MCD-LightGBM System for Intelligent Analyzing Heterogeneous Clinical Drug Therapeutic Effects.

Causal effect estimation of individual heterogeneity is a core issue in the field of causal inference, and its application in medicine poses an active and challenging problem. In high-risk decision-making domain such as healthcare, inappropriate treatments can have serious negative impacts on patients. Recently, machine learning-based methods have been proposed to improve the accuracy of causal effect estimation results. However, many of these methods concentrate on estimating causal effects of continuous outcome variables under binary intervention conditions, and give less consideration to multivariate intervention conditions or discrete outcome variables, thus limiting their scope of application. To tackle this issue, we combine the double machine learning framework with Light Gradient Boosting Machine (LightGBM) and propose a double LightGBM model. This model can estimate binary causal effects more accurately and in less time. Two cyclic structures were added to the model. Data correction method was introduced and improved to transform discrete outcome variables into continuous outcome variables. Multivariate Cyclic Double LightGBM model (MCD-LightGBM) was proposed to intelligently estimate multivariate treatment effects. A visual human-computer interaction system for heterogeneous causal effect estimation was designed, which can be applied to different types of data. This paper reports that the system improved the Logarithm of the Minimum Angle of Resolution (LogMAR) of visual acuity change after Vascular Endothelial Growth Factor (anti-VEGF) treatment in patients with diabetic macular degeneration. The improvement was observed in two clinical problems, from 0.05 to 0.33, and the readmission rate of diabetic patients after cure was reduced from 48.4% to 10.5%. The results above demonstrate the potential of the proposed system in predicting heterogeneous clinical drug treatment effects.

Integrated analysis reveals an aspartate metabolism-related gene signature for predicting the overall survival in patients with hepatocellular carcinoma.

BACKGROUND: Deregulating cellular metabolism is one of the prominent hallmarks of malignancy, with a critical role in tumor survival and growth. However, the role of reprogramming aspartate metabolism in hepatocellular carcinoma (HCC) are largely unknown. METHODS: The multi-omics data of HCC patients were downloaded from public databases. Univariate and multivariate stepwise Cox regression were used to establish an aspartate metabolism-related gene signature (AMGS) in HCC. The Kaplan-Meier and receiver operating characteristic curve analyses were performed to evaluate the predictive ability for overall survival (OS) in HCC patients. Gene set enrichment analysis and immune infiltration analysis were operated to determine the potential mechanisms underlying the AMGS. Single-cell RNA sequencing (scRNA-seq) data of liver cancer stem cells were visualized by t-SNE algorithm. In vivo and in vitro experiments were implemented to investigate the biological function of CAD in HCC. In addition, a nomogram based on the AMGS and clinicopathologic characteristics was constructed by univariate and multivariate Cox regression analyses. RESULTS: Patients in the high-AMGS subgroup exerted advanced tumor status and poor prognosis. Mechanistically, the high-AMGS subgroup patients had significantly enhanced proliferation and stemness-related pathways, increased infiltration of regulatory T cells and upregulated expression levels of suppressive immune checkpoints in the tumor immune microenvironment. Notably, scRNA-seq data revealed CAD, one of the aspartate metabolism-related gene, is significantly upregulated in liver cancer stem cells. Silencing CAD inhibited proliferative capacity and stemness properties of HCC cells in vitro and in vivo. Finally, a novel nomogram based on the AMGS showed an accurate prediction in HCC patients. CONCLUSIONS: The AMGS represents a promising prognostic value for HCC patients, providing a perspective for finding novel biomarkers and therapeutic targets for HCC.

New Phenanthro[9,10-d]oxazole-Based Fluorophores with Hybridized Local and Charge-Transfer Characteristics for Highly Efficient Blue Non-doped OLEDs with Negligible Efficiency Roll-Off.

It is vital to develop highly efficient non-doped blue organic light-emitting diodes (OLEDs) with high color purity and low-efficiency roll-off for applications in display and lighting. Herein, two blue D-A fluorophores TPA-PO and TPA-DPO are designed and synthesized, in which phenanthro[9,10-d]oxazole (PO) acts as the acceptor and triphenylamine as the donor. TPA-PO and TPA-DPO display good thermal stability and efficient luminescence efficiency in neat film. Results based on photophysical property and theoretical calculation demonstrate that TPA-PO and TPA-DPO possess the hybridized local and charge-transfer (HLCT) feature, which can utilize the triplet exciton to achieve highly efficient electroluminance (EL). The non-doped OLEDs with TPA-PO/TPA-DPO as pure emissive layer show the uniform EL emission peak at 468 nm, corresponding to CIE coordinates of (0.168, 0.187) and (0.167, 0.167), respectively. The TPA-DPO-based non-doped OLEDs provide the maximum external quantum efficiency (EQE) of 7.99% and high exciton utility efficiency of 48.4%~72.6%. Moreover, the TPA-DPO-based device exhibits low-efficiency roll-off, still maintaining the EQE of 6.03% at the high luminance of 5000 cd m-2. Those findings state clearly that PO is a promising building block of blue fluorophore with a potential HLCT feature to be applied in non-doped OLEDs.

