Incretin mimetics as a novel therapeutic option for hepatic steatosis.

BACKGROUND: Fat accumulation in the liver or non-alcoholic fatty liver disease (NAFLD) is regarded as a key pathogenic factor and component of the metabolic syndrome. It was reported that administration of the incretin mimetic exenatide reversed hepatic steatosis in an obese mouse model. We had the opportunity to study the effect of additional exenatide administration on liver fat content in a patient with type 2 diabetes. CASE REPORT: A 59-year-old male with poorly controlled type 2 diabetes was treated with exenatide in addition to metformin monotherapy. Following 44 weeks of exenatide therapy, mean the liver fat measured by liver spectroscopy declined from 15.8% to 4.3%. This dramatic decrease in liver fat was accompanied by significant beneficial changes in several cardiovascular disease risk factors and improvement of all liver enzymes, in particular alanine aminotransferase, the most important marker of liver steatosis. CONCLUSION: This case report suggests that the incretin mimetic exenatide decreases hepatic fat accumulation and may play a role in the future treatment of NAFLD, and the associated insulin resistance and cardiovascular risk factors in an ever-growing high-risk population.     

The Ki-67 protein interacts with members of the heterochromatin protein 1 (HP1) family: a potential role in the regulation of higher-order chromatin structure.

The expression of the nuclear protein Ki-67 (pKi-67) is strictly correlated with cell proliferation. Because of this, anti-Ki-67 antibodies can be used as operational markers to estimate the growth fraction of human neoplasia in situ. For a variety of tumours, the assessment of pKi-67 expression has repeatedly been proven to be of prognostic value for survival and tumour recurrence, but no cellular function has yet been ascribed to the Ki-67 protein. This study shows that a C-terminal domain of pKi-67 (Kon21) is able to bind to all three members of the mammalian heterochromatin protein 1 (HP1) family in vitro and in vivo. This interaction can be manipulated in living cells, as evidenced by ectopic expression of GFP-tagged HP1 proteins in HeLa cells, which results in a dramatic relocalization of endogenous pKi-67. Taken together, the data presented in this study suggest a role for pKi-67 in the control of higher-order chromatin structure.     

Quantitative proton magnetic resonance spectroscopy of cerebral metabolic disturbances in patients with MELAS

Four patients with clinically and genetically defined MELAS were examined using quantitative localized proton magnetic resonance spectroscopy of the brain. Acute and chronic lesions were located in the occipital lobe and mostly characterized by strongly elevated concentrations of lactate (Lac) and glucose (GIc) as well as severely reduced concentrations of total N-acetylaspartyl compounds (tNAA, neuroaxonal markers), glutamate (Glu), and total creatine. These findings indicate a high degree of nonoxidative glycolysis reflecting either impaired oxidative energy metabolism or the use of anaerobic metabolism by infiltrating macrophages as well as damage or loss of viable neuroaxonal tissue. In contrast, glial cell populations, in particular astrocytes, seem to remain unaffected as evidenced by unchanged concentrations of myo-inositol (glial marker). In addition, all patients including one who never experienced a stroke-like episode showed elevated Lac and Glc as well as reduced tNAA and Glu in tissues appearing normal on MRI. These disturbances were stronger in cortical gray matter and cerebellum than in white matter and indicate that neuroaxonal damage is not restricted to structural lesions. The steady presence of Lac is consistent with a reduced capacity of the mitochondrial oxidative energy metabolism resulting from impaired respiratory chain function.     

