Application value of indocyanine green fluorescence imaging in guiding sentinel lymph node biopsy diagnosis of gastric cancer: Meta-analysis.

BACKGROUND: Gastric cancer is a common malignant tumor of the digestive system worldwide, and its early diagnosis is crucial to improve the survival rate of patients. Indocyanine green fluorescence imaging (ICG-FI), as a new imaging technology, has shown potential application prospects in oncology surgery. The meta-analysis to study the application value of ICG-FI in the diagnosis of gastric cancer sentinel lymph node biopsy is helpful to comprehensively evaluate the clinical effect of this technology and provide more reliable guidance for clinical practice. AIM: To assess the diagnostic efficacy of optical imaging in conjunction with indocyanine green (ICG)-guided sentinel lymph node (SLN) biopsy for gastric cancer. METHODS: Electronic databases such as PubMed, Embase, Medline, Web of Science, and the Cochrane Library were searched for prospective diagnostic tests of optical imaging combined with ICG-guided SLN biopsy. Stata 12.0 software was used for analysis by combining the "bivariable mixed effect model" with the "midas" command. The true positive value, false positive value, false negative value, true negative value, and other information from the included literature were extracted. A literature quality assessment map was drawn to describe the overall quality of the included literature. A forest plot was used for heterogeneity analysis, and P < 0.01 was considered to indicate statistical significance. A funnel plot was used to assess publication bias, and P < 0.1 was considered to indicate statistical significance. The summary receiver operating characteristic (SROC) curve was used to calculate the area under the curve (AUC) to determine the diagnostic accuracy. If there was interstudy heterogeneity (I 2 > 50%), meta-regression analysis and subgroup analysis were performed. RESULTS: Optical imaging involves two methods: Near-infrared (NIR) imaging and fluorescence imaging. A combination of optical imaging and ICG-guided SLN biopsy was useful for diagnosis. The positive likelihood ratio was 30.39 (95%CI: 0.92-1.00), the sensitivity was 0.95 (95%CI: 0.82-0.99), and the specificity was 1.00 (95%CI: 0.92-1.00). The negative likelihood ratio was 0.05 (95%CI: 0.01-0.20), the diagnostic odds ratio was 225.54 (95%CI: 88.81-572.77), and the SROC AUC was 1.00 (95%CI: The crucial values were sensitivity = 0.95 (95%CI: 0.82-0.99) and specificity = 1.00 (95%CI: 0.92-1.00). The Deeks method revealed that the "diagnostic odds ratio" funnel plot of SLN biopsy for gastric cancer was significantly asymmetrical (P = 0.01), suggesting significant publication bias. Further meta-subgroup analysis revealed that, compared with fluorescence imaging, NIR imaging had greater sensitivity (0.98 vs 0.73). Compared with optical imaging immediately after ICG injection, optical imaging after 20 minutes obtained greater sensitivity (0.98 vs 0.70). Compared with that of patients with an average SLN detection number < 4, the sensitivity of patients with a SLN detection number ≥ 4 was greater (0.96 vs 0.68). Compared with hematoxylin-eosin (HE) staining, immunohistochemical (+ HE) staining showed greater sensitivity (0.99 vs 0.84). Compared with subserous injection of ICG, submucosal injection achieved greater sensitivity (0.98 vs 0.40). Compared with 5 g/L ICG, 0.5 and 0.05 g/L ICG had greater sensitivity (0.98 vs 0.83), and cT1 stage had greater sensitivity (0.96 vs 0.72) than cT2 to cT3 clinical stage. Compared with that of patients ≤ 26, the sensitivity of patients > 26 was greater (0.96 vs 0.65). Compared with the literature published before 2010, the sensitivity of the literature published after 2010 was greater (0.97 vs 0.81), and the differences were statistically significant (all P < 0.05). CONCLUSION: For the diagnosis of stomach cancer, optical imaging in conjunction with ICG-guided SLN biopsy is a therapeutically viable approach, especially for early gastric cancer. The concentration of ICG used in the SLN biopsy of gastric cancer may be too high. Moreover, NIR imaging is better than fluorescence imaging and may obtain higher sensitivity.

Identifying Factors Affecting the Survival of Patients with HIV-Associated B-Cell Lymphoma Using a Random Survival Forest Model.

