Human Adipose-Derived Microvessel Fragments: A Natural Vascularization Units for Ischemic Diseases.

BACKGROUND: In plastic surgery tissue transplantation, tissue ischemia limits transplanted tissue survival. Adipose-derived stem cells (ASCs) and stromal vascular fraction (SVF) show potential for promoting angiogenesis and rescuing ischemic conditions. However, when SVF and ASC suspensions are utilized without the protection of extracellular matrix, the retention rate of transplanted cells tends to be diminished, leading to an unsatisfactory therapeutic outcome. To overcome this, adipose tissue-derived microvascular fragments (ad-MVFs) have emerged as a promising solution. METHODS: We conducted enzymatic digestion on human adipose tissue to generate ad-MVFs. These fragments underwent a thorough characterization process, utilizing electron microscopy to assess their structural attributes and enabling a detailed analysis of their intricate morphology. Furthermore, our team investigated the cellular composition of these microvascular fragments, subsequently confirming their ability to enhance the viability of ischemic skin flaps. RESULTS: The resulting product primarily comprised fragments with sizes ranging from 20 to 50 µm, and some exhibited a sophisticated network-like structure. Electron microscopy examination revealed the presence of collagen components in the product. Additionally, flow cytometry analysis indicated a substantial abundance of adipose-derived stem cells and endothelial cells within these microvascular fragments. Significantly, when tested in treating an ischemic skin flap in a nude mouse model, the product exhibited superior therapeutic efficacy compared to SVF cell suspension. CONCLUSION: We have successfully generated human ad-MVFs and established standardized procedures. Compared with SVF, Ad-MVFs have a better effect in the treatment of ischemic diseases. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Establishment of Early Blood Perfusion Promotes CXCL12 Expression and Recruits Monocytes/Macrophages in Damaged Adipose Tissue in Mice Model.

BACKGROUND: Blood perfusion in the recipient site is important for adipose tissue repair after fat grafting. It delivers host-derived macrophages derived from monocytes in bone marrow to initiate inflammatory reactions and regenerative responses. According to the ability of CXCL12, a stromal cell-derived factor, to recruit monocytes/macrophages, we studied its effect on adipose tissue repair and regeneration under ischemic and normal conditions. METHODS: Each inguinal fat pad was crushed for 30 seconds with a clamp in mice (n = 35). The left inguinal vessels were divided and cut off (ischemic group), while the right inguinal vessels were kept patent (control group). Seven animals were sacrificed at 1, 3, 7, 14, and 30 days after surgery, and macrophages (Mac2 and CD206) and adipocytes (perilipin) were assessed. Levels of inflammatory factors (interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α) and CXCL12 were measured by quantitative PCR. RESULTS: The number of macrophages was higher in the control group than in the ischemic group at day 3 (10.33 ± 2.40 vs. 1.33 ± 0.33, p = 0.021). The percentage of M2 macrophages was higher in the control group than in the ischemic group at day 7 (p<0.05). The levels of inflammatory factors and CXCL12 were higher in the control group than in the ischemic group at the early stage (p = 0.038). CONCLUSIONS: Established blood perfusion leads to up-regulation of CXCL12 during adipose tissue repair and regeneration, which may increase recruitment of monocytes to damaged adipose tissue. These findings increase understanding of the cellular events involved in fat graft survival after grafting. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Type IV Collagen Promotes Adipogenic Differentiation of Adipose Stem Cells.

