A 0D-3D multi-scale model of the portal venous system coupled with the entire cardiovascular system applied to predict postsplenectomy hemodynamic metrics.

Splenectomy is a common surgery for portal hypertensive patients with splenomegaly. Although splenectomy is able to effectively relieve the complications of portal hypertension, it also increases the risk of portal venous system thrombosis remarkably. Previous studies demonstrated that the hemodynamic metrics of the portal venous system could be employed in predicting the risk of postsplenectomy thrombosis, and 3D models were utilized to simulate the blood flow in the portal venous system. Aiming to reflect the global effect of splenectomy and better simulate the hemodynamic metrics, in this study, a 0D-3D multi-scale model of the portal venous system coupled with the entire cardiovascular system was constructed based on population-averaged data in combination with patient-specific preoperative clinical measurements. The pre- and postoperative global blood flows as well as the variations were calculated successfully, and the flow field and time-averaged wall shear stress of the portal venous system were simulated. The model-simulated spatial distributions of the hemodynamic metrics in the portal venous system were comparable with the regions suffering from thrombosis after splenectomy. These results imply that the present model could reflect the reallocation of the blood flow in the splanchnic circulation after splenectomy and simulate the hemodynamic metrics of the portal venous system, which would promote the more accurate risk stratification of postsplenectomy thrombosis and improve the patient-specific postoperative management.Clinical Relevance- The computational model developed by the present study provides a feasible scheme for simulating postsplenectomy hemodynamic metrics of the portal venous system more accurately, which would benefit the risk prediction and prophylaxis of portal venous system thrombosis for portal hypertensive patients receiving splenectomy.

Prognostic analysis and outcome of hilar cholangiocarcinoma after radical resection: a retrospective study.

OBJECTIVES: The predictive factors affecting the survival of hilar cholangiocarcinoma (HC) are ambiguous. This study aimed to identify the predictors and recurrence patterns of HC. METHODS: A retrospective analysis of the clinicopathological findings of 126 patients with HC from 2009 to 2019 was performed. RESULTS: The proportion of Bismuth I and II HC in the recurrence group was higher than that in the non-recurrence group (p < 0.01). The recurrence group had poorer tumor differentiation, a more advanced N stage, and a higher incidence of perineural invasion compared with the non-recurrence group. N stage and tumor differentiation were independently associated with disease-free and overall survival of patients (p < 0.01). Bile duct resection (BDR) combined with hepatectomy was more favorable to disease-free and overall survivals than BDR alone in Bismuth I and II HC, although p values were marginal (p = 0.072 and p = 0.045). A higher proportion of patients in the non-recurrence group underwent BDR combined with hepatectomy than that in the recurrence group (p < 0.01). CONCLUSIONS: N stage and tumor differentiation are the two independent predictors of patient survival. BDR combined with hepatectomy is recommended for patients with Bismuth I and II hilar cholangiocarcinoma.

OBJETIVOS: Los predictores que afectan a la supervivencia del colangiocarcinoma hiliar son ambiguos. Este estudio tiene como objetivo identificar los factores predictivos y los patrones de recurrencia del colangiocarcinoma hiliar. MÉTODOS: Se aplicó un análisis retrospectivo con126 pacientes con colangiocarcinoma hiliar desde 2009 hasta 2019. RESULTADOS: La proporción de colangiocarcinoma hiliar Bismuth I y II en el grupo de recurrencia fue mayor que en el grupo de no recurrencia (p < 0.01). El tumor del grupo de recidiva tenía un estadio N más avanzado que el del grupo de no recidiva. El estadio N se asocia de forma independiente con la supervivencia libre de enfermedad y global del paciente (p < 0.01). La resección de la vía biliar combinada con la hepatectomía benefició más a la supervivencia libre de enfermedad y global que la resección de la vía biliar sola en el colangiocarcinoma hiliar (p = 0.072 y p = 0.045). Una mayor proporción de pacientes se sometió a resección de la vía biliar combinada con hepatectomía en el grupo de no recidiva que en el de recidiva (p < 0.01). CONCLUSIONES: El estadio N fue el predictor independiente. Se recomienda la resección de la vía biliar combinada con hepatectomía para los pacientes con colangiocarcinoma hiliar Bismuth I y II.

