High-fat diet promotes liver tumorigenesis via palmitoylation and activation of AKT.

OBJECTIVE: Whether and how the PI3K-AKT pathway, a central node of metabolic homeostasis, is responsible for high-fat-induced non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) remain a mystery. Characterisation of AKT regulation in this setting will provide new strategies to combat HCC. DESIGN: Metabolite library screening disclosed that palmitic acid (PA) could activate AKT. In vivo and in vitro palmitoylation assay were employed to detect AKT palmitoylation. Diverse cell and mouse models, including generation of AKT1C77S and AKT1C224S knock-in cells, Zdhhc17 and Zdhhc24 knockout mice and Akt1C224S knock-in mice were employed. Human liver tissues from patients with NASH and HCC, hydrodynamic transfection mouse model, high-fat/high-cholesterol diet (HFHCD)-induced NASH/HCC mouse model and high-fat and methionine/choline-deficient diet (HFMCD)-induced NASH mouse model were also further explored for our mechanism studies. RESULTS: By screening a metabolite library, PA has been defined to activate AKT by promoting its palmitoyl modification, an essential step for growth factor-induced AKT activation. Biologically, a high-fat diet could promote AKT kinase activity, thereby promoting NASH and liver cancer. Mechanistically, palmitoyl binding anchors AKT to the cell membrane in a PIP3-independent manner, in part by preventing AKT from assembling into an inactive polymer. The palmitoyltransferases ZDHHC17/24 were characterised to palmitoylate AKT to exert oncogenic effects. Interestingly, the anti-obesity drug orlistat or specific penetrating peptides can effectively attenuate AKT palmitoylation and activation by restricting PA synthesis or repressing AKT modification, respectively, thereby antagonising liver tumorigenesis. CONCLUSIONS: Our findings elucidate a novel fine-tuned regulation of AKT by PA-ZDHHC17/24-mediated palmitoylation, and highlight tumour therapeutic strategies by taking PA-restricted diets, limiting PA synthesis, or directly targeting AKT palmitoylation.

Nephrotoxicity assessment of podophyllotoxin-induced rats by regulating PI3K/Akt/mTOR-Nrf2/HO1 pathway in view of toxicological evidence chain (TEC) concept.

Adverse reactions to traditional Chinese medicine have hindered the healthy development and internationalization process of the traditional Chinese medicine industry. The critical issue that needs to be solved urgently is to evaluate the safety of traditional Chinese medicine systematically and effectively. Podophyllotoxin (PPT) is a highly active compound extracted from plants of the genus Podophyllum such as Dysosma versipellis (DV). However, its high toxicity and toxicity to multiple target organs affect the clinical application, such as the liver and kidney. Based on the concurrent effects of PPT's medicinal activity and toxicity, it would be a good example to conduct a systematic review of its safety. Therefore, this study revolves around the Toxicological Evidence Chain (TEC) concept. Based on PPT as the main toxic constituent in DV, observe the objective toxicity impairment phenotype of animals. Evaluate the serum biochemical indicators and pathological tissue sections for substantial toxic damage results. Using metabolomics, lipidomics, and network toxicology to evaluate the nephrotoxicity of PPT from multiple perspectives systematically. The results showed that PPT-induced nephrotoxicity manifested as renal tubular damage, mainly affecting metabolic pathways such as glycerophospholipid metabolism and sphingolipid metabolism. PPT inhibits the autophagy process of kidney cells through the PI3K/Akt/mTOR and Nrf2/HO1 pathways and induces the activation of oxidative stress in the body, thereby causing nephrotoxic injury. This study fully verified the feasibility of the TEC concept for the safety and toxicity evaluation of traditional Chinese medicine. Provide a research template for systematically evaluating the safety of traditional Chinese medicine.

Phosphatidic Acid Directly Regulates PINOID-Dependent Phosphorylation and Activation of the PIN-FORMED2 Auxin Efflux Transporter in Response to Salt Stress.

