RESUMO
The incomplete prediction of prognosis in esophageal squamous cell carcinoma (ESCC) patients is attributed to various therapeutic interventions and complex prognostic factors. Consequently, there is a pressing demand for enhanced predictive biomarkers that can facilitate clinical management and treatment decisions. This study recruited 491 ESCC patients who underwent surgical treatment at Huashan Hospital, Fudan University. We incorporated 14 blood metabolic indicators and identified independent prognostic indicators for overall survival through univariate and multivariate analyses. Subsequently, a metabolism score formula was established based on the biochemical markers. We constructed a nomogram and machine learning models utilizing the metabolism score and clinically significant prognostic features, followed by an evaluation of their predictive accuracy and performance. We identified alkaline phosphatase, free fatty acids, homocysteine, lactate dehydrogenase, and triglycerides as independent prognostic indicators for ESCC. Subsequently, based on these five indicators, we established a metabolism score that serves as an independent prognostic factor in ESCC patients. By utilizing this metabolism score in conjunction with clinical features, a nomogram can precisely predict the prognosis of ESCC patients, achieving an area under the curve (AUC) of 0.89. The random forest (RF) model showed superior predictive ability (AUC = 0.90, accuracy = 86%, Matthews correlation coefficient = 0.55). Finally, we used an RF model with optimal performance to establish an online predictive tool. The metabolism score developed in this study serves as an independent prognostic indicator for ESCC patients.
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As the world's fourth most deadly cancer, colorectal cancer (CRC) still needed the novel therapeutic drugs and target urgently. Although cyclin-dependent kinase 12 (CDK12) has been shown to be implicated in the malignancy of several types of cancer, its functional role and mechanism in CRC remain largely unknown. Here, we found that suppression of CDK12 inhibited tumor growth in CRC by inducing apoptosis. And CDK12 inhibition triggered autophagy by upregulating autophagy related gene 7 (ATG7) expression. Inhibition of autophagy by ATG7 knockdown and chloroquine (CQ) further decreased cell viability induced by CDK12 inhibition. Further mechanism exploration showed that CDK12 interacted with protein kinase B (AKT) regulated autophagy via AKT/forkhead box O3 (AKT/FOXO3) pathway. FOXO3 transcriptionally upregulated ATG7 expression and autophagy when CDK12 inhibition in CRC. Level of CDK12 and p-FOXO3/FOXO3 ratio were correlated with survival in CRC patients. Moreover, CDK12 inhibition improved the efficacy of anti-programmed cell death 1(PD-1) therapy in CRC murine models by enhancing CD8 + T cells infiltration. Thus, our study founded that CDK12 inhibition upregulates ATG7 triggering autophagy via AKT/FOXO3 pathway and enhances anti-PD-1 efficacy in CRC. We revealed the roles of CDK12/FOXO3/ATG7 in regulating CRC progression, suggesting potential biomarkers and therapeutic target for CRC.
Assuntos
Neoplasias Colorretais , Proteínas Proto-Oncogênicas c-akt , Humanos , Animais , Camundongos , Quinases Ciclina-Dependentes , Apoptose , Autofagia , Neoplasias Colorretais/tratamento farmacológico , Proteína Forkhead Box O3RESUMO
BACKGROUND: Glycolysis under normoxic conditions, known as the Warburg effect, confers a selective advantage for the survival and proliferation of many tumors. In this study, we investigated the role of estrogen-related receptor gamma (ESRRG) in metabolic reprogramming in esophageal squamous cell carcinoma (ESCC). METHODS: Bioinformatics analysis indicated that ESRRG expression was decreased in ESCC tissue and associated with poor clinical outcomes. We also examined the effects of altered ESRRG expression on the proliferation and metabolic reprogramming of ESCC cells. We explored the impact of ESRRG on Pyruvate kinase M2 (PKM2) expression and malignant behavior in ESCC. RESULTS: Our study revealed the inhibitory effects of ESRRG on the growth, tumorigenesis, and glycolysis activity of ESCC cells, which were mediated by the downregulation of PKM2 expression. We further demonstrated that ESRRG directly interacts with the PKM2 promoter to inhibit its activity in ESCC. Notably, the ESRRG-specific agonist, DY131, inhibited ESCC cell proliferation and glycolysis activity by modulating genes in the glycolysis pathway. Moreover, we verified that DY131 exhibits enhanced activity as an immune checkpoint inhibitor, considering the significance of the ESRRG-PKM2 axis in the lactate regulation of ESCC cells. CONCLUSION: Our findings provide novel insights into the role of ESRRG-PKM2 signaling in regulating ESCC cell metabolism and immune checkpoint regulation. Additionally, we suggest that DY131 holds promise as a promising therapeutic agent for ESCC treatment.
Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Regulação para Baixo , Carcinogênese , Ácido Láctico , Receptores de EstrogênioRESUMO
Esophageal squamous cell carcinoma (ESCC) is one of the major subtypes of esophageal cancer. More than half of the patients with ESCC in the world are in China, and the 5-year survival rate is less than 10%. As a new oral proteasome inhibitor, ixazomib has shown strong therapeutic effect in many solid tumors. In this study, we aimed to investigate the effects of ixazomib on the proliferation inhibition and apoptosis of ESCC cells. We used four human ESCC cell lines, cell viability assay, cell cycle and apoptosis assay, reverse-transcription polymerase chain reaction (RT-PCR), Western blot, immunohistochemistry, and ESCC xenografts model to clarify the roles of the therapeutic effect and mechanism of ixazomib in ESCC. Ixazomib significantly inhibited the proliferation and induced apoptosis in ESCC cells. RT-PCR results showed that the expressions of endoplasmic reticulum stress-related gene phorbol-12-myristate-13-acetate-induced protein 1 (NOXA) and MYC proto-oncogene (c-Myc) significantly increase after treatment with ixazomib in ESCC cells. When we knocked down the NOXA and c-Myc by small interfering RNA, the therapeutic effect of ixazomib markedly decreased, which confirmed that c-Myc/NOXA pathway played a key role in the treatment of ESCC with ixazomib. In vivo, the xenograft ESCC model mice were given 10 mg/kg of ixazomib every other day for 30 days. The results showed that the tumor size in the treatment group was significantly smaller than the control group. These results suggested that ixazomib is known to suppress proliferation and induce apoptosis in ESCC cell lines, and this effect was likely mediated by increased activation of the c-Myc/NOXA signaling pathways. SIGNIFICANCE STATEMENT: Esophageal squamous cell carcinoma (ESCC) is the common worldwide malignant tumor, but conventional chemotherapeutics suffer from a number of limitations. In this study, the results suggested that ixazomib suppresses proliferation and induces apoptosis in ESCC cell lines. Therefore, ixazomib may be a potential new strategy for ESCC therapy.
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Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Compostos de Boro/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Neoplasias Esofágicas/tratamento farmacológico , Glicina/análogos & derivados , Animais , Antineoplásicos/uso terapêutico , Compostos de Boro/farmacologia , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Neoplasias Esofágicas/metabolismo , Glicina/farmacologia , Glicina/uso terapêutico , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismoRESUMO
Oestrogen related receptor α participated in the regulation of oxidative metabolism and mitochondrial biogenesis, and was overexpressed in many cancers including triple-negative breast cancer. A set of new ERRα inverse agonists based on p-nitrobenzenesulfonamide template were discovered and compound 11 with high potent activity (IC50 = 0.80 µM) could significantly inhibit the transcription of ERRα-regulated target genes. By regulating the downstream signalling pathway, compound 11 could suppress the migration and invasion of the ER-negative MDA-MB-231 cell line. Furthermore, compound 11 demonstrated a significant growth suppression of breast cancer xenograft tumours in vivo (inhibition rate 23.58%). The docking results showed that compound 11 could form hydrogen bonds with Glu331 and Arg372 in addition to its hydrophobic interaction with ligand-binding domain. Our data implied that compound 11 represented a novel and effective ERRα inverse agonist, which had broad application prospects in the treatment of triple-negative breast cancer.
Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Nitrobenzenos/farmacologia , Receptores de Estrogênio/metabolismo , Sulfonamidas/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Nitrobenzenos/síntese química , Nitrobenzenos/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Receptor ERRalfa Relacionado ao EstrogênioRESUMO
OBJECTIVE: We described our initial experience of a new integrated oncology phamaceutical care practice to enhance the quality of pharmacy service and patient care in Huashan hospital.Data sources: A retrospective study was performed from August 2019 to September 2020. Patients were described as integrated pharmacy service group and routine care group. Medication adherence of patients in integrated pharmacy service group was recorded by the online management system. Patient satisfaction and the cumulative incidence of emergency room (ER) and outpatient visit were evaluated between two groups.Data summary: In total, 323 patients received the integrating oncology pharmacy service. The percentage of the patients missing administration every day was reduced from 29.7% to 0.3% within a 40-day monitoring and intervention period. There was a significant difference on patient satisfaction with pharmacy service in two groups (P < 0.05). Fewer patients in the integrated pharmacy service group visited clinic and ER compared with routine care group (33.1% vs. 59.2%; P < 0.05). CONCLUSIONS: As a new practice model, the integrated program is adopted to provide patient care and ongoing monitoring for cancer patients. The practice model delivers high continuity of care for cancer patients and improves communication and collaboration between healthcare professionals and oncology patients. The practice also provides the potential of developing hospital pharmaceutical service and optimizing disease prevention and treatment strategies.
