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Cholangiocarcinoma (CCA) is the second most common type of liver cancer, and is highly aggressive with very poor prognosis. CCA is classified into intrahepatic cholangiocarcinoma (iCCA) and extra-hepatic cholangiocarcinoma (eCCA), which is further stratified into perihilar (pCCA) and distal (dCCA). Cancer stem cells (CSCs) are a subpopulation of cancer cells capable of tumor initiation and malignant growth, and are also responsible for chemoresistance. Thus, CSCs play an important role in CCA carcinogenesis. Surface markers such as CD133, CD24, CD44, EpCAM, Sox2, CD49f, and CD117 are important for identifying and isolating CCA CSCs. CSCs are present in the tumor microenvironment (TME), termed ‘CSC niche’, where cellular components and soluble factors interact to promote tumor initiation. Epithelial-to-mesenchymal transition (EMT) is another important mechanism underlying carcinogenesis, involved in the invasiveness, metastasis and chemoresistance of cancer. It has been demonstrated that EMT plays a critical role in generating CSCs. Therapies targeting the surface markers and signaling pathways of CCA CSCs, proteins involved in TME, and immune checkpoint proteins are currently under investigation. Therefore, this review focuses on recent studies on the roles of CSCs in CCA; the possible therapeutic strategies targeting CSCs of CCA are also discussed.

Extracellular interaction between programmed death ligand-1 (PD-L1) and programmed cell death protein-1 (PD-1) leads to tumour-associated immune escape. Here we show that the immunosuppression activity of PD-L1 is stringently modulated by ubiquitination and N -glycosylation. We show that glycogen synthase kinase 3β (GSK3β) interacts with PD-L1 and induces phosphorylation-dependent proteasome degradation of PD-L1 by β-TrCP. In-depth analysis of PD-L1 N192, N200 and N219 glycosylation suggests that glycosylation antagonizes GSK3β binding. In this regard, only non-glycosylated PD-L1 forms a complex with GSK3β and β-TrCP. We also demonstrate that epidermal growth factor (EGF) stabilizes PD-L1 via GSK3β inactivation in basal-like breast cancer. Inhibition of EGF signalling by gefitinib destabilizes PD-L1, enhances antitumour T-cell immunity and therapeutic efficacy of PD-1 blockade in syngeneic mouse models. Together, our results link ubiquitination and glycosylation pathways to the stringent regulation of PD-L1, which could lead to potential therapeutic strategies to enhance cancer immune therapy efficacy. Programmed Death ligand-1 (PD-L1) protein mediates immune suppression in cancer. Here, the authors show that in breast cancer, PD-L1 expression can be up regulated post-translationally by glycosylation, which in turn acts through inhibiting GSK3β-mediated PD-L1 degradation.

Breast cancer is the most commonly diagnosed cancer and leading cause of cancer mortality among woman worldwide. The techniques of diagnosis, prognosis, and therapy monitoring of breast cancer are critical. Current diagnostic techniques are mammography and tissue biopsy; however, they have limitations. With the development of novel techniques, such as personalized medicine and genetic profiling, liquid biopsy is emerging as the less invasive tool for diagnosing and monitoring breast cancer. Liquid biopsy is performed by sampling biofluids and extracting tumor components, such as circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), cell-free mRNA (cfRNA) and microRNA (miRNA), proteins, and extracellular vehicles (EVs). In this review, we summarize and focus on the recent discoveries of tumor components and biomarkers applied in liquid biopsy and novel development of detection techniques, such as surface-enhanced Raman spectroscopy (SERS) and microfluidic devices.

Globally, breast cancer has remained the most commonly diagnosed cancer and the leading cause of cancer death among women. Breast cancer is a highly heterogeneous and phenotypically diverse group of diseases, which require different selection of treatments. Breast cancer stem cells (BCSCs), a small subset of cancer cells with stem cell-like properties, play essential roles in breast cancer progression, recurrence, metastasis, chemoresistance and treatments. Epigenetics is defined as inheritable changes in gene expression without alteration in DNA sequence. Epigenetic regulation includes DNA methylation and demethylation, as well as histone modifications. Aberrant epigenetic regulation results in carcinogenesis. In this review, the mechanism of epigenetic regulation involved in carcinogenesis, therapeutic resistance and metastasis of BCSCs will be discussed, and finally, the therapies targeting these biomarkers will be presented.

