Establishment and validation of multiclassification prediction models for pulmonary nodules based on machine learning.

BACKGROUND: Lung cancer is the leading cause of cancer-related death worldwide. This study aimed to establish novel multiclassification prediction models based on machine learning (ML) to predict the probability of malignancy in pulmonary nodules (PNs) and to compare with three published models. METHODS: Nine hundred fourteen patients with PNs were collected from four medical institutions (A, B, C and D), which were organized into tables containing clinical features, radiologic features and laboratory test features. Patients were divided into benign lesion (BL), precursor lesion (PL) and malignant lesion (ML) groups according to pathological diagnosis. Approximately 80% of patients in A (total/male: 632/269, age: 57.73 ± 11.06) were randomly selected as a training set; the remaining 20% were used as an internal test set; and the patients in B (total/male: 94/53, age: 60.04 ± 11.22), C (total/male: 94/47, age: 59.30 ± 9.86) and D (total/male: 94/61, age: 62.0 ± 11.09) were used as an external validation set. Logical regression (LR), decision tree (DT), random forest (RF) and support vector machine (SVM) were used to establish prediction models. Finally, the Mayo model, Peking University People's Hospital (PKUPH) model and Brock model were externally validated in our patients. RESULTS: The AUC values of RF model for MLs, PLs and BLs were 0.80 (95% CI: 0.73-0.88), 0.90 (95% CI: 0.82-0.99) and 0.75 (95% CI: 0.67-0.88), respectively. The weighted average AUC value of the RF model for the external validation set was 0.71 (95% CI: 0.67-0.73), and its AUC values for MLs, PLs and BLs were 0.71 (95% CI: 0.68-0.79), 0.98 (95% CI: 0.88-1.07) and 0.68 (95% CI: 0.61-0.74), respectively. The AUC values of the Mayo model, PKUPH model and Brock model were 0.68 (95% CI: 0.62-0.74), 0.64 (95% CI: 0.58-0.70) and 0.57 (95% CI: 0.49-0.65), respectively. CONCLUSIONS: The RF model performed best, and its predictive performance was better than that of the three published models, which may provide a new noninvasive method for the risk assessment of PNs.

ABCB1-mediated docetaxel resistance reversed by erastin in prostate cancer.

Docetaxel (Doc) currently serves as the primary first-line treatment for patients with castrate-resistant prostate cancer (CRPC). Erastin, a small molecule compound, can trigger inhibition of the cystine-glutamate reverse transport system and other pathways, leading to iron-dependent cell death (ferroptosis). Beyond its role in inducing cancer cell death, erastin demonstrates potential when combined with chemotherapy drugs to heighten cancer cell drug susceptibility. However, the augmentation by erastin of the effects of Doc treatment on prostate cancer, and the underlying mechanisms involved, remain unclear. In the present study, we determined the role and the underlying molecular mechanism of erastin against CRPC. The results showed that CRPC cell lines were resistant to Doc, and the expression of ferroptosis-related factors in drug-resistant cell lines was downregulated. Erastin, in synergy with Doc, exerts a pro-apoptotic effect. Erastin significantly inhibited the activity of ATP-binding cassette subfamily B member 1 (ABCB1) but did not change its protein expression and localization. Finally, in mice, erastin treatment dramatically reduced tumor growth in vivo. Taken together, our findings demonstrate that erastin enhances Doc-induced apoptosis to a certain extent and reverses Doc resistance in prostate cancer by inhibiting the activity of multidrug-resistant protein ABCB1.

