De Novo Purine Metabolism is a Metabolic Vulnerability of Cancers with Low p16 Expression.

p16 is a tumor suppressor encoded by the CDKN2A gene whose expression is lost in approximately 50% of all human cancers. In its canonical role, p16 inhibits the G1-S-phase cell cycle progression through suppression of cyclin-dependent kinases. Interestingly, p16 also has roles in metabolic reprogramming, and we previously published that loss of p16 promotes nucleotide synthesis via the pentose phosphate pathway. However, the broader impact of p16/CDKN2A loss on other nucleotide metabolic pathways and potential therapeutic targets remains unexplored. Using CRISPR knockout libraries in isogenic human and mouse melanoma cell lines, we determined several nucleotide metabolism genes essential for the survival of cells with loss of p16/CDKN2A. Consistently, many of these genes are upregulated in melanoma cells with p16 knockdown or endogenously low CDKN2A expression. We determined that cells with low p16/CDKN2A expression are sensitive to multiple inhibitors of de novo purine synthesis, including antifolates. Finally, tumors with p16 knockdown were more sensitive to the antifolate methotrexate in vivo than control tumors. Together, our data provide evidence to reevaluate the utility of these drugs in patients with p16/CDKN2Alow tumors as loss of p16/CDKN2A may provide a therapeutic window for these agents. SIGNIFICANCE: Antimetabolites were the first chemotherapies, yet many have failed in the clinic due to toxicity and poor patient selection. Our data suggest that p16 loss provides a therapeutic window to kill cancer cells with widely-used antifolates with relatively little toxicity.

Coordination Self-Assembled AuTPyP-Cu Metal-Organic Framework Nanosheets with pH/Ultrasound Dual-Responsiveness for Synergistically Triggering Cuproptosis-Augmented Chemotherapy.

Reactive oxygen species (ROS) mediated tumor cell death is a powerful anticancer strategy. Cuproptosis is a copper-dependent and ROS-mediated prospective tumor therapy strategy. However, the complex tumor microenvironment (TME), low tumor specificity, poor therapy efficiency, and lack of imaging capability impair the therapy output of current cuproptosis drugs. Herein, we designed a dual-responsive two-dimensional metal-organic framework (2D MOF) nanotheranostic via a coordination self-assembly strategy using Au(III) tetra-(4-pyridyl) porphine (AuTPyP) as the ligand and copper ions (Cu2+) as nodes. The dual-stimulus combined with the protonation of the pyridyl group in AuTPyP and deep-penetration ultrasound (US) together triggered the controlled release in an acidic TME. The ultrathin structure (3.0 nm) of nanotheranostics promoted the release process. The released Cu2+ was reduced to Cu+ by depleting the overexpressed glutathione (GSH) in the tumor, which not only activated the Ferredoxin 1 (FDX1)-mediated cuproptosis but also catalyzed the overexpressed hydrogen peroxide (H2O2) in the tumor into reactive oxygen species via Fenton-like reaction. Simultaneously, the released AuTPyP could specifically bind with thioredoxin reductase and activate the redox imbalance of tumor cells. These together selectively induced significant mitochondrial vacuoles and prominent tumor cell death but did not damage the normal cells. The fluorescence and magnetic resonance imaging (MRI) results verified this nanotheranostic could target the HeLa tumor to greatly promote the self-enhanced effect of chemotherapy/cuproptosis and tumor inhibition efficiency. The work helped to elucidate the controlled assembly of multiresponsive nanotheranostics and the high-specificity ROS regulation for application in anticancer therapy.

A Giant Heterometallic Polyoxometalate Nanocluster for Enhanced Brain-Targeted Glioma Therapy.

