Extended-Gate FET Biosensor Based on GaN Micropillar Array and Polycrystalline Layer: Application to Hg2+ Detection in Human Urine.

Owing to the separation of field-effect transistor (FET) devices from sensing environments, extended-gate FET (EGFET) biosensor features high stability and low cost. Herein, a highly sensitive EGFET biosensor based on a GaN micropillar array and polycrystalline layer (GMP) was fabricated, which was prepared by using simple one-step low-temperature MOCVD growth. In order to improve the sensitivity and detection limit of EGFET biosensor, the surface area and the electrical conductivity of extended-gate electrode can be increased by the micropillar array and the polycrystalline layer, respectively. The designed GMP-EGFET biosensor was modified with l-cysteine and applied for Hg2+ detection with a low limit of detection (LOD) of 1 ng/L, a high sensitivity of -16.3 mV/lg(µg/L) and a wide linear range (1 ng/L-24.5 µg/L). In addition, the detection of Hg2+ in human urine was realized with an LOD of 10 ng/L, which was more than 30 times lower than that of reported sensors. To our knowledge, it is the first time that GMP was used as extended-gate of EGFET biosensor.

Liver fibrosis showed a two-phase regression rate during long-term anti-HBV therapy by three-time biopsies assessments.

BACKGROUND: Evidence has proven that liver fibrosis or even cirrhosis can be reversed by anti-HBV treatment. However, the difference of fibrosis regression rates in short-term and long-term antiviral therapy remain unclear. Therefore, we aimed to identify the dynamic changes in fibrosis regression rate in patients with three-time liver biopsies during 5 years antiviral therapy. METHODS: CHB patients with three times of liver biopsies (baseline, after 1.5-year and 5-year antiviral therapy) from a prospective cohort were enrolled. All patients were biopsy-proved Ishak stage ≥ 3 at baseline (n = 92). Fibrosis regression was defined as Ishak stage decreased ≥ 1 or predominantly regressive categorized by P-I-R score. RESULTS: Totals of 65.2% (60/92) and 80.4% (74/92) patients attained fibrosis regression after 1.5-year and 5-year therapy, respectively. Median HBV DNA level declined from 6.5 log IU/ml (baseline) to 0 log IU/ml (1.5 years and 5 years, P < 0.001). The mean level of Ishak fibrosis stage in all patients decreased from stage 4.1 (baseline) to 3.7 (1.5 years) then 3.2 (5 years). Fibrosis regression rates were 0.27 stage/year between baseline to year 1.5 and 0.14 stage/year between year 1.5 and year 5. Furthermore, for patients who attained fibrosis regression after 5-year antiviral therapy, the two-phase regression rates were 0.39 stage/year (0 year-1.5 years) and 0.20 stage/year (1.5 years-5 years). This two-phase feature of regression rate was further confirmed by fully-quantification assessment of liver fibrosis based on SHG/TPEF. CONCLUSION: During the 5 years of long-term antiviral treatment, liver fibrosis rapidly regresses in the first 1.5 years before slowing down in the following 3.5 years.

Calcium-sensing receptor and NF-κB pathways in TN breast cancer contribute to cancer-induced cardiomyocyte damage via activating neutrophil extracellular traps formation.

Cardiovascular disorders are commonly prevalent in cancer patients, yet the mechanistic link between them remains poorly understood. Because neutrophil extracellular traps (NETs) have implications not just in cardiovascular diseases (CVD), but also in breast cancer (BC), it was hypothesized to contribute to CVD in the context of oncogenesis. We established a mouse model using nude mice to simulate liver metastasis of triple-negative BC (TNBC) through the injection of MDA-MB-231 cells. Multiple imaging and analysis techniques were employed to assess the cardiac function and structure, including echocardiography, HE staining, Masson staining, and transmission electron microscopy (TEM). MDA-MB-231 cells underwent treatment with a CaSR inhibitor, CaSR agonist, and NF-κB channel blocker. The phosphorylation of NF-κB channel protein p65 and the expression and secretion of IL-8 were assessed using qRT-PCR, Western Blot, and ELISA, respectively. In addition, MDA-MB-231 cells were co-cultured with polymorphonuclear neutrophils (PMN) under varying conditions. The co-localization of PMN extracellular myeloperoxidase (MPO) and DNA were observed by cellular immunofluorescence staining to identify the formation of NETs. Then, the cardiomyocytes were co-cultured with the above medium that contains NETs or not, respectively; the effects of NETs on cardiomyocytes apoptosis were perceived by flow cytometry. The ultrastructural changes of myocardial cells were perceived by TEM, and ELISA detected the levels of myocardial enzyme (LDH, MDA and SOD). Overall, according to our research, CaSR has been found to have a regulatory role in IL-8 secretion in MDA-MB-231 cells, as well as in the formation of NETs by PMN cells. These findings suggest CaSR-mediated stimulation in PMN can lead to increased NETs formation and subsequently to cytotoxicity in cardiomyocytes, which potentially via activation of the NF-κB signaling cascade of BC cell.

