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This study utilized independent component analysis to explore the abnormal functional connectivity (FC) in male participants with Internet gaming disorder (IGD). Functional magnetic resonance imaging and behavioral data were collected from 21 healthy controls (HC) and 18 IGD patients when they were performing a delay discounting task. Behavioral results revealed that the IGD patients showed higher delay discounting rates than HC. Two networks were found to be associated with IGD: (1) the executive control network containing the anterior cingulate cortex and the medial and superior frontal gyrus, and (2) the basal ganglia network containing the lentiform nucleus. Comparing to HC, IGD exhibited stronger FC when selecting small and now options. In addition, the delay discounting rates were positively correlated with the modulation of the two networks and the reaction time. The results suggested that the IGD patients have enhanced sensitivity to reward and decreased ability to control their impulsivity effectively, which leads to myopic decision making.

The Internet search engines, which have powerful search/sort functions and ease of use features, have become an indispensable tool for many individuals. The current study is to test whether the short-term Internet search training can make people more dependent on it. Thirty-one subjects out of forty subjects completed the search training study which included a pre-test, a six-day's training of Internet search, and a post-test. During the pre- and post- tests, subjects were asked to search online the answers to 40 unusual questions, remember the answers and recall them in the scanner. Un-learned questions were randomly presented at the recalling stage in order to elicited search impulse. Comparing to the pre-test, subjects in the post-test reported higher impulse to use search engines to answer un-learned questions. Consistently, subjects showed higher brain activations in dorsolateral prefrontal cortex and anterior cingulate cortex in the post-test than in the pre-test. In addition, there were significant positive correlations self-reported search impulse and brain responses in the frontal areas. The results suggest that a simple six-day's Internet search training can make people dependent on the search tools when facing unknown issues. People are easily dependent on the Internet search engines.

Background: BCAR3 has been implicated in various cancers, yet its role in thyroid cancer (TC) remains unclear. This study aimed to investigate the methylation status, functional effects, and underlying mechanisms of BCAR3 in TC. Methods: BCAR3 methylation was analyzed using matrix-assisted laser desorption/ionization–time-of-flight (MALDI-TOF) mass spectrometry in 422 TC and 371 benign thyroid nodule samples. Expression levels were assessed via immunohistochemistry, qPCR, and Western blot. Functional assays including proliferation, migration, and invasion were performed after BCAR3 knockdown. Rescue experiments using a PI3K activator were conducted to examine pathway mechanisms. Results: BCAR3 was significantly hypomethylated in TC compared to benign tissues (p < 0.001), with CpG_6 most strongly associated with TC risk (odds ratio, OR = 1.73, p < 0.001). Notably, BCAR3 hypomethylation was more pronounced in cases with larger tumor size and advanced disease stage. Furthermore, BCAR3 methylation showed differential patterns across TC subtypes, with medullary thyroid carcinoma exhibiting the lowest methylation levels. BCAR3 expression was upregulated in TC tissues and cell lines (p < 0.05). Mechanistically, BCAR3 knockdown reduced phosphorylation of AKT/mTOR and altered expression of epithelial-to-mesenchymal transition (EMT) marker, characterized by an increase in E-cadherin and decreases in Vimentin and N-cadherin, and consequently suppressed proliferation, migration, and invasion (p < 0.05). Rescue experiments with a PI3K activator showed a trend towards restoration of these effects, although not to the level of the control groups. Conclusions: BCAR3 hypomethylation contributes to TC cells’ proliferation, migration, and invasion by promoting AKT/mTOR activation and EMT. These findings highlight the potential of BCAR3 methylation as both a biomarker and a therapeutic target in TC.

Doxorubicin (DOX) leads to myocardial cell damage and irreversible heart failure, which limits the clinical application of DOX. Naringin has biological functions of inhibiting inflammation, oxidative stress and apoptosis. Our aim was to investigate whether Naringin could prevent DOX-related cardiotoxicity in mice. Naringin was administered by gavage and mice were intraperitoneally injected with doxorubicin (1 mg/kg/day) for 15 days. H&E, Masson, TUNEL and others experiments were examined. NRVMs and H9C2 cells were treated with Naringin and DOX in vitro . Using IF, ELISA and Western Blot to detect the effect of Naringin and ECHS1 on cells. The results showed that Naringin could prevent DOX related cardiac injury, inhibit cardiac oxidative stress, inflammation and apoptosis in vivo and in vitro . Inhibition of ECHS1 could interfere the effect of Naringin on DOX-induced myocardial injury. Naringin may provide a new cardiac protective tool for preventing the cardiotoxicity of anthracycline drugs.

