Effectiveness of Butorphanol in alleviating intra- and post-operative visceral pain following microwave ablation for hepatic tumor: a dual-central, randomized, controlled trial.

Many patients who underwent hepatic percutaneous microwave ablation (MWA) reported experiencing pain during the procedure. This study utilized a well-designed multicentral, randomized, and placebo-controlled format to investigate the effects of Butorphanol. Patients who underwent MWA were randomly assigned to either Butorphanol or normal saline group. The primary outcomes of the study were assessed by measuring the patients' intraoperative pain levels using a 10-point visual analog scale (VAS). Secondary outcomes included measuring postoperative pain levels at the 6-h mark (VAS) and evaluating comprehensive pain assessment outcomes. A total of 300 patients were divided between the control group (n = 100) and the experimental group (n = 200). Butorphanol showed statistically significant reductions in intraoperative pain levels compared to the placebo during surgery (5.00 ± 1.46 vs. 3.54 ± 1.67, P < 0.001). Significant differences were observed in postoperative pain levels at the 6-h mark and in the overall assessment of pain (1.39 + 1.21 vs. 0.65 + 0.81, P < 0.001). Butorphanol had a significant impact on reducing the heart rate of patients. The empirical evidence supports the effectiveness of Butorphanol in reducing the occurrence of visceral postoperative pain in patients undergoing microwave ablation for hepatic tumor. Furthermore, the study found no noticeable impact on circulatory and respiratory dynamics.

Self-Supplied Reactive Oxygen Species-Responsive Mitoxantrone Polyprodrug for Chemosensitization-Enhanced Chemotherapy under Moderate Hyperthermia.

Currently, the secondary development and modification of clinical drugs has become one of the research priorities. Researchers have developed a variety of TME-responsive nanomedicine carriers to solve certain clinical problems. Unfortunately, endogenous stimuli such as reactive oxygen species (ROS), as an important prerequisite for effective therapeutic efficacy, are not enough to achieve the expected drug release process, therefore, it is difficult to achieve a continuous and efficient treatment process. Herein, a self-supply ROS-responsive cascade polyprodrug (PMTO) is designed. The encapsulation of the chemotherapy drug mitoxantrone (MTO) in a polymer backbone could effectively reduce systemic toxicity when transported in vivo. After PMTO is degraded by endogenous ROS of the TME, another part of the polyprodrug backbone becomes cinnamaldehyde (CA), which can further enhance intracellular ROS, thereby achieving a sustained drug release process. Meanwhile, due to the disruption of the intracellular redox environment, the efficacy of chemotherapy drugs is enhanced. Finally, the anticancer treatment efficacy is further enhanced due to the mild hyperthermia effect of PMTO. In conclusion, the designed PMTO demonstrates remarkable antitumor efficacy, effectively addressing the limitations associated with MTO.

Balance of Gata3 and Ramp2 in hepatocytes regulates hepatic vascular reconstitution in postoperative liver regeneration.

BACKGROUND & AIMS: Post-hepatectomy liver failure (PHLF) leads to poor prognosis in patients undergoing hepatectomy, with hepatic vascular reconstitution playing a critical role. However, the regulators of hepatic vascular reconstitution remain unclear. In this study, we aimed to investigate the regulatory mechanisms of hepatic vascular reconstitution and identify biomarkers predicting PHLF in patients undergoing hepatectomy. METHODS: Candidate genes that were associated with hepatic vascular reconstitution were screened using adeno-associated virus vectors in Alb-Cre-CRISPR/Cas9 mice subjected to partial hepatectomy. The biological activities of candidate genes were estimated using endothelial precursor transfusion and associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) models. The level of candidates was detected in biopsies from patients undergoing ALPPS. Risk factors for PHLF were also screened using retrospective data. RESULTS: Downregulation of Gata3 and upregulation of Ramp2 in hepatocytes promoted the proliferation of liver sinusoidal endothelial cells and hepatic revascularization. Pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor A (VEGFA) played opposite roles in regulating the migration of endothelial precursors from bone marrow and the formation of new sinusoids after hepatectomy. Gata3 restricted endothelial cell function in patient-derived hepatic organoids, which was abrogated by a Gata3 inhibitor. Moreover, overexpression of Gata3 led to higher mortality in ALPPS mice, which was improved by a PEDF-neutralizing antibody. The expression of Gata3/RAMP and PEDF/VEGFA tended to have a negative correlation in patients undergoing ALPPS. A nomogram incorporating multiple factors, such as serum PEDF/VEGF index, was constructed and could efficiently predict the risk of PHLF. CONCLUSIONS: The balance of Gata3 and Ramp2 in hepatocytes regulates the proliferation of liver sinusoidal endothelial cells and hepatic revascularization via changes in the expression of PEDF and VEGFA, revealing potential targets for the prevention and treatment of PHLF. IMPACT AND IMPLICATIONS: In this study, we show that the balance of Gata3 and Ramp2 in hepatocytes regulates hepatic vascular reconstitution by promoting a shift from pigment epithelium-derived factor (PEDF) to vascular endothelial growth factor A (VEGFA) expression during hepatectomy- or ALLPS (associating liver partition and portal vein ligation for staged hepatectomy)-induced liver regeneration. We also identified serum PEDF/VEGFA index as a potential predictor of post-hepatectomy liver failure in patients who underwent hepatectomy. This study improves our understanding of how hepatocytes contribute to liver regeneration and provides new targets for the prevention and treatment of post-hepatectomy liver failure.

