Sevelamer reverses liver fibrosis by deactivation of hepatic stellate cells.

Liver fibrosis is a chronic liver disease characterized by a progressive wound healing response caused by chronic liver injury. Currently, there are no approved clinical treatments for liver fibrosis. Sevelamer is used clinically to treat hyperphosphatemia and has shown potential therapeutic effects on liver diseases. However, there have been few studies evaluating the therapeutic effects of sevelamer on liver fibrosis, and the specific mechanisms are still unclear. In this study, we investigated the antifibrotic effects of sevelamer-induced low inorganic phosphate (Pi) stress in vitro and in vivo and analyzed the detailed mechanisms. We found that low Pi stress could inhibit the proliferation of activated hepatic stellate cells (HSCs) by promoting apoptosis, effectively suppressing the migration and epithelial-mesenchymal transition (EMT) of hepatic stellate cells. Additionally, low Pi stress significantly increased the antioxidant stress response. It is worth noting that low Pi stress indirectly inhibited the activation and migration of HSCs by suppressing transforming growth factor ß (TGF-ß) expression in macrophages. In a rat model of liver fibrosis, oral administration of sevelamer significantly decreased blood phosphorus levels, improved liver function, reduced liver inflammation, and increased the antioxidant stress response in the liver. Our study revealed that the key mechanism by which sevelamer inhibited liver fibrosis involved binding to gastrointestinal phosphate, resulting in a decrease in blood phosphorus levels, the downregulation of TGF-ß expression in macrophages, and the inhibition of HSC migration and fibrosis-related protein expression. Therefore, our results suggest that sevelamer-induced low Pi stress can attenuate hepatic stellate cell activation and inhibit the progression of liver fibrosis, making it a potential option for the treatment of liver fibrosis and other refractory chronic liver diseases.

Th2-skewed peripheral T-helper cells drive B-cells in allergic bronchopulmonary aspergillosis.

INTRODUCTION: Patients with allergic bronchopulmonary aspergillosis (ABPA) suffer from repeated exacerbations. The involvement of T-cell subsets remains unclear. METHODS: We enrolled ABPA patients, asthma patients and healthy controls. T-helper type 1 (Th1), 2 (Th2) and 17 (Th17) cells, regulatory T-cells (Treg) and interleukin (IL)-21+CD4+T-cells in total or sorted subsets of peripheral blood mononuclear cells and ABPA bronchoalveolar lavage fluid (BALF) were analysed using flow cytometry. RNA sequencing of subsets of CD4+T-cells was done in exacerbated ABPA patients and healthy controls. Antibodies of T-/B-cell co-cultures in vitro were measured. RESULTS: ABPA patients had increased Th2 cells, similar numbers of Treg cells and decreased circulating Th1 and Th17 cells. IL-5+IL-13+IL-21+CD4+T-cells were rarely detected in healthy controls, but significantly elevated in the blood of ABPA patients, especially the exacerbated ones. We found that IL-5+IL-13+IL-21+CD4+T-cells were mainly peripheral T-helper (Tph) cells (PD-1+CXCR5-), which also presented in the BALF of ABPA patients. The proportions of circulating Tph cells were similar among ABPA patients, asthma patients and healthy controls, while IL-5+IL-13+IL-21+ Tph cells significantly increased in ABPA patients. Transcriptome data showed that Tph cells of ABPA patients were Th2-skewed and exhibited signatures of follicular T-helper cells. When co-cultured in vitro, Tph cells of ABPA patients induced the differentiation of autologous B-cells into plasmablasts and significantly enhanced the production of IgE. CONCLUSION: We identified a distinctly elevated population of circulating Th2-skewed Tph cells that induced the production of IgE in ABPA patients. It may be a biomarker and therapeutic target for ABPA.

Prediction model of no-response before the first transarterial chemoembolization for hepatocellular carcinoma: TACF score.

