Improving the classification of multiple sclerosis and cerebral small vessel disease with interpretable transfer attention neural network.

As an autoimmune-mediated inflammatory demyelinating disease of the central nervous system, multiple sclerosis (MS) is often confused with cerebral small vessel disease (cSVD), which is a regional pathological change in brain tissue with unknown pathogenesis. This is due to their similar clinical presentations and imaging manifestations. That misdiagnosis can significantly increase the occurrence of adverse events. Delayed or incorrect treatment is one of the most important causes of MS progression. Therefore, the development of a practical diagnostic imaging aid could significantly reduce the risk of misdiagnosis and improve patient prognosis. We propose an interpretable deep learning (DL) model that differentiates MS and cSVD using T2-weighted fluid-attenuated inversion recovery (FLAIR) images. Transfer learning (TL) was utilized to extract features from the ImageNet dataset. This pioneering model marks the first of its kind in neuroimaging, showing great potential in enhancing differential diagnostic capabilities within the field of neurological disorders. Our model extracts the texture features of the images and achieves more robust feature learning through two attention modules. The attention maps provided by the attention modules provide model interpretation to validate model learning and reveal more information to physicians. Finally, the proposed model is trained end-to-end using focal loss to reduce the influence of class imbalance. The model was validated using clinically diagnosed MS (n=112) and cSVD (n=321) patients from the Beijing Tiantan Hospital. The performance of the proposed model was better than that of two commonly used DL approaches, with a mean balanced accuracy of 86.06 % and a mean area under the receiver operating characteristic curve of 98.78 %. Moreover, the generated attention heat maps showed that the proposed model could focus on the lesion signatures in the image. The proposed model provides a practical diagnostic imaging aid for the use of routinely available imaging techniques such as magnetic resonance imaging to classify MS and cSVD by linking DL to human brain disease. We anticipate a substantial improvement in accurately distinguishing between various neurological conditions through this novel model.

TREM2 promotes macrophage polarization from M1 to M2 and suppresses osteoarthritis through the NF-κB/CXCL3 axis.

Objective: Osteoarthritis (OA) is the most prominent chronic arthritic disease, affecting over 3 billion people globally. Synovial macrophages, as immune cells, play an essential role in cartilage damage in OA. Therefore, regulating macrophages is crucial for controlling the pathological changes in OA. Triggering receptor expressed on myeloid cells 2 (TREM2), as expressed on immune cell surfaces, such as macrophages and dendritic cells, has suppressed inflammation and regulated M2 macrophage polarization but demonstrated an unknown role in synovial macrophage polarization in OA. This study aimed to investigate TREM2 expression downregulation in OA mice macrophages. Furthermore, the expression trend of TREM2 was associated with polarization-related molecule expression in macrophages of OA mice. Results: We used TREM2 knockout (TREM2-KO) mice to observe that TREM2 deficiency significantly exacerbated the joint inflammation response in OA mice, thereby accelerating disease progression. Separating macrophages and chondrocytes from TREM2-KO mice and co-cultivating them significantly increased chondrocyte apoptosis and inhibited chondrocyte proliferation. Further, TREM2 deficiency also significantly enhanced phosphatidylinositol 3-kinase(PI3K)/AKT signaling pathway activation, increasing nuclear factor kappa light chain enhancer of activated B cells (NF-κB) signaling and C-X-C Motif Chemokine Ligand 3 (CXCL3) expression. Furthermore, NF-κB signaling pathway inhibition significantly suppressed arthritis inflammation in OA mice, thereby effectively alleviating TREM2 deficiency-related adverse effects on chondrocytes. Notably, knocking down CXCL3 of TREM2-KO mice macrophages significantly inhibits inflammatory response and promotes chondrocyte proliferation. Intravenous recombinant TREM2 protein (soluble TREM2, sTREM2) injection markedly promotes macrophage polarization from M1 to M2 and improves the joint tissue pathology and inflammatory response of OA. Conclusion: Our study reveals that TREM2 promotes macrophage polarization from M1 to M2 during OA by NF-κB/CXCL3 axis regulation, thereby improving the pathological state of OA.