Misdiagnosis and delayed diagnosis of atypical autoimmune pancreatitis: Experience from clinical cases.

Autoimmune pancreatitis (AIP) is a fibro-inflammatory disease characterized by inflammation and fibrosis of the pancreas. It is a systemic disease that can affect multiple organs, including the bile ducts, kidneys, lungs, and other organs. However, due to its complex presentation, AIP is often challenging to diagnose, and misdiagnosis with pancreatic tumors can occur. In our study, we reviewed three cases of atypical AIP where patients had normal serum IgG4 levels, leading to initial misdiagnosis with pancreatic tumors. Delayed diagnosis resulted in irreversible pathologies such as retroperitoneal fibrosis. All three patients had bile duct involvement, and imaging findings were similar to those of tumors, further complicating the diagnosis. The correct diagnosis was confirmed only after diagnostic therapy. Our study aims to raise awareness of atypical AIP and improve diagnostic efficiency by analyzing the clinical characteristics of these patients.

LITAF inhibits colorectal cancer stemness and metastatic behavior by regulating FOXO1-mediated SIRT1 expression.

Lipopolysaccharide-induced tumor necrosis factor alpha factor (LITAF) is a transcription factor that activates the transcription of TNF-α and regulates the inflammatory response. LITAF has been found to have potential anti-cancer effects of in several tumors. However, the role of LITAF in colorectal cancer (CRC) remains unclear. Through a comprehensive pan-cancer analysis of the Cancer Genome Atlas (TCGA), LITAF was identified as a differentially downregulated gene in CRC. We hypothesized that LITAF may participate in the modulation of CRC progression. The present study was aimed to investigate the expression profile of LITAF in CRC and its effect on metastatic behavior and stemness as well as the underlying molecular mechanism. The expression profile of LITAF in CRC, and its relationship with the prognosis of CRC were explored using public databases. LITAF expression was detected by quantitative real-time PCR (qRT-PCR), western blot, and immunohistochemistry. Furthermore, the effects of overexpression or knockdown of LITAF on cell proliferation, apoptosis, migration, invasion, and stemness of CRC cells were investigated in vitro. The regulatory effect of LITAF on forkhead Box O 1 (FOXO1)-sirtuin 1 (SIRT1) signaling axis was also explored. In addition, a xenograft mouse model was used to investigate the in-vivo role of LITAF. LITAF was downregulated in tumor tissues and its expression was associated with the prognosis, pathological stage and liver metastasis. In-vitro experiments confirmed that LITAF inhibited tumor cell proliferation, migration, invasion and stemness, and induced cell apoptosis. In vivo experiments demonstrated that LITAF inhibited the tumorigenicity and liver metastasis in tumor-bearing mice. Additionally, LITAF promoted FOXO1-mediated SIRT1 inhibition, thus regulating cancer stemness and malignant phenotypes. LITAF was silenced in CRC and it participated in the progression of CRC by inhibiting CRC cell stemness, and malignant phenotypes. Therefore, LITAF may serve as a novel biomarker of CRC prognosis.

The E3 ubiquitin ligase SCF (FBXW10)-mediated LATS2 degradation regulates angiogenesis and liver metastasis in colorectal cancer.

F-box and WD repeat domain containing 10 (FBXW10) is a member of the FBXW subgroup that contains the WD40 domain. FBXW10 has been rarely reported in colorectal cancer (CRC) and its mechanism is unclear. To investigate the role of FBXW10 in CRC, we conducted in vitro and in vivo experiments. Through the database and our clinical samples, we found that FBXW10 expression was up-regulated in CRC, and it was positively correlated with CD31 expression. CRC patients with high FBXW10 expression levels had a poor prognosis. Overexpression of FBXW10 up-regulated cell proliferation, migration and vascular formation, while knockdown of FBXW10 had the opposite effects. Studies on the mechanism of FBXW10 in CRC showed that FBXW10 could ubiquitinate large tumor suppressor kinase 2 (LATS2) and promote its degradation with the Fbox region of FBXW10 played an essential role in this process. In vivo studies demonstrated that knockout of FBXW10 inhibited tumor proliferation and reduced liver metastasis. In conclusion, our study proved that FBXW10 was significantly overexpressed in CRC and was involved in the pathogenesis of CRC by affecting angiogenesis and liver metastasis. Mechanistically, FBXW10 degraded LATS2 through ubiquitination. Therefore, FBXW10-LATS2 can be used as a therapeutic target for CRC in subsequent studies.

