ABSTRACT
Patient-derived organoids (PDOs) have emerged as a promising platform for clinical and translational studies. A strong correlation exists between clinical outcomes and the use of PDOs to predict the efficacy of chemotherapy and/or radiotherapy. To standardize interpretation and enhance scientific communication in the field of cancer precision medicine, we revisit the concept of PDO-based drug sensitivity testing (DST). We present an expert consensus-driven approach for medication selection aimed at predicting patient responses. To further standardize PDO-based DST, we propose guidelines for clarification and characterization. Additionally, we identify several major challenges in clinical prediction when utilizing PDOs.
Subject(s)
Antineoplastic Agents , Consensus , Drug Development , Neoplasms , Organoids , Precision Medicine , Organoids/drug effects , Humans , Precision Medicine/methods , Neoplasms/drug therapy , Drug Development/methods , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Drug Screening Assays, Antitumor/methodsABSTRACT
Aberrant expression of G protein-coupled receptor class C group 5 member A (GPRC5A) has been reported in multiple cancers and is closely related to patient prognosis. However, the mechanistic role of GPRC5A in gallbladder cancer (GBC) remains unclear. Here, we determined tumor expression levels of GPRC5A and the molecular mechanisms by which GPRC5A regulates gallbladder cancer metastasis. We found that GPRC5A was significantly upregulated in GBC, correlating with poorer patient survival. Knocking down GPRC5A inhibited GBC cell metastasis both in vitro and in vivo. GRPRC5A knockdown resulted in downregulation of TNS4 expression through the JAK2-STAT3 axis. Clinically, GPRC5A expression positively correlated with TNS4. Finally, STAT3 bound to TNS4's promoter region, inducing its expression. Overall, GPRC5A showed high expression in GBC tissues, associated with poor patient prognosis. Our findings first demonstrate that the GPRC5A-JAK2-STAT3-TNS4 pathway promotes GBC cell metastasis, suggesting potential therapy targets.
Subject(s)
Gallbladder Neoplasms , Gene Expression Regulation, Neoplastic , Janus Kinase 2 , Receptors, G-Protein-Coupled , STAT3 Transcription Factor , Signal Transduction , Up-Regulation , Humans , Gallbladder Neoplasms/pathology , Gallbladder Neoplasms/genetics , Gallbladder Neoplasms/metabolism , Janus Kinase 2/metabolism , Janus Kinase 2/genetics , STAT3 Transcription Factor/metabolism , STAT3 Transcription Factor/genetics , Receptors, G-Protein-Coupled/metabolism , Receptors, G-Protein-Coupled/genetics , Cell Line, Tumor , Animals , Male , Female , Mice , Prognosis , Neoplasm Metastasis , Mice, Nude , Cell Movement , Middle Aged , Mice, Inbred BALB CABSTRACT
Gallbladder cancer (GBC) is the most common malignant tumor of the biliary system with the worst prognosis. Even after radical surgery, the majority of patients with GBC have difficulty achieving a clinical cure. The risk of tumor recurrence remains more than 65%, and the overall 5-year survival rate is less than 5%. The gut microbiota refers to a variety of microorganisms living in the human intestine, including bacteria, viruses and fungi, which profoundly affect the host state of general health, disease and even cancer. Over the past few decades, substantial evidence has supported that gut microbiota plays a critical role in promoting the progression of GBC. In this review, we summarize the functions, molecular mechanisms and recent advances of the intestinal microbiota in GBC. We focus on the driving role of bacteria in pivotal pathways, such as virulence factors, metabolites derived from intestinal bacteria, chronic inflammatory responses and ecological niche remodeling. Additionally, we emphasize the high level of correlation between viruses and fungi, especially EBV and Candida spp., with GBC. In general, this review not only provides a solid theoretical basis for the close relationship between gut microbiota and GBC but also highlights more potential research directions for further research in the future.
