Immune regulation and the tumor microenvironment in anti-PD-1/PDL-1 and anti-CTLA-4 therapies for cancer immune evasion: A bibliometric analysis.

This study aims to conduct a bibliometric analysis, employing visualization tools to examine literature pertaining to tumor immune evasion related to anti-CTLA-4 and anti-PD-1/PD-L1 therapy from 1999 to 2022. A special emphasis is placed on the interplay between tumor microenvironment, signaling pathways, immune cells and immune evasion, with data sourced from the Web of Science core collection (WoSCC). Advanced tools, including VOSviewer, Citespace, and Scimago Graphica, were utilized to analyze various parameters, such as co-authorship/co-citation patterns, regional contributions, journal preferences, keyword co-occurrences, and significant citation bursts. Out of 4778 publications reviewed, there was a marked increase in research focusing on immune evasion, with bladder cancer being notably prominent. Geographically, China, the USA, and Japan were the leading contributors. Prestigious institutions like MD Anderson Cancer Center, Harvard Medical School, Fudan University, and Sun Yat Sen University emerged as major players. Renowned journals in this domain included Frontiers in Immunology, Cancers, and Frontiers in Oncology. Ehen LP and Wang W were identified as prolific authors on this topic, while Topalian SL stood out as one of the most cited. Research current situation is notably pivoting toward challenges like immunotherapy resistance and the intricate signaling pathways driving drug resistance. This bibliometric study seeks to provide a comprehensive overview of past and current research trends, emphasizing the potential role of tumor microenvironment, signaling pathways and immune cells in the context of immune checkpoint inhibitors (ICIs) and tumor immune evasion.

Advances and prospects of natural dietary polyphenols as G-quadruplex stabilizers in biomedical applications.

G-quadruplexes (G4s) have arrested continuous interest in cancer research, and targeting G4s with small molecules has become an ideal approach for drug development. Plant-based dietary polyphenols have attracted much attention for their remarkable anti-cancer effects. Studies have suggested that polyphenols exhibit interesting scaffolds to bind G4s, which can effectively downregulate the proto-oncogenes by stabilizing those G4 structures. Therefore, this review not only summarizes studies on natural dietary polyphenols (including analogs) as G4 stabilizers, but also reveals their anti-cancer activities. Furthermore, the structural and antioxidant insights of polyphenols with G4s are discussed, and future development is proposed. These insights may pave the way for the development of the next generation of anti-cancer drugs targeting nucleic acids.

Kallistatin Deficiency Induces the Oxidative Stress-Related Epithelial-Mesenchymal Transition of Retinal Pigment Epithelial Cells: A Novel Protagonist in Age-Related Macular Degeneration.

Purpose: Retinal pigment epithelium (RPE) dysfunction induced by oxidative stress-related epithelial-mesenchymal transition (EMT) of RPE is the primary underlying mechanism of age-related macular degeneration (AMD). Kallistatin (KAL) is a secreted protein with an antioxidative stress effect. However, the relationship between KAL and EMT in RPE has not been determined. Therefore we aimed to explore the impact and mechanism of KAL in oxidative stress-induced EMT of RPE. Methods: Sodium iodate (SI) was injected intraperitoneally to construct the AMD rat model and investigate the changes in RPE morphology and KAL expression. KAL knockout rats and KAL transgenic mice were used to explain the effects of KAL on EMT and oxidative stress. In addition, Snail overexpressed adenovirus and si-RNA transfected ARPE19 cells to verify the involvement of Snail in mediating KAL-suppressed EMT of RPE. Results: AMD rats induced by SI expressed less KAL in the retina, and KAL knockout rats showed RPE dysfunction spontaneously where EMT and reactive oxygen species (ROS) production increased in RPE. In contrast, KAL overexpression attenuated EMT and ROS levels in RPE, even in TGF-ß treatment. Mechanistically, Snail reversed the beneficial effect of KAL on EMT and ROS reduction. Moreover, KAL ameliorated SI-induced AMD-like pathological changes. Conclusions: Our findings demonstrated that KAL inhibits oxidative stress-induced EMT by downregulating the transcription factor Snail. Herein, KAL knockout rats may be an appropriate animal model for observing spontaneous RPE dysfunction for AMD-like retinopathy, and KAL may represent a novel therapeutic target for treating dry AMD.

