Dose-response relationship between serum N-glycan markers and liver fibrosis in chronic hepatitis B.

BACKGROUND: Evaluation of liver fibrosis played a monumental role in the diagnosis and monitoring of chronic hepatitis B (CHB). We aimed to explore the value of serum N-glycan markers in liver fibrosis. METHODS: This multi-center (33 hospitals) study recruited 760 treatment-naïve CHB patients who underwent liver biopsy. Serum N-glycan markers were analyzed by DNA sequencer-assisted fluorophore-assisted with capillary electrophoresis (DSA-FACE) technology. First, we explore the relationship between 12 serum N-glycan markers and the fibrosis stage. Then, we developed a Px score for diagnosing significant fibrosis using the LASSO regression. Next, we compared the diagnostic performances between Px, LSM, APRI, and FIB-4. Finally, we explored the relationships between glycosyltransferase gene and liver fibrosis with RNA-transcriptome sequencing. RESULTS: We included 622 CHB participants: male-dominated (69.6%); median age 42.0 (IQR 34.0-50.0); 287 with normal ALT; 73.0% with significant fibrosis. P5(NA2), P8(NA3), and P10(NA4) were opposite to the degree of fibrosis, while other profiles (except for P0[NGA2]) increased with the degree of fibrosis. Seven profiles (P1[NGA2F], P2[NGA2FB], P3[NG1A2F], P4[NG1A2F], P7[NA2FB], P8[NA3], and P9[NA3Fb]) were selected into Px score. Px score was associated with an increased risk of significant fibrosis (for per Px score increase, the risk of significant fibrosis was increased by 3.54 times (OR = 4.54 [2.63-7.82]) in the fully-adjusted generalized linear model. p for trend was <0.001. The diagnostic performance of the Px score was superior to others. Glycosyltransferase genes were overexpressed in liver fibrosis, and glycosylation and glycosyltransferase-related pathways were significantly enriched. CONCLUSIONS: Serum N-glycan markers were positively correlated with liver fibrosis. Px score had good performance in distinguishing significant fibrosis.

The wall-associated receptor-like kinase CsWAKL01, positively regulated by the transcription factor CsWRKY53, confers resistance to citrus bacterial canker via regulation of phytohormone signaling.

Citrus bacterial canker (CBC) is a disease that poses a major threat to global citrus production and is caused by infection with Xanthomonas citri subsp. citri (Xcc). Wall-associated receptor-like kinase (WAKL) proteins play an important role in shaping plant resistance to various bacterial and fungal pathogens. In a prior report, CsWAKL01 was identified as a candidate Xcc-inducible gene found to be upregulated in CBC-resistant citrus plants. However, the functional role of CsWAKL01 and the mechanisms whereby it may influence resistance to CBC have yet to be clarified. Here, CsWAKL01 was found to localize to the plasma membrane, and the overexpression of the corresponding gene in transgenic sweet oranges resulted in the pronounced enhancement of CBC resistance, whereas its knockdown had the opposite effect. Mechanistically, the ability of CsWAKL01 was linked to its ability to reprogram jasmonic acid, salicylic acid, and abscisic acid signaling activity. CsWRKY53 was further identified as a transcription factor capable of directly binding the CsWAKL01 promoter and inducing its transcriptional upregulation. CsWRKY53 silencing conferred greater CBC susceptibility to infected plants. Overall, these data support a model wherein CsWRKY53 functions as a positive regulator of CsWAKL01 to enhance resistance to CBC via the reprogramming of phytohormone signaling. Together these results offer new insight into the mechanisms whereby WAKLs shape phytopathogen resistance while underscoring the potential value of targeting the CsWRKY53-CsWAKL01 axis when seeking to breed CBC-resistant citrus plant varieties.