Dissecting cellular heterogeneity and intercellular communication in cholangiocarcinoma: implications for individualized therapeutic strategies.

Background: Cholangiocarcinoma is characterized by significant cellular heterogeneity and complex intercellular communication, which contribute to its progression and therapeutic resistance. Therefore, unraveling this complexity is essential for the development of effective treatments. Methods: We employed single-cell RNA sequencing (scRNA-seq) to investigate cellular heterogeneity and intercellular communication in cholangiocarcinoma and adjacent normal tissues from two patients. Distinct cell types were identified, and gene ontology analyses were conducted to determine enriched pathways. Moreover, cell-cell communications were analyzed using CellChat, a computational framework. Additionally, we performed sub-clustering analysis of T cells and fibroblasts. Results: The scRNA-seq analysis revealed distinct cell clusters and diverse cellular compositions of cholangiocarcinoma. CellChat analysis underscored an amplified outgoing signal from fibroblasts within the tumor, suggesting their pivotal role in the tumor microenvironment. Furthermore, T cell sub-clustering analysis revealed an active immune response within the tumor and new tumor-specific T cell clonotypes, suggesting scope for targeted immunotherapies. Moreover, fibroblast sub-clustering analysis indicated distinct functional states and highlighted the role of activated fibroblasts in shaping intercellular communication, particularly via CD99 and FN1 signaling. Conclusion: Our findings reveal the intricate cellular heterogeneity and dynamic intercellular communication in cholangiocarcinoma, providing valuable insights into disease progression and potential therapeutic strategies.

Analysis of lymph node spread and its prognostic significance in ampullary adenocarcinoma: A retrospective study.

Background: Nodal status is a vital prognostic factor for ampullary adenocarcinoma. This study was designed to evaluate the clinical significance of the positive nodes in this disease. Methods: Data from 110 patients who underwent curative pancreatoduodenectomy for ampullary adenocarcinoma between January 2007 and December 2018 were retrospectively collected and analyzed. Results: The median number of lymph nodes per patient was 32 (20-46). Metastatic lymph nodes were found in 84 (76.4%) patients. In patients with positive nodules, the most commonly involved nodes were the #13 (80.1%) and #17 (78.6%) nodes, followed by #12 (69.0%) and #8 nodes (57.1%). Patients with 3-4 positive nodes among #13, #17, #12, and #8 had lower survival rates than those with 0 or 1-2 nodes. Conclusion: Ampullary adenocarcinoma commonly spreads to #13, #17, #12, and #8 lymph nodes. These nodes affected the patients' survival rates dramatically.

Predicting the risk of postsplenectomy thrombosis in patients with portal hypertension using computational hemodynamics models: A proof-of-concept study.

BACKGROUND: The high incidence of thrombosis in the portal venous system following splenectomy (a frequently adopted surgery for treating portal hypertension in patients with splenomegaly and hypersplenism) is a critical clinical issue. The aim of this study was to address whether quantification of postsplenectomy hemodynamics has potential value for assessing the risk of postsplenectomy thrombosis. METHODS: Computational models were constructed for three portal hypertensive patients treated with splenectomy based on their preoperative clinical data to quantify hemodynamics in the portal venous system before and after splenectomy, respectively. Each patient was followed up for three or five months after surgery and examined with CT to screen potential thrombosis. FINDINGS: The area ratio of wall regions exposed to low wall shear stress was small before splenectomy in all patients, which increased markedly after splenectomy and exhibited enlarged inter-patient differences. The largest area ratio of low wall shear stress and most severe flow stagnation after splenectomy were predicted for the patient suffering from postsplenectomy thrombosis, with the wall regions exposed to low wall shear stress corresponding well with the CT-detected distribution of thrombus. Further analyses revealed that postoperative hemodynamic characteristics were considerably influenced by the anatomorphological features of the portal venous system. INTERPRETATION: Postoperative hemodynamic conditions in the portal venous system are highly patient-specific and have a potential link to postsplenectomy thrombosis, which indicates that patient-specific hemodynamic studies may serve as a complement to routine clinical assessments for refining risk stratification and postoperative patient management.

