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PURPOSEOF REVIEW: The purpose of this review is to discuss the current understanding of the pegilodecakin (PEGylated interleukin 10) and its role in the inhibition of tumour growth and metastasis. This review also focuses on clinical data published to date that have evaluated the efficacy and safety of pegilodecakin. RECENT FINDINGS: Pegilodecakin has shown significant promise in preclinical models, notable for decreased tumour burden and fewer sites of metastatic disease across various malignancies. It has been most widely assessed in a phase I/Ib clinical trial against several solid tumours, leading to the phase II and III clinical trials containing pegilodecakin and its combination with other current treatments. However, the updated data have not shown higher efficacy in renal cell carcinoma, metastatic non-small cell lung cancer or pancreatic cancer, with respect to the controls, yet the adverse events presented more mixed results. Further investigation into combination therapies including pegilodecakin is ongoing. Pegilodecakin showed promise in preclinical and phase I clinical trials on its efficacy in several solid tumours, with expected regulation of IL-10 signalling pathway observed. However, the phase II and III trials did not justify its application as potential immunotherapy in selected cancers. Further evaluation of pegilodecakin's efficacy in other cancers, either as monotherapy or in combination with the current treatments, is worth investigating clinically, which warrants to better understand its potential clinical utility.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Renais , Neoplasias Pulmonares , Humanos , Interleucina-10/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Imunoterapia/métodos , Polietilenoglicóis/uso terapêutico , Neoplasias Renais/tratamento farmacológicoRESUMO
BACKGROUND: Papillary thyroid carcinoma (PTC) is the most common thyroid cancer. While many patients survive, a portion of PTC cases display high aggressiveness and even develop into refractory differentiated thyroid carcinoma. This may be alleviated by developing a novel model to predict the risk of recurrence. Ferroptosis is an iron-dependent form of regulated cell death (RCD) driven by lethal accumulation of lipid peroxides, is regulated by a set of genes and shows a variety of metabolic changes. To elucidate whether ferroptosis occurs in PTC, we analyse the gene expression profiles of the disease and established a new model for the correlation. METHODS: The thyroid carcinoma (THCA) datasets were downloaded from The Cancer Genome Atlas (TCGA), UCSC Xena and MisgDB, and included 502 tumour samples and 56 normal samples. A total of 60 ferroptosis related genes were summarised from MisgDB database. Gene set enrichment analysis (GSEA) and Gene set variation analysis (GSVA) were used to analyse pathways potentially involving PTC subtypes. Single sample GSEA (ssGSEA) algorithm was used to analyse the proportion of 28 types of immune cells in the tumour immune infiltration microenvironment in THCA and the hclust algorithm was used to conduct immune typing according to the proportion of immune cells. Spearman correlation analysis was performed on the ferroptosis gene expression and the correlation between immune infiltrating cells proportion. We established the WGCNA to identify genes modules that are highly correlated with the microenvironment of immune invasion. DEseq2 algorithm was further used for differential analysis of sequencing data to analyse the functions and pathways potentially involving hub genes. GO and KEGG enrichment analysis was performed using Clusterprofiler to explore the clinical efficacy of hub genes. Univariate Cox analysis was performed for hub genes combined with clinical prognostic data, and the results was included for lasso regression and constructed the risk regression model. ROC curve and survival curve were used for evaluating the model. Univariate Cox analysis and multivariate Cox analysis were performed in combination with the clinical data of THCA and the risk score value, the clinical efficacy of the model was further evaluated. RESULTS: We identify two subtypes in PTC based on the expression of ferroptosis related genes, with the proportion of cluster 1 significantly higher than cluster 2 in ferroptosis signature genes that are positively associated. The mutations of Braf and Nras are detected as the major mutations of cluster 1 and 2, respectively. Subsequent analyses of TME immune cells infiltration indicated cluster 1 is remarkably richer than cluster 2. The risk score of THCA is in good performance evaluated by ROC curve and survival curve, in conjunction with univariate Cox analysis and multivariate Cox analysis results based on the clinical data shows that the risk score of the proposed model could be used as an independent prognostic indicator to predict the prognosis of patients with papillary thyroid cancer. CONCLUSIONS: Our study finds seven crucial genes, including Ac008063.2, Apoe, Bcl3, Acap3, Alox5ap, Atxn2l and B2m, and regulation of apoptosis by parathyroid hormone-related proteins significantly associated with ferroptosis and immune cells in PTC, and we construct the risk score model which can be used as an independent prognostic index to predict the prognosis of patients with PTC.
