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Background: The identification of synovial fluid (SF) biomarkers that could anticipate the diagnosis of osteoarthritis (OA) is gaining increasing importance in orthopaedic clinical practice. This controlled trial aims to assess the differences between the SF proteome of patients affected by severe OA undergoing Total Knee Replacement (TKR) compared to control subjects (i.e., subjects younger than 35, undergoing knee arthroscopy for acute meniscus injury). Methods: The synovial samples were collected from patients with Kellgren Lawrence grade 3 and 4 knee osteoarthritis undergoing THR (study group) and young patients with meniscal tears and no OA signs undergoing arthroscopic surgery (control group). The samples were processed and analyzed following the protocol defined in our previous study. All of the patients underwent clinical evaluation using the International Knee Documentation Committee (IKDC) subjective knee evaluation (main outcome), Knee Society Clinical Rating System (KSS), Knee injury and Osteoarthritis Outcome Score (KOOS), and Visual Analogue Scale (VAS) for pain. The drugs’ assumptions and comorbidities were recorded. All patients underwent preoperative serial blood tests, including complete blood count and C-Reactive Protein (CRP). Results: The synovial samples’ analysis showed a significantly different fibrinogen beta chain (FBG) and alpha-enolase 1 (ENO1) concentration in OA compared to the control samples. A significant correlation between clinical scores, FBG, and ENO1 concentration was observed in osteoarthritic patients. Conclusions: Synovial fluid FBG and ENO1 concentrations are significantly different in patients affected by knee OA compared with non-OA subjects.

Edentulism is the condition of having lost natural teeth, and has serious social, psychological, and emotional consequences. The need for implant services in edentulous patients has dramatically increased during the last decades. In this study, the effects of concentrated growth factor (CGF), an autologous blood-derived biomaterial, in improving the process of osseointegration of dental implants have been evaluated. Here, permeation of dental implants with CGF has been obtained by using a Round up device. These CGF-coated dental implants retained a complex internal structure capable of releasing growth factors (VEGF, TGF-β1, and BMP-2) and matrix metalloproteinases (MMP-2 and MMP-9) over time. The CGF-permeated implants induced the osteogenic differentiation of human bone marrow stem cells (hBMSC) as confirmed by matrix mineralization and the expression of osteogenic differentiation markers. Moreover, CGF provided dental implants with a biocompatible and biologically active surface that significantly improved adhesion of endothelial cells on CGF-coated implants compared to control implants (without CGF). Finally, data obtained from surgical interventions with CGF-permeated dental implants presented better results in terms of optimal osseointegration and reduced post-surgical complications. These data, taken together, highlight new and interesting perspectives in the use of CGF in the dental implantology field to improve osseointegration and promote the healing process.

Objectives Prader–Willi syndrome (PWS) is a rare genetic syndrome characterized by hyperphagia and early development of morbid obesity. Cardiovascular disease (CVD) and metabolic syndrome (MetS) are major comorbidities in these patients leading to premature death. Inhibitory factor 1 (IF1) works as a regulatory protein, inhibiting the ATP hydrolase activity of mitochondrial ATP synthase and likely playing a role in lipid metabolism. We aimed to assay IF1 in adult patients with PWS evaluating any relationship with clinical, genetic and biochemical parameters. Methods We recruited 35 adult patients with genetically confirmed PWS. Results IF1 serum concentration displayed a normal distribution with an average value of 70.7 ± 22.6 pg/mL, a median value of 66.1 pg/mL. It was above the reference range only in one patient. All parameters were compared from both sides of IF1 median without displaying any significant differences. Patients with normal or low HDL-cholesterol did not present any difference as regards IF1 levels, which were not different between patients with and without MetS. Non-esterified fatty acids (NEFA) serum levels (r=0.623; p1. Cholesterol and its fractions did not present any correlation with IF1. Conclusions In this study we do not confirm that HDL-cholesterol and IF1 are correlated, but we show that in adult PWS patients, NEFA are correlated with serum IF1. This protein could play a role to some extent in determining the complex metabolic alterations in PWS patients.

The progressive improvement of lymphoma treatment has led to an important prolongation of patient survival and life expectancy. The principal international scientific societies of oncology now therefore recommend that long-term survivors of lymphoma join fertility programs. Specifically, fertile-age patients should be assisted by a multidisciplinary team, including specialists dedicated to fertility preservation in oncology, in order to support the completion of their reproductive project. In the general population, the use of Myo-Inositol and D-Chiro-Inositol (MI/DCI) has been demonstrated to be an effective choice to treat ovarian dysfunctions, with a consequent improvement in reproductive outcomes, so it may represent an adjuvant strategy for this purpose. We therefore conducted a pilot prospective case–control study to evaluate the potentialities of this nutritional supplement, with the aim of optimizing reproductive function in female long-term survivors of lymphoma. One group underwent oral supplementation with MI 1200 mg and DCI 135 mg per day for 12 months, compared with controls who underwent no treatment in the same period. After 12 months, FSH, LH, and progesterone levels, as well as oligomenorrhea and antral follicle count (AFC), were significantly improved in the MI/DCI group. In addition, a significantly higher mean value in FSH and LH and a significantly lower mean AFC value in the right ovary were observed in controls compared to the MI/DCI group. Despite the need for further investigation, MI/DCI could be considered a potential adjuvant strategy to restore ovarian function in female long-term survivors of lymphoma.

