A functional study reveals CsNAC086 regulated the biosynthesis of flavonols in Camellia sinensis.

MAIN CONCLUSION: CsNAC086 was found to promote the expression of CsFLS, thus promoting the accumulation of flavonols in Camellia sinensis. Flavonols, the main flavonoids in tea plants, play an important role in the taste and quality of tea. In this study, a NAC TF gene CsNAC086 was isolated from tea plants and confirmed its regulatory role in the expression of flavonol synthase which is a key gene involved in the biosynthesis of flavonols in tea plant. Yeast transcription-activity assays showed that CsNAC086 has self-activation activity. The transcriptional activator domain of CsNAC086 is located in the non-conserved C-terminal region (positions 171-550), while the conserved NAC domain (positions 1-170) does not have self-activation activity. Silencing the CsNAC086 gene using antisense oligonucleotides significantly decreased the expression of CsFLS. As a result, the concentration of flavonols decreased significantly. In overexpressing CsNAC086 tobacco leaves, the expression of NtFLS was significantly increased. Compared with wild-type tobacco, the flavonols concentration increased. Yeast one-hybrid assays showed CsNAC086 did not directly regulate the gene expression of CsFLS. These findings indicate that CsNAC086 plays a role in regulating flavonols biosynthesis in tea plants, which has important implications for selecting and breeding of high-flavonols-concentration containing tea-plant cultivars.

Selenium Ameliorated Oxidized Fish Oil-Induced Lipotoxicity via the Inhibition of Mitochondrial Oxidative Stress, Remodeling of Usp4-Mediated Deubiquitination, and Stabilization of Pparα.

Aims: Studies demonstrated that oxidized fish oil (OFO) promoted oxidative stress and induced mitochondrial dysfunction and lipotoxicity, which attenuated beneficial effects of fish oil supplements in the treatment of nonalcoholic fatty liver disease (NAFLD). The current study was performed on yellow catfish, a good model to study NAFLD, and its hepatocytes to explore whether selenium (Se) could alleviate OFO-induced lipotoxicity via the inhibition of oxidative stress and determine its potential mechanism. Results: The analysis of triglycerides content, oxidative stress parameters, and histological and transmission electronic microscopy observation showed that high dietary Se supplementation alleviated OFO-induced lipotoxicity, oxidative stress, and mitochondrial injury and dysfunction. RNA-sequencing and immunoblotting analysis indicated that high dietary Se reduced OFO-induced decline of peroxisome-proliferator-activated receptor alpha (Pparα) and ubiquitin-specific protease 4 (Usp4) protein expression. High Se supplementation also alleviated OFO-induced reduction of thioredoxin reductase 2 (txnrd2) messenger RNA (mRNA) expression level and activity. The txnrd2 knockdown experiments revealed that txnrd2 mediated Se- and oxidized eicosapentaenoic acid (oxEPA)-induced changes of mitochondrial reactive oxygen species (mtROS) and further altered Usp4 mediated-deubiquitination and stabilization of Pparα, which, in turn, modulated mitochondrial fatty acid ß-oxidation and metabolism. Mechanistically, Usp4 deubiquitinated Pparα and ubiquitin-proteasome-mediated Pparα degradation contributed to oxidative stress-induced mitochondrial dysfunction. Innovation: These findings uncovered a previously unknown mechanism by which Se and OFO interacted to affect lipid metabolism via the Txnrd2-mtROS-Usp4-Pparα pathway, which provides the new target for NAFLD prevention and treatment. Conclusion: Se ameliorated OFO-induced lipotoxicity via the inhibition of mitochondrial oxidative stress, remodeling of Usp4-mediated deubiquitination, and stabilization of Pparα. Antioxid. Redox Signal. 40, 433-452.

Construction and Validation of a Novel Nomogram for Predicting the Risk of Metastasis in a Luminal B Type Invasive Ductal Carcinoma Population.

