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1.
Cancer Lett ; 468: 14-26, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31600529

RESUMO

Deregulation of SOX9 in esophageal cancer has been reported. However, the regulatory mechanisms underlying SOX9 during esophageal squamous cell carcinoma (ESCC) progression remain poorly understood. Here, we independently confirmed the increased SOX9 expression in two ESCC cohorts and its correlation with poor prognosis. We demonstrated that SOX9 was required for maintaining self-renewal, motility, and chemoresistance in vitro and that ectopic expression of SOX9 promoted tumorigenicity in vivo. Screening for potential SOX9-regulated miRNAs revealed that target genes of differentially expressed miRNAs were enriched in the PI3K/AKT signaling pathway and identified the downregulated miR-203a as a candidate. Mechanistically, SOX9 activation caused repression of miR-203a transcription by binding to miR-203a promoter, thus preventing the miR-203a-mediated inhibition of multiple PI3K/AKT/mTOR components, including PIK3CA, AKT2, and RPS6KB1. The association between SOX9 expression and PI3K/AKT/mTOR signaling was further validated in clinical samples. Moreover, rapamycin treatment attenuated the SOX9-mediated malignant phenotypes and potentiated cisplatin-mediated inhibition of tumor growth. Together, these findings uncover a novel activation of the PI3K/AKT pathway by the SOX9/miR-203a axis and define a subgroup of patients who may benefit from targeted therapy.

2.
Adv Exp Med Biol ; 1179: 109-135, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31741335

RESUMO

Highly representative and relevant cell and mouse models are required for HBV study, including uncovering its lifecycle, investigation of the viral-host interaction, and development and evaluation of the novel antiviral therapy. During the past 40 years, both HBV cell culture models and animal models have evolved over several generations, each with significant improvement for specific purposes. In one aspect, HBV cell culture models experienced the original noninfection model including HBV plasmid DNA transfection and HBV genome integrated stable cells such as HepG2.2.15 which constitutively produces HBV virus and HepAD38 cells and its derivatives which drug-regulated HBV production. As for HBV infection models, HepaRG cells once dominated the HBV infection field for over a decade, but its complicated and labor-extensive cell differentiation procedures discouraged primary researchers from stepping in the field. The identification of human NTCP as HBV receptor evoked great enthusiasm of the whole HBV field, and its readily adaptive characteristic makes it popular in many HBV laboratories. Recombinant cccDNA (rc-cccDNA) emerged recently aiming to tackle the very basic question of how to eventually eradicate cccDNA without HBV real virus infection. In the other aspect, HBV transgenic mouse was firstly generated in the 1990s, which was helpful to decipher HBV production in vivo. However, the HBV transgenic mice were naturally immune tolerant to HBV viral products. Subsequently, a series of nonintegrated HBV mouse models were generated through plasmid hydrodynamic tail vein injection and viral vector-mediated delivery approaches, and HBV full life cycle was incomplete as cccDNA was not formed from HBV relaxed circular DNA (rcDNA). Human NTCP transgenic mouse still could not support productive HBV infection, and humanized mouse liver with human hepatocytes which supported whole HBV life cycle still dominates HBV infection in vivo, a value but expensive model until now. Other methods to empower mouse to carry HBV cccDNA were also exploited. In this chapter, we summarized the advantages and disadvantages of each model historically and provided protocols for HBV infection in HepG2-NTCP cells, HBV rc-cccDNA transfection in HepG2 cells, and HBV infection in NRG-Fah-/- liver humanized mouse.