Type IV collagen is a major component of the extracellular matrix in adipose tissue. It is secreted during the lipogenic differentiation of mesenchymal stem cells, but its direct impact and mechanism on the differentiation of adipose-derived stem cells (ASCs) into lipids are unclear. In this study, ASCs were obtained from human liposuction samples and cultured. Lipogenic induction of ASCs was achieved using lipogenic induction medium. Immunofluorescence analysis revealed differential expression of type IV collagen during the early and late stages of adipogenic induction, displaying a distinct morphological encapsulation of ASCs. Silencing of type IV collagen using siRNA resulted in a significant decrease in adipogenic capacity, as indicated by reduced lipid droplet formation and downregulation of adipogenic-related gene transcription. Conversely, supplementation of the culture medium with synthetic type IV collagen demonstrated enhanced adipogenic induction efficiency, accompanied by upregulation of YAP/TAZ protein expression and its downstream target gene transcription. Furthermore, inhibition of the YAP/TAZ pathway using the inhibitor Blebbistatin attenuated the functionality of type IV collagen, leading to decreased lipid droplet formation and downregulation of adipocyte maturation-related gene expression. These findings highlight the crucial role of type IV collagen in promoting adipogenic differentiation of ASCs and suggest its involvement in the YAP/TAZ-mediated Hippo pathway.No Level Assigned This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

TDASD: Generating medically significant fine-grained lung adenocarcinoma nodule CT images based on stable diffusion models with limited sample size.

BACKGROUND AND OBJECTIVES: Spread through air spaces (STAS) is an emerging lung cancer infiltration pattern. Predicting its spread through CT scans is crucial. However, limited STAS data makes this prediction task highly challenging. Stable diffusion is capable of generating more diverse and higher-quality images compared to traditional GAN models, surpassing the dominating GAN family models in image synthesis over the past few years. To alleviate the issue of limited STAS data, we propose a method TDASD based on stable diffusion, which is able to generate high-resolution CT images of pulmonary nodules corresponding to specific nodular signs according to the medical professionals. METHODS: First, we apply the stable diffusion method for fine-tuning training on publicly available lung datasets. Subsequently, we extract nodules from our hospital's lung adenocarcinoma data and apply slight rotations to the original nodule CT slices within a reasonable range before undergoing another round of fine-tuning through stable diffusion. Finally, employing DDIM and Ksample sampling methods, we generate lung adenocarcinoma nodule CT images with signs based on prompts provided by doctors. The method we propose not only safeguards patient privacy but also enhances the diversity of medical images under limited data conditions. Furthermore, our approach to generating medical images incorporates medical knowledge, resulting in images that exhibit pertinent medical features, thus holding significant value in tumor discrimination diagnostics. RESULTS: Our TDASD method has the capability to generate medically meaningful images by optimizing input prompts based on medical descriptions provided by experts. The images generated by our method can improve the model's classification accuracy. Furthermore, Utilizing solely the data generated by our method for model training, the test results on the original real dataset reveal an accuracy rate that closely aligns with the testing accuracy achieved through training on real data. CONCLUSIONS: The method we propose not only safeguards patient privacy but also enhances the diversity of medical images under limited data conditions. Furthermore, our approach to generating medical images incorporates medical knowledge, resulting in images that exhibit pertinent medical features, thus holding significant value in tumor discrimination diagnostics.

Multi-omics comprehensive analysis reveals the predictive value of N6-methyladenosine- related genes in prognosis and immune escape of bladder cancer.

BACKGROUND: N6-methyladenosine (m6A) is the most frequent RNA modification in mammals, and its role in bladder cancer (BC) remains rarely revealed. OBJECTIVE: To predict the value of m6A-related genes in prognosis and immunity in BC. METHODS: We performed multiple omics analysis of 618 TCGA and GEO patients and used principal component analysis (PCA) to calculate the m6A score for BC patients. RESULTS: We described the multiple omics status of 23 m6A methylation-related genes (MRGs), and four m6A clusters were identified, which showed significant differences in immune infiltration and biological pathways. Next, we intersected the differential genes among m6A clusters, and 11 survival-related genes were identified, which were used to calculate the m6A score for the patients. We found that the high-score (HS) group showed lower tumor mutation burden (TMB) and TP53 mutations and better prognosis than the low-score (LS) group. Lower immune infiltration, higher expression of PD-L1, PD-1, and CTLA4, and higher immune dysfunction and immune exclusion scores were identified in the LS group, suggesting a higher possibility of immune escape. Finally, the experimental verification shows that the m6A related genes, such as IGFBP1, plays an important role in the growth and metastasis of bladder cancer. CONCLUSIONS: These findings revealed the important roles of m6A MRGs in predicting prognosis, TMB status, TP53 mutation, immune functions and immunotherapeutic response in BC.