Long-term survival after neoadjuvant therapy for triple-negative breast cancer under different treatment regimens: a systematic review and network meta-analysis.

BACKGROUND: Triple-negative breast cancer (TNBC) is a life-threatening subtype of breast cancer with limited treatment options. Therefore, this network meta-analysis (NMA) aimed to evaluate and compare the effect of various neoadjuvant chemotherapy (NCT) options on the long-term survival of patients with TNBC. METHODS: PubMed, Embase, Medline, Cochrane Library, Web of Science, and major international conference databases were systematically searched for randomized controlled trials (RCTs) on the efficacy of various NCT options in patients with TNBC. Searches were performed from January 2000 to June 2023. Study heterogeneity was assessed using the I2 statistic. Hazard ratios (HRs) and 95% confidence intervals (CIs) were used to evaluate disease-free survival (DFS) and overall survival (OS). Odds ratios (ORs) and 95% CIs were used to evaluate the pathologic complete response (pCR). The primary outcome was DFS. RESULTS: We conducted an NMA of 21 RCTs involving 8873 patients with TNBC. Our study defined the combination of anthracyclines and taxanes as the preferred treatment option. On this basis, the addition of any of the following new drugs is considered a new treatment option: bevacizumab (B), platinum (P), poly-ADP-ribose polymerase inhibitors (PARPi), and immune checkpoint inhibitor (ICI). Based on the surface under the cumulative ranking curve (SUCRA) values, the top three SUCRA area values of DFS were taxanes, anthracycline, and cyclophosphamide (TAC; 89.23%); CT (84.53%); and B (81.06%). The top three SUCRA area values of OS were CT (83.70%), TAC (62.02%), and B-containing regimens (60.06%). The top three SUCRA area values of pCR were B + P-containing regimens (82.7%), ICI + P-containing regimens (80.2%), and ICI-containing regimens (61.8%). CONCLUSIONS: This NMA showed that standard chemotherapy is a good choice with respect to long-term survival. Moreover, B associated with P-containing regimens is likely to be the optimal treatment option for neoadjuvant TNBC in terms of pCR.

REMIMAZOLAM IMPROVES THE MARKERS OF POSTRESUSCITATION CEREBRAL INJURY IN A SWINE MODEL OF CARDIAC ARREST.

ABSTRACT: Introduction: Previous studies have manifested that those sedatives acting on γ-aminobutyric acid A (GABAa) receptor could produce effective brain protection against regional and global ischemic stimulation. The present study was designed to investigate the effect of a novel GABAa receptor agonist, remimazolam postconditioning (RP) on cerebral outcome after global ischemic stimulation induced by cardiac arrest and resuscitation in swine. Methods: A total of 24 swine were used in this study, in which the animals were randomly divided into the following three groups: sham group (n = 6), cardiopulmonary resuscitation (CPR) group (n = 9), and CPR + RP group (n = 9). The experimental model was established by the procedure of 10 min of cardiac arrest and 5 min of CPR. Those resuscitated swine in the CPR + RP group received an intravenous infusion of 2.5 mg/kg of remimazolam within 60 min. Postresuscitation cerebral injury biomarkers and neurological function were evaluated for a total of 24 h. At 24 h after resuscitation, brain cortex was harvested to evaluate the severity of pathologic damage, including tissue inflammation, oxidative stress, apoptosis, and necroptosis. Results: Baseline characteristics and CPR outcomes were not significantly different between the CPR and CPR + RP groups. After resuscitation, significantly greater cerebral injury and neurological dysfunction were observed in the CPR and CPR + RP groups than in the sham group. However, remimazolam postconditioning significantly alleviated cerebral injury and improved neurological dysfunction after resuscitation when compared with the CPR group. At 24 h after resuscitation, tissue inflammation, oxidative stress, and cell apoptosis and necroptosis were significantly increased in the CPR and CPR + RP groups when compared with the sham group. Nevertheless, the severity of pathologic damage mentioned previously were significantly milder in those swine treated with the remimazolam when compared with the CPR group. Conclusions: In a swine model of cardiac arrest and resuscitation, the remimazolam administered after resuscitation significantly improved the markers of postresuscitation cerebral injury and therefore protected the brain against global ischemic stimulation.

