Bariatric Revisionary Surgery for Failed or Complicated Vertical Banded Gastroplasty (VBG): Comparison of VBG Reoperation (re-VBG) versus Roux-en-Y Gastric Bypass-on-VBG (RYGB-on-VBG)

Background. Revision of failed bariatric procedures is a significant challenge for bariatric surgeons, because of the increasing number of recurring morbid obesity or complications, especially in patients with a previous Vertical Banded Gastroplasty (VBG). Methods. Since November 1998, 109 patients with failed or complicated VBG were followed in a retrospective study. 49 patients underwent re-VBG and, since 2004, 60 underwent Roux-en-Y Gastric Bypass-on-Vertical Banded Gastroplasty (RYGB-on-VBG). Results. At 3 years follow-up, mean BMI decreased from 37.4 to 31.2 Kg/m2 in the first group, and from 35.0 to 28.4 Kg/m2 in the second. Early complications were 7 (14.3%) in the first group and 4 (6.5%) in the second; late complications were 33 (59.1%) and 11 (18.3%), respectively. Conclusion. Although both operations seem to be effective as bariatric revision procedures in terms of BMI, the mid-term outcomes of RYGB-on-VBG demonstrate the lowest rate of complications and better quality of life

LPS-induced TNF-α factor mediates pro-inflammatory and pro-fibrogenic pattern in non-alcoholic fatty liver disease

Lipopolysaccharide (LPS) is currently considered one of the major players in non-alcoholic fatty liver disease (NAFLD) pathogenesis and progression. Here, we aim to investigate the possible role of LPS-induced TNF-α factor (LITAF) in inducing a pro-inflammatory and pro-fibrogenic phenotype of non-alcoholic steatohepatitis (NASH).We found that children with NAFLD displayed, in different liver-resident cells, an increased expression of LITAF which correlated with histological traits of hepatic inflammation and fibrosis. Total and nuclear LITAF expression increased in mouse and human hepatic stellate cells (HSCs). Moreover, LPS induced LITAF-dependent transcription of IL-1β, IL-6 and TNF-α in the clonal myofibroblastic HSC LX-2 cell line, and this effect was hampered by LITAF silencing. We showed, for the first time in HSCs, that LITAF recruitment to these cytokine promoters is LPS dependent. However, preventing LITAF nuclear translocation by p38MAPK inhibitor, the expression of IL-6 and TNF-α was significantly reduced with the aid of p65NF-ĸB, while IL-1β transcription exclusively required LITAF expression/activity. Finally, IL-1β levels in plasma mirrored those in the liver and correlated with LPS levels and LITAF-positive HSCs in children with NASH.In conclusion, a more severe histological profile in paediatric NAFLD is associated with LITAF over-expression in HSCs, which in turn correlates with hepatic and circulating IL-1β levels outlining a panel of potential biomarkers of NASH-related liver damage. The in vitro study highlights the role of LITAF as a key regulator of the LPS-induced pro-inflammatory pattern in HSCs and suggests p38MAPK inhibitors as a possible therapeutic approach against hepatic inflammation in NASH

Mitogen-activated kinase kinase kinase 1 inhibits hedgehog signaling and medulloblastoma growth through GLI1 phosphorylation

The aberrant activation of hedgehog (HH) signaling is a leading cause of the development of medulloblastoma, a pediatric tumor of the cerebellum. The FDA‑approved HH inhibitor, Vismodegib, which targets the transmembrane transducer SMO, has shown limited efficacy in patients with medulloblastoma, due to compensatory mechanisms that maintain an active HH‑GLI signaling status. Thus, the identification of novel actionable mechanisms, directly affecting the activity of the HH‑regulated GLI transcription factors is an important goal for these malignancies. In this study, using gene expression and reporter assays, combined with biochemical and cellular analyses, we demonstrate that mitogen‑activated kinase kinase kinase 1 (MEKK1), the most upstream kinase of the mitogen‑activated protein kinase (MAPK) phosphorylation modules, suppresses HH signaling by associating and phosphorylating GLI1, the most potent HH‑regulated transcription factor. Phosphorylation occurred at multiple residues in the C‑terminal region of GLI1 and was followed by an increased association with the cytoplasmic proteins 14‑3‑3. Of note, the enforced expression of MEKK1 or the exposure of medulloblastoma cells to the MEKK1 activator, Nocodazole, resulted in a marked inhibitory effect on GLI1 activity and tumor cell proliferation and viability. Taken together, the results of this study shed light on a novel regulatory mechanism of HH signaling, with potentially relevant implications in cancer therapy