Giant heterometallic polyoxometalate (POM) clusters with precise atom structures, flexibly adjustable and abundant active sites are promising for constructing functional nanodrugs. However, current POM drugs are almost vacant in orthotopic brain tumor therapy due to the inability to effectively penetrate the blood-brain barrier (BBB) and low drug activity. Here, we designed the largest (3.0 nm × 6.0 nm) transition-metal-lanthanide co-encapsulated POM cluster {[Ce10 Ag6 (DMEA)(H2 O)27 W22 O70 ][B-α-TeW9 O33 ]9 }2 88- featuring 238 metal centers via synergistic coordination between two geometry-unrestricted Ce3+ and Ag+ linkers with tungsten-oxo cluster fragments. This POM was combined with brain-targeted peptide to prepare a brain-targeted nanodrug that could efficiently traverse BBB and target glioma cells. The Ag+ active centers in the nanodrug specifically activate reactive oxygen species to regulate the apoptosis pathway of glioma cells with a low half-maximal inhibitory concentration (5.66 µM). As the first brain-targeted POM drug, it efficiently prolongs the survival of orthotopic glioma-bearing mice.

Dual-Site Förster Resonance Energy Transfer Route of Upconversion Nanoparticles-Based Brain-Targeted Nanotheranostic Boosts the Near-Infrared Phototherapy of Glioma.

Glioblastoma multiforme (GBM) is the most common malignant brain tumor with low survival, primarily due to the blood-brain barrier (BBB) and high infiltration. Upconversion nanoparticles (UCNPs)-based near-infrared (NIR) phototherapy with deep penetration is a promising therapy method against glioma but faces low photoenergy utilization that is induced by spectral mismatch and single-site Förster resonance energy transfer (FRET). Herein, we designed a brain-targeting NIR theranostic system with a dual-site FRET route and superior spectral matching to maximize energy utilization for synergistic photodynamic and photothermal therapy of glioma. The system was fabricated by Tm-doped UCNPs, zinc tetraphenylporphyrin (ZnTPP), and copper sulfide (CuS) nanoparticles under multioptimized modulation. First, the Tm-doping ratio was precisely adjusted to improve the relative emission intensity at 475 nm of UCNPs (11.5-fold). Moreover, the J-aggregate of ZnTPP increased the absorption at 475 nm (163.5-fold) of monomer; both together optimize the FRET matching between UCNPs and porphyrin for effective NIR photodynamic therapy. Simultaneously, the emission at 800 nm was utilized to magnify the photothermal effect of CuS nanoparticles for photothermal therapy via the second FRET route. After being modified by a brain-targeted peptide, the system efficiently triggers the synergistic phototherapy ablation of glioma cells and significantly prolongs the survival of orthotopic glioma-bearing mice after traversing the BBB and targeting glioma. This success of advanced spectral modulation and dual-site FRET strategy may inspire more strategies to maximize the photoenergy utilization of UCNPs for brain diseases.

De novo purine metabolism is a metabolic vulnerability of cancers with low p16 expression.

p16 is a tumor suppressor encoded by the CDKN2A gene whose expression is lost in ~50% of all human cancers. In its canonical role, p16 inhibits the G1-S phase cell cycle progression through suppression of cyclin dependent kinases. Interestingly, p16 also has roles in metabolic reprogramming, and we previously published that loss of p16 promotes nucleotide synthesis via the pentose phosphate pathway. Whether other nucleotide metabolic genes and pathways are affected by p16/CDKN2A loss and if these can be specifically targeted in p16/CDKN2A-low tumors has not been previously explored. Using CRISPR KO libraries in multiple isogenic human and mouse melanoma cell lines, we determined that many nucleotide metabolism genes are negatively enriched in p16/CDKN2A knockdown cells compared to controls. Indeed, many of the genes that are required for survival in the context of low p16/CDKN2A expression based on our CRISPR screens are upregulated in p16 knockdown melanoma cells and those with endogenously low CDKN2A expression. We determined that cells with low p16/Cdkn2a expression are sensitive to multiple inhibitors of de novo purine synthesis, including anti-folates. Tumors with p16 knockdown were more sensitive to the anti-folate methotrexate in vivo than control tumors. Together, our data provide evidence to reevaluate the utility of these drugs in patients with p16/CDKN2A-low tumors as loss of p16/CDKN2A may provide a therapeutic window for these agents.

A Brain-Targeting NIR-II Ferroptosis System: Effective Visualization and Oncotherapy for Orthotopic Glioblastoma.