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Carcinoma Papilar , Ferroptose , Neoplasias da Glândula Tireoide , Biomarcadores Tumorais , Carcinoma Papilar/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Recidiva Local de Neoplasia , Prognóstico , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Microambiente TumoralRESUMO
BACKGROUND: Therapeutic vaccines against cervical cancer remain ineffective. Previously, we demonstrated that blocking the signalling of a cytokine, interleukin 10, at the time of immunisation elicited significantly higher numbers of antigen specific T cells and inhibited tumour growth in mice. RESULTS: In the current paper, we demonstrate, in a HPV16 E6/E7 transformed TC-1 tumour mouse model, that despite increased antigen specific T cell numbers, blocking IL-10 signalling at the time of immunisation does not increase the survival time of the TC-1 tumour bearing mice compared to mice receiving the same immunisation with no IL-10 signalling blockade. Moreover, the function of tumour infiltrating T cells isolated 3 weeks post TC-1 transplantation is more suppressed than those isolated 2 weeks after tumour inoculation. We demonstrate that synthesized caerin peptides, derived from amphibian skin secretions, 1) were able to inhibit TC-1 tumour growth both in vitro and in vivo; 2) are environmentally stable; and 3) promote the secretion of pro-inflammatory interlukine-6 by TC-1 cells. Notably caerin peptides were able to increase the survival time of TC-1 tumour bearing mice after therapeutic vaccination with a HPV16E7 peptide-based vaccine containing IL-10 inhibitor, via recruiting increased levels of T cells to the tumour site. CONCLUSION: Caerin peptides increase the efficacy of a therapeutic vaccine by recruiting more T cells to the tumour site.
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Proteínas de Anfíbios/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Vacinas Anticâncer/uso terapêutico , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Proteínas de Anfíbios/uso terapêutico , Animais , Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Vacinas Anticâncer/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células HeLa , Humanos , Interleucina-10/antagonistas & inibidores , Interleucina-6/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Neoplasias Experimentais/tratamento farmacológico , Linfócitos T/metabolismoRESUMO
OBJECTIVE: We recently showed that host defense caerin peptides isolated from Australian frog tree were able to inhibit cervical cancer tumour cell growth in vitro. We wished to determine if radioactive isotope iodine-125 (125I) can be labeled to caerin 1.9 peptide and if this peptide is bioactive for breast cancer cells treatment. SUBJECTS AND METHODS: The biological function of caerin (1.1 and 1.9) peptides were investigated by in vitro 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay. The anti-cancer effect of 125I labeled caerin 1.9 was compared with unlabeled caerin 1.9 peptide. The tissue distribution of 125I labeled caerin 1.9 peptide was further studied in mice. RESULTS: In the current paper, we demonstrated that caerin peptides (1.1 and 1.9) were separately able to inhibit the viability of two breast cancer cell lines in vitro and this inhibition was more profound when these peptides were simultaneously applied. Moreover, 125I can be stably attached to caerin 1.9 peptide with high efficiency. Iodine-125 labeled caerin 1.9 inhibited breast cancer cells line MCF-7 viability more efficiently than free 125I and also than unlabeled caerin 1.9. Additionally, iodine-125 labeled caerin 1.9 in vivo imaging demonstrated that although slightly, it could be accumulated in tumor tissue. CONCLUSION: Our results from this totally original study indicated that radioactive isotope 125I labeled to caerin peptide 1.9 may be used to treat breast cancer while at the same time the response to treatment may be monitored by simultaneous imaging.