A novel ROS-activable self-immolative prodrug for tumor-specific amplification of oxidative stress and enhancing chemotherapy of mitoxantrone.

Reactive oxygen species (ROS) as well-known endogenous stimuli has been widely used to activate drug delivery systems (DDSs) for tumor-specific therapy. Unfortunately, endogenous ROS in the tumor microenvironment (TME) is not enough to achieve effective therapeutic efficacy and cancer cells have adapted to high oxidative stress by upregulating glutathione (GSH) level. Herein, we devised a novel ROS-activable self-immolative prodrug CASDB with both GSH-depletion ability and ROS self-supply competence. Then, an stimuli-responsive nanoplatform integrating CASDB with clinical chemotherapeutics mitoxantrone (MTO) and PLGA was fabricated (denoted as CMPs) through nanoprecipitation method. The CMPs could achieve desired accumulation at tumor tissues through enhanced permeability and retention (EPR) effects. Then the accumulated CMPs could induce tumor cell apoptosis efficiently. Especially, ROS in tumor sites could trigger the immolation of CASDB to generate CA and quinone methide (QM). Then CA and QM cooperatively promoted damage of mitochondria due to oxidative stress and led to cancer cells more sensitive to MTO. Accordingly, MTO could perturb cellular microenvironment of cancer cells then promote the degradation of CASDB. The experiment results demonstrated that CMPs were ideal for desirable synergetic tumor-specific anticancer therapy with negligible systemic toxicity. The half-maximal inhibitory concentrations (IC50) value of CMPs was 6.53 µM, while the IC50 values of MTO was 14.76 µM. And the CMPs group showed the strongest tumor suppressor effect with the tumor sizes increased to 1.2-fold (Control group: 20.6-fold, MTO only: 3.0-fold). This study should be inspirational for designing efficient prodrugs to overcome the handicaps of traditional chemotherapy.

ITCH facilitates proteasomal degradation of TXNIP in hypoxia- induced lung cancer cells.

BACKGROUND: Lung cancer (LC) is one of the most common cancers and a leading cause of cancer-related deaths worldwide. In many pathological conditions, particularly in the tumor microenvironment, cells and tissues frequently exist in a hypoxic state. Here, we evaluated Itchy E3 ubiquitin protein ligase (ITCH) expression in LC cells following hypoxia treatment. METHODS: LC cell lines were treated with hypoxic condition. Cell migration, invasion, inflammation, reactive oxygen species (ROS) production, and apoptosis of LC cells were determined by wound healing assay, Transwell invasive assay, ELISA, DCFH-DA staining, and flow cytometry, respectively. qPCR and WB were used to determine the expression of ITCH and TXNIP. Co-IP was performed to assess the interaction between ITCH and TXNIP. RESULTS: ITCH expression was downregulated in LC cells under hypoxic conditions. Next, LC cells were subjected to hypoxic conditions and changes in cell viability and metastasis were determined. Hypoxic conditions resulted in increased migration and invasion abilities of LC cells. Intracellular reactive oxygen species (ROS) production, inflammation, and apoptosis were also promoted by hypoxia. We found that ITCH overexpression led to the proteasomal degradation of thioredoxin-interacting protein (TXNIP), whereas the expression of the ITCH C830A mutant did not affect TXNIP levels in LC cells. The gain-of-function experiment demonstrated that migration, invasion, ROS generation, inflammation, and apoptosis of hypoxia-conditioned LC cells were ameliorated by ITCH overexpression, whereas the ITCH C830A mutant did not cause any changes in these phenotypes. Furthermore, the contribution of TXNIP knockdown and ITCH overexpression to the hypoxia-induced features in LC cells with ITCH C830A was found to be similar. CONCLUSION: Our results suggest a novel mechanism underlying the changes in ITCH-mediated malignant phenotypes of hypoxia-conditioned LC cells via TXNIP.