Causal relationship between affect disorders and endometrial cancer: a Mendelian randomisation study.

BACKGROUND: The aim was to assess the causal relationship between depression and anxiety disorders and endometrial cancer. METHOD: We performed two-sample Mendelian randomisation analysis using summary statistics from genome-wide association studies to assess associations of major depressive disorder, anxiety and stress-related disorders with endometrial cancer. The genome-wide association studies(GWASs) data were derived from participants of predominantly European ancestry included in the Genome-wide Association Research Collaboration. Inverse variance-weighted, MR-Egger and weighted median MR analyses were performed, together with a range of sensitivity analyses. RESULTS: Mendelian randomisation analysis showed no statistically significant genetic responsibility effect of anxiety and stress-related disorders on any pathological type of endometrial cancer. Only the effect of major depressive disorder under the inverse variance weighting method increasing the risk of endometrial endometrial cancer (effect 0.004 p = 0.047) and the effect of major depressive disorder under the MR-Egger method decreasing endometrial cancer of all pathology types (effect -0.691 p = 0.015) were statistically significant. Other Mendelian randomisation analyses did not show a statistically significant effect. CONCLUSION: Major depressive disorder(MDD), anxiety and stress-related disorders(ASRD) are not genetically responsible for endometrial cancer. We consider that emotional disorders may affect endometrial cancer indirectly by affecting body mass index. This study provides us with new insights to better understand the aetiology of endometrial cancer and inform prevention strategies.

This study used public genomic data to analyse association between affective disorders, including depression and anxiety, and endometrial cancer. Genes treated as instrumental variables help us understand the causal link between affective disorders and endometrial cancer through bioinformatics. In addition to this, we added type 2 diabetes, body mass index, polycystic ovary syndrome, and age at menopause for multivariate Mendelian randomisation analyses with the aim of reducing confounding bias. Because we consider these factors may potentially influence the relationship between affective disorders and endometrial cancer. Ultimately we believe that the association between depression and endometrial cancer is not as strong as that of obesity, due to the genetic correlation between depression and obesity.

JAM3: A prognostic biomarker for bladder cancer via epithelial­mesenchymal transition regulation

Understanding the intricate relationship between prognosis, immune function, and molecular markers in bladder cancer (BC) demands sophisticated analytical methods. To identify novel biomarkers for predicting prognosis and immune function in BC patients, we combined weighted gene co-expression network analysis (WGCNA) and least absolute shrinkage and selection operator (LASSO) regression analysis. This was conducted using data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Ultimately, we screened the junctional adhesion molecule 3 (JAM3) as an independent risk factor in BC. High levels of JAM3 were linked to adverse clinical parameters, such as higher T and N stages. Additionally, a JAM3-based nomogram model accurately predicted 1-, 3- and 5-year survival rates of BC patients, indicating potential clinical utility. Functional enrichment analysis revealed that high JAM3 expression activated the calcium signaling pathway, the extracellular matrix (ECM)-receptor interaction, and the PI3K-Akt signaling pathway, and was positively correlated with genes associated with epithelial­mesenchymal transition (EMT). Subsequently, we found that overexpression of JAM3 promoted the migration and invasion abilities in BC cells, regulating the expression levels of N-Cadherin, matrix metallopeptidase 2 (MMP2), and Claudin-1 thereby promoting EMT levels. Additionally, we showed that JAM3 was negatively correlated with anti-tumor immune cells such as CD8+T cells, while positively correlated with pro-tumor immune cells such as M2 macrophages, suggesting its involvement in immune cell infiltration. The immune checkpoint CD200 also showed a positive correlation with JAM3. Our findings revealed that elevated JAM3 levels are predictive of poor prognosis and immune cell infiltration in BC patients by regulating the EMT process.

Histological evaluation of monopolar and bipolar radiofrequency microneedling treatment in a porcine model.

