Glutamine metabolic competition drives immunosuppressive reprogramming of intratumour GPR109A+ myeloid cells to promote liver cancer progression.

OBJECTIVE: The metabolic characteristics of liver cancer drive considerable hurdles to immune cells function and cancer immunotherapy. However, how metabolic reprograming in the tumour microenvironment impairs the antitumour immune response remains unclear. DESIGN: Human samples and multiple murine models were employed to evaluate the correlation between GPR109A and liver cancer progression. GPR109A knockout mice, immune cells depletion and primary cell coculture models were used to determine the regulation of GPR109A on tumour microenvironment and identify the underlying mechanism responsible for the formation of intratumour GPR109A+myeloid cells. RESULTS: We demonstrate that glutamine shortage in liver cancer tumour microenvironment drives an immunosuppressive GPR109A+myeloid cells infiltration, leading to the evasion of immune surveillance. Blockade of GPR109A decreases G-MDSCs and M2-like TAMs abundance to trigger the antitumour responses of CD8+ T cells and further improves the immunotherapy efficacy against liver cancer. Mechanistically, tumour cells and tumour-infiltrated myeloid cells compete for glutamine uptake via the transporter SLC1A5 to control antitumour immunity, which disrupts the endoplasmic reticulum (ER) homoeostasis and induces unfolded protein response of myeloid cells to promote GPR109A expression through IRE1α/XBP1 pathway. The restriction of glutamine uptake in liver cancer cells, as well as the blockade of IRE1α/XBP1 signalling or glutamine supplementation, can eliminate the immunosuppressive effects of GPR109A+ myeloid cells and slow down tumour progression. CONCLUSION: Our findings identify the immunometabolic crosstalk between liver cancer cells and myeloid cells facilitates tumour progression via a glutamine metabolism/ER stress/GPR109A axis, suggesting that GPR109A can be exploited as an immunometabolic checkpoint and putative target for cancer treatment.

Novel quantitative immunohistochemistry method using histone H3, family 3B as the internal reference standard for measuring human epidermal growth factor receptor 2 expression in breast cancer.

BACKGROUND: Immunohistochemistry (IHC) is an essential technique in surgical and clinical pathology for detecting diagnostic, prognostic, and predictive biomarkers for personalized cancer therapy. However, the lack of standardization and reference controls results in poor reproducibility, and a reliable tool for IHC quantification is urgently required. The objective of this study was to describe a novel approach in which H3F3B (histone H3, family 3B) can be used as an internal reference standard to quantify protein expression levels using IHC. METHODS: The authors enrolled 89 patients who had human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC). They used a novel IHC-based assay to measure protein expression using H3F3B as the internal reference standard. H3F3B was uniformly expressed at the protein level in all tumor regions in cancer tissues. HER2 expression levels were measured with the H-score using HALO software. RESULTS: Kaplan-Meier analysis indicated that, among patients who had HER2-positive BC in The Cancer Genome Atlas data set and the authors' data set, the subgroup with low HER2 expression had a significantly better prognosis than the subgroup with high HER2 expression. Furthermore, the authors observed that HER2 expression levels were precisely evaluated using the proposed method, which can classify patients who are at higher risk of HER2-positive BC to receive trastuzumab-based adjuvant therapy. Dual-color IHC with H3F3B is an excellent tool for internal and external quality control of HER2 expression assays. CONCLUSIONS: The proposed IHC-based quantification method accurately assesses HER2 expression levels and provides insights for predicting clinical prognosis in patients with HER2-positive BC who receive trastuzumab-based adjuvant therapy.

Clonal expansion of shared T cell receptors reveals the existence of immune commonality among different lesions of synchronous multiple primary lung cancer.

