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Inflammatory bowel diseases (IBD), comprising Crohn’s disease (CD) and Ulcerative Colitis (UC), are multifactorial disorders characterized by a chronic inflammatory status with the secretion of cytokines and immune mediators. Biologic drugs targeting pro-inflammatory cytokines, such as infliximab, are broadly used in the treatment of IBD patients, but some patients lose responsiveness after an initial success. The research into new biomarkers is crucial for advancing personalized therapies and monitoring the response to biologics. The aim of this single center, observational study is to analyze the relationship between serum levels of 90K/Mac-2 BP and the response to infliximab, in a cohort of 48 IBD patients (30 CD and 18 UC), enrolled from February 2017 to December 2018. In our IBD cohort, high 90K serum levels were found at baseline in patients who then developed anti-infliximab antibodies at the fifth infusion (22 weeks after the first), becoming non-responders (9.76 ± 4.65 µg/mL compared to 6.53 ± 3.29 µg/mL in responder patients, p = 0.005). This difference was significant in the total cohort and in CD, but not significant in UC. We then analyzed the relationship between serum levels of 90K, C-reactive protein (CRP), and Fecal calprotectin. A significant positive correlation was found at baseline between 90K and CRP, the most common serum inflammation marker (R = 0.42, p = 0.0032). We concluded that circulating 90K could be considered a new non-invasive biomarker for monitoring the response to infliximab. Furthermore, 90K serum level determination, before the first infliximab infusion, in association with other inflammatory markers such as CRP, could assist in the choice of biologics for the treatment of IBD patients, thereby obviating the need for a drug switch due to loss of response, and so improving clinical practice and patient care.

Objective Atrophic gastritis may affect circulating ghrelin levels and, indirectly, body mass index. The aim of this study was to investigate the relationship between atrophic gastritis, focusing on autoimmune atrophic gastritis and advanced stages of atrophic gastritis, serum ghrelin levels and BMI. Methods Sixty-three patients, of whom 18 had autoimmune atrophic gastritis, 27 non-autoimmune antrum and corpus atrophic gastritis, and 18 non-atrophic gastritis or antrum-limited atrophic gastritis (control group) were assessed. All participants underwent endoscopy with multiple gastric biopsies. Atrophic gastritis was diagnosed by histology, classified according to the Updated Sydney System and staged by the Operative Link on Gastritis Assessment (OLGA) Classification. Total serum ghrelin, body weight and height were measured. Results Compared with control patients (144.6 ± 111 pg/ml), mean serum level of total ghrelin was higher in patients with autoimmune atrophic gastritis (226.08 ± 243.03 pg/ml, P = 0.65) and lower in those with both antrum and corpus atrophic gastritis (74.51 ± 37.38 pg/ml, P = 0.12), although differences were not statistically significant. Serum ghrelin decreased in patients with advanced OLGA stages of atrophic gastritis. In non-obese patients BMI was significantly lower in those with both antrum and corpus atrophic gastritis than in control patients (23.1 ± 1.8 vs. 24.5 ± 1.6, P = 0.01), also after adjustment for age and sex (P = 0.02); BMI was positively correlated with serum total ghrelin (r = 0.51, P < 0.001). Conclusion Advanced stages of atrophic gastritis, but not autoimmune atrophic gastritis, seem to be associated with lower serum levels of ghrelin and lower BMI. In non-obese patients, BMI was positively correlated with total serum ghrelin.

