In recent years, the use of laparoscopic techniques in total gastrectomy has gradually increased. Strong evidence is urgently needed to confirm the long-term oncological outcomes of laparoscopic-assisted total gastrectomy for resectable gastric cancer. The training set contained 811 gastric cancer patients from Fujian Medical University Union Hospital, and 267 gastric cancer patients in Putian University Affiliated Hospital were used as an external validation set. A minimum P value approach was used to evaluate the optimal threshold of recurrence-free survival to divide the patients into early and late recurrence cohorts based on the length of the postrecurrence survival. The training set had a 5-year actual overall survival rate of 62.5% and a 5-year actual recurrence-free survival rate of 60.3%. Of the 811 patients, 324 (40.0%) experienced recurrence, with the highest percentage of distant metastases (n = 199; 61.4%). Univariate and multivariate Cox regression analyses showed that pT stage, pN stage, nerve/lymphatic invasion, preoperative carcinoembryonic antigen, preoperative immunoinflammatory index (systemic immune-inflammatory index), and postoperative adjuvant chemotherapy were independent prognostic factors associated with overall survival and recurrence-free survival (all P < .05). The optimal cutoff time for distinguishing between early recurrence (n = 113; 34.9%) and late recurrence (n = 211; 65.1%) was the 12th postoperative month (P = .011). Factors associated with early recurrence included pT stage, pN stage, preoperative cancer antigen 72-4, cancer antigen 199, cancer antigen 125, and systemic immune-inflammatory index, based on which we constructed an early recurrence prediction model. The predictive evaluation indices of this model were significantly better than those of the American Joint Committee on Cancer Eighth Edition pTNM staging system; these results were also found in the external validation cohort. In this retrospective analysis, we found that laparoscopic-assisted total gastrectomy in patients with resectable gastric cancer had good long-term oncological outcomes, with an optimal cutoff time of 12 months postoperatively for early recurrence and late recurrence after laparoscopic-assisted total gastrectomy. The early recurrence prediction model constructed for patients with laparoscopic-assisted total gastrectomy may inform clinicians to develop more precise treatment and follow-up strategies.
Halofantrine (halo) is an antimalarial drug that has recently been proven to have the potential to treat Glioblastoma (GBM). The aim of the study is to explore the inhibitory effect of halos on GBM and its mechanism. The expression of ATP6V0D2 in GBM was analyzed using the Cancer Genome Atlas (TCGA), the comprehensive database of gene expression, and clinical patient samples. In vitro, we evaluated the inhibitory effect of halo on U251 cells; qPCR, Western blot, and immunofluorescence were used to detect the changes in ATP6V0D2 and autophagy-related genes and proteins. Transmission electron microscopy was used to detect the formation of autophagosomes. A stable ATP6V0D2 knockdown and overexpression model was constructed in U251 cells to verify the criticality of ATP6V0D2. The in vivo anti-tumor effect and mechanism of halo were evaluated using a U251 cell axillary tumor-bearing mouse model (independent experiment repeat number (n = 5) and tail vein administration injection. The expression level of ATP6V0D2 is relatively low in GBM patients. Halo upregulates ATP6V0D2 and induces cytotoxic autophagy (TA) in U251. Knockdown of ATP6V0D2 can inhibit halo-mediated TA and cytotoxicity, while overexpression can enhance these effects. Halo also demonstrated significant anti-GBM activity in vivo, and its mechanism was consistent with the results of in vitro studies. This study has preliminarily demonstrated that the anti-malarial drug halo can promote autophagy in GBM cells by upregulating the ATP6V0D2 gene, thereby exerting an anti-GBM effect. So far, no experimental studies have been conducted on the permeability of the blood-brain barrier within the halo body. Furthermore, the potential cardiac toxicity of halo is a point that deserves particular attention. Halo triggers cytotoxic autophagy in U251 cells by upregulating ATP6V0D2, establishing the key tumor suppressor factor status of ATP6V0D2 in GBM.
With the increasing frequency of electrocoagulation hemostasis used in endoscopic submucosal dissection (ESD), the incidence of postoperative bleeding is gradually decreasing, while the incidence of post-ESD electrocoagulation syndrome (PECS) is gradually increasing. Water cooling can reduce thermal injury to the intestinal wall after electrocoagulation. Therefore, this study intends to conduct a prospective, multi-center randomized controlled trial to explore the effectiveness of water cooling after electrocoagulation in reducing the occurrence of PECS. From November 2022 to October 2023, 420 patients were prospectively included. The patients were 1:1 randomly divided into two groups, named the standard ESD (S-ESD) group and the water-cooled ESD (W-ESD) group. The main outcome measure was the incidence of PECS. Secondary outcomes were ESD operative time, complete resection rates, and adverse effects. The incidence of PECS in the W-ESD group was significantly lower than that in the S-ESD group (7.6% vs. 17.1%, P = 0.003). The median operation time was also shorter in the W-ESD group than in the S-ESD group (37.0 minutes, IQR: 30.0-47.0 minutes vs 42.5 minutes, IQR: 33.0-60.0 minutes, P < 0.001). There was no significant difference in specimen size between the two groups (3.8cm2, IQR: 3.1-6.3cm2 vs 4.6cm2, IQR: 3.1-7.1cm2, P = 0.286), and the complete resection rate was 100%. No perforation occurred in any patient. Water-cooled ESD technology can significantly reduce the occurrence of PECS.
