PNO1 inhibits autophagy-mediated ferroptosis by GSH metabolic reprogramming in hepatocellular carcinoma.

Effective strategies for hepatocellular carcinoma, which is the second leading cause of death worldwide, remain limited. A growing body of emerging evidence suggests that ferroptosis activation is a novel promising approach for the treatment of this malignancy. Nevertheless, the potential therapeutic targets and molecular mechanisms of ferroptosis remain elusive. In this study, we found that PNO1 is a bona fide inhibitor of ferroptosis and that autophagy induced by PNO1 promotes cystine/glutamate antiporter SLC7A11 while increasing the synthesis and accumulation of intracellular glutamate. This increase is followed by an equally proportional addition in cystine uptake, which consequently enhances system Xc- activity that leads to the inhibition of ferroptosis. In the maintenance of redox homeostasis, system Xc- activated via PNO1-autophagy metabolism is responsible for maintaining cysteine for glutathione (GSH) synthesis, and the final GSH metabolic reprogramming protects HCC cells from ferroptosis. The combination of PNO1 inhibition with drugs causing ferroptosis induction, particularly sorafenib, the first-line drug associated with ferroptosis in liver cancer shows therapeutic promise in vitro and in vivo. Together, our findings indicated that PNO1 protects HCC cells from ferroptotic death through autophagy-mediated GSH metabolic remodeling, and we identified a candidate therapeutic target that may potentiate the effect of ferroptosis-based antitumor therapy.

Chiral FA Conjugated CdTe/CdS Quantum Dots for Selective Cancer Ablation.

Inducing apoptosis in cancer cells is considered a potential therapeutic mechanism underlying cancers. Here, chiral folic acid (FA) conjugated Cys-CdTe/CdS quantum dots (QDs) conjugated with a cancer-targeting ligand were fabricated to induce apoptosis in vivo. Ligand-induced chirality mechanism for FA-Cys-CdTe/CdS QDs was discussed, which is verified by density functional theory (DFT) simulation. Interestingly, we found that the circular dichroism (CD) signals of chiral QDs can effectively distinguish breast cancer cells from normal cells, where a sharp decrease in CD signal and absorption intensity can be seen. Notably, chiral FA-Cys-CdTe/CdS QDs showed significant apoptosis-inducing ability after the release of mitochondrial apoptotic factors. Furthermore, in vivo experiments showed that chiral FA-Cys-CdTe/CdS QDs provide an efficient cancer ablation through the apoptosis process with negligible toxicity, demonstrating their great potential utility in targeted anticancer agent for future clinic application.

Acute or Subacute, the Optimal Timing for Uncomplicated Type B Aortic Dissection: A Systematic Review and Meta-Analysis.

Objective: To evaluate the optimal timing (acute or subacute) of thoracic endovascular aortic repair (TEVAR) for uncomplicated B aortic dissection (uTBAD) through a systematic review and meta-analysis. Method: A comprehensive literature search was undertaken across three major databases (EMBASE/Medline, PubMed, and Cochrane Library) and was assessed until November 2021 to identify studies reporting the outcomes of TEVAR utilized to treat patients with uTBAD. The continuous variables were compared between the two groups using t-test and the categorical variables were compared using the χ2-test. A meta-analysis was used to produce pooled odds ratios for early and follow-up outcomes. The random effects models were applied. A statistical analysis was performed using R software v.4.1. Result: A comprehensive literature search found 490 citations published within the predetermined time span of the analysis. Three studies including 1,193 patients (acute group 718, subacute group 475) were finally included for downstream meta-analysis. An acute uTBAD group presented with higher rates both in 30-day complications (20.5 vs. 13.7%; p = 0.014) and mortality (4.6 vs. 1.3%; p = 0.004) than subacute group. The respiratory complications were significantly higher in the acute group than in the subacute group (10.8 vs. 5.0%; p = 0.015). The procedure success rate (90.8 vs. 93.6%; p = 0.329), the follow-up mortality (7.7 vs. 7.6%; p = 1) and dissection-related late mortality (3.9 vs. 5.3%; p = 0.603) showed no significant difference. Conclusion: Our meta-analysis suggested that despite significantly higher 30-day complications and 30-day mortality in the acute uTBAD group, there was no significant difference in the follow-up mortality between the two groups. Systematic Review Registration: PROSPERO, identifier: CRD42021247609.

An extracellular matrix-based signature associated with immune microenvironment predicts the prognosis of patients with hepatocellular carcinoma.

