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Head and neck squamous cell carcinomas (HNSCC) are the most common type of head and neck cancer with an unimproved prognosis over the past decades. Although the role of cancer-associated-fibroblast (CAF) has been demonstrated in HNSCC, the correlation between CAF-derived gene expression and patient prognosis remains unknown.A total of 528 patients from TCGA database and 270 patients from GSE65858 database were contained in this study. After extracting 66 CAF-related gene expression data from TCGA database, consensus clustering was performed to identify different HNSCC subtypes. Limma package was used to distinguish the differentially expression genes (DEGs) between these subtypes, followed by Lasso regression analysis to construct a prognostic model. The model was validated by performing Kaplan-Meier survival, ROC and risk curve, univariate and multivariate COX regression analysis. GO, KEGG, GSEA, ESTIMATE and ssGSEA analyses was performed to explort the potential mechanism leading to different prognosis.Based on the 66 CAF-related gene expression pattern we stratitied HNSCC patients into two previously unreported subtypes with different clinical outcomes. A prognostic model composed of 15 DEGs was constructed and validated. In addition, bioinformatics analysis showed that the prognostic risk of HNSCC patients was also negatively correlated to immune infiltration, implying the role of tumor immune escape in HNSCC prognosis and treatment option.The study develops a reliable prognostic prediction tool and provides a theoretical treatment guidance for HNSCC patients.

Background: Tumor regression grade (TRG) correlates with prognosis in patients with locally advanced rectal cancer (LARC), but there is controversy regarding the use of magnetic resonance imaging (MRI) for determining TRG. This study to evaluate the diagnostic value of change rate in signal intensity (SI) and volume (V) from MRI to TRG following preoperative chemoradiotherapy (CRT) in patiens with LARC.Materials and methods: This retrospective analysis examined 82 LARC patients who were admitted to our institution between Oct 2017 and Oct 2019. Patients underwent pre- and post-CRT T2-weighted (T2W), diffusion-weighted (DW)/apparent diffusion coefficient (ADC), and contrast-enhanced T1-weighted (ceT1W) MRI. Change rate of volume and relative SI ratio(%△V and %△SIR) from each sequence were determined. All LARCs were confirmed pathologically and classified into TRG 0, 1, 2 and 3. Descriptive statistics and receiver operating characteristic (ROC) analysis, with calculation of area under the curve (AUC), were used to compare the diagnostic performances. Results: Sixteen patients had TRG-0, 15 had TRG-1, 35 had TRG-2, and 16 had TRG-3. Except for ADC-%△SIR, the remaining%△V and %△SIR on T1W, DWI, and ceT1W had significant differences among the four groups. %△V and/or %△SIR did not distinguish TRG-1 from TRG-2 nor TRG-2 from TRG-3, but differences between other TRGs were identified by %△V and/or %△SIR on T2W, DWI, and ceT1W. The combined use of DW-%△V and T2W-%△SIR provided the best diagnostic performance in distinguishing of TRG-0 from TRG-2 (AUC: 0.954) and from TRG-3 (AUC: 1.000).Conclusions: Preoperative MRI of LARC patients can determine TRG and may improve selection of the preoperative therapy.

The immune profile in primary resected hypopharyngeal squamous cell carcinoma (HPSCC) and its prognostic value remain to be defined.We enrolled 100 patients with HPSCC underwent primary surgical resection at our department. HPSCC samples were examined using immunohistochemistry for the expressions of CD8, Foxp3, CD163, CD66B, programmed death ligand-1 (PD-L1), and interferon (IFN)-γ. The immune pattern of the tumor microenvironment (TME) was discriminated into inflamed and non-inflamed tumors based on the presence or absence of parenchymal CD8We found that 74% of HPSCC cases in our cohort were characterized by an immune-inflamed TME. Immune-inflamed patterns demonstrated an inferior survival with a significantly increased density of CD163The immune-inflamed pattern is the predominant preexisting immune phenotype in HPSCC and demonstrates immunosuppressive immune cell recruitment.

