Epidemiology and outcome of individuals with intraductal papillary neoplasms of the bile duct.

BACKGROUND: Intraductal papillary neoplasm of the bile duct (IPNB) is a rare distinct subtype of precursor lesions of biliary carcinoma. IPNB is considered to originate from luminal biliary epithelial cells, typically displays mucin-hypersecretion or a papillary growth pattern, and results in cystic dilatation[1]. IPNB develops anywhere in the intrahepatic and extrahepatic biliary tracts, and can occur in various pathological stages from low-grade dysplasia to invasive carcinoma. IPNBs have similar phenotypic changes in the occurrence and development of all subtypes, and the prognosis is significantly better than that of traditional (non-papillary) cholangiocarcinoma. AIM: To evaluate the clinicopathological features of IPNB to provide evidence-based guidance for treatment. METHODS: Invasive IPNB, invasive intraductal papillary mucinous neoplasm of the pancreas (IPMN), and traditional cholangiocarcinoma data for affected individuals from 1975 to 2016 were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Annual percentage changes (APCs) in the incidence and incidence-based (IB) mortality were calculated. We identified the independent predictors of overall survival (OS) and cancer-specific survival (CSS) in individuals with invasive IPNB. RESULTS: The incidence and IB mortality of invasive IPNB showed sustained decreases, with an APC of -4.5% (95%CI: -5.1% to -3.8%) and -3.3% (95%CI: -4.1% to -2.6%) (P < 0.001), respectively. Similar decreases in incidence and IB mortality were seen for invasive IPMN but not for traditional cholangiocarcinoma. Both OS and CSS for invasive IPNB were better than for invasive IPMN and traditional cholangiocarcinoma. A total of 1635 individuals with invasive IPNB were included in our prognosis analysis. The most common tumor sites were the pancreaticobiliary ampulla (47.9%) and perihilar tract (36.7%), but the mucin-related subtype of invasive IPNB was the main type, intrahepatically (approximately 90%). In the univariate and multivariate Cox regression analysis, age, tumor site, grade and stage, subtype, surgery, and chemotherapy were associated with OS and CSS (P < 0.05). CONCLUSION: Incidence and IB mortality of invasive IPNB trended steadily downward. The heterogeneity of IPNB comprises site and the tumor's mucin-producing status.

Bifidobacterium animalis A12 and Lactobacillus salivarius M18-6 Alleviate Alcohol Injury by keap1-Nrf2 Pathway and Thioredoxin System.

Excessive drinking can significantly damage people's health and well-being. Although some lactic acid bacterial strains have been previously shown to alleviate the symptoms of alcohol injury, the mechanism underlying these effects remains unclear. The aim of this study was to establish an alcohol injury model and examine the protective effect and mechanism of B. animalis A12 and L. salivarius M18-6. The results showed that A12 freeze-dried powder could maintain the survival rate of mice with alcohol injury at 100%. Compared with Alco group, L. salivarius M18-6 dead cell improved the survival rate of mice, attenuated liver steatosis, and significantly down-regulated serum Alanine transaminase (ALT) level; at the same time, it activated keap1-Nrf2 signaling pathway and up-regulated Superoxide dismutase (SOD), it protects mouse liver cells from oxidative stress induced by alcohol injury. In addition, B. animalis A12 can reduce the stress response to short-term alcohol intake and improve the ability of anti-oxidative stress by upregulating the level of isobutyric acid, reducing the level of keap1 protein in the liver of mice and upregulating the expression of thioredoxin genes (Txnrd1, Txnrd3, Txn1). Taken together, the results showed that B. animalis A12 and L. salivarius M18-6 alleviate alcohol injury in mice through keap1-Nrf2 signaling pathway and thioredoxin system.

[Distribution of Biodegradable Dissolved Organic Matter and Its Affecting Factors in a Typical Peri-urban Watershed in Yangtze River Delta].

