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1.
Mol Oncol ; 17(9): 1930-1942, 2023 09.
Article in English | MEDLINE | ID: mdl-37356061

ABSTRACT

A good response to neoadjuvant chemotherapy (NACT) is strongly associated with a higher curative resection rate and favorable outcomes for patients with gastric cancer (GC). We examined the utility of serial circulating tumor DNA (ctDNA) testing for monitoring NACT response and prognosis in stage II-III GC. Seventy-nine patients were enrolled to receive two cycles of NACT following gastrectomy with D2-lymphadenectomy. Plasma at baseline, post-NACT, and after surgery, and tissue at pretreatment and surgery were collected. We used a 425-gene panel to detect genomic alterations (GAs). Results show that the mean cell-free DNA concentration of patients with clinical stage III was significantly higher than patients with stage II (15.43 ng·mL-1 vs 14.40 ng·mL-1 ). After receiving NACT and surgery, the overall detection rate of ctDNA gradually reduced (59.5%, 50.8%, and 47.4% for baseline, post-NACT, and postsurgery). The maximum variant allele frequency (max-VAF) and the number of GAs decreased from 0.50% to 0.08% and from 2.9 to 1.7 after NACT. For patients with a partial response after NACT, the max-VAF and the number of GAs declined significantly, but they increased for patients with progressive disease. Patients with detectable ctDNA at baseline, after NACT, or after surgery have a worse overall survival (OS) than patients with undetectable ctDNA. The estimated 3-year OS was 73% for the post-NACT ctDNA-negative patients and 34% for ctDNA-positive. Patients with perpetual negative ctDNA before and after NACT have the best prognosis. In conclusion, ctDNA was proposed as a potential biomarker to predict prognosis and monitor the NACT response for stage II-III GC patients.


Subject(s)
Circulating Tumor DNA , Stomach Neoplasms , Humans , Stomach Neoplasms/drug therapy , Stomach Neoplasms/genetics , Neoadjuvant Therapy , Circulating Tumor DNA/genetics , DNA, Neoplasm/genetics , Liquid Biopsy , Biomarkers, Tumor/genetics
2.
Neuroscience ; 510: 109-128, 2023 02 01.
Article in English | MEDLINE | ID: mdl-36529294

ABSTRACT

Cerebral infarction is a common disease characterized by high mortality, a narrow therapeutic window, and limited therapeutic options. Recently, cell therapy based on gene modification has brought a glimmer of hope to the treatment of cerebral infarction although the explicit underlying mechanism is beyond being well dissected. In the present study, we constructed an animal model of middle cerebral artery occlusion (MCAO), compared differentially expressed genes (DEGs) between the sham and MCAO groups by single-cell RNA sequencing (scRNA-seq) to explore the potential cell death-related pathways involved in cerebral infarction, and transfected Manf into BMSCs by lentivirus. Subsequently, we injected BMSCs (bone marrow-derived mesenchymal stem cells), Manf-modified BMSCs, or lentivirus encoding Manf into the brain. Their effects on MANF content, apoptosis, pyroptosis, infarct volume in the brain, and neurological function were evaluated after MCAO. We found that the DEGs upregulated in four major cell clusters after MCAO and were enriched with not only apoptosis, ferroptosis, and necroptosis but also with pyroptosis-related pathways. In addition, transfection of Manf into BMSCs significantly increased the expression and secretion of MANF in BMSCs; BMSCs, Manf-modified BMSCs, and Manf treatment all resulted in an increase in Manf content in the brain, a decrease in the expression of apoptosis- and pyroptosis-related molecules, a reduction in infarct volume, and an improvement in neurological function after MCAO. Moreover, Manf-modified BMSCs have the strongest therapeutic effect. Collectively, Manf-modified BMSCs ameliorate ischemic injury after cerebral infarction by repressing apoptosis- and pyroptosis-related molecules, which represents a new cell therapy strategy for cerebral infarction.


