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Cancer cells have metabolic dependencies that distinguish them from their normal counterparts. Among these dependencies is an increased use of the amino acid glutamine to fuel anabolic processes. Indeed, the spectrum of glutamine-dependent tumours and the

Background Aortic aneurysms and dissections are highly lethal diseases for which an effective treatment strategy is critically needed to prevent disease progression. The nucleotide‐binding oligomerization domain–like receptor pyrin domain containing 3 (NLRP3)–caspase‐1 inflammasome cascade was recently shown to play an important role in aortic destruction and disease development. In this study, we tested the effects of MCC950, a potent, selective NLRP3 inhibitor, on preventing aortic destruction and aortic aneurysm and dissection formation. Methods and Results In a model of sporadic aortic aneurysm and dissection induced by challenging wild‐type mice with a high‐fat, high‐cholesterol diet and angiotensin II infusion, MCC950 treatment significantly inhibited challenge‐induced aortic dilatation, dissection, and rupture in different thoracic and abdominal aortic segments in both male and female mice. Aortic disease reduction by MCC950 was associated with the prevention of NLRP3–caspase‐1 upregulation, smooth muscle cell contractile protein degradation, aortic cell death, and extracellular matrix destruction. Further investigation revealed that preventing matrix metallopeptidase 9 (MMP‐9) expression and activation in macrophages is an important mechanism underlying MCC950's protective effect. We found that caspase‐1 directly activated MMP‐9 by cleaving its N‐terminal inhibitory domain. Moreover, the genetic knockdown of Nlrp3 or Casp‐1 in mice or treatment of mice with MCC950 diminished the challenge‐induced N‐terminal cleavage of MMP‐9, MMP‐9 activation, and aortic destruction. Conclusions Our findings suggest that the NLRP3–caspase‐1 inflammasome directly activates MMP‐9. Targeting the inflammasome with MCC950 is a promising approach for preventing aortic destruction and aortic aneurysm and dissection development.

Lu Di,1–3,* Kai Qian,2,4,* Chengrun Du,1,2 Chunying Shen,1,2 Ruiping Zhai,1,2 Xiayun He,1,2 Xiaoshen Wang,1,2 Tingting Xu,1,2 Chaosu Hu,1,2 Hongmei Ying1,2 1Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; 3Department of Oncology, Liyang People’s Hospital, Changzhou, Jiangsu 213000, China; 4Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China *These authors contributed equally to this work Background: Salivary duct carcinoma (SDC) is an extremely rare and highly malignant carcinoma, and surgical radical resection is the most effective therapy. However, there were quite a proportion of patients receiving non-radical resections, and how to treat them remained controversial. Thus, the aim of this study is to evaluate whether postoperative radiotherapy could be a salvage treatment of SDC in major salivary glands without radical operations.Patients and methods: We identified 40 pathologically diagnosed SDC patients who came to our hospital and did not receive radical operations. Thirty-three patients received at least one treatment (remedial operation, postoperative radiotherapy and chemotherapy), and seven patients only chose observation and received no further treatment. The prognostic indicators of the local–regional control (LRC) and distant disease-free survival were analyzed using the Kaplan–Meier methods and the Cox proportional hazards regression models.Results: Thirteen patients experienced local–regional recurrence or local progression, and distant metastases were observed in 15 patients. Through multivariate analysis, we found that postoperative radiotherapy was associated with better LRC, but this kind of treatment did not show significant efficacy in the prevention of distant metastasis.Conclusion: SDC is a rare, aggressive malignancy, and a substantial proportion of these patients experienced inadequate initial treatments. Although postoperative radiotherapy could not decrease distant metastases, it might help to improve LRC in patients with SDC. Keywords: salivary duct carcinoma, prognosis, non-radical resection, postoperative radiotherapy

Ronald Wihal Oei,1,2,* Lulu Ye,1,2,* Fangfang Kong,1,2 Chengrun Du,1,2 Ruiping Zhai,1,2 Tingting Xu,1,2 Chunying Shen,1,2 Xiaoshen Wang,1,2 Xiayun He,1,2 Lin Kong,1,2 Chaosu Hu,1,2 Hongmei Ying1,2 1Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 2Department of Oncology, Shanghai Medical College, Shanghai, People’s Republic of China *These authors contributed equally to this work Purpose: The aim of this article is to investigate the significance of pretreatment prognostic nutritional index (PNI), systemic immune-inflammation index (SII), and their combination in nasopharyngeal carcinoma (NPC) patients receiving intensity-modulated radiotherapy (IMRT).Materials and methods: A total of 585 patients were included. PNI and SII were calculated within 2 weeks prior to treatment. The optimal cutoff points were determined based on receiver operating characteristics curve analysis. The correlation between variables was analyzed. Kaplan–Meier method and Cox proportional hazards model were performed to evaluate the impact of both indices on overall survival (OS), progression-free survival (PFS) and distant metastasis-free survival (DMFS). Further propensity score matching (PSM) was carried out to minimize the effects of confounders. Results: The optimal cutoff point of 53.0 for PNI and 527.20 for SII were selected. Pearson correlation coefficient showed an inverse correlation between PNI and SII (r = –0.232, P < 0.001). Multivariate analysis demonstrated that pretreatment PNI was an independent prognostic factor for OS (P = 0.047) and DMFS (P = 0.002) while pretreatment SII was an independent prognostic factor for OS (P = 0.003), PFS (P = 0.002), and DMFS (P = 0.002). After PSM, both parameters remained as independent prognosticators of survival. Additional prognostic value was observed in the combined use of PNI and SII.Conclusion: Pretreatment PNI and SII are promising indicators of survival in NPC patients undergoing IMRT. They can be utilized to refine current TNM staging system in predicting prognosis and developing an individualized treatment in these patients. Keywords: prognostic nutritional index, systemic immune-inflammation index, nasopharyngeal carcinoma, intensity-modulated radiotherapy, prognostic factor, survival