Protein corona formation is widely viewed as an inevitable but poorly controlled event when nanoparticles encounter biological environments. Converting this interfacial layer into a programmable functional entityremains a major challenge. Here, we report an adaptive protein corona nanoassembly strategy that integrates cytokine signaling with endogenous antigen transport. Coordination-engineered manganese nanoscaffolds were assembled with interleukin-12 (IL-12) and protected by an enzyme-responsive hyaluronic acid shell to form nanoshuttles (NSs) capable of dynamic protein recruitment in the tumor microenvironment (TME). Following enzymatic activation, exposure of the cationic manganese surface promotes adaptive corona formation and efficient capture of tumor-derived antigens. The resulting antigen-associated nanoassemblies traffic to tumor-draining lymph nodes, where they facilitate dendritic cell cross-presentation and tumor-specific T-cell priming. This coordinated process couples intratumoral cytokine signaling with antigen delivery, generating potent systemic antitumor immunity at significantly reduced IL-12 doses. These findings establish adaptive protein corona nanoassembly as a chemical strategy for programming nano-bio interfaces to coordinate cytokine signaling and antigen transport.
Hilar cholangiocarcinoma (HCCA) is a malignant tumor at the hepatic hilum with poor prognosis and survival despite surgical resection. While existing staging systems, including AJCC, Gazzaniga T, MSKCC and Blumgart, provide prognostic frameworks, their predictive accuracy remains suboptimal. This study aimed to develop and validate a novel machine learning-based postoperative staging system to predict overall survival (OS) and enhance prognostic stratification for HCCA patients undergoing surgery. We retrospectively analyzed 426 HCCA patients who underwent surgical resection at Eastern Hepatobiliary Surgery Hospital (EHBH) between February 2011 and May 2022. Seventy clinical variables, encompassing demographic characteristics, laboratory parameters, and imaging data, were evaluated. Eight machine learning algorithms were employed for feature selection and model development. A multivariable Cox regression analysis was subsequently performed to establish a staging system. External validation was performed using an independent cohort of 88 HCCA patients for further evaluation. The final model incorporated key prognostic factors including tumor stage, vascular invasion, and tumor biomarkers (CA199,CA125,CEA). The CatBoost algorithm demonstrated superior performance on the validation set (AUC = 0.88). The developed EHBH-HCCA staging system based on CatBoost stratified patients into four risk levels, significantly differentiating 3-year survival outcomes (P < 0.001). Median survival times were: Level I (> 36 months), Level II (25.0 months), Level III (18.0 months), and Level IV (< 12 months). The system showed superior discrimination (Harrell's C-index: 0.717, 95% CI: 0.662-0.793) and predictive accuracy (Brier score: 0.144) compared with conventional staging systems. In the external validation cohort, the CatBoost model demonstrated good discriminative performance for 3-year survival prediction, with an AUC of 0.84. For survival time prediction, the TabNet model achieved an RMSE of 4.71 months, MAE of 3.49 months, and R² of 0.53. The EHBH-HCCA staging system provides enhanced prognostic stratification for HCCA patients following surgical resection. This novel approach offers potential for improved clinical decision-making and personalized treatment regimen.
The development of catalytic systems for the enantioselective epoxidation of sterically hindered trisubstituted alkenes using molecular oxygen (O₂) as the terminal oxidant remains a formidable challenge. Here, we report a biomimetic bifunctional photocatalyst that integrates a chiral manganese center and a covalently tethered anthraquinone photosensitizer within a single molecular scaffold. This unified design emulates the enzymatic principle of spatially coupled oxygen activation and chiral induction. Under visible light and ambient O₂, the catalyst enables the asymmetric epoxidation of challenging trisubstituted alkenes, including cyclic sulfones and linear α,β-unsaturated carbonyls, in up to 99% enantiomeric excess (ee), and also facilitates the efficient conversion of sulfilimines to (chiral) sulfoximines. Mechanistic studies reveal a cascade involving singlet-oxygen-mediated oxidation, oxidative decarboxylation, and acid-assisted O-O bond heterolysis to generate a high-valent Mn⁴⁺=O species as the key active intermediate. By unifying light harvesting, O₂ activation, and asymmetric catalysis in a precious-metal-free platform, this work establishes a versatile, sustainable strategy for the selective oxidation of traditionally recalcitrant substrates.
G1 to S phase transition 1 (GSPT1) represents a promising yet historically challenging therapeutic target for MYC-driven malignancies. Herein, we identified XYD113, a potent and highly selective GSPT1-targeting molecular glue degrader. XYD113 exhibits significant antiproliferative activity (IC50 < 100 nM) against multiple MYC-overexpressing cancer cell lines (22Rv1, MV4-11, MOLM-16, Calu-1, HS-SY-II), and induces GSPT1 degradation in a dose- and time-dependent manner, with potency comparable to that of the clinical candidate MRT-2359. It also exhibits excellent selectivity without degrading common glutarimide analog substrates (such as SALL4, IKZF1/2/3, or CK1α). Mechanistically, XYD113 acts as a molecular glue to facilitate CRBN-GSPT1 ternary complex formation, mediating GSPT1 degradation via the UPS in a CRBN-dependent manner. Additionally, XYD113 demonstrates favorable stability in liver microsomes. Notably, XYD113 effectively downregulates the expression of genes critical for the initiation and progression of prostate cancer. In vivo, oral administration of XYD113 (5 mg/kg, daily for 21 days) significantly inhibited 22Rv1 xenograft growth (TGI = 46%) and showed a favorable safety profile in BALB/c-nude mice. Together, these findings highlight XYD113 as a promising therapeutic degrader worthy of further development for the treatment of MYC-driven cancers.