Subject(s)
Bacteria , Gallbladder Neoplasms , Gastrointestinal Microbiome , Humans , Gallbladder Neoplasms/microbiology , Bacteria/classification , Bacteria/isolation & purification , Animals , Dysbiosis/microbiology , Virulence Factors , Fungi/pathogenicity , Fungi/classificationABSTRACT
Autophagy is an essential degradative process that governs the renewal of organelle and maintains the homeostasis of cellular microenvironment. Its dysregulation has been demonstrated to be an indicator for neuroinflammation. To elucidate the interrelationship between neuroinflammation and autophagy, optical probes are ideal tools as they offer a number of advantages such as high spatiotemporal resolution and non-invasive sensing, which help to visualize the physiological and pathological functions of interested analytes. However, single autophagy parameter-response probes may generate false-positive results since they cannot distinguish between neuroinflammation and other autophagic stimuli. In contrast, chemosensors that respond to two (or more) targets can improve selectivity by qualifying response conditions. Herein, a "dual-key-and-lock" strategy was applied to construct probe (Vis-NO) to selectively recognize autophagy under inflammation out of other stimuli. The red fluorescence of Vis-NO was lit up only in the simultaneously presence of high viscosity and nitric oxide (NO) in lysosome. Due to the characteristics of high viscosity and overexpressed NO within lysosomes, Vis-NO could be used to selectively identify autophagy during neuroinflammation, providing expanding insights into the interrelationship between autophagy, neuroinflammation and stroke in pathology, and informing about the mechanisms through which autophagy regulates inflammation.
Subject(s)
Autophagy , Biosensing Techniques , Neuroinflammatory Diseases , Nitric Oxide , Biosensing Techniques/methods , Biosensing Techniques/instrumentation , Animals , Neuroinflammatory Diseases/pathology , Nitric Oxide/metabolism , Nitric Oxide/analysis , Humans , Lysosomes/metabolism , Mice , Inflammation , Fluorescent Dyes/chemistryABSTRACT
Background: Direct liver invasion (DI) is a predominant pathway of gallbladder cancer (GBC) metastasis, but the molecular alterations associated with DI remain addressed. This study identified specific genes correlated with DI, which may offer a potential biomarker for the diagnosis and prognosis of advanced GBC. Methods: RNA samples from 3 patients with DI of GBC were used for RNA-seq analysis. Differentially expressed genes and metabolic pathways between primary tumor (T) and DI tissue was used to analyze aberrant gene expressions. Immunohistochemistry (IHC) of fatty acid binding protein 1 (FABP1) in 62 patients with DI was engaged to evaluate its association with clinicopathological characteristics and prognosis. IHC of CD3+ and CD8+ T cells was analyzed for their correlation with FABP1 expression, clinicopathological features and prognosis. Univariate and multivariate Cox hazards regression analyses were performed to identify independent prognostic factors for disease-free survival (DFS) and overall survival (OS). Results: FABP1 mRNA levels were significantly upregulated in DI region compared to T tissue. IHC results showed identical results with elevated FABP1 (p < 0.0001). Expression of FABP1 in DI region was significantly associated with lymph node metastasis (P = 0.028), reduced DFS (P = 0.013) and OS (P = 0.022); in contrast, its expression in T region was not associated with clinicopathological characteristics and prognosis (P > 0.05). The density of CD8+ T cells in DI region with higher FABP1 expression was significantly lower than that with lower FABP1 expression (p = 0.0084). Multivariate analysis unveiled those hepatic metastatic nodules (HR = 3.35, 95%CI: 1.37-8.15, P = 0.008) and FABP1 expression in DI region (HR = 2.01, 95%CI: 1.05-3.88, P = 0.036) were high risk factors for OS, and FABP1(HR = 2.05, 95%CI: 1.04-4.06, P = 0.039) was also a high risk factor for DFS. Conclusions: Elevated expression of FABP1 in DI region serves as a potential prognostic biomarker for advanced GBC with DI.
