Enhanced Osteolysis Targeted Therapy through Fusion of Exosomes Derived from M2 Macrophages and Bone Marrow Mesenchymal Stem Cells: Modulating Macrophage Polarization.

Aseptic loosening of prostheses is a highly researched topic, and wear particle-induced macrophage polarization is a significant cause of peri-prosthetic osteolysis. Exosomes derived from bone marrow mesenchymal stem cells (BMSCs-Exos) promote M2 polarization and inhibit M1 polarization of macrophages. However, clinical application problems such as easy clearance and lack of targeting exist. Exosomes derived from M2 macrophages (M2-Exos) have good biocompatibility, immune escape ability, and natural inflammatory targeting ability. M2-Exos and BMSCs-Exos fused exosomes (M2-BMSCs-Exos) are constructed, which targeted the osteolysis site and exerted the therapeutic effect of both exosomes. M2-BMSCs-Exos achieved targeted osteolysis after intravenous administration inhibiting M1 polarization and promoting M2 polarization to a greater extent at the targeted site, ultimately playing a key role in the prevention and treatment of aseptic loosening of prostheses. In conclusion, M2-BMSCs-Exos can be used as a precise and reliable molecular drug for peri-prosthetic osteolysis. Fused exosomes M2-BMSCs-Exos  were originally proposed and successfully prepared, and exosome fusion technology provides a new theoretical basis and solution for the clinical application of therapeutic exosomes.

L-shaped association between the GA/HbA1c ratio and all-cause mortality in U.S. adults with NAFLD: a cross-sectional study from the NHANES 1999-2004.

OBJECTIVE: It is currently unclear whether there is a relationship between the ratio of glycated albumin to hemoglobin A1c (GA/HbA1c) and mortality in individuals diagnosed with nonalcoholic fatty liver disease (NAFLD). The primary objective of the study was to investigate the relationship between the GA/HbA1c ratio and all-cause mortality in adults with NAFLD in the U.S. METHODS: The investigation included a total of 5,295 individuals aged ≥ 18 years who were diagnosed with NAFLD, these individuals were selected from the National Health and Nutrition Examination Survey conducted between 1999 and 2004. To evaluate the outcomes of death, the researchers relied on National Death Index (NDI) records up to December 31, 2019. To better understand the nonlinear relationship between the GA/HbA1c ratio and mortality among individuals with NAFLD, this study employed both subgroup and sensitivity analyses. Furthermore, Cox proportional hazards models and two-part Cox proportional hazards model were utilized. RESULTS: The study included a total of 5,295 adult patients with NAFLD in the U.S. During a median follow-up period of 16.9 years, there were 1,471 recorded deaths, including 419 cardiovascular deaths. After accounting for various factors, a higher GA/HbA1c ratio exhibited a positive and nonlinear association with an increased risk of all-cause mortality in patients with NAFLD. Furthermore, the study revealed an L-shaped relationship between the GA/HbA1c ratio and all-cause mortality, with the inflection point occurring at a GA/HbA1c ratio of 2.21. When the GA/HbA1c ratio exceeded 2.21, each 1-unit increase in the ratio was associated with a 33% increase in the adjusted hazard ratio (HR 1.33; 95% CI 1.14, 1.60) for all-cause mortality. CONCLUSIONS: A nonlinear correlation between the ratio of GA to HbA1c and all-cause mortality was observed in U.S. adults with NAFLD. In addition, an elevated GA/HbA1c ratio was linked to an increased risk of all-cause mortality in these patients.

Bacterial outer membrane vesicle-cancer cell hybrid membrane-coated nanoparticles for sonodynamic therapy in the treatment of breast cancer bone metastasis.