Previous clinic models for patients with hepatocellular carcinoma (HCC) receiving transarterial chemoembolization (TACE) mainly focused on the overall survival, whereas a simple-to-use tool for predicting the response to the first TACE and the management of risk classification before TACE are lacking. Our aim was to develop a scoring system calculated manually for these patients. A total of 437 patients with hepatocellular carcinoma (HCC) who underwent TACE treatment were carefully selected for analysis. They were then randomly divided into two groups: a training group comprising 350 patients and a validation group comprising 77 patients. Furthermore, 45 HCC patients who had recently undergone TACE treatment been included in the study to validate the model's efficacy and applicability. The factors selected for the predictive model were comprehensively based on the results of the LASSO, univariate and multivariate logistic regression analyses. The discrimination, calibration ability and clinic utility of models were evaluated in both the training and validation groups. A prediction model incorporated 3 objective imaging characteristics and 2 indicators of liver function. The model showed good discrimination, with AUROCs of 0.735, 0.706 and 0.884 and in the training group and validation groups, and good calibration. The model classified the patients into three groups based on the calculated score, including low risk, median risk and high-risk groups, with rates of no response to TACE of 26.3%, 40.2% and 76.8%, respectively. We derived and validated a model for predicting the response of patients with HCC before receiving the first TACE that had adequate performance and utility. This model may be a useful and layered management tool for patients with HCC undergoing TACE.

Heterozygous CARD9 mutation favors the development of allergic bronchopulmonary aspergillosis.

BACKGROUND: Previous research demonstrated that a homozygous mutation of g.136372044G>A (S12N) in caspase recruitment domain family member 9 ( CARD9 ) is critical for producing Aspergillus fumigatus -induced ( Af -induced) T helper 2 (T H 2)-mediated responses in allergic bronchopulmonary aspergillosis (ABPA). However, it remains unclear whether the CARD9S12N mutation, especially the heterozygous occurrence, predisposes the host to ABPA. METHODS: A total of 61 ABPA patients and 264 controls (including 156 healthy controls and 108 asthma patients) were recruited for sequencing the CARD9 locus to clarify whether patients with this heterozygous single-nucleotide polymorphisms are predisposed to the development of ABPA. A series of in vivo and in vitro experiments, such as quantitative real-time polymerase chain reaction, flow cytometry, and RNA isolation and quantification, were used to illuminate the involved mechanism of the disease. RESULTS: The presence of the p.S12N mutation was associated with a significant risk of ABPA in ABPA patients when compared with healthy controls and asthma patients, regardless of Aspergillus sensitivity. Relative to healthy controls without relevant allergies, the mutation of p.S12N was associated with a significant risk of ABPA (OR: 2.69 and 4.17 for GA and AA genotypes, P = 0.003 and 0.029, respectively). Compared with patients with asthma, ABPA patients had a significantly higher heterozygous mutation (GA genotype), indicating that p.S12N might be a significant ABPA-susceptibility locus ( aspergillus sensitized asthma: OR: 3.02, P = 0.009; aspergillus unsensitized asthma: OR: 2.94, P = 0.005). The mutant allele was preferentially expressed in ABPA patients with heterozygous CARD9S12N , which contributes to its functional alterations to facilitate Af -induced T H 2-mediated ABPA development. In terms of mechanism, Card9 wild-type ( Card9WT ) expression levels decreased significantly due to Af -induced decay of its messenger RNA compared to the heterozygous Card9S12N . In addition, ABPA patients with heterozygous CARD9S12N had increased Af -induced interleukin-5 production. CONCLUSION: Our study provides the genetic evidence showing that the heterozygous mutation of CARD9S12N , followed by allele expression imbalance of CARD9S12N , facilitates the development of ABPA.

KLF14/miR-1283/TFAP2C axis inhibits HER2-positive breast cancer progression via declining tumor cell proliferation.

MiR-1283 has been identified as a tumor suppressor in some malignancies. Whereas, the role of miR-1283 in HER2-positive (HER2+) breast cancer, particularly its role in regulating cell proliferation, one of the most significant features of tumor progression, is unclear. The related microRNA screened by the breast cancer sample GSE131599 dataset were detected in HER2+ breast cancer tissues and cell lines. Then, the obtained miR-1283 was overexpressed in SKBR3 and BT-474 cells followed by relevant functional assays concerning cell proliferation and apoptosis. The xenograft mouse model was induced and the effect of miR-1283 on tumor growth and cell proliferation was examined. The target of miR-1283 and the transcription factor regulating miR-1283 were predicted and identified. Finally, the influence of transcription factor KLF14 on cell proliferation and apoptosis was investigated. An integrated analysis confirmed that miR-1283 expression was significantly decreased in HER2+ breast cancer tissues. Also, by q-RT-PCR detection, miR-1283 expression was markedly reduced in HER2+ breast cancer tissues and cell lines. The miR-1283 overexpression prevented the proliferation and enhanced apoptosis of HER2+ breast cancer cells, as well as inhibited tumor growth. Mechanistically, miR-1283 inhibited TFAP2C expression by targeting the 3'-untranslated regions of TFAP2C messenger RNA, and the KLF14 enhanced miR-1283 level via binding to its promoter. The result subsequently confirmed the KLF14/miR-1283 signaling suppressed cell proliferation in HER2+ breast cancer. Our results suggested that the KLF14/miR-1283/TFAP2C axis inhibited HER2+ breast cancer progression, which might provide novel insight into mechanical exploration for this disease.

