Antagonist of Growth Hormone-Releasing Hormone Potentiates the Antitumor Effect of Pemetrexed and Cisplatin in Pleural Mesothelioma.

Pleural mesothelioma (PM) is an aggressive cancer with poor prognosis and no effective therapies, mainly caused by exposure to asbestos. Antagonists of growth hormone-releasing hormone (GHRH) display strong antitumor effects in many experimental cancers, including lung cancer and mesothelioma. Here, we aimed to determine whether GHRH antagonist MIA-690 potentiates the antitumor effect of cisplatin and pemetrexed in PM. In vitro, MIA-690, in combination with cisplatin and pemetrexed, synergistically reduced cell viability, restrained cell proliferation and enhanced apoptosis, compared with drugs alone. In vivo, the same combination resulted in a strong growth inhibition of MSTO-211H xenografts, decreased tumor cell proliferation and increased apoptosis. Mechanistically, MIA-690, particularly with chemotherapeutic drugs, inhibited proliferative and oncogenic pathways, such as MAPK ERK1/2 and cMyc, and downregulated cyclin D1 and B1 mRNAs. Inflammatory pathways such as NF-kB and STAT3 were also reduced, as well as oxidative, angiogenic and tumorigenic markers (iNOS, COX-2, MMP2, MMP9 and HMGB1) and growth factors (VEGF and IGF-1). Overall, these findings strongly suggest that GHRH antagonists of MIA class, such as MIA-690, could increase the efficacy of standard therapy in PM.

Autism Spectrum Disorder from the Womb to Adulthood: Suggestions for a Paradigm Shift.

The wide spectrum of unique needs and strengths of Autism Spectrum Disorders (ASD) is a challenge for the worldwide healthcare system. With the plethora of information from research, a common thread is required to conceptualize an exhaustive pathogenetic paradigm. The epidemiological and clinical findings in ASD cannot be explained by the traditional linear genetic model, hence the need to move towards a more fluid conception, integrating genetics, environment, and epigenetics as a whole. The embryo-fetal period and the first two years of life (the so-called 'First 1000 Days') are the crucial time window for neurodevelopment. In particular, the interplay and the vicious loop between immune activation, gut dysbiosis, and mitochondrial impairment/oxidative stress significantly affects neurodevelopment during pregnancy and undermines the health of ASD people throughout life. Consequently, the most effective intervention in ASD is expected by primary prevention aimed at pregnancy and at early control of the main effector molecular pathways. We will reason here on a comprehensive and exhaustive pathogenetic paradigm in ASD, viewed not just as a theoretical issue, but as a tool to provide suggestions for effective preventive strategies and personalized, dynamic (from womb to adulthood), systemic, and interdisciplinary healthcare approach.

Dietary approach and gut microbiota modulation for chronic hepatic encephalopathy in cirrhosis.

Hepatic encephalopathy (HE) is a common and serious neuropsychiatric complication of cirrhosis, acute liver failure, and porto-systemic shunting. HE largely contributes to the morbidity of patients with liver disease, severely affecting the quality of life of both patients and their relatives and being associated with poor prognosis. Its presentation is largely variable, manifesting with a broad spectrum of cognitive abnormalities ranging from subtle cognitive impairment to coma. The pathogenesis of HE is complex and has historically been linked with hyperammonemia. However, in the last years, it has become evident that the interplay of multiple actors, such as intestinal dysbiosis, gut hyperpermeability, and neuroinflammation, is of crucial importance in its genesis. Therefore, HE can be considered a result of a dysregulated gut-liver-brain axis function, where cognitive impairment can be reversed or prevented by the beneficial effects induced by "gut-centric" therapies, such as non-absorbable disaccharides, non-absorbable antibiotics, probiotics, prebiotics, and fecal microbiota transplantation. In this context dietary modifications, by modulating the intestinal milieu, can also provide significant benefit to cirrhotic patients with HE. This review will provide a comprehensive insight into the mechanisms responsible for gut-liver-brain axis dysregulation leading to HE in cirrhosis. Furthermore, it will explore the currently available therapies and the most promising future treatments for the management of patients with HE, with a special focus on the dietary approach.

HLA-DQ Genotyping, Duodenal Histology, and Response to Exclusion Diet in Autistic Children With Gastrointestinal Symptoms.