Background Smith-Lemli-Opitz syndrome (SLOS) is a rare genetic neurodevelopmental disorder caused by the defect in the 7-dehydrocholesterol reductase. This defect leads to the deficiency of cholesterol biosynthesis with accumulation of 7-dehydrocholesterol. Inhibitory factor 1 (IF1) is a well-known mitochondrial protein. Recently, it has been discovered in the human serum where it is reported to be involved in the HDL-cholesterol intake. Here we report the IF1 presence in the serum of two paediatric SLOS dizygotic twins treated with dietary cholesterol supplementation. Case presentation The patients showed a typical phenotype. They started dietary supplementation with cholesterol when 2 months old. The cholesterol intake was periodically titrated on the basis of weight increase and the twin 1 required a larger supplementation than the twin 2 during the follow-up. When 6.4-year-old, they underwent IF1 assay that was 7-fold increased in twin 2 compared to twin 1 (93.0 pg/ml vs 13.0 pg/ml, respectively). Conclusions We report, for the first time, the presence of circulating IF1 in the serum of SLOS patients, showing different levels among them. Our findings confirm that IF1 could be a novel research target in cholesterol-related disorders and also in SLOS, and could contribute to the general debate on IF1 as a new modulator of cholesterol levels.

The scientific community has definitely demonstrated the importance of the use of mouthwash in daily oral hygiene. In our pilot study, we tested the effectiveness of a novel mouth rinse containing sea salt, xylitol, and lysozyme. Streptococcus mutans (S. mutans) growth, and plaque index in adolescent patients aged 14&ndash, 17 years, were observed. The bacterial load was investigated by in vitro microbiological analysis, the plaque index was assessed through the O&rsquo, Leary&rsquo, s Plaque Control Record (PCR). The study has shown that the use of a sea salt-based mouthwash in daily oral hygiene reduces the bacterial levels of S. mutans (p &lt, 0.01) linked to the combined action of xylitol and lysozyme, together with the action of sea salt. Our preliminary data confirm and improve the main results reported in the scientific literature on the importance of the use of xylitol, lysozyme, and sea salt in oral health.

Dysregulation of de novo lipogenesis (DNL) has recently gained strong attention as being one of the critical factors that contribute to the assessment of non-alcoholic fatty liver disease (NAFLD). NAFLD is often diagnosed in patients with dyslipidemias and type 2 diabetes; thus, an interesting correlation can be deduced between high hematic free fatty acids and glucose excess in the DNL dysregulation. In the present study, we report that, in a cellular model of NAFLD, the coexistence of elevated glucose and FFA conditions caused the highest cellular lipid accumulation. Deepening the molecular mechanisms of the DNL dysregulation—RT-qPCR and immunoblot analysis demonstrated increased expression of mitochondrial citrate carrier (CiC), cytosolic acetyl-CoA carboxylase 1 (ACACA), and diacylglycerol acyltransferase 2 (DGAT2) involved in fatty acids and triglycerides synthesis, respectively. XBP-1, an endoplasmic reticulum stress marker, and SREBP-1 were the transcription factors connected to the DNL activation. Quercetin (Que), a flavonoid with strong antioxidant properties, and noticeably reduced the lipid accumulation and the expression of SREBP-1 and XBP-1, as well as of their lipogenic gene targets in steatotic cells. The anti-lipogenic action of Que mainly occurs through a strong phosphorylation of ACACA, which catalyzes the committing step in the DNL pathway. The high level of ACACA phosphorylation in Que-treated cells was explained by the intervention of AMPK together with the reduction of enzymatic activity of PP2A phosphatase. Overall, our findings highlight a direct anti-lipogenic effect of Que exerted through inhibition of the DNL pathway by acting on ACACA/AMPK/PP2A axis; thus, suggesting this flavonoid as a promising molecule for the NAFLD treatment.

Hepatic de novo lipogenesis (DNL), the process by which carbohydrates are converted into lipids, is strictly controlled by nutritional and hormonal status. 3,5-Diiodo-L-thyronine (T2), a product of the 3,5,3'-triiodo-L-thyronine (T3) peripheral metabolism, has been shown to mimic some T3 effects on lipid metabolism by a short-term mechanism independent of protein synthesis. Here, we report that T2, administered for 1 week to hypothyroid rats, increases total fatty acid synthesis from acetate in isolated hepatocytes. Studies carried out on liver subcellular fractions demonstrated that T2 not only increases the activity and the expression of acetyl-CoA carboxylase and fatty acid synthase but also of other proteins linked to DNL such as the mitochondrial citrate carrier and the cytosolic ATP citrate lyase. Parallelly, T2 stimulates the activities of enzymes supplying cytosolic NADPH needed for the reductive steps of DNL. With respect to both euthyroid and hypothyroid rats, T2 administration decreases the hepatic mRNA level of SREBP-1, a transcription factor which represents a master regulator of DNL. However, when compared to hypothyroid rats T2 significantly increases, without bringing to the euthyroid value, the content of both mature (nSREBP-1), and precursor (pSREBP-1) forms of the SREBP-1 protein as well as their ratio. Moreover, T2 administration strongly augmented the nuclear content of ChREBP, another crucial transcription factor involved in the regulation of lipogenic genes. Based on these results, we can conclude that in the liver of hypothyroid rats the transcriptional activation by T2 of DNL genes could depend, at least in part, on SREBP-1- and ChREBP-dependent mechanisms. © 2019 IUBMB Life, 2019.

