Impact of nomenclature as metabolic associated steatotic liver disease on steatotic liver disease prevalence and screening: a prospective population survey in Asians.

BACKGROUND AND AIM: The introduction of the latest nomenclature, metabolic associated steatotic liver disease (MASLD), proposed by the multi-society without Asian society consensus statement, aims to redefine the diagnostic criteria for metabolic associated fatty liver disease (MAFLD). However, its effect on the epidemiology in Asia remains unclear. METHOD: We conducted a population-based cross-sectional survey on fatty liver disease using multistage stratified random sampling of participants from Guangzhou, a representative area in China (ChiCTR2000033376). Demographic, socioeconomic, lifestyle, and laboratory data were collected. Hepatic steatosis and the severity of fibrosis were assessed using FibroScan. RESULTS: A total of 7388 individuals were recruited, the proportion of which meeting the definitions for nonalcoholic fatty liver disease (NAFLD), MAFLD, and MASLD were 2359 (31.9%), 2666 (36.1%), and 2240 (30.3%), respectively. One hundred and twenty (1.6%) patients had cryptogenic SLD, and 537 (7.3%) patients were diagnosed with MetALD. MASLD did not significantly differ from NAFLD and MAFLD, except that MAFLD patients had a lower proportion of males, hypertension, and diabetes and were less likely to consume tea (P < 0.05). Both cryptogenic SLD and MASLD non-MAFLD patients exhibited milder hepatic steatosis and a lower frequency of liver injury than NAFLD, MAFLD, or MASLD patients (all P < 0.05). An increased HOMA-IR (adjusted OR: 1.33, 95% CI: 1.10-2.03) was associated with higher risk of moderate-to-severe steatosis for MASLD non-MAFLD patients, while consuming more cups of tea (P for trend = 0.015) showed inverse associations. CONCLUSION: Irrespective of terminology used is that fatty liver disease is highly prevalent in the Han Chinese population. Differences in insulin resistance and lifestyle risk factors are associated with redefinition disparities.

Simultaneous immobilization of sediment internal phosphorus, arsenic and tungsten by lanthanum carbonate capping.

In this study, lanthanum carbonate (LC) was selected as a capping agent to examine its effectiveness in immobilizing sediment internal phosphorus (P), arsenic (As) and tungsten (W). With a 180-day incubation experiment, it was determined that LC capping efficiently reduced the concentrations of soluble reactive P (SRP), soluble As and soluble W in pore water, with the highest reduction rate of 83.39%, 56.21% and 68.52%, respectively. The primary mechanisms involved in the adsorption of P, As and W by LC were precipitation reactions and ligand exchange. Additionally, P, As and W were immobilized by LC capping through the transformation of fractions from mobile and less stable forms to more stable forms. Furthermore, LC capping led to an increase in the Eh value, which promoted the oxidation of soluble Fe (Ⅱ) and soluble Mn. The significantly positive correlation and synchronized variations observed between SRP, soluble As, soluble W, and soluble Fe (II) indicated that the effects of LC on Fe redox played a crucial role in immobilizing sediment internal P, As and W. However, the oxidation of Mn, promoted by LC, played a more significant role in immobilizing sediment internal As than P and W. These effects resulted in LC capping achieving the highest reduction of SRP, soluble As and soluble W flux at 145.22, 22.19, and 0.58 µg m-2d-1. It is of note that LC capping did not lead to an elevated release hazard of Co, Ni, Cu, and Pb, barring Cd. Besides, LC capping did not modify the entire microbial communities in the sediment, but altered the proportional representation of specific microorganisms. Generally, LC has potential as a capping agent capable of simultaneously immobilizing sediment internal P, As and W.

A combined study on Vallisneria spiralis and lanthanum modified bentonite to immobilize arsenic in sediments.

