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Acute myeloid leukemia (AML) exhibits pronounced heterogeneity and chemotherapy resistance. Aberrant programmed cell death (PCD) implicated in AML pathogenesis suggests PCD-related signatures could serve as biomarkers to predict clinical outcomes and drug response. We utilized 13 PCD pathways, including apoptosis, pyroptosis, ferroptosis, autophagy, necroptosis, cuproptosis, parthanatos, entotic cell death, netotic cell death, lysosome-dependent cell death, alkaliptosis, oxeiptosis, and disulfidptosis to develop predictive models based on 73 machine learning combinations from 10 algorithms. Bulk RNA-sequencing, single-cell RNA-sequencing transcriptomic data, and matched clinicopathological information were obtained from the TCGA-AML, Tyner, and GSE37642-GPL96 cohorts. These datasets were leveraged to construct and validate the models. Additionally, in vitro experiments were conducted to substantiate the bioinformatics findings. The machine learning approach established a 6-gene pan-programmed cell death-related genes index (PPCDI) signature. Validation in two external cohorts showed high PPCDI associated with worse prognosis in AML patients. Incorporating PPCDI with clinical variables, we constructed several robust prognostic nomograms that accurately predicted prognosis of AML patients. Multi-omics analysis integrating bulk and single-cell transcriptomics revealed correlations between PPCDI and immunological features, delineating the immune microenvironment landscape in AML. Patients with high PPCDI exhibited resistance to conventional chemotherapy like doxorubicin but retained sensitivity to dasatinib and methotrexate (FDA-approved drugs for other leukemias), suggesting the potential of PPCDI to guide personalized therapy selection in AML. In summary, we developed a novel PPCDI model through comprehensive analysis of diverse programmed cell death pathways. This PPCDI signature demonstrates great potential in predicting clinical prognosis and drug sensitivity phenotypes in AML patients.
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Biomarcadores Tumorais , Leucemia Mieloide Aguda , Aprendizado de Máquina , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Prognóstico , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Feminino , Masculino , Morte Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Pessoa de Meia-Idade , TranscriptomaRESUMO
The activation of ferroptosis presents a versatile strategy for enhancing the antitumor immune responses in cancer therapy. However, developing ferroptosis inducers that combine high biocompatibility and therapeutic efficiency remains challenging. In this study, we propose a novel approach using biological nanoparticles derived from outer membrane vesicles (OMVs) of Escherichia coli for tumor treatment, aiming to activate ferroptosis and stimulate the immune responses. Specifically, we functionalize the OMVs by anchoring them with ferrous ions via electrostatic interactions and loading them with the STING agonist-4, followed by tumor-targeting DSPE-PEG-FA decoration, henceforth referred to as OMV/SaFeFA. The anchoring of ferrous ions endows the OMVs with peroxidase-like activity, capable of inducing cellular lipid peroxidation by catalyzing H2O2 to â¢OH. Furthermore, OMV/SaFeFA exhibits pH-responsive release of ferrous ions and the agonist, along with tumor-targeting capabilities, enabling tumor-specific therapy while minimizing side effects. Notably, the concurrent activation of the STING pathway and ferroptosis elicits robust antitumor responses in colon tumor-bearing mouse models, leading to exceptional therapeutic efficacy and prolonged survival. Importantly, no acute toxicity was observed in mice receiving OMV/SaFeFA treatments, underscoring its potential for future tumor therapy and clinical translation.