[Machine learning algorithms for identifying autism spectrum disorder through eye-tracking in different intention videos]. / ä¸åŒæ„å›¾åœºæ™¯çœ¼åŠ¨æ³¨è§†æ¨¡å¼æœºå™¨å­¦ä¹ ç®—æ³•è¯†åˆ«å­¤ç‹¬ç—‡è°±ç³»éšœç¢çš„ç ”ç©¶.

OBJECTIVES: To investigate the differences in visual perception between children with autism spectrum disorder (ASD) and typically developing (TD) children when watching different intention videos, and to explore the feasibility of machine learning algorithms in objectively distinguishing between ASD children and TD children. METHODS: A total of 58 children with ASD and 50 TD children were enrolled and were asked to watch the videos containing joint intention and non-joint intention, and the gaze duration and frequency in different areas of interest were used as original indicators to construct classifier-based models. The models were evaluated in terms of the indicators such as accuracy, sensitivity, and specificity. RESULTS: When using eight common classifiers, including support vector machine, linear discriminant analysis, decision tree, random forest, and K-nearest neighbors (with K values of 1, 3, 5, and 7), based on the original feature indicators, the highest classification accuracy achieved was 81.90%. A feature reconstruction approach with a decision tree classifier was used to further improve the accuracy of classification, and then the model showed the accuracy of 91.43%, the specificity of 89.80%, and the sensitivity of 92.86%, with an area under the receiver operating characteristic curve of 0.909 (P<0.001). CONCLUSIONS: The machine learning model based on eye-tracking data can accurately distinguish ASD children from TD children, which provides a scientific basis for developing rapid and objective ASD screening tools.

Intramedullary administration of tranexamic acid reduces bleeding in proximal femoral nail antirotation surgery for intertrochanteric fractures in elderly individuals: A randomized controlled trial.

PURPOSE: Intertrochanteric fractures undergoing proximal femoral nail antirotation (PFNA) surgery are associated with significant hidden blood loss. This study aimed to explore whether intramedullary administration of tranexamic acid (TXA) can reduce bleeding in PFNA surgery for intertrochanteric fractures in elderly individuals. METHODS: A randomized controlled trial was conducted from January 2019 to December 2022. Patients aged over 60 years with intertrochanteric fractures who underwent intramedullary fixation surgery with PFNA were eligible for inclusion and grouped according to random numbers. A total of 249 patients were initially enrolled, of which 83 were randomly allocated to the TXA group and 82 were allocated to the saline group. The TXA group received intramedullary perfusion of TXA after the bone marrow was reamed. The primary outcomes were total peri-operative blood loss and post-operative transfusion rate. The occurrence of adverse events was also recorded. Continuous data was analyzed by unpaired t-test or Mann-Whitney U test, and categorical data was analyzed by Pearson Chi-square test. RESULTS: The total peri-operative blood loss (mL) in the TXA group was significantly lower than that in the saline group (577.23 ± 358.02 vs. 716.89 ± 420.30, p = 0.031). The post-operative transfusion rate was 30.67 % in the TXA group and 47.95 % in the saline group (p = 0.031). The extent of post-operative deep venous thrombosis and the 3-month mortality rate were similar between the 2 groups. CONCLUSION: We observed that intramedullary administration of TXA in PFNA surgery for intertrochanteric fractures in elderly individuals resulted in less peri-operative blood loss and decreased transfusion rate, without any adverse effects, and is, thus, recommended.

Allele-specific DNA methylation and gene expression during shoot organogenesis in tissue culture of hybrid poplar.