MRI-based radiomics nomogram in patients with high-risk placenta accreta spectrum: can it aid in the prenatal diagnosis of intraoperative blood loss?

PURPOSE: To develop and validate the nomogram by combining MRI-derived radiomics and clinical features for preoperatively predicting massive intraoperative blood loss (IBL) in high-risk placenta accreta spectrum (PAS) patients. METHODS: A total of 152 high-risk PAS patients from Hospital A were enrolled and constituted the training cohort, and 64 patients from Hospital B constituted the validation cohort. Clinical features were analyzed retrospectively. Placental regions of interest were manually positioned on sagittal T2-weighted HASTE images for each patient to extract quantitative radiomics features. Clinical model, radiomics model, and nomogram were built to predict the risk of massive IBL. The diagnostic performance was assessed using the area under the receiver operating characteristic curve (AUC) and the DeLong test. Decision curve analysis (DCA) was performed to determine the performance of the best predictive model. RESULTS: The nomogram (AUC = 0.866 and 0.876, respectively) and radiomics model (AUC = 0.821 and 0.855, respectively) outperformed the clinical model (AUC = 0.685 and 0.619, respectively) both in the training and validation cohorts (Delong test, P < 0.05). Furthermore, the nomogram performed best with an accuracy of 0.844, sensitivity of 0.882, and specificity of 0.830 for differentiating massive IBL in the validation cohort. DCA confirmed the clinical utility of the nomogram. CONCLUSION: The nomogram can be used to noninvasively predict massive IBL patients and guide obstetricians to make reasonable preoperative treatment plans.

Evaluation of the safety and efficacy of transarterial sevelamer embolization in a rabbit liver cancer model: A challenge on the size rule for vascular occlusion.

As the most efficient method to treat hepatocellular carcinoma in the immediate or advanced stage, transarterial chemoembolization (TACE) is coming into the era of microsphere (MP). Drug-eluting beads have shown their huge potential as an embolic agent and drug carrier for chemoembolization, but their sizes are strictly limited to be above 40 µm, which was considered to occlude vessels in a safe mode. microsphere smaller than 40 µm is easy to be washed out and transported to the normal liver lobe or other organs, causing severe adverse events and failed embolization. To determine whether sevelamer ultrafine particle (0.2-0.5 µm) is qualified as a safe and efficient embolic agent, we investigated the safety and therapeutic efficiency of transarterial sevelamer embolization (TASE) in the VX2 rabbit liver cancer model, aiming to challenge the "40 µm" rule on the selection criteria of the MP. In a four-arm study, blank bead (Callisphere, 100-300 µm), luminescent polystyrene microsphere (10, 100 µm), and sevelamer particle were transarterially administered to evaluate the threshold size of the MP size for intrahepatic or extrahepatic permeability. Another four-arm study was designed to clarify the safety and efficiency of preclinical transarterial sevelamer embolizationTASE tests over other techniques. Sham (saline), TASE, C-TACE, and D-TACE (n = 6) were compared in terms of serum chemistry, histopathology, and tumor necrosis ratio. In the first trials, the "40 µm" rule was detectable on the VX2 cancer model, but the regulation has no application to the new embolic agent as sevelamer ultrafine particles have not been found to leak out from the VX2 lesions, only found in the embolized vessels. Pathology proves that less viable tumor residue was found 2 weeks after the procedure, evidencing a better therapeutic outcome. No adverse events were found except for a short stress response. These results indicate that sevelamer is a safe and efficient embolic as an alternative to the current MP-based embolization therapy techniques.

Sevelamer arsenite nanoparticle as a Pi-responsive drug carrier and embolic agent for chemoembolization.