Background: There have been no reports about the application of random survival forest (RSF) model to predict disease progression of HIV-associated B-cell lymphoma. Methods: A total of 44 patients with HIV-associated B-cell lymphoma who were referred to Nanjing Second Hospital from 2012 to 2019 were included. The RSF model was used to find predictors of survival, and the results of the RSF model were compared with those of the Cox model. The data were analyzed using R software (version 4.1.1). Results: One-, 2-, and 3-year survival rates were 74.5%, 57.7%, and 48.6%, respectively, and the median survival was 59.0 months. The first 3 most important predictors of survival included lactate dehydrogenase (LDH), absolute monocyte count (AMC), and white blood cells (WBCs) count. The median survival of high-risk patients was only 4.0 months. Areas under the curve (AUCs) of the RSF model remained at more than 0.90 at 1, 2, and 3 years. The RSF model displayed a lower prediction error rate (21.9%) than the Cox model (25.4%). Conclusions: Lactate dehydrogenase, AMC, and WBCs count are the most important prognostic predictors for patients with HIV-associated B-cell lymphoma. Much larger prospective and/or multicentre studies are required to validtae this RSF model.

Identification of EGFR R776H germline mutations in a patient with multifocal lung adenocarcinoma: A case report and literature review.

The advancement of molecular pathology techniques has led to the discovery of rare EGFR mutations for targeted therapy in lung cancer. Additionally, a substantial body of evidence indicates a connection between the development of lung cancer and genetic variations in the EGFR gene. Here, we present a case report of a patient with multifocal lung adenocarcinoma who possessed a rare germline mutation, EGFR R776H. An investigation into the family history of the patient exposed the notable incidence of lung adenocarcinoma, indicating a plausible genetic vulnerability to the ailment. To be specific, the patient's older brother and sister both suffered from lung cancer, which underlines the hereditary predisposition. Furthermore, it should be noted that the patient's daughter has inherited the germline mutation and also presented with multiple lung ground-glass nodules, emphasizing the clinical importance of this genetic variation. Following the lobectomy, the patient received treatment with almonertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), and at the latest follow-up, the patient has achieved partial remission. This case highlights the significance of taking into account germline possibilities when multiple lesions carry the same mutation. It stresses the importance of acquiring a comprehensive family history and performing genetic testing on leukocytes. Moreover, for the infrequent EGFR R776H mutation, third generation EGFR-TKIs may be a viable option.

Small extracellular vesicles of organoid-derived human retinal stem cells remodel Müller cell fate via miRNA: A novel remedy for retinal degeneration.

Remodeling retinal Müller glial fate, including gliosis inhibition and pro-reprogramming, represents a crucial avenue for treating degenerative retinal diseases. Stem cell transplantation exerts effects on modulating retinal Müller glial fate. However, the optimized stem cell products and the underlying therapeutic mechanisms need to be investigated. In the present study, we found that retinal progenitor cells from human embryonic stem cell-derived retinal organoids (hERO-RPCs) transferred extracellular vesicles (EVs) into Müller cells following subretinal transplantation into RCS rats. Small EVs from hERO-RPCs (hERO-RPC-sEVs) were collected and were found to delay photoreceptor degeneration and protect retinal function in RCS rats. hERO-RPC-sEVs were taken up by Müller cells both in vivo and in vitro, and inhibited gliosis while promoting early dedifferentiation of Müller cells. We further explored the miRNA profiles of hERO-RPC-sEVs, which suggested a functional signature associated with neuroprotection and development, as well as the regulation of stem cell and glial fate. Mechanistically, hERO-RPC-sEVs might regulate the fate of Müller cells by miRNA-mediated nuclear factor I transcription factors B (NFIB) downregulation. Collectively, our findings offer novel mechanistic insights into stem cell therapy and promote the development of EV-centered therapeutic strategies.

Maternal cardiovascular health in early pregnancy and the risk of congenital heart defects in offspring.

BACKGROUND: Congenital heart disease (CHD) is the predominant birth defect. This study aimed to explore the association between maternal cardiovascular health (CVH) and the CHD risk in offspring. METHODS: We used the prospective data from the Fujian Birth Cohort Study, collected from March 2019 to December 2022 on pregnant women within 14 weeks of gestation. Overall maternal CVH was assessed by seven CVH metrics (including physical activity, smoking, sleep duration, body mass index, blood pressure, total cholesterol, and fasting plasma glucose), with each metric classified as ideal, intermediate or poor with specific points. Participants were further allocated into high, moderate and low CVH categories based on the cumulative CVH score. The association with offspring CHD was determined with log-binominal regression models. RESULTS: A total of 19810 participants aged 29.7 (SD: 3.9) years were included, with 7846 (39.6%) classified as having high CVH, 10949 (55.3%) as having moderate CVH, and 1015 (5.1%) as having low CVH. The average offspring CHD rate was 2.52%, with rates of 2.35%, 2.52% and 3.84% across the high, moderate and low CVH categories, respectively (P = 0.02). Adjusted relative risks (RRs) of having offspring CHD were 0.64 (95% CI: 0.45-0.90, P = 0.001) for high CVH and 0.67 (95% CI: 0.48-0.93, P = 0.02) for moderate CVH compared to low CVH. For individual metrics, only ideal total cholesterol was significantly associated with lower offspring CHD (RR: 0.73, 95% CI: 0.59-0.83, P = 0.002). CONCLUSIONS: Pregnant women of high or moderate CVH categories in early pregnancy had reduced risks of CHD in offspring, compared to those of low CVH. It is important to monitor and improve CVH during pre-pregnancy counseling and early prenatal care.