Outcomes of adolescent and young patients with hepatocellular carcinoma after curative liver resection: a retrospective study.

BACKGROUND: The risk of HCC is documented to be age-related. The outcomes of young HCC patients on postoperative prognosis are not well understood. The study aims to compare the characteristic differences between adolescent and young (AYA) and non-AYA HCC patients. METHODS: We performed a retrospective analysis of the clinical and pathological findings and the survival of 243 HCC patients who underwent operations between 2007 and 2018. RESULTS: The AYA group had a higher AFP level and a higher prevalence of family history of HCC or other cancers than the non-AYA group (P < 0.01 and P < 0.05). AYA patients had more unfavorable pathological characteristics including bigger lesion size, microvascular invasion, portal vein invasion, and hepatic capsule invasion. They also had a more unfavorable Edmondson grade and less tumor capsule formation (P < 0.01). Age was an independent predictor of survival in HCC patients. AYA patients had poorer disease-free and overall survival than non-AYA patients did (P < 0.01). Patients under 30 years old had an even poorer disease-free survival than those aged 30-40 (P = 0.047). CONCLUSIONS: AYA patients exhibited a higher recurrence rate and disease-related death rate with more unfavorable pathological characteristics. Enhanced follow-up for young HCC patients should be applied.

Predictors and Recurrence Patterns After Radical Surgery in Ampulla of Vater Cancer: Comparative Analysis Between Early and Late Recurrence.

Objective: Tumor recurrence remains the main dilemma after surgical treatment of ampulla of Vater carcinoma. This study was designed to identify the prognostic factors and evaluate the recurrence patterns of ampulla of Vater cancer. Methods: A total of 286 patients who underwent surgical resection of ampulla of Vater cancer in two medical centers from January 2000 to October 2016 were collected. Data on clinicopathologic factors, survival rate, and recurrence patterns were retrospectively analyzed. Results: A total of 158 patients (55.2%) survived without evidence of recurrence (non-recurrence), whereas 65 (22.7%) and 63 patients (22.1%) suffered from recurrence of the disease within 12 months (early recurrence) and after 12 months (late recurrence), respectively. Early-recurrence patients exhibited a more advanced disease (advanced tumor stage, lymph node involvement, pancreas invasion, and late TNM stage) than late-recurrence patients. The first or primary location of cancer recurrence in 33 patients (25.8%) was locoregional. Metastasis developed in the liver in 30 patients (23.4%), peritoneum in 13 patients (10.2%), lungs in 10 patients (7.8%), and para-aortic or superior mesenteric artery lymph node in 10 patients (7.8%). Multiple metastases were observed in 26 patients (20.3%). Conclusion: The most common patterns of postoperative recurrence are locoregional and recurrent liver metastasis. The recurrence patterns with the worst prognosis are peritoneal and multiple metastases.

m5 C and m6 A modification of long noncoding NKILA accelerates cholangiocarcinoma progression via the miR-582-3p-YAP1 axis.