OBJECTIVE: Increased data showed that genes related to extracellular matrix (ECM) are important to hepatocellular carcinoma (HCC) development. In contrast, no research was carried out that proposed that ECM-related genes should be reliable prognostic signature. METHODS: This study used data from The Cancer Genome Atlas along with The International Cancer Genome Consortium to gather ECM-related gene expression as well as clinical information related to the extracellular matrix. The least absolute shrinkage, Cox analysis, along with selection operator Cox regression and random forest have been utilized for establishing an ECM-related prognostic models. RESULTS: A series of investigations led us to identify 13 ECMs which we utilized to construct a prognostic signature with a larger area under the curve of 0.808. HCC patients have been categorized into 2 main groups based on the risk score formula: low risk along with high risk. The findings of the Kaplan-Meier curve revealed that there had been a statistically significant difference between these two groups. Our ECM-related signature can be utilized as independent predictor of survival in HCC. Low-risk patients stratified by the final model presented higher sensitivity to 8 targeted drugs (especially sorafenib) and 2 common chemo-drugs. Our gene set enrichment analysis outcomes recommended that high-risk group have been enriched in ECM, tumorigenesis, as well as immune-related pathways. Immune cell analysis showed that high-risk group had lower cell fraction of CD8+ T cells, Macrophages M1, B naïve cells, memory resting CD4+ T cells, Monocytes, resting Dendritic cells and activated Mast cells, along with higher PD-1 and CTLA4 expression levels as compared to low-risk group. CONCLUSION: Our identified ECM-related signature can also give new insight into underlying mechanisms along with therapeutic strategies in order to treat HCC.

Surgical Conversion for Initially Unresectable Locally Advanced Hepatocellular Carcinoma Using a Triple Combination of Angiogenesis Inhibitors, Anti-PD-1 Antibodies, and Hepatic Arterial Infusion Chemotherapy: A Retrospective Study.

BACKGROUND: Recent research has shown that selected patients with initially unresectable hepatocellular carcinoma (HCC) are able to achieve conversion to resectable disease through systemic or local therapy. Combination regimens comprised of drugs with different mechanisms of action have shown better outcomes than single-drug or single-approach-based treatments; however, to date, combination regimens investigated as part of conversion therapy strategies have been two drug combinations with reported issues of relatively low surgical conversion and objective response rates. In this study, we investigated the efficacy and safety of triple combination therapy with angiogenesis inhibitors, programmed death-1 inhibitors and hepatic arterial infusion chemotherapy for surgical conversion of advanced HCC. METHODS: This was a single-center, retrospective, single-arm study of patients with unresectable HCC who received at least one cycle of triple combination therapy with an oral anti-angiogenic drug, programmed death-1 inhibitors and hepatic arterial infusion chemotherapy between August 2019 and August 2020. Endpoints included the overall response rate (ORR), surgical conversion rate, time to response and safety. Treatment response was assessed using the modified Response Evaluation Criteria in Solid Tumors (mRECIST) and RECIST v1.1. RESULTS: In total, 34 patients were included in this study, of whom 25 completed treatment evaluation. The best ORR was 96.0% (24/25); 48.0% (n = 12) had a complete response, 48.0% (n = 12) had a partial response, and 4.0% (n = 1) had stable disease. The median time to response was 50.5 (95% CI, 31.02-64.00) days and the surgical conversion rate was 60% (15/25). Of the 25 patients, 56.0% (n = 14) received surgical resection and 28.0% (n = 7) had a pathologic complete response. Toxic side effects were manageable. CONCLUSION: A triple combination therapy regimen of angiogenesis inhibitors, programmed death-1 inhibitors and hepatic arterial infusion chemotherapy showed significant therapeutic effect with an extremely high surgical conversion rate in patients with initially unresectable HCC.

Oriented Proton-Conductive Nanochannels Boosting a Highly Conductive Proton-Exchange Membrane for a Vanadium Redox Flow Battery.