Assuntos
Vírus da Hepatite B , Animais , Linhagem Celular , DNA Viral , Modelos Animais de Doenças , Vírus da Hepatite B/fisiologia , Hepatócitos/virologia , Humanos , Replicação Viral
3.
Int J Hyg Environ Health ; 223(1): 116-123, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31588015

RESUMO

Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) and malondialdehyde (MDA) are commonly used biomarkers of oxidative stress. However, their associations with air pollutant exposure have not been consistent across studies. We hypothesize that the inconsistency is partly due to confounding of circulating melatonin. We analyzed urinary 6-sulfatoxymelatonin (aMT6s), a surrogate of circulating melatonin, along with 8-OHdG and MDA, in 159 healthy adults who had not taken melatonin supplementation. Within the natural range of endogenously-generated aMT6s (0.3-93.5 ng/mg creatinine) measured in this study, increasing aMT6s levels were significantly associated with increasing concentrations of 8-OHdG and MDA. Measurements of PM2.5, ozone (O3), and nitrogen dioxide (NO2), coupled with time-activity data, were used to calculate time-averaged personal exposures 12 -hour (12h) and 24-hour (24h) prior to urine collection. Without controlling for aMT6s, the relationships between pollutant exposure and 8-OHdG or MDA were not clear. After controlling for aMT6s, an interquartile range (IQR) increase in 12h PM2.5 and 12h NO2 exposure was associated with 6.1% [95%CI: 1.6%-10.8%] and 8.6% [1.3%-16.5%] increase in MDA, respectively. An IQR increase in 12h O3 exposure was associated with a 5.7% [1.9%-9.7%] in 8-OHdG. The findings suggest the need for controlling for aMT6s as a confounder in using urinary 8-OHdG and MDA as biomarkers of oxidative stress related to short-term air pollution exposure.

4.
J Nanosci Nanotechnol ; 20(5): 3013-3018, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31635641

RESUMO

Molybdenum disulfide (MoS2) was synthesized via hydrothermal process under the assistance of citric acid, which exhibited high photocatalytic property in the application of methylene blue (MB) degradation. The flower ball microstructure of MoS2 changed with different amounts of citric acid. X-ray diffraction (XRD), Scanning electron microscope (SEM), UV-Vis diffuse reflectance spectra have been employed to characterize the samples. It improved the photocatalytic efficiency nearly 19.77% compared to MoS2 without citric acid. When H2O2 was added, the synergistic effect of MoS2 and hydrogen peroxide (H2O2) was observed in photocatalytic reaction system, which degraded MB completely within 40 min under visible light irradiation.

5.
Chemosphere ; 238: 124664, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31472349

RESUMO

Chemosensors have already demonstrated potential for the detection and imaging of metal ions in solutions and biological systems, however, their applications to soil analysis are limited. This study explores the potential of utilizing a chemosensor for the detection of exchangeable Cu2+ in soils via qualitative (solution visual color change) and quantitative (UV-Vis spectrophotometry) approaches. Montmorillonite and kaolin clays were doped with Cu(NO3)2 solutions from 2.5 to 50 mM, and contaminated soil samples were collected from a historic copper mine. The exchangeable Cu2+ was extracted using a standard CaCl2 cation exchange approach, and the Cu2+ concentration in the resulting solutions determined by UV-Vis spectrophotometry, using a chemosensor, and compared to traditional ICP-MS analysis. Analytical results showed that the chemosensor provided a visual response in contaminated soils at concentrations of 25 µM and quantitative detection to concentrations of 1 µM using UV-Vis spectrophotometry. This work demonstrates the first reported chemosensor for exchangeable Cu2+ with application to soil systems.

6.
Mol Cancer Res ; 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31792079

RESUMO

Chronic hepatitis B virus (HBV) infection is a major risk factor for the development of hepatocellular carcinoma (HCC), which represents one of the most common cancers worldwide. Recent studies suggest that HBV's protein X (HBx) plays a crucial role in HCC development and progression. Earlier genome-wide analysis identified that the receptor for hyaluronan-mediated motility (RHAMM) represents a putative oncogene and is overexpressed in many human cancers, including HCC. However, the mechanism underlying RHAMM upregulation and its role in tumorigenesis remain unclear. Here, we show that ectopic expression of HBx activates the PI3K/Akt/Oct-1 pathway and upregulates RHAMM expression in HCC cells. HBx overexpression leads to dissociation of C/EBPß from the RHAMM gene promoter, thereby inducing RHAMM upregulation. RHAMM knockdown attenuates HBx-induced cell migration and invasion in vitro. In mice, HBx promotes cancer cell colonization via RHAMM upregulation, resulting in enhanced metastasis. Analysis of gene expression datasets reveals that RHAMM mRNA level is upregulated in HCC patients with poor prognosis. Implications: These results indicate that RHAMM expression is upregulated by HBx, a process that depends on inhibition of C/EBPß activity and activation of the PI3K/Akt/Oct-1 pathway. These results have several implications for the treatment of HBV-positive HCC involving upregulation of RHAMM and cancer metastasis.