CDKN1A regulation on chondrogenic differentiation of human chondrocytes in osteoarthritis through single-cell and bulk sequencing analysis.

Objective: Chondrocyte death is the hallmark of cartilage degeneration during osteoarthritis (OA). However, the specific pathogenesis of cell death in OA chondrocytes has not been elucidated. This study aims to validate the role of CDKN1A, a key programmed cell death (PCD)-related gene, in chondrogenic differentiation using a combination of single-cell and bulk sequencing approaches. Design: OA-related RNA-seq data (GSE114007, GSE55235, GSE152805) were downloaded from Gene Expression Omnibus database. PCD-related genes were obtained from GeneCards database. RNA-seq was performed to annotate the cell types in OA and control samples. Differentially expressed genes (DEGs) among those cell types (scRNA-DEGs) were screened. A nomogram of OA was constructed based on the featured genes, and potential drugs targeting the featured genes were predicted. The presence of key genes was confirmed using Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR), Western blot (WB), and immunohistochemistry (IHC). Micromass culture and Alcian blue staining were used to determine the effect of CDKN1A on chondrogenesis. Results: Six cell types, namely HomC, HTC, RepC, preFC, FC, and RegC, were annotated in scRNA-seq data. Five featured genes (JUN, CDKN1A, HMGB2, DDIT3, and DDIT4) were screened by multiple biological information analysis methods. TAXOTERE had the highest ability to dock with DDIT3. Functional analysis indicated that CDKN1A was enriched in processes related to collagen catabolism and acts as a positive regulator of autophagy. Additionally, CDKN1A was found to be associated with several KEGG pathways, including those involved in acute myeloid leukemia and autoimmune thyroid disease. CDKN1A was confirmed down-regulated in the joint tissues of OA mouse model and OA model cell. Inhibiting the expression of CDKN1A can significantly suppress the differentiation of OA chondrocytes. Conclusion: Our findings highlight the critical role of CDKN1A in promoting cartilage formation in both in vivo and in vitro and suggest its potential as a therapeutic target for OA treatment.

Incidence of antibody-drug conjugate-related fatigue in patients with breast cancer: A systematic review and meta-analysis.

BACKGROUND: Numerous studies have reported the efficacy of antibody-drug conjugates (ADCs) for treating breast cancer. However, during cytotoxic drug treatment, long-term disabling fatigue is common. Moreover, studies in the relevant literature have indicated that fatigue can significantly increase the incidence of depression and sleep disorders. Therefore, this meta-analysis aims to evaluate the incidence of fatigue in breast cancer survivors treated with ADCs. METHODS: PubMed, EMBASE, Web of Science, and Cochrane Library databases were systematically searched for articles and conference abstracts published before March 16, 2023. Further, two authors independently extracted data from the included studies. The primary outcome of this study was the incidence of all-grade fatigue caused by the use of ADCs in patients with breast cancer. Finally, a random-effects model was used to calculate the incidence and 95% confidence intervals (CIs) of the outcome. RESULTS: Overall, 7963 patients from 31 studies were included in this meta-analysis to assess the incidence of fatigue caused by the use of approved and marketed ADCs in patients with breast cancer. Notably, the incidence of all-grade fatigue during ADC monotherapy was 39.84% (95% CI, 35.09%-44.69%). In subgroup analyses, among ADCs, the incidence of trastuzumab deruxtecan-induced fatigue was the highest, with an all-grade fatigue incidence of 47.05% (95% CI, 42.38%-51.75%). Meanwhile, the incidence of trastuzumab emtansine (T-DM1)-induced all-grade fatigue was 35.17% (95% CI, 28.87%-41.74%), which was the lowest among ADCs. Further, the incidence of all-grade fatigue due to sacituzumab govitecan was 42.82% (95% CI, 34.54%-51.32%), which was higher than that due to T-DM1. Moreover, the incidence of fatigue was higher with T-DM1 combination therapy than with monotherapy. CONCLUSIONS: Clinicians have highlighted the high incidence of ADC-related fatigue and its negative impact on patients' physical and mental health, making fatigue an important research variable. The results of this study will further contribute to a comprehensive understanding of ADCs, which have some clinical importance and are of great benefit to patients with breast cancer.