Cholangiocarcinoma (CCA) is a severe malignancy originating from the bile duct and the second most common primary liver cancer. NF-kappa B interacting lncRNA (NKILA) is a functional lncRNA, which play important role in human cancers. However, the role and underlying mechanism of NKILA in CCA remains largely unknown. Here, our study demonstrated that NKILA was significantly upregulated in CCA tissues and cells. Overexpression of NKILA is associated with advanced TNM stage, lymph node and distant metastasis, and also indicated poor prognosis in CCA patients. Functionally, NKILA facilitated CCA growth and metastasis in vitro and in vivo. The 5-methylcytosine (m5 C) methyltransferase NSUN2 interacts with NKILA, increasing its m5 C level and promoting its interaction with YBX1. Moreover, NKILA physically interacted with and suppressed miR-582-3p, which was regulated by METTL3-mediated N6 -methyladenosine (m6 A) modification. Finally, we showed that YAP1 was a target of NKILA via miR-582-3p and NKILA functioned partially via YAP1 in CCA. Taken together, our findings indicate a novel regulatory mechanism of NKILA for promoting CCA progression and that NKILA may be a promising target for CCA treatment.

Changes in Fat Oxidation and Body Composition after Combined Exercise Intervention in Sedentary Obese Chinese Adults.

(1) Background: Evidence suggests that aerobic exercise and high-intensity interval training (HIIT) might increase fat oxidation and reduce fat. However, limited research has examined the effects of combining progressive aerobic exercise and HIIT interventions in sedentary adults with overweight and obesity, and differences in its effects between men and women remain unclear. The purpose of this study was to investigate the effects of combined progressive aerobic exercise and HIIT (CAEH) on fat oxidation and fat reduction in sedentary Chinese adults and compare sex differences in sedentary adults after seven weeks. (2) Methods: Eighty-four sedentary obese adults were enrolled and allocated to two groups in baseline (experimental (EXP) group:42; control (CON) group:42), and fifty-six subjects (EXP:31; CON:25) completed the experiments and were included in the final analysis. Subjects in the EXP group performed CAEH three times per week for seven weeks. Subjects in the CON group were advised to continue with their normal daily activities. Anthropometric, lipid profile, cardiorespiratory fitness, and fat oxidation outcomes were assessed before and after the intervention. (3) Results: After seven weeks of the CAEH intervention, compared with the CON group, the EXP group showed significant increases in fat oxidation at rest (FO_rest) (+0.03 g/min, p < 0.01), maximal fat oxidation (MFO) (+0.05 g/min, p < 0.01), and maximal oxygen intake (VO2max) (+3.2 mL/kg/min, p < 0.01). The changes in the percentages of the FO_rest (+57%) and the VO2max (+16%) were significantly greater (+20%, +6%) in males than in females (p < 0.05, p < 0.05). The body mass index (BMI) (-1.2 kg/m2, p < 0.01), body fat percentage (-3.2%, p < 0.001), visceral fat area (-12.8 cm2, p < 0.001), and total cholesterol (TC) levels (-0.4 mmol/L, p < 0.05) were significantly decreased in the EXP group. (4) Conclusions: Seven weeks of the CAEH intervention effectively improved FO_rest, MFO, and VO2max in sedentary obese adults, and the improvements in FO_rest and VO2max were more pronounced in males than in females. CAEH also improved body composition and TC levels in sedentary obese adults.

Influences of Anatomorphological Features of the Portal Venous System on Postsplenectomy Hemodynamic Characteristics in Patients With Portal Hypertension: A Computational Model-Based Study.