BACKGROUND AND OBJECTIVE: Fractional radiofrequency microneedling (FRM) is widely used as an option for skin rejuvenation, however there is a lack of histological evidence for the various energy delivery systems available. The objective was to assess thermal denaturation of tissue and the wound healing response in monopolar mode versus bipolar mode. Histological analysis was performed to demonstrate the efficacy of automatic impedance feedback system in monopolar mode. STUDY DESIGN AND METHODS: In this study, the acute thermal effects caused by monopolar FRM treatment to the dorsal skin of pigs were assessed histologically by hematoxylin & eosin (H&E) staining. Then, one session of either monopolar or bipolar FRM was used to treat one or the other side of the pig using varying power levels and pulse widths. The acute and chronic tissue reactions were assessed using H&E, immunofluorescence, and western blot analysis at 0, 14, 30, and 90 days after treatment. The efficacy of the impedance feedback system was also monitored histologically. RESULTS: High-energy FRM treatment produced tissue loss and necrosis. The power level and pulse duration significantly affected the coagulation amount. Histopathology at 0, 14, 30, and 90 days showed that the skin tissue reaction was more pronounced for bipolar compared to monopolar FRM. Immunofluorescence showed the expression of TGF-ß, Ki67, MMP3, and elastin increased dramatically with both modes, but were higher in the bipolar FRM treated side. The automatic impedance feedback system could effectively adjust the output energy. CONCLUSIONS: We found that bipolar FRM produced greater thermal effects, more collagen coagulation, and more pronounced molecular changes compared with monopolar mode in a porcine animal model.

Dietary patterns associated with the incidence of hypertension among adult Japanese males: application of machine learning to a cohort study.

PURPOSE: The previous studies that examined the effectiveness of unsupervised machine learning methods versus traditional methods in assessing dietary patterns and their association with incident hypertension showed contradictory results. Consequently, our aim is to explore the correlation between the incidence of hypertension and overall dietary patterns that were extracted using unsupervised machine learning techniques. METHODS: Data were obtained from Japanese male participants enrolled in a prospective cohort study between August 2008 and August 2010. A final dataset of 447 male participants was used for analysis. Dimension reduction using uniform manifold approximation and projection (UMAP) and subsequent K-means clustering was used to derive dietary patterns. In addition, multivariable logistic regression was used to evaluate the association between dietary patterns and the incidence of hypertension. RESULTS: We identified four dietary patterns: 'Low-protein/fiber High-sugar,' 'Dairy/vegetable-based,' 'Meat-based,' and 'Seafood and Alcohol.' Compared with 'Seafood and Alcohol' as a reference, the protective dietary patterns for hypertension were 'Dairy/vegetable-based' (OR 0.39, 95% CI 0.19-0.80, P = 0.013) and the 'Meat-based' (OR 0.37, 95% CI 0.16-0.86, P = 0.022) after adjusting for potential confounding factors, including age, body mass index, smoking, education, physical activity, dyslipidemia, and diabetes. An age-matched sensitivity analysis confirmed this finding. CONCLUSION: This study finds that relative to the 'Seafood and Alcohol' pattern, the 'Dairy/vegetable-based' and 'Meat-based' dietary patterns are associated with a lower risk of hypertension among men.

A predictive model of immune infiltration and prognosis of head and neck squamous cell carcinoma based on cell adhesion-related genes: including molecular biological validation.

