Inhibition of autophagy-related protein 7 enhances anti-tumor immune response and improves efficacy of immune checkpoint blockade in microsatellite instability colorectal cancer.

BACKGROUND: The efficacy of anti-PD-1 therapy is primarily hindered by the limited T-cell immune response rate and immune evasion capacity of tumor cells. Autophagy-related protein 7 (ATG7) plays an important role in autophagy and it has been linked to cancer. However, the role of ATG7 in the effect of immune checkpoint blockade (ICB) treatment on high microsatellite instability (MSI-H)/mismatch repair deficiency (dMMR) CRC is still poorly understood. METHODS: In this study, patients from the cancer genome altas (TCGA) COAD/READ cohorts were used to investigate the biological mechanism driving ATG7 development. Several assays were conducted including the colony formation, cell viability, qRT-PCR, western blot, immunofluorescence, flow cytometry, ELISA, immunohistochemistry staining and in vivo tumorigenicity tests. RESULTS: We found that ATG7 plays a crucial role in MSI-H CRC. Its knockdown decreased tumor growth and caused an infiltration of CD8+ T effector cells in vivo. ATG7 inhibition restored surface major histocompatibility complex I (MHC-I) levels, causing improved antigen presentation and anti-tumor T cell response by activating reactive oxygen species (ROS)/NF-κB pathway. Meanwhile, ATG7 inhibition also suppressed cholesterol accumulation and augmentation of anti-tumor immune responses. Combining ATG7 inhibition and statins improved the therapeutic benefit of anti-PD-1 in MSI-H CRC. Importantly, CRC patients with high expression of both ATG7 and recombinant 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) experienced worse prognosis compared to those with low ATG7 and HMGCR expression. CONCLUSIONS: Inhibition of ATG7 leads to upregulation of MHC-I expression, augments immune response and suppresses cholesterol accumulation. These findings demonstrate that ATG7 inhibition has therapeutic potential and application of statins can increase the sensitivity to immune checkpoint inhibitors.

Creatine kinase elevation in chronic hepatitis B patients with telbivudine therapy: influence of telbivudine plasma concentration and single nucleotide polymorphisms of TK2, RRM2B, and NME4.

PURPOSE: To study the correlations of genetic variants of telbivudine phosphorylase kinases and telbivudine plasma concentration with creatine kinase elevation in chronic hepatitis B patients who received telbivudine. METHODS: An observational study was performed in China chronic hepatitis B patients receiving telbivudine therapy at 600 mg once daily. Plasma concentration was measured 12 h after taking telbivudine using ultra-performance liquid chromatography-tandem mass spectrometry and SNPs located in RRM2B, TK2, and NME4 was detected by MALDI-TOF mass spectrometry. All statistical analyses were performed with R 4.3.1 and all graphs were drawn by Origin 2023b and P value < 0.05 was considered statistically significant. RESULTS: A total of 140 patients receiving telbivudine therapy were recruited with a median plasma concentration of 952.49 (781.07-1238.98) ng/mL. The value of plasma concentration was proportional to the grade of creatine kinase elevation and the best telbivudine plasma concentration threshold to discriminate the grade 3/4 CK elevation was 1336.61 ng/mL. Multivariate analysis revealed that plasma concentration and rs3826160 were the independent risk factor of telbivudine-induced creatine kinase elevation. Patients with TC and CC genotype in rs3826160 not only had a higher incidence of creatine kinase elevation but also a higher plasma concentration than TT genotype carriers. CONCLUSION: Chronic hepatitis B patients with TC and CC genotype in rs3826160 have high telbivudine plasma concentration are at risk of elevated creatine kinase.

Dopant effect on the optical and thermal properties of the 2D organic-inorganic hybrid perovskite (HDA)2PbBr4.