The increase in the detection rate of synchronous multiple primary lung cancer (MPLC) has posed remarkable clinical challenges due to the limited understanding of its pathogenesis and molecular features. Here, comprehensive comparisons of genomic and immunologic features between MPLC and solitary lung cancer nodule (SN), as well as different lesions of the same patient, were performed. Compared with SN, MPLC displayed a lower rate of EGFR mutation but higher rates of BRAF, MAP2K1, and MTOR mutation, which function exactly in the upstream and downstream of the same signaling pathway. Considerable heterogeneity in T cell receptor (TCR) repertoire exists among not only different patients but also among different lesions of the same patient. Invasive lesions of MPLC exhibited significantly higher TCR diversity and lower TCR expansion than those of SN. Intriguingly, different lesions of the same patient always shared a certain proportion of TCR clonotypes. Significant clonal expansion could be observed in shared TCR clonotypes, particularly in those existing in all lesions of the same patient. In conclusion, this study provided evidences of the distinctive mutational landscape, activation of oncogenic signaling pathways, and TCR repertoire in MPLC as compared with SN. The significant clonal expansion of shared TCR clonotypes demonstrated the existence of immune commonality among different lesions of the same patient and shed new light on the individually tailored precision therapy for MPLC.

Rod-Shaped Liquid Plasticine as Cuttable Minireactor for Photodynamic Therapy of Tumors.

Photodynamic therapy (PDT) has emerged as a promising non-invasive approach for cancer treatment. Enhancing its efficacy and understanding its absorption-induced attenuation are significant while the solutions are limited, particularly for the latter. In this study, a rod-shaped liquid plasticine (LP), comprised of a tumor cell solution encased by a nanoparticle monolayer, is used to serve as a powerful minireactor for addressing these issues. The channel structure, openness, and cuttability of the LP reactor are exploited for providing benefits to PDT. The resulting PDT efficacy is several times higher than those from droplet reactors with common spherical shapes. The attenuation law, which is fundamental in PDT yet poorly understood due to the lack of experimental approaches, is preliminarily uncovered here from the perspective of in vitro experiments by using the LP's cuttability, affording quantitative understanding on this difficult subject. These findings provide insights into the widely-concerned topics in PDT, and highlight the great potential of an LP reactor in offering innovation power for the biochemical and biomedical arenas.

MRI-Based Breast Cancer Classification and Localization by Multiparametric Feature Extraction and Combination Using Deep Learning.

BACKGROUND: Deep learning (DL) have been reported feasible in breast MRI. However, the effectiveness of DL method in mpMRI combinations for breast cancer detection has not been well investigated. PURPOSE: To implement a DL method for breast cancer classification and detection using feature extraction and combination from multiple sequences. STUDY TYPE: Retrospective. POPULATION: A total of 569 local cases as internal cohort (50.2 ± 11.2 years; 100% female), divided among training (218), validation (73) and testing (278); 125 cases from a public dataset as the external cohort (53.6 ± 11.5 years; 100% female). FIELD STRENGTH/SEQUENCE: T1-weighted imaging and dynamic contrast-enhanced MRI (DCE-MRI) with gradient echo sequences, T2-weighted imaging (T2WI) with spin-echo sequences, diffusion-weighted imaging with single-shot echo-planar sequence and at 1.5-T. ASSESSMENT: A convolutional neural network and long short-term memory cascaded network was implemented for lesion classification with histopathology as the ground truth for malignant and benign categories and contralateral breasts as healthy category in internal/external cohorts. BI-RADS categories were assessed by three independent radiologists as comparison, and class activation map was employed for lesion localization in internal cohort. The classification and localization performances were assessed with DCE-MRI and non-DCE sequences, respectively. STATISTICAL TESTS: Sensitivity, specificity, area under the curve (AUC), DeLong test, and Cohen's kappa for lesion classification. Sensitivity and mean squared error for localization. A P-value <0.05 was considered statistically significant. RESULTS: With the optimized mpMRI combinations, the lesion classification achieved an AUC = 0.98/0.91, sensitivity = 0.96/0.83 in the internal/external cohorts, respectively. Without DCE-MRI, the DL-based method was superior to radiologists' readings (AUC 0.96 vs. 0.90). The lesion localization achieved sensitivities of 0.97/0.93 with DCE-MRI/T2WI alone, respectively. DATA CONCLUSION: The DL method achieved high accuracy for lesion detection in the internal/external cohorts. The classification performance with a contrast agent-free combination is comparable to DCE-MRI alone and the radiologists' reading in AUC and sensitivity. EVIDENCE LEVEL: 3. TECHNICAL EFFICACY: Stage 2.

Prevalence and progression of pneumonia in immunocompetent adults with varicella.

