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BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease harboring significant microenvironment heterogeneity, especially for the macrophages. Tumor-associated macrophages (TAMs) orchestrate PDAC malignancy, but their dynamics during disease progression remains poorly understood. There is a pressing need to identify the molecular mechanism underlying tumor-macrophage interactions and thus design novel therapeutic strategies. METHODS: Herein, we developed an insilico computational method incorporating bulk and single-cell transcriptome profiling to characterize macrophage heterogeneity. CellPhoneDB algorithm was applied to infer macrophage-tumor interaction networks, whereas pseudotime trajectory for dissecting cell evolution and dynamics. RESULTS: We demonstrated myeloid compartment was an interactive hub of tumor microenvironment (TME) essential for PDAC progression. Dimensionality reduction classified seven clusters within the myeloid cells wherein five subsets of macrophages were characterized by diverse cell states and functionality. Remarkably, tissue-resident macrophages and inflammatory monocyte were identified as potential sources of TAMs. Further, we uncovered several ligand-receptor pairs lining tumor cells and macrophages. Among them, HBEGF-CD44, HBEGF-EGFR, LGALS9-CD44, LGALS9-MET, and GRN-EGFR were correlated with worse overall survival. Notably, as in vitro experiments indicated, TAM-derived HBEGF promoted proliferation and invasion of the pancreatic cancer cell line. CONCLUSION: Together, our work deciphered a comprehensive single-cell atlas of the macrophage compartment of PDAC and provided novel macrophage-tumor interaction features with potential value in developing targeted immunotherapies and molecular diagnostics for predicting patient outcome.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/genética , Carcinoma Ductal Pancreático/genética , Macrófagos , Comunicação Celular/genética , Receptores ErbB , Microambiente Tumoral/genética , Neoplasias PancreáticasRESUMO
We have been interested in the development of rubisco-based biomimetic systems for reversible CO2 capture from air. Our design of the chemical CO2 capture and release (CCR) system is informed by the understanding of the binding of the activator CO2 (A CO2 ) in rubisco (ribulose-1,5-bisphosphate carboxylase/oxygenase). The active site consists of the tetrapeptide sequence Lys-Asp-Asp-Glu (or KDDE) and the Lys sidechain amine is responsible for the CO2 capture reaction. We are studying the structural chemistry and the thermodynamics of CO2 capture based on the tetrapeptide CH3 CO-KDDE-NH2 ("KDDE") in aqueous solution to develop rubisco mimetic CCR systems. Here, we report the results of 1 H NMR and 13 C NMR analyses of CO2 capture by butylamine and by KDDE. The carbamylation of butylamine was studied to develop the NMR method and with the protocol established, we were able to quantify the oligopeptide carbamylation at much lower concentration. We performed a pH profile in the multi equilibrium system and measured amine species and carbamic acid/carbamate species by the integration of 1 H NMR signals as a function of pH in the range 8≤pH≤11. The determination of ΔG1 (R) for the reaction R-NH2 +CO2 â â ${ \mathbin{{\stackrel{\textstyle\rightarrow} { {\smash{\leftarrow}\vphantom{_{\vbox to.5ex{\vss}}}} } }} }$ R-NH-COOH requires the solution of a multi-equilibrium equation system, which accounts for the dissociation constants K2 and K3 controlling carbonate and bicarbonate concentrations, the acid dissociation constant K4 of the conjugated acid of the amine, and the acid dissociation constant K5 of the alkylcarbamic acid. We show how the multi-equilibrium equation system can be solved with the measurements of the daughter/parent ratio X, the knowledge of the pH values, and the initial concentrations [HCO3 - ]0 and [R-NH2 ]0 . For the reaction energies of the carbamylations of butylamine and KDDE, our best values are ΔG1 (Bu)=-1.57â kcal/mol and ΔG1 (KDDE)=-1.17â kcal/mol. Both CO2 capture reactions are modestly exergonic and thereby ensure reversibility in an energy-efficient manner. These results validate the hypothesis that KDDE-type oligopeptides may serve as reversible CCR systems in aqueous solution and guide designs for their improvement.