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Ferroptose , Ferroptose/efeitos dos fármacos , Animais , Camundongos , Linhagem Celular Tumoral , Membrana Externa Bacteriana , Escherichia coli , Humanos , Nanopartículas/química , Feminino , Camundongos Endogâmicos BALB C , Peroxidação de Lipídeos/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Neoplasias do Colo/tratamento farmacológico , ÍonsRESUMO
N6-methyladenosine (m6A) serves as the most abundant posttranscription modification. However, the role of m6A in tumorigenesis and chemotherapeutic drugs sensitivity remains largely unclear. Present research focuses on the potential function of the m6A writer KIAA1429 in tumor development and sorafenib sensitivity in liver cancer. We found that the level of KIAA1429 was significantly elevated in liver cancer tissues and cells and was closely associated with poorer prognosis. Functionally, KIAA1429 promoted the proliferation and Warburg effect of liver cancer cells in vitro and in vivo. RNA-seq and MeRIP-seq analysis revealed the glycolysis was one of the most affected pathways by KIAA1429, and m6A-modified HK1 was the most likely targeted gene to regulate the Warburg effect. KIAA1429 depletion decreased Warburg effect and increased sorafenib sensitivity in liver cancer. Mechanistically, KIAA1429 could affect the m6A level of HK1 mRNA through directly binding with it. Moreover, KIAA1429 cooperated with the m6A reader HuR to enhance HK1 mRNA stability, thereby upregulating its expression. These findings demonstrated that KIAA1429/HK1 axis decreases the sensitivity of liver cancer cells to sorafenib by regulating the Warburg effect, which may provide a novel therapeutic target for liver cancer treatment.
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Antineoplásicos , Hexoquinase , Neoplasias Hepáticas , Camundongos Nus , Sorafenibe , Efeito Warburg em Oncologia , Humanos , Sorafenibe/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/genética , Camundongos , Efeito Warburg em Oncologia/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Hexoquinase/metabolismo , Hexoquinase/genética , Camundongos Endogâmicos BALB C , Linhagem Celular Tumoral , MasculinoRESUMO
INTRODUCTION: Eucommia ulmoides is a unique monophyletic and tertiary relict in China and is listed as a national second-class precious protected tree species. Eucommia ulmoides, recognized as a traditional Chinese medicine, can tonify the liver and kidneys and strengthen bones and muscles. Modern pharmacological research has proved that Eucommia ulmoides has multiple osteoprotective effects, including prohibiting the occurrence of osteoporosis and arthritis and enhancing the healing of bone fractures and bone defects. AIM: To check its osteotropic effects, which may provide ideas for its potential use for the development of novel drugs to treat osteoporosis, this study evaluated the effect of total flavonoids from Eucommia ulmoides leaves (TFEL) on the acquisition of Peak Bone Mass (PBM) in young female rats. MATERIALS AND METHODS: TFEL was isolated, and its purity was confirmed by using a UV spectrophotometer. TFEL with a purity of 85.09% was administered to 6-week-old female rats by oral gavage at a low (50), mid (100), or high (200 mg/kg/d) dose, and the control group was administrated only with the same volume of water. After 13 weeks of treatment, the rats were sacrificed, and serum, different organs, and limb bones (femurs and tibias) were harvested, and the bone turnover markers, organ index, Bone Mineral Density (BMD), biomechanical property, and microstructure parameters were assayed. Furthermore, molecular targets were screened, and network pharmacology analyses were conducted to reveal the potential mechanisms of action of TFEL. RESULTS: Oral administration of TFEL for 13 weeks decreased the serum level of bone resorption marker TRACP-5b. As revealed by micro-computer tomography analysis, it elevated BMD even at a low dose (50 mg/kg/d) and improved the microstructural parameters, which were also confirmed by H&E histological staining. However, TFEL showed no effects on body weights, organ index, and micromorphology in the uterus. In our network pharmacology study, an intersection analysis screened out 64 shared targets, with quercetin, kaempferol, naringenin, and apigenin regulating the greatest number of targets associated with osteoporosis. Flavonoids in Eucommia ulmoides inhibited the occurrence of osteoporosis potentially through targeting signaling pathways for calcium, VEGF, IL-17, and NF-κB. Furthermore, AKT1, EGFR, PTGS2, VEGFA, and CALM were found to be potentially important target genes for the osteoprotective effects of flavonoids in Eucommia ulmoides. CONCLUSION: The above results suggested that TFEL can be used to elevate the peak bone mass in adolescence in female individuals, which may prevent the occurrence of postmenopausal osteoporosis, and the good safety of TFEL also suggests that it can be used as a food additive for daily life to improve the bone health.
