Targeting HIF-1α with Specific DNA Yokes for Effective Anticancer Therapy.

Hypoxia, a ubiquitous hallmark in cancer, underscores the significance of targeting HIF-1α, the principal transcriptional factor of hypoxic responses, for effective cancer therapy. Herein, DNA yokes, a novel class of DNA nanomaterials harboring specific HIF-1α binding sequences (hypoxia response elements, HREs), are introduced as nanopharmaceuticals for cancer treatment. Comprising a basal tetrahedral DNA nanostructure and four HRE-bearing overhanging chains, DNA yokes exhibit exceptional stability and prolonged intracellular retention. The investigation reveals their capacity to bind HIF-1α, thereby disrupting its interaction with the downstream genomic DNAs and impeding transcriptional activity. Moreover, DNA yokes facilitate HIF-1α degradation via the ubiquitination pathway, thereby sequestering it from downstream targets and ultimately promoting its degradation. In addition, DNA yokes attenuate cancer cell proliferation, migration, and invasion under hypoxic conditions, while also displaying preferential accumulation within tumors, thereby inhibiting tumor growth and metastasis in vivo. This study pioneers a novel approach to cancer therapy through the development of DNA-based drugs characterized by high stability and low toxicity to normal cells, positioning DNA yokes as promising candidates for cancer treatment.

Brain Network Characterization of Preterm Infants With Bronchopulmonary Dysplasia.

BACKGROUND: Bronchopulmonary dysplasia (BPD) affects the microstructure of white matter in preterm infants, but its influence on the changes of the brain structural network has not been elaborated. This study aims to investigate the connectivity characteristics of the brain structural network of BPD by using diffusion tensor imaging. METHODS: Thirty-three infants with BPD and 26 infants without BPD were enrolled in this study. Brain structural networks were constructed utilizing automated anatomic labeling mapping by tracing the fibers between each pair of regions in individual space. We calculated network metrics such as global efficiency, local efficiency, clustering coefficients, characteristic path length, and small-worldness. Then we compared the network metrics of these infants with those of 57 healthy term infants of comparable postmenstrual age at magnetic resonance imaging scan. Finally, network-based statistics was used to analyze the differences in brain network connectivity between the groups with and without BPD. RESULTS: Preterm infants with BPD had higher local efficiency and clustering coefficient, lower global efficiency, and longer characteristic path length. Also, preterm infants with BPD had decreased strength of limbic connections mainly in four brain regions: the left lingual gyrus, the left calcarine fissure and surrounding cortex, the right parahippocampal gyrus, and the left precuneus. CONCLUSIONS: Our findings suggest that preterm infants with BPD have lower network integration and higher segregation at term-equivalent age, which may reflect a compensatory mechanism. In addition, BPD affects brain regions involved in visual as well as cognitive functions; these findings provide a new approach to diagnose potential brain damage in preterm infants with BPD.

Modified Suture Button Latarjet Procedure With Coracoacromial Ligament And Pectoralis Minor Preservation Achieves Good Clinical Outcomes at 2-Year Follow-up: Case Series of Latarjet Technique.

