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Ling Chen

Publications and source records attributed to Ling Chen.

At least 19 recordsLinked to original sources
PubMed2026

Spatial proteomics reveals four-stage molecular evolution in cancer immunotherapy-related gastritis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, yet immune-related adverse events (irAEs) including immunotherapy-related gastritis (IRAEG) pose significant clinical challenges-often necessitating treatment interruption that may compromise antitumor efficacy. IRAEG presents with atypical symptoms, lacks specific biomarkers, and shows histopathological overlap with other forms of gastritis, complicating diagnosis and management. Despite increasing clinical recognition, a systematic understanding of spatial molecular alterations across the full disease course remains limited. Here, we used spatial proteomics to map the molecular landscape of IRAEG during disease progression and to define stage-specific patterns of molecular evolution relevant to cancer immunotherapy management. METHODS: We analyzed tissue samples from seven patients, including four non-immunotherapy-related gastritis controls and three cancer patients who developed IRAEG following ICI therapy for solid tumors, sampled longitudinally across four disease stages: baseline (G1), acute severe inflammation (G2), early recovery (G3), and complete recovery (G4). Using laser capture microdissection coupled with data-independent acquisition mass spectrometry, we profiled 177 spatially resolved gastric tissue regions. Multiplex immunohistochemistry and immunofluorescence characterized features of the immune microenvironment, while Gene Ontology, KEGG pathway analysis, Gene Set Variation Analysis, and xCell inference enabled functional, metabolic, and immune profiling. Key immune and NET-related findings were further validated by multiplex immunofluorescence in an independent, expanded cohort of IRAEG and non-immunotherapy-related gastritis samples. RESULTS: IRAEG was characterized by widespread HLA molecule activation and enhanced antigen processing, resembling the immune phenotype observed in organ transplant rejection. The acute G2 stage exhibited excessive neutrophil extracellular trap formation, profound metabolic suppression, and collapse of immune homeostasis-features that may inform early intervention strategies to preserve ICI treatment continuity. During early recovery (G3), inflammatory injury transitioned toward repair, marked by activation of fatty acid metabolism and PPAR signaling. Notably, even at complete clinical recovery (G4), more than 1,000 proteins remained differentially expressed, reflecting sustained enhancement of metabolic and immune functions and establishing a distinct molecular "memory" state with implications for ICI rechallenge decisions. CONCLUSIONS: These findings define four molecularly distinct stages of IRAEG progression and recovery. The stage-specific signatures identified here serve as candidate biomarkers for diagnosis, disease staging, and therapeutic response assessment, and may guide clinical decisions regarding irAE management, treatment modification, and safe ICI rechallenge to support continued antitumor therapy.

Humans↗
PubMed2026

Differentiating hemorrhagic shock and organophosphate poisoning through integrated skin microbiome-metabolome signatures.

Accurate determination of cause of death and estimation of postmortem interval (PMI) are critical yet challenging tasks in forensic science, particularly in cases with rapid demise and absence of obvious morphological abnormalities. We employed an integrative multi-omics approach to characterize postmortem microbial succession and metabolic alterations on facial skin in mouse models of hemorrhagic shock (HS) and organophosphorus poisoning (OP) across three decomposition stages: bloating (2 days), active decay (8 days), and advanced decay (16 days). Metagenomic profiling revealed significantly reduced &#x3b1;-diversity in HS compared with OP throughout all stages (p&#x2009;<&#x2009;0.001), accompanied by stage-dependent compositional shifts, including early enrichment of Firmicutes in HS and Proteobacteria in OP. A total of 237 differential taxa were identified, with Providencia and Morganella predominating in OP, whereas Staphylococcus and Corynebacterium dominated bloating stage of HS. Untargeted metabolomics uncovered distinct cause-of-death-linked metabolites, notably elevated 2'-deoxycytidine-5'-diphosphate in early OP and persistent cholic acid/cholate accumulation in HS at later PMI. Functional analysis highlighted histidine and phosphate/phosphonate metabolism as key discriminatory pathways, exhibiting stage-specific oscillations and strong correlations with characteristic taxa. These findings demonstrate that skin-based metagenomic-metabolomic integration provides robust, mechanistically informed biomarkers for both PMI estimation and cause-of-death differentiation, offering a minimally invasive and temporally dynamic tool for forensic investigations.