Breast cancer bone metastasis is a terminal-stage disease and is typically treated with radiotherapy and chemotherapy, which causes severe side effects and limited effectiveness. To improve this, Sonodynamic therapy may be a more safe and effective approach in the future. Bacterial outer membrane vesicles (OMV) have excellent immune-regulating properties, including modulating macrophage polarization, promoting DC cell maturation, and enhancing anti-tumor effects. Combining OMV with Sonodynamic therapy can result in synergetic anti-tumor effects. Therefore, we constructed multifunctional nanoparticles for treating breast cancer bone metastasis. We fused breast cancer cell membranes and bacterial outer membrane vesicles to form a hybrid membrane (HM) and then encapsulated IR780-loaded PLGA with HM to produce the nanoparticles, IR780@PLGA@HM, which had tumor targeting, immune regulating, and Sonodynamic abilities. Experiments showed that the IR780@PLGA@HM nanoparticles had good biocompatibility, effectively targeted to 4T1 tumors, promoted macrophage type I polarization and DC cells activation, strengthened anti-tumor inflammatory factors expression, and presented the ability to effectively kill tumors both in vitro and in vivo, which showed a promising therapeutic effect on breast cancer bone metastasis. Therefore, the nanoparticles we constructed provided a new strategy for effectively treating breast cancer bone metastasis.

Electrochemically Driven Nickel-Catalyzed Halogenation of Unsaturated Halide and Triflate Derivatives.

A robust electrochemically driven nickel-catalyzed halogen exchange of unsaturated halides and triflates (Br to Cl, I to Cl, I to Br, and OTf to Cl) is reported. A combination of NiCl2 ⋅ glyme as the precatalyst, 2,2'-bipyridine as a ligand, NMP as the solvent, and electrochemistry allowed the generation of a nickel species that promotes reductive elimination of the desired product. This paired electrochemical halogenation is compatible with a range of unsaturated halides and triflates, including heterocycles, dihaloarenes, and alkenes with good functional-group tolerance. Joint experimental and theoretical mechanistic investigations highlighted three catalytic events: i) oxidative addition of the aryl halide to a Ni(0) species to deliver a Ni(II) intermediate; ii) halide metathesis at Ni(II); iii) electrochemical oxidation of Ni(II) to Ni(III) to enable the formation of the desired aryl halide upon reductive elimination. This methodology allows the replacement of heavy halogens (I or Br) or polar atoms (O) with the corresponding lighter and more lipophilic Cl group to block undesired reactivity or modify the properties of drug and agrochemical candidates.

Robot Assisted Laparoscopy Combined with Thoracoscopy in the Treatment of Hepatocellular Carcinoma with Inferior Vena Cava Tumor Thrombus.