In this study, a novel double-stranded RNA (dsRNA) mycovirus, tentatively designated Fusarium solani partitivirus 4 (FsPV4), was isolated from the Fusarium solani strain GF7, a phytopathogenic fungus responsible for tobacco root rot. The genome of FsPV4 consists of two dsRNA segments, referred to as dsRNA1 (2312 bp in length) and dsRNA2 (2213 bp in length). The dsRNA 1 and dsRNA 2 were predicted to encode an RNA-dependent RNA polymerase (RdRp) and a coat protein (CP), respectively. Sequence analysis revealed that the RdRp of FsPV4 showed significant sequence similarity to the RdRps of partitiviruses, with Aplosporella javeedii partitivirus 1 being the best match (identity: 60.76%). Phylogenetic analysis of the RdRp showed that FsPV4 clustered robustly within the genus Betapartitivirus of the family Partitiviridae. This represents the first report of a betapartitivirus infecting F. solani, providing a potential candidate for the biological control of F. solani-mediated plant diseases.
Current mathematical models of tumor growth are often limited by a scarcity of quantitative immune data, leading to imprecise characterizations of tumor progression. To address this limitation, we developed a novel coupled Tumor-Immune-Radiotherapy dynamics model by integrating time-resolved flow cytometry data.
Approach: An MC38 tumor-bearing mouse model was established to evaluate distinct radiotherapy fractionation regimens (Control, 5 Gy × 5, and 8 Gy × 3). Flow cytometry was employed to dynamically quantify the temporal evolution of tumor-infiltrating lymphocytes. By integrating the Linear-Quadratic model and immune cytotoxicity into the Gompertz equation, a dynamic coupled mathematical model was formulated. Least squares fitting was applied to experimental data to calibrate parameters governing immune-mediated tumor suppression and promotion.
Main results: The proposed immune-growth coupled framework demonstrated superior goodness-of-fit compared to conventional models for both hypofractionated (8 Gy × 3) and medium-dose (5 Gy × 5) regimens. Notably, the incorporation of a dynamic temporal dimension facilitated the estimation of immune intervention timing, revealing that the onset of immune synergy is distinct and critically dictated by the selected dose fractionation strategy.
Significance: The coupled model established herein not only accurately predicts tumor growth dynamics but also serves as a robust, biologically validated computational tool for predicting the efficacy of fractionation schemes and providing strategic recommendations for immunotherapy scheduling.
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Nitrite is a harmful substance generated in Litopenaeus vannamei farming systems, largely originating from the inadequate breakdown of surplus feed and shrimp feces. Its accumulation in the water can affect the growth and physiological functions of shrimp, damage the immune system, and even cause mass mortality, thus becoming a key environmental factor restricting the green development of the industry. Under nitrite stress, the eyestalk, as an important neuroendocrine regulatory center in crustaceans, participates in the stress adaptation of the organism and exerts a protective effect by regulating energy metabolism and immune function. However, the molecular regulatory mechanism of the eyestalk in response to nitrite stress remains unclear. In this study, single-cell RNA sequencing (scRNA-seq) technology was used to analyze the heterogeneity of eyestalk cells in L. vannamei under nitrite stress. A total of 18, 394 high-quality cells were obtained, and six major cell subpopulations, including Neurosecretory cell, Motor neuron, Sensory neuron, Interneuron, Neurogliocyte, and Support cell, were identified. Differential expression analysis identified 839 differentially expressed genes, and different cell types showed distinct specific responses to nitrite stress. Functional enrichment analysis indicated that pathways such as glycolysis, oxidative phosphorylation, ribosome function, and endoplasmic reticulum protein processing were significantly activated, while signal transduction and DNA repair-related pathways were inhibited. Further analysis revealed that nitrite stress could induce mitochondrial function changes and trigger oxidative stress, thereby affecting the neuroendocrine system function of the eyestalk. This study provided insights into transcriptomic responses of the eyestalk to nitrite stress at the single-cell level, laying a theoretical foundation for the management of aquaculture environments.