A finite-time path following scheme of unmanned surface vessels with an optimization strategy.

The path-following problem of unmanned surface vessels (USVs) is solved in this paper, considering unknown interference, energy-saving strategy, input constraints, and input rate of change constraints. Firstly, the USV model considering lumped interference is given, while an interference observer based on finite-time theory is used for interference estimation where the convergence time is specified. Then, to accelerate the USV convergence to a given path, a novel improved adaptive finite-time line-of-sight (IAFTLOS) scheme is developed. The proposed IAFTLOS scheme makes the cross-path error with finite-time convergence. At the same time, an adaptive time-varying looking distance law is designed to improve the convergence performance further. Next, nonlinear model predictive control is introduced to deal with rates of change and input constraints. In addition, an energy-saving strategy is incorporated into the design of the controller. Finally, stable control of the whole cascade system is achieved, and comparative simulation cases verify the feasibility and robustness of the entire system.

The correlation between systemic inflammatory markers and efficiency for advanced gastric cancer patients treated with ICIs combined with chemotherapy.

Currently lacking research to explore the correlation between inflammatory markers and the efficacy of immune checkpoint inhibitors (ICIs) combined with chemotherapy in the treatment of advanced gastric cancer. This study is a retrospective study and included patients with advanced gastric cancer who receiving ICIs combined with chemotherapy from January 2020 to December 2022. We analysed the relationship between systemic inflammatory markers and the efficacy of ICIs combined chemotherapy and constructed a clinical prediction model. A nomogram was constructed based on the results of the bidirectional stepwise regression model. A total of 197 patients were enrolled in the training group, with a median follow-up period of time 26 months. Kaplan Meier analysis showed that the median OS of patients with low systemic immune-inflammatory index (SII) and low platelet to lymphocyte ratio (PLR) was superior to those with high SII and PLR. Univariate and multivariate Cox regression analysis showed that SII, NLR, PLR, and N stage as independent prognostic factors for OS. Adding SII to the conventional model improved the predictive ability of the 12-month OS. A total of 95 patients were included in the validation group, and external validation of the SII-based nomogram showed favourable predictive performance. Baseline SII, PLR, and N stage may serve as independent predictive factors for survival outcomes in advanced gastric cancer patients undergoing ICIs combined with chemotherapy. The SII-based nomogram can provide intuitive and accurate prognosis prediction of individual patients.

Screening Single Nucleotide Polymorphisms Predicting the Efficacy of Electroacupuncture for Fatigue Treatment in Patients with Breast Cancer Following Adjuvant Chemotherapy.

