ObjectiveTo investigate the protective effect and mechanism of Wendan Ningxin granules （WNG） on susceptibility to atrial fibrillation （AF） in mice with inflammatory injury. Methods100 C57BL/6 mice were divided into a blank control group， a model group， a low-dose WNG group （2.34 g·kg^-1·d^-1）， a high-dose WNG group （4.68 g·kg^-1·d^-1）， and an amiodarone positive control group （0.091 g·kg^-1·d^-1）， with 20 mice in each group. Except for the blank control group， mice in other groups received intraperitoneal injections of lipopolysaccharide （LPS） to establish an inflammatory injury model. Treatment groups received continuous intragastric administration of their respective interventions for four weeks. During the fourth week， the treatment groups received LPS injections concurrently with their treatments. The blank control and model groups received distilled water （10 mL·kg^-1·d^-1） by gavage， with a gavage volume of 10 mL·kg^-1 for all groups， once daily. Hematoxylin-eosin （HE） staining and Sirius red staining were used to observe atrial tissue morphology and fibrosis degree. Immunohistochemistry was used to assess the expression of α-smooth muscle actin （α-SMA） in mouse atrial tissue. Electrophysiological detection was performed using a multi-channel electrophysiology mapping system to measure AF inducibility， AF duration， and atrial effective refractory period （AERP）. High-resolution optical mapping was used to measure action potential duration （APD） dispersion， conduction heterogeneity index， and calcium transient （CaT） dispersion. Real-time quantitative polymerase chain reaction （Real-time PCR） was used to detect mRNA expression of proteins related to diastolic calcium leakage in mouse atria： Ca²⁺/calmodulin-dependent protein kinase Ⅱ（CaMKⅡ）， ryanodine receptor 2（RyR2）， sarco/endoplasmic reticulum Ca²⁺-ATPase （SERCA）， and sodium-calcium exchanger （NCX）. Western blot analysis was performed to detect the expression of CaMKII， RyR2， SERCA， and NCX proteins in myocardial tissue from each group. Enzyme-linked immunosorbent assay （ELISA） was used to measure serum levels of inflammatory factors interleukin-1β （IL-1β） and tumor necrosis factor-α （TNF-α）. ResultsPathological staining results showed that compared with the blank control group， the model group exhibited disrupted atrial tissue structure， inflammatory cell infiltration， atrial fibrosis， and diffuse infiltration of numerous brown α-SMA positive cells in the atrial interstitium （P<0.01）. AF could be induced by electrical stimulation with a longer duration. AERP was shortened， while APD dispersion， conduction heterogeneity index， and CaT dispersion were increased （P<0.01）. The expression of proteins associated with diastolic calcium leakage， including CaMKⅡ， RyR2， and NCX1， showed elevated mRNA and protein levels， whereas SERCA2a mRNA and protein expression decreased （P<0.05）. Serum levels of inflammatory factors IL-1β and TNF-α were elevated （P<0.01）. Compared with the model group， intervention with WNG alleviated cardiac structural damage， reduced inflammatory cell infiltration， improved atrial fibrosis， and reduced the diffuse infiltration of α-SMA positive cells （P<0.01）. AF inducibility and AF duration upon electrical stimulation were significantly reduced （P<0.05）， AERP was prolonged （P<0.05）， mRNA and protein expression of CaMKⅡ， RyR2， and NCX1-proteins associated with diastolic calcium leakage-were reduced， whilst mRNA and protein expression of SERCA2a increased （P<0.05）， and serum levels of IL-1β and TNF-α were decreased （P<0.01）. ConclusionBoth low‑ and high‑dose WNG can effectively reduce susceptibility to inflammation-related AF. The mechanism by which WNG reduce AF susceptibility may be related to regulating proteins involved in sarcoplasmic reticulum diastolic calcium leak， thereby improving cardiac electrical remodeling， and alleviating inflammation-induced myocardial fibrosis， thus improving cardiac structural remodeling.