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Proteínas de Anfíbios/química , Proteínas de Anfíbios/uso terapêutico , Peptídeos Catiônicos Antimicrobianos/química , Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Neoplasias da Mama/radioterapia , Radioisótopos do Iodo/uso terapêutico , Sequência de Aminoácidos , Proteínas de Anfíbios/farmacocinética , Animais , Peptídeos Catiônicos Antimicrobianos/farmacocinética , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos da radiação , Transformação Celular Neoplásica , Feminino , Humanos , Marcação por Isótopo , Células MCF-7 , Camundongos , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Distribuição TecidualRESUMO
BACKGROUND: Cancer therapeutic vaccine induced cytotoxic T cell (CTL) responses are pivotal for the killing of tumour cells. Blocking interleukin 10 (IL-10) signalling at the time of immunization increases vaccine induced CTL responses and improves prevention of tumour growth in animal models compared to immunization without an IL-10 signalling blockade. Therefore, this immunization strategy may have potential to curtail cancer in a clinical setting. However, IL-10 deficiency leads to autoimmune disease in the gut. Blocking IL-10 at the time of immunization may result in unwanted side effects, especially immune-pathological diseases in the intestine. METHODS: We investigated whether blocking IL-10 at the time of immunization results in intestinal inflammation responses in a mouse TC-1 tumour model and in a NOD autoimmune disease prone mouse model. RESULTS: We now show that blocking IL-10 at the time of immunization increases IL-10 production by CD4+ T cells in the spleen and draining lymph nodes, and does not result in blood cell infiltration to the intestines leading to intestinal pathological changes. Moreover, immunization with papillomavirus like particles combined with simultaneously blocking IL-10 signalling does not increase the incidence of autoimmune disease in Non-obese diabetic (NOD) mice. CONCLUSIONS: Our results indicate that immunization with an IL-10 inhibitor may facilitate the generation of safe, effective therapeutic vaccines against chronic viral infection and cancer.
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Linfócitos T CD4-Positivos/imunologia , Imunização/efeitos adversos , Imunização/métodos , Interleucina-10/antagonistas & inibidores , Intestinos/imunologia , Transdução de Sinais/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Anticorpos/imunologia , Doenças Autoimunes/imunologia , Linfócitos T CD4-Positivos/metabolismo , Proliferação de Células , Modelos Animais de Doenças , Feminino , Interleucina-10/imunologia , Interleucina-10/metabolismo , Intestinos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD/imunologia , Camundongos Knockout , Proteínas de Fusão Oncogênica/imunologia , Proteínas Oncogênicas Virais/imunologia , Proteínas E7 de Papillomavirus/química , Proteínas E7 de Papillomavirus/imunologia , Baço/citologia , Baço/imunologiaRESUMO
We recently reported that blockade of IL-10 signalling at the time of a human papillomavirus (HPV) long E7 peptide/LPS immunization leads to the regression of established HPV-16 immortalized tumours in mice similar to that induced by long E7 peptide/incomplete Freund's adjuvant (IFA)-based vaccination. In this paper, we demonstrated that blockade of IL-10 signalling at the time of long E7 peptide/LPS could elicit stronger T cells responses and render the tumour more accessible for immune cell infiltration than vaccination with long E7 peptide/IFA. Furthermore, priming with long E7 peptide/LPS and IL10 signalling blockade then boosting with long E7 peptide/IFA elicits stronger CD8+ T cell responses than long E7 peptide/IFA immunization. The results suggest that priming with long E7 peptide/LPS and IL10 signalling inhibitor, then boosting with long E7 peptide/IFA elicits may lead to better HPV infection related tumour regression in clinic.
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Vacinas Anticâncer/imunologia , Interleucina-10/antagonistas & inibidores , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/virologia , Transdução de Sinais , Linfócitos T/imunologia , Adjuvantes Imunológicos/farmacologia , Animais , Modelos Animais de Doenças , ELISPOT , Feminino , Humanos , Lipopolissacarídeos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas E7 de Papillomavirus/imunologia , Infecções por Papillomavirus/complicações , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/imunologiaRESUMO
Interleukin 10 is a cytokine with the ability to reduce or terminate inflammation. Chronic viral infection, such as infection of chronic hepatitis B, hepatitis C and HIV, has increased levels of interleukin 10 in peripheral blood. Serum IL-10 levels are also high in certain cancers. Blocking IL-10 signalling at the time of immunisation clears chronic viral infection and prevents tumour growth in animal models. We review recent advances in this area, with the emphasis on potential use of this novel strategy to treat chronic viral infection and cancer in human.