Subject(s)
Carcinoma in Situ , Carcinoma , Gallbladder Neoplasms , Humans , CD8-Positive T-Lymphocytes , Fatty Acid-Binding Proteins/genetics , Gallbladder Neoplasms/genetics , Liver , PrognosisABSTRACT
As one of the key components of supercapacitors, electrolyte is intensively investigated to promote the fast development of the energy supply system under extremely cold conditions. However, high freezing point and sluggish ion transport kinetics for routine electrolytes hinder the application of supercapacitors at low temperatures. Resultantly, the liquid electrolyte should be oriented to reduce the freezing point, accompanied by other superior characteristics, such as large ionic conductivity, low viscosity and outstanding chemical stability. In this review, the intrinsically physical parameters and microscopic structure of low-temperature electrolytes are discussed thoroughly, then the previously reported strategies that are used to address the associated issues are summarized subsequently from the aspects of aqueous and non-aqueous electrolytes (organic electrolyte and ionic liquid electrolyte). In addition, some advanced spectroscopy techniques and theoretical simulation to better decouple the solvation structure of electrolytes and reveal the link between the key physical parameters and microscopic structure are briefly presented. Finally, the further improvement direction is put forward to provide a reference and guidance for the follow-up research.
ABSTRACT
In recent years, significant advancements have been made in the synthesis and application of 1,3-dienes. This specific structural motif has garnered significant attention from researchers in materials science and biology due to its unique aggregation-induced emission (AIE) properties and extensive conjugation systems. The luminescent characteristics of these compounds are notably influenced by the geometry of the two double bonds. Therefore, it is essential to consolidate stereoselective synthetic strategies for 1,3-dienes. This comprehensive review seeks to elucidate the diverse techniques employed to attain stereo-control in the synthesis of 1,3-diene-based AIE luminogens (AIEgens). Particular emphasis is placed on comprehending the determinants of stereoselectivity and exploring the array of substrates amenable to these methods. Furthermore, the review underscores the AIE properties exhibited by these compounds and their extensive utility in organic light-emitting diodes (OLEDs), stimuli-responsive materials, sensors, bioimaging, and photodynamic therapy (PDT).
ABSTRACT
Bile acids (BAs) constitute essential components of cholesterol metabolites that are synthesized in the liver, stored in the gallbladder, and excreted into the intestine through the biliary system. They play a crucial role in nutrient absorption, lipid and glucose regulation, and the maintenance of metabolic homeostasis. In additional, BAs have demonstrated the ability to attenuate disease progression such as diabetes, metabolic disorders, heart disease, and respiratory ailments. Intriguingly, recent research has offered exciting evidence to unveil their potential antitumor properties against various cancer cell types including tamoxifen-resistant breast cancer, oral squamous cell carcinoma, cholangiocarcinoma, gastric cancer, colon cancer, hepatocellular carcinoma, prostate cancer, gallbladder cancer, neuroblastoma, and others. Up to date, multiple laboratories have synthesized novel BA derivatives to develop potential drug candidates. These derivatives have exhibited the capacity to induce cell death in individual cancer cell types and display promising anti-tumor activities. This review extensively elucidates the anticancer activity of natural BAs and synthetic derivatives in cancer cells, their associated signaling pathways, and therapeutic strategies. Understanding of BAs and their derivatives activities and action mechanisms will evidently assist anticancer drug discovery and devise novel treatment.
ABSTRACT
Carbon materials with hierarchical porous structures hold great potential for redox electrolyte-enhanced supercapacitors. However, restricted by the intrinsic inert and nonpolar characteristics of carbon, the energy barrier of anchoring redox electrolytes on the pore walls is relatively high. As such, the redox process at the interface less occurs, and the rate of mass transfer is impaired, further leading to a poor electrochemical performance. Here, a ferricyanide anion-philic interface made of in situ inserted boron species into carbon rings is constructed for enhanced charge storage in supercapacitors. Profiting from the unique component-driven effects, the polar anchoring sites on the pore wall can be built to grasp the charged redox ferricyanide anion from the bulk electrolyte and promote the redox process; the dynamics process is fastened correspondingly. Especially, the boron atoms in BC2O and BCO2 units with higher positive natural bond orbital values in the carbon skeleton are pinpointed as intrinsic active sites to bind the negatively charged nitrogen atoms in the ferricyanide anion via electrostatic interaction, confirmed by density functional theoretical calculations. This will suppress the shuttle and diffusion effects of the ferricyanide anion from the surface of the electrode to the bulk electrolyte. Finally, the well-designed PC-3 with high content of BC2O and BCO2 units can reach 1099 F g-1 at 2 mV s-1, which is a more than 2-fold increase over boron-free units of carbon (428 F g-1). The work offers a novel version for designing high-performance carbon materials with unique yet reaction species-philic effects.