Tryptophan 650 of human granulocyte colony-stimulating factor (G-CSF) receptor, implicated in the activation of JAK2, is also required for G- CSF-mediated activation of signaling complexes of the p21ras route

Granulocyte colony-stimulating factor (G-CSF) induces rapid phosphorylation of JAK kinases as well as activation of the p21ras route through interaction with its specific receptor (G-CSF-R). The cytoplasmic membrane-proximal region of G-CSF-R (amino acids 631 to 684) is necessary for proliferation induction and activation of JAK2. In contrast, activation of Shc and Syp, signaling molecules implicated in the p21ras signaling route, depends on the phosphorylation of tyrosine residues located in the membrane-distal region (amino acids 685 to 813) of G-CSF-R. We investigated whether G-CSF-induced activation of signaling complexes of the p21ras route depends on the function of the membrane-proximal cytoplasmic region of G-CSF-R. A G- CSF-R mutant was constructed in which tryptophan 650 was replaced by arginine and expressed in BAF3 cells (BAF/W650R). In contrast to BAF3 cell transfectants expressing wild-type G-CSF-R, BAF/W650-R cells did not proliferate and did not show activation of JAK2, STAT1, or STAT3 in response to G-CSF. Immunoprecipitations with anti-Shc and anti-Grb2 antisera showed that mutant W650R also failed to activate Syp and Shc. These data indicate that the membrane-proximal cytoplasmic domain of G- CSF-R is not only crucial for proliferative signaling and activation of JAK2 and STATs, but is also required for activation of the p21ras route, which occurs via the membrane-distal region of G-CSF-R.     

Surgical Management of Gastro-oesophageal Reflux Disease After One Anastomosis Gastric Bypass — a Systematic Review

Gastro-oesophageal reflux disease (GORD) after one anastomosis gastric bypass (OAGB) remains a concern. We reviewed the current literature on revisional surgery after OAGB for GORD. MEDLINE, EMBASE, and PubMed databases were searched. We identified 21 studies, appraising 13,658 OAGB patients. A total of 230 (1.6%) patients underwent revisional surgery for GORD. Revision to Roux-en-Y configuration was performed in 211 (91.7%) patients. Six (2.6%) patients had a Braun entero-enterostomy added to the OAGB. Thirteen (5.6%) patients underwent excluded stomach fundoplication (ESF). Reflux symptoms resolved in 112 (48.6%) patients, persisted in 13 (5.6%) patients, and were not reported in 105 (45.6%) patients. Revisional surgery after OAGB for GORD appears to be rare, and when required, conversion to Roux-en-Y configuration is the commonest choice.

     

Quality assessment of robot assisted thoracic surgical resection of non-small cell lung cancer: nodal upstaging and mediastinal recurrence

BackgroundRobot assisted thoracic surgery (RATS) is the minimally invasive surgical technique of choice for treatment of patients with non-small cell lung cancer (NSCLC), at the Isala Hospital. The aim of this study is to compare clinical and pathological staging results and mediastinal recurrence after RATS for anatomical resections of lung cancer as surrogate markers for quality of mediastinal lymph node dissection (MLND).MethodsThis single institute retrospective study was conducted in patients who underwent RATS for NSCLC. Excluded were patients with a history of concurrent malignant disease, with other previous neoplasms, with small cell lung cancer (SCLC) and patients in whom the robotic technique was converted to thoracotomy, prior to lymph node dissection. Data were obtained from the hospital database. The difference between clinical and pathological staging was expressed as upstaging and downstaging. Computed Tomography scanning was used for follow-up, and diagnosis of mediastinal recurrence.ResultsFrom November 2011 to May 2016, 227 patients underwent RATS at Isala Hospital Zwolle, the Netherlands. Of those, 130 (mean age, 69.5±9.3 years) met the eligibility criteria. Preoperative mediastinal lymph node staging was done by endoscopic ultrasound/endobronchial ultrasound, by positron emission tomography (PET) or mediastinoscopy. In 14 patients (10.8%) unforeseen N2 disease was found, 6 patients (4.6%) were upstaged from cN0 to pN2 and 8 patients (6.2%) were upstaged from cN1 to pN2. Mediastinal recurrence was detected in 7 patients (5.4%) during a median follow-up of 54 months (range, 1.5–102 months).ConclusionsIn patients with NSCLC, who underwent anatomical resection by means of RATS, an unforeseen N2 disease rate of 10.8% was demonstrated and a mediastinal recurrence rate of 5.4%. It is concluded that robotic surgery provides an accurate lymph node dissection.