Submerged plants and lanthanum-modified bentonite (LMB) have important applications for the remediation of contaminated sediments; however, their combined effect on arsenic (As) removal has not been comprehensively evaluated. In this study, the physicochemical properties and changes in soluble As in sediments treated with LMB, Vallisneria spiralis (V. spiralis), and LMB + V. spiralis were observed at three time points (days 15, 35, and 66), and the changes in microbial and As species in sediments on day 66 were analyzed. LMB + V. spiralis treatment was the most effective for As removal. On day 66, the average concentrations of soluble As at a depth of 0-100 mm decreased by 12.71%, 48.81%, and 59.73% following treatment with LMB, V. spiralis, and LMB + V. spiralis, respectively. Further analysis showed that LMB is more effective at removing As(V) than V. spiralis, while V. spiralis is more effective at removing As(III), and the combination of LMB + V. spiralis is more effective for removing both As(III) and As(V) than individual LMB and V. spiralis treatments. LMB + V. spiralis enhanced the transformation of mobile As to Fe2O3/oxyhydroxide-bound As in sediments and the activity of As-oxidizing microorganisms. LMB promoted the growth of V. spiralis and enhanced the removal of As. This study indicates that this combination is an effective method for removing mobile As from sediments, and could effectively inhibit the release of As from sediments to overlying water.

Normalization of γ-glutamyl transferase levels is associated with better metabolic control in individuals with nonalcoholic fatty liver disease.

BACKGROUND: The normalization of liver biochemical parameters usually reflects the histological response to treatment for nonalcoholic fatty liver disease (NAFLD). Researchers have not clearly determined whether different liver enzymes exhibit various metabolic changes during the follow-up period in patients with NAFLD. METHODS: We performed a retrospective analysis of patients with NAFLD who were receiving therapy from January 2011 to December 2019. Metabolism indexes, including glucose levels, lipid profiles, uric acid levels and liver biochemical parameters, were measured. Magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) and liver ultrasound were used to evaluate steatosis. All patients received recommendations for lifestyle modifications and guideline-recommended pharmacological treatments with indications for drug therapy for metabolic abnormalities. RESULTS: Overall, 1048 patients with NAFLD were included and received lifestyle modification recommendations and pharmaceutical interventions, including 637 (60.7%) patients with abnormal GGT levels and 767 (73.2%) patients with abnormal ALT levels. Patients with concurrent ALT and GGT abnormalities presented higher levels of metabolism indexes and higher liver fat content than those in patients with single or no abnormalities. After 12 months of follow-up, the cumulative normalization rate of GGT was considerably lower than that of ALT (38% vs. 62%, P < 0.001). Greater weight loss resulted in higher cumulative normalization rates of GGT and ALT. Weight loss (OR = 1.21, 95% CI 1.11-1.32, P < 0.001), ALT normalization (OR = 2.75, 95% CI 1.41-5.36, P = 0.01) and lower TG and HOMA-IR values (OR = 2.03, 95% CI 1.11-3.71, P = 0.02; OR = 2.04, 95% CI 1.07-3.89, P = 0.03) were independent protective factors for GGT normalization. Elevated baseline GGT (OR = 0.99, 95% CI 0.98-0.99, P = 0.01) was a risk factor. CONCLUSIONS: For NAFLD patients with concurrently increased ALT and GGT levels, a lower normalization rate of GGT was observed, rather than ALT. Good control of weight and insulin resistance was a reliable predictor of GGT normalization.

Label free Impedimetric Immunosensor for effective bladder Cancer detection in clinical urine samples.

Galectin-1 protein has been recently recognized as a valuable urinary biomarker for the diagnosis and prognosis of bladder cancer. Herein, we present a sensitive and specific impedimetric immunosensor for the quantitative and label free detection of Galectin-1 protein in clinical urine samples. The immunosensor consists of nine gold interdigitated microelectrodes (3 × 3 array), which can simultaneously monitor multiple immunoreactions by analyzing the normalized impedance variations at each microelectrode during immunosensing. To obtain enhanced sensitivities, we have utilized Galectin-1/Al2O3 nanoprobes (Galectin-1 antibody conjugated to alumina nanoparticles) that can be selectively trapped on the microelectrode surface using positive dielectrophoresis (p-DEP). Preliminary studies highlight the feasibility of the proposed immunosensor for Gal -1 detection in T24 cell lysate spiked phosphate buffer saline and artificial urine samples with a limit of detection that is estimated to be in the pg/ml range. To verify its practical feasibility, we have tested the immunosensor for Galectin-1 detection in clinical urine samples obtained from normal patients and those diagnosed with bladder cancer. Analysis of the clinical tests shows that the median normalized impedance variation during immunosensing for 22 cancer patients and 26 normal patients is 27% and 10%, respectively, with an identified cutoff point of 19.5% above which the sensitivity and specificity of bladder cancer detection was 82.1% and 80.8%, respectively. Based on these results, the proposed immunosensor shows promise for bladder cancer diagnosis and prognosis in a point of care format, thus enabling improved public health monitoring.

