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Protein kinase 2 (CK2) is an enzyme ubiquitously present and exhibits extensive kinase activity. It has been strongly linked to tumor progression through the abnormal phosphorylation of key proteins. Research has consistently demonstrated that CK2 is deregulated in various cancer types, with enhanced protein expression and nuclear distribution in tumor cells. CK2 plays a crucial role in a complex network that promotes cell infiltration, migration, proliferation, apoptosis, and cancer progression through multiple pathways, including PI3K/AKT, JAK2/STAT3, ATF4/CDKN1, and HSP90/Cdc37. In addition to its role in cancer growth, there is mounting evidence that CK2 may also affect the immunological dynamics of cancer by altering immune cell functions within the tumor microenvironment, thus facilitating tumor immune evasion. Recent research has increasingly focused on CK2, recognizing it as a therapeutic objective for oncological interventions. This review will critically examine the structure and signaling pathways of CK2, highlighting the significance of further research aimed at enhancing our understanding of the CK2 machinery. Finally, we conclude by refining therapeutic options, notably transitioning from non-pharmacological techniques to strategic CK2 inhibitor use. This development shortens the path to the desired outcome, establishing a pioneering standard in cancer therapy.
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Astragalus polysaccharide (APS) derived from A. membranaceus plays a crucial role in traditional Chinese medicine. These polysaccharides have shown antitumor effects and are considered safe. Thus, they have become increasingly important in cancer immunotherapy. APS can limit the spread of cancer by influencing immune cells, promoting cell death, triggering cancer cell autophagy, and impacting the tumor microenvironment. When used in combination with other therapies, APS can enhance treatment outcomes and reduce toxicity and side effects. APS combined with immune checkpoint inhibitors, relay cellular immunotherapy, and cancer vaccines have broadened the application of cancer immunotherapy and enhanced treatment effectiveness. By summarizing the research on APS in cancer immunotherapy over the past two decades, this review elaborates on the anticancer mechanism of APS and its use in cancer immunotherapy and clinical trials. Considering the multiple roles of APS, this review emphasizes the importance of using APS as an adjunct to cancer immunotherapy and compares other polysaccharides with APS. This discussion provides insights into the specific mechanism of action of APS, reveals the molecular targets of APS for developing effective clinical strategies, and highlights the wide application of APS in clinical cancer therapy in the future.
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Immunotherapy has emerged as a potential approach for breast cancer treatment. However, the rigid stromal microenvironment and low immunogenicity of breast tumors strongly reduce sensitivity to immunotherapy. To sensitize patients to breast cancer immunotherapy, hyaluronic acid-modified zinc peroxide-iron nanocomposites (Fe-ZnO2@HA, abbreviated FZOH) were synthesized to remodel the stromal microenvironment and increase tumor immunogenicity. The constructed FZOH spontaneously generated highly oxidative hydroxyl radicals (·OH) that degrade hyaluronic acid (HA) in the tumor extracellular matrix (ECM), thereby reshaping the tumor stromal microenvironment and enhancing blood perfusion, drug penetration, and immune cell infiltration. Furthermore, FZOH not only triggers pyroptosis through the activation of the caspase-1/GSDMD-dependent pathway but also induces ferroptosis through various mechanisms, including increasing the levels of Fe2+ in the intracellular iron pool, downregulating the expression of FPN1 to inhibit iron efflux, and activating the p53 signaling pathway to cause the failure of the SLC7A11-GSH-GPX4 signaling axis. Upon treatment with FZOH, 4T1 cancer cells undergo both ferroptosis and pyroptosis, exhibiting a strong immunogenic response. The remodeling of the tumor stromal microenvironment and the immunogenic response of the cells induced by FZOH collectively compensate for the limitations of cancer immunotherapy and significantly enhance the antitumor immune response to the immune checkpoint inhibitor αPD-1. This study proposes a perspective for enhancing immune therapy for breast cancer.
