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Abstract Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy after hepatocellular carcinoma, with poor prognosis and limited treatment options. The genomic features of ICC in Chinese patients remain largely unknown. In this study, we perform deep whole-exome sequencing of 204 Chinese primary ICCs and characterize genomic alterations and clonal evolution, and reveal their associations with patient outcomes. We identify six mutational signatures, including Signatures A and F, which are highly similar to previously described signatures linked to aristolochic acid and aflatoxin exposures, respectively. We also identify 13 significantly mutated genes in the ICC samples, including SAV1. We find that SAV1 was mutated in 2.9% (20/672) of 672 ICC samples. SAV1 mutation is associated with lower SAV1 protein levels, higher rates of tumor recurrence, and shorter overall patient survival. Biofunctional investigations reveal a tumor-suppressor role of SAV1: its inactivation suppresses Hippo signaling, leading to YAP activation, thereby promoting tumor growth and metastasis. Collectively, our results delineate the genomic landscape of Chinese ICCs and identify SAV1 as a potential driver of ICC.

Backgrounds/Aims Intrahepatic cholangiocarcinoma (ICC) is a highly desmoplastic tumor with poor prognosis even after curative resection. We investigated the associations between the composition of the ICC stroma and immune cell infiltration and aimed to develop a stromal-immune signature to predict prognosis in surgically treated ICC. Methods We recruited 359 ICC patients and performed immunohistochemistry to detect α-smooth muscle actin (α-SMA), CD3, CD4, CD8, Foxp3, CD68, and CD66b. Aniline was used to stain collagen deposition. Survival analyses were performed to detect prognostic values of these markers. Recursive partitioning for a discrete-time survival tree was applied to define a stromal-immune signature with distinct prognostic value. We delineated an integrated stromal-immune signature based on immune cell subpopulations and stromal composition to distinguish subgroups with different recurrence-free survival (RFS) and overall survival (OS) time. Results We defined four major patterns of ICC stroma composition according to the distributions of α-SMA and collagen: dormant (α-SMAlow/collagenhigh), fibrogenic (α-SMAhigh/collagenhigh), inert (α-SMAlow/collagenlow), and fibrolytic (α-SMAhigh/collagenlow). The stroma types were characterized by distinct patterns of infiltration by immune cells. We divided patients into six classes. Class I, characterized by high CD8 expression and dormant stroma, displayed the longest RFS and OS, whereas Class VI, characterized by low CD8 expression and high CD66b expression, displayed the shortest RFS and OS. The integrated stromal-immune signature was consolidated in a validation cohort. Conclusions We developed and validated a stromal-immune signature to predict prognosis in surgically treated ICC. These findings provide new insights into the stromal-immune response to ICC.

Abstract Patients with hepatocellular carcinoma (HCC) have poor long-term survival following curative resection because of the high rate of tumor early recurrence. Little is known about the trajectory of genomic evolution from primary to early-recurrent HCC. In this study, we performed whole-genome sequencing (WGS) on 40 pairs of primary and early-recurrent hepatitis B virus (HBV)-related HCC tumors from patients who received curative resection, and from four patients whose primary and recurrent tumor were extensively sampled. We identified two recurrence patterns: de novo recurrence (18/40), which developed genetically independently of the primary tumor and carried different HCC drivers, and ancestral recurrence (22/40), which was clonally related to the primary tumor and progressed more rapidly than de novo recurrence. We found that the recurrence location was predictive of the recurrence pattern: distant recurrence tended to display the de novo pattern, whereas local recurrence tended to display the ancestral pattern. We then uncovered the evolutionary trajectories based on the subclonal architecture, driver-gene mutations, and mutational processes observed in the primary and recurrent tumors. Multi-region WGS demonstrated spatiotemporal heterogeneity and polyclonal, monophyletic dissemination in HCC ancestral recurrence. In addition, we identified recurrence-specific mutations and copy-number gains in BCL9, leading to WNT/β-catenin signaling activation and an immune-excluded tumor microenvironment, which suggests that BCL9 might serve as a new therapeutic target for recurrent HCC. Collectively, our results allow us to view with unprecedented clarity the genomic evolution during HBV-related HCC early recurrence, providing an important molecular foundation for enhanced understanding of HCC with implications for personalized therapy to improve patient survival.