Toxicity of enzymatic oxidation products of spermine to human melanoma cells (M14): sensitisation by heat and MDL 72527

AbstractIn situ formation of cytotoxic metabolites by an enzyme-catalyzed reaction is a recent approach in cancer chemotherapy. We demonstrate that multidrug resistant human melanoma cells (M14 ADR) are more sensitive than the corresponding wild type cells (M14 WT) to hydrogen peroxide and aldehydes, the products of bovine serum amine oxidase (BSAO)-catalyzed oxidation of spermine. Hydrogen peroxide was mainly responsible for the loss of cell viability. With about 20%, the aldehydes formed from spermine contribute also to cytotoxicity. Elevation of temperature from 37 °C to 42 °C decreased survival of both cell lines by about one log unit. Pre-treatment with N1,N4-bis(2,3-butadienyl)-1,4-butanediamine (MDL 72527), a lysosomotropic compound, sensitized cells to toxic spermine metabolites. MDL 72527 (at 300 μM) produced in M14 cells numerous cytoplasmic vacuoles which, however, disappeared by 24 h, even in the presence of the drug. Mitochondrial damage, as observed by transmission electron microscopy, correlated better with the cytotoxic effects of the treatment than vacuole formation. Since the release of lysosomal enzymes causes oxidative stress and apoptosis, we suggest that the lysosomotropic effect of MDL 72527 is the major reason for its sensitizing effect

Endoplasmic Reticulum stress induces hepatic stellate cell apoptosis and contributes to fibrosis resolution.

BACKGROUND: Survival of hepatic stellate cells (HSCs) is a hallmark of liver fibrosis, while the induction of HSC apoptosis may induce recovery. Activated HSC are resistant to many pro-apoptotic stimuli. To this issue, the role of Endoplasmic Reticulum (ER) stress in promoting apoptosis of HSCs and consequently fibrosis resolution is still debated. AIM: To evaluate the potential ER stress-mediated apoptosis of HSCs and fibrosis resolution METHODS: HSCs were incubated with the ER stress agonists, tunicamycin or thapsigargin. In vivo, HSC were isolated from normal, bile duct-ligated (BDL) and bile duct-diverted (BDD) rats. RESULTS: In activated HSC, the specific inhibitor of ER stress-induced apoptosis, calpastatin, is significantly increased vs. quiescent HSCs. Calpain is conversely reduced in activated HSCs. This pattern of protein expression provides HSCs resistance to the ER stress signals of apoptosis (apoptosis-resistant phenotype). However, both tunicamycin and thapsigargin are able to induce apoptosis in HSCs in vitro, completely reversing the calpain/calpastatin pattern expression. Furthermore, in vivo, the fibrosis resolution observed in rat livers subjected to bile duct ligation (BDL) and subsequent bile duct diversion (BDD), leads to fibrosis resolution through a mechanism of HSCs apoptosis, potentially associated with ER stress: in fact, BDD rat liver shows an increased number of apoptotic HSCs associated with reduced calapstatin and increased calpain protein expression, leading to an apoptosis-sensible phenotype. CONCLUSIONS: ER stress sensitizes HSC to apoptosis both in vitro and in vivo. Thus, ER stress represents a key target to trigger cell death in activated HSC and promotes fibrosis resolution

