Chromatin organization and behavior in HRAS-transformed mouse fibroblasts.

In higher eukaryotic cells, a string of nucleosomes, where long genomic DNA is wrapped around core histones, are rather irregularly folded into a number of condensed chromatin domains, which have been revealed by super-resolution imaging and Hi-C technologies. Inside these domains, nucleosomes fluctuate and locally behave like a liquid. The behavior of chromatin may be highly related to DNA transaction activities such as transcription and repair, which are often upregulated in cancer cells. To investigate chromatin behavior in cancer cells and compare those of cancer and non-cancer cells, we focused on oncogenic-HRAS (Gly12Val)-transformed mouse fibroblasts CIRAS-3 cells and their parental 10T1/2 cells. CIRAS-3 cells are tumorigenic and highly metastatic. First, we found that HRAS-induced transformation altered not only chromosome structure, but also nuclear morphology in the cell. Using single-nucleosome imaging/tracking in live cells, we demonstrated that nucleosomes are locally more constrained in CIRAS-3 cells than in 10T1/2 cells. Consistently, heterochromatin marked with H3K27me3 was upregulated in CIRAS-3 cells. Finally, Hi-C analysis showed enriched interactions of the B-B compartment in CIRAS-3 cells, which likely represents transcriptionally inactive chromatin. Increased heterochromatin may play an important role in cell migration, as they have been reported to increase during metastasis. Our study also suggests that single-nucleosome imaging provides new insights into how local chromatin is structured in living cells.

[A Case of Significant Ejection Fraction Reduction and Heart Failure Induced by Osimertinib].

BACKGROUND: In recent years, osimertinib has been increasingly used as a therapeutic drug for epidermal growth factor receptor(EGFR)mutation-positive lung cancer, with heart failure rarely reported as an adverse event. We report here a case of a significantly decreased ejection fraction and heart failure that were induced by osimertinib. We consider the case important and include a discussion of relevant previous reports. CASE: The patient was a 73-year-old woman who had been on oral gefitinib as first-line treatment for EGFR mutation-positive(exon19 deletion)non-small cell lung cancer for approximately 1 year and 2 months. Thereafter, she tested positive for an EGFR resistance mutation(T790M); and accordingly, oral osimerti- nib was started at 80mg/day as second-line treatment. After continuing this treatment for 6 months with no particular adverse events, she visited our hospital and was found to have dyspnea on exertion and increased pleural effusion. Based on these findings, cancer relapse was suspected, and the patient was hospitalized for detailed examinations. She was diagnosed with heart failure based on the elevated BNP level that was found in a blood test and CT and echocardiography findings, and her ejection fraction deteriorated to 19% from a pretreatment level of 59%. The conditions improved after diuretic and b- blocker treatment. Given the absence of any possible cause of heart failure or reduced ejection fraction in her past history of illness and medication, we concluded that these conditions were induced by osimertinib. CONCLUSION: While heart failure induced by EGFR-TKIs has been rarely reported, osimertinib may cause cardiomyopathy due to human epidermal growth factor receptor type 2(HER2)inhibitory activity.

[Case of Primary Mediastinal Non-Seminomatous Germ Cell Tumor with Pathological Complete Response after Induction Chemotherapy and Residual Tumor Resection Accompanied by Late-Onset Bilateral Pneumothorax].

A man in his late teens presented to our hospital with left-sided chest pain. CT showed a 12 cm sized anterior mediastinal tumor and tiny nodules in the bilateral lower lobe of the lungs. The patient also had elevated serum AFP and hCG levels. Pathological findings of the CT-guided biopsy specimen suggested a yolk sac tumor, and no testicular abnormality was seen on ultrasound. Following whole body examination, he was diagnosed with primary mediastinal non-seminomatous germ cell tumor. After sperm cryopreservation, 4 courses of BEP(bleomycin[BLM]plus etoposide[ETP]plus cisplatin[CDDP]) chemotherapy were administered to normalize the tumor markers. The mediastinal tumor shrank but was still widely in contact with the left pulmonary artery. He underwent mediastinal tumor resection and segmentectomy of the left upper lobe via a median sternotomy. The maximum tumor size was 9 cm in diameter, and pathological examination of the specimen revealed only an immature teratoma with no malignant findings. At the same time, both the lower lung nodules were resected and pathologically identified as intrapulmonary lymph nodes. No recurrence was observed, but 6 months after surgery, he made an emergency visit to our department due to dyspnea. Bilateral pneumothorax was detected, and chest tube insertion was rapidly performed that improved with only right chest drainage. Cytology of the right hemorrhagic pleural effusion showed no evidence of malignancy. It was possible that a postoperative right-to-left shunt of the anterior mediastinum was present, leading to bilateral pneumothorax.