Synergistic interaction of fatty acids and oxysterols impairs mitochondrial function and limits liver adaptation during nafld progression

The complete mechanism accounting for the progression from simple steatosis to steatohepatitis in nonalcoholic fatty liver disease (NAFLD) has not been elucidated. Lipotoxicity refers to cellular injury caused by hepatic free fatty acids (FFAs) and cholesterol accumulation. Excess cholesterol autoxidizes to oxysterols during oxidative stress conditions. We hypothesize that interaction of FAs and cholesterol derivatives may primarily impair mitochondrial function and affect biogenesis adaptation during NAFLD progression. We demonstrated that the accumulation of specific non-enzymatic oxysterols in the liver of animals fed high-fat+high-cholesterol diet induces mitochondrial damage and depletion of proteins of the respiratory chain complexes. When tested in vitro, 5α-cholestane-3β,5,6β-triol (triol) combined to FFAs was able to reduce respiration in isolated liver mitochondria, induced apoptosis in primary hepatocytes, and down-regulated transcription factors involved in mitochondrial biogenesis. Finally, a lower protein content in the mitochondrial respiratory chain complexes was observed in human non-alcoholic steatohepatitis. In conclusion, hepatic accumulation of FFAs and non-enzymatic oxysterols synergistically facilitates development and progression of NAFLD by impairing mitochondrial function, energy balance and biogenesis adaptation to chronic injury

B-type natriuretic peptide as a biochemical marker of left ventricular diastolic function: Assessment in asymptomatic patients 1 year after valve replacement for aortic stenosis.

Objectives: Left ventricular (LV) diastolic dysfunction after aortic valve replacement (AVR) carries a substantial risk of development of heart failure and reduced survival. In addition to echocardiography, B-type natriuretic peptide (BNP) provides a powerful incremental assessment of diastolic function. This study evaluates BNP as a marker of LV diastolic dysfunction in a cohort of patients with preserved LV ejection fraction who underwent AVR for pure aortic stenosis and the relationship between BNP values and the grade of LV diastolic dysfunction. Methods A total of 113 patients were included in the study. Echocardiographic evaluation was performed preoperatively, 5 days postoperatively and at 12-month follow-up, to assess LV dimensional and functional parameters. Diastolic function was labelled as normal, mild, moderate or severe dysfunction. Concomitantly, BNP levels were evaluated. Results Mild to severe diastolic dysfunction occurred preoperatively in all patients. At 12-month follow-up, 65 (62.5%) patients had mild and 25 (24.1%) moderate to severe diastolic dysfunction. BNP values, categorized for quartile distribution, correlated with diastolic dysfunction grade (P < 0.001 for each comparison). At receiver operating characteristic analysis, the BNP level of 120 pg/ml was 91% sensitive and 85% specific for diastolic disease, while 300 pg/ml was 80% sensitive and 91% specific for moderate or severe diastolic dysfunction. Twelve months after AVR, BNP values were strongly correlated with the significant echocardiographic parameters suggestive of diastolic dysfunction (P ≤ 0.006 in all cases). Conclusions The BNP level following AVR is related to diastolic disease severity and may complement echocardiographic evaluation when symptoms are unclear and LV function is difficult to interpret

Treatment of a rapidly expanding thoracoabdominal aortic aneurysm after endovascular repair of descending thoracic aortic aneurysm in an old patient.

Background: Aortic pathology progression and/or procedure related complications following endovascular repair should always be considered mostly in older patients. We herein describe a hybrid procedure for treatment of rapidly expanding thoracoabdominal aneurysm following endovascular treatment of a descending thoracic aortic aneurysm in an older patient. Case presentation: A 82-year-old man at 18 months after endovascular surgery for a contained rupture of descending thoracic aortic aneurysm revealed a type IV thoracoabdominal aneurysm with significant increase of the aortic diameters at superior mesenteric and renal artery levels. A hybrid approach consisting of preventive visceral vessel revascularization and endovascular repair of entire abdominal aorta was performed. Under general anaesthesia and by xyphopubic laparotomy, the infrarenal aneurysmatic aorta and common iliac arteries were replaced by a bifurcated woven prosthetic graf. From each of the prosthetic branches two reverse 14x7 mm bifurcated PTFE prosthetic grafts were anastomized to both renal arteries and to the celiac axis and superior mesenteric artery, respectively. Vessel ischemia was restricted to the time required for anastomosis. Three 10 cm Gore endovascular stent-grafts for a total length of 15 cm, were used. The overlapping of the stent-grafts was carried out from the bottom upwards, starting from the aorto-iliac prosthetic body up to the healthy segment of thoracic aorta, 40 mm from the previous stent-grafts. The patient was discharged on the 9th postoperative day. Conclusion: This technique offers the advantage of a less invasive treatment, reducing the risk of paraplegia, visceral ischaemia and pulmonary complications, mostly in older patients

Long-Term Results at 10 Years of Pouch Resizing for Roux-en-Y Gastric Bypass Failure