The Impact of Lifestyle Interventions in High-Risk Early Breast Cancer Patients: A Modeling Approach from a Single Institution Experience

none21noA healthy lifestyle plays a strategic role in the prevention of BC. The aim of our prospective study is to evaluate the effects of a lifestyle interventions program based on special exercise and nutrition education on weight, psycho-physical well-being, blood lipid and hormonal profile among BC patients who underwent primary surgery. From January 2014 to March 2017, a multidisciplinary group of oncologists, dieticians, physiatrists and an exercise specialist evaluated 98 adult BC female patients at baseline and at different time points. The patients had at least one of the following risk factors: BMI ≥ 25 Kg/m2, high testosterone levels, high serum insulin levels or diagnosis of MS. Statistically significant differences are shown in terms of BMI variation with the lifestyle interventions program, as well as in waist circumference and blood glucose, insulin and testosterone levels. Moreover, a statistically significant difference was reported in variations of total Hospital Anxiety and Depression Scale (HADS) score, in the anxiety HADS score and improvement in joint pain. Our results suggested that promoting a healthy lifestyle in clinical practice reduces risk factors involved in BC recurrence and ensures psycho-physical well-being.openMirco Pistelli, Valentina Natalucci, Laura Scortichini, Veronica Agostinelli, Edoardo Lenci, Sonia Crocetti, Filippo Merloni, Lucia Bastianelli, Marina Taus, Daniele Fumelli, Gloria Giulietti, Claudia Cola, Marianna Capecci, Roberta Serrani, Maria Gabriella Ceravolo, Maurizio Ricci, Albano Nicolai, Elena Barbieri, Giulia Nicolai, Zelmira Ballatore, Agnese Savini and Rossana BerardiPistelli, Mirco; Natalucci, Valentina; Scortichini, Laura; Agostinelli, Veronica; Lenci, Edoardo; Crocetti, Sonia; Merloni, Filippo; Bastianelli, Lucia; Taus, Marina; Fumelli, Daniele; Giulietti, Gloria; Cola, Claudia; Capecci, Marianna; Serrani, Roberta; Gabriella Ceravolo, Maria; Ricci, Maurizio; Nicolai, Albano; Barbieri, Elena; Nicolai, Giulia; Ballatore, Zelmira; Savini and Rossana Berardi, Agnes

Indici per la valutazione della qualit? ecologica dei laghi

Collection of methods to evaluate lake quality using biological element

The Exendin-4 in experimental therapy of NASH

Base di partenza scientifica/scopo dello studio: Una dieta ad alto contenuto lipidico ed uno stile di vita sedentario, tipico dei paesi occidentali, portano a sviluppare insulino-resistenza e nonalcoholic fatty liver disease (NAFLD)/steatoepatite (NASH). Recenti studi hanno dimostrato che il Glucagon-like-peptide-1 (Glp-1) è in grado di influenzare il metabolismo glucidico epatico. Lo scopo del nostro studio è stato quello di dimostrare la presenza nel fegato del suo specifico recettore (Glp-1R), e di valutare l’effetto dell’exendina-4, un analogo del Glp-1, sui meccanismi epatici di trasduzione del segnale. Metodi: L’espressione del Glp-1R è stata valutata in biopsie epatiche umane e nei fegati provenienti da ratti trattati con dieta ad alto contenuto lipidico (High-Fat Diet, HFD). L’effetto dell’exendina-4 (100nM) è stato valutato in epatociti isolati da ratti alimentati per tre mesi con HFD. Risultati: Glp-1R è espresso nel fegato umano, sebbene ridotto in pazienti affetti da NASH. Analogamente, negli epatociti isolati da ratti NASH, alimentati per tre mesi con HFD, l’espressione del recettore per il Glp1 e di PPARγ e l’attività di PPARα risultano essere diminuite rispetto agli epatociti isolati da ratti alimentati con dieta di controllo. L’incubazione degli epatociti con exendina-4, aumenta l’espressione di PPARγ, che esercita la sua azione insulino-sensibilizzante, riducendo la fosforilazione di JNK. Inoltre l’exendina-4 aumenta l’attività di PKA, e la fosforilazione di Akt e AMPK, determinando un aumento PKA-dipendente dell’attività di PPARα. Conclusioni: Il Glp1 ha un diretto effetto sugli epatociti, attivando geni coinvolti nella β-ossidazione degli acidi grassi, e nell’insulino-sensibilità. Gli analoghi del Glp1 potrebbero essere un promettente approccio terapeutico nel trattamento dell’insulino-resistenza, in pazienti affetti da NAFLD/NASH