Dissolved organic matter (DOM) plays key roles in the carbon biogeochemical cycle, and biodegradable dissolved organic matter (BDOM) is one of the key fractions of DOM. Rapid urbanization and intensive human activities substantially influence the distribution of DOM at the watershed scale. Identifying the spatial and temporal variability in BDOM has become an important and urgent issue of water quality control in rapid urbanization areas. However, limited studies have been conducted to explore the role of human activities on the occurrence and distribution of BDOM in peri-urban watersheds. In this study, the spatial and temporal distribution of BDOM and related affecting factors were investigated in a typical peri-urban watershed (Zhangxi watershed) located at Ningbo City in Yangtze River Delta. Water samples were collected in wet and dry seasons in 2019 based on topographic features, land use, and intensity of human activities. The BDOM were characterized by fluorescence excitation-emission matrix and parallel factor analysis (EEM-PARAFAC), and land use patterns were analyzed using the Source-Sink Landscape Model. The results of this study showed that the BDOM concentrations ranged from 0.57 to 6.80 mg·L-1. Obvious spatial and temporal heterogeneities of BDOM were found at the watershed scale, and significantly higher concentrations of BDOM were observed in the wet season than those in the dry season. Furthermore, relatively high concentrations of BDOM were found in areas with relatively higher intensive human activities. Two fluorescent components (a terrestrial humic-like substance and protein-like substance) were observed using the PARAFAC model. The results of spatial analysis showed that terrestrial humic-like fluorescent components were closely positively correlated with anthropogenic parameters (percentages of agricultural and urban land and ratio of source and sink landscapes). The results showed that the occurrence and distribution of BDOM were strongly influenced by human activities, which could provide scientific guidance for water quality control and related land management in peri-urban aquatic ecosystems.

FBXO22 Accelerates Pancreatic Cancer Growth by Deactivation of the Hippo Pathway via Destabilizing LATS2.

BACKGROUND: Dysregulation of ubiquitin ligases plays a crucial role in the development and progression of various human tumors. F-box only protein 22 (FBXO22), an F-box E3 ubiquitin ligase, has been reported to participate in diverse aspects of cancer progression. However, the clinical significance and biological function of FBXO22 in pancreatic cancer remain poorly understood. AIMS: This study aimed to investigate the role of FBXO22 in promoting pancreatic cancer growth. METHODS: FBXO22 expression was detected in pancreatic cancer and adjacent normal tissues using qRT-PCR, western blotting, and immunohistochemistry. Ectopic expression and knockdown of FBXO22 were performed to measure the impact on pancreatic cancer cells growth by CCK-8, colony formation, and tumorigenicity assay. Bioinformatics analysis uncovered the potential correlation between FBXO22 and various signaling pathways. Western blotting and immunoprecipitation were performed to identify FBXO22-interacting proteins. RESULTS: We observed that FBXO22 was upregulated in samples obtained from patients with pancreatic cancer compared with its levels in the adjacent normal tissues, and an elevated FBXO22 level was obviously associated with poor prognosis among patients with pancreatic cancer. FBXO22 knockdown impaired pancreatic cancer cell growth both in vitro and in vivo, whereas FBXO22 overexpression accelerated pancreatic cancer cell growth. Furthermore, we found that FBXO22 contributed to pancreatic cancer cell growth by deactivating the Hippo pathway. Mechanistically, FBXO22 directly interacts with and destabilizes the large tumor suppressor 2 (LATS2), which is a critical regulator of the Hippo pathway. Blocking LATS2 leads to the loss of FBXO22-mediated oncogenic effect in pancreatic cancer. CONCLUSIONS: These findings provide new insights into the upstream regulation of the Hippo pathway inactivation in pancreatic cancer growth and identify FBXO22 as a potential therapeutic target for this lethal malignant tumor.

Efficacy and safety of sirolimus early conversion protocol in liver transplant patients with hepatocellular carcinoma: A single-arm, multicenter, prospective study.

