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2.
Redox Biol ; 69: 103007, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38150993

RESUMO

Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors and the fourth leading cause of cancer-related death globally, which is characterized by complicated pathophysiology, high recurrence rate, and poor prognosis. Our previous study has demonstrated that disulfiram (DSF)/Cu could be repurposed for the treatment of HCC by inducing ferroptosis. However, the effectiveness of DSF/Cu may be compromised by compensatory mechanisms that weaken its sensitivity. The mechanisms underlying these compensatory responses are currently unknown. Herein, we found DSF/Cu induces endoplasmic reticulum stress with disrupted ER structures, increased Ca2+ level and activated expression of ATF4. Further studies verified that DSF/Cu induces both ferroptosis and cuproptosis, accompanied by the depletion of GSH, elevation of lipid peroxides, and compensatory increase of xCT. Comparing ferroptosis and cuproptosis, it is interesting to note that GSH acts at the crossing point of the regulation network and therefore, we hypothesized that compensatory elevation of xCT may be a key aspect of the therapeutic target. Mechanically, knockdown of ATF4 facilitated the DSF/Cu-induced cell death and exacerbated the generation of lipid peroxides under the challenge of DSF/Cu. However, ATF4 knockdown was unable to block the compensatory elevation of xCT and the GSH reduction. Notably, we found that DSF/Cu induced the accumulation of ubiquitinated proteins, promoted the half-life of xCT protein, and dramatically dampened the ubiquitination-proteasome mediated degradation of xCT. Moreover, both pharmacologically and genetically suppressing xCT exacerbated DSF/Cu-induced cell death. In conclusion, the current work provides an in-depth study of the mechanism of DSF/Cu-induced cell death and describes a framework for the further understanding of the crosstalk between ferroptosis and cuproptosis. Inhibiting the compensatory increase of xCT renders HCC cells more susceptible to DSF/Cu, which may provide a promising synergistic strategy to sensitize tumor therapy and overcome drug resistance, as it activates different programmed cell death.


Assuntos
Carcinoma Hepatocelular , Ferroptose , Neoplasias Hepáticas , Humanos , Dissulfiram/farmacologia , Dissulfiram/química , Cobre/química , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Peróxidos Lipídicos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética
3.
Cancer Cell Int ; 23(1): 69, 2023 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-37062830

RESUMO

Stomach adenocarcinoma (STAD) is the third leading cause of cancer-related deaths and the fifth most prevalent malignancy worldwide. Mitochondrial respiratory chain complexes play a crucial role in STAD pathogenesis. However, how mitochondrial respiratory chain complex genes (MRCCGs) affect the prognosis and tumor microenvironment in STAD remains unclear. In this study, we systematically analyzed genetic alterations and copy number variations of different expression densities of MRCCGs, based on 806 samples from two independent STAD cohorts. Then we employed the unsupervised clustering method to classify the samples into three expression patterns based on the prognostic MRCCG expressions, and found that they were involved in different biological pathways and correlated with the clinicopathological characteristics, immune cell infiltration, and prognosis of STAD. Subsequently, we conducted a univariate Cox regression analysis to identify the prognostic value of 1175 subtype-related differentially expressed genes (DEGs) and screened out 555 prognostic-related genes. Principal component analysis was performed and developed the MG score system to quantify MRCCG patterns of STAD. The prognostic significance of MG Score was validated in three cohorts. The low MG score group, characterized by increased microsatellite instability-high (MSI-H), tumor mutation burden (TMB), PD-L1 expression, had a better prognosis. Interestingly, we demonstrated MRCCG patterns score could predict the sensitivity to ferroptosis inducing therapy. Our comprehensive analysis of MRCCGs in STAD demonstrated their potential roles in the tumor-immune-stromal microenvironment, clinicopathological features, and prognosis. Our findings highlight that MRCCGs may provide a new understanding of immunotherapy strategies for gastric cancer and provide a new perspective on the development of personalized immune therapeutic strategies for patients with STAD.