Lead-based two-dimensional organic-inorganic hybrid perovskites (2D HOIPs) are popular materials with various optical properties, which can be tuned through metal ion doping. Due to the size and valence misfit, metal ion dopants in 2D lead-based HOIPs are still limited. In this work, Mn2+, Sb3+ and Bi3+ are doped into 2D (HDA)2PbBr4 (HDA = protonated dopamine) successfully. As a result, the dopants in 2D (HDA)2PbBr4 can induce their characteristic optical spectra, which is studied at different temperatures and excitation powers. The temperature-dependent energy transfer in the Mn-doped sample has been clarified, in which abnormal phenomena including negative thermal quenching have been observed. In addition, the dopant ions can impact the phase transition temperatures of the samples, especially lowering their crystallization temperatures greatly. The mussel-inspired organic cation, feasible metal ion regulation, and superior stability provide (HDA)2PbBr4 potential for further applications.

Clinical outcomes and medical resource utilization of toripalimab combination therapy versus bevacizumab plus chemotherapy in advanced non-squamous non-small cell lung cancer.

OBJECTIVE: This study aimed to evaluate the real-world clinical efficacy and safety, economic burdens and medical resource utilization (MRU) of toripalimab treatment patterns compared with bevacizumab plus chemotherapy (BCP) for patients with advanced non-squamous NSCLC in China. METHODS: Progression-free survival (PFS), adverse drug reactions (ADR) and the costs of drugs, laboratory testing, imageology examinations (including CT, B ultrasound, MRI), medical service, nursing, treatment, genetic test and medical disposable material were compared between two groups. A retrospective observational study was conducted with electronic medical records from Fudan University Huashan hospital. Data was obtained from established electronic medical records (EMRs) and patient surveys. Survival time from the study enrollment to disease progression or death plus from 1st progression disease (PD) in the maintenance phase to 2nd PD (PFS II), adverse events (AE), direct medical costs, MRU and AE-related costs were collected and compared between toripalimab group and BCP group. A total of 246 patients were enrolled. RESULTS: Toripalimab combination therapy has significantly prolonged PFS comparing with BCP (13.8 months vs. 6.2 months, p < .001). A statistically significant improvement in PFS was observed favoring all toripalimab regimen subgroups compared with the bevacizumab group. Patients in toripalimab group occupied more overall resource consumption, more direct medical costs ($47,056.9 vs. $29,951.0, p < .0001) and AE-related costs ($4,500.2 vs. $784.4, p < .0001) than BCP group. Although patients in the toripalimab group used more drugs to prevent AEs ($4,500.2 vs. $784.4, p < .0001), they still experienced more AEs than patients in BCP group (51.4% vs. 41.4%). CONCLUSION: Toripalimab combination therapy could significantly prolonged PFS for patients with advanced non-squamous NSCLC compared with BCP, but at the expense of more MRU, costs and AEs.

Corrigendum: Difference of gut microbiota between patients with negative and positive HBeAg in chronic hepatitis B and the effect of tenofovir alafenamide on intestinal flora.

[This corrects the article DOI: 10.3389/fmicb.2023.1232180.].

Difference of gut microbiota between patients with negative and positive HBeAg in chronic hepatitis B and the effect of tenofovir alafenamide on intestinal flora.