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Tumour-associated macrophages (TAMs) abundantly infiltrate high-grade gliomas and orchestrate immune response, but their diversity in isocitrate dehydrogenase (IDH)-differential grade 4 gliomas remains largely unknown. This study aimed to dissect the transcriptional states, spatial distribution, and clinicopathological significance of distinct monocyte-derived TAM (Mo-TAM) and microglia-derived TAM (Mg-TAM) clusters across glioblastoma-IDH-wild type and astrocytoma-IDH-mutant-grade 4 (Astro-IDH-mut-G4). Single-cell RNA sequencing was performed on four cases of human glioblastoma and three cases of Astro-IDH-mut-G4. Cell clustering, single-cell regulatory network inference, and gene set enrichment analysis were performed to characterize the functional states of myeloid clusters. The spatial distribution of TAM subsets was determined in human glioma tissues using multiplex immunostaining. The prognostic value of different TAM-cluster specific gene sets was evaluated in the TCGA glioma cohort. Profiling and unbiased clustering of 24,227 myeloid cells from glioblastoma and Astro-IDH-mut-G4 identified nine myeloid cell clusters including monocytes, six Mo/Mg-TAM subsets, dendritic cells, and proliferative myeloid clusters. Different Mo/Mg-TAM clusters manifest functional and transcriptional diversity controlled by specific regulons. Multiplex immunostaining of subset-specific markers identified spatial enrichment of distinct TAM clusters at peri-vascular/necrotic areas in tumour parenchyma or at the tumour-brain interface. Glioblastoma harboured a substantially higher number of monocytes and Mo-TAM-inflammatory clusters, whereas Astro-IDH-mut-G4 had a higher proportion of TAM subsets mediating antigen presentation. Glioblastomas with a higher proportion of monocytes exhibited a mesenchymal signature, increased angiogenesis, and worse patient outcome. Our findings provide insight into myeloid cell diversity and its clinical relevance in IDH-differential grade 4 gliomas, and may serve as a resource for immunotherapy development. © 2022 The Pathological Society of Great Britain and Ireland.
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Astrocitoma , Neoplasias Encefálicas , Glioblastoma , Glioma , Astrocitoma/genética , Astrocitoma/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Glioblastoma/genética , Glioblastoma/patologia , Glioma/genética , Humanos , Isocitrato Desidrogenase/genética , Mutação , Macrófagos Associados a TumorRESUMO
Glioma stem cells (GSCs) are self-renewing tumor cells with multi-lineage differentiation potential and the capacity of construct glioblastoma (GBM) heterogenicity. Mitochondrial morphology is associated with the metabolic plasticity of GBM cells. Previous studies have revealed distinct mitochondrial morphologies and metabolic phenotypes between GSCs and non-stem tumor cells (NSTCs), whereas the molecules regulating mitochondrial dynamics in GBM cells are largely unknown. Herein, we report that carnitine palmitoyltransferase 1A (CPT1A) is preferentially expressed in NSTCs, and governs mitochondrial dynamics and GSC differentiation. Expressions of CPT1A and GSC marker CD133 were mutually exclusive in human GBMs. Overexpression of CPT1A inhibited GSC self-renewal but promoted mitochondrial fusion. In contrast, disruption of CPT1A in NSTCs promoted mitochondrial fission and reprogrammed NSTCs toward GSC feature. Mechanistically, CPT1A overexpression increased the phosphorylation of dynamin-related protein 1 at Ser-637 to promote mitochondrial fusion. In vivo, CPT1A overexpression decreased the percentage of GSCs, impaired GSC-derived xenograft growth and prolonged tumor-bearing mice survival. Our work identified CPT1A as a critical regulator of mitochondrial dynamics and GSC differentiation, indicating that CPT1A could be developed as a molecular target for GBM cell-differentiation strategy.