Plant tissue regeneration is critical for genetic transformation and genome editing techniques. During the regeneration process, changes in epigenetic modifications accompany the cell fate transition. However, how allele-specific DNA methylation in two haplotypes contributes to the transcriptional dynamics during regeneration remains elusive. Here we applied an inter-species hybrid poplar (Populus alba × P. glandulosa cv. 84 K) as a system to characterize the DNA methylation landscape during de novo shoot organogenesis at allele level. Both direct and indirect shoot organogenesis showed a reduction in genome-wide DNA methylation. At gene level, non-expressed genes were hypermethylated in comparison with expressed genes. Among the genes exhibiting significant correlations between levels of DNA methylation and gene expression, the expression patterns of 75% of genes were negatively correlated with DNA methylation in the CG context, whereas the correlation patterns in the CHH context were the reverse. The allele-biased DNA methylation was consistent during shoot organogenesis, with fewer than one-thousandth of allele-specific methylation regions shifted. Analysis of allele-specific expression revealed that there were only 1909 genes showing phase-dependent allele-biased expression in the regeneration process, among which the allele pairs with greater differences in transcription factor binding sites at promoter regions exhibited greater differences in allele expression. Our results indicated a relatively independent transcriptional regulation in two subgenomes during shoot organogenesis, which was contributed by cis-acting genomic and epigenomic variations.

Survivin as a potential biomarker in the diagnosis of bladder cancer: A systematic review and meta-analysis.

Early detection, diagnosis, and treatment take on critical significance in preventing and treating bladder cancer. As indicated by numerous studies, survivin can serve as a biomarker of bladder cancer, whereas the results of a wide variety of studies have been controversial. This paper is to assess the accuracy of survivin in the diagnosis of bladder cancer by a meta-analysis. The studies regarding the diagnosis of bladder cancer using survivin were systematically retrieved from the CNKI, WanFang, CBM, VIP, Web of science, cochrane library and pubmed were extracted, and the literature quality was assessed. Meta-analysis was conducted using STATA 16.0 MP. 2,082 relevant studies were searched, and 40 studies were finally covered for meta-analysis. The pooled specificity and pooled sensitivity of survivin mRNA was 0.95 (95%CI: 0.91, 0.97) and 0.94 (95%CI: 0.88, 0.97). The pooled specificity and pooled sensitivity of survivin protein reached 0.95 (95%CI: 0.90, 0.97) and 0.87 (95%CI: 0.78, 0.92). The pooled positive likelihood ratio, pooled negative likelihood ratio, the area under the curve, and diagnostic odds ratio for survivin mRNA reached 17.7 (95%CI: 10.3, 30.6), 0.07 (95%CI: 0.04, 0.12), 0.98 (95%CI: 0.97, 0.99) and 266 (95%CI: 114, 621), respectively. For survivin protein was 16.4 (95%CI: 7.9, 33.9), 0.14 (95%CI: 0.08, 0.24), 0.97 (95%CI: 0.95, 0.98) and 117 (95%CI: 38, 357), respectively. Survivin takes on great significance in diagnosing bladder cancer. However, due to some limitations in the number and quality of covered studies, this conclusion should be validated through additional higher quality clinical studies.

Hydrophobic association: A facile approach to prepare physical cross-linked gelatin hydrogel with desirable thermal stability, flexibility and self-healing ability.

Methacrylic anhydride was added to 20 % gelatin solution to prepare gelatin methacryloyl (GelMA) but an unexpected gelation process was observed within several minutes. The experimental data revealed that the methacryloyl substitution can increase the hydrophobicity of gelatin and the micellar diameter in solution. Therefore, we speculated that the methacryloyl substitution caused the formation of micellar cross-links based on the hydrophobic residues of gelatin and the methacryloyl groups, thus obtaining the hydrophobic association hydrogels. The thixotropic and tensile experiments confirmed that GelMA hydrogel possessed the features of hydrophobic association hydrogels like self-healing and stretchable abilities. The rheological experiments revealed that the gelation rate and the mechanical strength of the GelMA hydrogels were in direct proportion to the concentration of GelMA and the degree of methacryloyl substitution. GelMA hydrogels possessed desirable thermal stability that it didn't melt after being heated to 90 °C. Furthermore, the MTT assays and calcein AM/PI staining revealed that GelMA hydrogel was biocompatible. These results collectively confirm that the hydrophobic association is a prospective and facile approach to prepare gelatin hydrogel with desirable properties for further application.

Salidroside Protects Chondrocytes against IL-1ß-Induced Injury and Alleviates Osteoarthritis Progression by Activating the Nrf2 Pathway.