ABSTRACT
Glutathione (GSH) depletion-induced ferroptosis has emerged as a promising treatment for malignant cancer. It works by inactivating glutathione peroxidase 4 (GPX4) and facilitating lipid peroxidation. However, effectively delivering inducers and depleting intracellular GSH remains challenging due to the short half-lives and high hydrophobicity of small-molecule ferroptosis inducers. These inducers often require additional carriers. Herein, diselenide-containing polymers can consume GSH to induce ferroptosis for pancreatic cancer therapy. The diselenide bonds are controllably built into the backbone of the polycarbonate with a targeting peptide CRGD (Cys-Arg-Gly-Asp), which allows for self-assembly into stable nanoparticles (denoted CRNSe) for self-delivery. Significantly, at a concentration of 12 µg mL-1, CRNSe binds to the active site cysteine of GSH resulting in a thorough depletion of GSH. In contrast, the disulfide-containing analog only causes a slight decrease in GSH level. Moreover, the depletion of GSH inactivates GPX4, ultimately inducing ferroptosis due to the accumulation of lipid peroxide in BxPC-3 cells. Both in vitro and in vivo studies have demonstrated that CRNSe exhibits potent tumor suppressive ability with few side effects on normal tissue. This study validates the anti-tumor mechanism of diselenide-containing polymers in addition to apoptosis and also provides a new strategy for inherently inducing ferroptosis in cancer therapy.
Subject(s)
Ferroptosis , Glutathione , Ferroptosis/drug effects , Humans , Glutathione/metabolism , Animals , Cell Line, Tumor , Mice , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , Nanoparticles/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Polymers/chemistry , Polymers/pharmacology , Mice, Nude , Polycarboxylate Cement/chemistry , Oligopeptides/chemistry , Oligopeptides/pharmacology , Mice, Inbred BALB CABSTRACT
BACKGROUND: The progression of gallbladder cancer (GBC) is accompanied by abnormal fatty acid ß-oxidation (FAO) metabolism. Different types of lipids perform various biological functions. This study aimed to determine the role of acyl carnitines in the molecular mechanisms of GBC progression. METHODS: Distribution of lipids in GBC was described by LC-MS-based lipidomics. Cellular localization, expression level and full-length of lncBCL2L11 were detected using fluorescence in situ hybridization (FISH) assays, subcellular fractionation assay and 5' and 3' rapid amplification of the cDNA ends (RACE), respectively. In vitro and in vivo experiments were used to verify the biological function of lncBCL2L11 in GBC cells. Methylated RNA Immunoprecipitation (MeRIP) was performed to detect the methylation levels of lncBCL2L11. RNA pull-down assay and RNA immunoprecipitation (RIP) assay were used to identify lncBCL2L11 interacting proteins. Co-Immunoprecipitation (Co-IP) and Western blot assay were performed to validate the regulatory mechanism of lncBCL2L11 and THO complex. RESULTS: Acylcarnitines were significantly up-regulated in GBC tissues. High serum triglycerides correlated to decreased survival in GBC patients and promoted tumor migration. LncBCL2L11 was identified in the joint analysis of highly metastatic cells and RNA sequencing data. LncBCl2L11 prevented the binding of THOC6 and THOC5 and causes the degradation of THOC5, thus promoting the accumulation of acylcarnitines in GBC cells, leading to the malignant progression of cancer cells. In addition, highly expressed acylcarnitines stabilized the expression of lncBCL2L11 through N6-methyladenosine methylation (m6A), forming a positive feedback regulation in tumor dissemination. CONCLUSIONS: LncBCL2L11 is involved in gallbladder cancer metastasis through FAO metabolism. High lipid intake is associated with poor prognosis of GBC. Therefore, targeting lncBCL2L11 and its pathway-related proteins or reducing lipid intake may be significant for the treatment of GBC patients.