Pneumonia is the most common complication of varicella infections. Although previous studies have tended to focus mainly on immunocompromised patients, varicella pneumonia can also occur in healthy adults. Therefore, in this study, we aimed to assess the progression of varicella pneumonia in immunocompetent hosts. This retrospective study involved immunocompetent adult outpatients with varicella who attended the adult Fever Emergency facility of Peking University Third Hospital from April 1, 2020, to October 31, 2022. Varicella pneumonia was defined as a classic chickenpox-type rash in patients with infiltrates on chest computed tomography. The study included 186 patients, 57 of whom had a contact history of chickenpox exposure. Antiviral pneumonia therapy was administered to 175 patients by treating physicians. Computed tomography identified pneumonia in 132 patients, although no deaths from respiratory failure occurred. Seventy of the discharged patients were subsequently contacted, all of whom reported being well. Follow-up information, including computed tomography findings, was available for 37 patients with pneumonia, among whom 24 reported complete resolution whereas the remaining 13 developed persistent calcifications. Notably, we established that the true incidence of varicella pneumonia is higher than that previously reported, although the prognosis for immunocompetent hosts is generally good.

Safety and efficacy of CT-guided percutaneous microwave ablation for stage I non-small cell lung cancer in patients with comorbid idiopathic pulmonary fibrosis.

OBJECTIVES: To evaluate the safety and efficacy of microwave ablation (MWA) for stage I non-small cell lung cancer (NSCLC) in patients with idiopathic pulmonary fibrosis (IPF). MATERIALS AND METHODS: A retrospective single-center cohort study was conducted in patients with clinical stage I NSCLC who underwent CT-guided MWA from Nov 2016 to Oct 2021. The patients were divided into the IPF group and the non-IPF group. The primary endpoints were 90-day adverse events and hospital length of stay (HLOS). The secondary endpoints included overall survival (OS) and progression-free survival (PFS). RESULTS: A total of 107 patients (27 with IPF and 80 without IPF) were finally included for analysis. No procedure-related acute exacerbation of IPF or death occurred post-MWA. The rates of adverse events were similar between the groups (48.6% vs. 47.7%; p = 0.998). The incidence of grade 3 adverse events in the IPF group was higher than that in the non-IPF group without a significant difference (13.5% vs. 4.6%; p = 0.123). Median HLOS was 5 days in both groups without a significant difference (p = 0.078). The 1-year and 3-year OS were 85.2%/51.6% in the IPF group, and 97.5%/86.4% in the non-IPF group. The survival of patients with IPF was significantly poorer than the survival of patients without IPF (p < 0.001). There was no significant difference for PFS (p = 0.271). CONCLUSION: MWA was feasible in the treatment of stage I NSCLC in patients with IPF. IPF had an adverse effect on the survival of stage I NSCLC treated with MWA. CLINICAL RELEVANCE STATEMENT: CT-guided microwave ablation is a well-tolerated and effective potential alternative treatment for stage I non-small cell lung cancer in patients with idiopathic pulmonary fibrosis. KEY POINTS: • Microwave ablation for stage I non-small cell lung cancer was well-tolerated without procedure-related acute exacerbation of idiopathic pulmonary fibrosis and death in patients with idiopathic pulmonary fibrosis. • No differences were observed in the incidence of adverse events between patients with idiopathic pulmonary fibrosis and those without idiopathic pulmonary fibrosis after microwave ablation (48.6% vs. 47.7%; p = 0.998). • The 1-year and 3-year overall survival rates (85.2%/51.6%) in the idiopathic pulmonary fibrosis group were worse than those in the non- idiopathic pulmonary fibrosis group (97.5%/86.4%) (p < 0.001).

Development and validation of dietary depression index in Chinese adults.