PURPOSES: To evaluate if the modified suture button Latarjet procedure with coracoacromial ligament (CAL) and pectoralis minor (PM) preservation could achieve excellent outcomes at the 2-year follow-up. METHODS: During January 2019 to January 2021, data of patients who underwent the modified suture button Latarjet with CAL and PM preservation in our department was collected. The glenoid bone loss of these patients were above 20% or over 10% with high demands for exercise. Partial coracoid osteotomy was based on the results of the preoperative 3-dimensional computed tomography (3D CT) evaluation of the glenoid defect area (GDA) and corresponding coracoid process morphology. The preoperative and postoperative clinical results were assessed. The minimal clinically important difference (MCID) was utilized to compare improvement in clinical outcomes. Graft-glenoid union and remodeling were assessed using postoperative 3D CT, and magnetic resonance imaging (MRI) was performed to confirm the integrity of the CAL and PM postoperatively. RESULTS: 35 patients were included in this study; the mean follow-up time was 26.9 ± 1.9 months. No case of recurrent dislocation or sublaxity. Significant improvements were observed in mean visual analog scale (VAS) scores for pain during motion, American Shoulder and Elbow Surgeons (ASES) score, Rowe score, and Walch-Duplay score (P < .001). The percentage of patients achieving at least an MCID improvement in clinical outcomes was: VAS 85.71%; ASES 97.14%; Rowe 100%; Walch-Duplay 97.14%. 33 patients (94.3% of all cases) were able to return to their preoperative sport levels, 34 grafts (97.1%) achieved bone union (1 soft union) in 6.3±2.2 months, and the coracoid grafts restored 97.1±4.0% of the perfect fitting circle (PFC) at the last follow-up. Postoperative CT scan showed that 31 grafts (88.6%) were placed ideally in vertical view. In the axial view, 25 grafts (82.9%) were flushed to the glenoid, whereas 1 and 5 grafts were fixed medially and laterally, respectively. The CAL and PM were visualized postoperatively. No arthropathy was observed in any patient at the last follow-up. CONCLUSIONS: The modified suture button Latarjet procedure with CAL and PM preservation obtained good clinical and radiological results without recurrence or complications. A substantial majority of patients (>85%) achieved the MCID for the VAS, ASES, ROWE, and Walch-Duplay scores. Additionally, the malpositioned graft (17.1%) did not cause arthropathy of the joints at 2-year follow-up.

No side effects on rabbit retina or vitreous microenvironment by nd:YAG laser vitreolysis.

BACKGROUND: To explore the safety of Neodymium:Yttrium-aluminum-garnet (Nd:YAG) laser vitreolysis based on the histological examination of the retina and the alteration of vitreous cytokines in the rabbits. METHODS: Nine male New Zealand rabbits underwent Nd:YAG laser vitreolysis of 10 mJ x 500 pulses in the left eyes, while the right eyes were used as controls. Intraocular pressure, color fundus photography, and ultrasound B scan were measured before, as well as 1 day, 4 weeks, and 12 weeks after Nd:YAG laser vitreolysis. Three rabbits were euthanized 1 day, 4 weeks, and 12 weeks after treatment, respectively. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and hematoxylin-eosin (H&E) staining were used to look for pathological changes in the retina. An enzyme-linked immunosorbent assay (ELISA) was utilized to detect the expression of vascular endothelial growth factor (VEGF) and some inflammatory cytokines, including interferon inducible protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1) and interlenkin 6 (IL-6) in the vitreous humor. The ascorbic acid (AsA) and total reactive antioxidant potential (TRAP) in the vitreous humor were also measured. RESULTS: Following Nd:YAG laser vitreolysis, the levels of VEGF, IP-10, MCP-1, IL6, AsA, and TRAP in the vitreous humor did not change substantially (P > 0.05). There were no detectable pathological changes in the retinal tissues, and no apoptotic signal was found. CONCLUSIONS: Rabbits tolerate Nd:YAG laser vitreolysis without observable impact on retinal tissue or the microenvironment of the vitreous.

Effect of different shapes of steel fibers and palygorskite-nanofibers on performance of ultra-high-performance concrete.

Herein, a practical ultra-high-performance concrete (UHPC) was created by adding two different shapes of steel fibers and curing them at ambient temperature using palygorskite-nanofiber (PN) as the modifier. The compressive strength, flexural strength, water absorption capacity, and porosity were analyzed to determine the effects of the steel fibers and PNs on the UHPC mechanical and physical properties. The steel fibers and PNs were found to improve these properties. The UHPC mechanical properties were outstanding at 1.5% fiber dosage, while physical properties were excellent at 1.0% fiber dosage. The mechanical and physical characteristics of UHPC were preferably at a PN dosage of 0.2% and the fiber dosage of 1.0%. The compressive and flexural strengths of straight-steel-fiber UHPC were 145.57 and 19.67 MPa, respectively, i.e., 42.0 and 109.4% higher than those of the reference specimens (i.e., those without fibers or PNs); the water absorption capacity and porosity decreased by 50.1 and 60.7%, respectively. The compressive and flexural strengths of hooked-end-steel-fiber UHPC were 18.3 and 96.0% higher than those of the reference specimens, respectively, and the water absorption capacity and porosity decreased by 43.2 and 29.8%, respectively. These results could provide vital information for the promotion and practical application of UHPC.