In this work, we propose a sulfonated poly (ether ether ketone) (SPEEK) composite proton-conductive membrane based on a 3-(1-hydro-imidazolium-3-yl)-propane-1-sulfonate (Him-pS) additive to break through the trade-off between conductivity and selectivity of a vanadium redox flow battery (VRFB). Specifically, Him-pS enables an oriented distribution of the SPEEK matrix to construct highly conductive proton nanochannels throughout the membrane arising from the noncovalent interaction. Moreover, the "acid-base pair" effect from an imidazolium group and a sulfonic group further facilitates the proton transport through the nanochannels. Meanwhile, the structure of the acid-base pair is further confirmed based on density functional theory calculations. Material and electrochemical characterizations indicate that the nanochannels with a size of 16.5 nm are vertically distributed across the membrane, which not only accelerate proton conductivity (31.54 mS cm-1) but also enhance the vanadium-ion selectivity (39.9 × 103 S min cm-3). Benefiting from such oriented proton-conductive nanochannels in the membrane, the cell delivers an excellent Coulombic efficiency (CE, ≈ 98.8%) and energy efficiency (EE, ≈ 78.5%) at 300 mA cm-2. More significantly, the cell maintains a stable energy efficiency over 600 charge-discharge cycles with only a 5.18% decay. Accordingly, this work provides a promising fabrication strategy for a high-performance membrane of VRFB.

Angiotensin-converting enzyme inhibitors have adverse effects in anti-angiogenesis therapy for hepatocellular carcinoma.

At present, anti-angiogenic drugs (AADs) are widely used in the systemic treatment of hepatocellular carcinoma (HCC) or other types of cancer, and have achieved good anti-cancer effect, whereas treatment-related proteinuria can affect the routine use of AADs, which in turn abates the overall efficacy. Currently, most clinicians prescribe angiotensin-converting enzyme inhibitors (ACEIs) to alleviate proteinuria according to diabetic nephropathy guidelines or expert recommendations. However, the efficacy of ACEIs in reducing AAD-related proteinuria and its effect on the anticancer effect of AADs is unknown. Our clinical data showed that some HCC patients experienced tumor progression by ACEIs administration for the treatment of proteinuria caused by AADs. Here, we confirmed that in different tumor-bearing mouse models, ACEIs did not delay the appearance of proteinuria or alleviate proteinuria caused by AADs but compromised the anticancer efficacy of AADs. This effect is unrelated to the change in the VEGF signaling pathway. Our data showed that the combination of ACEIs and AADs flared the production of kidney-derived erythropoietin (EPO). In turn, EPO compromises the anti-angiogenic effects of AADs and decreases antitumor activity. In conclusion, for the treatment of proteinuria caused by AADs, ACEIs have no efficacy while also promoting AADs resistance. This finding is of great significance to guide clinical standardized management of side effects of anti-angiogenic therapy for cancer patients.

Apatinib as an alternative therapy for advanced hepatocellular carcinoma.

Angiogenesis plays an important role in the occurrence and development of tumors. Registered tyrosine kinase inhibitors targeting vascular endothelial growth factor reduce angiogenesis. Apatinib, a tyrosine kinase inhibitor, can specifically inhibit vascular endothelial growth factor receptor 2, showing encouraging anti-tumor effects in a variety of tumors including advanced hepatocellular carcinoma (HCC). This article intends to review the clinical research and application prospects of apatinib in the field of HCC.

Novel Biomimic Crystalline Colloidal Array for Fast Detection of Trace Parathion.

A novel gold doped inverse opal photonic crystal (IO PC) was successfully fabricated with combination of molecularly imprinted technical for the fast determination of parathion. First, a closest silica array arrangement behaved as the 3D photonic crystal precursors to build the opal photonic crystal (O PC). Second, the parathion-containing polymeric solution with gold nanoparticles was drawn into the 3D array cracks. After polymerization, the well-designed O PC was treated with HF solution for the etching of the silica skeleton. Finally, the template parathion was removed and the Au-MIP IO PCs were obtained. The morphology of SiO2 and Au NPs was characterized by transmission electron microscopy (TEM), and the eluted influence of the IO PCs was monitored by scanning electron microscopy (SEM). The cross-linking effect was well optimized according to the best spectrum signal of parathion. The as-synthesized Au-MIP IO PCs displayed the specificity toward parathion and the selectivity to other competitive pesticide molecules. The response time was only 5 min, and the parathion could be well detected from real water samples. The recoveries were between 95.5% and 101.5%.

Ultrasensitive Sensing Material Based on Opal Photonic Crystal for Label-Free Monitoring of Transferrin.

