Human serum albumin-based drug-free macromolecular therapeutics induce apoptosis in chronic lymphocytic leukemia patient cells by crosslinking of CD20 and/or CD38 receptors.

This study explores the efficacy of human serum albumin (HSA)-based Drug-Free Macromolecular Therapeutics (DFMT) in treating Chronic Lymphocytic Leukemia (CLL), a prevalent adult leukemia subtype. DFMT, a novel strategy, employs biomimetic crosslinking of CD20 and CD38 receptors on malignant B cells without the need for low molecular weight drugs. Apoptosis is initiated via a two-step process: i) Recognition of a bispecific engager, Fab' fragment conjugated with morpholino oligonucleotide (Fab'-MORF1), by a cell surface antigen; followed by ii) crosslinking of the MORF1-decorated cells with a multivalent effector, HSA holding multiple copies of complementary MORF2, HSA-(MORF2)x. Herein we evaluated the efficacy of HSA-based DFMT in the treatment of 56 samples isolated from patients diagnosed with CLL. Fab' fragments from Obinutuzumab (OBN) and Isatuximab (ISA) were employed in the synthesis of anti-CD20 (Fab'OBN-MORF1) and anti-CD38 (Fab'ISA-MORF1) bispecific engagers. The efficacy of DFMT was significantly influenced by the expression levels of CD20 and CD38 receptors. Dual-targeting DFMT strategies (CD20 + CD38) were more effective than single-target approaches, particularly in samples with elevated receptor expression. Pretreatment of patient cells with gemcitabine or ricolinostat markedly increased cell surface CD20 and CD38 expression, respectively. Apoptosis was effectively initiated in 62.5% of CD20-targeted samples and in 42.9% of CD38-targeted samples. Our findings demonstrate DFMT's potential in personalized CLL therapy. Further research is needed to validate these outcomes in a larger number of patient samples and to explore DFMT's applicability to other malignancies.

CNOT7 regulates lipid deposition in nonalcoholic fatty liver disease.

BACKGROUND: In recent years, the incidence rate of nonalcoholic fatty liver disease (NAFLD) has ascended with the increasing number of metabolic diseases such as obesity and diabetes, which will bring great medical burden to society. At present, multiple scientific experiments have found that the CCR4-NOT complex can participate in regulating obesity and energy metabolism. This study is designed to explore the role and mechanism of CCR4-NOT transcription complex subunit 7 (CNOT7), a subunit of the CCR4-NOT complex in liver lipid deposition. METHODS: To establish the NAFLD cell model, palmitic acid (PA) was utilized to stimulate HepG2 cells and LO2 cells, promoting intracellular lipid deposition. CNOT7 was knockdown by siRNA and lentivirus to evaluate the effect of CNOT7 in NAFLD. RESULTS: Our results demonstrated that the expression of CNOT7 was increased in the NAFLD cell model. After knocking down CNOT7, the lipid deposition declined in HepG2 or LO2 cells treated by PA reduced. We found the lipid synthesis genes and the lipid uptake and transport factors in the CNOT7 knockdown group were significantly downregulated compared to the non-knockdown group. Furthermore, knockdown of CNOT7 might promote fatty acid oxidation. CONCLUSION: Knocking down CNOT7 can improve lipid deposition and CNOT7 may be a potential therapeutic target for NAFLD.

Etiology including epigenetic defects of retinoblastoma.

Retinoblastoma (RB), originating from the developing retina, is an aggressive intraocular malignant neoplasm in childhood. Biallelic loss of RB1 is conventionally considered a prerequisite for initiating RB development in most RB cases. Additional genetic mutations arising from genome instability following RB1 mutations are proposed to be required to promote RB development. Recent advancements in high throughput sequencing technologies allow a deeper and more comprehensive understanding of the etiology of RB that additional genetic alterations following RB1 biallelic loss are rare, yet epigenetic changes driven by RB1 loss emerge as a critical contributor promoting RB tumorigenesis. Multiple epigenetic regulators have been found to be dysregulated and to contribute to RB development, including noncoding RNAs, DNA methylations, RNA modifications, chromatin conformations, and histone modifications. A full understanding of the roles of genetic and epigenetic alterations in RB formation is crucial in facilitating the translation of these findings into effective treatment strategies for RB. In this review, we summarize current knowledge concerning genetic defects and epigenetic dysregulations in RB, aiming to help understand their links and roles in RB tumorigenesis.