CXCR4 overexpression in chronic lymphocytic leukemia associates with poorer prognosis: A prospective, single-center, observational study.

Controversial data have been reported on the prognostic value of C-X-C motif chemokine receptor 4 (CXCR4) in chronic lymphocytic leukemia (CLL). This prospective, single-center, observational study aimed to evaluate the role of CXCR4 in the pathophysiology of CLL and its prognostic role. A total of 158 patients of CLL were enrolled, and CXCR4 expression on CLL cells was detected by flow cytometry (FCM) at initial diagnosis. The patients were divided into 2 groups according to the CXCR4 mean fluorescence intensity (MFI) median. Also, four patient specimens from the CXCR4low and CXCR4high groups were selected for RNASeq analysis. The progression-free survival (PFS) of CLL patients in the CXCR4high group was significantly shorter than the CXCR4low group, with a median follow-up time of 27 months (log-rank P < 0.001). Moreover, CXCR4 overexpression (MFI > 3376) was an independent marker of poor PFS in CLL patients (P < 0.001). Analysis of RNASeq results revealed that CXCR4 plays an important role in the migration of CLL. Collectively, CXCR4 expression levels on leukemia cells can be detected rapidly by FCM. CXCR4 overexpression was significantly associated with poorer prognosis in CLL patients within a shorter follow-up time.

Study on the ameliorative effect of honeysuckle on DSS-induced ulcerative colitis in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Honeysuckle, first documented in the Miscellaneous Records of Famous Physicians, is known for its ability to expel toxin and cool blood to stop diarrhea. Modern pharmacological research has shown that honeysuckle has anti-inflammatory, antibacterial, antioxidant, and immune-regulating effects and is widely used in clinical practice. However, the effect of honeysuckle on ulcerative colitis (UC) is still not fully understood, which presents challenges for quality control, research and development. AIM OF THE STUDY: This study aimed to determine the anti-inflammatory properties and mechanism of action of aqueous extracts of honeysuckle in the treatment of ulcerative colitis. MATERIALS AND METHODS: The dextran sodium sulfate (DSS) induced-ulcerative colitis mouse model was established, and the mice were divided into five groups: the control group, the model group, and the low, medium, and high dose honeysuckle treatment groups. RESULTS: All dose groups of honeysuckle were found to significantly reduce IL-6 and TNF-α levels and regulate DSS-induced mRNA levels of CLDN4, COX-2, IL-6, INOS, MUC-2, occludin and NLRP3. The high-dose group displayed the most effective inhibition, and a differentially expressed mRNA detection indicated abnormal mRNA expression. The 16sRNA sequencing revealed that the honeysuckle was able to significantly upregulate the abundance of beneficial bacteria and downregulate the abundance of harmful bacteria. The study of short-chain fatty acids revealed that the levels of acetic, propionic, isobutyric, valeric and isovaleric acids were significantly increased after administering honeysuckle at medium and high doses. CONCLUSION: Honeysuckle reduces the production of pro-inflammatory cytokines, increases the content of short-chain fatty acids and restores the intestinal ecological balance, resulting in better therapeutic effects.

CXC chemokines: Potential biomarker and immunotherapeutic target for uterine corpus endometrial carcinoma.