Subject(s)
Carnitine/analogs & derivatives , Gallbladder Neoplasms , Humans , Gallbladder Neoplasms/genetics , In Situ Hybridization, Fluorescence , RNA , Lipids , Cell Line, Tumor , Cell Proliferation , Gene Expression Regulation, Neoplastic , Nuclear Proteins/metabolism , RNA-Binding Proteins/geneticsABSTRACT
Gemcitabine-based chemotherapy is a cornerstone of standard care for gallbladder cancer (GBC) treatment. Still, drug resistance remains a significant challenge, influenced by factors such as tumor-associated microbiota impacting drug concentrations within tumors. Enterococcus faecium, a member of tumor-associated microbiota, was notably enriched in the GBC patient cluster. In this study, we investigated the biochemical characteristics, catalytic activity, and kinetics of the cytidine deaminase of E. faecium (EfCDA). EfCDA showed the ability to convert gemcitabine to its metabolite 2',2'-difluorodeoxyuridine. Both EfCDA and E. faecium can induce gemcitabine resistance in GBC cells. Moreover, we determined the crystal structure of EfCDA, in its apo form and in complex with 2', 2'-difluorodeoxyuridine at high resolution. Mutation of key residues abolished the catalytic activity of EfCDA and reduced the gemcitabine resistance in GBC cells. Our findings provide structural insights into the molecular basis for recognizing gemcitabine metabolite by a bacteria CDA protein and may provide potential strategies to combat cancer drug resistance and improve the efficacy of gemcitabine-based chemotherapy in GBC treatment.
Subject(s)
Antimetabolites, Antineoplastic , Cytidine Deaminase , Deoxycytidine , Drug Resistance, Neoplasm , Enterococcus faecium , Gallbladder Neoplasms , Gemcitabine , Humans , Antimetabolites, Antineoplastic/metabolism , Antimetabolites, Antineoplastic/pharmacology , Antimetabolites, Antineoplastic/therapeutic use , Bacterial Proteins/metabolism , Bacterial Proteins/genetics , Bacterial Proteins/chemistry , Cell Line, Tumor , Cytidine Deaminase/metabolism , Cytidine Deaminase/genetics , Cytidine Deaminase/chemistry , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Deoxycytidine/metabolism , Deoxycytidine/chemistry , Enterococcus faecium/enzymology , Enterococcus faecium/genetics , Gallbladder Neoplasms/drug therapy , Gallbladder Neoplasms/genetics , Gallbladder Neoplasms/microbiology , Gemcitabine/metabolism , Gemcitabine/pharmacology , Gemcitabine/therapeutic useABSTRACT
Pancreatic cancer (PC) is a highly malignant cancer characterized by poor prognosis, high heterogeneity, and intricate heterocellular systems. Selecting an appropriate experimental model for studying its progression and treatment is crucial. Patient-derived models provide a more accurate representation of tumor heterogeneity and complexity compared to cell line-derived models. This review initially presents relevant patient-derived models, including patient-derived xenografts (PDXs), patient-derived organoids (PDOs), and patient-derived explants (PDEs), which are essential for studying cell communication and pancreatic cancer progression. We have emphasized the utilization of these models in comprehending intricate intercellular communication, drug responsiveness, mechanisms underlying tumor growth, expediting drug discovery, and enabling personalized medical approaches. Additionally, we have comprehensively summarized single-cell analyses of these models to enhance comprehension of intercellular communication among tumor cells, drug response mechanisms, and individual patient sensitivities.