Platelet mitochondria, a potent immune mediator in neurological diseases.

Dysfunction of the immune response is regarded as a prominent feature of neurological diseases, including neurodegenerative diseases, malignant tumors, acute neurotraumatic insult, and cerebral ischemic/hemorrhagic diseases. Platelets play a fundamental role in normal hemostasis and thrombosis. Beyond those normal functions, platelets are hyperactivated and contribute crucially to inflammation and immune responses in the central nervous system (CNS). Mitochondria are pivotal organelles in platelets and are responsible for generating most of the ATP that is used for platelet activation and aggregation (clumping). Notably, platelet mitochondria show marked morphological and functional alterations under heightened inflammatory/oxidative stimulation. Mitochondrial dysfunction not only leads to platelet damage and apoptosis but also further aggravates immune responses. Improving mitochondrial function is hopefully an effective strategy for treating neurological diseases. In this review, the authors discuss the immunomodulatory roles of platelet-derived mitochondria (PLT-mitos) in neurological diseases and summarize the neuroprotective effects of platelet mitochondria transplantation.

Targeting SphK1/2 by SKI-178 inhibits prostate cancer cell growth.

Sphingosine kinases (SphK), including SphK1 and SphK2, are important enzymes promoting progression of prostate cancer. SKI-178 is a novel and highly potent SphK1/2 dual inhibitor. We here tested the potential anti-prostate cancer cell activity of SKI-178. Bioinformatics analyses and results from local tissues demonstrated that that both SphK1 and SphK2 are upregulated in human prostate cancer tissues. Ectopic overexpression of SphK1 and SphK2, by lentiviral constructs, promoted primary prostate cancer cell proliferation and migration. In primary human prostate cancer cells and immortalized cell lines, SKI-178 potently inhibited cell viability, proliferation, cell cycle progression and cell migration, causing robust cell death and apoptosis. SKI-178 impaired mitochondrial functions, causing mitochondrial depolarization, reactive oxygen species production and ATP depletion.SKI-178 potently inhibited SphK activity and induced ceramide production, without affecting SphK1/2 expression in prostate cancer cells. Further, SKI-178 inhibited Akt-mTOR activation and induced JNK activation in prostate cancer cells. Contrarily, a constitutively-active Akt1 construct or the pharmacological JNK inhibitors attenuated SKI-178-induced cytotoxicity in prostate cancer cells. In vivo, daily intraperitoneal injection of a single dose of SKI-178 potently inhibited PC-3 xenograft growth in nude mice. SphK inhibition, ceramide production, ATP depletion and lipid peroxidation as well as Akt-mTOR inactivation and JNK activation were detected in PC-3 xenograft tissues with SKI-178 administration. Together, targeting SphK1/2 by SKI-178 potently inhibited prostate cancer cell growth in vitro and in vivo.

N-cadherin cleavage: A critical function that induces diabetic retinopathy fibrosis via regulation of ß-catenin translocation.

Retinal fibrosis is a severe pathological change in the late stage of diabetic retinopathy and is also the leading cause of blindness. We have previously revealed that N-cadherin was significantly increased in type 1 and type 2 diabetic mice retinas and the fibrovascular membranes from proliferative diabetic retinopathy (PDR) patients. However, whether N-cadherin directly induces retinal fibrosis in DR and the related mechanism is unknown. Here, we investigated the pathogenic role of N-cadherin in mediating retinal fibrosis and further explored the relevant therapeutic targets. We found that the level of N-cadherin was significantly increased in PDR patients and STZ-induced diabetic mice and positively correlated with the fibrotic molecules Connective Tissue Growth Factor (CTGF) and fibronectin (FN). Moreover, intravitreal injection of N-cadherin adenovirus significantly increased the expression of FN and CTGF in normal mice retinas. Mechanistically, overexpression of N-cadherin promotes N-cadherin cleavage, and N-cadherin cleavage can further induce translocation of non-p-ß-catenin in the nucleus and upregulation of fibrotic molecules. Furthermore, we found a novel N-cadherin cleavage inhibitor, pigment epithelial-derived factor (PEDF), which ameliorated the N-cadherin cleavage and subsequent retinal fibrosis in diabetic mice. Thus, our findings provide novel evidence that elevated N-cadherin level not only acts as a classic EMT maker but also plays a causative role in diabetic retinal fibrosis, and targeting N-cadherin cleavage may provide a strategy to inhibit retinal fibrosis in DR patients.