Objective: To investigate the anti-tumor effect of knockdown of telomerase reverse transcriptase (TERT) in melanoma and its potential clinical value. Methods: Employed TERT knockdown strategy and evaluated the expression of target gene by Western blot analysis and RT-qPCR. The in vitro effects of TERT knockdown strategy were evaluated by cell proliferation, apoptosis, migration and invasion assays in A375 cells line, and the in vivo effects were evaluated via a xenografts mouse tumor model. Results: Following TERT knockdown, a significant downregulation of both mRNA transcripts and protein expression were observed (P＜0.001). Knockdown of TERT inhibited the proliferation, migration, and invasion of melanoma cells in vitro, while enhancing apoptosis and inducing significant G0/G1 phase cell cycle arrest [The values for cell viability, number of invasive cells, 24-hour wound healing rate, apoptosis ratio, and G0/G1 phase ratio in the Con group were (100.00±6.51)%, (270.22±19.31) cells, (49.72±1.90)%, (7.13±0.36)%, and (46.69±0.45)%, respectively; in the Neg group, they were (95.80±5.33)%, (260.67±16.52) cells, (52.32±1.68)%, (7.23±0.70)%, and (47.48±0.15)%, respectively; and in the shRNA group, they were (60.80±5.29)%, (106.67±14.11) cells, (20.75±4.64)%, (12.76±0.48)%, and (59.77±0.64)%, respectively, all P＜0.05]. The results of subcutaneous tumorigenesis experiment in nude mice indicated that stably knockdown TERT in melanoma cells attenuated the tumorigenicity. Conclusion: TERT silencing effectively suppresses melanoma progression and metastasis, demonstrating its potential as a novel therapeutic target for melanoma treatment. 目的： 探讨沉默端粒酶逆转录酶（TERT）对黑色素瘤生物学功能的影响及潜在临床价值。 方法： 构建shRNA慢病毒沉默A375细胞系TERT基因，通过实时荧光定量聚合酶链反应和Western blot法检测目的基因和蛋白的表达，通过细胞计数试剂盒8法、流式细胞术、Transwell和划痕实验分析评估靶向沉默TERT的体外抗肿瘤活性，并通过异种移植瘤模型评估其体内抗肿瘤活性。 结果： 沉默TERT后其mRNA及蛋白表达均降低（均P＜0.001）。沉默TERT后黑色素瘤细胞的体外增殖、迁移、侵袭能力降低，凋亡增加，并发生了明显的G0/G1期阻滞［Con组细胞活力、侵袭数、24 h划痕愈合率、凋亡比例、G0/G1期比例分别为（100.00±6.51）%、（270.22±19.31）个、（49.72±1.90）%、（7.13±0.36）%、（46.69±0.45）%，Neg组分别为（95.80±5.33）%、（260.67±16.52）个、（52.32±1.68）%、（7.23±0.70）%、（47.48±0.15）%，shRNA组分别为（60.80±5.29）%、（106.67±14.11）个、（20.75±4.64）%、（12.76±0.48）%、（59.77±0.64）%；均P＜0.05］。裸鼠皮下成瘤实验结果提示，沉默TERT的黑色素瘤细胞成瘤能力减弱。 结论： 沉默TERT可抑制黑色素瘤的生长和转移，TERT有望成为黑色素瘤新的治疗靶点。.
The rapid evolution of deep learning is revolutionizing critical care medicine by enabling highly accurate early warning systems. These systems are capable of predicting diverse clinical deteriorations, including acute kidney injury, myocardial infarction, and circulatory failure. While demonstrating strong predictive capabilities, conventional deep learning models face two fundamental limitations in clinical implementation: their opaque decision-making processes and limited generalizability across diverse patient populations and care environments. To address these challenges, we present a causally-informed deep learning framework that integrates causal discovery to jointly identify the causal drivers of clinical outcomes alongside prediction. This approach yields two unique advantages: demonstrating the explicit interpretation of the prediction while exhibiting decent performance when applied to unfamiliar environments. Benefiting from these features, our approach achieves superior accuracy across six different critical deteriorations and also demonstrates improved generalizability across diverse patient groups compared to various baseline algorithms. Besides, we provide explicit causal pathways to serve as references for assistant clinical diagnosis and potential interventions. By incorporating causal reasoning into clinical prediction, our approach can enhance clinical decision support through both reliable forecasting and transparent physiological interpretation, paving the way for more trustworthy AI implementation in critical care.
Objective: To investigate the expression of miR-527 in bladder urothelial cell carcinoma tissues (UCC) and cell lines, and to explore the mechanism by which miR-527 inhibits bladder cancer cell migration and promotes apoptosis through targeting Bcl-2. Methods: The expression of miR-527 in bladder UCC was analyzed using The Cancer Genome Atlas database. The expression of miR-527 in bladder UCC cell lines was verified by real-time quantitative reverse transcription polymerase chain reaction. The relationship between miR-527 and its target gene Bcl-2 was validated using a dual-luciferase reporter assay. miR-527 inhibitor and miR-527 mimic were constructed for cell transfection. Cell migration and apoptosis were assessed using wound healing assay and flow cytometry. Protein expression was detected by Western blot. In vivo tumorigenesis and the expressions of Bcl-2 and Ki-67 were evaluated using a nude mouse cell-derived xenograft model and immunohistochemistry. Results: Analysis of The Cancer Genome Atlas database revealed that miR-527 expression was significantly higher in bladder cancer