Deep learning-based model for difficult transfemoral access prediction compared with human assessment in stroke thrombectomy.

BACKGROUND: In mechanical thrombectomy (MT), extracranial vascular tortuosity is among the main determinants of procedure duration and success. Currently, no rapid and reliable method exists to identify the anatomical features precluding fast and stable access to the cervical vessels. METHODS: A retrospective sample of 513 patients were included in this study. Patients underwent first-line transfemoral MT following anterior circulation large vessel occlusion stroke. Difficult transfemoral access (DTFA) was defined as impossible common carotid catheterization or time from groin puncture to first carotid angiogram >30 min. A machine learning model based on 29 anatomical features automatically extracted from head-and-neck computed tomography angiography (CTA) was developed to predict DTFA. Three experienced raters independently assessed the likelihood of DTFA on a reduced cohort of 116 cases using a Likert scale as benchmark for the model, using preprocedural CTA as well as automatic 3D vascular segmentation separately. RESULTS: Among the study population, 11.5% of procedures (59/513) presented DTFA. Six different features from the aortic, supra-aortic, and cervical regions were included in the model. Cross-validation resulted in an area under the receiver operating characteristic (AUROC) curve of 0.76 (95% CI 0.75 to 0.76) for DTFA prediction, with high sensitivity for impossible access identification (0.90, 95% CI 0.81 to 0.94). The model outperformed human assessment in the reduced cohort [F1-score (95% CI) by experts with CTA: 0.43 (0.37 to 0.50); experts with 3D segmentation: 0.50 (0.46 to 0.54); and model: 0.70 (0.65 to 0.75)]. CONCLUSIONS: A fully automatic model for DTFA prediction was developed and validated. The presented method improved expert assessment of difficult access prediction in stroke MT. Derived information could be used to guide decisions regarding arterial access for MT.

Development and validation of a novel sleep health score in the sleep heart health study.

BACKGROUND: There is a lack of consensus in evaluating multidimensional sleep health, especially concerning its implication for mortality. A validated multidimensional sleep health score is the foundation of effective interventions. METHODS: We obtained data from 5706 participants in the Sleep Heart Health Study. First, random forest-recursive feature elimination algorithm was used to select potential predictive variables. Second, a sleep composite score was developed based on the regression coefficients from a Cox proportional hazards model evaluating the associations between selected sleep-related variables and mortality. Last, we validated the score by constructing Cox proportional hazards models to assess its association with mortality. RESULTS: The mean age of participants was 63.2 years old, and 47.6% (2715/5706) were male. Six sleep variables, including average oxygen saturation (%), spindle density (C3), sleep efficiency (%), spindle density (C4), percentage of fast spindles (%) and percentage of rapid eye movement (%) were selected to construct this multidimensional sleep health score. The average sleep composite score in participants was 6.8 of 22 (lower is better). Participants with a one-point increase in sleep composite score had an 10% higher risk of death (hazard ratio = 1.10, 95% confidence interval: 1.08-1.12). CONCLUSIONS: This study constructed and validated a novel multidimensional sleep health score to better predict death based on sleep, with significant associations between sleep composite score and all-cause mortality. Integrating questionnaire information and sleep microstructures, our sleep composite score is more appropriately applied for mortality risk stratification.

Reactive Oxygen Species-Responsive Delivery of a Notch Inhibitor to Alleviate Nonalcoholic Steatohepatitis by Inhibiting Hepatic de Novo Lipogenesis and Inflammation.