Translational albumin nanocarrier caging photosensitizer for efficient cancer photodynamic therapy.

It still remains a great challenge to efficiently treat malignant cancers which severely threaten human health. Photodynamic therapy (PDT) as a localized therapeutic modality has improved the therapeutic efficacy via chemical damage through reactive oxygen species (ROS). However, their efficacy is severely hampered by insufficient targeted delivery of photosensitizers owing to the lack of suitable carrier with facile preparation process and the clinical applicability. Herein, we applied clinically approved human serum albumin as the nanoreactor to encapsulate photosensitizers Chlorin e6 (Ce6) for enhancing their tumor accumulation and subsequently potent PDT effect against bladder cancer models. Albumin-loaded Chlorin e6 nanoparticles (CA-NPs) with rational nanoscale size exhibit increased reactive oxygen species production and excellent resistance to photobleaching. Moreover, CA-NPs could be efficiently internalized by tumor cells and locate in the lysosome, while they rapidly translocate to cytosol after irradiation to induce remarkable cytotoxicity (IC50 ∼5.8 µg/ml). Furthermore, CA-NPs accumulate effectively in tumor tissue to afford total eradication of murine bladder tumor after single injection. More importantly, we also evidence the superior PDT effect in fresh human bladder tumor tissues via abundant reactive oxygen species generation and subsequent cell apoptosis. These findings demonstrate that human serum albumin acts as a universal tool to load small organic photoactivatable molecule with remarkable effectiveness and readiness for clinical translation.

Two-sample Mendelian randomization study reveals no causal relationship between inflammatory bowel disease and urological cancers.

Background: The relationship between inflammatory bowel disease (IBD) and urological cancers has been identified in epidemiological and observational studies, while the causality remains uncertain. We examined whether IBD is causally associated with urological cancers in a Mendelian randomization (MR) study. Methods: The causal relationship between IBD, its main subtypes, and urological cancers was investigated using genome-wide association study data. To obtain more reliable conclusions, all outcomes were divided into training and validation sets. Eligible single-nucleotide polymorphisms were selected as instrumental variables based on MR analysis assumptions. The inverse variance-weighted (IVW) method was employed as the main method along with four other complementary methods. Results: In this two-sample MR study, no genetic evidence for the causal effect of IBD on urological cancers was found in either the training or validation sets using the IVW method. Similarly, we did not observe any significant association between Crohn's disease or ulcerative colitis and urological cancers. The results of the other methods are in accordance with those obtained using the IVW method. Conclusion: In this study, we confirmed that IBD is not a causal genetic risk factor for urological cancer in a European population.

Identification of Diagnostic Markers in Infantile Hemangiomas.