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Acute myeloid leukemia (AML) is a heterogeneous disease with rapid progression and frequent mutations. Sideroflexin3 (SFXN3) has been shown to be involved in various neurodegenerative diseases. However, the role of SFXN3 in AML remains unclear. The level and prognostic value of SFXN3 were assessed in pan-cancer, especially AML, based on the data obtained from the TCGA database. The effect and mechanism of SFXN3 in AML were measured by fluorescence-activated cell sorting (FACS), qRT-PCR, western blotting in vitro and in vivo. The correlation between SFXN3 and the infiltration of immune cells in AML was assessed via cibersort and ssGSEA analyses. SFXN3 is expressed at higher levels in AML, and high SFXN3 level is associated with decreased overall survival rate (OSR) in AML. Next, knockdown of SFXN3 results in enhanced cell apoptosis and dropped cell proliferation. Then, knockdown of SFXN3 caused a reduction in the expression of CyclinD1 (CCND1) and nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NFKB1). Finally, SFXN3 may related to the immunosuppressive state of AML. Increased SFXN3 expression is detected in AML, which indicates a poor prognosis and may link to immunosuppressive state of AML. In addition, SFXN3 can inhibit AML cells apoptosis and promote cell proliferation via enhancing CCND1 and NFKB1 levels.
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Pirarubicin (THP) is a new generation of cell cycle non-specific anthracycline-based anticancer drug. In the clinic, THP and THP combination therapies have been shown to be effective in hepatocellular carcinoma (HCC) patients with transcatheter arterial chemoembolization (TACE) without serious side effects. However, drug resistance limits its therapeutic efficacy. Berberine (BBR), an isoquinoline alkaloid, has been shown to possess antitumour properties against various malignancies. However, the synergistic effect of BBR and THP in the treatment of HCC is unknown. In the present study, we demonstrated for the first time that BBR sensitized HCC cells to THP, including enhancing THP-induced growth inhibition and apoptosis of HCC cells. Moreover, we found that BBR sensitized THP by reducing the expression of autophagy-related 4B (ATG4B). Mechanistically, the inhibition of HIF1α-mediated ATG4B transcription by BBR ultimately led to attenuation of THP-induced cytoprotective autophagy, accompanied by enhanced growth inhibition and apoptosis in THP-treated HCC cells. Tumor-bearing experiments in nude mice showed that the combination treatment with BBR and THP significantly suppressed the growth of HCC xenografts. These results reveal that BBR is able to strengthen the killing effect of THP on HCC cells by repressing the ATG4B-autophagy pathway, which may provide novel insights into the improvement of chemotherapeutic efficacy of THP, and may be conducive to the further clinical application of THP in HCC treatment.
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Apoptose , Proteínas Relacionadas à Autofagia , Autofagia , Berberina , Carcinoma Hepatocelular , Doxorrubicina , Neoplasias Hepáticas , Camundongos Nus , Berberina/farmacologia , Berberina/análogos & derivados , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Autofagia/efeitos dos fármacos , Animais , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Proteínas Relacionadas à Autofagia/metabolismo , Proteínas Relacionadas à Autofagia/genética , Camundongos , Apoptose/efeitos dos fármacos , Doxorrubicina/farmacologia , Doxorrubicina/análogos & derivados , Ensaios Antitumorais Modelo de Xenoenxerto , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Camundongos Endogâmicos BALB C , Antineoplásicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Cisteína EndopeptidasesRESUMO
BACKGROUND: Sorafenib is the first-line therapy for patients with advanced-stage HCC, but its clinical cure rate is unsatisfactory due to adverse reactions and drug resistance. Novel alternative strategies to overcome sorafenib resistance are urgently needed. Oxyberberine (OBB), a major metabolite of berberine in vivo, exhibits potential antitumor potency in various human malignancies, including liver cancer. However, it remains unknown whether and how OBB sensitizes liver cancer cells to sorafenib. METHODS: Cell viability, trypan blue staining and flow cytometry assays were employed to determine the synergistic effect of OBB and sorafenib on killing HCC cells. PCR, western blot, co-immunoprecipitation and RNA interference assays were used to decipher the mechanism by which OBB sensitizes sorafenib. HCC xenograft models and clinical HCC samples were utilized to consolidate our findings. RESULTS: We found for the first time that OBB