Background The inner membrane mitochondrial protein (IMMT) is a central unit of the mitochondrial contact site and cristae organizing system (MICOS). While researchers continue to demonstrate the physiological function of IMMT in regulating mitochondrial dynamics and preserving mitochondrial structural integrity, the roles of IMMT in clinicopathology, the tumor immune microenvironment (TIME), and precision oncology in breast cancer (BC) remain unclear. Methods Multi-omics analysis was used here to evaluate the diagnostic and prognostic value of IMMT. Web applications aimed at analyzing the whole tumor tissue, single cells, and spatial transcriptomics were used to examine the relationship of IMMT with TIME. Gene set enrichment analysis (GSEA) was employed to determine the primary biological impact of IMMT. Experimental verification using siRNA knockdown and clinical specimens of BC patients confirmed the mechanisms behind IMMT on BC cells and the clinical significance, respectively. Potent drugs were identified by accessing the data repositories of CRISPR-based drug screenings. Results High IMMT expression served as an independent diagnostic biomarker, correlated with advanced clinical status, and indicated a poor relapse-free survival (RFS) rate for patients with BC. Although, the contents of Th1, Th2, MSC, macrophages, basophil, CD4 + T cell and B cell, and TMB levels counteracted the prognostic significance. Single-cell level and whole-tissue level analyses revealed that high IMMT was associated with an immunosuppressive TIME. GSEA identified IMMT perturbation as involved in cell cycle progression and mitochondrial antioxidant defenses. Experimental knockdown of IMMT impeded the migration and viability of BC cells, arrested the cell cycle, disturbed mitochondrial function, and increased the ROS level and lipid peroxidation. The clinical values of IMMT were amenable to ethnic Chinese BC patients, and can be extrapolated to some other cancer types. Furthermore, we discovered that pyridostatin acted as a potent drug candidate in BC cells harboring an elevated IMMT expression. Conclusion This study combined a multi-omics survey with experimental verification to reveal the novel clinical significance of IMMT in BC, demonstrating its role in TIME, cancer cell growth and mitochondrial fitness, and identified pyridostatin as a promising drug candidate for the development of precision medicine.

Oral cancer, particularly oral squamous cell carcinoma (OSCC), often exhibits resistance to standard treatments like surgery, chemotherapy, and radiation therapy (RT). Magnolol, a bioactive compound from the bark of Magnolia officinalis, is recognised for its anti‐inflammatory, antioxidant, antimicrobial, and antitumor properties. This study aims to explore magnolol's potential to enhance the therapeutic efficacy of RT in oral cancer models. Using MOC1‐bearing animals, we evaluated the combined effect of magnolol and RT. The results showed that magnolol significantly suppressed tumour growth, delayed progression, and reduced tumour weight compared to control groups. Immune profiling revealed that magnolol plus RT promoted positive immune regulation by increasing M1 macrophages, dendritic cells, and activated cytotoxic T cells, while suppressing negative regulators like myeloid‐derived suppressor cells (MDSCs) and regulatory T cells (Tregs). Immunohistochemical analysis also demonstrated enhanced activation of apoptosis‐related pathways including the cleavage of caspase‐3, ‐8, and ‐9. Furthermore, the combination of magnolol and RT did not induce significant toxicity, as evidenced by stable body weight, normal tissue pathology, and normal liver and kidney function markers. Notably, the phosphorylation levels of EGFR and NF‐κB were significantly reduced in the magnolol plus RT group, similar to the effects seen with erlotinib plus RT. In conclusion, these findings highlight magnolol's ability to enhance the efficacy of RT in oral cancer by targeting the EGFR/NF‐κB axis, inducing apoptosis, and modulating immune responses, presenting a promising therapeutic strategy for OSCC.

The major challenge in the fabrication of fluorescent silica nanoparticles (FSNs) based on dye-doped silica nanoparticles (DDSNs) is aggregation-caused fluorescence quenching. Here, we constructed an FSN based on a double emission enhancement (DEE) platform. A thio-reactive fluorescence turn-on molecule, N-butyl-4-(4-maleimidostyryl)-1,8-naphthalimide (CS), was bound to a silane coupling agent, (3-mercaptopropyl)-trimethoxysilane (MPTMS), and the product N-butyl-4-(3-(trimethoxysilyl-propylthio)styryl)-1,8-naphthalimide (CSP) was further used to fabricate a core–shell nanoparticle through the Stöber method. We concluded that the turn-on emission by CSP originated from the photoinduced electron transfer (PET) between the maleimide moiety and the CSP core scaffold, and the second emission enhancement was attributed to the aggregation-induced emission enhancement (AIEE) in CSP when encapsulated inside a core–shell nanoparticle. Thus, FSNs could be obtained through DEE based on a combination of PET and AIEE effects. Systematic investigations verified that the resulting FSNs showed the traditional solvent-independent and photostable optical properties. The results implied that the novel FSNs are suitable as biomarkers in living cells and function as fluorescent visualizing agents for intracellular imaging and drug carriers.