Background: Postoperative distant metastasis is the main cause of death in breast cancer patients. We aimed to construct a nomogram to predict the risk of metastasis of luminal B type invasive ductal carcinoma. Methods: We applied the data of 364 luminal B type breast cancer patients between 2008 and 2013. Patients were categorized into modeling group and validation group randomly (1:1). The breast cancer metastasis nomogram was developed from the logistic regression model using clinicopathological variables. The area under the receiver-operating characteristic curve (AUC) was calculated in modeling group and validation group to evaluate the predictive accuracy of the nomogram. Results: The multivariate logistic regression analysis showed that tumor size, No. of the positive level 1 axillary lymph nodes, human epidermal growth factor receptor 2 (HER2) status and Ki67 index were the independent predictors of the breast cancer metastasis. The AUC values of the modeling group and the validation group were 0.855 and 0.818, respectively. The nomogram had a well-fitted calibration curve. The positive and negative predictive values were 49.3% and 92.7% in the modeling group, and 47.9% and 91.0% in the validation group. Patients who had a score of 60 or more were thought to have a high risk of breast cancer metastasis. Conclusions: The nomogram has a great predictive accuracy of predicting the risk of breast cancer metastasis. If patients had a score of 60 or more, necessary measures, like more standard treatment methods and higher treatment adherence of patients, are needed to take to lower the risk of metastasis and improve the prognosis.

Enrofloxacin (ENR) exposure induces lipotoxicity by promoting mitochondrial fragmentation via dephosphorylation of DRP1 at S627 site.

Enrofloxacin (ENR) is a kind of widespread hazardous pollutant on aquatic ecosystems and causes toxic effects, such as disorders of metabolism, on aquatic animals. However, its potential mechanisms at an environmental concentration on metabolic disorders of aquatic organisms remain unclear. Herin, we found that hepatic lipotoxicity was induced by ENR exposure, which led to ENR accumulation, oxidative stress, mitochondrial fragmentation, and fatty acid transfer blockage from lipid droplets into fragmented mitochondria. ENR-induced lipotoxicity and mitochondrial ß-oxidation down-regulation were mediated by reactive oxygen species (ROS). Moreover, dynamin-like protein 1 (DRP1) mediated ENR-induced mitochondrial fragmentation and changes of lipid metabolism. Mechanistically, ENR induced increment of DRP1 mitochondrial localization via dephosphorylating DRP1 at S627 and promoted its interaction with mitochondrial fission factor (MFF), leading to mitochondria fragmentation. For the first time, our study provides an innovative mechanistic link between hepatic lipotoxicity and mitochondrial fragmentation under ENR exposure, and thus identifies previously unknown mechanisms for the direct relationship between environmental ENR concentration and lipotoxicity in aquatic animals. Our study provides innovative insights for toxicological mechanisms and environmental risk assessments of antibiotics in aquatic environment.

CD24 May Serve as an Immunotherapy Target in Triple-Negative Breast Cancer by Regulating the Expression of PD-L1.

Purpose: CD24 mediates a "don't eat me" signal to escape the immune environment. However, the correlation between CD24 and PD-L1 is unclear. This study aimed to assess if CD24 can serve as a target for immunotherapy of triple-negative breast cancer (TNBC). Methods: Data on CD24 expression in breast cancer were acquired using the Oncomine and UALCAN tools. The role of CD24 expression on the prognosis of patients with TNBC was assessed using Kaplan-Meier analyses. Subsequently, STRING and TISIDB databases were used to construct protein-protein interaction networks and to explore immune-related molecules regulated by CD24. Immunofluorescence and immunohistochemistry assays were conducted to validate CD24 and PD-L1 expression and tumor infiltration lymphocyte (TIL) level. Survival analysis was also performed to explore the effect of CD24 and PD-L1 expression and TIL level in patients with TNBC. ShRNA was also used to explore the regulation role of CD24 on PD-L1 expression. Results: CD24 expression was significantly higher in breast cancer than in normal tissues, with high expression being significantly associated with a worse prognosis. CD24 was found to be significantly regulated by chemokines, immunoinhibitors, immunostimulators and TILs. Furthermore, CD24 expression showed a significant positive correlation with PD-L1 expression and a negative correlation with TIL level. In association with PD-L1, CD24 was found to positively regulate lymphocyte costimulation, T cell costimulation, and leukocyte activation. Furthermore, CD24 and PD-L1 co-expression contributed to worse survival outcomes. In addition, CD24 expression was found to attenuate the positive effects of high-level TILs on the prognosis of patients with TNBC. CD24 can also regulate the expression of PD-L1 in TNBC cells. Conclusion: CD24 may attenuate the positive effects of high TIL levels on survival and may facilitate the immune escape of TNBC by regulating PD-L1 expression. Thus, it is a potential target for immunotherapy in TNBC.

Sirt3-Sod2-mROS-Mediated Manganese Triggered Hepatic Mitochondrial Dysfunction and Lipotoxicity in a Freshwater Teleost.

