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Intratumoral heterogeneity remains as a major challenge in the treatment resistance of prostate cancer. Understanding the mechanism of prostate cancer heterogeneity is essential for developing effective therapies. In this study, we reported the heterogeneous activation of Wnt/β-catenin signaling in prostate cancer. We developed a Wnt/β-catenin signaling reporting system to directly characterize the differences between Wnt/β-catenin signaling active (GFP+) and inactive (GFP-) cells. Compared to GFP- cells, GFP+ cells demonstrated cancer stem cell properties with higher colony formation efficiency, slower cell cycle, higher resistance to docetaxel and higher expression of cancer stem cell markers. In addition, we found that Wnt/β-catenin signaling is negatively correlated with H3K27me3 levels. Further studies demonstrated that Wnt/β-catenin signaling affected H3K27me3 levels by regulating the expression of KDM6A, one of the H3K27me3 demethylases. H3K27me3 suppressed Wnt/β-catenin signaling by directly silencing LEF1 promoter. Together, our studies suggest that Wnt/β-catenin signaling makes a major contribution to prostate cancer heterogeneity and targeting both Wnt/β-catenin signaling active and inactive populations is essential for developing more effective therapies.

Bile leaks are rare but potentially devastating iatrogenic or posttraumatic complications. This is being diagnosed more frequently since the advent of laparoscopic cholecystectomy and propensity toward nonsurgical management in select trauma patients. Timely recognition and accurate characterization of a bile leak is crucial for favorable patient outcomes and involves a multimodal imaging approach. Management is driven by the type and extent of the biliary injury and requires multidisciplinary cooperation between interventional radiologists, endoscopists, and hepatobiliary/transplant surgeons. Interventional radiologists have a vital role in both the diagnosis and management of bile leaks. Percutaneous interventional procedures aid in the characterization of a bile leak and in its initial management via drainage of fluid collections. Most bile leaks resolve with decompression of the biliary system which is routinely done via endoscopic retrograde cholangiopancreaticography. Some bile leaks can be definitively treated percutaneously while others necessitate surgical repair. The primary principle of percutaneous management is flow diversion away from the site of a leak with the placement of transhepatic biliary drainage catheters. While this can be accomplished with relative ease in some cases, others call for more advanced techniques. Bile duct embolization or sclerosis may also be required in cases where a leaking bile duct is isolated from the main biliary tree.

Objective To investigate the plasma fibrinogen gamma‐chain concentration in preeclampsia patients and explore its value in preeclampsia prediction and auxiliary diagnosis. Methods Follow‐up of pregnant women who regularly attended perinatal care at two hospitals in China was performed, and clinical data and plasma samples were collected at each examination until delivery. The gamma‐chain concentration was detected by Western blotting, and Quantity One Software was used for gamma‐chain grayscale value measurements. Results Forty‐two patients with preeclampsia and 42 control patients completed the follow‐up. In the control group, the gamma‐chain concentration at 32 weeks of gestation was higher than that at 20 weeks of gestation, but the difference was not statistically significant (p > 0.05). In the experimental group, the gamma‐chain concentration at preeclampsia diagnosis was significantly higher than that at 20 weeks of gestation (p, To investigate the plasma fibrinogen gamma‐chain concentration in preeclampsia patients and explore its value in preeclampsia prediction and auxiliary diagnosis. Follow‐up of pregnant women who regularly attended perinatal care at two hospitals in china was performed, and clinical data and plasma samples were collected at each examination until delivery. The gamma‐chain concentration was detected by Western blotting, and Quantity One Software was used for gamma‐chain grayscale value measurements. Forty‐two patients with preeclampsia and 42 control patients completed the follow‐up. In the control group, the gamma‐chain concentration at 32 weeks gestation was higher than that at 20 weeks gestation, but the difference was not statistically significant (p > 0.05). In the experimental group, the gamma‐chain concentration at preeclampsia diagnosis was significantly higher than that at 20 weeks gestation (p

As an important component of innate immunity, human circulating γδ T cells function in rapid responses to infections and tumorigenesis. MicroRNAs (miRNAs) play a critical regulatory role in multiple biological processes and diseases. Therefore, how the functions of circulating human γδ T cells are regulated by miRNAs merits investigation. In this study, we profiled the miRNA expression patterns in human peripheral γδ T cells from 21 healthy donors and identified 14 miRNAs that were differentially expressed between peripheral αβ T cells and γδ T cells. Of the 14 identified genes, 7 miRNAs were downregulated, including miR-150-5p, miR-450a-5p, miR-193b-3p, miR-365a-3p, miR-31-5p, miR-125b-5p and miR-99a-5p, whereas the other 7 miRNAs were upregulated, including miR-34a-5p, miR-16-5p, miR-15b-5p, miR-24-3p, miR-22-3p, miR-22-5p and miR-9-5p, in γδ T cells compared with αβ T cells. In subsequent functional studies, we found that both miR-125b-5p and miR-99a-5p downregulated γδ T cell activation and cytotoxicity to tumor cells. Overexpression of miR-125b-5p or miR-99a-5p in γδ T cells inhibited γδ T cell activation and promoted γδ T cell apoptosis. Additionally, miR-125b-5p knockdown facilitated the cytotoxicity of γδ T cells toward tumor cells in vitro by increasing degranulation and secretion of IFN-γ and TNF-α. Our findings improve the understanding of the regulatory functions of miRNAs in γδ T cell activation and cytotoxicity, which has implications for interventional approaches to γδ T cell-mediated cancer therapy.

