Genomic and transcriptomic characteristics of 12 novel primary cell lines derived from three patients with cholangiocarcinoma.

Cholangiocarcinoma (CCA) is an aggressive bile duct malignancy with poor prognosis. To improve our understanding of the biological characteristics of CCA and develop effective therapies, appropriate preclinical models are required. Here, we established and characterized 12 novel patient-derived primary cancer cell (PDPC) models using multi-region sampling. At the genomic level of PDPCs, we observed not only commonly mutated genes, such as TP53, JAK3, and KMT2C, consistent with the reports in CCA, but also specific mutation patterns in each cell line. In addition, specific expression patterns with distinct biological functions and pathways involved were also observed in the PDPCs at the transcriptomic level. Furthermore, the drug-sensitivity results revealed that the PDPCs exhibited different responses to the six commonly used compounds. Our findings indicate that the established PDPCs can serve as novel in vitro reliable models to provide a crucial molecular basis for improving the understanding of tumorigenesis and its treatment.

Exploration of the Corrosion Behavior of Electroless Plated Ni-P Amorphous Alloys via X-ray Photoelectron Spectroscopy.

A Ni-P amorphous alloy was deposited on a low carbon steel substrate via electroless plating. Further, the prepared samples were crystallized under the high temperature with a range from 200 °C to 500 °C in air for 1 h. The crystallization process was studied via XRD, AFM, and XPS, and anodic electrochemical behavior was investigated by potentiostatic methods in a 3.5 wt% NaCl solution. The experimental results indicate that the diffusion, dissolution, and enrichment of the component elements in the Ni-P alloy are essential during crystallization because the various corrosion behaviors corresponding to Ni and P are directly affected. More importantly, under the 400 °C treatment, H2PO2- was enriched in the alloy, which effectively hinders the anodic dissolution of nickel and forms a complete adsorption layer on the surface of the alloy. Our results demonstrate that P can effectively block the anodic dissolution of Ni during the corrosion process, and the crystallization process can effectively promote the surface enrichment of P to improve the corrosion resistance of the coating.

[Effect of Intolerance of Uncertainty on Fear of Childbirth in Primiparas : A Moderated Mediating Model].

Objective: To explore the mediating effect of childbirth self-efficacy on the impact pathway of intolerance of uncertainty on the fear of childbirth in primiparas in the second and third trimesters and the potential moderating effect of perceived partner responsiveness. Methods: A total of 429 primiparas in their second and third trimesters completed the survey, which included general information questionnaire, Intolerance of Uncertainty Scale, Childbirth Self-Efficacy Inventory, Perceived Partner Responsiveness Scale, and Childbirth Attitudes Questionnaire. Rank sum test was used to compare the scores for the fear of childbirth among different groups and Spearman's correlation was used to analyze the scores for all the scales. In addition, the data were centrally processed by using PROCESS V3.4.1 Model 4 (a simple mediation model), Model 5 (the direct path of the mediation model was regulated), and non-parametric Bootstrap method to test the mediation effect and moderation effect. Results: The study showed that 54.31% of the participants experienced fear of childbirth. Their scores for intolerance of uncertainty, childbirth self-efficacy, and perceived partner responsiveness were 15.00 (8.00), 240.00 (75.00), and 72.00 (19.00), respectively. There were significant differences in the scores for the fear of childbirth scale among pregnant women of different age groups, gestational weeks, employment statuses, and average per capita monthly income of the family ( P<0.05). According to our findings, intolerance of uncertainty directly and positively impacted on fear of childbirth ( ß=0.76, P<0.001), with childbirth self-efficacy playing partial mediation role between them, its indirect effect being 0.05 and the contribution rate being 6.17%. In addition, after the scores of Perceived Partner Responsiveness Scale were added to the model, perceived partner responsiveness had no significant predictive effect for fear of childbirth, but the product term of the scores for Perceived Partner Responsiveness Scale and Intolerability Uncertainty Scale had significant predictive effect for fear of childbirth ( ß=0.01, P<0.05), which suggested that perceived partner responsiveness also played a moderating role between intolerance of uncertainty and fear of childbirth. Conclusion: Health care providers can help primiparas reduce fear of childbirth and improve their childbirth experience by reducing perceived intolerance of uncertainty, improving family support, and teaching coping strategies.