A new opal photonic crystal (PC) sensing material, allowing label-free detection of transferrin (TRF), is proposed in the current study. This photonic crystal was prepared via a vertical convective self-assembly method with monodisperse microspheres polymerized by methyl methacrylate (MMA) and 3-acrylamidophenylboronic acid (AAPBA). FTIR, TG, and DLS were used to characterize the components and particle size of the monodisperse microspheres. SEM was used to observe the morphology of the PC. The diffraction peak intensity decreases as the TRF concentration increase. This was due to the combination of TRF to the boronic acid group of the photonic crystal. After condition optimization, a standard curve was obtained and the linear range of TRF concentration was from 2 × 10-3 ng/mL to 200 ng/mL. Measurement of TRF concentration in simulated urine sample was also investigated using the sensing material. The results indicated that the PC provided a cheap, label-free, and easy-to-use alternative for TRF determination in clinical diagnostics.

Tailor-Made Boronic Acid Functionalized Magnetic Nanoparticles with a Tunable Polymer Shell-Assisted for the Selective Enrichment of Glycoproteins/Glycopeptides.

Biomedical sciences, and in particular biomarker research, demand efficient glycoproteins enrichment platforms. In this work, we present a facile and time-saving method to synthesize phenylboronic acid and copolymer multifunctionalized magnetic nanoparticles (NPs) using a distillation-precipitation polymerization (DPP) technique. The polymer shell is obtained through copolymerization of two monomers-affinity ligand 3-acrylaminophenylboronic acid (AAPBA) and a hydrophilic functional monomer. The resulting hydrophilic Fe3O4@P(AAPBA-co-monomer) NPs exhibit an enhanced binding capacity toward glycoproteins by an additional functional monomer complementary to the surface presentation of the target protein. The effects of monomer ratio of AAPBA to hydrophilic comonomers on the binding of glycoproteins are systematically investigated. The morphology, structure, and composition of all the synthesized microspheres are characterized by transmission electron microscopy (TEM), X-ray powder diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, thermogravimetric analysis (TGA), and vibrating sample magnetometer (VSM). The hydrophilic Fe3O4@P(AAPBA-co-monomer) microspheres show an excellent performance in the separation of glycoproteins with high binding capacity; And strong magnetic response allows them to be easily separated from solution in the presence of an external magnetic field. Moreover, both synthetic Fe3O4@P(AAPBA) and copolymeric NPs show good adsorption to glycoproteins in physiological conditions (pH 7.4). The Fe3O4@P(AAPBA-co-monomer) NPs are successfully utilized to selectively capture and identify the low-abundance glycopeptides from the tryptic digest of horseradish peroxidase (HRP). In addition, the selective isolation and enrichment of glycoproteins from the egg white samples at physiological condition is obtained by Fe3O4@P(AAPBA-co-monomer) NPs as adsorbents.

The synthesis of magnetic lysozyme-imprinted polymers by means of distillation-precipitation polymerization for selective protein enrichment.

A protein imprinting approach for the synthesis of core-shell structure nanoparticles with a magnetic core and molecularly imprinted polymer (MIP) shell was developed using a simple distillation-precipitation polymerization method. In this work, Fe3O4 magnetic nanoparticles were first synthesized through a solvothermal method and then were conveniently surface-modified with 3-(methacryloyloxy)propyltrimethoxylsilane as anchor molecules to donate vinyl groups. Next a high-density MIP shell was coated onto the surface of the magnetic nanoparticles by the copolymerization of functional monomer acrylamide (AAm), cross-linking agent N,N'-methylenebisacrylamide (MBA), the initiator azodiisobutyronitrile (AIBN), and protein in acetonitrile heated at reflux. The morphology, adsorption, and recognition properties of the magnetic molecularly imprinted nanoparticles were investigated by transmission electron microscopy (TEM), scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), vibrating sample magnetometer (VSM), and rebinding experiments. The resulting MIP showed a high adsorption capacity (104.8 mg g(-1)) and specific recognition (imprinting factor=7.6) to lysozyme (Lyz). The as-prepared Fe3O4@Lyz-MIP nanoparticles with a mean diameter of 320 nm were coated with an MIP shell that was 20 nm thick, which enabled Fe3O4@Lyz-MIP to easily reach adsorption equilibrium. The high magnetization saturation (40.35 emu g(-1)) endows the materials with the convenience of magnetic separation under an external magnetic field and allows them to be subsequently reused. Furthermore, Fe3O4@Lyz-MIP could selectively extract a target protein from real egg-white samples under an external magnetic field.

A combination of distillation-precipitation polymerization and click chemistry: fabrication of boronic acid functionalized Fe3O4 hybrid composites for enrichment of glycoproteins.