Background: Based on the holistic approach to prevention diabetic disease, the role of periodontal inflammation in type 2 diabetes mellitus (T2DM) is under intensive scrutiny. Data from clinical trials have shown benefit from a periodontal therapy in providing patients with type 2 diabetes improvement despite relatively disappointing long-terms response rates. The aim of this study was to investigate the short-term glycemic control level and systemic inflammatory status after periodontal therapy. Methods: This was a randomized trial with a 6-months follow-up. Participants aged 56.4 ± 7.9 years with diagnosed type 2 diabetes and periodontitis were enrolled. Among the 187 type 2 diabetic patients, 93 were randomly assigned to receive non-surgical periodontal treatment immediately and 94 to receive the delayed treatment. Within and between groups comparison was done during the study period, and the differences between groups were assessed. Results: The difference between HbA1c values at baseline (Mdn = 7.7) and 6 months after non-surgical periodontal treatment (Mdn = 7.2) was statistically significant, U = 3174.5, p = 0.012, r = 0.187. However, although technically a positive correlation, the relationship between the glycated hemoglobin value and periodontal variables was weak. The differences between both the groups over 6 months were not statistically considerable, failing to reach statistical significance. At 6 months the difference between groups about the C-reactive protein (CRP) levels was statistically significant, U=1839.5, p = 0, r = 0.472, with a lower concentration for the intervention group. Furthermore, the intervention group showed a statistically significant difference between baseline and 6 months evaluation (U = 2606.5, p = 0, r = 0.308). Conclusions: The periodontal intervention potentially may allow individuals with type 2 diabetes to improve glycemic control and CRP concentrations, and diabetes alters the periodontal status.

BACKGROUND: Probiotics are living microorganisms that confer a health benefit when administered in adequate amounts. There is evidence in the current literature about the importance of probiotic use in pregnancy. The early supplementation of probiotics in the perinatal and postnatal periods seems to have a positive impact on the overall mother’s health and future health of infants. AIM: Our pilot study aimed to test the ability of specific probiotics strains in combination with the kiwi-unique enzyme actinidin to improve the availability of folic acid in 20 pregnant women. METHODS: We investigate 20 pregnant women in early (4–10 weeks) (6 patients), intermedium (11–20 weeks) (6 patients), and late (21–30 weeks) (8 patients) pregnancy. RESULTS: Our findings show that the tested formula promotes increased concentration of serum folate in women’s blood and contributes to the control of blood sugar and body weight, regardless of the gestational period (early, intermediate or late). CONCLUSIONS: Our data support the main results reported in the scientific literature about the importance of probiotics intake in pregnancy.

In recent years, substantive attention has been drawn to the relationship between oral microbiome homeostatic equilibrium disruption and systemic health, demonstrating the negative impacts of this reciprocal biological interplay. Increasingly, there is a concern over the potential noxious effect of oral microbiome dysbiosis on obstetric poor outcomes, focusing on preterm birth. This epidemiological observation remains unexplained, although biologically plausible mechanism has been proposed. Intrauterine infection has long been associated with adverse pregnancy, when the elicitation of an immune response is determinant. There is evidence that Fusobacterium nucleatum (FN), a Gram-negative anaerobe ubiquitous in the oral cavity, infects the mouse placenta originating in the decidua basalis. Based on the current data in literature, we performed a review to provide resources for the explanation of the potential impact of microbiome dysbiosis on poor obstetric outcomes, focusing on the role of FN.

Background: Diabetes is known to be one of the major global epidemic diseases, significantly associated with mortality and morbidity worldwide, conferring a substantial burden to the health care system. The epidemiological transition of this chronic disease tends to worsen unless preventive health strategies are implemented. Appropriate screening devices and standardized methods are crucial to prevent this potentially inauspicious life condition. Currently, the glucometer is the conventional device employed for blood glucose level determination that outputs the blood glucose reading. Glucometer performed in the dental office may be an important device in screening diabetes, so it can be addressed during a periodontal examination. Because gingival blood is a useful source to detect the glucose level, the focus is placed on the opportunity that might provide valuable diagnostic information. This study aimed to compare gingival crevicular blood with finger-stick blood glucose measurements using a self-monitoring glucometer, to evaluate whether gingival crevicular blood could be an alternative to allow accurate chairside glucose testing. Methods: A cross-sectional comparative study was performed among a 31&ndash, 67-year-old population. Seventy participants with diagnosed type 2 diabetes and seventy healthy subjects, all with positive bleeding on probing, were enrolled. The gingival crevicular blood was collected using a glucometer to estimate the blood glucose level and compared with finger-stick blood glucose level. Results: The mean capillary blood glucose and gingival crevicular blood levels from all samples were, respectively, 160.42 &plusmn, 31.31 mg/dL and 161.64 &plusmn, 31.56 mg/dL for diabetic participants and 93.51 &plusmn, 10.35 mg/dL and 94.47 &plusmn, 9.91 mg/dL for healthy patients. In both groups, the difference between gingival crevicular blood and capillary blood glucose levels was non-significant (P &lt, 0.05). The highly significant correlation between capillary blood glucose and gingival crevicular blood (r = 0.9834 for diabetic patients and r = 0.8153 for healthy participants) in both the groups was found. Conclusions: Gingival crevicular blood test was demonstrated as a feasible and useful primary screening tool test for detecting diabetes and for glucose estimation in non-diabetic patients. Use of gingival crevicular blood for screening is an attractive way of identifying a reasonable option of finger-stick blood glucose measurement under the appropriate circumstances. Rapid assessment may precede diagnostic evaluation in diabetic as well as healthy patients with acute severe bleeding. In addition, gingival crevicular blood levels may be needed to monitor the diabetic output.