7.
Brief Bioinform ; 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31792500

RESUMO

Numerous studies have shown that copy number variation (CNV) in lncRNA regions play critical roles in the initiation and progression of cancer. However, our knowledge about their functionalities is still limited. Here, we firstly provided a computational method to identify lncRNAs with copy number variation (lncRNAs-CNV) and their driving transcriptional perturbed subpathways by integrating multidimensional omics data of cancer. The high reliability and accuracy of our method have been demonstrated. Then, the method was applied to 14 cancer types, and a comprehensive characterization and analysis was performed. LncRNAs-CNV had high specificity in cancers, and those with high CNV level may perturb broad biological functions. Some core subpathways and cancer hallmarks widely perturbed by lncRNAs-CNV were revealed. Moreover, subpathways highlighted the functional diversity of lncRNAs-CNV in various cancers. Survival analysis indicated that functional lncRNAs-CNV could be candidate prognostic biomarkers for clinical applications, such as ST7-AS1, CDKN2B-AS1 and EGFR-AS1. In addition, cascade responses and a functional crosstalk model among lncRNAs-CNV, impacted genes, driving subpathways and cancer hallmarks were proposed for understanding the driving mechanism of lncRNAs-CNV. Finally, we developed a user-friendly web interface-LncCASE (http://bio-bigdata.hrbmu.edu.cn/LncCASE/) for exploring lncRNAs-CNV and their driving subpathways in various cancer types. Our study identified and systematically characterized lncRNAs-CNV and their driving subpathways and presented valuable resources for investigating the functionalities of non-coding variations and the mechanisms of tumorigenesis.

8.
Nano Lett ; 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31793303

RESUMO

Metastasis is the primary cause of cancer morbidity and mortality. To gain effective diagnosis and treatment, precise imaging of tumor metastasis is highly required. Here we prepared a persistent luminescent nanoparticles (PLNPs) containing hydrogel (PL-gel) for targeted, sustained and autofluorescence-free tumor metastasis imaging. PLNPs offered a renewable long-lasting near infrared (NIR) emitting without in situ radiation, favoring the deep tissue penetration imaging without background interference. PLNPs were conjugated with 4-carboxyphenyl boronic acid (CPBA) yielding PLNPs-CPBA, which specifically recognized metastatic breast cancer cells (MBA-MD-231), and enabled receptor-mediated endocytosis for specific cancer cell labeling. The PLNPs-CPBA labeled cancer cells possessed sensitive imaging performance and high viability without influence upon the migration and invasiveness of cancer cells for long-term tracking. PLNPs-CPBA were further encapsulated inside alginate to generate PL-gel for sustained PLNPs-CPBA release and tumor cell labeling, and the PL-gel showed enhanced renewable persistent luminescence compared to the PLNPs-CPBA suspension. The metastasis in mouse breast cancer model was continuously tracked by persistent luminescence imaging, showing that PL-gel achieved noninvasive and highly selective imaging of tumors metastasis without background interference. Our PL-gel could be rationally designed to specifically target to other types of cancer cells and thus provide a powerful and generic platform for the study of tumor metastasis.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31793992
10.
Aging (Albany NY) ; 112019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31790364