Remodeling of auxin distribution during the integration of plant growth responses with the environment requires the precise control of auxin influx and efflux transporters. The plasma membrane-localized PIN-FORMED (PIN) proteins facilitate auxin efflux from cells, and their activity is regulated by reversible phosphorylation. How PIN modulates plant cellular responses to external stresses and whether its activity is coordinated by phospholipids remain unclear. Here, we reveal that, in Arabidopsis (Arabidopsis thaliana), the phosphatidic acid (PA)-regulated PINOID (PID) kinase is a crucial modulator of PIN2 activity and auxin redistribution in response to salt stress. Under salt stress, loss of phospholipase D function impaired auxin redistribution and resulted in markedly reduced primary root growth; these effects were reversed by exogenous PA. The phospholipase D-derived PA interacted with PID and increased PID-dependent phosphorylation of PIN2, which activated auxin efflux and altered auxin accumulation, promoting root growth when exposed to salt stress. Ablation of the PA binding motif not only diminished PID accumulation at the plasma membrane but also abolished PA-promoted PID phosphorylation of PIN2 and its function in coping with salt stress; however, this ablation did not affect inflorescence and cotyledon development or PIN2-dependent gravitropic and halotropic responses. Our data indicate a role for PA in coupling extracellular salt signaling to PID-directed PIN2 phosphorylation and polar auxin transport, highlighting the importance of lipid-protein interactions in the spatiotemporal regulation of auxin signaling.

Safety and Efficacy of Computed Tomography-Guided Iodine-125 Brachytherapy as a Salvage Treatment for Locoregional Lymph Node Recurrence of Esophageal Cancer.

PURPOSE: To investigate the clinical safety and efficacy of computed tomography (CT)-guided iodine-125 (125I) brachytherapy as a salvage treatment for esophageal cancer with locoregional lymph node recurrence (LNR). MATERIALS AND METHODS: This retrospective study included patients with esophageal cancer who developed locoregional LNR after initial curative resection followed by CT-guided 125I brachytherapy as a salvage treatment (January 2014 to January 2020). Local tumor progression-free survival (LTPFS) was assessed using Response Evaluation Criteria in Solid Tumors, v1.1. Clinical response was evaluated with the Numerical Rating Scale pain score, and adverse events were evaluated with the Common Terminology Criteria for Adverse Events (v5.0). A layered Cox proportional hazards model was used to determine independent factors affecting LTPFS. RESULTS: A total of 52 patients (mean age, 60 years) were included in this study. The median follow-up was 9.3 months (range, 4.3-12 months). The median LTPFS was 7.0 months (interquartile range, 5.0-9.5 months). The local control rates were 100%, 94.2%, 59.6%, and 13.4% at 1, 3, 6, and 12 months, respectively. The overall survival rates were 100%, 100%, 82.6%, and 36.5% at 1, 3, 6, and 12 months, respectively. The number of locoregional LNRs (hazard ratio [HR], 2.38 [95% confidence interval {CI}, 1.11-5.10]; P = .026), clinical stage at diagnosis (HR, 8.12 [95% CI, 3.19-20.66]; P < .001), and pathologic stage (HR, 5.74 [95% CI, 2.14-15.39]; P = .001) were independent factors for LTPFS. The rate of pain relief was 96.4% (27 of 28). Treatment-related death was not observed. CONCLUSIONS: CT-guided 125I radioactive seed implantation resulted in pain relief and short to midterm local control.

I-125 seeds brachytherapy with transcatheter arterial chemoembolization for subcapsular hepatocellular carcinoma.

BACKGROUND: I-125 seeds brachytherapy (ISB) has been used to improve the clinical effectiveness of transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). We aim to appraise the safety and clinical efficacy of combined ISB and TACE for the treatment of subcapsular HCC. MATERIALS AND METHODS: A retrospective investigative study extending from January 2017 to December 2020, involved individuals suffering from subcapsular HCC, who were subjected to TACE treatment with or without ISB in our center. The clinical effectiveness was compared between 2 groups. RESULTS: Sixty-four patients, in total, with subcapsular HCC had to undergo TACE with (n = 32) or without (n = 32) ISB in our center. After CT-guided ISB, only 2 (6.3%) patients experienced a self-limited pneumothorax. Combined treatment resulted in a significantly higher complete response (56.3% vs. 18.8%, P = 0.002) and total response (90.7% vs. 59.4%, P = 0.004) rates than that of TACE alone. In comparison to the TACE alone group, the median progression-free survival was substantially longer in the combined treatment group (11 months vs. 5 months, P = 0.016). Further, 15 and 28 patients in combined and TACE alone groups respectively died within the follow-up. The median OS was comparable between combined and TACE alone groups (22 months vs. 18 months, P = 0.529). CONCLUSIONS: Combined TACE and ISB therapy is a safe treatment method for individuals suffering from subcapsular HCC. When compared, combined treatment had significantly enhanced clinical efficacy as a subcapsular HCC therapy, in comparison to TACE alone.