Exposure to excessive manganese (Mn) is toxic to humans and animals. However, the toxic effects and mechanisms of excessive Mn influencing the vertebrates have been highly overlooked. In the present study, dietary Mn overload significantly increased hepatic lipid and Mn contents, decreased superoxide dismutase 2 (Sod2) activity, increased the Sod2 acetylation level, and induced mitochondrial dysfunction; Mn induced mitochondrial dysfunction through Mtf1/sirtuin 3 (Sirt3)-mediated acetylation of Sod2 at the sites K55 and K70. Meanwhile, mitochondrial oxidative stress was involved in Mn-induced lipotoxicity. Mechanistically, Mn-induced lipotoxicity was via oxidative stress-induced Hsf1 nucleus translocation and its DNA binding capacity to the regions of a peroxisome proliferator-activated receptor g (pparg) promoter, which in turn induced the transcription of lipogenic-related target genes. For the first time, our study demonstrated that Mn-induced hepatic lipotoxicity via a mitochondrial oxidative stress-dependent Hsf1/Pparg pathway and Mtf1/sirt3-mediated Sod2 acetylation participated in mitochondrial dysfunction. Considering that lipid metabolism and lipotoxicity are widely used as the biomarkers for environmental assessments of pollutants, our study provided innovative and important insights into Mn toxicological and environmental evaluation in aquatic environments.

Manganese-Induced Oxidative Stress Contributes to Intestinal Lipid Deposition via the Deacetylation of PPARγ at K339 by SIRT1.

Aims: Excessive manganese (Mn) exposure is toxic, and induces lipid deposition, but the underlying mechanisms remain elusive. Herein, we explored how dietary Mn supplementation affects lipid deposition and metabolism in the intestine of vertebrates using the yellow catfish Pelteobagrus fulvidraco as the model. Results: High-Mn (H-Mn) diet increased intestinal Mn content, promoted lipid accumulation and lipogenesis, and inhibited lipolysis. In addition, it induced oxidative stress, upregulated metal-response element-binding transcription factor-1 (MTF-1), and peroxisome proliferator-activated receptor gamma (PPARγ) protein expression in the nucleus, induced PPARγ acetylation, and the interaction between PPARγ and retinoid X receptor alpha (RXRα), while it downregulated sirtuin 1 (SIRT1) expression and activity. Mechanistically, Mn activated the MTF-1/divalent metal transporter 1 (DMT1) pathway, increased Mn accumulation in the mitochondria, and induced oxidative stress. This in turn promoted lipid deposition via deacetylation of PPARγ at K339 by SIRT1. Subsequently, PPARγ mediated Mn-induced lipid accumulation through transcriptionally activating fatty acid translocase, stearoyl-CoA desaturase 1, and perilipin 2 promoters. Innovation: These studies uncover a previously unknown mechanism by which Mn induces lipid deposition in the intestine via the oxidative stress-SIRT1-PPARγ pathway. Conclusion: High dietary Mn intake activates MTF-1/DMT1 and oxidative stress pathways. Oxidative stress-mediated PPARγ deacetylation at K339 site contributes to increased lipid accumulation. Our results provided a direct link between Mn and lipid metabolism via the oxidative stress-SIRT1-PPARγ axis. Antioxid. Redox Signal. 37, 417-436.

Mitochondria-Dependent Oxidative Stress Mediates ZnO Nanoparticle (ZnO NP)-Induced Mitophagy and Lipotoxicity in Freshwater Teleost Fish.

Due to many special characteristics, zinc oxide nanoparticles (ZnO NPs) are widely used all over the world, leading to their wide distribution in the environment. However, the toxicities and mechanisms of environmental ZnO NP-induced changes of physiological processes and metabolism remain largely unknown. Here, we found that addition of dietary ZnO NPs disturbed hepatic Zn metabolism, increased hepatic Zn and lipid accumulation, downregulated lipolysis, induced oxidative stress, and activated mitophagy; N,N,N',N'-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN, Zn2+ ions chelator) alleviated high ZnO NP-induced Zn and lipid accumulation, oxidative stress, and mitophagy. Mechanistically, the suppression of mitochondrial oxidative stress attenuated ZnO NP-activated mitophagy and ZnO NP-induced lipotoxicity. Taken together, our study elucidated that mitochondrial oxidative stress mediated ZnO NP-induced mitophagy and lipotoxicity; ZnO NPs could be dissociated to free Zn2+ ions, which partially contributed to ZnO NP-induced changes in oxidative stress, mitophagy, and lipid metabolism. Our study provides novel insights into the impacts and mechanism of ZnO NPs as harmful substances inducing lipotoxicity of aquatic organisms, and accordingly, metabolism-relevant parameters will be useful for the risk assessment of nanoparticle materials in the environment.