RESUMO

BACKGROUND AND AIMS: Epidemiological studies have shown that increasing parity is associated with risk of hypertension and diabetes in parous women. However, the relationship between the parity degree with chronic kidney disease (CKD) is still unknown. RESULTS: Parous women with higher parity had increased age, body mass index, waist circumference, systolic blood pressure, fasting plasma glucose, fasting insulin and decreased high-density lipoprotein cholesterol, eGFR and education levels. Compared with women with one-child birth, those with more than two-child births had greater prevalence of increased urinary albumin excretion (odds ratios [ORs] 1.53, 95% confidence intervals [CI], 1.03 - 2.28) and CKD (ORs 1.79, 95% CI, 1.24 - 2.58) after multiple adjustments. In dose-response analysis, a nonlinear relationship of parity degree with albuminuria and CKD was detected. CONCLUSION: Parity is associated with higher prevalence of albuminuria and CKD in middle-aged and elderly Chinese women. METHODS: We conducted a community-based study in 6,946 women to investigate the association of parity with albuminuria and CKD. Increased urinary albumin excretion was defined as albumin-to-creatinine ratio (ACR) greater or equal than 30 mg/g. CKD was defined as estimated glomerular filtration rate (eGFR) less than 60 mL/min per 1.73 m² or presence of albuminuria.

11.
J Hematol Oncol ; 12(1): 127, 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31783892

RESUMO

Asparagine-linked (N-linked) glycosylation is ubiquitous and can stabilize immune inhibitory PD-1 protein. Reducing N-linked glycosylation of PD-1 may decrease PD-1 expression and relieve its inhibitory effects on CAR-T cells. Considering that the codon of Asparagine is aac or aat, we wondered if the adenine base editor (ABE), which induces a·t to g·c conversion at specific site, could be used to reduce PD-1 suppression by changing the glycosylated residue in CAR-T cells. Our results showed ABE editing altered the coding sequence of N74 residue of PDCD1 and downregulated PD-1 expression in CAR-T cells. Further analysis showed ABE-edited CAR-T cells had enhanced cytotoxic functions in vitro and in vivo. Our study suggested that the single base editors can be used to augment CAR-T cell therapy.

12.
BMJ Open ; 9(12): e028518, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31796472

RESUMO

INTRODUCTION: Portal hypertension (PH) is a severe disease with a poor outcome. Hepatic venous pressure gradient (HVPG), the current gold standard to detect PH, is available only in few hospitals due to its invasiveness and technical difficulty. This study aimed to establish and assess a novel model to calculate HVPG based on biofluid mechanics. METHODS AND ANALYSIS: This is a prospective, randomised, non-controlled, multicentre trial. A total of 248 patients will be recruited in this study, and each patient will undergo CT, blood tests, Doppler ultrasound and HVPG measurement. The study consists of two independent and consecutive cohorts: original cohort (124 patients) and validation cohort (124 patients). The researchers will establish and improve the HVPG using biofluid mechanics (HVPGBFM)model in the original cohort and assess the model in the validation cohort. ETHICS AND DISSEMINATION: The study was approved by the Scientific Research Projects Approval Determination of Independent Ethics Committee of Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (approval number 2017-430 T326). Study findings will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT03470389.

13.
Diabetes Ther ; 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31797230

RESUMO

INTRODUCTION: Laparoscopic bariatric surgery is necessary for obese patients who cannot control body weight through daily diet and exercise, or other non-surgical ways. Three kinds of laparoscopic bariatric surgery, namely Roux-en-Y gastric bypass, sleeve gastrectomy, and sleeve gastrectomy with jejunal bypass, are available for weight loss in clinical practice, but their comparative effects are unclear. In this study, these were compared to illustrate their clinical effects. METHODS: A case-control study was conducted on 175 participants who fulfilled the inclusion criteria of laparoscopic bariatric surgery, while the controls were the same subjects before and after surgery, as well as with different surgeries specifically. Standardized weight loss measures were compared using analysis of covariance, with months from surgery as the covariant, including percentage total weight loss and excess body mass index (BMI) loss. RESULTS: A total of 175 patients were enrolled in this study (age 38 ± 10 years; BMI 46 ± 5 kg/m2), with a mean postsurgery follow-up of 18 ± 6 months. No significant difference was included among the enlisted patients before bariatric surgery. However, after surgery according to personal health indexes of patients and professional assessment by doctors, patients specifically receiving one of Roux-en-Y gastric bypass, sleeve gastrectomy, and sleeve gastrectomy with jejunal bypass had no significant difference between weight loss and BMI, while the most important factors were dietary control and exercise after bariatric surgery. CONCLUSION: This study suggests that bariatric surgery is only a prerequisite for weight loss, and the long-term dietary control and exercise can help patients achieve optimal weight loss.