Optimization of pleural multisite anesthetic technique during CT-guide microwave ablation of peripheral lung malignancy for improving treatment tolerance.

OBJECTIVE: To assess the effect and safety of subpleural multisite anesthesia based on the area of thermal radiation during CT-guided lung malignancy microwave ablation (MWA) on the incidence of moderate or severe pain and the analgesic drug usage. MATERIALS AND METHODS: Consecutive patients with lung malignancies were retrospectively evaluated between January 2016 and December 2019. Patients undergoing CT-guided lung malignancy MWA were either given in the method of (a) standard subpleural puncture point anesthesia between January 2016 and June 2018 and (b) subpleural multisite anesthesia based on the area of thermal radiation between July 2018 and December 2019. The relationship between local anesthesia mode and moderate or severe pain, and pain medications usage was assessed by using multivariable logistic regression models. RESULTS: A total of 243 consecutive patients were included in the study. Moderate or severe pain occurred in 84 of 124 (67.7%) patients with subpleural puncture point anesthesia and in 20 of 119 (16.8%) patients with subpleural anesthesia in the area of thermal radiation (p=.001). The intravenous pain medication was required in 56 of 124 (45.2%) patients with subpleural puncture point anesthesia and in 9 of 119 (7.6%) patients with subpleural multisite anesthesia based on the area of thermal radiation (p=.001). Local anesthesia methods (p = 0.001), pleura-to-lesion distance (p=.02) and tumor size (p=.015) were independent risk factors for developing moderate or severe pain. There were no differences in adverse events and local tumor progression rate. CONCLUSIONS: Subpleural multisite anesthesia based on the area of thermal radiation for peripheral lung malignancy MWA can result in lower intraprocedural pain compared with the subpleural puncture point anesthesia. Thus, a subpleural multisite anesthesia technique may be most helpful when performing MWA of peripheral malignancy in patients who are not sedated with general or intravenous anesthesia.

Results Obtained with the Protege EverFlex Self-expanding Bare Stent in Interventional Treatment of Spontaneous Isolated Visceral Artery Dissection.

OBJECTIVE: We evaluated the early and midterm results of the endovascular approach with a certain type of bare stent to treat spontaneous isolated visceral artery dissection (SIVAD). METHODS: 28 patients with symptomatic SIVAD were selected from two hospitals from July 2014 to September 2020. All patients had symptoms of acute persistent abdominal pain accompanied by varying degrees of nausea and vomiting. The diagnosis of SIVAD was made according to the multidetector CT angiography (CTA) findings. We retrospectively analyzed the patients' medical records. According to our previous clinical experience, the Protege EverFlex self-expanding bare stent was used in these patients, and we subsequently followed up the patients to record and analyze their outcomes after surgery. The imaging results before and after the operations were compared. RESULTS: All 28 patients were successfully implanted with Protege EverFlex stents. The true lumen blood flow of the SIVAD recovered during the operation. The residual stenosis rate was less than 30%, and the technical success rate was 100%. There were no complications, such as bleeding, intestinal necrosis, digestive tract perforation, liver failure or spleen infarction. The abdominal pain was relieved or eliminated in all patients. CONCLUSION: The Protege EverFlex self-expanding bare stent and the endovascular approach could be a minimally invasive, safe and effective treatment method for SIVAD with a high success rate and a relatively low price.

Comparison of 125 Iodine Seed-Loaded Stents with Different Diameters in Esophageal Cancer: A Multicenter Retrospective Cohort Study.