Objective: Previous studies have suggested diet was associated with depressive symptoms. We aimed to develop and validate Dietary Depression Index (DDI) based on dietary prediction of depression in a large Chinese cancer screening cohort.Methods: In the training set (n = 2729), we developed DDI by using intake of 20 food groups derived from a food frequency questionnaire to predict depression as assessed by Patient Health Questionnaire-9 based on the reduced rank regression method. Sensitivity, specificity, positive predictive value, and negative predictive value were used to assess the performance of DDI in evaluating depression in the validation dataset (n = 1176).Results: Receiver operating characteristic analysis was constructed to determine the best cut-off value of DDI in predicting depression. In the study population, the DDI ranged from -3.126 to 1.810. The discriminative ability of DDI in predicting depression was good with the AUC of 0.799 overall, 0.794 in males and 0.808 in females. The best cut-off values of DDI for depression prediction were 0.204 overall, 0.330 in males and 0.034 in females. DDI was a validated method to assess the effects of diet on depression.Conclusion: Among individual food components in DDI, fermented vegetables, fresh vegetables, whole grains and onions were inversely associated, whereas legumes, pickled vegetables and rice were positively associated with depressive symptoms.

Exploration of small molecule compounds targeting abdominal aortic aneurysm based on CMap database and molecular dynamics simulation.

OBJECTIVE: The mitigation of abdominal aortic aneurysm (AAA) growth through pharmaceutical intervention offers the potential to avert the perils associated with AAA rupture and the subsequent need for surgical intervention. Nevertheless, the existing effective drugs for AAA treatment are limited, necessitating a pressing exploration for novel therapeutic medications. METHODS: AAA-related transcriptome data were downloaded from GEO, and differentially expressed genes (DEGs) in AAA tissue were screened for GO and KEGG enrichment analyses. Small molecule compounds and their target proteins with negative connectivity to the AAA expression profile were predicted in the Connectivity Map (CMap) database. Molecular docking and molecular dynamics simulation were performed to predict the binding of the target protein to the small molecule compound, and the MM/GBSA method was used to calculate the binding free energy. Cluster analysis was performed using the cluster tool in the GROMACS package. An AAA cell-free model was built, and CETSA experiments were used to demonstrate the binding ability of small molecules to the target protein in cells. RESULTS: A total of 2244 DEGs in AAA were obtained through differential analysis, and the DEGs were mainly enriched in the tubulin binding biological function and cell cycle pathway. The CMap results showed that Apicidin had a potential therapeutic effect on AAA with a connectivity score of -97.74, and HDAC4 was the target protein of Apicidin. Based on literature, HDAC4-Apicidin was selected as the subsequent research object. The lowest affinity of Apicidin-HDAC4 molecular docking was -8.218 kcal/mol. Molecular dynamics simulation results indicated that Apicidin-HDAC4 could form a stable complex. MM/GBSA analysis showed a total binding free energy of -55.40 ± 0.79 kcal/mol, and cluster analysis showed that there were two main conformational clusters during the binding process, accounting for 22.4% and 57.8%, respectively. Apicidin could form hydrogen bonds with surrounding residues for stable binding. CETSA experiment proved the stable binding ability of Apicidin and HDAC4. CONCLUSION: Apicidin inhibited HDAC4 in AAA and exhibited favorable protein-ligand interactions and stability, making it a potential candidate drug for treating AAA.

Automated segmentation of liver and hepatic vessels on portal venous phase computed tomography images using a deep learning algorithm.

BACKGROUND: CT-image segmentation for liver and hepatic vessels can facilitate liver surgical planning. However, time-consuming process and inter-observer variations of manual segmentation have limited wider application in clinical practice. PURPOSE: Our study aimed to propose an automated deep learning (DL) segmentation algorithm for liver and hepatic vessels on portal venous phase CT images. METHODS: This retrospective study was performed to develop a coarse-to-fine DL-based algorithm that was trained, validated, and tested using private 413, 52, and 50 portal venous phase CT images, respectively. Additionally, the performance of the DL algorithm was extensively evaluated and compared with manual segmentation using an independent clinical dataset of preoperative contrast-enhanced CT images from 44 patients with hepatic focal lesions. The accuracy of DL-based segmentation was quantitatively evaluated using the Dice Similarity Coefficient (DSC) and complementary metrics [Normalized Surface Dice (NSD) and Hausdorff distance_95 (HD95) for liver segmentation, Recall and Precision for hepatic vessel segmentation]. The processing time for DL and manual segmentation was also compared. RESULTS: Our DL algorithm achieved accurate liver segmentation with DSC of 0.98, NSD of 0.92, and HD95 of 1.52 mm. DL-segmentation of hepatic veins, portal veins, and inferior vena cava attained DSC of 0.86, 0.89, and 0.94, respectively. Compared with the manual approach, the DL algorithm significantly outperformed with better segmentation results for both liver and hepatic vessels, with higher accuracy of liver and hepatic vessel segmentation (all p < 0.001) in independent 44 clinical data. In addition, the DL method significantly reduced the manual processing time of clinical postprocessing (p < 0.001). CONCLUSIONS: The proposed DL algorithm potentially enabled accurate and rapid segmentation for liver and hepatic vessels using portal venous phase contrast CT images.