Targeted degradation of NDUFS1 by agrimol B promotes mitochondrial ROS accumulation and cytotoxic autophagy arrest in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a global public health problem with increased morbidity and mortality. Agrimol B, a natural polyphenol, has been proved to be a potential anticancer drug. Our recent report showed a favorable anticancer effect of agrimol B in HCC, however, the mechanism of action remains unclear. Here, we found agrimol B inhibits the growth and proliferation of HCC cells in vitro as well as in an HCC patient-derived xenograft (PDX) model. Notably, agrimol B drives autophagy initiation and blocks autophagosome-lysosome fusion, resulting in autophagosome accumulation and autophagy arrest in HCC cells. Mechanistically, agrimol B downregulates the protein level of NADH:ubiquinone oxidoreductase core subunit S1 (NDUFS1) through caspase 3-mediated degradation, leading to mitochondrial reactive oxygen species (mROS) accumulation and autophagy arrest. NDUFS1 overexpression partially restores mROS overproduction, autophagosome accumulation, and growth inhibition induced by agrimol B, suggesting a cytotoxic role of agrimol B-induced autophagy arrest in HCC cells. Notably, agrimol B significantly enhances the sensitivity of HCC cells to sorafenib in vitro and in vivo. In conclusion, our study uncovers the anticancer mechanism of agrimol B in HCC involving the regulation of oxidative stress and autophagy, and suggests agrimol B as a potential therapeutic drug for HCC treatment.

Investigation of key miRNAs and Target-mRNA in Kaposi's sarcoma using bioinformatic methods.

Kaposi's sarcoma (KS) is the second most common tumor in human immunodeficiency virus (HIV) infected patients worldwide. While many miRNAs have been confirmed to be involved in KS biological processes, no relevant studies have combined miRNA and mRNA expression profiles using KS patient tissue biopsies. In this study, we performed transcriptome sequencing on tumor and normal tissues from four KS patients and identified differentially expressed mRNA and miRNA, further performed target gene prediction and enrichment analysis. 19,551 target-mRNAs were identified by predicting 106 miRNAs, with 553 overlapping with 571 significantly differentially expressed mRNAs. Enrichment analysis showed significant involvement of the Ubiquitin-mediated proteolysis pathway. Additionally, the miRNA-mRNA interaction network was established, and the topological score of Cytohubba's algorithm was calculated for comparison with three other datasets. The Mutual Clustering Coefficient (MCC) scoring ranking placed ZBTB34, NFIB, and RORA as the top three mRNAs, while hsa-miR-16-5p, hsa-miR-27a-3p, hsa-miR-340-5p, hsa-miR-182-5p, and hsa-miR-186-5p ranked as the top five miRNAs. Hsa-miR-101-3p is the only miRNA that appears both in the top 10 MCC scores and at the intersection of the other two datasets. Finally, qRT-PCR was used to validate the findings at the cellular level. In summary, the miRNA analysis results indicated that hsa-miR-101-3p could be used as a potential diagnostic or therapeutic marker in future studies. Moreover, the mRNA analysis results suggested that the histone binding pathways involved in mRNAs and ubiquitin-related biological processes were closely associated with KS and could serve as promising biomarkers for the diagnosis and treatment of this disease.

Time trends in the burden of low back pain and its associated risk factors in China from 1990 to 2019.

Background: From 1990 to 2019, low back pain (LBP) was the leading cause of years lived with disability (YLDs) in China. However, the change patterns of LBP and its risk factors in China remain unclear. Methods: Data from the Global Burden of Disease Study 2019 were used. We used the join-point regression model and age-period-cohort analysis to evaluate the time trends of attributable risk factors on the burden of LBP. Results: In 2019, the risk factors included in this analysis accounted for 4.36 million YLDs of LBP, representing 42.2% of all YLDs of LBP in China, with 2.86 million due to occupational ergonomic factors, 1.74 million due to smoking, and 0.46 million due to high body mass index (BMI). The age-standardized YLD rates of LBP showed downward trends during 1990-2019, while there was a faster decline between 1990 and 1994. The curves of local drifts, which reflected the average annual percentage change across age groups, showed an increasing trend with age for high BMI and smoking, and a downward trend for occupational ergonomic factors. The YLD rates for LBP increased dramatically with age for high BMI, while it reached a peak at 40-60 years old for occupational ergonomic factors, and 65-80 years old for smoking. The period and cohort rate ratios of LBP YLD decreased in the past 3 decades for occupational ergonomic factors and smoking, while increased for high BMI. Conclusions: Our results provided strong evidence that there were diverse changing patterns for different risk factors, highlighting the need for risk-specific strategies. The translational potential of this article: China has the largest senior population and the fastest aging population in the world. Given that LBP typically occurs in the senior population, there would be an increasing LBP burden on China's health system. This suggests that effective strategies for LBP prevention should be strictly implemented in China, particularly in the senior population, which is of crucial translational potential.