Background: There is a lack of consensus in optimal management of portal vein thrombosis (PVT) in patients with cirrhosis. The purpose of this study is to compare the safety and thrombosis burden change for cirrhotic patients with non-tumoral PVT managed by transjugular intrahepatic portosystemic shunt (TIPS) only, anticoagulation only, or no treatment. Methods: This single-center retrospective study evaluated 52 patients with cirrhosis and non-tumoral PVT managed by TIPS only (14), anticoagulation only (11), or no treatment (27). The demographic, clinical, and imaging data for patients were collected. The portomesenteric thrombosis burden and liver function tests at early follow-up (6–9 months) and late follow-up (9–16 months) were compared to the baseline. Adverse events including bleeding and encephalopathy were recorded. Results: The overall portomesenteric thrombosis burden improved in eight (72%) TIPS patients, three (27%) anticoagulated patients, and two (10%) untreated patients at early follow-up (p = 0.001) and in seven (78%) TIPS patients, two (29%) anticoagulated patients, and three (17%) untreated patients in late follow-up (p = 0.007). No bleeding complications attributable to anticoagulation were observed. Conclusion: TIPS decreased portomesenteric thrombus burden compared to anticoagulation or no treatment for cirrhotic patients with PVT. Both TIPS and anticoagulation were safe therapies.

To investigate whether serum levels of 19 eicosanoids are associated with pre-eclampsia.A case-control study was performed using data for pregnant women with pre-eclampsia, normotensive pregnant women, and nonpregnant women, for all of whom serum samples had been collected at a hospital in Shanghai, China, between December 2012 and December 2013. Ultra-performance liquid chromatography-tandem mass spectrometry was used to measure the serum levels of 19 eicosanoids.Overall, 49 pregnant women with pre-eclampsia, 26 normotensive pregnant women, and 14 nonpregnant women were included. Women with pre-eclampsia had significantly higher serum levels of 11,12-epoxyeicosatrienoic acid (11,12-EET), the hydroxyeicosatetraenoic acids 5-HETE, 8-HETE, 12-HETE, and 15-HETE, and leukotriene B4 than did women with a normal pregnancy and nonpregnant women, both before and after the onset of pre-eclampsia (P0.01 for all comparisons). Women with severe pre-eclampsia had significantly higher serum levels of 5-HETE, 15-HETE, and leukotriene B4 than did women with mild pre-eclampsia, women with a normal pregnancy, and nonpregnant women (P0.01 for all comparisons).The eicosanoids 11,12-EET, 5-HETE, 8-HETE, 12-HETE, 15-HETE, and leukotriene B4 might play important parts in the occurrence and development of pre-eclampsia.

Circulating γδ T cells In healthy Individuals rapidly respond to bacterial and viral pathogens. Many studies have demonstrated that γδ T cells are activated and expanded by Listeria monocytogenes (L. monocytogenes), a foodborne bacterial pathogen with high fatality rates. However, the roles of γδ T cells during L. monocytogenes infection are not clear. In the present study, we characterized the morphological characteristics of phagocytosis in γδ T cells after L. monocytogenes infection using transmission electron microscopy. Results show activation markers including human leucocyte antigen DR (HLA-DR) and lymph node-homing receptor CCR7 on γδ T cells were upregulated after stimulation via L. monocytogenes. Significant proliferation and differentiation of primary αβ T cells was also observed after coculture of peripheral blood mononuclear cells with γδ T cells anteriorly stimulated by L. monocytogenes. L. monocytogenes infection decreased the percentage of γδ T cells in mouse intraepithelial lymphocytes (IELs) and increased MHC-II expression on the surface of γδ T cells in vivo. Our findings shed light on antigen presentation of γδ T cells during L. monocytogenes infection.

MicroRNAs play crucial roles in modulating immune system. miR-146a, a potent feedback suppressor of NF-κB signaling, was shown to limit the innate immune response and myelopoiesis in a knockout mouse model. Here, we observed high lymphopoiesis demonstrated as mild splenomegaly and severe lymphadenopathy in a miR-146a transgenic mouse model. Overexpression of miR-146a resulted in enhanced proliferation and reduced apoptosis of T cells. More activated CD4+ T cells or effector memory T cells were observed in transgenic mice even under physiological conditions. Importantly, as one of the key steps to generate central tolerance, the positive selection of thymocytes is impaired in transgenic mice, resulting in more CD4+CD8+ double-positive thymocytes but fewer CD4+CD8− and CD4−CD8+ single-positive thymocytes. The maturation of selected CD4−CD8+ thymocytes was also impaired, leading to more severe loss of CD4−CD8+ than CD4+CD8− thymocytes in thymus of transgenic mice. Gene expression profiling analysis identified nine positive selection-associated genes, which were downregulated in transgenic mice, including genes encoding major histocompatibility complex class I/II molecules, IL-7 receptor α chain, and Gimap4, whose downregulation may contribute to the impairment of positive selection. Gimap4 was verified as a novel target of miR-146a. These findings further extend our understanding of the function of miR-146a in T cell biology and identify a novel regulatory mechanism underlying the positive selection during T cell development.