Near-infrared-II (NIR-II) ferroptosis activators offer promising potentials in in vivo theranostics of deep tumors, such as glioma. However, most cases are nonvisual iron-based systems that are blind for in vivo precise theranostic study. Additionally, the iron species and their associated nonspecific activations might trigger undesired detrimental effects on normal cells. Considering gold (Au) is an essential cofactor for life and it can specifically bind to tumor cells, Au(I)-based NIR-II ferroptosis nanoparticles (TBTP-Au NPs) for brain-targeted orthotopic glioblastoma theranostics are innovatively constructed. It achieves the real-time visual monitoring of both the BBB penetration and the glioblastoma targeting processes. Moreover, it is first validated that the released TBTP-Au specifically activates the effective heme oxygenase-1-regulated ferroptosis of glioma cells to greatly extend the survival time of glioma-bearing mice. This new ferroptosis mechanism based on Au(I) may open a new way for the fabrication of advanced and high-specificity visual anticancer drugs for clinical trials.

Melanoma-associated repair-like Schwann cells suppress anti-tumor T-cells via 12/15-LOX/COX2-associated eicosanoid production.

Peripheral glia, specifically the Schwann cells (SCs), have been implicated in the formation of the tumor microenvironment (TME) and in cancer progression. However, in vivo and ex vivo analyses of how cancers reprogram SC functions in different organs of tumor-bearing mice are lacking. We generated Plp1-CreERT/tdTomato mice which harbor fluorescently labeled myelinated and non-myelin forming SCs. We show that this model enables the isolation of the SCs with high purity from the skin and multiple other organs. We used this model to study phenotypic and functional reprogramming of the SCs in the skin adjacent to melanoma tumors. Transcriptomic analyses of the peritumoral skin SCs versus skin SCs from tumor-free mice revealed that the former existed in a repair-like state typically activated during nerve and tissue injury. Peritumoral skin SCs also downregulated pro-inflammatory genes and pathways related to protective anti-tumor responses. In vivo and ex vivo functional assays confirmed immunosuppressive activities of the peritumoral skin SCs. Specifically, melanoma-reprogrammed SCs upregulated 12/15-lipoxygenase (12/15-LOX) and cyclooxygenase (COX)-2, and increased production of anti-inflammatory polyunsaturated fatty acid (PUFA) metabolites prostaglandin E2 (PGE2) and lipoxins A4/B4. Inhibition of 12/15-LOX or COX2 in SCs, or EP4 receptor on lymphocytes reversed SC-dependent suppression of anti-tumor T-cell activation. Therefore, SCs within the skin adjacent to melanoma tumors demonstrate functional switching to repair-like immunosuppressive cells with dysregulated lipid oxidation. Our study suggests the involvement of the melanoma-associated repair-like peritumoral SCs in the modulation of locoregional and systemic anti-tumor immune responses.

Whole genome sequencing for metastatic mutational burden in extraskeletal myxoid chondrosarcoma.

Extraskeletal myxoid chondrosarcoma (EMC) is an ultra-rare cancer that makes up less than 3% of all soft tissue sarcomas. It most often arises in the soft tissues of the proximal limbs and has a higher incidence in males. Though EMC has a good prognosis, it has an indolent course with high rates of local recurrence as well as metastasis to the lungs. EMC is characterized in 70% of cases by an EWS1-NR4A3 translocation, leading to constitutive expression of NR4A3. Structural variants (SVs) in EMC, especially large-scale genomic alterations, have not been well studied and studies are severely limited by sample size. In this study, we describe Whole Genome Sequencing (WGS) of a rare case of matched EMC primary tumor, lung metastasis, and pelvic metastasis to identify genomic alterations. We examined somatic variants, copy number variants (CNVs), and larger scale SVs such as translocations and breakend points. While the primary tumor and lung metastasis had similar somatic variations and CNVs, the pelvic metastasis had more unique SVs with especially increased mutational burden of SVs in chromosome 2. This suggests that different molecular drivers appear in more advanced, relapsing EMC compared with the primary tumor and early lung metastasis. Genomic studies such as ours may identify novel molecular complexities in rare cancers that may be leveraged for therapeutic strategies and precision medicine.