Application of low dose pancreas perfusion CT combined with enhancement scanning in diagnosis of pancreatic neuroendocrine tumors.

PURPOSE: To explore the diagnostic value of pancreatic perfusion CT combined with contrast-enhanced CT in one-time scanning (PCECT) in pancreatic neuroendocrine tumors (PNETs) and to evaluate the difference of perfusion parameters between different grades of PNETs. MATERIALS AND METHODS: From October 2016 to December 2018, forty consecutive patients with histopathological-proven PNETs were identified retrospectively that received PCECT for the preoperative PNETs evaluation. Two board certified radiologists who were blinded to the clinical data evaluated the images independently. The image characters of PNETs vs. tumor-free pancreatic parenchymal and different grades of PNETs were analyzed. RESULTS: One-time PCECT scanning had a detection rate of 89.1% for PNETs, which was higher than the detection accuracy of the perfusion CT only (83.6%). The perfusion parameters of PNETs including blood volume (BV), blood flow (BF), mean slope of increase (MSI), and capillary surface permeability (PS) were significantly increased than those of tumor-free pancreatic parenchyma (p < 0.05, respectively). For differential comparison between grade I (G1) and grade II (G2) tumors, the parameters of BF and impulse residue function (IRF) of tumor tissue were significantly higher in the G2 tumors (p < 0.05, for both). In this study, the total radiation dose of the whole PCECT scan was 16.241 ± 2.289 mSv. CONCLUSION: The one-time PCECT scan may improve the detection of PNETs according to morphological features and perfusion parameters with a relative small radiation dose. The perfusion parameters of BF and IRF may be used to help distinguish G1 and G2 tumors in the preoperative evaluation.

Long noncoding RNA Hotair facilitates retinal endothelial cell dysfunction in diabetic retinopathy.

BACKGROUND: Retinal endothelial cell (REC) dysfunction induced by diabetes mellitus (DM) is an important pathological step of diabetic retinopathy (DR). Long noncoding RNAs (lncRNAs) have emerged as novel modulators in DR. The present study aimed to investigate the role and mechanism of lncRNA Hotair in regulating DM-induced REC dysfunction. METHODS: The retinal vascular preparations and immunohistochemical staining assays were conducted to assess the role of Hotair in retinal vessel impairment in vivo. The EdU, transwell, cell permeability, CHIP, luciferase activity, RIP, RNA pull-down, and Co-IP assays were employed to investigate the underlying mechanism of Hotair-mediated REC dysfunction in vitro. RESULTS: Hotair expression was significantly increased in diabetic retinas and high glucose (HG)-stimulated REC. Hotair knockdown inhibited the proliferation, invasion, migration, and permeability of HG-stimulated REC in vitro and reduced the retinal acellular capillaries and vascular leakage in vivo. Mechanistically, Hotair bound to LSD1 to inhibit VE-cadherin transcription by reducing the H3K4me3 level on its promoter and to facilitate transcription factor HIF1α-mediated transcriptional activation of VEGFA. Furthermore, LSD1 mediated the effects of Hotair on REC function under HG condition. CONCLUSION: The Hotair exerts its role in DR by binding to LSD1, decreasing VE-cadherin transcription, and increasing VEGFA transcription, leading to REC dysfunction. These findings revealed that Hotair is a potential therapeutic target of DR.

LDOC1 is differentially expressed in thyroid cancer and display tumor-suppressive function in papillary thyroid carcinoma.