Background: It is established that inflammation is involved in the pathogenesis of Type 2 Diabetes Mellitus (T2DM) by promoting insulin resistance and impaired beta cell function in the pancreas. Among the hypothesized independent risk factors implicated in the pathogenetic basis of disease, periodontal infection has been proposed to promote an amplification of the magnitude of the advanced glycation end product (AGE)-mediated upregulation of cytokine synthesis and secretion. These findings suggest an interrelationship between periodontal disease and type 2 diabetes, describing poor metabolic control in subjects with periodontitis as compared to nondiabetic subjects and more severe periodontitis in subjects with T2DM as compared to a healthy population, with a significant positive correlation between periodontal inflammatory parameters and glycated hemoglobin level. Results from clinical trials show that periodontal treatment is able to improve glycemic control in subjects with diabetes. Many therapeutic strategies have been developed to improve periodontal conditions in conjunction with conventional treatment, among which ozone (O3) is of specific concern. The principal aim of this trial was to compare the clinical effectiveness of an intensive periodontal intervention consisting of conventional periodontal treatment in conjunction with ozone gas therapy in reducing glycated hemoglobin level in type 2 diabetic patients and standard periodontal treatment. Methods: This study was a 12-month unmasked randomized trial and included 100 patients aged 40&ndash, 74 years older, with type 2 diabetes mellitus diagnosed. All the patients received conventional periodontal treatment, or periodontal treatment in conjunction with ozone gas therapy in a randomly assigned order (1:1). The primary outcome was a clinical measure of glycated hemoglobin level at 3, 6, 9 and 12 months from randomization. Secondary outcomes were changes in periodontal inflammatory parameters. Results: At 12 months, the periodontal treatment in conjunction with ozone gas therapy did not show significant differences than standard therapy in decreasing glycated hemoglobin (HbA1C) level and the lack of significant differences in balance is evident. Conclusions: Although the change was not significant, periodontal treatment in conjunction with the gaseous ozone therapy tended to reduce the levels of glycated hemoglobin. The study shows a benefit with ozone therapy as compared to traditional periodontal treatment.

The emergence of link between periodontal disease and diabetes has created conditions for analyzing new interdisciplinary approach making toward tackling oral health and systemic issues. As periodontal disease is a readily modifiable risk factor this association has potential clinical implications. The aim of this paper was systematically review the extant literature related to analytics data in order to identify the association between type 1 diabetes (T1DM) in childhood and adolescence with periodontal inflammation. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a database search between 2004 and 2019. A manual search of the literature was conducted as an additional phase of the search process, with the aim of identifying studies that were missed in the primary search. One hundred and thirty-nine records were screened and 10 fulfilled the inclusion criteria. Most studies were of moderate methodological quality. Outcomes included assessments of diabetes and periodontal status. In diabetic populations, compared to healthy subjects, interindividual differences in periodontal status are reflected in higher severity of periodontal inflammation. The most reported barriers to evidence uptake were the intrinsic limits of cross-sectional report data and relevant research, and lack of timely research output. Based on the evidence presented within the literature, the aforementioned biomarkers correlate with poor periodontal status in type 1 diabetic patients. Whilst the corpus of the evidence suggests that there may be an association between periodontal status and type 1 diabetes, study designs and methodological limitations hinder interpretation of the current research.

Aim: Diabetes and periodontal disease are both chronic pathological conditions linked by several underlying biological mechanisms, in which the inflammatory response plays a critical role, and their association has been largely recognized. Recently, attention has been given to diabetes as an important mediator of vascular endothelial growth factor (VEGF) overexpression in periodontal tissues, by virtue of its ability to affect microvasculature. This review aims to summarize the findings from studies that explored VEGF expression in diabetic patients with periodontitis, compared to periodontally healthy subjects. Materials and Methods: A systematic literature review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A PubMed search of select medical subject heading (MeSH) terms was carried out to identify all studies reporting findings about VEGF expression in periodontal tissues of diabetic patients up to May 2018. The inclusion criteria were studies on VEGF expression in periodontally diseased tissues of diabetic patients compared with nondiabetic subjects, with any method of analysis, and published in the English language. Results: Eight articles met the inclusion criteria. Immunohistochemistry was used in six of the studies, reverse transcriptase polymerase chain reaction (real-time RT-PCR) aiming to quantify mRNA VEGF expression was used in one study, and ELISA analysis was used for one study. Compared with nondiabetic patients, a higher VEGF expression in gingival tissue and gingival crevicular fluid (GCF) samples in diabetic patients with periodontitis was reported. Conclusions: Overall, novel evidence for the VEGF expression within the periodontal tissue of diabetic patients paves the way for further studies on the role of this protein in neovascularization physiology and pathophysiology in microvasculature of the periodontium.