tissues than in normal bladder tissues, whereas Bcl-2 protein expression was significantly lower. Dual-luciferase reporter assay confirmed that miR-527 directly targeted Bcl-2. Inhibition of miR-527 significantly upregulated Bcl-2 mRNA and protein levels (both P＜0.01), enhanced cell migration, and reduced apoptosis [migration rate: (100.00±0.00)% in the miR-527 inhibitor group vs. (47.74 ± 2.18)% in the T24 control group; apoptosis rate: (2.68±1.28)% vs. (11.82±5.19)%; both P＜0.05]. Overexpression of miR-527 produced opposite effects [migration rate: (45.22±3.66)% in the miR-527 overexpression group vs. (100.00±0.00)% in the UMUC-3 control group; apoptosis rate: (11.74±0.64)% vs. (3.81±0.75)%; both P＜0.05]. In animal experiments, overexpression of miR-527 significantly inhibited tumor growth and reduced the expressions of Bcl-2 and Ki-67 in tumor tissues, whereas inhibition of miR-527 promoted tumor growth, increased tumor cellular atypia, and enhanced the expressions of Bcl-2 and Ki-67. Conclusions: miR-527, as a tumor-associated gene, is highly expressed in bladder cancer tissues. Overexpression of miR-527 inhibits the growth and migration of bladder cancer cells and induces apoptosis by negatively regulating the Bcl-2. 目的： 探讨miR-527在膀胱尿路上皮癌组织和细胞系中的表达及其通过靶向Bcl-2抑制膀胱癌细胞迁移并促进癌细胞凋亡的机制。 方法： 利用癌症基因组图谱数据库分析miR-527在膀胱尿路上皮癌组织中的表达，通过实时荧光定量逆转录聚合酶链反应验证膀胱尿路上皮癌细胞系中miR-527的表达，双荧光素酶报告基因验证miR-527与靶基因Bcl-2的关系，构建miR-527 inhibitor和miR-527 mimic进行细胞转染，细胞划痕实验及流式细胞术检测细胞迁移和凋亡情况，Western blot检测相关蛋白表达，裸鼠细胞源性异种移植和免疫组化验证体内成瘤和Bcl-2、Ki-67表达情况。 结果： 通过癌症基因组图谱数据库分析，膀胱癌组织中miR-527表达显著高于正常膀胱组织，Bcl-2蛋白表达显著降低。双荧光素酶报告基因实验证实miR-527可直接靶向Bcl-2。抑制miR-527表达后，Bcl-2 mRNA及蛋白表达水平显著升高（均P＜0.01），细胞迁移能力增强，凋亡细胞减少［T24细胞miR-527抑制组、T24细胞对照组细胞迁移率：（100.00±0.00）%、（47.74±2.18）%，细胞凋亡率：（2.68±1.28）%、（11.82±5.19）%，均P＜0.05］，但过表达miR-527则相反［UMUC-3细胞miR-527过表达组和UMUC-3 细胞对照组细胞迁移率：（45.22±3.66）%、（100.00±0.00）%，细胞凋亡率：（11.74±0.64）%、（3.81±0.75）%，均P＜0.05］。在动物实验中，过表达miR-527显著抑制肿瘤生长，肿瘤组织中Bcl-2及Ki-67表达减弱；抑制miR-527则促进肿瘤生长，肿瘤细胞异型性增加，Bcl-2及Ki-67表达增强。 结论： miR-527作为一种肿瘤相关基因，在膀胱癌组织中高表达，同时过表达miR-527可通过靶向负调控Bcl-2基因抑制膀胱癌肿瘤细胞生长和迁移，并诱导肿瘤细胞凋亡。.
The classic donor-acceptor (D-A) conjugated polymers are highly developed in organic electronics for their potential in organic light-emitting diodes, organic field-effect transistors, and organic photovoltaics. Since 2017, we reported aggregation-induced radical (AIR) and ground-state charge transfer (GSCT), which render these materials sensitive to oxygen doping and low stability in devices. In this work, we propose a strategy to design oxygen-rich conjugated radical (ORCR) by intentionally incorporating oxygen-centered radicals into the D-A backbones. A series of D-A polymers were synthesized via atom-economical direct arylation polymerization, followed by quantitative post-synthetic dealkylation to yield the corresponding oxygen-radical polymers. The introduction of oxygen radicals showed highly lowered bandgap and highly quenched fluorescence, signaling an enhanced non-radiative relaxation pathway. Electron paramagnetic resonance confirmed their high spin concentration with high air stability. Notably, BDTO2-BBT exhibited an extraordinary photothermal conversion temperature of 170°C under 808 nm laser irradiation for 60 s, maintaining performance over multiple cycles. This study reported robust open-shell ORCR materials but also provides a simple design paradigm for stable high-spin organic radical semiconductors.
Arsenic is a toxic substance widely present in the environment, and arsenic-containing pesticides and fertilizers are widely used in agricultural production. However, arsenic can enter the human body through the food chain, posing a serious threat to human health. The liver is an important metabolic and detoxification organ in living organisms and is particularly vulnerable to exogenous toxins. Transient receptor potential mucolipin 1 (TRPML1) and Inositol 1,4,5-trisphosphate receptor (IP3R), as calcium-transporting proteins on cellular organelles, play key roles in maintaining intracellular calcium homeostasis as well as organelle function and cell signaling. However, studies on the mechanism of intracellular calcium signaling in arsenic-induced liver injury are lacking. We found that arsenic impeded the endoplasmic reticulum-lysosome calcium transport process and induced impaired lysosomal activity and lysosome-associated autophagy blockage through this pathway, which ultimately led to chicken liver injury. Notably, TRPML1 and IP3R proteins are key proteins involved in the above process. This study demonstrates that arsenic induces calcium transport disruption between the endoplasmic reticulum and lysosomes via TRPML1 and IP3R proteins. This disruption impairs lysosomal function and blocks autophagy. Furthermore, this represents the first validation of this mechanism in a chicken model, offering new insights into investigating the risks of environmental arsenic exposure to human health.