BACKGROUND: Osteoarthritis (OA) is a common disease that causes pain to many older adults. Because the pathogenesis is not fully elucidated, effective drug therapies are currently lacking. This study aimed to determine how salidroside (Sal)-mediated reduction of osteoarthritis development in mice worked and to identify the underlying mechanism. METHODS: Using in vitro experiments, ATDC5 cells were treated with various concentrations of Sal and interleukin (IL)-1ß for 24 hours to mimic OA. An enzyme-linked immunosorbent assay (ELISA) was conducted to detect the production of pro-inflammatory cytokines and reactive oxygen species (ROS). Western blotting was performed to observe the nuclear factor-kappa B (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways. In in vivo experiments, pathological examination was used to assess the effects of Sal on alleviating OA progression in mice. Nrf2 signaling and its downstream proteins were further tested by immunofluorescence analysis. RESULTS: The results showed that both pro-inflammatory cytokines and ROS were significantly reduced following Sal treatment in a concentration-dependent manner. Western blotting revealed that Sal could inhibit the expression of the NF-κB/hypoxia-inducible factor-2α pathway and activate the Nrf2/heme oxygenase-1 pathway. In vivo experiments showed that the cartilage surface in the saline-treated group eroded to a greater extent than the Sal-treated groups (p < 0.001). Immunohistochemistry analysis revealed that matrix metallopeptidase (MMP) 9, MMP13, and a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5) decreased expression level. In contrast, collagen-II and aggrecan increased in the Sal-treated groups compared to the saline-treated group. CONCLUSIONS: Our findings indicate that Sal can alleviate OA progression by promoting anti-oxidant expression and inhibiting degradation enzyme expression. These findings suggest that Sal inhibits the NF-κB pathway and its downstream targets through up-regulating the Nrf2 pathway.

Variant allele frequency in circulating tumor DNA correlated with tumor disease burden and predicted outcomes in patients with advanced breast cancer.

PURPOSE: In patients with first-line advanced breast cancer (ABC), the correlation between ctDNA variant allele frequency (VAF) and tumor disease burden, and its prognostic value remains poorly investigated. METHODS: This study included patients with ABC diagnosed at Peking University Cancer Hospital who performed ctDNA test before receiving first-line treatment. Baseline plasma samples were collected for assessing ctDNA alterations and VAF with next-generation sequencing. The sum of tumor target lesion diameters (SLD) was measured with imaging methods according to RECIST 1.1 criteria. RESULTS: The final cohort included 184 patients. The median age of the cohort was 49.4 (IQR: 42.3-56.8) years. The median VAF was 15.6% (IQR: 5.4%-33.7%). VAF showed positive correlation with SLD in patients with relatively large tumor lesions (r = 0.314, p = 0.003), but not in patients with small tumor lesions (p = 0.226). VAF was associated with multiple metastasis sites (p = 0.001). Multivariate Cox regression analysis showed that high VAF was associated with shorter overall survival (OS) (HR: 3.519, 95% confidence interval (CI): 2.149-5.761), and first-line progression-free survival (PFS) (HR: 2.352, 95%CI: 1.462-3.782). Combined VAF and SLD improved prediction performance, both median OS and PFS of patients in VAF(H)/SLD(H) group were significantly longer than VAF(L)/SLD(L) group (mOS: 49.3 vs. 174.1 months; mPFS: 9.6 vs. 25.3 months). CONCLUSION: ctDNA VAF associated with tumor disease burden, and was a prognostic factor for patients with ABC. A combination of ctDNA test and radiographic imaging might enhance tumor burden evaluation, and improve prognosis stratification in patients with ABC.

Protists regulate microbially mediated organic carbon turnover in soil aggregates.

Soil protists, the major predator of bacteria and fungi, shape the taxonomic and functional structure of soil microbiome via trophic regulation. However, how trophic interactions between protists and their prey influence microbially mediated soil organic carbon turnover remains largely unknown. Here, we investigated the protistan communities and microbial trophic interactions across different aggregates-size fractions in agricultural soil with long-term fertilization regimes. Our results showed that aggregate sizes significantly influenced the protistan community and microbial hierarchical interactions. Bacterivores were the predominant protistan functional group and were more abundant in macroaggregates and silt + clay than in microaggregates, while omnivores showed an opposite distribution pattern. Furthermore, partial least square path modeling revealed positive impacts of omnivores on the C-decomposition genes and soil organic matter (SOM) contents, while bacterivores displayed negative impacts. Microbial trophic interactions were intensive in macroaggregates and silt + clay but were restricted in microaggregates, as indicated by the intensity of protistan-bacterial associations and network complexity and connectivity. Cercozoan taxa were consistently identified as the keystone species in SOM degradation-related ecological clusters in macroaggregates and silt + clay, indicating the critical roles of protists in SOM degradation by regulating bacterial and fungal taxa. Chemical fertilization had a positive effect on soil C sequestration through suppressing SOM degradation-related ecological clusters in macroaggregate and silt + clay. Conversely, the associations between the trophic interactions and SOM contents were decoupled in microaggregates, suggesting limited microbial contributions to SOM turnovers. Our study demonstrates the importance of protists-driven trophic interactions on soil C cycling in agricultural ecosystems.