Targeting CD8+ T cells with natural products for tumor therapy: Revealing insights into the mechanisms.

BACKGROUND: Despite significant advances in cancer immunotherapy over the past decades, such as T cell-engaging chimeric antigen receptor (CAR)-T cell therapy and immune checkpoint blockade (ICB), therapeutic failure resulting from various factors remains prevalent. Therefore, developing combinational immunotherapeutic strategies is of great significance for improving the clinical outcome of cancer immunotherapy. Natural products are substances that naturally exist in various living organisms with multiple pharmacological or biological activities, and some of them have been found to have anti-tumor potential. Notably, emerging evidences have suggested that several natural compounds may boost the anti-tumor effects through activating immune response of hosts, in which CD8+ T cells play a pivotal role. METHODS: The data of this review come from PubMed, Web of Science, Google Scholar, and ClinicalTrials (https://clinicaltrials.gov/) with the keywords "CD8+ T cell", "anti-tumor", "immunity", "signal 1", "signal 2", "signal 3", "natural products", "T cell receptor (TCR)", "co-stimulation", "co-inhibition", "immune checkpoint", "inflammatory cytokine", "hesperidin", "ginsenoside", "quercetin", "curcumin", "apigenin", "dendrobium officinale polysaccharides (DOPS)", "luteolin", "shikonin", "licochalcone A", "erianin", "resveratrol", "procyanidin", "berberine", "usnic acid", "naringenin", "6-gingerol", "ganoderma lucidum polysaccharide (GL-PS)", "neem leaf glycoprotein (NLGP)", "paclitaxel", "source", "pharmacological activities", and "toxicity". These literatures were published between 1993 and 2023. RESULTS: Natural products have considerable advantages as anti-tumor drugs based on the various species, wide distribution, low price, and few side effects. This review summarized the effects and mechanisms of some natural products that exhibit anti-tumor effects via targeting CD8+ T cells, mainly focused on the three signals that activate CD8+ T cells: TCR, co-stimulation, and inflammatory cytokines. CONCLUSION: Clarifying the role and underlying mechanism of natural products in cancer immunotherapy may provide more options for combinational treatment strategies and benefit cancer therapy, to shed light on identifying potential natural compounds for improving the clinical outcome in cancer immunotherapy.

WET-UNet: Wavelet integrated efficient transformer networks for nasopharyngeal carcinoma tumor segmentation.

Nasopharyngeal carcinoma is a malignant tumor that occurs in the epithelium and mucosal glands of the nasopharynx, and its pathological type is mostly poorly differentiated squamous cell carcinoma. Since the nasopharynx is located deep in the head and neck, early diagnosis and timely treatment are critical to patient survival. However, nasopharyngeal carcinoma tumors are small in size and vary widely in shape, and it is also a challenge for experienced doctors to delineate tumor contours. In addition, due to the special location of nasopharyngeal carcinoma, complex treatments such as radiotherapy or surgical resection are often required, so accurate pathological diagnosis is also very important for the selection of treatment options. However, the current deep learning segmentation model faces the problems of inaccurate segmentation and unstable segmentation process, which are mainly limited by the accuracy of data sets, fuzzy boundaries, and complex lines. In order to solve these two challenges, this article proposes a hybrid model WET-UNet based on the UNet network as a powerful alternative for nasopharyngeal cancer image segmentation. On the one hand, wavelet transform is integrated into UNet to enhance the lesion boundary information by using low-frequency components to adjust the encoder at low frequencies and optimize the subsequent computational process of the Transformer to improve the accuracy and robustness of image segmentation. On the other hand, the attention mechanism retains the most valuable pixels in the image for us, captures the remote dependencies, and enables the network to learn more representative features to improve the recognition ability of the model. Comparative experiments show that our network structure outperforms other models for nasopharyngeal cancer image segmentation, and we demonstrate the effectiveness of adding two modules to help tumor segmentation. The total data set of this article is 5000, and the ratio of training and verification is 8:2. In the experiment, accuracy = 85.2% and precision = 84.9% can show that our proposed model has good performance in nasopharyngeal cancer image segmentation.