Clinical Characteristics and Pathogen Spectrum of Male Genital Fungal Infections in Nanchang Area, South China.

The cutaneous fungal infections in male genitalia are relatively rare, and often present with various atypical clinical symptoms. It was mainly reported in a small number of case reports, while data with large number of patients were rarely reported. In this study, we reported 79 male patients with cutaneous fungal infections on scrotum or penis. The fungal infections were confirmed by microscopic examination directly and fungus culture. Clinical characteristics and predisposing factors were also collected. Of these 79 patients, 72 has lesions on scrotum, 5 on penis and 2 on both scrotum and penis. Trichophyton (T.) rubrum is the most common pathogen, found in 50 (67.6%) patients, which presented diverse clinical manifestation such as majorly erythematous, dry diffused scaly lesions without a clear border, slightly powdery and scutular scalings. Candida (C.) albicans is the secondly common pathogen, found in 21 (28.4%) patients, which also presented diverse lesions such as erythematous with dry whitish scaly lesions and erythematous erosion. The predisposing factors mainly included concomitant fungal infections on sites other than genitalia, especially inguinal region (tinea cruris), application of corticosteroid and high moisture. In conclusion, cutaneous fungal infections in male genitalia could be caused by different fungi, showed atypical or mild clinical appearances in most cases and might be a fungus reservoir, emphasizing the necessity to timely perform the fungi examinations and corresponding therapy.

Treatment techniques and resource recovery of source-separated urine: a bibliometric analysis and literature review.

Human urine, which is high in nutrients, acts as a resource as well as a contaminant. Indiscriminate urine discharge causes environmental pollution and wastes resources. To elucidate the research status and developmental trajectory of source-separated urine (SSU) treatment and recovery, this study was based on the Web of Science Core Collection (WOSCC) database and used the bibliometric software VOSviewer and CiteSpace to conduct a comprehensive and in-depth bibliometric analysis of the related literature in this field. The findings revealed a general upward trend in SSU treatment and recovery from 2000 to 2023. The compendium of 894 scholarly articles predominantly focused on the disciplines of Environmental Sciences, Environmental Engineering, and Water Resources. China and the USA emerged as the foremost contributors. Keyword co-occurrence mapping, clustering, and burst analysis have shown that the recovery of nitrogen and phosphorus from urine is currently the main focus, with future prospects leaning toward the retrieval of biochemicals and chemical energy. This study systematically categorizes and compares the developmental status, current advancements, and research progress in this field. The findings of this study provide a valuable reference for understanding developmental pathways in this field of research.

Alkalinity control in sludge propels the conversion of concrete slurry waste into micro- and nano-sized biogenic CaCO3.

The utilization of Bacillus sp. for the production of bio-CaCO3 in concrete crack repair and strength enhancement has attracted considerable attention. However, microbial-induced calcium carbonate precipitation (MICP) has yet to be explored as a precedent with activated sludge. Here calcium sourced from concrete slurry waste (CSW) and carbon from sludge microbial ß-oxidation under alkaline were used to generate micro/nano CaCO3. The results indicate that the main crystalline form of the generated precipitated particles is calcite, with a particle size ranging from 0.7 to 10 µm. Minimal heavy metals were found in the supernatant following settling. And at the optimum pH of 8.5-9, carbon capture reached 743 mg L-1, and CaCO3 production reached 1,191 mg L-1, and dominant phylum were Proteobacteria and Bacteroidota, with Thauera being a prevalent genus adept in ß-oxidation. Mass balance analysis showed that alkali promotes microbial ß-oxidation of organisms to produce CO2 and facilitate storage. Thus, the alkaline regulation of metabolism between microbe and CSW provides a novel way of sludge to initiate MICP.