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Infecções por HIV/imunologia , Hepatite B Crônica/imunologia , Hepatite C Crônica/imunologia , Interleucina-10/imunologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Animais , Infecções por HIV/terapia , Hepatite B Crônica/terapia , Hepatite C Crônica/terapia , Humanos , Imunoterapia , Linfócitos T/virologiaRESUMO
Glioblastoma, the most aggressive form of brain cancer, poses a significant global health challenge with a considerable mortality rate. With the predicted increase in glioblastoma incidence, there is an urgent need for more effective treatment strategies. In this study, we explore the potential of caerin 1.1 and 1.9, host defence peptides derived from an Australian tree frog, in inhibiting glioblastoma U87 and U118 cell growth. Our findings demonstrate the inhibitory impact of caerin 1.1 and 1.9 on cell growth through CCK8 assays. Additionally, these peptides effectively curtail the migration of glioblastoma cells in a cell scratch assay, exhibiting varying inhibitory effects among different cell lines. Notably, the peptides hinder the G0/S phase replication in both U87 and U118 cells, pointing to their impact on the cell cycle. Furthermore, caerin 1.1 and 1.9 show the ability to enter the cytoplasm of glioblastoma cells, influencing the morphology of mitochondria. Proteomics experiments reveal intriguing insights, with a decrease in CHI3L1 expression and an increase in PZP and JUNB expression after peptide treatment. These proteins play roles in cell energy metabolism and inflammatory response, suggesting a multifaceted impact on glioblastoma cells. In conclusion, our study underscores the substantial anticancer potential of caerin 1.1 and 1.9 against glioblastoma cells. These findings propose the peptides as promising candidates for further exploration in the realm of glioblastoma management, offering new avenues for developing effective treatment strategies.
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Proliferação de Células , Regulação para Baixo , Glioblastoma , Mitocôndrias , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Proliferação de Células/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Respiração Celular/efeitos dos fármacos , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/metabolismo , Movimento Celular/efeitos dos fármacosRESUMO
OBJECTIVES: With rising rates of maxillofacial fracture, postoperative infection following rigid internal fixation is an important issue that requires immediate resolution. It is important to explore an alternative antibacterial method apart from conventional antibiotics. A controlled experiment was conducted to evaluate the effectiveness of a caerin 1.9 peptide-coated titanium plate in reducing mandibular infection in New Zealand (NZ) rabbits, aiming to minimise the risk of post-metallic implantation infection. METHODS: Twenty-two NZ rabbits were randomly divided into 3 groups. The experiment group received caerin 1.9 peptide-coated titanium plates and mixed oral bacteria exposure. The control group received normal titanium plates with mixed oral bacteria exposure. The untreated group served as a control to prove that bacteria in the mouth can cause infection. Weight, temperature, hepatic function, and C-reactive protein levels were measured. Wound and bone conditions were evaluated. Further analysis included local infection, anatomic conditions, histology, and bacterial load. RESULTS: No significant differences were found in temperature, weight, blood alanine aminotransferase, and C-reactive protein levels amongst the 3 groups. The experiment group showed the lowest amount of bacterial RNA in wounds. Additionally, the experiment group had higher peripheral lymphocyte counts compared to the control group and lower neutrophil counts on the third and seventh day postoperatively. Histologic analysis revealed lower levels of inflammatory cell infiltration, bleeding, and areas of necrosis in the experimental group compared with the controls. CONCLUSIONS: A caerin 1.9-coated titanium plate is able to inhibit bacterial growth in a NZ rabbit mandibular mixed bacteria infection model and is worth further investigation.
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Deregulated microRNAs (miRNAs) are small noncoding RNAs that are involved in the carcinogenesis of various cancers, including lung cancer. HIF1a has been suggested to be a master regulator of hypoxia-induced cell proliferation. The relationship between HIF1a expression and the progression of non-small cell lung cancer (NSCLC) is not fully understood, and whether HIF1a expression is regulated by miRNAs in this process remains unclear. In this study, we found that the upregulation of HIF1a expression and the reduction in miR-199a levels were highly associated with NSCLC progression. NSCLC cells derived from cancer tissues with low miR-199a levels showed high HIF1a expression and high proliferation capacity. Moreover, HIF1a and glycolysis inhibitors suppress the proliferation of NSCLC cells. MiR-199a overexpression suppressed the hypoxia-induced proliferation of NSCLC cells through targeting elevated HIF1a and blocking the downstream upregulation of PDK1 without affecting AKT activation. Together, these results indicate that downregulation of miR-199a is essential for hypoxia-induced proliferation through derepressing the expression of HIF1a expression and affecting HIF1a mediated glycolytic pathway in NSCLC progression.