Early Predictors of Cardiovascular Disease Risk in Nonalcoholic Fatty Liver Disease: Non-obese Versus Obese Patients.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is regarded as a risk factor of cardiovascular disease (CVD). However, the association between non-obese NAFLD and CVD has not been well established. AIM: We aimed to compare the CVD risk between non-obese and obese NAFLD patients, and explored the factors associated with subclinical atherosclerosis. METHOD: Consecutive NAFLD patients estimated by magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) were recruited. Liver fat content (LFC) and liver stiffness were measured with MRI-PDFF and shear wave elastography, respectively. CVD risk was estimated by atherosclerosis index (AI), carotid intima-media thickness, carotid plaque, and Framingham risk score (FRS). RESULTS: This study included 543 NAFLD patients. The presence of carotid intima-media thickening and carotid plaque, FRS, and AI were comparable between non-obese and obese patients. Age increased per 10 years (OR 9.68; P < 0.001) and liver fibrosis (liver stiffness > 6.1 kPa, OR 4.42; P = 0.004) were significant factors associated with carotid intima-media thickening in non-obese patients, while age increased per 10 years (OR 2.02; P < 0.001), liver fibrosis (OR 2.18; P = 0.039), and LFC > 10% (OR 2.29; P = 0.021) were independent predictors in obese patients. Only elevated triglyceride was significantly associated with carotid plaque in non-obese patients (OR 2.42; P = 0.033), while age increased per 10 years (OR 1.77; P = 0.002) and LFC > 10% (OR 2.83; P = 0.019) were significant predictors in obese patients. CONCLUSIONS: Liver stiffness and age were strongly predictive of subclinical atherosclerosis in all NAFLD, while LFC was an additional predictor in obese NAFLD patients. Our findings highlight that early CVD screening strategy should be established for NAFLD patients according to different BMIs.

In-situ observations of internal dissolved heavy metal release in relation to sediment suspension in lake Taihu, China.

Despite laboratory experiments that have been performed to study internal heavy metal release, our understanding of how heavy metals release in shallow eutrophic lakes remains limited for lacking in-situ evidence. This study used automatic environmental sensors and a water sampling system to conduct high-frequency in-situ observations (1-hr intervals) of water environmental variables and to collect water samples (3-hr intervals), with which to examine the release of internal heavy metals in Lake Taihu, China. Under conditions of disturbance by strong northerly winds, sediment resuspension in both the estuary area and the lake center caused particulate heavy metal resuspension. However, the patterns of concentrations of dissolved heavy metals in these two areas were complex. The concentrations of dissolved Se and Mo increased in both areas, indicating that release of internal dissolved Se and Mo is triggered by sediment resuspension. The concentrations of dissolved Ni, Zn, As, Mn, Cu, V, and Co tended to increase in the estuary area but decrease in the lake center. The different trends between these two areas were controlled by pH and cyanobacteria, which are related to eutrophication. During the strong northerly winds, the decrease in concentrations of dissolved heavy metals in the lake center was attributable primarily to absorption by the increased suspended solids, and to growth-related assimilation or surface adsorption by the increased cyanobacteria. The findings of this study suggest that, short-term changes of environmental conditions are very important in relation to reliable monitoring and risk assessment of heavy metals in shallow eutrophic lakes.

Butyrate ameliorated-NLRC3 protects the intestinal barrier in a GPR43-dependent manner.