Currently, there are no recommendations or guidelines concerning the preferred diameter of esophageal stents for palliative treatment, owing to the lack of adequate evidence. We therefore conducted a retrospective cohort study to evaluate whether 18 mm stents would achieve a similar function of dysphagia relief with fewer complications and longer survival compared to 20 mm stents. Esophageal cancer patients who underwent 125 iodine seed-loaded stent placement with a diameter of either 18 mm (n = 103) or 20 mm (n = 54) were included at five hospitals in China. The stabilized inverse probability of treatment weighting (IPTW) was used to control potential confounding factors and bias that are inherent in a retrospective study. The primary endpoint was dysphagia relief. Stent-related complications and overall survival were assessed as the secondary endpoints. In the IPTW-adjusted analysis, no significant difference was found in the dysphagia score between the two groups either at 1 week after stent placement or at the last week before death. Despite a comparable rate of overall complications, there was a significantly lower incidence of severe retrosternal pain (15.4% vs. 32.7%, p = 0.013) and a trend toward longer survival (median survival, 176 days [95% confidence interval (CI) 144 to 209] vs. 109 days [92 to 126], p = 0.057) in the 18 mm group. An irradiated stent with a diameter of 18 mm showed a similar outcome of dysphagia relief to that achieved with a 20 mm diameter stent, but halved the incidence of retrosternal pain after stent placement.

Risk Prediction for Early Biliary Infection after Percutaneous Transhepatic Biliary Stent Placement in Malignant Biliary Obstruction.

PURPOSE: To establish a nomogram for predicting the occurrence of early biliary infection (EBI) after percutaneous transhepatic biliary stent (PTBS) placement in malignant biliary obstruction (MBO). MATERIALS AND METHODS: In this multicenter study, patients treated with PTBS for MBO were allocated to a training cohort or a validation cohort. The independent risk factors for EBI selected by multivariate analyses in the training cohort were used to develop a predictive nomogram. An artificial neural network was applied to assess the importance of these factors in predicting EBI. The predictive accuracy of this nomogram was determined by concordance index (c-index) and a calibration plot, both internally and externally. RESULTS: A total of 243 patients (training cohort: n = 182; validation cohort: n = 61) were included in this study. The independent risk factors were length of obstruction (odds ratio [OR], 1.061; 95% confidence interval [CI], 1.013-1.111; P = .012), diabetes (OR, 5.070; 95% CI, 1.917-13.412; P = .001), location of obstruction (OR, 2.283; 95% CI, 1.012-5.149; P = .047), and previous surgical or endoscopic intervention (OR, 3.968; 95% CI, 1.709-9.217; P = .001), which were selected into the nomogram. The c-index values showed good predictive performance in the training and validation cohorts (0.792 and 0.802, respectively). The optimum cutoff value of risk was 0.25. CONCLUSIONS: The nomogram can facilitate the early and accurate prediction of EBI in patients with MBO who underwent PTBS. Patients with high risk (> 0.25) should be administered more effective prophylactic antibiotics and undergo closer monitoring.

Nomogram and Artificial Neural Network for Prognostic Performance on the Albumin-Bilirubin Grade for Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization.

PURPOSE: To construct the albumin-bilirubin (ALBI) grade and the Child-Turcotte-Pugh (CTP) score based on nomograms, as well as to develop an artificial neural network (ANN) to compare the prognostic performance of the 2 scores for hepatocellular carcinoma (HCC) that has undergone transarterial chemoembolization. MATERIALS AND METHODS: This multicentric retrospective study included patients with HCC who underwent transarterial chemoembolization monotherapy as an initial treatment at 4 institutions between January 2008 and December 2016. In the training cohort, significant risk factors associated with overall survival (OS) were identified by univariate and multivariate analyses. The prognostic nomograms and ANN were established and then validated in 2 validation cohorts. RESULTS: A total of 838 patients (548, 115, and 175 in the training cohort and validation cohorts 1 and 2, respectively) were included. The median OS was 10.4, 15.7, and 9.2 months in the training cohort and validation cohorts 1 and 2, respectively. In the training cohort, both ALBI grade and CTP score were identified as significant risk factors. The ALBI grade and CTP score based on nomograms were established separately and showed similar prognostic performance when assessed externally in validation cohorts (C-index in validation cohort 1: 0.823 vs 0.802, P = .417; in validation cohort 2: 0.716 vs 0.729, P = .793). ANN showed that ALBI grade had higher importance on survival prediction than CTP score. CONCLUSIONS: ALBI grade performs at least no worse than CTP score regarding survival prediction for HCC receiving transarterial chemoembolization. Considering the easy application, ALBI grade has the potential to be regarded as an alternative to CTP score.