PHF5A promotes colorectal cancerprogression by alternative splicing of TEAD2.

Dysregulated alternative splicing (AS) plays critical roles in driving cancer progression, and the underlying mechanisms remain largely unknown. Here, we demonstrated that PHF5A, a component of U2 small nuclear ribonucleoproteins, was frequently upregulated in colorectal cancer (CRC) samples and associated with poor prognosis. PHF5A promoted proliferation and metastasis of CRC cells in vitro and in vivo. Transcriptomic analysis identified PHF5A-regulated AS targets and pathways. Particularly, PHF5A induced TEAD2 exon 2 inclusion to activate YAP signaling, and interference of TEAD2-L partially reversed the PHF5A-mediated tumor progression. Pharmacological inhibition of PHF5A using pladienolide B had potent antitumor activity. Collectively, these data revealed the oncogenic role of PHF5A in CRC through regulating AS and established PHF5A as potential therapeutic target.

Durable electromagnetic interference (EMI) shielding ramie fabric with excellent flame retardancy and Self-healing performance.

Although more and more attention has been paid to electromagnetic interference (EMI) shielding fabric materials due to increasing electromagnetic waves pollution, little attention to their fire safety behavior and durability in practical use. Herein, durable EMI shielding ramie fabric with flame retardant and self-healing performance were fabricated by depositing ammonium polyphosphate (APP)/polyethyleneimine (PEI) layer, MXene sheets and polycaprolactone (PCL) layer. The resultant multifunctional fabric could self-extinguish and the peak heat release rate (pHRR) value reduced about 74.3% for the modified ramie fabric that contains about 12 wt% of PEI/APP bilayer compared with pure ramie fabric. Furthermore, the ramie fabric coated by a increasing amount of MXene sheets changed from insulating to conductive, thus gradually improving their EMI shielding performance, which exhibit a high electrical conductivity of 900.56 S/m with an outstanding SE value of 35 dB at a 1.2 mg/cm2 content in the X-band. Besides, When the multifunctional fabric was cut off under external force, it could achieve self-healing and the EMI shielding performance can recover to 34 dB due to the low melting point and good fluidity of PCL. Thus, this multifunctional fabric holds great promise for wearable intelligent cloth, EMI shielding and other fields.

Prediction of Pretreatment 18F-FDG-PET/CT Parameters on the Outcome of First-Line Therapy in Patients with Metastatic Breast Cancer.

OBJECTIVE: 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) can provide prognostic information, especially 18F-FDG uptake has been proven to be a predictor for the prognosis of various tumors. Nevertheless, the prognosis of other PET parameters in the metastatic setting remains unclear. This study was aimed at investigating pretreatment parameters based on 18F-FDG-PET/CT so as to estimate the progression-free survival (PFS) of metastatic breast cancer (MBC) patients receiving first-line treatment. METHODS: MBC patients who underwent a whole-body 18F-FDG-PET/CT prior to first-line therapy were enrolled. The heterogeneity parameter of PET/CT was analyzed, including heterogeneity index (HI) and general parameters (metabolic tumor volume (MTV), total lesion glycolysis (TLG), maximum standardized uptake value (SUVmax) and mean SUV (SUVmean). PFS was used to evaluate the treatment outcome. Kaplan-Meier method was adopted to carry out survival analysis and Log rank test was conducted to make a comparison. RESULTS: A total of 177 MBC patients were selected, in which 68 were in De novo stage IV. Thirty patients were human epidermal growth factor receptor 2 (HER2)-positive, 60 patients were triple-negative, and 87 patients were hormone receptor (HR)-positive and HER2-negative. In the whole population, patients with high baseline SUVmax, SUVmean, MTV, TLG or HI were associated with lower PFS (P=0.028, 0.005, 0.017, 0.026 and 0.035, respectively). Among the patients in De novo stage IV, those with high HI at baseline had significantly shorter PFS (P=0.001). In HR+/HER2- and HER2+ subgroups, only baseline HI showed the predictive value of PFS (P=0.023 and 0.049, respectively). In the triple-negative subgroup, high baseline SUVmax, MTV or TLG showed the predictive value of worse PFS (P=0.030, 0.011 and 0.023, respectively). CONCLUSION: Pretreatment 18F-FDG-PET/CT parameters show the predictive value of PFS in MBC patients receiving first-line treatment. However, predictive PET/CT parameters might be different in patients with different molecular subtypes and De novo stage IV.