Background: Severe liver diseases, such as liver fibrosis, cirrhosis, and liver cancer, are mainly caused by hepatitis B virus (HBV). This study investigated the differences between gut microbiota in HBeAg-positive and negative groups of patients with chronic hepatitis B (CHB) and investigated the effect of tenofovir alafenamide (TAF) on gut microbiota. Methods: This prospective study included patients with CHB not taking nucleoside antivirals (No-NAs group, n = 95) and those taking TAF (TAF group, n = 60). We divided CHB patients into two groups according to the HBeAg status of the subjects on the day of data collection. Phase 1 are HBeAg-negative patients and phase 2 are HBeAg-positive patients. We investigated the improvement of clinical symptoms by TAF, as well as differences in gut microbiota between different groups by 16S rRNA high-throughput sequencing. Results: Gut microbiota demonstrated significant differences between patients with HBeAg-positive and -negative CHB. Both the No-NAs and TAF Phase 2 subgroups demonstrated significantly increased microbiota richness and diversity, showing greater heterogeneity. Additionally, the Phase 2 subgroup exhibited a low abundance of pathways associated with glucose metabolism and amino acid metabolism. The TAF group demonstrated a significantly decreased HBV load, alanine aminotransferase, and aspartate aminotransferase and a significant increase in prealbumin compared with the No-NAs group. No significant difference was found in uric acid, creatinine, blood calcium, inorganic phosphorus, eGFR, and ß2-microglobulin concentrations between the two groups. Additionally, the urea level in the TAF group was significantly lower than that in the No-NAs group, but with no significant effect on other indicators such as eGFR and ß2-microglobulin. Conclusion: This study revealed significant differences in gut microbiota composition and function between patients with HBeAg-positive and -negative CHB.

Green synthesis of carbon-supported ultrafine ZnS nanoparticles for superior lithium-ion batteries.

Zinc sulfide (ZnS) is a promising anode material for lithium-ion batteries (LIBs) because of its high theoretical capacity, abundance, cost-effectiveness, and environmental friendliness. Herein, a hydrangea-like ZnS-carbon composite (ZnS-NC) is synthesized through the hydrothermal method and subsequent pyrolysis of a supramolecular precursor guanosine. The resulting composite comprises ultrafine ZnS nanoparticles firmly stabilized on a nitrogen-doped carbon matrix, featuring mesoporous channels and high surface areas. When utilized as an anode material for LIBs, the initial discharge specific capacity of the ZnS-NC electrode reaches an impressive value of 944 mA h g-1 at 1.0 A g-1, and even after 450 cycles, it maintains a reversible capacity of 597 mA h g-1. Compared with pure ZnS, the ZnS-NC composite exhibits significantly improved rate performance and cycling stability. This enhancement in Li-storage performance can be attributed to a synergistic effect within the ZnS-NC composite, which arises from the large exposed active site area, efficient ion/electron transfer, and strong interaction between the ZnS nanoparticles and the carbon framework. Overall, this work presents an eco-friendly approach for developing metal sulfide-carbon composites with exceptional potential for energy storage applications.

Exploration on the development of public hospital-sponsored telemedicine platform: A case study in China.

BACKGROUND: As a result of recent advancements, Internet hospitals have been a typic kind of telemedicine platform in China. The platforms can now provide a wide range of medical services while breaking through the limitations of time and space with excellent accessibility. OBJECTIVE: This study aims to give a comprehensive description on the role extension of a public hospital-sponsored Internet hospital in China from the aspects of the characteristics, patient's benefit and satisfaction, the workload of pharmacists and pharmaceutical care. METHODS: The total number of online prescriptions and detailed information were obtained automatically from the Internet hospital information system from Huashan Hospital Fudan University. Age, sex, associated prescription departments, time of prescription, payment methods, expenditure, drug category and delivery region were included in the analysis. A follow-up questionnaire was distributed as an electronic form that was collected and analyzed through the Internet to evaluate patients' satisfaction and time/economic benefits. RESULTS: A total of 51,777 patients visited Internet hospital and purchased required drugs from May 2020 to March 2022. The top 5 online prescription departments were dermatology (83.11%), neurology (6.85%), infectious diseases (3.27%), gastroenterology (2.35%) and cardiology (2.03%) departments. During this period, the audit pharmacists reviewed an average of 240 prescriptions per day, and the consultant pharmacists replied to about 42 consultations per day. 77.89% patients living in westsourth China benefited most from the Internet hospitals. They saved longest time (5 days) and the most expenses ($450-600). We observed an average patient satisfaction score higher than 4.5 in majority dimensions, including drug accessibility, effective in communication and confidence in medical staff. During closed-off management period between April to May in 2022, a total of 194,388 drugs were prescribed and delivered to 19,442 patients with the total payments of $1,547,001.2. Compared with those before closed-off management, the proportion of patients visiting dermatology department reduced from 83.11% to 54.87%. There was a significant increase in the number of patients visited general practice medicine department. The pharmacists extended their working hours by 5 h per day. In 2 months close-off management, the audit pharmacists reviewed an average of 320 prescriptions per day, and the consultant pharmacists replied to about 138 consultations per day. CONCLUSIONS: The characteristics of patients in terms of department and disease profiles in the Internet hospital were consistent with those preponderant disciplines in the entity hospital. Patients benefited from the Internet hospital not only in saving times, but also in reducing medical expenses. During the close-off management period, the distribution of departments and disease profiles changed dramatically. These changes indicated that the Internet hospital was no longer just an extension of in-hospital services, but played an important role in fighting the epidemic, changed the mode of patients' medical treatment and hospital diagnosis and treatment at special times.