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Neoplasias , Serviço de Farmácia Hospitalar , Serviço Hospitalar de Emergência , Humanos , Adesão à Medicação , Neoplasias/tratamento farmacológico , Estudos RetrospectivosRESUMO
BACKGROUND: The chemotherapy resistance and toxicity of chemotherapy are major problems in breast cancer treatment. However, candidate biomarkers for predicting clinical outcomes and better prognosis remain lacking. METHODS: In this study, we analyzed possible impact of 8 genetic variants of fibroblast growth factor receptor1-4 (FGFR1-4) on the treatment response and toxicities in 211 breast cancer patients. DNA was extracted from peripheral blood cells, and the genotypes were examined using the TaqMan Pre-Designed SNP Genotyping Assays. RESULTS: The FGFR4 rs1966265 and FGFR2 rs2981578 contributed to clinical outcome of breast cancer treated with docetaxel-epirubicin-cyclophosphamide (CET)-based chemotherapy. For rs1966265, AA genotype had significant correlation with the clinical response to neoadjuvant chemotherapy (NCT) when compared with GG and AG/GG genotype (P = 0.019 and P = 0.004, respectively). Moreover, A allele of FGFR2 rs2981578 had significant rates of response (P = 0.025). In addition, rs2420946 CC genotype was associated with higher frequency of toxicities compared with TT and CT/TT genotypes (P = 0.038 and P = 0.019, respectively). Also, rs2981578 AG genotype showed higher frequency of toxicities compared with GG genotype (P < 0.0001). CONCLUSIONS: The results suggest these polymorphisms, especially rs1966265 and rs2981578, might be candidate pharmacogenomics factors to the response and prognosis prediction for individualized CET-based chemotherapy in breast cancer patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Polimorfismo de Nucleotídeo Único , Receptores de Fatores de Crescimento de Fibroblastos/genética , Adulto , Idoso , Alelos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Ciclofosfamida/administração & dosagem , Docetaxel/administração & dosagem , Epirubicina/administração & dosagem , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Razão de Chances , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Resultado do TratamentoRESUMO
Creatine kinase elevation is commonly reported in telbivudine-treated patients. However, little is known about the relationship between this adverse drug reaction and plasma concentration. In this study, a sensitive, rapid and safe quantitative bioanalytical method has been established by using LC-MS/MS for the determination of telbivudine in a clinical study of chronic hepatitis B patients. The assay was linear in a dynamic 10-10,000 ng/mL range (r2 > 0.999) and total analysis time was 6 min in this method. The validated method was applied to quantitatively determine plasma concentration in chronic hepatitis B patients during long-term telbivudine treatment. The results revealed that telbivudine concentration in the creatine kinase-elevated group (707.92-2788.78 ng/mL) was significantly higher than those with normal creatine kinase (412.63-1108.32 ng/mL). This method was adapted for therapeutic drug monitoring.
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Antivirais/sangue , Cromatografia Líquida de Alta Pressão/métodos , Hepatite B Crônica/tratamento farmacológico , Espectrometria de Massas em Tandem/métodos , Timidina/análogos & derivados , Adulto , Antivirais/administração & dosagem , Antivirais/uso terapêutico , Creatina Quinase/sangue , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Telbivudina , Timidina/administração & dosagem , Timidina/sangue , Timidina/uso terapêutico , Adulto JovemRESUMO
PURPOSE: Cervical cancer remains the most gruesome health problem in women worldwide as it ranks third in incidence. Despite recent developments in the treatment options of cervical cancer, the survival of patients not fit for surgical treatment rather remains poor. The main purpose of the current research was to determine the anticancer effect of farnesol in HeLa human cervical cancer cells together with studying its impact on apoptosis induction, mitochondrial membrane potential (MMP) and PI3K/Akt signalling cascade. METHODS: Cell viability was estimated by MTT assay while clonogenic assay was used to assess the effects on colony formation tendency in these cells. Fluorescence microscopy indicated apoptosis induction while flow cytometry showed the farnesol effects on the loss of MMP. RESULTS: Farnesol exerted both dose and time-dependent antiproliferative effects on cervical cancer cells with IC50 values of 33.5, 23.8 and 17.6 µM at 24, 48 and 72 hrs time intervals, respectively. Colony formation of HeLa cells was considerably affected in a dose-dependent manner with the addition of farnesol to the cell culture. Farnesol-treated cells mostly emitted orange fluorescence indicating apoptotic cell death and this effect increased with increasing dose of the compound. Furthermore, farnesol induced considerable reduction in the number of cells with depolarized mitochondria corresponding to a reduction of MMP. With increase in the dosage of farnesol, there was a noticeable decrease in the expression levels of PI3K, p-PI3K and p-Akt proteins. CONCLUSIONS: In brief, this study showed that farnesol -a naturally occurring sesquiterpene- exerts powerful antiproliferative activity via apoptosis induction, loss of MMP and downregulation of the expression levels of PI3K, p-PI3K and p-Akt proteins.
