Journal of Translational Medicine最新文献

Background: We aimed to determine the potential predictive value of the intra-tumoral microbiome as a marker of the response to external beam radiation therapy (EBRT) in cervical cancer (CC).

Methods: A prospective longitudinal trial of 36 CC patients receiving pelvic radiotherapy was designed to investigate microbial characteristic signatures and diversity (alpha and beta) of multiple sites (tumor, vaginal, gut, urethral, and oral) in the superior response (SR) and inferior response (IR) groups of CC patients by 16S rRNA sequencing. Utilized the least absolute shrinkage and selection operator (LASSO) logistic regression method to analyze clinicopathological factors that potentially influenced the efficacy of EBRT. LEfSe analysis highlighted the microbiome features that best distinguished the categorized patient samples. Selected parameters were validated with Spearman correlation analysis, receiver operating characteristic (ROC) area under the curve (AUC) analysis and Kaplan-Meier survival analysis.

Results: Firstly, in our cohort, LASSO logistic regression analysis revealed no association between clinicopathological factors and EBRT efficacy. Subsequently, we employed 16S rRNA sequencing to compare microbiome differences across multiple sites and their correlations with major clinicopathological factors. We discovered that the intra-tumoral microbiome was independent of clinicopathologic features and represented the most direct and reliable reflection of the microbial differences between the SR and IR groups. We found lower alpha diversity in the tumor microbiome of SR group and identified the most relevant microbiome taxa (Bifidobacteriaceae, Beijerinckiaceae, and Orbaceae) associated with the efficacy of the response to EBRT in CC patients. We then conducted ROC analysis, finding that specific microbial taxa had an AUC of 0.831 (95% CI, 0.667-0.995), indicating the potential of these taxa as biomarkers for predicting EBRT efficacy. Kaplan-Meier survival analysis showed a better prognosis for patients with lower alpha diversity and higher relative abundance of Bifidobacteriaceae.

Conclusions: Our data suggested that intra-tumoral specific microbiome taxa and lower alpha diversity may play an important role in the CC patient sensitivity to EBRT and offer novel potential biomarkers for predicting the response to EBRT efficacy.

Objectives: Circadian rhythm disruption (CRD) is implicated with numerous gastrointestinal motility diseases, with the enteric nervous system (ENS) taking main responsibility for the coordination of gastrointestinal motility. The purpose of this study is to explore the role of circadian rhythms in ENS remodeling and to further elucidate the underlying mechanisms.

Methods: First, we established a jet-lagged mice model by advancing the light/dark phase shift by six hours every three days for eight weeks. Subsequent changes in gastrointestinal motility and the ENS were then assessed. Additionally, a triple-transgenic mouse strain (Nestin-creER^T2 × Ngfr-DreER^T2: DTRGFP) was utilized to track the effects of CRD on the differentiation of enteric neural precursor cells (ENPCs). RNA sequencing was also performed to elucidate the underlying mechanism.

Results: Compared to the control group, CRD significantly accelerated gastrointestinal motility, evidenced by faster intestinal peristalsis (P < 0.01), increased fecal output (P < 0.01), and elevated fecal water content (P < 0.05), as well as enhanced electrical field stimulation induced contractions (P < 0.05). These effects were associated with an increase in the number of glial cells and nitrergic neurons in the colonic myenteric plexus. Additionally, ENPCs in the colon showed a heightened differentiation into glial cells and nitrergic neurons. Notably, the NR1D1/nuclear factor-kappaB (NF-κB) axis played a crucial role in the CRD-mediated changes in ENPCs differentiation. Supplementation with NR1D1 agonist or NF-κB antagonist was able to restore gastrointestinal motility and normalize the ENS in jet-lagged mice.

Conclusions: CRD regulates the differentiation of ENPCs through the NR1D1/NF-κB axis, resulting in dysfunction of the ENS and impaired gastrointestinal motility in mice.