Animals↗
PubMed2026

Insights into the fate and dynamics of antibiotic resistance in multidrug-resistant Bacillus cereus during in vitro simulated gastrointestinal digestion.

Bacillus cereus, an important pathogen responsible for causing foodborne diseases worldwide, releases pore-forming enterotoxins, which target host epithelial cells, leading to osmotic lysis and ultimately manifesting as diarrheal syndrome. Moreover, some B. cereus strains carry antimicrobial resistance genes that confer multidrug resistance against a spectrum of antibiotics. Characterizing the survival traits of multidrug-resistant (MDR) B. cereus strains in the intestinal microenvironment is essential for developing targeted strategies to effectively manage diarrheal foodborne diseases caused by this pathogen. This study used whole-genome sequencing (WGS) to evaluate the pre- and post-digestion toxigenic potential, antimicrobial resistance profiles, and genetic diversity of MDR B. cereus strains isolated from food samples in Guangdong Province, China. The four B. cereus isolates investigated in this study exhibited a genetic diversity, as determined by multilocus sequence typing analysis of WGS data. All four isolates produced the diarrheal toxins Hbl, Nhe, and CytK to varying levels, indicative of their potential to cause outbreaks of foodborne diseases. Each of the four isolates exhibited resistance to more than three classes of antibiotics, fulfilling the criterion for multidrug resistance. At an initial concentration of 9 log colony-forming units (CFU)/mL, the intestinal concentration of these four isolates crossed the threshold required to induce widespread diarrhea in the general population. Under rice slurry protection, all tested isolates maintained intestinal concentration beyond the threshold when the initial concentration was increased to &#x2265;8 log CFU/mL. Moreover, the upregulations of genes associated with acid tolerance, bile tolerance and stress response were observed in the surviving MDR B. cereus isolates. Digestion markedly altered the antibiotic resistance profiles of the MDR B. cereus isolates. In the absence of a food matrix, the MDR isolates lost their resistance to imipenem, meropenem, amoxicillin-clavulanic acid, and trimethoprim-sulfamethoxazole post-digestion and was influenced by the initial concentration of the strains. In the presence of food matrix rice slurry, the effects of digestion on the antibiotic resistance of MDR B. cereus isolates can be mitigated, enabling them to maintain their antibiotic resistance to the greatest extent. Most remarkably, after digestion, the isolates Bce055 and Bce166 exhibited newly emergent resistance to cefotetan and trimethoprim-sulfamethoxazole, respectively. Our findings clarify the fate of MDR B. cereus isolates in the gastrointestinal tract and inform the development of prevention and control strategies for foodborne diseases caused by this pathogen.

Drug Resistance, Multiple, Bacterial↗
PubMed2026

Artificial intelligence-assisted histopathological diagnosis of endocervical gastric-type adenocarcinoma: a multicenter model development and validation study.

Endocervical gastric-type adenocarcinoma (GAS) is one of the most aggressive subtypes of cervical cancer and is frequently underdiagnosed due to morphological ambiguity, leading to delayed diagnosis. Despite the availability of molecular and genomic assays, their high cost, complexity, and limited reproducibility restrict clinical use. This study therefore proposes a highly sensitive artificial intelligence (AI)-assisted diagnostic system for GAS based exclusively on H&E-stained histopathological images. We included 309 slides from 96 GAS cases collected at Peking University Third Hospital from January 2018 to January 2025, representing the largest GAS cohort reported to date for AI research. In addition, we incorporated other morphologically analogous diseases, encompassing a total of 1,320 slides sourced from four categories: normal cervical mucosa (NORM), benign endocervical lesion entities (BELE), HPV-associated adenocarcinoma (HPVA), and endometrioid carcinoma with mucinous differentiation (ECMD). We developed GASPath, based on a novel multiple instance learning framework that efficiently captures fine-grained morphological variations from H&E-stained images. Beyond internal validation, GASPath was evaluated across 12 independent retrospective cohorts and further subjected to large-scale real-world validation on more than 7,000 samples from March 2024 to April 2025. Across three stages, GASPath demonstrated high performance. In internal validation (Stage I), it achieved an accuracy of 0.980 (95% CI 0.977-0.983) and an ROC-AUC of 0.995 (95% CI 0.994-0.997). In external validation (Stage II), the sensitivity reached 0.902 and improved to 0.968 with proposed strategies. For biopsy samples, GASPath achieved an ROC-AUC of 0.990 (95% CI 0.984-0.997). In large-scale real-world deployment (Stage III, n&#x2009;=&#x2009;7,056), GASPath achieved a balanced accuracy of 0.953, with 100% sensitivity for GAS (45/45 cases correctly identified). The heatmaps highlight morphological features of GAS that are easily underestimated, such as irregular, angulated glands, subtle loss of nuclear polarity, and mild cytologic atypia, which show substantial morphological overlap with other diagnostic categories. GASPath enables high-sensitivity detection of GAS in routine H&E-stained slides, obviating the need for extensive auxiliary testing while preventing underdiagnosis and misdiagnosis. This advancement addresses a critical gap by streamlining diagnostic workflows without compromising accuracy. Its implementation could enable cost-effective, scalable AI-assisted diagnostics, potentially transforming the early detection and management of this aggressive cancer subtype.