OBJECTIVES: A correlation between autism spectrum disorders (ASDs) and gastrointestinal (GI) problems, and a possible link between gluten consumption and ASD have been increasingly reported. Gluten/casein-free diet (GCFD) is often undertaken, with conflicting results. This study aimed at evaluating the distribution of human leukocyte antigen (HLA)-DQ2/DQ8 typing among patients with ASD with GI symptoms, together with its correlation with duodenal histology and response to GCFD. METHODS: Between 2002 and 2015 all patients with ASD with GI symptoms referred to our outpatient clinic, displaying clinical, laboratory, or ultrasound findings suggestive of organic disease, underwent endoscopy, celiac disease (CD) serum antibodies testing and HLA-DQ2/DQ8 genotyping. Patients were prescribed a 6-month GCFD, and then clinically reassessed. RESULTS: Among 151 enrolled patients, 134 (89%) were negative for CD-specific antibodies; 72 (48%) were positive for HLA-DQ2/DQ8; and 56 (37%) showed duodenal microscopic inflammation. Clinical improvement was observed in non-CD patients irrespective of the rigorous or partial adherence to the diet, being the difference nonstatistically significant. Response to diet was related to the presence of histological duodenal alterations at baseline (odds ratio 11.323, 95% confidence interval 1.386-92.549 for Marsh 2 pattern), but not to HLA-DQ2/DQ8 positivity (odds ratio 1.120, 95% confidence interval 0.462-2.716). CONCLUSIONS: Our data suggest that children with ASD with GI symptoms have a high prevalence of duodenal intraepithelial lymphocytic infiltration, which seems to be linked to a mechanism other than autoimmune response to gluten consumption. Alteration of duodenal histology, but not the HLA-DQ2/DQ8 status, was associated with clinical response to the diet.

The role of microbiota in autism spectrum disorders.

Autism spectrum disorder (ASD) defines a set of neurodevelopmental disorders characterized by persistent deficits in social communication and interaction, along with repetitive patterns of behavior. Symptoms generally appear in the early developmental period and cause significant impairment in individual and social functioning. In recent years the increased prevalence of ASD, along with the evidence of a significant link between autism and gastrointestinal (GI) disturbances, raised a special interest in exploring the reciprocal influences between gut and brain. Investigators highlighted the existence of a so-called "gut-brain axis," empowering the hypothesis that GI abnormalities could trigger neuropsychiatric symptoms in ASD. Intestinal microbiota is thought to play a pivotal role in gut and systemic homeostasis, in central nervous system development, as well as in behavioral modulation and recurrent microbial imbalances have been shown in gut microbiota of autistic people. In this review we analyze current knowledge about intestinal microbiota and the relevance and role of dysbiosis in ASD. The most accredited theories about gut-brain interaction will be reviewed, along with current scientific evidence supporting the relationship between microbial imbalances and impairment of neurodevelopment. Finally, we will focus on the results of different therapeutic approaches in this context: administration of pre- and probiotics, antibiotics, fecal microbiota transplantation and special diets and dietary supplements.

Is serum uric acid a predictive factor of response to IFN-treatment in patients with chronic hepatitis C infection?

Several factors, including metabolic profile, are predictive of response to standard antiviral therapy in patients with chronic hepatitis C. In a retrospective study, it was investigated whether uric acid, involved in metabolic syndrome, could be included. A total of 153 patients (56.2% males; mean age 45.7 +/- 11.3 years) treated with pegylated-interferon and ribavirin were included. Eighty-five were infected with hepatitis C virus (HCV) genotype 1 or 4 and 68 with genotype 2 or 3. Viral load was >1,000,000 IU/ml in 101, < or =1,000,000 IU/ml in 35 and unknown in 17 patients. Ishak fibrosis score was < or =4 in 81, >4 in 15 and unknown in 57 patients. Mean serum uric acid was 5.05 +/- 1.3 mg/dl. Sustained virological response (negative serum HCV-RNA 6 months after treatment cessation) was achieved in 102 patients (67%). In the final logistic model, serum uric acid level > or =5.8 mg/dl (OR = 0.46; 95% CI: 0.30-0.62), viral load (OR = 0.29; 95% CI: 0.09-0.92) and HCV genotype (OR = 0.23; 95% CI: 0.09-0.60) were identified as the most important factors independently influencing clinical outcome. The prognostic role of serum uric acid was confirmed on the sub-sample reporting Ishak fibrosis score (OR = 0.49; 95% CI: 0.28-0.85). Serum uric acid level > or =5.8 mg/dl is predictive of poor response to HCV treatment. Prospective studies are needed to clarify the issue.

Daily dose of interferon alpha-2b and ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection: a randomised controlled study.