Mammalian target of rapamycin (mTOR) inhibitor as an attractive drug target with promising antitumor effects has been widely investigated. High quality clinical trial has been conducted in liver transplant (LT) recipients in Western countries. However, the pertinent studies in Eastern world are paucity. Therefore, we designed a clinical trial to test whether sirolimus can improve recurrence-free survival (RFS) in hepatocellular carcinoma (HCC) patients beyond the Milan criteria after LT. This is an open-labeled, single-arm, prospective, multicenter, and real-world study aiming to evaluate the clinical outcomes of early switch to sirolimus-based regimens in HCC patients after LT. Patients with a histologically proven HCC and beyond the Milan criteria will be enrolled. The initial immunosuppressant regimens are center-specific for the first 4-6 weeks. The following regimens integrated sirolimus into the regimens as a combination therapy with reduced calcineurin inhibitors based on the condition of patients and centers. The study is planned for 4 years in total with a 2-year enrollment period and a 2-year follow-up. We predict that sirolimus conversion regimen will provide survival benefits for patients particular in the key indicator RFS as well as better quality of life. If the trial is conducted successfully, we will have a continued monitoring over a longer follow-up time to estimate indicator of overall survival. We hope that the outcome will provide better evidence for clinical decision-making and revising treatment guidelines based on Chinese population data. Trial register: Trial registered at http://www.chictr.org.cn: ChiCTR2100042869.

Clinically significant drug-drug interaction between tacrolimus and fluconazole in stable renal transplant recipient and literature review.

WHAT IS KNOWN AND OBJECTIVE: Clinical use of fluconazole against fungal infections in renal transplant patients is complicated by the potentially marked and unpredictable drug-drug interactions (DDIs). We report a case of tacrolimus-fluconazole DDI in a stable renal transplant recipient and describe the mechanism, magnitude and duration of this DDI through a literature review. CASE SUMMARY: A 38-year-old woman experienced a 9.1-fold increase in dose-normalized tacrolimus trough level (trough concentration/weight-normalized daily dose) and an 87% decrease in weight-normalized daily dose (daily dose/body weight) in the treatment of documented Candida albicans oesophagitis by fluconazole. After discontinuation of fluconazole for 161 day, a 26% reduction in weight-normalized daily dose was required to maintain therapeutic exposure. WHAT IS NEW AND CONCLUSION: Oral fluconazole has a more significant impact on its drug interactions with tacrolimus than intravenous fluconazole. Gene screening for CYP3A5 6986 A>G and ABCB1 3435 C>T in organ transplant recipients may help in preventing DDI and facilitating tacrolimus dose adjustment.

Determination of the complexity and diversity of the TCR ß-chain CDR3 repertoire in bladder cancer using high-throughput sequencing.

The present study aimed to investigate the complexity and diversity of the T lymphocyte immune repertoire in patients with bladder cancer. To do so, the immune state of patients was assessed. The study also aimed to elucidate the aetiology and pathogenesis of bladder cancer to provide a novel theoretical basis for disease prevention, diagnosis, treatment and prognosis monitoring. Cancerous and paracancerous (control) tissue samples were collected from five patients diagnosed with muscle-invasive bladder cancer. Multiplex polymerase chain reaction and Illumina high-throughput sequencing were used to determine the characteristics and clonal diversity of the T-cell receptor (TCR) ß-chain complementarity-determining region 3 (CDR3) gene in the cancerous and paracancerous tissues of patients with bladder cancer. The degree of clonal expansion in malignant samples was significantly higher than in adjacent samples. Furthermore, ΤCRß variable (TRBV), ΤCRß diversity (TRBD) and ΤCRß joining (TRBJ) repertoires were significantly different in cancerous samples compared with adjacent samples. In addition, 13 identified V-J pairs were highly expressed in cancerous samples whereas they had low expression in control samples. In conclusion, the degree of T-cell clonal expansion in bladder cancerous tissue was higher than in paracancerous tissue, whereas the immune diversity of the tissues of patients with bladder cancer was significantly lower. The DNA sequence and amino acid sequences, and V-J combination level may be used to comprehensively understand the diversity and characteristics of TCR CDR3 in bladder cancer and paracancerous tissues, and to evaluate the immune status of bladder cancer to develop therapeutic targets and biomarkers for prognosis monitoring.

Extending a Gray Lattice Boltzmann Model for Simulating Fluid Flow in Multi-Scale Porous Media.