Irradiation stents vs. conventional metal stents for unresectable malignant biliary obstruction: A multicenter trial.

BACKGROUND & AIMS: Placement of an irradiation stent has been demonstrated to offer longer patency and survival than an uncovered self-expandable metallic stent (SEMS) in patients with unresectable malignant biliary obstruction (MBO). We aim to further assess the efficacy of an irradiation stent compared to an uncovered SEMS in those patients. METHODS: We performed a randomized, open-label trial of participants with unresectable MBO at 20 centers in China. A total of 328 participants were allocated in parallel to the irradiation stent group (ISG) or the uncovered SEMS group (USG). Endpoints included stent patency (primary), technical success, relief of jaundice, overall survival, and complications. RESULTS: The first quartile stent patency time (when 25% of the patients experienced stent restenosis) was 212 days for the ISG and 104 days for the USG. Irradiation stents were significantly associated with a decrease in the rate of stent restenosis (9% vs. 15% at 90 days; 16% vs. 27% at 180 days; 21% vs. 33% at 360 days; p = 0.010). Patients in the ISG obtained longer survival time (median 202 days vs. 140 days; p = 0.020). No significant results were observed in technical success rate (93% vs. 95%; p = 0.499), relief of jaundice (85% vs. 80%; p = 0.308), and the incidence of grade 3 and 4 complications (8.5% vs. 7.9%; p = 0.841). CONCLUSIONS: Insertion of irradiation stents instead of uncovered SEMS could improve patency and overall survival in patients with unresectable MBO. LAY SUMMARY: For patients with unresectable malignant biliary obstruction (MBO), placement of a self-expandable metallic stent (SEMS) is a recommended palliative modality to relieve pruritus, cholangitis, pain, and jaundice. However, restenosis is a main pitfall after stent placement. Data from this first multicenter randomized controlled trial showed that insertion of an irradiation stent provided longer patency and better survival than a conventional metal stent. ClinicalTrials.gov ID: NCT02001779.

Endovascular Denervation: A New Approach for Cancer Pain Relief?

PURPOSE: To evaluate the effects of endovascular denervation (EDN) on abdominal cancer pain relief. MATERIALS AND METHODS: From April 2017 to February 2018, 7 cancer patients (2 males and 5 females) were enrolled in this study. The diagnoses of the patients included 3 pancreatic cancer, 2 cervical carcinoma, 1 cholangiocarcinoma, and 1 esophageal cancer with retroperitoneum lymph nodes invasion. Denervation was carried out at the abdominal aorta close to the origin of celiac artery and superior mesenteric artery with the use of a multielectrode radiofrequency ablation catheter with settings of time 120 seconds and temperature 60°C. The primary end point was improvement in pain scores. The secondary end points included change in quality of life, intake of narcotics, and the safety of EDN. RESULTS: All of the patients experienced pain relief. The pain scores as measured by means of visual analog scores at 1, 2, 4, 8, and 12 weeks after the procedure were significantly lower than before the operation (P < .001). A > 4 score reduction was observed in all cases. A significant reduction in narcotics use within 3 months after the operation was also seen. The quality of life scores of the patients improved significantly (P < .005) with better sleep. No severe treatment-related adverse events or major complications were observed. CONCLUSIONS: EDN is a safe and effective means to alleviate pain caused by cancer and may serve as a new approach for cancer pain relief and palliative care.

Effects of Multi-Electrode Renal Denervation on Insulin Sensitivity and Glucose Metabolism in a Canine Model of Type 2 Diabetes Mellitus.