BACKGROUND: Intestinal barrier dysfunctions are related to dysbacteriosis and chronic gut inflammation in type 2 diabetes. Although there is emerging evidence that the chronic gut inflammatory response is stimulated by nucleotide-binding oligomerization domain-like receptors (NLRs), the relationship and precise mechanism between NLRC3 and the colonic epithelial barrier remains largely elusive. METHODS: We investigated the function and mechanism of NLRC3 in the colonic tissues of diabetic mice and colonic epithelial cell lines. The regulatory mechanism between NLRC3, butyrate and tight junctions was elucidated via a transepithelial electrical resistance measurement, transmission electron microscopy, RNA interference and western blotting. RESULTS: In this study, we found that NLRC3 expression was decreased in the colonic tissues of diabetic mice. NLRC3 over-expression ameliorated colonic epithelial barrier integrity and up-regulated tight junction proteins in colonic epithelial cells. Knockdown of TRAF6 diminished NLRC3-induced ZO-1/occludin expression. In addition, we demonstrated that butyrate could stimulate NLRC3 expression in both diabetic mice and colonic epithelial cells. GPR43 on colonic epithelial cells is involved in the activation of NLRC3 induced by butyrate. CONCLUSION: Our findings demonstrated that NLCR3 could ameliorate colonic epithelial barrier integrity in diabetes mellitus in a TRAF6-dependent manner, and NLCR3 was stimulated by butyrate via binding GPR43 on colonic epithelial cells.

Epigenetic modification of TLE1 induce abnormal differentiation in diabetic mice intestinal epithelium.

The intestinal epithelium cells (IECs) in diabetes mellitus (DM) patients have been proven to be abnormally differentiated. During the differentiation of IECs, epigenetic modification acts as an important regulator. In this study, we aimed to examine the epigenetic alteration of Transducin-like Enhancer of Split 1 (TLE1), a multitask transcriptional co-repressor, contributing to the differentiation homeostasis in IECs of DM mice. The IECs of type 2 diabetic mice model were isolated and collected. Methylation states of whole genomic DNA promoter regions were investigated by microarray. Methylated-specific PCR was used to detect the methylation state of TLE1 promoter in DM mice IECs. The expression of TLE1, Hes1, and differentiated cell markers were measured through real-time PCR, Western blots, and immunohistochemistry; by transfection assay, TLE1 or Hes1 was independently down-regulated in intestinal epithelium cell line, IEC-6. Subsequent modulation on TLE1, Hes1, and differentiated intestinal cell markers were detected. Global gene promoter regions in DM intestinal epithelium were less methylated comparing to normal control. The expression of TLE1 was significantly increased via hypomethylated activation in DM mice IECs. Hes1 was significantly suppressed and the terminal cell markers abnormally expressed in DM mice IECs (P < 0.05). Inhibition or induction on the abundance of TLE1 in IEC-6 cell line resulted in the corresponding dysregulation of Hes1 and intestinal epithelium differentiation (P < 0.05). Demethylation of TLE1 promoter region activates the self-expression in diabetic mice IECs. Subsequently, TLE1, through the transcriptional suppression on expression of Hes1, contributes to the aberrant differentiation of IECs in DM mice.

Proteomic Identification of the Galectin-1-Involved Molecular Pathways in Urinary Bladder Urothelial Carcinoma.

Among various heterogeneous types of bladder tumors, urothelial carcinoma is the most prevalent lesion. Some of the urinary bladder urothelial carcinomas (UBUCs) develop local recurrence and may cause distal invasion. Galectin-1 de-regulation significantly affects cell transformation, cell proliferation, angiogenesis, and cell invasiveness. In continuation of our previous investigation on the role of galectin-1 in UBUC tumorigenesis, in this study, proteomics strategies were implemented in order to find more galectin-1-associated signaling pathways. The results of this study showed that galectin-1 knockdown could induce 15 down-regulated proteins and two up-regulated proteins in T24 cells. These de-regulated proteins might participate in lipid/amino acid/energy metabolism, cytoskeleton, cell proliferation, cell-cell interaction, cell apoptosis, metastasis, and protein degradation. The aforementioned dys-regulated proteins were confirmed by western immunoblotting. Proteomics results were further translated to prognostic markers by analyses of biopsy samples. Results of cohort studies demonstrated that over-expressions of glutamine synthetase, alcohol dehydrogenase (NADP⁺), fatty acid binding protein 4, and toll interacting protein in clinical specimens were all significantly associated with galectin-1 up-regulation. Univariate analyses showed that de-regulations of glutamine synthetase and fatty acid binding protein 4 in clinical samples were respectively linked to disease-specific survival and metastasis-free survival.