4.
Infect Drug Resist ; 15: 3693-3702, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35859909

RESUMO

Background: Interleukin-26 (IL-26) is an atypical proinflammatory cytokine due to its binding to circulating double-stranded DNA and direct antibacterial activity. Although IL-26 has been confirmed to be involved in the pathophysiology of cancer, chronic inflammatory diseases and infections, the diagnostic and prognostic values of IL-26 levels in syphilis patients are not clear. This study aimed to investigate IL-26 levels in different stages of syphilis progression. Methods: A total of 30 healthy controls and 166 patients with syphilis at different stages of disease progression were enrolled. Serum IL-26 levels were quantified in accordance with the protocols of RayBio® Human Interleukin-26 Enzyme Linked Immunosorbent Assay (ELISA) kits. Clinical laboratory diagnostic parameters and blood analysis data were detected and collected according to clinical medical laboratory standards. Results: The levels of serum IL-26 were significantly higher in neurosyphilis patients than in healthy subjects (6.87 (4.36, 12.14) and 1.67 (0.09, 4.89) pg/µL, respectively; ****p < 0.0001), latent syphilis (1.48 (0.40, 2.05) pg/µL, ****p < 0.0001), seroresistant syphilis (0.81 (0.20, 2.91) pg/µL, ****p < 0.0001) and secondary syphilis (1.66 (0.41, 4.25) pg/µL, ****p < 0.0001) with data presented as the median with interquartile range. The concentration of serum IL-26 was most sensitive to serum low-density lipoprotein concentration (r = -0.438, **p = 0.004) in latent syphilis, urine epithelial cells (r = 0.459, **p = 0.003) in seroresistant syphilis, and serum creatinine levels (r = 0.463, **p = 0.004) and urea creatinine ratio levels (r = 0.500, **p = 0.008) in secondary syphilis patients. There was no significant correlation with the concentration of IL-26 and toluidine red unheated serum test (TRUST) titers in each type of syphilis patient. Conclusion: Circulating IL-26 in serum displays diagnostic potential in the progression of neurosyphilis and warrants further evaluation in clinical trials.

5.
Clin Chim Acta ; 532: 37-44, 2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35594922

RESUMO

BACKGROUND: IgE multiple myeloma (MM) is a rare subtype of MM that is easily misdiagnosed. We report a rare case of IgE-MM and investigate the application of the SLiM-CRAB criteria to screen for high-risk smoldering MM (SMM) patients, so as to summarize the causes and methods used to prevent missed diagnosis or misdiagnosis in IgE-MM. METHODS: The serum monoclonal protein (M-protein) classification and IgE quantification was performed and sent to several individual institutions. The results were collected and the causes of IgE detection defects were analyzed. RESULTS: Upon admission to our hospital, the patient's serum free kappa light chain was 1069.9 mg/L, free lambda light chain was 9.2 mg/L, and free kappa/lambda ratio was 115.9, which met the SLiM criteria, but without CRAB features. Immunofixation electrophoresis (IF) showed "M-like protein aggregation bands" in all lanes. After pretreatment with 1% ß-mercaptoethanol to depolymerize the aggregation of monoclonal protein, the "M-like protein aggregation bands disappeared. The other five institutions did not provide the correct typing results. The quantification of serum IgE was as high as 2.06 × 107 IU/mL, whereas 7 other testing institutions reported IgE levels ranging from 1.0 to 1100 IU/mL. CONCLUSION: High-risk biomarkers in SLiM criteria can achieve good therapeutic effects in rare IgE-MM patients. Serum immunofixation performed without antisera against IgE, insufficient identification of the lytic bands produced by high macromolecule aggregation in IF, and the absence of a prozone effect avoidance procedure during IgE quantitative detection are the primary causes of missed diagnosis or misdiagnosis in patients with IgE-MM.


