrosis factor alpha. Hepatic lipids, triglycerides and cholesterol were higher in HFF rats, while a significant decrease in Stearoyl-CoA desaturase activity was found in this tissue. A marked increase in the protein amount of complex I, concomitant to a decrease in its contribution to mitochondrial respiration, was found in HFF rats. Lipid peroxidation and Nitro-Tyrosine content, taken as markers of oxidative stress, as well as NADPH oxidase activity, were significantly higher in HFF rats, while the antioxidant enzyme catalase decreased in these rats. Myeloperoxidase activity and lipocalin content increased, while peroxisome proliferator activated receptor gamma decreased in HFF rats. The present results provide evidence that middle-aged rats show susceptibility to a short-term &ldquo, exhibiting altered redox homeostasis, insulin resistance, and early mitochondrial alterations in the liver. Therefore, this type of dietary habits should be drastically limited to pursue a &ldquo, healthy aging&rdquo more...

Endogenous reactive oxygen species (ROS) are by-products of the aerobic metabolism of cells and have an important signalling role as secondary messengers in various physiological processes, including cell growth and development. However, the excessive production of ROS, as well as the exposure to exogenous ROS, can cause protein oxidation, lipid peroxidation and DNA damages leading to cell injuries. ROS accumulation has been associated to the development of health disorders such as neurodegenerative and cardiovascular diseases, inflammatory bowel disease and cancer. We report that spores of strain SF185, a human isolate of Bacillus megaterium, have antioxidant activity on Caco-2 cells exposed to hydrogen peroxide and on a murine model of dextran sodium sulfate-induced oxidative stress. In both model systems spores exert a protective state due to their scavenging action: on cells, spores reduce the amount of intracellular ROS, while in vivo the pre-treatment with spores protects mice from the chemically-induced damages. Overall, our results suggest that treatment with SF185 spores prevents or reduces the damages caused by oxidative stress. The human origin of SF185, its strong antioxidant activity, and its protective effects led to propose the spore of this strain as a new probiotic for gut health. more...

Purpose: to assess whether MRI T stage of breast cancer lesions (BCLs) is affected by maximum diameter (MD) measured at different post-contrast time points (TPs) on different acquisition planes on dynamic contrast-enhanced (DCE) MRI sequence. Methods: 53 DCE-MRI examinations of patients with BCLs were retrospectively selected. MD of BCLs was measured on axial, coronal and sagittal planes on DCE images at five different post-contrast TPs. Friedman test followed by Bonferroni-adjusted Wilcoxon-signed rank test for post-hoc analysis was performed to evaluate differences among the five measurements. Reliability of the measurements was evaluated with the intraclass correlation coefficient analysis. Differences between pathological and MRI T stage assessed at each TP on each acquisition plane were assessed using the Wilcoxon-sign rank test; p values more...

Persistence of damage induced by unhealthy diets during youth has been little addressed. Therefore, we investigated the impact of a short-term fructose-rich diet on liver metabolic activity in adolescent rats and the putative persistence of alterations after removing fructose from the diet. Adolescent rats were fed a fructose-rich diet for three weeks and then switched to a control diet for further three weeks. Body composition and energy balance were not affected by fructose-rich diet, while increased body lipids and lipid gain were found after the rescue period. Switching to a control diet reversed the upregulation of plasma fructose, uric acid, lipocalin, and haptoglobin, while plasma triglycerides, alanine aminotransferase, lipopolysaccharide, and tumor necrosis factor alpha remained higher. Hepatic steatosis and ceramide were increased by fructose-rich diet, but reversed by returning to a control diet, while altered hepatic response to insulin persisted. Liver fatty acid synthase and stearoyl-CoA desaturase (SCD) activities were upregulated by fructose-rich diet, and SCD activity remained higher after returning to the control diet. Fructose-induced upregulation of complex II-driven mitochondrial respiration, peroxisome proliferator-activated receptor-gamma coactivator 1 alpha, and peroxisome proliferator activated receptor α also persisted after switching to control diet. In conclusion, our results show prolonged fructose-induced dysregulation of liver metabolic activity. more...

Purpose Myeloid sarcoma (MS) of the orbit is an uncommon condition in occurring in children, generally coupled to myeloproliferative neoplasms. Observations We describe two rare cases of orbital MS in young boys with aggressive local symptoms but without evidence of acute myeloid leukemia (AML), both patients underwent orbitotomy for gross-tumor resection and biopsy. At follow up, there was no evidence of recurrence nor evolution of the myeloproliferative neoplasms clinically and by radiological and laboratory work-up. We also provide a detailed description of the magnetic resonance imaging presentation, with an extensive pathological analysis correlation. Conclusions and importance A comprehensive revision of the literature on isolated orbital MS was carried out with particular emphasis on clues for differential diagnosis and treatment options, stressing the need to consider MS even in the absence of sign and symptoms of an underlying myeloproliferative disorders. more...

