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Clinical evidence indicates that drug resistance is a great obstacle in breast cancer therapy. It renders the disease uncontrollable and causes high mortality. Multiple mechanisms contribute to the development of drug resistance, but the underlying cause is usually a shift in the genetic composition of tumor cells. It is increasingly feasible to engineer the genome with the clustered regularly interspaced short palindromic repeats (CRISPR)/associated (Cas)9 technology recently developed, which might be advantageous in overcoming drug resistance. This article discusses how the CRISPR/Cas9 system might revert resistance gene mutations and identify potential resistance targets in drug‐resistant breast cancer. In addition, the challenges that impede the clinical applicability of this technology and highlight the CRISPR/Cas9 systems are presented. The CRISPR/Cas9 system is poised to play an important role in preventing drug resistance in breast cancer therapy and will become an essential tool for personalized medicine. The application of the CRISPR/Cas9 system for editing drug resistant genes and identifying potential targets in drug resistant breast cancer is discussed. It is proposed that, with further development, the CRISPR/Cas9 system can play a more important role in preventing drug resistance in breast cancer therapy and that it will become essential in personalized and precision medicine.

The microbiome in a specific human organ has been well-studied, but few reports have investigated the multi-organ microbiome as a whole. Here, we aim to analyse the intra-individual inter-organ and intra-organ microbiome in deceased humans. We collected 1608 samples from 53 sites of 7 surface organs (oral cavity, esophagus, stomach, small intestine, appendix, large intestine and skin; n  = 33 subjects) and performed microbiome profiling, including 16S full-length sequencing. Microbial diversity varied dramatically among organs, and core microbial species co-existed in different intra-individual organs. We deciphered microbial changes across distinct intra-organ sites, and identified signature microbes, their functional traits, and interactions specific to each site. We revealed significant microbial heterogeneity between paired mucosa-lumen samples of stomach, small intestine, and large intestine. Finally, we established the landscape of inter-organ relationships of microbes along the digestive tract. Therefore, we generate a catalogue of bacterial composition, diversity, interaction, functional traits, and bacterial translocation in human at inter-organ and intra-organ levels. Given that the human body is composed of many microbial niches, and there have been few reports on the biogeography of the microbiome, the authors analyse the intra-individual inter-organ and intra-organ microbiome of seven surface organs of deceased individuals.

Mitochondria-derived reactive oxygen species (mROS) are produced at a variety of sites and affect the function of bio-molecules. The anti-oxidant system from both mitochondria and cytosol tightly coordinate to maintain the redox balance of cells and reduce damage from mROS. Mitochondrial DNA (mtDNA) are highly susceptible to mROS, and are easily oxidized to accumulate DNA modifications. Frequent oxidative damages in mtDNA have been associated with neurological degeneration, inflammasomes, tumorigenesis, and malignant progression. Among mitochondrial DNA repair pathways, the base excision repair pathway has been extensively characterized to remove some of oxidative damages in mtDNA as efficiently as the nuclear base excision repair. The implications of other pathways remain unclear. This review focuses on: (i) Sources of mROS and the antioxidant system to balance redox status; (ii) major mtDNA lesions or damages from mROS-mediated oxidation and the reported repair pathways or repairing factors; (iii) cellular response of oxidized mtDNA and methods to identify oxidatively generated DNA modifications in pathological conditions. DNA damages caused by mROS have been increasingly implicated in diseases and aging, and thus we critically discuss methods of the oxidative modifications evaluation and the complexity of non-canonical DNA repair pathways in mitochondria.