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Neoplasias Encefálicas , Carnitina O-Palmitoiltransferase , Glioblastoma , Glioma , Dinâmica Mitocondrial , Animais , Neoplasias Encefálicas/metabolismo , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Linhagem Celular Tumoral , Glioblastoma/metabolismo , Glioma/metabolismo , Humanos , Camundongos , Células-Tronco Neoplásicas/metabolismoRESUMO
Glioma progression is accompanied with increased tumor tissue stiffness, yet the underlying mechanisms are unclear. Herein, we employed atomic force microscopy analysis to show that tissue stiffness was higher in isocitrate dehydrogenase (IDH)-wild type gliomas than IDH-mutant gliomas. Bioinformatic analyses revealed that tissue inhibitor of metalloproteinase-1 (TIMP1) was one of the preferentially upregulated genes in IDH-wild type gliomas as compared to IDH-mutant gliomas, and its higher expression indicated worse prognosis of glioma patients. TIMP1 intensity determined by immunofluorescence staining on glioma tissues positively correlated with glioma tissue stiffness. Mechanistically, TIMP1 expression was positively correlated with the gene expression of two predominant extracellular matrix components, tenascin C and fibronectin, both of which were also highly expressed in IDH-wild type gliomas. By introducing IDH1-R132H-containing vectors into human IDH1-wild type glioma cells to obtain an IDH1-mutant cell line, we found that IDH1 mutation increased the TIMP1 promoter methylation through methylation-specific PCR. More importantly, IDH1-R132H mutation decreased both the expression of TIMP1, fibronectin, tenascin C, and the tumor tissue stiffness in IDH1-mutant glioma xenografts in contrast to IDH1-wild type counterparts. Moreover, TIMP1 knockdown in IDH-wild type glioma cells inhibited the expression of tenascin C and fibronectin, and decreased tissue stiffness in intracranial glioma xenografts. Conclusively, we revealed an IDH mutation status-mediated mechanism in regulating glioma tissue stiffness through modulating TIMP1 and downstream extracellular matrix components.
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Neoplasias Encefálicas , Glioma , Humanos , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Fibronectinas/genética , Neoplasias Encefálicas/metabolismo , Tenascina/genética , Inibidor Tecidual de Metaloproteinase-1/genética , Glioma/metabolismo , Mutação , Matriz Extracelular/metabolismoRESUMO
Immunochromatography testing strips (ICTs) promise to become the point-of-care test format for early diagnosis due to their convenience, low cost, and simplification. However, the insufficient signal intensity and limited sensitivity of this format hamper their application. Herein, we overcame these limitations by integrating rod-like ferric oxyhydroxide (ß-FeOOH) nanoparticles with ICTs. By varying the concentration of PEI, a one-pot, mild-temperature hydrolysis method was adapted for the synthesis and morphology regulation of ß-FeOOH nanorod. Due to the excellent enzyme-like catalytic activity toward peroxidase substrates (TMB) in the presence of hydrogen peroxide (H2O2), the ß-FeOOH nanorod in ICTs served as a signal generator and the nanozyme for signal amplification. The proof-of-concept work was performed for the detection of human chorionic gonadotropin (hCG). A two fold improvement of detection sensitivity was achieved compared to the sensitivity of conventional Au NPs-based ICTs. These results show that ß-FeOOH-based ICT has a potential application in POCT detection in clinical diagnostics.
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Gonadotropina Coriônica/química , Cromatografia de Afinidade/instrumentação , Compostos Férricos/química , Nanotubos/química , Peroxidase/metabolismo , Cromatografia de Afinidade/métodos , Peroxidase/química , Sensibilidade e Especificidade , TemperaturaRESUMO
Rubisco is the enzyme responsible for CO2 fixation in nature, and it is activated by CO2 addition to the amine group of its lysine 201 side chain. We are designing rubisco-based biomimetic systems for reversible CO2 capture from ambient air. The oligopeptide biomimetic capture systems are employed in aqueous solution. To provide a solid foundation for the experimental solution-phase studies of the CO2 capture reaction, we report here the results of computational studies of the thermodynamics of CO2 capture by small alkylamines in aqueous solution. We studied CO2 addition to methyl-, ethyl-, propyl-, and butylamine with the consideration of the full conformational space for the amine and the corresponding carbamic acids and with the application of an accurate solvation model for the potential energy surface analyses. The reaction energies of the carbamylation reactions were determined based on just the most stable structures (MSS) and based on the ensemble energies computed with the Boltzmann distribution (BD), and it is found that ΔGBD ≈ ΔGMSS. The effect of the proper accounting for the molecular translational entropies in solution with the Wertz approach are much more significant, and the free energy of the capture reactions ΔWGBD is more negative by 2.9 kcal/mol. Further accounting for volume effects in solution results in our best estimates for the reaction energies of the carbamylation reactions of ΔWABD = -5.4 kcal/mol. The overall difference is ΔGBD - ΔWABD = 2.4 kcal/mol for butylamine carbamylation. The full conformational space analyses inform about the conformational isomerizations of carbamic acids, and we determined the relevant rotational profiles and their transition-state structures. Our detailed studies emphasize that, more generally, solution-phase reaction energies should be evaluated with the Helmholtz free energy and can be affected substantially by solution effects on translational entropies.