MT1JP-mediated miR-24-3p/BCL2L2 axis promotes Lenvatinib resistance in hepatocellular carcinoma cells by inhibiting apoptosis.

PURPOSE: Lenvatinib is a long-awaited alternative to Sorafenib for first-line targeted therapy of patients with advanced hepatocellular carcinoma (HCC). However, resistance to Lenvatinib results in tumor progression and has become a major obstacle to improving the prognosis of HCC patients. Exploring the mechanisms underlying Lenvatinib resistance is considered essential for the treatment of advanced HCC. METHODS: Lenvatinib resistant HCC (LR-HCC) cells were generated and potential long non-coding RNAs (Lnc-RNAs) upregulated in LR-HCC cells were identified by RNA sequencing. The effects of upregulated Lnc-RNAs were evaluated in vitro in cell models and in vivo in experimental animals using quantitative cell viability and apoptosis assays. RESULTS: We found that Lnc-RNA MT1JP (MT1JP) was upregulated in LR-HCC cells and inhibited the apoptosis signaling pathway. In addition, we found that sponging of microRNA-24-3p by MT1JP released Bcl-2 like 2 (BCL2L2), an anti-apoptotic protein, thereby forming a positive-feedback loop. The role of this feedback loop was validated using rescue assays. Additionally, we found that upregulation of MT1JP and BCL2L2 impaired the sensitivity of HCC cells to Lenvatinib both vitro and vivo. CONCLUSIONS: Our results suggest a novel molecular feedback loop between MT1JP and apoptosis signaling in Lenvatinib sensitive HCC cells.

Self-healable castor oil-based waterborne polyurethane/MXene film with outstanding electromagnetic interference shielding effectiveness and excellent shape memory performance.

Recently, the increasing demands of the portable devices and flexible electronics have caused lots of electromagnetic wave pollution. MXene, a novel two-dimensional material, was considered as a promising two-dimensional material for preparing flexible electromagnetic interference (EMI) shielding films. Herein, we firstly synthesized a series of flexible and self-healable EMI shielding waterborne polyurethane (ADWPU) films by mechanically blending with Ti3C2Tx (ADWPU-T). Interestingly, the self-assembling between ADWPU and Ti3C2Tx constructed a tunable analogical structure providing reflection-absorption-multiple reflection shielding mechanism. Furthermore, the ADWPU-T emulsions were prepared from castor oil which is a low-cost and eco-friendly biomass polyol. The chain extender 2-aminophenyl disulfide endow a reversible dynamic polymer network which leading to shape memory performance (45°C heat treatment) and self-healing ability (60°C, 5 min healed). Above all, these multifunctional flexible films also exhibited outstanding EMI shielding performance (51.37 dB) and performed less decrement after 200 times bending and 80°C aging test for five days. Therefore, this work would provide a novel promising method for preparing responsive electromagnetic interference shielding products and smart electronic devices.

High Serum Levels of Cholesterol Increase Antitumor Functions of Nature Killer Cells and Reduce Growth of Liver Tumors in Mice.

