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.

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.

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).

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.

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.

Diagnostic accuracy of alpha-defensin in periprosthetic joint infection: a systematic review and meta-analysis.

BACKGROUND: Alpha-defensin, a novel biomarker, has shown great potential for the accurate diagnosis of periprosthetic joint infection (PJI) in recent years: many published studies have presented encouraging results. Nevertheless, the diagnostic accuracy of alpha-defensin is inconsistent across published studies. Moreover, the optimum value of the diagnostic threshold urgently needs to be ascertained. This meta-analysis sought to estimate the precision of alpha-defensin for the diagnosis of PJI and, where possible, to confirm the threshold. METHOD: We systematically searched PubMed, Embase, Cochrane, Web of Knowledge, and ClinicalTrials.gov for relevant literature on alpha-defensin in the diagnosis of PJI (searching publications from the inception of each database until February 2017, with no language restriction). Pooled sensitivity, specificity, diagnostic odds ratios, and likelihood ratios were the indexes used for assessment, with the use of a random-effects model. RESULT: Eleven of the 426 studies that evaluated the diagnostic accuracy of alpha-defensin in periprosthetic joint infection (PJI) were included in this analysis. The pooled diagnostic sensitivity of alpha-defensin for PJI was 0.96 (95% confidence interval [CI], 0.87 to 0.99) and the specificity was 0.95 (95% CI, 0.91 to 0.97). Since there was substantial heterogeneity among studies, based on the inconsistency index (I2), threshold, site of arthroplasty, study design and techniques for the alpha-defensin test, subgroup analyses were performed to estimate the impacts of these variables on heterogeneity. CONCLUSION: In summary, this meta-analysis clearly lends support to the conclusion that alpha-defensin is a promising addition to the current methods for diagnosis of PJI.

In Vivo Kinematics of the Tibiotalar and Subtalar Joints in Asymptomatic Subjects: A High-Speed Dual Fluoroscopy Study.

Measurements of joint kinematics are essential to understand the pathomechanics of ankle disease and the effects of treatment. Traditional motion capture techniques do not provide measurements of independent tibiotalar and subtalar joint motion. In this study, high-speed dual fluoroscopy images of ten asymptomatic adults were acquired during treadmill walking at 0.5 m/s and 1.0 m/s and a single-leg, balanced heel-rise. Three-dimensional (3D) CT models of each bone and dual fluoroscopy images were used to quantify in vivo kinematics for the tibiotalar and subtalar joints. Dynamic tibiotalar and subtalar mean joint angles often exhibited opposing trends during captured stance. During both speeds of walking, the tibiotalar joint had significantly greater dorsi/plantarflexion (D/P) angular ROM than the subtalar joint while the subtalar joint demonstrated greater inversion/eversion (In/Ev) and internal/external rotation (IR/ER) than the tibiotalar joint. During balanced heel-rise, only D/P and In/Ev were significantly different between the tibiotalar and subtalar joints. Translational ROM in the anterior/posterior (AP) direction was significantly greater in the subtalar than the tibiotalar joint during walking at 0.5 m/s. Overall, our results support the long-held belief that the tibiotalar joint is primarily responsible for D/P, while the subtalar joint facilitates In/Ev and IR/ER. However, the subtalar joint provided considerable D/P rotation, and the tibiotalar joint rotated about all three axes, which, along with translational motion, suggests that each joint undergoes complex, 3D motion.

Does the subtalar joint compensate for ankle malalignment in end-stage ankle arthritis?