Impaired synaptic plasticity and decreased glutamatergic neuron excitability induced by SIRT1/BDNF downregulation in the hippocampal CA1 region are involved in postoperative cognitive dysfunction.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common complication after anesthesia/surgery, especially among elderly patients, and poses a significant threat to their postoperative quality of life and overall well-being. While it is widely accepted that elderly patients may experience POCD following anesthesia/surgery, the exact mechanism behind this phenomenon remains unclear. Several studies have indicated that the interaction between silent mating type information regulation 2 homologue 1 (SIRT1) and brain-derived neurotrophic factor (BDNF) is crucial in controlling cognitive function and is strongly linked to neurodegenerative disorders. Hence, this research aims to explore how SIRT1/BDNF impacts cognitive decline caused by anesthesia/surgery in aged mice. METHODS: Open field test (OFT) was used to determine whether anesthesia/surgery affected the motor ability of mice, while the postoperative cognitive function of 18 months old mice was evaluated with Novel object recognition test (NORT), Object location test (OLT) and Fear condition test (FC). The expressions of SIRT1 and other molecules were analyzed by western blot and immunofluorescence staining. The hippocampal synaptic plasticity was detected by Golgi staining and Long-term potentiation (LTP). The effects of SIRT1 and BDNF overexpression as well as chemogenetic activation of glutamatergic neurons in hippocampal CA1 region of 18 months old vesicular glutamate transporter 1 (VGLUT1) mice on POCD were further investigated. RESULTS: The research results revealed that older mice exhibited cognitive impairment following intramedullary fixation of tibial fracture. Additionally, a notable decrease in the expression of SIRT1/BDNF and neuronal excitability in hippocampal CA1 glutamatergic neurons was observed. By increasing levels of SIRT1/BDNF or enhancing glutamatergic neuron excitability in the CA1 region, it was possible to effectively mitigate synaptic plasticity impairment and ameliorate postoperative cognitive dysfunction. CONCLUSIONS: The decline in SIRT1/BDNF levels leading to changes in synaptic plasticity and neuronal excitability in older mice could be a significant factor contributing to cognitive impairment after anesthesia/surgery.

Genome-wide identification and characterization of the sweet orange (Citrus sinensis) basic helix-loop-helix (bHLH) family reveals a role for CsbHLH085 as a regulator of citrus bacterial canker resistance.

Citrus bacterial canker (CBC) is a harmful bacterial disease caused by Xanthomonas citri subsp. citri (Xcc), negatively impacting citrus production worldwide. The basic helix-loop-helix (bHLH) transcription factor family plays crucial roles in plant development and stress responses. This study aimed to identify and annotate bHLH proteins encoded in the Citrus sinensis genome and explore their involvement and functional importance in regulating CBC resistance. A total of 135 putative CsbHLHs TFs were identified and categorized into 16 subfamilies. Their chromosomal locations, collinearity, and phylogenetic relationships were comprehensively analyzed. Upon Xcc strain YN1 infection, certain CsbHLHs were differentially regulated in CBC-resistant and CBC-sensitive citrus varieties. Among these, CsbHLH085 was selected for further functional characterization. CsbHLH085 was upregulated in the CBC-resistant citrus variety, was localized in the nucleus, and had a transcriptional activation activity. CsbHLH085 overexpression in Citrus significantly enhanced CBC resistance, accompanied by increased levels of salicylic acid (SA), jasmonic acid (JA), reactive oxygen species (ROS), and decreased levels of abscisic acid (ABA) and antioxidant enzymes. Conversely, CsbHLH085 virus-induced gene silencing resulted in opposite phenotypic and biochemical responses. CsbHLH085 silencing also affected the expression of phytohormone biosynthesis and signaling genes involved in SA, JA, and ABA signaling. These findings highlight the crucial role of CsbHLH085 in regulating CBC resistance, suggesting its potential as a target for biotechnological-assisted breeding citrus varieties with improved resistance against phytopathogens.

EH domain-containing protein 2 (EHD2): Overview, biological function, and therapeutic potential.