The leucine zipper downregulated in cancer 1 (LDOC1) has been proposed as a regulator of transcription and cell signaling. We have previously demonstrated that LDOC1 is differentially expressed in papillary thyroid carcinoma (PTC), this study was designed to characterize LDOC1 expression in thyroid follicle originated cancer tissues and to specifically evaluate its function in thyroid carcinogenesis. LDOC1 expression was performed in human normal thyroid and thyroid cancer. LDOC1 function was characterized, in two PTC cell lines (TPC1 and BCPAP), through the analysis of in vitro cell proliferation, apoptosis, migration, and invasion along with in vivo tumor xenograft growth. Transduced BCPAP cells were stimulated with tumor necrosis factor α, and the levels of nuclear P65, Bax, Bcl-2, c-Myc, and XIAP were assessed. A luciferase reporter assay was used to measure nuclear factor-κB (NF-κB) activity, and the functional connection between LDOC1 effect and NF-κB activity was determined using a specific NF-κB inhibitor. Our results revealed that LDOC1 was translocated from the nucleus to the cytoplasm in human thyroid cancer, and was significantly downregulated in PTC compared with normal thyroid. LDOC1 overexpression in TPC1 resulted in a significant suppression of the malignant phenotype, whereas LDOC1 ablation in BCPAP promoted this phenotype. Additional studies demonstrated that LDOC1 ablation facilitated nuclear P65 expression and NF-κB activity. NF-κB inhibition reversed the effects of LDOC1 ablation on proliferation, apoptosis, migration, and invasion. Our findings confirmed that LDOC1 is a novel therapeutic target in PTC and provides new insight into the role of LDOC1 in PTC progression, through NF-κΒ signaling suppression.

Biosynthesis of selenium nanoparticles and their protective, antioxidative effects in streptozotocin induced diabetic rats.

Green synthesis of selenium nanoparticles (Se NPs) was performed by mixing Hibiscus sabdariffa (roselle plant) leaf extract with the solution of selenious acid (H2SeO3) under continuous stirring conditions resulting the roselle plant secondary metabolites conjugated Se NPs. The existence of functional groups of roselle plant secondary metabolites on the surface of prepared Se NPs was confirmed by Fourier transform infrared spectroscopy (FTIR). The formation of crystalline nanoparticles with anisotropic shape was confirmed by transmission electron microscopy (TEM) images. Furthermore, we also studied anti-oxidative and protective effects of Se NPs in streptozotocin (STZ) induced diabetes rats. These STZ induced diabetic rats were daily exposed to Se NPs or/and insulin treatment and the effect of Se NPs on the factors correlated to oxidative damage in the rat testes were evaluated. The biochemical studies showed that the Se NPs are capable to enhance the serum testosterone reduction caused due to STZ induced diabetes. In addition, Se NPs can significantly reduce the oxidative stress indicators of the testicular tissue such as nitric oxide and lipid peroxidation. However, the treatment of Se NPs on the STZ induced diabetic rats increased the activities of antioxidant enzyme as well as the glutathione content in testicular tissues. Furthermore, microscopic studies revealed that the Se NPs are capable of preventing the histological damage in the testes of STZ induced diabetic rats. Altogether, these results explained the possible effects of Se NPs in attenuating oxidative damage induced by diabetes, especially in the testicular tissue.

JIP3 knockout protects mice against high fat diet-induced liver injury.

Multiple pathways contribute to nonalcoholic fatty liver disease (NAFLD) in response to high fat diets (HFD). A homolog of mammalian JNK-interacting protein 3 (JIP3), also known as JSAP-1, activates different components in various signaling pathways to modulate cellular processes. The purpose of this study was to examine the role of JIP3 in obesity-related pathologies pathway. Wild-type (WT) C57BL/6 and JIP3-knockout (JIP3-/-) mice were randomized to chow or HFD. HFD-fed WT mice increased hepatic JIP3 expression. Mice lacking JIP3 exhibited reduced weight gain, hepatic steatosis, insulin resistance, lipid accumulation, oxidative stress and inflammatory response in mice fed a HFD, which were, importantly, dependent on various signaling pathways. Lipogenesis-linked pathway was inhibited in JIP3-/- mice after HFD, while PPARα/γ were increased. Additionally, JIP3-/- inhibited hepatic oxidative stress, evidenced by down-regulation of total reactive oxygen species (ROS), H2O2, O2.-, malondialdehyde (MDA), xanthine oxidase (XO), inducible nitric oxide synthase (iNOS), and up-regulation of superoxide dismutase (SOD) and total antioxidant capacity (TAC) in mice after HFD feeding, which might be related to nuclear respiratory factor 2 (Nrf-2) pathway activation. Further, inflammatory response was blocked in JIP3-/- mice fed with HFD. The process might be attributed to the suppression of toll-like receptors (TLRs), p-nuclear factor kappa B (NF-κB) and p-c-Jun-N-terminal kinase (JNK). Thus, JIP3 absence is associated with decreased lipogenesis, oxidative stress and inflammation, supplying a new target for NAFLD treatment.