Brain damage caused by acute hypoxia is associated with the physiological activities of mitochondria. Although mitochondria being dynamically regulated, our comprehensive understanding of the response of specific brain cell types to acute hypoxia remains ambiguous. Tumor necrosis factor receptor-associated protein 1 (TRAP1), a mitochondrial-based molecular chaperone, plays a role in controlling mitochondrial movements. Herein, we demonstrated that acute hypoxia significantly alters mitochondria morphology and functionality in both in vivo and in vitro brain injury experiments. Summary-data-based Mendelian Randomization (SMR) analyses revealed possible causative links between mitochondria-related genes and hypoxia injury. Advancing the protein-protein interaction network and molecular docking further elucidated the associations between TRAP1 and mitochondrial dynamics. Furthermore, it was shown that TRAP1 knockdown levels variably affected the expression of key mitochondrial dynamics proteins (DRP1, FIS1, and MFN1/2) in primary hippocampal neurons, astrocytes, and BV-2 cell, leading to changes in mitochondrial structure and function. Understanding the function of TRAP1 in altering mitochondrial physiological activity during hypoxia-induced acute brain injury could help serve as a potential therapeutic target to mitigate neurological damage.

Background: Cancer immunotherapy, particularly immune checkpoint inhibitors (ICBs) such as anti-PD-1 antibodies, has revolutionised cancer treatment, although response rates vary among patients. Previous studies have demonstrated that caerin 1.1 and 1.9, host-defence peptides from the Australian tree frog, enhance the effectiveness of anti-PD-1 and therapeutic vaccines in a murine TC-1 model by activating tumour-associated macrophages intratumorally.

Methods: We employed a murine B16 melanoma model to investigate the therapeutic potential of caerin 1.1 and 1.9 in combination with anti-CD47 and a therapeutic vaccine (triple therapy, TT). Tumour growth of caerin-injected primary tumours and distant metastatic tumours was assessed, and survival analysis conducted. Single-cell RNA sequencing (scRNAseq) of CD45⁺ cells isolated from distant tumours was performed to elucidate changes in the tumour microenvironment induced by TT.

Results: The TT treatment significantly reduced tumour volumes on the treated side compared to untreated and control groups, with notable effects observed by Day 21. Survival analysis indicated extended survival in mice receiving TT, both on the treated and distant sides. scRNAseq revealed a notable expansion of conventional type 1 dendritic cells (cDC1s) and CD4⁺CD8⁺ T cells in the TT group. Tumour-associated macrophages in the TT group shifted toward a more immune-responsive M1 phenotype, with enhanced communication observed between cDC1s and CD8⁺ and CD4⁺CD25⁺ T cells. Additionally, TT downregulated M2-like macrophage marker genes, particularly in MHCIIhi and tissue-resident macrophages, suppressing Cd68 and Arg1 expression across all macrophage types. Differential gene expression analysis highlighted pathway alterations, including upregulation of oxidative phosphorylation and MYC target V1 in Arg1^hi macrophages, and activation of pro-inflammatory pathways in MHCII^hi and tissue-resident macrophages.

Conclusion: Our findings suggest that caerin 1.1 and 1.9, combined with immunotherapy, effectively modulate the tumour microenvironment in primary and secondary tumours, leading to reduced tumour growth and enhanced systemic immunity. Further investigation into these mechanisms could pave the way for improved combination therapies in advanced melanoma treatment.

Breast cancer is the most common cancer type among women. Despite advanced treatment strategies, some patients still face challenges in disease control, prompting the exploration of new therapeutic approaches. N6-Methyladenosine (m6A) methylation modification regulates RNA and plays a crucial role in various tumor biological processes, closely linked to breast cancer occurrence, development, prognosis, and treatment. M6A regulators impact breast cancer progression, development, and drug resistance by modulating RNA metabolism and tumor-related pathways. Researchers have begun to understand the regulatory mechanisms of m6A methylation in breast cancer. This paper discusses the roles of m6A regulators in breast cancer progression, prognosis, and treatment, offering new perspectives for breast cancer diagnosis and treatment.