Splenectomy, as an effective surgery for relieving complications caused by portal hypertension, is often accompanied by a significantly increased incidence of postoperative thrombosis in the portal venous system (PVS). While the underlying mechanisms remain insufficiently understood, the marked changes in hemodynamic conditions in the PVS following splenectomy have been suggested to be a potential contributing factor. The aim of this study was to investigate the influences of the anatomorphological features of the PVS on hemodynamic characteristics before and after splenectomy, with emphasis on identifying the specific anatomorphological features that make postoperative hemodynamic conditions more clot-promoting. For this purpose, idealized computational hemodynamics models of the PVS were constructed based on general anatomical structures and population-averaged geometrical parameters of the PVS. In the models, we incorporated various anatomorphological variations to represent inter-patient variability. The analyses of hemodynamic data were focused on the spatial distribution of wall shear stress (WSS) and the area ratio of wall regions exposed to low WSS (ALS). Obtained results showed that preoperative hemodynamic conditions were comparable among different models in terms of space-averaged WSS and ALS (all were small) irrespective of the considerable differences in spatial distribution of WSS, whereas, the inter-model differences in ALS were significantly augmented after splenectomy, with the value of ALS reaching up to over 30% in some models, while being smaller than 15% in some other models. Postoperative ALS was mainly determined by the anatomical structure of the PVS, followed by some morphogeometrical parameters, such as the diameter and curvature of the splenic vein, and the distance between the inferior mesenteric vein and splenoportal junction. Relatively, the angles between tributary veins and trunk veins only had mild influences on ALS. In addition, a marked increase in blood viscosity was predicted after splenectomy, especially in regions with low WSS, which may play an additive role to low WSS in initiating thrombosis. These findings suggest that the anatomical structure and some morphogeometrical features of the PVS are important determinants of hemodynamic conditions following splenectomy, which may provide useful clues to assessing the risk of postsplenectomy thrombosis based on medical imaging data.

Characterization of B cell-mediated PD-1/PD-L1 interaction in pancreatic cancer patients.

Pancreatic ductal adenocarcinoma (PDAC) is a common type of pancreatic cancer with one of the worst survival rate of all malignancies. Recent studies have identified that immunosuppressive B cells could employ the PD-1/PD-L1 pathway to suppress antitumour T cell responses; hence, we examined the expression and function of PD-L1 in B cells. We found that the PD-L1 expression was significantly enriched in tumour-infiltrating (TI) B cells than in peripheral blood (PB) B cells from the same patients. Additionally, the PB B cells from stage III and stage IV PDAC patients presented significantly higher PD-L1 than the PB B cells from healthy controls. High PD-L1 expression in PB B cells could be achieved by stimulation via CpG and less effectively via anti-BCR plus CD40L, but not by coculture with pancreatic cancer cell lines in vitro. Also, STAT1 and STAT3 inhibition significantly suppressed PD-L1 upregulation in stimulated B cells. CpG-stimulated PB B cells could inhibit the IFN-γ expression and proliferation of CD8 T cells in a PD-L1-dependent manner. Also, TI CD8 T cells incubated with whole TI B cells presented significantly lower IFN-γ expression and lower proliferation, than TI CD8 T cells incubated with PD-L1+  cell-depleted TI B cells, suggesting that PD-L1+  B cells could also suppress CD8 T cells in the tumour. Overall, this study identified that B cells could suppress CD8 T cells via PD-L1 expression, indicating a novel pathway of immuno-regulation in pancreatic cancer.

Global sensitivity analysis of hepatic venous pressure gradient (HVPG) measurement with a stochastic computational model of the hepatic circulation.

Hepatic venous pressure gradient (HVPG) is a widely employed surrogate of portal pressure gradient (PPG) in the diagnosis of portal hypertension (PHT). However, little is known about how HVPG measurement is affected by the complex vascular changes associated with PHT. In this study, we employed a computational method to quantitatively evaluate the sensitivity of HVPG measurement to various vascular factors involved in the development of sinusoidal PHT, aiming to provide a theoretical reference to guide the clinical application of HVPG measurement. The method consisted of developing a lumped-parameter model of the hepatic circulation to simulate HVPG measurement, stochastic parameter sampling used to represent a wide range of pathological conditions, and global sensitivity analysis performed to identify factors that dominate the accuracy of HVPG measurement. The major findings included 1) presinusoidal portal vascular resistance (Rpxs) and splanchnic vascular resistance (Rspl) were the major factors determining the relative difference (EHVPG) between HVPG and PPG; 2) hepatic arteriolar resistance and portosystemic collateral resistance had little influence on EHVPG although they relate closely to the severity of PHT; and 3) postsinusoidal vascular resistance (Rpts) only mildly affected EHVPG, despite its marked influence on HVPG and PPG. Moreover, stochastic simulations calibrated to HVPG/PPG data measured in a patient cohort revealed that misdiagnosis of clinically significant PHT with HVPG was more likely to occur in the presence of high Rspl combined with low Rpxs and Rpts. These findings suggest that understanding patient-specific vascular conditions can help to improve the application or interpretation of HVPG measurement.