Long Stress Induced Non-Coding Transcripts 5 (LSINCT5) Promotes Hepatocellular Carcinoma Progression Through Interaction with High-Mobility Group AT-hook 2 and MiR-4516.

BACKGROUND Long non-coding RNAs (lncRNAs) have been implicated in various human cancer types. However, the underlying mechanisms involved in hepatocellular carcinoma (HCC) progression remain poorly understood. MATERIAL AND METHODS In this study, lncRNA array was used to identify HCC related lncRNAs. RNA immunoprecipitation (RIP) followed mass spectrometry was used to explore lncRNA binding proteins. Western blot, quantitative PCR, tumor sphere formation, migration and viability assay were performed to evaluate the oncogenic role of lncRNAs. RESULTS We identified a novel lncRNA named long stress induced non-coding transcripts 5 (LSINCT5) which facilitates HCC progression. LSINCT5 was significantly upregulated in both HCC specimens and cell lines and correlates with poor survival. In vitro experiments showed that LSINCT5 promoted migration and viability of HepG2 and Huh7 cells. The in vivo xenograft mouse model also confirmed an oncogenic role for LSINCT5. RIP in combination with mass spectrometry identified HMGA2 as the LSINCT5 binding partner. LSINCT5 could bind to HMGA2 and decrease proteasome-mediated HMGA2 degradation leading to EMT activation. LSINCT5 also served as a competing endogenous RNA (ceRNA) for miR-4516, resulting in increased STAT3/BclxL expression and attenuated apoptosis. CONCLUSIONS Our data have collectively established a lncRNA LSINCT5 mediated process during HCC carcinogenesis and might have provided novel insight into therapeutic targeting.

Effect of hyperlipidemia on the incidence of cardio-cerebrovascular events in patients with type 2 diabetes.

BACKGROUND: This study was to explore the effect of hyperlipidemia on the incidence of cardio-cerebrovascular diseases in patients with type 2 diabetes. METHODS: Three hundred ninety five patients with type 2 diabetes in our hospital from January 2012 to January 2016 were followed up with an average of 3.8 years. The incidence of cardio-cerebrovascular diseases between diabetes combined with hyperlipidemia group (195 patients) and diabetes group (200 patients) were made a comparison. Multivariable Cox's proportional hazards regression model was used to analyze the effect of hyperlipidemia on the incidence of cardio-cerebrovascular diseases in patients with type 2 diabetes. RESULTS: Diastolic blood pressure, systolic blood pressure, high-density lipoprotein, low-density lipoprotein, body mass index and hyper-sensitive C-reactive protein were higher in diabetes combined with hyperlipidemia group than in diabetes group (P < 0.05). At the end of the follow-up period, all-cause mortality, cardio-cerebrovascular diseases mortality, and the incidence of myocardial infarction, cerebral infarction, cerebral hemorrhage and total cardiovascular events were significantly higher in diabetes combined with hyperlipidemia group than in diabetes group (P < 0.05). The analysis results of multivariable Cox's proportional hazards regression model showed that the risks of myocardial infarction and total cardiovascular events in diabetes combined with hyperlipidemia group were respectively 1.54 times (95%CI 1.13-2.07) and 1.68 times (95%CI 1.23-2.24) higher than those in diabetes group. Population attributable risk percent of all-cause mortality and total cardiovascular events in patients with type 2 diabetes combined with hyperlipidemia was 9.6% and 26.8%, respectively. CONCLUSIONS: Hyperlipidemia may promote vascular endothelial injury, increasing the risk of cardio-cerebrovascular diseases in patients with type 2 diabetes. Medical staffs should pay attention to the control of blood lipids in patients with type 2 diabetes to delay the occurrence of cardio-cerebrovascular diseases.

Knockdown of SALL4 inhibits the proliferation and reverses the resistance of MCF-7/ADR cells to doxorubicin hydrochloride.