Biomimetic Dp44mT-nanoparticles selectively induce apoptosis in Cu-loaded glioblastoma resulting in potent growth inhibition.

Selective targeting of elevated copper (Cu) in cancer cells by chelators to induce tumor-toxic reactive oxygen species (ROS) may be a promising approach in the treatment of glioblastoma multiforme (GBM). Previously, the Cu chelator di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT) attracted much interest due to its potent anti-tumor activity mediated by the formation of a highly redox-active Cu-Dp44mT complex. However, its translational potential was limited by the development of toxicity in murine models of cancer reflecting poor selectivity. Here, we overcame the limitations of Dp44mT by incorporating it in new biomimetic nanoparticles (NPs) optimized for GBM therapy. Biomimetic design elements enhancing selectivity included angiopeptide-2 functionalized red blood cell membrane (Ang-M) camouflaging of the NPs carrier. Co-loading Dp44mT with regadenoson (Reg), that transiently opens the blood-brain-barrier (BBB), yielded biomimetic Ang-MNPs@(Dp44mT/Reg) NPs that actively targeted and traversed the BBB delivering Dp44mT specifically to GBM cells. To further improve selectivity, we innovatively pre-loaded GBM tumors with Cu. Oral dosing of U87MG-Luc tumor bearing mice with diacetyl-bis(4-methylthiosemicarbazonato)-copperII (Cu(II)-ATSM), significantly enhanced Cu-level in GBM tumor. Subsequent treatment of mice bearing Cu-enriched orthotopic U87MG-Luc GBM with Ang-MNPs@(Dp44mT/Reg) substantially prevented orthotopic GBM growth and led to maximal increases in median survival time. These results highlighted the importance of both angiopeptide-2 functionalization and tumor Cu-loading required for greater selective cytotoxicity. Targeting Ang-MNPs@(Dp44mT/Reg) NPs also down-regulated antiapoptotic Bcl-2, but up-regulated pro-apoptotic Bax and cleaved-caspase-3, demonstrating the involvement of the apoptotic pathway in GBM suppression. Notably, Ang-MNPs@(Dp44mT/Reg) showed negligible systemic drug toxicity in mice, further indicating therapeutic potential that could be adapted for other central nervous system disorders.

Brain-Targeted Aggregation-Induced-Emission Nanoparticles with Near-Infrared Imaging at 1550 nm Boosts Orthotopic Glioblastoma Theranostics.

A remaining challenge in the treatment of glioblastoma multiforme (GBM) is surmounting the blood-brain barrier (BBB). Such a challenge prevents the development of efficient theranostic approaches that combine reliable diagnosis with targeted therapy. In this study, brain-targeted near-infrared IIb (NIR-IIb) aggregation-induced-emission (AIE) nanoparticles are developed via rational design, which involves twisting the planar molecular backbone with steric hindrance. The resulting nanoparticles can balance competing responsiveness demands for radiation-mediated NIR fluorescence imaging at 1550 nm and non-radiation NIR photothermal therapy (NIR-PTT). The brain-targeting peptide apolipoprotein E peptide (ApoE) is grafted onto these nanoparticles (termed as ApoE-Ph NPs) to target glioma and promote efficient BBB traversal. A long imaging wavelength 1550 nm band-pass filter is utilized to monitor the in vivo biodistribution and accumulation of the nanoparticles in a model of orthotopic glioma, which overcomes previous limitations in wavelength range and equipment. The results demonstrate that the ApoE-Ph NPs have a higher PTT efficiency and significantly enhanced survival of mice bearing orthotopic GBM with moderate irradiation (0.5 W cm-2 ). Collectively, the work highlights the smart design of a brain-targeted NIR-II AIE theranostic approach that opens new diagnosis and treatment options in the photonic therapy of GBM.

Noncovalent Self-Assembled Smart Gold(III) Porphyrin Nanodrug for Synergistic Chemo-Photothermal Therapy.