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Neoplasias da Mama , Neoplasias , Humanos , Feminino , Neoplasias da Mama/terapia , Ácido Hialurônico , Imunoterapia , Peróxidos , Zinco , Microambiente Tumoral , Linhagem Celular TumoralRESUMO
Oncolytic bacteria can trigger innate immune activity. However, the antitumour efficacy of inactivated bacteria is poor, and attenuated live bacteria pose substantial safety risks. Here we show that intratumourally injected paraformaldehyde-fixed bacteria coated with manganese dioxide potently activate innate immune activity, modulate the immunosuppressive tumour microenvironment and trigger tumour-specific immune responses and abscopal antitumour responses. A single intratumoural administration of mineralized Salmonella typhimurium suppressed the growth of multiple types of subcutaneous and orthotopic tumours in mice, rabbits and tree shrews and protected the cured animals against tumour rechallenge. We also show that mineralized bacteria can be administered via arterial embolization to treat orthotopic liver cancer in rabbits. Our findings support the further translational testing of oncolytic mineralized bacteria as potent and safe antitumour immunotherapeutics.
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Imunoterapia , Salmonella typhimurium , Microambiente Tumoral , Animais , Salmonella typhimurium/fisiologia , Camundongos , Coelhos , Imunoterapia/métodos , Óxidos , Compostos de Manganês/química , Linhagem Celular Tumoral , Humanos , Feminino , Imunidade InataRESUMO
Objectives: To understand the sleep quality and its influencing factors in patients with type 2 diabetes mellitus (T2DM) who suffered diabetic peripheral neuropathy (DPN), and provide evidence for clinicians to carry out comprehensive intervention measures to improve the sleep quality of patients. Methods: Patients who were admitted to the Endocrinology Department of Affiliated Hospital of Zunyi Medical University were recruited from May to December 2022, and the investigation were conducted by face-to-face interview. The questionnaires included PSQI questionnaire and influencing factors, such as lifestyle and health status. Results: Among the 193 patients, 40.4% of the patients never took physical examination, 56.5% of the patients had duration of illness greater than 5 years, 61.7% of the patients had had an operation, 10.4% of the patients had bad dietary status, and 55.4% of the patients had physical pain. In addition, the PSQI general score was 8.34 ± 3.98, the occurrence rate of poor sleep quality (PSQI ≥ 8) was 54.4%, and the results showed that sleep quality of the physical pain group was worse than the no pain group. Moreover, the results of multivariate analysis revealed that the factors affecting sleep quality were lower frequency of exercise, bad dietary status, lower frequency of physical examination, longer duration of illness, and smoking, and the OR and 95% CI were [1.40, 1.04â¼1.89], [3.42, 1.86â¼6.29], [1.49, 1.01â¼2.20], [1.78, 1.09â¼2.92], [2.38, 1.17â¼4.88], respectively. Conclusion: Patients with DPN have higher risk of poor sleep quality. Moreover, there were many risk factors associated with poor sleep quality, clinicians and health policymakers should timely detect and effectively intervene in these factors to improve the sleep quality, which is important to enhance the quality of life of T2DM patients complicated with DPN.
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Diabetes Mellitus Tipo 2 , Neuropatias Diabéticas , Humanos , Diabetes Mellitus Tipo 2/complicações , Neuropatias Diabéticas/epidemiologia , Qualidade do Sono , Qualidade de Vida , Dor/complicaçõesRESUMO
Colorectal cancer (CRC) is one of the most common malignancies, and at the initial visit, most patients are diagnosed with metastatic CRC (mCRC). However, immunotherapy is only and highly effective in a very small proportion of patients with mCRC having mismatch repair defect (dMMR)/high microsatellite instability, and the majority of the patients with mCRC having mismatch repair proficient (pMMR)/microsatellite stability (MSS) cannot benefit from it. At present, many clinical studies of immunotherapy combined with tyrosine kinase inhibitors (TKIs) are trying to regulate the immune microenvironment of pMMR/MSS mCRC, transforming a "cold tumor" into a "hot tumor," which has not only surprising effects but also certain limitations, i.e., the response could not be specific to metastasis. Therefore, regarding the bottleneck encountered by immunotherapy in patients with patients pMMR/MSS mCRC, this study summarized current research and possible mechanisms of immunotherapy combined with local therapy for metastasis, including radiotherapy, ablation, and transcatheter arterial chemoembolization.