EH domain-containing protein 2 (EHD2) is a member of the EHD protein family and is mainly located in the plasma membrane, but can also be found in the cytoplasm and endosomes. EHD2 is also a nuclear-cytoplasmic shuttle protein. After entering the cell nuclear, EHD2 acts as a corepressor of transcription to inhibit gene transcription. EHD2 regulates a series of biological processes. As a key regulator of endocytic transport, EHD2 is involved in the formation and maintenance of endosomal tubules and vesicles, which are critical for the intracellular transport of proteins and other substances. The N-terminal of EHD2 is attached to the cell membrane, while its C-terminal binds to the actin-binding protein. After binding, EHD2 connects with the actin cytoskeleton, forming the curvature of the membrane and promoting cell endocytosis. EHD2 is also associated with membrane protein trafficking and receptor signaling, as well as in glucose metabolism and lipid metabolism. In this review, we highlight the recent advances in the function of EHD2 in various cellular processes and its potential implications in human diseases such as cancer and metabolic disease. We also discussed the prospects for the future of EHD2. EHD2 has a broad prospect as a therapeutic target for a variety of diseases. Further research is needed to explore its mechanism, which could pave the way for the development of targeted treatments.

Integrated genomic and proteomic analyses identify PYGL as a novel experimental therapeutic target for clear cell renal cell carcinoma.

Sunitinib, the first-line targeted therapy for metastatic clear cell renal cell carcinoma (ccRCC), faces a significant challenge as most patients develop acquired resistance. Integrated genomic and proteomic analyses identified PYGL as a novel therapeutic target for ccRCC. PYGL knockdown inhibited cell proliferation, cloning capacity, migration, invasion, and tumorigenesis in ccRCC cell lines. PYGL expression was increased in sunitinib-resistant ccRCC cell lines, and CP-91149 targeting the PYGL could restore drug sensitivity in these cell lines. Moreover, chromatin immune-precipitation assays revealed that PYGL upregulation is induced by the transcription factor, hypoxia-inducible factor 1α. Overall, PYGL was identified as a novel diagnostic biomarker by combining genomic and proteomic approaches in ccRCC, and sunitinib resistance to ccRCC may be overcome by targeting PYGL.

Which roads lead to access? A global landscape of six COVID-19 vaccine innovation models.

BACKGROUND: Unequal and inequitable access to Covid-19 vaccines in low- and middle-income countries (L&MICs) was a major political, ethical and public health failure in the pandemic. However, vaccine developers' practices were not monolithic, but rather, took diverse approaches to supplying different countries, with important implications for global access. RESULTS: Using data on R&D investments, regulatory approvals, manufacturing and purchase agreements, and vaccine deliveries, we identified six distinct innovation models that apply across the 14 COVID-19 vaccines with more international presence from 2020-2022. "Western Early Arrivers" Pfizer/BioNTech and Moderna supplied the largest volumes quickly and prioritized high-income countries (HICs) from registration to vaccine delivery. "Western Latecomers" Janssen and Novavax supplied intermediate volumes later, also prioritizing HICs but with a greater proportion to L&MICs. "Major Chinese Developers" Sinopharm and Sinovac supplied intermediate volumes early, primarily to middle-income countries (MICs). "Russian Developer" Gamaleya completed development early but ultimately supplied small volumes, primarily to middle-income countries (MICs). "Cosmopolitan Developer" Oxford/AstraZeneca supplied large volumes early to HICs and MICs at the lowest prices. Finally, "Small MIC Developers" CanSino, Bharat Biotech, Medigen, Finlay Institute and the Center for Genetic Engineering and Biotechnology (CGEB), exported relatively small volumes to a few MICs. Low-income countries (LICs) were not targeted by any developer, and received far fewer doses, later, than any other income group. Almost all developers received public funding and other forms of support, but we found little evidence that such support was leveraged to expand global access. CONCLUSIONS: Each of the six innovation models has different implications for which countries get access to which vaccines, how quickly, and at which prices. Each offers different strengths and weaknesses for achieving equitable access. Our findings also suggest that Western firms had the greatest capacity to develop and deliver vaccines quickly during the pandemic, but such capacity is rapidly becoming more globally distributed with MICs playing a significant role, especially in supplying other MICs. Given the critical role of public support in enabling pandemic vaccine development and supply, governments have both the capacity and responsibility to craft international rules that will make responses to future pandemics more equitable and effective.

Green synthesis of iron nanoparticles using mulberry leaf extract: characterization, identification of active biomolecules, and catalytic activity.