Subject(s)
Organoids , Pancreatic Neoplasms , Single-Cell Analysis , Tumor Microenvironment , Humans , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/metabolism , Single-Cell Analysis/methods , Animals , Organoids/metabolism , Tumor Microenvironment/genetics , Cell Communication/genetics , Precision MedicineABSTRACT
Gallbladder cancer (GBC) is among the most common malignancies of biliary tract system due to its limited treatments. The immunotherapeutic targets for T cells are appealing, however, heterogeneity of T cells hinds its further development. We systematically construct T cell atlas by single-cell RNA sequencing; and utilized the identified gene signatures of high_CNV_T cells to predict molecular subtyping towards personalized therapeutic treatments for GBC. We identified 12 T cell subtypes, where exhausted CD8+ T cells, activated/exhausted CD8+ T cells, and regulatory T cells were predominant in tumors. There appeared to be an inverse relationship between Th17 and Treg populations with Th17 levels significantly reduced, whereas Tregs were concomitantly increased. Furthermore, we first established subtyping criterion to identify three subtypes of GBC based on their pro-tumorigenic microenvironments, e.g., the type 1 group shows more M2 macrophages infiltration, while the type 2 group is infiltrated by highly exhausted CD8+ T cells, B cells and Tregs with suppressive activities. Our study provides valuable insights into T cell heterogeneity and suggests that molecular subtyping based on T cells might provide a potential immunotherapeutic strategy to improve GBC treatment.
Subject(s)
CD8-Positive T-Lymphocytes , Gallbladder Neoplasms , Humans , CD8-Positive T-Lymphocytes/metabolism , Gallbladder Neoplasms/genetics , Gallbladder Neoplasms/therapy , Gallbladder Neoplasms/metabolism , T-Lymphocytes, Regulatory/pathology , Immunotherapy , Macrophages/pathology , Tumor MicroenvironmentABSTRACT
Neutrophils are increasingly recognized as key players in the tumor immune response and are associated with poor clinical outcomes. Despite recent advances characterizing the diversity of neutrophil states in cancer, common trajectories and mechanisms governing the ontogeny and relationship between these neutrophil states remain undefined. Here, we demonstrate that immature and mature neutrophils that enter tumors undergo irreversible epigenetic, transcriptional, and proteomic modifications to converge into a distinct, terminally differentiated dcTRAIL-R1+ state. Reprogrammed dcTRAIL-R1+ neutrophils predominantly localize to a glycolytic and hypoxic niche at the tumor core and exert pro-angiogenic function that favors tumor growth. We found similar trajectories in neutrophils across multiple tumor types and in humans, suggesting that targeting this program may provide a means of enhancing certain cancer immunotherapies.
Subject(s)
Cellular Reprogramming , Neoplasms , Neovascularization, Pathologic , Neutrophils , Humans , Neoplasms/blood supply , Neoplasms/immunology , Neutrophils/immunology , Proteomics , Cellular Reprogramming/genetics , Cellular Reprogramming/immunology , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/immunology , Receptors, TNF-Related Apoptosis-Inducing Ligand/immunology , Epigenesis, Genetic , Hypoxia , Transcription, GeneticABSTRACT
Altered three-dimensional architecture of chromatin influences various genomic regulators and subsequent gene expression in human cancer. However, knowledge of the topological rearrangement of genomic hierarchical layers in cancer is largely limited. Here, by taking advantage of in situ Hi-C, RNA-sequencing, and chromatin immunoprecipitation sequencing (ChIP-seq), we investigated structural reorganization and functional changes in chromosomal compartments, topologically associated domains (TADs), and CCCTC binding factor (CTCF)-mediated loops in gallbladder cancer (GBC) tissues and cell lines. We observed that the chromosomal compartment A/B switch was correlated with CTCF binding levels and gene expression changes. Increased inter-TAD interactions with weaker TAD boundaries were identified in cancer cell lines relative to normal controls. Furthermore, the chromatin short loops and cancer unique loops associated with chromatin remodeling and epithelial-mesenchymal transition activation were enriched in cancer compared with their control counterparts. Cancer-specific enhancer-promoter loops, which contain multiple transcription factor binding motifs, acted as a central element to regulate aberrant gene expression. Depletion of individual enhancers in each loop anchor that connects with promoters led to the inhibition of their corresponding gene expressions. Collectively, our data offer the landscape of hierarchical layers of cancer genome and functional alterations that contribute to the development of GBC.