Role of galectin-1 in urinary bladder urothelial carcinoma cell invasion through the JNK pathway.

Human galectin-1 is a member of the galectin family, proteins with conserved carbohydrate-recognition domains that bind galactoside. Galectin-1 is highly expressed in various tumors and participates in various oncogenic processes. However, detailed descriptions of the function of galectin-1 in urinary bladder urothelial carcinoma have not been reported. Our previous cohort investigation showed that galectin-1 is associated with tumor invasiveness and is a possible independent prognostic marker of urinary bladder urothelial carcinoma. The present study aimed to clarify the relevance of galectin-1 expression level to tumor progression and invasion. In order to decipher a mechanism for the contribution of galectin-1 to the malignant behavior of urinary bladder urothelial carcinoma, two bladder cancer cell lines (T24 and J82) were established with knockdown of galectin-1 expression by shRNA. Bladder cancer cells with LGALS1 gene silencing showed reduced cell proliferation, lower invasive capability, and lower clonogenicity. Extensive signaling pathway studies indicated that galectin-1 participated in bladder cancer cell invasion by mediating the activity of MMP9 through the Ras-Rac1-MEKK4-JNK-AP1 signaling pathway. Our functional analyses of galectin-1 in urinary bladder urothelial carcinoma provided novel insights into the critical role of galectin-1 in tumor progression and invasion. These results revealed that silencing the galectin-1-mediated MAPK signaling pathway presented a novel strategy for bladder cancer therapy.

BCAT1 overexpression is an indicator of poor prognosis in patients with urothelial carcinomas of the upper urinary tract and urinary bladder.

AIMS: Amino acid biosynthesis is one of the cardinal events of carcinogenesis that has not been investigated in urothelial carcinoma (UC). By data-mining a published transcriptomic database of UCs of urinary bladder (UBUCs) (GSE31684), we identified branched-chain amino acid transaminase 1 (BCAT1) as the most significantly stepwise up-regulated gene during tumour progression among those associated with the amino acid biosynthetic process (GO:0008652). Accordingly, we analysed BCAT1 transcript and protein expression with their clinicopathological significance. METHODS AND RESULTS: We used real-time reverse transcription-polymerase chain reaction (RT-PCR) to detect BCAT1 transcript levels in 20 UCs of upper tract (UTUCs) and 20 UBUCs, respectively. Immunohistochemical study was performed to determine BCAT1 protein expression in 340 UTUCs and 295 UBUCs. Higher BCAT1 transcript levels were associated with higher pT status in both groups (P < 0.05). BCAT1 protein overexpression was also associated significantly with adverse clinicopathological features, e.g. advanced pT stage, nodal metastasis, high pathological grade, etc. (P < 0.05). BCAT1 overexpression predicted worse disease-specific survival and metastasis-free survival in both univariate and multivariate analyses (P ≤ 0.001). CONCLUSION: BCAT1 overexpression is associated with advanced tumour status, and implies adverse clinical outcomes of UCs, suggesting that its role in tumour progression could serve as a prognostic biomarker and a novel therapeutic target in UC.

Downregulation of lncRNA-MALAT1 Affects Proliferation and the Expression of Stemness Markers in Glioma Stem Cell Line SHG139S.

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is among the most abundant and highly conserved lncRNAs, which has been detected in a wide variety of human tumors, including gastric cancer, gallbladder cancer, and so on. Previous research has showed that MALAT1 can activate LTBP3 gene in mesenchymal stem cells. However, the specific roles of MALAT1 in glioma stem cells (GSCs) remain unclear. In this study, we aimed to identify the effects of MALAT1 on proliferation and the expression of stemness markers on glioma stem cell line SHG139S. Our results showed that downregulation of MALAT1 suppressed the expression of Sox2 and Nestin which are related to stemness, while downregulation of MALAT1 promoted the proliferation in SHG139S. Further research on the underlying mechanism showed that the effects of MALAT1 downregulation on SHG139S were through regulating ERK/MAPk signaling activity. And we also found that downregulation of MALAT1 could activate ERK/MAPK signaling and promoted proliferation in SHG139 cells. These findings show that MALAT1 plays an important role in regulating the expression of stemness markers and proliferation of SHG139S, and provide a new research direction to target the progression of GSCs.