Research trends between diabetes mellitus and bariatric surgery researches: Bibliometric analysis and visualization from 1998 to 2023.

This study conducted a bibliometric analysis using the Web of Science Core Collection (WOSCC) to explore the relationship between diabetes mellitus and bariatric surgery (BS) from January 1985 to August 2023. No publications were found between 1985 and 1998. However, from 1998 to 2023, a total of 9,496 English articles were identified, accumulating 291,289 citations (241,563 excluding self-citations) and achieving an H-Index of 197. Leading contributors to the field were the United States, China, and Italy. Noteworthy authors in this area of research included Philip R. Schauer, Wei-Jei Lee, and Carel W. le Roux. The major journals that featured this research were 'Obesity Surgery,' 'Diabetes Care,' and 'Surgery for Obesity and Related Diseases.' The most highly cited article focused on lifestyle, diabetes, and cardiovascular risks 10 years after BS, emphasizing the significant attention given to the nutritional, cardiac, and general internal medicine impacts of diabetes and BS. The increase in research output during the review period indicates a growing interest in the relationship between diabetes and BS, providing a valuable reference for future studies in this evolving field.

Up-regulation of MIC19 promotes growth and metastasis of hepatocellular carcinoma by activating ROS/NF-κB signaling.

BACKGROUND: Mitochondrial malfunction has been well-recognized as a critical step in the pathogenesis of many types of diseases, including cancer. MIC19 is a core a subunit of the MICOS complex that plays a critical role in maintaining the normal function of mitochondria. However, the biological functions of MIC19 in human hepatocellular carcinoma (HCC) remain unclear. METHODS: The expression level of MIC19 in HCC was evaluated by bioinformatics analysis, quantitative real-time PCR and immunohistochemistry staining assays. Cell growth and metastasis experiments were used to assess the biological functions of MIC19 in HCC cells. FINDINGS: MIC19 expression was frequently upregulated in both human HCC specimens and cell lines, and its upregulation is closely associated with patients' survival. Results from loss-of-function and gain-of-function experiments demonstrated that knockdown of MIC19 significantly attenuated, while overexpression of MIC19 enhanced, the proliferation, colony formation, migration and invasion abilities of HCC cells. Mechanistically, we found that MIC19 has no effect on mitochondrial energy production, while activated ROS/NF-κB signaling, which was required for MIC19-promoted HCC growth and metastasis. INTERPRETATION: Our findings suggest that MIC19 play a critical oncogenic role in HCC, implying that MIC19 may serve as a potential therapeutic target in the treatment of HCC.

[The Study of Recombinant Interfering Lentiviruses and Overexpressed Adenovirus Vectors Targeting Human c-Cbl Gene： Construction, Identification and Efficacy].

OBJECTIVE: To construct recombinant lentivirus and adenovirus which regulate the expression of c-Cbl gene and evaluate their efficacy. METHODS: The interference lentivirus and overexpressed adenovirus targeting human c-Cbl gene were constructed by gene recombination technology. Quantitative PCR and western blotting were used to detect the expression changes in c-Cbl gene and its transcription after leukemia cells (HL60,THP1) were infected by virus. RESULTS: Three recombinant interfering lentiviral vectors targeting human c-Cbl genes to successfully constructed and were identified by DNA sequencing, and the titers of the packaged viruses were all greater than 1×108 TU/ml. Among them, shRNA-2 lentivirus had the highest interference efficiency, and the expression of c-Cbl gene and CBL protein were decreased about 95% and 60% respectively after leukemia cells were infected with shRNA-2; In addition, the recombinant overexpression adenovirus targeting human c-Cbl gene was packaged successfully with the virus titer greater than 1×109 TU/ml. When leukemia cells were infected with adenovirus, the expression of c-Cbl gene and CBL protein were up-regulated about 10 times and 1.5 times respectively. CONCLUSION: Both recombinant interfering lentivirus and overexpression adenovirus can efficiently infect leukemia cells and affect the expressions of c-Cbl gene and CBL protein. It will lay a preliminary foundation for the subsequent study on the function of c-Cbl gene in tumor cells.