Mussel-Inspired Two-Dimensional Halide Perovskite Facilitated Dopamine Polymerization and Self-Adhesive Photoelectric Coating.

Polydopamine (PDA) is a good adhesion agent for lots of gels inspired by the mussel, whereas hybrid organic-inorganic perovskites (HOIPs) usually exhibit extraordinary optoelectronic performance. Herein, mussel-inspired chemistry has been integrated with two-dimensional HOIPs first, leading to the preparation of new crystal (HDA)2PbBr4 (1) (DA = dopamine). The organic cation dopamine can be introduced into PDA resulting in a thin film of (HPDA)2PbBr4 (PDA-1). The dissolved inorganic components of layered perovskite in DMF solution together with H2O2 addition can facilitate DA polymerization greatly. More importantly, PDA-1 can inherit an excellent semiconductor property of HOIPs and robust adhesion of the PDA hydrogel resulting in a self-adhesive photoelectric coating on various interfaces.

Determination of telbivudine in the plasma of chronic hepatitis B patients in long-term treatment by high-performance liquid chromatographic-tandem mass spectrometry.

Creatine kinase elevation is commonly reported in telbivudine-treated patients. However, little is known about the relationship between this adverse drug reaction and plasma concentration. In this study, a sensitive, rapid and safe quantitative bioanalytical method has been established by using LC-MS/MS for the determination of telbivudine in a clinical study of chronic hepatitis B patients. The assay was linear in a dynamic 10-10,000 ng/mL range (r2 > 0.999) and total analysis time was 6 min in this method. The validated method was applied to quantitatively determine plasma concentration in chronic hepatitis B patients during long-term telbivudine treatment. The results revealed that telbivudine concentration in the creatine kinase-elevated group (707.92-2788.78 ng/mL) was significantly higher than those with normal creatine kinase (412.63-1108.32 ng/mL). This method was adapted for therapeutic drug monitoring.

Cumulative incidence and risk factors of creatine kinase elevation associated with telbivudine.

PURPOSE: An increasing number of studies are reporting a high frequency of creatine kinase (CK) elevation during telbivudine therapy; however, few reports have focused on the cumulative incidence and risk factors of CK elevation. This study was performed to investigate the cumulative incidence and risk factors of CK elevation in Chinese patients treated with telbivudine. METHODS: In this observational study, patients with chronic hepatitis B receiving telbivudine therapy between July 2008 and December 2013 were enrolled. The cumulative incidence of CK elevation was analyzed using the Kaplan-Meier method combined with the log rank test. Risk factors were determined using Cox proportional hazards regression models. RESULTS: A total of 207 eligible patients were analyzed. The cumulative incidence of CK elevation at 12, 24, 36, 48, 60, and 72 months was 51.2 %, 68.9 %, 75.1 %, 78.1 %, 78.1 %, and 78.1 %, respectively. Multivariate analysis revealed that male and lower baseline estimated glomerular filtration rate (eGFR) were significant risk factors for CK elevation. CONCLUSIONS: The cumulative incidence of CK elevation after long-term telbivudine use is quite high, and gender and baseline eGFR may be useful predictors. However, when combined with regular monitoring of CK levels, especially for patients with lower eGFR, telbivudine is a relatively safe nucleoside analog treatment for chronic hepatitis B.