Dietary Nano-ZnO Is Absorbed via Endocytosis and ZIP Pathways, Upregulates Lipogenesis, and Induces Lipotoxicity in the Intestine of Yellow Catfish.

Nano-sized zinc oxide (nano-ZnO) affects lipid deposition, but its absorption patterns and mechanisms affecting lipid metabolism are still unclear. This study was undertaken to investigate the molecular mechanism of nano-ZnO absorption and its effects on lipid metabolism in the intestinal tissues of a widely distributed freshwater teleost yellow catfish Pelteobagrus fulvidraco. We found that 100 mg/kg dietary nano-ZnO (H-Zn group) significantly increased intestinal Zn contents. The zip6 and zip10 mRNA expression levels were higher in the H-Zn group than those in the control (0 mg/kg nano-ZnO), and zip4 mRNA abundances were higher in the control than those in the L-Zn (50 mg/kg nano-ZnO) and H-Zn groups. Eps15, dynamin1, dynamin2, caveolin1, and caveolin2 mRNA expression levels tended to reduce with dietary nano-ZnO addition. Dietary nano-ZnO increased triglyceride (TG) content and the activities of the lipogenic enzymes glucose 6-phosphate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase (6PGD), and isocitrate dehydrogenase (ICDH), upregulated the mRNA abundances of lipogenic genes 6pgd, fatty acid synthase (fas), and sterol regulatory element binding protein 1 (srebp1), and reduced the mRNA expression of farnesoid X receptor (fxr) and small heterodimer partner (shp). The SHP protein level in the H-Zn group was lower than that in the control and the L-Zn group markedly. Our in vitro study indicated that the intestinal epithelial cells (IECs) absorbed nano-ZnO via endocytosis, and nano-Zn-induced TG deposition and lipogenesis were partially attributable to the endocytosis of nano-ZnO in IECs. Mechanistically, nano-ZnO-induced TG deposition was closely related to the metal responsive transcription factor 1 (MTF-1)-SHP pathway. Thus, for the first time, we found that the lipogenesis effects of nano-ZnO probably depended on the key gene shp, which is potentially regulated by MTF1 and/or FXR. This novel signaling pathway of MTF-1 through SHP may be relevant to explain the toxic effects and lipotoxicity ascribed to dietary nano-ZnO addition.

Dietary Marginal and Excess Selenium Increased Triglycerides Deposition, Induced Endoplasmic Reticulum Stress and Differentially Influenced Selenoproteins Expression in the Anterior and Middle Intestines of Yellow Catfish Pelteobagrus fulvidraco.

Selenium (Se) is an essential micro-mineral and plays important roles in antioxidant responses, and also influences lipid metabolism and selenoprotein expression in vertebrates, but the effects and mechanism remain unknown. The study was undertaken to decipher the insights into dietary Se influencing lipid metabolism and selenoprotein expression in the anterior and middle intestine (AI and MI) of yellow catfish Pelteobagrus fulvidraco. Yellow catfish (weight: 8.27 ± 0.03 g) were fed a 0.03- (M-Se), 0.25- (A-Se), or 6.39- (E-Se) mg Se/kg diet for 12 wk. AI and MI were analyzed for triglycerides (TGs) and Se concentrations, histochemistry and immunofluorescence, enzyme activities, and gene and protein levelsassociated with antioxidant responses, lipid metabolism, endoplasmic reticulum (ER) stress, and selenoproteome. Compared to the A-Se group, M-Se and E-Se diets significantly decreased weight gain (WG) and increased TGs concentration in the AI and MI. In the AI, compared with A-Se group, M-Se and E-Se diets significantly increased activities of fatty acid synthase, expression of lipogenic genes, and suppressed lipolysis. In the MI, compared to the A-Se group, M-Se and E-Se diets significantly increased activities of lipogenesis and expression of lipogenic genes. Compared with A-Se group, E-Se diet significantly increased glutathione peroxidase (GPX) activities in the AI and MI, and M-Se diet did not significantly reduce GPX activities in the AI and MI. Compared with the A- Se group, E-Se diet significantly increased glutathione peroxidase (GPX) activities in the plasma and liver, and M-Se diet significantly reduced GPX activities in the plasma and liver. Compared with the A-Se group, M-Se and E-Se groups also increased glucose-regulated protein 78 (GRP78, ER stress marker) protein expression of the intestine. Dietary Se supplementation also differentially influenced the expression of the 28 selenoproteins in the AI and MI, many of which possessed antioxidant characteristics. Compared with the A-Se group, the M-Se group significantly decreased mRNA levels of txnrd2 and txnrd3, but made no difference on mRNA levels of these seven GPX proteins in the MI. Moreover, we characterized sterol regulatory element binding protein 1c (SREBP1c) binding sites of three ER-resident proteins (selenom, selenon, and selenos) promoters, and found that Se positively controlled selenom, selenon, and selenos expression via SREBP1c binding to the selenom, selenon, and selenos promoter. Thus, dietary marginal and excess Se increased TGs deposition of yellow catfish P. fulvidraco, which might be mediated by ER-resident selenoproteins expression and ER stress.