ABSTRACT
ABSTRACT: Biliary tract cancers (BTC), a heterogeneous disease with poor prognosis, including gallbladder cancer (GBC), intrahepatic cholangiocarcinoma (ICC), and extrahepatic cholangiocarcinoma (ECC). Although surgery is currently the primary regimen to treat BTC, most BTC patients are diagnosed at an advanced stage and miss the opportunity of surgical eradication. As a result, non-surgical therapy serves as the main intervention for advanced BTC. In recent years, immunotherapy has emerged as one of the most promising therapies in a number of solid cancers, and it includes immune checkpoint inhibitors (ICIs) monotherapy or combined therapy, tumor vaccines, oncolytic virus immunotherapy, adoptive cell therapy (ACT), and cytokine therapy. However, these therapies have been practiced in limited clinical settings in patients with BTC. In this review, we focus on the discussion of latest advances of immunotherapy in BTC and update the progress of multiple current clinical trials with different immunotherapies.
Subject(s)
Bile Duct Neoplasms , Biliary Tract Neoplasms , Cholangiocarcinoma , Humans , Biliary Tract Neoplasms/drug therapy , Immunotherapy , Bile Ducts, IntrahepaticABSTRACT
The intrinsic physical and mechanical properties of red blood cells (RBCs), including their geometric and rheological characteristics, can undergo changes in various circulatory and metabolic diseases. However, clinical diagnosis using RBC biophysical phenotypes remains impractical due to the unique biconcave shape, remarkable deformability, and high heterogeneity within different subpopulations. Here, we combine the hydrodynamic mechanisms of fluid-cell interactions in micro circular tubes with a machine learning method to develop a relatively high-throughput microfluidic technology that can accurately measure the shear modulus of the membrane, viscosity, surface area, and volume of individual RBCs. The present method can detect the subtle changes of mechanical properties in various RBC components at continuum scales in response to different doses of cytoskeletal drugs. We also investigate the correlation between glycosylated hemoglobin and RBC mechanical properties. Our study develops a methodology that combines microfluidic technology and machine learning to explore the material properties of cells based on fluid-cell interactions. This approach holds promise in offering novel label-free single-cell-assay-based biophysical markers for RBCs, thereby enhancing the potential for more robust disease diagnosis.
Subject(s)
Erythrocyte Deformability , Erythrocytes , Viscosity , Rheology , Microfluidics/methodsABSTRACT
Gallbladder cancer (GBC) is a major malignant carcinoma of the biliary tract with extremely poor prognosis. Currently, there is no useful therapy strategies for GBC treatment, indicating the unmet mechanism researches for GBC. In this study, our data showed that SNHG15 expression significantly up-regulated and its high expression associated with poor overall survival of patients suffer from GBC. Functional experiments showed that SNHG15 depletion delayed the proliferation and enhanced the apoptosis of GBC tumor cells under the nutrition stress condition, which further confirmed in the subcutaneous xenograft model and liver metastasis model. Mechanistically, SNHG15 could interact with AMPK and facilitate the phosphorylation of AMPK to Tuberous sclerosis complex TSC2, resulting in mTOR suppression and autophagy enhancement, and finally, conferring the GBC cell sustain proliferation under nutrition stress. Taken together, our findings revealed that SNHG15 promotes GBC tumor progression by enhancing the autophagy under poor nutrition tumor microenvironment, which could be a promising targets for GBC.
Subject(s)
Carcinoma , Gallbladder Neoplasms , Humans , AMP-Activated Protein Kinases/metabolism , Cell Line, Tumor , Cell Proliferation/genetics , Gallbladder Neoplasms/genetics , Gallbladder Neoplasms/pathology , Gene Expression Regulation, Neoplastic , Tumor Microenvironment , AnimalsABSTRACT
Cancer stands as a serious malady, posing substantial risks to human well-being and survival. This underscores the paramount necessity to explore and investigate novel antitumor medications. Nitrogen-containing compounds, especially those derived from natural sources, form a highly significant category of antitumor agents. Among these, antitumor agents with six-membered aromatic nitrogen heterocycles have consistently attracted the attention of chemists and pharmacologists. Accordingly, we present a comprehensive summary of synthetic strategies and clinical implications of these compounds in this review. This entails an in-depth analysis of synthesis pathways for pyridine, quinoline, pyrimidine, and quinazoline. Additionally, we explore the historical progression, targets, mechanisms of action, and clinical effectiveness of small molecule inhibitors possessing these structural features.