Comprehensive analysis of common serum liver enzymes as prospective predictors of hepatocellular carcinoma in HBV patients.

BACKGROUND: Serum liver enzymes are frequently tested in clinics to aid disease diagnosis. Large observational studies indicated that these enzymes might predict cancer risk and mortality. However, no prospective study has reported on their relationships with the risk of HBV-related hepatocellular carcinoma (HCC). METHODOLOGY/PRINCIPAL FINDINGS: We evaluated the predictive values of four routinely tested liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], and gamma-glutamyltransferase [GGT]) in HCC risk in a prospectively enrolled clinical cohort of 588 Korean American HBV patients. For all four enzymes, the baseline level as well as the average and maximum levels during the first 1 or 2 years of follow-up were analyzed using multivariate Cox proportional hazards model. Patients were categorized into a normal or an elevated group based on the clinical cut-off of each enzyme. During a median follow-up of 7.5 years, 52 patients (incidence rate, 8.8%) developed HCC. The incidence rates were higher in the elevated groups for all four enzymes. The most significant finding was for GGT, with the highest incidence rate of 16.4% in the elevated group compared to 4.6% in the normal group (P<0.001). Compared to patients with normal baseline GGT, those with elevated GGT exhibited a significantly increased HCC risk with a hazards ratio (HR) of 2.60 (95% confidence interval [CI], 1.41-4.77, P = 0.002). Further analyses revealed a cumulative effect between baseline GGT and ALP (HR = 3.41, 95% CI 1.54-7.56, P = 0.003). CONCLUSIONS SIGNIFICANCE: Serum GGT might predict HCC risk in HBV patients individually or jointly with other enzymes.

Relative telomere length: a novel non-invasive biomarker for the risk of non-cirrhotic hepatocellular carcinoma in patients with chronic hepatitis B infection.

BACKGROUND AND AIMS: Telomere length has emerged as a promising risk predictor of various cancers including hepatocellular carcinoma (HCC). However, the majority of studies in this area measured telomere length in hepatocytes and one in lymphocytes with conflicting results. Moreover, no studies have been reported on using circulating DNA telomere length as a non-invasive HCC biomarker. METHODS: We conducted a nested case-control study to determine the relative telomere length (RTL) in serum DNA from 140 hepatitis B virus (HBV)-related HCC cases and 280 frequency-matched cancer-free HBV controls. RESULTS: Cases had a significantly longer RTL (median, 0.31; range, 0.02-2.31) than controls (median, 0.20; range, 0.01-1.60) (P = 0.003). Consistently, longer RTLs conferred a significantly increased HCC risk compared to short RTLs in a univariate logistic regression analysis (odds ratio [OR] = 1.55, 95% confidence interval [CI] = 1.02-2.33, P = 0.038). This association attenuated after multivariate adjustment (OR = 1.40, 95% CI = 0.90-2.19, P = 0.132). In a quartile analysis, a significant dose-response relationship was noted in univariate analysis (P(trend) = 0.017) which was again attenuated in multivariate analysis (P(trend) = 0.079). Further analyses revealed that the significant association between serum RTL and HCC risk was evident in non-cirrhotic (OR = 3.54, 95% CI 1.58-7.93 P = 0.002), but not cirrhotic (OR = 0.95, 95% CI 0.55-1.64, P = 0.860) HBV patients. Moreover, the significantly increased HCC risk conferred by cirrhosis was modulated by RTL with a significant interaction effect (P(interaction) = 0.013). CONCLUSIONS: RTL in circulating cell-free serum DNA could potentially be used as a novel non-invasive biomarker for non-cirrhotic HCC. Prospective cohort studies are warranted to validate this finding and assess its clinical significance in HCC prevention.