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Carcinoma Pulmonar de Células não Pequenas/genética , Hipóxia Celular/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Pulmonares/genética , MicroRNAs/genética , Linhagem Celular Tumoral , Proliferação de Células , Glicólise/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , MicroRNAs/metabolismo , Proteínas Serina-Treonina Quinases/biossíntese , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil , Regulação para CimaRESUMO
Multidrug-resistant (MDR) bacteria are considered a health threat worldwide, and this problem is set to increase over the decades. The ESKAPE, a group of six pathogens including Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp. is the major source of concern due to their high death incidence and nosocomial acquired infection. Host defence peptides (HDPs) are a class of ribosomally synthesised peptides that have shown promising results in combating MDR, including the ESKAPE group, in- and outside bacterial biofilms. However, their poor pharmacokinetics in physiological mediums may impede HDPs from becoming viable clinical candidates. To circumvent this problem, chemical engineering of HDPs has been seen as an emergent approach to not only improve their pharmacokinetics but also their efficacy against pathogens. In this review, we explore several chemical modifications of HDPs that have shown promising results, especially against ESKAPE pathogens, and provide an overview of the current findings with respect to each modification.
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Peptídeos Catiônicos Antimicrobianos , Enterococcus faecium , Humanos , Klebsiella pneumoniae , Enterobacter , Pseudomonas aeruginosa , Antibacterianos/farmacologiaRESUMO
BACKGROUND: Cervical cancer (CC) is the 3rd most common cancer in women and the 4th leading cause of deaths in gynaecological malignancies, yet the exact progression of CC is inconclusive, mainly due to the high complexity of the changing tumour microenvironment (TME) at different stages of tumorigenesis. Importantly, a detailed comparative single-nucleus transcriptomic analysis of tumour microenvironment (TME) of CC patients at different stages is lacking. METHODS: In this study, a total of 42,928 and 29,200 nuclei isolated from the tumour tissues of stage-I and II CC patients and subjected to single-nucleus RNA sequencing (snRNA-seq) analysis. The cell heterogeneity and functions were comparatively investigated using bioinformatic tools. In addition, label-free quantitative mass spectrometry based proteomic analysis was carried out. The proteome profiles of stage-I and II CC patients were compared, and an integrative analysis with the snRNA-seq was performed. RESULTS: Compared with the stage-I CC (CCI) patients, the immune response relevant signalling pathways were largely suppressed in various immune cells of the stage-II CC (CCII) patients, yet the signalling associated with cell and tissue development was enriched, as well as metabolism for energy production suggested by the upregulation of genes associated with mitochondria. This was consistent with the quantitative proteomic analysis that showed the dominance of proteins promoting cell growth and intercellular matrix development in the TME of CCII group. The interferon-α and γ responses appeared the most activated pathways in many cell populations of the CCI patients. Several collagens, such as COL12A1, COL5A1, COL4A1 and COL4A2, were found significantly upregulated in the CCII group, suggesting their roles in diagnosing CC progression. A novel transcript AC244205.1 was detected as the most upregulated gene in CCII patients, and its possible mechanistic role in CC may be investigated further. CONCLUSIONS: Our study provides important resources for decoding the progression of CC and set the foundation for developing novel approaches for diagnosing CC and tackling the immunosuppressive TME.
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Neoplasias do Colo do Útero , Humanos , Feminino , Neoplasias do Colo do Útero/patologia , Proteômica/métodos , Microambiente Tumoral/genética , Perfilação da Expressão Gênica , Transformação Celular NeoplásicaRESUMO
IMPORTANCE: Caerin 1.1 and caerin 1.9, natural antimicrobial peptides derived from tree frogs, have demonstrated the ability to inhibit the growth of antibiotic-resistant bacteria, comparable to certain widely used antibiotics. Additionally, these peptides exhibit the capacity to prevent or treat biofilms formed by bacteria in conjunction with bodily components. The mechanisms underlying their antibacterial effects were investigated through a mouse model of bacterial skin infection, utilizing proteomic analysis as a technological approach.