BACKGROUND: Physiological changes that occur during pregnancy involve, as a natural consequence, also modifications of oral microbiome. However, the addition with microbial imbalance due to pre-existing periodontal infection might impair a pathological alteration in the phylogenetic community structure and composition in the oral cavity, exacerbating an inflammatory status, and becoming a potential risk factor for preterm birth. From the empirical findings about the relationship between periodontal pathogens and systemic diseases, a clear interest focused on the potential impact of some periodontal pathogens on the preterm birth risk has emerged. AIM: Exploration of the potential interdependence existing between dysbiosis of oral microbiome and changes in maternal-fetal barrier in premature rupture of membranes. MATERIALS AND METHODS: In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a Medline search was performed for studies focusing on oral microbioma and its association with pre-term birth, and completed by additional hand searching. Two reviewers independently selected studies and extracted data. The search was restricted to only reports written in English. RESULTS: The electronic search produced 66 items. Six duplicates were found. Among the collected studies, 56 were discarded because they met the exclusion criteria. The articles and reports in our review showed a connection between preterm birth and altered oral microbiome, suggesting a potential key role of Fusobacterium nucleatum, a notable periodontal pathogen involved in several pathological periodontal conditions, in increasing the risk of premature birth. CONCLUSIONS: Since F. nucleatum is frequently associated with preterm birth, it is coherent to hypothesize a potential role for the oral microbiota for preterm birth risk. Further studies should be carried out to determine the changes of the oral microflora in pregnancy and to provide comprehensive knowledge of the diversity of oral bacteria involved in preterm birth.

Sepsis is a life-threatening condition that accounts for numerous deaths worldwide, usually complications of common community infections (i.e., pneumonia, etc), or infections acquired during the hospital stay. Sepsis and septic shock, its most severe evolution, involve the whole organism, recruiting and producing a lot of molecules, mostly proteins. Proteins are dynamic entities, and a large number of techniques and studies have been devoted to elucidating the relationship between the conformations adopted by proteins and what is their function. Although molecular dynamics has a key role in understanding these relationships, the number of protein structures available in the databases is so high that it is currently possible to build data sets obtained from experimentally determined structures. Techniques for dimensionality reduction and clustering can be applied in exploratory data analysis in order to obtain information on the function of these molecules, and this may be very useful in immunology to better understand the structure-activity relationship of the numerous proteins involved in host defense, moreover in septic patients. The large number of degrees of freedom that characterize the biomolecules requires special techniques which are able to analyze this kind of data sets (with a small number of entries respect to the number of degrees of freedom). In this work we analyzed the ability of two different types of algorithms to provide information on the structures present in three data sets built using the experimental structures of allosteric proteins involved in sepsis. The results obtained by means of a principal component analysis algorithm and those obtained by a random projection algorithm are largely comparable, proving the effectiveness of random projection methods in structural bioinformatics. The usefulness of random projection in exploratory data analysis is discussed, including validation of the obtained clusters. We have chosen these proteins because of their involvement in sepsis and septic shock, aimed to highlight the potentiality of bioinformatics to point out new diagnostic and prognostic tools for the patients.

Sorafenib is an oral kinase inhibitor that enhances survival in patients affected by advanced hepatocellular carcinoma (HCC). According to the results of two registrative trials, this drug represents a gold quality standard in the first line treatment of advanced HCC. Recently, lenvatinib showed similar results in terms of survival in a non-inferiority randomized trial study considering the same subset of patients. Unlike other targeted therapies, currently predictive and prognostic markers in HCC patients treated with sorafenib are lacking. Their identification could help clinicians in the daily management of these patients, mostly in light of the new therapeutic options available in the first.

Hepatocellular carcinoma is the most common primary liver cancer and the fourth leading cause of cancer death worldwide. A total of 70–80% of patients are diagnosed at an advanced stage with a dismal prognosis. Sorafenib had been the standard care for almost a decade until 2018 when the Food and Drug Administration approved an alternative first-line agent namely lenvatinib. Cabozantinib, regorafenib, and ramucirumab also displayed promising results in second line settings. FOLFOX4, however, results in an alternative first-line treatment for the Chinese clinical oncology guidelines. Moreover, nivolumab and pembrolizumab, two therapeutics against the Programmed death (PD)-ligand 1 (PD-L1)/PD1 axis have been recently approved for subsequent-line therapy. However, similar to other solid tumors, the response rate of single agent targeting PD-L1/PD1 axis is low. Therefore, a lot of combinatory approaches are under investigation, including the combination of different immune checkpoint inhibitors (ICIs), the addition of ICIs after resection or during loco-regional therapy, ICIs in addition to kinase inhibitors, anti-angiogenic therapeutics, and others. This review focuses on the use of ICIs for the hepatocellular carcinoma with a careful assessment of new ICIs-based combinatory approaches.

Osteoimmunology was coined about twenty years ago to identify a strict cross talk between bone niche and immune system both in physiological and pathological activities, including cancer. Several molecules are involved in the complex interaction between bone niche, immune and cancer cells. The Receptor Activator ok NF-kB (RANK)/RANK Ligand (RANKL/Osteoprotegerin (OPG) pathway plays a crucial role in bone cells/cancer interactions with subsequently immune system control failure, bone destruction, inhibition of effect and metastasis outcome. The bidirectional cross talk between bone and immune system could became a potential target for anticancer drugs. Several studies evidenced a direct anticancer role with improved survival of bone-targeted therapies such as bisphosphonates and RANKL antagonist Denosumab. Conversely, initial data evidenced a possible anti-bone resorption effect of systemic anticancer drugs through and immunomodulation activity, i.e. new generation antiandrogens (Abiraterone) in prostate cancer. All data could open a future rationale of combined bone, immunologic and targeted therapies in cancer treatment.