Objective: To investigate the trend in incidence and change in age at onset of lung cancer in in Wujiang District, Suzhou City, Jiangsu Province from 2012 to 2021, so as to provide a basis for strengthening targeted prevention and control of lung cancer. Methods: Data of lung cancer incidence from 2012 to 2021 were collected through the Wujiang District Tumor Follow-up Registration Information System. The crude incidence, truncated incidence for 35 to 64 years, and cumulative incidence for 0 to 74 years were calculated. Chinese population-standardized incidence, Chinese population-standardized average age at onset, and Chinese population-standardized incidence proportion were calculated using the age structure of the standard population from the Fifth National Population Census in 2000. The trend in incidence of lung cancer from 2012 to 2021 was evaluated using average annual percent change (AAPC). The trend in the Chinese population-standardized average age at onset of lung cancer from 2012 to 2021 was evaluated using a linear regression model. Results: From 2012 to 2021, the crude incidence, the Chinese population-standardized incidence and truncated incidence for 35 to 64 years of lung cancer in Wujiang District were 84.57/100 000, 37.28/100 000 and 52.10/100 000, respectively, all showing upward trends (AAPC=2.489%, 2.034% and 4.654%, all P<0.05). The cumulative incidence for 0 to 74 years was 4.48%, showing no significant trend (P>0.05). The Chinese population-standardized incidence was higher in males than in females (48.16/105 vs. 26.81/105). The Chinese population-standardized incidence of lung cancer in females showed an upward trend (AAPC=8.174%, P<0.05), while the trend in males was not statistically significant (P>0.05). The crude incidence of lung cancer showed upward trends in the total population and females aged 0-<45 years (AAPC=18.287% and 25.343%, both P<0.05) and those aged 45-<55 age group (AAPC=8.003% and 17.629%, both P<0.05). The Chinese population-standardized average age at onset of lung cancer in total population and females decreased from 67.58 and 65.48 years in 2012 to 60.15 and 54.88 years in 2021, with an average annual reduction of 0.611 and 0.964 years, respectively (both P<0.05). The Chinese population-standardized incidence proportion showed upward trends for the total population and females under 65 years (AAPC=3.879% and 4.639%, both P<0.05). No statistically significant trends were observed in the Chinese population-standardized average age at onset or incidence proportion in males (both P>0.05). Conclusions From 2012 to 2021, the incidence of lung cancer in Wujiang District showed an increasing trend and a trend toward younger onset age. Young and middle-aged females had emerged as a key target population for lung cancer prevention and control.

ObjectiveTo investigate the whole genomic characteristics and phylogenetic relationships of clinical isolates of enteroaggregative Escherichia coli (EAEC) in diarrhea outpatients in Pudong New Area, Shanghai. MethodsBased on the diarrheal disease surveillance network in Pudong New Area, Shanghai, whole-genome sequencing was performed on a total of 55 EAEC strains isolated from fecal samples of the diarrhea outpatients from January 2015 to December 2019. The genome analyses based on raw sequencing data encompassed genome size, coding genes, dispersed repeat sequences, genomic islands, and protein coding regions, and pan-genome analyses were conducted simultaneously. Contigs sequences assays were performed to analyze molecular characteristics including serotypes, antibiotic resistance genes, and virulence factors. The phylogenetic clusters and multilocus sequence typing (MLST) were identified, and a phylogenetic tree was constructed. ResultsEAEC exhibited an open pan-genome. The predominant serotype of EAEC in diarrhea outpatients in Pudong New Area was O130:H27, and the carriage rate of β-lactam resistance genes was the highest (67.27%, 37/55). A total of 29 virulence factors and 106 virulence genes were identified, phylogenic group B1 was the predominant group, and clonal group CC31 was the dominant clonal group. The strain distribution was highly heterogeneous. ConclusionThe genomic characteristics of EAEC displayed significant strain polymorphism. It is necessary to develop effective strategies for differential diagnosis and improve detection capabilities for infection with EAEC of different serotypes and genotypes.

OBJECTIVE: To assess the cardioprotective effect and impact of Qishen Granules (QSG) on different ischemic areas of the myocardium in heart failure (HF) rats by evaluating its metabolic pattern, substrate utilization, and mechanistic modulation. METHODS: In vivo, echocardiography and histology were used to assess rat cardiac function; positron emission tomography was performed to assess the abundance of glucose metabolism in the ischemic border and remote areas of the heart; fatty acid metabolism and ATP production levels were assessed by hematologic and biochemical analyses. The above experiments evaluated the cardioprotective effect of QSG on left anterior descending ligation-induced HF in rats and the mode of energy metabolism modulation. In vitro, a hypoxia-induced H9C2 model was established, mitochondrial damage was evaluated by flow cytometry, and nuclear translocation of hypoxia-inducible factor-1 α (HIF-1 α) was observed by immunofluorescence to assess the mechanism of energy metabolism regulation by QSG in hypoxic and normoxia conditions. RESULTS: QSG regulated the pattern of glucose and fatty acid metabolism in the border and remote areas of the heart via the HIF-1 α pathway, and improved cardiac function in HF rats. Specifically, QSG promoted HIF-1 α expression and entry into the nucleus at high levels of hypoxia (P<0.05), thereby promoting increased compensatory glucose metabolism; while reducing nuclear accumulation of HIF-1 α at relatively low levels of hypoxia (P<0.05), promoting the increased lipid metabolism. CONCLUSIONS QSG regulates the protein stability of HIF-1 α, thereby coordinating energy supply balance between the ischemic border and remote areas of the myocardium. This alleviates the energy metabolism disorder caused by ischemic injury.
Animals ; Myocardial Infarction/physiopathology* ; Male ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism* ; Rats, Sprague-Dawley ; Glucose/metabolism* ; Drugs, Chinese Herbal/therapeutic use* ; Energy Metabolism/drug effects* ; Rats ; Fatty Acids/metabolism* ; Myocardium/pathology*