BACKGROUND: Patients with ankle arthritis often present with concomitant hindfoot deformity, which may involve the tibiotalar and subtalar joints. However, the possible compensatory mechanisms of these two mechanically linked joints are not well known. QUESTIONS/PURPOSES: In this study we sought to (1) compare ankle and hindfoot alignment of our study cohort with end-stage ankle arthritis with that of a control group; (2) explore the frequency of compensated malalignment between the tibiotalar and subtalar joints in our study cohort; and (3) assess the intraobserver and interobserver reliability of classification methods of hindfoot alignment used in this study. METHODS: Between March 2006 and September 2013, we performed 419 ankle arthrodesis and ankle replacements (380 patients). In this study, we evaluated radiographs for 233 (56%) ankles (226 patients) which met the following inclusion criteria: (1) no prior subtalar arthrodesis; (2) no previously failed total ankle replacement or ankle arthrodesis; (3) with complete conventional radiographs (all three ankle views were required: mortise, lateral, and hindfoot alignment view). Ankle and hindfoot alignment was assessed by measurement of the medial distal tibial angle, tibial talar surface angle, talar tilting angle, tibiocalcaneal axis angle, and moment arm of calcaneus. The obtained values were compared with those observed in the control group of 60 ankles from 60 people. Only those without obvious degenerative changes of the tibiotalar and subtalar joints and without previous surgeries of the ankle or hindfoot were included in the control group. Demographic data for the patients with arthritis and the control group were comparable (sex, p=0.321; age, p=0.087). The frequency of compensated malalignment between the tibiotalar and subtalar joints, defined as tibiocalcaneal angle or moment arm of the calcaneus being greater or smaller than the same 95% CI statistical cutoffs from the control group, was tallied. All ankle radiographs were independently measured by two observers to determine the interobserver reliability. One of the observers evaluated all images twice to determine the intraobserver reliability. RESULTS: There were differences in medial distal tibial surface angle (86.6°±7.3° [95% CI, 66.3°-123.7°) versus 89.1°±2.9° [95% CI, 83.0°-96.3°], p<0.001), tibiotalar surface angle (84.9°±14.4° [95% CI, 45.3°-122.7°] versus 89.1°±2.9° [95% CI, 83.0°-96.3°], p<0.001), talar tilting angle (-1.7°±12.5° [95% CI, -41.3°-30.3°) versus 0.0°±0.0° [95% CI, 0.0°-0.0°], p=0.003), and tibiocalcaneal axis angle (-7.2°±13.1° [95% CI, -57°-33°) versus -2.7°±5.2° [95% CI, -13.3°-9.0°], p<0.001) between patients with ankle arthritis and the control group. Using the classification system based on the tibiocalcaneal angle, there were 62 (53%) and 22 (39%) compensated ankles in the varus and valgus groups, respectively. Using the classification system based on the moment arm of the calcaneus, there were 68 (58%) and 20 (35%) compensated ankles in the varus and valgus groups, respectively. For all conditions or methods of measurement, patients with no or mild degenerative change of the subtalar joint have a greater likelihood of compensating coronal plane deformity of the ankle with arthritis (p<0.001-p=0.032). The interobserver and intraobserver reliability for all radiographic measurements was good to excellent (the correlation coefficients range from 0.820 to 0.943). CONCLUSIONS: Substantial ankle malalignment, mostly varus deformity, is common in ankles with end-stage osteoarthritis. The subtalar joint often compensates for the malaligned ankle in static weightbearing. LEVEL OF EVIDENCE: Level III, diagnostic study.

Construction of MXene-mediated inorganic-organic quaternary ammonium salt-hybrid coating for fire safety and multi-mode synergistic antibacterial of cotton fabric.

With the continuous development of the society, there is a growing demand for the durability, versatility and multifunction of cott fabrics. In this work, the cotton fabric is coated with multifunctional coating via dip-coating of transition metal carbide (MXene) and then encapsulation of dimethyloctadecyl [3-trimethoxysilopropyl] ammonium chloride (QAS). In view of MXene with excellent light absorption and photothermal conversion efficiency, the controllable antibacterial performance of the cotton fabric is further improved. Benefiting from the encapsulation of QAS, CF@P@M@QAS fabric shows mechanical stability (24 h washing, 1000 cycles folding test and 100 cyclic abrasion) and hydrophobicity. Meantime, the QAS on the surface of multifunctional cotton fabric significantly increases antibacterial activity, and the antibacterial rate can reach to 100 % against Staphylococcus aureus (S. aureus) and 98 % Escherichia coli (E. coli). Besides, CF@P@M@QAS cotton fabric also integrates functions of fire safety and physical therapy. Thus, this multifunctional cotton fabric based MXene offers a novel solution for extending its application in medical electronics and physical therapy.

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.

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.

Minimally invasive reconstruction of lateral ligaments of the ankle using semitendinosus autograft.

BACKGROUND: Multiple techniques have been described for reconstruction of the lateral ligaments of the ankle. Most require extensive exposure and dissection, which may lead to potential problems with wound healing, higher risk of nerve injury, fibrosis, and stiffness. This study reports on the results of a minimally invasive method to reconstruct the ligaments using a semitendinosus tendon autograft and achieve a stable ankle while avoiding these problems. MATERIALS AND METHODS: From September 2006 to May 2010, 25 patients (14 males, 11 females) with chronic ankle instability underwent lateral ligament reconstruction. The average age was 32.4 (range, 17 to 62) years old. A semitendinosus autograft was harvested through 2 small knee incisions. For the ankle reconstruction, 4 small incisions of 5 mm each were made at the medial and lateral side of the fibular tip, the talar neck, and the middle of the calcaneus. Anatomical reconstruction of the anterior talofibular ligament (ATFL) and calcaneofibular ligament (CFL) was then performed through these small incisions. The mean final follow-up was 32.3 (range, 12 to 56) months. AOFAS questionnaires were used to measure clinical outcomes and donor site morbidity and patient satisfaction are also reported. Preoperative and postoperative stress tests were performed and radiographic parameters were measured. RESULTS: The mean AOFAS score increased on average from 71.1 to 95.1 (P < .001). Two patients reported residual instability on uneven ground. No patient reported weakness or disability from the donor site. The satisfaction level was excellent in 20 patients and good in 5 patients. Significant improvement in stress radiographic parameters was noted for the talar tilt angle, with reduction from a mean of 14.0 to 3.8 degrees (P < .001); anterior talar displacement reduced from a mean of 12.3 to 4.6 mm (P < .001). CONCLUSION: Reconstruction of the lateral ankle ligaments using a semitendinosus tendon autograft and a minimally invasive approach can achieve a stable ankle while avoiding extensive exposure and risk of nerve injury. LEVEL OF EVIDENCE: Level IV, retrospective case series.