A gray lattice Boltzmann model has previously been developed by the authors of this article to simulate fluid flow in porous media that contain both resolved pores and grains as well as aggregates of unresolved smaller pores and grains. In this model, a single parameter is introduced to prescribe the amount of fluid to be bounced back at each aggregate cell. This model has been shown to recover Darcy-Brinkman flow but with effective viscosity and permeability correlated through the model parameter. In this paper, we prove that the model parameter relates to the fraction of the solid phase of a sub-pore system for a specific set of bounce-back conditions. We introduce an additional parameter to the model, and this enables flow simulation in which cases with variable effective viscosity and permeability can be specified by selecting the two parameters independently. We verify and validate the model for layered channel cases and mathematically analyze fluid momentum and energy losses for the single- and two-parameter models to explain the roles of the parameters in their conservation. We introduce a strategy to upgrade our model to an isotropic version. We discuss the fundamental differences between our model and the Brinkman body-force LBM scheme.

3-D Modelling and Experimental Comparison of Reactive Flow in Carbonates under Radial Flow Conditions.

We use a two-scale continuum model to simulate reactive flow and wormhole formation in carbonate rocks under 3-D radial flow conditions. More specifically, we present a new structure-property relationship based on the fractal geometry theory, to describe the evolution of local permeability, pore radius, and specific area with porosity variation. In the numerical calculation, to improve the convergence rate, the heterogeneous medium in question is extended by adding a thin layer of homogeneous porous medium to its inlet. We compare the simulation results with the available experimental observations and find that they are qualitatively consistent with each other. Additionally, sensitivity analysis of the dissolution process with respect to acid injection rate and rock heterogeneity, including heterogeneity magnitude and correlation length, is presented.

Investigation of Growth Phase-Dependent Acid Tolerance in Bifidobacteria longum BBMN68.

The underlying mechanisms imparting the growth phase-dependent acid tolerance have not been extensively investigated. In this study, we compared the acid resistance of the Bifidobacterium longum strain BBMN68 from different growth phases at lethal pH values (pH 2.5, 3.0, and 3.5), and analyzed the activity of H(+)-ATPase, the composition of fatty acids, and the mRNA abundance of ffh, uvrA, recA, lexA, groES, and dnaK in cells from different growth phases. The results indicated that the survival rates of cells from early stationary (ES) and late stationary (LS) growth phases at lethal pH values were significantly higher than those of exponential growth phase cells. Our findings indicated that by inducing a continuously auto-acidizing environment during cell growth, the acid resistance of ES and LS cells was strengthened. The higher activity of H(+)-ATPase, the decrease in unsaturated fatty acids, and the increased expression of genes involved in DNA repair and protein protection in the cells in stationary growth phase were all implicated in the significantly increased acid resistance of ES and LS cells compared with exponential growth phase cells of the B. longum strain BBMN68.

Impact of roux-en Y gastric bypass surgery on prognostic factors of type 2 diabetes mellitus: meta-analysis and systematic review.

Our aim is to clarify the features of complete type 2 diabetes mellitus (T2DM) remission in patients who undergo Roux-en Y gastric bypass surgery, to better determine factors affecting the outcome of T2DM surgery. A search was conducted for original studies on Medline, PubMed and Elsevier from inception until October 28, 2014. All of the articles included in this study were assessed with the application of predetermined selection criteria and were divided into two groups: Roux-en Y gastric bypass surgery for T2DM patients in remission or non-remission. The meta-analysis results demonstrated that fasting C-peptide values were significantly associated with increased remission (C-peptide: 95%CI = 0.2-1.0) whereas T2DM duration, patient age, preoperative insulin use, preoperative fasting blood glucose values and preoperative glycosylated haemoglobin values were significantly associated with reduced remission (T2DM duration: 95%CI = -1.2 - -0.7; age: 95%CI = -0.5 - -0.1; percentage of preoperative insulin users: odd ratio = 0.10, 95%CI = 0.07-0.15; preoperative fasting blood glucose: 95%CI = -0.9 - -0.5; preoperative glycosylated haemoglobin: 95%CI = -1.1 - -0.4). However, the results demonstrated that body mass index was not statistically different (body mass index: 95%CI = -0.2-0.6). The results of the systematic review demonstrated that smaller waist circumference; lower total cholesterol, triglycerides and low-density lipoprotein levels, increased higher high-density lipoprotein levels, shorter cardiovascular disease history and less preoperative prevalence of hypertension contribute to the increased postoperative remission rate. Better results are obtained in younger patients with less severe diabetes, a smaller waist circumference, higher preoperative high-density lipoprotein, lower preoperative total cholesterol, triglycerides and low-density lipoprotein levels and fewer other complications of shorter durations.