With the increased prevalence of nonalcoholic steatohepatitis (NASH) in the world, effective pharmacotherapy in clinical practice is still lacking. Previous studies have shown that dibenzazepine (DBZ), a Notch inhibitor, could alleviate NASH development in a mouse model. However, low bioavailability, poor water solubility, and extrahepatic side effects restrict its clinical application. To overcome these barriers, we developed a reactive oxygen species (ROS)-sensitive nanoparticle based on the conjugation of bilirubin to poly(ethylene glycol) (PEG) chains, taking into account the overaccumulation of hepatic ROS in the pathologic state of nonalcoholic steatohepatitis (NASH). The PEGylated bilirubin can self-assemble into nanoparticles in an aqueous solution and encapsulate insoluble DBZ into its hydrophobic cavity. DBZ nanoparticles (DBZ Nps) had good stability, rapidly released DBZ in response to H2O2, and effectively scavenged intracellular ROS of hepatocytes. After systemic administration, DBZ Nps could accumulate in the liver of the NASH mice, extend persistence in circulation, and improve the bioavailability of DBZ. Furthermore, DBZ Nps significantly improved glucose intolerance, relieved hepatic lipid accumulation and inflammation, and ameliorated NASH-induced liver fibrosis. Additionally, DBZ Nps had no significant extrahepatic side effects. Taken together, our results highlight the potential of the ROS-sensitive DBZ nanoparticle as a promising therapeutic strategy for NASH.

Practice of standardization of CLSI M45 A3 antimicrobial susceptibility testing of Infrequently Isolated or Fastidious Bacteria strains isolated from blood specimens in Guangdong Province 2017-2021.

The concentration of antimicrobial agents in environments like water and food has increased rapidly, which led to a rapid increase in antimicrobial resistance levels in the environment. Monitoring of bacterial resistance levels is considered as a necessary means to control the bacterial resistance. Reference standards are critical for antimicrobial susceptibility testing. CLSI M45 A3 standard defines pathogenic microorganisms that cause infections less frequently than those covered by CLSI M02, M07, and M100 as Infrequently Isolated or Fastidious Bacteria and specifies antimicrobial susceptibility testing methods. Our study investigated the epidemiology and antimicrobial susceptibility testing data of Infrequently Isolated or Fastidious Bacteria strains isolated from blood specimens in 70 hospitals in Guangdong Province between 2017 and 2021. We defined testing methods other than those specified in CLSI M45 A3 as "Non-Standardized." The proportion of standardized antimicrobial susceptibility testing for penicillin increased significantly (Corynebacterium spp. 17.4% vs. 50.0% p < 0.05; Micrococcus spp. 50.0% vs. 77.8% p < 0.05; Abiotrophia spp. and Granulicatella spp. 21.4% vs. 90.9% p < 0.001), while for cefotaxime (Corynebacterium spp. 0.0% vs. 45.2% p < 0.05; Abiotrophia spp. and Granulicatella spp. 0.0% vs. 14.3% p = 0.515) and vancomycin increased finitely. Non-standardized methods were used for all other antimicrobials. Due to limitations in the economic and medical environment, some clinical laboratories are unable to fully comply with CLSI M45 A3 standard. We recommend that CLSI should add breakpoints for disk diffusion method to improve the standardization of antimicrobial susceptibility testing.

Cobalt telluride regulated by nickel for efficient electrooxidation of 5-hydroxymethylfurfural.