Assessment of transient elastography in diagnosing MAFLD and the early effects of sleeve gastrectomy on MAFLD among the Chinese population.

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) has become a prevalent chronic liver disease among patients with obesity. Bariatric surgery, such as sleeve gastrectomy (SG), shows promise in improving the unfavorable condition of MAFLD. Transient elastography (TE) can be utilized to assess the extent of steatosis and liver fibrosis, providing a noninvasive method for preoperative prediction and postoperative evaluation of MAFLD. This study aims to investigate the effectiveness of TE in diagnosing MAFLD by evaluating liver steatosis and tissue stiffness, as well as assessing the early impact of SG in the treatment of obesity-associated MAFLD. METHODS: In this study, the authors collected preoperative and 6-month postoperative data from patients with obesity who were diagnosed with MAFLD by intraoperative liver biopsy. The patients underwent SG at our hospital between August 2021 and April 2023. The authors estimated the diagnostic accuracy for the steatosis and fibrosis categories using the area under the receiver operating characteristic curve (AUROC). The authors also evaluated the influence of disease prevalence on the positive predictive value and negative predictive value. MAFLD diagnosis was based on the liver steatosis activity and fibrosis scoring system. The authors used univariate and multivariate logistic regression analyses to identify factors contributing to severe MAFLD. To visualize the results, the authors created a nomogram and enhanced it with bootstrap resampling for internal validation. Additionally, the authors plotted receiver operating characteristic and calibration curves. The authors compared preoperative and postoperative data, including general information, laboratory tests, and TE results, to assess the early impact of SG in the treatment of obesity-associated MAFLD. RESULTS: Based on the results of liver biopsy, the AUROC for controlled attenuation parameter (CAP) in identifying steatosis was found to be 0.843 (95% CI: 0.729-0.957) for S≥S1, 0.863 (95% CI: 0.786-0.940) for S≥S2, and 0.872 (95% CI: 0.810-0.934) for S=S3. The Youden limits for S≥S1, S≥S2, and S≥S3 were determined to be 271 dB/m, 292 dB/m, and 301 dB/m, respectively. Similarly, the AUROC for liver stiffness measurement (LSM)/E in detecting liver fibrosis was 0.927 (95% CI: 0.869-0.984) for F≥F2, 0.919 (95% CI: 0.824-0.979) for F≥F3, and 0.949 (95% CI: 0.861-0.982) for F=F4, with Youden cutoff values of 7.5 kPa, 8.3 kPa, and 10.4 kPa, respectively. Patients with A≥3 and/or F≥3 were classified as having severe MAFLD. Multivariate logistic regression analysis identified CAP, E, LDL, and AST as the best diagnostic factors for severe MAFLD, and a nomogram was constructed based on these factors. The AUROC of the nomogram for the assessment of severe MAFLD was 0.824 (95% CI: 0.761-0.887), which was further validated by 1000 bootstrap resamplings with a bootstrap model area under curve of 0.823. Finally, after a 6-month follow-up period, the steatosis grade and fibrosis stage of the patients were graded based on the optimal cutoff values for CAP and LSM. Significant reductions in BMI, waist circumference, HbA1c, fasting glycemia, triglycerides, high density lipoprotein (HDL), glutamic pyruvic transaminase (ALT), glutamic oxaloacetic transaminase (AST), gamma glutamyl transpeptidase (GGT), CAP, LSM, steatosis grade, and fibrosis stage were observed compared to the preoperative values. CONCLUSION: In this prospective study, the authors investigated the use of CAP and LSM as alternatives to liver biopsy for evaluating hepatic steatosis and fibrosis in patients with obesity combined with MAFLD. Furthermore, the authors examined the impact of SG on metabolic indicators and the progression of fatty liver disease during the early postoperative period, and observed significant improvements in both aspects.

Erythrodermic mycosis fungoides: A case report.