Carvedilol Plus NUC for Patients With HBV-Compensated Cirrhosis Under Virological Suppression: A Randomized Open-Label Trial.

INTRODUCTION: Portal hypertension progression can be relieved after controlling the etiology of liver cirrhosis. Whether beta-blockers could additionally enhance the effects during treatment, particularly for small esophageal varices (EV), was unclear. This study aims to assess the efficacy of add-on carvedilol to delay EV progression during anti-hepatitis B virus (HBV) treatment in HBV-related cirrhosis. METHODS: This randomized controlled trial enrolled patients with virologically suppressed HBV-compensated cirrhosis and small/medium EV. The participants were randomly assigned to receive nucleos(t)ide analog (NUC) or carvedilol 12.5 mg plus NUC (1:1 allocation ratio). The primary end point was the progression rate of EV at 2 years of follow-up. RESULTS: A total of 238 patients (small EV, 77.3%) were randomized into 119 NUC and 119 carvedilol plus NUC (carvedilol [CARV] combination group). Among them, 205 patients (86.1%) completed paired endoscopies. EV progression rate was 15.5% (16/103) in the NUC group and 12.7% (13/102) in the CARV combination group (relative risk = 0.79, 95% confidence interval 0.36-1.75, P = 0.567). Subgroup analysis on medium EV showed the CARV combination group had a more favorable effect in promoting EV regression (43.5% vs 13.1%, P = 0.022) than NUC alone, but not in small cases ( P = 0.534). The incidence of liver-related events (decompensation, hepatocellular carcinoma, or death/liver transplantation) within 2 years was similar between the 2 groups (11.2% vs 10.4%, P = 0.881). DISCUSSION: The overall results did not show statistically significant differences between the added carvedilol strategy and NUC monotherapy in preventing EV progression in patients with virologically suppressed HBV-compensated cirrhosis. However, the carvedilol-added approach might offer improved outcomes specifically for patients with medium EV (NCT03736265).

Revealing the Mutually Enhanced Mechanism of Necroptosis and Immunotherapy Induced by Defect Engineering and Piezoelectric Effect.

Owing to low immunogenicity-induced immune escape and short-term circulating immune responses, the efficiency of immunotherapy is unsatisfactory. Therefore, triggering immunogenic cell death and establishing a long-term, mutually reinforced treatment modality are urgent challenges. In this study, ultrathin CaBi2 Nb2 O9 nanosheets with tunable oxygen vacancies (abbreviated as CBNO-OV1) are prepared for synergistic necroptosis and immunotherapy. The optimized vacancy concentration significantly improves the piezoelectric effect under ultrasound irradiation, thereby considerably improving the generation of reactive oxygen species (ROS). Density functional theory shows that oxygen vacancies can improve the efficiency of electron hole separation by suppressing their recombination, thus resulting in enhanced piezocatalytic activity. Moreover, the piezoelectric effect improves the permeability of tumor cell membranes, thus resulting in Ca2+ influx. Additionally, CBNO-OV1 also releases a portion of Ca2+ , which induces necroptosis assisted by explosive ROS. Ribonucleic acid transcription tests suggest the mechanisms associated with immune response activation and necroptosis. More importantly, necroptosis can trigger a significant immune response in vivo, thus activating macrophage M1 polarization through the NF-kappa B pathway and promoting T-cell differentiation.Tumor Necrosis Factor-α differentiated from macrophages conversely promotes necroptosis, thus realizing a mutually enhanced effect. This study demonstrates the feasibility of mutually reinforced necroptosis and immunotherapy for amplifying tumor efficacy.