Background: Roux-en-Y gastric bypass (RYGB) is currently one of the most performed bariatric procedures and it is associated with rapid weight loss. However, weight loss failure and weight regain after RYGB occurs in approximately 30% and 3-5% of patients, respectively, and represent a serious issue. RYGB pouch resizing is a surgical option that may be offered to selected patients with RYGB failure. The aim of this study is to assess long-term results of pouch resizing for RYGB failure. Materials and Methods: From February 2009 to November 2011, 20 consecutive patients underwent gastric pouch resizing for RYGB failure in our tertiary bariatric center. The primary outcome was the rate of failure (%EWL &lt; 50% with at least one metabolic comorbidity) after at least 10 years from pouch resizing. Gastroesophageal Reflux Disease (GERD) was also assessed. Results: Twenty patients (18 women (90%)) were included and seventeen (85%) joined the study. The failure rate of pouch resizing was 47%. Mean %EWL and mean BMI were 47%, and 35.1 kg/m(2), respectively. Some of the persistent co-morbidities further improved or resolved after pouch resizing. Seven patients (41%) presented GERD requiring daily PPI with a significantly lower GERD-HQRL questionnaire score after pouch resizing (p &lt; 0.001). Conclusion: Pouch resizing after RYGB results in a failure rate of 47% at the 10-year follow-up while the resolution of comorbidities is maintained over time despite a significant weight regain

Results ofstandard stapler closure of pancreatic remnanat after distal spleno-pancreatectomy for adenocarcinoma

Background/Aim: The purpose of this study was to evaluate the results of stapled closure of the pancreatic remnant after cold-knife section of the pancreatic isthmus and distal pancreatectomy for adenocarcinoma. Methods: A retrospective evaluation of 57 consecutive patients undergoing distal spleno-pancreatectomy for adenocarcinoma was performed. The pancreatic isthmus was systematically straight-sectioned with a cold knife, and the remnant was stapled close without additional stitches or adjuncts. The study’s main endpoints were postoperativemortality, the occurrence of a pancreatic fistula, the need for a re-operation, the postoperative length of stay in the hospital, the rate of re-admission, and late survival. Results: Postoperative mortality was absent. Seventeen patients (29.8%) presented a pancreatic fistula of grade A in seven cases (41.2%), grade B in eight cases (47.1%), and grade C in two cases (11.8%). Re-operation was required in the two patients (3.5%) with grade C fistula in order to drain an intra-abdominal abscess. The mean postoperative length of stay in the hospital was 15 days (range, 6–62 days). No patient required re-admission. Twenty-nine patients (50.8%) were alive and free from disease, respectively, 12 patients (21.1%) at 12 months, 13 patients (22.8%) at 60 months, and four patients (7.0%) at 120 months from the operation. The remaining patients died of metastatic disease 9–37 months from the operation. Lastly, disease-related mortality was 49.1%. Conclusion: Stapler closure of the pancreatic remnant allows good postoperative results, limiting the formation of pancreatic fistula to the lower limit of its overall reported incidence

HDAC class I inhibitor domatinostat sensitizes pancreatic cancer to chemotherapy by targeting cancer stem cell compartment via FOXM1 modulation

Pancreatic ductal adenocarcinoma (PDAC) represents an unmet clinical need due to the very poor prognosis and the lack of effective therapy. Here we investigated the potential of domatinostat (4SC-202), a new class I histone deacetylase (HDAC) inhibitor, currently in clinical development, to sensitize PDAC to first line standard gemcitabine (G)/taxol (T) doublet chemotherapy treatment. Methods: Synergistic anti-tumor effect of the combined treatment was assessed in PANC1, ASPC1 and PANC28 PDAC cell lines in vitro as well as on tumor spheroids and microtissues, by evaluating combination index (CI), apoptosis, clonogenic capability. The data were confirmed in vivo xenograft models of PANC28 and PANC1 cells in athymic mice. Cancer stem cells (CSC) targeting was studied by mRNA and protein expression of CSC markers, by limiting dilution assay, and by flow cytometric and immunofluorescent evaluation of CSC mitochondrial and cellular oxidative stress. Mechanistic role of forkhead box M1 (FOXM1) and downstream targets was evaluated in FOXM1-overexpressing PDAC cells. Results: We showed that domatinostat sensitized in vitro and in vivo models of PDAC to chemotherapeutics commonly used in PDAC patients management and particularly to GT doublet, by targeting CSC compartment through the induction of mitochondrial and cellular oxidative stress. Mechanistically, we showed that domatinostat hampers the expression and function of FOXM1, a transcription factor playing a crucial role in stemness, oxidative stress modulation and DNA repair. Domatinostat reduced FOXM1 protein levels by downregulating mRNA expression and inducing proteasome-mediated protein degradation thus preventing nuclear translocation correlated with a reduction of FOXM1 target genes. Furthermore, by overexpressing FOXM1 in PDAC cells we significantly reduced domatinostatinducing oxidative mitochondrial and cellular stress and abolished GT sensitization, both in adherent and spheroid cells, confirming FOXM1 crucial role in the mechanisms described. Finally, we found a correlation of FOXM1 expression with poor progression free survival in PDAC chemotherapy-treated patients