The relationship between serum CXCL1 and PTEN mRNA levels and disease severity and prognosis in patients with acute cerebral infarction / 国际检验医学杂志

Objective To investigate the relationship between the levels of serum CXC chemokine ligand 1(CXCL1)and phosphatase and tensin homology deleted on chromosome ten(PTEN)mRNA in patients with acute cerebral infarction and the severity and prognosis of the disease.Methods A total of 102 patients with acute cerebral infarction admitted to the hospital from March 2022 to March 2023 were enrolled in the study as the experimental group,and 85 healthy people who underwent physical examination in the hospital during the same period were enrolled as the control group.Serum samples of fasting venous blood were collected from people enrolled in the study.The serum CXCL1 level was detected by using enzyme-linked immunosorbent as-say.Real-time fluorescence quantitative PCR(qPCR)was used to detect the relative expression level of serum PTEN mRNA(hereinafter referred to as the level).According to the National Institutes of Health Stroke Scale(NIHSS)score,the patients in the experimental group were divided into three groups with different de-grees of neurological impairment(severe group,moderate group and mild group),and the serum CXCL1 and PTEN mRNA levels of the three groups were compared.According to the cerebral infarction volume evaluated by computed tomography(CT)or magnetic resonance imaging(MRI),the patients in the experimental group were divided into small infarction group,medium infarction group and large infarction group,and the serum CXCL1 and PTEN mRNA levels of the three groups were compared.According to the modified Rankin scale(mRS),the patients in the experimental group were divided into the good prognosis group and the poor prog-nosis group,and the serum CXCL1 and PTEN mRNA levels were compared between the two groups.Pearson correlation was used to analyze the correlation between serum CXCL1 and PTEN mRNA levels in patients with acute cerebral infarction.Multivariate Logistic regression analysis was used to analyze the factors affect-ing the prognosis of patients with acute cerebral infarction.Results The proportion of patients with a history of diabetes and hypertension and serum CXCL1 and PTEN mRNA levels in the experimental group were high-er than those in the control group,and the differences were statistically significant(P＜0.05).With the in-crease of the degree of neurological impairment,the serum CXCL1 level and PTEN mRNA level increased,and there were significant differences among the severe group,moderate group,and mild group(P＜0.05).With the increase of infarction size,the serum levels of CXCL1 and PTEN mRNA increased,and there were signifi-cant differences among small infarction group,medium infarction group,and large infarction group(P＜0.05).Compared with the good prognosis group,the poor prognosis group had significantly higher proportions of patients with a history of diabetes,a history of hypertension,and serum CXCL1 and PTEN mRNA levels(P＜0.05).There was a positive correlation between serum CXCL1 level and PTEN mRNA level in patients with acute cerebral infarction(r=0.479,P＜0.001).The levels of serum CXCL1 and PTEN mRNA,history of diabetes and hypertension were all influencing factors for the prognosis of patients with acute cerebral in-farction(P＜0.05).Conclusion The levels of serum CXCL1 and PTEN mRNA in patients with acute cere-bral infarction increase,which can be used to evaluate the disease severity and prognosis of patients.

A mitochondrial iron-responsive pathway regulated by DELE1.

The heme-regulated kinase HRI is activated under heme/iron deficient conditions; however, the underlying molecular mechanism is incompletely understood. Here, we show that iron-deficiency-induced HRI activation requires the mitochondrial protein DELE1. Notably, mitochondrial import of DELE1 and its subsequent protein stability are regulated by iron availability. Under steady-state conditions, DELE1 is degraded by the mitochondrial matrix-resident protease LONP1 soon after mitochondrial import. Upon iron chelation, DELE1 import is arrested, thereby stabilizing DELE1 on the mitochondrial surface to activate the HRI-mediated integrated stress response (ISR). Ablation of this DELE1-HRI-ISR pathway in an erythroid cell model enhances cell death under iron-limited conditions, suggesting a cell-protective role for this pathway in iron-demanding cell lineages. Our findings highlight mitochondrial import regulation of DELE1 as the core component of a previously unrecognized mitochondrial iron responsive pathway that elicits stress signaling following perturbation of iron homeostasis.