Regression of Liver Fibrosis in Patients on Hepatitis B Therapy Is Associated With Decreased Liver-Related Events.

BACKGROUND & AIMS: Liver fibrosis in patients with chronic hepatitis B can regress with successful antiviral therapy. However, the long-term clinical benefits of fibrosis regression have not been fully elucidated. This study investigated the association between biopsy-proven fibrosis regression by predominantly progressive, indeterminate, and predominantly regressive (P-I-R) score and liver-related events (LREs) in chronic hepatitis B patients. METHODS: Patients with on-treatment liver biopsy and significant fibrosis/cirrhosis (Ishak stage ≥3) were included in this analysis. Fibrosis regression was evaluated according to the P-I-R score of the Beijing Classification. LREs were defined as decompensations, hepatocellular carcinoma, liver transplantation, or death. The Cox proportional hazards model was used to determine associations of fibrosis regression with LREs. RESULTS: A total of 733 patients with Ishak stages 3/4 (n = 456; 62.2%) and cirrhosis (Ishak stages 5/6; n = 277; 37.8%) by on-treatment liver biopsy were enrolled. According to the P-I-R score, fibrosis regression, indeterminate, and progression were observed in 314 (42.8%), 230 (31.4%), and 189 (25.8%) patients, respectively. The 7-year cumulative incidence of LREs was 4.1%, 8.7%, and 18.1% in regression, indeterminate, and progression, respectively (log-rank, P < .001). Compared with patients with fibrosis progression, those with fibrosis regression had a lower risk of LREs (adjusted hazard ratio, 0.40; 95% CI, 0.16-0.99; P = .047), followed by the indeterminate group (adjusted hazard ratio, 0.86; 95% CI, 0.40-1.85; P = .691). Notably, this favorable association also was observed in patients with cirrhosis or low platelet counts (<150 × 109/L). CONCLUSIONS: Antiviral therapy-induced liver fibrosis regression assessed by P-I-R score is associated with reduced LREs. This shows the utility of histologic fibrosis regression assessed by on-treatment P-I-R score as a surrogate endpoint for clinical events in patients with hepatitis B virus-related fibrosis or early cirrhosis.

Recompensation in treatment-naïve HBV-related decompensated cirrhosis: a 5-year multi-center observational study comparing patients with ascites and bleeding.

BACKGROUND AND AIMS: Recompensation between patients with ascites and bleeding was unknown in treatment-naïve HBV-related decompensated cirrhosis. METHODS: In this retrospective multi-center study, treatment-naïve HBV-related decompensated patients were enrolled at first decompensating event of ascites and/or variceal bleeding. Further complications and clinical characteristics were collected using standard case report form every 6 months to year-5 of antiviral treatment. Recompensation was defined as maintaining free of decompensation for one year and achieving liver function within Child-Pugh A and/or MELD < 10. RESULTS: Totally, 170 (170/298, 57.0%) patients in ascites group of 298 (298/383, 77.8%) treatment-naïve decompensated patients and 33 (33/85, 38.8%) in bleeding group of 85 (85/383, 22.2%) patients, achieved recompensation. Ascites group had higher 5-year rate of recompensation than bleeding group (63.3% vs. 46.5%, p = 0.012), respectively. Patients achieving recompensation in ascites group maintained lower rate of second decompensation than these in bleeding group (at year-5: 26.7% vs. 43.3%, p = 0.032). Specifically, recompensated patients in ascites group had predominantly 5-year rate of further ascites (24.0%) and lower rate of further bleeding (6.0%), which differed from the pattern of these in bleeding group, with lower rate of further ascites (16.0%, p = 0.599) and significantly higher rate of further bleeding (33.9%, p < 0.001). Both patients had superior long-term prognosis (death/LT rate at year-5: 0.6% vs. 3.0%, p = 0.196). CONCLUSION: Ascites patients could achieve higher rate of recompensation through antiviral therapy than bleeding patients. Recompensated patients in ascites group had better prognosis in terms of preventing further bleeding.

Distinct on-treatment HCC risks associated with different decompensation events in HBV patients with cirrhosis.