Background: Focal adhesion serves as a bridge between tumour cells and the extracellular matrix (ECM) and has multiple roles in tumour invasion, migration, and therapeutic resistance. However, studies on focal adhesion-related genes (FARGs) in head and neck squamous cell carcinoma (HNSCC) are limited. Methods: Data on HNSCC samples were obtained from The Cancer Genome Atlas and GSE41613 datasets, and 199 FARGs were obtained from the Molecular Signatures database. The integrated datasets' dimensions were reduced by the use of cluster analysis, which was also used to classify patients with HNSCC into subclusters. A FARG signature model was developed and utilized to calculate each patient's risk score using least extreme shrinkage and selection operator regression analysis. The risk score was done to quantify the subgroups of all patients. We evaluated the model's value for prognostic prediction, immune infiltration status, and therapeutic response in HNSCC. Preliminary molecular and biological experiments were performed to verify these results. Results: Two different HNSCC molecular subtypes were identified according to FARGs, and patients with C2 had a shorter overall survival (OS) than those with C1. We constructed an FARG signature comprising nine genes. We constructed a FARG signature consisting of nine genes. Patients with higher risk scores calculated from the FARG signature had a lower OS, and the FARG signature was considered an independent prognostic factor for HNSCC in univariate and multivariate analyses. FARGs are associated with immune cell invasion, gene mutation status, and chemosensitivity. Finally, we observed an abnormal overexpression of MAPK9 in HNSCC tissues, and MAPK9 knockdown greatly impeded the proliferation, migration, and invasion of HNSCC cells. Conclusion: The FARG signature can provide reliable prognostic prediction for patients with HNSCC. Apart from that, the genes in this model were related to immune invasion, gene mutation status, and chemosensitivity, which may provide new ideas for targeted therapies for HNSCC.

Comprehensive Analysis of SLC35A2 in Pan-Cancer and Validation of Its Role in Breast Cancer.

Purpose: Elucidation of the oncogenic role of SLC35A2 in human tumors and the potential function and clinical significance in breast cancer. Methods: Pan-cancer analysis was performed via various bioinformatics tools to explain the pathogenic role of SLC35A2. A prognostic nomogram was also developed based on the SLC35A2 expression and clinicopathological characteristics in breast cancer patients. In addition, the role of SLC35A2 was validated in breast cancer by in vivo and in vitro experiments. Results: SLC35A2 expression is increased in 27 tumor types, and its high expression is substantially correlated with poor prognosis in patients with a variety of cancers. Receiver operating characteristic (ROC) curves showed that SLC35A2 expression levels could accurately distinguish most tumor tissues from normal tissues. High SLC35A2 expression was linked to increased immune infiltration in myeloid-derived suppressor cells (MDSC), as well as immune checkpoints, ferroptosis-related genes, tumor mutational burden (TMB), and microsatellite instability (MSI). SLC35A2 may be involved in tumorigenesis by regulating the glycosylation process. Furthermore, multivariate Cox analysis showed that SLC35A2 was an independent prognostic factor for breast cancer. And the nomogram model had good predictive accuracy for the prognosis of breast cancer patients. Meanwhile, cellular experiments demonstrated that knockdown of SLC35A2 could significantly inhibit the proliferation, migration and invasion of breast cancer cells, while increasing the protein level of E-cadherin and decreasing N-cadherin. A nude mouse xenograft model showed that inhibition of SLA35A2 expression could significantly inhibit tumor growth. Conclusion: SLC35A2 has good diagnostic and prognostic values in multiple cancers and is closely related to tumor immune infiltration. In addition, SLA35A2 as an oncogene in breast cancer may be involved in the progression of epithelial mesenchymal transition (EMT).

Lactate promotes neuronal differentiation of SH-SY5Y cells by lactate-responsive gene sets through NDRG3-dependent and -independent manners.

Lactate serves as the major glucose alternative to an energy substrate in the brain. Lactate level is increased in the fetal brain from the middle stage of gestation, indicating the involvement of lactate in brain development and neuronal differentiation. Recent reports show that lactate functions as a signaling molecule to regulate gene expression and protein stability. However, the roles of lactate signaling in neuronal cells remain unknown. Here, we showed that lactate promotes the all stages of neuronal differentiation of SH-SY5Y and Neuro2A, human and mouse neuroblastoma cell lines, characterized by increased neuronal marker expression and the rates of neurites extension. Transcriptomics revealed many lactate-responsive genes sets such as SPARCL1 in SH-SY5Y, Neuro2A, and primary embryonic mouse neuronal cells. The effects of lactate on neuronal function were mainly mediated through monocarboxylate transporters 1 (MCT1). We found that NDRG family member 3 (NDRG3), a lactate-binding protein, was highly expressed and stabilized by lactate treatment during neuronal differentiation. Combinative RNA-seq of SH-SY5Y with lactate treatment and NDRG3 knockdown shows that the promotive effects of lactate on neural differentiation are regulated through NDRG3-dependent and independent manners. Moreover, we identified TEA domain family member 1 (TEAD1) and ETS-related transcription factor 4 (ELF4) are the specific transcription factors that are regulated by both lactate and NDRG3 in neuronal differentiation. TEAD1 and ELF4 differently affect the expression of neuronal marker genes in SH-SY5Y cells. These results highlight the biological roles of extracellular and intracellular lactate as a critical signaling molecule that modifies neuronal differentiation.