DELE1 is protective for mitochondrial cardiomyopathy.

Mitochondrial dysfunction in heart triggers an integrated stress response (ISR) through phosphorylation of eIF2α and subsequent ATF4 activation. DAP3 Binding Cell Death Enhancer 1 (DELE1) is a mitochondrial protein recently found to be critical for mediating mitochondrial stress-triggered ISR (MSR)-induced eIF2α-ATF4 pathway activation. However, the specific role of DELE1 in heart at baseline or in response to mitochondrial stress remains largely unknown. In this study, we report that DELE1 is dispensable for cardiac development and function under baseline conditions. Conversely, DELE1 is essential for mediating an adaptive response to mitochondrial dysfunction-triggered stress in the heart, playing a protective role in mitochondrial cardiomyopathy.

OMA1-mediated integrated stress response protects against ferroptosis in mitochondrial cardiomyopathy.

Cardiomyopathy and heart failure are common manifestations in mitochondrial disease caused by deficiencies in the oxidative phosphorylation (OXPHOS) system of mitochondria. Here, we demonstrate that the cardiac-specific loss of the assembly factor Cox10 of the cytochrome c oxidase causes mitochondrial cardiomyopathy in mice, which is associated with OXPHOS deficiency, lysosomal defects, and an aberrant mitochondrial morphology. Activation of the mitochondrial peptidase Oma1 in Cox10-/- mice results in mitochondrial fragmentation and induction of the integrated stress response (ISR) along the Oma1-Dele1-Atf4 signaling axis. Ablation of Oma1 or Dele1 in Cox10-/- mice aggravates cardiomyopathy. ISR inhibition impairs the cardiac glutathione metabolism, limits the selenium-dependent accumulation of the glutathione peroxidase Gpx4, and increases lipid peroxidation in the heart, ultimately culminating in ferroptosis. Our results demonstrate a protective role of the Oma1-Dele1-mediated ISR in mitochondrial cardiomyopathy and link ferroptosis to OXPHOS deficiency and mitochondrial disease.

Response to dacomitinib in advanced non-small-cell lung cancer harboring the rare delE709_T710insD mutation: A case report.

BACKGROUND: Tyrosine kinase inhibitors (TKI) have been the standard first-line therapy for advanced non-small cell lung cancer (NSCLC) of epidermal growth factor receptor (EGFR) sensitive mutations. Uncommon EGFR mutations are increasingly reported with the development of next-generation sequencing. However, their sensitivity to TKIs is variable with limited clinical evidence. CASE SUMMARY: Here, we report a patient with the rare delE709_T710insD mutation, who showed the favorable efficacy of dacomitinib and achieved a partial response with a progression-free survival of 7.0 mo. CONCLUSION: To our knowledge, this is the first report displaying the clinical efficacy of dacomitinib for patients with delE709_T710insD, which may help to provide alternatives in non-classical variant NSCLC patients. Further studies are warranted to make the optimal choice of EGFR-TKI for rare mutations.

The Mitochondrial PHB2/OMA1/DELE1 Pathway Cooperates with Endoplasmic Reticulum Stress to Facilitate the Response to Chemotherapeutics in Ovarian Cancer.

