G1 and G2 colorectal neuroendocrine neoplasms (NENs) are a group of rare and indolent diseases. We aimed to delineate their genetic characteristics and explore their metastatic mechanisms.
Abstract Background Mitochondrial autophagy is closely related to the pathogenesis of osteoarthritis, In order to explore the role of mitochondrial autophagy related genes in Knee Osteoarthritis (KOA) and its molecular mechanism. Methods KOA-related transcriptome data were extracted from the Gene Expression Omnibus (GEO) database, and the differences were analyzed. Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were implemented to explore the function of differentially expressed mitochondrial autophagy genes (DEMGs). The STRING website was used to construct a protein-protein interaction (PPI) network among DEMGs to identify hub DEMGs. Support vector machine recursive feature elimination (SVM-RFE) method was used to construct the hub DEMG diagnosis model. Receiver operating characteristic (ROC) curve was painted to access the diagnostic value of hub DEMGs. After the immune infiltration analysis was completed, biomarkers were obtained through correlation analysis of differential immune cells and hub DEMGs. Results In total, fifteen DEMGs were screened in patients with KOA. Subsequent enrichment analyses showed that these DEMG strains were mainly enriched in the mitophagy-animal, shigellosis, autophagy-animal and FoxO signal pathways. In addition, 5 hub DEMGs (BNIP3L, BNIP3, MAP1LC3B, ULK1 and FOXO3) were identified by SVM-RFE. The area under the curve (AUC) value of BNIP3 and FOXO3 was greater than 0.75 in the training and validation sets, indicating the decent diagnostic value for KOA. Immune-infiltration and correlation analysis showed that BNIP3 and FOXO3 were significantly correlated with three different immune cells, including primary B cells, M0 macrophage, and M2 macrophage. Thus, BNIP3 and FOXO3 were treated as biomarkers for the diagnosis of KOA. Conclusion In conclusion, two biomarkers (BNIP3 and FOXO3) related to mitochondrial autophagy were acquired between KOA and nomal samples by bioinformatics analysis, which might supply a new insight for the treatment and evaluation of KOA.
Lung cancer is one of the most important causes of cancer-related mortality worldwide. Human cytochrome P450 2A13 enzyme (CYP2A13) is predominantly expressed in the respiratory tract and could catalyze various carcinogens. In this study, we quantified CYP2A13 expression in non-small cell lung cancer (NSCLC) tissues and examined the relation between CYP2A13 and clinicopathologic factors. Thirty-five paired lung cancer and normal tissues were studied for the expression of the CYP2A13 gene by using real-time PCR and Western blot-ting assays. We also investigated the relationship between CYP2A13 expression and clinicopathologic factors such as age, gender, histology and lymph node status in tumor tissues. SPSS (17.0) statistical software was applied for data analysis. The real-time PCR results showed that there was no significant difference in the CYP2A13 mRNA transcript levels between tumor and paired normal tissues in the 35 samples and in 12 paired squamous cell car-cinomas. In adenocarcinoma, the expression of CYP2A13 mRNA in tumor tissues was 12.5% of that in adjacent tissues (P < 0.05) and it was not associated with age, gender, histology and lymph node status of the patients. The amounts of CYP2A13 proteins detected by Western blotting assays correlated well with those of the correspond-ing mRNAs. In conclusion, the expression of CYP2A13 was downregulated in lung adenocarcinoma. CYP2A13 may be involved in the development and progression of lung adenocarcinoma.
Obesity and overweight are widespread issues in adults, children, and adolescents globally, and have caused a noticeable rise in obesity-related complications such as type 2 diabetes mellitus (T2DM). Chronic low-grade inflammation is an important promotor of the pathogenesis of obesity-related T2DM. This proinflammatory activation occurs in multiple organs and tissues. Immune cell-mediated systemic attack is considered to contribute strongly to impaired insulin secretion, insulin resistance, and other metabolic disorders. This review focused on highlighting recent advances and underlying mechanisms of immune cell infiltration and inflammatory responses in the gut, islet, and insulin-targeting organs (adipose tissue, liver, skeletal muscle) in obesity-related T2DM. There is current evidence that both the innate and adaptive immune systems contribute to the development of obesity and T2DM.