Gastrointestinal tumors are the main causes of death among the patients. These tumors are mainly diagnosed in the advanced stages and their response to therapy is unfavorable. In spite of the development of conventional therapeutics including surgery, chemotherapy, radiotherapy and immunotherapy, the treatment of these tumors is still challenging. As a result, the new therapeutics based on (nano)biotechnology have been introduced. Hydrogels are polymeric 3D networks capable of absorbing water to swell with favorable biocompatibility. In spite of application of hydrogels in the treatment of different human diseases, their wide application in cancer therapy has been improved because of their potential in drug and gene delivery, boosting chemotherapy and immunotherapy as well as development of vaccines. The current review focuses on the role of hydrogels in the treatment of gastrointestinal tumors. Hydrogels provide delivery of drugs (both natural or synthetic compounds and their co-delivery) along with gene delivery. Along with delivery, hydrogels stimulate phototherapy (photothermal and photodynamic therapy) in the suppression of these tumors. Besides, the ability of hydrogels for the induction of immune-related cells such as dendritic cells can boost cancer immunotherapy. For more specific cancer therapy, the stimuli-responsive types of hydrogels including thermo- and pH-sensitive hydrogels along with their self-healing ability have improved the site specific drug delivery. Moreover, hydrogels are promising for diagnosis, circulating tumor cell isolation and detection of biomarkers in the gastrointestinal tumors, highlighting their importance in clinic. Hence, hydrogels are diagnostic and therapeutic tools for the gastrointestimal tumors.

Background: Neoadjuvant chemotherapy (NACT) became a standard treatment strategy for patients with inflammatory breast cancer (IBC) because of high disease aggressiveness. However, given the heterogeneity of IBC, no molecular feature reliably predicts the response to chemotherapy. Whole-exome sequencing (WES) of clinical tumor samples provides an opportunity to identify genomic alterations associated with chemosensitivity.

Methods: We retrospectively applied WES to 44 untreated IBC primary tumor samples and matched normal DNA. The pathological response to NACT, assessed on operative specimen, distinguished the patients with versus without pathological complete response (pCR versus no-pCR respectively). We compared the mutational profiles, spectra and signatures, pathway mutations, copy number alterations (CNAs), HRD, and heterogeneity scores between pCR versus no-pCR patients.

Results: The TMB, HRD, and mutational spectra were not different between the complete (N = 13) versus non-complete (N = 31) responders. The two most frequently mutated genes were TP53 and PIK3CA. They were more frequently mutated in the complete responders, but the difference was not significant. Only two genes, NLRP3 and SLC9B1, were significantly more frequently mutated in the complete responders (23% vs. 0%). By contrast, several biological pathways involved in protein translation, PI3K pathway, and signal transduction showed significantly higher mutation frequency in the patients with pCR. We observed a higher abundance of COSMIC signature 7 (due to ultraviolet light exposure) in tumors from complete responders. The comparison of CNAs of the 3808 genes included in the GISTIC regions between both patients' groups identified 234 genes as differentially altered. The CIN signatures were not differentially represented between the complete versus non-complete responders. Based on the H-index, the patients with heterogeneous tumors displayed a lower pCR rate (11%) than those with less heterogeneous tumors (35%).

Conclusions: This is the first study aiming at identifying correlations between the WES data of IBC samples and the achievement of pCR to NACT. Our results, obtained in this 44-sample series, suggest a few subtle genomic alterations associated with pathological response. Additional investigations are required in larger series.

Ovarian cancer is a prevalent gynecologic malignancy with the second-highest mortality rate among gynecologic malignancies. Platinum-based chemotherapy is the first-line treatment for ovarian cancer; however, a majority of patients with ovarian cancer experience relapse and develop platinum resistance following initial treatment. Despite extensive research on the mechanisms of platinum resistance at the nuclear level, the issue of platinum resistance in ovarian cancer remains largely unresolved. It is noteworthy that mitochondrial DNA (mtDNA) exhibits higher affinity for platinum compared to nuclear DNA (nDNA). Mutations in mtDNA can modulate tumor chemosensitivity through various mechanisms, including DNA damage responses, shifts in energy metabolism, maintenance of Reactive Oxygen Species (ROS) homeostasis, and alterations in mitochondrial dynamics. Concurrently, retrograde signals produced by mtDNA mutations and their subsequent cascades establish communication with the nucleus, leading to the reorganization of the nuclear transcriptome and governing the transcription of genes and signaling pathways associated with chemoresistance. Furthermore, mitochondrial translocation among cells emerges as a crucial factor influencing the effectiveness of chemotherapy in ovarian cancer. This review aims to explore the role and mechanism of mitochondria in platinum resistance, with a specific focus on mtDNA mutations and the resulting metabolic reprogramming, ROS regulation, changes in mitochondrial dynamics, mitochondria-nucleus communication, and mitochondrial transfer.