Clinical and molecular significance of homologous recombination deficiency positive non-small cell lung cancer in Chinese population: An integrated genomic and transcriptional analysis.

Objective: The clinical significance of homologous recombination deficiency (HRD) in breast cancer, ovarian cancer, and prostate cancer has been established, but the value of HRD in non-small cell lung cancer (NSCLC) has not been fully investigated. This study aimed to systematically analyze the HRD status of untreated NSCLC and its relationship with patient prognosis to further guide clinical care. Methods: A total of 355 treatment-naïve NSCLC patients were retrospectively enrolled. HRD status was assessed using the AmoyDx Genomic Scar Score (GSS), with a score of ≥50 considered HRD-positive. Genomic, transcriptomic, tumor microenvironmental characteristics and prognosis between HRD-positive and HRD-negative patients were analyzed. Results: Of the patients, 25.1% (89/355) were HRD-positive. Compared to HRD-negative patients, HRD-positive patients had more somatic pathogenic homologous recombination repair (HRR) mutations, higher tumor mutation burden (TMB) (P<0.001), and fewer driver gene mutations (P<0.001). Furthermore, HRD-positive NSCLC had more amplifications in PI3K pathway and cell cycle genes, MET and MYC in epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) mutant NSCLC, and more PIK3CA and AURKA in EGFR/ALK wild-type NSCLC. HRD-positive NSCLC displayed higher tumor proliferation and immunosuppression activity. HRD-negative NSCLC showed activated signatures of major histocompatibility complex (MHC)-II, interferon (IFN)-γ and effector memory CD8+ T cells. HRD-positive patients had a worse prognosis and shorter progression-free survival (PFS) to targeted therapy (first- and third-generation EGFR-TKIs) (P=0.042). Additionally, HRD-positive, EGFR/ALK wild-type patients showed a numerically lower response to platinum-free immunotherapy regimens. Conclusions: Unique genomic and transcriptional characteristics were found in HRD-positive NSCLC. Poor prognosis and poor response to EGFR-TKIs and immunotherapy were observed in HRD-positive NSCLC. This study highlights potential actionable alterations in HRD-positive NSCLC, suggesting possible combinational therapeutic strategies for these patients.

ICT diffusion and financial development: Comparing high, middle, and low-income countries.

Given the importance of ICT diffusion in the development of the financial sector, this analysis is an effort to analyze the transmission channels between the two in high-income and middle and low-income economies over 2001-2019. We have used three variables, including the ICT index, individuals using the internet, and mobile subscribers, to represent ICT and three indices, including the financial development index, financial institution index, and financial market index, to make our results reliable and robust. We utilized a GMM method for conducting the empirical analysis. Generally, our results imply that ICT diffusion positively impacts financial development in high-income economies and negatively impacts middle and low-income economies. Our findings suggest that middle- and low-income-economy policymakers should follow the footprint of the high-income economies and increase the role of ICT in the financial sector for its development.

A core scientific problem in the treatment of central nervous system diseases: newborn neurons.

It has long been asserted that failure to recover from central nervous system diseases is due to the system's intricate structure and the regenerative incapacity of adult neurons. Yet over recent decades, numerous studies have established that endogenous neurogenesis occurs in the adult central nervous system, including humans'. This has challenged the long-held scientific consensus that the number of adult neurons remains constant, and that new central nervous system neurons cannot be created or renewed. Herein, we present a comprehensive overview of the alterations and regulatory mechanisms of endogenous neurogenesis following central nervous system injury, and describe novel treatment strategies that target endogenous neurogenesis and newborn neurons in the treatment of central nervous system injury. Central nervous system injury frequently results in alterations of endogenous neurogenesis, encompassing the activation, proliferation, ectopic migration, differentiation, and functional integration of endogenous neural stem cells. Because of the unfavorable local microenvironment, most activated neural stem cells differentiate into glial cells rather than neurons. Consequently, the injury-induced endogenous neurogenesis response is inadequate for repairing impaired neural function. Scientists have attempted to enhance endogenous neurogenesis using various strategies, including using neurotrophic factors, bioactive materials, and cell reprogramming techniques. Used alone or in combination, these therapeutic strategies can promote targeted migration of neural stem cells to an injured area, ensure their survival and differentiation into mature functional neurons, and facilitate their integration into the neural circuit. Thus can integration replenish lost neurons after central nervous system injury, by improving the local microenvironment. By regulating each phase of endogenous neurogenesis, endogenous neural stem cells can be harnessed to promote effective regeneration of newborn neurons. This offers a novel approach for treating central nervous system injury.