Subject(s)
Brain Injuries , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells , Animals , Bone Marrow , Infarction, Middle Cerebral Artery/drug therapy , Mesenchymal Stem Cell Transplantation/methods , Pyroptosis
3.
Front Genet ; 13: 909482, 2022.
Article in English | MEDLINE | ID: mdl-36238162

ABSTRACT

Background: Ischemic stroke (IS) is a common and serious neurological disease, and multiple pathways of cell apoptosis are implicated in its pathogenesis. Recently, extensive studies have indicated that pyroptosis is involved in various diseases, especially cerebrovascular diseases. However, the exact mechanism of interaction between pyroptosis and IS is scarcely understood. Thus, we aimed to investigate the impact of pyroptosis on IS-mediated systemic inflammation. Methods: First, the RNA regulation patterns mediated by 33 pyroptosis-related genes identified in 20 IS samples and 20 matched-control samples were systematically evaluated. Second, a series of bioinformatics algorithms were used to investigate the contribution of PRGs to IS pathogenesis. We determined three composition classifiers of PRGs which potentially distinguished healthy samples from IS samples according to the risk score using single-variable logistic regression, LASSO-Cox regression, and multivariable logistic regression analyses. Third, 20 IS patients were classified by unsupervised consistent cluster analysis in relation to pyroptosis. The association between pyroptosis and systemic inflammation characteristics was explored, which was inclusive of immune reaction gene sets, infiltrating immunocytes and human leukocyte antigen genes. Results: We identified that AIM2, SCAF11, and TNF can regulate immuno-inflammatory responses after strokes via the production of inflammatory factors and activation of the immune cells. Meanwhile, we identified distinct expression patterns mediated by pyroptosis and revealed their immune characteristics, differentially expressed genes, signaling pathways, and target drugs. Conclusion: Our findings lay a foundation for further research on pyroptosis and IS systemic inflammation, to improve IS prognosis and its responses to immunotherapy.

4.
Int J Biol Markers ; 37(4): 386-394, 2022 Dec.
Article in English | MEDLINE | ID: mdl-35791673

ABSTRACT

BACKGROUND: Non-invasive liquid biopsies of circulating tumor DNA (ctDNA) is a rapidly growing field in the research of non-small cell lung cancer (NSCLC). In this study, factors affecting the concordance of mutations in paired plasma and tissue and the detection rate of ctDNA in real-world Chinese patients with NSCLC were identified. METHODS: Peripheral blood and paired formalin-fixed paraffin-embedded tumor tissue samples from 125 NSCLC patients were collected and analyzed by sequencing 15 genes. Serological biomarkers were tested by immunoassay. RESULTS: The overall concordance between tumor and plasma samples and the detection rate of somatic mutations in ctDNA was 69.2% and 78.4%, respectively. The concordance and detection rate raised with clinical stage were stage I: 14.3%, 14.3%; stage II: 53.3%, 60.0%; stage III: 71.4%, 78.1%; stage IV: 74.1%, 85.2%. With increased tumor diameter, the concordance and detection rate raised from 33.33% to 71.64% and 33.33% to 80.8%, respectively. For patients with partial response, stable disease, progressive disease, and who were treatment-naïve, the concordance and detection rates were 0.0%, 62.7%, 75.2, 73.6%, and 16.7%, 61.9%, 83.3%, 86.5%, respectively. Serological markers: CEA, CA125, NSE, and CYFRA21-1 were significantly higher for patients with detectable somatic alterations in ctDNA than in those who were ctDNA negative (17.08 ng/mL vs. 3.95 ng/mL, 21.63 U/mL vs. 18.27 U/mL, 17.68 U/mL vs. 14.14 U/mL, and 6.55 U/mL vs. 3.81 U/mL, respectively). CONCLUSION: Advanced-stage, treatment naïve or poor therapy outcome, and large tumor size were associated with a high concordance and detection rate. Patients with detectable mutations in ctDNA had a higher level of carcinoembryonic antigen, CA125, NSE, and CYFRA21-1.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Circulating Tumor DNA , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/pathology , Circulating Tumor DNA/genetics , Lung Neoplasms/pathology , High-Throughput Nucleotide Sequencing , Mutation , CA-125 Antigen , DNA , China , Biomarkers, Tumor/genetics
5.
IUBMB Life ; 72(3): 465-475, 2020 03.
Article in English | MEDLINE | ID: mdl-31828927