Background/Objectives: Atopic dermatitis (AD) is a chronic inflammatory skin condition with rising global prevalence. Increasing maternal antibiotic use during pregnancy has raised concerns about its potential link to childhood allergic diseases, including AD. However, existing meta-analyses have yielded inconsistent results. A systematic review and meta-analysis were conducted to investigate the association between prenatal antibiotic exposure, including intrapartum antibiotic prophylaxis (IAP), and the risk of AD developing in offspring. Methods: A systematic search protocol (PROSPERO ID: CRD42024577804) was conducted up to 29 August 2024, across the PubMed, Embase, and Cochrane databases. Cohort and case–control studies reporting associations between maternal antibiotic exposure during pregnancy or intrapartum and the risk of AD in offspring were included. Data were analyzed using RevMan Web and Comprehensive Meta-Analysis software. Results: Twenty studies involving 3,256,929 mother–child pairs were reviewed. The meta-analysis data demonstrated that prenatal antibiotic exposure was associated with AD in the main analysis (odds ratio [OR]: 1.12, 95% CI 1.03–1.21), but not in a separate analysis with a pooled hazard ratio (HR) (HR: 1.12, 95% CI 0.96–1.31). Trim-and-fill correction for significant publication bias (Egger’s test p = 0.003) in the main analysis resulted in a non-significant effect size (OR: 1.09, 95% CI 0.99–1.20). Subgroup analysis and meta-regression suggested that publication years and sample sizes contributed significant heterogeneity (p < 0.05). Regarding IAP and the risk of AD, no association was found (OR: 1.62, 95% CI 0.87–3.00). Conclusions: Current evidence in the existing literature does not support a positive relationship between antibiotic exposure, either during pregnancy or in the intrapartum period, and the risk of development of AD in offspring. However, substantial heterogeneity and the very low certainty of evidence limit the strength of our findings. Further studies that address confounders more thoroughly are needed to confirm these results.

(1) Background: methionine cycle is not only essential for cancer cell proliferation but is also critical for metabolic reprogramming, a cancer hallmark. Hepatic and extrahepatic tissues methionine adenosyltransferases (MATs) are products of two genes, MAT1A and MAT2A that catalyze the formation of S-adenosylmethionine (SAM), the principal biological methyl donor. Glycine N-methyltransferase (GNMT) further utilizes SAM for sarcosine formation, thus it regulates the ratio of SAM:S-adenosylhomocysteine (SAH). (2) Methods: by analyzing the TCGA/GTEx datasets available within GEPIA2, we discovered that breast cancer patients with higher MAT2A had worse survival rate (p = 0.0057). Protein expression pattern of MAT1AA, MAT2A and GNMT were investigated in the tissue microarray in our own cohort (n = 252) by immunohistochemistry. MAT2A C/N expression ratio and cell invasion activity were further investigated in a panel of breast cancer cell lines. (3) Results: GNMT and MAT1A were detected in the cytoplasm, whereas MAT2A showed both cytoplasmic and nuclear immunoreactivity. Neither GNMT nor MAT1A protein expression was associated with patient survival rate in our cohort. Kaplan–Meier survival curves showed that a higher cytoplasmic/nuclear (C/N) MAT2A protein expression ratio correlated with poor overall survival (5 year survival rate: 93.7% vs. 83.3%, C/N ratio ≥ 1.0 vs. C/N ratio < 1.0, log-rank p = 0.004). Accordingly, a MAT2A C/N expression ratio ≥ 1.0 was determined as an independent risk factor by Cox regression analysis (hazard ratio = 2.771, p = 0.018, n = 252). In vitro studies found that breast cancer cell lines with a higher MAT2A C/N ratio were more invasive. (4) Conclusions: the subcellular localization of MAT2A may affect its functions, and elevated MAT2A C/N ratio in breast cancer cells is associated with increased invasiveness. MAT2A C/N expression ratio determined by IHC staining could serve as a novel independent prognostic marker for breast cancer.

Background and Objectives: Live birth rates in women with diminished ovarian reserve (AMH < 2.0 ng/mL) undergoing in vitro fertilization (IVF) remain under 20%. While Chinese herbal medicine (CHM) is often used to treat infertility and support IVF, its effectiveness in this group is unclear. This study assessed live birth outcomes by treatment type and patient characteristics. Materials and Methods: We retrospectively analyzed 240 infertile women with low ovarian reserve and partners with normal sperm. Of these, 63 were in the control group, 118 received CHM only, and 59 received IVF with CHM. Logistic regression and a nomogram were used to assess live birth outcomes. Results: The live birth rate was 5% in the control group, 32% in the CHM-only group, and 42% in the mixed treatment group. Univariate analysis showed that both treatment type and patient age were significantly associated with live birth outcomes. In multivariate logistic regression, CHM-only treatment was significantly associated with an increased likelihood of live birth (odds ratio [OR]: 8.98, p = 0.001), as was the mixed treatment group (OR = 18.77, p < 0.001), with the control group as the reference. Women aged ≤37 had significantly higher live birth rates (OR = 3.24, p = 0.018), using those over 37 as the reference group. A predictive model was developed based on age, AMH level, and treatment type, achieving an area under the curve (AUC) of 0.756 for predicting live birth probability. Conclusions: This clinical prediction model offers guidance for couples and clinicians on pregnancy outcomes in low ovarian reserve patients treated with CHM alone or alongside IVF.