Inorganic sulfides prevent osimertinib-induced mitochondrial dysfunction in human iPS cell-derived cardiomyocytes.

Despite the widespread recognition of the global concern regarding the onset of cardiovascular diseases in a significant number of patients following cancer treatment, definitive strategies for prevention and treatment remain elusive. In this study, we established systems to evaluate the influence of anti-cancer drugs on the quality control of mitochondria, pivotal for energy metabolism, using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor used for treatment in lung cancer, reportedly increases the risk of cardiovascular disease. However, its underlying mechanism is largely unknown. Here, we found that the treatment of hiPSC-CMs with osimertinib and doxorubicin, but not trastuzumab and cisplatin, revealed a concentration-dependent impairment of respiratory function accompanied by mitochondrial fission. We previously reported the significant role of sulfur metabolism in maintaining mitochondrial quality in the heart. Co-treatment with various inorganic sulfur donors (Na2S, Na2S2, Na2S3) alongside anti-cancer drugs demonstrated that Na2S attenuated the cardiotoxicity of osimertinib but not doxorubicin. Osimertinib decreased intracellular reduced sulfur levels, while Na2S treatment suppressed the sulfur leakage, suggesting its potential in mitigating osimertinib-induced cardiotoxicity. These results imply the prospect of inorganic sulfides, such as Na2S, as a seed for precision pharmacotherapy to alleviate osimertinib's cardiotoxic effects.

Case Report: Resolution of remitting seronegative symmetrical synovitis with pitting edema during nivolumab therapy for gastric cancer.

The anti-programmed cell death-1 (PD-1) antibody nivolumab has been shown to significantly prolong the survival of patients with unresectable advanced or recurrent gastric cancer (AGC). However, immune-related adverse events (irAEs), which show different profiles from those of cytotoxic agents or conventional molecular-targeted drugs including tyrosine kinase inhibitors, have been reported. Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is a rare autoimmune disorder with acute-onset, rheumatoid factor-negative, symmetric synovitis associated with limb edema observed in elderly persons. A case of RS3PE syndrome that developed after administration of nivolumab for advanced gastric cancer is reported. This is the first report of a case of RS3PE syndrome as an irAE caused by nivolumab in a patient with gastric cancer.

A case of vasovagal syncope associated with carotid sinus hypersensitivity: Effectiveness of tilt training and subsequent squatting.

A 43-year-old man fainted on a train and was transported to our hospital by an ambulance. No structural heart diseases or neurological abnormalities were observed. Electrocardiogram on admission demonstrated a junctional escape rhythm with bradycardia at 39 bpm. Sick sinus syndrome was excluded from electrophysiological studies. He had lifelong episodes of recurrent syncope that occurred due to emotional stress in daily life and pain associated with medical procedures. Since both the head-up tilt and carotid sinus massage tests showed a positive response, he was diagnosed with vasovagal syncope (VVS) and carotid sinus hypersensitivity. He was encouraged to continue the modified tilt training at home, which included leaning on the wall and squatting if leaning was intolerant. Thereafter, syncope was not observed in his daily life. This case highlights the importance of an accurate diagnosis, full education, and home training for recurrent syncope. This case also suggests that the carotid sinus may be involved in the neural network that causes VVS. Learning objective: Reflex syncope includes both vasovagal syncope (VVS) and carotid sinus syndrome (CSS); however, VVS is discriminated from CSS according to current guidelines. We encountered a case of VVS associated with carotid sinus hypersensitivity. Recurrent syncope disappeared with modified tilt training characterized by conventional tilting and subsequent squatting when tilting was intolerant. This case indicates that the carotid sinus may be involved in the neural network responsible for VVS.

[Covalent drug discovery targeting G protein-coupled receptors].

G protein-coupled receptors (GPCRs) play pivotal roles in converting physicochemical stimuli due to environmental changes to intracellular responses. After ligand stimulation, many GPCRs are desensitized and then recycled or degraded through phosphorylation and ß-arrestin-dependent internalization, an important process to maintain protein quality control of GPCRs. However, it is unknown how GPCRs with low ß-arrestin sensitivity are controlled. Here we unmasked a ß-arrestin-independent GPCR internalization, named Redox-dependent Alternative Internalization (REDAI), focusing on ß-arrestin-resistant purinergic P2Y6 receptor (P2Y6R). P2Y6R is highly expressed in macrophage and pathologically contributes to the development of colitis in mice. Natural electrophiles including in functional foods induce REDAI-mediated P2Y6R degradation leading to anti-inflammation in macrophages. Prevention of Cys220 modification on P2Y6R resulted in aggravation of the colitis. These results strongly suggest that targeting REDAI on GPCRs will be a breakthrough strategy for the prevention and treatment of inflammatory diseases.

Case Report: QT Prolongation and Abortive Sudden Death Observed in an 85-Year-Old Female Patient With Advanced Lung Cancer Treated With Tyrosine Kinase Inhibitor Osimertinib.

Cardiac arrest occurred in an 85-year-old female administered osimertinib for advanced lung cancer expressing epidermal growth factor receptor (EGFR) mutations. Electrocardiogram (ECG) recorded at recurrence of spontaneous circulation showed sinus rhythm associated with mild QT prolongation (QTc = 455 ms) to which silent myocardial ischemia and coadministration of itraconazole and herbal drug causing hypokalemia (2.1 mEq/L) may have contributed. Discontinuation of osimertinib, itraconazole and herbal drug, potassium supplementation and percutaneous coronary intervention alleviated QT prolongation (QTc = 432 ms). Osimertinib is the third-generation tyrosine kinase inhibitor lengthening QT interval, and careful monitoring of ECG, serum potassium and drugs coadministered during chemotherapy including osimertinib are highly required.