BACKGROUND: Breast cancer is the most frequent malignancy in women and drug resistance is the major obstacle for its successful chemotherapy. In the present study, we analyzed the involvement of an oncofetal gene, sal-like 4 (SALL4), in the tumor proliferation and drug resistance of human breast cancer. RESULTS: Our study showed that SALL4 was up-regulated in the drug resistant breast cancer cell line, MCF-7/ADR, compared to the other five cell lines. We established the lentiviral system expressing short hairpin RNA to knockdown SALL4 in MCF-7/ADR cells. Down-regulation of SALL4 inhibited the proliferation of MCF-7/ADR cells and induced the G1 phase arrest in cell cycle, accompanied by an obvious reduction of the expression of cyclinD1 and CDK4. Besides, down-regulating SALL4 can re-sensitize MCF-7/ADR to doxorubicin hydrochloride (ADMh) and had potent synergy with ADMh in MCF-7/ADR cells. Depletion of SALL4 led to a decrease in IC50 for ADMh and an inhibitory effect on the ability to form colonies in MCF-7/ADR cells. With SALL4 knockdown, ADMh accumulation rate of MCF-7/ADR cells was increased, while the expression of BCRP and c-myc was significantly decreased. Furthermore, silencing SALL4 also suppressed the growth of the xenograft tumors and reversed their resistance to ADMh in vivo. CONCLUSION: SALL4 knockdown inhibits the growth of the drug resistant breast cancer due to cell cycle arrest and reverses tumor chemo-resistance through down-regulating the membrane transporter, BCPR. Thus, SALL4 has potential as a novel target for the treatment of breast cancer.

Upregulated LASP-1 correlates with a malignant phenotype and its potential therapeutic role in human cholangiocarcinoma.

LIM and SH3 protein 1 (LASP-1) is demonstrated to play a key role in occurrence and development of tumors. However, the expression and function of LASP-1 in cholangiocarcinoma (CCA) remain largely unexplored. This study aimed to investigate the effect of regulated LASP-1 expression on migration, invasion, proliferation, and apoptosis of CCA cells and on tumorigenesis in vivo, and to examine clinico-oncological correlates of LASP-1 expression. Expression of LASP-1 by immunohistochemistry was evaluated in CCA tissue samples. HCCC-9810 and RBE cells were transfected with the LASP-1 small interfering RNA (siRNA), and the effect of knocking down LASP-1 gene expression on cell migration, invasion, proliferation, and apoptosis were examined by wound healing, transwell assays, CCK-8 assays, colony formation, and flow cytometry assays, respectively. Xenograft tumor model was used to validate the effect of downregulated LASP-1 in vivo. Our results demonstrated that LASP-1 was over-expressed in CCA tissues, positively correlating with larger tumors, poor histological differentiation, lymph node metastasis, advanced TNM stage, and poor prognosis in CCA patients (P < 0.05). Downregulation of LASP-1 in HCCC-9810 and RBE cell lines significantly increased cell apoptosis and suppressed cell migration, invasion, and proliferation in vitro and tumorigenesis in vivo. Our results indicate that LASP-1 may essentially involve in the metastasis and growth of CCA and clinical significance of LASP-1 may reside in function as a biomarker to predict prognosis and as a promising therapeutic strategy for CCA patients by the inhibition of LASP-1 expression.

[Predictive value of liver enzymes and alcohol consumption for risk of type 2 diabetes].

OBJECTIVE: To compare the predictive value of liver enzymes and alcohol consumption for determining risk of type 2 diabetes (T2DM). METHODS: A cross-sectional study was conducted in Zhengzhou with a total of 2, 693 men.Participants' height, weight, and histories of smoking and drinking were recorded. Levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT) and blood glucose, as well as related metabolic indexes were detected. RESULTS: Moderate daily alcohol consumption (more than 35 g ethanol/week and less than 140 g ethanol/week) decreased the risk of type 2 diabetes (OR =0.376, 95% CI:0.306 -0.463, P less than 0.05) but increased risk for higher levels of GGT and ALT (OR GGT =3.012, 95% CI:2.357-3.849, Pless than 0.01; ORALT =1.473, 95% CI:1.043-2.081, Pless than 0.05). In joint analyses of alcohol consumption and liver enzymes, the group of nondrinkers/light drinkers (less than or equal to 35 g ethanol/week) in the fourth quartile of GGT levels had the highest risk for type 2 diabetes (OR =12.219, 95% CI:6.217-24.016, P less than 0.01). The relationship of ALT and daily alcohol consumption with the risk of type 2 diabetes was almost the same as that of GGT (nondrinkers/light drinkers in the fourth quartile of ALT levels (OR =5.357, 95% CI:3.070-9.350, P less than 0.0 1). CONCLUSION: GGT, ALT and daily alcohol consumption were independently associated with risk of type 2 diabetes. Nondrinkers/light drinkers with the highest levels ofGGT orALT were at high risk of type 2 diabetes.