Recent advances in drug delivery of celastrol for enhancing efficiency and reducing the toxicity.

Celastrol is a quinone methyl triterpenoid monomeric ingredient extracted from the root of Tripterygium wilfordii. Celastrol shows potential pharmacological activities in various diseases, which include inflammatory, obesity, cancer, and bacterial diseases. However, the application prospect of celastrol is largely limited by its low bioavailability, poor water solubility, and undesired off-target cytotoxicity. To address these problems, a number of drug delivery methods and technologies have been reported to enhance the efficiency and reduce the toxicity of celastrol. We classified the current drug delivery technologies into two parts. The direct chemical modification includes nucleic acid aptamer-celastrol conjugate, nucleic acid aptamer-dendrimer-celastrol conjugate, and glucolipid-celastrol conjugate. The indirect modification includes dendrimers, polymers, albumins, and vesicular carriers. The current technologies can covalently bond or encapsulate celastrol, which improves its selectivity. Here, we present a review that focalizes the recent advances of drug delivery strategies in enhancing the efficiency and reducing the toxicity of celastrol.

The advantages of multi-level omics research on stem cell-based therapies for ischemic stroke.

Stem cell transplantation is a potential therapeutic strategy for ischemic stroke. However, despite many years of preclinical research, the application of stem cells is still limited to the clinical trial stage. Although stem cell therapy can be highly beneficial in promoting functional recovery, the precise mechanisms of action that are responsible for this effect have yet to be fully elucidated. Omics analysis provides us with a new perspective to investigate the physiological mechanisms and multiple functions of stem cells in ischemic stroke. Transcriptomic, proteomic, and metabolomic analyses have become important tools for discovering biomarkers and analyzing molecular changes under pathological conditions. Omics analysis could help us to identify new pathways mediated by stem cells for the treatment of ischemic stroke via stem cell therapy, thereby facilitating the translation of stem cell therapies into clinical use. In this review, we summarize the pathophysiology of ischemic stroke and discuss recent progress in the development of stem cell therapies for the treatment of ischemic stroke by applying multi-level omics. We also discuss changes in RNAs, proteins, and metabolites in the cerebral tissues and body fluids under stroke conditions and following stem cell treatment, and summarize the regulatory factors that play a key role in stem cell therapy. The exploration of stem cell therapy at the molecular level will facilitate the clinical application of stem cells and provide new treatment possibilities for the complete recovery of neurological function in patients with ischemic stroke.

Hsa_circ_0003356 suppresses gastric cancer progression via miR-556-5p/FKBP5 axis.

BACKGROUND: CircRNAs are implicated in the tumorigenesis of various human cancers. This study aims to explore how circ_0003356 contributes to the development of gastric cancer (GC). METHODS: Circ_0003356 expression was analyzed in GSE184882 dataset and validated in our cohort of GC patients and human GC cell lines. The correlations between circ_0003356 levels and prognostic parameters were analyzed. The contribution of circ_0003356 in GC cell malignant behaviors such as cell survival, apoptosis and invasion were investigated by circ_0003356 overexpression in GC cell lines. The downstream targets of circ_0003356 were predicted and verified in vitro and in vivo. The in vivo function of circ_0003356 was studied as well in a xenograft mouse model. RESULTS: Circ_0003356 expressed at a low level in human GC tissues and cells, which was closely associated with poor outcome of GC patients. Circ_0003356 overexpression induced GC cell apoptosis while depressed the growing, migration and invasive abilities through miR-556-5p/FKBP5 axis. In vivo model showed retarded tumor growth when circ_0003356-overexpressed cells were inoculated. CONCLUSION: Circ_0003356 is identified as a potential biomarker of the prognosis of human gastric cancer, and circ_0003356/miR-556-5p/FKBP5 axis could be a promising target in gastric cancer treatment.