MicroRNA-542-3p functions as a tumor suppressor via directly targeting survivin in hepatocellular carcinoma.

MicroRNA-542-3p (miR-542-3p) functions as a tumor suppressor in many human cancers, but its biological roles in hepatocellular carcinoma (HCC) remains to be further explored. In our study, we revealed that miR-542-3p was frequently down-expressed in HCC cell lines and tissues using real-time quantitative reverse-transcription PCR (qRT-PCR). Overexpression of miR-542-3p inhibits the proliferation of HCC cells via induction of apoptosis and cell cycle arrest. Furthermore, we confirmed that survivin was a direct target of miR-542-3p in HCC cells, and overexpression of survivin attenuated the miR-542-3p-induced inhibition of HCC cell proliferation. A negative association between miR-542-3p and survivin mRNA levels was also found in HCC tissues. These findings showed that miR-542-3p inhibits the proliferation of HCC cells by targeting survivin, indicating that miR-542-3p/survivin signaling axis might serve as a potential therapeutic target in the treatment of HCC.

A computational model of the hepatic circulation applied to analyze the sensitivity of hepatic venous pressure gradient (HVPG) in liver cirrhosis.

Measurement of hepatic venous pressure gradient (HVPG) is currently widely adopted to provide an estimate of portal pressure gradient (PPG) in the diagnosis and treatment of portal hypertension associated with liver cirrhosis. Despite the well-documented clinical utility of HVPG, it remains poorly understood how the relationship between HVPG and PPG is affected by factors involved in the pathogenesis and progression of cirrhosis. In the study, a computational model of the hepatic circulation calibrated to in vivo data was developed to simulate the procedure of HVPG measurement and quantitatively investigate the error of HVPG relative to PPG under various pathophysiological conditions. Obtained results confirmed the clinical consensus that HVPG is applicable to the assessment of portal hypertension caused by increased vascular resistance located primarily at the sinusoidal and postsinusoidal sites rather than at the presinusoidal site. On the other hand, our study demonstrated that the accuracy of HVPG measurement was influenced by many factors related to hepatic hemodynamics even in the case of sinusoidal portal hypertension. For instance, varying presinusoidal portal vascular resistance significantly altered the difference between HVPG and PPG, while an enhancement in portosystemic collateral flow tended to improve the accuracy of HVPG measurement. Moreover, it was found that presinusoidal and postsinusoidal vascular resistances interfered with each other with respect to their influence on HVPG measurement. These findings suggest that one should take into account patient-specific pathological conditions in order to achieve a better understanding and utilization of HVPG in the clinical practice.

Circulating follicular helper T cells presented distinctively different responses toward bacterial antigens in primary biliary cholangitis.

Primary biliary cholangitis (PBC) is a chronic and progressive cholestatic liver disease with unknown causes. The initiation of PBC is associated with bacterial infections and abnormal immune correlates, such as the presence of self-reactive anti-mitochondrial antibodies and shifted balance of T cell subsets. In particular, the CD4+CXCR5+ follicular helper T (Tfh) cells are highly activated in PBC patients and are significantly associated with PBC severity, but the underlying reasons are unknown. In this study, we found that the circulating CD4+CXCR5+ T cells were enriched with the interferon (IFN)-γ-secreting Th1-subtype and the interleukin (IL)-17-secreting Th17-subtype, but not the IL-4-secreting Th2 subtype. We further demonstrated that a host of microbial motifs, including Pam3CSK4, poly(I:C), LPS, imiquimod, and CpG, could significantly stimulate IFN-γ, IL-17, and/or IL-21 from circulating CD4+CXCR5+ T cells in PBC patients, especially in the presence of monocytes and B cells. Whole bacterial cells of Escherichia coli, Novosphingobium aromaticivorans, and Mycobacterium gordonae, could also potently stimulate IFN-γ, IL-17, and/or IL-21 production from circulating CD4+CXCR5+ T cells. But interestingly, while the whole cell could potently stimulate circulating CD4+CXCR5+ T cells from both healthy controls and PBC patients, the cell protein lysate could only potently stimulate circulating CD4+CXCR5+ T cells from PBC patients, but not those from healthy controls, suggesting that circulating CD4+CXCR5+ T cells in PBC patients had distinctive antigen-specificity from those in healthy individuals. Together, these data demonstrated that bacterial antigen stimulation is a potential source of aberrant Tfh cell activation in PBC patients.