Autophagy is an essential degradation pathway that assists eukaryote survival under multiple stress conditions. Autophagosomes engulfing cargoes accomplish degradation only when they have matured through fusing with lysosomes or vacuoles. However, the molecular machinery mediating autophagosome maturation in plants remains unknown. Using the combined approaches of mass spectrometry, biochemistry, reverse genetics and microscopy, we uncover that UVRAG, a subunit of the class III phosphatidylinositol 3-kinase complexes in Nicotiana benthamiana, plays an essential role in autophagsome maturation via ATG14-assisted recruitment to autophagosomes and by facilitating RAB7 activation. An interaction between N. benthamiana UVRAG and ATG14 was observed in vitro and in vivo, which strikingly differed from their mutually exclusive appearance in different PI3KC3 complexes in yeast and mammals. This interaction increased the localisation of UVRAG on autophagosomes and enabled the convergence of autophagic and late endosomal structures, where they contributed to fusions between these two types of organelles by recruiting the essential membrane fusion factors RAB7 GTPase and the homotypic fusion and protein sorting (HOPS) complex. In addition, we uncovered a joint contribution of ATG14 and UVRAG to geminiviral infection, beyond autophagy. Our study provides insights into the mechanisms of autophagosome maturation in plants and expands the understanding of organisations and roles of the PI3KC3 complexes.

Significant pancreatic islet dysfunction and loss shortly after transplantation to the liver limit the widespread implementation of this procedure in the clinic. Nonimmune factors such as reactive oxygen species and inflammation have been considered as the primary driving force for graft failure. The adipokine adiponectin plays potent roles against inflammation and oxidative stress. Previous studies have demonstrated that systemic administration of adiponectin significantly prevented islet loss and enhanced islet function at post-transplantation period. In vitro studies indicate that adiponectin protects islets from hypoxia/reoxygenation injury, oxidative stress as well as TNF-α-induced injury. By applying adenovirus mediated transfection, we now engineered islet cells to express exogenous adiponectin gene prior to islet transplantation. Adenovirus-mediated adiponectin transfer to a syngeneic suboptimal islet graft transplanted under kidney capsule markedly prevented inflammation, preserved islet graft mass and improved islet transplant outcomes. These results suggest that adenovirus-mediated adiponectin gene therapy would be a beneficial clinical engineering approach for islet preservation in islet transplantation.

Abnormal kynurenine (Kyn) metabolism has been closely linked to the pathogenesis of rheumatoid arthritis (RA). The aims of this study were to investigate the role of tryptophan 2,3-dioxygenase 2 (TDO2), a rate-limiting enzyme that converts tryptophan (Trp) to Kyn, in regulating fibroblast-like synoviocyte (FLS)-mediated synovial inflammation in autoimmune arthritis.The expression of TDO2 was determined by immunohistochemistry, confocal laser scanning fluorescence microscopy, imaging flow cytometry and Western blot. TDO2 activity was tested by HPLC and colorimetric assay. TDO2 siRNA and TDO2 inhibitor 680C91 were used to inhibit TDO2 in AA-FLS function in vitro. A rat model of adjuvant-induced arthritis (AA) was used to evaluate the in vivo effect of allopurinol (Allo), a TDO2 inhibitor.TDO2 expression was strongly increased in synovial tissue and FLS of RA and AA. Immune cells were found to express high amount of TDO2 proteins at the peak stage of AA. Pharmacological inhibition or knockdown of TDO2 in AA-FLS resulted in a reduced proliferation, secretion, migration and invasion. Kyn restored the inhibitory effect of TDO2 inhibition on activation of AA-FLS. Allo treatment ameliorated the arthritis severity and decreased the activity of TDO2.Our results suggest that elevated TDO2 expression may contribute to synovial inflammation and joint destruction during arthritis. Therefore, targeting TDO2 activity and the Kyn pathway of Trp degradation may represent a potential therapeutic strategy in RA.

Shallow lakes, the most numerous waterbodies on Earth, are susceptible to climate warming and nutrient enrichment whose effects on the microbial functional potentials are not yet fully understood, however. Here, we applied a microarray-based technology termed GeoChip 5.0 to investigate microbial functional genes at the beginning of April in shallow lake ecosystems simulated in mesocosms that have been undergoing nutrient enrichment and warming for 9 yr. Our results showed that warming exacerbated the impact of nutrient enrichment on microbial metabolic potentials and significantly elevated the microbial autotrophy potentials, carbon degradation potentials (e.g., starch, hemicellulose, cellulose, and chitin), and polyphosphate mobilization potentials. We also observed that warming enhanced the impacts of nutrient enrichment on microbial functional gene structure. The combination of warming and nutrient enrichment increased the deterministic effect from phytoplankton, causing higher interlinking of microbial functional genes involved in the carbon, nitrogen, phosphorus, and sulfur cycling in correlation-based networks. Overall, we propose that the joint effect of warming and nutrient enrichment promoted the autotrophic carbon supply and the heterotrophic carbon demand and changed the carbon fluxes in the experimental mesocosms.