Association between ambient air pollution and hyperuricemia in traffic police officers in China: a cohort study.

To evaluate the association between ambient air pollution and hyperuricemia, we prospectively followed 1748 traffic police officers without hyperuricemia at baseline (2009-2014) from 11 districts in Guangzhou, China. We calculated six-year average PM10, SO2 and NO2 concentrations using data collected from air monitoring stations. The hazard ratios for hyperuricemia per 10 µg/m3 increase in air pollutants were 1.46 (95% CI: 1.28-1.68) for PM10, 1.23 (95% CI: 1.00-1.51) for SO2, and 1.43 (95% CI: 1.26-1.61) for NO2. We also identified changes in the ratio of serum uric acid to serum creatinine concentrations (ua/cre) per 10 µg/m3 increase in air pollutants as 11.54% (95% CI: 8.14%-14.93%) higher for PM10, 5.09% (95% CI: 2.76%-7.42%) higher for SO2, and 5.13% (95% CI: 2.35%-7.92%) higher for NO2, respectively. Long-term exposure to ambient air pollution was associated with a higher incidence of hyperuricemia and an increase in ua/cre among traffic police officers.

Functional Analysis of Steroidogenic Factor 1 (sf-1) and 17α-Hydroxylase/Lyase (cyp17α) Promoters in Yellow Catfish Pelteobagrus fulvidraco.

The present study was performed to clone and characterize the structures and functions of steroidogenic factor 1 (sf-1) and 17α-hydroxylase/lyase (cyp17α) promoters in yellow catfish Pelteobagrus fulvidraco, a widely distributed freshwater teleost. We successfully obtained 1981 and 2034 bp sequences of sf-1 and cyp17α promoters, and predicted the putative binding sites of several transcription factors, such as Peroxisome proliferator-activated receptor alpha (PPARα), Peroxisome proliferator-activated receptor gamma (PPARγ) and Signal transducer and activator of transcription 3 (STAT3), on sf-1 and cyp17α promoter regions, respectively. Overexpression of PPARγ significantly increased the activities of sf-1 and cyp17α promoters, but overexpression of PPARα significantly decreased the promoter activities of sf-1 and cyp17α. Overexpression of STAT3 reduced the activity of the sf-1 promoter but increased the activity of the cyp17α promoter. The analysis of site-mutation and electrophoretic mobility shift assay suggested that the sf-1 promoter possessed the STAT3 binding site, but did not the PPARα or PPARγ binding sites. In contrast, only the PPARγ site, not PPARα or STAT3 sites, was functional with the cyp17α promoter. Leptin significantly increased sf-1 promoter activity, but the mutation of STAT3 and PPARγ sites decreased leptin-induced activation of sf-1 promoter. Our findings offered the novel insights into the transcriptional regulation of sf-1 and cyp17α and suggested leptin regulated sf-1 promoter activity through STAT3 site in yellow catfish.

Isolation and Characterization of Three Sodium-Phosphate Cotransporter Genes and Their Transcriptional Regulation in the Grass Carp Ctenopharyngodon idella.