Background: Infantile Hemangiomas (IHs) are common benign vascular tumors of infancy that may have serious consequences. The research on diagnostic markers for IHs is scarce. Methods: The "limma" R package was applied to identify differentially expressed genes (DEGs) in developing IHs. Plugin ClueGO in Cytoscape software performed functional enrichment of DEGs. The Search Tool for Retrieving Interacting Genes (STRING) database was utilized to construct the PPI network. The least absolute shrinkage and selection operator (LASSO) regression model and support vector machine recursive feature elimination (SVM-RFE) analysis were used to identify diagnostic genes for IHs. The receiver operating characteristic (ROC) curve evaluated diagnostic genes' discriminatory ability. Single-gene based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) was conducted by Gene Set Enrichment Analysis (GSEA). The chemicals related to the diagnostic genes were excavated by the Comparative Toxicogenomics Database (CTD). Finally, the online website Network Analyst was used to predict the transcription factors targeting the diagnostic genes. Results: A total of 205 DEGs were singled out from IHs samples of 6-, 12-, and 24-month-old infants. These genes principally participated in vasculogenesis and development-related, endothelial cell-related biological processes. Then we mined 127 interacting proteins and created a network with 127 nodes and 251 edges. Furthermore, LASSO and SVM-RRF algorithms identified five diagnostic genes, namely, TMEM2, GUCY1A2, ISL1, WARS, and STEAP4. ROC curve analysis results indicated that the diagnostic genes had a powerful ability to distinguish IHs samples from normal samples. Next, the results of GSEA for a single gene illustrated that all five diagnostic genes inhibited the "valine, leucine, and isoleucine degradation" pathway in the development of IHs. WARS, TMEM2, and STEAP4 activated the "blood vessel development" and "vasculature development" in IHs. Subsequently, inhibitors targeting TMEM2, GUCY1A2, ISL1, and STEAP4 were mined. Finally, 14 transcription factors regulating GUCY1A2, 14 transcription factors regulating STEAP4, and 26 transcription factors regulating ISL1 were predicted. Conclusion: This study identified five diagnostic markers for IHs and further explored the mechanisms and targeting drugs, providing a basis for diagnosing and treating IHs.

Downregulation of MCF2L Promoted the Ferroptosis of Hepatocellular Carcinoma Cells through PI3K/mTOR Pathway in a RhoA/Rac1 Dependent Manner.

Methods and Results: The levels of MCF2L were detected by PCR and western blotting assay. The effect of MCF2L on ferroptosis was confirmed by MTT, colony formation assay, Brdu, in vivo animal experiment, and the content of Iron, GSH, ROS, and MDA. The underlying mechanisms were explored by PCR, western blotting, and affinity precipitation assay. Our findings demonstrated that MCF2L is remarkedly upregulated in HCC tissues, and sorafenib can induce the levels of MCF2L, suggesting that MCF2L might function in sorafenib resistance of HCC. Further analysis showed that downregulation of MCF2L enhances HCC cell death induced by sorafenib, and ferroptosis inhibitor can reverse this process. Subsequent experiments showed that downregulation of MCF2L elevates the content of Iron, ROS, and MDA, which are all indicators of ferroptosis. Finally, mechanism analysis showed that MCF2L regulates the PI3K/AKT pathway in a RhoA/Rac1 dependent manner. Conclusions: Our study showed that targeting MCF2L may be a hopeful method to overcome sorafenib-resistance through inducing ferroptosis in HCC.

[Expression of TNFAIP6 in oral verrucous carcinoma and oral squamous cell carcinoma and its relationship with clinicopathology].

PURPOSE: This study was designed to establish a 3-dimentional finite element system to simulate the clinical scenario where labial segment was retracted with sliding mechanism in extraction cases treated by individualized lingual orthodontics. METHODS: A typical clinical case was selected. The subject was diagnosed with Class I malocclusion with alveolar protrusion and treated with extraction of 4 first premolars. The subject was under the treatment stage of frontal retraction by eBrace system, an individualized lingual appliance. The subject was also taken cone-beam CT (CBCT) based on which digital 3D reconstruction of dentition structures was formed with Mimics software. With the aid of software platform Pro/E 4.0, the important anatomical structures were defined, and relevant lingual devices, including lingual brackets, arch-wires, mini-screws and other accessories were formed. With the aids of software platform Geomagic Studio 13.0, the 3-dimentional structural mode, featuring maxillary alveolar, upper dentition, periodontal ligament, miniscrew and lingual applicance, were constructed. With the assistance of Ansys Workbench 15.0, 3D model for finite element system was finalised by conducting model meshing and defining the mechanical properties and the interface relations of the selected materials. RESULTS: Based on the digital information drawn from CBCT image, a 3-dimentional finite element system was successfully created, featuring all the elements mimicking the clinical scenario for En masse retraction. This system enabled an insight study on the effects of various retraction modes controlling the incisal torque and maintaining the dental arch integrity. CONCLUSIONS: The creation of a finite element system in this study is based on the digital data from the CBCT image of a real patient diagnosed with prognathic malocclusion and treated by lingual appliance. The clinical scenario of labial segment retraction via sliding mechanism is simulated in this finite element model.