BACKGROUND: Facing the 0.7-22% incidence rate of hepatocellular carcinoma (HCC) with inferior vena cava tumor thrombus (IVCTT), there are usually no obvious symptoms and signs when the tumor thrombus completely blocks the IVCTT in the early stage.1.J Gastroenterol. 29:41-46;2.Hepatogastroenterology. 41:154-157;3.Clin Cardiol. 19:211-213; Once diagnosed, it is the end-stage manifestation without unified treatment for HCC with IVCTT, bringing poor prognosis. Without active treatment, the median survival time is only 3 months. Previous scholars believed that patients with IVCTT should not adopt active surgical treatment. With the advance of technology, active surgical treatment has significantly lengthened the survival time with IVCTT.4.Ann Surg Oncol. 20:914-22;5.World J Surg Oncol. 11:259;6.Hepatogastroenterology. 58:1694-1699; However, for patients with HCC and IVCTT, open surgery was always selected in the past by opening the diaphragm through the combined thoracoabdominal incision to block the superior and subhepatic vena cava, leading long incision and huge trauma. With the development of minimally invasive techniques, laparoscopy thoracoscopy has showed great advantages in the treatment of HCC with IVCTT. A patient underwent laparoscopic with thoracoscopic resection of tumor and cancer thrombectomy after neoadjuvant therapy and then survived after follow-up.7.Ann Surg Oncol. 29:5548-5549 Therefore, it used as a first reported case of robot-assisted laparoscopic with thoracoscopic treatment of HCC complicated inferior vena cava cancer thrombectomy. METHODS: A 41-year-old man had a liver space-occupying lesion discovered during his medical examination 2 months ago. The diagnosis of HCC with IVCTT was confirmed by enhanced CT and biopsy specimen in the first hospitalization. A combination of TACE, targeted therapy, and immunotherapy plan was applied for the patient after multidisciplinary treatment (MDT). Specifically, Lenvatinib was taken orally 8 mg daily and 160 mg of toripalimab was given intravenously every 3 weeks. His reexamination CT showed that the tumor was more advanced after 2 months of treatment. The surgical operation was performed based on comprehensive consideration. The patient was placed in the left lateral decubitus position, and a thoracoscopic prefabricated the inferior vena cava above diaphragm blocking device was pulled out of the incision. The patient was switched to a supine position with the head of the bed raised 30 degrees. The gallbladder was removed first after entering the abdominal cavity, then prefabricated first hilar blocking band. Sterile rubber glove edges and hemo-lock were used to fabricate the blocking device. The novel hepatic inflow occlusion device is a safe, reliable, and convenient technique that is associated with favorable perioperative outcomes and low risk of conversion.8.Surg Endosc. 34:2807-2813 The liver along the middle hepatic vein was cut to expose the anterior wall of the inferior vena cava, then prefabricated posterior inferior vena cava blocking belt and right hepatic vein blocking belt. Finally, the first portal of liver, right hepatic vein, retrohepatic inferior vena cava, and inferior vena cava above diaphragm were blocked in sequence, so that accomplishing tumor resection and thrombectomy of inferior vena cava. It should be emphasized that before the inferior vena cava is completely sutured, the retrohepatic inferior vena cava blocking device should be released to allow blood flow to flush the inferior vena cava. Moreover, transesophageal ultrasound is required to real-time monitor inferior vena cava blood flow and IVCTT. Some images of the operation are shown in Fig. 1. Fig. 1 (a) Layout of the trocar. ①Make a 3cm small incision between the right anterior axillary line and the midaxillary line, parallel to the fourth and fifth intercostal spaces; a puncture hole in the next intercostal space for endoscope; ②2cm above the intersection of umbilicus horizontal line and axillary front line; ③Intersection of right clavicular midline and umbilical horizontal line; ④Superior margin of umbilicus; ⑤The midpoint of '④ & ⑥'; ⑥2cm below the intersection of left clavicular midline and left costal margin. (b) Prefabricated the inferior vena cava blocking device above diaphragm by thoracoscopic. (c) The smooth tumor thrombus protruding into the inferior vena cava RESULTS: It took 475 min to finish the operation, and the loss of blood was estimated as 300 ml. The patient was discharged from hospital 8 days after the operation without postoperative complication. HCC was confirmed by postoperative pathology. CONCLUSIONS: Robot surgical system reduces the limitations of laparoscopic surgery by offering a stable three-dimensional view, 10-times-enlarged image, restored eye-hand axis, and excellent dexterity with the endowristed instruments, which has several advantages over open operation such as diminished blood loss, reduced morbidity, and shorter hospital stay.9.Chirurg. 88:7-11;10.BMC Surg. 11:2;11.Minerva Chir. 64:135-146; Furthermore, it could favor the operative feasibility of difficult resections reducing the conversion rate and playing a role to extend the indications of liver resection to minimally invasive approaches. It may provide new curative options in patients deemed inoperable with conventional surgery, such as HCC with IVCTT.12.Biosci Trends. 16:178-188;13.J Hepatobiliary Pancreat Sci. 29:1108-1123.

Recent advances in the role of exosomes in liver fibrosis.

BACKGROUND AND AIM: We aim to summarize the current status of research on the role of exosomes in liver fibrosis. METHODS: A review of the relevant literature was performed and the key findings were presented. RESULTS: Most studies focused on the role of exosomes derived from mesenchymal stem cells, other types of stem cells, and liver resident cells including hepatocytes, cholangiocytes, and hepatic stellate cells in liver fibrosis. Exosomes have been reported to play an essential role in the inactivation or activation of hepatic stellate cells through the delivery of non-coding RNAs and proteins. In recent years, this exosome cargo has become a research hotspot. CONCLUSIONS: Recent studies have indicated the potential therapeutic benefit of exosomes in liver fibrosis.

A study of simulation training in laparoscopic bilioenteric anastomosis on a 3D-printed dry lab model.