14.
World J Gastroenterol ; 25(43): 6404-6415, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31798277

RESUMO

BACKGROUND: Developing mitochondrial regulators/nutrients from natural products to remedy mitochondrial dysfunction represent attractive strategies for therapy of non-alcoholic fatty liver disease (NAFLD). Polygonatum kingianum (PK) has been traditionally used in China as a medicinal and nutritional ingredient for centuries and can alleviate high-fat diet (HFD)-induced NAFLD by promoting mitochondrial functions. To date, the underlying molecular mechanism of PK for treating mitochondrial dysfunctions and thus alleviating NAFLD remains unclear. AIM: To identify the molecular mechanism behind the mitochondrial regulatory action of PK against HFD-induced NAFLD in rats. METHODS: NAFLD model was induced in rats with HFD. The rats were intragastrically administered PK (4 g/kg per day) for 14 wk. Metabolites in hepatic mitochondrial samples were profiled through ultra-high performance liquid chromatography/mass spectrometry followed by multivariate statistical analysis to find the potential biomarkers and metabolic pathways. RESULTS: PK significantly restored the metabolites' levels in the mitochondrial samples. Ten potential biomarkers were identified in the analyzed samples. These biomarkers are involved in riboflavin metabolism. CONCLUSION: PK can alleviate HFD-induced NAFLD by regulating the riboflavin metabolism and further improving the mitochondrial functions. Thus, PK is a promising mitochondrial regulator/nutrient for alleviating NAFLD-associated diseases.

15.
Brief Bioinform ; 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31799597

RESUMO

Drug sensitivity has always been at the core of individualized cancer chemotherapy. However, we have been overwhelmed by large-scale pharmacogenomic data in the era of next-generation sequencing technology, which makes it increasingly challenging for researchers, especially those without bioinformatic experience, to perform data integration, exploration and analysis. To bridge this gap, we developed RNAactDrug, a comprehensive database of RNAs associated with drug sensitivity from multi-omics data, which allows users to explore drug sensitivity and RNA molecule associations directly. It provides association data between drug sensitivity and RNA molecules including mRNAs, long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) at four molecular levels (expression, copy number variation, mutation and methylation) from integrated analysis of three large-scale pharmacogenomic databases (GDSC, CellMiner and CCLE). RNAactDrug currently stores more than 4 924 200 associations of RNA molecules and drug sensitivity at four molecular levels covering more than 19 770 mRNAs, 11 119 lncRNAs, 438 miRNAs and 4155 drugs. A user-friendly interface enriched with various browsing sections augmented with advance search facility for querying the database is offered for users retrieving. RNAactDrug provides a comprehensive resource for RNA molecules acting in drug sensitivity, and it could be used to prioritize drug sensitivity-related RNA molecules, further promoting the identification of clinically actionable biomarkers in drug sensitivity and drug development more cost-efficiently by making this knowledge accessible to both basic researchers and clinical practitioners. Database URL: http://bio-bigdata.hrbmu.edu.cn/RNAactDrug.

16.
Waste Manag ; 102: 635-644, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31785523

RESUMO

Indium is one of the components with great recycling value in waste LCDs. Degradation of organic materials and the remain of indium in the solid phase can be simultaneously achieved by hydrothermal pretreatment via parameter regulation. Indium was transferred from the solid phase to the liquid phase by using sulfuric acid after hydrothermal pretreatment. Di-(2-ethylhexyl) phosphoric acid diluted by sulfonated kerosene and hydrochloric acid were used as extractant and stripping agent respectively to purify and concentrate indium from acidic leaching solution. The results indicated that the leaching yield of indium reached 100% under the optimal condition of reaction time of 40 min, reaction temperature of 70-80 °C, acid concentration of 0.5 M and solid-liquid (S/L) ratio of 1:2 g/mL. Given conditions of extraction time of 3 min at the organic phase to aqueous phase (O/A) ratio of 1:10 by 20% D2EHPA and stripping time of 10 min at the (O/A) ratio of 10:1 by 4 M HCl, the recovery efficiency of indium reached 97.25%. In addition, acid leaching process did not change the surface topography and molecular structure of glass substrate and had no negative effect on subsequent recycling of glass. The kinetic equation of leaching yield and reaction time at the temperature of 80 °C is 1 - (1 - y)1/3 = 0.0215 t. The reaction activation energy of metal indium leaching process is 50.64 kJ/mol.