Uterine corpus endometrial carcinoma (UCEC) is one of the most common type of gynecological malignancies. Multiple lines of evidence indicated that CXC chemokines exerted an anti-tumor immunological role in the tumor microenvironment which were critical regulators of cancer immunity. However, the relevance of CXC chemokines in the evaluation of prognosis and immune infiltration of UCEC remains to be explored. This study utilized various online databases, including TCGA, UALCAN, Kaplan-Meier Plotter, cBioPortal, TIMER2.0, TISIDB, and MethSurv to perform the analysis. Gene expression data from the TCGA-UCEC dataset indicated decreased expression of CXCL2/12 and increased expression of CXCL14/17. CXCL2/12 expression was negatively whereas CXCL14/17 expression was positively correlated with clinicopathological features of UCEC patients, including cancer stage, patients' age, weight and menopause status. Patients with higher CXCL12/14 expression corresponded with better clinical outcomes, which were not influenced by the genetic alterations. The differential expression of CXCL2/12/14/17 was not only significantly correlated with immune infiltration levels, but also the abundance of immune checkpoint inhibitors. Heatmaps of DNA methylation of CXCL2/12/14/17 were investigated, and 4 CpGs of CXCL2, 16 CpGs of CXCL12, 3 CpGs of CXCL14/17 were identified where altered methylation affected the prognosis of UCEC patients. These findings provided novel insights into the immunologic features of UCEC and might pave the way toward the prognostic evaluation and immunotherapy selection based on CXCL2/12/14/17 expression status.

A sialyltransferases-related gene signature serves as a potential predictor of prognosis and therapeutic response for bladder cancer.

BACKGROUND: Aberrant glycosylation, catalyzed by the specific glycosyltransferase, is one of the dominant features of cancers. Among the glycosyltransferase subfamilies, sialyltransferases (SiaTs) are an essential part which has close linkages with tumor-associated events, such as tumor growth, metastasis and angiogenesis. Considering the relationship between SiaTs and cancer, the current study attempted to establish an effective prognostic model with SiaTs-related genes (SRGs) to predict patients' outcome and therapeutic responsiveness of bladder cancer. METHODS: RNA-seq data, clinical information and genomic mutation data were downloaded (TCGA-BLCA and GSE13507 datasets). The comprehensive landscape of the 20 SiaTs was analyzed, and the differentially expressed SiaTs-related genes were screened with "DESeq2" R package. ConsensusClusterPlus was applied for clustering, following with survival analysis with Kaplan-Meier curve. The overall survival related SRGs were determined with univariate Cox proportional hazards regression analysis, and the least absolute shrinkage and selection operator (LASSO) regression analysis was performed to generate a SRGs-related prognostic model. The predictive value was estimated with Kaplan-Meier plot and the receiver operating characteristic (ROC) curve, which was further validated with the constructed nomogram and decision curve. RESULTS: In bladder cancer tissues, 17 out of the 20 SiaTs were differentially expressed with CNV changes and somatic mutations. Two SiaTs_Clusters were determined based on the expression of the 20 SiaTs, and two gene_Clusters were identified based on the expression of differentially expressed genes between SiaTs_Clusters. The SRGs-related prognostic model was generated with 7 key genes (CD109, TEAD4, FN1, TM4SF1, CDCA7L, ATOH8 and GZMA), and the accuracy for outcome prediction was validated with ROC curve and a constructed nomogram. The SRGs-related prognostic signature could separate patients into high- and low-risk group, where the high-risk group showed poorer outcome, more abundant immune infiltration, and higher expression of immune checkpoint genes. In addition, the risk score derived from the SRGs-related prognostic model could be utilized as a predictor to evaluate the responsiveness of patients to the medical therapies. CONCLUSIONS: The SRGs-related prognostic signature could potentially aid in the prediction of the survival outcome and therapy response for patients with bladder cancer, contributing to the development of personalized treatment and appropriate medical decisions.

Anti-Glioma Effects of Ligustilide or n-Butylphthalide on Their Own and the Synergistic Effects with Temozolomide via PI3K/Akt Signaling Pathway.

Background: Ligustilide (LIG) and n-butylphthalide (NBP) have neuroprotective effects in cerebral ischemia; however, their roles in gliomas are not well-known.This study aimed to explore the anti-glioma effects of LIG and NBP individually and the synergistic effects of temozolomide (TMZ) via the PI3K/Akt Signaling Pathway. Materials and Methods: Cytotoxicity of LIG and NBP alone and in combination with TMZ in U251 cells was determined using the CCk-8. The effect of compounds alone or in combination on cell migration was detected using the wound healing assay, and the invasion was evaluated by transwell assays, respectively. Cell apoptosis was quantified by flow cytometry and the changed expressions of proteins were detected by Western blotting. Results: The results showed that LIG and NBP significantly inhibited the growth of U251 cells at concentrations of 4-10 µg/mL and 1.5-6 µg/mL in a dose-dependent manner (p<0.05, p<0.01). The combination of 20 µg/mL TMZ with LIG in the concentration range of 4-10 µg/mL or with NBP of 0.5-6 µg/mlachieved synergistic effect towardsU251 cells. LIG and NBP, alone or in combination with TMZ, markedly inhibited cell invasion (p< 0.001) and enhanced apoptosis (p< 0.05). The combination of TMZ with LIG or NBP markedly inhibited cell migration (p< 0.001). Western blot analysis showed that LIG, NBP, and TMZ, alone and in combination, significantly decreased the expression of Bcl-2, p-PI3K, and p-Akt, and increased the expression of Bax. Conclusion: Both LIG and NBP exert anti-glioma effects on their own through the PI3K/Akt pathway and enhance TMZ-mediated anti-glioma efficiency via the same pathway.