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Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Farneseno Álcool/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Neoplasias do Colo do Útero/tratamento farmacológico , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Feminino , Células HeLa , Humanos , Potencial da Membrana Mitocondrial/genética , Transdução de Sinais/efeitos dos fármacos , Neoplasias do Colo do Útero/genéticaRESUMO
BACKGROUND: Olaparib combined with paclitaxel has previously shown a significant improvement in overall survival versus placebo plus paclitaxel as second-line therapy in a phase 2 study in Asian patients with advanced gastric cancer, especially in those with ataxia-telangiectasia mutated protein (ATM)-negative tumours. Here, we report the primary efficacy and safety analyses from a subsequent phase 3 trial. METHODS: This double-blind, randomised, placebo-controlled, phase 3 study (GOLD) recruited Asian patients aged 18 years or older (≥20 years if Japanese) with advanced gastric cancer that had progressed following, or during, first-line chemotherapy. Patients were randomly assigned (1:1) to receive oral olaparib (100 mg twice daily) plus paclitaxel (80 mg/m2 intravenously) or matching placebo plus paclitaxel. Randomisation was done through an interactive voice response system and no stratification factors were used. Patients and investigators were masked to treatment allocation. Two co-primary populations were assessed: the overall population of all patients and patients whose tumours were ATM-negative (identified after randomisation, before the data cutoff date, March 28, 2016). The primary endpoint in both populations was overall survival (defined as the time from the date of randomisation until death from any cause before data cutoff); a significant difference was defined as p<0·025. Efficacy was assessed in the intention-to-treat populations and safety in patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov, number NCT01924533 (study ID, D081BC00004), and is ongoing but no longer recruiting participants. FINDINGS: Between Sept 3, 2013, and March 28, 2016, 643 patients were enrolled from 58 study sites in hospitals and medical centres in China, Japan, South Korea, and Taiwan. 525 eligible patients were randomly assigned: 263 to receive olaparib plus paclitaxel and 262 to receive placebo plus paclitaxel. 94 patients were determined to have ATM-negative tumours before unmasking for the primary analysis (48 in the olaparib plus paclitaxel group and 46 in the placebo plus paclitaxel group). Overall survival did not differ between treatment groups in the overall patient population (median overall survival 8·8 months [95% CI 7·4-9·6] in the olaparib group vs 6·9 months [6·3-7·9] in the placebo group; HR 0·79 [97·5% CI 0·63-1·00]; p=0·026) or in the ATM-negative population (12·0 months [7·8-18·1] vs 10·0 months [6·4-13·3]; 0·73 [0·40-1·34]; p=0·25). In the overall patient population, the most common grade 3 or worse adverse events in the olaparib plus paclitaxel group were neutropenia (78 [30%] of 262 patients), leucopenia (42 [16%]), and decreased neutrophil count (40 [15%]); in the placebo plus paclitaxel group, they were neutropenia (59 [23%] of 259 patients), leucopenia (27 [10%]), and decreased white blood cell count (21 [8%]). Adverse events with an outcome of death causally related to study treatment (according to investigator assessment) were reported in two patients: liver injury in one patient (<1%) in the olaparib plus paclitaxel group and cardiac failure in one patient (<1%) in the placebo plus paclitaxel group. INTERPRETATION: The GOLD study did not meet its primary objective of showing a significant improvement in overall survival with olaparib in the overall or ATM-negative population of Asian patients with advanced gastric cancer. The study generated informative efficacy and safety data regarding the use of olaparib in combination with a chemotherapeutic agent and provides a foundation for future studies in this difficult-to-treat patient population. FUNDING: AstraZeneca.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Paclitaxel/administração & dosagem , Ftalazinas/administração & dosagem , Piperazinas/administração & dosagem , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/mortalidade , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ásia , Progressão da Doença , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Paclitaxel/efeitos adversos , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Modelos de Riscos Proporcionais , Indução de Remissão , Neoplasias Gástricas/patologia , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Optimum management strategies for patients with advanced non-small-cell lung cancer (NSCLC) with acquired resistance to EGFR tyrosine-kinase inhibitors are undefined. We aimed to assess the efficacy and safety of continuing gefitinib combined with chemotherapy versus chemotherapy alone in patients with EGFR-mutation-positive advanced NSCLC with acquired resistance to first-line gefitinib. METHODS: The randomised, phase 3, multicentre IMPRESS study was done in 71 centres in 11 countries in Europe and the Asia-Pacific region. Eligible