BACKGROUND: Mycosis fungoides is the most common primary cutaneous T-cell lymphoma, whereas generalized erythroderma is rare. In this report, we describe a case of mycosis fungoides with generalized erythroderma using complete clinical data and [18F]fluoroDglucose positron emission tomography/computed tomography (18F-FDG PET/CT) images. CASE SUMMARY: Systemic skin redness with desquamation for three years confirmed mycosis fungoides within one month. The patient underwent left axillary lymphadenectomy biopsy; pathological biopsy suggested abnormal T-cell lesions consistent with mycosis fungoides involving lymph nodes. The patient received methotrexate, 5 mg twice weekly, as part of their chemotherapy regimen. Patients January half after discharge, no obvious cause of high fever, left axillary lymph nodes with red heat pain, and rupture entered our hospital for treatment. CONCLUSION: The 18F-FDG PET/CT is essential for early diagnosis and timely treatment.

Inhibition of Sema4D attenuates pressure overload-induced pathological myocardial hypertrophy via the MAPK/NF-κB/NLRP3 pathways.

Sema4D (CD100) is closely related to pathological and physiological processes, including tumor growth, angiogenesis and cardiac development. Nevertheless, the role and mechanism of Sema4D in cardiac hypertrophy are still unclear to date. To assess the impact of Sema4D on pathological cardiac hypertrophy, TAC surgery was performed on C57BL/6 mice which were transfected with AAV9-mSema4D-shRNA or AAV9-mSema4D adeno-associated virus by tail vein injection. Our results indicated that Sema4D knockdown mitigated cardiac hypertrophy, fibrosis and dysfunction when exposed to pressure overload, and Sema4D downregulation markedly inhibited cardiomyocyte hypertrophy induced by angiotensin II. Meanwhile, Sema4D overexpression had the opposite effect in vitro and in vivo. Furthermore, analysis of signaling pathways showed that Sema4D activated the MAPK pathway during cardiac hypertrophy induced by pressure overload, and the pharmacological mitogen-activated protein kinase kinase 1/2 inhibitor U0126 almost completely reversed Sema4D overexpression-induced deteriorated phenotype, resulting in improved cardiac function. Further research indicated that myocardial hypertrophy induced by Sema4D was closely related to the expression of the pyroptosis-related proteins PP65, NLRP3, caspase-1, ASC, GSDMD, IL-18 and IL-1ß. In conclusion, our study demonstrated that Sema4D regulated the process of pathological myocardial hypertrophy through modulating MAPK/NF-κB/NLRP3 pathway, and Sema4D may be the promising interventional target of cardiac hypertrophy and heart failure.

Downregulation of B4GALT5 attenuates cardiac fibrosis through Lumican and Akt/GSK-3ß/ß-catenin pathway.

Virtually all forms of cardiac disease exhibit cardiac fibrosis as a common trait, which ultimately leads to adverse ventricular remodeling and heart failure. To improve the prognosis of heart disease, it is crucial to halt the progression of cardiac fibrosis. Protein function is intricately linked with protein glycosylation, a vital post-translational modification. As a fundamental member of the ß1,4-galactosyltransferase gene family (B4GALT), ß1,4-galactosyltransferase V (B4GALT5) is associated with various disorders. In this study, significant levels of B4GALT5 expression were observed in cardiac fibrosis induced by transverse aortic constriction (TAC) or TGFß1 and the activation of cardiac fibroblasts (CFs). Subsequently, by administering AAV9-shB4GALT5 injections to TAC animals, we were able to demonstrate that in vivo B4GALT5 knockdown decreased the transformation of CFs into myofibroblasts (myoFBs) and reduced the deposition of cardiac collagen fibers. In vitro tests revealed the same results. Conversely, both in vivo and in vitro experiments indicated that overexpression of B4GALT5 stimulates CFs activation and exacerbates cardiac fibrosis. Initially, we elucidated the primary mechanism by which B4GALT5 regulates the Akt/GSK-3ß/ß-catenin pathway and directly interacts with laminin, thereby affecting cardiac fibrosis. Our findings demonstrate that B4GALT5 promotes cardiac fibrosis through the Akt/GSK-3ß/ß-catenin pathway and reveal laminin as the target protein of B4GALT5.