[The correlation study of liver enzymes level and risk of type 2 diabetes].

OBJECTIVE: To investigate the correlation between serum liver enzymes and onset of type 2 diabetes mellitus (T2DM). METHODS: A total of 8 779 individuals subjected to a Zhengzhou community survey were enrolled in the study and were tested for the following serum biochemical parameters, including ALT, AST, γ-glutamyl transferase (GGT), TC, TG and blood glucose. All subjects were divided into four groups (Q1-Q4) according to the quartiles of their liver enzyme levels. Logistic regression was performed to explore the odd ratio (OR) for the onset of T2DM in groups of Q2-Q4 compared with the group of Q1.ROC curve was used to analyze the predictive value of elevated liver enzymes for the onset of T2DM. RESULTS: When the quartiles were defined by the GGT level, compared with the group of Q1, the OR for the group of Q4 was 4.043 (95%CI 2.759-5.924) in the male and 4.239 (95%CI 3.172-5.664) in the female, which was higher than the OR when the quartiles were defined by the ALT level. In the ROC curve, the AUC of GGT was larger than those of ALT, AST, BMI, waist circumference and TG, with 0.63 for the male and 0.68 for the female. CONCLUSIONS: Serum level of GGT is more closely correlated with the onset of T2MD than the level of ALT or AST. Even the increase of serum GGT within physiological range is a risk factor for the onset of T2DM.

Multidimensional Optimization of Saccharomyces cerevisiae for Carotenoid Overproduction.

Microbial synthesis of carotenoids is a highly desirable alternative to plant extraction and chemical synthesis. In this study, we investigated multidimensional strategies to improve the carotenoid synthesis in the industrial workhorse of Saccharomyces cerevisiae. First, we rewired the yeast central metabolism by optimizing non-oxidative glycolysis pathway for an improved acetyl-CoA supply. Second, we restricted the consumption of farnesyl pyrophosphate (FPP) by the down-regulation of squalene synthase using the PEST degron. Third, we further explored the human lipid binding/transfer protein saposin B (hSapB)-mediated metabolic sink for an enhanced storage of lipophilic carotenoids. Last, the copper-induced GAL expression system was engineered to function in the yeast-peptone-dextrose medium for an increased biomass accumulation. By combining the abovementioned strategies, the final engineered yeast produced 166.79 ± 10.43 mg/l ß-carotene in shake flasks, which was nearly 5-fold improvement of the parental carotenoid-producing strain. Together, we envision that multidimensional strategies reported here might be applicable to other hosts for the future industrial development of carotenoid synthesis from renewable feedstocks.

HBV infection effects prognosis and activates the immune response in intrahepatic cholangiocarcinoma.

BACKGROUND: The impact of HBV infection on the prognosis of patients with intrahepatic cholangiocarcinoma (ICC) remains uncertain, and the underlying mechanism has not been elucidated. This study aims to explore the potential mechanism via clinical perspectives and immune features. METHODS: We retrospectively reviewed 1308 patients with ICC treated surgically from January 2007 to January 2015. Then, we compared immune-related markers using immunohistochemistry staining to obtain the gene expression profile GSE107943 and related literature for preliminary bioinformatics analysis. Subsequently, we conducted a drug sensitivity assay to validate the role of TNFSF9 in the ICC organoid-autologous immune cell coculture system and in the patient-derived organoids-based xenograft platform. RESULTS: The analysis revealed that tumors in patients without HBV infection exhibited greater size and a higher likelihood of lymphatic metastasis, tumor invasion, and relapse. After resection, HBV-infected patients had longer survival time than uninfected patients (p<0.01). Interestingly, the expression of immune-related markers in HBV-positive patients with ICC was higher than that in uninfected patients (p<0.01). The percentage of CD8+ T cells in HBV-positive tissue was higher than that without HBV infection (p<0.05). We screened 21 differentially expressed genes and investigated the function of TNFSF9 through bioinformatics analyses. The expression of TNFSF9 in ICC organoids with HBV infection was lower than that in organoids without HBV infection. The growth of HBV-negative ICC organoids was significantly inhibited by inhibiting the expression of TNFSF9 with a neutralizing antibody. Additionally, the growth rate was faster in HbsAg (-) ICC patient-derived organoids-based xenograft model than in HbsAg (+) group. CONCLUSIONS: The activation of the immune response induced by HBV infection makes the prognosis of HBV-positive patients with ICC differ from that of uninfected patients.