sensitized liver cancer cells to sorafenib, enhancing its inhibitory effect on cell growth and induction of apoptosis in vitro. Interestingly, we observed that OBB enhanced the sensitivity of HCC cells to sorafenib by reducing ubiquitin-specific peptidase 7 (USP7) expression, a well-known tumor-promoting gene. Mechanistically, OBB inhibited notch homolog 1-mediated USP7 transcription, leading to the downregulation of V-Myc avian myelocytomatosis viral oncogene homolog (c-Myc), which synergized with sorafenib to suppress liver cancer. Furthermore, animal results showed that cotreatment with OBB and sorafenib significantly inhibited the tumor growth of liver cancer xenografts in mice. CONCLUSIONS: These results indicate that OBB enhances the sensitivity of liver cancer cells to sorafenib through inhibiting notch homolog 1-USP7-c-Myc signaling pathway, which potentially provides a novel therapeutic strategy for liver cancer to improve the effectiveness of sorafenib.
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Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Animais , Camundongos , Sorafenibe/farmacologia , Peptidase 7 Específica de Ubiquitina/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas c-myc/farmacologia , Transdução de Sinais , Linhagem Celular Tumoral , Receptor Notch1/uso terapêuticoRESUMO
Macroautophagy/autophagy-mediated anoikis resistance is crucial for tumor metastasis. As a key autophagy-related protein, ATG4B has been demonstrated to be a prospective anti-tumor target. However, the existing ATG4B inhibitors are still far from clinical application, especially for tumor metastasis. In this study, we identified a novel circRNA, circSPECC1, that interacted with ATG4B. CircSPECC1 facilitated liquid-liquid phase separation of ATG4B, which boosted the ubiquitination and degradation of ATG4B in gastric cancer (GC) cells. Thus, pharmacological addition of circSPECC1 may serve as an innovative approach to suppress autophagy by targeting ATG4B. Specifically, the circSPECC1 underwent significant m6A modification in GC cells and was subsequently recognized and suppressed by the m6A reader protein ELAVL1/HuR. The activation of the ELAVL1-circSPECC1-ATG4B pathway was demonstrated to mediate anoikis resistance in GC cells. Moreover, we also verified that the above pathway was closely related to metastasis in tissues from GC patients. Furthermore, we determined that the FDA-approved compound lopinavir efficiently enhanced anoikis and prevented metastasis by eliminating repression of ELAVL1 on circSPECC1. In summary, this study provides novel insights into ATG4B-mediated autophagy and introduces a viable clinical inhibitor of autophagy, which may be beneficial for the treatment of GC with metastasis.
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Anoikis , Autofagia , Cisteína Endopeptidases , Lopinavir , RNA Circular , Anoikis/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Humanos , RNA Circular/metabolismo , RNA Circular/genética , Linhagem Celular Tumoral , Cisteína Endopeptidases/metabolismo , Lopinavir/farmacologia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Proteínas Relacionadas à Autofagia/metabolismo , Animais , Camundongos , Ubiquitinação/efeitos dos fármacosRESUMO
Background: Patients with leukemia rely on social and family support. This study aimed to explore the knowledge, attitude, and practice (KAP) toward leukemia among family members of patients with leukemia and the general population in southeast China. Methods: A cross-sectional study was conducted in September 2022 in southeast China (Anhui Province). The KAP scores and demographic data were assessed by questionnaire and analyzed by multivariable logistic regression and structural equation modeling. Results: A total of 760 valid questionnaires were collected, including 117 (15.39%) answered by family members of patients with leukemia. The mean knowledge (8.30 ± 2.79 vs. 8.72 ± 2.56, P = 0.103), attitude (52.17 ± 5.52 vs. 52.27 ± 5.53, P = 0.862), and practice (8.06 ± 2.00 vs. 8.18 ± 2.05, P = 0.547) scores were comparable among family members and the general population. Higher knowledge scores [OR = 1.18 (1.10, 1.27), P < 0.001] and higher attitude scores [OR = 1.05 (1.02, 1.09), P = 0.002] were independently associated with better practice scores. Being a family member of a patient with leukemia had no significant effect on the KAP scores. Conclusion: The participants demonstrated satisfactory knowledge, positive attitude, and appropriate practices toward leukemia, suggesting that access to information about leukemia to the general public might be sufficient in China. Health education might effectively improve knowledge, which could translate into improved attitude and practice.