BACKGROUND AND AIMS: The relationship between serum cholesterol level and development of hepatocellular carcinoma (HCC) remains unclear. We investigated the effects of serum cholesterol level on development of liver tumors in mice. METHODS: We performed studies with C57BL/6J mice, mice with disruption of the low-density lipoprotein receptor gene (Ldlr-/-mice), and mice with conditional deletion of nature killer (NK) cells (NKdele mice). Some C57BL/6J and NKdele mice were given injections of diethylinitrosamine to induce liver tumor formation. Mice were placed on a normal diet (ND) or high-cholesterol diet (HCD) to induce high serum levels of cholesterol. We also studied mice with homozygous disruption of ApoE (ApoE-/- mice), which spontaneously develop high serum cholesterol. C57BL/6J and NKdele mice on the ND or HCD were implanted with Hep1-6 (mouse hepatoma) cells and growth of xenograft tumors and lung metastases were monitored. Blood samples were collected from mice and analyzed by biochemistry and flow cytometry; liver and tumor tissues were collected and analyzed by histology, immunohistochemistry, and RNA-sequencing analysis. NK cells were isolated from mice and analyzed for cholesterol content, lipid raft formation, immune signaling, and changes in functions. We obtained matched tumor tissues and blood samples from 30 patients with HCC and blood samples from 40 healthy volunteers; levels of cholesterol and cytotoxicity of NK cells were measured. RESULTS: C57BL/6J mice on HCD and ApoE-/- mice with high serum levels of cholesterol developed fewer and smaller liver tumors and lung metastases after diethylinitrosamine injection or implantation of Hep1-6 cells than mice on ND. Liver tumors from HCD-fed mice and ApoE-/- mice had increased numbers of NK cells compared to tumors from ND-fed mice. NKdele mice or mice with antibody-based depletion for NK cells showed similar tumor number and size in ND and HCD groups after diethylinitrosamine injection or implantation of Hep1-6 cells. NK cells isolated from C57BL/6J mice fed with HCD had increased expression of NK cell-activating receptors (natural cytotoxicity triggering receptor 1 and natural killer group 2, member D), markers of effector function (granzyme B and perforin), and cytokines and chemokines compared with NK cells from mice on ND; these NK cells also had enhanced cytotoxic activity against mouse hepatoma cells, accumulated cholesterol, increased lipid raft formation, and immune signaling activation. NK cells isolated from HCD-fed Ldlr-/- mice did not have increased cholesterol content or cytotoxic activity against mouse hepatoma cells compared with ND-fed Ldlr-/- mice. Serum levels of cholesterol correlated with number and activity of NK cells isolated from human HCCs. CONCLUSIONS: Mice with increased serum levels of cholesterol due to an HCD or genetic disruption of ApoE develop fewer and smaller tumors after injection of hepatoma cells or a chemical carcinogen. We found cholesterol to accumulate in NK cells and activate their effector functions against hepatoma cells. Strategies to increase cholesterol uptake by NK cells can be developed for treatment of HCC.

[Outcome of corrective osteotomy of shortened medial foot column after old talar neck fracture].

OBJECTIVE: To investigate the effectiveness of corrective osteotomy for shortened medial foot column after old talar neck fracture. METHODS: The clinical data of 10 patients with shortened medial foot column after old talar neck fracture between June 2012 and May 2017 was retrospectively analyzed. There were 7 males and 3 females with an average age of 45.8 years (mean, 21-67 years). The time from fracture to corrective osteotomy was 9-60 months (mean, 20.9 months). The preoperative visual analogue scale (VAS) score was 7.1±1.2, the American Orthopaedic Foot and Ankle Society (AOFAS) score was 48.5±12.3, and the short-form 36 health survey scale (SF-36) score was 46.7±10.5. All 10 cases received open wedge osteotomy of medial talus. Among them, 2 received subtalar fusion and Achilles tendon lengthening, 2 lateralizing calcaneal osteotomy, and 2 Achilles tendon lengthening. RESULTS: All incisions healed by first intention. All patients were followed up 13-72 months (mean, 38.0 months). The X-ray film showed that the angle between longitudinal axis of 1st metatarsal bone and talus increased from (-9.6±4.5) ° before operation to (1.3±2.7) ° at last follow-up ( t=16.717, P=0.000); the angle between longitudinal axis of calcaneus and tibia increased from (-12.0±7.4) ° before operation to (-1.5±4.8) ° at last follow-up ( t=5.711, P=0.000). At last follow-up, the VAS score, AOFAS score, and SF-36 score were 1.6±1.0, 88.3±5.4, and 85.4±9.2, respectively, which increased significantly when compared with the preoperative scores ( t=13.703, P=0.000; t=14.883, P=0.000; t=16.919, P=0.000). X-ray film and CT showed that the osteotomy and arthrodesis sites healed well at 2-4 months after operation. CONCLUSION: It's a proper procedure of anatomic reduction and reconstruction for patients with shortened medial foot column and good articular cartilage morphology after old talar fracture. Opening wedge osteotomy of medial talus is recommended and can obtain satisfactory clinical and radiographic results.