Intra- and Peri-tumoral Radiomics Based on Dynamic Contrast Enhanced-MRI to Identify Lymph Node Metastasis and Prognosis in Intrahepatic Cholangiocarcinoma.

BACKGROUND: Lymph node metastasis (LNM) in patients with intrahepatic cholangiocarcinoma (iCCA) affects treatment strategies and prognosis. However, preoperative imaging is not reliable enough for identifying LNM. PURPOSE: To develop and validate a radiomics nomogram based on dynamic contrast enhanced (DCE)-MR images for identifying LNM and prognosis in iCCA. STUDY TYPE: Retrospective. SUBJECTS: Two hundred four patients with pathologically proven iCCA who underwent curative-intent resection and lymphadenectomy (training cohort: N = 107, internal test cohort: N = 46, and external test cohort: N = 51). FIELD STRENGTH/SEQUENCE: T1- and T2-weighted imaging, diffusion-weighted imaging and DCE imaging at 1.5 T or 3.0 T. ASSESSMENT: Radiomics features were extracted from intra- and peri-tumoral regions on preoperative DCE-MR images. Imaging features were evaluated by three radiologists, and significant variables in univariable and multivariable regression analysis were included in clinical model. The best-performing radiomics signature and clinical characteristics (intrahepatic duct dilatation, MRI-reported LNM) were combined to build a nomogram. Patients were divided into high-risk and low-risk groups based on their nomogram scores (cutoff = 0.341). Patients were followed up for 1-102 months (median 12) after surgery, the overall survival (OS) and recurrence-free survival (RFS) were calculated. STATISTICAL TESTS: Receiver operating characteristic (ROC) curve, calibration, decision curve, Delong test, Kaplan-Meier curves, log rank test. Two tailed P < 0.05 was considered statistically significant. RESULTS: The nomogram incorporating intra- and peri-tumoral radiomics features, intrahepatic duct dilatation and MRI-reported LNM obtained the best discrimination for LNM, with areas under the ROC curves of 0.946, 0.913, and 0.859 in the training, internal, and external test cohorts. In the entire cohort, high-risk patients had significantly lower RFS and OS than low-risk patients. High-risk of LNM was an independent factor of unfavorable OS and RFS. DATA CONCLUSION: The nomogram integrating intra- and peri-tumoral radiomics signatures has potential to identify LNM and prognosis in iCCA. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

The inflammatory injury of porcine small intestinal epithelial cells induced by deoxynivalenol is related to the decrease in glucose transport.

The present study aimed to investigate the effects of deoxynivalenol (DON) stimulation on inflammatory injury and the expression of the glucose transporters sodium-dependent glucose transporter 1 (SGLT1) and glucose transporter protein 2 (GLU2) in porcine small intestinal epithelial cells (IPEC-J2). Additionally, the study aimed to provide initial insights into the connection between the expression of glucose transporters and the inflammatory injury of IPEC-J2 cells. DON concentration and DON treatment time were determined using the CCK­8 assay. Accordingly, 1.0 µg/mL DON and treatment for 24 h were chosen for subsequent experiments. Then IPEC-J2 cells were treated without DON (CON, N = 6) or with 1 µg/mL DON (DON, N = 6). Lactate dehydrogenase (LDH) content, apoptosis rate, and proinflammatory cytokines including interleukin (IL)-1ß, Il-6, and tumor necrosis factor α (TNF-α) were measured. Additionally, the expression of AMP-activated protein kinase α1 (AMPK-α1), the content of glucose, intestinal alkaline phosphatase (AKP), and sodium/potassium-transporting adenosine triphosphatase (Na+/K+-ATPase) activity, and the expression of SGLT1 and GLU2 of IPEC-J2 cells were also analyzed. The results showed that DON exposure significantly increased LDH release and apoptosis rate of IPEC-J2 cells. Stimulation with DON resulted in significant cellular inflammatory damage, as evidenced by a significant increase in proinflammatory cytokines (IL-1ß, IL-6, and TNF-α). Additionally, DON caused damage to the glucose absorption capacity of IPEC-J2 cells, indicated by decreased levels of glucose content, AKP activity, Na+/K+-ATPase activity, AMPK-α1 protein expression, and SGLT1 expression. Correlation analysis revealed that glucose absorption capacity was negatively correlated with cell inflammatory cytokines. Based on the findings of this study, it can be preliminarily concluded that the cell inflammatory damage caused by DON may be associated with decreased glucose absorption.