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A polymer/silica hybrid 3D waveguide thermo-optic (TO) mode switch based on cascaded asymmetric directional couplers (ADCs) is theoretically designed and simulated, where the spatial modes of a few-mode silica waveguide can be switched to various single-mode polymer waveguides placed above the few-mode silica waveguide. A beam propagation method is employed to optimize the dimensional parameters of the mode switch to convert the LP11a and LP11b modes of the few-mode silica waveguide to the LP01 mode of two single-mode polymer waveguides using the cascaded ADC 1 and ADC 2. The coupling ratios are higher than 96.4% (93.4%) and 95.1% (92.8%) for the ADC 1 and ADC 2, respectively, under the TE (TM) polarization within the wavelength range from 1530 to 1570 nm, which shows good wavelength independence. Furthermore, the monolayer graphene is introduced as the heating electrode and buried on the surface of the polymer core to increase the heating efficiency and reduce the power consumption. The power consumption for ADC 1 and ADC 2 is 16.69 mW and 17.35 mW, respectively. Compared to the traditional TO switch with an aluminum (Al) heating electrode, the heating efficiency of the presented device can be improved by â¼30%. Moreover, the response speed of the TO mode switch with a 3D waveguide structure was also significantly improved. Compared to the device with Al electrodes, the introduced graphene electrodes can improve the switching speed of the device by â¼60%. The presented TO mode switch with its small size and easy integration should find applications in reconfigurable mode division multiplexing systems.
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Glioblastoma multiforme (GBM) is characterized by highly invasive growth, which leads to extensive infiltration and makes complete tumor excision difficult. Since cytoskeleton proteins are related to leading processes and cell motility, and through analysis of public GBM databases, we determined that an actin-interacting protein, zyxin (ZYX), may involved in GBM invasion. Our own glioma cohort as well as the cancer genome atlas (TCGA), Rembrandt, and Gravendeel databases consistently showed that increased ZYX expression was related to tumor progression and poor prognosis of glioma patients. In vitro and in vivo experiments further confirmed the oncogenic roles of ZYX and demonstrated the role of ZYX in GBM invasive growth. Moreover, RNA-seq and mass-spectrum data from GBM cells with or without ZYX revealed that stathmin 1 (STMN1) was a potential target of ZYX. Subsequently, we found that both mRNA and protein levels of STMN1 were positively regulated by ZYX. Functionally, STMN1 not only promoted invasion of GBM cells but also rescued the invasion repression caused by ZYX loss. Taken together, our results indicate that high ZYX expression was associated with worse prognosis and highlighted that the ZYX-STMN1 axis might be a potential therapeutic target for GBM.