Diet-induced hepatic steatosis activates Ras to promote hepatocarcinogenesis via CPT1α.

Aberrant activation of the RAS cascade ubiquitously occurs in human hepatocellular carcinomas (HCC), regardless of rare mutations of RAS. However, the association between the Ras cascade and hepatic steatosis during hepatocarcinogenesis remains under-investigated. Here, the variation in the constitutive activity of Ras signaling and HCC incidence was found in a nonalcoholic fatty liver disease (NAFLD)-HCC mouse model, and Ras activity was induced by hepatic steatosis. Even in hepatocyte-specific expression of KrasG12D (Alb-Cre/KrasG12D, Krashep) mice, mutagenic activation of Ras signaling was still significantly enhanced by NAFLD, with downregulation of negative regulators. Interestingly, hepatic steatosis could be alleviated by persistent activation of Ras, whereas Ras accelerated DNA damage and HCC progression through Carnitine palmitoyltransferase 1A (CPT1α). A close correlation between active Ras and CPT1α was also shown in clinical steatosis peri-tumor tissues of HCC samples and experimental models. CPT1α inhibitor etomoxir (ETO) largely ameliorated active Ras-drived HCC. These findings can provide a novel link between steatosis and Ras activity in liver cancer.

[Biomechanical study on repair and reconstruction of talar lesion by three-dimensional printed talar components].

Objective: To explore the feasibility of the repair and reconstruction of large talar lesions with three-dimensional (3D) printed talar components by biomechanical test. Methods: Six cadaveric ankle specimens were used in this study and taken CT scan and reconstruction. Then, 3D printed talar component and osteotomy guide plate were designed and made. After the specimen was fixed on an Instron mechanical testing machine, a vertical pressure of 1 500 N was applied to the ankle when it was in different positions (neutral, 10° of dorsiflexion, and 14° of plantar flexion). The pressure-bearing area and pressure were measured and calculated. Then osteotomy on specimen was performed and 3D printed talar components were implanted. And the biomechanical test was performed again to compare the changes in pressure-bearing area and pressure. Results: Before the talar component implantation, the pressure-bearing area of the talus varied with the ankle position in the following order: 10° of dorsiflexion > neutral position > 14° of plantar flexion, showing significant differences between positions ( P<0.05). The pressure exerted on the talus varied in the following order: 10° of dorsiflexion < neutral position < 14° of plantar flexion, showing significant differences between positions ( P<0.05). The pressure-bearing area and pressure were not significantly different between before and after talar component implantations in the same position ( P>0.05). The pressure on the 3D printed talar component was not significantly different from the overall pressure on the talus ( P>0.05). Conclusion: Application of the 3D printed talar component can achieve precise repair and reconstruction of the large talar lesion. The pressure on the repaired site don't change after operation, indicating the clinical feasibility of this approach.

Cholesterol inhibits hepatocellular carcinoma invasion and metastasis by promoting CD44 localization in lipid rafts.

Cholesterol plays a vital role in modulating the action of membrane proteins critical to cellular function. The effect of serum cholesterol on the prognosis of hepatocellular carcinoma (HCC) patients remains uncertain. Here, we report that high levels of cholesterol predict good survival and low disease recurrence after surgery. Cholesterol could significantly suppress migration and invasion of HCC cells and restrain metastasis of HCC in mice. High levels of cholesterol promoted CD44 translocation into lipid rafts and attenuated CD44-Ezrin binding, which are crucial for cell migration and cancer metastasis. The suppressive effect of cholesterol on HCC metastasis was abolished by the downregulation of CD44 or its palmitoylation inhibitor, which blocked CD44 localization in lipid rafts. Furthermore, pharmacologically promoting CD44 retention inside lipid rafts obviously attenuated HCC migration and invasion, providing a potential therapeutic strategy to prolong the survival of HCC patients.