The newest Oxford Nanopore R10.4.1 full-length 16S rRNA sequencing enables the accurate resolution of species-level microbial community profiling.

The long-read amplicon provides a species-level solution for the community. With the improvement of nanopore flowcells, the accuracy of Oxford Nanopore Technologies (ONT) R10.4.1 has been substantially enhanced, with an average of approximately 99%. To evaluate its effectiveness on amplicons, three types of microbiomes were analyzed by 16S ribosomal RNA (hereinafter referred to as "16S") amplicon sequencing using Novaseq, Pacbio sequel II, and Nanopore PromethION platforms (R9.4.1 and R10.4.1) in the current study. We showed the error rate, recall, precision, and bias index in the mock sample. The error rate of ONT R10.4.1 was greatly reduced, with a better recall in the case of the synthetic community. Meanwhile, in different types of environmental samples, ONT R10.4.1 analysis resulted in a composition similar to Pacbio data. We found that classification tools and databases influence ONT data. Based on these results, we conclude that the ONT R10.4.1 16S amplicon can also be used for application in environmental samples. IMPORTANCE The long-read amplicon supplies the community with a species-level solution. Due to the high error rate of nanopore sequencing early on, it has not been frequently used in 16S studies. Oxford Nanopore Technologies (ONT) introduced the R10.4.1 flowcell with Q20+ reagent to achieve more than 99% accuracy as sequencing technology advanced. However, there has been no published study on the performance of commercial PromethION sequencers with R10.4.1 flowcells on 16S sequencing or on the impact of accuracy improvement on taxonomy (R9.4.1 to R10.4.1) using 16S ONT data. In this study, three types of microbiomes were investigated by 16S ribosomal RNA (rRNA) amplicon sequencing using Novaseq, Pacbio sequel II, and Nanopore PromethION platforms (R9.4.1 and R10.4.1). In the mock sample, we displayed the error rate, recall, precision, and bias index. We observed that the error rate in ONT R10.4.1 is significantly lower, especially when deletions are involved. First and foremost, R10.4.1 and Pacific Bioscience platforms reveal a similar microbiome in environmental samples. This study shows that the R10.4.1 full-length 16S rRNA sequences allow for species identification of environmental microbiota.

Lysophosphatidic Acid Signalling Regulates Human Sperm Viability via the Phosphoinositide 3-Kinase/AKT Pathway.

Lysophosphatidic acid (LPA) signalling is essential for maintaining germ cell viability during mouse spermatogenesis; however, its role in human spermatozoa is unknown. We previously demonstrated that peroxiredoxin 6 (PRDX6) calcium-independent phospholipase A2 (iPLA2) releases lysophospholipids such as LPA or arachidonic acid (AA) and that inhibiting PRDX6 iPLA2 activity impairs sperm cell viability. The exogenous addition of LPA bypassed the inhibition of PRDX6 iPLA2 activity and maintained the active phosphoinositide 3-kinase (PI3K)/AKT pathway. Here, we aimed to study PI3K/AKT pathway regulation via LPA signalling and protein kinases in maintaining sperm viability. The localization of LPARs in human spermatozoa was determined using immunocytochemistry, and P-PI3K and P-AKT substrate phosphorylations via immunoblotting. Sperm viability was determined using the hypo-osmotic swelling test. LPAR1, 3, 5 and 6 were located on the sperm plasma membrane. The inhibition of LPAR1-3 with Ki16425 promoted the impairment of sperm viability and decreased the phosphorylation of PI3K AKT substrates. Inhibitors of PKC, receptor-type PTK and PLC impaired sperm viability and the PI3K/AKT pathway. Adding 1-oleoyl-2-acetyl-snglycerol (OAG), a cell-permeable analog of diacylglycerol (DAG), prevented the loss of sperm viability and maintained the phosphorylation of PI3K. In conclusion, human sperm viability is supported by LPAR signalling and regulated by PLC, PKC and RT-PTK by maintaining phosphorylation levels of PI3K and AKT substrates.

A novel hepatitis B virus capsid assembly modulator QL-007 inhibits HBV replication and infection through altering capsid assembly.