Arsenic trioxide (As2O3, ATO) has limited therapeutic benefit to treat solid tumors, whether used alone or in combination. Nanoscale drug delivery vehicles have great potential to overcome the limitation of the utility of ATO by rapid renal clearance and dose-limiting toxicity. Polymeric materials ranging from gelatin foam to synthetic polymers such as poly(vinyl alcohol) were developed for vascular embolic or chemoembolic applications. Recently, we have introduced sevelamer, an oral phosphate binder, as a new polymeric embolic for vascular interventional therapy. In this paper, sevelamer arsenite nanoparticle with a polygonal shape and a size of 50-300 nm, synthesized by anionic exchange from sevelamer chloride, was developed as a Pi-responsive bifunctional drug carrier and embolic agent for chemoembolization therapy. At the same arsenic dosage, sevelamer arsenite-induced severer tumor necrosis than ATO on the VX2 cancer model. In vitro tests evidenced that Pi deprivation by sevelamer could enhance ATO's anticancer effect. The results showed that ATO in Pi starvation reduced cell viability, induced more apoptosis, and diminished the mitochondrial membrane potential (Δψm) of cells since Pi starvation helps ATO to further down-regulate Bcl-2 expression, up-regulate Bax expression, enhance the activation of caspase-3 and increase the release of cytochrome c, and the production of excessive reactive oxygen species (ROS). Sevelamer arsenite not only plays a Pi-activated nano-drug delivery system but also integrated anticancer drug with embolic for interventional therapy. Therefore, our results presented a new administration route of ATO as well as an alternative chemoembolization therapy.

Pi-inducedin-situaggregation of sevelamer nanoparticles for vascular embolization.

Decades have witnessed rapid progress of polymeric materials for vascular embolic or chemoembolic applications. Commercially available polymeric embolics range from gelatin foam to synthetic polymers such as poly(vinyl alcohol). Current systems under investigation include tunable, bioresorbable microspheres composed of chitosan or poly(ethylene glycol) derivatives,in situgelling liquid embolics with improved safety profiles, and radiopaque embolics that are trackablein vivo. In this paper, we proposed a concept of 'responsive embolization'. Sevelamer, clinically proved as an inorganic phosphate binder, was ground into nanoparticles. Sevelamer nanoparticle is highly mobile and capable of swelling and aggregating in the presence of endogenous inorganic phosphate, thereby effectively occluding blood flow in the vessel as it was administered as an embolic agent for interventional therapy. Moreover, citrated sevelamer nanoparticles delayed the aggregation, preferable to penetrate deeply into the capillary system. On the rabbit VX2 liver cancer model, both sevelamer particles aggregates occlude the tumor feeding artery, but backflow was found for the pristine one, thereby citrate passivation of sevelamer nanoparticles endows it have potential from 'bench to bedside' as a new type of vascular embolic.

Intratumoral Pi deprivation benefits chemoembolization therapy via increased accumulation of intracellular doxorubicin.

It is a decade-long controversy that transarterial chemoembolization (TACE) has definite priority over transarterial embolization (TAE) in treating patients with hepatocellular carcinoma (HCC), since HCC cells are regularly resistant to chemotherapy by enhanced expression of proteins that confer drug resistance, and ABC transporters pump the intracellular drug out of the cell. We addressed this issue by modulating the chemo-environment. In an animal model, sevelamer, a polymeric phosphate binder, was introduced as an embolic agent to induce intratumoral inorganic phosphate (Pi) starvation, and trans-arterially co-delivered with doxorubicin (DOX). The new type of TACE was named as DOX-TASE. This Pi-starved environment enhanced DOX tumoral accumulation and retention, and DOX-TASE thereby induced more severe tumor necrosis than that induced by conventional TACE (C-TACE) and drug-eluting bead TACE (D-TACE) at the same dose. In vitro tests showed that Pi starvation increased the cellular accumulation of DOX in an irreversible manner and enhanced cytotoxicity and cell apoptosis by suppressing the expression of ABC transporters (P-glycoprotein (P-gp), BCRP, and MRP1) and the production of intracellular ATP. Our results are indicative of an alternative interventional therapy combining chemotherapy with embolization more effectively.

Circular RNA circ-ERBB2 promotes HER2-positive breast cancer progression and metastasis via sponging miR-136-5p and miR-198.