Definition of a new blood cell count score for early survival prediction for non-small cell lung cancer patients treated with atezolizumab: Integrated analysis of four multicenter clinical trials.

Importance: Blood cell count test (BCT) is a robust method that provides direct quantification of various types of immune cells to reveal the immune landscape to predict atezolizumab treatment outcomes for clinicians to decide the next phase of treatment. Objective: This study aims to define a new BCTscore model to predict atezolizumab treatment benefits in non-small lung cell cancer (NSCLC) patients. Design Setting and Participants: This study analyzed four international, multicenter clinical trials (OAK, BIRCH, POPLAR, and FIR trials) to conduct post-hoc analyses of NSCLC patients undergoing atezolizumab (anti-PD-L1) single-agent treatment (n = 1,479) or docetaxel single-agent treatment (n = 707). BCT was conducted at three time points: pre-treatment (T1), the first day of treatment cycle 3 (T2), and first day of treatment cycle 5 (T3). Univariate and multivariate Cox regression analyses were conducted to identify early BCT biomarkers to predict atezolizumab treatment outcomes in NSCLC patients. Main Outcomes and Measures: Overall survival (OS) was used as the primary end point, whereas progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors (RECIST), clinical benefit (CB), and objective response rate (ORR) were used as secondary end points. Results: The BCT biomarkers of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) at time point T3 and neutrophil-to-monocyte ratio (NMR) at time point T2 with absolute cutoff values of NLR_T3 = 5, PLR_T3 = 180, and NMR_T2 = 6 were identified as strong predictive biomarkers for atezolizumab (Ate)-treated NSCLC patients in comparison with docetaxel (Dtx)-treated patients regarding OS (BCTscore low risk: HR Ate vs. Dtx = 1.54 (95% CI: 1.04-2.27), P = 0.031; high risk: HR Ate vs. Dtx = 0.84 (95% CI: 0.62-1.12), P = 0.235). The identified BCTscore model showed better OS AUC in the OAK (AUC12month = 0.696), BIRCH (AUC12month = 0.672) and POPLAR+FIR studies (AUC12month = 0.727) than that of each of the three single BCT biomarkers. Conclusion and Relevance: The BCTscore model is a valid predictive and prognostic biomarker for early survival prediction in atezolizumab-treated NSCLC patients.

Identification of the novel HLA-B*15:625 allele in a Chinese marrow donor.

A novel HLA allele HLA-B*15:625 was identified in a Chinese marrow donor.

Differentiation of three Asparagus species by UHPLC-MS/MS based molecular networking identification and chemical profile analysis.

Asparagi Radix (AR), a traditional Chinese medicine, is the dried roots of Asparagus cochinchinensis (Lour.) Merr. Modern pharmacological studies have shown that AR has various excellent bioactivities, such as antioxidative, antitumor, antibacterial, anti-inflammatory, and hypoglycemic effects. However, the quality control method of AR is incomplete and there are various AR adulterants in markets due to their similar morphological characters. Here, holistic and practical quality evaluation methods were developed to chemically distinguish three common Asparagus species in markets, including Asparagus cochinchinensis (Lour.) Merr., Asparagus officinalis L., and Asparagus lycopodineus (Baker) F.T.Wang & Tang. The chemical constituents of three species were rapidly tentatively annotated using a combination of ultra-high pressure liquid chromatography-linear ion trap-orbitrap high resolution mass spectrometry (UHPLC-LTQ-Orbitrap-MS) and molecular networking (MN). Fifty-six steroidal saponins were annotated, including common and characteristic chemical constituents of the three Asparagus species. Besides, to establish holistic and practical methods to differentiate three Asparagus species, an HPLC-ELSD (evaporative light scattering detector) was applied for fingerprint analysis and content determination of the sum of protoneodioscin and protodioscin of twenty samples. Each Asparagus species showed characteristic chemical profile and AR showed much higher level of the sum of protoneodioscin and protodioscin than that in the others. The above analyses showed that the three Asparagus species mainly contain steroidal saponins and the developed HPLC-ELSD profile of saponin can be used to differentiate them. In conclusion, this study reveals the different chemical constituents of three Asparagus species and provides relatively feasible quality evaluation methods for them which are essential for the rational utilization of these Asparagus species.