Background Extrachromosomal circular DNA (eccDNA) has potential in tumor diagnosis, particularly for improving diagnostic accuracy and early cancer detection; however, many challenges remain in its application to clinical practice. Methods We conducted a Circle‐Seq analysis on clinical samples at different stages of colorectal cancer progression to examine the dynamic changes of eccDNA during the progression of colorectal cancer. We used breakpoint-specific PCR to verify candidate eccDNAs identified by Circle‐Seq. The results were further validated using the AOM/DSS-induced colorectal cancer model. Results There was an increase in the abundance of eccDNA with the progression of colorectal cancer. The genes associated with these eccDNA molecules were primarily related to signaling pathways involved in tumor development and metastasis. Our analysis also revealed that eccDNA abundance positively correlates with gene expression, and eccDNA derived from specific genes has potential value for the early diagnosis of tumors. Conclusions This study revealed a connection between eccDNA and colorectal cancer progression and highlights the clinical potential of eccDNA for the early diagnosis of colorectal cancer.

Tumor budding is a long-established independent adverse prognostic marker for colorectal cancer (CRC), yet assessment of tumor budding was not reproducible. Therefore, development of precise diagnostic approaches to tumor budding is in demand. In this study, we first performed bioinformatic analysis in our single-center CRC patients’ cohort (n = 84) and identified tumor budding-associated hub genes using the weighted gene co-expression network analysis (WGCNA). A machine learning methodology was used to identify hub genes and construct a prognostic signature. Nomogram model was used to identified hub genes score for tumor budding, and the receiver operating characteristic (ROC) curve and calibration plot indicated high accuracy and stability of hub gene score for predicted the prognosis of CRC. The association between budding-associated hub genes and score and prognosis of CRC were further verified in TCGA CRC cohort (n = 342). Then gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were applied to explore the signaling pathways related to the tumor budding and validated by immunohistochemistry (IHC) of our clinical samples. Subsequently, immune infiltration analysis demonstrated that there was a high correlation between hub genes score and M2-like macrophages infiltrated in tumor tissue. In addition, somatic mutation and chemotherapeutic response prediction were analyzed based on the risk signature. In summary, we established a tumor budding diagnostic molecular model, which can improve tumor budding assessment and provides a promising novel molecular marker for immunotherapy and prognosis of CRC.

Colorectal cancer (CRC) poses a substantial global health concern, exhibits inconspicuous early symptoms, and is typically diagnosed at advanced stages leading to unfavorable outcomes. The intricate tumor microenvironment plays a crucial role in CRC development and progression, where chemokines contribute significantly. These chemokines exhibit widespread expression within tumor cells, facilitating immune cell infiltration, angiogenesis, and the establishment of distant metastases. The dysregulation of various chemokines in the context of CRC has emerged as a pivotal factor in the disease's pathogenesis. To explore the relationship between chemokine gene expression and CRC patient survival, as well as to clarify their biological roles,We conducted RNA-sequencing (RNA-seq) analysis on a cohort of 88 CRC patients with tumor samples, thereby enabling a detailed exploration of chemokine involvement in CRC. This study was rigorously augmented using comprehensive datasets from The Cancer Genome Atlas (TCGA), ensuring a robust analysis of gene expression patterns associated with clinical outcomes. Through data analysis, we identified key genes from the chemokine family thought pertinent to CRC outcomes. Consequently, we constructed a novel prognostic model based on the risk score derived from these chemokine expressions. Validation against clinical metadata, executed through immunohistochemistry analysis, affirmed the relevance and accuracy of our model in predicting patient survival. Our findings illuminate the critical role of chemokines in shaping the immune microenvironment of CRC, thereby highlighting potential therapeutic targets for future treatment strategies. Our new prognostic model could provide important information for the development of targeted therapies for CRC, enhancing personalized treatment approaches andultimately improving survival for CRC patients.

In the original publication [...]