Interactions between the mitochondrial inner and outer membranes and between mitochondria and other organelles closely correlates with the sensitivity of ovarian cancer to cisplatin and other chemotherapeutic drugs. However, the underlying mechanism remains unclear. Recently, the mitochondrial protease OMA1, which regulates internal and external signals in mitochondria by cleaving mitochondrial proteins, was shown to be related to tumor progression. Therefore, we evaluated the effect of OMA1 on the response to chemotherapeutics in ovarian cancer cells and the mouse subcutaneous tumor model. We found that OMA1 activation increased ovarian cancer sensitivity to cisplatin in vivo and in vitro. Mechanistically, in ovarian cancer, OMA1 cleaved optic atrophy 1 (OPA1), leading to mitochondrial inner membrane cristae remodeling. Simultaneously, OMA1 induced DELE1 cleavage and its cytoplasmic interaction with EIF2AK1. We also demonstrated that EIF2AK1 cooperated with the ER stress sensor EIF2AK3 to amplify the EIF2S1/ATF4 signal, resulting in the rupture of the mitochondrial outer membrane. Knockdown of OMA1 attenuated these activities and reversed apoptosis. Additionally, we found that OMA1 protease activity was regulated by the prohibitin 2 (PHB2)/stomatin-like protein 2 (STOML2) complex. Collectively, OMA1 coordinates the mitochondrial inner and outer membranes to induce ovarian cancer cell death. Thus, activating OMA1 may be a novel treatment strategy for ovarian cancer.

Complete Response to Afatinib of an EGFR Exon 18 delE709_T710insD-Mutated Stage IV Lung Adenocarcinoma.

INTRODUCTION: Epidermal growth factor receptor (EGFR) mutations are frequently found in patients with lung adenocarcinomas, 90% being deletions in exon 19 or point mutation in exon 21. Three generations of tyrosine kinase inhibitors (TKIs) targeting EGFR mutations are available and have changed patient prognosis but less data is available on exon 18 mutations and their sensitivity to TKI therapy. Exon 18 delE709_T710insD accounts for 0.06% (16/27,294) of all EGFR mutations and is an oncogenic driver. Several partial responses to afatinib have been described. CASE DESCRIPTION: We report the first case, to the best of our knowledge, of the complete response to afatinib of a 57-year-old patient with stage IV lung adenocarcinoma with a delE709_T710insD mutation in the EGFR gene detected by next-generation sequencing. Oral afatinib was prescribed and despite treatment interruptions and dosage tapering due to cutaneous adverse events, a complete response was achieved 12 months after treatment initiation and is currently maintained at 17 months. CONCLUSION: When EGFR mutation is suspected, complete DNA sequencing of exons 18 to 21 should be carried out and we suggest that afatinib should be the first-line treatment for exon 18 delE709_T710insD-mutated advanced lung adenocarcinomas. LEARNING POINTS: Rare EGFR gene mutations are not detected by standard diagnostic kits.DNA sequencing is required to diagnose rare mutations of the EGFR gene.delE709_T710insD-mutated stage IV lung adenocarcinomas respond to afatinib.

Sensing, signaling and surviving mitochondrial stress.

Mitochondrial fidelity is a key determinant of longevity and was found to be perturbed in a multitude of disease contexts ranging from neurodegeneration to heart failure. Tight homeostatic control of the mitochondrial proteome is a crucial aspect of mitochondrial function, which is severely complicated by the evolutionary origin and resulting peculiarities of the organelle. This is, on one hand, reflected by a range of basal quality control factors such as mitochondria-resident chaperones and proteases, that assist in import and folding of precursors as well as removal of aggregated proteins. On the other hand, stress causes the activation of several additional mechanisms that counteract any damage that may threaten mitochondrial function. Countermeasures depend on the location and intensity of the stress and on a range of factors that are equipped to sense and signal the nature of the encountered perturbation. Defective mitochondrial import activates mechanisms that combat the accumulation of precursors in the cytosol and the import pore. To resolve proteotoxic stress in the organelle interior, mitochondria depend on nuclear transcriptional programs, such as the mitochondrial unfolded protein response and the integrated stress response. If organelle damage is too severe, mitochondria signal for their own destruction in a process termed mitophagy, thereby preventing further harm to the mitochondrial network and allowing the cell to salvage their biological building blocks. Here, we provide an overview of how different types and intensities of stress activate distinct pathways aimed at preserving mitochondrial fidelity.

Efficacy of afatinib treatment for lung adenocarcinoma harboring exon 18 delE709_T710insD mutation.