Replacing the anodic oxygen evolution reaction (OER) in water splitting with 5-hydroxymethylfurfural oxidation reaction (HMFOR) can not only reduce the energy required for hydrogen production but also yield the valuable chemical 2,5-furandicarboxylic acid (FDCA). Co-based catalysts are known to be efficient for HMFOR, with high-valent Co being recognized as the main active component. However, efficiently promoting the oxidation of Co2+ to produce high-valent reactive species remains a challenge. In this study, Ni-doped CoTe (CoNiTe) nanorods were prepared as efficient catalysts for HMFOR, achieving a high HMFOR current density of 65.3 mA cm-2 at 1.50 V. Even after undergoing five successive electrolysis processes, the Faradaic efficiency (FE) remained at approximately 90.7 %, showing robust electrochemical durability. Mechanistic studies indicated that Ni doping changes the electronic configuration of Co, enhancing its charge transfer rate and facilitating the oxidation of Co2+ to high-valent CoO2 species. This work reveals the effect of Ni doping on the reconfiguration of the active phase during HMFOR.

Nanoscopic Imaging of Self-Propelled Ultrasmall Catalytic Nanomotors.

Ultrasmall nanomotors (<100 nm) are highly desirable nanomachines for their size-specific advantages over their larger counterparts in applications spanning nanomedicine, directed assembly, active sensing, and environmental remediation. While there are extensive studies on motors larger than 100 nm, the design and understanding of ultrasmall nanomotors have been scant due to the lack of high-resolution imaging of their propelled motions with orientation and shape details resolved. Here, we report the imaging of the propelled motions of catalytically powered ultrasmall nanomotors─hundreds of them─at the nanometer resolution using liquid-phase transmission electron microscopy. These nanomotors are Pt nanoparticles of asymmetric shapes ("tadpoles" and "boomerangs"), which are colloidally synthesized and observed to be fueled by the catalyzed decomposition of NaBH4 in solution. Statistical analysis of the orientation and position trajectories of fueled and unfueled motors, coupled with finite element simulation, reveals that the shape asymmetry alone is sufficient to induce local chemical concentration gradient and self-diffusiophoresis to act against random Brownian motion. Our work elucidates the colloidal design and fundamental forces involved in the motions of ultrasmall nanomotors, which hold promise as active nanomachines to perform tasks in confined environments such as drug delivery and chemical sensing.

Luteolin Alleviates Cadmium-Induced Kidney Injury by Inhibiting Oxidative DNA Damage and Repairing Autophagic Flux Blockade in Chickens.

Chickens are a major source of meat and eggs in human food and have significant economic value. Cadmium (Cd) is a common environmental pollutant that can contaminate feed and drinking water, leading to kidney injury in livestock and poultry, primarily by inducing the generation of free radicals. It is necessary to develop potential medicines to prevent and treat Cd-induced nephrotoxicity in poultry. Luteolin (Lut) is a natural flavonoid compound mainly extracted from peanut shells and has a variety of biological functions to defend against oxidative damage. In this study, we aimed to demonstrate whether Lut can alleviate kidney injury under Cd exposure and elucidate the underlying molecular mechanisms. Renal histopathology and cell morphology were observed. The indicators of renal function, oxidative stress, DNA damage and repair, NAD+ content, SIRT1 activity, and autophagy were analyzed. In vitro data showed that Cd exposure increased ROS levels and induced oxidative DNA damage and repair, as indicated by increased 8-OHdG content, increased γ-H2AX protein expression, and the over-activation of the DNA repair enzyme PARP-1. Cd exposure decreased NAD+ content and SIRT1 activity and increased LC3 II, ATG5, and particularly p62 protein expression. In addition, Cd-induced oxidative DNA damage resulted in PARP-1 over-activation, reduced SIRT1 activity, and autophagic flux blockade, as evidenced by reactive oxygen species scavenger NAC application. The inhibition of PARP-1 activation with the pharmacological inhibitor PJ34 restored NAD+ content and SIRT1 activity. The activation of SIRT1 with the pharmacological activator RSV reversed Cd-induced autophagic flux blockade and cell injury. In vivo data demonstrated that Cd treatment caused the microstructural disruption of renal tissues, reduced creatinine, and urea nitrogen clearance, raised MDA content, and decreased the activities or contents of antioxidants (GSH, T-SOD, CAT, and T-AOC). Cd treatment caused oxidative DNA damage and PARP-1 activation, decreased NAD+ content, decreased SIRT1 activity, and impaired autophagic flux. Notably, the dietary Lut supplement observably alleviated these alterations in chicken kidney tissues induced by Cd. In conclusion, the dietary Lut supplement alleviated Cd-induced chicken kidney injury through its potent antioxidant properties by relieving the oxidative DNA damage-activated PARP-1-mediated reduction in SIRT1 activity and repairing autophagic flux blockade.