BACKGROUND: There are few studies on simulation training in laparoscopic bilioenteric anastomosis. There is also a lack of mature and reliable training models for bilioenteric anastomosis. In this study, we aimed to assess a feasible training model for bilioenteric anastomosis. Surgeons can improve their surgical ability by performing laparoscopic bilioenteric anastomosis on this model through repeated training. METHOD: The original articles related to simulation training in surgical anastomosis were identified from January 2000 to November 2021 in the Clarivate Analytics Web of Science Core Collection database. We conducted a bibliometric analysis based on the country of these publications and the type of anastomosis. A 3D-printed bilioenteric anastomosis model was applied in this study. Baseline data of 15 surgeons (5 surgeons of Attendings, 5 surgeons of Fellows, and 5 surgeons of Residents) were collected. The bilioenteric anastomosis data, including the operation time and operation score, were recorded and analyzed. A study of the learning curve was also performed for further assessment. RESULT: Surgeons at different levels of experience exhibited different levels of performance in conducting laparoscopic bilioenteric anastomosis on this model. Experienced surgeons completed their first training session in a shorter time and obtained a higher surgical score. In turn, repeated training significantly shortened the time of laparoscopic bilioenteric anastomosis for each trainer and improved the surgical score. Surgeons with different levels of experience needed different numbers of cases to reach the stable period of the learning curve. Experienced surgeons were able to reach a proficient level through fewer training cases. CONCLUSION: A suitable biliary-enteric anastomosis model can help surgeons conduct simulation training and provide experience and skill accumulation for future real operations. Our training model performed well in this study and can effectively accomplish this goal.

PLGA nanoparticles engineering extracellular vesicles from human umbilical cord mesenchymal stem cells ameliorates polyethylene particles induced periprosthetic osteolysis.

The wear particle-induced dissolution of bone around implants is a significant pathological factor in aseptic loosening, and controlling prosthetic aseptic loosening holds crucial social significance. While human umbilical cord mesenchymal stem cell-derived exosomes (HucMSCs-Exos, Exos) have been found to effectively promote osteogenesis and angiogenesis, their role in periprosthetic osteolysis remains unexplored. To enhance their in vivo application, we engineered HucMSCs-Exos-encapsulated poly lactic-co-glycolic acid (PLGA) nanoparticles (PLGA-Exos). In our study, we demonstrate that PLGA-Exos stimulate osteogenic differentiation while inhibiting the generation of reactive oxygen species (ROS) and subsequent osteoclast differentiation in vitro. In vivo imaging revealed that PLGA-Exos released exosomes slowly and maintained a therapeutic concentration. Our in vivo experiments demonstrated that PLGA-Exos effectively suppressed osteolysis induced by polyethylene particles. These findings suggest that PLGA-Exos hold potential as a therapeutic approach for the prevention and treatment of periprosthetic osteolysis. Furthermore, they provide novel insights for the clinical management of osteolysis.

Phase-Controlled Synthesis of Nickel-Iron Nitride Nanocrystals Armored with Amorphous N-Doped Carbon Nanoparticles Nanocubes for Enhanced Overall Water Splitting.

Transition metal nitrides (TMNs) nanostructures possess distinctive electronic, optical, and catalytic properties, showing great promise to apply in clean energy, optoelectronics, and catalysis fields. Nonetheless, phase-regulation of NiFe-bimetallic nitrides nanocrystals or nanohybrid architectures confronts challenges and their electrocatalytic overall water splitting (OWS) performances are underexplored. Herein, novel pure-phase Ni2+ x Fe2- x N nanocrystals armored with amorphous N-doped carbon (NC) nanoparticles nanocubes (NPNCs) are obtained by controllable nitridation of NiFe-Prussian-blue analogues derived oxides/NC NPNCs under Ar/NH3 atmosphere. Such Ni2+ x Fe2- x N/NC NPNCs possess mesoporous structures and show enhanced electrocatalytic activity in 1 m KOH electrolyte with the overpotential of 101 and 270 mV to attain 10 and 50 mA cm-2 current toward hydrogen and oxygen evolution reactions, outperforming their counterparts (mixed-phase NiFe2 O4 /Ni3 FeN/NC and NiFe oxides/NC NPNCs). Remarkably, utilizing them as bifunctional catalysts, the assembled Ni2+ x Fe2- x N/NC||Ni2+ x Fe2- x N/NC electrolyzer only needs 1.51 V cell voltage for driving OWS to approach 10 mA cm-2 water-splitting current, exceeding their counterparts and the-state-of-art reported bifunctional catalysts-based devices, and Pt/C||IrO2 couples. Additionally, the Ni2+ x Fe2- x N/NC||Ni2+ x Fe2- x N/NC manifests excellent durability for OWS. The findings presented here may spur the development of advanced TMNs nanostructures by combining phase, structure engineering, and hybridization strategies and stimulate their applications toward OWS or other clean energy fields.

