Extracellular Matrix Stiffness Regulates DNA Methylation by PKCα-Dependent Nuclear Transport of DNMT3L.

Extracellular matrix (ECM) stiffness has profound effects on the regulation of cell functions. DNA methylation is an important epigenetic modification governing gene expression. However, the effects of ECM stiffness on DNA methylation remain elusive. Here, it is reported that DNA methylation is sensitive to ECM stiffness, with a global hypermethylation under stiff ECM condition in mouse embryonic stem cells (mESCs) and embryonic fibroblasts compared with soft ECM. Stiff ECM enhances DNA methylation of both promoters and gene bodies, especially the 5' promoter regions of pluripotent genes. The enhanced DNA methylation is functionally required for the loss of pluripotent gene expression in mESCs grown on stiff ECM. Further experiments reveal that the nuclear transport of DNA methyltransferase 3-like (DNMT3L) is promoted by stiff ECM in a protein kinase C α (PKCα)-dependent manner and DNMT3L can be binding to Nanog promoter regions during cell-ECM interactions. These findings unveil DNA methylation as a novel target for the mechanical sensing mechanism of ECM stiffness, which provides a conserved mechanism for gene expression regulation during cell-ECM interactions.

[Differences of Energy Spectrum CT Findings between Small Cell Lung Cancer with Mediastinal Lymph Node Metastasis and Mediastinal Sarcoidosis].

Objective To compare the differences of energy spectrum CT between small cell lung cancer(SCLC)with mediastinal lymph node metastasis and mediastinal sarcoidosis.Methods Twenty-five SCLC patients with mediastinal lymph node metastasis(SCLC group)and 26 patients with mediastinal sarcoidosis(sarcoidosis group)confirmed by bronchoscopy and biopsy in Tangshan People's Hospital from January 2018 to June 2019 were selected as the research objects.The CT value,iodine concentration,water concentration and energy spectrum curve slope under different single energy levels were compared between SCLC group and sarcoidosis group.Results The single-energy CT values of 40-80 keV segments in the arterial phase of the SCLC group were significantly higher than those in the sarcoidosis group(all P <0.05).The single-energy CT values of 90-140 keV segments were not significantly different from those in the sarcoidosis group(all P >0.05).The single-energy CT values of 40-90 keV segments in venous phase of the SCLC group were significantly higher than those of the sarcoidosis group(all P <0.05),and the single-energy CT values of 100-140 keV segments were not significantly different from those of the sarcoidosis group(all P >0.05).The concentrations of iodine in the arterial phase and venous phase of the SCLC group were(11.56±4.06)µg/cm 3 and(13.39±0.87)µg/cm 3,respectively,which were significantly higher than those [(4.43±3.85)µg/cm 3,t=11.564,P=0.026;(7.23±2.71)µg/cm 3,t=13.653,P=0.021] in the sarcoidosis group.The concentrations of water in the arterial and venous phases of the SCLC group were(1040.67±5.62)mg/cm 3 and(1035.23±8.57)mg/cm 3,respectively,which showed no statistically significant difference compared with those [(1028.87±6.94)mg/cm 3,t=3.155,P=1.861;(1021.53±4.68)mg/cm 3,t=3.265,P=1.687] in the sarcoidosis group.The slopes of energy spectrum curve at 40-70 keV,70-100 keV and 100-140 keV in venous phase of the SCLC group were significantly higher than those of the sarcoidosis group(all P <0.05),whereas they showed no significant difference between the two groups in arterial phase(all P >0.05).Conclusion The differences between SCLC with mediastinal lymph node metastasis and mediastinal sarcoidosis can be shown on the single-energy CT values of 40-80 keV in arterial phase and 40-90 keV in venous phase,iodine concentrations in arterial phase and venous phase,and the slope of energy spectrum curve in venous phase.

[Different Energy Spectrum CT Findings between Anterior Mediastinal Lymphoma and Thymic Carcinoma].