Exon 18 delE709_T710insD is an extremely rare mutation in epidermal growth factor receptor (EGFR) in non-small-cell lung cancer (NSCLC); the efficacy of EGFR tyrosine kinase inhibitors against this mutation remains unclear. In this case report, we report a case of NSCLC harboring EGFR exon 18 delE709_T710insD that was not detected by a commercially available assay, but was detected by a next-generation sequencing cancer panel. A 56-year old female patient with advanced NSCLC was diagnosed as EGFR-mutation-negative using the PNAClamp method. ALK rearrangement was also absent and she received cytotoxic chemotherapies. Clinical characteristics, including adenocarcinoma histology and no history of smoking, implied the presence of a driver mutation, so a next-generation-sequencing Oncomine® Cancer Research Panel was conducted in the patient's clinical course and the EGFR exon 18 delE709_T710insD mutation was detected. The patient started afatinib as sixth-line treatment and her pulmonary lesion significantly decreased in size. Afatinib was continued for 7 months until disease progressed.

Identification of G-quadruplex structures that possess transcriptional regulating functions in the Dele and Cdc6 CpG islands.

BACKGROUND: G-quadruplex is a DNA secondary structure that has been shown to play an important role in biological systems. In a previous study, we identified 1998 G-quadruplex-forming sequences using a mouse CpG islands DNA microarray with a fluorescent-labeled G-quadruplex ligand. Among these putative G-quadruplex-forming sequences, G-quadruplex formation was verified for 10 randomly selected sequences by CD spectroscopy and DMS footprinting analysis. In this study, the biological function of the 10 G-quadruplex-forming sequences in the transcriptional regulation has been analyzed using a reporter assay. RESULTS: When G-quadruplex-forming sequences from the Dele and Cdc6 genes have been cloned in reporter vectors carrying a minimal promoter and the luciferase gene, luciferase expression is activated. This has also been detected in experiments applying a promoterless reporter vector. Mutational analysis reveals that guanine bases, which form the G-tetrads, are important in the activation. In addition, the activation has been found to decrease by the telomestatin derivative L1H1-7OTD which can bind to the G-quadruplex DNA. When Dele and Cdc6 CpG islands, containing the G-quadruplex-forming sequence, have been cloned in the promoterless reporter vector, the luciferase expression is activated. Mutational analysis reveals that the expression level is decreased by mutation on Dele G-quadruplex; however, increased by mutation on Cdc6 G-quadruplex. CONCLUSION: Dele and Cdc6 G-quadruplex formation is significant in the transcriptional regulation. Dele and Cdc6 G-quadruplex DNA alone possess enhancer and promotor function. When studied in more complex CpG islands Dele G-quadruplex also demonstrates promotor activity, whereas Cdc6 G-quadruplex may possess a dual function of transcriptional regulation.

EGFR exon 18 delE709_T710insD mutated stage IV lung adenocarcinoma with response to afatinib.

Epidermal Growth Factor Receptor (EGFR) targetable mutations have changed the landscape for treatment of advanced stage non-small cell lung cancer in recent years. Three generations of tyrosine kinase inhibitors are now available to target cancers harboring these mutations. The most common EGFR mutations occur in Exons 19 and 21. Exon 18 mutations are extremely rare comprising of 4.1% of all EGFR mutations and the delE709_T710insD mutation accounts for only 0.16% of mutations when occurring as a sole mutation, however, the frequency can vary with the kit utilized for testing. The rarity makes the clinical relevance of these mutations largely unknown. We report a case of a 52year old female with bilateral advanced adenocarcinoma of the lung harboring the delE709_T710insD mutation with significant clinical and radiographic response to treatment with afatinib. We discuss the reported cases of delE709_T710insD mutated non-small cell lung cancer variably treated with geftinib, erlotinib or afatinib. This particular exon 18 mutation seems to preferentially respond to afatinib as reported in two cases including the current case, and in an in vitro experimental model. These reports have implications in guiding decisions for treatment of patients harboring rare EGFR mutations.