Reducing Overpotential of Lithium-Oxygen Batteries by Diatomic Metal Catalyst Orbital Matching Strategy.

Aprotic Li-O2 batteries have sparked attention in recent years due to their ultrahigh theoretical energy density. Nevertheless, their practical implementation is impeded by the sluggish reaction kinetics at the cathode. Comprehending the catalytic mechanisms is pivotal to developing efficient cathode catalysts for high-performance Li-O2 batteries. Herein, the intrinsic activity map of Li-O2 batteries is established based on the specific adsorption mode of O2 induced by diatomic catalyst orbital matching and the transfer-acceptance-backdonation mechanism, and the four-step screening strategy based on the intrinsic activity map is proposed. Guided by the strategy, FeNi@NC and FeCu@NC promising durable stability with a low overpotential are screened out from 27 Fe-Metal diatomic catalysts. Our research not only provides insights into the fundamental understanding of the reaction mechanism of Li-O2 batteries but also accelerates the rational design of efficient Li-O2 batteries based on the structure-activity relationship.

Luteolin alleviates cadmium-induced metabolism disorder through antioxidant and anti-inflammatory mechanisms in chicken kidney.

Cadmium (Cd) is a common environmental pollutant associated with an increased incidence of renal metabolic diseases. Luteolin (Lut), a natural flavonoid, is widely used for its multifaceted therapeutic properties in inflammatory diseases. However, whether Lut protects against Cd-induced nephrotoxicity is still equivocal. The present study investigated the effects of Lut supplementation on renal oxidative stress, inflammation and metabolism and their related mechanisms. Therefore, 40 chickens were treated with Cd and/or Lut with automatic water and free food intake for 1 mo and then the kidney tissues were collected to explore this issue. In this study, Cd exposure induced renal glycolipid metabolism disorders and resultant kidney damage by periodic acid Schiff (PAS) staining, Oil Red O staining, total cholesterol (TC), triglyceride (TG), and glucose (Glu) levels in kidney, which were significantly ameliorated by Lut. Moreover, Lut also normalized the expression levels of factors related to Cd-disturbed glycolipid metabolism, improving metabolic homeostasis, and contributing to alleviating kidney damage. Furthermore, Lut demonstrated therapeutic potential against Cd-induced renal oxidative stress and inflammation by enhancing antioxidant capacity and inhibiting cytokine production in the kidney tissues. Mechanistically, Lut activated the AMPK/SIRT1/FOXO1 signaling pathway, attenuating oxidative stress and inflammatory responses, ameliorating the metabolic disturbance. In conclusion, these observations demonstrate that Lut treatment activates AMPK/SIRT1/FOXO1 signaling pathway, decreases oxidative stress and inflammation response, which may contribute to prevent Cd-induced metabolism disorder and consequent kidney damage.

Metagenomic and transcriptomic analysis revealing the impact of oxytetracycline and ciprofloxacin on gut microbiota and gene expression in the Chinese giant salamander (Andrias davidianus).