PURPOSE: To evaluate the effects of multi-electrode catheter-based renal denervation (RDN) on insulin sensitivity and glucose metabolism in a type 2 diabetes mellitus (T2DM) canine model. MATERIALS AND METHODS: Thirty-three dogs were divided equally into 3 groups: bilateral renal denervation (BRDN) group, left renal denervation (LRDN) group, and sham operation (SHAM) group. Body weight and blood biochemistry were measured at baseline, 20 weeks, and 32 weeks, and renal angiography and computerized tomographic (CT) angiography were determined before the procedure and 1 month, 2 months, and 3 months after the procedure. Western blot was used to identify the activities of gluconeogenic enzymes and insulin-signaling proteins. RESULTS: Fasting plasma glucose (9.64 ± 1.57 mmol/L vs 5.12 ± 1.08 mmol/L; P < .0001), fasting insulin (16.19 ± 1.43 mIU/mL vs 5.07 ± 1.13 mIU/mL; P < .0001), and homeostasis-model assessment of insulin resistance (HOMA-IR; 6.95 ± 1.33 vs 1.15 ± 0.33; P < .0001) in the BRDN group had significantly decreased at the 3-month follow-up compared with the SHAM group. Western blot analyses showed that RDN suppressed the gluconeogenetic genes, modulated insulin action, and activated insulin receptors-AKT signaling cascade in the liver. CT angiography and histopathologic analyses did not show any dissection, aneurysm, thrombus, or rupture in any of the renal arteries. CONCLUSIONS: These findings identified that multi-electrode catheter-based RDN could effectively decrease gluconeogenesis and glycogenolysis, resulting in improvements in insulin sensitivity and glucose metabolism in a T2DM canine model.

Peroxisomal CuAOζ and its product H2O2 regulate the distribution of auxin and IBA-dependent lateral root development in Arabidopsis.

Root system architecture depends on endogenous and environmental signals, including polar transport of the phytohormone auxin, reactive oxygen species (ROS), nutrient availability, and stresses. In our study, we describe a novel Arabidopsis thaliana peroxisome-localized copper amine oxidase ζ (CuAOζ), which is highly expressed in cortical cells, and the ROS derived from CuAOζ are essential for lateral root (LR) development. Loss of CuAOζ results in retarded auxin-induced ROS generation, PINFORMED2 (PIN2)-mediated auxin transport, and LR development in response to added indole-3-butyric acid. Auxins enhance CuAOζ protein levels and their cellular translocation toward the plasma membrane in the cortex. CuAOζ interacts physically with PEROXINS5 via an N-terminal signal tag, Ser-Lys-Leu, and is transported into the peroxisome upon this interaction, which is required for the functions of CuAOζ in the auxin response. Together, our results suggest a peroxisomal ROS-based auxin signaling pathway involving spatiotemporal-dependent CuAOζ functional regulation of PIN2 homeostasis, auxin distribution, and LR development.

Safety and Efficacy of Irradiation Stent Placement for Malignant Portal Vein Thrombus Combined with Transarterial Chemoembolization for Hepatocellular Carcinoma: A Single-Center Experience.

PURPOSE: To assess feasibility, safety, and preliminary efficacy of an irradiation portal vein stent for portal vein tumor thrombosis (PVTT) in patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Between October 2012 and September 2015, 25 of 40 patients (mean age of 55.5 y) with PVTT caused by HCC were recruited for treatment with an irradiation portal vein stent (self-expandable stent loaded with iodine-125 seeds) at a single hospital. Liver function was classified as Child-Pugh class A in 15 patients (60%) and class B in 10 patients (40%). The Eastern Cooperative Oncology Group performance status score was 0 in 3 patients (12%), 1 in 13 patients (52%), and 2 in 9 patients (36%). Transarterial chemoembolization was performed after stent placement. Outcomes were measured in terms of technical success, complications, stent patency, and overall survival. RESULTS: The technical success rate was 92.0% (23/25). No complications grade 3 or higher according to Common Terminology Criteria for Adverse Events were observed. Median stent patency period was 8.0 months (range, 0.6-30.0 months). Between 7 and 955 days after stent placement, 65 cycles of transarterial chemoembolization were performed with a mean of 2.8 cycles per patient. Median survival was 12.5 months (range, 0.6-35.7 months). CONCLUSIONS: Placement of an irradiation portal vein stent appears feasible and safe and may prolong the patency of the portal vein. It is a promising technique for combining recanalization of an occluded portal vein and brachytherapy.