OBJECTIVES: Long-term treatment with nucleoside analog (NA) reduces the risks for decompensation and hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients with compensated cirrhosis (CC). However, whether antiviral therapy has differential efficacy on the risks for decompensation and HCC is insufficiently elucidated. Therefore, we investigated the disease state transition, focusing on decompensation event-specific HCC risk in NA-treated CHB patients with CC. METHODS: We prospectively followed up on 1163 NA-treated CHB patients with CC every six months for up to seven years. The cumulative incidence and risk of HCC were analyzed by the Kaplan-Meier method and competing risk model. The multistate model was used to estimate the transition probabilities to HCC from different disease states. RESULTS: HCC predominated the first liver-related events, with a 5-year cumulative incidence of 9.0%, followed by decompensation (8.3%, including 7.9% nonbleeding decompensation and 2.4% variceal bleeding) and 0.2% death. The decompensation stage had a significantly higher 5-year cumulative HCC incidence than the CC stage (27.6% vs. 9.1%; HR = 2.42, 95% CI: 1.24, 4.71). Furthermore, nonbleeding decompensation events had a higher 5-year transition probability to HCC than bleeding (27.6% vs. 15.8%; HR = 2.69, 95% CI: 1.41, 4.17). Viral suppression modified the on-treatment transition risk to HCC (1-year: HR = 0.45, 95% CI: 0.28, 0.73; 3-year: HR = 0.23, 95% CI: 0.14, 0.38). An online calculator was developed to facilitate HCC risk stratification. CONCLUSIONS: In NA-treated CHB patients with compensated cirrhosis, the risk was higher for HCC than for decompensation; more importantly, different decompensation events conferred distinct HCC risks.

Dynamic changes in three biomarkers predict early-stage hepatocellular carcinoma in patients with chronic hepatitis B receiving antiviral therapy.

PURPOSE: Patients with chronic hepatitis B (CHB) remain at risk for hepatocellular carcinoma during antiviral therapy. We aimed to clarify the values of alpha-fetoprotein (AFP), lectin-reactive fraction of AFP (AFP-L3), and des-γ-carboxyprothrombin (DCP) for early warning of HCC. METHODS: A total of 1348 CHB patients received antiviral therapy and follow-up every 26 weeks. Eighty-four patients with HCC were age-, sex-, and cirrhosis-matched with 168 controls. AFP, AFP-L3, and DCP were compared between the groups from 104 weeks before HCC diagnosis (- 104 w) to the time of diagnosis (0 w). RESULTS: Of the 84 HCC patients, 60 (71.4%) had early-stage HCC, AFP increased from - 26 w, and AFP-L3 and DCP increased from - 78 w. However, levels were unchanged in controls. ΔAFP, ΔAFP-L3, and ΔDCP showed similar abilities for predicting HCC (P > 0.05). Receiver operating characteristic curve analysis showed that AFP had better diagnostic performance for HCC than AFP-L3, DCP, or their combination. The cut-off values of AFP, AFP-L3, and DCP were 5.3 ng/mL, 1.05%, and 31.5 mAU/mL, respectively. Notably, lower AFP values were required to diagnose HCC in patients with detectable HBV DNA (4.1 ng/mL) or elevated alanine aminotransferase (5.2 ng/mL). CONCLUSIONS: Changes in AFP, AFP-L3, and DCP can help to predict HCC in CHB patients receiving antiviral therapy. A lower AFP value is needed to diagnose HCC, especially in patients with detectable HBV DNA or elevated alanine aminotransferase.

Hepatocellular carcinoma prediction model performance decreases with long-term antiviral therapy in chronic hepatitis B patients.