Glucose is one of the most basic nutrients necessary to sustain animal life and plays a crucial role in animal body composition and energy metabolism. Previous studies suggested a link between glucose absorption and inflammatory injury. In the present study, deoxynivalenol (DON) stimulation caused severe inflammatory injury and reduced the glucose absorption capacity of IPEC-J2 cells. Pearson's correlation analysis revealed a negative correlation between glucose absorption capacity and cell inflammatory cytokines. Ultimately, it can be speculated that the cellular inflammatory response triggered by DON may be related to the altered expression of glucose transporters.

Centrosome amplification and aneuploidy driven by the HIV-1-induced Vpr•VprBP•Plk4 complex in CD4+ T cells.

HIV-1 infection elevates the risk of developing various cancers, including T-cell lymphoma. Whether HIV-1-encoded proteins directly contribute to oncogenesis remains unknown. We observe that approximately 1-5% of CD4+ T cells from the blood of people living with HIV-1 exhibit over-duplicated centrioles, suggesting that centrosome amplification underlies the development of HIV-1-associated cancers by driving aneuploidy. Through affinity purification, biochemical, and cellular analyses, we discover that Vpr, an accessory protein of HIV-1, hijacks the centriole duplication machinery and induces centrosome amplification and aneuploidy. Mechanistically, Vpr forms a cooperative ternary complex with an E3 ligase subunit, VprBP, and polo-like kinase 4 (Plk4). Unexpectedly, however, the complex enhances Plk4's functionality by promoting its relocalization to the procentriole assembly and induces centrosome amplification. Loss of either Vpr's C-terminal 17 residues or VprBP acidic region, the two elements required for binding to Plk4 cryptic polo-box, abrogates Vpr's capacity to induce these events. Furthermore, HIV-1 WT, but not its Vpr mutant, induces multiple centrosomes and aneuploidy in human primary CD4+ T cells. We propose that the Vpr•VprBP•Plk4 complex serves as a molecular link that connects HIV-1 infection to oncogenesis and that inhibiting the Vpr C-terminal motif may reduce the occurrence of HIV-1-associated cancers.

Ningxin-Tongyu-Zishen formula alleviates the senescence of granulosa cells on D-galactose-induced premature ovarian insufficiency mice.

Ningxin-Tongyu-Zishen formula (NTZF) is a clinical experience formula for the treatment of premature ovarian insufficiency (POI) in traditional Chinese medicine (TCM), and the potential mechanism is unknown. For in vivo experiments, POI mouse models (C57BL/6 mice), were constructed by subcutaneous injection of D-galactose (D-gal, 200 mg/kg). After treatment of NTZF (10.14, 20.27, 40.54 g/kg;) or estradiol valerate (0.15 mg/kg), ovarian function, oxidative stress (OS) and protein expression of Sirt1/p53 were evaluated. For in vitro experiments, H2O2 (200 µM) was used to treat KGN to construct ovarian granulosa cells (OGCs) cell senescence model. Pretreatment with NTZF (1.06 mg/mL) or p53 inhibitor (Pifithrin-α, 1 µM) was performed before induction of senescence, and further evaluated the cell senescence, OS, mRNA and protein expression of Sirt1/p53. In vivo, NTZF improved ovarian function, alleviated OS and Sirt1/p53 signaling abnormalities in POI mice. In vitro experiments showed that NTZF reduced the level of OS and alleviated the senescence of H2O2-induced KGN. In addition, NTZF activated the protein expression of Sirt1, inhibited the mRNA transcription and protein expression of p53 and p21. Alleviating OGCs senescence and protecting ovarian function through Sirt1/p53 is one of the potential mechanisms of NTZF in the treatment of POI.

The protective effect of intranasal immunization with influenza virus recombinant adenovirus vaccine on mucosal and systemic immune response.