Chemotherapy-induced fatigue reduces not only the quality of life of patients but also effect their recurrence-free survival rate. Although electroacupuncture can relieve fatigue, it has limited affect on some patients. Therefore, appropriate biomarkers are needed to help screen patients who can benefit from electroacupuncture treatment of fatigue. We conducted this study to explore the predictive ability of SNPs on the efficacy of electroacupuncture in the treatment of fatigue in patients with breast cancer after adjuvant chemotherapy. Our study included breast cancer patients with fatigue after receiving paclitaxel and/or anthracycline based adjuvant chemotherapy. The patients were divided into the electroacupuncture group and the control group. The electroacupuncture treatment group received adjuvant chemotherapy and electroacupuncture treatment, while the control group only received adjuvant chemotherapy, and then compared the fatigue relief degree of two groups. In addition, we used NCBI dbSNP and PharmGKB databases to select fatigue related genes and their SNPs. We collected peripheral blood from the included patients for SNPs typing, and recorded the efficacy of electroacupuncture to analyzed the correlation between different SNPs and therapeutic efficacy. The side effects of electroacupuncture treatment were also recorded. 76 patients in the electroacupuncture group and 48 patients in the control group were enrolled. In the electroacupuncture group, 63 patients (82.9%) experienced moderate to severe fatigue (BFI score > 3). After electroacupuncture treatment, the number of patients with a BFI score of > 3 was 46 (60.5%). Therefore, the fatigue symptoms of 26.9% patients were significantly improved (P < 0.05). In the control group, which did not receive electroacupuncture treatment, 40 of 48 patients had a BFI score of > 3. Following the same observation time used in the electroacupuncture group, 36 patients had a BFI score of > 3 points. Thus, fatigue was not significantly relieved in the control group (83.3% vs. 75.0%, P > 0.05). We included 56 patients in our analysis of the correlation between SNPs and electroacupuncture treatment effects. We divided the patients into an effective group and ineffective group according to therapeutic effects. Our results indicated that the effective rate of electroacupuncture treatment with IL1A rs3783550 AC and CC genotypes was higher than that with other genotypes (AC: 84.6%, CC: 81.8%, AA: 33.0%, P < 0.05). Similarly, the effective rate of electroacupuncture treatment with HTR1A rs6295 GG and CC genotypes was higher than that with other genotypes (GG: 63.0%, CC: 55.6%, GC: 18.2%, P < 0.05). However, no other genotypes were related to the effect of electroacupuncture treatment on fatigue. Our result showed that electroacupuncture has therapeutic effect on fatigue after adjuvant chemotherapy for breast cancer and the side effects are tolerable. In addition, IL1A rs3763550 and HTR1A rss6295 can predict the therapeutic effect of electroacupuncture on fatigue after adjuvant chemotherapy in breast cancer, which helps to better screen patients who can benefit from electroacupuncture treatment.

Hypoxia-activated glutamine antagonist prodrug combined with combretastatin A4 nanoparticles for tumor-selective metabolic blockade.

6-Diazo-5-oxo-L-norleucine (DON) is a potent glutamine antagonist with toxic side effects; in order to reduce these effects, multiple prodrugs have been designed. However, there are currently no reports of a DON prodrug with a defined mechanism to achieve high tumor selectivity. To improve the selective toxicity of DON to tumor cells while reducing systemic toxicity, a hypoxia-activated prodrug, termed HDON, was designed. HDON achieved remarkable tumor suppression of 76.4 ± 5.2% without leading to weight loss in an H22 murine liver cancer model with high hypoxia. Moreover, to augment the therapeutic efficacy of HDON, combretastatin A4 nanoparticles were used to aggravate tumor hypoxia of MC38 murine colon cancer and 4T1 murine breast cancer, activate HDON to DON, and stimulate a robust anti-tumor immune response while selectively killing in tumor cells in vivo, achieving significantly elevated tumor suppression rates of 98.3 ± 3.4% and 98.1 ± 3.1%, with cure rates of 80.0% and 20.0%, respectively.

Immunoswitch Nanomodulators Enable Active Targeting and Selective Proliferation of Regulatory T Cells for Multiple Sclerosis Therapy.

Interleukin-2 (IL-2) used in multiple sclerosis (MS) therapy modulates the balance between regulatory T (Treg) cells and effector T (Teff) cells. However, the off-target activation of Teff cells by IL-2 limits its clinical application. Therefore, a rapidly prepared immunoswitch nanomodulator termed aT-IL2C NPs was developed, which specifically recognized Treg cells with high TIGIT expression thanks to the presence of an anti-TIGIT and an IL-2/JES6-1 complex (IL2C) being delivered to Treg cells but not to Teff cells with low TIGIT expression. Then, IL2C released IL-2 due to the specific expression of the high-affinity IL-2 receptor on Treg cells, thus enabling the active targeting and selective proliferation of Treg cells. Moreover, the anti-TIGIT of aT-IL2C NPs selectively inhibited the proliferation of Teff cells while leaving the proliferation of Treg cells unaffected. In addition, since the IL-2 receptor on Teff cells had medium-affinity, the IL2C hardly released IL-2 to Teff cells, thus enabling the inhibition of Teff cell proliferation. The treatment of experimental autoimmune encephalomyelitis (EAE) mice with aT-IL2C NPs ameliorated the severity of the EAE and restored white matter integrity. Collectively, this work described a potential promising agent for effective MS therapy.