The aim of our study is to investigate the efficacy of metronomic cyclophosphamide plus low dose of corticosteroids in advanced or metastatic castration-resistant prostate cancer (CRPC) before, between, and after standard chemotherapy, such as docetaxel and cabazitaxel, and new hormonal treatments, such as abiraterone and enzalutamide. A retrospective analysis was performed on 37 patients. Cyclophosphamide was given orally 50 mg per day together with low dose of corticosteroids, namely dexametasone orally 1 mg per day or prednisone 10 mg per day. Seventeen patients (51%) showed a PSA decline≥ 50%. Median progression-free survival (PFS) and overall survival (OS) were 11 and 28 months, respectively. Median PFS and OS in the subgroup of patients with a PSA decline ≥ 50% were 14 and 35 months, respectively. Treatment was very well tolerated. We suggest that oral metronomic cyclophosphamide plus low dose of oral dexamethasone or prednisone may be a good and safe therapeutic option not only in those CRPC patients unfit for standard treatments but also in those heavily pre-treated patients.

Immune suppressed renal transplant patients are more prone to developing oral tissue alterations due to medications associated with a pleiotropic set of side effects involving the oral cavity. Drug-induced gingival overgrowth (DIGO) is the most commonly encountered side effect resulting from administration of calcineurin inhibitors such as cyclosporine-A (CsA), the standard first-line treatment for graft rejection prevention in transplant patients. Pathogenesis of gingival overgrowth (GO) is determined by the interrelation between medications and a pre-existing inflammatory periodontal condition, the main modifiable risk factor. Severity of gingival hyperplasia clinical manifestation is also related to calcium channel blocker association, frequently provided in addition to pharmacological therapy of transplant recipients. Specifically, nifedipine-induced enlargements have a higher prevalence rate compared to amlodipine-induced enlargements, 47.8% and 3.3% respectively. Available epidemiological data show a gender difference in prevalence, whereby males are generally more frequently affected than females. The impact of GO on the well-being of an individual is significant, often leading to complications related to masticatory function and phonation, a side effect that may necessitate switching to the tacrolimus drug that, under a similar regimen, is associated with a low incidence of gingival lesion. Early detection and management of GO is imperative to allow patients to continue life-prolonging therapy with minimal morbidity. The purpose of this study was threefold: firstly, to determine the prevalence and incidence of GO under the administration of CsA and Tacrolimus, secondly, to assess the correlation between periodontal status before and after periodontal therapy and medications on progression or recurrence of DIGO, and finally, to analyse the effect of immunosuppressant in association to the channel blocker agents on the onset and progression of gingival enlargement. We compared seventy-two renal transplant patients, including 33 patients who were receiving CsA, of which 25% were also receiving nifedipine and 9.72% also receiving amlodipine, and 39 patients who were receiving tacrolimus, of which 37.5% were also receiving nifedipine and 5.55% also receiving amlodipine, aged between 35 and 60 years. Medical and pharmacological data were recorded for all patients. Clinical periodontal examination, in order to establish the inflammatory status and degree of gingival enlargement, was performed at baseline (T0), 3 months (T1), 6 months (T2), and 9 months (T3). All patients were subjected to periodontal treatment. Statistically significant correlation between the reduction of the mean value of periodontal indices and degree of gingival hyperplasia at the three times was revealed. The prevalence of GO in patients taking cyclosporine was higher (33.3%) in comparison with those taking tacrolimus (14.7%). In accordance with previous studies, this trial highlighted the clinical significance of the pathological substrate on stimulating drug-induced gingival lesion, confirming the key role of periodontal inflammation in pathogenesis of gingival enlargement, but did not confirm the additional effect of calcium-channel blocker drugs in inducing gingival enlargement.

Quercetin (Que), a widely distributed flavonoid in the human diet, exerts neuroprotective action because of its property to antagonize oxidative stress. Here, we investigated the effects of Que on lipid synthesis in C6 glioma cells. A rapid Que-induced inhibition of cholesterol and, to a lesser extent, of fatty acid synthesis from [1-14C]acetate was observed. The maximum decrease was detected at the level of palmitate, the end product of de novo fatty acid synthesis. The effect of Que on the enzyme activities of acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FAS), the two enzymes of this pathway, was investigated directly in situ in permeabilized C6 cells. An inhibitory effect on ACC1 was observed after 4 h of 25 μM Que treatment, while FAS activity was not affected. A reduction of polar lipid biosynthesis was also detected. A remarkable decrease of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) activity, regulatory enzyme of cholesterol synthesis, was evidenced. Expression studies demonstrated that Que acts at transcriptional level, by reducing the mRNA abundance and protein amount of ACC1 and HMGCR. Deepening the molecular mechanism, we found that Que decreased the expression of SREBP-1 and SREBP-2, transcriptional factors representing the main regulators of de novo fatty acid and cholesterol synthesis, respectively. Que also reduced the nuclear content of ChREBP, a glucose-induced transcription factor involved in the regulation of lipogenic genes. Our results represent the first evidence that a direct and rapid downregulatory effect of Que on cholesterol and de novo fatty acid synthesis is elicited in C6 cells.

Proteomic analysis shows that treatment of keratinocytes cultures with all trans retinoic acid (ATRA), under condition in which it inhibits cell growth, results in marked decrease of the level of the F1-beta subunit of the catalytic sector of the mitochondrial FoF1 ATP synthase complex. Enzymatic analysis shows in ATRA-treated keratinocytes a consistent depression of the ATPase activity, with decreased olygomycin sensitivity, indicating an overall alteration of the ATP synthase complex. These findings, together with the previously reported inhibition of respiratory complex I, show that depression of the activity of oxidative phosphorylation enzymes is involved in the cell growth inhibitory action of ATRA. (C) 2016 Elsevier Inc. All rights reserved.