Identification of invasion-metastasis associated MiRNAs in gallbladder cancer by bioinformatics and experimental validation.

BACKGROUND: Recent studies exploring the roles of invasion-metastasis associated miRNAs in gallbladder cancer (GBC) are limited. In the study, we aimed to identify the invasion-metastasis associated miRNAs in GBC by bioinformatics and experimental validation. METHODS: MiRNAs of different expression were identified by comparing GBC tumor samples with different survival from Gene Expression Omnibus database. MiRTarBase was used for identifying the potential target genes of miRNAs. Then, we performed Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. And miRNA-gene and protein-protein interaction (PPI) network were constructed for hub genes evaluation. We further explored and compared miR-642a-3p and miR-145-5p expression in both The Cancer Genome Atlas database and our hospital data. Finally, quantitative real-time PCR, wound healing assay, and Transwell assay were conducted to validate the invasion-metastasis associated miRNAs in GBC. RESULTS: In GSE104165 database, 25 up-regulated and 97 down-regulated miRNAs were detected with significantly different expression in GBC tumor samples. Then, 477 potential target genes were identified from the 2 most up-regulated miRNAs (miR-4430 and miR-642a-3p) and 268 genes from the 2 most down-regulated miRNAs (miR-451a and miR-145-5p). After GO and KEGG analysis, mTOR and PI3K-Akt signaling pathways were found associated with the potential target genes. Based on PPI network, the top 10 highest degree hub nodes were selected for hub genes. Furthermore, the miRNA-hub gene network showed significant miR-642a-3p up-regulation and miR-145-5p down-regulation in both GBC tissues and cell lines. In the experimental validation, miR-145-5p up-regulation and miR-642a-3p down-regulation were confirmed to suppress GBC invasion and metastasis. CONCLUSIONS: MiR-642a-3p and miR-145-5p were identified as invasion-metastasis associated miRNAs via bioinformatics and experimental validation, and both up-regulation of miR-642a-3p and down-regulation of miR-145-5p would be served as novel treatment options for GBC in the future.

Inhibition of AMPK/PFKFB3 mediated glycolysis synergizes with penfluridol to suppress gallbladder cancer growth.

BACKGROUND: Penfluridol (PF) is an FDA-approved antipsychotic drug that has recently been shown to have anticancer activity. However, the anticancer effects and underlying mechanisms of PF are not well-established in gallbladder cancer (GBC). METHODS: The anticancer efficacy of PF on GBC was investigated via a series of cell functions experiments, including cell viability, colony formation, apoptosis assays, and so on. The corresponding signaling changes after PF treatment were explored by western blotting. Then, nude mice were utilized to study and test the anticancer activity of PF in vivo. Besides, glucose consumption and lactic production assays were used to detect the glycolysis alteration. RESULTS: In this study, we discovered that PF greatly inhibited the proliferation and invasion ability of GBC cells (GBCs). The glucose consumption and lactic generation ability of GBCs were dramatically elevated following PF treatment. Additionally, we discovered that inhibiting glycolysis could improve PF's anticancer efficacy. Further studies established that the activation of the AMPK/PFKFB3 signaling pathway medicated glycolysis after PF treatment. We proved mechanistically that inhibition of AMPK/PFKFB3 singling pathway mediated glycolysis was a potential synergetic strategy to improve the anticancer efficacy of PF on GBC. CONCLUSIONS: By inhibiting AMPK, the anticancer effects of PF on GBCs were amplified. As a result, our investigations shed new light on the possibility of repurposing PF as an anticancer drug for GBC, and AMPK inhibition in combination with PF may represent a novel therapeutic strategy for GBC. Video abstract.