Contradictory effects of mitochondria- and non-mitochondria-targeted antioxidants on hepatocarcinogenesis by altering DNA repair in mice.

Conflicting effects of antioxidant supplementation on cancer prevention or promotion is of great concern to healthy people and cancer patients. Despite recent studies about antioxidants accelerating the progression of lung cancer and melanoma, antioxidants may still play a role in cancer prevention. Both tumor and antioxidants types influence the actual efficacy. However, little is known about the impact of different types of antioxidants on primary hepatocellular carcinoma (HCC), including non-mitochondrial- and mitochondrial-targeted antioxidants. Utilizing mouse models of chemical hepatocarcinogenesis, we showed that administration of non-mitochondria-targeted antioxidants N-acetylcysteine (NAC) and the soluble vitamin E analog, Trolox, prevented tumorigenesis, whereas administration of mitochondria-targeted antioxidants SS-31 (the mitochondria-targeted peptide) and Mito-Q (a derivative of ubiquinone) facilitated tumorigenesis. RNA sequencing revealed that NAC and SS-31 caused very different changes in the oxidation-reduction state and DNA damage response. In diethylnitrosamine (DEN)-treated primary hepatocytes, NAC and Trolox alleviated DNA damage by activating ataxia-telangiectasia mutated (ATM)/ATM and Rad3-related (ATR) for DNA repair whereas SS-31 and Mito-Q aggravated damage by inactivating them. Interestingly, partial recovery of SS-31-scavengened mitochondrial reactive oxygen species (mtROS) could alleviate SS-31-aggravated DNA damage. Localization of ATM between mitochondria and nuclei was altered after NAC and SS-31 treatment. Furthermore, blockage of phospho-ATR (p-ATR) led to the recurrence of NAC-ameliorated DEN HCC. In contrast, reactivation of p-ATR blocked SS-31-promoted DEN HCC. Conclusion: These results demonstrate that the type of antioxidants plays a previously unappreciated role in hepatocarcinogenesis, and provide a mechanistic rationale for exploring the therapeutic use of antioxidants for liver cancer. (Hepatology 2018;67:623-635).

Constructing 3D Polyphosphazene Nanotube@Mesoporous Silica@Bimetallic Phosphide Ternary Nanostructures via Layer-by-Layer Method: Synthesis and Applications.

A novel ternary nanostructure polyphosphazene nanotube (PZS)@ mesoporous silica (M-SiO2)@bimetallic phosphide (CoCuP) was facilely fabricated, using PZS as the template, where large amount of cetyltrimethylammonium bromide molecules were anchored to PZS via a similar layer-by-layer assembly strategy, and then uniform M-SiO2 shells can be formed successfully by Hyeon's coating method. Subsequently, the three-dimensional (3D) nanostructure on the basis of bimetallic phosphide (CoCuP) interconnected with PZS@M-SiO2 was synthesized via a convenient, mild hydrothermal route. It is noted that incorporating well-designed PZS@M-SiO2@CoCuP led to significant decrease on fire hazard of thermoplastic polyurethane (TPU), that is, 58.2% and 19.4% reductions in peak heat release rate and total heat release, respectively, as well as lower toxic hydrogen cyanide and carbon monoxide yield accompanied by higher graphitized char layer. In the case of TPU/PZS@M-SiO2@CoCuP system, the storage modulus at -97 °C was dramatically improved by 62.6%, and glass transition temperature was shifted to higher value, compared to those of pure TPU. The enhanced fire safety and mechanical property for TPU composites can be ascribed to tripartite cooperative effect from respective parts (CoCuP and M-SiO2) plus the PZS.

Graphitic carbon nitride/phosphorus-rich aluminum phosphinates hybrids as smoke suppressants and flame retardants for polystyrene.