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N6-methyladenosine (m6A), a dynamically reversible modification in eukaryotic RNAs, modulates gene expression and pathological processes in various tumors. KIAA1429, the largest component of the m6A methyltransferase complex, plays an important role in m6A modification. However, the underlying mechanism of KIAA1429 in hepatocellular carcinoma (HCC) remains largely unknown. Immunohistochemical assay was performed to examine the expression of KIAA1429 in HCC tissues. Transwell, wound healing and animal experiments were used to investigate the influence of KIAA1429 on cell migration and invasion. The mRNA high-throughput sequencing (RNA-seq) and methylated RNA immunoprecipitation sequencing (MeRIP-seq) were performed to screen the downstream target of KIAA1429. RNA stability assays, RNA immunoprecipitation assay (RIP), MeRIP-qPCR and luciferase assay were used to evaluate the relationship between KIAA1429 and the m6A-modified genes. Results showed that the expression level of KIAA1429 was significantly higher in HCC tissues than in adjacent tissues, and the upregulation of KIAA1429 could promote HCC metastasis in vitro and in vivo. Mechanistically, we confirmed that KIAA1429 negatively regulated the tumor suppressor, Rho family GTPase 3 (RND3), by decreasing its mRNA stability in coordination with the m6A reader YTHDC1. Moreover, we demonstrated that KIAA1429 could regulate the m6A modification of RND3 mRNA via its RNA binding domain. Our data indicated that KIAA1429 exerted its oncogenic role by inhibiting RND3 expression in an m6A-dependent manner, suggesting that KIAA1429 might be a potential prognostic biomarker and therapeutic target in HCC.
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Adenina , Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Adenina/análogos & derivados , Carcinoma Hepatocelular/genética , Regulação para Baixo , Neoplasias Hepáticas/genética , RNA , RNA Mensageiro , HumanosRESUMO
Sorafenib is currently the first-line treatment for patients with advanced liver cancer, but its therapeutic efficacy declines significantly after a few months of treatment. Therefore, it is of great importance to investigate the regulatory mechanisms of sorafenib sensitivity in liver cancer cells. In this study, we provided initial evidence demonstrating that circPHKB, a novel circRNA markedly overexpressed in sorafenib-treated liver cancer cells, attenuated the sensitivity of liver cancer cells to sorafenib. Mechanically, circPHKB sequestered miR-1234-3p, resulting in the up-regulation of cytochrome P450 family 2 subfamily W member 1 (CYP2W1), thereby reducing the killing effect of sorafenib on liver cancer cells. Moreover, knockdown of circPHKB sensitized liver cancer cells to sorafenib in vivo. The findings reveal a novel circPHKB/miR-1234-3p/CYP2W1 pathway that decreases the sensitivity of liver cancer cells to sorafenib, suggesting that circPHKB and the axis may serve as promising targets to improve the therapeutic efficacy of sorafenib against liver cancer.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , Humanos , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , MicroRNAs/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Regulação para Cima , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Família 2 do Citocromo P450/genéticaRESUMO