The synergistic effects of microplastics (MPs) and co-existing pollutants, particularly their impact on aquatic organisms, is an emerging concern. The influence of MPs on the bioconcentration and biotransformation of organophosphate flame retardants (OPFRs) in organisms remains poorly understood. This study investigated the impact of polystyrene microplastics (PS-MPs) on the bioconcentration and metabolism of 2-ethylhexyl diphenyl phosphate (EHDPHP), a specific OPFR, in common carp. Results indicated that the adsorption kinetics of PS-MPs on EHDPHP conformed to the pseudo-second-order kinetic model (R2 > 0.961), indicating a high adsorption capacity. Both the linear model (R2 = 0.995) and Freundlich model (R2 = 0.996) described effectively the adsorption isotherms. Compared with EHDPHP exposure alone, the presence of PS-MPs potentially reduced the bioconcentration of EHDPHP in fish tissues without significantly altering its distribution. Notably, the bioconcentration factors (BCFs) and half-life (t1/2) of EHDPHP were elevated in fish. Furthermore, 14 metabolites, primarily formed through hydroxylation metabolism, were identified, suggesting that PS-MPs may amplify EHDPHP's hydroxylation process. These results offer critical insights into the environmental behavior and risk assessments of MPs and OPFRs, underscoring the need for comprehensive ecological studies in this area.
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Antibody-drug conjugates (ADCs) are covalently conjugated molecules composed of a monoclonal antibody, a payload, and a linker. They represent an innovative therapeutic approach that combines the precise targeting capability of target therapies with the cytotoxic effects of chemotherapeutic agents. Given the unique molecular structure of ADCs, drug-related adverse reactions have drawn a considerable attention. Based on the safety data of ADCs currently available in the field of lung cancer, the common adverse drug reactions primarily involve the digestive system, hematologic system, hepatobiliary system, pulmonary system, skin, eyes, sensory nervous system, and musculoskeletal system. Unlike other cancer types, lung cancer is characterized by complex disease subtypes and molecular pathological mechanisms, as well as diverse treatment modalities. Moreover, patients with advanced lung cancer often have comorbidities such as chronic obstructive pulmonary disease and pulmonary inflammation, making the comprehensive management of ADC-related adverse reactions even more challenging. To address this, the Precision Treatment Branch of Thoracic Oncology, Chinese Geriatric Health Association, has taken the lead in organizing a multidisciplinary panel of domestic experts in gastroenterology, dermatology, respiratory medicine, ophthalmology and oncology, to discuss and jointly formulate the "Consensus of Chinese experts on the multidisciplinary management of adverse reactions to antibody-drug conjugates in the treatment of Lung Cancer (2025 edition)". A total of 21 recommendations are proposed in this consensus, covering pre-ADC safety assessments, comprehensive monitoring and management of relevant adverse reactions during ADC treatment, patient education, and medication guidance for special populations. The consensus aims is to provide clinicians with practical guidelines for the application of ADC, thereby maximizing therapeutic benefits for patients with lung cancer. 抗体药物偶联物（ADC）由单克隆抗体、有效载荷和连接子3部分共价偶联组成，是将靶向药物的精准定位与化疗药物的细胞毒性杀伤作用相结合的创新疗法。鉴于ADC独特的分子结构，其药物相关的不良反应一直备受关注。根据已披露的肺癌领域ADC安全性数据，目前常见的药物不良反应主要涉及消化系统、血液系统、肝胆系统、肺部、皮肤、眼部、外周感觉神经系统及肌肉骨骼系统等。与其他癌种不同的是，肺癌不仅疾病亚型及分子病理学机制复杂，治疗模式多样，而且晚期肺癌患者常合并慢性阻塞性肺疾病、肺部炎症等多种共患病，致使ADC相关不良反应的全程化管理更具挑战。为此，由中国老年保健协会胸部肿瘤精准治疗分会专业委员会牵头，组织国内消化科、皮肤科、呼吸科、眼科及肿瘤科等多学科专家讨论并联合制定了《抗体药物偶联物治疗肺癌不良反应多学科管理专家共识（2025版）》，共提出21条推荐意见，贯穿ADC使用前安全评估、ADC治疗期间发生相关不良反应的全面监测管理、ADC治疗的患者教育以及特殊人群的用药指导，旨在为临床医师提供切实可行的ADC应用参考准则，确保肺癌患者治疗获益最大化。.