Presence of onco-fetal neighborhoods in hepatocellular carcinoma is associated with relapse and response to immunotherapy.

Onco-fetal reprogramming of the tumor ecosystem induces fetal developmental signatures in the tumor microenvironment, leading to immunosuppressive features. Here, we employed single-cell RNA sequencing, spatial transcriptomics and bulk RNA sequencing to delineate specific cell subsets involved in hepatocellular carcinoma (HCC) relapse and response to immunotherapy. We identified POSTN+ extracellular matrix cancer-associated fibroblasts (EM CAFs) as a prominent onco-fetal interacting hub, promoting tumor progression. Cell-cell communication and spatial transcriptomics analysis revealed crosstalk and co-localization of onco-fetal cells, including POSTN+ CAFs, FOLR2+ macrophages and PLVAP+ endothelial cells. Further analyses suggest an association between onco-fetal reprogramming and epithelial-mesenchymal transition (EMT), tumor cell proliferation and recruitment of Treg cells, ultimately influencing early relapse and response to immunotherapy. In summary, our study identifies POSTN+ CAFs as part of the HCC onco-fetal niche and highlights its potential influence in EMT, relapse and immunotherapy response, paving the way for the use of onco-fetal signatures for therapeutic stratification.

Identification and functional analysis of cytochrome P450 complement in Streptomyces virginiae IBL14.

BACKGROUND: As well known, both natural and synthetic steroidal compounds are powerful endocrine disrupting compounds (EDCs) which can cause reproductive toxicity and affect cellular development in mammals and thus are generally regarded as serious contributors to water pollution. Streptomyces virginiae IBL14 is an effective degradative strain for many steroidal compounds and can also catalyze the C25 hydroxylation of diosgenin, the first-ever biotransformation found on the F-ring of diosgenin. RESULTS: To completely elucidate the hydroxylation function of cytochrome P450 genes (CYPs) found during biotransformation of steroids by S. virginiae IBL14, the whole genome sequencing of this strain was carried out via 454 Sequencing Systems. The analytical results of BLASTP showed that the strain IBL14 contains 33 CYPs, 7 ferredoxins and 3 ferredoxin reductases in its 8.0 Mb linear chromosome. CYPs from S. virginiae IBL14 are phylogenetically closed to those of Streptomyces sp. Mg1 and Streptomyces sp. C. One new subfamily was found as per the fact that the CYP Svu001 in S. virginiae IBL14 shares 66% identity only to that (ZP_05001937, protein identifer) from Streptomyces sp. Mg1. Further analysis showed that among all of the 33 CYPs in S. virginiae IBL14, three CYPs are clustered with ferredoxins, one with ferredoxin and ferredoxin reductase and three CYPs with ATP/GTP binding proteins, four CYPs arranged with transcriptional regulatory genes and one CYP located on the upstream of an ATP-binding protein and transcriptional regulators as well as four CYPs associated with other functional genes involved in secondary metabolism and degradation. CONCLUSIONS: These characteristics found in CYPs from S. virginiae IBL14 show that the EXXR motif in the K-helix is not absolutely conserved in CYP157 family and I-helix not absolutely essential for the CYP structure, too. Experimental results showed that both CYP Svh01 and CYP Svu022 are two hydroxylases, capable of bioconverting diosgenone into isonuatigenone and ß-estradiol into estriol, respectively.

Quantitative energy spectrum CT in differential diagnosis of aldosterone-producing adenoma and cortisol-producing adenoma.