BACKGROUND/AIMS: Existing hepatocellular carcinoma (HCC) prediction models are derived mainly from pretreatment or early on-treatment parameters. We reassessed the dynamic changes in the performance of 17 HCC models in patients with chronic hepatitis B (CHB) during long-term antiviral therapy (AVT). METHODS: Among 987 CHB patients administered long-term entecavir therapy, 660 patients had 8 years of follow-up data. Model scores were calculated using on-treatment values at 2.5, 3, 3.5, 4, 4.5, and 5 years of AVT to predict threeyear HCC occurrence. Model performance was assessed with the area under the receiver operating curve (AUROC). The original model cutoffs to distinguish different levels of HCC risk were evaluated by the log-rank test. RESULTS: The AUROCs of the 17 HCC models varied from 0.51 to 0.78 when using on-treatment scores from years 2.5 to 5. Models with a cirrhosis variable showed numerically higher AUROCs (pooled at 0.65-0.73 for treated, untreated, or mixed treatment models) than models without (treated or mixed models: 0.61-0.68; untreated models: 0.51-0.59). Stratification into low, intermediate, and high-risk levels using the original cutoff values could no longer reflect the true HCC incidence using scores after 3.5 years of AVT for models without cirrhosis and after 4 years of AVT for models with cirrhosis. CONCLUSION: The performance of existing HCC prediction models, especially models without the cirrhosis variable, decreased in CHB patients on long-term AVT. The optimization of existing models or the development of novel models for better HCC prediction during long-term AVT is warranted.

Dual-inhibition of lactate metabolism and Prussian blue-mediated radical generation for enhanced chemodynamic therapy and antimetastatic effect.

Numerous research studies have proved that lactate is pivotal in tumor proliferation, metastasis, and recurrence, so disrupting the lactate metabolism in the tumor microenvironment (TME) has become one of the effective methods of tumor treatment. Herein, we have developed a versatile nanoparticle (HCLP NP) based on hollow Prussian blue (HPB) as the functional carrier for loading α-cyano-4-hydroxycinnamate (CHC), and lactate oxidase (LOD), followed by coating with polyethylene glycol to enhance chemodynamic therapy (CDT) and the antimetastatic effect of cancer. The obtained HCLP NPs would be degraded under endogenous mild acidity within the TME to simultaneously release CHC and LOD. CHC inhibits the expression of monocarboxylate transporter 1 in tumors, thereby interrupting the uptake of lactate from the outside and alleviating tumor hypoxia by reducing lactate aerobic respiration. Meanwhile, the released LOD can catalyze the decomposition of lactate into hydrogen peroxide, further enhancing the efficacy of CDT by generating plenty of toxic reactive oxygen species through the Fenton reaction. The strong absorbance at about 800 nm endows HCLP NPs with excellent photoacoustic imaging properties. Both in vitro and in vivo studies have demonstrated that HCLP NPs can inhibit tumor growth and metastasis, providing a new possibility for tumor therapy.

A new glutamine synthetase index to evaluate hepatic lobular restoration in advanced fibrosis during anti-HBV therapy.

Hepatic lobular architecture distortion is a deleterious turning point and a crucial histological feature of advanced liver fibrosis in chronic liver diseases. Regression of fibrosis has been documented in chronic hepatitis B (CHB) patients. However, whether lobular architecture could be restored following fibrosis regression after antiviral therapy is still unclear. Glutamine synthetase (GS) is generally expressed by perivenular hepatocytes around hepatic veins (HV). In this study, we defined abnormal lobular architecture (GSPT ) as GS expressing in the vicinity of portal tracts (PT), which denotes parenchymal extinction and lobular collapse. We defined normal lobular architecture (GSHV ) as GS positivity area not approximating PTs. Therefore, we propose a new GS-index, defined as the percentage of GSHV /(GSHV + GSPT ), to evaluate the extent of architectural disruption and restoration. We evaluated 43 CHB patients with advanced fibrosis (Ishak stage ≥4). Posttreatment liver biopsy was performed after 78 weeks of anti-HBV therapy. The median GS-index improved from 7% (interquartile range [IQR]: 0%-23%) at baseline to 36% (IQR: 20%-57%) at Week 78 (p < 0.001). Totals of 22 patients (51%) had significant GS-index improvement from 0% (IQR: 0%-13%) to 55% (IQR: 44%-81%), while the other half had almost no change between 17% (IQR: 0%-33%) to 20% (IQR: 12%-31%). When GS-index78w ≥ 50% was used to define hepatic lobular restoration, 37% of patients (16/43) achieved lobular restoration, with much improvement in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels (median value of ∆/Baseline in ALT: restored vs. nonrestored was 79.1% vs. 48.8%, p = 0.018; median value of ∆/Baseline in AST: restored vs. nonrestored was 69.1% vs. 32.5%, p = 0.005). More importantly, lobular restoration correlated with fibrosis regression (median value of ∆/Baseline in Ishak stage: restored vs. nonrestored was 25.0% vs. 0%, p = 0.008). Therefore, in the era of antiviral therapy for CHB, restoration of hepatic lobular architecture is achievable in patients with advanced fibrosis. GS-index provides additional insight into fibrosis regression that goes beyond collagen degradation.