Objective To investigate the differences in energy spectrum CT findings between anterior mediastinal lymphoma and thymic carcinoma. Methods Twenty-two cases of anterior mediastinal lymphoma and 28 cases of thymic carcinoma confirmed by biopsy in Tangshan People's Hospital were selected.The CT values and changes of iodine content and water content in lesion sites were measured by energy spectrum analysis software.The differences between anterior mediastinal lymphoma and thymic carcinoma were compared. Results The single-energy CT value of 40-80 keV in thymus carcinoma was higher than that in anterior mediastinal lymphoma(P=0.001,P=0.037,P=0.042,P=0.034,P=0.002;P=0.016,P=0.013,P=0.018,P=0.024,P=0.012).The difference in the single-energy CT value of 90-110 keV between anterior mediastinal lymphoma and thymic carcinoma showed no statistical significance(all P>0.05).The concentrations of water in the arterial and venous stages of thymic carcinoma were significantly lower than those in the anterior mediastinal lymphoma(P=0.030,P=0.037),whereas the iodine concentrations were significantly higher(P=0.026,P=0.000). Conclusion Anterior mediastinal lymphoma and thymic carcinoma have remarkably different 40-80 keV single energy CT value and iodine concentration in arterial and venous phases,which may be helpful for the differential diagnosis of these two malignancies.

[Correlation between Coronary Artery Tortuosity and Stenosis in Patients with Myocardial Bridge].

Objective To analyze the correlation between tortuosity and stenosis in patients with myocardial bridge(MB)on the left anterior descending artery(LAD). Methods Data of patients with MB on the LAD,which was discovered by coronary computed tomography angiography(CCTA),in the Affiliated Hospital of North China University of Science and Technology from October 2015 to December 2018 were retrospectively analyzed.Among them 278 patients with tortuosity on LAD and 278 patients without tortuosity were selected.The clinical charateristics(age,gender,hypertension,hyperlipidemia,diabetes,smoking history,and family history)as well as the incidence and severity of stenosis of LAD were recorded and compared. Results The incidence of coronary artery stenosis in the non-tortuosity group(57.6%)was significantly lower than that in the tortuosity group(71.9%)($\bar{χ}$=12.608,P<0.001).It was also significantly higher in mild tortuosity group(78.5%)than in non-tortuosity group(57.6%)($\bar{χ}$=20.462,P<0.001)and moderate tortuosity group(61.5%)($\bar{χ}$=7.872,P=0.005).The degree of coronary artery stenosis was significantly different between tortuosity group and non-tortuosity group,and the tortuosity group was more likely to have more severe stenosis than the non-tortuosity group(Z=-3.292,P=0.001).The stenosis degree of the patients with no,mild,moderate and severe tortuosity was significantly different(H=17.787,P<0.001),and the differences had a rank correlation(rs=0.169,P=0.000).However,the incidence of stenosis was not significantly different among the none,moderate,and severe tortuosity groups(all P>0.05).There was no significant difference among the incidence of stenosis among the mild,moderate,and severe coronary artery tortuosity group(all P>0.05). Conclusions Patients with coronary artery tortuosity are more likely to have coronary artery stenosis than those without tortuosity.The stenosis rate in patients with mild tortuosity is higher than in patients without tornuosity or with moderate tortuosity.Patients with mild tortuosity are more likely to experience more severe stenosis,while those without tortuosity are more likely to have milder stenosis.

[Correlation of Coronary Artery Tortuosity Caused by Myocardial Bridge with Coronary Atherosclerosis].

Objective To evaluate the potential correlation between coronary artery tortuosity caused by myocardial bridge and coronary atherosclerosis. Methods The data of 88 patients with suspected coronary heart disease in the Affiliated Hospital of North China University of Science and Technology during the period from March 2015 to June 2016 were retrospectively analyzed.Coronary artery tortuosity caused by myocardial bridge was diagnozed by computed tomography coronary angiography.Meanwhile,the contemporary data of patients diagnosed with coronary artery tortuosity without myocardial bridge were selected as the control group.The coronary atherosclerosis as well as coronary artery stenosis were observed,and clinical data including age,gender,hypertension,hyperlipidemia,diabetes,smoking history,family history,and body mass index(BMI) were collected and compared.The incidence of coronary atherosclerosis in terms of whole coronary artery,anterior segment of tortuosity,tortuosity segment,and posterior segment of tortuosity was compared firstly,followed by the comparisons of the differences in coronary artery stenosis degree in terms of anterior segment of tortuosity,tortuosity segment,and posterior segment of tortuosity.Finally,the differences of the incidence of coronary atherosclerosis in the complete MB group,incomplete MB group,and non-MB group with different degrees of tortuosity were compared.Results The incidences of coronary atherosclerosis on whole coronary artery(χ2=15.565,P=0.000),anterior segment of tortuosity(χ2=8.606,P=0.003),tortuosity segment(χ2=13.475,P=0.000) and posterior segment of tortuosity(χ2=4.314,P=0.038) in the MB group were significantly lower than those in the non-MB group.The incidences of mild stenosis in anterior segment of tortuosity(χ2=6.988,P=0.008),tortuosity segment(χ2=10.050,P=0.002),and posterior segment of tortuosity(χ2=4.314,P=0.038) in the MB group were significantly lower than those in the non-MB group.However,the incidences of moderate and severe stenosis on anterior segment of tortuosity(χ2=0.586,P=0.444),tortuosity segment(χ2=1.356,P=0.244),and posterior segment of tortuosity were not significantly different between these two groups.The incidence of coronary atherosclerosis on anterior segment of tortuosity of mild(χ2=13.526,P=0.000) and moderate tortuosity(Fisher exact probability,P=0.015) in the complete MB group was significantly lower than that in the non-MB group;however,the severe tortuosity was not significantly different(Fisher exact probability,P=0.155).The incidence of coronary atherosclerosis on anterior segment of tortuosity of mild tortuosity(χ2=9.167,P=0.002) in the incomplete MB group was significantly lower than that in the non-MB group;however,no significant difference of moderate(Fisher exact probability,P=0.047) and severe tortuosity(Fisher exact probability,P=0.031) was identified between these two groups(P>0.0167).Finally,no significant difference of the incidence of coronary atherosclerosis on anterior segment of tortuosity of mild(χ2=1.239,P=0.266),moderate(Fisher exact probability,P=1.000),and severe tortuosity(Fisher exact probability,P=1.000) was identified between the complete MB group and the incomplete MB group.Conclusions Compared with non-MB patients,patients with coronary artery tortuosity caused by MB(especially complete MB) tend to have lower incidences of coronary atherosclerosis and mild coronary stenosis.However,coronary artery tortuosity caused by MB is not correlated with moderate or severe coronary stenosis.