Elucidation of the Application of Blood Test Biomarkers to Predict Immune-Related Adverse Events in Atezolizumab-Treated NSCLC Patients Using Machine Learning Methods.

Background: Development of severe immune-related adverse events (irAEs) is a major predicament to stop treatment with immune checkpoint inhibitors, even though tumor progression is suppressed. However, no effective early phase biomarker has been established to predict irAE until now. Method: This study retrospectively used the data of four international, multi-center clinical trials to investigate the application of blood test biomarkers to predict irAEs in atezolizumab-treated advanced non-small cell lung cancer (NSCLC) patients. Seven machine learning methods were exploited to dissect the importance score of 21 blood test biomarkers after 1,000 simulations by the training cohort consisting of 80%, 70%, and 60% of the combined cohort with 1,320 eligible patients. Results: XGBoost and LASSO exhibited the best performance in this study with relatively higher consistency between the training and test cohorts. The best area under the curve (AUC) was obtained by a 10-biomarker panel using the XGBoost method for the 8:2 training:test cohort ratio (training cohort AUC = 0.692, test cohort AUC = 0.681). This panel could be further narrowed down to a three-biomarker panel consisting of C-reactive protein (CRP), platelet-to-lymphocyte ratio (PLR), and thyroid-stimulating hormone (TSH) with a small median AUC difference using the XGBoost method [for the 8:2 training:test cohort ratio, training cohort AUC difference = -0.035 (p < 0.0001), and test cohort AUC difference = 0.001 (p=0.965)]. Conclusion: Blood test biomarkers currently do not have sufficient predictive power to predict irAE development in atezolizumab-treated advanced NSCLC patients. Nevertheless, biomarkers related to adaptive immunity and liver or thyroid dysfunction warrant further investigation.

Video-assisted thoracoscopic treatment as two-day surgery for lung neoplasms: a propensity-matched analysis.

BACKGROUND: Enhanced recovery after surgery programs have reduced complications and shortened hospital stays after lung resection. This study aimed to determine whether video-assisted thoracoscopic surgery performed as a two-day surgery for lung neoplasms was safe and cost-effective. METHODS: This retrospective, propensity-matched, cohort analysis was conducted from January 2020 to August 2020. Among 959 patients who underwent video-assisted thoracoscopic surgery, 739 underwent inpatient surgery and 220 underwent two-day surgery. Propensity-matched analysis, incorporating preoperative variables, was used to compare postoperative complications, post-discharge follow-up results, and hospitalization costs between the groups. RESULTS: Propensity matching estimated 218 patients in each group. The mean length of hospital stay was shorter in the two-day surgery group (2.17 ± 0.89 days) than in the inpatient surgery group (6.31 ± 2.13 days) (P < 0.001). Delayed removal of chest tubes accounted for over half of the delayed discharges in the inpatient (17 [54.8%]) and two-day surgery (13 [65.0%]) groups. The postoperative pneumonia/atelectasis incidence was lower in the two-day surgery group than in the inpatient surgery group (P = 0.032). The two-day surgery group patients were readmitted to the hospital due to massive pleural effusion, pneumothorax, fever, severe chest pain, and physical weakness. The mean total hospitalization cost in the two-day surgery group was lower than that in the inpatient surgery group (¥ 33,926.1 versus ¥ 38,422.7, P < 0.001). Basic medical, nursing, drug, laboratory-related, and nonsurgical consumable costs in the two-day surgery group were significantly reduced. CONCLUSIONS: Two-day surgery is a safe, feasible, and cost-effective procedure for selected patients with lung neoplasms when combined with accurate preoperative evaluations, successful intraoperative assessments, and effective postoperative health care guidance.

Dynamic alternations of RANKL/OPG ratio expressed by cementocytes in response to orthodontic­induced external apical root resorption in a rat model.

