Mitochondrial protein import determines lifespan through metabolic reprogramming and de novo serine biosynthesis.

Sustained mitochondrial fitness relies on coordinated biogenesis and clearance. Both processes are regulated by constant targeting of proteins into the organelle. Thus, mitochondrial protein import sets the pace for mitochondrial abundance and function. However, our understanding of mitochondrial protein translocation as a regulator of longevity remains enigmatic. Here, we targeted the main protein import translocases and assessed their contribution to mitochondrial abundance and organismal physiology. We find that reduction in cellular mitochondrial load through mitochondrial protein import system suppression, referred to as MitoMISS, elicits a distinct longevity paradigm. We show that MitoMISS triggers the mitochondrial unfolded protein response, orchestrating an adaptive reprogramming of metabolism. Glycolysis and de novo serine biosynthesis are causatively linked to longevity, whilst mitochondrial chaperone induction is dispensable for lifespan extension. Our findings extent the pro-longevity role of UPRmt and provide insight, relevant to the metabolic alterations that promote or undermine survival and longevity.

Untargeted Plasma Metabolomics Unravels a Metabolic Signature for Tissue Sensitivity to Glucocorticoids in Healthy Subjects: Its Implications in Dietary Planning for a Healthy Lifestyle.

In clinical practice, differences in glucocorticoid sensitivity among healthy subjects may influence the outcome and any adverse effects of glucocorticoid therapy. Thus, a fast and accurate methodology that could enable the classification of individuals based on their tissue glucocorticoid sensitivity would be of value. We investigated the usefulness of untargeted plasma metabolomics in identifying a panel of metabolites to distinguish glucocorticoid-resistant from glucocorticoid-sensitive healthy subjects who do not carry mutations in the human glucocorticoid receptor (NR3C1) gene. Applying a published methodology designed for the study of glucocorticoid sensitivity in healthy adults, 101 healthy subjects were ranked according to their tissue glucocorticoid sensitivity based on 8:00 a.m. serum cortisol concentrations following a very low-dose dexamethasone suppression test. Ten percent of the cohort, i.e., 11 participants, on each side of the ranking, with no NR3C1 mutations or polymorphisms, were selected, respectively, as the most glucocorticoid-sensitive and most glucocorticoid-resistant of the cohort to be analyzed and compared with untargeted blood plasma metabolomics using gas chromatography-mass spectrometry (GC-MS). The acquired metabolic profiles were evaluated using multivariate statistical analysis methods. Nineteen metabolites were identified with significantly lower abundance in the most sensitive compared to the most resistant group of the cohort, including fatty acids, sugar alcohols, and serine/threonine metabolism intermediates. These results, combined with a higher glucose, sorbitol, and lactate abundance, suggest a higher Cori cycle, polyol pathway, and inter-tissue one-carbon metabolism rate and a lower fat mobilization rate at the fasting state in the most sensitive compared to the most resistant group. In fact, this was the first study correlating tissue glucocorticoid sensitivity with serine/threonine metabolism. Overall, the observed metabolic signature in this cohort implies a worse cardiometabolic profile in the most glucocorticoid-sensitive compared to the most glucocorticoid-resistant healthy subjects. These findings offer a metabolic signature that distinguishes most glucocorticoid-sensitive from most glucocorticoid-resistant healthy subjects to be further validated in larger cohorts. Moreover, they support the correlation of tissue glucocorticoid sensitivity with insulin resistance and metabolic syndrome-associated pathways, further emphasizing the need for nutritionists and doctors to consider the tissue glucocorticoid sensitivity in dietary and exercise planning, particularly when these subjects are to be treated with glucocorticoids.

Metabolic Profiling Indicates Diversity in the Metabolic Physiologies Associated With Maternal Postpartum Depressive Symptoms.

Background: Postpartum depression (PPD) is a devastating disease requiring improvements in diagnosis and prevention. Blood metabolomics identifies biological markers discriminatory between women with and those without antenatal depressive symptoms. Whether this cutting-edge method can be applied to postpartum depressive symptoms merits further investigation. Methods: As a substudy within the Biology, Affect, Stress, Imagine and Cognition Study, 24 women with PPD symptom (PPDS) assessment at 6 weeks postpartum were included. Controls were selected as having a score of ≤ 6 and PPDS cases as ≥12 on the Edinburgh Postnatal Depression Scale. Blood plasma was collected at 10 weeks postpartum and analyzed with gas chromatography-mass spectrometry metabolomics. Results: Variations of metabolomic profiles within the PPDS samples were identified. One cluster showed altered kidney function, whereas the other, a metabolic syndrome profile, both previously associated with depression. Five metabolites (glycerol, threonine, 2-hydroxybutanoic acid, erythritol, and phenylalanine) showed higher abundance among women with PPDSs, indicating perturbations in the serine/threonine and glycerol lipid metabolism, suggesting oxidative stress conditions. Conclusions: Alterations in certain metabolites were associated with depressive pathophysiology postpartum, whereas diversity in PPDS physiologies was revealed. Hence, plasma metabolic profiling could be considered in diagnosis and pathophysiological investigation of PPD toward providing clues for treatment. Future studies require standardization of various subgroups with respect to symptom onset, lifestyle, and comorbidities.