It is important to explore the regulatory mechanism of phosphorus homeostasis in fish, which help avoid the risk of P toxicity and prevent P pollution in aquatic environment. The present study obtained the full-length cDNA sequences and the promoters of three SLC20 members (slc20a1a, slc20a1b and slc20a2) from grass carp Ctenopharyngodon idella, and explored their responses to inorganic phosphorus (Pi). Grass carp SLC20s proteins possessed conservative domains and amino acid sites relevant with phosphorus transport. The mRNAs of three slc20s appeared in the nine tissues, but their expression levels were tissue-dependent. The binding sites of three transcription factors (SREBP1, NRF2 and VDR) were predicted on the slc20s promoters. The mutation and EMSA analysis indicated that: (1) SREBP1 binding site (-783/-771 bp) negatively but VDR (-260/-253 bp) binding site positively regulated the activities of slc20a1a promoter; (2) SREBP1 (-1187/-1178 bp), NRF2 (-572/-561 bp) and VDR(615/-609 bp) binding sites positively regulated the activities of slc20a1b promoter; (3) SREBP1 (-987/-977 bp), NRF2 (-1469/-1459 bp) and VDR (-1124/-1117 bp) binding sites positively regulated the activities of the slc20a2 promoter. Moreover, Pi incubation significantly reduced the activities of three slc20s promoters, and Pi-induced transcriptional inactivation of slc20s promoters abolished after the mutation of the VDR element but not SREBP1 and NRF2 elements. Pi incubation down-regulated the mRNA levels of three slc20s. For the first time, our study elucidated the transcriptional regulatory mechanisms of SLC20s and their responses to Pi, which offered new insights into the Pi homeostatic regulation and provided the basis for reducing phosphorus discharge into the waters.

Functional Analysis of Two Zinc (Zn) Transporters (ZIP3 and ZIP8) Promoters and Their Distinct Response to MTF1 and RREB1 in the Regulation of Zn Metabolism.

ZIP (zinc-regulated transporters, iron-regulated transporter-like protein) family plays an important role in organism Zn balance. This research identified the promoter regions of ZIP3 and ZIP8, two members of ZIP family, from a freshwater teleost yellow catfish Pelteobagrus fulvidraco, characterized the binding sequences of the metal-responsive transcription factor-1 (MTF-1) and Ras responsive element binding protein 1 (RREB1) on their promoter regions. The present study cloned and obtained the 2027 bp of ZIP3 promoter and 1664 bp of ZIP8 promoter, and predicted several key elements on their promoters, such as the binding sites of CREB (cAMP-response element binding protein), KLF4 (Kruppel like factor 4), MTF-1 and RREB1. The sequence deletion from -361 bp to -895 bp down-regulated the luciferase activity of ZIP3 promoter, and the deletion from -897 bp to -1664 bp down-regulated the luciferase activity of ZIP8 promoter. Within different deletion plasmids, the relative luciferase activities of ZIP3 and ZIP8 promoters changes to Zn incubation in a Zn concentration-dependent manner. The site mutagenesis and EMSA (electrophoretic mobility shift assay) found that the -1327 bp/-1343 bp MTF-1 binding site and the -248 bp/-267 bp RREB1 binding site on the ZIP3 promoter, and the -1543 bp/-1557 bp MTF-1 binding site on the ZIP8 promoter are functional sites. Low Zn increased the binding capability between MTF-1 and its responsive site on the ZIP3 promoter, and high Zn increased the transcriptional activation ZIP3 by RREB1; Zn also promoted the binding ability between MTF-1 and its responsive element on the ZIP8 promoter. This study provides the first direct evidence for the response elements of MTF-1 and RREB1 on ZIP3 and MTF-1 on ZIP8 to Zn, which are very important for the evaluation of Zn nutrition and toxicity in vertebrates.

Delaying adjuvant chemotherapy in advanced gastric cancer patients: Risk factors and its impact on survival outcome.

Adjuvant chemotherapy following the curative resection could improve the survival outcome of advanced gastric cancer (GC) patients. However, it is unclear whether delayed initiation of adjuvant chemotherapy had a negative impact on survival outcome in GC patients. The purpose of this study was to review current published literature about the impact of delaying adjuvant chemotherapy on survival outcome and summarize risk factors for delaying adjuvant chemotherapy. Delayed initiation of adjuvant chemotherapy was quite frequent in GC patients who underwent gastrectomy due to postoperative complications, poor nutritional status, comorbid diseases and socioeconomic status. Therefore, it is important for these patients to have a sufficient and smooth transition from surgery to initiation of adjuvant chemotherapy. Based on current available evidence, there is no specific timing interval for the initiation of adjuvant chemotherapy in GC patients. Earlier initiation of adjuvant chemotherapy (<4 weeks) may not be mandatory for GC patients who underwent curative resection. However, the patients should be recommended to receive adjuvant chemotherapy within 6-8 weeks if their performance status and nutritional status were deemed to be appropriate. Minimizing postoperative complications and providing requisite nutritional advice may be helpful for timely initiation of adjuvant chemotherapy.