PAD4-dependent citrullination of nuclear translocation of GSK3ß promotes colorectal cancer progression via the degradation of nuclear CDKN1A.

Peptidylarginine deiminase 4 (PAD4), a Ca2+-dependent enzyme, catalyzes the conversion of arginine to citrulline and has been strongly associated with many malignant tumors. However, the molecular mechanisms of PAD4 in the development and progression of colorectal cancer (CRC) remain unclearly defined. In our study, PAD4 expression was increased in CRC tissues and cells, and was closely related to tumor size, lymph node metastasis. Moreover, the transcription factor KLF9 directly bound to PADI4 gene promoter, leading to overexpression of PAD4 in CRC cells, which augmented cell growth and migration. We revealed that PAD4 interacted with and citrullinated glycogen synthase kinase-3ß (GSK3ß) in CRC cells, and GSK3ß Arg-344 was the dominating PAD4-citrullination site. Furthermore, IgL2 and catalytic domains of PAD4 directly bound to the kinase domain of GSK3ß in CRC cells. Mechanistically, PAD4 promoted the transport of GSK3ß from the cytoplasm to the nucleus, thereby increasing the ubiquitin-dependent proteasome degradation of nuclear cyclin-dependent kinase inhibitor 1 (CDKN1A). Our study is the first to reveal the details of a critical PAD4/GSK3ß/CDKN1A signaling axis for CRC progression, and provides evidence that PAD4 is a potential diagnosis biomarker and therapeutic target in CRC.

Targeting adipokines in polycystic ovary syndrome and related metabolic disorders: from experimental insights to clinical studies.

Polycystic ovary syndrome (PCOS) affects approximately 15% of women of reproductive age worldwide. It is the most prevalent endocrine disorder with marked risks for female infertility, type 2 diabetes mellitus (T2DM), psychiatric disorders and gynecological cancers. Although the pathophysiology of PCOS remains largely elusive, growing evidence suggests a close link with obesity and its related metabolic disorders. As a highly active endocrine cell population, hypertrophic adipocytes in obesity have disturbed production of a vast array of adipokines, biologically active peptides that exert pleiotropic effects on homeostatic regulation of glucose and lipid metabolism. In parallel with their crucial roles in the pathophysiology of obesity-induced metabolic diseases, adipokines have recently been identified as promising targets for novel therapeutic strategies for multiple diseases. Current treatments for PCOS are suboptimal with insufficient alleviation of all symptoms. Novel findings in adipokine-targeted agents may provide important insight into the development of new drugs for PCOS. This Review presents an overview of the current understanding of mechanisms that link PCOS to obesity and highlights emerging evidence of adipose-ovary crosstalk as a pivotal mediator of PCOS pathogenesis. We summarize recent findings of preclinical and clinical studies that reveal the therapeutic potential of adipokine-targeted novel approaches to PCOS and its related metabolic disorders. We also discuss the critical gaps in knowledge that need to be addressed to guide the development of adipokine-based novel therapies for PCOS.

Circ_CEA promotes the interaction between the p53 and cyclin-dependent kinases 1 as a scaffold to inhibit the apoptosis of gastric cancer.