BACKGROUND: Circular RNAs (circRNAs) are pivotal regulators of various human cancers and circ-ERBB2 is abnormally expressed in breast cancer cells. However, the role and mechanism of circ-ERBB2 in HER2-positive breast cancer are still unknown. METHODS: The circ-ERBB2 expressions in the tumor tissues of HER2-positive breast cancer patients were tested using quantitative real-time PCR. The circ-ERBB2 function was investigated by cell counting kit 8 assay, Transwell, flow cytometry and Western blot. Mechanistically, fluorescence in situ hybridization, RNA immunoprecipitation, RNA pull-down and dual-luciferase reporter gene assays were conducted to confirm the interaction between circ-ERBB2 and miR-136-5p or miR-198 in HER2-positive breast cancer cells. RESULTS: Circ-ERBB2 was elevated in the tumor tissues of HER2-positive breast cancer patients. Functionally, the interference with circ-ERBB2 repressed HER2-positive breast cancer cell proliferation, migration, invasion and accelerated cell apoptosis. Furthermore, the mechanistic analysis corroborated that circ-ERBB2 acted as a competing endogenous RNA for miR-136-5p or miR-198 to relieve the repressive influence of miR-136-5p or miR-198 on its target transcription factor activator protein 2C (TFAP2C). Meanwhile, in vivo assays further corroborated the oncogenic function of circ-ERBB2 in HER2-positive breast cancer. CONCLUSIONS: Circ-ERBB2 accelerated HER2-positive breast cancer progression through the circ-ERBB2/miR-136-5p/TFAP2C axis or the circ-ERBB2/miR-198/TFAP2C axis.

Nanosized drug-eluting bead for transcatheter arterial chemoembolization (ND-TACE).

Commercially available drug-eluting embolization beads (100-500 µm) reduced the occurrence of adverse events related to an anticancer drug, but were unascertained to remarkably benefit the transcatheter arterial chemoembolization (TACE) treatment of intermediate-stage liver cancer. Dextran-coated arsenite nanoparticles with the size ranging from 400 to 600 nm were developed as a nanosized drug-eluting bead (NDEB) for chemoembolization therapy of the rabbit VX2 liver tumor. We fully characterized their relevant physicochemistry and drug release properties. Their hemolysis was investigated before vessel embolization. The introduction of the NDEB allowed continuous embolization of tumor feeding vessels and sustained release of arsenic trioxide, thereby causing severe tumor necrosis and reduced vascularity. Sonography including B mode ultrasound, color Doppler flow imaging (CDFI) and dynamic contrast-enhanced ultrasound (CEUS) were performed to evaluate the tumor vascularity and viability. Additionally, its hepatotoxicity was tolerable at a medium dose. NDEB-TACE might be an effective therapeutic strategy for interventional therapy.

Grade Prediction of Bleeding Volume in Cesarean Section of Patients With Pernicious Placenta Previa Based on Deep Learning.

In order to predict the amount of bleeding in the cesarean section of the patients with Pernicious Placenta Previa (PPP), this study proposed an automatic blood loss prediction method based on Magnetic Resonance Imaging (MRI) uterus image. Firstly, the DeepLab-V3 + network was used to segment the original MRI abdominal image to obtain the uterine region image. Then, the uterine region image and the corresponding blood loss data were trained by Visual Geometry Group Network-16 (VGGNet-16) network. The classification model of blood loss level was obtained. Using a dataset of 82 positive samples and 128 negative samples, the proposed method achieved accuracy, sensitivity and specificity of 75.61, 73.75, and 77.46% respectively. The experimental results showed that this method can not only automatically identify the uterine region of pregnant women, but also objectively determine the level of intraoperative bleeding. Therefore, this method has the potential to reduce the workload of the attending physician and improve the accuracy of experts' judgment on the level of bleeding during cesarean section, so as to select the corresponding hemostasis measures.

Intratumoral inorganic phosphate deprivation: A new anticancer strategy?