The synthesis of iron-based nanoparticles (Fe NPs) using traditional preparation methods suffered from the disadvantages of high cost, environmental harm, and easy agglomeration. In this study, a novel eco-friendly method was proposed for the synthesis of iron nanomaterials (ML-Fe NPs): using antioxidant components extracted from mulberry leaf to reduce divalent iron (II). The preparation conditions of ML-Fe NPs were optimized by orthogonal tests. The prepared ML-Fe NPs exhibited an amorphous core-shell structure, displaying excellent dispersion and stability. During the synthesis process of ML-Fe NPs, the polyphenol molecules in mulberry leaf extract played a dominant role. A possible synthetic mechanism involving complexation, reduction, and encapsulation was proposed. Furthermore, the ML-Fe NPs were utilized to construct an ML-Fe NPs/peroxymonosulfate catalytic system for the degradation of Rhodamine B dye wastewater. The ML-Fe NPs demonstrated remarkable catalytic potential, achieving a 99% degradation efficiency for Rhodamine B within a span of 40 min.

The CsAP2-09-CsWRKY25-CsRBOH2 cascade confers resistance against citrus bacterial canker by regulating ROS homeostasis.

Citrus bacterial canker (CBC) is a serious bacterial disease caused by Xanthomonas citri subsp. citri (Xcc) that adversely impacts the global citrus industry. In a previous study, we demonstrated that overexpression of an Xcc-inducible apetala 2/ethylene response factor encoded by Citrus sinensis, CsAP2-09, enhances CBC resistance. The mechanism responsible for this effect, however, is not known. In the present study, we showed that CsAP2-09 targeted the promoter of the Xcc-inducible WRKY transcription factor coding gene CsWRKY25 directly, activating its transcription. CsWRKY25 was found to localize to the nucleus and to activate transcriptional activity. Plants overexpressing CsWRKY25 were more resistant to CBC and showed higher expression of the respiratory burst oxidase homolog (RBOH) CsRBOH2, in addition to exhibiting increased RBOH activity. Transient overexpression assays in citrus confirmed that CsWRKY25 and CsRBOH2 participated in the generation of reactive oxygen species (ROS) bursts, which were able to restore the ROS degradation caused by CsAP2-09 knockdown. Moreover, CsWRKY25 was found to bind directly to W-box elements within the CsRBOH2 promoter. Notably, CsRBOH2 knockdown had been reported previously to reduce the CBC resistance, while demonstrated in this study, CsRBOH2 transient overexpression can enhance the CBC resistance. Overall, our results outline a pathway through which CsAP2-09-CsWRKY25 transcriptionally reprograms CsRBOH2-mediated ROS homeostasis in a manner conducive to CBC resistance. These data offer new insight into the mechanisms and regulatory pathways through which CsAP2-09 regulates CBC resistance, highlighting its potential utility as a target for the breeding of CBC-resistant citrus varieties.

Global, regional, and national burdens of cirrhosis in children and adolescents aged under 19 years from 1990 to 2019.

BACKGROUND & AIMS: Cirrhosis was the leading cause of morbidity and mortality in adults, but data on the burden and trends were sparse in children and adolescents. We aimed to assess the trends in 204 countries and territories over the past 30 years in children and adolescents aged 0-19 years. METHODS: Data on cirrhosis was collected by the Global Burden of Disease (GBD) 2019 database from 1990 to 2019. We reported on the number, rates, and average annual percentage changes (AAPCs) of incidence and disability-adjusted life-years (DALYs) of cirrhosis at global, regional, and national level. RESULTS: Globally, the incident numbers of cirrhosis in children and adolescents increased from 204,767 in 1990 to 241,364 in 2019, an increase of 17.9%, with an AAPC 0.13(0.10 to 0.16). Prevalence (AAPC = - 2.27[- 2.39 to - 2.15]), mortality (AAPC = - 1.68 [- 1.86 to - 1.5]), and DALYs rate (AAPC = - 1.72[- 1.88 to - 1.56]) of cirrhosis have decreased significantly. Cirrhosis incident rates varied between different ages. Cirrhosis caused by alcohol use (AAPC = 1[0.8 to 1.1]; incidence cases increased 48%), hepatitis C (AAPC = 0.4 [0.4 to 0.5]), NAFLD (AAPC = 0.5 [0.3 to 0.6]) have been increasing, while only hepatitis B (- 0.3[- 0.4 to - 0.2]) decreasing. Incidence cases of cirrhosis were increased in low (101.6%) and low-middle sociodemographic index (SDI 21.1%) areas, while decreasing in middle and above SDI areas. At the regional level, the largest increases count was observed in Sub-Saharan Africa. CONCLUSIONS: Global incidence rate of cirrhosis has been increasing, while the DALYs rate has been decreasing in children and adolescents. Morbidity of cirrhosis caused by hepatitis B declined, while hepatitis C, NAFLD, and alcohol use increased.