Abstract Background Plasmacytoid dendritic cells (pDCs) are present in various primary and metastatic human neoplasms; however, their clinical significance in intrahepatic cholangiocarcinoma is not clear. Methods To evaluate pDCs’ distributions in and around tumors as well as their potential function and predictive value for prognosis in patients undergoing curative resection, we performed immunohistochemistry to examine the expression of pDC marker BDCA2, and CD3, CD4, CD8 and Foxp3 in intratumoral and peritumoral tissues from 359 patients with intrahepatic cholangiocarcinoma and compared with prognostic and clinicopathologic factors. Results Results showed that patients with high numbers of BDCA2+ pDCs in peritumoral tissues were more likely to have elevated levels of carbohydrate antigen 19-9 and gamma-glutamyl transferase, larger and more tumors, advanced tumor-node-metastasis staging, more vascular/bile duct invasion, and lymphatic metastasis in association with greater chance of recurrence and shorter overall survival. Peritumoral tissues with larger numbers of pDCs also showed increased Foxp3+ regulatory T cell infiltration, both of which were found to be independent factors for predicting time to recurrence and overall survival. By contrast, patient outcomes were not associated with the presence of intratumoral pDCs. Conclusions Peritumoral pDC infiltration may indicate an immune tolerogenic peritumor microenvironment and can be used to predict a poor prognosis for patients undergoing curative resection for intrahepatic cholangiocarcinoma.

Abstract. Background:. Glioma is the most common primary malignant tumor in the central nervous system. Because of the resistance of glioma to chemoradiotherapy and its aggressive growth, the survival rate of patients with glioma has not improved. This study aimed to disclose the effect of retinol dehydrogenase 10 (RDH10) on the migration and invasion of glioma cells, and to explore the potential mechanism. Methods:. Reverse transcription-polymerase chain reaction (RT-PCR) was used to determine the expression levels of RDH10 in healthy glial cells and glioma cells. Human glioma cell strains, U87 and U251, were infected with negative control or RDH10-interfering lentiviruses. RT-PCR and Western blotting were performed to determine the knockdown efficiency. Scratch and transwell assays were used to assess cell migration and invasion after RDH10 knockdown. Finally, changes in transforming growth factor-β (TGF-β)/SMAD signaling pathway-related expression were examined by Western blotting. Differences between groups were analyzed by one-way analysis of variance. Results:. RDH10 was highly expressed in glioma cells. Compared with the control group, RDH10 knockdown significantly reduced RDH10 messenger RNA and protein expression levels in U87 and U251 glioma cells (U87: 1.00 ± 0.08 vs. 0.22 ± 0.02, t = 16.55, P

Objective To investigate the application of neuroendoscopy and curative effect of lateral skull base surgery via transcranial approach. Methods Clinical data of 142 cases undergoing endoscopic lateral skull base surgeries via transcranial approach from July 2015 to July 2018 were retrospectively analyzed. There were 32 cases of primary hemifacial spasm, 56 cases of primary trigeminal neuralgia, 2 cases of primary glossopharyngeal neuralgia, 15 cases of epidermoid cyst, 14 cases of acoustic neuroma, 3 cases of trigeminal schwannoma, 18 cases of pontocerebellar trigone meningioma, and 2 cases of jugular foramen schwannoma. Among them, 90 cases (32 cases of primary hemifacial spasm, 56 cases of primary trigeminal neuralgia and 2 cases of primary glossopharyngeal neuralgia) underwent endoscopic microvascular decompression (MVD) via transcranial approach, and 52 cases (15 cases of epidermoid cyst, 14 cases of acoustic neuroma, 3 cases of trigeminal schwannoma, 18 cases of pontocerebellar trigone meningioma, and 2 cases of jugular foramen schwannoma) underwent endoscopic removal of lateral skull base tumors via transcranial approach. Results All the operations were performed under endoscopy, including 96 cases (67.61%) operated by single hand (the endoscope was held by a pneumatic arm) and the rest 46 cases (32.39%) operated by both hands. The cure rate of MVD was 87.78% (79/90) and the total removal rate of lateral skull base tumors was 90.38% (47/52). The mean follow-up period was (23.46 ± 8.93) months. There was no death or other serious complications. Conclusions The complex lateral skull base surgery via transcranial approach can be performed by neuroendoscope with pneumatic endoscopic fixed arm. It has the advantages of near and multi-angle observation, clear visual field, full exposure and high recognition of nerve and blood vessels. However, the requirements for endoscopic technology, instruments and assistive equipments are high, and it is necessary to receive relevant trainings and experiences in endoscopic surgery. DOI: 10.3969/j.issn.1672-6731.2019.03.008