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Neoplasias Encefálicas , Glioblastoma , Invasividade Neoplásica/patologia , Zixina , Animais , Biomarcadores Tumorais , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Linhagem Celular Tumoral , Movimento Celular/genética , Técnicas de Silenciamento de Genes , Glioblastoma/diagnóstico , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/mortalidade , Humanos , Camundongos , Camundongos Endogâmicos NOD , Prognóstico , Estatmina/análise , Estatmina/genética , Estatmina/metabolismo , Zixina/análise , Zixina/genética , Zixina/metabolismoRESUMO
Neonatal early-onset sepsis (EOS) is associated with high morbidity and mortality. Accurate early diagnosis is crucial for prompt treatment and a better clinical outcome. We aimed to identify new biomarkers for the diagnosis of EOS. A total of 152 neonates with a risk of EOS were divided into an EOS group and a non-EOS group according to the conventional diagnostic criteria. Blood samples were collected within 0-24, 24-48, and 48-72 h after birth. Serum levels of progranulin (PGRN), interleukin (IL)-33, IL-17a, IL-23, IL-6, tumor necrosis factors α (TNF-α), interferon γ (IFN-γ), granulocyte-macrophage colony-stimulating factor (GM-CSF), procalcitonin (PCT), and C-reactive protein (CRP) were determined. PGRN levels were significantly elevated in the EOS neonates compared with the levels in the non-EOS neonates (1.53 vs. 0.77 ng/ml (median), P < 0.001), with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.76 (P < 0.001). Compared with PGRN, IL-33, IL-17a, IL-23, IL-6, PCT, and CRP showed significant (AUC > 0.70) but slightly less predictive power for EOS within the same time range. Stepwise multivariate regression analysis identified PGRN, IL-33, and PCT as independent predictors of EOS. In addition, the combined measurements of PGRN, IL-33, and PCT showed significantly higher predictive power for EOS than any of the three markers alone. PGRN showed greater efficacy for predicting EOS than the traditional markers PCT and CRP as well as other potential markers tested in this study. PGRN may serve as an effective biomarker for the early diagnosis of EOS.
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Interleucina-33/sangue , Sepse Neonatal/sangue , Sepse Neonatal/diagnóstico , Pró-Calcitonina/sangue , Progranulinas/sangue , Biomarcadores/sangue , Feminino , Humanos , Recém-Nascido , Masculino , Análise Multivariada , Curva ROC , Análise de Regressão , Fator de Necrose Tumoral alfaRESUMO
The simultaneous determination of two binding parameters for metal ions on an immobilized metal affinity chromatography column was performed by frontal chromatography. In this study, the binding parameters of Cu(2+) to l-glutamic acid were measured, the metal ion-binding characteristics of the complex ligand were evaluated. The linear correlation coefficients were all greater than 99%, and the relative standard deviations of two binding parameters were 0.58 and 0.059%, respectively. The experiments proved that the frontal chromatography method was accurate, reproducible, and could be used to determine the metal-binding parameters of the affinity column. The effects of buffer pH, type, and concentration on binding parameters were explored by uniform design experiment. Regression, matching and residual analyses of the models were performed. Meanwhile, the optimum-binding conditions of Cu(2+) on the l-glutamic acid-silica column were obtained. Under these binding conditions, observations and regression values of two parameters were similar, and the observation values were the best. The results demonstrated that high intensity metal affinity column could be effectively prepared by measuring and evaluating binding parameters using frontal chromatography combined with a uniform design experiment. The present work provided a new mode for evaluating and preparing immobilized metal affinity column with good metal-binding behaviors.
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Ovarian cancer, ranking as the seventh most prevalent malignancy among women globally, faces significant challenges in diagnosis and therapeutic intervention. The difficulties in early detection are amplified by the limitations and inefficacies inherent in current screening methodologies, highlighting a pressing need for more efficacious diagnostic and treatment strategies. Phage display technology emerges as a pivotal innovation in this context, utilizing extensive phage-peptide libraries to identify ligands with specificity for cancer cell markers, thus enabling precision-targeted therapeutic strategies. This technology promises a paradigm shift in ovarian cancer management, concentrating on targeted drug delivery systems to improve treatment accuracy and efficacy while minimizing adverse effects. Through a meticulous review, this paper evaluates the revolutionary potential of phage display in enhancing ovarian cancer therapy, representing a significant advancement in combating this challenging disease. Phage display technology is heralded as an essential instrument for developing effective immunodiagnostic and therapeutic approaches in ovarian cancer, facilitating early detection, precision-targeted medication, and the implementation of customized treatment plans.