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Oncolytic viruses (OVs) for cancer treatment are in a rapid stage of development, and the direct tumor lysis and activation of a comprehensive host immune response are irreplaceable advantages of cancer immunotherapy. However, excessive antiviral immune responses also restrict the spread of OVs in vivo and the infection of tumor cells. Macrophages are functionally diverse innate immune cells that phagocytose tumor cells and present antigens to activate the immune response, while also limiting the delivery of OVs to tumors. Studies have shown that the functional propensity of macrophages between OVs and tumor cells affects the overall therapeutic effect of oncolytic virotherapy. How to effectively avoid the restrictive effect of macrophages on OVs and reshape the function of tumor-associated macrophages in oncolytic virotherapy is an important challenge we are now facing. Here, we review and summarize the complex dual role of macrophages in oncolytic virotherapy, highlighting how the functional characteristics of macrophage plasticity can be utilized to cooperate with OVs to enhance anti-tumor effects, as well as highlighting the importance of designing and optimizing delivery modalities for OVs in the future.
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Neoplasias , Terapia Viral Oncolítica , Vírus Oncolíticos , Humanos , Imunoterapia , Macrófagos/patologiaRESUMO
Anoikis resistance, a notable factor in osteosarcoma, plays a significant role in tumor invasion and metastasis. This study seeks to identify a distinct gene signature that is specifically associated with the anoikis subcluster in osteosarcoma. Clinical, single-cell, and transcriptional data from TARGET and GEO datasets were used to develop a gene signature for osteosarcoma based on the anoikis subcluster. Univariate Cox and LASSO regression analyses were employed. The signature's predictive value was evaluated using time-dependent ROC and Kaplan-Meier analyses. Functional enrichment analyses and drug sensitivity analyses were conducted. Validation of three modular genes was performed using RT-qPCR and Western blotting. Signature (ZNF583, CGNL1, CXCL13) was developed to predict overall survival in osteosarcoma patients, targeting the anoikis subcluster. The signature demonstrated good performance in external validation. Stratification based on the signature revealed significantly different prognoses. The signature was an independent prognostic factor. The low-risk group showed enhanced immune cell infiltration and improved immune function. Drug sensitivity analysis indicated efficacy of chemotherapy agents. Prognostic nomograms incorporating the signature provided greater predictive accuracy and clinical utility. Signatures related to the anoikis subcluster play a significant role in osteosarcoma progression. Incorporating these findings into clinical decision-making can improve osteosarcoma treatment and patient outcomes.
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Neoplasias Ósseas , Osteossarcoma , Humanos , Anoikis/genética , Prognóstico , Imunoterapia , Osteossarcoma/genética , Osteossarcoma/terapia , Neoplasias Ósseas/genética , Neoplasias Ósseas/terapiaRESUMO
Tumor vaccines aim to activate dormant or unresponsive tumor-specific T lymphocytes by using tumor-specific or tumor-associated antigens, thus enhancing the body's natural defense against cancer. However, the effectiveness of tumor vaccines is limited by the presence of tumor heterogeneity, low immunogenicity, and immune evasion mechanisms. Fortunately, multifunctional nanoparticles offer a unique chance to address these issues. With the advantages of their small size, high stability, efficient drug delivery, and controlled surface chemistry, nanomaterials can precisely target tumor sites, improve the delivery of tumor antigens and immune adjuvants, reshape the immunosuppressive tumor microenvironment, and enhance the body's anti-tumor immune response, resulting in improved efficacy and reduced side effects. Nanovaccine, a type of vaccine that uses nanotechnology to deliver antigens and adjuvants to immune cells, has emerged as a promising strategy for cancer immunotherapy due to its ability to stimulate immune responses and induce tumor-specific immunity. In this review, we discussed the compositions and types of nanovaccine, and the mechanisms behind their anti-tumor effects based on the latest research. We hope that this will provide a more scientific basis for designing tumor vaccines and enhancing the effectiveness of tumor immunotherapy.