Self-assembly is a powerful means to fabricate multifunctional smart nanotheranostics. However, the complicated preparation, toxicity of responsive carriers, and low loading efficiency of drug cargo hinder the outcome. Herein, we developed a responsive carrier-free noncovalent self-assembly strategy of a metallized Au(III) tetra-(4-pyridyl) porphine (AuTPyP) anticancer drug for the preparation of a heat/acid dual-stimulated nanodrug, and it generated a better photothermal effect than monomers under irradiation. The photothermal effect promoted the protonation of the hydrophobic pyridyl group and the following release into tumorous acidic microenvironments. With cRGD modification, the released drug induced the aggravation of intracellular reactive oxygen species (ROS) via the activity inhibition of thioredoxin reductase (TrxR) for synergistic chemo-photothermal therapy of tumors.

Multicomponent Self-Assembly of a Giant Heterometallic Polyoxotungstate Supercluster with Antitumor Activity.

The hierarchical aggregation of molecular nanostructures from multiple components is a grand synthetic challenge, which requires highly selective linkage control. We demonstrate how two orthogonal linkage groups, that is, organotin and lanthanide cations, can be used to drive the aggregation of a giant molecular metal oxide superstructure. The title compound {[(Sn(CH3 )2 )2 O]4 {[CeW5 O18 ] [TeW4 O16 ][CeSn(CH3 )2 ]4 [TeW8 O31 ]4 }2 }46- (1 a) features dimensions of ca. 2.2×2.3×3.4 nm3 and a molecular weight of ca. 25 kDa. Structural analysis shows the hierarchical aggregation from several independent subunits. Initial biomedical tests show that 1 features an inhibitory effect on the proliferation of HeLa cells based on an apoptosis pathway. In vivo experiments in mice reveal the antiproliferative activity of 1 and open new paths for further development of this new compound class.

High Expression of Interleukin-33/ST2 Predicts the Progression and Poor Prognosis in Chronic Hepatitis B Patients with Hepatic Flare.

BACKGROUND: Interleukin-33 (IL-33), along with its receptor suppression of tumorigenicity 2 (ST2), is capable of regulating immune responses. Immunologically mediated events play a critical role in the acute phase of chronic hepatitis B (CHB) infection. The present study primarily aimed to determine whether the IL-33/ST2 axis could be used as a reliable biomarker to predict disease progression and prognosis. METHODS: The study included 130 cases of CHB, with 48 cases in stable condition, 50 cases of progression to hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF), and 32 cases of progression to HBV related pre-ACLF. The demographic data and laboratory test results were recorded and compared among the groups. The blood samples for the measurement of serum IL-33 and soluble ST2 (sST2) levels were collected at admission and evaluated twice using the ELISA method. RESULTS: The patients in which the disease progressed to HBV-ACLF had the highest serum IL-33 and sST2 levels among the three groups (p<0.001). The correlation analysis showed that the serum IL-33 levels were associated with the levels of ALT (r = 0.367, p<0.001), AST (r = 0.456, p<0.001) and the MELD score (r = 0.377, p = 0.001). The area under the curve (AUC) of IL-33 and sST2 levels for differentiation of disease progression were 0.861 (95% CI: 0.787-0.934, p<0.001) and 0.788 (95% CI: 0.692-0.884, p<0.001), respectively. The serum IL-33 levels combined with the MELD score had the highest 90-day mortality prediction efficiency, with an AUC of 0.918 (95% CI: 0.859-0.977, p<0.001), a sensitivity of 92.3%, and a specificity of 88.7%. CONCLUSIONS: The IL-33/sST2 axis could be used to evaluate the progression and mortality in CHB patients with hepatic flare. The combinatorial use of multiple indicators could achieve the highest diagnostic and predictive accuracy.

The influence of suture materials on the biomechanical behavior of suture-meniscal specimens: a comparative study in a porcine model.