Clarification of the molecular pathway of Taiwan local pomegranate fruit juice underlying the inhibition of urinary bladder urothelial carcinoma cell by proteomics strategy.

BACKGROUND: Pomegranate fruit has been shown to exhibit the inhibitory activity against prostate cancer and lung cancer in vitro and in vivo, which might be a resource for chemoprevention and chemotherapy of cancer. Our previous documented findings indicated that treatment of urinary bladder urothelial carcinoma cell with the ethanol extract isolated from the juice of pomegranate fruit grown in Taiwan could inhibit tumor cell. In this study we intended to uncover the molecular pathway underlying anti-cancer efficacy of Taiwan pomegranate fruit juice against urinary bladder urothelial carcinoma. METHODS: We exploited two-dimensional gel electrophoresis coupled with tandem mass spectrometry to find the de-regulated proteins. Western immunoblotting was used to confirm the results collected from proteomics study. RESULTS: Comparative proteomics indicated that 20 proteins were differentially expressed in ethanol extract-treated T24 cells with 19 up-regulated and 1 down-regulated proteins. These de-regulated proteins were involved in apoptosis, cytoskeleton regulation, cell proliferation, proteasome activity and aerobic glycolysis. Further studies on signaling pathway demonstrated that ethanol extract treatment might inhibit urinary bladder urothelial carcinoma cell proliferation through restriction of PTEN/AKT/mTORC1 pathway via profilin 1 up-regulation. It also might evoke cell apoptosis through Diablo over-expression. CONCLUSIONS: The results of this study provide a global picture to further investigate the anticancer molecular mechanism of pomegranate fruit.

Galectin-1 dysregulation independently predicts disease specific survival in bladder urothelial carcinoma.

PURPOSE: Galectin-1 is highly expressed in various tumors and participates in various oncogenic processes. Our previous proteomics investigation demonstrated that galectin-1 is up-regulated in high compared to nonhigh grade lesions. Thus, in the current cohort study we clarified the correlation of galectin-1 over expression with various clinicopathological features and prognosis. MATERIALS AND METHODS: We selected 185 cases of consecutively treated primary localized bladder urothelial carcinoma for study. Transurethral resection of bladder tumor was performed in all patients followed by radical cystectomy in those with T2 to T4 tumors. Pathological slides were examined to determine cytoplasmic galectin-1 immuno-expression and correlate galectin-1 dysregulation with various clinicopathological factors and disease specific survival. RESULTS: Positive galectin-1 immuno-expression in tumors was significantly linked to pT status (p = 0.0295), histological grade (p = 0.037), vascular invasion (p = 0.0287) and nodal status (p = 0.0012). Galectin-1 over expression in tumors significantly predicted disease specific survival at the univariate (p = 0.0002) and multivariate levels (p = 0.03, HR 2.438, 95% CI 1.090-5.451). In situ hybridization indicated that the LGALS1 gene was amplified in 43 specimens in an independent cohort of 56 snap frozen tumor specimens. Association analysis showed that an increased LGALS1 mRNA level was linked to bladder urothelial carcinoma invasiveness (p = 0.016) and LGALS1 gene amplification was significantly associated the amount of GAL-1 protein in tumors (p <0.0001). On the univariate level gene amplification was also closely linked to disease specific survival (p = 0.0006). CONCLUSIONS: These results reveal that galectin-1 over expression is a possible independent factor for bladder cancer prognosis.

FGF7 Over Expression is an Independent Prognosticator in Patients with Urothelial Carcinoma of the Upper Urinary Tract and Bladder.