Background: In the phase 3 BFORE trial (NCT02130557), treatment with bosutinib resulted in a significantly higher major molecular response rate at 12months versus imatinib in the modified intent-to-treat (mITT) population of patients with newly diagnosed chronic phase chronic myeloid leukemia (CP CML). Assessment of patient-reported outcomes (PROs) was an exploratory objective. Methods: Patients with newly diagnosed CP CML were randomized 1:1 to receive once-daily bosutinib 400mg or imatinib 400mg as first-line therapy. Patients completed the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) and EuroQoL-5 Dimensions (EQ-5D) questionnaires at baseline, every 3 months for the first 24 months of treatment, every 6 months thereafter, and at treatment completion. We report PRO results at month 12 in the mITT population (bosutinib: n = 246; imatinib: n = 241). Results: Mean FACT-Leu combined and subscale scores were similar at baseline in the bosutinib and imatinib arms; at month 12, all scores demonstrated improvement or maintenance of health-related quality of life (HRQoL) in both treatment arms. Repeated-measures mixed-effects models showed no significant difference between bosutinib and imatinib for any FACT-Leu score. Functional health status, as measured by EQ-5D, also demonstrated improvement or maintenance with bosutinib and imatinib at month 12. Conclusions: Similar improvements in PROs compared with baseline were seen after 12 months of treatment with first-line bosutinib or imatinib in the BFORE trial. Newly diagnosed patients with CP CML receiving bosutinib or imatinib can preserve or improve HRQoL during treatment, although clinical efficacy was superior with bosutinib more...

Sweeteners have become integrating components of the typical western diet, in response to the spreading of sugar-related pathologies (diabetes, obesity and metabolic syndrome) that have stemmed from the adoption of unbalanced dietary habits. Sweet proteins are a relatively unstudied class of sweet compounds that could serve as innovative sweeteners, but their introduction on the food market has been delayed by some factors, among which is the lack of thorough metabolic and toxicological studies. We have tried to shed light on the potential of a sweet protein, MNEI, as a fructose substitute in beverages in a typical western diet, by studying the metabolic consequences of its consumption on a Wistar rat model of high fat diet-induced obesity. In particular, we investigated the lipid profile, insulin sensitivity and other indicators of metabolic syndrome. We also evaluated systemic inflammation and potential colon damage. MNEI consumption rescued the metabolic derangement elicited by the intake of fructose, namely insulin resistance, altered plasma lipid profile, colon inflammation and translocation of lipopolysaccharides from the gut lumen into the circulatory system. We concluded that MNEI could represent a valid alternative to fructose, particularly when concomitant metabolic disorders such as diabetes and/or glucose intolerance are present. more...

Bosutinib is a Src/Abl tyrosine kinase inhibitor indicated for adults with newly-diagnosed Philadelphia positive chronic myeloid leukemia or with resistant/intolerant disease. We report the final results of a phase I/II study of second-line bosutinib in chronic phase chronic myeloid leukemia patients after imatinib failure (n=284). Median follow up and treatment durations were 54.8 (range 0.6-96.3) and 25.6 (0.2-96.3) months, respectively. At years 2 and 5, 54% and 40% of patients, respectively, remained on bosutinib. Cumulative major cytogenetic response and complete cytogenetic response rates (newly-attained or maintained from baseline) were 58% and 46%, respectively, by year 2 and 60% and 50% by year 5. Kaplan-Meier probability of maintaining major and complete cytogenetic response was 76% and 78%, respectively, at year 2 and 71% and 69% at year 5. Cumulative incidence of on-treatment disease progression/death was similar at years 5 (19%) and 2 (15%); Kaplan-Meier overall survival was 91% at year 2 and 84% at year 5. Of 169 patients who had discontinued bosutinib by year 5, 38 did so after year 2, most commonly for disease progression (n=11). Most adverse events initially occurred within two years. Overall, gastrointestinal events were the most common (diarrhea 86%, nausea 46%, vomiting 37%); the most common grade 3/4 toxicity was thrombocytopenia (25%). None of the 4 on-treatment deaths in years 3-5 were related to bosutinib. Bosutinib demonstrated durable efficacy and manageable toxicity through year 5 confirming its importance in the treatment of chronic phase chronic myeloid leukemia patients resistant/intolerant to prior imatinib. This trial was registered at clinicaltrials.gov identifier: 00261846. more...

Dietary fats and sugars were identified as risk factors for overweight and neurodegeneration, especially in middle-age, an earlier stage of the aging process. Therefore, our aim was to study the metabolic response of both white adipose tissue and brain in middle aged rats fed a typical Western diet (high in saturated fats and fructose, HFF) and verify whether a similarity exists between the two tissues. Specific cyto/adipokines (tumor necrosis factor alpha (TNF-&alpha, ), adiponectin), critical obesity-inflammatory markers (haptoglobin, lipocalin), and insulin signaling or survival protein network (insulin receptor substrate 1 (IRS), Akt, Erk) were quantified in epididymal white adipose tissue (e-WAT), hippocampus, and frontal cortex. We found a significant increase of TNF-&alpha, in both e-WAT and hippocampus of HFF rats, while the expression of haptoglobin and lipocalin was differently affected in the various tissues. Interestingly, adiponectin amount was found significantly reduced in e-WAT, hippocampus, and frontal cortex of HFF rats. Insulin signaling was impaired by HFF diet in e-WAT but not in brain. The above changes were associated with the decrease in brain derived neurotrophic factor (BDNF) and synaptotagmin I and the increase in post-synaptic protein PSD-95 in HFF rats. Overall, our investigation supports for the first time similarities in the response of adipose tissue and brain to Western diet. more...