Different prognostic significance of signet ring cell histology for early and advanced gastric cancer patients: a systematic review and meta-analysis.

OBJECTIVE: To review relevant studies and perform a meta-analysis to evaluate the prognostic significance of signet ring cell (SRC) histology for gastric cancer (GC) patients. METHODS: Systematic literature search was performed using PubMed and Embase databases. The relevant data were extracted and the association between SRC histology and survival outcome were evaluated using a fixed-effect or random-effect model. RESULTS: A total of 21 studies were included in this meta-analysis. The prevalence of SRC histology varied from 8.7% to 50%. SRC histology type was associated with poorer OS (HR: 1.12, 95%CI: 1.01-1.23, P = 0.034; I2 = 85.1%) and DFS (HR: 1.17, 95%CI: 1.00-1.37, P = 0.040; I2 = 63.6%). The subgroup analysis indicated that SRC type had a better OS than non-SRC type for early GC patients (HR: 0.60, 95%CI: 0.48-0.75, P < 0.001; I2 = 33.7%). However, it was a poor prognostic factor for advanced GC when excluding stage IV patients (HR: 1.18, 95%CI: 1.07-1.29, P < 0.001; I2 = 6.5%). SRC type had a higher risk of peritoneal recurrence than non-SRC type (OR: 1.36, 95%CI: 1.06-1.75, P = 0.017; I2 = 1.3%). CONCLUSION: SRC type had a distinctly different prognostic significance for early and advanced GC patients. SRC type was associated with better survival outcomes in early GC patients, but it was a predictive factor for poor survival in advanced GC patients.

Clinicopathologic Features, Survival Outcome, and Prognostic Factors in Gastric Cancer Patients 18-40 Years of Age.

Purpose: Whether young patients with gastric cancer (GC) had a distinct prognostic outcome from older patients remains controversial. The objective of this study was to investigate the clinicopathologic characteristics and prognostic factors of young GC patients and evaluate the survival outcome in comparison to their older counterparts. Methods: We retrospectively reviewed clinicopathologic and survival data of 2022 patients who underwent curative resection for GC. All patients were divided into the young patient group (18-40 years) and older patient group (>40 years) according to the patient age. Clinicopathologic characteristics and prognostic factors of young GC patients were analyzed, and the survival difference between the two groups was compared. Results: The incidence of GC in the patients 18-40 years of age was 8.1% (164/2022). The young patient group had different clinicopathologic features from the older group, including a significant female predominance, a larger number of retrieved lymph nodes, a higher proportion of undifferentiated histology type, and middle or lower 1/3 GC. However, the survival outcome of young patients was similar to that of their older counterparts (5-year disease free survival [DFS]: 47.0% vs. 44.0%, p = 0.247), even when comparison based on the TNM stage was made. Deeper tumor invasion (T3-T4 stage, hazard ratios [HR]: 5.791, 95% confidence intervals [CIs]: 2.908-11.533, p < 0.001), lymph node metastasis (HR: 2.500, 95% CIs: 1.308-4.781, p = 0.006), and lymphovascular invasion (HR: 2.191, 95% CIs: 1.306-3.677, p = 0.003) were independent prognostic factors for young GC patients. Conclusions: Young age (18-40 years) was not associated with poorer survival outcome in GC patients. However, early diagnosis and curative resection with adequate lymphadenectomy will still be necessary for improving the survival outcome of young GC patients.

Perineural invasion as a predictive factor for survival outcome in gastric cancer patients: a systematic review and meta-analysis.