PURPOSE: Urothelial carcinoma of the bladder and upper tract is the most common tumor type in the urinary tract but its molecular pathogenesis and survival determinants remain obscure. By data mining a published transcriptomic database of bladder urothelial carcinoma (GSE31684) we identified FGF7 as the most significant gene up-regulated during urothelial carcinoma progression. We then used our well characterized urothelial carcinoma cohort to analyze FGF7 transcript and protein expression, and its clinicopathological significance. MATERIALS AND METHODS: We performed real-time reverse transcriptase-polymerase chain reaction assay to determine the FGF7 transcript level in 30 fresh samples each of upper tract and bladder urothelial carcinoma. Immunohistochemistry evaluated by H-score was used to determine FGF7 protein expression in 340 upper tract and 295 bladder urothelial carcinomas. Transcript and protein expression were correlated with clinicopathological features. We further evaluated the prognostic significance of FGF7 protein expression for disease specific and metastasis-free survival. RESULTS: An increased FGF7 transcript level was associated with higher pT stage in upper tract and bladder urothelial carcinoma (p = 0.003 and <0.001, respectively). In the upper tract and bladder carcinoma groups FGF7 protein over expression was also significantly associated with advanced pT status (each p <0.001), lymph node metastasis (p = 0.002 and <0.001), high histological grade (p = 0.019 and <0.001), vascular invasion (each p <0.001), perineural invasion (p = 0.002 and 0.021) and frequent mitoses (p = 0.002 and 0.042, respectively). FGF7 over expression predicted dismal disease specific and metastasis-free survival on univariate and multivariate analysis. CONCLUSIONS: Our study shows that FGF7 over expression is associated with advanced clinical features in patients with upper tract and bladder urothelial carcinoma, justifying its potential prognostic value for urothelial carcinoma.

PLA2G2A overexpression is associated with poor therapeutic response and inferior outcome in rectal cancer patients receiving neoadjuvant concurrent chemoradiotherapy.

AIMS: The aim of this study was to investigate the prognostic impact of group IIA phospholipase A2 (PLA2G2A) expression and its role in predicting the response to neoadjuvant concurrent cheomoradiotherapy (CCRT) in rectal cancer. METHODS AND RESULTS: Through analysing a public transcriptome of rectal cancers, the PLA2G2A gene was identified as a significant predictor for CCRT response. We validated the expression of PLA2G2A using immunohistochemistry in the pretreatment tumour specimens from 172 patients with rectal cancer. The results were correlated with clinicopathological features, tumour regression grade, overall survival (OS), disease-free survival (DFS) and local recurrence-free survival (LRFS). High expression of PLA2G2A was associated with advanced pretreatment tumour status (P = 0.001), advanced pretreatment nodal status (P = 0.010), advanced post-treatment tumour status (P = 0.002) and lower tumour regression grade (P = 0.006). Furthermore, PLA2G2A expression was correlated negatively with gamma H2A histone family, member X (γ-H2AX) expression (P < 0.001, r = -0.580). More importantly, high expression of PLA2G2A emerged as an adverse prognostic factor for OS (P = 0.0190), DFS (P < 0.0001) and LRFS (P < 0.0001). In multivariate analysis, it remained independently prognostic for shorter DFS (P = 0.014) and LRFS (P = 0.012). CONCLUSIONS: High expression of PLA2G2A was associated with poor therapeutic response and worse survival in patients with rectal cancer receiving neoadjuvant CCRT, justifying PLA2G2A as an important marker to predict CCRT response and outcome.

The prognostic impact of lipid biosynthesis-associated markers, HSD17B2 and HMGCS2, in rectal cancer treated with neoadjuvant concurrent chemoradiotherapy.