Circular RNAs (circRNAs) have been reported to play essential roles in tumorigenesis and progression. This study aimed to identify dysregulated circRNAs in gastric cancer (GC) and investigate the functions and underlying mechanism of these circRNAs in GC development. Here, we identify circ_CEA, a circRNA derived from the back-splicing of CEA cell adhesion molecule 5 (CEA) gene, as a novel oncogenic driver of GC. Circ_CEA is significantly upregulated in GC tissues and cell lines. Circ_CEA knockdown suppresses GC progression, and enhances stress-induced apoptosis in vitro and in vivo. Mechanistically, circ_CEA interacts with p53 and cyclin-dependent kinases 1 (CDK1) proteins. It serves as a scaffold to enhance the association between p53 and CDK1. As a result, circ_CEA promotes CDK1-mediated p53 phosphorylation at Ser315, then decreases p53 nuclear retention and suppresses its activity, leading to the downregulation of p53 target genes associated with apoptosis. These findings suggest that circ_CEA protects GC cells from stress-induced apoptosis, via acting as a protein scaffold and interacting with p53 and CDK1 proteins. Combinational therapy of targeting circ_CEA and chemo-drug caused more cell apoptosis, decreased tumor volume and alleviated side effect induced by chemo-drug. Therefore, targeting circ_CEA might present a novel treatment strategy for GC.

Takotsubo syndrome and respiratory diseases: a systematic review.

Takotsubo syndrome (TTS) is a rare cardiovascular condition characterized by reversible ventricular dysfunction and a presentation resembling that of acute myocardial infarction. An increasing number of studies has shown the association of respiratory diseases with TTS. Here, we comprehensively reviewed the literature and examined the available evidence for this association. After searching PubMed, EMBASE, and Cochrane Library databases, two investigators independently reviewed 3117 studies published through May 2021. Of these studies, 99 met the inclusion criteria (n = 108 patients). In patients with coexisting respiratory disease and TTS, the most common TTS symptom was dyspnoea (70.48%), followed by chest pain (24.76%) and syncope (2.86%). The most common type of TTS was apical, accounting for 81.13% of cases, followed by the midventricular (8.49%), basal (8.49%), and biventricular (1.89%) types. Among the TTS cases, 39.82% were associated with obstructive lung disease and 38.89% were associated with pneumonia. Coronavirus disease 2019 (COVID-19), which has been increasingly reported in patients with TTS, was identified in 29 of 42 (69.05%) patients with pneumonia. The overall mortality rate for patients admitted for respiratory disease complicated by TTS was 12.50%. Obstructive lung disease and pneumonia are the most frequently identified respiratory triggers of TTS. Medications and invasive procedures utilized in managing respiratory diseases may also contribute to the development of TTS. Furthermore, the diagnosis of TTS triggered by these conditions can be challenging due to its atypical presentation. Future prospective studies are needed to establish appropriate guidelines for managing respiratory disease with concurrent TTS.

The Efficacy of the Systemic Immune-Inflammation Index and Prognosis Nutritional Index for the Diagnosis of Venous Thromboembolism in Gastrointestinal Cancers.

Purpose: This study aimed to analyze the association between venous thromboembolism (VTE) and inflammatory markers like systemic immune-inflammation index (SII) and prognosis nutritional index (PNI), and to evaluate their efficacy for the diagnosis of VTE in patients with gastrointestinal malignancies. Patients and Methods: A total of 1326 patients with the initial diagnosis of gastrointestinal cancer in the First Affiliated Hospital of Anhui Medical University (AHMU) were enrolled in the training cohort. Univariate and multivariate analysis was used to pinpoint independent predictors of VTE, which were eventually visualized as the nomogram models. The Akaike Information Criterion (AIC) was used to screen the best model. The receiver operating characteristic curve (ROC) and the clinical decision curve analysis (DCA) were utilized to evaluate the models' predictive performance in the training queue and another external sample of 250 patients at the Second Affiliated Hospital of AHMU. Results: A total of 476 patients were complicated with VTE in the training cohort. Multifactorial analysis of clinical characteristics and inflammatory markers showed that PNI, SII, age, tumor location, and therapy were independent risk factors of VTE, visualized as model A. Another model B was constructed by adding coagulation markers to the previous analysis. Model B was the best prediction model with the minimum AIC value, followed by model A with an AUC of 0.806 (95% CI 0.782~0.830) which was similar to model B's 0.832 (95% CI 0.810~0.855) but significantly higher than the currently widely used Khorana score's 0.592 (95% CI 0.562~0.621) and the CATS score's 0.682 (95% CI 0.653~0.712). The external verification yielded similar findings, with the AUC being 0.792 (95% CI 0.734~0.851), 0.834 (95% CI 0.778~0.890), 0.655 (95% CI 0.582~0.729), and 0.774 (95% CI 0.699~0.849) respectively. The DCA curves demonstrated that new models had excellent usefulness in screening patients with a high VTE risk. Conclusion: The SII and PNI were simple and viable inflammatory markers associated with VTE, and the nomogram based on them and clinical features had a meaningful clinical utility for VTE in patients with gastrointestinal malignancies.