patients were aged at least 18 years with histologically confirmed, chemotherapy-naive, stage IIIB-IV EGFR-mutation-positive advanced NSCLC with previous disease control with first-line gefitinib and recent disease progression (Response Evaluation Criteria in Solid Tumors version 1.1). Participants were randomly assigned (1:1) by central block randomisation to oral gefitinib 250 mg or placebo once daily in tablet form; randomisation did not include stratification factors. All patients also received the platinum-based doublet chemotherapy cisplatin 75 mg/m(2) plus pemetrexed 500 mg/m(2) on the first day of each cycle. After completion of a maximum of six chemotherapy cycles, patients continued their randomly assigned treatment until disease progression or another discontinuation criterion was met. All study investigators and participants were masked to treatment allocation. The primary endpoint was progression-free survival in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. The study has completed enrolment, but patients are still in follow-up for overall survival. This trial is registered with ClinicalTrials.gov, number NCT01544179. FINDINGS: Between March 29, 2012, and Dec 20, 2013, 265 patients were randomly assigned: 133 to the gefitinib group and 132 to the placebo group. At the time of data cutoff (May 5, 2014), 98 (74%) patients had disease progression in the gefitinib group compared with 107 (81%) in the placebo group (hazard ratio 0·86, 95% CI 0·65-1·13; p=0·27; median progression-free survival 5·4 months in both groups [95% CI 4·5-5·7 in the gefitinib group and 4·6-5·5 in the placebo group]). The most common adverse events of any grade were nausea (85 [64%] of 132 patients in the gefitinib group and 81 [61%] of 132 patients in the placebo group) and decreased appetite (65 [49%] and 45 [34%]). The most common adverse events of grade 3 or worse were anaemia (11 [8%] of 132 patients in the gefitinib group and five [4%] of 132 patients in the placebo group) and neutropenia (nine [7%] and seven [5%]). 37 (28%) of 132 patients in the gefitinib group and 28 (21%) of 132 patients in the placebo group reported serious adverse events. INTERPRETATION: Continuation of gefitinib after radiological disease progression on first-line gefitinib did not prolong progression-free survival in patients who received platinum-based doublet chemotherapy as subsequent line of treatment. Platinum-based doublet chemotherapy remains the standard of care in this setting. FUNDING: AstraZeneca.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Administração Oral , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ásia , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Cisplatino/administração & dosagem , Progressão da Doença , Intervalo Livre de Doença , Esquema de Medicação , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Europa (Continente) , Feminino , Gefitinibe , Predisposição Genética para Doença , Glutamatos/administração & dosagem , Guanina/administração & dosagem , Guanina/análogos & derivados , Humanos , Infusões Intravenosas , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Pemetrexede , Fenótipo , Modelos de Riscos Proporcionais , Estudos Prospectivos , Inibidores de Proteínas Quinases/administração & dosagem , Quinazolinas/administração & dosagem , Fatores de Tempo , Resultado do TratamentoRESUMO
CONTEXT: Obesity is associated with a number of diseases with metabolic abnormalities such as type 2 diabetes (T2D). OBJECTIVE: We investigate the effects of tectorigenin on 3T3-L1 preadipocyte differentiation and adipocytokines secretion. MATERIALS AND METHODS: The effects of tectorigenin on adipocyte differentiation were studied using Oil Red O staining. Effects of tectorigenin on adipogenesis-related genes expression and adipocytokines secretion were measured by the real-time quantitative RT-PCR and ELISA method, respectively. Reporter gene assays were performed to determine the PPARγ and NF-κB transactivation. We also used [(3)H]-2-deoxy-d-glucose to study the glucose uptake, and the IKK/NF-κB signaling pathway was assessed by western blot analysis. HFD/STZ rats were used to evaluate the therapeutic efficacies of tectorigenin. RESULTS: Tectorigenin 10, 25, 50, and 75 µM inhibited 3T3-L1 adipogenesis and related genes transcription. TNF-α-induced changes of IL-6, MCP-1, as well as adiponectin in 3T3-L1 were markedly reversed by tectorigenin at 75 µM. Further investigation using reporter gene revealed that tectorigenin was a partial PPARγ agonist with an IC50 value of 13.3 µM. Tectorigenin improved basal and insulin-stimulated glucose uptake in mature 3T3-L1 adipocytes. Moreover, tectorigenin antagonized TNF-α-induced NF-κB transactivation and p65 nuclear translocation. Although tectorigenin (50 and 100 mg/kg) displayed the ability to promote insulin sensitivity and improve glucose metabolism in HFD/STZ rats, it did not cause significant side effects such as body weight gain, fluid retention, or cardiac hypertrophy. DISCUSSION AND CONCLUSION: These results suggest that tectorigenin may ameliorate hyperglycemia by blocking preadipocyte differentiation and adipocytokines secretion in which PPARγ and NF-κB signaling pathways were involved.