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Técnicas de Visualização da Superfície Celular , Neoplasias Ovarianas , Biblioteca de Peptídeos , Feminino , Humanos , Neoplasias Ovarianas/terapia , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/imunologia , Biomarcadores Tumorais , Animais , Imunoterapia/métodosRESUMO
In the advancement of Inflammatory Bowel Disease (IBD) treatment, existing therapeutic methods exhibit limitations; they do not offer a complete cure for IBD and can trigger adverse side effects. Consequently, the exploration of novel therapies and multifaceted treatment strategies provides patients with a broader range of options. Within the framework of IBD, gut microbiota plays a pivotal role in disease onset through diverse mechanisms. Bacteriophages, as natural microbial regulators, demonstrate remarkable specificity by accurately identifying and eliminating specific pathogens, thus holding therapeutic promise. Although clinical trials have affirmed the safety of phage therapy, its efficacy is prone to external influences during storage and transport, which may affect its infectivity and regulatory roles within the microbiota. Improving the stability and precise dosage control of bacteriophages-ensuring robustness in storage and transport, consistent dosing, and targeted delivery to infection sites-is crucial. This review thoroughly explores the latest developments in IBD treatment and its inherent challenges, focusing on the interaction between the microbiota and bacteriophages. It highlights bacteriophages' potential as microbiome modulators in IBD treatment, offering detailed insights into research on bacteriophage encapsulation and targeted delivery mechanisms. Particular attention is paid to the functionality of various carrier systems, especially regarding their protective properties and ability for colon-specific delivery. This review aims to provide a theoretical foundation for using bacteriophages as microbiome modulators in IBD treatment, paving the way for enhanced regulation of the intestinal microbiota.
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Bacteriófagos , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Terapia por Fagos , Humanos , Terapia por Fagos/métodos , Doenças Inflamatórias Intestinais/terapia , Bacteriófagos/fisiologia , AnimaisRESUMO
Renal cell carcinoma (RCC) is recognized as one of the three primary malignant tumors affecting the urinary system, posing a significant risk to human health and life. Despite advancements in understanding RCC, challenges persist in its diagnosis and treatment, particularly in early detection and diagnosis due to issues of low specificity and sensitivity. Consequently, there is an urgent need for the development of effective strategies to enhance diagnostic accuracy and treatment outcomes for RCC. In recent years, with the extensive research on materials for applications in the biomedical field, some materials have been identified as promising for clinical applications, e.g., in the diagnosis and treatment of many tumors, including RCC. Herein, we summarize the latest materials that are being studied and have been applied in the early diagnosis and treatment of RCC. While focusing on their adjuvant effects, we also discuss their technical principles and safety, thus highlighting the value and potential of their application. In addition, we also discuss the limitations of the application of these materials and possible future directions, providing new insights for improving RCC diagnosis and treatment.
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Monocyte-derived tumor-associated macrophages (Mo-TAMs) intensively infiltrate diffuse gliomas with remarkable heterogeneity. Using single-cell transcriptomics, we chart a spatially resolved transcriptional landscape of Mo-TAMs across 51 patients with isocitrate dehydrogenase (IDH)-wild-type glioblastomas or IDH-mutant gliomas. We characterize a Mo-TAM subset that is localized to the peri-necrotic niche and skewed by hypoxic niche cues to acquire a hypoxia response signature. Hypoxia-TAM destabilizes endothelial adherens junctions by activating adrenomedullin paracrine signaling, thereby stimulating a hyperpermeable neovasculature that hampers drug delivery in glioblastoma xenografts. Accordingly, genetic ablation or pharmacological blockade of adrenomedullin produced by Hypoxia-TAM restores vascular integrity, improves intratumoral concentration of the anti-tumor agent dabrafenib, and achieves combinatorial therapeutic benefits. Increased proportion of Hypoxia-TAM or adrenomedullin expression is predictive of tumor vessel hyperpermeability and a worse prognosis of glioblastoma. Our findings highlight Mo-TAM diversity and spatial niche-steered Mo-TAM reprogramming in diffuse gliomas and indicate potential therapeutics targeting Hypoxia-TAM to normalize tumor vasculature.