Background: Patients with aldosterone-producing adenoma (APA) and cortisol-producing adenoma (CPA) show some similar clinical symptoms, and a large overlap of conventional imaging manifestations, which make the differentiation difficult. The purpose of our study was to explore the value of gemstone spectral imaging (GSI) dual-energy computed tomography (DECT) in differential diagnosis of APA and CPA, screen out meaningful energy spectral indicators and provide theoretical basis for the differential diagnosis of the two. Methods: We retrospectively analyzed the imaging and clinical data of 30 patients with APA and 27 patients with CPA who underwent GSI DECT in The First Affiliated Hospital of Zhengzhou University (a tertiary care institution). Patients were consecutively enrolled in this study, and the quantitative DECT parameters were compared between the APA and CPA groups by two-sample test. The diagnostic efficacies were evaluated by receiver operating characteristic (ROC) analysis. Results: DECT parameters including CT (computed tomography) values at 40-70 keV in the arterial phase, concentrations of I (H2O) and fat (I) in the arterial phase, and the effective atomic number in the venous phase, were significantly different between the APA and CPA groups (all P<0.001), and the area under the curve (AUC) values are 0.80, 0.79, 0.88, 0.76, 0.82, 0.87, and 0.86. Conclusions: DECT quantitative parameters can effectively identify APA and CPA, the CT values at 40 and 60 keV in the arterial phase, the normalized CT value at 60 keV, the I (H2O), fat (I) concentration in the arterial phase and the effective atomic number parameter in the venous phase had valuable diagnostic performance.

Technical comparison of continuous versus intermittent perfusion computed tomography computed tomography scans of the human pancreas.

Background: Pancreatic perfusion computed tomography (CT) imaging is increasingly used for neoplastic grading, predicting prognosis, and evaluating the response to therapy. To optimize the clinical pancreatic CT perfusion imaging methods, we evaluated 2 different CT scanning protocols concerning pancreas perfusion parameters. Methods: A retrospective study was conducted on 40 patients who underwent whole pancreas CT perfusion scanning in The First Affiliated Hospital of Zhengzhou University. Of these 40 patients, 20 patients in group A underwent continuous perfusion scanning, while 20 patients in group B underwent intermittent perfusion scanning. For group A, continuous axial scanning was performed 25 times, and the total scan time was 50 s. For group B, arterial phase helical perfusion scanning was performed 8 times, and then venous phase helical perfusion scanning was performed 15 times, with a total scan time of 64.6 to 70.0 s. A comprehensive list of perfusion parameters between different parts of the pancreas and the 2 groups were compared. The effective radiation dose for the 2 scanning methods was analyzed. Results: The parameter of the mean slope of increase (MSI) at different pancreatic parts in group A differed (P=0.028). The pancreas head had the lowest value, and the tail had the highest (about a 20% difference). In group A compared to group B, the blood volume of the pancreatic head was smaller (15.256±2.925 vs. 16.953±3.602), the positive enhanced integral was smaller (0.307±0.050 vs. 0.344±0.060) and the permeability surface was larger (34.205±9. 612 vs. 24.377±8.413); the blood volume of the pancreatic neck was smaller (13.940±2.691 vs. 17.173±3.918), the positive enhanced integral was smaller (0.304±0.088 vs. 0.361±0.051) and the permeability surface was larger (34.898±11.592 vs. 25. 794±8.149); the blood volume of the pancreatic body was smaller (16.142±4.006 vs. 18.401±2.513), the positive enhanced integral was smaller (0.305±0.093 vs. 0.342±0.048) and the permeability surface was larger (28.861±10.448 vs. 22.158±6. 017); the blood volume of the pancreatic tail was smaller (16.446±3.709 vs. 17.374±3.781), the positive enhanced integral was smaller (0.304±0.057 vs. 0.350±0.073) and the permeability surface was larger (27.823±8.228 vs. 21.509±7.768) (P<0.05). The effective radiation dose in the intermittent scan mode was slightly lower at 16.657±2.259 mSv than in the continuous scan mode (17.973±3.698 mSv). Conclusions: Different CT scanning intervals had a significant influence on whole pancreas blood volume, permeability surface, and positive enhanced integral. These demonstrate the high sensitivity of intermittent perfusion scanning for identifying perfusion abnormalities. Therefore, for the diagnosis of pancreatic diseases, intermittent pancreatic CT perfusion may be more advantageous.