Hemoglobin/Red Blood Cell Distribution Width Ratio in Peripheral Blood Is Positively Associated with Prognosis of Patients with Primary Hepatocellular Carcinoma.

BACKGROUND The prognostic value of the hemoglobin/red blood cell distribution width ratio in primary hepatocellular carcinoma remains unknown. This study aimed to analyze the correlation between hemoglobin/red blood cell distribution width ratio and hepatocellular carcinoma prognosis. MATERIAL AND METHODS Medical records of hepatocellular carcinoma patients were analyzed retrospectively. The hemoglobin/red blood cell distribution width ratio cut-off value was determined as 0.987 by receiver operating characteristic curve analysis. Patients were divided into high- and low-level groups, and the clinical data were compared. The correlation among the ratio levels, progression-free survival, and overall survival was measured with univariate and multivariate Cox regression analyses. The prognostic utility of the ratio combined with alpha-fetoprotein was analyzed using Kaplan-Meier survival curves and log-rank detection, and the correlation between the ratio and tumor staging was studied using one-way analysis of variance. RESULTS This study included 252 patients. Sex, smoking and alcohol consumption history, body mass index, surgery, staging, platelet/lymphocyte ratio, and hemoglobin/red blood cell distribution width ratio were associated with progression-free and overall survival (P<0.05). The ratio, alpha-fetoprotein, hemoglobin, staging, and surgery were independent risk factors for progression-free survival (P<0.05), and the ratio, alpha-fetoprotein, hemoglobin, body mass index, HBsAg, staging, and surgery were independent risk factors for overall survival (P<0.05). Patients with low ratio levels and high alpha-fetoprotein levels had the worst prognosis. CONCLUSIONS Low hemoglobin/red blood cell distribution width ratio levels are associated with poor patient prognosis and are potential tumor prognosis markers.

Vimentin binds to a novel tumor suppressor protein, GSPT1-238aa, encoded by circGSPT1 with a selective encoding priority to halt autophagy in gastric carcinoma.

Circular RNAs (circRNAs) are covalently closed, endogenous molecules that are widespread in eukaryotes. Recent evidence indicates that circRNAs play important roles in carcinogenesis. Several circRNAs have been reported to comprise translatable RNA; however, whether circRNAs encode functional proteins remains unknown. In our study, circRNA sequencing was carried out using five pathologically diagnosed gastric carcinoma (GC) samples and their paired adjacent normal tissues, we characterized the circRNA GSPT1 (circGSPT1), which is expressed at low levels in GC. Antibody detections, and mass spectrometry were used to validate active circRNA translation. The spanning junction open reading frame in circGSPT1, driven by an internal ribosome entry site (IRES), encodes a functional peptide, termed GSPT1-238aa. Interestingly, GSPT1-238aa tends to select the start codon used to initiate translation. This is the first finding of selective translation driven by IRES. CircGSPT1 and GSPT1-238aa halted the proliferation, migration, and invasion in GC cells in vitro. We also confirmed that the vimentin/Beclin1/14-3-3 complex interacts with GSPT1-238aa and modulates autophagy via the PI3K/AKT/mTOR signaling pathway in GC cells. Our study reveals that GSPT1-238aa, a novel protein encoded by circGSPT1, halts GC tumorigenesis. We also provide insights into the function and underlying molecular mechanisms of GSPT1-238aa in GC and suggest that this protein represents a novel target for GC treatment.