The core protein allosteric modulators (CpAMs) have shown great potential as highly effective antiviral drugs against hepatitis B virus (HBV) in preclinical studies and clinical trials. In this study, we evaluated a small molecule compound called QL-007, which could potentially influence capsid assembly, using HBV replicated and susceptible cell models as well as mice infected with rAAV-HBV. QL-007 significantly inhibited HBV replication in a dose-dependent manner both in vitro and in vivo, resulting in significant decreases in HBV DNA, 3.5 kb HBV RNA and HBeAg. Furthermore, QL-007 not only induced the formation of misshaped Cp149 capsids but also possessed the capability to disassemble HBV capsids. It is noteworthy that QL-007 effectively reduced cccDNA biosynthesis in de novo infections. Mechanistically, QL-007 blocked the encapsidation of pgRNA and induced aberrant polymers assembly at concentrations ≥100 nM, while having no impact on the stability of core proteins. In conclusion, our findings underscore the potential of QL-007 as an effective agent against HBV replication and introduce it as a novel CpAM for the antiviral treatment of chronic hepatitis B.

Multifocal Raman Spectrophotometer for Examining Drug-Induced and Chemical-Induced Cellular Changes in 3D Cell Spheroids.

Cell spheroids offer alternative in vitro cell models to monolayer cultured cells because they express complexities similar to those of in vivo tissues, such as cellular responses to drugs and chemicals. Raman spectroscopy emerged as a powerful analytical tool for detecting chemical changes in living cells because it nondestructively provides vibrational information regarding a target. Although multiple iterations are required in drug screening to determine drugs to treat cell spheroids and assess the inter-spheroid heterogeneity, current Raman applications used in spheroids analysis allow the observation of only a few spheroids owing to the low throughput of Raman spectroscopy. In this study, we developed a multifocal Raman spectrophotometer that enables simultaneous analysis of multiple spheroids in separate wells of a regular 96-well plate. By utilizing 96 focal spots excitation and parallel signal collection, our system can improve the throughput by approximately 2 orders of magnitude compared to a conventional single-focus Raman microscope. The Raman spectra of HeLa cell spheroids treated with anticancer drugs and HepG2 cell spheroids treated with free fatty acids were measured simultaneously, and concentration-dependent cellular responses were observed in both studies. Using the multifocal Raman spectrophotometer, we rapidly observed chemical changes in spheroids, and thus, this system can facilitate the application of Raman spectroscopy in analyzing the cellular responses of spheroids.

The deep learning algorithm estimates chest radiograph-based sex and age as independent risk factors for future cardiovascular outcomes.

Objectives: Chest X-rays (CXRs) convey much illegible physiological information that deep learning model (DLM) has been reported interpreting successfully. Since the electrocardiogram age established by DLM was revealed as a heart biological marker, we hypothesize that CXR age has similar potential to describe the heart and lung states. Therefore, we developed a DLM to predict sex and age through CXR and analyzed its relation with future cardiovascular diseases (CVD). Methods: A total of 90,396 CXRs aged 20 to 90 were collected and separated into a development set with 53,102 CXRs and demographic information pairs, a tuning set with 7073 pairs, an internal validation set with 17,364 pairs, and an external validation set with 12,857 pairs. The study trained DLM with development set for estimating age and sex and compared them to actual information. Results: The mean absolute errors of predicted age were 4.803 and 4.313 years in the internal and external validation sets, respectively. The area under the curve of sex analysis was 0.9993 and 0.9988 in the internal and external validation sets, respectively. Patients whose CXR age was 5 years older than chronologic age lead to higher risk of all-cause mortality (hazard ratio (HR): 2.42, 95% confidence interval (CI): 2.00-2.92), cardiovascular (CV)-cause mortality (HR: 7.57, 95% CI: 4.55-12.60), new-onset heart failure (HR: 2.07, 95% CI: 1.56-2.76), new-onset chronic kidney disease (HR: 1.73, 95% CI: 1.46-2.05), new-onset acute myocardial infarction (HR: 1.80, 95% CI: 1.12-2.92), new-onset stroke (HR: 1.45, 95% CI: 1.10-1.90), new-onset coronary artery disease (HR: 1.26, 95% CI: 1.04-1.52), and new-onset atrial fibrillation (HR: 1.43, 95% CI: 1.01-2.02). Conclusions: Using DLM to predict CXR age provided additional information for future CVDs. Older CXR age is an accessible risk classification tool for clinician use.

Application and Resistance Mechanisms of Lenvatinib in Patients with Advanced Hepatocellular Carcinoma.