Excessive antibiotic use has led to the spread of antibiotic resistance genes (ARGs), impacting gut microbiota and host health. However, the effects of antibiotics on amphibian populations remain unclear. We investigated the impact of oxytetracycline (OTC) and ciprofloxacin (CIP) on Chinese giant salamanders (Andrias davidianus), focusing on gut microbiota, ARGs, and gene expression by performing metagenome and transcriptome sequencing. A. davidianus were given OTC (20 or 40 mg/kg) or CIP (50 or 100 mg/kg) orally for 7 days. The results revealed that oral administration of OTC and CIP led to distinct changes in microbial composition and functional potential, with CIP treatment having a greater impact than OTC. Antibiotic treatment also influenced the abundance of ARGs, with an increase in fluoroquinolone and multi-drug resistance genes observed post-treatment. The construction of metagenome-assembled genomes (MAGs) accurately validated that CIP intervention enriched fish-associated potential pathogens Aeromonas hydrophila carrying an increased number of ARGs. Additionally, mobile genetic elements (MGEs), such as phages and plasmids, were implicated in the dissemination of ARGs. Transcriptomic analysis of the gut revealed significant alterations in gene expression, particularly in immune-related pathways, with differential effects observed between OTC and CIP treatments. Integration of metagenomic and transcriptomic data highlighted potential correlations between gut gene expression and microbial composition, suggesting complex interactions between the host gut and its gut microbiota in response to antibiotic exposure. These findings underscore the importance of understanding the impact of antibiotic intervention on the gut microbiome and host health in amphibians, particularly in the context of antibiotic resistance and immune function.

Efficacy and safety of simple analgesics for acute treatment of episodic tension-type headache in adults: a network meta-analysis.

OBJECTIVE: Tension-type headache is the most common type of primary headache and results in a huge socioeconomic burden. This network meta-analysis (NMA) aimed to compare the efficacy and safety of simple analgesics for the treatment of episodic tension-type headache (ETTH) in adults. METHODS: We searched the Cochrane Library, PubMed, Web of Science, Embase, Chinese BioMedical Literature database and International Clinical Trials Registry Platform databases for eligible randomized clinical trials reporting the efficacy and/or safety of simple analgesics. A Bayesian NMA was performed to compare relative efficacy and safety. The surface under the cumulative ranking curve (SUCRA) was calculated to rank interventions. PROSPERO registration number: CRD42018090554. RESULTS: We highlighted six studies including 3507 patients. For the 2 h pain-free rate, the SUCRA ranking was ibuprofen > diclofenac-K > ketoprofen > acetaminophen > naproxen > placebo. All drugs except naproxen reported a higher 2 h pain-free rate than placebo, with a risk ratio (RR) of 2.86 (95% credible interval, CrI: 1.62-5.42) for ibuprofen and 2.61 (1.53-4.88) for diclofenac-K. For adverse events rate, the SUCRA ranking was: metamizol > diclofenac-K > ibuprofen > lumiracoxib > placebo > aspirin > acetaminophen > naproxen > ketoprofen. The adverse event rates of all analgesics were no higher than those of placebo, except for ketoprofen. Moreover, all drugs were superior to placebo in the global assessment of efficacy. In particular, the RR of lumiracoxib was 2.47 (1.57-4.57). Global heterogeneity I2 between the studies was low. CONCLUSIONS: Simple analgesics are considered more effective and safe as a placebo for ETTH in adults. Our results suggest that ibuprofen and diclofenac-K may be the two best treatment options for patients with ETTH from a comprehensive point of view (both high-quality evidence).

To our knowledge, this is the first network meta-analysis comparing the available data on adult patients with episodic tension-type headache (ETTH) treated with different simple analgesics recommended by the current guidelines.Ibuprofen (400 mg) and diclofenac-K (12.5 mg, 25 mg) are potentially the most effective and safe treatment options, supported by high-quality evidence.

Association of gastrointestinal microbiome and obesity with gestational diabetes mellitus-an updated globally based review of the high-quality literatures.