Construction and validation of a nomogram for predicting diabetes remission at 3 months after bariatric surgery in patients with obesity combined with type 2 diabetes mellitus.

AIM: Bariatric metabolic surgery (BMS) is a proven treatment option for patients with both obesity and type 2 diabetes mellitus (T2DM). However, there is a lack of comprehensive reporting on the short-term remission rates of diabetes, and the existing data are inadequate. Hence, this study aimed to investigate the factors that may contribute to diabetes remission (DR) in patients with obesity and T2DM, 3 months after undergoing BMS. Furthermore, our objective was to develop a risk-predicting model using a nomogram. METHODS: In total, 389 patients with obesity and T2DM, who had complete preoperative information and underwent either laparoscopic sleeve gastrectomy or laparoscopic gastric bypass surgery between January 2014 and May 2023, were screened in the Chinese Obesity and Metabolic Surgery Database. The patients were randomly divided into a training set (n = 272) and a validation set (n = 117) in a 7:3 ratio. Potential factors for DR were analysed through univariate and multivariate logistic regression analyses and then modelled using a nomogram. The model's performance was evaluated using receiver operating characteristic curves and the area under the curve (AUC). Calibration plots were used to assess prediction accuracy and decision curve analyses were conducted to evaluate the clinical usefulness of the model. RESULTS: Glycated haemoglobin, triglycerides, duration of diabetes, insulin requirement and hypercholesterolaemia were identified as independent factors influencing DR. We have incorporated these five indicators into a nomogram, which has shown good efficacy in both the training cohort (AUC = 0.930) and validation cohort (AUC = 0.838). The calibration plots indicated that the model fits well in both the training and the validation cohorts, and decision curve analyses showed that the model had good clinical applicability. CONCLUSION: The prediction model developed in this study holds predictive value for short-term DR following BMS in patients with obesity and T2DM.

BR109, a Novel Fully Humanized T-Cell-Engaging Bispecific Antibody with GPRC5D Binding, Has Potent Antitumor Activities in Multiple Myeloma.

At present, multiple myeloma (MM) is still an essentially incurable hematologic malignancy. Although BCMA-targeted therapies have achieved remarkable results, BCMA levels were found to be downregulated in patients with MM who relapsed after these treatments. Therefore, the search for other antigens specific to MM has become a priority. Independently of BCMA expression, G-protein-coupled receptor family C group 5 member D (GPRC5D) is mainly expressed in the plasma cells of MM patients, while it is expressed in a limited number of normal tissues. Combining MM-specific antigen GPRC5D and T-cell-mediated therapies would be a promising therapeutic strategy for MM. Recently, we constructed a new anti-GPRC5D × anti-CD3 T-cell-engaging bispecific antibody (TCB), BR109, which was capable of binding to human GPRC5D and human CD3ε. Moreover, BR109 was proven to have relatively good stability and antitumor activity. BR109 could specifically trigger T-cell-mediated cytotoxicity against many GPRC5D-positive MM cells in vitro. Meanwhile, antitumor activity was demonstrated in MM cell line xenograft mouse models with human immune cell reconstitution. These preclinical studies have formed a solid foundation for the evaluation of MM treatment efficacy in clinical trials.

Novel diagnostic biomarkers of oxidative stress, immune- infiltration characteristics and experimental validation of SERPINE1 in colon cancer.