Interactions of Essential Oil Components to Their Payloads in Supramolecular Particulate Carriers of Cyclodextrin Metal-Organic Frameworks.

Essential oil (EO) is widely used in the pharmaceutical, cosmetic, agriculture, and food industries because of its aromatic, antioxidant, and antibacterial properties. However, the weak interactions caused by small contact area with various substrates pose significant challenges to experimental detection and molecular simulation. In this study, the main components and contents of compound essential oil (CEO) were determined by gas chromatography-mass spectrometry (GC-MS) and gas chromatography (GC), respectively. As a result, 11 components were screened out from CEO and their contents were measured. And synthetic essential oil (SEO) was deployed as a simplified CEO model for subsequent research according to the above result. In addition, a porous cyclodextrin metal-organic framework (CD-MOF) was used to load SEO, and the detailed process of experimental determination and molecular simulation prediction of the content of volatile oil components in CD-MOF was shown. The results of experiments and molecular simulations have consistently proved that CD-MOF had a selective absorption effect on SEO components. Furthermore, the interaction mechanism and release characteristics of these components in CD-MOF were investigated. The results of the release kinetics analysis provided references for the identification of the diffusion type of each component. In conclusion, the strategies established in this article provide ideas for the experimental detection and molecular simulation of multi-component competitive existence in carriers under weak interactions.

Impact of total intravenous anesthesia and total inhalation anesthesia as the anesthesia maintenance approaches on blood glucose level and postoperative complications in patients with type 2 diabetes mellitus: a double-blind, randomized controlled trial.

BACKGROUND: Diabetes mellitus is a prevalent metabolic disease in the world. Previous studies have shown that anesthetics can affect perioperative blood glucose levels which related to adverse clinical outcomes. Few studies have explored the choice of general anesthetic protocol on perioperative glucose metabolism in diabetes patients. We aimed to compare total intravenous anesthesia (TIVA) with total inhalation anesthesia (TIHA) on blood glucose level and complications in type 2 diabetic patients undergoing general surgery. METHODS: In this double-blind controlled trial, 116 type 2 diabetic patients scheduled for general surgery were randomly assigned to either the TIVA group or TIHA group (n = 56 and n = 60, respectively). The blood glucose level at different time points were measured and analyzed by the repeated-measures analysis of variance. The serum insulin and cortisol levels were measured and analyzed with t-test. The incidence of complications was followed up and analyzed with chi-square test or Fisher's exact test as appropriate. The risk factors for complications were analyzed using the logistic stepwise regression. RESULTS: The blood glucose levels were higher in TIHA group than that in TIVA group at the time points of extubation, 1 and 2 h after the operation, 1 and 2 days after the operation, and were significantly higher at 1 day after the operation (10.4 ± 2.8 vs. 8.1 ± 2.1 mmol/L; P < 0.01). The postoperative insulin level was higher in TIVA group than that in TIHA group (8.9 ± 2.9 vs. 7.6 ± 2.4 IU/mL; P = 0.011). The postoperative cortisol level was higher in TIHA group than that in TIVA group (15.3 ± 4.8 vs. 12.2 ± 8.9 ug/dL ; P = 0.031). No significant difference regarding the incidence of complications between the two groups was found based on the current samples. Blood glucose level on postoperative day 1 was a risk factor for postoperative complications (OR: 1.779, 95%CI: 1.009 ~ 3.138). CONCLUSIONS: TIVA has less impact on perioperative blood glucose level and a better inhibition of cortisol release in type 2 diabetic patients compared to TIHA. A future large trial may be conducted to find the difference of complications between the two groups. TRIAL REGISTRATION: The protocol registered on the Chinese Clinical Trials Registry on 20/01/2020 (ChiCTR2000029247).

Effects of TCPP and TCEP exposure on human corneal epithelial cells: Oxidative damage, cell cycle arrest, and pyroptosis.