Early diagnosis and therapy are critical to improve the prognosis of patients with pancreatic cancer. However, conventional imaging does not significantly increase the capability to detect early stage disease. In this study, we developed a multifunctional theranostic nanoplatform for accurate diagnosis and effective treatment of pancreatic cancer. We developed a theranostic nanoparticle (NP) based on gold nanocages (AuNCs) modified with hyaluronic acid (HA) and conjugated with anti-Glypican-1 (anti-GPC1) antibody, oridonin (ORI), gadolinium (Gd), and Cy7 dye. We assessed the characteristics of GPC1-Gd-ORI@HAuNCs-Cy7 NPs (ORI-GPC1-NPs) including morphology, hydrodynamic size, stability, and surface chemicals. We measured the drug loading and release efficiency in vitro. Near-infrared fluorescence (NIRF)/magnetic resonance imaging (MRI) and therapeutic capabilities were tested in vitro and in vivo. ORI-GPC1-NPs demonstrated long-time stability and fluorescent/MRI properties. Bio-transmission electron microscopy (bio-TEM) imaging showed that ORI-GPC1-NPs were endocytosed into PANC-1 and BXPC-3 (overexpression GPC1) but not in 293 T cells (GPC1- negative). Compared with ORI and ORI-NPs, ORI-GPC1-NPs significantly inhibited the viability and enhanced the apoptosis of pancreatic cancer cells in vitro. Moreover, blood tests suggested that ORI-GPC1-NPs showed negligible toxicity. In vivo studies showed that ORI-GPC1-NPs enabled multimodal imaging and targeted therapy in pancreatic tumor xenografted mice. ORI-GPC1-NP is a promising theranostic platform for the simultaneous diagnosis and effective treatment of pancreatic cancer.

Research has shown that mutations in the KRAS , NRAS , and BRAF genes are linked to resistance to anti-EGFR therapies in colorectal cancer (CRC) patients. HER2-targeted therapies are increasingly being recommended for individuals with HER2 overexpression. The evaluation of KRAS , NRAS , BRAF , and HER2 statuses has become an important part of precise diagnosis for CRC. However, conventional molecular or protein testing can be time-consuming and expensive. This study aims to predict the status of KRAS , NRAS , BRAF , and HER2 through the analysis of whole-slide pathology features from CRC samples stained with Hematoxylin-Eosin (H&E) for KRAS , NRAS , and BRAF , and by utilizing Immunohistochemistry (IHC) for HER2. In this study, 435 CRC patients were enrolled from Jiangsu Province Hospital of Chinese Medicine. Using the clustering-constrained attention-based multiple-instance learning (CLAM) model, we constructed four models for predicting the statuses of KRAS , NRAS , BRAF , and HER2 based on whole-slide images (WSIs). This single‑center study used patient‑level internal cross‑validation to train and evaluate weakly supervised CLAM models for predicting KRAS, NRAS, BRAF, and HER2 status from whole‑slide images. The mean area under the receiver operating characteristic (ROC) curve (AUC) values (95% CI) were KRAS 0.8958 (0.8575, 0.9340), NRAS 0.9367 (0.8893, 0.9829), BRAF 0.9876 (0.9744, 1.0000), and HER2 3 + versus non‑3 + 0.99 (0.98–1.00). Given the extremely small NRAS+ ( n  = 14) and BRAF+ ( n  = 21) cohorts, these estimates are statistically fragile and should be interpreted as hypothesis‑generating pending external validation. Our model-generated heatmaps showing KRAS , NRAS , BRAF mutation patterns and HER2 expression levels generally matched the regions identified by the pathologists. This method provides new insights to predict gene mutations and protein expression using deep learning. This single-center study used patient-level internal cross-validation. Robustness and clinical applicability cannot be assumed without external, multi-center validation, and the present results should be interpreted as hypothesis-generating.

Background The incidence of thyroid cancer (TC) has significantly increased, highlighting the need for effective and objective approaches for the early diagnosis of TC. This study aimed to explore RASGEF1C methylation as a biomarker for papillary thyroid cancer (PTC). Methods Formalin-fixed paraffin-embedded samples from a total of 363 PTC and 409 benign thyroid nodules from multiple centers were analyzed. RASGEF1C methylation profiles were examined via MALDI-TOFF mass spectrometry. Statistical analysis was performed via logistic regression adjusted for covariates, nonparametric tests, and receiver operating characteristic (ROC) analysis. Additionally, 40 follicular thyroid cancer samples, 45 medullary thyroid cancer samples, and 7 anaplastic thyroid samples from three hospitals were afterward collected to compare methylation patterns across subtypes. Results Hypomethylation of RASGEF1C in PTC was observed vs. BTN (all odds ratios (ORs) ≥ 1.57, p values < 0.001). Stratification analysis revealed a more pronounced association in younger patients, especially for BRAF V600E-positive PTC patients, than in individuals with benign tumors (all ORs ≥ 1.89, p values < 0.001). ROC analysis further demonstrated the outstanding diagnostic power of RASGEF1C hypomethylation for BRAF V600E-positive PTC cases (area under the curve (AUC) = 0.93), for cases < 55 years old (AUC = 0.88), and even for patients with a tumor length ≤ 1 cm (AUC = 0.83). Moreover, we observed the lowest RASGEF1C methylation level in anaplastic thyroid carcinoma, the most aggressive subtype of TC. Our results revealed similar RASGEF1C hypomethylation between chronic lymphocytic thyroiditis and papillary thyroid cancer, whereas RASGEF1C methylation in subacute thyroiditis patients was similar to that in the other benign subtypes. Conclusion Our study revealed RASGEF1C methylation as a promising biomarker for distinguishing and classifying benign and malignant thyroid tumors and even provided epigenetic evidence for the inflammatory-cancer transformation. Nevertheless, the limitation of tissue-based biomarkers should be well noted, and the development of more accessible biomarkers warrants further exploration in the future.