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.

Hierarchical Ti3C2Tx@BPA@PCL for flexible polyurethane foam capable of anti-compression, self-extinguishing and flame-retardant.

It is of great importance to fabricate flexible polyurethane foam (FPUF) with superior mechanical properties and flame retardancy for practical applications. Herein, organosilicon and phenyl phosphorus compounds were synthesized and grafted on the surface of Ti3C2Tx (Ti3C2Tx@BPA@PCL) via in-situ polymerization. Then, the FPUF composites were fabricated, combining intrinsic flame retardancy (9,10-dihydro-9-oxa-10-phosphaphenanthrene 10-oxide-diethanolamine: DH-DOPO) (addition amount: 20 wt%) and Ti3C2Tx@BPA@PCL (addition amount: 4 wt%). Attributed to the rigid structure of Ti3C2Tx@BPA@PCL, the tensile strength and compression strength of FPUF showed 24.0% and 253% increase, respectively. In addition, anti-fatigue properties of FPUF composites during the cyclical test were dramatically enhanced. In contrast to pure FPUF, 36.1% and 44.0% reductions in peak heat release rate (pHRR) and total heat release (THR) were achieved for the FPUF containing Ti3C2Tx@BPA@PCL and DH-DOPO, the production rate of carbon dioxide (CO2) and carbon oxide (CO) also decreased by 40.3% and 52.1%, respectively. FPUF4 showed self-extinguishing behavior, and passed the vertical burning test (VBT). This work provides a facile approach to preparing high-performance FPUF with enhanced mechanical property and flame retardancy.

Anti-Fogging, Frost-Resistant transparent and flexible silver Nanowire-Ti3C2Tx MXene based composite films for excellent electromagnetic interference shielding ability.

The development of electronics proposes higher requirements for flexible, transparent, and conductive materials with high electromagnetic shielding performance in viewing windows. Flexible transparent films have been fabricated by collaborating one-dimensional silver nanowires (AgNWs) and novel two-dimensional Ti3C2Tx MXene sheets on PET films with an external polymeric coating consisting of poly (vinyl alcohol) (PVA) and poly(styrene sulfonate) (PSS). Especially, the combination of different dimensional nanomaterials effectively establishes a conductive network that exhibits a synergistic effect on excellent electromagnetic interference (EMI) shielding performance, which is superior to that of pure AgNW network or Ti3C2Tx network to some extent. By optimizing the AgNWs content (0.05 mg/cm2) and Ti3C2Tx sheets content (0.01 mg/cm2), the PET/AgNW/Ti3C2Tx/PVA-PSS film exhibits a transmittance of 81% and a desirable EMI SE value of 30.5 dB. In addition, the film shows outstanding anti-fogging and frost-resistant properties due to the remarkable water absorption capacity of PVA and PSS on the external surface. Considering its efficiency and simplicity, this transparent conductive film has promising applications in flexible transparent electronic devices and optical related fields.

Functionalizing Ti3C2Tx for enhancing fire resistance and reducing toxic gases of flexible polyurethane foam composites with reinforced mechanical properties.

Flexible polyurethane foam (FPUF) is the most used polyurethane, but the highly flammable characteristic limits its widespread usage. In this work, ZIF-8@Ti3C2Txwas synthesized to reduce the heat and toxic gases of FPUF. Flame-retardant FPUF was characterized by cone calorimeter (Cone), thermogravimetric analysis/fourier-transform infrared spectroscopy (TG-FTIR), tensileand compression tests. Compared with pure FPUF, these results showed that the peak of heat release rate (PHRR), total heat release (THR), CO and HCN of FPUF6 decreased by 46%, 69%, 27% and 43.5%, respectively. Moreover, the tensile and compression strength of FPUF6 demonstrated a 52% and 130% increment, respectively. The superior dual metal catalytical charring-forming effect and physical barrier effect of ZIF-8@Ti3C2Tx were achieved. In summary, a simple and reliable strategy for preparing flame-retardant FPUF with reinforced mechanical and fire safety properties was provided.