Treatment-related adverse events of antibody-drug conjugates in clinical trials: A systematic review and meta-analysis.

Background: The wide use of antibody-drug conjugates (ADCs) is transforming the cancer-treatment landscape. Understanding the treatment-related adverse events (AEs) of ADCs is crucial for their clinical application. We conducted a meta-analysis to analyze the profile and incidence of AEs related to ADC use in the treatment of solid tumors and hematological malignancies. Methods: We searched the PubMed, Embase, and Cochrane Library databases for articles published from January 2001 to October 2022. The overall profile and incidence of all-grade and grade ≥ 3 treatment-related AEs were the primary outcomes of the analysis. Results: A total of 138 trials involving 15,473 patients were included in this study. The overall incidence of any-grade treatment-related AEs was 100.0% (95% confidence interval [CI]: 99.9%-100.0%; I 2 = 89%) and the incidence of grade ≥ 3 treatment-related AEs was 6.2% (95% CI: 3.0%-12.4%; I² = 99%). Conclusions: This study provides a comprehensive overview of AEs related to ADCs used for cancer treatment. ADC use resulted in a high incidence of any-grade AEs but a low incidence of grade ≥ 3 AEs. The AE profiles and incidence differed according to cancer type, ADC type, and ADC components.

[Prokaryotic expression and biological activities of the hemolysin BL subunit of a pathogenic Bacillus cereus of cattle origin].

Bacillus cereus belongs to Gram-positive bacteria, which is widely distributed in nature and shows certain pathogenicity. Different B. cereus strains carry different subsets of virulence factors, which directly determine the difference in their pathogenicity. It is therefore important to study the distribution of virulence factors and the biological activity of specific toxins for precise prevention and control of B. cereus infection. In this study, the hemolysin BL triayl was expressed, purified, and characterized. The results showed that the bovine pathogenic B. cereus hemolysin BL could be expressed and purified in the prokaryotic expression system, and the bovine pathogenic B. cereus hemolysin BL showed hemolysis, cytotoxicity, good immunogenicity and certain immune protection in mice. In this study, the recombinant expression of hemolysin BL triayl was achieved, and the biological activity of hemolysin BL of bovine pathogenic ceroid spore was investigated. This study may facilitate further investigating the pathogenic mechanism of B. cereus hemolysin BL and developing a detection method for bovine pathogenic B. cereus disease.

Genome-wide identification and expression analysis of PYL family genes and functional characterization of GhPYL8D2 under drought stress in Gossypium hirsutum.

Cotton is a crucial economic crop, serving as a natural fiber source for the textile industry. However, drought stress poses a significant threat to cotton fiber quality and productivity worldwide. Pyrabactin Resistance 1-Like (PYL) proteins, as abscisic acid (ABA) receptors, play a crucial role in adverse stress responses, but knowledge about the PYLs in cotton remains limited. In our study, we identified 40 GhPYL genes in Gossypium hirsutum through a genome-wide analysis of the cotton genome database. Our analysis revealed that the PYL family formed three distinct subfamilies with typical family characteristics in G. hirsutum. Additionally, through quantitative expression analysis, including transcriptome dataset and qRT-PCR, we found that all GhPYLs were expressed in all tissues of G. hirsutum, and all GhPYLs were differentially expressed under drought stress. Among them, GhPYL4A1, GhPY5D1, GhPY8D2, and a member of the type 2C protein phosphatases clade A family in Gossypium hirsutum (GhPP2CA), GhHAI2D, showed significant differences in expression levels within 12 h after stress treatment. Our protein interaction analysis and BiFC demonstrated the complex regulatory network between GhPYL family proteins and GhPP2CA proteins. We also found that there is an interaction between GhPYL8D2 and GhHAI2D, and through drought treatment of transgenic cotton, we found that GhPYL8D2 played a vital role in the response of G. hirsutum to drought through stomatal control via co-regulation with GhHAI2D. Our findings provide useful insights into the regulation of GhPYL family genes that occur in response to abiotic stresses in cotton.

Expression and clinical significance of METTL3 in colorectal cancer.