Increasing evidence has revealed that cancer cells undergoing an intermediate state, partial epithelial mesenchymal transition (p‐EMT), tend to metastasize rather than complete EMT. We performed a comprehensive analysis of E‐cadherin and 25 p‐EMT‐related genes in HCC to explore the roles and regulatory mechanisms of them in HCC. We analysed E‐cadherin and 25 p‐EMT‐related genes in HCC and constructed an mRNA‐miRNA‐lncRNA ceRNA subnetwork containing p‐EMT‐related genes by bioinformatic approaches. IHC was used to identify the protein expression of key p‐EMT‐related genes, P4HA2, ITGA5, MMP9, MT1X and SPP1. Complete EMT is not necessary for HCC progression. Overexpression of P4HA2, ITGA5, MMP9, SPP1 and down‐regulation of MT1X were found in HCC tissues, which were significantly associated with poor prognosis of HCC patients. By means of stepwise reverse prediction and validation from mRNA to lncRNA, an mRNA‐miRNA‐lncRNA ceRNA subnetwork correlated with HCC prognosis was identified by expression and survival analysis. This study implied that key p‐EMT‐related genes P4HA2, ITGA5, MMP9, MT1X, SPP1 could be prognostic biomarkers and potential targets of therapy for HCC patients. We constructed an mRNA‐miRNA‐lncRNA subnetwork containing p‐EMT‐related genes successfully, among which each component might be utilized as a prognostic biomarker of HCC.

Purpose To establish a prognostic model to estimate the cancer‐specific survival (CSS) for urothelial carcinoma of bladder (UCB) patients after radical cystectomy (RC). Methods A total of 8650 candidates (2004–2011) obtained from the Surveillance, Epidemiology, and End Results (SEER) database were randomly split into development cohort (n = 4323) and validation cohort (n = 4327). We performed Cox regression analysis to identify prognostic factors and Kaplan‐Meier analysis to assess survival outcome. A nomogram predicting CSS was constructed. Its performance was validated by calibration curves, the receiver operating characteristic (ROC) curves, concordance index (C‐index), decision curve analysis (DCA), the net reclassification improvement (NRI), and the integrated discrimination improvement (IDI). Results The nomogram incorporated marital status, T stage, N stage, tumor size, and chemotherapy. In validation cohort, C‐index of the nomogram was 0.707. AUC of the nomogram and AJCC stage were 0.767 versus 0.674. Calibration plots for 3‐ and 5‐year CSS displayed good concordance. DCA curves of the nomogram exhibited larger benefits than the AJCC stage. The NRI and IDI indicated the nomogram outperformed AJCC stage. Conclusions We have established a prognostic nomogram with improved discriminative ability and clinical benefits for UCB patients after RC. The nomogram alongside an easy access web tool may assist clinicians in optimizing the postoperative management., This population‐based study has established a nomogram and its derived webserver to predict cancer‐specific survival probabilities for patients with urothelial carcinoma of the bladder after radical cystectomy. The model’s discriminative abilities, accuracy and clinical benefits were validated and performed better than traditional AJCC stage.

Direct sulfonamidation of quinoxalin-2(1H)-one derivatives has been developed using a readily available Cu salt as the catalyst and inexpensive ammonium persulfate as the oxidant in moderate conditions. Owing to the feature of handy operation and good functional group tolerance, this method provides a convenient and efficient access to curative 3-sulfonamidated quinoxalin-2(1H)-one scaffolds.

The platysma skin flap was used for laryngeal reconstruction after vertical partial laryngectomy to improve the postoperative voice quality of patients with T2 and T3 glottic laryngeal carcinoma. Sixty-nine patients with unilateral T2 and T3 glottic laryngeal carcinoma were included. Forty-six patients received vertical partial laryngectomy, and a platysma skin flap was used for laryngeal reconstruction. The other 23 patients underwent transoral laser microsurgery. Subjective and objective examinations were performed to evaluate laryngeal morphology after the surgery. Acceptable voice quality was achieved for 46 patients who underwent vertical partial laryngectomy. Flap vibrational waves occurred in 19 cases (41.3%). The platysma skin flap is an ideal tissue for the reconstruction of articulation structure in open surgery of T2 and T3 unilateral glottic laryngeal carcinoma.

