OBJECTIVE: To explore relationship between increase of fibrous and fatty in atrioventricular node (AVN) and narrowing of the AVN artery. To analyze the cause of pathological fibrosis and fatty infiltration in AVN. METHODS: One hundred and nineteen cases of sudden cardiac death determined by autopsy were selected and the histological sections were examined with Image-pro plus software to calculate the AVN area, AVN artery inside-diameter, AVN artery lumen area(LA) , AVN artery perimeter area(PA), fibrous area and fatty area. All cases were divided into two groups: narrowing of artery group and normal control group. The changes of the PA/LA value and the fibrous and fatty contents were evaluated. RESULTS: The PA/LA value is the highest in 21-40 age group. The difference of the fatty contents and total interstitial tissue was statistical significance in the two groups under 40 years of age. CONCLUSION There is some relationship between the narrowing of the AVN artery and the increase of interstitial contents in AVN.
Adolescent ; Adult ; Age Factors ; Atrioventricular Node/pathology* ; Child ; Coronary Stenosis/pathology* ; Coronary Vessels/pathology* ; Death, Sudden, Cardiac/etiology* ; Female ; Fibrosis ; Forensic Pathology ; Heart Conduction System/pathology* ; Humans ; Lipid Metabolism ; Male ; Middle Aged ; Retrospective Studies ; Young Adult

Objective: The clinical characteristics and outcomes of patients with chronic myeloid leukemia (CML) who had discontinued tyrosine kinase inhibitors (TKI) therapy were analyzed retrospectively. Methods: Clinical data of 109 cases of chronic CML patients who had discontinued TKI therapy in seven centers were retrospectively analyzed from June 1, 2005 to March 1, 2018. 91 cases with complete clinical data were enrolled in this study. We aimed to observe the status of patients with treatment free remission (TFR) after TKI therapy discontinuation and its prognostic factors. Results: 38 of 91 patients lost MMR after a median follow-up of 9 months and the estimated TFR was 52.6%. 31 of 38 patients who met the definition of molecular relapse resumed TKI treatment immediately and regained the major molecular response (MMR) with a median time of 3 months (range, 1-12 months). No significant difference was found in median course of imatinib therapy between the TFR group and the relapse. Similarly, duration to MMR, age and gender also showed no difference between the two groups. The longer duration of MMR maintenance (more than 24 months), the lower relapse rate was observed (P=0.027). Conclusion TKI might be safely discontinued in part of CML patients.

Biological rhythms controlled by the circadian clock are absent in embryonic stem cells (ESCs). However, they start to develop during the differentiation of pluripotent ESCs to downstream cells. Conversely, biological rhythms in adult somatic cells disappear when they are reprogrammed into induced pluripotent stem cells (iPSCs). These studies indicated that the development of biological rhythms in ESCs might be closely associated with the maintenance and differentiation of ESCs. The core circadian gene Clock is essential for regulation of biological rhythms. Its role in the development of biological rhythms of ESCs is totally unknown. Here, we used CRISPR/CAS9-mediated genetic editing techniques, to completely knock out the Clock expression in mouse ESCs. By AP, teratoma formation, quantitative real-time PCR and Immunofluorescent staining, we did not find any difference between Clock knockout mESCs and wild type mESCs in morphology and pluripotent capability under the pluripotent state. In brief, these data indicated Clock did not influence the maintaining of pluripotent state. However, they exhibited decreased proliferation and increased apoptosis. Furthermore, the biological rhythms failed to develop in Clock knockout mESCs after spontaneous differentiation, which indicated that there was no compensational factor in most peripheral tissues as described in mice models before (DeBruyne et al., 2007b). After spontaneous differentiation, loss of CLOCK protein due to Clock gene silencing induced spontaneous differentiation of mESCs, indicating an exit from the pluripotent state, or its differentiating ability. Our findings indicate that the core circadian gene Clock may be essential during normal mESCs differentiation by regulating mESCs proliferation, apoptosis and activity.
Animals ; Apoptosis ; Base Sequence ; CLOCK Proteins ; genetics ; metabolism ; CRISPR-Cas Systems ; Cell Differentiation ; Cell Proliferation ; Cellular Reprogramming ; Circadian Clocks ; genetics ; Gene Editing ; Gene Expression Regulation ; Gene Knockout Techniques ; Hepatocyte Nuclear Factor 3-beta ; genetics ; metabolism ; Induced Pluripotent Stem Cells ; cytology ; metabolism ; Mice ; Mouse Embryonic Stem Cells ; cytology ; metabolism ; SOXB1 Transcription Factors ; genetics ; metabolism

Dysregulation of circadian rhythms associates with cardiovascular disorders. It is known that deletion of the core circadian gene Bmal1 in mice causes dilated cardiomyopathy. However, the biological rhythm regulation system in mouse is very different from that of humans. Whether BMAL1 plays a role in regulating human heart function remains unclear. Here we generated a BMAL1 knockout human embryonic stem cell (hESC) model and further derived human BMAL1 deficient cardiomyocytes. We show that BMAL1 deficient hESC-derived cardiomyocytes exhibited typical phenotypes of dilated cardiomyopathy including attenuated contractility, calcium dysregulation, and disorganized myofilaments. In addition, mitochondrial fission and mitophagy were suppressed in BMAL1 deficient hESC-cardiomyocytes, which resulted in significantly attenuated mitochondrial oxidative phosphorylation and compromised cardiomyocyte function. We also found that BMAL1 binds to the E-box element in the promoter region of BNIP3 gene and specifically controls BNIP3 protein expression. BMAL1 knockout directly reduced BNIP3 protein level, causing compromised mitophagy and mitochondria dysfunction and thereby leading to compromised cardiomyocyte function. Our data indicated that the core circadian gene BMAL1 is critical for normal mitochondria activities and cardiac function. Circadian rhythm disruption may directly link to compromised heart function and dilated cardiomyopathy in humans.

Cardiomyopathy, Dilated/metabolism* ; Humans ; Microfilament Proteins/metabolism* ; Models, Cardiovascular ; Mutation ; Myocytes, Cardiac ; Pluripotent Stem Cells/metabolism* ; Transcription Factors/metabolism* ; Troponin T/metabolism*