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In recent years, oncolytic viruses (OVs) have emerged as an effective means of treating cancer. OVs have multiple oncotherapeutic functions including specifically infecting and lysing tumor cells, initiating immune cell death, attacking and destroying tumor angiogenesis and triggering a broad bystander effect. Oncolytic viruses have been used in clinical trials and clinical treatment as drugs for cancer therapy, and as a result, oncolytic viruses are required to have long-term storage stability for clinical use. In the clinical application of oncolytic viruses, formulation design plays a decisive role in the stability of the virus. Therefore, this paper reviews the degradation factors and their degradation mechanisms (pH, thermal stress, freeze-thaw damage, surface adsorption, oxidation, etc.) faced by oncolytic viruses during storage, and it discusses how to rationally add excipients for the degradation mechanisms to achieve the purpose of maintaining the long-term stability of oncolytic viral activity. Finally, the formulation strategies for the long-term formulation stability of oncolytic viruses are discussed in terms of buffers, permeation agents, cryoprotectants, surfactants, free radical scavengers, and bulking agent based on virus degradation mechanisms.
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Vitamin C, a small organic molecule, is widely found in fruits and vegetables and is an essential nutrient in the human body. Vitamin C is closely associated with some human diseases such as cancer. Many studies have shown that high doses of vitamin C have anti-tumor ability and can target tumor cells in multiple targets. This review will describe vitamin C absorption and its function in cancer treatment. We will review the cellular signaling pathways associated with vitamin C against tumors depending on the different anti-cancer mechanisms. Based on this, we will further describe some applications of the use of vitamin C for cancer treatment in preclinical and clinical trials and the possible adverse events that can occur. Finally, this review also assesses the prospective advantages of vitamin C in oncology treatment and clinical applications.
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Ácido Ascórbico , Neoplasias , Humanos , Estudos Prospectivos , Vitaminas , Transdução de SinaisRESUMO
An ultrasensitive electrochemical immunosensor based on signal amplification of the deposition of the electroactive ferrocene-tyramine (Fc-Tyr) molecule, catalyzed by horseradish peroxidase (HRP), was constructed for the detection of the liver cancer marker Glypican-3 (GPC3). Functional electroactive molecule Fc-Tyr is reported to exhibit both the enzymatic cascade catalytic activity of tyramine signal amplification (TSA) and the excellent redox properties of ferrocene. In terms of design, the low matrix effects inherent in using the magnetic bead platforms, a quasi-homogeneous system, allowed capturing the target protein GPC3 without sample pretreatment, and loading HRP to trigger the TSA, which induced a large amount of Fc-Tyr deposited on the electrode surface layer by layer as a signal probe for the detection of GPC3. The concept of Fc-Tyr as an electroactive label was validated, GPC3 biosensor exhibited high selectivity and sensitivity to GPC3 in the range of 0.1 ng mL-1-1 µg mL-1. Finally, the sensor was used simultaneously with ELISA to assess GPC3 levels in the serum of clinical liver cancer patients, and the results showed consistency, with a recovery of 98.33-105.35% and a relative standard deviation (RSD) of 4.38-8.18%, providing a theoretical basis for achieving portable, rapid and point of care testing (POCT) of tumor markers.