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Acinetobacter baumannii , Camundongos , Animais , Proteômica , Antibacterianos/farmacologia , Peptídeos/farmacologia , Biofilmes , Testes de Sensibilidade MicrobianaRESUMO
A 54-year-old male was diagnosed with extensive liver metastasis and small nodule metastasis in the lungs from gastric adenocarcinoma [Her-2 (-)]. The patient achieved significant partial response (PR) after chemotherapy combined with anti-angiogenesis therapy but developed progressive disease (PD) after 5 months. Then, the chemotherapeutic and anti-angiogenic drugs were replaced. Meanwhile, the delivery route of some chemotherapeutic drugs was changed, and some chemotherapeutic drugs were given via transcatheter arterial chemoembolization (TACE) to achieve PR, and PD developed after 3 months of remission maintenance. During chemotherapy combined with anti-angiogenesis, the application of programmed cell death-1 (PD-1) inhibitor achieved PR again and maintained for 5 months before disease progression. The progression of the lesions in the left lobe of the liver and the hepatic hilar lymph nodes was significant. Hence, chemotherapy was terminated and gamma stereotactic body radiation therapy (SBRT) was performed on left lobe lesions and hilar lymph nodes. The lesions both inside and outside the radiation field regressed significantly, reaching PR and abscopal effects. The immune-related adverse events (irAEs) occurred, including erythema and black and luster hair. The abscopal effects of lesion reduction in the radiation field and the enhancement of the immune function stimulated by radiation are a highlight of the combination of radiation and immunotherapy. In the end, the patient died of gastrointestinal failure, with overall survival of 18 months.
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OBJECTIVE: The aim of this study was to analyze and compare the therapeutic effects of 131I-caerin 1.1 and 131I-c(RGD)2 on TE-1 esophageal cancer cell xenografts. METHODS: (1) The in vitro antitumor effects of the polypeptides caerin 1.1 and c(RGD)2 were verified by MTT and clonogenic assays. 131I-caerin 1.1 and 131I-c(RGD)2 were prepared by chloramine-T (Ch-T) direct labeling, and their basic properties were measured. The binding and elution of 131I-caerin 1.1, 131I-c(RGD)2, and Na131I (control group) in esophageal cancer TE-1 cells were studied through cell binding and elution assays. (2) The antiproliferative effect and cytotoxicity of 131I-caerin 1.1, 131I-c(RGD)2, Na131I, caerin 1.1 and c(RGD)2 on TE-1 cells were detected by Cell Counting Kit-8 (CCK-8) assay. (3) A nude mouse esophageal cancer (TE-1) xenograft model was established to study and compare the efficacy of 131I-caerin 1.1 and 131I-c(RGD)2 in internal radiation therapy for esophageal cancer. RESULTS: (1) Caerin 1.1 inhibited the in vitro proliferation of TE-1 cells in a concentration-dependent manner, with an IC50 of 13.00 µg/mL. The polypeptide c(RGD)2 had no evident inhibitory effect on the in vitro proliferation of TE-1 cells. Therefore, the antiproliferative effects of caerin 1.1 and c(RGD)2 on esophageal cancer cells were significantly different (P < 0.05). The clonogenic assay showed that the clonal proliferation of TE-1 cells decreased as the concentration of caerin 1.1 increased. Compared with the control group (drug concentration of 0 µg/mL), the caerin 1.1 group showed significantly lower clonal proliferation of TE-1 cells (P < 0.05). (2) The CCK-8 assay showed that 131I-caerin 1.1 inhibited the in vitro proliferation of TE-1 cells, while 131I-c(RGD)2 had no evident inhibitory effect on proliferation. The two polypeptides showed significantly different antiproliferative effects on esophageal cancer cells at higher concentrations (P < 0.05). Cell binding and elution assays showed that 131I-caerin 1.1 stably bound to TE-1 cells. The cell binding rate of 131I-caerin 1.1 was 15.8 % ± 1.09 % at 24 h and 6.95 % ± 0.22 % after 24 h of incubation and elution. The cell binding rate of 131I-c(RGD)2 was 0.06 % ± 0.02 % at 24 h and 0.23 % ± 0.11 % after 24 h of incubation and elution. (3) In the in vivo experiment, 3 days after the last treatment, the tumor sizes of the phosphate-buffered saline (PBS) group, caerin 1.1 group, c(RGD)2 group, 131I group, 131I-caerin 1.1 group, and 131I-c(RGD)2 group were 68.29 ± 2.67 mm3, 61.78 ± 3.58 mm3, 56.67 ± 5.65 mm3, 58.88 ± 1.71 mm3, 14.40 ± 1.38 mm3, and 60.14 ± 0.47 mm3, respectively. Compared with the other