Female↗
PubMed2007

Influence of anti-washout agents on the rheological properties and injectability of a calcium phosphate cement.

Anti-washout-type calcium phosphate cement (aw-CPC) was prepared by introducing chitosan, sodium alginate, or modified starch into the powder phase of CPC, respectively. The results showed that these cements cannot be washed out and set within approximately 10-30 min even if the pastes were immersed in distilled water immediately and were shaken in a shaker after mixing and moulding. To our knowledge, it is the first report about the influence of the content of these anti-washout additives on the rheological properties and injectability of the cement. Moreover, novel approach of yield stress measurement was used to evaluate the injectability of the pastes. A modified starch was originally used as anti-washout agent for CPC. This study provided a convenient way to use the injectable CPC with good anti-washout performance when the paste was exposed to blood. The aw-CPC had potential prospects for the wider applications in surgery such as orthopaedics, oral, and maxillofacial surgery.

Alginates↗
PubMed2007

Self-setting properties of a beta-dicalcium silicate reinforced calcium phosphate cement.

Beta-dicalcium silicate was used to reinforce the injectable calcium phosphate cement (iCPC) for the first time in this study. The influence of the content of beta-dicalcium silicate on the mechanical properties, setting time, rheological properties, injectability, phase evolution, microstructure, and biodegradability of iCPC was systematically investigated. The results demonstrated that the addition of 8 wt % beta-dicalcium silicate obviously enhanced the compressive strength of the CPC from 26.5 to 47.5 MPa, and did not significantly influence the biodegradability, setting time, injectability, phase evolution, and microstructure of the CPC. The beta-dicalcium silicate-reinforced iCPC with relatively high mechanical property should have potential prospects for the wider applications in surgery such as orthopedics, oral, and maxillofacial surgery.

Bone Cements↗
PubMed2006

A novel approach to phylogenetic tree construction using stochastic optimization and clustering.

BACKGROUND: The problem of inferring the evolutionary history and constructing the phylogenetic tree with high performance has become one of the major problems in computational biology. RESULTS: A new phylogenetic tree construction method from a given set of objects (proteins, species, etc.) is presented. As an extension of ant colony optimization, this method proposes an adaptive phylogenetic clustering algorithm based on a digraph to find a tree structure that defines the ancestral relationships among the given objects. CONCLUSION: Our phylogenetic tree construction method is tested to compare its results with that of the genetic algorithm (GA). Experimental results show that our algorithm converges much faster and also achieves higher quality than GA.

Algorithms↗
PubMed2006

An improved ant colony algorithm with diversified solutions based on the immune strategy.

BACKGROUND: Ant colony algorithm has emerged recently as a new meta-heuristic method, which is inspired from the behaviours of real ants for solving NP-hard problems. However, the classical ant colony algorithm also has its defects of stagnation and premature. This paper aims at remedying these problems. RESULTS: In this paper, we propose an adaptive ant colony algorithm that simulates the behaviour of biological immune system. The solutions of the problem are much more diversified than traditional ant colony algorithms. CONCLUSION: The proposed method for improving the performance of traditional ant colony algorithm takes into account the polarization of the colonies, and adaptively adjusts the distribution of the solutions obtained by the ants. This makes the solutions more diverse so as to avoid the stagnation and premature phenomena.