Burden of infectious diseases and bacterial antimicrobial resistance in China: a systematic analysis for the global burden of disease study 2019.

Background: Infectious diseases and antimicrobial resistance (AMR) has become pressing concerns in China. We aimed to comprehensively investigate the burden of them. Methods: Data on infectious diseases and AMR were collected by the Global Antimicrobial Resistance Burden study 2019. Multinomial network meta-regression, logistic regression, and ensemble Spatiotemporal Gaussian process regression were used to fit the number and rate in DisMod-MR 2.1 modelling framework. We reported the number and rates of the disease burdens of 12 infectious syndromes by age and sex; described the burden caused by 43 pathogens; estimated the AMR burden of 22 bacteria and bacteria-antibiotics combinations. Findings: There were an estimated 1.3 million (95% uncertainty intervals, UI 0.8-1.9) infection-related deaths, accounting for 12.1% of the total deaths in China 2019. Males were 1.5 times more affected than females. Bloodstream infections (BSIs) were most lethal infectious syndrome, associating with 521,392 deaths (286,307-870,583), followed by lower respiratory infections (373,175), and peritoneal and intra-abdominal infections (152,087). These five leading pathogens were S aureus, A baumannii, E coli, S pneumoniae, and E spp., which were associated with 41.2% (502,658/1,218,693) of all infection-related deaths. The pathogens of different infectious syndromes exhibited significant heterogeneity. In 2019, more than 600 thousand deaths were associated with AMR, including 145 thousand deaths attributable to AMR. The top 3 AMR attributable to death were carbapenems-resistance A baumannii (18,143), methicillin-resistance S aureus (16,933) and third-generation cephalosporins-resistance E coli (8032). Interpretation: Infectious diseases and bacterial antimicrobial resistance were serious threat to public health in China, related to 1.3 million and more than 600 thousand deaths per-year, respectively. Antimicrobial stewardship was urgent. Funding: This work was supported by National Natural Science Foundation of China (82270626); China Mega-Project for Infectious Diseases (2017ZX10203202, 2013ZX10002005); the Project of Beijing Science and Technology Committee (Z191100007619037).

Rising pharmaceutical innovation in the Global South: a landscape study.

BACKGROUND: There is growing interest in pharmaceutical innovation in low- and middle-income countries (LMICs), but information on existing activities, capacities, and outcomes is scarce. We mapped available data at the global level, and studied the national pharmaceutical innovation systems of Bangladesh and Colombia to shed light on pharmaceutical research and development (R&D) in the Global South, including challenges and prospects, to help fill existing knowledge gaps. METHODS: We gathered and analyzed data from three types of sources: literature, semi-structured interviews with key informants, and publicly available data on R&D funding, R&D scientific capacity measured by human resources, and clinical trial activities. RESULTS: Pharmaceutical R&D activities are occurring in many LMICs, but 16 countries have emerged as frontrunners. Investment in R&D in LMICs has increased in the past decade, particularly from middle-income countries (MICs). Capacity is also growing, with an increase in the number of research organizations and the amount of funding available from external sources. The total number of clinical trials and the proportion of trials in LMICs increased markedly, and there is also growing activity in the earlier, more innovative and riskier Phase 1 and 2 trials. Non-commercial entities comprise the majority of clinical trial funders and sponsors in LMICs. Finally, investments have borne fruit, as indicated by a number of innovative medicines developed in LMICs. The Bangladesh and Colombia country studies showed that there is still a need for both targeted R&D policies to strengthen capacities in the pharmaceutical sector, and more government support to overcome the challenges of a lack of funding and coordination among different actors. CONCLUSIONS: By triangulating between the data sources, it was possible to paint a broad picture of who was involved in pharmaceutical R&D in LMICs, in which particular countries, for which diseases, in which R&D phases, and with what results-as well as how these trends have changed over time. Prioritizing pharmaceutical R&D is an important strategy for better meeting health needs. The trendlines are promising, but focused attention is still needed to realize the potential for greater innovation in the Global South.