Tris(2-chloroisopropyl) phosphate (TCPP) and Tris(2-chloroethyl) phosphate (TCEP) are the widely used organophosphorus flame retardants indoors and easily accessible to the eyes as the common adhesive components of dust and particle matter, however, hardly any evidence has demonstrated their corneal toxicity. In this study, the adverse effects of TCPP, TCEP, and TCPP + TCEP exposure on human corneal epithelial cells (HCECs) were investigated. The cell viability and morphology, intracellular reactive oxygen species (ROS), cell cycle, and the expressions of cell cycle and pyroptosis-related genes were assessed to explain the underlying mechanisms. Compared to individual exposure, co-exposure to TCPP20+TCEP20 showed higher cytotoxicity with a sharp decrease of >30% in viability and more serious oxidative damage by increasing ROS production to 110.92% compared to the control group. Furthermore, the cell cycle arrested at the S phase (36.20%) was observed after combined treatment, evidenced by the upregulation of cyclin D1, CDK2, CDK4, CDK6, p21, and p27. Interestingly, pyroptosis-related genes GSDMD, Caspase-1, NLRP3, IL-1ß, IL-18, NLRP1, and NLRC4 expressions were promoted with cell swelling and glowing morphology. Oxidative stress and cell cycle arrest probably acted as a key role in TCPP20+TCEP20-induced cytotoxicity and pyroptosis in HCECs. Our results suggested that TCPP20+TCEP20 co-exposure induced severer corneal damage, further illustrating its significance in estimating indoor health hazards to humans.

A convolutional neural network-based, quantitative complete blood count scattergram-mapping framework promptly screens acute promyelocytic leukemia with high sensitivity.

BACKGROUND: Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML) characterized by its rapidly progressive and fatal clinical course if untreated, although it is curable if treated in a timely manner. Promptly screening patients who have results that are suspicious for APL is vital to overcome early death. METHODS: The authors developed an innovative framework consisting of ResNet-18, a convolutional neural network architecture, with the objective of quantitatively mapping a complete blood count (CBC) scattergram to quickly and robustly indicate a probable susceptibility to APL. Three hundred and twenty scattergrams of the white blood cell differential channel from 51 patients with APL, 510 scattergrams from 105 patients who had non-APL AML, and 320 scattergrams from 320 healthy controls were randomly stratified at a ratio of 4:1 and split into training and testing data sets to accomplish five-fold cross-validation. RESULTS: Both the area under the curve and the average precision of >0.99 were achieved in each fold. Three hundred four of the 320 APL scattergrams (95%) were correctly flagged by the model, which outcompeted the CBC review rules recommended by the International Society of Laboratory Hematology (all p < .001). External validation based on an independent testing data set that included 56 scattergrams from 31 patients with APL, 56 scattergrams from 55 patients with non-APL AML, and 64 scattergrams from 64 healthy controls also confirmed the sensitivity and specificity of the framework. CONCLUSIONS: To the authors' knowledge, their convolutional neural network-based framework is the first to use scattergram output from routine CBC analysis to map suspicious APL early with outstanding sensitivity, specificity, and precision. The authors also describe a new CBC workflow incorporating this framework upstream of the morphologic review, which would provide the earliest flag for APL. PLAIN LANGUAGE SUMMARY: The authors propose an innovative way to visualize complete blood counts (CBCs) by mapping the difference in white blood cell counts using automated CBC analysis to identify potential acute promyelocytic leukemia (APL) using a convolutional neural network (CNN), which can eliminate the potential pitfalls of manual observation. Analyses of an unprecedented, realistic data set validated that the quantitative relationship between the CBC scattergram and an APL abnormality is highly consistent. This is the first study to date focusing on screening for APL using scattergrams of the difference in white blood cell counts from routine CBC tests and has significant clinical relevance. The authors recommend using this method even before analyzing cell images, which could provide the earliest way to screen for APL in a sensitive and accurate way.

[Mechanism of Sijunzi Decoction in treatment of Alzheimer's disease based on UPLC-Q-TOF-MS, network pharmacology, and experimental verification].