Algorithms↗
PubMed2006

In vitro anti-tumor immune response induced by dendritic cells transfected with hTERT recombinant adenovirus.

Transduction with recombinant, replication-defective adenoviral (Ad) vectors encoding a transgene is an efficient method for gene transfer into human dendritic cells (DC). Several studies have demonstrated that epitopes of the human telomerase reverse transcriptase gene (hTERT) can produce CTLs specific for malignant tumors. In this study, we constructed an hTERT recombinant adenovirus (rAd-hTERT) using DNA recombination. We found that human dendritic cells transduced with rAd-hTERT could effectively induce hTERT-specific cytotoxic T lymphocytes (CTLs) in vitro against various tumor cell lines, which were hTERT-positive and HLA-A2 matched. We also found that these hTERT-specific CTLs could not lyse autologous lymphocytes with low telomerase activity. Further studies revealed that rAd-hTERT transduced DCs could increase secretion of IFN-gamma by effector cells when they were co-cultured with hTERT-positive and HLA-A2 matched tumor cell lines. These data suggest that an hTERT vaccine can induce anti-tumor immunity against various tumor cells expressing hTERT in a HLA-A2-restricted fashion in vitro. The transduction of DCs with rAd-hTERT offers a great opportunity in cancer immunotherapy.

Adenoviridae↗
PubMed2006

Enhancement of hydrolysis and acidification of solid organic waste by a rotational drum fermentation system with methanogenic leachate recirculation.

A cascade process of a rotational drum fermentation system with leachate recirculation from a methanogenic to the acidogenic reactor was constructed to enhance the hydrolysis and acidification of solid organic waste. Using fresh soybean meal as substrates, two process configurations, Cascade process 1 and 2, without and with leachate recirculation, respectively were employed to perform the experimental estimation under mesophilic condition and a total HRT of 20 days. An apparent first-order hydrolysis rate constant of 9.0 x 10(-3)/d for Cascade process 1 at pH 4.5-4.6, and 15.8 x 10(-3)/d for Cascade process 2 at pH 4.6-5.2 were obtained. The apparent VS degradation ratios ranged from 16.5% to 21.1% and total VA (as acetic acid) from 14.5 to 16.7 g/L. Occupying ratios for ionized VA decreased from 40.5% to 35.3% for Cascade process 1 and increased to 68.5% for Cascade process 2. However, occupying ratios of acetic acid decreased from 96.1% to 94.3% for Cascade process 1 and to 72.6% for Cascade process 2, whereas propionic acid and butyric acid ratios increased in acidogenesis of Cascade process 2. The leachate recirculation promoted hydrolysis of substrate in Cascade process 2, where apparent hydrolysis rate constant and VS degradation ratio were higher than that of Cascade process 1.

Acetic Acid↗
PubMed2006

The effect of Fe0/Fe2+/Fe3+ on nitrobenzene degradation in the anaerobic sludge.

The influence of Fe(0)/Fe(2+)/Fe(3+) on the nitrobenzene (NB) degradation in the anaerobic granular sludge was studied and the results demonstrated that: adding iron powder into the anaerobic sludge could exert an accelerative effect on the NB degradation and the degradation rate was faster than that by using iron or the anaerobic sludge alone. The external addition of Fe(2+)/Fe(3+) exhibited different influences on the NB degradation depending on the concentrations of Fe(2+)/Fe(3+) and the solution's pH. When Fe(2+)/Fe(3+) are less than 100 mg/L at pH 6, Fe(2+)/Fe(3+) inhibited the NB degradation slightly, and when Fe(2+)/Fe(3+) was 100-200 mg/L, the NB degradation was enhanced. When pH was shifted to 9, Fe(2+) of lower than 100 mg/L promoted the NB degradation, and 200 mg/L Fe(2+) inhibit the NB degradation. The synergism of combined use of iron and the anaerobic sludge in treating NB wastewater was proposed, and adjusting the concentrations of Fe(2+)/Fe(3+) in the anaerobic sludge according to the pH of the wastewater could be an effective method to obtain a high removal rate of NB.

Bacteria, Anaerobic↗
PubMed2006

Dehydroepiandrosterone sulfate prevents ischemia-induced impairment of long-term potentiation in rat hippocampal CA1 by up-regulating tyrosine phosphorylation of NMDA receptor.