The aim of the present study was to investigate the alterations in the formation of cementocytes in response to orthodontic forces and to evaluate the contribution of these cells in the biological changes of tooth movement and associated root resorption. A total of 90 Sprague Dawley rats were randomly assigned to the control, high force, and low force groups. Intrusion forces of 10 and 50 g were applied on the rat molar to induce tooth intrusion. The tooth movement was observed from 0 to 14 days by micro­computed tomography, bone histometric analysis, tartrate­resistant acid phosphatase staining, as well as reverse transcription­quantitative PCR and immunofluorescence staining assays. The results suggested that under low force conditions, osteoclasts were distributed at a higher frequency on the bone side than on the root side. Under high force conditions, both sides suffered osteoclast infiltration. In the low force group, the cementocytes exhibited downregulated sclerostin (SOST) and osteoprotegerin (OPG) mRNA levels and a lower receptor activator of nuclear factor­κB ligand (RANKL)/OPG ratio over a certain period of time. The expression levels of these genes were lower compared with those of the osteocytes at each time­point. In the high force group, both cementocytes and osteocytes upregulated the SOST and RANKL/OPG ratio on days 7 and 14, while the cementocytes expressed higher levels of SOST mRNA than those noted in the osteocytes. These data suggested that cementocytes responded to the orthodontic force via modulation of the RANKL/OPG ratio and SOST expression. The biological response of cementocytes contributed to the mechanotransduction and homoeostasis of the roots under compression. Excessive forces may act as a negative factor of this regulatory role. These results expand our knowledge on the function of cementocytes.

IL25 Enhanced Colitis-Associated Tumorigenesis in Mice by Upregulating Transcription Factor GLI1.

Interleukin-25 (IL17E/IL25) plays a critical role in colitis and intestinal homeostasis. However, the expression and biological role of IL25 in colorectal cancer is not properly understood. In this study, we show that IL25 is mainly expressed by cancer stem cells in the colorectal cancer microenvironment. Genetic deletion of IL25 inhibited tumor formation and growth and prolonged survival in AOM/DSS-treated mice. IL25 stimulated cancer organoid and cancer cells sphere formation and prevented the tumor from chemotherapy-induced apoptosis. Mechanistically, IL25 upregulated stem cell genes LGR5, CD133, and ABC transporters via activating the Hedgehog signaling pathway. IL25 inhibited phosphorylation of AMPK and promoted GLI1 accumulation to maintain cancer stem cells. Moreover, IL25 expression was associated with poor survival in patients with metastatic colorectal cancer. Taken together, our work reveals an immune-associated mechanism that intrinsically confers cancer cell stemness properties. Our results first demonstrated that IL25, as a new potent endogenous Hedgehog pathway agonist, could be an important prognostic factor and therapeutic target for CRC.

Application of artificial intelligence in a real-world research for predicting the risk of liver metastasis in T1 colorectal cancer.

BACKGROUND: Liver is the most common metastatic site of colorectal cancer (CRC) and liver metastasis (LM) determines subsequent treatment as well as prognosis of patients, especially in T1 patients. T1 CRC patients with LM are recommended to adopt surgery and systematic treatments rather than endoscopic therapy alone. Nevertheless, there is still no effective model to predict the risk of LM in T1 CRC patients. Hence, we aim to construct an accurate predictive model and an easy-to-use tool clinically. METHODS: We integrated two independent CRC cohorts from Surveillance Epidemiology and End Results database (SEER, training dataset) and Xijing hospital (testing dataset). Artificial intelligence (AI) and machine learning (ML) methods were adopted to establish the predictive model. RESULTS: A total of 16,785 and 326 T1 CRC patients from SEER database and Xijing hospital were incorporated respectively into the study. Every single ML model demonstrated great predictive capability, with an area under the curve (AUC) close to 0.95 and a stacking bagging model displaying the best performance (AUC = 0.9631). Expectedly, the stacking model exhibited a favorable discriminative ability and precisely screened out all eight LM cases from 326 T1 patients in the outer validation cohort. In the subgroup analysis, the stacking model also demonstrated a splendid predictive ability for patients with tumor size ranging from one to50mm (AUC = 0.956). CONCLUSION: We successfully established an innovative and convenient AI model for predicting LM in T1 CRC patients, which was further verified in the external dataset. Ultimately, we designed a novel and easy-to-use decision tree, which only incorporated four fundamental parameters and could be successfully applied in clinical practice.