The novel allele, A*11:264, was identified in a Chinese individual by sequence-based typing.

Combined teriparatide and denosumab increases spine and hip bone mineral density more than either drug alone. The effect of this combination on skeletal microstructure and microarchitecture, however, is unknown. Because skeletal microstructure and microarchitecture are important components of skeletal integrity, we performed high-resolution peripheral QCT assessments at the distal tibia and radius in postmenopausal osteoporotic women randomized to receive teriparatide 20-µg daily (n=31), denosumab 60-mg every 6 months (n=33), or both (n=30) for 12 months. In the teriparatide group, total volumetric BMD (vBMD) did not change at either anatomic site but increased in both other groups at both sites. The increase in vBMD at the tibia was greater in the combination group (3.1±2.2%) than both the denosumab (2.2±1.9%) and teriparatide groups (−0.3±1.9%) (p

The novel allele, HLA-B*15:388, was identified in a Chinese bone marrow donor by sequence-based typing.

In postmenopausal osteoporotic women, denosumab fully inhibits teriparatide-induced bone resorption at approved doses. This property of denosumab is distinct from that of alendronate and likely contributes to the efficacy of combination denosumab and teriparatide therapy. Whether denosumab fully inhibits bone resorption when challenged by a higher dose of teriparatide is unknown.We aimed to define the comparative ability of denosumab and alendronate to block the acute proresorptive effects of high-dose teriparatide.In this randomized controlled trial, bone resorption (serum C-telopeptide [CTX]) was measured in 25 postmenopausal women prior to and 4 hours after a single 40-μg sc teriparatide injection. Subjects then received either a single injection of denosumab 60 mg or oral alendronate 70 mg weekly for 8 weeks. After 8 weeks, serum CTX was again measured before and 4 hours after a teriparatide a 40-μg injection.The primary outcome was the between-group difference in the teriparatide-induced change in CTX from baseline to week 8.At baseline, 40 μg of teriparatide induced similar 4-hour increases in mean CTX in both groups (alendronate 47% ± 14%, denosumab 46% ± 16%). After 8 weeks, teriparatide was still able to stimulate bone resorption in women treated with alendronate (mean CTX increase of 43% ± 29%) but not in women treated with denosumab (-7% ± 11%; P.001 for between group comparison).Denosumab, but not alendronate, fully inhibits the ability of high-dose teriparatide to increase bone resorption acutely. These results suggest that combining denosumab with a more potent anabolic stimulus may result in greater separation between bone resorption and formation and hence greater increases in bone mass.

During pregnancy, disorders in uterine spiral artery remodeling (USAR) cause preeclampsia and other diseases. The aim of this study was to investigate the effect of 20-hydroxyeicosatetraenoic acid (20-HETE) on the biological behavior of human villous trophoblasts (HVTs) and human uterine vascular smooth muscle cells (HUVSMCs), and explore the role of 20-HETE in USAR. 20-HETE and its inhibitor HET0016 were used to study migration, invasion and apoptosis in the HVT and HVT-HUVSMC models. 20-HETE inhibited the migration and invasion of HVTs, and inhibited apoptosis in HUVSMCs and HUVSMCs co-cultured with HVTs. 20-HETE had thus obvious effects on the biological behavior of HVTs and HUVSMCs. These effects may cause USAR disorders and vascular dysfunction, leading to preeclampsia.

During liver resection, bleeding remains the most important challenge. A reduction in blood loss and avoiding the need for a blood transfusion are important objectives for liver surgeons today. The authors compared the intra- and postoperative course of patients undergoing laparoscopic liver resections under intermittent total pedicle occlusion (IPO), hemihepatic vascular occlusion (HVO), and selective vascular occlusion (SVO).Retrospective analysis was conducted of patient data from 41 cases of laparoscopic liver resection in three groups of patients under different occlusion methods, including 15 cases of IPO, 15 cases of HVO, and 11 cases of SVO. The advantages and disadvantages of the various methods were compared, as well as blood loss, operation time, changes in postoperative liver function, and complications.There was no operative death in any of the 41 patients. Generally, there was no significant difference among the three groups in blood loss, clamping time, or operative time. After the operation, the effect on liver function for the HVO and SVO groups was significantly less severe than that for the IPO group (P.05). The incidence of postoperative complications was mainly related to IPO and the larger amount of bleeding.Both HVO and SVO are feasible in laparoscopic hepatectomy and have the advantage of reducing liver remnant ischemia injury and modality rate over IPO. HVO is easy to do for left lateral lobe or resection of the left half of the liver. SVO is suitable for right lobe resection.