Background: In mouse models of atherosclerosis, knockout of the PLA2G2A gene has been shown to reduce the volume of atherosclerotic plaques. Clinical trials have demonstrated the potential of using the sPLA2 inhibitor Varespladib in combination with statins to reduce lipid levels. However, this approach has not yielded the expected results in reducing the risk of cardiovascular events. Therefore, it is necessary to further investigate the mechanisms of PLA2G2A.

Methods: Single-cell transcriptome data from two sets of carotid plaques, combined with clinical patient information. were used to describe the expression characteristics of PLA2G2A in carotid plaques at different stages. In order to explore the mechanisms of PLA2G2A, we conducted enrichment analysis, cell-cell communication analysis and single-cell regulatory network inference and clustering analyses. We validated the above findings at the cellular level.

Results: Our findings indicate that PLA2G2A is primarily expressed in vascular fibroblasts and shows significant cell interactions with macrophages in the early-stage, especially in complement and inflammation-related pathways. We also found that serum sPLA2 levels have stronger diagnostic value in patients with mild carotid artery stenosis. Subsequent comparisons of single-cell transcriptomic data from early and late-stage carotid artery plaques corroborated these findings and predicted transcription factors that might regulate the progression of early carotid atherosclerosis (CA) and the expression of PLA2G2A.

Conclusions: Our study discovered and validated that PLA2G2A is highly expressed by vascular fibroblasts and promotes plaque progression through the activation of macrophage complement and coagulation cascade pathways in the early-stage of CA.

Aims: The present study aims to develop a nano-delivery system that encapsulates berberine (BBR) into PLGA-based nanoparticles (BPL-NPs), to treat ulcerative colitis (UC). Furthermore, the therapeutic efficacy and molecular targeting mechanisms of BPL-NPs in the management of UC are thoroughly examined.

Methods: Emulsion solvent-driven methods were used to self-assemble BBR and PLGA into nanoparticles, resulting in the development of the nano-delivery system (BPL-NPs). The therapeutic effectiveness of BPL-NPs was evaluated using a dextran sulfate sodium (DSS)-induced model of ulcerative colitis in mice and a lipopolysaccharide (LPS)-induced model of inflammation in THP-1 macrophages. The interaction between Mφs and NCM-460 cells was investigated using a co-culture system. The molecular targeting ability of BPL-NPs in the treatment of UC was validated through in vitro as well as in vivo experiments.

Results: The BPL-NPs demonstrated a particle size of 184 ± 22.4 nm, enhanced dispersibility in deionized water, and a notable encapsulation efficiency of 31.1 ± 0.2%. The use of BPL-NPs clearly improved the clinical symptoms and pathological changes associated with UC in mice while also ensuring minimal toxicity. In addition, BPL-NPs improved intestinal epithelial cell apoptosis and enhanced the function of the intestinal barrier by inhibiting M1 Mφs infiltration and IL-6 signaling pathway in mice with UC. Furthermore, the BPL-NPs were found to selectively target the IL-6/IL-6R axis during the M1 Mφs-induced apoptosis of NCM460 cells.

Conclusion: The BPL-NPs were confirmed to harbor anti-inflammatory effects both in vitro and in vivo, along with enhanced water solubility and bioactivity. In addition, the precise targeting of the IL-6/IL-6R axis was confirmed as the mechanism by which the BPL-NPs exerted therapeutic effects in UC, as demonstrated in both in vitro as well as in vivo studies.