Biomedical sciences, and in particular biomarker research, demand efficient glycoprotein enrichment platforms. In this paper, a facile and efficient approach combining distillation-precipitation polymerization (DPP) and click chemistry was developed to synthesize boronic acid ligand-modified magnetic nanoparticles for the enrichment of glycoproteins. Due to the relatively large amount of benzyl chloride groups introduced by DPP on the magnetic core, which easily can be transferred into azide groups, the alkyne-phenylboronic acid ligands were immobilized onto the surface of Fe3O4 with high efficiency via the Cu(i)-catalyzed azide-alkyne cycloaddition (CuAAC) 'click' reaction. The morphology, structure and composition of the resulting core-shell Fe3O4@poly(4-vinylbenylchloride)@amidophenylboronic acid (Fe3O4@pVBC@APBA) nanocomposites were characterized by transmission electron microscopy, X-ray powder diffraction, vibrating sample magnetometry, Fourier transform infrared spectroscopy, thermogravimetric analysis and X-ray photoelectron spectrometry. The Fe3O4@pVBC@APBA microspheres held a ∼50 nm polymeric shell, and exhibited high magnetic response to an external magnetic field. The binding results demonstrated that Fe3O4@pVBC@APBA possessed high adsorption capacity and remarkable selectivity to glycoproteins. Moreover, the glycoproteins in the egg white sample could be enriched under physiological conditions (pH 7.4) as well, due to the lower pKa value of the alkyne-phenylboronic acid ligand. The high stability and selectivity of Fe3O4@pVBC@APBA for the glycoproteins were retained over several separation cycles. This boronate affinity material has potential applications in biomedical and biotechnological fields including drug delivery and biosensing.

Facile synthesis of a Ni(ii)-immobilized core-shell magnetic nanocomposite as an efficient affinity adsorbent for the depletion of abundant proteins from bovine blood.

In this study, a facile and efficient separation of abundant proteins from bovine blood using core-shell structure nanoparticles with a magnetic core and an immobilized metal affinity ligand iminodiacetic acid (IDA) chelating Ni(ii) is presented. Firstly, Fe3O4 magnetic nanoparticles (MNPs) were synthesized through a solvothermal method and then were conveniently surface-modified with 3-(methacryloyloxy) propyltrimethoxylsilane as anchor molecules to donate vinyl groups. Next a high density poly(4-vinylbenzylchloride) (PVBC) shell was synthesized on the surface of silica-coated Fe3O4 MNPs via distillation-precipitation polymerization. After the PVBC shell reacted with iminodiacetic acid (IDA) in alkaline aqueous solution, the magnetite was charged with Ni2+ to form Ni(ii)-IDA functionalized hybrid Fe3O4@PVBC@IDA-Ni MNPs. Transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), thermogravimetric analysis (TGA) and a vibrating sample magnetometer (VSM) were employed to evaluate the size, morphology and magnetic property of the resulting magnetic nanospheres. The high saturation magnetization (48.1 emu g-1) provides the materials with the convenience of magnetic separation under an external magnetic field and they can be subsequently reused. The core-shell Fe3O4@PVBC@IDA-Ni MNPs exhibit excellent performance in the separation of protein bovine hemoglobin (BHb), and the binding capacity is as high as 1988 mg g-1. In addition, the Fe3O4@PVBC@IDA-Ni MNPs can be used in selective removal of abundant protein Hb in the bovine blood samples. This opens a novel route for its future application in removing abundant protein in proteomic analysis.

A self-assembled polydopamine film on the surface of magnetic nanoparticles for specific capture of protein.

In this study, we report a facile method for the preparation of core-shell magnetic molecularly imprinted polymers (MIPs) for protein recognition. Uniform carboxyl group functionalized Fe(3)O(4) nanoparticles (NPs) were synthesized using a solvothermal method. Magnetic MIPs were synthesized by self-polymerization of dopamine in the presence of template protein on the surface of the Fe(3)O(4) NPs. A thin layer of polydopamine can be coated on Fe(3)O(4) NPs via dopamine self-polymerization and the imprinted polydopamine shells can be controlled by the mass ratio of Fe(3)O(4) NPs and dopamine. More importantly, there is a critical value of polydopamine shell thickness for the maximum rebinding capacity. The as-prepared lysozyme-imprinted Fe(3)O(4)@polydopamine NPs show high binding capacity and acceptable specific recognition behavior towards template proteins. This method provides the possibility for the separation and enrichment of abundant proteins in proteomic analysis.