BACKGROUND Few studies have examined intestinal motility disorders, which are disabling conditions associated with chronic functional constipation, whose pathogenesis is actually not well-defined. AIM To investigate the relationship between serum 25-hydroxyvitamin D levels and functional chronic constipation associated to intestinal motility disorders. METHODS We performed a prospective case-control study, from May-June to November 2017. Glucose/lactulose breath tests, radiopaque markers (multiple capsule techniques) and wireless motility capsule analysis were used to assess colonic and oro-cecal transit time, after excluding small-intestinal bacterial overgrowth condition. Then, we measured 25-hydroxyvitamin D levels in patients with intestinal motility disorders and we further evaluated the influence of intestinal motility disorders on psychological symptoms/quality of life using validated questionnaires, the Irritable Bowel Syndrome Quality of life (IBS-QOL), the Short Form Health Survey 12, and the Hospital Anxiety and Depression Scale 14 (HADS-14 A and HADS-14 D). RESULTS We enrolled 86 patients with chronic functional constipation associated to intestinal motility disorders and 86 matched healthy subjects. Patients with intestinal motility disorders had lower 25-hydroxyvitamin D levels (P < 0.001), and they showed a significant impairment of all health-related quality of life and psychological tests (IBS-QOL, Short Form Health Survey 12-Physical Component Summary, Short Form Health Survey 12-Mental Component Summary, HADS-14 A and HADS-14 D), as compared to the control group (P < 0.001), which significantly correlated with low vitamin D levels (r = - 0.57, P < 0.001; r = 0.21, P = 0.01; r = - 0.48, P < 0.001; r = - 0.57, P < 0.001; r = - 0.29, P < 0.001, respectively). At multivariate analysis vitamin D low levels remained a significant independent risk factor for the occurrence of intestinal motility disorder (odds ratio = 1.19; 95% confidence interval: 1.14-1.26, P < 0.001). CONCLUSION Vitamin D deficiency, anxiety and depression symptoms are commonly associated with chronic functional constipation induced by intestinal motility disorders. Vitamin D serum levels should be routinely measured in these patients.

Background: Elevated fasting remnant cholesterol (REM-C) levels have been associated with an increased cardiovascular risk in patients with metabolic syndrome (Mets) and Non-Alcoholic Fatty Liver Disease (NAFLD). We aimed to estimate the effect of different diets on REM-C levels in patients with MetS, as well as the association between NAFLD and REM-C. Methods: This is a secondary analysis of the MEDIDIET study, a parallel-arm Randomized Clinical Trial (RCT). We examined 237 people with MetS who underwent Liver Ultrasound (LUS) to assess the NAFLD score at baseline, 3-, and 6-months follow-up. Subjects were randomly assigned to the Mediterranean diet (MD), Low Glycemic Index diet (LGID), or Low Glycemic Index Mediterranean diet (LGIMD). REM-C was calculated as [total cholesterol&ndash, low density lipoprotein cholesterol (LDL-C)&ndash, high density lipoprotein cholesterol (HDL-C)]. Results: REM-C levels were higher in subjects with moderate or severe NAFLD than in mild or absent ones. All diets had a direct effect in lowering the levels of REM-C after 3 and 6 months of intervention. In adherents subjects, this effect was stronger among LGIMD as compared to the control group. There was also a significant increase in REM-C levels among Severe NAFLD subjects at 3 months and a decrease at 6 months. Conclusions: fasting REM-C level is independently associated with the grade of severity of NAFLD. LGIMD adherence directly reduced the fasting REM-C in patients with MetS.

SCOPE The study aims to investigate the effects of fresh table grape consumption in healthy subjects on circulating levels of the most common human microRNAs (miRNAs). The regulatory network governed by these modulated miRNAs is also investigated. METHODS AND RESULTS Autumn Royal table grape, used in this study, is chosen for its high polyphenolic content and antioxidant properties. The study is a randomized controlled trial, in which 40 consecutive subjects are recruited on a voluntary basis and randomly assigned to two groups of the study, the control group, receiving only dietary recommendations and a grape group receiving a daily dose of 5 g of fresh table grape per kg of body weight for 21 days. All analyses are performed at baseline and after 21 days of dietary treatment. Circulating miRNAs levels are detected by Real-Time quantitative PCR (RT-qPCR) followed by bioinformatic functional analysis. The study identifies 20 circulating miRNAs differentially expressed in healthy subjects after grape intake, and in particular, 18 of 20 are down-regulated and 2 are up-regulated. CONCLUSION The dietary intake of table grape affects circulating miRNAs levels in healthy subjects, particularly the miRNAs related to pathways involved in counteracting cancer development, including gastrointestinal cancers.