Regulatory T cells: A suppressor arm in post-stroke immune homeostasis.

The activation of the immune system and the onset of pro- and anti-inflammatory responses play crucial roles in the pathophysiological processes of ischaemic stroke (IS). CD4+ regulatory T (Treg) cells is the main immunosuppressive cell population that is studied in the context of peripheral tolerance, autoimmunity, and the development of chronic inflammatory diseases. In recent years, more studies have focused on immune modulation after IS, and Treg cells have been demonstrated to be essential in the remission of inflammation, nerve regeneration, and behavioural recovery. However, the exact effects of Treg cells in the context of IS remain controversial, with some studies suggesting a negative correlation with stroke outcomes. In this review, we aim to provide a comprehensive overview of the current understanding of Treg cell involvement in post-stroke homeostasis. We summarized the literature focusing on the temporal changes in Treg cell populations after IS, the mechanisms of Treg cell-mediated immunomodulation in the brain, and the potential of Treg cell-based therapies for treatment. The purposes of the current article are to address the importance of Treg cells and inspire more studies to help physicians, as well as scientists, understand the whole map of immune responses during IS.

Mining electronic health records using artificial intelligence: Bibliometric and content analyses for current research status and product conversion.

BACKGROUND: The use of Electronic Health Records is the most important milestone in the digitization and intelligence of the entire medical industry. AI can effectively mine the immense medical information contained in EHRs, potentially assist doctors in reducing many medical errors. OBJECTIVE: This article aims to summarize the research status and trends in using AI to mine medical information from EHRs for the past thirteen years and investigate its information application. METHODS: A systematic search was carried out in 5 databases, including Web of Science Core Collection and PubMed, to identify research using AI to mine medical information from EHRs for the past thirteen years. Furthermore, bibliometric and content analysis were used to explore the research hotspots and trends, and systematically analyze the conversion rate of research resources in this field. RESULTS: A total of 631 articles were included and analyzed. The number of published articles has increased rapidly after 2017, with an average annual growth rate of 55.73%. The US (41.68%) and China (19.65%) publish the most articles, but there is a lack of international cooperation. The extraction of disease lesions is a hot topic at present, and the research topic is gradually shifting from disease risk grading to disease risk prediction. Classification (66%), and regress (15%) are the main implemented AI tasks. For AI algorithms, deep learning (31.70%), decision tree algorithms family (26.47%), and regression algorithms family (17.43%) are used most frequently. The funding rate for publications is 69.26%, and the input-output conversion rate is 21.05%. CONCLUSIONS: Over the past decade, the use of AI to mine medical information from EHRs has been developing rapidly. However, it is necessary to strengthen international cooperation, improve EHRs data availability, focus on interpretable AI algorithms, and improve the resource conversion rate in future research.

The Self-Assembly Soluplus Nanomicelles of Nobiletin in Aqueous Medium Based on Solid Dispersion and Their Increased Hepatoprotective Effect on APAP-Induced Acute Liver Injury.