The study identified the blood-entering components of Sijunzi Decoction after gavage administration in rats by UPLC-Q-TOF-MS/MS, and investigated the mechanism of Sijunzi Decoction in treating Alzheimer's disease by virtue of network pharmacology, molecular docking, and experimental verification. The blood-entering components of Sijunzi Decoction were identified based on the mass spectra and data from literature and databases. The potential targets of the above-mentioned blood-entering components in the treatment of Alzheimer's disease were searched against PharmMapper, OMIM, DisGeNET, GeneCards, and TTD. Next, STRING was employed to establish a protein-protein interaction(PPI) network. DAVID was used to perform the Gene Ontology(GO) annotation and the Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment. Cytoscape 3.9.0 was used to carry out visual analysis. AutoDock Vina and PyMOL were used for molecular docking of the blood-entering components with the potential targets. Finally, the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt) signaling pathway enriched by the KEGG analysis was selected for validation by animal experiments. The results showed that 17 blood-entering components were detected in the serum samples after administration. Among them, poricoic acid B, liquiritigenin, atractylenolide Ⅱ, atractylenolide Ⅲ, ginsenoside Rb_1, and glycyrrhizic acid were the key components of Sijunzi Decoction in treating Alzheimer's disease. HSP90AA1, PPARA, SRC, AR, and ESR1 were the main targets for Sijunzi Decoction to treat Alzheimer's disease. Molecular docking showed that the components bound well with the targets. Therefore, we hypothesized that the mechanism of Sijunzi Decoction in treating Alzheimer's disease may be associated with the PI3K/Akt, cancer treatment, and mitogen-activated protein kinase(MAPK) signaling pathways. The results of animal experiments showed that Sijunzi Decoction significantly attenuated the neuronal damage in the hippocampal dentate gyrus area, increased the neurons, and raised the ratios of p-Akt/Akt and p-PI3K/PI3K in the hippocampus of mice. In conclusion, Sijunzi Decoction may treat Alzheimer's disease by activating the PI3K/Akt signaling pathway. The findings of this study provide a reference for further studies about the mechanism of action and clinical application of Sijunzi Decoction.

Organoid-derived human retinal progenitor cells promote early dedifferentiation of Müller glia in Royal College of Surgeons rats.

AIM: To explore whether the subretinal transplantation of retinal progenitor cells from human embryonic stem cell-derived retinal organoid (hERO-RPCs) could promote Müller glia dedifferentiation and transdifferentiation, thus improving visual function and delaying retinal degenerative progression. METHODS: hERO-RPCs were subretinally transplanted into Royal College of Surgeons (RCS) rats. Electroretinography (ERG) recording was performed at 4 and 8wk postoperation to assess retinal function. Using immunofluorescence, the changes in outer nuclear layer (ONL) thickness and retinal Müller glia were explored at 2, 4, and 8wk postoperation. To verify the effect of hERO-RPCs on Müller glia in vitro, we cocultured hERO-RPCs with Müller glia with a Transwell system. After coculture, Ki67 staining and quantitative polymerase chain reaction (qPCR) were performed to measure the proliferation and mRNA levels of Müller glia respectively. Cell migration experiment was used to detect the effect of hERO-RPCs on Müller glial migration. Comparisons between two groups were performed by the unpaired Student's t-test, and comparisons among multiple groups were made with one-way ANOVA followed by Tukey's multiple comparison test. RESULTS: The visual function and ONL thickness of RCS rats were significantly improved by transplantation of hERO-RPCs at 4 and 8wk postoperation. In addition to inhibiting gliosis at 4 and 8wk postoperation, hERO-RPCs significantly increased the expression of dedifferentiation-associated transcriptional factor in Müller glia and promoted the migration at 2, 4 and 8wk postoperation, but not the transdifferentiation of these cells in RCS rats. In vitro, using the Transwell system, we found that hERO-RPCs promoted the proliferation and migration of primary rat Müller glia and induced their dedifferentiation at the mRNA level. CONCLUSION: These results show that hERO-RPCs might promote early dedifferentiation of Müller glia, which may provide novel insights into the mechanisms of stem cell therapy and Müller glial reprogramming, contributing to the development of novel therapies for retinal degeneration disorders.

κ-Opioid Receptors Improve Vascular Endothelial Dysfunction in Salt-Sensitive Hypertension via PI3K/Akt/eNOS Signaling Pathway.