Abstract Background Long noncoding RNAs (lncRNAs) are functionally associated with cancer development and progression. Although gene copy number variation (CNV) is common in hepatocellular carcinoma (HCC), it is not known how CNV in lncRNAs affects HCC progression and recurrence. We aimed to identify a CNV‐related lncRNA involved in HCC progression and recurrence and illustrate its underlying mechanisms and prognostic value. Methods We analyzed the whole genome sequencing (WGS) data of matched cancerous and noncancerous liver samples from 49 patients with HCC to identify lncRNAs with CNV. The results were validated in another cohort of 238 paired HCC and nontumor samples by TaqMan copy number assay. We preformed Kaplan‐Meier analysis and log‐rank test to identify lncRNA CNV with prognostic value. We conducted loss‐ and gain‐of‐function studies to explore the biological functions of LINC01133 in vitro and in vivo. The competing endogenous RNAs (ceRNAs) mechanism was clarified by microRNA sequencing (miR‐seq), quantitative real‐time PCR (qRT‐PCR), western blot, and dual‐luciferase reporter assays. We confirmed the binding mechanism between lncRNA and protein by RNA pull‐down, RNA immunoprecipitation, qRT‐PCR, and western blot analyses. Results Genomic copy numbers of LINC01133 were increased in HCC, which were positively related with the elevated expression of LINC01133. Increased copy number of LINC01133 predicted the poor prognosis in HCC patients. LINC01133 overexpression in HCC cells promoted proliferation and aggressive phenotypes in vitro, and facilitated tumor growth and lung metastasis in vivo, whereas LINC01133 knockdown had the opposite effects. LINC01133 sponged miR‐199a‐5p, resulting in enhanced expression of SNAI1, which induced epithelial‐to‐mesenchymal transition (EMT) in HCC cells. In addition, LINC01133 interacted with Annexin A2 (ANXA2) to activate the ANXA2/STAT3 signaling pathway. Conclusions LINC01133 promotes HCC progression by sponging miR‐199a‐5p and interacting with ANXA2. LINC01133 CNV gain is predictive of poor prognosis in patients with HCC.

This study aimed to investigate the preventive effects of lactoferrin (Lf) on chronic alcoholic liver injury (ALI) in female mice. Female C57BL/6J mice were randomly divided into four groups: control group (CON), ethanol administration group (EtOH), low-dose Lf treatment group (LLf), and high-dose Lf group (HLf). In the last three groups, chronic ALI was induced by administering 20% ethanol ad libitum for 12 weeks. Mice in the CON and EtOH groups were fed with AIN-93G diet. Meanwhile, 0.4% and 4% casein in the AIN-93G diet were replaced by Lf as the diets of LLf and HLf groups, respectively. HLf significantly reduced hepatic triglyceride content and improved pathological morphology. HLf could inhibit cytochrome P450 2E1 overexpression and promote alcohol dehydrogenase-1 expression. HLf activated protein kinase B and AMP-activated protein kinase (AMPK), as well as upregulating nuclear-factor-erythroid-2-related factor-2 expression to elevate hepatic antioxidative enzyme activities. AMPK activation also benefited hepatic lipid metabolism. Meanwhile, HLf had no obvious beneficial effects on gut microbiota. In summary, Lf could alleviate chronic ALI in female mice, which was associated with redox balance and lipid metabolism regulation.

Dynamic loads such as the train vibration load usually act on the shield tunnel lining in the long term, which could make the initial flaws in shield segment propagate and gradually weaken the robustness of the tunnel structure. In this paper, a three-dimensional numerical model of shield tunnel lining structure with the initial defect is built to study its dynamic reaction and fatigue crack propagation under the train vibration load. Furthermore, the damage to intact shield segment caused by train vibration load is studied by employing the rain-flow counting method and the Miner damage theory, and a rational fatigue life estimation for the concrete shield tunnel lining is finally made. Results show that crack propagation is influenced by both the train speed and train axle, the higher the train speed, the longer the final crack, and train axle has a larger influence than train speed on the crack propagation in shield tunnel segment. The shield tunnel lining structure of Nanjing Metro Line 5 can meet the demand of working for a hundred years under the current working conditions.

