Transcriptomics Coupled with Proteomics Reveals Osimertinib-induced Myocardial Mitochondrial Dysfunction.

Osimertinib, an irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) used for cancer treatment, can cause significant cardiac toxicity. However, the specific mechanism of osimertinib-induced cardiotoxicity is not fully understood. In this study, we administered osimertinib to mice and neonatal rat ventricular myocytes (NRVMs). We observed significant structural and functional damage to the hearts of these mice, along with a marked increase in cardiac injury biomarkers and accompanying ultrastructural damage to mitochondria. We integrated 4D label-free protein quantification and RNA-Seq methods to analyze the sequencing data of NRVMs under osimertinib treatment (0 and 2.5µM). Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis evidenced that differentially expressed genes (DEGs)and differentially expressed proteins (DEPs) were distinctly enriched for oxidative phosphorylation (OXPHOs). Simultaneously, osimertinib primarily affected the contents of adenosine triphosphate (ATP). Further investigations revealed that osimertinib disrupts the functions of the ATP synthase (complex V), leading to a reduction in ATP production. Taken together, our data demonstrated that osimertinib causes mitochondrial dysfunction, which in turn leads to the onset of cardiac toxicity.

Nomograms based on ratio indexes to predict severity and prognosis in immune checkpoint inhibitors-related myocarditis: a retrospective analysis.

PURPOSE: Immune checkpoint inhibitors-related myocarditis (ICI-M) is one of the immune-related adverse events (irAEs), which is rare and highly lethal. This study aimed to establish nomograms based on ratio biomarkers to predict the severity and prognosis of ICI-M. METHODS: We retrospectively examined patients with advanced cancers who were also diagnosed with ICI-M at the Fourth Hospital of Hebei Medical University. The patients of ICI-M were divided into mild and severe groups and a 40-day following up was carried out. The major adverse cardiovascular events(MACEs) were regarded as the endpoint. Nomogram-based models were established and validated. RESULTS: Seventy-seven patients were involved, including 31 severe cases(40.3%). Lactate dehydrogenase-to-albumin ratio(LAR) combined with the change rate from baseline to onset of LAR( ▵ LAR) which performed best to diagnose the severe ICI-M was identified to establish the nomogram-based model. The bootstrap-corrected concordance index [0.752 95% confidence interval (CI): 0.635 - 0.866] and calibration plot with good degree of fitting confirmed this diagnostic model. Neutrophil-to-high-density lipoprotein cholesterol ratio(NHR) and LAR were also screened into the nomogram-based model for 40-day MACEs after ICI-M, which performed well by validating for concordance index(0.779 95% CI: 0.677 - 0.865)and calibration plots after being bootstrap-corrected. Moreover, a  ≥ 101% increase in LAR significantly separated patients in MACE-free survival. CONCLUSION: Ratio indexes at onset and their change rates from baseline showed good diagnostic value for the severity of ICI-M and prognostic value for subsequent MACEs, particularly LAR, NHR and their change rates. The nomogram-based models of ratio indexes could provide a potential choice for early detection and monitor of the severe ICI-M and subsequent MACEs.

LncRNA PSMA3-AS1 promotes cell proliferation, migration, and invasion in ovarian cancer by activating the PI3K/Akt pathway via the miR-378a-3p/GALNT3 axis.

The crucial roles of the long noncoding RNAs (lncRNAs) in the development of ovarian cancer (OC) have been extensively studied. According to the prediction result from the Kaplan-Meier Plotter database, high expression of lncRNA proteasome subunit α type-3 antisense RNA1 (PSMA3-AS1) is associated with the poor prognosis in patients with OC. Thus, the study aimed to investigate the role of lncRNA PSMA3-AS1 in OC. Reverse transcription quantitative polymerase chain reaction analysis revealed that PSMA3-AS1 expression was significantly upregulated in OC cells and tissues. PSMA3-AS1 silencing inhibited OC cell proliferation, migration, and invasion, as shown by results of cell counting kit-8, colony formation, wound healing, and Transwell assays, respectively. Additionally, PSMA3-AS1 deficiency suppressed tumor growth in vivo. Mechanistically, luciferase reporter and RNA pulldown assays implied that PSMA3-AS1 served as a competing endogenous RNA for miR-378a-3p to upregulate the expression of polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3). GALNT3 was a target gene of miR-378a-3p in OC. Moreover, PSMA3-AS1 activated the PI3K/Akt pathway by upregulating GALNT3 expression. Overall, PSMA3-AS1 promotes OC cell proliferation, migration, invasion, and xenograft tumor growth by activating the PI3K/Akt pathway via the miR-378a-3p/GALNT3 axis.

Clinical characteristics and risk factors for death in patients with stress cardiomyopathy in the ICU.