κ-Opioid receptors (κ-OR) are widely used to regulate the activity of the cardiovascular system. To explore the effect and mechanism of κ-OR on salt-sensitive hypertensive endothelial dysfunction, we used Dah1 rats to construct a rat model of salt-sensitive hypertension on a high-salt (HS) diet. Then, the rats were treated with κ-OR activators U50,488H (1.25 mg/kg) and inhibitor nor-BNI (2.0 mg/kg) for 4 weeks, respectively. The rat aortas were collected to detect the contents of NO, ET-1, AngII, NOS, T-AOC, SO, and NT. Protein expression was determined for NOS, Akt, and Caveolin-1. In addition, the vascular endothelial cells were extracted, and the levels of NO, TNF-α, IL-1, IL-6, IL-8, IL-10, p-Akt, and p-eNOS in cell supernatants were detected. In vivo results showed that compared with the HS group, treated with U50,488H promoted rats' vasodilation by increasing the NO content and decreasing ET-1 and AngII contents. U50,488H reduced endothelial cell apoptosis and attenuated vascular, smooth muscle cell and endothelial cell injury. U50,488H also enhanced the rats' response to oxidative stress by increasing the NOS and T-AOC contents. Moreover, U50,488H increased the eNOS, p-eNOS, Akt, and p-AKT expression and decreased the iNOS and Caveolin-1 expression. In vitro results showed that U50,488H promoted NO, IL-10, p-Akt, and p-eNOS levels in endothelial cell supernatants versus the HS group. And U50,488H reduced the adhesion of peripheral blood mononuclear cells and polymorphonuclear neutrophils to endothelial cells and the migration function of polymorphonuclear neutrophils. Our study suggested that κ-OR activation may improve vascular endothelial dysfunction in salt-sensitive hypertensive rats through the PI3K/Akt/eNOS signaling pathway. This may be a potential therapeutic approach in the treatment of hypertension.

Prognostic value of cross-lineage expression of the myeloid-associated antigens CD13 and CD33 in adult B-lymphoblastic leukemia: A large real-world study of 1005 patients.

BACKGROUND: Cross-lineage expression of the myeloid-associated antigens CD13/CD33 is common in adult B-lymphoblastic leukemia (B-ALL) patients, yet its prognostic value is still controversial. METHODS: We conducted a retrospective study of 1005 de novo adult B-ALL patients from January 2009 to December 2019 in our hospital. Logistic and Cox regression were used to analyze the prognostic value of CD13/CD33 expression in B-ALL. A Cox regression model was established to predict overall survival (OS) for B-ALL patients. RESULTS: Of the 1005 B-ALL patients, 53.7% (n = 540) aberrantly expressed CD13/CD33 (CD13/CD33+ ). Patients in the CD13/CD33+ group showed a higher incidence of BCR::ABL1 rearrangement and minimal/measurable residual disease (MRD) positivity but similar complete remission rate, relapse-free survival, mortality, and OS with CD13/CD33- . CD13/CD33+ patients had a higher risk of MRD positivity than CD13/CD33- patients. Notably, CD13/CD33+ patients who underwent tyrosine kinase inhibitor (TKI) therapy had a better long-term prognosis than those without TKI experience. Sex, group based on CD13/CD33 expression and TKI experience and white blood cell count were variables independently associated with OS. The Cox regression model integrating these three variables showed a moderate performance for OS prediction (C-index: 0.724). CONCLUSIONS: In real-world practice, CD13/CD33 expression can predict the risk of MRD in patients without TKI experience, but has no adverse effect on the prognosis of adult B-ALL patients. Incorporating CD13/CD33 into the standard antibody panels of B-ALL diagnosis and MRD measurements can help predict relapse risk and decisions on therapy options.

Sponge-liked Silica Nanoporous Particles for Sustaining Release and Long-Term Antibacterial Activity of Natural Essential Oil.

To improve the sustained release and long-term antibacterial activity of Chimonanthus nitens Oliv. essential oil (CEO), novel sponge-liked nanoporous silica particles (SNP) were synthesized via the soft template method, which was employed as a biocompatible carrier to prepare spong-liked nanoporous silica particles loading with CEO (CEO-SNP) through physical adsorption. The structure and properties of the samples were characterized via N2 adsorption/desorption measurements, thermogravimetry (TGA), Fourier transform infrared, SEM and TEM. The result showed that the SNP exhibited an excellent loading capability of CEO up to 76.3%. The thermal stability and release behavior of the CEO were significantly improved via the physical adsorption of the SNP materials. The release profile of CEO was in accordance with the first-order kinetic model, which meant that the release mechanism was drug Fick's diffusion. The antibacterial evaluation results demonstrated that the CEO-SNP exhibited strong antibacterial activity against S. aureus, E. coli and P. aeruginosa. The antibacterial results have shown that the CEO-SNP could destroy the cell structure of bacteria, and result in the generation of oxidative stress and the release of nucleic acid. After storage of 30 d at 25 °C, the CEO-SNP still had the stronger antibacterial activity towards S. aureus, E. coli and P. aeruginosa in comparison with CEO. Therefore, the sponge-like silica nanoporous particles seemed to be a promising carrier for long-term stability and antibacterial delivery of CEO.