Assuntos
Adipogenia/fisiologia , Adipocinas/metabolismo , Diferenciação Celular/fisiologia , Isoflavonas/farmacologia , NF-kappa B/metabolismo , PPAR gama/metabolismo , Células 3T3-L1 , Adipogenia/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologiaRESUMO
Abnormal proliferation of vascular smooth muscle cells (VSMCs) plays an important role in several pathological processes of cardiovascular diseases. In this study, the effects of XCT790, a potent and selective inverse agonist of estrogen-related receptor alpha (ERRalpha), on rat VSMCs proliferation and related signal pathways were investigated. The proliferative activity of VSMCs was determined by CCK-8 assay. The mRNA levels of ERRalpha, PGC-1alpha, OPN and MCAD were assayed by RT-PCR. The protein levels of ERRalpha, ERK2 and p-ERK1/2 were evaluated by Western blotting. ELISA was used to assess the protein expression of VEGF. The results showed that XCT790 (5-20 micromol x L(-1)) inhibited rat VSMCs proliferation, and the expression of ERRalpha and its target genes, as well as p-ERK1/2, were also inhibited. XCT790 inhibited VSMCs proliferation in a dose-dependent manner at the dose range from 5 to 20 micromol x L(-1) and in a time-dependent manner at the dose range from 10 to 20 micromol x L(-1). These findings demonstrate that XCT790 inhibits rat VSMCs proliferation by down-regulating the gene level of ERRalpha and thus inhibiting the ERK signal pathway, suggesting that ERRalpha may be a novel potential target for therapeutic approaches to inhibit VSMCs proliferation, which plays an important role in several cardiovascular diseases.
Assuntos
Proliferação de Células/efeitos dos fármacos , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/citologia , Nitrilas/farmacologia , Receptores de Estrogênio/metabolismo , Tiazóis/farmacologia , Animais , Caderinas/genética , Caderinas/metabolismo , Células Cultivadas , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Relação Dose-Resposta a Droga , Proteínas Ativadoras de GTPase/genética , Proteínas Ativadoras de GTPase/metabolismo , Sistema de Sinalização das MAP Quinases , Masculino , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Nitrilas/administração & dosagem , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Fosforilação , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Estrogênio/genética , Tiazóis/administração & dosagem , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor ERRalfa Relacionado ao EstrogênioRESUMO
A total of 162 non-small cell lung cancer (NSCLC) patients were divided into discovery (N = 68) and validation (N = 94) groups. Nine Janus kinase/Signal transducer and activator of transcription (JAK/STAT) pathway-related single nucleotide polymorphisms were selected to explore the potential associations between genetic polymorphisms and adverse drug reactions (ADRs). The TT genotype of STAT6 rs324011 was significantly associated with severe ADRs in the recessive genetic model (TT vs. CC + CT, OR = 13.5, 95% CI = 2.12-86.09, p = 0.006 in the discovery group; OR = 8.41, 95% CI = 1.95-36.19, p = 0.004 in the validation group). The T allele was associated with a higher incidence of severe ADRs than was the C allele of rs324011 (OR = 3.67, 95% CI = 1.46-9.19, p = 0.006 in the discovery group; OR = 3.17, 95% CI = 1.44-6.99, p = 0.004 in the validation group). Patients with the CC genotype in STAT3 rs1053023 (and rs1053005) or the TT genotype of STAT6 rs324011 were likely to experience severe epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) related ADRs.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Polimorfismo de Nucleotídeo Único , Receptores ErbB , China , Inibidores de Proteínas Quinases/uso terapêutico , Mutação , Fator de Transcrição STAT6/genética , Fator de Transcrição STAT3RESUMO
Ecologically feasible strategies for constructing superhydrophobic surfaces offer versatile applications in waterproofing, self-cleaning, selective absorption, and corrosion protection. Herein, we prepared low-surface-energy branched-chain-enriched micronanorod (F@SiO2@MNC) by hydrolyzing silane coupling agent and modifying fluoropolymer using micro-nanocellulose extracted from waste straw (Chinese hemp). These rods were sprayed and adhered to various substrates precoated with a binder, resulting in superhydrophobic surfaces. F@SiO2@MNC addition allowed for the formation of stable spherical liquid droplets when in contact with different types of aqueous liquids. Furthermore, these surfaces demonstrated excellent self-cleaning, robustness, abrasion resistance, UV resistance, cycling stability, and other multifunctionalities. They significantly enhanced the mechanical properties of filter paper, effectively separated oil water mixtures, and improved the corrosion resistance of metals. Our proposed strategy represents a novel approach for developing multifunctional coatings assembled from micronanocellulose.