A recombinant adenovirus vector encoding the light chain of human coagulation factor VII and IgG1 Fc fragment to targeting tissue factor for colorectal cancer immunotherapy in the mouse model.

PURPOSE: Over expression of tissue factor (TF) occurs in more than 50 % of colorectal cancer (CRC). Therefore, TF represents an attractive target antigen for immunotherapy in CRC. METHODS: Here, we assessed the safety and efficacy of a recombinant adenovirus vector encoding the light chain of human coagulation factor VII (hfVII-LC) and human IgG1 Fc fragment (hIgG1-Fc), termed "benc vector," by targeting TF in the mouse model with colon cancer. Benc vector was administered intravenously or intratumorally in SCID mice with TF over-expressing HT-29 colon cancer. The safety and efficacy of benc vector were observed during animal experiments. RESULTS: Complete inhibition of tumor growth (5/5) was observed not only in the intravenously injection of benc vector group but also in the intratumorally of benc vector group. We also observed a precautionary effect on lung metastases of HT-29 cells by intratumoral injection of benc vector. In the control group of animals given empty control vector, all animals (5/5) developed lung tumors and exhibited a higher number of nodules after injection with HT-29 cells via the tail vein. In contrast, only three animals (3/5) in the treatment group receiving benc vector had any observable lung metastases and a lower number of nodules. No animals died and no bleeding was observed both in treatment groups and control groups. Moreover, only moderate liver damage was detected in mice receiving benc vector by intravenous injections. CONCLUSIONS: Benc vector encoding hfVII-LC and hIgG1-Fc can effectively inhibit tumor growth and metastases in SCID mice with TF over-expressing colon cancer and shows promise as an agent for CRC immunotherapy.

SHIFT: an implementation for lattice Boltzmann simulation in low-porosity porous media.

The lattice Boltzmann (LB) method has proven to be a promising method for simulating fluid dynamics in porous media. When fluid flow in pores is the only concern, a standard LB implementation, which stores one or two sets of particle distribution functions (PDFs) for both pore and solid cells, wastes a large amount of memory, especially for low-porosity media. This paper proposes a LB implementation scheme that stores a single set of PDFs for pore cells only and therefore makes it possible to simulate flow through larger and more-realistic porous models. A unique feature of this scheme is that it decomposes all PDFs into a set of 1D arrays in such a way that each array corresponds to a set of pore cells that connect one another along a pair of opposite LB velocity directions. This allows LB propagation and a standard bounce-back rule to be realized together as one or two circular shifting operations on every array. For this reason, this scheme is called SHIFT. Although PDFs are not stored in an efficient way for LB collision operation, it is shown that the incurred overhead could be reduced by properly arranging PDF arrays according to the pore structures. A D3Q15 LB implementation of SHIFT using the lattice Bhatnagar-Gross-Krook model is applied to simulate the Stokes flow through models of four natural and synthetic rock samples with porosities ranging from about 10% to 38%. Results show that SHIFT requires 36-82 % less memory than a comparable D3Q15 LB does, which stores a single set of PDF for both pore and solid cells. SHIFT achieves minimum performances of over 11 and 3.8 mega-lattice-updates-per-second (MLUPS) for the combined propagation and bounce-back operation and the collision operation, respectively, and therefore a minimum of 2.8 MLUPS in total on a computer with one AMD Opteron 2218. The performance of the collision operation is significantly improved for all cases when a simple K -mean clustering technique is employed to rearrange PDF arrays. It is argued and shown that the number of PDF arrays per pore cell and the length frequency of PDF arrays are useful measurements on the geometry and topology of the pore structures and these characteristics are able to explain SHIFT performance variations.