17.
Biomed Pharmacother ; 122: 109587, 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31786466

RESUMO

BACKGROUND: There is no standard treatment for stage IV soft tissue sarcoma (STS) after the failure of Adriamycin-based chemotherapy. This phase II study (NCT03121846) assessed the efficacy and safety of apatinib (YN968D1), a new tyrosine kinase inhibitor that targets VEGFR-2, for patients with stage IV STS after chemotherapy failure. METHODS: Forty-two subjects with stage IV STSs who had failed chemotherapy and who received Apatinib were recruited between September 2015 and February 2018. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were the PFS rate (PFR), objective response rate (ORR), and disease control rate (DCR) at week 12. Treatment-related adverse effects (AEs) were evaluated. RESULTS: Forty-two subjects were evaluated for AEs and 38 subjects were evaluated for efficacy. At 12 weeks, the PFR, ORR, and DCR were 70%, 26.32% (10/38), and 86.84% (33/38), respectively. Regarding overall responses, the ORR and DCR were 23.68% (9/38) and 57.89% (22/38), respectively. The median PFS was 7.87 months, and the median overall survival (OS) was 17.55 months. The most common AEs included hypertension (n = 18, 42.86%), hand-foot-skin reaction (n = 15, 35.71%), apositia (n = 13, 30.95%), and proteinuria (n = 11, 26.19%). No subjects had grade 4 AEs and 11 subjects (26.19%) experienced grade 3 AEs, mainly hypertension, hand-foot-skin reaction, proteinuria, apositia, fatigue, pain, and dysgeusia. Notably, the subjects who experienced hypertension, hand-foot-skin reaction, or proteinuria had significantly longer OS than those without these AEs (P = 0.0003). CONCLUSION: With the largest Chinese STS cohort to date, we report that apatinib show good efficacy in advanced STS subjects with significant higher ORR and some adverse events may predict prognosis.

18.
Front Immunol ; 10: 2358, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31681271

RESUMO

A typical inflammatory response sequentially progresses from pro-inflammatory, immune suppressive to inflammatory repairing phases. Although the physiological inflammatory response resolves in time, severe acute inflammation usually sustains immune tolerance and leads to high mortality, yet the underlying mechanism is not completely understood. Here, using the leukemia-derived THP-1 human monocytes, healthy and septic human peripheral blood mononuclear cells (PBMC), we report that endotoxin dose-dependent switch of nicotinamide adenine dinucleotide (NAD) biosynthesis pathways sustain immune tolerant status. Low dose endotoxin triggered nicotinamide phosphoribosyltransferase (NAMPT)-dependent NAD salvage activity to adapt pro-inflammation. In contrast, high dose endotoxin drove a shift of NAD synthesis pathway from early NAMPT-dependent NAD salvage to late indoleamine 2,3-dioxygenase-1 (IDO1)-dependent NAD de novo biosynthesis, leading to persistent immune suppression. This is resulted from the IDO1-dependent expansion of nuclear NAD pool and nuclear NAD-dependent prolongation of sirtuin1 (SIRT1)-directed epigenetics of immune tolerance. Inhibition of IDO1 activity predominantly decreased nuclear NAD level, which promoted sequential dissociations of immunosuppressive SIRT1 and RelB from the promoter of pro-inflammatory TNF-α gene and broke endotoxin tolerance. Thus, NAMPT-NAD-SIRT1 axis adapts pro-inflammation, but IDO1-NAD-SIRT1-RelB axis sustains endotoxin tolerance during acute inflammatory response. Remarkably, in contrast to the prevention of sepsis death of animal model by IDO1 inhibition before sepsis initiation, we demonstrated that the combination therapy of IDO1 inhibition by 1-methyl-D-tryptophan (1-MT) and tryptophan supplementation rather than 1-MT administration alone after sepsis onset rescued sepsis animals, highlighting the translational significance of tryptophan restoration in IDO1 targeting therapy of severe inflammatory diseases like sepsis.