Background Early gastric carcinoma is heterogeneous and can be divided into early gastric cardiac carcinoma (EGCC) and early gastric non-cardiac carcinoma (EGNCC) groups. At present, differences in clinicopathology remains obscure between EGCC and EGNCC fundus–corpus and antrum–angularis–pylorus subgroups, especially between EGCC with and without oesophageal invasion. Methods In this study, we studied 329 consecutive early gastric carcinoma radical gastrectomies with 70 EGCCs and 259 EGNCCs. Results Compared to the EGNCC antrum–angularis–pylorus (n = 181), but not fundus–corpus (n = 78), sub-group, EGCC showed significantly older age, lower prevalence of the grossly depressed pattern, better tumor differentiation, higher percentage of tubular/papillary adenocarcinoma, but lower frequency of mixed poorly cohesive carcinoma with tubular/papillary adenocarcinoma, and absence of lymph node metastasis (LNM) in tumors with invasion up to superficial submucosa (SM1). In contrast, pure poorly cohesive carcinoma was less frequently seen in EGCCs than in EGNCCs, but mixed poorly cohesive carcinoma with tubular/papillary adenocarcinomas was significantly more common in the EGNCC antrum–angularis–pylorus sub-group than in any other group. No significant differences were found between EGCC and EGNCC sub-groups in gender, tumor size, H. pylori infection rate, and lymphovascular/perineural invasion. EGCC with oesophageal invasion (n = 22), compared to EGCC without (n = 48), showed no significant differences in the H. pylori infection rate and oesophageal columnar, intestinal, or pancreatic metaplasia, except for a higher percentage of the former in size > 2 cm and tubular differentiation. Conclusions There exist distinct clinicopathologic differences between EGCC and EGNCC sub-groups; EGCC was indeed of gastric origin. Further investigations with larger samples are needed to validate these findings.

The relationship between autophagy and tumour is well studied, but tumour cell morphological changes associated with autophagy defects are rarely reported, especially in renal cell carcinoma (RCC). We collected 10 renal tumour samples with characteristic eosinophilic cytoplasmic inclusions (ECIs) and found that the ECIs were majorly composed of sequestosome 1/P62, neighbor of BRCA1 gene 1 (NBR1), PEX14, and CATALASE1 (CAT1). Further, transmission electron microscopy analysis revealed that ECIs were aggregates of proteinaceous material and peroxisomes. These results confirmed that ECIs in RCCs were the products of autophagy defects. The presence of ECIs was correlated with high Fuhrman grade components of RCCs. Whole-exome sequencing (WES) and Sanger sequencing confirmed that tumours with ECIs showed somatic mutations or high frequency of genetic variations in autophagy-related (ATG) genes, such as ATG7 , ATG5 , and ATG10 . These results indicate that nucleotide changes in ATG genes are associated with autophagy defect, ECI formation, and even tumour grade in RCCs.

Background Our previous studies demonstrated that S100A16 promotes adipogenesis and is involved in weight gain attenuation induced by dietary calcium. Till now, the function of S100A16 in the breast cancer remains to be elucidated. Results In this study, we observed that S100A16 was expressed in higher levels in human breast cancer tissues compared with paired adjacent non-cancerous tissues. Further examination showed that overexpression of S100A16 in MCF-7 cells could increase cell proliferation and colony formation. One major mechanistic change was that S100A16 was able to up-regulate the transcription factors Notch1, ZEB1, and ZEB2, which had the capacities to directly repress the expression of epithelial markers E-cadherin and β-catenin but increase mesenchymal markers N-cadherin and vimentin, a characterized phenotype of epithelial-mensenchymal transition (EMT). In addition to display with morphologic change, migration and invasion were increased in S100A16 over-expressed MCF-7 cells. Importantly, knockdown of Notch1 by specific siRNA could reverse the EMT induced by S100A16 overexpression, which confirmed that Notch1 played a critical role in the process of EMT induced by S100A16. Conclusions All together, our data indicated that S100A16 had a potential function to regulate some embryonic transcription factors to promote EMT in breast cancer cells which may be an important target site for the therapy of breast cancer.