Lenvatinib, a multitargeted tyrosine kinase inhibitor (TKI), is one of the preferred targeted drugs for the treatment of advanced hepatocellular carcinoma (aHCC). Since the REFLECT study showed that lenvatinib was noninferior to sorafenib in overall survival (OS), lenvatinib monotherapy has been widely used for aHCC. Moreover, lenvatinib combination therapy, especially lenvatinib combined with immune checkpoint inhibitors (ICIs), has shown more encouraging clinical results. However, drug development and comprehensive treatment have not significantly improved the prognosis, and lenvatinib resistance is often encountered in treatment. The underlying molecular mechanism of lenvatinib resistance is still unclear, and studies to solve drug resistance are ongoing. The molecular mechanisms of lenvatinib resistance in patients with aHCC include the regulation of signaling pathways, the regulation of noncoding RNAs, the impact of the immune microenvironment, tumor stem cell activation and other mechanisms. This review aims to (1) summarize the progress of lenvatinib in treating aHCC, (2) delineate the known lenvatinib resistance mechanisms of current therapy, and (3) describe the development of therapeutic methods intended to overcome these resistance mechanisms.

Fruit rot causing by Athelia rolfsii (Sclerotium rolfsii) on jackfruit (Artocarpus heterophyllus) in China.

Artocarpus heterophyllus, known as jackfruit, was a tropical fruit and cultivated extensively as nutritional and medicinal properties in southern China in recent year. During July 2022, fruit rot was observed on the fruits at the bottom of jackfruit trees in an orchard in Zhanjiang, Guangdong (N21°9' 27" E110°17' 54") 3-4 days after typhoon. The incidence rate of fruit was about 0.3%. The initial symptom was white mycelia appearing on the surface of fruits. Mycelia with rhizomorphs spread rapidly over the fruits, formed white, often fan-shaped mats with the rapeseed size sclerotia. The infected fruits were water-soaked, quickly became rotten, and fell off. Sclerotia from disease fruits were incubated on PDA with 50 mg/L ampicillin at 25-28℃ in the dark for 2 days. Hyphae tips were transferred to get the purified isolates. Colonies with a radial growth rate of 23.2 mm/day had abundant aerial mycelia and profuse sclerotia on PDA. Hyphae of the isolates were transparent, branched, with clamp connections at septa, usually 2.9-8.3 µm (Ave. 5.8 µm) (n>30) wide. Aerial mycelia were whitish-cottony, with many narrow rhizomorphs. Spherical sclerotia developed at about 10 days after incubation, and gradually changed from white to tan-to-dark brown, and mature sclerotia were about 1.7 mm in size. The morphological characteristics was similar to those of Sclerotium rolfsii (teleomorph: Athelia rolfsii). To accurately identify the fungus, the internal transcribed spacer gene (ITS) and large subunit rRNA gene (LSU) of isolate CASS-BLM-1 were PCR amplified with primer pairs ITS1/ITS4 (White et al 1990) and V9G/LR5 (Klaubauf et al 2014). The amplicons were sequenced and deposited in GenBank with accession number OP535473 (ITS) and OP535474 (LSU). BLASTn results showed that the nucleotide sequences of ITS and LSU had high identity with corresponding sequences of A. rolfsii isolates CBS 191.62 (ITS: MH858139, 472/474(99.58%); LSU: MH869724, 882/885(99.66%)) (Vu et al 2019). Phylogenetic analysis based on ITS sequence data was obtained according to maximum likelihood method using MEGA analysis software, CASS-BLM1 was grouped in A. rolfsii clade with 100% bootstrap support value. Based on morphology and DNA sequences, the fungus was identified as A. rolfsii (anamorph: S. rolfsii). To fulfil Koch's postulates, healthy fruits on the tree and detached fruits were inoculated with 7-day-old sclerotia of isolate CASS-BLM1. Five unwound sites and five wound sites with a sterile needle were tested on each fruit and a sclerotium was put at each site. Fruits not inoculated with sclerotia were used as control the test was repeated three times. All fruit were enclosed in transparent plastic bags with sterile absorbent cotton moistened with sterile distilled water. The indoor and outdoor temperatures ranged from 25 to 30 ℃. Three days later, white mycelia were observed on all inoculation sites, and 5 days later, the inoculated fruits began to rot, while control fruits remained healthy. The same fungus with identical morphology and DNA sequences was re-isolated from the inoculated sites. Previously, A. rolfsii was reported to cause fruit rot disease on jackfruit in Bangladesh (Elahi et al 2021), this is the first report of A. rolfsii causing fruit rot on jackfruit in China. A. rolfsii is suitable for high temperature and humidity environment (Punja 1985), this report will help farmers to diagnose this disease, especially to strengthen the disease prevention during the typhoon season.