Arabidopsis phospholipase D alpha 1-derived phosphatidic acid regulates microtubule organization and cell development under microtubule-interacting drugs treatment.

Phospholipase D (PLD) and its product phosphatidic acid (PA) are emerging as essential regulators of cytoskeleton organization in plants. However, the underlying molecular mechanisms of PA-mediated microtubule reorganization in plants remain largely unknown. In this study, we used pharmacological and genetic approaches to analyze the function of Arabidopsis thaliana PLDα1 in the regulation of microtubule organization and cell development in response to microtubule-affecting drugs. Treatment with the microtubule-stabilizing drug paclitaxel resulted in less growth inhibition and decreased rightward slant of roots, longitudinal alignment of microtubules, and enhanced length of hypocotyl epidermal cells in the pldα1 mutant, the phenotype of which was rescued by exogenous application of PA. Moreover, the pldα1 mutant was sensitive to the microtubule-disrupting drugs oryzalin and propyzamide in terms of seedling survival ratio, left-skewing angle of roots and microtubule organization. In addition, both disruption and stabilization of microtubules induced by drugs activated PLDα1 activity. Our findings demonstrate that in A. thaliana, PLDα1/PA might regulate cell development by modulating microtubule organization in an activity-dependent manner.

A Modified Model for Assessment for Retreatment with Transarterial Chemoembolization in Chinese Hepatocellular Carcinoma Patients.

PURPOSE: To develop a modified assessment for retreatment with transarterial chemoembolization (mART) score that may be more suitable for Chinese patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Chinese patients with HCC who were treated with transarterial chemoembolization in four hospitals were included. A univariate analysis and a multivariate forward Cox regression analysis were used to identify significant prognostic factors of overall survival (OS). A point scoring model was subsequently developed from the training cohort, and the validation process was performed in the validation cohort. RESULTS: The study included 259 patients (124 patients in the training cohort and 135 patients in the validation cohort). Increase in Child-Pugh scores relative to the baseline (P < .001), Barcelona Clinic Liver Cancer (BCLC) stage B before first transarterial chemoembolization (P = .001), and absence of radiologic tumor response (P < .001) were identified as negative prognostic factors for OS and were used to create the mART scores. BCLC staging was substituted for aspartate aminotransferase increase in the mART scores. The mART scores differentiated two groups with distinct prognosis by a cutoff score of 2.5 points (22.9 mo [95% confidence interval (CI), 17.4-28.4] vs 8.9 mo [95% CI, 7.5-10.3] in median survival; P < .001). In the validation cohort, the C index in assessment for retreatment with transarterial chemoembolization (ART) criteria was 0.64, whereas it was 0.82 in mART criteria. CONCLUSIONS: In Chinese patients with HCC, mART score of > 2.5 before second transarterial chemoembolization was associated with poor prognosis. The mART score was probably better validated compared with the ART score.

Conventional stents versus stents loaded with (125)iodine seeds for the treatment of unresectable oesophageal cancer: a multicentre, randomised phase 3 trial.