Objective: To investigate the effects of miR-1910-3p on proliferation, invasion, epithelial-mesenchymal transition (EMT) and in vivo tumor growth of lung adenocarcinoma (LUAD) cells. Methods: Bioinformatics analysis was performed using The Cancer Genome Atlas (TCGA) database and the Starbase database to compare the expression of miR-1910-3p between LUAD tissues and adjacent normal tissues. In vitro experiments were conducted using human LUAD cell lines (H1299, A549) and normal lung epithelial cells (BEAS-2B). The expression level of miR-1910-3p was verified by real-time quantitative polymerase chain reaction (RT-qPCR). H1299 and A549 cells were transfected with liposomes to establish miR-1910-3p overexpression (mimic group), knockdown (inhibitor group) and negative control (NC group) cell models. Cell proliferation was assessed using the Cell Counting Kit-8 (CCK-8) assay and plate colony formation assay. Cell invasion was evaluated by Transwell invasion assay. The protein expression changes of EMT markers (E-cadherin, N-cadherin, Vimentin, Snail) were quantitatively analyzed by Western blot. For in vivo experiments, a subcutaneous xenograft model was established in nude mice, and tumor growth was monitored on days 7, 14, 21 and 28. At the end of the experiment, the nude mice were euthanized and the tumors were harvested for analysis. Results: Bioinformatics analysis showed that the expression level of miR-1910-3p was significantly higher in LUAD tissues than in adjacent normal tissues (P＜0.01). RT-qPCR results confirmed that compared with BEAS-2B cells, the relative expression levels of miR-1910-3p were significantly upregulated in A549 and H1299 LUAD cell lines (both P＜0.05). CCK-8 assay results showed that compared with the mimic NC group, overexpression of miR-1910-3p significantly enhanced the proliferative activity of A549 cells [mimic NC group (111.00±7.69)% vs. miR-1910-3p mimic group (119.70±7.54)%, P＜0.01] and H1299 cells [mimic NC group (113.40±15.21)% vs. miR-1910-3p mimic group (118.3±18.82)%, P＜0.01]; conversely, compared with the inhibitor NC group, knockdown of miR-1910-3p significantly inhibited the proliferative activity of A549 cells [inhibitor NC group (115.90±11.39)% vs. miR-1910-3p inhibitor group (111.90±8.83)%, P＜0.05] and H1299 cells [inhibitor NC group (113.20±15.34)% vs. miR-1910-3p inhibitor group (109.60±12.53)%, P＜0.05]. Plate colony formation assay showed that compared with the mimic NC group, overexpression of miR-1910-3p significantly enhanced the colony formation ability of A549 cells [mimic NC group (18.96±1.92)% vs. miR-1910-3p mimic group (37.33±3.66)%, P＜0.01] and H1299 cells [mimic NC group (22.86±2.78)% vs. miR-1910-3p mimic (42.33±2.58)%, P＜0.01]; conversely, compared with the inhibitor NC group, knockdown of miR-1910-3p significantly inhibited the colony forming ability of A549 cells [inhibitor NC group (19.46±3.33)% vs. miR-1910-3p inhibitor group (10.79±2.86)%, P＜0.01] and H1299 cells [inhibitor NC group (22.63±1.27)% vs. miR-1910-3p inhibitor group (12.96±1.45)%, P＜0.01]. Western blot analysis showed that compared with the mimic NC group, overexpression of miR-1910-3p significantly upregulated the expression of N-cadherin, Vimentin and the transcription factor Snail, while downregulating the expression level of E-cadherin (all P＜0.05). Transwell invasion assay showed that compared with the mimic NC group, overexpression of miR-1910-3p significantly enhanced the invasion ability of A549 cells [mimic NC group (333.00±35.68) vs. miR-1910-3p mimic group (521.67±46.92), P＜0.01] and H1299 cells [mimic NC group (341.67 ±32.87) vs. miR-1910-3p mimic group (537.66±33.13), P＜0.01]; conversely, compared with the inhibitor NC group, knockdown of miR-1910-3p significantly inhibited the invasive ability of A549 cells [inhibitor NC group (363.67±49.24) vs. miR-1910-3p inhibitor group (211.33±27.79), P＜0.01] and H1299 cells [inhibitor NC group (351.67±24.11) vs. miR-1910-3p inhibitor group (154.33±9.29), P＜0.01]. Subcutaneous xenograft experiment in nude mice showed that compared with the mimic NC group, overexpression of miR-1910-3p significantly promoted tumor growth in vivo, manifested as an increased tumor weight and volume (both P＜0.01). In the mimic NC group, tumor weights on days 7, 14, 21 and 28 were (0.08±0.01) g, (0.18±0.03) g, (0.41±0.06) g and (0.73±0.06) g, respectively; in the the miR-1910-3p mimic group, tumor weights on days 7, 14, 21 and 28 were (0.07±0.01) g, (0.35±0.06) g, (0.72±0.08) g, and (0.96±0.09) g, respectively. In the mimic NC group, tumor volumes on days 7, 14, 21 and 28 were (132.00±1.00) mm3, (254.67±7.10) mm3, (530.67± 42.71) mm3 and (853.33±74.10) mm3; in the miR-1910-3p mimic group, tumor volumes on days 7, 14, 21 and 28 were (132.00±2.00) mm3, (425.33±29.94) mm3, (829.00±62.00) mm3, and (1 123.33±95.38) mm3, respectively. Conclusion: miR-1910-3p acts an oncogene in LUAD, promoting tumor cell proliferation, invasion and in vivo tumorigenesis by activating EMT process. 