Impaired diabetic wound healing is associated with the persistence of chronic inflammation and excessive oxidative stress, which has become one of the most serious clinical challenges. Wound dressings with anti-inflammatory and reactive oxygen species (ROS)-scavenging properties are desirable for diabetic wound treatment. In this study, a shape-adaptable, biodegradable, biocompatible, antioxidant, and immunomodulatory interleukin-33 (IL-33)-cytogel is developed by encapsulating IL-33 into physically cross-linked DNA hydrogels and used as wound dressings to promote diabetic wound healing. The porous microstructures and biodegradable properties of the IL-33-cytogel ensure the local sustained-release of IL-33 in the wound area, where the sustained-release of IL-33 is maintained for at least 7 days. IL-33-cytogel can induce local accumulation of group 2 innate lymphoid cells (ILC2s) and regulatory T cells (Tregs), as well as M1-to-M2 transition at the wound sites. Additionally, the antioxidant and biocompatible characteristics of DNA hydrogels promote the scavenging of intracellular ROS without affecting cell viability. As a result, local inflammation in the diabetic wound area is resolved upon IL-33-cytogel treatment, which is accompanied by improved granulation tissue regeneration and accelerated wound closure. This study demonstrates a promising strategy in tissue engineering and regenerative medicine by incorporating DNA hydrogels and cytokine immunotherapy for promoting diabetic wound healing.

Objectives Microbiota dysbiosis in inflammatory bowel disease (IBD) has been widely reported. The gut microbiota connect diet to the metabolism by producing small molecules via diverse metabolic pathways. In this study we aimed to investigate the dietary preferences of IBD patients, and to explore the interactions among gut microbiota composition, dietary components, and metabolites in relation to IBD. Methods Dietary preferences of IBD patients (including those with ulcerative colitis [UC] and Crohn's disease [CD]) and health controls were investigated, and their gut microbiota were analyzed using 16S rRNA gene sequencing and metagenomic analyses of fecal and biopsy samples. The metabolite profiles of the samples were then analyzed using gas and liquid chromatography-mass spectrometry analyses. Results The daily intake of folic acid, niacin, vitamins C and D, calcium, and selenium differed significantly between patients with IBD and healthy controls. A decrease in long-chain (such as arachidic, and oleic acid) and medium-chain fatty acids (sebacic acid and isocaproic acid) as well as bile acid was observed in patients with IBD. Compared with healthy controls, 22 microbial species (including Sulfolobus acidocaldarius, and Clostridium clostridioforme CAG132) in the UC group and 37 microbial species (such as Bacteroides fragilis and Fusobacterium nucleatum) in the CD group were found to be correlated to diet and metabolites. Bacteroides fragilis was enriched in patients with IBD and associated with multi-nutrients, and 21 metabolites including 25-hydroxyvitamin D3 and taurolithocholic acid. Conclusions This study provides an interaction network to identify key micronutrients, microbiota components and metabolites that contribute to IBD.

In December 2019, an outbreak of coronavirus disease 2019 (COVID-19) emerged in Wuhan, China. Although it has been reported that some COVID-19 patients showed elevated liver biochemistries, there are few studies regarding clinical features and prognosis of these patients. In this multicenter, retrospective study, we collected data on laboratory-confirmed COVID-19 patients from three hospitals in Wuhan, China, who died or were discharged between February 1, 2020, and February 20, 2020. The data on demographics, comorbidities, clinical symptoms, laboratory examinations on admission, complications, treatment, and outcome were collected. A total of 482 patients were enrolled in this study. Of those, 142 (29.5%) patients showed abnormal liver biochemistries on admission, and patients with elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) accounted for 67.6%, 69.0%, and 16.2%, respectively. Those with abnormal liver biochemistries showed higher percentages of severe cases and comorbidities and were more likely to have dyspnea, chest distress or pain, and increased hemoglobin (Hb) on admission. Higher rates of complications and mortality and worse recovery when discharged were observed in patients with abnormal AST or TBIL. The multivariable regression analysis showed that chest distress or pain (odds ratio [OR], 1.765; P = 0.018), dyspnea (OR, 2.495; P = 0.001), elevated C-reactive protein [CRP] level (OR, 1.007; P = 0.008), elevated white blood count (WBC) (OR, 1.139; P = 0.013), and elevated Hb concentration (OR, 1.024; P = 0.001) were independent factors associated with elevated liver biochemistries in COVID-19 patients. Conclusion: Elevated liver biochemistries were common in COVID-19 patients. Patients with hypoxia or severe inflammation are more likely to experience increased liver biochemistries on admission. Those with abnormal AST or TBIL on admission are more likely to suffer from severe complications and death.