Purpose: APAP-induced liver injury (AILI) is a common cause of acute liver failure (ALF). Nobiletin (NOB) is a potential hepatoprotective agent for the treatment of APAP-induced liver injury. However, the poor solubility and low bioavailability of NOB hinders its application. In this study, a novel self-assembly nano-drug delivery system of nobiletin (solid dispersion of NOB, termed as NOB/SD) was developed based on solid dispersion technology to improve the bioavailability and hepatoprotective ability of NOB for APAP-induced liver injury therapy. Methods: The optimized NOB/SD system was constructed using the amphiphilic copolymers of Soluplus and PVP/VA 64 via hot melt extrusion technology (HME). NOB/SD was characterized by solubility, physical interaction, drug release behavior, and stability. The bioavailability and hepatoprotective effects of NOB/SD were evaluated in vitro and in vivo. Results: NOB/SD maintained NOB in matrix carriers in a stable amorphous state, and self-assembled NOB-loaded nanomicelles in water. Nanostructures based on solid dispersion technology exhibited enhanced solubility, improved release behavior, and promoted cellular uptake and anti-apoptosis in vitro. NOB/SD displayed significantly improved bioavailability in healthy Sprague Dawley (SD) rats in vivo. Furthermore, NOB/SD alleviated the APAP-induced liver injury by improving anti-oxidative stress with reactive oxygen species (ROS) scavenging and nuclear factor erythroid 2-related factor 2 (Nrf2) activation. Conclusion: These results suggested that NOB/SD could be considered as a promising hepatoprotective nano-drug delivery system for attenuating APAP-induced acute liver injury with superior bioavailability and efficient hepatoprotection, which might provide an effective strategy for APAP-induced acute liver injury prevention and treatment.

How to predict the outcome of primary brainstem hemorrhage: Six-year results of a single-center retrospective analysis.

Primary brainstem hemorrhage (PBH) is one of the most fatal intracranial hemorrhages, evaluating the prognosis in the early stage is vital for appropriate therapeutic planning. Our study aimed to identify risk factors for 30-day mortality and 90-day functional recovery of PBH. Data from 63 patients with PBH admitted to Beijing Chaoyang Hospital between 2016 and 2022 were retrieved for this study. We grouped the patients according to 30-day survival or 90-day functional recovery. Independent risk factors of 30-day mortality and 90-day functional recovery were identified by univariate and multivariate logistic regression analyses. 31 patients (49.2%) died within 30 days and 22 patients (34.9%) achieved better functional recovery. By multivariate analysis, Glasgow coma scale <9 on admission and tachycardia were significantly associated with 30-day mortality, while the hematoma volume >5 mL was an independent risk factor for 90-day functional recovery. Initial level of consciousness, tachycardia, massive hematoma were risk factors for prognosis, which must be seriously evaluated for therapeutic planning.

Clinical significance of serum S100 calcium-binding protein A12 concentrations in patients with community-acquired pneumonia.

OBJECTIVE: This study aimed to investigate the clinical significance of serum S100 calcium-binding protein A12 (S100A12) concentrations in patients with community-acquired pneumonia (CAP). METHODS: This was a case-control study. We selected 120 patients with CAP treated in Xichang People's Hospital from January to June 2022 as the case group. Sixty healthy adults without a history of basic diseases were selected as the control group. The patients in the case group were divided into the low S100A12 and high S100A12 subgroups. Serum S100A12, C-reactive protein (CRP), and procalcitonin (PCT) concentrations, the leukocyte count, and other study parameters were compared. RESULTS: Serum S100A12, CRP, and PCT concentrations and the leukocyte count were higher in the case group than in the control group. The baseline confusion, urea, respiratory rate, blood pressure, and age ≥ 65 score, baseline pneumonia severity index score, and 30-day mortality rate were higher in the high S100A12 subgroup than in the low S100A12 subgroup. Serum CRP and PCT concentrations and the leukocyte count were higher in the high S100A12 subgroup than in the low S100A12 subgroup. CONCLUSION: Patients with high serum S100A12 concentrations have more severe CAP, a more serious inflammatory reaction, and higher 30-day mortality.

Factors associated with persistent positive in HBV DNA level in patients with chronic Hepatitis B receiving entecavir treatment.