BACKGROUND: This study aimed to investigate the clinical manifestations and risk factors for 28-day mortality in patients with stress cardiomyopathy (SC) in the intensive care unit (ICU). METHODS: This retrospective study was carried out from April 2015 to March 2021. Fifty-five patients in the ICU were diagnosed with SC. Two patients were excluded due to a history of atrial fibrillation (AF), and 53 patients were enrolled in the study. Baseline demographics and clinical characteristics were collected, and the 28-day mortality rate was calculated. Multivariate and univariate logistic regression analyses were used to determine the significant predictors of 28-day mortality. RESULTS: Of the 53 patients, almost half (47.17%) were male. The most common stress trigger was sepsis (37.74%). Due to sedation and tracheal intubation, 49.06% of SC patients were unable to express their symptoms, and only 3.77% of patients presented with chest pain. The proportion of patients with complications of systolic heart failure and cardiogenic shock was 77.36% and 39.62%, respectively. The mean Acute Physiology and Chronic Health Evaluation (APACHE) II score when patients were admitted into the ICU was 21.17±8.41, and the Sequential Organ Failure Assessment (SOFA) score at diagnosis of SC was 9.30±4.56. Eighteen (33.96%) SC patients had new-onset AF while in the ICU. The 28-day mortality rate in patients with SC in the ICU was 64.15%. Univariate analysis found that 5 variables [SOFA score at diagnosis of SC, estimated glomerular filtration rate (eGFR) <60 mL/min at diagnosis of SC, maximum norepinephrine dose, new-onset AF, and systolic heart failure] were correlated with 28-day mortality in patients with SC in the ICU. Multivariate logistic regression analysis suggested SOFA score at diagnosis of SC (P=0.042), eGFR <60 mL/min at diagnosis of SC (P=0.027), and new-onset AF (P=0.043) as independent predictors of 28-day mortality. CONCLUSIONS: Male patients with SC were relatively more common in the ICU than in the cardiology unit. Sepsis was a common stress trigger. The 28-day mortality rate was very high. The SOFA score and eGFR <60 mL/min at diagnosis of SC and new-onset AF may have influenced patients' short-term prognosis.

Stress cardiomyopathy following thyroidectomy in a premenopausal woman with thyroid cancer: case report and review of the literature.

Stress cardiomyopathy (SC) is a poorly recognized heart disease that was initially regarded as a benign condition. Recently, it has been shown that SC may be associated with severe clinical complications including death and that its prevalence is probably underestimated. The disease is characterized by transient systolic and diastolic left ventricular (LV) dysfunction with a variety of wall-motion abnormalities. It predominantly affects postmenopausal women and is often preceded by an emotional or physical trigger, but the condition has also been reported with no evident trigger. The striking preponderance of postmenopausal females suggests a hormonal influence. Potentially, declining oestrogen levels after menopause increase the susceptibility to SC in women. Oestrogens can influence vasomotor tone via up-regulation of endothelial NO synthase. Also, there is evidence that oestrogens can attenuate catecholamine-mediated vasoconstriction and decrease the sympathetic response to mental stress in perimenopausal women. Rare cases of SC following thyroidectomy in premenopausal women have been described. Currently, the pathogenesis of SC remains obscure, several possible hypotheses include catecholamine induced myocardial spasm or catecholamine related myocardial stunning, metabolic disorders and coronary microvascular damage. So prompt diagnosis and optimal management are crucial to obtaining a good outcome for the patient. We report an extremely rare case of SC induced by thyroidectomy in a premenopausal woman with cancer, and share our personal experience by reviewing the literature.

miR-378a-3p sensitizes ovarian cancer cells to cisplatin through targeting MAPK1/GRB2.

Ovarian cancer has gradually become one of the commonest gynecological tumor in the world. Although various therapies have been developed by researchers, the chemoresistance of ovarian cancer is still a huge challenge. MircroRNAs (miRNAs) have been widely studied due to their anti-oncogenic functions. MiR-378a-3p has been reported to sensitize breast cancer cells to chemotherapy. Here, we hypothesized that miR-378a-3p is a potential chemosensitizer in ovarian cancer. Firstly, miR-378a-3p was uncovered to down-regulated in ovarian cancer tissues and cell lines through using qRT-PCR analysis and northern blot analysis. According to the result of Kaplan Meier analysis, low expression of miR-378a-3p is closely associated with unfavorable prognosis of ovarian cancer patients. Subsequently, gain-of function assays indicated that miR-378a-3p suppressed cell proliferation and promoted cell apoptosis. Moreover, miR-378a-3p was found to enhance cisplatin sensitivity of ovarian cancer cells. Mechanism investigations suggested that MAPK1 and GRB2 are two targets of miR-378a-3p. Finally, rescue assays revealed that MAPK1 and GRB2 can reverse the effects of miR-378a-3p on chemosensitivity of ovarian cancer cells. In conclusion, miR-378a-3p enhanced the sensitivity of ovarian cancer cells to cisplatin through targeting MAPK1 and GRB2.