The retaining structure of a shield tunnel is usually subjected to static loading; however, cyclic loading such as the vibration loading of the train will act on the lining structure year after year that cannot be neglected. Due to the complex manufacturing and assembling process of the lining segment, initial defects in the segment are inevitable. Such defects will propagate under the cyclic loading such as the train vibration, which may cause a large threat to the shield tunnel system. In this paper, a defective shield tunnel lining segment under cyclic loading is studied by both a full-scale experiment and three-dimensional numerical simulations to investigate its fracture properties and failure mechanism and make a rational estimate of its fatigue life. Results show that crack propagation of the defective shield tunnel segment can be identified as several different stages based on its deformation characteristics, and the failure pattern of the segment is determined by its initial defects. The results by the experiment and numerical investigation are in good agreement for each other.

Cerebral ventricular infection (CVI) is one of the most dangerous complications in neurosurgery because of its high mortality and disability rates. Few studies have examined the application of neuroendoscopic surgical techniques (NESTs) to assess and treat CVI. This multicenter, retrospective study was conducted using clinical data of 32 patients with CVI who were assessed and treated by NESTs in China. The patients included 20 men and 12 women with a mean age of 42.97 years. NESTs were used to obliterate intraventricular debris and pus, fenestrate or incise the intraventricular compartment and reconstruct cerebrospinal fluid circulation, and remove artificial material. Intraventricular irrigation with antibiotic saline was applied after neuroendoscopic surgery (NES). Secondary hydrocephalus was treated by endoscopic third ventriculostomy or a ventriculoperitoneal shunt. Neuroendoscopic findings of CVI were used to classify patients into Grade I (n = 3), Grade II (n = 13), Grade III (n = 10), and Grade IV (n = 6) CVI. The three patients with grade I CVI underwent one NES, the 23 patients with grade II/III CVI underwent two NESs, and patients with grade IV CVI underwent two (n = 3) or three (n = 3) NESs. The imaging features and grades of neuroendoscopy results were positively related to the number of neurosurgical endoscopic procedures. Two patients died of multiple organ failure and the other 30 patients fully recovered. Among the 26 patients with secondary hydrocephalus, 18 received ventriculoperitoneal shunt and 8 underwent endoscopic third ventriculostomy. There were no recurrences of CVI during the 6- to 76-month follow-up after NES. Application of NESTs is an innovative method to assess and treat CVI, and its neuroendoscopic classification provides an objective, comprehensive assessment of CVI. The study trial was approved by the Institutional Review Board of Beijing Shijitan Hospital, Capital Medical University, China.

AIM: To assess the efficacy and safety of orthokeratology for reducing the progression of myopia in Asia children. METHODS: Seven databases, including the Cochrane Library, Medline, EMbase, CBM, CNKI, VIP, and WanFang Data, were searched. The published languages were limited to English and Chinese. The risk bias tool provided by Cochrance cooperation and methodological index for non-randomized studies(MINORS)scale were used to assess the risk bias of included studies(randomized controlled trials and controlled trials). The published biases of included studies were assessed with funnel plot. Meta-analysis was performed with Review Manager 5.3. RESULTS: Seven eligible studies, including 478 children, were included, 250 cases in ortho-k group, 228 cases in control group. The Meta-analysis indicated that change in axial length of ortho-k group was significantly less than the control group \〖WMD=-0.31, 95%CI(-0.35, -0.26), PCONCLUSION: The overall findings suggested that orthokeratology might slow the progression of myopia in children of Asia.

Burkholderia pseudomallei is a gram-negative, facultative intracellular bacterium, which causes a disease known as melioidosis. Professional phagocytes represent a crucial first line of innate defense against invading pathogens. Uptake of pathogens by these cells involves the formation of a phagosome that matures by fusing with early and late endocytic vesicles, resulting in killing of ingested microbes. Host Rab GTPases are central regulators of vesicular trafficking following pathogen phagocytosis. However, it is unclear how Rab GTPases interact with B. pseudomallei to regulate the transport and maturation of bacterial-containing phagosomes. Here, we showed that the host Rab32 plays an important role in mediating antimicrobial activity by promoting phagosome maturation at an early phase of infection with B. pseudomallei. And we demonstrated that the expression level of Rab32 is increased through the downregulation of the synthesis of miR-30b/30c in B. pseudomallei infected macrophages. Subsequently, we showed that B. pseudomallei resides temporarily in Rab32-positive compartments with late endocytic features. And Rab32 enhances phagosome acidification and promotes the fusion of B. pseudomallei-containing phagosomes with lysosomes to activate cathepsin D, resulting in restricted intracellular growth of B. pseudomallei. Additionally, Rab32 mediates phagosome maturation depending on its guanosine triphosphate/guanosine diphosphate (GTP/GDP) binding state. Finally, we report the previously unrecognized role of miR-30b/30c in regulating B. pseudomallei-containing phagosome maturation by targeting Rab32 in macrophages. Altogether, we provide a novel insight into the host immune-regulated cellular pathway against B. pseudomallei infection is partially dependent on Rab32 trafficking pathway, which regulates phagosome maturation and enhances the killing of this bacterium in macrophages.