Influenza virus is a kind of virus that poses several hazards of animal and human health. Therefore, it is important to develop an effective vaccine to prevent influenza. To this end we successfully packaged recombinant adenovirus rAd-NP-M2e-GFP expressing multiple copies of influenza virus conserved antigens NP and M2e and packaged empty vector adenovirus rAd-GFP. The effect of rAd-NP-M2e-GFP on the activation of dendritic cell (DC) in vitro and in vivo was detected by intranasal immunization. The results showed that rAd-NP-M2e-GFP promoted the activation of DC in vitro and in vivo. After the primary immunization and booster immunization of mice through the nasal immune way, the results showed that rAd-NP-M2e-GFP induced enhanced local mucosal-specific T cell responses, increased the content of SIgA in broncho alveolar lavage fluids (BALF) and triggered the differentiation of B cells in the germinal center. It is proved that rAd-NP-M2e-GFP can significantly elicit mucosal immunity and systemic immune response. In addition, rAd-NP-M2e-GFP could effectively protect mice after H1N1 influenza virus challenge. To lay the foundation and provide reference for further development of influenza virus mucosal vaccine in the future.

Distal Junctional Failures in Degenerative Thoracolumbar Hyperkyphosis.

OBJECTIVE: Degenerative thoracolumbar hyperkyphosis (DTH) is a disease that negatively affects individual health and requires surgical intervention, yet the ideal surgical approach and complications, especially distal junctional failures (DJF), remain poorly understood. This study aims to investigate DJF in DTH and to identify the risk factors for DJF so that we can improve surgical decision-making, and advance our knowledge in the field of spinal surgery to enhance patient outcomes. METHODS: This study retrospectively reviewed 78 cases (late osteoporotic vertebral compression fracture [OVCF], 51; Scheuermann's kyphosis [SK], 17; and degenerative disc diseases [DDD], 10) who underwent corrective surgery in our institute from 2008 to 2019. Clinical outcomes were assessed using health-related quality of life (HRQOL) measures, including the visual analogue scale (VAS) scores for back and leg pain, the Oswestry disability index (ODI), and the Japanese Orthopaedic Association (JOA) scoring system. Multiple radiographic parameters, such as global kyphosis (GK) and thoracolumbar kyphosis (TLK), were assessed to determine radiographic outcomes. Multivariate logistic regression analysis was employed to identify the risk factors associated with DJF. RESULTS: HRQOL improved, and GK, TLK decreased at the final follow-up, with a correction rate of 67.7% and 68.5%, respectively. DJF was found in 13 of 78 cases (16.7%), two cases had wedging in the disc (L3-4) below the instrumentation, one case had a fracture of the lowest instrumented vertebrae (LIV), one case had osteoporotic fracture below the fixation, nine cases had pull-out or loosening of the screws at the LIV and three cases (23.1%) required revision surgery. The DJF group had older age, lower computed tomography Hounsfield unit (CT HU), longer follow-up, more blood loss, greater preoperative sagittal vertical axis (SVA), and poorer postoperative JOA and VAS scores (back). The change in TLK level was larger in the non-DJF group. Post-sagittal stable vertebrae (SSV) moved cranially compared with pre-SSV. CONCLUSION: Age, CT HU, length of follow-up, estimated blood loss, and preoperative SVA were independent risk factors for DJF. We recommend fixation of the two vertebrae below the apex vertebrae for DTH to minimize surgical trauma.

A Potential biomarker for the early diagnosis of OSCC: saliva and serum PrPC.