Abstract The innate immune pathway is receiving increasing attention in cancer therapy. This pathway is ubiquitous across various cell types, not only in innate immune cells but also in adaptive immune cells, tumor cells, and stromal cells. Agonists targeting the innate immune pathway have shown profound changes in the tumor microenvironment (TME) and improved tumor prognosis in preclinical studies. However, to date, the clinical success of drugs targeting the innate immune pathway remains limited. Interestingly, recent studies have shown that activation of the innate immune pathway can paradoxically promote tumor progression. The uncertainty surrounding the therapeutic effectiveness of targeted drugs for the innate immune pathway is a critical issue that needs immediate investigation. In this review, we observe that the role of the innate immune pathway demonstrates heterogeneity, linked to the tumor development stage, pathway status, and specific cell types. We propose that within the TME, the innate immune pathway exhibits multidimensional diversity. This diversity is fundamentally rooted in cellular heterogeneity and is manifested as a variety of signaling networks. The pro-tumor effect of innate immune pathway activation essentially reflects the suppression of classical pathways and the activation of potential pro-tumor alternative pathways. Refining our understanding of the tumor’s innate immune pathway network and employing appropriate targeting strategies can enhance our ability to harness the anti-tumor potential of the innate immune pathway and ultimately bridge the gap from preclinical to clinical application.
This study aimed to develop and validate a multiregional radiomic-based composite model to predict symptomatic radiation pneumonitis (SRP) in non-small cell lung cancer (NSCLC) patients treated with stereotactic body radiation therapy (SBRT).
The rapid development of Chinese large language models (LLMs) poses big challenges for efficient LLM evaluation. While current initiatives have introduced new benchmarks or evaluation platforms for assessing Chinese LLMs, many of these focus primarily on capabilities, usually overlooking potential alignment and safety issues. To address this gap, we introduce OpenEval, an evaluation testbed that benchmarks Chinese LLMs across capability, alignment and safety. For capability assessment, we include 12 benchmark datasets to evaluate Chinese LLMs from 4 sub-dimensions: NLP tasks, disciplinary knowledge, commonsense reasoning and mathematical reasoning. For alignment assessment, OpenEval contains 7 datasets that examines the bias, offensiveness and illegalness in the outputs yielded by Chinese LLMs. To evaluate safety, especially anticipated risks (e.g., power-seeking, self-awareness) of advanced LLMs, we include 6 datasets. In addition to these benchmarks, we have implemented a phased public evaluation and benchmark update strategy to ensure that OpenEval is in line with the development of Chinese LLMs or even able to provide cutting-edge benchmark datasets to guide the development of Chinese LLMs. In our first public evaluation, we have tested a range of Chinese LLMs, spanning from 7B to 72B parameters, including both open-source and proprietary models. Evaluation results indicate that while Chinese LLMs have shown impressive performance in certain tasks, more attention should be directed towards broader aspects such as commonsense reasoning, alignment, and safety.
Neurofibromatosis type 1 (NF1) is a genetic disorder that predisposes individuals to develop benign and malignant tumors of the nerve sheath. Understanding the signatures of cancer stem cells (CSCs) for NF1-associated tumors may facilitate the early detection of tumor progression. Background: Neural crest cells, the cell of origin of NF1-associated tumors, can initiate multiple tumor types, including melanoma, neuroblastoma, and schwannoma. CSCs within these tumors have been reported; however, identifying and targeting CSC populations remains a challenge. Results: This study aims to leverage existing studies on neural crest-derived CSCs to explore markers pertinent to NF1 tumorigenesis. By focusing on the molecular and cellular dynamics within these tumors, we summarize CSC signatures in tumor maintenance, progression, and treatment resistance. Conclusion: A review of these signatures in the context of NF1 will provide insights into NF1 tumor biology and pave the way for developing targeted therapies and improving treatment outcomes for NF1 patients.
Abstract Activating cGAS‐STING pathway has great potential to achieve effective antitumor immunotherapy. However, mutant p53 (mutp53), a commonly observed genetic alteration in over 50% of human cancer, will impede the therapeutic performance of the cGAS‐STING pathway. Herein, multifunctional ZIF‐8@MnO 2 nanoparticles are constructed to degrade mutp53 and facilitate the cGAS‐STING pathway. The synthesized ZIF‐8@MnO 2 can release Zn 2+ and Mn 2+ in cancer cells to induce oxidative stress and cytoplasmic leakage of fragmented mitochondrial double‐stranded DNAs (dsDNAs). Importantly, the released Zn 2+ induces variable degradation of multifarious p53 mutants through proteasome ubiquitination, which can alleviate the inhibitory effects of mutp53 on the cGAS‐STING pathway. In addition, the released Mn 2+ further increases the sensitivity of cGAS to dsDNAs as immunostimulatory signals. Both in vitro and in vivo results demonstrate that ZIF‐8@MnO 2 effectively promotes the cGAS‐STING pathway and synergizes with PD‐L1 checkpoint blockades, leading to remarkable regression of local tumors as well as distant metastases of breast cancer. This study proposes an inorganic metal ion‐based nanoplatform to enhance the cGAS‐STING‐mediated antitumor immunotherapy, especially to those tumors with mutp53 expression.
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