BACKGROUND: The study explores an innovative teaching mode that integrates Icourse, DingTalk, and online experimental simulation platforms to provide online theoretical and experimental resources for clinical biochemistry practical courses. These platforms, combined with flipped classroom teaching, aim to increase student engagement and benefit in practical courses, ultimately improving the effectiveness of clinical biochemistry practical teaching. METHODS: In a prospective cohort study, we examined the impact of integrating the Icourse and DingTalk platforms to provide theoretical knowledge resources and clinical cases to 48 medical laboratory science students from the 2019 and 2020 grades. Students were assigned to the experimental group using an overall sampling method, and had access to relevant videos through Icourse before and during class. Using a flipped classroom approach, students actively participated in the design, analysis, and discussion of the experimental technique. For the experimental operation part, students participated in virtual simulation experiments and actual experiments. Overall, the study aimed to evaluate students' theoretical and operational performance after completing the practical course. To collect feedback, we distributed a questionnaire to students in the experimental group. For comparison, we included 42 students from the grades of 2017 and 2018 who received traditional instruction and were evaluated using standard textbooks as the control group. RESULTS: The experimental group scored significantly higher than the control group on both the theoretical and experimental operational tests (82.45 ± 3.76 vs. 76.36 ± 3.96, P = 0.0126; 92.03 ± 1.62 vs. 81.67 ± 4.19, P < 0.001). The survey revealed that the experimental group preferred the teaching mode that combined the flipped classroom with the virtual simulation platform. This mixed method effectively promoted understanding of basic knowledge (93.8%, 45/48), operative skills (89.6%, 43/48), learning interest (87.5%, 42/48), clinical thinking (85.4%, 41/48), self-learning ability (91.7%, 44/48), and overall satisfaction compared with traditional methods (P < 0.05). This study demonstrates that an innovative teaching approach significantly improves the quality of clinical biochemistry practical courses and promotes students' professional development and self-directed learning habits. CONCLUSION: Incorporating virtual simulation with flipped classrooms into clinical biochemistry practical teaching is an efficient and well-received alternative to traditional methods.
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Aprendizagem , Estudantes , Humanos , Estudos Prospectivos , Inquéritos e Questionários , Projetos de Pesquisa , Currículo , Aprendizagem Baseada em Problemas/métodosRESUMO
BACKGROUND: DNA hypermethylation plays a critical role in the occurrence and progression of acute myeloid leukemia (AML). The mitochondrial serine transporter, SFXN3, is vital for onecarbon metabolism and DNA methylation. However, the impact of SFXN3 on the occurrence and progression of AML has not been reported yet. OBJECTIVE: In this study, we hypothesized that SFXN3 indicates a poor prognosis and suggested tailored treatment for AML patients. METHODS: We used GEPIA and TCGA repository data to analyze the expression of SFXN3 and its correlation with survival in AML patients. RT-qPCR was used to detect the SFXN3 level in our enrolled AML patients and volunteers. Additionally, Whole Genome Bisulfite Sequencing (WGBS) was used to detect the genomic methylation level in individuals. RESULTS: Through the TCGA and GEPIA databases, we found that SFXN3 was enriched in AML patients, predicting shorter survival. Furthermore, we confirmed that SFXN3 was primarily overexpressed in AML patients, especially non-M3 patients, and that high SFXN3 in non-M3 AML patients was found to be associated with poor outcomes and frequent blast cells. Interestingly, non-M3 AML patients with high SFXN3 levels who received hypomethylating therapy showed a higher CR ratio. Finally, we found that SFXN3 could promote DNA methylation at transcription start sites (TSS) in non-M3 AML patients. These sites were found to be clustered in multiple vital cell functions and frequently accompanied by mutations in DNMT3A and NPM1. CONCLUSION: In conclusion, SXFN3 plays an important role in the progression and hypermethylation in non-M3 AML patients and could be a potential biomarker for indicating a high CR rate for hypomethylating therapy.