Two-year free of complications during antiviral therapy predicts stable re-compensation in immediate-treatment HBV-related decompensated cirrhosis.

BACKGROUND AND AIMS: Disease progression could be altered or even reversed in decompensated patients with HBV-related cirrhosis once they initiate antiviral therapy. However, little is known about the stable re-compensation in these patients. METHODS: In this retrospective study, HBV-related liver cirrhosis patients were consecutively enrolled at the first decompensated event of ascites or variceal hemorrhage (VH), and divided into immediate-treatment, on-treatment and delayed/no treatment groups. Patients were followed up to at least presence of second decompensation event or to June 2021. Re-compensation was defined as patients who did not occur second (further) decompensation during follow-up. RESULTS: A total of 130 HBV-related decompensated cirrhotic patients were included with a median follow-up of 61.0 (41.6, 72.0) months. The cumulative incidence of re-compensation at year 6 was 39.0, 9.8 and 6.6 in immediate-treatment, on-treatment and delayed/no treatment group (p = 0.001). Among 87 patients in immediate-treatment group, thirty-seven (37/87, 42.5%) were recognized as stable re-compensation. Seventy percent (35/50) of second decompensated events occurred in the first 2 years. In patients free of 2-year decompensated complications, about 71.2% (37/52) maintained stable re-compensation. The cumulative incidence of death (and/or transplantation) and HCC in patients free of 2-year decompensated complications or not was 2.9 vs. 27.3% (HR 9.4, 95% CI 2.2-40.0, p = 0.002) and 12.6 vs. 37.7% (HR 4.5, 95% CI 1.5-13.3, p = 0.006), respectively. CONCLUSIONS: In decompensated patients with HBV-related cirrhosis, about 40% in immediate-treatment group maintained stable re-compensation during 6 years of antiviral therapy. Two-year free of complications could predict stable re-compensation.

Comparative Performance of 14 HCC Prediction Models in CHB: A Dynamic Validation at Serial On-Treatment Timepoints.

INTRODUCTION: To assess comparative performance of 14 hepatocellular carcinoma (HCC) prediction models in chronic hepatitis B (CHB) patients using on-treatment values at different timepoints. METHODS: Based on a nationwide prospective cohort of 986 treatment-naive CHB patients undergoing entecavir therapy with every 26-week follow-up, 14 HCC risk scores were calculated using on-treatment values at week 26, 52, 78, and 104, respectively. Model performance predicting 3-year HCC was assessed using time-dependent area under the receiver operating characteristic curve (AUC) and calibration index. Model cutoffs were validated through common diagnostic accuracy measures. RESULTS: During median 4.7-year follow-up, 56 (7.5%) developed HCC. Discrimination using on-treatment values within first 2 years was generally acceptable for most models (AUCs ranging from 0.68 to 0.81), except for REACH-B, NGM-HCC, and PAGE-B, although AUCs slightly decreased from week 26 to 104. Of these, REAL-B, CAMD, GAG-HCC, AASL-HCC, LSM-HCC, mPAGE-B, and mREACH-BII showed highest discrimination with AUCs ranging from 0.76 to 0.81, 0.72 to 0.76, 0.70 to 0.76, and 0.71 to 0.74 when reassessment at week 26, 52, 78, and 104, respectively. With reassessment within first 2 years, both REAL-B and CAMD calibrated well (Brier score ranging from 0.037 to 0.052). Of 9 models reporting cutoffs, REAL-B, AASL-HCC, and mPAGE-B using on-treatment values could identify 30%-40% of patients as low risk with minimal HCC incidence in the low-risk group (0.40% [REAL-B]-1.56% [mPAGE-B]). DISCUSSION: In this undergoing antiviral treatment CHB cohort, most HCC prediction models performed well even using on-treatment values during first 2 years, particularly REAL-B, AASL-HCC, CAMD, and mPAGE-B model.

Dual Glutathione Depletion Enhanced Enzyme Catalytic Activity for Hyperthermia Assisted Tumor Therapy on Semi-Metallic VSe2/Mn-CS.