Neoadjuvant concurrent chemoradiotherapy has been widely used for rectal cancer to improve local tumor control. The varied response of individual tumors encouraged us to search for useful biomarkers to predict the therapeutic response. The study was aimed to evaluate the prognostic impact of lipid biosynthesis-associated biomarkers in rectal cancer patients treated with preoperative chemoradiotherapy. Through analysis of the previously published gene expression profiling database focusing on genes associated with lipid biosynthesis, we found that HSD17B2 and HMGCS2 were the top two significantly upregulated genes in the non-responders. We further evaluated their expression by immunohistochemistry in the pre-treatment tumor specimens from 172 patients with rectal cancer and statistically analyzed the associations between their expression and various clinicopathological factors, as well as survival. High expression of HMGCS2 or HSD17B2 was significantly associated with advanced pre- and post-treatment tumor or nodal status (P < 0.001) and lower tumor regression grade (P < 0.001). More importantly, high expression of either HMGCS2 or HSD17B2 was of prognostic significance, with HMGCS2 overexpression indicating poor prognosis for disease-free survival (P = 0.0003), local recurrence-free survival (P = 0.0115), and metastasis-free survival (P = 0.0119), while HSD17B2 overexpression was associated with poor prognosis for disease-free survival (P <0.0001), local recurrence-free survival (P = 0.0009), and metastasis-free survival (P < 0.0001). In multivariate analysis, only HSD17B2 overexpression remained as an independent prognosticator for shorter disease-free survival (P < 0.001) and metastasis-free survival (P = 0.008). In conclusion, high expression of either HSD17B2 or HMGCS2 predicted poor susceptibility of rectal cancer to preoperative chemoradiotherapy. Both acted as promising prognostic factors, particularly HSD17B2.

HAS3 underexpression as an indicator of poor prognosis in patients with urothelial carcinoma of the upper urinary tract and urinary bladder.

Via data mining a published transcriptomic database of UBUC (GSE31684), we discovered hyaluronan synthase-3 (HAS3) as the most significant gene stepwise downregulated from early tumorigenesis to progression among those associated with hyaluronan synthase activity (GO:0050501). We consequently analyzed HAS3 protein expression and their association with clinicopathological factors and survival in our well-characterized cohort of urothelial carcinoma of upper urinary tract (UTUC) and urinary bladder (UBUC). HAS3 expression was assessed by immunohistochemistry and evaluated by using H score method in 295 UBUCs and 340 UTUCs, respectively. HAS3 protein expression statuses were further correlated with clinicopathological parameters and evaluated the prognostic significance for disease-specific survival (DSS) and metastasis-free survival (MeFS). HAS3 protein underexpression was significantly associated with advanced pT status, nodal metastasis, high histological grade, vascular invasion, and frequent mitoses in both groups of UCs. HAS3 underexpression not only predicted poorer DSS and MeFS with univariate analysis, but also indicated dismal DSS and MeFS in multivariate analysis. HAS3 underexpression is associated with advanced tumor stage and adverse pathological features, as well as implies inferior clinical outcomes for both groups of patients with UTUCs and UBUCs, suggesting its critical role in tumor progression in UCs and may serve as a prospective prognostic biomarker and a novel therapeutic target in UCs.

Overexpression of DNAJC12 predicts poor response to neoadjuvant concurrent chemoradiotherapy in patients with rectal cancer.

Genes associated with protein folding have been found to have certain prognostic significance in a subset of cancers. The aim of this study is to evaluate the clinical impact of DNAJC12 expression in patients with rectal cancers receiving neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery. Through data mining from a public transcriptomic dataset of rectal cancer focusing on genes associated with protein folding, we found that DNAJC12, a member of the HSP40/DNAJ family, was the most significant such gene correlated with the CCRT response. We further evaluated the expression of DNAJC12 by immunohistochemistry in the pre-treatment tumor specimens from 172 patients with rectal cancers. From this set, we statistically analyzed the association of DNAJC12 expression with various clinicopathological factors, tumor regression grade, overall survival (OS), disease-free survival (DFS) and local recurrence-free survival (LRFS). High expression of DNAJC12 was significantly associated with advanced pre- and post-treatment tumor status (P<0.001), advanced pre- and post-treatment nodal status (P<0.001), increased vascular invasion (P=0.015), increased perineural invasion (P=0.023) and lower tumor regression grade (P=0.009). More importantly, high expression of DNAJC12 was found to be correlated with poor prognosis for OS (P=0.0012), DFS (P<0.0001) and LRFS (P=0.0001). In multivariate analysis, DNAJC12 overexpression still emerged as an independent prognosticator for shorter OS (P=0.040), DFS (P<0.001) and LRFS (P=0.016). The data indicate that DNAJC12 overexpression acts as a negative predictive factor for the response to neoadjuvant CCRT and was significantly associated with shorter survival in patients with rectal cancers receiving neoadjuvant CCRT followed by surgery.