The study provided a qualitative investigation into problematic mobile phone use among the youth athlete population. The study aimed to identify the factors which contributed to problematic use, the effects of problematic use, and suggestions on how to help youth athletes overcome problematic use. Four focus groups sessions were conducted with a total of 21 Singaporean youth athletes (aged 12–18 years old) from four different sports. The data was analysed using reflexive thematic analysis. The findings indicated various factors which contributed to problematic use, namely personal attributes, needs fulfilment, and external influences. Effects of problematic use included areas such as shrinkage of time, performance deficits, and undesirable behaviours. There were various suggestions on how to overcome problematic use, which included strengthening internal resources and tapping into sources of external help. Future research should seek to use the knowledge derived from this study to create interventions to help youth athletes deal with their problematic mobile phone use. [ABSTRACT FROM AUTHOR]

Abstract Background Islet dysfunction and destruction are the common cause for both type 1 and type 2 diabetes mellitus (T2DM). The islets of Langerhans are highly vascularized miniorgans, and preserving the structural integrity and full function of the microvascular endothelium is vital for protecting the islets from the infiltration of immune cells and secondary inflammatory attack. Mesenchymal stromal cell (MSC)-based therapies have been proven to promote angiogenesis of the islets; however, the underlying mechanism for the protective role of MSCs in the islet endothelium is still vague. Methods In this study, we used MS-1, a murine islet microvascular endothelium cell line, and an MSC-MS1 transwell culturing system to investigate the protective mechanism of rat bone marrow-derived MSCs under oxidative stress in vitro. Cell apoptosis was detected by TUNEL staining, annexin V/PI flow cytometry analysis, and cleaved caspase 3 western blotting analysis. Endothelial cell activation was determined by expression of intercellular cell adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM), as well as eNOS phosphorylation/activation. The changes of VCAM-1, eNOS, and the β-catenin expression were also tested in the isolated islets of T2DM rats infused with MSCs. Results We observed that treating MS-1 cells with H2O2 triggered significant apoptosis, induction of VCAM expression, and reduction of eNOS phosphorylation. Importantly, coculturing MS-1 cells with MSCs prevented oxidative stress-induced apoptosis, eNOS inhibition, and VCAM elevation in MS-1 cells. Similar changes in VCAM-1 and eNOS phosphorylation could also be observed in the islets isolated from T2DM rats infused with MSCs. Moreover, MSCs cocultured with MS-1 in vitro or their administration in vivo could both result in an increase of β-catenin, which suggested activation of the β-catenin-dependent Wnt signaling pathway. In MS-1 cells, activation of the β-catenin-dependent Wnt signaling pathway partially mediated the protective effects of MSCs against H2O2-induced apoptosis and eNOS inhibition. Furthermore, MSCs produced a significant amount of Wnt4 and Wnt5a. Although both Wnt4 and Wnt5a participated in the interaction between MSCs and MS-1 cells, Wnt4 exhibited a protective role while Wnt5a seemed to show a destructive role in MS-1 cells. Conclusions Our observations provide evidence that the orchestration of the MSC-secreted Wnts could promote the survival and improve the endothelial function of the injured islet endothelium via activating the β-catenin-dependent Wnt signaling in target endothelial cells. This finding might inspire further in-vivo studies.

Abstract Background Clinical prognostic parameters of liver metastasis from pancreatic adenocarcinoma have not been specifically identified.This study is to explore the risk factors of liver metastasis in advanced pancreatic adenocarcinoma (PDAC) patients in China. Methods A multicenter cohort study was conducted to explore whether liver metastasis in locally advanced and metastatic PDAC could be reflected by some common laboratory indexes. We collected 1787 advanced PDAC patients from three participating hospitals between 2004 and 2014. The associations between some laboratory indexes and risks of liver metastases were analyzed. Results Results have shown that 87% of stage IV patients developed synchronous liver metastasis. Primary tumor location (body/tail vs. head/neck, OR 0.55, 95% CI 0.36-0.83), primary tumor diameter (≥20 mm vs.