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Adrenomedulina , Neoplasias Encefálicas , Glioblastoma , Macrófagos Associados a Tumor , Humanos , Glioblastoma/patologia , Glioblastoma/tratamento farmacológico , Glioblastoma/irrigação sanguínea , Glioblastoma/genética , Glioblastoma/metabolismo , Animais , Adrenomedulina/genética , Adrenomedulina/metabolismo , Camundongos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Macrófagos Associados a Tumor/metabolismo , Neovascularização Patológica/genética , Microambiente Tumoral , Isocitrato Desidrogenase/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Linhagem Celular Tumoral , Macrófagos/metabolismo , Hipóxia CelularRESUMO
Cholera, a persistent global public health concern, continues to cause outbreaks in approximately 30 countries and territories this year. The imperative to safeguard water sources and food from Vibrio cholerae, the causative pathogen, remains urgent. The bacterium is mainly disseminated via ingestion of contaminated water or food. Despite the plate method's gold standard status for detection, its time-consuming nature, taking several days to provide results, remains a challenge. The emergence of novel virulence serotypes raises public health concerns, potentially compromising existing detection methods. Hence, exploiting Vibrio cholerae toxin testing holds promise due to its inherent stability. Immunobiosensors, leveraging antibody specificity and sensitivity, present formidable tools for detecting diverse small molecules, encompassing drugs, hormones, toxins, and environmental pollutants. This review explores cholera toxin detection, highlighting phage display-based nano immunosensors' potential. Engineered bacteriophages exhibit exceptional cholera toxin affinity, through specific antibody fragments or mimotopes, enabling precise quantification. This innovative approach promises to reshape cholera toxin detection, offering an alternative to animal-derived methods. Harnessing engineered bacteriophages aligns with ethical detection and emphasizes sensitivity and accuracy, a pivotal stride in the evolution of detection strategies. This review primarily introduces recent advancements in phage display-based nano immunosensors for cholera toxin, encompassing technical aspects, current challenges, and future prospects.
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Bacteriófagos , Cólera , Vibrio cholerae , Humanos , Toxina da Cólera , Cólera/microbiologia , ÁguaRESUMO
BACKGROUND: Tumors of the gastrointestinal tract impose a substantial healthcare burden due to their prevalence and challenging prognosis. METHODS: We conducted a review of peer-reviewed scientific literature using reputable databases (PubMed, Scopus, Web of Science) with a focus on oncolytic virus therapy within the context of gastrointestinal tumors. Our search covered the period up to the study's completion in June 2023. INCLUSION AND EXCLUSION CRITERIA: This study includes articles from peer-reviewed scientific journals, written in English, that specifically address oncolytic virus therapy for gastrointestinal tumors, encompassing genetic engineering advances, combined therapeutic strategies, and safety and efficacy concerns. Excluded are articles not meeting these criteria or focusing on non-primary gastrointestinal metastatic tumors. RESULTS: Our review revealed the remarkable specificity of oncolytic viruses in targeting tumor cells and their potential to enhance anti-tumor immune responses. However, challenges related to safety and efficacy persist, underscoring the need for ongoing research and improvement. CONCLUSION: This study highlights the promising role of oncolytic virus therapy in enhancing gastrointestinal tumor treatments. Continued investigation and innovative combination therapies hold the key to reducing the burden of these tumors on patients and healthcare systems.