BACKGROUND: Repair of a meniscal tear is indicated in certain conditions. Despite extensive research on the biomechanics of various repair methods, there has been minimal investigation of whether the suture material influences the meniscal-suture construct. The purpose of this study was to compare the biomechanical properties of nine different suture materials under cyclic and load-to-failure conditions. METHODS: Ninety porcine menisci were randomly allocated to simple suture placement using either Ultrabraid®, Ultratape®, Magnum Wire®, TigerWire®, TigerTape®, LabralTape®, Orthocord®, 0 FiberWire®, or 2-0 FiberWire®. Each suture-meniscus specimen underwent cyclic loading followed by load-to-failure testing. Elongation, maximum load to failure, stiffness, and mode of failure were recorded and compared between each suture type using non-parametric testing. Mean ± standard deviation was reported and the statistical significance was p < 0.05. RESULTS: Elongation during cyclic loading was lowest with 2-0 FiberWire (0.95 ± 0.17 mm); this value was statistically significantly different than the results for all other sutures except 0 FiberWire® (1.09 ± 0.17 mm, p = 0.79), TigerWire® (1.09 ± 0.29 mm, p = 0.85), TigerTape® (1.39 ± 0.29 mm, p = 0.08), and LabralTape® (1.20 ± 0.33 mm, p = 0.41). The highest elongation was seen with Ultrabraid® (1.91 ± 0.34 mm); this value was statistically significantly greater than the results for all other suture materials except Orthocord® (1.59 mm ± 0.31 mm, p = 0.46) and Magnum Wire® (1.43 ± 0.25 mm, p = 0.14). Load to failure was highest for TigerTape® (287.43 ± 41.15 N), and this result was statistically significantly different than the results for all other sutures except LabralTape® (271.34 ± 48.48 N, p = 0.99) and TigerWire® (251.03 ± 25.8 N, p = 0.51). Stiffness was highest for LabralTape® (195.77 ± 49.06 N/mm), and this result was statistically significantly different than the results for all other sutures except TigerWire® (186.49 ± 19.83 N/mm, p = 0.45) and TigerTape® (173.35 ± 15.60 N/mm, p = 0.19). The majority of sutures failed by pullout (n = 46, 51%) or tearing (n = 40, 45%). CONCLUSION: Suture design and material affect the biomechanical behavior of porcine meniscal-suture specimens. LabralTape®, TigerWire®, and TigerTape® demonstrated better overall combinations of low elongation, high maximum load to failure, and high stiffness.

Central metal-derived co-assembly of biomimetic GdTPP/ZnTPP porphyrin nanocomposites for enhanced dual-modal imaging-guided photodynamic therapy.

Dual-modal imaging guided photodynamic therapy (PDT) of multifunctional nanocomposites holds great promise for precision tumor theranostics. However, poor heterogeneous interfacial compatibility between functional components, low hydrophilicity and complicated preparation of nanocomposites remain major obstacles for further bioapplication. Herein, a facile central metal-derived co-assembly strategy is developed to effectively integrate gadolinium porphyrin (GdTPP) contrast agent and Zinc porphyrin (ZnTPP) photosensitizer into a homogeneous GdTPP/ZnTPP nanocomposites (GZNs). GZNs possesses the following advantages: (1) Greatly improved interfacial compatibility facilitated by incorporating two metalporphyrins with same group (phenyl-) and different central metal atoms (Zn and Gd) leading to higher yield (4.7-5 fold) than either monocomponent nanoparticles. (2) Poor dispersity of GdTPP nanoparticles is greatly improved after integrating with ZnTPP blocks. (3) The GZNs inherit excellent fluorescence imaging, high relaxation rate (8.18 mM-1 s-1) and singlet oxygen production from two raw metalporphyrins. After camouflaging with homotypic cancer cell membrane for immunologic escape, the HeLa membrane coated GZNs (mGZNs) show enhanced in vivo MR/FL imaging guided anti-tumor targeting efficiency of 80.6% for HeLa cells. Our new strategy using central metal-derived co-assembly of homogeneous building blocks greatly improves interfacial compatibility to achieve combined functions for visualized cancer theranostics.

Genome-wide mapping of 5-hydroxymethylcytosines in circulating cell-free DNA as a non-invasive approach for early detection of hepatocellular carcinoma.