Assuntos
Cannabis , Dióxido de Silício , Corrosão , Interações Hidrofóbicas e Hidrofílicas , ChinaRESUMO
Carfilzomib, a second-generation proteasome inhibitor, has been approved as a treatment for relapsed and/or refractory multiple myeloma. Nevertheless, the molecular mechanism by which Carfilzomib inhibits esophageal squamous cell carcinoma (ESCC) progression largely remains to be determined. In the present study, we found that Carfilzomib demonstrated potent anti-tumor activity against esophageal squamous cell carcinoma both in vitro and in vivo. Mechanistically, carfilzomib triggers mitochondrial apoptosis and reprograms cellular metabolism in ESCC cells. Moreover, it has been identified that activating transcription factor 3 (ATF3) plays a crucial cellular target role in ESCC cells treated with Carfilzomib. Overexpression of ATF3 effectively antagonized the effects of carfilzomib on ESCC cell proliferation, apoptosis, and metabolic reprogramming. Furthermore, the ATF3 protein is specifically bound to lactate dehydrogenase A (LDHA) to effectively suppress LDHA-mediated metabolic reprogramming in response to carfilzomib treatment. Research conducted in xenograft models demonstrates that ATF3 mediates the anti-tumor activity of Carfilzomib. The examination of human esophageal squamous cell carcinoma indicated that ATF3 and LDHA have the potential to function as innovative targets for therapeutic intervention in the treatment of ESCC. Our findings demonstrate the novel function of Carfilzomib in modulating ESCC metabolism and progression, highlighting the potential of Carfilzomib as a promising therapeutic agent for the treatment of ESCC.
Assuntos
Fator 3 Ativador da Transcrição , Antineoplásicos , Carcinoma de Células Escamosas , Neoplasias Esofágicas , Oligopeptídeos , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Oligopeptídeos/farmacologia , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Xenoenxertos , Transplante de Neoplasias , Humanos , Animais , Camundongos , Camundongos Endogâmicos BALB C , Proliferação de Células/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Apoptose , Reprogramação Metabólica/efeitos dos fármacos , Fator 3 Ativador da Transcrição/metabolismoRESUMO
OBJECTIVE: This study aimed to evaluate the real-world clinical efficacy and safety, economic burdens and medical resource utilization (MRU) of toripalimab treatment patterns compared with bevacizumab plus chemotherapy (BCP) for patients with advanced non-squamous NSCLC in China. METHODS: Progression-free survival (PFS), adverse drug reactions (ADR) and the costs of drugs, laboratory testing, imageology examinations (including CT, B ultrasound, MRI), medical service, nursing, treatment, genetic test and medical disposable material were compared between two groups. A retrospective observational study was conducted with electronic medical records from Fudan University Huashan hospital. Data was obtained from established electronic medical records (EMRs) and patient surveys. Survival time from the study enrollment to disease progression or death plus from 1st progression disease (PD) in the maintenance phase to 2nd PD (PFS II), adverse events (AE), direct medical costs, MRU and AE-related costs were collected and compared between toripalimab group and BCP group. A total of 246 patients were enrolled. RESULTS: Toripalimab combination therapy has significantly prolonged PFS comparing with BCP (13.8 months vs. 6.2 months, p < .001). A statistically significant improvement in PFS was observed favoring all toripalimab regimen subgroups compared with the bevacizumab group. Patients in toripalimab group occupied more overall resource consumption, more direct medical costs ($47,056.9 vs. $29,951.0, p < .0001) and AE-related costs ($4,500.2 vs. $784.4, p < .0001) than BCP group. Although patients in the toripalimab group used more drugs to prevent AEs ($4,500.2 vs. $784.4, p < .0001), they still experienced more AEs than patients in BCP group (51.4% vs. 41.4%). CONCLUSION: Toripalimab combination therapy could significantly prolonged PFS for patients with advanced non-squamous NSCLC compared with BCP, but at the expense of more MRU, costs and AEs.
Assuntos
Anticorpos Monoclonais Humanizados , Bevacizumab , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológicoRESUMO
SIRT6 is a key member of the mammalian sirtuin family of conserved nicotinamide adenine dinucleotide (NAD+ )-dependent deacetylases. Previous studies have shown that SIRT6 can regulate metabolism, DNA damage repair and aging. Ovarian aging process usually share similar mechanisms with general aging, which is characterized by decreases in both numbers of ovarian follicles and the quality of oocytes. It is reported that the expression level of SIRT6 was significantly decreased in the ovaries of aged mice, and the level of SIRT6 was positively correlated with ovarian reserve, indicating that SIRT6 may be potential markers of ovarian aging. However, its biological roles in follicular development are still unclear. Here, we explored the effect of SIRT6 on follicular development and found that ovarian development was interrupted in SIRT6 knockout (KO) mice, leading to disruptions of puberty and the estrus cycle, significant decreases in numbers of secondary and antral follicles, and decreased collagen in the ovarian stroma. Plod1, a lysyl hydroxylase that is vital for collagen crosslinking and deposition, was decreased at both the mRNA and protein levels in SIRT6-deficient ovaries and granulosa cells (GCs). Additionally, we found abnormal estrogen levels in both SIRT6 KO mice and SIRT6 KD GCs, accompanied by decreases in the levels of the estrogen biosynthesis genes Cyp11a1, Cyp19a1, Mgarp, and increases in the levels of TNF-α and NF-κB. These results confirmed the effect of SIRT6 on follicular development and revealed a possible molecular mechanism for SIRT6 involvement in follicular development via effects on estrogen biosynthesis and collagen formation.