BACKGROUND: Colon cancer (CC) is a prevalent malignant tumor that affects the colon in the gastrointestinal tract. Its aggressive nature, strong invasiveness, and rapid progression make it a significant health concern. In addition, oxidative stress can lead to the production of reactive oxygen species (ROS) that surpass the body's antioxidant defense capacity, causing damage to proteins, lipids, and DNA, potentially promoting tumor development. However, the relationship between CC and oxidative stress requires further investigation. METHODS: We collected gene expression data and clinical data from 473 CC patients from The Cancer Genome Atlas (TCGA) dataset. Additionally, we obtained 433 oxidative stress genes from Genecards ( https://www.genecards.org/ ). Using univariate, multivariate, and LASSO Cox regression analyses, we developed predictive models for oxidative stress-related genes in CC patients. To validate the models, we utilized data from the Gene Expression Omnibus (GEO) database. We assessed the accuracy of the models through various techniques, including the creation of a nomogram, receiver operating characteristic curve (ROC) analysis, and principal component analysis (PCA). The Cytoscape program was utilized to identify hub genes among differentially expressed genes (DEGs) in tumor patients using the TCGA dataset. Subsequently, we conducted survival analysis, clinical relevance analysis, and immune cell relevance analysis for the intersected genes obtained by combining the hub genes with the genes from the predictive models. Moreover, we investigated the mRNA expression and potential functions of these intersected genes using a range of experimental approaches. RESULTS: In both the TCGA and GSE17538 datasets, patients classified as high-risk had significantly shorter overall survival compared to those in the low-risk group (TCGA: p < 0.001; GSE17538: p = 0.010). As a result, we decided to further investigate the role of SERPINE1. Our survival analysis revealed that patients with high expression of SERPINE1 had a significantly lower probability of survival compared to those with low expression (p < 0.05). Additionally, our clinical correlation analysis showed a significant relationship between SERPINE1 expression and T, N, and M stages, as well as tumor grade. Furthermore, our immune infiltration correlation analysis demonstrated notable differences in multiple immune cells between the high- and low-expression groups of SERPINE1. To validate our findings, we conducted experimental tests and observed that knocking down SERPINE1 in colon cancer cells resulted in significant reductions in cell viability and proliferation. Interestingly, we also noticed an increase in oxidative stress parameters, such as ROS and MDA levels, while the levels of reduced GSH decreased upon SERPINE1 knockdown. These findings suggest that the antineoplastic effect of silencing SERPINE1 may be associated with the induction of oxidative stress. CONCLUSION: In conclusion, this study introduces a new approach for the early diagnosis and treatment of CC, and further exploration of SERPINE1 could potentially lead to a significant advancement.

CircIQGAP1 regulates RCAN1 and RCAN2 through the mechanism of ceRNA and promotes the growth of malignant glioma.

Circular RNA (circRNA) is one of non-coding RNA with specific circular structure, which has been found to be involved in regulating a series of malignant biological behaviors in many malignant tumors. In this study, based on the IDH1 molecular typing of gliomas, we identified a significant downregulation of circRNA (circIQGAP1) expression in IDH1 mutant gliomas by high-throughput sequencing. In 79 tissue samples, we confirmed that circIQGAP1 expression was significantly downregulated in IDH1 mutant gliomas, and that low circIQGAP1 expression was positively associated with better prognosis. Knockdown of circIQGAP1 in glioma cell lines inhibited glioma cell malignancy and conversely overexpression of circIQGAP1 promoted glioma malignancy. circIQGAP1 regulated glioma cell migration, proliferation, invasion and apoptosis through miR-1256/RCAN1/Bax/Bcl-2/Caspase3 and miR-622/RCAN2/Bax/Bcl-2/Caspase3 axes. These results suggest that circIQGAP1 plays an important role in glioma development, promotes tumor growth, and is a potential therapeutic target for glioma.

SIX4, a potential therapeutic target for estrogen receptor-positive breast cancer patients, is associated with low promoter methylation level.

Aim: To investigate SIX4 in breast cancer. Methods: Publicly available online tools were used to analyze the expression, methylation and prognostic significance of SIX4 in breast cancer, as well as its immunohistochemistry. Results: High SIX4 levels were associated with low SIX4 promoter methylation, especially in estrogen receptor-positive breast cancer. Increased SIX4 was related to advanced stage and decreased immune infiltration. Gene set enrichment analysis found that the SIX4-correlated genes were enriched in transcriptional processing and immune response. Patients with high SIX4 expression tended to have poor survival, especially those with estrogen receptor-positive breast cancer. Conclusion: High SIX4 expression in breast cancer plays an oncogenic role, promoting the development of malignancies through suppressing the immune response, especially in luminal subtypes, and is associated with a low promoter methylation level.

A Web-Based Calculator to Predict Early Death Among Patients With Bone Metastasis Using Machine Learning Techniques: Development and Validation Study.