OBJECTIVE: The lack of highly sensitive and specific diagnostic biomarkers is a major contributor to the poor outcomes of patients with hepatocellular carcinoma (HCC). We sought to develop a non-invasive diagnostic approach using circulating cell-free DNA (cfDNA) for the early detection of HCC. DESIGN: Applying the 5hmC-Seal technique, we obtained genome-wide 5-hydroxymethylcytosines (5hmC) in cfDNA samples from 2554 Chinese subjects: 1204 patients with HCC, 392 patients with chronic hepatitis B virus infection (CHB) or liver cirrhosis (LC) and 958 healthy individuals and patients with benign liver lesions. A diagnostic model for early HCC was developed through case-control analyses using the elastic net regularisation for feature selection. RESULTS: The 5hmC-Seal data from patients with HCC showed a genome-wide distribution enriched with liver-derived enhancer marks. We developed a 32-gene diagnostic model that accurately distinguished early HCC (stage 0/A) based on the Barcelona Clinic Liver Cancer staging system from non-HCC (validation set: area under curve (AUC)=88.4%; (95% CI 85.8% to 91.1%)), showing superior performance over α-fetoprotein (AFP). Besides detecting patients with early stage or small tumours (eg, ≤2.0 cm) from non-HCC, the 5hmC model showed high capacity for distinguishing early HCC from high risk subjects with CHB or LC history (validation set: AUC=84.6%; (95% CI 80.6% to 88.7%)), also significantly outperforming AFP. Furthermore, the 5hmC diagnostic model appeared to be independent from potential confounders (eg, smoking/alcohol intake history). CONCLUSION: We have developed and validated a non-invasive approach with clinical application potential for the early detection of HCC that are still surgically resectable in high risk individuals.

Trends in Physician Reimbursement for Spinal Procedures Since 2010.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To identify trends in spinal procedure reimbursement in our practice since 2010. SUMMARY OF BACKGROUND DATA: In an uncertain healthcare climate with continuous reform, trends in physician reimbursement are unclear. Market forces of supply and demand, legislation imposing penalties for quality measures, local competition, and geographic location have the potential to affect reimbursement. An emphasis on quality-of-care and cost reduction is placed on providers and insurers. In a high-cost area such as spine surgery, it is unknown what the reimbursement trends have been over the last 7 years of major healthcare reforms. METHODS: We collected payments received data for the 20 most commonly billed Current Procedural Terminology (CPT) codes for spinal surgery from January 2010 to December 2016. Payments were adjusted for inflation using the Consumer Price Index for Medical Care in the Northeastern United States. Insurers were separated into four groups: Medicare, Medicaid, Private Insurance, and Workers Compensation and No Fault (WC/NF). Using a weighted average to adjust for variation in procedures performed, average payments were trended over time. Average payments were trended by insurance group averaged by CPT code. RESULTS: After adjusting for inflation, average overall payments for spinal claims from 2010 to 2016 increased 13.6%. Average reimbursement declined 1.9% from 2010 to 2013 and rose 16.8% from 2014 to 2016. Average Medicaid payments increased 150.1% since 2010 whereas average Medicare payments rose 4.9%. Average reimbursement from private insurers and WC/NF claims decreased 16.2% and 8.5%, respectively, from 2010 to 2013; increasing 14.2% and 12.5%, respectively, from 2014 to 2016. From 2010 to 2016, reimbursement for private insurance decreased 9.3% and increased 8.2% for WC/NF claims. CONCLUSION: Since 2010, inflation-adjusted reimbursement for spinal procedures increased in our practice. There was a decline from 2010 to 2013. Increases occurred from 2014 to 2016 across all insurers. Medicaid payments more than doubled since 2010. LEVEL OF EVIDENCE: 3.

Developing a pH-sensitive Al(OH)3 layer-mediated UCNP@Al(OH)3/Au nanohybrid for photothermal therapy and fluorescence imaging in vivo.