OBJECTIVES: The purpose of this review is to investigate the relationship between gastrointestinal microbiome, obesity, and gestational diabetes mellitus (GDM) in an objective manner. METHODS: We conducted a thorough and comprehensive search of the English language literatures published in PubMed, Web of Science, and the Cochrane Library from the establishment of the library until 12 December 2023. Our search strategy included both keywords and free words searches, and we strictly applied inclusion and exclusion criteria. Meta-analyses and systematic reviews were prepared. RESULTS: Six high-quality literature sources were identified for meta-analysis. However, after detailed study and analysis, a certain degree of heterogeneity was found, and the credibility of the combined analysis results was limited. Therefore, descriptive analyses were conducted. The dysbiosis of intestinal microbiome, specifically the ratio of Firmicutes/Bacteroides, is a significant factor in the development of metabolic diseases such as obesity and gestational diabetes. Patients with intestinal dysbiosis and obesity are at a higher risk of developing GDM. CONCLUSIONS: During pregnancy, gastrointestinal microbiome disorders and obesity may contribute to the development of GDM, with all three factors influencing each other. This finding could aid in the diagnosis and management of patients with GDM through further research on their gastrointestinal microbiome.

Salivary metabolites are promising noninvasive biomarkers of drug-induced liver injury.

BACKGROUND: Drug-induced liver injury (DILI) is one of the most common adverse events of medication use, and its incidence is increasing. However, early detection of DILI is a crucial challenge due to a lack of biomarkers and noninvasive tests. AIM: To identify salivary metabolic biomarkers of DILI for the future development of noninvasive diagnostic tools. METHODS: Saliva samples from 31 DILI patients and 35 healthy controls (HCs) were subjected to untargeted metabolomics using ultrahigh-pressure liquid chromatography coupled with tandem mass spectrometry. Subsequent analyses, including partial least squares-discriminant analysis modeling, t tests and weighted metabolite coexpression network analysis (WMCNA), were conducted to identify key differentially expressed metabolites (DEMs) and metabolite sets. Furthermore, we utilized least absolute shrinkage and selection operato and random fores analyses for biomarker prediction. The use of each metabolite and metabolite set to detect DILI was evaluated with area under the receiver operating characteristic curves. RESULTS: We found 247 differentially expressed salivary metabolites between the DILI group and the HC group. Using WMCNA, we identified a set of 8 DEMs closely related to liver injury for further prediction testing. Interestingly, the distinct separation of DILI patients and HCs was achieved with five metabolites, namely, 12-hydroxydodecanoic acid, 3-hydroxydecanoic acid, tetradecanedioic acid, hypoxanthine, and inosine (area under the curve: 0.733-1). CONCLUSION: Salivary metabolomics revealed previously unreported metabolic alterations and diagnostic biomarkers in the saliva of DILI patients. Our study may provide a potentially feasible and noninvasive diagnostic method for DILI, but further validation is needed.

Analysis of the causes of primary revision after unicompartmental knee arthroplasty: A case series.

BACKGROUND: Unicompartmental knee arthroplasty (UKA) has great advantages in the treatment of unicompartmental knee osteoarthritis, but its revision rate is higher than that of total knee arthroplasty. AIM: To summarize and analyse the causes of revision after UKA. METHODS: This is a retrospective case series study in which the reasons for the first revision after UKA are summarized. We analysed the clinical symptoms, medical histories, laboratory test results, imaging examination results and treatment processes of the patients who underwent revision and summarized the reasons for primary revision after UKA. RESULTS: A total of 13 patients, including 3 males and 10 females, underwent revision surgery after UKA. The average age of the included patients was 67.62 years. The prosthesis was used for 3 d to 72 months. The main reasons for revision after UKA were improper suturing of the surgical opening (1 patient), osteophytes (2 patients), intra-articular loose bodies (2 patients), tibial prosthesis loosening (2 patients), rheumatoid arthritis (1 patient), gasket dislocation (3 patients), anterior cruciate ligament injury (1 patient), and medial collateral ligament injury with residual bone cement (1 patient). CONCLUSION: The causes of primary revision after UKA were gasket dislocation, osteophytes, intra-articular loose bodies and tibial prosthesis loosening. Avoidance of these factors may greatly reduce the rate of revision after UKA, improve patient satisfaction and reduce medical burden.