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Técnicas Biossensoriais , Neoplasias Hepáticas , Nanopartículas Metálicas , Humanos , Imunoensaio/métodos , Nanopartículas Metálicas/química , Técnicas Biossensoriais/métodos , Metalocenos , Glipicanas , Peroxidase do Rábano Silvestre/química , Neoplasias Hepáticas/diagnóstico , Tiramina/química , Técnicas Eletroquímicas , Ouro/química , Limite de DetecçãoRESUMO
OBJECTIVE: To identify variables that may predict psychological distress in patients with an enterostomy. METHODS: Investigators recruited 77 patients with a stoma from a stoma clinic according to the inclusion criteria. Patients' psychological distress was assessed with the Distress Thermometer (DT) tool, and their personality type was determined by the Eysenck Personality Questionnaire. Researchers also collected demographic and disease-related data. Predictive values were estimated using multiple regression analyses. RESULTS: The mean DT score of all patients was 5.94 (SD, 1.81), and approximately 85.7% consistently suffered from psychological distress. Being unmarried and having peristomal complications were associated with higher psychological distress, whereas having a monthly income 5,000 ¥ or more was associated with lower levels of distress. Moreover, patients with a melancholic personality type tended to have higher DT scores, which could act as a strong independent predictor for psychological distress. CONCLUSIONS: The majority of patients with a stoma endured moderate to severe psychological distress during follow-up care. Exploring the related factors that predict the levels of psychological distress could enable clinicians to identify at-risk patients as early as possible and thus provide optimal care for improving patients' quality of life.
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Neoplasias Colorretais , Enterostomia , Angústia Psicológica , Humanos , Estudos Transversais , Qualidade de Vida/psicologia , Neoplasias Colorretais/cirurgia , Neoplasias Colorretais/psicologia , Estresse Psicológico/etiologia , Estresse Psicológico/psicologia , Inquéritos e QuestionáriosRESUMO
OBJECTIVES: The distance from skin to the hyoid bone (DSHB) and skin to the anterior commissure of vocal cords (DSAC) are reliable parameters for pre-operative airway ultrasound assessment in awake patients and can be assessed in comatose patients. This study aimed to inspect its feasibility and accuracy in predicting difficult laryngoscopy for comatose patients. METHODS: A prospective cohort study included patients with a Glasgow Coma Scale (GCS) of ≤8 who underwent emergency tracheal intubation between November 2019 and August 2020. The outcome was difficult laryngoscopy and classified according to the Cormack-Lehane grading. RESULTS: A total of 151 patients were included in the study. Fifty-two (34.4%) patients were categorized as having difficult laryngoscopy. The DSHB add DSAC (hereinafter referred to as the "DSBAC") was superior to either parameter alone in the predictive performance, and the optimal cut-off value was 1.90. To optimize the predictive value, DSBAC (adjusted odds ratio [OR]: 7.76; 95% confidence interval [CI]: 2.88-20.94; P < .001), GCS (adjusted OR: 1.39; 95% CI: 3.93-26.28; P = .039), mandibular retraction (adjusted OR: 8.20; 95% CI: 1.92-35.09; P = .005) and edentulous (adjusted OR: 4.23; 95% CI: 1.40-12.80; P = .011) were included in a multivariable model and constructed a nomogram. Discrimination and calibration statistics were satisfactory, with C-index above 0.80 from both model development and internal validation. CONCLUSIONS: Ultrasound-derived factor, DSBAC, can be easily assessed and help predict difficult laryngoscopy among comatose patients. A simple nomogram including only four clinical items exhibited excellent discrimination performance and was useful when comatose patients underwent emergency tracheal intubation.
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Coma , Laringoscopia , Humanos , Laringoscopia/métodos , Coma/diagnóstico por imagem , Estudos Prospectivos , Intubação Intratraqueal/métodos , UltrassonografiaRESUMO
It is an exigent need for the development of hydrogel dressings with desirable injectability, good adhesive, antibacterial, and wound healing promotion properties. Herein, the multifunctional injectable hydrogels with good tissue adhesion are designed based on Ag-doped Mo2C-derived polyoxometalate (AgPOM) nanoparticles, urea, gelatin, and tea polyphenols (TPs) for antibacterial and wound healing acceleration. After being injected into the tissue, urea diffuses out under the concentration gradient, and TPs and gelatin chains recombine to trigger the in situ formation of hydrogel with excellent adhesiveness. AgPOM fixed in the hydrogel could not only react with hydrogen peroxide in the infection site to generate singlet oxygen to kill the bacteria but also convert near-infrared light into heat under 1060 nm laser irradiation to realize sterilization. In vitro studies display the high bactericidal ability of the hydrogel against drug-resistant Staphylococcus aureus and also exhibit a prominent therapeutic effect on infected wounds through synergistic photothermal/chemodynamic therapy and accelerate wound healing. Hence, the injectable hydrogel with AgPOM as the antimicrobial agent can be a novel therapeutic agent for drug-resistant bacteria-infected wounds and wound healing promotion.