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Metilação de DNA , Leucemia Mieloide Aguda , Humanos , Metilação de DNA/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mutação , Regulação Leucêmica da Expressão Gênica , PrognósticoRESUMO
PURPOSE: Cancer stemness represents the tumor-initiation and self-renewal potentials of cancer stem cells. It is involved in prostate cancer progression and resistance to therapy. Herein, we aimed to unveil the stemness features, establish a novel prognostic model, and identify potential therapeutic targets. METHODS: 26 stemness-related signatures were obtained from StemChecker. The expression profiles and clinical traits of TCGA-PRAD were obtained from TCGA and cBioPortal, respectively. GSE5446 and GSE70769 cohorts were acquired from GEO. PRAD_MSKCC cohort was also retrieved via the cBioPortal. The consensus clustering method was used for stemness subclusters classification. WGCNA was used to identify hub genes related to the stemness subcluster. The most important feature was explored in vitro. RESULTS: Prostate cancer patients of TCGA-PRAD were divided into two subclusters (C1 and C2) based on the enrichment scores of the 26 stemness-related signatures. C1 was characterized by decreased survival, rich infiltrations of M0 macrophages and regulatory T cells, minimum sensitivity to chemotherapy, and a low response to immunotherapy. Hub genes of the red module with the highest correlation with C1 were subsequently identified by WGCNA and subjected to stemness-related risk model construction based on the machine-learning framework. Prostate cancer patients with high stemness scores had unfavorable prognosis, immunosuppressive tumor microenvironment, minimum sensitivity to chemotherapy, and a low response to immunotherapy. MXD3, the most important factor of the model, can regulate the stemness traits of prostate cancer cells. CONCLUSIONS: Our study depicted the stemness landscapes of prostate cancer and characterized two subclusters with diverse prognoses and tumor immune microenvironments. A stemness-risk signature was developed and demonstrated prospective implications in predicting prognosis and precision medicine.
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Neoplasias da Próstata , Masculino , Humanos , Estudos Prospectivos , Prognóstico , Neoplasias da Próstata/genética , Neoplasias da Próstata/terapia , Próstata , Medicina de Precisão , Microambiente Tumoral/genéticaRESUMO
The present study aimed to investigate the efficacy and safety of flumatinib in patients newly diagnosed with chronic myeloid leukemia in the chronic phase (CML-CP). A retrospective study was conducted using five patients newly diagnosed with CML-CP who received flumatinib (600 mg/day). Results of the present study demonstrated that all five patients with CML-CP that were treated with flumatinib achieved the optimal molecular response within three months. In addition, two patients experienced major molecular response (MMR), and one patient acquired undetectable molecular residual disease, which was maintained for more than one year. Moreover, one patient exhibited grade 3 hematological toxicity, two patients exhibited transient diarrhea, one patient exhibited vomiting and one patient exhibited a rash with pruritus. No second-generation tyrosine kinase inhibitor-specific adverse cardiovascular events occurred in any patients. In conclusion, flumatinib exhibits high efficacy and high early molecular response rate in patients newly diagnosed with CML-CP. The majority of patients obtained MMR within three months, and the adverse reactions experienced were mild and tolerable.
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Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Estudos Retrospectivos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Resultado do Tratamento , Inibidores de Proteínas Quinases/efeitos adversos , Benzamidas , Aminopiridinas , Antineoplásicos/efeitos adversosAssuntos
Azacitidina , Compostos Bicíclicos Heterocíclicos com Pontes , População do Leste Asiático , Leucemia Mieloide Aguda , Sulfonamidas , Humanos , Azacitidina/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Sulfonamidas/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológicoRESUMO
Liver cancer is the most common and frequentlyoccurring cancer. In addition to radiotherapy, chemotherapy and surgery are recommended as part of liver cancer treatment. The efficacy of sorafenib and sorafenib-based combination treatment against tumors has been verified. Although, clinical trials have revealed that some individuals are not sensitive to sorafenib therapy, and current therapeutic approaches are ineffective. Consequently, it is urgent to explore effective drug combinations and innovative techniques for increasing the effectiveness of sorafenib in the curing of liver tumor. Herein, we show that dihydroergotamine mesylate (DHE), an anti-migraine agent, could effectively suppress liver cancer cells proliferation by inhibiting STAT3 activation. However, DHE can enhance the protein stability of Mcl-1 by activating ERK, making DHE less effective in apoptosis induction. Specifically, DHE enhances the effects of sorafenib on liver cancer cells, such as decreased viability and increased apoptosis. Furthermore, the mixture of sorafenib and DHE could enhance DHE-triggered STAT3 suppression and inhibit DHE-mediated ERK-Mcl-1 pathway activation. In vivo, the combination of sorafenib with DHE produced a substantial synergy in suppressing tumour growth and causing apoptosis, ERK inhibition and Mcl-1 degradation. These findings suggest that DHE can effectively inhibit cell proliferation and enhance sorafenib anti-cancer activity in liver cancer cells. The current study provides some new insights that DHE asa novel anti-liver cancer therapeutic agent has been shown to improve treatment outcomes of sorafenib, which might be helpful in order to advance sorafenib in liver cancer therapeutics.