ABSTRACT

Glioma, like most cancers, possesses a unique bioenergetic state of aerobic glycolysis known as the Warburg effect, which is a dominant phenotype of most tumor cells. Glioma tumors exhibit high glycolytic metabolism with increased lactate production. Data derived from the gene expression profiling interactive analysis (GEPIA) database show that pyruvate dehydrogenase kinase 1 (PDK1) is significantly highly expressed in glioma tissues compared with corresponding normal tissues. PDK1 is a key enzyme in the transition of glycolysis to tricarboxylic acid cycle, via inactivating PDH and converting oxidative phosphorylation to Warburg effect, resulting in increment of lactate production. Silencing of PDK1 expression resulted in reduced lactate and ATP, accumulation of ROS, mitochondrial damage, decreased cell growth, and increased cell apoptosis. Aberrant expression of miR-128 has been observed in many human malignancies. Mechanistically, we discover that overexpressed miR-128-3p disturbs the Warburg effect in glioma cells via reducing PDK1. Our experiments confirmed that the miR-128-3p/PDK1 axis played a pivotal role in cancer cell metabolism and growth. Collectively, these findings suggest that therapeutic strategies to modulate the Warburg effect, such as targeting of PDK1, might act as a potential therapeutic target for glioma treatment.


Subject(s)
Brain Neoplasms/genetics , Glioma/genetics , MicroRNAs/genetics , Mitochondria/pathology , Pyruvate Dehydrogenase Acetyl-Transferring Kinase/genetics , Adenosine Triphosphate/metabolism , Apoptosis/genetics , Brain Neoplasms/pathology , Cell Line, Tumor , Cell Proliferation/genetics , Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Neoplastic , Gene Knockdown Techniques , Glioma/pathology , Humans , Lactic Acid/metabolism , Mitochondria/genetics , Mitochondria/metabolism , Pyruvate Dehydrogenase Acetyl-Transferring Kinase/metabolism , Reactive Oxygen Species/metabolism
6.
Neurol Sci ; 36(7): 1105-12, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25663086

ABSTRACT

P300 event-related potential component may sensitively predict mild cognitive impairment (MCI) progression. Here, pooled effect size estimates of P300 amplitude and latency were computed at midline electrodes among controls, MCI patients, and Alzheimer's disease (AD) patients. Baseline data were compared to one-year follow-up data. MCI patients showed decreased P300 amplitude and prolonged latency compared to controls. Pooled standardized mean differences (SMDs) were -0.67 (95 % CI -1.12 to -0.23, P = 0.003) and 0.90 (95 % CI 0.66-1.14, P < 0.00001), respectively. P300 latency decreased in MCI compared to AD patients where the pooled SMD was -0.52 (95 % CI -0.85 to -0.18, P = 0.003). Amplitude and latency differed between MCI baseline and follow-up. Pooled SMDs were 0.47 (95 % CI 0.29 to -0.65, P < 0.00001) and -0.52 (95 % CI -0.71 to -0.34, P < 0.00001), respectively. Group differences in MCI P300 latency existed compared to control and AD patients. P300 latency may therefore be a sensitive indicator for early cognitive decline or disease progression in MCI patients and identifying elderly patient progression to MCI and/or AD.


Subject(s)
Cognitive Dysfunction/diagnosis , Cognitive Dysfunction/physiopathology , Diagnosis, Differential , Event-Related Potentials, P300/physiology , Alzheimer Disease/physiopathology , Databases, Bibliographic/statistics & numerical data , Disease Progression , Electroencephalography , Humans , Physical Stimulation , Reaction Time/physiology
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