Efficacy and safety of PEG-rhG-CSF versus rhG-CSF in preventing chemotherapy-induced-neutropenia in early-stage breast cancer patients.

BACKGROUND: To compare the clinical value of recombinant human granulocyte colony-stimulating factor (rhG-CSF) and pegylated rhG-CSF(PEG-rhG-CSF) in early-stage breast cancer (EBC) patients receiving adjuvant chemotherapy, compare the efficacy of PEG-rhG-CSF with different dose and explore the timing of rhG-CSF rescue treatment. METHODS: Patients in two PEG-rhG-CSF subgroups were given 3 mg or 6 mg PEG-rhG-CSF within 24 ~ 48 h after chemotherapy for preventing myelosuppression, while patients in the rhG-CSF group were given rhG-CSF. Observation indicators include the incidence of febrile neutropenia (FN) and grade 3/4 chemotherapy-induced-neutropenia (CIN), the overall levels and nadir values of white blood cells (WBC) and absolute neutrophil count (ANC), comparison of WBC and ANC curves over time, the incidence of CIN-related complications, the incidence of adverse events in each group and the timing of rescue treatment for rhG-CSF. RESULTS: There was no significant difference in the incidence of FN in the first cycle among the groups (P = 0.203). But the incidence of ≥ 3 grade CIN in two PEG-rhG-CSF subgroups was significantly lower than that in the rhG-CSF group (P < 0.001). The overall WBC and ANC levels in the PEG-rhG-CSF group were significantly higher than those in the rhG-CSF group (P < 0.001). In terms of CIN-related complications, less chemotherapy delay rate (1.1 vs. 7.5%, P = 0.092), less dose reduction rate (6.9 vs. 7.5%, P = 1.000), less antibiotic use rate (3.4 vs. 17.5%, P = 0.011) and less proportion of rhG-CSF rescue therapy (24.1 vs. 85.0%, P < 0.001) in the PEG-rhG-CSF group, and there were no significant differences between PEG-rhG-CSF subgroups. In the incidence of adverse events among the groups, there were no statistical differences. All patients undergoing rhG-CSF rescue treatment were mainly 4 grade (63.6%) and 3 grade (25.5%) CIN, and 10.9% of patients with 1 ~ 2 grade CIN who had high infection risk or had been infected. CONCLUSION: PEG-rhG-CSF has better efficacy and equal tolerance compared with rhG-CSF in preventing CIN in EBC patients receiving EC regimen. Moreover, a half-dose 3 mg PEG-rhG-CSF also had good efficacy. Last, patients with ≥ 3 grade CIN and others who have been assessed to be at high risk of infection or have co-infection should consider rhG-CSF or even antibiotic rescue treatment.

Treatment with FAP-targeted zinc ferrite nanoparticles for rheumatoid arthritis by inducing endoplasmic reticulum stress and mitochondrial damage.

Rheumatoid arthritis (RA) is a common chronic inflammatory disease characterized by the proliferation of fibroblast-like synoviocytes (FLS), pannus development, cartilage, and bone degradation, and, eventually, loss of joint function. Fibroblast activating protein (FAP) is a particular product of activated FLS and is highly prevalent in RA-derived fibroblast-like synoviocytes (RA-FLS). In this study, zinc ferrite nanoparticles (ZF-NPs) were engineered to target FAP+ (FAP positive) FLS. ZF-NPswere discovered to better target FAP+ FLS due to the surface alteration of FAP peptide and to enhance RA-FLS apoptosis by activating the endoplasmic reticulum stress (ERS) system via the PERK-ATF4-CHOP, IRE1-XBP1 pathway, and mitochondrial damage of RA-FLS. Treatment with ZF-NPs under the influence of an alternating magnetic field (AMF) can significantly amplify ERS and mitochondrial damage via the magnetocaloric effect. It was also observed in adjuvant-induced arthritis (AIA) mice that FAP-targeted ZF-NPs (FAP-ZF-NPs) could significantly suppress synovitis in vivo, inhibit synovial tissue angiogenesis, protect articular cartilage, and reduce M1 macrophage infiltration in synovium in AIA mice. Furthermore, treatment of AIA mice with FAP-ZF-NPs was found to be more promising in the presence of an AMF. These findings demonstrate the potential utility of FAP-ZF-NPs in the treatment of RA.