ABSTRACT The microbiome in fermentation has direct impacts on the quality of fermented foods and is of great scientific and commercial interest. Despite considerable effort to explain the microbial metabolism associated with food fermentation, the role of the microbiome in pu-erh tea fermentation remains unknown. Here, we applied integrated meta-omics approaches to characterize the microbiome in two repeated fermentations of pu-erh tea. Metabarcoding analysis of bacterial 16S rRNA genes showed a decrease in the proportion of Proteobacteria and an increase in the abundance of Firmicutes during fermentation. Metabarcoding analysis of fungal internal transcribed spacer (ITS) sequence demonstrated that Rasamsonia, Thermomyces, and Aspergillus were dominant at the intermediate stage, whereas Aspergillus was dominant at other stages in fermentation. Metaproteomics analysis assigned primary microbial metabolic activity to metabolism and identified microbial carbohydrate-active enzymes involved in the degradation of polysaccharides including cellulose, xylan, xyloglucan, pectin, starch, lignin, galactomannan, and chitin. Metabolomics and high-performance liquid chromatography analysis revealed that levels of phenolic compounds, including gallates, decreased whereas contents of gallic acid and ellagic acid significantly increased after fermentation (P

The mechanisms underlying pathophysiological regulation of tissue macrophage (Mφ) subsets remain poorly understood. From the expression of 207 Mφ genes comprising 31 markers for 10 subsets, 45 transcription factors (TFs), 56 immunometabolism enzymes, 23 trained immunity (innate immune memory) enzymes, and 52 other genes in microarray data, we made the following findings. (1) When 34 inflammation diseases and tumor types were grouped into eight categories, there was differential expression of the 31 Mφ markers and 45 Mφ TFs, highlighted by 12 shared and 20 group-specific disease pathways. (2) Mφ in lung, liver, spleen, and intestine (LLSI-Mφ) express higher M1 Mφ markers than lean adipose tissue Mφ (ATMφ) physiologically. (3) Pro-adipogenic TFs C/EBPα and PPARγ and proinflammatory adipokine leptin upregulate the expression of M1 Mφ markers. (4) Among 10 immune checkpoint receptors (ICRs), LLSI-Mφ and bone marrow (BM) Mφ express higher levels of CD274 (PDL-1) than ATMφ, presumably to counteract the M1 dominant status via its reverse signaling behavior. (5) Among 24 intercellular communication exosome mediators, LLSI- and BM- Mφ prefer to use RAB27A and STX3 than RAB31 and YKT6, suggesting new inflammatory exosome mediators for propagating inflammation. (6) Mφ in peritoneal tissue and LLSI-Mφ upregulate higher levels of immunometabolism enzymes than does ATMφ. (7) Mφ from peritoneum and LLSI-Mφ upregulate more trained immunity enzyme genes than does ATMφ. Our results suggest that multiple new mechanisms including the cell surface, intracellular immunometabolism, trained immunity, and TFs may be responsible for disease group-specific and shared pathways. Our findings have provided novel insights on the pathophysiological regulation of tissue Mφ, the disease group-specific and shared pathways of Mφ, and novel therapeutic targets for cancers and inflammations.

Background Thoracic aortic aneurysm (TAA) and dissection (TAD) are characterized by progressive disorganization of the aortic wall matrix, including elastin, a highly immunogenic molecule. Whether acquired autoimmune responses can be detected in TAA/TAD patients who are smokers is unknown. The objectives of this study were to determine whether TAA/TAD smokers have increased T‐cell responses to human elastin fragments, and to determine whether autoimmune responses in TAA/TAD smokers are dependent on chronic obstructive pulmonary disease. Methods and Results In a cross‐sectional study (N=86), we examined peripheral blood CD4+ T cell responses to elastin fragments in never‐, former‐, or current‐smokers with or without TAA/TAD. CD4+ T cells were co‐cultured with irradiated autologous peripheral blood CD1a+/CD14+ antigen presenting cells pulsed with or without elastin fragments to measure cytokine production. Baseline plasma concentration of anti‐elastin antibodies and elastin‐degrading enzymes (eg, matrix metalloproteinase‐9, and ‐12, and neutrophil elastase) were measured in the same cohort. elastin fragment‐specific CD4+ T cell expression of interferon‐γ, and anti‐elastin antibodies were dependent on history of smoking in TAA/TAD patients but were independent of chronic obstructive pulmonary disease. Matrix metalloproteinase‐9, and ‐12, and neutrophil elastase plasma concentrations were also significantly elevated in ever‐smokers with TAA/TAD. Conclusions Cigarette smoke is associated with loss of self‐tolerance and induction of elastin‐specific autoreactive T‐ and B‐cell responses in patients with TAA/TAD. Development of peripheral blood biomarkers to track immunity to self‐antigens could be used to identify and potentially prognosticate susceptibility to TAA/TAD in smokers.