Several new multikinase inhibitors have recently been introduced into clinical practice for hepatocellular carcinoma (HCC) therapy. Small increases in survival were reported as well as considerable toxicity. There is thus a need for effective therapies with lower toxicities. We examined whether a combination of sorafenib and regorafenib might also be effective at very low concentrations, with resulting potential for lessened clinical toxicity. MTT test, clonogenic assay, Ki67 staining and cell cycle analysis were assessed for cell proliferation and Annexin V and western blotting analysis relative to the expression of cleaved Caspase-3 and BID for cell apoptosis. In these experimental conditions cell growth and migration were potently inhibited and apoptosis induced even in HCC cells producing high alpha fetoprotein (AFP) levels (clinically worse prognosis). The combination also inhibited levels of the two HCC biomarkers, AFP and des gamma carboxy prothrombin (DCP). Additional inhibition of Vascular Endothelial Growth Factor Receptor (VEGFR) or Insulin-like Growth Factor 1 Receptor (IGF1R) enhanced effects on AFP and DCP levels, cell growth inhibition and MAPK and PI3K/Akt signaling inhibition due to sorafenib/regorafenib combination. These combinations have the potential for decreased toxicity while simultaneously enhancing therapeutic effects. This potential decrease in toxicity is being explored in ongoing studies.

Objective:In the postmenopausal period, most women suffer vasomotor symptoms (VMS). It is well-known that VMS can worsen the quality of life. Diet seems to play a relevant role in the development of VMS, but the effect of diet on VMS is mainly limited to observational studies, and analyses of nutritional supplements. The aim of this study was thus to determine the efficacy of a lactoovo- vegetarian (LOVe) diet rich in omega-3 fatty acids vs. a lacto-ovo-vegetarian diet rich in EVO (extra-virgin olive oil) in reducing VMS frequency in postmenopausal women.Methods:A two-arms (lacto-ovo-vegetarian diet with EVO vs. lacto-ovo-vegetarian diet rich in omega-3) randomized-controlled trial with a follow-up period of 16 weeks. We considered as primary outcome the change in the Kupperman index (follow-up vs. baseline evaluation, reported as delta, D) and in its subscales. Secondary outcomes included changes in common anthropometric and biohumoral measurements.Results:Among 54 women randomly assigned to a study group, 40 (mean age 55.1±5.4 years) completed the study and complied with their assigned diet. Women randomized to the omega-3 group (n=18) showed significant improvements, compared to the EVO group (n=22), in Kupperman index (Δ=-11.4±9.8 vs. -5.9±8.2; p=0.045), hot flashes (Δ=-3.3±3.4 vs. -1.3±2.6; p=0.04), and a marginally significant improvement in nervousness (Δ=-1.7±1.7 vs. -0.8±1.5; p=0.07). No significant differences were observed for the secondary outcomes. No relevant side effects were reported.Conclusion:After 16 weeks, a lacto-ovo-vegetarian diet rich in omega-3 reduced VMS frequency in postmenopausal women more than the lacto-ovo-vegetarian diet rich in EVO.

Background:Systematic difference between thyroid-stimulating hormone (TSH) immunoassays may produce misleading interpretation when samples of the same patients are measured with different methods. The study aims were to evaluate whether systematic differences are present among TSH immunoassays, and whether it is possible to obtain a better harmonization among TSH methods using results obtained in external quality assessment (EQA) schemes.Methods:Seven Italian clinical laboratories measured TSH in 745 serum samples of healthy subjects and patients with thyroid disorders. These samples were also re-measured by two reference laboratories of the study with the six TSH immunoassays most popular in Italy after 2 months of storage at −80 °C. Moreover, these data were compared to 53,823 TSH measurements, obtained by laboratories participant to 2012–2015 EQA annual cycles in 72 quality control samples (TSH concentrations from about 0.1 mIU/L to 18.0 mIU/L). TSH concentrations were recalibrated using a mathematical approach based on the principal component analysis (PCA).Results:Systematic differences were found between the most popular commercially available TSH immunoassays. TSH concentrations measured by the clinical laboratories were very closely correlated to those measured with the same method by reference laboratories after 2 months of storage at −80 °C. After recalibration using the PCA approach the variation of TSH values significantly decreased from a median pre-calibration value of 13.53% (10.79%–16.53%) to 9.63% (6.90%–13.21%) after recalibration.Conclusions:Our data suggest that EQA schemes are useful to improve harmonization among TSH immunoassays and also to produce some mathematical formulas, which can be used by clinicians to better compare TSH values measured with different methods.