The "Deep Subarcuate Fossa" sign and three types of anomalous subarcuate loops encountered during vestibular schwannoma removal.

BACKGROUND: An anomalous subarcuate loop (SL) of the anteroinferior cerebellar artery (AICA) is a rare anatomic variation, which increases the complexity and risk of vestibular schwannoma (VS) removal. However, preoperative diagnosis of this anomaly remains difficult. The aim of this study was to report three types of anomalous SLs encountered during VS removal and to describe the "Deep Subarcuate Fossa (SF)" sign and its significance in the diagnosis and treatment of an osseous-penetrating SL. METHODS: We prospectively observed 963 patients with newly/recently diagnosed VS who underwent surgical treatment performed by the senior author (P.Z.) from 2012 to 2021 and identified 16 patients with an anomalous SL. The SF was retrospectively measured on preoperative thin-slice temporal bone computed tomography in 963 patients. RESULTS: Three types of anomalous SLs were encountered during VS removal: the apex of the SL was embedded in the dorsal tumor capsule (type I, 1 case), the dura (type II, 8 cases), or the dura and bone (type III, 7 cases) surrounding the SF. The depth of the SF in 7 patients with a type III anomalous SL ranged from 2.3 to 7.0 mm (3.56 ± 1.56 mm), which was significantly larger than that in 845 patients without an osseous-penetrating SL (1.23 ± 0.43 mm) (p = 0.008). When the depth of the SF exceeded 2 mm, the sensitivity and precision of the diagnosis of a type III anomalous SL were 100% (7/7) and 31.8% (7/22), respectively. CONCLUSION: Three types of anomalous SLs may be encountered during VS removal, and AICA displacement is recommended before tumor removal. The "Deep SF" sign may indicate the existence of a type III anomalous SL and it can predict the depth of the AICA in the bone and guide the drilling of the bone around the vessel loop.

Risk factors and consequences of conversion in minimally invasive distal pancreatectomy.

Background: Although recent studies have reported potential benefits of laparoscopic approach in distal pancreatectomy, reports of conversion during minimally invasive distal pancreatectomy (MIDP) were limited. Methods: This was a retrospective study using data from Sir Run Run Shaw Hospital around May 2013 to December 2018. Outcomes of patients who had conversions during MIDP were compared with patients with successful MIDP and with patients undergoing open distal pancreatectomy (ODP). Results: Two-hundred and eighty-three cases were included in this study: 225 (79.5%) had MIDP, 30 (10.6%) had conversions and 28 (9.9%) had outpatient department. The risk factors for conversion included large lesion size (heart rates [HR]: 5.632, 95% confidencevinterval [CI]: 1.036-1.450, P = 0.018) and pancreatic cancer (HR: 6.957, 95% CI: 1.359-8.022, P = 0.009). Compared with MIDP, those who required conversion were associated with longer operations (P = 0.003), higher blood loss (P < 0.001) and more severe of the complications (P < 0.001). However, no statistically significant differences were found between the conversion group and ODP. Conclusions: Large lesion size and pancreatic cancer were reported to be independent risk factors for conversion during MIDP. As for post-operative outcomes, the outcomes of successfully MIDP were better than those for conversion. However, conversion did not lead to worsening outcomes when compared with ODP.

Molecular understanding of charge storage and charging dynamics in supercapacitors with MOF electrodes and ionic liquid electrolytes.

We performed constant-potential molecular dynamics simulations to analyse the double-layer structure and capacitive performance of supercapacitors composed of conductive metal-organic framework (MOF) electrodes and ionic liquids. The molecular modelling clarifies how ions transport and reside inside polarized porous MOFs, and then predicts the corresponding potential-dependent capacitance in characteristic shapes. The transmission line model was adopted to characterize the charging dynamics, which further allowed evaluation of the capacitive performance of this class of supercapacitors at the macroscale from the simulation-obtained data at the nanoscale. These 'computational microscopy' results were supported by macroscopic electrochemical measurements. Such a combined nanoscale-to-macroscale investigation demonstrates the potential of MOF supercapacitors for achieving unprecedentedly high volumetric energy and power densities. It gives molecular insights into preferred structures of MOFs for accomplishing consistent performance with optimal energy-power balance, providing a blueprint for future characterization and design of these new supercapacitor systems.

