Loss of MTCH-1 suppresses age-related proteostasis collapse through the inhibition of programmed cell death factors.

The age-related loss of protein homeostasis (proteostasis) is at the heart of numerous neurodegenerative diseases. Therefore, finding ways to preserve proteome integrity in aged cells may be a powerful way to promote long-term health. Here, we show that reducing the activity of a highly conserved mitochondrial outer membrane protein, MTCH-1/MTCH2, suppresses age-related proteostasis collapse in Caenorhabditis elegans without disrupting development, growth, or reproduction. Loss of MTCH-1 does not influence proteostasis capacity in aged tissues through previously described pathways but instead operates by reducing CED-4 levels. This results in the sequestration of HSP-90 by inactive CED-3, which in turn leads to an increase in HSF-1 activity, transcriptional remodeling of the proteostasis network, and maintenance of proteostasis capacity with age. Together, our findings reveal a role for programmed cell death factors in determining proteome health and suggest that inhibiting MTCH-1 activity in adulthood may safeguard the aging proteome and suppress age-related diseases.

Neuronal SKN-1B modulates nutritional signalling pathways and mitochondrial networks to control satiety.

The feeling of hunger or satiety results from integration of the sensory nervous system with other physiological and metabolic cues. This regulates food intake, maintains homeostasis and prevents disease. In C. elegans, chemosensory neurons sense food and relay information to the rest of the animal via hormones to control food-related behaviour and physiology. Here we identify a new component of this system, SKN-1B which acts as a central food-responsive node, ultimately controlling satiety and metabolic homeostasis. SKN-1B, an ortholog of mammalian NF-E2 related transcription factors (Nrfs), has previously been implicated with metabolism, respiration and the increased lifespan incurred by dietary restriction. Here we show that SKN-1B acts in two hypothalamus-like ASI neurons to sense food, communicate nutritional status to the organism, and control satiety and exploratory behaviours. This is achieved by SKN-1B modulating endocrine signalling pathways (IIS and TGF-ß), and by promoting a robust mitochondrial network. Our data suggest a food-sensing and satiety role for mammalian Nrf proteins.

Ten-year experience with peritoneal mesothelioma.

PURPOSE: Peritoneal mesothelioma is a rare disease that remains confined to the peritoneal surfaces for long. Cytoreductive surgery (CRS) combined with hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) is the most effective treatment and complete cytoreduction is the most significant prognostic indicator of long-term survival. This study attempted to present the results of CRS in combination with hyperthermic intraperitoneal chemotherapy in patients with peritoneal mesothelioma and identify the prognostic indicators of survival. METHODS: The files of patients with peritoneal mesothelioma were retrospectively reviewed. Morbidity, hospital mortality, recurrences, and the sites of recurrence were recorded. Survival and recurrence were correlated to performance status, age, extent of peritoneal dissemination, tumor grade, tumor volume, and completeness of cytoreduction. RESULTS: From 2005-2017, 29 patients underwent 33 cytoreductions for peritoneal mesothelioma. Hospital mortality and morbidity were 3% and 27.3% respectively. The median and 8-year survival were 66 and 62% months, respectively. The completeness of cytoreduction was the single prognostic indicator of survival, and the tumor grade the single prognostic indicator of recurrence. CONCLUSION: CRS combined with HIPEC is the therapeutic strategy that may provide long-term survival.

The effect of hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) as an adjuvant in patients with resectable pancreatic cancer.

Background - aims: The long-term survival of pancreatic cancer is poor even after potentially curative resection. The incidence of local-regional failures is high. There is evidence that hyperthermic intraperitoneal intraoperative chemotherapy (HIPEC) is effective in controlling the local-regional failures. The purpose of the study is to identify the effect of HIPEC after surgical removal of pancreatic carcinoma. Patients - Methods: Prospective study including 33 patients with resectable pancreatic carcinomas. All patients underwent surgical resection (R0) and ΗIPEC as an adjuvant. Morbidity and hospital mortality were recorded. The patients were followed-up for 5 years. Survival was calculated. Recurrences and the sites of failure were recorded. RESULTS: The mean age of the patients was 67.8 ± 11.1 years (38-86). The hospital mortality was 6.1% (2 patients) and the morbidity 24.2% (8 patients). The overall 5-year survival was 24%. The mean and median survival was 33 and 13 months, respectively. The median follow-up time was 11 months. The recurrence rate was 60.6% (20 patients). Three patients were recorded with local-regional failures (9.1%) and the others with liver metastases. CONCLUSIONS: It appears that HIPEC as an adjuvant following potentially curative resection (R0) of pancreatic carcinoma may effectively control the local-regional disease. Prospective randomised studies are required.

Treating peritoneal mesothelioma with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. A case series and review of the literature.

BACKGROUND: Encouraging results on survival of patients with malignant peritoneal mesothelioma have been shown with the use of cytoreductive surgery and perioperative intraperitoneal chemotherapy. This study explores the impact of aggressive surgical treatment on overall survival of peritoneal mesothelioma. METHODS: This is a retrospective analysis of prospectively collected clinical data of all patients with diagnosis of malignant peritoneal mesothelioma treated in a designated referral centre in Greece. All patients were offered cytoreductive surgery and intraperitoneal chemotherapy. Patient's characteristics, operative reports, pathology reports, and discharge summaries were stored in an electronic database and later reviewed and analysed. RESULTS: Cytoreduction for peritoneal mesothelioma was performed on 20 patients (15 men and 5 women) with a mean age of 59.4 years (SD 16.1). Mean peritoneal cancer index was 16.1 (SD 10.4) and the median completeness of cytoreduction score was 2 (range 1-2). Mean overall survival was 46.8 months (SE 4.03) with a mean of 21.4 and median of 18 months of follow-up. Disease-specific survival was 100% for the observed period. Univariate analysis showed the completeness of cytoreduction as the only possible predictor of survival. A median of 10 (range 4-14) peritonectomy procedures were performed per patient. Median hospital stay was 14 (range 10-57 days). Grade III and IV complications occurred post-operatively in 5 patients (25%). Two patients died in the post-operative period of pulmonary embolism and myocardial infarction. CONCLUSION: Cytoreductive surgery with HIPEC has proved the most effective treatment even when taking account of the cost of significant morbidity.

Bilateral polyorchidism associated with intraabdominal cryptorchidism: a case report.

OBJECTIVE: The aim of this study was to present a rare congenital anomaly of polyorchidism and to review the current management. CLINICAL PRESENTATION AND INTERVENTION: We report the case of a 19-year-old man who was referred for the treatment of an indirect left inguinal hernia. The ultrasound demonstrated a testis on the right side with an additional mass. The preoperative laboratory studies were normal. At surgery, a solid mass consistent with an ectopic testis was removed. The histological evaluation showed the presence of a fourth testis without malignancy, confirming the diagnosis of bilateral, double testes associated with intraabdominal cryptorchidism, which was removed for histology. The postoperative endocrinological evaluation revealed hypergonadotrophic hypogonadism. The patient was followed up conservatively. CONCLUSION: Polyorchidism should be included in the differential diagnosis of a solid extratesticular mass, and its management should be conservative.