BACKGROUND: Patients with bone metastasis often experience a significantly limited survival time, and a life expectancy of <3 months is generally regarded as a contraindication for extensive invasive surgeries. In this context, the accurate prediction of survival becomes very important since it serves as a crucial guide in making clinical decisions. OBJECTIVE: This study aimed to develop a machine learning-based web calculator that can provide an accurate assessment of the likelihood of early death among patients with bone metastasis. METHODS: This study analyzed a large cohort of 118,227 patients diagnosed with bone metastasis between 2010 and 2019 using the data obtained from a national cancer database. The entire cohort of patients was randomly split 9:1 into a training group (n=106,492) and a validation group (n=11,735). Six approaches-logistic regression, extreme gradient boosting machine, decision tree, random forest, neural network, and gradient boosting machine-were implemented in this study. The performance of these approaches was evaluated using 11 measures, and each approach was ranked based on its performance in each measure. Patients (n=332) from a teaching hospital were used as the external validation group, and external validation was performed using the optimal model. RESULTS: In the entire cohort, a substantial proportion of patients (43,305/118,227, 36.63%) experienced early death. Among the different approaches evaluated, the gradient boosting machine exhibited the highest score of prediction performance (54 points), followed by the neural network (52 points) and extreme gradient boosting machine (50 points). The gradient boosting machine demonstrated a favorable discrimination ability, with an area under the curve of 0.858 (95% CI 0.851-0.865). In addition, the calibration slope was 1.02, and the intercept-in-large value was -0.02, indicating good calibration of the model. Patients were divided into 2 risk groups using a threshold of 37% based on the gradient boosting machine. Patients in the high-risk group (3105/4315, 71.96%) were found to be 4.5 times more likely to experience early death compared with those in the low-risk group (1159/7420, 15.62%). External validation of the model demonstrated a high area under the curve of 0.847 (95% CI 0.798-0.895), indicating its robust performance. The model developed by the gradient boosting machine has been deployed on the internet as a calculator. CONCLUSIONS: This study develops a machine learning-based calculator to assess the probability of early death among patients with bone metastasis. The calculator has the potential to guide clinical decision-making and improve the care of patients with bone metastasis by identifying those at a higher risk of early death.

Application of three-dimensional (3D) bioprinting in anti-cancer therapy.

Three-dimensional (3D) bioprinting is a novel technology that enables the creation of 3D structures with bioinks, the biomaterials containing living cells. 3D bioprinted structures can mimic human tissue at different levels of complexity from cells to organs. Currently, 3D bioprinting is a promising method in regenerative medicine and tissue engineering applications, as well as in anti-cancer therapy research. Cancer, a type of complex and multifaceted disease, presents significant challenges regarding diagnosis, treatment, and drug development. 3D bioprinted models of cancer have been used to investigate the molecular mechanisms of oncogenesis, the development of cancers, and the responses to treatment. Conventional 2D cancer models have limitations in predicting human clinical outcomes and drug responses, while 3D bioprinting offers an innovative technique for creating 3D tissue structures that closely mimic the natural characteristics of cancers in terms of morphology, composition, structure, and function. By precise manipulation of the spatial arrangement of different cell types, extracellular matrix components, and vascular networks, 3D bioprinting facilitates the development of cancer models that are more accurate and representative, emulating intricate interactions between cancer cells and their surrounding microenvironment. Moreover, the technology of 3D bioprinting enables the creation of personalized cancer models using patient-derived cells and biomarkers, thereby advancing the fields of precision medicine and immunotherapy. The integration of 3D cell models with 3D bioprinting technology holds the potential to revolutionize cancer research, offering extensive flexibility, precision, and adaptability in crafting customized 3D structures with desired attributes and functionalities. In conclusion, 3D bioprinting exhibits significant potential in cancer research, providing opportunities for identifying therapeutic targets, reducing reliance on animal experiments, and potentially lowering the overall cost of cancer treatment. Further investigation and development are necessary to address challenges such as cell viability, printing resolution, material characteristics, and cost-effectiveness. With ongoing progress, 3D bioprinting can significantly impact the field of cancer research and improve patient outcomes.