19.
Radiat Oncol ; 14(1): 190, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31685005

RESUMO

BACKGROUND: We aimed to ascertain population-based practice patterns and survival outcomes of postoperative radiotherapy following breast conserving-surgery (BCS) in elderly women (aged ≥65 years) with early-stage pure mucinous breast carcinoma (PMBC). METHODS: Patients aged ≥65 years diagnosed with T1-2N0 and hormone receptor-positive PMBC between 1990 and 2010 were identified from the Surveillance, Epidemiology, and End Results database. Binomial logistic regression, Kaplan-Meier method, Multivariate Cox proportional hazards models, and propensity score matching (PSM) were used for statistical analysis. RESULTS: We enrolled 3416 patients, including 1225 (35.9%) and 2191 (64.1%) in the no-radiotherapy and radiotherapy cohorts, respectively. The percentage of patients receiving postoperative radiotherapy following BCS was significantly lower after 2004 (59.5% between 2004 and 2010), relative to that before 2004 (71.1% between 1990 and 2003; P < 0.001). Before PSM, the 10-year breast cancer-specific survival (BCSS) rates were 98.1 and 93.2% for patients with and without postoperative radiotherapy (log-rank test, P < 0.001), respectively. In the PSM cohort, receiving postoperative radiotherapy was associated with better BCSS rates, with 10-year BCSS rates of 97.6 and 94.5% in patients with and without postoperative radiotherapy, respectively (log-rank test, P = 0.001). Multivariate Cox proportional analysis indicated that receiving postoperative radiotherapy was an independent factor associated with better BCSS before (P < 0.001) and after PSM (P = 0.001), relative to those not receiving postoperative radiotherapy. CONCLUSIONS: This study shows a decreasing utilization of postoperative radiotherapy following BCS of elderly PMBC patients over time. However, postoperative radiotherapy following BCS should be administered for elderly women with PMBC owing to independent association with better survival.

20.
Theranostics ; 9(25): 7648-7665, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695792

RESUMO

Alternative splicing (AS) has emerged as a key event in tumor development and microenvironment formation. However, comprehensive analysis of AS and its clinical significance in head and neck squamous cell carcinoma (HNSC) is urgently required. Methods: Genome-wide profiling of AS events using RNA-Seq data from The Cancer Genome Atlas (TCGA) program was performed in a cohort of 464 patients with HNSC. Cancer-associated AS events (CASEs) were identified between paired HNSC and adjacent normal tissues and evaluated in functional enrichment analysis. Splicing networks and prognostic models were constructed using bioinformatics tools. Unsupervised clustering of the CASEs identified was conducted and associations with clinical, molecular and immune features were analyzed. Results: We detected a total of 32,309 AS events and identified 473 CASEs in HNSC; among these, 91 were validated in an independent cohort (n = 15). Functional protein domains were frequently altered, especially by CASEs affecting cancer drivers, such as PCSK5. CASE parent genes were significantly enriched in pathways related to HNSC and the tumor immune microenvironment, such as the viral carcinogenesis (FDR < 0.001), Human Papillomavirus infection (FDR < 0.001), chemokine (FDR < 0.001) and T cell receptor (FDR < 0.001) signaling pathways. CASEs enriched in immune-related pathways were closely associated with immune cell infiltration and cytolytic activity. AS regulatory networks suggested a significant association between splicing factor (SF) expression and CASEs and might be regulated by SF methylation. Eighteen CASEs were identified as independent prognostic factors for overall and disease-free survival. Unsupervised clustering analysis revealed distinct correlations between AS-based clusters and prognosis, molecular characteristics and immune features. Immunogenic features and immune subgroups cooperatively depict the immune features of AS-based clusters. Conclusion: This comprehensive genome-wide analysis of the AS landscape in HNSC revealed novel AS events related to carcinogenesis and immune microenvironment, with implications for prognosis and therapeutic responses.

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