treatment groups, the 131I-caerin 1.1 group had significantly smaller tumor sizes (P < 0.001). After treatment, the tumors were isolated and weighed. The tumor weights in the PBS group, caerin 1.1 group, c(RGD)2 group, 131I group, 131I-caerin 1.1 group, and 131I-c(RGD)2 group were 39.50 ± 9.54 mg, 38.25 ± 5.38 mg, 38.35 ± 9.53 mg, 28.25 ± 8.50 mg, 9.50 ± 4.43 mg, and 34.75 ± 8.06 mg, respectively. The tumor weights in the 131I-caerin 1.1 group were significantly lighter than those in the other groups (P < 0.01). CONCLUSION: 131I-caerin 1.1 has tumor-targeting properties, is capable of targeted binding to TE-1 esophageal cancer cells, can be stably retained in tumor cells, and has an evident cytotoxic killing effect, while 131I-c(RGD)2 has no evident cytotoxic effect. 131I-caerin 1.1 better suppressed tumor cell proliferation and tumor growth than pure caerin 1.1, 131I-c(RGD)2, and pure c(RGD)2.
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Neoplasias Esofágicas , Animais , Camundongos , Humanos , Xenoenxertos , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/radioterapia , Neoplasias Esofágicas/metabolismo , Peptídeos/farmacologia , Oligopeptídeos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , ApoptoseRESUMO
Caerin 1.9 is a natural peptide derived from the skin secretions of the Australian tree frog (Litoria) with broad-spectrum antimicrobial and anticancer bioactivity. It improves the efficacy of a therapeutic vaccine and immune checkpoint inhibitor therapy when injected intratumorally and inhibits TC-1 tumor growth when applied topically through intact skin in a TC-1 murine tumor model. This paper investigated the pharmaceutical kinetic profile, the tissue distribution, and the acute safety investigation of Caerin 1.9 peptide in Sprague Dawley (SD) rats. The results showed that subcutaneous injection of Caerin 1.9 at 100 mg/kg is safe and does not cause mortality or organ malfunction in the recipient rats. For the consecutive injection of F3 at 10 mg/kg, the peak concentration (C max) of F3 displayed at 1 hr after injection in male rats was 591 ng/mL, the average drug retention time was 0.807 hr, T 1/2 was 4.58 hr, and AUC0-last was 1890 h × ng/mL. In female rats, C max was 256 ng/mL, with an average drug retention time of 2.96 hr, T 1/2 of 1.33 hr, and AUC0-last of 740 h × ng/mL. The results showed that the concentration of Caerin 1.9 in the peripheral blood peaked at 1 hour. As injected concentration increased, T 1/2 extended, and C max, AUC0-last, and volume of distribution at a steady state all increased. After 14 days of repeated subcutaneous injection at 10.0 mg/kg, no accumulation of Caerin 1.9 in plasma was observed. The results of tissue distribution showed that the Caerin 1.9 is below the LC-MS/MS detection threshold at a minimum concentration of 40 ng/g. In conclusion, Caerin 1.9 is well tolerated in rats and could be used with current immunotherapies for better management of solid tumors and genital warts.
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Macrophages are one of the essential components of the tumour microenvironment (TME) of many cancers and show complex heterogeneity and functions. More recent research has been focusing on the characterisation of tumour-associated macrophages (TAMs). Previously, our study demonstrated that caerin 1.1/1.9 peptides significantly improve the therapeutic efficacy of combined specific immunotherapy and immune checkpoint blockade in a murine transplantable tumour model (TC-1). In this study, the mice inoculated with TC-1 tumour were immunised differently. The TAMs were isolated using flow cytometry and characterised by cytokine ELISA. The survival rates of mice with different treatments containing caerin 1.1/19 were assessed comparatively, including those with/without macrophage depletion. The single-cell RNA sequencing (scRNA-seq) data of previous studies were integrated to further reveal the functions of TAMs with the treatments containing caerin 1.1/1.9. As a comparison, the TAMs of stage I and II cervical cancer patients were analysed using scRNA-seq analysis. We demonstrate that caerin induced tumour clearance is associated with infiltration of tumours by IL-12 secreting Ly6C+F4/80+ macrophages exhibiting enhanced IFN-α response signalling, renders animals resistant to further tumour challenge, which is lost after macrophage depletion. Our results indicate that caerin 1.1/1.9 treatment has great potential in improving current immunotherapy efficacy.