Nanohybrids fabricated with upconversion nanoparticles (UCNPs) and gold nanoparticles (NPs) hold great promise for near-infrared photothermal therapy (NIR-PTT) and upconversion fluorescence imaging. However, the obstacles of poor solubility in water and finite hydrophilic modification method for UCNPs limit their application in biological fields. Herein, we report a novel UCNP@Al(OH)3/Au nanohybrid mediated by a highly hydrophilic and biocompatible Al(OH)3 layer to realize a synergistic targeted PTT and fluorescence imaging capability to U87MG tumor-bearing mice under NIR light irradiation. The modification with Al(OH)3 layers can improve the water solubility of UCNPs. And cytotoxicity assays and hemolysis assay showed that the modification with Al(OH)3 layers makes UCNPs have low cytotoxicity and good biocompatibility. In addition, the Al(OH)3 layers are thin enough to allow fluorescence resonance energy transfer (FRET) between UCNPs and gold NPs to occur, giving the NPs a good PTT effect for tumor-bearing mice. Meanwhile, as the pH-sensitive Al(OH)3 layers decompose in acidic tumor microenvironments with Au NPs detached from their surface, the FRET effect no longer occurred, subsequently leading to the fluorescence intensity of naked UCNPs being recovered for good imaging effects. The study suggests that Al(OH)3 mediation layer as a promising hydrophilic nanoplatform can potentially be used for the preparation of superior hydrophilic NPs and pH-stimulated drug release carriers for theranostic application in vivo.

pH-Dependent Assembly of Porphyrin-Silica Nanocomposites and Their Application in Targeted Photodynamic Therapy.

Structurally controlled nanoparticles, such as core-shell nanocomposite particles by combining two or more compositions, possess enhanced or new functionalities that benefited from the synergistic coupling of the two components. Here we report new nanocomposite particles with self-assembled porphyrin arrays as the core surrounded by amorphous silica as the shell. The synthesis of such nanocomposite nanoparticles was conducted through a combined surfactant micelle confined self-assembly and silicate sol-gel process using optically active porphyrin as a functional building block. Depending on kinetic conditions, these particles exhibit structure and function at multiple length scales and locations. At the molecular scale, the porphyrins as the building blocks provide well-defined macromolecular structures for noncovalent self-assembly and unique chemistry for high-yield generation of singlet oxygen for photodynamic therapy (PDT). On the nanoscale, controlled noncovalent interactions of the porphyrin building block result in an extensive self-assembled porphyrin network that enables efficient energy transfer and impressive fluorescence for cell labeling, evidenced by absorption and photoluminescence spectra. Finally, the thin silicate shell on the nanoparticle surface allows easy functionalization, and the resultant targeting porphyrin-silica nanocomposites can selectively destroy tumor cells upon receiving light irradiation.

Utility and Safety of Tolvaptan in Cirrhotic Patients with Hyponatremia: a Prospective Cohort Study

Abstract: Introduction and aim. Hyponatremia is common in patients with decompensated cirrhosis and is associated with increased mortality. Tolvaptan, a vasopressor V2 receptor antagonist, can increase free wáter excretion, but its efficacy and safety in cirrhotic patients remain unclear. Material and methods. We studied the usage and safety of tolvaptan in cirrhotic patients in a real-life, non-randomized, multicenter prospective cohort study. Forty-nine cirrhotic patients with hyponatremia were treated with tolvaptan 15 mg daily, and 48 patients not treated with tolvaptan in the same period served as controls. Improvement in serum sodium level was defined as an increase in serum sodium from < 125 to ≥ 125 mmol/L or from 125-134 to ≥ 135 mmol/L on day 7. Results. Twenty-three (47%) patients in the tolvaptan group and 17 (35%) in the control group had normal serum sodium on day 7 (p = 0.25). Serum sodium improved in 30 (61%) patients in the tolvaptan group and 17 (35%) patients in the control group (p = 0.011). Adverse events occurred in 46-47% of patients in both groups, and tolvaptan was not associated with worsened liver function. No patient with normal serum sodium on day 7 died within 30 days of treatment, whereas 16% of those with persistent hyponatremia died (p = 0.0019). Conclusion. In conclusion, short-term tolvaptan treatment is safe and can improve serum sodium level in cirrhotic patients with hyponatremia. Normalization of serum sodium level is associated with better survival.