Folate-conjugated and pH-responsive polymeric micelles for target-cell-specific anticancer drug delivery.

In this study, we developed a folate (FA)-conjugated and pH-responsive active targeting micellar system for anti-cancer drug delivery. In this system, FA was attached to the terminal of the hydrophilic segment of poly(lactic acid)-poly(L-lysine) (PLA-PLL), and PLL was modified by a citric acid group. The FA receptor-mediated active targeting and electrostatic interaction between micelles and cell membrane due to a negative-to-positive charge reversal was combined in one micellar anti-cancer drug delivery system to enhance the tumour targeting and cellular internalisation of micelles. In vitro and in vivo anti-cancer studies demonstrated that the doxorubicin-loaded, FA-conjugated and pH-responsive polymeric micelles possess an enhanced and effective cancer efficiency. STATEMENT OF SIGNIFICANCE: Negatively charged nano-carriers prolonged anti-cancer drugs' blood circulation. However it is difficult to be internalised. Therefore, a negative-to-positive charged micelle surface could improve selectivity for tumour cells and increase uptake chance. In this study, we developed a folate (FA)-conjugated and pH-responsive active targeting micellar system for anti-cancer drug delivery. The FA receptor-mediated active targeting and electrostatic interaction between micelles and cell membrane due to a negative-to-positive charge reversal was combined in one micellar anti-cancer drug delivery system to enhance the tumour targeting and cellular internalisation of micelles. In vitro and in vivo anti-cancer studies demonstrated that the doxorubicin-loaded, FA-conjugated and pH-responsive polymeric micelles possess an enhanced and effective cancer efficiency.

MicroRNA-191 acts as a tumor promoter by modulating the TET1-p53 pathway in intrahepatic cholangiocarcinoma.

Current treatment of intrahepatic cholangiocarcinoma (ICC) remains ineffective because knowledge of ICC carcinogenesis is unclear. Increasing evidence suggests that microRNAs (miRNAs), including miR-191, play an important role in tumorigenesis; but expression and biological functions of miR-191 in ICC remain to be established. This study investigated the functions and underlying mechanisms of miR-191 in ICC. ICC miRNA profiles were generated in five pairs of ICC and matched to normal bile duct tissues by next-generation sequencing technology; ICC miRNA profiles were verified in 18 pairs of ICC tissues and normal bile duct tissues by quantitative RT-PCR. The miR-191-associated mechanisms in ICC were investigated in vitro and in vivo, and clinical outcomes associated with miR-191 were correlated in 84 patients. Our results showed that miR-191 expression was significantly increased in ICC compared with the adjacent normal bile duct tissues (P < 0.001). Overexpression of miR-191 promoted proliferation, invasion, and migration of cholangiocarcinoma cells in vitro and in vivo. The elevated miR-191 expression reduced the expression level of ten-eleven translocation 1 (TET1)-a direct target gene of miR-191 in ICC, which catalyzes demethylation. The reduced TET1 expression level allowed the methylated CpG-rich regions at the p53 gene transcription start site stay methylated, leading to reduced p53 expression level, which compromises p53's anticancer vigor. Finally, miR-191 was found to be an independent risk factor for poor prognosis in patients with ICC (overall survival, hazard ratio = 3.742, 95% confidence interval 2.080-6.733, P < 0.001; disease-free survival, hazard ratio = 2.331, 95% confidence interval 1.346-4.037, P = 0.003). CONCLUSION: Our results suggest that overexpressed miR-191 is associated with ICC progression through the miR-191/TET1/p53 pathway. (Hepatology 2017;66:136-151).