BACKGROUND: The combination of stent insertion and single high-dose brachytherapy is a feasible and safe palliative treatment regimen in patients with unresectable oesophageal cancer. We aimed to further assess the efficacy of this treatment strategy compared to a conventional covered stent in patients with dysphagia caused by unresectable oesophageal cancer. METHODS: In this multicentre, single-blind, randomised, phase 3 trial, we enrolled patients with unresectable oesophageal cancer from 16 hospitals in China. We included adult patients (aged ≥ 20 years) with progressive dysphagia, unresectable tumours due to extensive lesions, metastases, or poor medical condition, and with clear consciousness, cooperation, and an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-3. Eligible patients were randomly assigned (in 1:1 ratio, no stratification) to receive either a stent loaded with (125)iodine radioactive seeds (irradiation group) or a conventional oesophageal stent (control group). The primary endpoint was overall survival. Survival analyses were done in a modified intention-to-treat group. This study is registered with ClinicalTrials.gov, number NCT01054274. FINDINGS: Between Nov 1, 2009, and Oct 31, 2012, 160 patients were randomly assigned to receive treatment with either an irradiation stent (n=80) or a conventional stent (n=80). During a median follow-up of 138 days (IQR 72-207), 148 stents (73 in the irradiation group and 75 in the control group) were successfully placed into the diseased oesophagus in 148 participants. Median overall survival was 177 days (95% CI 153-201) in the irradiation group versus 147 days (124-170) in the control group (p=0.0046). Major complications and side-effects of the treatment were severe chest pain (17 [23%] of 73 patients in the irradiation group vs 15 [20%] of 75 patents in the control group), fistula formation (six [8%] vs five [7%]), aspiration pneumonia (11 [15%] vs 14 [19%]), haemorrhage (five [7%] vs five [7%]), and recurrent dysphagia (21 [28%] vs 20 [27%]). INTERPRETATION: In patients with unresectable oesophageal cancer, the insertion of an oesophageal stent loaded with (125)iodine seeds prolonged survival when compared with the insertion of a conventional covered self-expandable metallic stent.

[Percutaneous vertebroplasty for treatment of painful osteoporotic vertebral compression fractures: a retrospective analysis of clinical efficacy].

OBJECTIVE: To evaluate the clinical efficacy and radiological changes in patients with painful osteoporotic vertebral compression fractures (OVCFs) after percutaneous vertebroplasty (PVP). METHODS: Retrospective analysis was conducted on 195 vertebrae in 142 patients with painful OVCFs treated with vertebroplasty in our hospital from May 2007 to June 2012. The scores of visual analogue scale (VAS) were recorded and the heights of vertebral bodies and Cobb angles were measured in the mid-sagittal plane of the reformatted images at 64-detector row CT during the period of follow-up. Polymethylmethacrylate (PMMA) distribution in vertebrae and whether leakage was observed on CT within 3 days after PVP. The changes in VAS, heights of vertebral bodies and Cobb angles were compared between the cases with and without leakages. RESULTS: The successful rate of technique of PVP was 100%. The mean volume of PMMA injected in each vertebra was (4.5 ± 1.1) ml and (6.0 ± 1.2) ml respectively in thoracic and lumbar. The mean follow-up was (17 ± 6) months. Asymptomatic leakages of PMMA were demonstrated by CT in 38 patients with 43 vertebrae (22.1%). The average decrease in VAS was 5.25 and 1.12 respectively in 24 hours and a month after PVP. The changes in VAS respectively at 1 month, 3 months, 6 months and more than 1 year after procedure were not significantly different.In postoperative 3 days, the average increase in height of vertebral body was 1.55 mm anteriorly and 1.38 mm centrally, the average reduction in Cobb angle were 2.37°. The heights and Cobb angles of vertebral bodies between in 3 days and in more than 1 year after PVP were not significantly different. The scores of VAS and the changes in vertebral body heights and Cobb angles between the patients with or without cement leakages were not significantly different during the period of follow-up. CONCLUSION: PVP is an effective treatment for patients with painful OVCFs that provides immediate and sustained pain relief, increases in the heights of vertebral bodies injected in cement and keeps stable radiological progression within at least 1 year after PVP. Asymptomatic cement leakages around vertebrae have no influence on pain relief and vertebral stability in this group of patients.

Exploring immune-related pathogenesis in lung injury: Providing new insights Into ALI/ARDS.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) represent a significant global burden of morbidity and mortality, with lung injury being the primary cause of death in affected patients. The pathogenesis of lung injury, however, remains a complex issue. In recent years, the role of the immune system in lung injury has attracted extensive attention worldwide. Despite advancements in our understanding of various lung injury subtypes, significant limitations persist in both prevention and treatment. This review investigates the immunopathogenesis of ALI/ARDS, aiming to elucidate the pathological processes of lung injury mediated by dendritic cells (DCs), natural killer (NK) cells, phagocytes, and neutrophils. Furthermore, the article expounds on the critical contributions of gut microbiota, inflammatory pathways, and cytokine storms in the development of ALI/ARDS.