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The clinical efficacy, serum tumor markers, and miR-34 expression levels of bronchial artery embolization (BAE) in patients with lung cancer with hemoptysis are investigated. 92 patients with lung cancer hemoptysis treated in our hospital from January 2019 to December 2021 are randomly selected, and 92 patients are randomly divided into the conservative group and the BAE group according to the number table method, with 46 patients in each group. The efficacy, overall survival (OS) rate, coagulation function, hemoptysis volume, serum tumor markers, and miR-34 expression are compared among all groups at different time points. The experimental results show that the BAE treatment can promote the expression of miR-34 and inhibit the expression of tumor markers, so it can improve the efficacy of patients with lung cancer hemoptysis, improve the symptoms of hemoptysis and coagulation function, and prolong the life cycle of patients.
Assuntos
Neoplasias Pulmonares , MicroRNAs , Biomarcadores Tumorais , Artérias Brônquicas , Hemoptise/terapia , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/terapia , MicroRNAs/genética , Estudos RetrospectivosRESUMO
Antibiotic resistance-related bacterial infections and cancers become huge challenges in human health in the 21st century. A number of naturally derived antimicrobial peptides possess multiple functions in host defense, including anti-infective and anticancer activities. One of which is known as the caerin 1 family peptides. The microbicidal properties of these peptides have been long discussed. The recent studies also established the usage of two members in this family, caerin 1.1 and caerin 1.9, in antimultiple antibiotic-resistant bacteria species. It is increasingly evident that caerin 1.1 and caerin 1.9 also contain additional activities in the suppression of tumor. In this review, we briefly outline the therapeutic potentials and possible mechanism of action of caerin 1.1 and 1.9 in the treatment of multiple antibiotic-resistant bacterial infection and cancer immunotherapy.
Assuntos
Anti-Infecciosos , Infecções Bacterianas , Neoplasias , Proteínas de Anfíbios/farmacologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Peptídeos Catiônicos Antimicrobianos/química , Peptídeos Catiônicos Antimicrobianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Bactérias , Infecções Bacterianas/tratamento farmacológico , Humanos , Imunoterapia , Neoplasias/tratamento farmacológicoRESUMO
Objective: To investigate the effect of the 131I-labeled high-affinity peptides Caerin 1.1 and Caerin 1.9 for the treatment of A549 human NSCLC cells. Methods: â 3-[4,5-Dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and plate clone formation assays were performed to confirm the in vitro anti-tumor activity of Caerin 1.1 and Caerin 1.9. â¡ Chloramine-T was used to label Caerin 1.1 and Caerin 1.9 with 131I, and the Cell Counting Kit 8 assay was performed to analyze the inhibitory effect of unlabeled Caerin 1.1, unlabeled Caerin 1.9, 131I-labeled Caerin 1.1, and 131I-labeled Caerin 1.9 on the proliferation of NSCLC cells. An A549 NSCLC nude mouse model was established to investigate the in vivo anti-tumor activity of unlabeled Caerin 1.1, unlabeled Caerin 1.9, 131I-labeled Caerin 1.1, and 131I-labeled Caerin 1.9. Results: â Caerin 1.1 and Caerin 1.9 inhibited the proliferation of NSCLC cells in vitro in a concentration-dependent manner. The half-maximal inhibitory concentration was 16.26 µg/ml and 17.46 µg/ml, respectively, with no significant intergroup difference (P>0.05). â¡ 131I-labeled Caerin 1.1 and 131I-labeled Caerin 1.9 were equally effective and were superior to their unlabeled versions in their ability to inhibit the proliferation and growth of NSCLC cells (P>0.05). Conclusions: 131I-labeled Caerin 1.1 and 131I-labeled Caerin 1.9 inhibit the proliferation and growth of NSCLC cells and may become potential treatments for NSCLC.