Background: Oral squamous cell carcinoma (OSCC) is frequently diagnosed at an advanced stage, and the high mortality of patients is mainly due to the delay of diagnosis. Cellular prion protein (PrPC) contributes to the occurrence and development of many malignant tumors. However, little has been known about the clinical and diagnostic value of PrPC in OSCC. This study investigated the levels of PrPC in the saliva and serum of patients with OSCC, OPMD and control group and their diagnostic value. Methods: The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and Clinical Proteome Tumor Analysis Consortium (CPTAC) databases were analyzed to evaluate the expression of human prion protein gene (PRNP) mRNA and PrPC in OSCC. Enzyme-linked Immunosorbent Assay (ELISA) was utilized to detect the expression of PrPC in saliva and serum samples of OSCC, OPMD and control groups. Furthermore, diagnostic value and clinical significance of PrPC in OSCC was identified. Protein-protein interaction (PPI) network was constructed by STRING. GO and KEGG analysis were performed by ClusterProfiler. Results: The levels of PRNP mRNA and PrPC in OSCC were significantly higher than those in the control group from databases (P<0.05). Besides, salivary and serum PrPC of OSCC patients showed increased levels compared with OPMD and control groups (P<0.05). The expression of salivary and serum PrPC of OSCC was correlated with the degree of differentiation (P<0.05), and the expression of PrPC from CPTAC was related to tumor stage of OSCC (P<0.05). The areas under the diagnostic curves (AUCs) of salivary and serum PrPC were 0.807 and 0.671, respectively. GO and KEGG analysis revealed that PrPC might be related to cell adhesion, cell differentiation, signal transduction and apoptosis, and participate in the pathways of focal adhesion, PI3K-Akt signaling pathway and ECM- receptor interaction in OSCC. Conclusion: PrPC in saliva and serum may be a potential biomarker for early diagnosis of OSCC.

The effect of c-Fos on the prognosis, proliferation, and invasion of oral squamous cell carcinoma.

OBJECTIVE: This study aimed to determine the role of c-Fos in growth and invasion of oral squamous cell carcinoma (OSCC). METHODS: Immunohistochemistry was used to assess c-Fos expression in 94 OSCC tissues and 30 adjacent normal tissues, the correlation between c-Fos expression and clinicopathological characteristics was examined, and Kaplan-Meier and Cox analysis were used to investigate the role of c-Fos in predicting the prognosis of OSCC patients. The effects of c-Fos on the growth and invasion of OSCC were disclosed by overexpression and knockdown of c-Fos. Furthermore, based on bioinformatics prediction, the effect of miR-155-5p on c-Fos expression was examined, and dual-luciferase reporter assay system was used to determine whether miR-155-5p regulated the transcriptional activity of c-Fos in OSCC. RESULTS: c-Fos was markedly increased in OSCC tissues and cells. c-Fos upregulation indicates a poor prognosis in OSCC patients, and c-Fos promotes cell proliferation, migration, and invasion in OSCC. miR-155-5p could regulate the expression and the transcriptional activity of c-Fos by directly targeting the c-Fos 3'-UTR. CONCLUSION: This study demonstrated that c-Fos contributed to the progression of OSCC and may act as a potential target for OSCC therapy, and a potential prognostic biomarker of OSCC.

A study on genotypes and phenotypes of short stature caused by epigenetic modification gene variants.

Mendelian disorders of the epigenetic machinery (MDEMs) are caused by genetic mutations, a considerable fraction of which are associated with epigenetic modification. These MDEMs exhibit phenotypic overlap broadly characterized by multiorgan abnormalities. The variant detected in genes associated with epigenetic modification can lead to short stature accompanied with multiple system abnormalities. This study is aimed at presenting and summarizing the diagnostic rate, clinical, and genetic profile of MDEMs-associated short stature. Two hundred and fourteen short-stature patients with multiorgan abnormalities were enrolled. Clinical information and whole exome sequence (WES) were analyzed for these patients. WES identified 33 pathogenic/likely pathogenic variants in 19 epigenetic modulation genes (KMT2A, KMT2D, KDM6A, SETD5, KDM5C, HUWE1, UBE2A, NIPBL, SMC1A, RAD21, CREBBP, CUL4B, BPTF, ANKRD11, CHD7, SRCAP, CTCF, MECP2, UBE3A) in 33 patients (15.4%). Of note, 19 variants had never been reported previously. Furthermore, these 33 variants were associated with 16 different disorders with overlapping clinical features characterized by development delay/intelligence disability (31/33; 93.9%), small hands (14/33; 42.4%), clinodactyly of the 5th finger (14/33; 42.4%), long eyelashes (13/33; 39.4%), and hearing impairment (9/33; 27.3%). Additionally, several associated phenotypes are reported for the first time: clubbing with KMT2A variant, webbed neck with SETD5 variant, retinal detachment with CREBBP variant, sparse lateral eyebrow with HUWE1 variant, and long palpebral fissure with eversion of the lateral third of the low eyelid with SRCAP variant.Conclusions: Our study provided a new conceptual framework for further understanding short stature. Specific clinical findings may indicate that a short-stature patient may have an epigenetic modified gene variant.