We have reported that dehydroepiandrosterone sulfate (DHEAS) reduces the threshold for long-term potentiation (LTP) in Shaffer collateral-CA1 synapses through the amplification of Src-dependent NMDA receptor signaling. The present study is a follow-up of the above reports, aiming at evaluating the effects of DHEAS on the impaired LTP in reversible forebrain ischemic rats. Transient (20 min) incomplete forebrain ischemia led to an impaired LTP in the hippocampal CA1 region without damages to the basal synaptic transmission between the Shaffer collaterals and pyramidal neurons. Repetitive administrations of DHEAS (20 mg/kg for 3 days) from the first 3 h of reperfusion, but not acute DHEAS application (50 microM), prevent the impairment of LTP produced by ischemia. Co-administration of the specific sigma(1) receptor antagonist NE100 with DHEAS completely prevented the protective effect of DHEAS. In contrast, progesterone (PRGO) not only had no protective effect against the ischemic LTP impairment, but also attenuated the protective effect of DHEAS on the impaired LTP. Tyrosine phosphorylation of NMDA receptor subunit 2B (NR2B) significantly decreased after ischemia, whereas that of NR1 had no obvious change. Furthermore, the repetitive administration of DHEAS improved the reduction in tyrosine phosphorylation of NR2B. These findings suggest that the repetitive activation of sigma(1) receptor induced by DHEAS might prevent the ischemic LTP impairment through regulating the tyrosine phosphorylation of NR2B.

2-Amino-5-phosphonovalerate↗
PubMed2006

Regioselective protection at N-2 and derivatization at C-3 of indazoles.

Indazoles are regioselectively protected at N-2 by a 2-(trimethylsilyl)ethoxymethyl (SEM) group using novel conditions. The SEM group can efficiently direct regioselective C-3 lithiation, and the resulting nucleophile can react with a wide range of electrophiles to generate novel indazole derivatives. The SEM group can be removed by treatment with TBAF in THF or aqueous HCl in EtOH.

Indazoles↗
PubMed2006

Chronic DHEAS administration facilitates hippocampal long-term potentiation via an amplification of Src-dependent NMDA receptor signaling.

Dehydroepiandrosterone sulfate (DHEAS) has well characterized effects on memory and cognitive performances. Recently we have reported that repetitive administration of DHEAS lowers the threshold pulse number in inducing activity-dependent long-term potentiation (LTP) in rat hippocampal Schaffer collateral-CA1 synapses, in which a sub-threshold high frequency stimulation (HFS, 30 pulses at 100 Hz) for normal rats could induce robust LTP in DHEAS-treated rats (Chen et al., 2006). Here we report that the sub-threshold HFS could trigger the phosphorylation of Src and ERK2 in the DHEAS-treated rats, but not in control rats. We found in slices obtained from the DHEAS-treated rats that NMDA-induced intracellular Ca2+([Ca2+]i) transients in CA1 pyramidal neurons were significantly potentiated, which was essential for the Src and ERK2 phosphorylations. The activation of ERK2, a downstream factor of Src family kinase, was required for the DHEAS-facilitated LTP. The Src family kinase inhibitor PP2, but not its inactive homologue PP3, attenuated the NMDA-induced [Ca2+]i increase and abolished the DHEAS-facilitated LTP. These findings suggest that the chronic administration of DHEAS brings the NMDA receptor (NMDAr) to a potentiated state that causes an enough level of [Ca2+]i increase for LTP induction even by the sub-threshold HFS. The potentiated [Ca2+]i transient by the sub-threshold HFS may trigger the Src phosphorylation that will further potentiate NMDAr followed by an activation of ERK2 and LTP induction. This novel postsynaptic NMDAr/Src-mediated signal amplification through "NMDAr-Ca2+-->Src-->NMDAr-Ca2+" cycle may play a pivotal role in the DHEAS-facilitated LTP induction.

Analysis of Variance↗
PubMed2006

Effect of strut chordae transection on mitral valve leaflet biomechanics.