Tumor epidemiology, as well as tumor microenvironments and cancer cell signaling study, has been presented with statistical relevance of inorganic phosphate (Pi) to tumorigenesis. Although serum Pi is still not acknowledged as a clinical tumor biomarker, abnormally high Pi concentration in serum or tumor lesions is gradually recognized as a characteristic of malignancy. On the other hand, phosphate binder (e.g. La2 (CO3)3, Fosrenols) has been clinically approved to treat hyperphosphatemia, a metabolic disease characterized by a high serum phosphate level. We hypothesize that, if reducing phosphate burden comes to benefit tumor therapy, could systemic or intratumoral administration of phosphate binder effectively deprive tumor Pi concentration, and then inhibit tumor growth and metastases? From the past clinical and preclinical outcomes, we'd conclude that Pi is not only a metabolite during tumor growth but also a force to trigger tumor progression and metastases. Two types of cancer models were developed to initiate this study. Firstly, a patient-derived xenograft mouse model of colorectal cancer was designed, where mice were administered systemically or intratumorally with lanthanum acetate (a molecular phosphate binder), and the serum or intratumoral Pi concentration levels were found to a dropdown. Secondly, a rabbit VX2 liver tumor was set up for the local-regional therapy model, where lanthanum acetate was intratumorally administered by the standard transcatheter arterial chemoembolization procedure, and it significantly reduced intratumoral Pi concentration. Therefore, Pi deprivation by phosphate binder might be a new anticancer strategy if reducing phosphate burden could effectively arrest tumor growth and delay metastatic progression.

Will Arsenic Trioxide Benefit Treatment of Solid Tumor by Nano- Encapsulation?

Arsenic trioxide (ATO) has remarkably enhanced therapeutic efficacy in treating both newly diagnosed and relapsed patients suffering from Acute Promyelocytic Leukemia (APL). Unfortunately, whether as a single agent, component of combined chemotherapy, or as a chemosensitizer or radiosensitizer combined with interventional therapy/radiotherapy, it did not benefit treatment of solid tumor (liver cancer, bladder cancer, glioma, breast cancer, cervical cancer, colorectal cancer, lung cancer, and melanoma) as seen from the clinical trials reported from the published journals or FDA-approved trials in the past decades. The clinical outcome failed to live up to our expectations, which was attributed to severe systemic toxicity and inappropriate pharmacokinetic such as low delivery efficiency and rapid renal elimination. Nanomedicine is designed to fuel up pharmaceuticals and polish off adverse effects by the moderation of their absorption, distribution, metabolism, and excretion. Nevertheless, quite a few nanodrugs (such as Doxil, Abraxane) were approved to be used clinically, and "from bench to bedside" it seems to be no easy way for most of them, such as nano-ATO. Encapsulating ATO into several types of nano-vehicles (liposome, polymer micelle, porous silicon, etc.), nano-TO can improve pharmacokinetic and become a prominent candidate to penetrate into tumor tissue, but so far no nano- ATO clinical trials have been approved around the world. On summarizing the clinical trials of ATO on solid tumor and preclinical study of nano-ATO, it is believed there is still a chance for ATO to play a critical co-helper in a comprehensive therapy to fight with solid tumor.

Sustained release of arsenic trioxide benefits interventional therapy on rabbit VX2 liver tumor.

The benefit of chemotherapy as a constituent of transcatheter arterial chemoembolization (TACE) is still in debate. Recently we have developed arsenic trioxide nanoparticle prodrug (ATONP) as a new anticancer drug, but its systemic toxicity is a big issue. In this preclinical TACE study, ATONP emulsified in lipiodol behaved as drug-eluting bead manner. Sustained release of arsenic from ATONP within occluded tumor caused very low arsenic level in plasma, avoiding the "rushing out" effect as ATO did. Correspondingly, intratumoral arsenic accumulation and inorganic phosphate deprivation were simultaneously observed, and arsenic concentration was much higher as ATONP was transarterially administered than ATO, or intravenously injected. Tumor necrosis and apoptosis were remarkably more severe in ATONP group than ATO, but no significant hepatic and renal toxicity was perceived. In brief, ATONP alleviated arsenic toxicity and boosted the therapeutic effect of TACE via Pi-activated drug sustainable release.

A retrospective analysis of the treatment on abdominal aortic balloon occlusion-related thrombosis by continuous low-flow diluted heparin.