Semimetallic nanomaterials as photothermal agents for bioimaging and cancer therapy have attracted tremendous interest. However, the poor photothermal stability, low biocompatibility, and single component limit their therapeutic efficiency in cancer treatment. Here, manganese-doped VSe2 semimetallic nanosheets were prepared and subsequently modified with chitosan (named VSe2/Mn-CS NSs) for combined enzyme catalytic and photothermal therapy. VSe2/Mn-CS NSs show high photothermal property with a photothermal conversion efficiency of 34.61% upon 808 nm near-infrared laser irradiation. In the tumor microenvironment, VSe2/Mn-CS NSs can convert endogenous H2O2 into lethal hydroxyl radicals (•OH) to induce cancer cell apoptosis. The interaction between glutathione (GSH) and Se-Se bonds in VSe2/Mn-CS NSs results in the depletion of GSH level, and the valence states transition of manganese ions is also beneficial for the GSH consumption. This dual depletion of GSH markedly enhances the peroxidase (POD) activity, leading to the high •OH production and the improved therapeutic effect. What is more, the T1-weighted magnetic resonance and photoacoustic imaging endow VSe2/Mn-CS NSs with the ability to guide and track the treatment process. Our study provides a research strategy for the application of semimetallic nanomaterials in cancer diagnosis and treatment.

Tailoring Silica-Based Nanoscintillators for Peroxynitrite-Potentiated Nitrosative Stress in Postoperative Radiotherapy of Colon Cancer.

The development of a manageable reactive nitrogen species-potentiated nitrosative stress induction system for cancer therapy has remained elusive. Herein, tailored silica-based nanoscintillators were reported for low-dosage X-ray boosting for the in situ formation of highly cytotoxic peroxynitrite (ONOO-). Significantly, cellular nitrosative stress revolving around the intracellular protein tyrosine nitration through ONOO- pathways was explored. High-energy X-rays were directly deposited on silica-based nanoscintillators, forming the concept of an open source and a reduced expenditure-aggravated DNA damage strategy. Moreover, the resultant ONOO-, along with the released nitric oxide, not only can act as "oxygen suppliers" to combat tumor hypoxia but also can induce mitochondrial damage to initiate caspase-mediated apoptosis, further improving the therapeutic efficacy of radiotherapy. Thus, the design of advanced nanoscintillators with specific enhanced nitrosative stress offers promising potential for postoperative radiotherapy of colon cancer.

On-Demand Generation of Peroxynitrite from an Integrated Two-Dimensional System for Enhanced Tumor Therapy.

Nanosystem-mediated tumor radiosensitization strategy combining the features of X-ray with infinite penetration depth and high atomic number elements shows considerable application potential in clinical cancer therapy. However, it is difficult to achieve satisfactory anticancer efficacy using clinical radiotherapy for the majority of solid tumors due to the restrictions brought about by the tumor hypoxia, insufficient DNA damage, and rapid DNA repair during and after treatment. Inspired by the complementary advantages of nitric oxide (NO) and X-ray-induced photodynamic therapy, we herein report a two-dimensional nanoplatform by the integration of the NO donor-modified LiYF4:Ce scintillator and graphitic carbon nitride nanosheets for on-demand generation of highly cytotoxic peroxynitrite (ONOO-). By simply adjusting the Ce3+ doping content, the obtained nanoscintillator can realize high radioluminescence, activating photosensitive materials to simultaneously generate NO and superoxide radical for the formation of ONOO- in the tumor. Obtained ONOO- effectively amplifies therapeutic efficacy of radiotherapy by directly inducing mitochondrial and DNA damage, overcoming hypoxia-associated radiation resistance. The level of glutamine synthetase (GS) is downregulated by ONOO-, and the inhibition of GS delays DNA damage repair, further enhancing radiosensitivity. This work establishes a combinatorial strategy of ONOO- to overcome the major limitations of radiotherapy and provides insightful guidance to clinical radiotherapy.

Constructing virus-like SiOx/CeO2/VOx nanozymes for 1064 nm light-triggered mild-temperature photothermal therapy and nanozyme catalytic therapy.