Strut chordae transection (SCT) has been recommended as a surgical treatment for mitral regurgitation (MR) arising from ischemic heart disease. However, little is known about the contribution of anterior strut chordae to leaflet tissue mechanics. In this study, experimental measurements of mitral valve deformation under quasi-static pressure loading were performed on isolated pig hearts before and after transecting both strut chordae. Biplane video images of markers placed on the anterior leaflet surface were used to reconstruct the 3D position of the markers. The 2D nonhomogeneous deformations in the anterior leaflet were calculated by least squares fit to the 3D marker coordinates in successive pressure loading states. Results show that the anterior leaflet undergoes large, anisotropic and nonhomogeneous deformation, with a significant radial stretch gradient and smaller, uniform circumferential stretch. Following chordal transection, the radial deformation decreases. A gradient in the circumferential stretch is observed as an increase from the annulus toward the coaptation line. Without the support provided by the strut chordae, the center portion of the anterior leaflet experienced a substantial change in shape in response to the systolic pressure, altering the load-bearing mechanism in the valvular structure. The shift of the deformation distribution suggests that additional strain energy is absorbed by the circumferentially oriented collagen fibers following SCT and may result in long-term tissue remodeling. This study provides detailed biomechanical data for interpreting the results of previous investigations of SCT, as well as for exploring a greater understanding of how SCT affects MR through computational modeling.

Animals↗
PubMed2006

Mutations induced by carcinogenic doses of aristolochic acid in kidney of Big Blue transgenic rats.

Aristolochic acid (AA) is present in at least 65 different kinds of plants, many of which are used as herbal folk remedies. AA is considered one of the most potent plant carcinogens in humans and animals. It has been associated with the development of urothelial cancers in humans, and kidney and forestomach tumors in rats. In the present study, we used the Big Blue transgenic rat model to evaluate the mutagenicity of AA in kidney of rats and to define the mechanism of action for the tumor induction by AA. Groups of six male Big Blue transgenic rats were gavaged with 0, 0.1, 1.0 and 10.0mgAA/kg body weight 5 times a week for 12 weeks, a treatment protocol that resulted in tumors in kidneys and other tissues. The animals were sacrificed 1 day after the final treatment and the kidneys were isolated for assays to determine the mutant frequencies (MFs) and types of mutations induced by AA in the transgenic cII gene. AA treatment resulted in a strong linear relationship between MF inductions and treatment dose (R(2)=0.998). The cII MFs were 29+/-6x10(-6), 78+/-21x10(-6), 242+/-104x10(-6) and 1319+/-360x10(-6) in the control, low, medium and high dose treatment groups, respectively (p<0.001 for all pair wise comparisons among the four treatment groups). These MFs correlated strongly with tumor incidences induced by the different doses of AA (Mengs et al., 1982). Sequence analysis of the cII mutants revealed that there was a statistically significant difference between the mutational spectra in the AA-treated and control rats (p<0.05). A:T-->T:A transversion was the predominant type of mutation in the AA-treated rats whereas G:C-->A:T transition was the main type of mutations in the control rats. These results suggest that AA induces kidney tumors in rats though a mutagenic mechanism of action.

Amino Acid Substitution↗
PubMed2006

The glycoprotein hGC-1 binds to cadherin and lectins.

Human granulocyte colony stimulating factor stimulated clone-1 (hGC-1, also known as GW112, OLM4, and hOlfD) is an olfactomedin-related glycoprotein of unknown function. We performed a series of biochemical studies to characterize its function. Using hGC-1 purified from baculovirus Sf9 cells we demonstrated that hGC-1 is a secreted glycoprotein containing N-linked carbohydrate chains and forms disulfide-bonded multimers. It binds to cell surfaces and to the locutions ricinus communis agglutinin I, concanavalin A and wheat germ agglutinin. Purified hGC-1 enhanced NIH3T3 and 293T/17 cell spreading and attachment, as did hGC-1-enriched culture supernatants of 293T/17 cells transfected with an hGC-1 expression vector. Coimmunoprecipitation studies demonstrated that hGC-1 interacts with cadherin in 293T/17 cells. This interaction depends on the C-terminal olfactomedin domain, but does not require the five well-conserved cysteine residues. However, cysteine residues at 83, 85, 246 and 437 are essential for secretion, and cysteine 226 is critical for hGC-1 multimer formation. Our studies demonstrated that hGC-1, an extracellular matrix glycoprotein, facilitates cell adhesion. Its potential interaction with endogenous cell surface lectins and cadherin may mediate this function.

Animals↗