Metabolism has been shown to integrate with epigenetics and transcription to modulate cell fate and function. Beyond meeting the bioenergetic and biosynthetic demands of T-cell differentiation, whether metabolism might control T-cell fate by an epigenetic mechanism is unclear. Here, through the discovery and mechanistic characterization of a small molecule, (aminooxy)acetic acid, that reprograms the differentiation of T helper 17 (T17) cells towards induced regulatory T (iT) cells, we show that increased transamination, mainly catalysed by GOT1, leads to increased levels of 2-hydroxyglutarate in differentiating T17 cells. The accumulation of 2-hydroxyglutarate resulted in hypermethylation of the Foxp3 gene locus and inhibited Foxp3 transcription, which is essential for fate determination towards T17 cells. Inhibition of the conversion of glutamate to α-ketoglutaric acid prevented the production of 2-hydroxyglutarate, reduced methylation of the Foxp3 gene locus, and increased Foxp3 expression. This consequently blocked the differentiation of T17 cells by antagonizing the function of transcription factor RORγt and promoted polarization into iT cells. Selective inhibition of GOT1 with (aminooxy)acetic acid ameliorated experimental autoimmune encephalomyelitis in a therapeutic mouse model by regulating the balance between T17 and iT cells. Targeting a glutamate-dependent metabolic pathway thus represents a new strategy for developing therapeutic agents against T17-mediated autoimmune diseases.

Purpose: No antiangiogenic treatment is yet approved for extrapancreatic neuroendocrine tumors (NET). Surufatinib (HMPL-012, previously named sulfatinib) is a small-molecule inhibitor targeting vascular endothelial growth factor receptors, fibroblast growth factor receptor 1 and colony-stimulating factor 1 receptor. We conducted a single-arm phase Ib/II study of surufatinib in advanced NETs.Patients and Methods: Patients with histologically welldifferentiated, low or intermittent grade, inoperable or metastatic NETs were enrolled into a pancreatic or extrapancreatic NET cohort. Patients were treated with surufatinib 300 mg orally, once daily. The primary endpoints were safety and objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (version 1.1).Results: Of the 81 patients enrolled, 42 had pancreatic NETs and 39 had extrapancreatic NETs. Most patients had radiologic progression within 1 year prior to enrollment (32 patients in each cohort). In the pancreatic and extrapancreatic NET cohorts, ORRs were 19% [95% confidence intervals (CI), 9-34] and 15% (95% CI, 6-31), disease control rates were 91% (95% CI, 77-97) and 92% (95% CI, 79-98), and median progression-free survival was 21.2 months (95% CI, 15.9-24.8) and 13.4 months (95% CI, 7.6-19.3), respectively. The most common grade !3 treatment-related adverse events were hypertension (33%), proteinuria (12%), hyperuricemia (10%), hypertriglyceridemia, and diarrhea (6% for each), and increased alanine aminotransferase (5%).Conclusions: Surufatinib showed encouraging antitumor activity and manageable toxicities in patients with advanced NETs. Two ongoing phase III studies, validating the efficacy of surufatinib in patients with NETs, will contribute to the clinical evidence.

Postoperative delirium (POD) is a common complication following surgery and anesthesia (Surgery/Anesthesia). Mitochondrial dysfunction, which is demonstrated by energy deficits and excessively activated oxidative stress, has been reported to contribute to POD. The dynamic balance between mitochondrial fusion and fission processes is critical in regulating mitochondrial function. However, the impact of Surgery/Anesthesia on mitochondrial fusion/fission dynamics remains unclear. Here, we evaluate the effects of laparotomy under 1.4% isoflurane anesthesia for 2 hours on mitochondrial fission/fusion dynamics in the brain of aged mice. Mice in Surgery/Anesthesia group showed unbalanced fission/fusion dynamics, with decreased DISC1 expression and increased expression of Drp1 and Mfn2 in the mitochondrial fraction, leading to excessive mitochondrial fission and disturbed mitochondrial morphogenesis in the hippocampus and prefrontal cortex. In addition, surgical mice presented mitochondrial dysfunction, demonstrated by abnormally activated oxidative stress (increased ROS level, decreased SOD level) and energy deficits (decreased levels of ATP and MMP). Surgery/Anesthesia also decreased the expression of neuronal/synaptic plasticity-related proteins such as PSD-95 and BDNF. Furthermore, Surgery/Anesthesia induced delirium-like behavior in aged mice. In conclusion, Surgery/Anesthesia disturbed mitochondrial fission/fusion dynamics and then impaired mitochondrial function in the brain of aged mice; these effects may be involved in the underlying mechanism of POD.