Assuntos
Ovário , Sirtuínas , Animais , Feminino , Camundongos , Estrogênios/metabolismo , Mamíferos/metabolismo , Oócitos/metabolismo , Folículo Ovariano/metabolismo , Ovário/metabolismo , Sirtuínas/genética , Sirtuínas/metabolismo , Pró-Colágeno-Lisina 2-Oxoglutarato 5-Dioxigenase/metabolismoRESUMO
CONTEXT: The COVID-19 pandemic has had a global impact on food security and nutrition, both in the short and long term. The influence on school-age children, adolescents, and young adults may be particularly significant and long-lasting. OBJECTIVE: This systematic review and meta-analysis aimed to quantify the impact of the COVID-19 pandemic on dietary habits among school-age children, adolescents, and young adults worldwide. DATA SOURCES: PubMed, Web of Science, and Embase were searched from inception to October 5, 2023. DATA EXTRACTION: We included observational studies published in English that reported dietary quality scores and dietary intake quantities during and before the COVID-19 pandemic among school-age children, adolescents, and young adults. We included a total of 22 cohort studies and 20 cross-sectional studies of high or moderate quality. DATA ANALYSIS: We conducted a meta-analysis, expressing dietary quality scores and dietary intake quantities as standardized mean differences (SMD) with 95% confidence intervals (CIs). For studies with low heterogeneity, we used a fixed-effects model; otherwise, we applied a random-effects model. The Newcastle-Ottawa Scale was employed by 2 reviewers independently to evaluate methodological quality. The analysis indicated that, overall, juice intake increased (SMD = 0.12, 95% CI: 0.04 to 0.20), while alcohol consumption reduced during the COVID-19 pandemic (SMD = -0.28, 95% CI: -0.47 to -0.08). However, the age-stratified results varied. Among school-age children, intake of fruit, dairy products, sugar, and juice increased. Adolescents showed an increase in meal frequency and vegetable intake. Young adults showed reduced carbohydrate and alcohol intakes, while protein and dairy product intakes increased, based on limited included studies. CONCLUSION: Dietary changes in school-age children from before to during the pandemic were mixed, while dietary behavior changes in adolescents and young adults tended to be more positive. Considering the lasting effects of negative dietary behaviors, attention should be given to addressing the increased sugar and juice intakes. It is also crucial that caregivers and researchers monitor whether positive dietary behaviors will rebound after returning to normal study and life. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42023420923.
RESUMO
OBJECTIVES: The use of tumor-informed circulating tumor DNA (ctDNA) testing in patients with early-stage disease before surgery is limited, mainly owing to restricted tissue access and extended turnaround times. This study aimed to evaluate the clinical value of a tumor-naïve, methylation-based cell-free DNA assay in a large cohort of patients with resected NSCLC. METHOD: We analyzed presurgical plasma samples from 895 patients with EGFR and anaplastic lymphoma kinase-wild-type, clinical stage I or II NSCLC. The ctDNA status was evaluated for its prognostic significance in relation to tumor volume, metabolic activity, histologic diagnosis, histologic subtypes, and clinical-to-pathologic TNM upstaging. RESULTS: Presurgical ctDNA detection was observed in 55 of 414 patients (13%) with clinical stage I lung adenocarcinoma (LUAD) and was associated with poor recurrence-free survival (2-year recurrence-free survival 69% versus 91%; log-rank p < 0.001), approaching that of clinical stage II LUAD. Presurgical ctDNA detection was not prognostic in patients with clinical stage II LUAD or non-LUAD. Within LUAD, tumor volume and positron emission tomography avidity interacted to predict presurgical ctDNA detection. Moreover, presurgical ctDNA detection was predictive of the postsurgical discovery of International Association for the Study of Lung Cancer grade 3 tumors (p < 0.001) and pathologic TNM upstaging (p < 0.001). Notably, presurgical ctDNA detection strongly correlated with higher programmed death-ligand 1 expression in tumors (positive rates 28% versus 55%, p < 0.001), identifying a subgroup likely to benefit from anti-programmed death-ligand 1 therapies. CONCLUSION: These findings support the integration of ctDNA testing into routine diagnostic workflows in early-stage NSCLC without the need for tumor tissue profiling. Furthermore, it is clinically useful in identifying patients at high risk who might benefit from innovative treatments, including neoadjuvant immune checkpoint inhibitors.