AIMS: The prognostic significance of perineural invasion (PNI) for gastric cancer (GC) patients was under debate. This study aimed to review relevant studies and evaluate the impact of PNI on the survival outcome of GC patients. METHODS: Systematic literature search was performed using PubMed and Embase databases. The relevant data were extracted, and the association between PNI and clinicopathological characteristics or survival outcome in GC patients were evaluated using a fixed-effect model or random-effect model. RESULTS: A total 13 studies involving 7004 GC patients were included in this meta-analysis. The positive rate of PNI was 35.9% (2512/7004) in GC patients, ranging from 6.9% to 75.6%. There were significant relationships between PNI and a series of unfavourable clinicopathological factors including undifferentiated histology type (OR: 1.78, 95% CI 1.37 to 2.33, p<0.001; I2=75.3%), diffuse type (OR: 1.96, 95% CI 1.07 to 3.60, p=0.029; I2=79.5%), lymphatic invasion (OR: 7.00, 95% CI 3.76 to 13.03, p<0.001; I2=83.6%), vascular invasion (OR: 5.79, 95% CI 1.59 to 21.13, p=0.008; I2=95.8%), deeper tumour invasion (OR: 4.79, 95% CI 3.65 to 6.28, p<0.001; I2=65.0%) and lymph node metastasis (OR: 3.60, 95% CI 2.37 to 5.47, p<0.001; I2=89.6%). In addition, PNI was significantly associated with worse survival outcome in GC patients (HR: 1.69, 95% CI 1.38 to 2.06, p<0.001; I2=71.0%). CONCLUSION: PNI was frequently detected in surgically resected specimens of GC patients, and it was a predictive factor for survival outcomes in these patients.

Comparison of short-term surgical outcome between 3D and 2D laparoscopy surgery for gastrointestinal cancer: a systematic review and meta-analysis.

BACKGROUND: Three-dimensional (3D) laparoscopic surgery is becoming more popular with the development of laparoscopic devices. The objective of this study was to explore whether the 3D imaging system could improve surgical outcomes of laparoscopic surgery for gastrointestinal cancer compared with the 2D imaging system. METHODS: Systematic literature search was performed using PubMed and Embase databases and relevant data were extracted. Surgical quality, postoperative complications, and postoperative recovery between 3D and 2D laparoscopic surgery groups were compared using a fixed or random effect model. RESULTS: A total of 12 studies involving 1456 patients (3D group 683 patients and 2D group 773 patients) were included in this meta-analysis. The results indicated that mean operation time was significantly shorter in 3D group than in 2D group (WMD, - 9.08; 95% CI, - 14.77, - 3.40; P = 0.002; I2 = 70.3%), especially for gastric cancer patients (WMD, - 14.61; 95% CI, - 26.00, - 3.23, P = 0.012; I2 = 74.1%). In addition, 3D laparoscopic surgery for gastric cancer had an advantage than 2D group in reducing the amount of intraoperative blood loss (WMD, - 13.60, 95% CI, - 21.48, - 5.72; P = 0.001; I2 = 0%). The number of retrieved lymph nodes in 3D group was not significantly different from that in 2D group, regardless of laparoscopic gastrectomy (WMD, 1.10; 95% CI, - 0.67, 2.88; P = 0.222; I2 = 18.8%) and laparoscopic colorectal surgery (WMD, 0.55, 95% CI; - 1.99, 3.09; P = 0.671; I2 = 76.9%). In addition, there was no significant difference between 3D and 2D laparoscopic surgery for postoperative complications and postoperative recovery. CONCLUSION: Main advantages of 3D laparoscopic gastrectomy for gastric cancer were that it could shorten the operation time and reduce the amount of intraoperative blood loss. However, 3D laparoscopic surgery had no obvious advantage over 2D laparoscopic surgery for colorectal cancer patients.

Dexamethasone induces aberrant macrophage immune function and apoptosis.

Glucocorticoids (GCs) are known potent clinical drugs, however, their mode of action is still complex and debatable. Macrophages are the most important target of GCs and play a key role in tumor immunity in vivo, but their relationship is also controversial. In the present study, the lentivirus system was used to overexpress and knock down the level of transcription factor Krüppel­like factor 9 (KLF9). The results revealed that dexamethasone (Dex) induced ROS generation and mitochondria­dependent apoptosis in RAW 264.7 cells via the KLF9. In addition, overexpression of KLF9 significantly increased apoptosis of RAW 264.7 cells. Notably, ELISA assay revealed that increased expression of KLF9 inhibited LPS­induced COX­2 expression and reduced COX­2­derived prostaglandin E2 and pro­inflammatory cytokine secretion. Furthermore, a co­culture system was used to reveal that overexpression of KLF9 in RAW 264.7 cells promoted HepG2 cell survival. In summary, it is reported that KLF9 promoted apoptosis of proinflammatory macrophages, and suppressed the antitumor effects, which can be selectively targeted by GCs as a novel mechanism to suppress antineoplastic activity.