The construction of nanoplatforms with combined photothermal properties and cascading enzymatic activities has become an active area of anticancer research. However, the overheating of photothermal therapy (PTT) and the specific properties of tumor microenvironment (TME) greatly impaired the therapeutic efficiency. Herein, we rationally fabricated a virus-like SiOx/CeO2/VOx (SCV) nanoplatform for 1064 nm near-infrared (NIR) triggered mild-temperature PTT and nanozyme catalytic therapy. Firstly, the virus-like shape of SiOx/CeO2/VOx made it favorable for cell adhesion and improved its phagocytosis in cells, and the SCV generated an effective PTT effect upon 1064 nm laser irradiation. Particularly, the produced VO2+ in TME could be used as a heat shock protein inhibitor to inhibit the expression of heat shock protein 60 (HSP60) to enhance the PTT efficiency. Moreover, the SCV nanozyme exhibited obvious peroxidase-mimic (POD) catalytic activity, which could generate highly toxic free radical ions (˙OH) under acidic conditions. The mild-temperature heat and ˙OH produced by enzymatic catalysis effectively blocked the tumor growth, as verified firmly by in vitro and in vivo tests. Our designed virus-like SCV nanozyme with POD mimic enzyme activity and a mild photothermal effect may provide a new way of thinking about the combination therapy model.

Europium Doped Silicon Quantum Dot As a Novel FRET Based Dual Detection Probe: Sensitive Detection of Tetracycline, Zinc, and Cadmium.

The imbalance of Zn2+ /Cd2+ in the human body can lead to many serious diseases due to the overuse of antibiotics and deposition in animal products. Developing a functional material for detecting is challenging and in demand. Herein, silicon quantum dots (SiQDs) are designed as a functional platform for the detection of tetracycline and Zn2+ /Cd2+ . The COOH functionalized SiQDs with the emission wavelength of 450 nm are chelated with Eu(NO3 )3 to form SiQDs-Eu3+ ratio fluorescent probes, which can be used to detect tetracycline (TCs) and Zn2+ /Cd2+ by fluorescence resonance energy transfer (FRET) principle sequentially. The fluorescent probe showed good linearity between ion concentration and fluorescence enhancement. The detection limit of TCs and Zn2+ /Cd2+ are 0.2 × 10-6  m and 3 × 10-6  m, respectively, when the pH of the solution is 7.4. In addition, the synthesized SiQDs-Eu3+ exhibited good stability (from 94.9% to 103.1%). The relative standard deviations (RSD, n = 10) of human serum and urine were both less than 3%. Therefore, the SiQDs-Eu3+ ratio fluorescence probe will provide a good application prospect in actual sample detection.

Health-related quality of life improves after entecavir treatment in patients with compensated HBV cirrhosis.

BACKGROUND AND AIM: Antiviral therapy is effective in decreasing disease progression in HBV cirrhosis. However, the long-term effect of antiviral therapy on health-related quality of life (HRQoL) in patients with compensated HBV cirrhosis is unknown. METHODS: The patients with compensated HBV cirrhosis enrolled in a randomized controlled trial of entecavir-based therapy were recruited in the present study, if they had HRQoL score at 5-year follow-up or who developed liver-related events (LRE) during follow-up were included. HRQoL was measured with 36-Item Short-Form Health Survey (SF-36) and EuroQol-5D (EQ-5D) at baseline and yearly during follow-up. LRE was defined as the development of decompensation, HCC, or death. RESULTS: A total of 161 patients were included in the present study, with a median age of 48.0 (41.0, 53.0) years, 77.6% being male and 37.2% being HBeAg-positive. During 5 years, 45 patients developed LRE. All eight dimensions of SF-36 were significantly improved after 5 years of antiviral therapy (all p < 0.001), with all dimensions improved more than five points except for physical functioning. Proportion of patients reporting no problems in all five dimensions in EQ-5D increased from 57.8 to 72.0%; visual analogue scale (VAS) and utility index (UI) increased significantly (VAS 79.8 ± 16.4 to 84.4 ± 13.2, UI 0.91 ± 0.13 to 0.95 ± 0.10, both p < 0.001). HRQoL improved or kept stable in the majority of patients who had LRE during follow-up, even stratified by Baveno VI criteria for clinically significant portal hypertension. CONCLUSION: After 5 years of ETV treatment, HRQoL significantly improved in patients with compensated HBV cirrhosis. (NCT01943617, NCT02849132).