目的： 探讨miR-1910-3p对肺腺癌细胞增殖、侵袭、上皮-间质转化（EMT）和体内肿瘤生长的影响。 方法： 通过癌症基因组图谱数据库和Starbase数据库进行生物信息学分析，分析miR-1910-3p在肺腺癌组织与癌旁正常组织中的表达差异。体外实验采用人肺腺癌细胞系（H1299、A549）及正常肺上皮细胞（BEAS-2B），应用实时荧光定量聚合酶链反应（RT-qPCR）验证miR-1910-3p表达水平。H1299和A549细胞分别通过脂质体转染法构建miR-1910-3p过表达（mimic组）、沉默（inhibitor组）及阴性对照（NC组）细胞模型。采用细胞计数试剂盒8（CCK-8）、平板克隆形成实验评估细胞增殖能力，Transwell侵袭实验检测细胞侵袭能力，Western blot技术定量分析EMT标志物（E-cadherin、N-cadherin、Vimentin、Snail）的蛋白表达变化。体内实验建立裸鼠皮下移植瘤模型，分别于第7天、第14天、第21天及第28天监测肿瘤生长情况，实验终点处死裸鼠并取瘤分析。 结果： 生物信息学分析显示，与癌旁正常组织比较，miR-1910-3p在肺腺癌组织中表达水平升高（P<0.01）。RT-qPCR验证结果显示，与BEAS-2B细胞比较，miR-1910-3p在肺腺癌细胞系A549细胞和H1299细胞中的相对表达水平均上调（均P<0.05）。CCK-8检测结果显示，与mimic NC组比较，过表达miR-1910-3p能够促进A549细胞［mimic NC组（111.00±7.69）%，miR-1910-3p mimic组（119.70±7.54）%，P<0.01］和H1299细胞［mimic NC组（113.40±15.21）%，miR-1910-3p mimic组（118.3±18.82）%，P<0.01］的增殖能力；反之，与inhibitor NC组比较，敲低miR-1910-3p能够抑制A549细胞［inhibitor NC组（115.90±11.39）%，miR-1910-3p inhibitor组（111.90±8.83）%，P<0.05］和H1299细胞［inhibitor NC组（113.20±15.34）%，miR-1910-3p inhibitor组（109.60±12.53）%，P<0.05］的增殖能力。平板克隆实验表明，与mimic NC组比较，过表达miR-1910-3p能够促进A549细胞［mimic NC组（18.96±1.92）%，miR-1910-3p mimic组（37.33±3.66）%，P<0.01］和H1299细胞［mimic NC组（22.86±2.78）%，miR-1910-3p mimic组（42.33±2.58）%，P<0.01］的克隆形成能力；反之，与inhibitor NC组比较，敲低miR-1910-3p能够抑制A549细胞［inhibitor NC组（19.46±3.33）%，miR-1910-3p inhibitor组（10.79±2.86）%，P<0.01］和H1299细胞［inhibitor NC组（22.63±1.27）%，miR-1910-3p inhibitor组（12.96±1.45）%，P<0.05］的克隆形成能力。Western blot分析结果显示，与mimic NC组比较，过表达miR-1910-3p能够同时上调N-cadherin、Vimentin及Snail转录因子的表达，下调E-cadherin的表达水平（均P<0.05）。Transwewll检测结果显示，与mimic NC组比较，过表达miR-1910-3p能够促进A549细胞［mimic NC组（333.00±35.68）个，miR-1910-3p mimic组（521.67±46.92）个，P<0.01］和H1299细胞［mimic NC组（341.67±32.87）个，miR-1910-3p mimic组（537.66±33.13）个，P<0.01］的侵袭能力；反之，与inhibitor NC组比较，敲低miR-1910-3p能够抑制A549细胞［inhibitor NC组（363.67±49.24）个，miR-1910-3p inhibitor组（211.33±27.79）个，P<0.01］和H1299细胞［inhibitor NC组（351.67±24.11）个，miR-1910-3p inhibitor组（154.33±9.29）个，P<0.01］的侵袭能力。裸鼠皮下成瘤实验显示，与mimic NC组比较，过表达miR-1910-3p能够促进裸鼠体内肿瘤生长，肿瘤重量和体积增加（均P<0.01）。mimic NC组裸鼠第7天、第14天、第21天及第28天肿瘤重量分别为（0.08±0.01）g、（0.18±0.03）g、（0.41±0.06）g和（0.73±0.06）g；miR-1910-3p mimic组分别为（0.07±0.01）g、（0.35±0.06）g、（0.72±0.08）g和（0.96±0.09）g。mimic NC组裸鼠第7天、第14天、第21天及第28天肿瘤体积分别为（132.00±1.00）mm3、（254.67±7.10）mm3、（530.67±42.71）mm3和（853.33±74.10）mm3；miR-1910-3p mimic组分别为（132.00±2.00）mm3、（425.33±29.94）mm3、（829.00±62.00）mm3和（1 123.33±95.38）mm3。 结论： miR-1910-3p在肺腺癌中发挥促癌基因作用，其通过激活EMT进程促进肿瘤细胞增殖、侵袭及体内成瘤。.
ObjectiveTo examine the association between the percentage of peripheral natural killer cells and thyroid autoimmunity in women with a history of miscarriage and assess whether B-cells mediate this association.MethodsThis retrospective cross-sectional study was conducted on 927 women with a history of miscarriage treated at the Affiliated Hospital of Guizhou Medical University (2021-2023). Peripheral T-cell, B-cell, and natural killer cell subsets and thyroid antibodies were assessed. Multivariable logistic regression, restricted cubic splines, and mediation analyses were performed.ResultsWomen with thyroid autoimmunity had lower percentage of peripheral natural killer cells and higher percentage of B-cells than those without thyroid autoimmunity (both p < 0.001). The percentage of peripheral natural killer cells demonstrated a consistent inverse association with thyroid autoimmunity after adjustment (adjusted odds ratios: 0.00; 95% confidence interval: 0.00-0.02; all p < 0.001). Restricted cubic spline analysis indicated a nonlinear dose-response relationship that was stronger in women aged ≥35 years and in those without recurrent miscarriages. B-cells partially mediated the association between the percentage of peripheral natural killer cells and thyroid autoimmunity (31.4% of the total effect; ab = -0.166; p < 0.001).ConclusionLower percentage of peripheral natural killer cells is linked to higher odds of thyroid autoimmunity in women with a history of miscarriage, and B-cells partly explain this relationship, supporting the use of peripheral immune profiling to identify thyroid autoimmunity risk.