OBJECTIVE: The treatment of patients with hepatitis C virus (HCV) genotype 1 infection remains disappointing. METHODS: In 1999, we started a multicentre study comparing two regimens of recombinant interferon (IFN) alpha-2b plus ribavirin. Group A (90 patients) received ribavirin plus IFN alpha-2b 5 MU/day for 1 month (induction therapy) followed by IFN alpha-2b 5 MU thrice weekly for 5 months. Group B (85 patients) received ribavirin plus IFN alpha-2b 5 MU thrice weekly for 6 months. Responders in both arms received IFN alpha-2b 3 MU thrice weekly for a further 6 months. A follow-up evaluation was performed at 18 months. RESULTS: One hundred and seventy-five consecutive treatment-naive patients with HCV genotype 1 infection were enrolled in the study. A sustained virological response (SVR) was obtained in 51 (29%) patients: 28 in group A (31%) and 23 in group B (27%). HCV-RNA clearance was greater at 3 months among patients who received induction therapy (57 vs 39%; p < 0.02). Age, sex, and initial viral load did not influence the achievement of a SVR. HCV clearance at the end of the study was lower in cirrhotic patients (3/26 vs 48/149; p < 0.05). The only SVR in patients with cirrhosis occurred in those from group A (p < 0.05). Both regimens were well tolerated. CONCLUSIONS: This study confirms the low rate of SVR in treatment-naive patients with HCV genotype 1 infection treated with IFN alpha-2b plus ribavirin. A 4-week induction regimen was slightly superior to standard IFN alpha-2b plus ribavirin. Although the number of patients with cirrhosis was low, induction therapy seemed to be more effective in cirrhotics. Given its safety and tolerability, the induction regimen evaluated here may be a therapeutic option in treatment-naive patients with HCV genotype 1 infection.

Feasibility and safety of G-CSF administration to induce bone marrow-derived cells mobilization in patients with end stage liver disease.

BACKGROUND/AIMS: To evaluate feasibility, safety and pattern of bone marrow-derived cells (BMC) mobilization in patients with end stage liver cirrhosis following granulocyte-colony stimulating factor (G-CSF) administration. METHODS: Eight patients with severe liver cirrhosis (Child-Pugh score B-C, spleen diameter less than 170 mm) were included. They were treated with G-CSF (5 microg/kg b.i.d for three consecutive days) to mobilize BMC, evaluated as circulating CD34+ve cells (flow cytometry) and myeloid CFU-GM progenitors (in vitro colony growth assay). Co-expression in CD34+ve cells markers of differentiation (Thy1, CD133, CXCR4, c1qRp) were investigated on CD34+ve cells by double direct immunofluorescence. Data from 40 healthy haematopoietic stem cell donors were used as controls. RESULTS: Mobilization of CD34+ve cells occurred in all patients. It was paralleled by expansion of circulating CFU-GM progenitors. Circulating CD34+ve cells co-expressed epithelial and stem cell markers in both cirrhotics and volunteer stem cell donors. G-CSF was well tolerated, no adverse event occurred, a significant reversible increase of splenic longitudinal diameter was observed. CONCLUSIONS: (i) G-CSF mobilization of BMC co-expressing epithelial and stem markers occurred in all cirrhotic patients; (ii) splenomegaly up to 170 mm does not prevent safe BMC mobilization following G-CSF in patients with end stage liver disease; (iii) mobilized BMC may represent an easy immature cell source potentially useful for novel approaches for liver regeneration.

Posttransplantation chronic renal damage in nonrenal transplant recipients.

BACKGROUND: The growing problem of relentless deterioration of renal function in patients who undergo transplantation of nonrenal solid organs is bound to have an increasingly important impact as it may not only worsen patient morbidity and mortality but also increase transplantation costs. METHODS: We reviewed the literature in order to provide a sum of the most important data on the incidence, clinical picture, renal pathology pattern, damage mechanisms, and risk factors, along with strategies for prevention and treatment of chronic renal damage following nonrenal solid organ transplantation. RESULTS: Literature data report that 10% to 80% of transplanted patients have some degree of renal dysfunction and that they share a common clinical picture characterized by relentless asymptomatic progression, frequent hypertension, mild urinary abnormalities, and pathology features of vascular, glomerular, tubular, and interstitial involvement. These changes are very similar to those reported for chronic nephrotoxicity from calcineurin inhibitors. The occurrence of end-stage renal disease (ESRD) requiring chronic dialysis has been reported in up to 20% of nonrenal transplant recipients. Although there are some organ-specific differences, a group of common risk factors has been recognized, including the use of calcineurin inhibitors as immunosuppressive agents, age, pretransplantation renal function, intraoperative/perioperative factors, concomitant use of other nephrotoxic drugs, infections, and posttransplantation acute renal failure. CONCLUSION: Calcineurin inhibitor-induced nephrotoxicity is a growing problem and, as the age of recipients of nonrenal organs is increasing, this problem is destined to increase. It would therefore be advisable for nephrologists to share their experiences in immunomodulation with other specialties, so as to favor the cautious extension of calcineurin inhibitor-sparing protocols to the area of life-saving transplants.