This paper addresses a study of inner-tank sloshing effect on motion responses of a Floating Liquefied Natural Gas (FLNG) system, through experimental analysis and numerical modeling. To investigate hydrodynamic characteristics of FLNG under the conditions of with and without LNG-tank sloshing, a series of numerical simulations were carried out using potential flow solver SESAM. To validate the numerical simulations, model tests on the FLNG system was conducted in both liquid and solid ballast conditions with 75% tank filling level in height. Good correlations were observed between the measured and predicted results, proving the feasibility of the numerical modeling technique. On the verified numerical model, Response Amplitude Operators (RAOs) of the FLNG with 25% and 50% tank filling levels were calculated in six degrees of freedom. The influence of tank sloshing with varying tank filling levels on the RAOs has been presented and analyzed. The results showed that LNG-tank sloshing has a noticeable impact on the roll motion response of the FLNG and a moderate tank filling level is less helpful in reducing the roll motion response.

The horizontal stability of a Single-Point Moored (SPM) Floating Liquefied Natural Gas (FLNG) facility is investigated. Both numerical and experimental studies have been conducted for this SPM FLNG. The numerical simulations feature well the experimental data. The effects of the turret locations are studied based on the validated numerical model. Statistic results of the vessel’s motions with different turret locations are conducted and compared. The results show that the longitudinal location of the turret has a significant influence on the horizontal stability, which has a strong relationship with the yaw and roll motions. The calculated top tensions on the hawsers also develop a regular change as changing the turret’s location. The investigation will provide a brief of principles with more details for the design of the ongoing project.

In the title compound, C18H26N2O6S2, all bond lengths and angles are normal. The crystal structure is stabilized by intermolecular N—H...O hydrogen bonds.

In the title compound, C9H13ClN6O2S, all bond lengths and angles are normal. The 1,3,5-triazine ring exhibits a half-chair conformation. In the crystal structure, weak intermolecular C—H...N and C—H...O hydrogen bonds link the molecules into layers parallel to the bc plane.

As the development of tight gas fields enters the stable production stage, condensate oil forms a complex oil--water emulsifying system under the action of bubble drainage agent, corrosion inhibitor, hydrate inhibitor, and other additives to increase and stabilize production, as well as the formation of particulate matter. A new demulsification and flocculation agent suitable for condensate emulsifying system is developed to make the system unstable and the oil beads coalesce. In this paper, a polyether--quaternary ammonium salt reverse demulsifier (PPA) was synthesized by grafting a cationic group onto a five-membered block polyether X-75. A new type of demulsification--flocculation agent (CQ) was obtained through the complex modification of PPA and inorganic coagulant polyaluminum ferric chloride. Fourier-transform infrared spectroscopy, X-ray photoelectron spectroscopy, and gel chromatograph were used to characterize the group and molecular structure. The reaction parameters were optimized by single-factor experiment and the response surface method, and the demulsification--flocculation mechanism was determined by zeta potential, interfacial tension, and fractal dimension. Results showed the PPA demulsifier has active groups (block polyether) and cationic groups (polyquaternary ammonium salt) at the oil--water interface at the same time and can play a synergistic role between them. Single-factor experiment and response surface optimization showed CQ concentration and temperature were key factors affecting the demulsification-- flocculation effect. When CQ concentration was 547 mg/L, settling temperature was 27.9°C and PPA accounted for 71%. After settling for 30 min, the oil content and the concentration of total suspended solids (TSS) in the water decreased to 21.26 and 7.0 mg/L, respectively, which met the water quality requirements of reinjection (oil content ≤ 30 mg/L, TSS concentration ≤ 15 mg/L). By neutralizing and displacing active substances at the oil--water interface and sweeping by net trapping, CQ can coagulate oil beads and suspended particles to form large flocs and realize the efficient separation of oil beads, suspended particles, and water. [ABSTRACT FROM AUTHOR]