Methyltransferase-like 3 (METTL3) belongs to the class I MTase family, and it has been proved that METTL3 is highly expressed in a variety of tumors and promotes tumor progression. Our previous studies have shown that METTL3 is highly expressed in gastric cancer tissues compared with para-cancer tissues, and its expression level is negatively correlated with good postoperative prognosis of patients. To explore the expression of METTL3 in colorectal cancer (CRC) tissue and the relationship between METTL3 and the clinicopathologic features and prognosis of CRC patients. The expression of METTL3 in cancer tissues and adjacent tissues of 180 patients with colorectal cancer was analyzed by tissue microarray and immunohistochemistry. The clinicopathologic features of patients with different METTL3 expression levels were analyzed. The expression level of METTL3 in colorectal cancer tissues was higher than that in adjacent tissues (P < .05). There were statistically significant differences in the expression of METTL3 in clinical stage, survival time and distant metastasis (all P < .05). The expression level of METTL3 in colorectal cancer tissues with tumor-node-metastasis stage III and IV and distant metastasis was higher than that in clinical stage I and II and without distant metastasis (P < .05). Patients with high METTL3 expression had a higher overall mortality rate compared to patients with low METTL3 expression, and the difference was statistically significant (P < .05). Univariate Cox regression analysis suggested that tumor distant metastasis, vascular invasion, pathological grade, lymph node metastasis and METTL3 expression level were risk factors for overall survival in CRC patients (all P < .05). Multivariate Cox regression analysis suggested that low pathological grade (hazard ratio = 1.695, 95% confidence interval: 1.116-2.274, P = .005) and high METTL3 expression (hazard ratio = 2.156, 95% confidence interval: 1.587-2.725, P < .001) could be used as independent risk factors for prognosis assessment. The expression of METTL3 was increased in colorectal cancer, and METTL3 was closely related to clinical stage, distant metastasis and prognosis of colorectal cancer.

Progress in the application of Enterococcus faecium in animal husbandry.

As a probiotic, enterococcus faecium (E. faecium) has the characteristics of high temperature resistance, gastric acid resistance, bile salt resistance, etc. It can also effectively improve animal performance and immunity and improve the animal's intestinal environment, so in recent years it has been more widely used in the livestock industry. However, due to the improper use of antibiotics and the growing environmental stress of strains, the drug resistance of enterococcus faecium has become more and more serious, and because some enterococcus faecium carry virulence genes, leading to the emergence of pathogenic strains, its safety issues have been widely concerned. This paper focuses on the biological characteristics of enterococcus faecium, the application of this bacterium in animal husbandry and the safety issues in its use, with a view to providing a reference for the application of enterococcus faecium in the development of animal husbandry.

Preparation of an Ultrahigh-DAR PDL1 monoclonal antibody-polymeric-SN38 conjugate for precise colon cancer therapy.

Antibody-drug conjugates (ADCs) are the most potent active tumor-targeting agents used clinically. However, the preparation of ADCs with high drug-to-antibody ratios (DARs) remains a major challenge. Herein, a Fab-nondestructive SN38-loaded antibody-polymeric-drug conjugate (APDC), aPDL1-NPLG-SN38, was prepared that had a DAR as high as 72 for the first time, by increased numbers of payload binding sites via the carboxyl groups of poly (l-glutamic acid) (PLG). The bonding of Fc-III-4C peptide with PLG-graft-mPEG/SN38 (Fc-NPLG-SN38) was achieved using a click reaction between azide and DBCO groups. The aPDL1-NPLG-SN38 conjugate was then synthesized by the high-affinity interaction between the Fc-III-4C peptide in Fc-NPLG-SN38 and the crystallizable fragment (Fc) of PDL1 monoclonal antibody (aPDL1). This approach avoided the potential deleterious effects on the Fab structure of the monoclonal antibody. The aqueous environment used in its preparation helped maintain monoclonal antibody recognition capability. Through the specific recognition by aPDL1 of PDL1 that is highly expressed on MC38 tumors, the accumulation of aPDL1-NPLG-SN38 in the tumors was 2.8-fold greater than achieved with IgG-NPLG-SN38 that had no active tumor-targeting capability. aPDL1-NPLG-SN38 exhibited excellent therapeutic properties in both medium-sized and large MC38 tumor animal models. The present study provides the details of a novel preparation strategy for SN38-loaded ADCs having a high DAR.