Assuntos
Mieloma Múltiplo , Mieloma Múltiplo Latente , Técnicas de Laboratório Clínico , Humanos , Imunoglobulina E , Cadeias Leves de Imunoglobulina , Cadeias kappa de Imunoglobulina , Cadeias lambda de Imunoglobulina , Mieloma Múltiplo/diagnóstico , Agregados Proteicos
6.
Clin Chim Acta ; 509: 295-303, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32592711

RESUMO

AIMS: Here, we explored the potential application and selection of neuroendocrine biomarkers in the diagnosis and treatment of small cell lung cancer. METHODS: We retrospectively analyzed 118 patients with small cell lung cancer (SCLC), 166 patients with non-small cell lung cancer (NSCLC), 33 patients with benign lung disease (BLD), and 200 healthy individuals admitted to Zhejiang Provincial People's Hospital between January 1, 2015 and May 31, 2019. All the patients were newly diagnosed with either SCLC, NSCLC, or BLD and previously untreated. Peripheral blood levels of ProGRP, NSE, CEA, and CYFRA21-1 were analyzed during the follow-up treatment, and 2-fold upper limit of reference intervals were defined as effective elevation. We used paired results to analyze the diagnostic efficiency of proGRP and NSE on SCLC. RESULTS: In the 118 SCLC patients, proGRP levels were significantly higher compared with NSE levels. The diagnostic efficiencies of NSE and ProGRP for SCLC were 0.8554 and 0.9053, respectively. The combined diagnostic efficiency (0.9426) was higher relative to NSE, but there was no significant difference compared with proGRP. The effective elevation rate of proGRP was 45.3% higher than that of NSE in the limited stage of SCLC. In the extensive disease of SCLC patients, 70.7% cases had more than 10-fold increase in proGRP value, whereas 56.9% cases had less than 5-fold increase in NSE value. Compared with pre-treatment, the median concentrations of proGRP increased by 204.0% higher than that of NSE (71.3%) in the progressive group. Besides, the dynamic change in imaging characteristics and tumor size had a strong correlation with the levels of proGRP. SIGNIFICANCE: ProGRP is a reliable neuroendocrine biomarker in SCLC. The effective elevation of proGRP has a potential diagnostic and efficacy value in the evaluation of SCLC. However, the combined detection of proGRP and NSE does not significantly improve the diagnosis of lung cancer.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Antígenos de Neoplasias , Biomarcadores Tumorais , Humanos , Queratina-19 , Neoplasias Pulmonares/diagnóstico , Fragmentos de Peptídeos , Fosfopiruvato Hidratase , Proteínas Recombinantes , Estudos Retrospectivos , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Carcinoma de Pequenas Células do Pulmão/terapia
7.
Clin Chim Acta ; 500: 42-46, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31626761

RESUMO

OBJECTIVE: Human epididymis protein 4 (HE4) has been suggested as a new biomarker for the detection of ovarian cancer. Because there are few reports on HE4 in terms of ovarian cancer diagnosis in the Chinese population, we evaluated the diagnostic performances of HE4 and the ROMA in Chinese women with pelvic masses. METHODS: The serum concentrations of CA 125 and HE4 in 318 Chinese women with pelvic masses (39 of which were ovarian cancers) were determined. RESULTS: For the discrimination of benign gynecological diseases from ovarian cancer, the sensitivity and specificity values were 87.2% and 75.8% for the ROMA and 51.3% and 97.3% for HE4. The ROMA also showed higher sensitivity than HE4 in both the early and advanced stages. In the ROC curve analysis, the AUC values for ROMA, HE4 and CA 125 were 0.927, 0.907 and 0.785, respectively. CONCLUSIONS: As a new tumor marker, HE4 shows high specificity and efficacy in the Chinese population, while the ROMA that combines HE4 and CA 125 shows high sensitivity and a high Youden's index. These markers should be extended to China since they have good diagnostic performances.


Assuntos
Algoritmos , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/diagnóstico , Proteína 2 do Domínio Central WAP de Quatro Dissulfetos/metabolismo , China , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Curva ROC
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