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Neoplasias Gastrointestinais , Neoplasias , Terapia Viral Oncolítica , Vírus Oncolíticos , Humanos , Terapia Viral Oncolítica/efeitos adversos , Vírus Oncolíticos/genética , Neoplasias/patologia , Neoplasias Gastrointestinais/terapia , Engenharia Genética , ImunoterapiaRESUMO
Immune checkpoint inhibitors (ICIs) have been an encouraging treatment method in non-small cell lung cancer (NSCLC). However, bone and liver metastases are considered to restrain immunotherapy efficacy. Since serum alkaline phosphatase (ALP) is associated with bone and liver metastases, it was investigated whether serum ALP could be a novel biomarker to predict the efficacy of ICIs treatment. In the present study, 143 patients with NSCLC receiving ICIs treatment were retrospectively analyzed. The objective response rate (ORR) was compared between the ALP high and low groups, bone metastasis and non-bone metastasis groups, and liver metastasis or non-liver metastasis groups. The associations between clinical characteristics, including ALP level, bone or liver metastasis and median progression-free survival (mPFS) time were analyzed by univariate and multivariate Cox regression analysis. It was found that bone metastasis was associated with a lower ORR (24 vs. 43%; P<0.05) and shorter mPFS (10.2 vs. 17.3 months; P=0.010) in patients with NSCLC receiving ICIs. Liver metastasis was associated with lower ORR (22 vs. 38%; P<0.05), but not with mPFS (P=0.119). The ALP level was higher in patients with bone or liver metastasis than in those without (119.6 or 103.6 vs. 83.3 U/l, respectively; P<0.05). Higher ALP levels were also associated with bone or liver metastasis, lower ORR (20 vs. 39%; P<0.05) and shorter mPFS (8.5 vs. 15.4 months; P=0.009). Cox regression analysis demonstrated that ALP was an independent prognostic indicator of mPFS (hazard ratio, 1.856; 95% confidence interval, 1.030-3.343; P=0.040). In conclusion, pretreatment levels of serum ALP might be a predictive indicator of clinical outcome in patients with NSCLC after ICIs treatment.
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OBJECTIVE: Menstrual lifespan (ML) is an important biological characteristic for women. Rare evidence has established the associations between menopause age (MI), geriatric depression and healthy longevity. This study aimed to address these associations in Chinese oldest-old and centenarian women, and explore their related factors in order to provide strategy support for healthy aging. METHODS: The China Hainan Centenarian Cohort Study provides a population-based sample in Hainan, China. A total of 723 women including 318 centenarian women and 405 oldest-old women aged 80-99 years were included in this study. Data on demographic information were collected using a structured questionnaire. Physical examination and blood samples were obtained following standard procedure. Geriatric Depression Scale (GDS-15) was used to evaluate depressive symptoms for all participants. RESULTS: The proportions of participants with depression and longevity were 19.78 % (143 older adults) and 43.98 % (318 older adults), respectively. After adjusting for a wide range of other covariates in multiple logistic regression analyses, ML was positively and significantly associated with depression and longevity [Exp(ß) 1.076 and 1.121; P < 0.05 for all]. In multiple linear regression analyses, there were significantly positive associations of ML with GDS-15 (ß = 0.061) and age (ß = 0.238, p < 0.05 for all) after adjusting for all covariates. CONCLUSIONS: This study provides epidemiological evidence that menstrual lifespan has positive associations with geriatric depression and healthy longevity in Chinese oldest-old and centenarian women. Future researches should focus on the effects of intervening MI on psychological health and successful longevity.
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Centenários , Depressão , Longevidade , Menstruação , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , China/epidemiologia , Estudos de Coortes , Depressão/epidemiologia , População do Leste AsiáticoRESUMO
Dyslipidemia and cognitive impairment are common among old adults and the occurrence of them rises exponentially with increasing age. Evidences of the relationships between serum lipids and cognitive impairment are inconsistent or equivocal among older adults. This study aimed to investigate the associations between lipid profiles and late-life cognitive impairment among oldest-old and centenarian adults. In this cross-sectional study, serum lipids were biochemically measured among 606 oldest-old adults and 653 centenarians, and cognitive function was evaluated using mini-mental state examination (MMSE). Multivariate linear and logistic regression analyses were performed to explore the associations between serum lipids and cognitive impairment. Results showed participants with cognitive impairment had lower total cholesterol (TC) levels compared with those without cognitive impairment (p < 0.05). TC levels were positively associated with MMSE (p < 0.05). Furthermore, a negative association was observed between TC levels and cognitive impairment (p for trend = 0.002). This negative association remained statistically significant after adjusting for confounders (p for trend = 0.028). These results suggested that older adults with higher TC levels were likely to have better cognitive function. Taking immoderate cholesterol-lowering drugs among older adults is questionable and requires investigation, and cognitive performance of old adults with lower TC levels deserves more attention.