Organic-Solvent-Free "Lego-Like" Modular Preparation of Fab-Nondestructive Antibody-Drug Conjugates with Ultrahigh Drug-to-Antibody Ratio.

Antibody-drug conjugates (ADCs) have exciting possibilities in targeted tumor therapy. However, in the existing ADC preparation processes, the random attachment of the payloads to the antigen-binding fragments (Fab) greatly increases the risk of disrupting its antigen recognition ability, while the drug-antibody ratio (DAR) is low, leading to a cumbersome preparation process and low drug delivery efficiency. Herein, poly(glutamic acid) is used to expand the number of drug binding sites, based on the "click chemistry" of azide and DBCO, and the high affinity of Fc-III-4C peptide to the crystalline fragment (Fc) of the monoclonal antibodies. Various antibody-polymer-drug conjugates are obtained with ultrahigh DAR using this organic-solvent-free "Lego-like" modular construction. Among them, aHER2-P-MMAE with DAR of 41.6 achieves tumor growth inhibition (TGI) of 99.7% for both medium-sized and large SKOV-3 ovarian tumors, and aPDL1-P-MMAE (DAR = 40.7) achieves TGI of 98.5% for MC38 colon tumors. In summary, a universal platform is created to prepare Fab-nondestructive ADCs with ultrahigh DAR, which can be used to develop precision medicine for personalized anticancer therapy.

Towards a constructed order of co-governance: Understanding the state-society dynamics of neighbourhood collaborative responses to COVID-19 in urban China.

The state-society relationship in neighbourhood governance has been a focal topic in the urban governance literature, though the existing scholarship was primarily drawn from non-crisis situations. Adopting a mixed-methods approach, this study investigates the intricate state-society dynamics manifested at the neighbourhood scale as state and societal actors collaborated during China's COVID-19 responses. Our study reveals a pattern of collaborative rather than confrontational dynamics between resident committees and other stakeholders during pandemic responses, which reflects the emergence of a constructed order of neighbourhood co-governance in urban China. Previous community-building reforms consolidated the political legitimacy, power and capacity of resident committees, which were empowered to play a critical coordinating role in bridging hierarchical state mobilisation and horizontal stakeholders in the collaborative pandemic responses. These findings contribute to a more nuanced understanding of neighbourhood co-governance in the international literature and provide lessons for resilience governance from a comparative lens.

An MMAE-loaded PDL1 active targeting nanomedicine for the precision treatment of colon cancer.

Tumor-active-targeting drugs such as antibody-drug conjugates have emerged as promising accurate therapeutic agents. However, their complex preparations risk compromising the targeting ability of the fragment antigen binding (Fab) region and promote aggregation over long-term storage. Here, we propose a tumor-active-targeting nanomedicine, aPDL1-PLG-MMAE, that effectively targets programmed death-ligand 1 (PDL1) high-expressing tumors and delivers monomethyl auristatin E (MMAE). aPDL1-PLG-MMAE consists of an anti-PDL1 monoclonal antibody (aPDL1) and poly(L-glutamic acid) (PLG) grafted Fc-III-4C peptide/Val-Cit-PAB-MMAE (Fc-PLG-MMAE). Fc-PLG-MMAE was obtained by conjugating the Fc-III-4C peptide and Val-Cit-PAB-MMAE to PLG via amide condensation. The strong affinity between the fragment crystallizable (Fc) region of aPDL1 and the Fc-III-4C peptide enabled aPDL1 and Fc-PLG-MMAE to self-assemble into aPDL1-PLG-MMAE after four hours of coincubation in PBS. As this nanomedicine can be quickly prepared for immediate use, the required antibodies can be stored separately from the Fc-PLG-MMAE portion for extended periods, which also facilitates transport. Moreover, aPDL1-PLG-MMAE demonstrated robust tumor recognition and targeting effects on MC38 colon cancer cells, resulting in potent therapeutic efficacy without significant toxicities.