N-Aryl and N-Alkyl Carbamates from 1 Atmosphere of CO2.

We have successfully isolated and characterized the zinc carbamate complex (phen)Zn(OAc)(OC(=O)NHPh) (1; phen=1,10-phenanthroline), formed as an intermediate during the Zn(OAc)2 /phen-catalyzed synthesis of organic carbamates from CO2 , amines, and the reusable reactant Si(OMe)4 . Density functional theory calculations revealed that the direct reaction of 1 with Si(OMe)4 proceeds via a five-coordinate silicon intermediate, forming organic carbamates. Based on these results, the catalytic system was improved by using Si(OMe)4 as the reaction solvent and additives like KOMe and KF, which promote the formation of the five-coordinated silicon species. This sustainable and effective method can be used to synthesize various N-aryl and N-alkyl carbamates, including industrially important polyurethane raw materials, starting from CO2 under atmospheric pressure.

Adjuvant transarterial chemoembolization to sorafenib in unresectable hepatocellular carcinoma: A meta-analysis.

BACKGROUND AND AIM: An increasing number of transarterial chemoembolization (TACE) plus sorafenib combination therapy has been applied for unresectable hepatocellular carcinoma (HCC). However, it remains controversial whether combination therapy is superior to sorafenib monotherapy. Therefore, we aimed to perform a meta-analysis to evaluate the efficacy and safety of the combination therapy of TACE plus sorafenib for unresectable HCC. METHODS: This meta-analysis was based on the relative outcomes from a specific search of online databases between January 2008 and November 2019, and subgroup analyses were conducted to identify potential predictive factors. RESULTS: A total of 3868 patients (TACE plus sorafenib vs sorafenib, 1181 vs 2687) were identified from nine studies, including one randomized controlled trial and eight retrospective cohort studies. The pooled results revealed that TACE plus sorafenib combination therapy significantly improves overall survival with the combined hazard ratio 0.74 (95% confidence interval [CI] = 0.66-0.84, P < 0.001), time to progression (hazard ratio = 0.73, 95%CI = 0.65-0.82, P < 0.001), and objective response rate (odds ratio = 2.19, 95% CI = 1.31-3.66, P = 0.003). Subgroup analysis indicated that patients who developed macrovascular invasion achieve significantly great overall survival (P for interaction = 0.001) with combination therapy, in contrast to nonmacrovascular invasion patients. In addition, no significant differences in adverse events were observed. CONCLUSION: This meta-analysis demonstrated that TACE plus sorafenib combination therapy is superior to sorafenib monotherapy and should be recommended as an optimal treatment choice for unresectable HCC.

DUSP6 mediates T cell receptor-engaged glycolysis and restrains TFH cell differentiation.

Activated T cells undergo metabolic reprogramming and effector-cell differentiation but the factors involved are unclear. Utilizing mice lacking DUSP6 (DUSP6-/-), we show that this phosphatase regulates T cell receptor (TCR) signaling to influence follicular helper T (TFH) cell differentiation and T cell metabolism. In vitro, DUSP6-/- CD4+ TFH cells produced elevated IL-21. In vivo, TFH cells were increased in DUSP6-/- mice and in transgenic OTII-DUSP6-/- mice at steady state. After immunization, DUSP6-/- and OTII-DUSP6-/- mice generated more TFH cells and produced more antigen-specific IgG2 than controls. Activated DUSP6-/- T cells showed enhanced JNK and p38 phosphorylation but impaired glycolysis. JNK or p38 inhibitors significantly reduced IL-21 production but did not restore glycolysis. TCR-stimulated DUSP6-/- T cells could not induce phosphofructokinase activity and relied on glucose-independent fueling of mitochondrial respiration. Upon CD28 costimulation, activated DUSP6-/- T cells did not undergo the metabolic commitment to glycolysis pathway to maintain viability. Unexpectedly, inhibition of fatty acid oxidation drastically lowered IL-21 production in DUSP6-/- TFH cells. Our findings suggest that DUSP6 connects TCR signaling to activation-induced metabolic commitment toward glycolysis and restrains TFH cell differentiation via inhibiting IL-21 production.