The activities of lipogenic enzymes appear to fluctuate with changes in the level and type of dietary fats. Polyunsaturated fatty acids (PUFAs) are known to induce on hepatic de novo lipogenesis (DNL) the highest inhibitory effect, which occurs through a long-term adaptation. Data on the acute effects of dietary fatty acids on DNL are lacking. In this study with rats, the acute 1-day effect of high-fat (15 % w/w) diets (HFDs) enriched in saturated fatty acids (SFAs) or unsaturated fatty acids (UFAs), i.e., monounsaturated (MUFA) and PUFA, of the ω-6 and ω-3 series on DNL and plasma lipid level was investigated; a comparison with a longer time feeding (21 days) was routinely carried out. After 1-day HFD administration UFA, when compared to SFA, reduced plasma triacylglycerol (TAG) level and the activities of the lipogenic enzymes acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), a decreased activity of the citrate carrier (CIC), a mitochondrial protein linked to lipogenesis, was also detected. In this respect, ω-3 PUFA was the most effective. On the other hand, PUFA maintained the effects at longer times, and the acute inhibition induced by MUFA feeding on DNL enzyme and CIC activities was almost nullified at 21 days. Mitochondrial fatty acid composition was slightly but significantly changed both at short- and long-term treatment, whereas the early changes in mitochondrial phospholipid composition vanished in long-term experiments. Our results suggest that in the early phase of administration, UFA coordinately reduced both the activities of de novo lipogenic enzymes and of CIC. ω-3 PUFA showed the greatest effect.

Background: Malnutrition-inflammation complex syndrome (MICS) is a common and usually concurrent condition occurring in patients undergoing hemodialysis (HD), with a pathogenesis linked to biological and in situ environmental traditional risk factors. Periodontitis, one of the major types of infection-driven inflammation, often co-occurs in the in the hemodialysis population and correlates with markers of malnutrition and inflammation, such as albumin, creatinine, and C-reactive protein. Aim: The present study aimed to determine whether the periodontal inflammatory status parameters correlate with the albumin, creatinine, and C-reactive protein serum concentrations in HD patients, and investigate whether periodontal treatment improves these markers of nutritional and systemic inflammation. Materials and Methods: The serum creatinine, albumin, and C-reactive Protein (CRP) levels were measured at baseline and after non-surgical periodontal treatment, at 3 months and 6 months. Results: At 3 months, a significant correlation between plaque index and C-reactive protein (p = 0.012), bleeding on probing and C-reactive protein (p &lt, 0.0019), and clinical attachment level and C-reactive protein (p = 0.022) was found. No significant correlation was found between clinical periodontal parameters and nutrition markers at each time. Conclusions: Our results confirmed the association between C-reactive protein serum concentration and periodontal inflammatory status, but further research is necessary to identify the contributing role of periodontitis on the onset and progression of MICS.

Hepatic de novo lipogenesis (DNL), the process by which carbohydrates are converted into lipids, is strictly controlled by nutritional and hormonal status. 3,5-Diiodo-L-thyronine (T2), a product of the 3,5,3'-triiodo-L-thyronine (T3) peripheral metabolism, has been shown to mimic some T3 effects on lipid metabolism by a short-term mechanism independent of protein synthesis. Here, we report that T2, administered for 1 week to hypothyroid rats, increases total fatty acid synthesis from acetate in isolated hepatocytes. Studies carried out on liver subcellular fractions demonstrated that T2 not only increases the activity and the expression of acetyl-CoA carboxylase and fatty acid synthase but also of other proteins linked to DNL such as the mitochondrial citrate carrier and the cytosolic ATP citrate lyase. Parallelly, T2 stimulates the activities of enzymes supplying cytosolic NADPH needed for the reductive steps of DNL. With respect to both euthyroid and hypothyroid rats, T2 administration decreases the hepatic mRNA level of SREBP-1, a transcription factor which represents a master regulator of DNL. However, when compared to hypothyroid rats T2 significantly increases, without bringing to the euthyroid value, the content of both mature (nSREBP-1), and precursor (pSREBP-1) forms of the SREBP-1 protein as well as their ratio. Moreover, T2 administration strongly augmented the nuclear content of ChREBP, another crucial transcription factor involved in the regulation of lipogenic genes. Based on these results, we can conclude that in the liver of hypothyroid rats the transcriptional activation by T2 of DNL genes could depend, at least in part, on SREBP-1- and ChREBP-dependent mechanisms. © 2019 IUBMB Life, 2019.