Overexpression of Cdc20 may serve as an independent predictor for BCR in patients of clinically localized PCa undergoing LRP without neoadjuvant therapy.

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The objective of this study was to evaluate the differences between normal and pale, soft, exudative (PSE)-like chicken breast meat in the chemical composition, pH, color, water binding capacity, textural properties, salt-soluble protein (SSP) extraction as well as dynamic rheological properties. Compared with normal meat, PSE-like chicken meat showed similar moisture, fat, and ash content (P > 0.05), but significantly lower protein content (P < 0.05). It had a significantly higher L* and lower pH and SSP extraction (P < 0.05). Heated PSE-like meat batter had lower water-binding capacity, textural characteristics (P < 0.05) and reduced gel elasticity (G′) and viscosity. However, the color variation of PSE-like meat gels was decreased. No significant changes were observed in the SSP electrophoretic patterns by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). In conclusion, PSE-like poultry meat changed the chemical composition and impaired protein functionality; however, the difference in color was small when used in further products.Keywords: PSE-like; chicken; gel properties; salt-soluble protein; dynamic rheology El objetivo del presente estudio se dirigió a evaluar las diferencias existentes entre la carne de pechuga de pollo normal y la de tipo PSE en términos de su composición química, pH, color, capacidad de retención de agua, propiedades texturales, extracción de proteína soluble en sal (PSS), así como sus propiedades reológicas dinámicas. En comparación con la carne de pollo normal, se constató que la carne de pollo tipo PSE exhibe un contenido de humedad, de grasa y de ceniza similar (P > 0,05), mientras que su contenido de proteína es significativamente inferior (P < 0,05). Asimismo, se observó que la carne tipo PSE tiene un nivel de L* más elevado, en tanto su pH y su extracción SSP son inferiores (P < 0,05). Al ser calentada, la masa de carne tipo PSE acusa niveles inferiores de capacidad de retención de agua, de características texturales (P < 0,05), reduciéndose, al mismo tiempo, la elasticidad de gel (G′) y la viscosidad. Sin embargo, en los geles de carne tipo PSE se constató la disminución de la variación de color. Frente a la aplicación de la SDS-PAGE, no se observaron cambios significativos en los patrones electroforéticos en la PSS. Se concluye que la composición química de la carne de pollo tipo PSE se ve alterada, lo cual limita su funcionalidad proteica. Sin embargo, la diferencia de color es reducida si se utiliza en productos posteriores.

No abstract

Background Thrombospondin type 1 domain containing 7A (THSD7A) was recently identified target autoantigen in membranous nephropathy (MN). However, patients with positive THSD7A expression were prone to have malignancies. THSD7A was found to be expressed in a variety of malignant tumors. In this study, we investigated the histologic expression of THSD7A in colorectal or breast cancers, as well as the relationship between THSD7A expression and proteinuria in the patients with cancers. Method A total of 101 patients were enrolled in the study, 81 of them had colorectal cancer and 20 had breast cancer. THSD7A expression was detected by immunohistochemical staining in tumor tissues. The clinical and laboratory parameters of these patients before their tumor resection were collected. Results Positive expression rates of THSD7A in the two types of tumor tissues were very high, 97.5% in colorectal cancer, and 100% in breast cancer. THSD7A expression was also detected in lymph nodes of two patients with lymph node metastasis. Total 11 patients (10.9%) had proteinuria before surgery. Among the 4 patients who had proteinuria and were followed up, the proteinuria of 3 patients disappeared after surgery. Conclusions The positive rate of THSD7A expression was very high in human colorectal cancer or breast cancer. It might be an important link between malignant tumors and kidney diseases. Electronic supplementary material The online version of this article (10.1186/s12882-019-1489-5) contains supplementary material, which is available to authorized users.