Role of cellular, molecular and tumor microenvironment in hepatocellular carcinoma: Possible targets and future directions in the regorafenib era.

Hepatocellular carcinoma (HCC) remains as one of the major causes of cancer-related mortality, despite the recent development of new therapeutic options. Regorafenib, an oral multikinase inhibitor, is the first systemic therapy that has a survival benefit for patients with advanced HCC that have a poor response to sorafenib. Even though regorafenib has been approved by the FDA, the clinical trial for regorafenib treatment does not show significant improvement in overall survival. The impaired efficacy of regorafenib caused by various resistance mechanisms, including epithelial-mesenchymal transitions, inflammation, angiogenesis, hypoxia, oxidative stress, fibrosis and autophagy, still needs to be resolved. In this review, we provide insight on regorafenib microenvironmental, molecular and cellular mechanisms and interactions in HCC treatment. The aim of this review is to help physicians select patients that would obtain the maximal benefits from regorafenib in HCC therapy.

The role of interfacial H-bonding on the electrical properties of UV-cured resin filled with hydroxylated Al2O3 nanoparticles.

Surface hydroxylation of crude Al2O3 (c-Al2O3) nanoparticles by H2O2 was conducted to tailor the electrical properties of UV-cured resin. The hydroxyl groups on Al2O3 particles were designed to establish hydrogen bonding between the hydroxyl and carboxyl groups, which favors the enhancement of interfacial strength between fillers and UV-cured resin matrix. The effect of interfacial strength on the electrical properties was investigated. Owing to the improved interfacial strength, it can be conjectured that a larger volume of the interaction zone exists in UV-cured resin/hydroxylated Al2O3 (UV/h-Al2O3) composites. As a consequence, the number of deeper traps is increased, restraining the charge migration and raising the charge injection barrier. Thus, UV/h-Al2O3 composites exhibit remarkably enhanced breakdown strength, improved volume resistivity and suppressed space charge accumulation in comparison with that of UV/c-Al2O3 composites at the same filler content. It was found that the addition of 0.5 wt% h-Al2O3 increases the AC breakdown strength and volume resistivity by 15.5% and 367.9%, respectively. Our results suggest that hydroxylation is an efficient way to improve the electrical properties of UV-cured resin nanocomposites, thus promoting stereolithography 3D printing in the application of electrical and electronic fields.

IgA1 isolated from Henoch-Schönlein purpura children promotes proliferation of human mesangial cells in vitro.

Previous studies show that the proliferation of human mesangial cells (HMCs) played a significant part in the pathogenesis of Henoch-Schönlein purpura nephritis (HSPN). The aim of this study was to explore the proliferation of HMCs induced by IgA1 isolated from the sera of HSP patients. HMCs were cultured in three different types of media, including IgA1 from patients with HSP (HSP IgA1 group), healthy children (healthy IgA1 group) and medium (control group). The proliferation of HMCs incubated with IgA1 was determined by cell counting kit-8 assay and bromodeoxyuridine incorporation. The expression of ERK1/2 and phosphatidylinositol 3 kinase/protein kinase B/mammalian targets of the rapamycin (PI3K/AKt/mTOR) signals and transferrin receptor (TfR/CD71) was detected with the methods of immunoblotting. The results indicated that the proliferation of HMCs significantly increased in the HSP IgA1 group compared with that in the control group or the healthy IgA1 group (P < 0.001). Moreover, we found that IgA1 isolated from HSP patients activated ERK and PI3K/AKt/mTOR signals, and markedly increased TfR/CD71 expression in HMCs. These effects induced by IgA1 isolated from patients with HSP were inhibited by human TfR polyclonal antibody (hTfR pAb) and soluble human transferrin receptor (sTfR), indicating that IgA1-induced HMC proliferation and ERK1/2 and PI3K/AKt/mTOR activation were dependent on TfR/CD71 engagement. Altogether, these data suggested that TfR/CD71 overexpression and ERK1/2 and PI3K/AKt/mTOR activation were engaged in HMC proliferation induced by IgA1 from HSP patients, which might be related to the mesangial injury of HSPN.