Thrombosis is one of the serious complications related to prophylactic balloon occlusion of the abdominal aorta (PBOAA). This study aims to retrospectively analyze the efficacy and safety of continuous low-flow infusion of diluted heparin saline to prevent this complication related to PBOAA and further to provide the theory and evidences for using PBOAA.A study was carried out at our hospital from March 2016 to December 2018. Women with pernicious placenta previa (PPP) were treated PBOAA to prevent massive bleeding during CS. According to whether continuous low-flow infusion of diluted heparin saline was used to prevent catheter-related thrombosis or not, they were divided into 2 groups, the test group and the control group. The incidence of thrombosis between the 2 groups was compared and the effective treatment of thrombosis was also discussed. The comparison of nonparametric values was accomplished by using Fisher exact test. Statistical significance was set at P < .05.There were 31 women with PPP who received PBOAA during CS who were included in our study. Six of 19 women in control group (31.6%) developed thrombotic complications, while none of 12 women in test group. There were statistically significant differences in the incidence of thrombosis between the 2 groups (P = .037). There was no statistically significant difference in the amount of estimated blood loss and blood transfusion during CS between the 2 groups, nor was there statistically significant difference in the hospital days after CS (P > .05). All 6 women with thrombotic complications had no positive symptoms and thrombotic sequelae. The managements of thrombus included systemic anticoagulation, catheter-directed thrombolysis, and catheter-directed anticoagulation. One of the 6 women was lost to follow-up, and the thrombus of the other 5 women were completely dissolved. No other adverse outcomes or complications related to PBOAA were observed in all women in this study.Continuous low-flow infusion of diluted heparin saline is a safe procedure when PBOAA is performed for patients with PPP. It can effectively reduce or even avoid thrombosis without increasing intraoperative blood loss during CS for PPP patients.

METTL1 overexpression is correlated with poor prognosis and promotes hepatocellular carcinoma via PTEN.

RNA methylation is emerging as an important regulator of gene expression. Dysregulation of methyltransferase that is essential for RNA modification contributes to the development and progression of human cancers. Here we show that methyltransferase-like 1 (METTL1) is upregulated in hepatocellular carcinoma (HCC) and exhibits oncogenic activities via PTEN/AKT signaling pathway. High expression of METTL1 is correlated with larger tumor size, higher serum AFP level, tumor vascular invasion, and poor prognosis in two independent cohorts containing 892 patients with HCC. Multivariate analyses suggest METTL1 as an independent factor for unfavorable overall survival. In vitro studies demonstrate that METTL1 overexpression promotes cell proliferation and migration, whereas its knockdown results in opposite phenotypes. Gene set enrichment analysis (GSEA) indicates PTEN pathway is activated in patients with low METTL1 expression. Ectopic expression of PTEN or inhibition of AKT activity significantly attenuates the METTL1-mediated malignant phenotypes. In clinical samples, METTL1 expression is reversely associated with PTEN expression. Combination of low METTL1 expression and high PTEN expression is significantly correlated with overall survival, more so than either METTL1 or PTEN expression alone. Collectively, our data suggest that METTL1 serves as a promising prognostic biomarker and that targeting METTL1/PTEN axis may provide therapeutic potential in HCC intervention. KEY MESSAGES: METTL1 is upregulated in HCC and correlated with poor outcomes. METTL1 promotes cell proliferation and migration in HCC. METTL1 exerts oncogenic activities via suppression of PTEN signaling.

Endovascular Treatment of Post-traumatic Superior Mesenteric Arteriovenous Fistula: A Case Report.

Superior mesenteric arteriovenous fistulae (SMAVFs) are extremely rare with no consensus about therapeutic indications and optimal approach. Here, we present a case of a symptomatic SMAVF found in a young patient a few years after a penetrating abdominal injury. Following a complex clinical management of the acute status, we successfully managed the fistula with 3 covered stents in 2 consecutive endovascular procedures. Technical details of the performed procedures, including the main pitfalls and chosen solutions, have been explored and discussed.

DHX33 expression is increased in hepatocellular carcinoma and indicates poor prognosis.

DEAH-box helicase 33 (DHX33) has been implicated in ribosome biogenesis, mRNA translation and inflammation. However, the role of DHX33 in human cancer is rarely studied. Here, we showed that DHX33 expression was significantly increased in hepatocellular carcinoma (HCC), compared with the adjacent nontumorous tissues. In a cohort of 520 patients, DHX33 expression in HCC was closely associated with tumor size (P = 0.007), serum AFP level (P = 0.011), and tumor capsule (P = 0.030). Kaplan-Meier analysis indicated high DHX33 expression was correlated with worse overall and disease-free survival, and higher recurrence rate. The prognostic value of DHX33 was further confirmed by stratified survival analysis. Multivariate analysis revealed DHX33 as an independent prognostic factor for poor overall survival (Hazard Ratio = 1.772, 95% confident interval: 1.451-2.165, P < 0.0001). Our data therefore suggest DHX33 is overexpressed in HCC and serves as a promising prognostic biomarker for this deadly disease.