Introduction: The clinical significance of persistent positive in Hepatitis B Virus (HBV) DNA level in patients receiving antiviral therapy is not well known. We investigated factors associated with persistent viremia (PV) in patients with chronic hepatitis B (CHB) given 78-week entecavir. Methods: A total of 394 treatment-naïve CHB patients who had undergone liver biopsy at baseline and week 78 of treatment were analyzed in this prospective multicentre study. We identified patients with PV (above the lower limit of quantification, 20 IU/ml) after 78 weeks of entecavir therapy. Stepwise, forward, multivariate regression analyses of specified baseline parameters were apllied to identify factors associated with PV. Futhermore, we assessed the incidence of hepatocellular carcinoma (HCC) in all patients using models of the risk of HCC development. Results: Of the 394 patients, 90 (22.8%) still with PV after 78-week antiviral treatment. Factors associated significantly with PV (vs complete virological response, CVR) were HBV DNA level ≥8 log10 IU/mL (OR, 3.727; 95% CI, 1.851-7.505; P < 0.001), Anti-HBc level < 3 log10 IU/mL (OR, 2.384; 95% CI, 1.223-4.645; P=0.011), and HBeAg seropositivity (OR, 2.871; 95% CI, 1.563-5.272; P < 0.001). Patients with PV were less likely to have fibrosis progression and HCC development than those with the CVR. Of the 11 HBeAg-positive patients with HBV DNA level ≥8 log10 IU/mL and Anti-HBc level < 3 log10 IU/mL at baseline, 9 (81.8%) had persistent positivity in HBV DNA level and 0 had fibrosis progression at week 78 of treatment. Discussion: In conclusion, HBV DNA level ≥8 log10 IU/mL, Anti-HBc level < 3 log10 IU/mL and HBeAg seropositivity at baseline contribute to PV in patients with CHB receiving 78-week antiviral treatment. In addition, the rate of fibrosis progression and the risk of HCC development in patients with PV were kept low. The complete protocol for the clinical trial has been registered at clinicaltrials.gov (NCT01962155 and NCT03568578).

CPNE1 mediates glycolysis and metastasis of breast cancer through activation of PI3K/AKT/HIF-1α signaling.

CPNE1 regulates multiple signaling pathways and can stimulate cell proliferation and differentiation by activating the AKT-mTOR signaling pathway. In addition, CPNE1 is associated with various cancers; however, its role in breast cancer, particularly in TNBC, has not been fully elucidated. Our study aimed to reveal the impact of the CPNE1/PI3K/AKT/HIF-1α axis on TNBC. We first measured the expression of CPNE1 in the tumor tissues of TNBC patients and examined its prognostic value. Subsequently, we used sh-CPNE1 and overexpression vectors to transfect TNBC cell lines and analyzed cell viability, migration, and invasive abilities using colony formation and CCK-8 assays. Metabolites were analyzed through metabolomics. We found that higher expression of CPNE1 predicted poor prognosis in TNBC patients. Knockdown of CPNE1 reduced the viability, migration, invasion, and proliferation capabilities of TNBC cells. Furthermore, metabolomics analysis showed that glucose metabolism was the most dominant pathway, and knockdown of CPNE1 significantly limited the glycolytic activity of TNBC cells. We verified these conclusions in mouse models. Additionally, we overexpressed CPNE1 and treated TNBC cell lines with a PI3K inhibitor (LY294002). The results indicated that CPNE1 promoted aerobic glycolysis in TNBC cells through the PI3K/AKT/HIF-1α signaling pathway. This suggests that CPNE1 regulates cell glycolysis and participates in the development of TNBC. Our study may provide a new therapeutic target for TNBC treatment.

Non-coding RNAs in renal cell carcinoma: Implications for drug resistance.

Renal cell carcinoma (RCC) represents a malignant tumor of the urinary system. Individuals with early-stage RCC could be cured by surgical treatment, but a considerable number of cases of advanced RCC progress to drug resistance. Recently, numerous reports have demonstrated that a variety of non-coding RNAs (ncRNAs) contribute to tumor occurrence and development. ncRNAs can act as oncogenic or tumor suppressor genes to regulate proliferation, migration, drug resistance and other processes in RCC cells through a variety of signaling pathways. Considering the lack of treatment options for advanced RCC after drug resistance, ncRNAs may be a good choice as biomarkers of drug resistance in RCC and targets to overcome drug resistance. In this review, we discussed the effects of ncRNAs on drug resistance in RCC and the great potential of ncRNAs as a biomarker of or a new therapeutic method in RCC.