Galectin-3 is an endogenous lectin that binds glycan epitopes of cell membrane and some extracellular glycoproteins such as integrins and laminin. Galectin-3 is involved in several biological activities including regulation of cellular cycle, modulation of adhesion and tumor progression and metastasis. 90K/Mac-2BP glycoprotein is also a serum galectin-3 ligand. 90K is able to modulate the immune reaction against tumors and viruses and its level increases in sera of several neoplastic diseases. In our study, we have evaluated levels of both glycoproteins in sera of non metastatic colon cancer patients. Interestingly, galectin-3 ranged higher in cancer patients than in controls (p

Sorafenib was shown in clinical trial to enhance survival in hepatocellular carcinoma (HCC) patients, but with minimal tumor shrinkage. To correlate several indices of HCC growth at various drug concentrations, HCC cells were grown in various low concentrations of two multikinase inhibitors, regorafenib (Stivarga) and sorafenib (Nexavar) and their effects were examined on alpha-fetoprotein (AFP), cell growth, migration, and invasion. In two AFP positive human HCC cell lines, AFP was inhibited at 0.1-1 µM drug concentrations. Cell migration and invasion were also inhibited at similar low drug concentrations. However, 10-fold higher drug concentrations were required to inhibit cell growth in both AFP positive and negative cells. To investigate this concentration discrepancy of effects, cells were then grown for prolonged times and sub-cultured in low drug concentrations and then their growth was re-tested. The growth in these drug-exposed cells was found to be slower than cells without prior drug exposure and they were also more sensitive to subsequent drug challenge. Evidence was also found for changes in cell signaling pathways in these slow-growth cells. Low multikinase inhibitor concentrations thus modulate several aspects of HCC cell biology.

90K/Mac-2BP glycoprotein is involved in the immune defense against a variety of neoplasms and viral infections, modulating the activity of several effectors such as natural killer cells. Quite interestingly, 90K/Mac-2BP is associated to a poor response to interferon (IFN) alpha in hepatitis C virus (HCV) infected patients. Here, in 70 consecutive HCV chronic patients, we have evaluated 90K basal levels as a response predictor to combined therapy with Peginterferon and Ribavirin. We have found higher 90K levels in genotype 1/4 than in genotype 2/3 (p = 0.006) and in 62.5% of non-responders than in 20% of responders (p < 0.001). Genotype 1/4, higher 90K and gamma glutamyl transferase (gammaGT) levels resulted independently associated to a status of refractoriness to therapy. Consequently, evaluation of 90K serum levels seems to be a promising useful marker of response to combined therapy in HCV disease.

The purpose of the study was to evaluate 90K/MAC-2BP, a glycoprotein member of the Scavenger Receptor Cystein Rich superfamily, in the seminal plasma of infertile male patients with male accessory gland infection in order to investigate a putative autoimmune pathogenesis. 90K seminal concentration and sperm parameters were evaluated in 50 patients with male accessory gland infection at baseline and after cycles of treatment with Levofluoxacin 500 mg daily for 15 days plus serratiopeptidase 10 mg daily for 30 days. Treatment was continued for up to 6 cycles in cases of persistant bacteriospermia and/or clinical and ejaculatory signs of the disease. Patients with persistant male accessory gland infection after 6 cycles were defined as nonresponders. The same parameters were evaluated at baseline and after a 2-month period in 30 healthy controls. Patients with male accessory gland infection showed impaired sperm parameters and had lower seminal 90K concentration compared to controls. After treatment, seminal 90K level significantly increased in patients compared to controls. Twenty-two patients responded to treatment (44%), while 28 were nonresponders (56%). No difference in pretreatment and posttreatment sperm parameters and seminal 90K was observed between the 2 subgroups. Thirteen patients (26%) had identifiable bacteriospermia: significantly less pretreatment seminal 90K was observed compared to patients without bacteriospermia. Seminal 90K is decreased in patients with male accessory gland infection, and may be restored by a treatment with quinolones. However, the clinical utility of a 90K assay in these patients remains uncertain, as its level is not predictive of response to treatment.