Mycophenolic acid (MPA), the active moiety of both mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS), serves as a primary immunosuppressant for maintaining solid organ transplants. Therapeutic drug monitoring (TDM) enhances treatment outcomes through tailored approaches. This study aimed to develop an evidence-based guideline for MPA TDM, facilitating its rational application in clinical settings. The guideline plan was drawn from the Institute of Medicine and World Health Organization (WHO) guidelines. Using the Delphi method, clinical questions and outcome indicators were generated. Systematic reviews, Grading of Recommendations Assessment, Development, and Evaluation (GRADE) evidence quality evaluations, expert opinions, and patient values guided evidence-based suggestions for the guideline. External reviews further refined the recommendations. The guideline for the TDM of MPA (IPGRP-2020CN099) consists of four sections and 16 recommendations encompassing target populations, monitoring strategies, dosage regimens, and influencing factors. High-risk populations, timing of TDM, area under the curve (AUC) versus trough concentration (C₀), target concentration ranges, monitoring frequency, and analytical methods are addressed. Formulation-specific recommendations, initial dosage regimens, populations with unique considerations, pharmacokinetic-informed dosing, body weight factors, pharmacogenetics, and drug‍-‍drug interactions are covered. The evidence-based guideline offers a comprehensive recommendation for solid organ transplant recipients undergoing MPA therapy, promoting standardization of MPA TDM, and enhancing treatment efficacy and safety.
Mycophenolic Acid/administration & dosage* ; Drug Monitoring/methods* ; Humans ; Organ Transplantation ; Immunosuppressive Agents/administration & dosage* ; Delphi Technique

Triple-negative breast cancer is therapeutically challenging due to the low expression of tumor markers and 'cold' tumor immunosuppressive microenvironment. Here, we present a dual-targeting peptide-drug conjugate (PDC) for tumor inhibition. Our PDC efficiently and selectively delivers cytotoxic Monomethyl Auristatin E (MMAE) into tumor cells via C-X-C chemokine receptor type 4 (CXCR4) and folate receptor 1 (FOLR1) for synergistic inhibition of growth and metastasis. Our results show that the dual-targeting PDC has potent antitumor activity in cultured human cells and several murine transplanted tumor models without apparent toxicity. The combination of dual-targeting PDC and radiotherapy modulates the tumor immunosuppressive microenvironment by increasing CD8⁺ T cell infiltration and attenuating the proportion of myeloid-derived suppressor and regulatory T cells. Therefore, our dual-targeting PDC represents a promising new strategy for cancer therapy that rebalances the immune system and promotes tumor regression.

Dysregulated RNA splicing is a well-recognized characteristic of colorectal cancer (CRC); however, its intricacies remain obscure, partly due to challenges in profiling full-length transcript variants at the single-cell level. Here, we employ high-depth long-read scRNA-seq to define the full-length transcriptome of colorectal epithelial cells in 12 CRC patients, revealing extensive isoform diversities and splicing alterations. Cancer cells exhibited increased transcript complexity, with widespread 3'-UTR shortening and reduced intron retention. Distinct splicing regulation patterns were observed between intrinsic-consensus molecular subtypes (iCMS), with iCMS3 displaying even higher splicing factor activities and more pronounced 3'-UTR shortening. Furthermore, we revealed substantial shifts in isoform usage that result in alterations of protein sequences from the same gene with distinct carcinogenic effects during tumorigenesis of CRC. Allele-specific expression analysis revealed dominant mutant allele expression in key oncogenes and tumor suppressors. Moreover, mutated PPIG was linked to widespread splicing dysregulation, and functional validation experiments confirmed its critical role in modulating RNA splicing and tumor-associated processes. Our findings highlight the transcriptomic plasticity in CRC and suggest novel candidate targets for splicing-based therapeutic strategies.
Humans ; Colorectal Neoplasms/metabolism* ; RNA Isoforms/metabolism* ; Single-Cell Analysis ; RNA Splicing ; Gene Expression Regulation, Neoplastic ; RNA, Neoplasm/metabolism* ; Transcriptome