Puerarin Attenuates Iron Overload-Induced Ferroptosis in Retina through a Nrf2-Mediated Mechanism.

SCOPE: Age-related increases in retinal iron are involved in the development of retinal degeneration. The recently discovered iron-dependent mechanism of cell death known as ferroptosis has been linked to a wide range of pathologies. However, its role in iron overload-induced retinal degeneration is still uncertain. Puerarin has been associated with retinal protection. The purpose of this research is to determine how puerarin prevents retinal ferroptosis under iron overload conditions. METHODS AND RESULTS: Models of iron overload in Kunming mice, 661W cell, and ARPE-19 cell are established. Increased iron deposition significantly worsens retinal pathology, decreases cell viability, and induces ferroptotic changes. Puerarin mitigates iron overload-induced ferroptosis by decreasing excessive iron through the regulation of iron handling proteins and lowering lipid peroxidation through the inhibition of cyclooxygenase 2 expression and activation of the nuclear factor-E2-related factor 2 (Nrf2) signaling pathway and downstream ferroptosis-related proteins (solute carrier family 7 member 11, glutathione peroxidase 4 and heme oxygenase-1). The protective effect of puerarin on ferroptosis is diminished by the Nrf2-specific inhibitor ML385. CONCLUSION: These findings suggest targeting ferroptosis may be a novel strategy for the management of retinal degeneration. Puerarin may exert some of its ocular benefits by attenuating ferroptosis.

Carvedilol induces pyroptosis through NLRP3-caspase1-ASC inflammasome by nuclear migration of NF-κB in prostate cancer models.

BACKGROUND: Pyroptosis is an inflammatory type of programmed cell death, and could overcome the drug-resistance induced by anti-apoptotic effect of cancers. Carvedilol (CVL), a ß-adrenergic receptors antagonist, has shown anti-inflammatory response and anti-cancer effect. The aim of this study is to investigate whether pyroptosis can be activated by CVL in prostate cancer (PCa). METHODS AND RESULTS: Datasets were used to analyze the expressions of pyroptosis-related proteins. Intracellular morphological change, cell viability, LDH and Il-1ß release by cells,, and Hoechst/PI staining were used to detect the occurrence of pyroptosis. Realtime-PCR, western blot, immunofluorescence, and immunohistochemistry (IHC) were used to investigate the expressions of pyroptosis-related proteins. Datasets analyze showed the expressions of NLRP3, Caspase 1, ASC and GSDMD were all decreased in PCa comparing with normal tissues, but without prognostic significance. CVL treatment weakened the viabilities of PCa cells. Cell morphology changing, cytoplasmic vacuole formation, membrane integrity loss, LDH and IL-1ß release and PI positive cells increasing were observed. NLRP3, Caspase 1, ASC, GSDMD and N-GSDMD expressions were elevated after CVL treatment, accompanied by a tendency of NF-κB transferring into nucleus. In vivo, CVL inhibited the growth of subcutaneous transplanted tumor. IHC showed CVL increased the expressions of NLRP3, ASC, and GSDMD, and decreased the expression of Ki-67 in transplanted tumor tissues. CONCLUSION: This study demonstrated that CVL could induce pyroptosis in PCa cells through NLRP3-caspase1-ASC inflammasome by promoting nuclear translocation of NF-κB, which would lay a foundation for the application of adrenergic receptor antagonist in PCa.

Early gastric cancer recurrence after endoscopic submucosal dissection: Not to be ignored!

This editorial comments on the article "Efficacy of multi-slice spiral computed tomography in evaluating gastric cancer recurrence after endoscopic submucosal dissection". We focus on the importance of paying more attention to post-endoscopic submucosal dissection (ESD) gastric cancer recurrence in patients with early gastric cancer (EGC) and how to manage it effectively. ESD has been a well-known treatment and the mainstay for EGC, with the advantages of less invasion and fewer complications when compared with traditional surgical procedures. Despite a lower local recurrence rate after ESD, the problem of postoperative recurrence in patients with EGC has become increasingly non-ignorable with the global popularization of ESD technology and the increasing number of post-ESD patients.