In this study we assessed the prognostic significance of 90K/MAC-2BP serum levels in a group of 40 hepatocellular carcinoma patients. This glycoprotein is a new, interesting serum marker that reflects the immune reaction of the host against certain viral infections and tumors such as breast, ovarian and pancreatic cancer. Hepatocellular carcinoma (HCC) is one of the most widespread tumors in the world. AFP is currently the most useful marker for HCC, in spite of its poor diagnostic sensitivity. In this study 40 cirrhotic HCC patients were enrolled. The prevalence of viral hepatic infections in this group was 73% for HCV, 8% for HBV, and 8% for both viruses. Thirteen percent of the patients showed non-virus-related liver damage. 90K serum levels were assayed by an ELISA kit and AFP levels by a chemiluminescent enzyme immunometric system. The overall survival curves were estimated by the Kaplan-Meier method, taking into account age, sex, 90K and AFP serum levels. Statistical analysis showed a highly significant influence on overall survival of age below 70 years and 90K serum levels below the cutoff of 14 ng/mL. Serum AFP (≤20 ng/mL) had positive prognostic value only when it was associated with 90K levels (p

In the past 20 years, several factors were detected in the human seminal plasma and proposed as markers for spermatogenesis. Human chorionic gonadotropin (hCG) and its beta-subunit were therefore investigated, and their seminal levels were found to be higher than those detected in the serum and to correlate with sperm parameters.We designed a retrospective study to determine the suitability of hCG free beta-subunit concentration in the seminal plasma of fertile and infertile male patients as marker of spermatogenesis.A total of 79 infertile male patients were divided into four groups by their semen analysis results (group 1 [n=8]: azoospermia; group 2 [n=21]: severe oligozoospermia; group 3 [n=40]: oligoasthenospermia (OAS); group 4 [n=10]: asthenospermia) and 10 healthy volunteers of proven fertility were evaluated.The hCG free beta-subunit levels in the seminal plasma were found to be significantly higher (P0.0001) in the control group in respect to those assayed in the infertile patients and showed a correlation with sperm count (r=0.5) and total motile sperm density (r=0.5). Twenty-five patients were on treatment with oral Mesterolone (100mg daily) plus Tamoxifen (20mg daily) for 3-6 months. Apart from a significant improvement (P0.05) in sperm morphology, no significant changes in sperm count and motility were observed after the treatment in all the patients. In the seminal plasma of 10 patients who showed a significant increase in sperm count, hCG free beta-subunit levels were found to be significantly higher compared to those detected in the remaining patients (P0.01). In all patients, these levels remained unchanged after the treatment.The evidence regarding the positive correlation between hCG free beta-subunit levels in the seminal plasma and sperm concentration is consistent with the previous results regarding hCG levels. A previous study demonstrated that testosterone levels in seminal plasma correlated with sperm concentrations; from the same evidence regarding hCG we hypothesize that seminal plasma testosterone and hCG levels are correlated. Thus, hCG may play a paracrine role in the intratesticular regulation of testosterone secretion.

Glycoprotein 90K/MAC-2BP is a member of the scavenger receptor cystein-rich protein superfamily, which is thought to be involved in immune surveillance, defending the body against pathogens and cancer. 90K serum levels are elevated in patients with cancer of various origins and in viral infections, such as human immunodeficiency virus and hepatitis C virus (HCV). Because in patients with HCV-related cirrhosis the incidence of hepatocellular carcinoma (HCC) is high, in the present paper we examined, by means of an enzyme-linked immunosorbent assay, the 90K serum levels in 103 patients with liver cirrhosis, and in 69 with HCC, and compared them to alpha-fetoprotein, the reference tumor marker for this neoplasm. Serum levels of 90K (cut-off 14 microg/ml) were elevated both in cirrhosis (39%) and HCC (46%) compared to controls (14.1 microg/ml vs. 10.6 microg/ml in cirrhosis, and 14.8 microg/ml vs. 9.1 microg/ml in HCC, p < or = 0.001). There was a significant association with the presence of anti-HCV antibodies. 90K was found to be a non-specific tumor marker which is complementary to alpha-fetoprotein on the basis of its probable different biological significance. In fact, 74% of HCC patients had at least one positive marker. Combined use of 90K and alpha-fetoprotein could improve the sensitivity of a single test in the diagnosis of HCC.