Assuntos
Di-Hidroergotamina , Neoplasias Hepáticas , Humanos , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Di-Hidroergotamina/farmacologia , Di-Hidroergotamina/uso terapêutico , Proteína de Sequência 1 de Leucemia de Células Mieloides , Neoplasias Hepáticas/metabolismo , Apoptose , Linhagem Celular Tumoral , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêuticoRESUMO
Evidence shows that chaperone-mediated autophagy (CMA) is involved in cancer cell pathogenesis and progression. However, the potential role of CMA in breast cancer angiogenesis remains unknown. We first manipulated CMA activity by knockdown and overexpressing of lysosome-associated membrane protein type 2A (LAMP2A) in MDA-MB-231, MDA-MB-436, T47D and MCF7 cells. We found that the tube formation, migration and proliferation abilities of human umbilical vein endothelial cells (HUVECs) were inhibited after cocultured with tumor-conditioned medium from breast cancer cells of LAMP2A knockdown. While the above changes were promoted after cocultured with tumor-conditioned medium from breast cancer cells of LAMP2A overexpression. Moreover, we found that CMA could promote VEGFA expression in breast cancer cells and in xenograft model through upregulating lactate production. Finally, we found that lactate regulation in breast cancer cells is hexokinase 2 (HK2) dependent, and knockdown of HK2 can significantly reduce the ability of CMA-mediated tube formation capacity of HUVECs. Collectively, these results indicate that CMA could promote breast cancer angiogenesis via regulation of HK2-dependent aerobic glycolysis, which may serve as an attractive target for breast cancer therapies.
Assuntos
Neoplasias da Mama , Autofagia Mediada por Chaperonas , Humanos , Feminino , Neoplasias da Mama/patologia , Autofagia , Meios de Cultivo Condicionados , Proteína 2 de Membrana Associada ao Lisossomo/metabolismo , Proteínas de Membrana Lisossomal/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Glicólise , Linhagem Celular TumoralRESUMO
Circulating nitrate is actively absorbed by salivary glands and secreted into the oral cavity, where it is reduced to nitrite by oral nitrate-reducing bacteria. This process has previously been considered harmful because nitrate and nitrite can promote the formation of potentially carcinogenic N-nitrosamines. However, recent studies have shown that nitrate may have other physiological functions, and it can serve as a precursor for the systemic production of nitric oxide (NO) and perform NO-like functions, such as promoting vasodilation, regulating metabolic diseases, alleviating senescence, and protecting the digestive system. Inside the oral cavity, NO is likely to inhibit sensitive species as part of the nonspecific oral immune system. Exogenous administration of nitrate can maintain a balance in the pH of saliva. Oral nitrate-reducing bacteria can control the progression of caries by metabolizing lactic acid and reducing its accumulation, which is beneficial to the homeostasis of the oral microecology. In the current manuscript, we reviewed nitrate-reducing bacteria and their nitrate-metabolizing functions during the development of caries. Furthermore, we listed the effects of probiotics and dietary modification, which may be a promising method to prevent the occurrence of caries. We believe that this review provides novel ideas for the prevention of caries and treatment in clinical settings.