Francesco Perri,1 Salvatore Pisconti,1 Manuel Conson,2,3 Roberto Pacelli,2,3 Giuseppina Della Vittoria Scarpati,2 Antonio Gnoni,1 Carmine D’Aniello,1 Carla Cavaliere,1 Antonella Licchetta,1 Laura Cella,2,3 Mario Giuliano,4,5 Concetta Schiavone,7 Sara Falivene,7 Giuseppe Di Lorenzo,4 Carlo Buonerba,6 Vincenzo Ravo,7 Paolo Muto7 1Medical Oncology Unit, POC S Annunziata, Taranto, 2Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, 3Institute of Biostructures and Bioimaging, National Council of Research, Naples, 4Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy; 5Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA; 6Division of Oncology, Centro di riferimento Oncologico di Basilicata, IRCCS Rionero in Vulture, Potenza, 7Department of Radiotherapy, Istituto Nazionale per la Cura dei Tumori-Fondazione G. Pascale. IRCCS di Napoli, Naples, Italy Background: The clinical benefits of postoperative radiation therapy (PORT) for patients with thymoma are still controversial. In the absence of defined guidelines, prognostic factors such as stage, status of surgical margins, and histology are often considered to guide the choice of adjuvant treatment (radiotherapy and/or chemotherapy). In this study, we describe our single-institution experience of three-dimensional conformal PORT administered as adjuvant treatment to patients with thymoma. Methods: Twenty-two consecutive thymoma patients (eleven male and eleven female) with a median age of 52 years and treated at our institution by PORT were analyzed. The patients were considered at high risk of recurrence, having at least one of the following features: stage IIB or III, involved resection margins, or thymic carcinoma histology. Three-dimensional conformal PORT with a median total dose on clinical target volume of 50 (range 44–60) Gy was delivered to the tumor bed by 6–20 MV X-ray of the linear accelerator. Follow-up after radiotherapy was done by computed tomography scan every 6 months for 2 years and yearly thereafter.Results: Two of the 22 patients developed local recurrence and four developed distant metastases. Median overall survival was 100 months, and the 3-year and 5-year survival rates were 83% and 74%, respectively. Median disease-free survival was 90 months, and the 5-year recurrence rate was 32%. On univariate analysis, pathologic stage III and presence of positive surgical margins had a significant impact on patient prognosis. Radiation toxicity was mild in most patients and no severe toxicity was registered. Conclusion: Adjuvant radiotherapy achieved good local control and showed an acceptable toxicity profile in patients with high-risk thymoma. Keywords: thymoma, adjuvant treatment, three-dimensional conformal radiotherapy, local control, toxicity&nbsp

Nonalcoholic fatty liver disease (NAFLD) represents the most common chronic liver disease in western countries, being considered the hepatic manifestation of metabolic syndrome. Cumulative lines of evidence suggest that olive oil, used as primary source of fat by Mediterranean populations, may play a key role in the observed health benefits on NAFLD. In this review, we summarize the state of the art of the knowledge on the protective role of both major and minor components of olive oil on lipid metabolism during NAFLD. In particular, the biochemical mechanisms responsible for the increase or decrease in hepatic lipid content are critically analyzed, taking into account that several studies have often provided different and/or conflicting results in animal models fed on olive oil-enriched diet. In addition, new findings that highlight the hypolipidemic and the antisteatotic actions of olive oil phenols are presented. As mitochondrial dysfunction plays a key role in the pathogenesis of NAFLD, the targeting of these organelles with olive oil phenols as a powerful therapeutic approach is also discussed.

Hepatocellular carcinoma (HCC) is a heterogeneous disease that usually develops within liver cirrhosis. Cancerogenesis in HCC is not a clear process and, at present, there is not a well-defined sequence of DNA mutations able to explain the entire process, from normal hepatocyte to HCC. Lately, the impact of some oncogenes on HCC development has been studied and some of these genes belong to the MAPKinases pathway, highlighting the importance of downstream effectors stimulated by the interaction between extracellular growth factors and tyrosine kinase receptors. Unfortunately, drugs able to interfere with the aforementioned pathway showed no positive results in clinical trials. A number of preclinical studies have focused the attention on epigenetic changes in HCC cells, focusing on the extensive DNA hypermetilation as a factor causing the knockout of several tumor suppressor genes. Cancerogenesis of HCC, at least at an early phase, could be sustained by epigenetic changes. Finally, some authors have tried to classify HCC on the basis of gene mutations found after performing an extensive genome sequencing, and interestingly, they have identified different classes of HCC on the basis of different clusters of mutated genes. HCC is not characterized by a unique driver mutation, as the case of EGFR mutations for lung cancer or K-Ras mutations for colorectal cancer, thus it is, at present, very difficult to identify a reliable target for antitumoral therapy. This review focuses on current translational research and molecular targets in the treatment of HCC.

Mitochondria are fundamental organelles producing energy and reactive oxygen species (ROS); their impaired functions play a key role in endothelial dysfunction. Hydroxytyrosol (HT), a well-known olive oil antioxidant, exerts health benefits against vascular diseases by improving endothelial function. However, the HT role in mitochondrial oxidative stress in endothelial dysfunction is not clear yet. To investigate the HT effects on mitochondrial ROS production in the inflamed endothelium, we used an in vitro model of endothelial dysfunction represented by cultured endothelial cells, challenged with phorbol myristate acetate (PMA), an inflammatory, prooxidant, and proangiogenic agent. We found that the pretreatment of endothelial cells with HT (1–30 μmol/L) suppressed inflammatory angiogenesis, a crucial aspect of endothelial dysfunction. The HT inhibitory effect is related to reduced mitochondrial superoxide production and lipid peroxidation and to increased superoxide dismutase activity. HT, in a concentration-dependent manner, improved endothelial mitochondrial function by reverting the PMA-induced reduction of mitochondrial membrane potential, ATP synthesis, and ATP5β expression. In PMA-challenged endothelial cells, HT also promoted mitochondrial biogenesis through increased mitochondrial DNA content and expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, nuclear respiratory factor-1, and mitochondrial transcription factor A. These results highlight that HT blunts endothelial dysfunction and pathological angiogenesis by ameliorating mitochondrial function, thus suggesting HT as a potential mitochondria-targeting antioxidant in the inflamed endothelium.