The Re2Sn2O7 (Re = Nd, Sm, Gd) on the enhancement of fire safety and physical performance of Polyolefin/IFR cable materials.

Polyolefin (PO) cables used in confined spaces need to have low smoke, low heat release, low toxic gas release and excellent physical properties. In this work, a series of rare earth stannates Re2Sn2O7 (RES, Re = Nd, Sm, Gd) with high temperature catalytic performance were prepared by hydrothermal method for synergistic flame retardant PO/IFR. The flame retardancy, heat release, smoke density, toxic gas release and physical properties of PO composites were thoroughly studied in detail. The RES could enhance the vertical burning rating and the limiting oxygen index (LOI) of PO/IFR composites. Moreover, the residual char of the thermogravimetric analysis increased from 9.7% to 11.4 wt% after the RES added in PO/IFR system. Interestingly, the PO/IFR system containing Gd2Sn2O7 exhibits the lowest peak heat release rate of 233.7 kW/m2. Excellent flame resistance due to the formation of a complete and compact protective char layer. In addition, the toxic release of PO during combustion is also effectively reduced by introducing the RES. The tube furnace combustion test shows that the emission of carbon oxide (CO) and hydrogen cyanide (HCN) of PO/IFR/Gd2Sn2O7 are the lowest. It can be attributed to the catalytic effect of rare earth elements and the blocking effect of the dense char layer. In addition, compared with the PO/IFR composites, the PO/IFR/RES system demonstrate higher mechanical properties and volume resistivity. Therefore, the addition of RES has a positive effect on improving the physical properties and fire safety properties of the PO/IFR cable composites, especially suitable for using in confined spaces.

The improvement of fire safety performance of flexible polyurethane foam by Highly-efficient P-N-S elemental hybrid synergistic flame retardant.

Herein, three different phosphorus-containing compounds (methyl phosphoryl dichloride, phenyl phosphoryl dichloride and phenyl dichlorophosphate) were reacted with 2-aminobenzothiazole respectively, and a series of synergistic flame retardants with phosphorus, nitrogen and sulfur elements were synthesized, named MPBT, PPBT and POBT respectively. Then, they were added to prepare flame-retardant flexible polyurethane foam (FPUF). Through the analysis of thermal stability, pyrolysis, heat release and smoke release behavior, the influence of different phosphorus-containing structures on the flame-retardant performance of FPUF was studied, and their flame-retardant mechanism was explored in detail. Among them, MPBT had the highest flame retardant efficiency with the same addition amount (10 wt%). The limiting oxygen index (LOI) value of PU/10.0% MPBT reached 22.5 %, and it successfully passed the vertical burning test. Subsequently, the addition amount of MPBT was increased and the best comprehensive performance of flame-retardant FPUF was explored. The results showed that the LOI value of PU/15.0% MPBT was increased to 23.5%. As for PU/15.0% MPBT, the peak heat release rate (PHRR) was 453 KW/m2, which was reduced by 46.64 %; and the flame retardancy index (FRI) value was also increased to 6.88. At the same time, the mechanical properties of flame-retardant FPUF were studied. The tensile strength of PU/15.0% MPBT reached 170 KPa, and the permanent deformation of FPUF/10% MPBT was only 4 %, showing its excellent resilience. The above results show that this phosphorus-containing element hybrid synergistic flame retardant (MPBT) has a very good application prospect in the field of flame-retardant polymer materials.

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.

Design of copper salt@graphene nanohybrids to accomplish excellent resilience and superior fire safety for flexible polyurethane foam.

Flexible polyurethane foam (FPUF) is the most commonly used polyurethane, but its highly flammable characteristics makes it ignite easily and release a lot of heat and toxic gases. Here, the effect of different forms of copper salt modified graphene (rGO@CuO, rGO@Cu2O and rGO@CSOH) on improving the fire protection efficiency and mechanical property of FPUF is explored. Hybrid FPUF is characterized by thermogravimetric analysis (TGA), cone calorimeter, thermogravimetric analysis/Fourier transform infrared spectroscopy (TG-IR), tension, compression, and falling ball rebound testing. Compared with pure FPUF, the FPUF/rGO@CSOH show a significant decreasement in reducing the heat release of FPUF, the PHRR and THR are reduced by 36.9% and 29.4%, respectively. While the FPUF/rGO@Cu2O demonstrate excellent smoke and toxic gases suppression in FPUF, the PSPR and TSR are reduced by 24.6% and 51.9%, and the COP and COY are also reduced by 51.9% and 55.3%, respectively. After adding the copper salt hybrid, the buffering performance of FPUF did not change. Fortunately, the tensile and compressive strength increase obviously. The flame retardant and smoke suppression mechanism of hybrid FPUF has also been studied. This article gives a effective strategy for the preparation of FPUF with outstanding mechanical property, flame retardant and smoke suppression properties.