BACKGROUND: Neoadjuvant chemoradiotherapy followed by radical surgery has been a common practice for patients with locally advanced rectal cancer, but the response rate varies among patients. This study aimed to develop a ResNet-Vision Transformer based magnetic resonance imaging (MRI)-endoscopy fusion model to precisely predict treatment response and provide personalized treatment. METHODS: In this multicenter study, 366 eligible patients who had undergone neoadjuvant chemoradiotherapy followed by radical surgery at eight Chinese tertiary hospitals between January 2017 and June 2024 were recruited, with 2928 pretreatment colonic endoscopic images and 366 pelvic MRI images. An MRI-endoscopy fusion model was constructed based on the ResNet backbone and Transformer network using pretreatment MRI and endoscopic images. Treatment response was defined as good response or non-good response based on the tumor regression grade. The Delong test and the Hanley-McNeil test were utilized to compare prediction performance among different models and different subgroups, respectively. The predictive performance of the MRI-endoscopy fusion model was comprehensively validated in the test sets and was further compared to that of the single-modal MRI model and single-modal endoscopy model. RESULTS: The MRI-endoscopy fusion model demonstrated favorable prediction performance. In the internal validation set, the area under the curve (AUC) and accuracy were 0.852 (95% confidence interval [CI]: 0.744-0.940) and 0.737 (95% CI: 0.712-0.844), respectively. Moreover, the AUC and accuracy reached 0.769 (95% CI: 0.678-0.861) and 0.729 (95% CI: 0.628-0.821), respectively, in the external test set. In addition, the MRI-endoscopy fusion model outperformed the single-modal MRI model (AUC: 0.692 [95% CI: 0.609-0.783], accuracy: 0.659 [95% CI: 0.565-0.775]) and the single-modal endoscopy model (AUC: 0.720 [95% CI: 0.617-0.823], accuracy: 0.713 [95% CI: 0.612-0.809]) in the external test set. CONCLUSION The MRI-endoscopy fusion model based on ResNet-Vision Transformer achieved favorable performance in predicting treatment response to neoadjuvant chemoradiotherapy and holds tremendous potential for enabling personalized treatment regimens for locally advanced rectal cancer patients.
Humans ; Rectal Neoplasms/diagnostic imaging* ; Magnetic Resonance Imaging/methods* ; Male ; Female ; Middle Aged ; Neoadjuvant Therapy/methods* ; Aged ; Adult ; Chemoradiotherapy/methods* ; Endoscopy/methods* ; Treatment Outcome

Nuclear receptor co-activator 4 (NCOA4) acts as a selective cargo receptor that binds to ferritin, a cytoplasmic iron storage complex. By mediating ferritinophagy, NCOA4 regulates iron metabolism and releases free iron in the body, thus playing a crucial role in a variety of biological processes, including growth, development, and metabolism. Recent studies have shown that NCOA4-mediated ferritinophagy is closely associated with the occurrence and development of iron metabolism-related diseases, such as liver fibrosis, renal cell carcinoma, and neurodegenerative diseases. In addition, a number of clinical drugs have been identified to modulate NCOA4-mediated ferritinophagy, significantly affecting disease progression and treatment efficacy. This paper aims to review the current research progress on the role of NCOA4-mediated ferritinophagy in related diseases, in order to provide new ideas for targeted clinical therapy.
Humans ; Nuclear Receptor Coactivators/physiology* ; Ferritins/metabolism* ; Animals ; Neurodegenerative Diseases/metabolism* ; Iron/metabolism* ; Autophagy/physiology* ; Liver Cirrhosis/metabolism* ; Carcinoma, Renal Cell/metabolism* ; Kidney Neoplasms/physiopathology*

Traditional Chinese medicine(TCM) resources are the essential material foundation for the development of TCM. The national survey of TCM resources serves as a periodic summary of these resources, ensuring the continuity, prosperity, and development of TCM in China. Since 1949, four national surveys of TCM resources have been conducted. The fourth survey incorporated an investigation into traditional knowledge related to TCM resources, including the traditional medicinal knowledge of Chinese ethnic minorities, with the goal of systematically exploring, preserving, and inheriting this knowledge. This manuscript provides an overview of the basic findings from the first three national surveys of TCM resources, while also clarifying the concepts, categories, forms, carriers, and acquisition pathways of traditional knowledge related to TCM resources. A preliminary summary of the findings from traditional knowledge investigations reported in current literature is also presented. Based on the fourth survey, this manuscript emphasizes the urgency of developing public medical knowledge through empirically-based investigations, the excavation, and compilation of traditional knowledge. It also outlines the potential for conducting "precise" investigations based on first-hand data obtained from the survey, as well as facilitating the discovery and evaluation of new medicines using traditional knowledge related to ethnic minority medicinal practices. This manuscript is expected to provide valuable insights for promoting the health and industrial development of ethnic minority populations in the post-"survey" phase.
Humans ; Medicine, Chinese Traditional ; China/ethnology* ; Minority Groups ; Ethnicity ; Drugs, Chinese Herbal/therapeutic use* ; Health Knowledge, Attitudes, Practice/ethnology* ; Surveys and Questionnaires