Graphitic carbon nitride/organic aluminum hypophosphites (g-C3N4/OAHPi) hybrids, i.e., CPDCPAHPi and CBPODAHPi, were synthesized by esterification and salification reactions, and then incorporated into polystyrene (PS) to prepare composites through a melt blending method. Structure and morphology characterizations demonstrated the successful synthesis of PDCPAHPi, BPODAHPi and their hybrids. The g-C3N4 protected OAHPi from external heat and thus improved the thermal stability of OAHPi. Combining g-C3N4 with OAHPi contributed to reduction in peak of heat release rate, total heat release and smoke production rate of PS matrix. Reduced smoke released has also been demonstrated by smoke density chamber testing. Additionally, introduction of the hybrids led to decreased release of flammable aromatic compounds. These properties improvement could be attributed to gas phase action and physical barrier effect in condensed phase: phosphorus-containing low-energy radicals generated from OAHPi effectively captured high-energy free-radicals evolved from PS; g-C3N4 nanosheets retarded the permeation of heat and the escape of volatile degradation products. Therefore, g-C3N4/OAHPi hybrids will provide a potential strategy to reduce the fire hazards of PS.

Osteochondral autograft transplantation with biplanar distal tibial osteotomy for patients with concomitant large osteochondral lesion of the talus and varus ankle malalignment.

BACKGROUND: Osteochondral lesions of the talus (OLTs) are amongst the most common foot and ankle disorders. Varus ankle malalignment causes stress concentration on medial side of the joint, resulting in OLTs and osteoarthritis. For large symptomatic OLTs (>10 mm), Osteochondral autograft transplantation is usually recommended. This article highlights biplanar distal tibial osteotomy as an approach and management for patients with concomitant large OLTs and varus ankle malalignment. METHODS: From January 2012 to July 2014, 13 patients (6 male and 7 female) underwent surgery in our faculty and their average age was 55.4 (ranging from 34 to 69) years old. Oblique medial malleolar osteotomy was performed to expose the talar lesion, followed by an osteochondral autograft transplantation and distal tibial opening-wedge osteotomy. Weight-bearing X-rays were conducted and used for the measurement of radiographic parameters such as the tibial articular surface (TAS) and tibial lateral surface (TLS) angles. Ankle function of the subjects was evaluated according to the American Orthopaedic Foot and Ankle Society-Ankle and Hindfoot score (AOFAS-AH) questionnaires and Visual Analog Scale (VAS). RESULTS: 11 patients completed the follow-up over a mean period of 21.2 months. The average area of talar lesion was 135.9 mm2 while the average depth was 11.4 mm. The mean time for osseous union was 8.5 weeks. Donor site morbidity was not recorded in any of the cases. The mean AOFAS-AH and VAS improved from 53 to 90 points (p < 0.05) and 6.7 to 1.9 points (p < 0.05) respectively. The mean TAS angle improved from 83.1 to 90.3° (p < 0.05). CONCLUSIONS: Biplanar distal tibial osteotomy with the combination of osteochondral autograft transplantation could be used to address patients with concomitant large OLTs and varus ankle malalignment as this technique provides excellent visualization of the talar defect, favorable biomechanical environment for the ankle joint with high rate of good and excellent results.

Optimization of hindfoot alignment radiography.

Background Cobey and Buck described methods to evaluate hindfoot alignment, but it is still unclear which method is better and easier to perform in clinical practice. Purpose To evaluate the optimal method for radiography of hindfoot alignment. Material and Methods We randomly selected 50 patients visiting the foot and ankle surgery outpatient department who underwent hindfoot alignment radiography between 1 July and 31 August 2015. Radiographs were taken using both Cobey's and Buck's methods. The patients were divided into three groups by calcaneal inclination angle. We assessed the calcaneotibial angle, calcaneovertical angle, and the distance from the bottom of the calcaneus to the mid-tibial axis. A comparative analysis was performed separately using the t-test. Results One hundred pairs of data for Cobey's and Buck's methods were obtained. The angles were analyzed separately in valgus, normal, and varus situations. The results showed no significant difference between Cobey's method and Buck's method regardless of any situation ( P > 0.05). Regarding the distance between the bottom of the calcaneus and the mid-tibial axis, the average result of Buck's method was about 1 mm larger than that of Cobey's method in the valgus and normal cases ( P < 0.05), except for varus cases ( P > 0.05). Conclusion Cobey's and Buck's techniques are the classic and popular hindfoot alignment assessment methods. The use of Buck's technique resulted in a better image with a less technical procedure and less time requirement. It is worthy of being popularized and used routinely for hindfoot radiography.