SIRT1/P53 in retinal pigment epithelial cells in diabetic retinopathy: a gene co-expression analysis and He-Ying-Qing-Re formula treatment.

Objective: Diabetic retinopathy (DR) is a severe diabetic complication that leads to severe visual impairment or blindness. He-Ying-Qing-Re formula (HF), a traditional Chinese medicinal concoction, has been identified as an efficient therapy for DR with retinal vascular dysfunction for decades and has been experimentally reported to ameliorate retinal conditions in diabetic mice. This study endeavors to explore the therapeutic potential of HF with key ingredients in DR and its underlying novel mechanisms. Methods: Co-expression gene modules and hub genes were calculated by weighted gene co-expression network analysis (WGCNA) based on transcriptome sequencing data from high-glucose-treated adult retinal pigment epithelial cell line-19 (ARPE-19). The chromatographic fingerprint of HF was established by ultra-performance liquid chromatography coupled with high-resolution mass spectrometry (UPLC-Q-TOF-MS). The molecular affinity of the herbal compound was measured by molecular docking. Reactive oxygen species (ROS) was measured by a DCFDA/H2DCFDA assay. Apoptosis was detected using the TUNEL Assay Kit, while ELISA, Western blot, and real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) were used for detecting the cytokine, protein, and mRNA expressions, respectively. Results: Key compounds in HF were identified as luteolin, paeoniflorin, and nobiletin. For WGCNA, ME-salmon ("protein deacetylation") was negatively correlated with ME-purple ("oxidative impairment") in high-glucose-treated ARPE-19. Luteolin has a high affinity for SIRT1 and P53, as indicated by molecular docking. Luteolin has a hypoglycemic effect on type I diabetic mice. Moreover, HF and luteolin suppress oxidative stress production (ROS and MDA), inflammatory factor expression (IL-6, TNF-α, IL1-ß, and MCP-1), and apoptosis, as shown in the in vivo and in vitro experiments. Concurrently, treatment with HF and luteolin led to an upregulation of SIRT1 and a corresponding downregulation of P53. Conclusion: Using HF and its active compound luteolin as therapeutic agents offers a promising approach to diabetic retinopathy treatment. It primarily suppressed protein acetylation and oxidative stress via the SIRT1/P53 pathway in retinal pigment epithelial cells.

Development and application of a deep learning-based comprehensive early diagnostic model for chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a frequently diagnosed yet treatable condition, provided it is identified early and managed effectively. This study aims to develop an advanced COPD diagnostic model by integrating deep learning and radiomics features. METHODS: We utilized a dataset comprising CT images from 2,983 participants, of which 2,317 participants also provided epidemiological data through questionnaires. Deep learning features were extracted using a Variational Autoencoder, and radiomics features were obtained using the PyRadiomics package. Multi-Layer Perceptrons were used to construct models based on deep learning and radiomics features independently, as well as a fusion model integrating both. Subsequently, epidemiological questionnaire data were incorporated to establish a more comprehensive model. The diagnostic performance of standalone models, the fusion model and the comprehensive model was evaluated and compared using metrics including accuracy, precision, recall, F1-score, Brier score, receiver operating characteristic curves, and area under the curve (AUC). RESULTS: The fusion model exhibited outstanding performance with an AUC of 0.952, surpassing the standalone models based solely on deep learning features (AUC = 0.844) or radiomics features (AUC = 0.944). Notably, the comprehensive model, incorporating deep learning features, radiomics features, and questionnaire variables demonstrated the highest diagnostic performance among all models, yielding an AUC of 0.971. CONCLUSION: We developed and implemented a data fusion strategy to construct a state-of-the-art COPD diagnostic model integrating deep learning features, radiomics features, and questionnaire variables. Our data fusion strategy proved effective, and the model can be easily deployed in clinical settings. TRIAL REGISTRATION: Not applicable. This study is NOT a clinical trial, it does not report the results of a health care intervention on human participants.