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Staphylococcus aureus Resistente à Meticilina , Adesivos Teciduais , Infecção dos Ferimentos , Humanos , Hidrogéis/farmacologia , Adesivos Teciduais/farmacologia , Gelatina/farmacologia , Cicatrização , Bactérias , Antibacterianos/farmacologia , Infecção dos Ferimentos/tratamento farmacológicoRESUMO
Adenine base editors (ABEs) catalyze A-to-G transitions showing broad applications, but their bystander mutations and off-target editing effects raise safety concerns. Through structure-guided engineering, we found ABE8e with an N108Q mutation reduced both adenine and cytosine bystander editing, and introduction of an additional L145T mutation (ABE9), further refined the editing window to 1-2 nucleotides with eliminated cytosine editing. Importantly, ABE9 induced very minimal RNA and undetectable Cas9-independent DNA off-target effects, which mainly installed desired single A-to-G conversion in mouse and rat embryos to efficiently generate disease models. Moreover, ABE9 accurately edited the A5 position of the protospacer sequence in pathogenic homopolymeric adenosine sites (up to 342.5-fold precision over ABE8e) and was further confirmed through a library of guide RNA-target sequence pairs. Owing to the minimized editing window, ABE9 could further broaden the targeting scope for precise correction of pathogenic single-nucleotide variants when fused to Cas9 variants with expanded protospacer adjacent motif compatibility. bpNLS, bipartite nuclear localization signals.
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Adenina , Edição de Genes , Animais , Camundongos , Ratos , Mutação , Citosina , Sistemas CRISPR-Cas/genética , RNA Guia de Sistemas CRISPR-CasRESUMO
PURPOSE: The specific risk factors of metastatic and nonmetastatic esophageal neuroendocrine carcinoma (NEC) are still uncertain. Whether primary site surgery is necessary for all patients with esophageal NEC is unknown. METHODS: Patients with esophageal NEC in the Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2014 were selected. STATA 12 was used to analyze the clinical and pathological features of esophageal NEC. RESULTS: In total, 241 patients with esophageal NEC were included. Metastatic patients had shorter overall survival than nonmetastatic patients (6.03 versus 11.90 months, respectively). Prognostic factors varied between metastatic and nonmetastatic esophageal NEC. The location of the primary tumor is a key point for the prognosis of esophageal NEC. For nonmetastatic esophageal NEC, patients with tumors in the upper third of the esophagus had the worst survival, and patients with metastatic esophageal NEC with a primary tumor in the lower part of the esophagus tended to have an increased risk of death. Moreover, age ≥68 years (hazard ratio [HR] = 2.05; 95% confidence interval [CI]: 1.28-3.31; P < 0.01) and large cell carcinoma (HR = 2.79; 95% CI: 1.30-6.00; P < 0.01) were independent risk factors in patients with metastatic esophageal NEC. Primary site resection benefited patients with nonmetastatic esophageal NEC (HR = 0.20; 95% CI: 0.07-0.56; P < 0.01) rather than patients with metastatic esophageal NEC (HR = 0.91; 95% CI: 0.29-2.83; P > 0.05). CONCLUSIONS: Our study presented that primary tumor location is an important risk factor for nonmetastatic esophageal NEC patients. Age and pathological type are important risk factors for patients with metastatic esophageal NEC. Nonmetastatic esophageal NEC will benefit from primary tumor resection. Systematic treatment is recommended for metastatic esophageal NEC.