Computed Tomography-Guided Percutaneous Radiofrequency Ablation of the Splanchnic Nerves as a Single Treatment for Pain Reduction in Patients with Pancreatic Cancer.

The aim of this paper is to prospectively evaluate the efficacy and safety of percutaneous computed tomography (CT)-guided radiofrequency (RF) neurolysis of splanchnic nerves as a single treatment for pain reduction in patients with pancreatic cancer. Patients with pancreatic ductal adenocarcinoma suffering from abdominal pain refractory to conservative medication who underwent CT-guided neurolysis of splanchnic nerves by means of continuous radiofrequency were prospectively evaluated for pain and analgesics reduction as well as for survival. In all patients, percutaneous neurolysis was performed with a bilateral retrocrural paravertebral approach at T12 level using a 20 Gauge RF blunt curved cannula with a 1cm active tip electrode. Self-reported pain scores were assessed before and at the last follow-up using a pain inventory with numeric visual scale (NVS) units. The mean patient age was 65.4 ± 10.8 years (male-female: 19-11). The mean pain score prior to RF neurolysis of splanchnic nerves was 9.0 NVS units; this score was reduced to 2.9, 3.1, 3.6, 3.8, and 3.9 NVS units at 1 week, 1, 3, 6, and 12 months respectively (p < 0.001). Significantly reduced analgesic usage was reported in 28/30 patients. Two grade I complications were reported according to the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) classification system. According to the results of the present study, solely performed computed tomography-guided radiofrequency neurolysis of splanchnic nerves can be considered a safe and efficacious single-session technique for pain palliation in patients with pancreatic ductal adenocarcinoma suffering from abdominal pain refractory to conservative medication. Although effective in pain reduction the technique seems to have no effect upon survival improvement.

Contribution of Histone Deacetylases in Prognosis and Therapeutic Management of Cholangiocarcinoma.

Cholangiocarcinoma (CCA), a malignant tumor that occurs in the epithelium of the biliary tract, has a very poor prognosis because affected patients are frequently diagnosed at an advanced stage and recurrence after resection is common. Over the last two decades, our understanding of the molecular biology of this malignancy has expanded, and various studies have explored targeted therapy for CCA in order to improve patient survival. The histone acetylation/deacetylation equilibrium is affected in carcinogenesis, leading to altered chromatin structure and therefore changes in gene expression. Understanding the molecular identity of histone deacetylases (HDACs), their cellular interactions and potential role as anticancer agents will help us develop new therapeutic strategies for CCA-affected patients. Furthermore, HDAC inhibitors act on cellular stress response pathways and decrease cancer angiogenesis. Downregulation of pro-angiogenic genes such as vascular endothelial growth factor (VEGF), hypoxia inducible factor-1 (HIF-1), and endothelial nitric oxide synthase (eNOS) inhibit formation of new vessels and can negatively affect the metastatic process. Finally, recent clinical trials prove that administration of both HDAC inhibitors and DNA-targeting chemotherapeutic agents, such as topoisomerase inhibitors, DNA intercalating agents, inhibitors of DNA synthesis, covalently modifying DNA agents, and ionizing radiation, maximizes the anticancer effect by increasing the cytotoxic efficiency of a variety of DNA-damaging anticancer drugs. Therefore, combination therapy of classic chemotherapeutic drugs with HDAC inhibitors can act synergistically for the patients' benefit.

Carcinosarcomas of the esophagus: systematic review of a rare nosologic entity.

PURPOSE: The purpose of this study was to systematically review the literature of esophageal carcinosarcomas (ECS) and report epidemiologic and clinicopathologic data for this rare entity. We also attempted to shed light to the biologic behavior of ECSs with special reference to factors that may affect disease-free (DES) and overall survival (OS). METHODS: A systematic literature review was performed using MEDLINE, EMBASE and the Cochrane Library databases (Search date: 12 May 2017). The search strategy referred to  carcinosarcoma OR pseudosarcoma OR polypoid carcinoma OR sarcomatoid carcinoma OR spindle-cell squamous cell carcinoma OR metaplastic carcinoma OR pseudosarcomatous carcinoma AND esophagus. A total number of 103 ECS patients was identified.   Results: ECs most frequently occur in middle-aged as well as elderly men with a history of smoking or drinking. Middle and/or lower esophagus remains the most common location. Imaging plays a pivotal role in the management of ECS by delineating the anatomic extent of the tumor and thereby determining the appropriate therapeutic strategy. Nevertheless, immunohistochemistry is the gold standard for the diagnosis of carcinosarcomas, since it has been demonstrated that CEA, EMA, pancreatin, chromogranin A, CD56 and synaptophysin staining are highly specific markers for the carcinomatous components, while desmin, vimentin and smooth muscle/sarcomeric actin show affinity for the sarcomatous elements. Esophagectomy has been traditionally considered the treatment modality of choice. Endoscopic procedures, including mucosal resection and submucosal dissection have also been proposed. Alternative therapies, such as radio- and chemotherapy proved insufficient. CONCLUSION: ECS is a rare tumor. Immunohistochemistry is the gold standard for the diagnosis of this disease. Esophagectomy has been traditionally considered the treatment modality of choice. Endoscopic procedures have also been proposed while potential benefit of alternative therapies, such as radiotherapy and chemotherapy remains controversial.