Monitoring of the quality change of cherry tomatoes during storage is very important for the quality control of cherry tomatoes. In this study, the soluble solids content (SSC), reducing sugars (RSs), titratable acids (TAs), ascorbic acid (AA) and lycopene of cherry tomatoes during storage at 0, 4, 10 or 25 °C were measured, and the kinetic models were established. The results showed that the zero-order reaction combined with the Arrhenius kinetic model could be used for the prediction of changes in SS, RS and AA content. The first-order reaction combined with the Arrhenius kinetic model could be used for the prediction of changes in the TA and lycopene content. The volatile compounds of cherry tomatoes were simultaneously determined by the gas chromatography–mass spectrometry (GC–MS) and electronic nose (E-nose). A total of 104 volatile compounds were identified by GC–MS. Orthogonal partial least squares discriminant analysis (OPLS-DA) showed that there were 13 different metabolites among cherry tomatoes with different freshness. The accuracies of Fisher’s models based on E-nose for discriminating freshness of cherry tomatoes stored at 0, 4, 10 and 25 °C were 96%, 100%, 92% and 90%, respectively. This study provides a theoretical basis for the quality control of cherry tomatoes during storage.

Chemotherapy resistance plays a pivotal role in the prognosis and therapeutic failure of patients with colorectal cancer (CRC). Cisplatin (DDP)-resistant cells exhibit an inherent ability to evade the toxic chemotherapeutic drug effects which are characterized by the activation of slow-cycle programs and DNA repair. Among the elements that lead to DDP resistance, O6-methylguanine (O6-MG)-DNA-methyltransferase (MGMT), a DNA-repair enzyme, performs a quintessential role. In this study, we clarify the significant involvement of MGMT in conferring DDP resistance in CRC, elucidating the underlying mechanism of the regulatory actions of MGMT. A notable upregulation of MGMT in DDP-resistant cancer cells was found in our study, and MGMT repression amplifies the sensitivity of these cells to DDP treatment in vitro and in vivo. Conversely, in cancer cells, MGMT overexpression abolishes their sensitivity to DDP treatment. Mechanistically, the interaction between MGMT and cyclin dependent kinase 1 (CDK1) inducing slow-cycling cells is attainted via the promotion of ubiquitination degradation of CDK1. Meanwhile, to achieve nonhomologous end joining, MGMT interacts with XRCC6 to resist chemotherapy drugs. Our transcriptome data from samples of 88 patients with CRC suggest that MGMT expression is co-related with the Wnt signaling pathway activation, and several Wnt inhibitors can repress drug-resistant cells. In summary, our results point out that MGMT is a potential therapeutic target and predictive marker of chemoresistance in CRC. [Display omitted] •The expression of MGMT positively correlates with DDP tolerance in CRC.•Activation of the Wnt pathway stimulates MGMT expression in CRC.•Degradation of CDK1 by MGMT induces slow cycling cells.•MGMT recruits XRCC6 to restore nonhomologous end joining.

Barrett’s esophagus (BE) is a precancerous lesion of esophageal adenocarcinoma (EAC). It is a pathological change in which the squamous epithelium distal esophagus is replaced by columnar epithelium. Loss of P53 is involved in the development of BE and is taken as a risk factor for the progression. We established a HET1A cell line with P53 stably knockdown by adenovirus vector infection, followed by 30 days of successive acidic bile salt treatment. MTT, transwell assay, and wound closure assay were applied to assess cell proliferation and migration ability. The expression of key factors was analyzed by RT-qPCR, western blotting and immunohistochemical staining. Our data show that the protein expression level of P53 reduced after exposure to acidic bile salt treatment, and the P53 deficiency favors the survival of esophageal epithelial cells to accommodate the stimulation of acidic bile salts. Furthermore, exposure to acidic bile salt decreases cell adhesions by repressing the JAK/STAT signaling pathway and activating VEGFR/AKT in P53-deficient esophageal cells. In EAC clinical samples, P53 protein expression is positively correlated with that of ICAM1 and STAT3 and negatively correlated with VEGFR protein expression levels. These findings elucidate the role of P53 in the formation of BE, explain the mechanism of P53 deficiency as a higher risk of progression for BE formation, and provide potential therapeutic targets for EAC.