Impact of Myocardial Bridge-mural Coronary Artery on Myocardial Functions.

Objective To study the impact of myocardial bridge (MB)-mural coronary artery (MCA) on myocardial functions.Methods Totally 82 patients presenting with chest tightness and chest pain who were diagnosed with the MB in the left anterior descending artery by CT coronary angiography were enrolled as the MB group,in which the thickness and length of MB and the systolic stenosis degree of MCA were measured.In addition,82 healthy subjects,as confirmed by health check-up,were set as the control group.The age,gender,body mass index (BMI),heart rate (HR),smoking history,interventricular septal thickness,left ventricular posterior wall thickness,diameter of left atrium,left ventricular end-diastolic diameter,left ventricular end-systolic diameter,left ventricular ejection fraction,and the cases of E'/A'<1 were compared between MB group and control group.The potential correlations among the thicken/length of MB,the systolic stenosis degree of MCA and early diastolic peak strain rate(SRe)/late diastolic peak strain rate(SRa) were analyzed.Results The age (t=0.97,P=0.65),gender (χ2=0.10,P=0.75),BMI (t=1.82,P=0.07),HR (t=0.87,P=0.39) and smoking history (χ2=0.43,P=0.51) were not significantly difference between these two group.The interventricular septal thickness (t=1.54,P=0.13),left ventricular posterior wall thickness (t=1.47,P=0.14),diameter of left atrium (t=1.62,P=0.11),left ventricular end-diastolic diameter (t=0.49,P=0.63),left ventricular end-systolic diameter (t=1.29,P=0.20),and left ventricular ejection fraction (t=0.56,P=0.57) were also not significantly different between the normal and MB group.However,there was significant difference in the cases of E'/A'<1 (χ2=38.22,P=0.00).The SRe (r=-0.97,P=0.00;r=-0.93,P=0.00)and SRa (r=-0.89,P=0.00;r=-0.90,P=0.00) the left ventricular anterior wall were negatively correlated with the thickness of MB and the systolic stenosis degree of MCA and were not correlated with the length of MB (r=-0.09,P=0.76;r=-0.13,P=0.66).Conclusions MB is not correlated with myocardial systolic function,but can affect myocardial diastolic function.When the MB thickness increases,the systolic stenosis degree of MCA increases,the myocardial diastolic function gradually decreases,but the MB length is not related to myocardial systolic function.

Impact of Myocardial Bridge-mural Coronary Artery on Myocardial Blood Supply.

Objective To explore the impact of myocardial bridge-mural coronary artery (MB-MCA) on myocardial blood supply. Methods The imaging data of 74 patients with the isolate MB in the left anterior descending artery undergoing 256-slice CT coronary angiography and myocardial perfusion imaging (MPI) were retrospectively analyzed. The subjects were divided into incomplete and complete MB types. The length of MB and the systolic stenosis degree of MCA were measured.The type and length of MB and the systolic stenosis degree of MCA (according to Noble grade) were compared between the normal and abnormal MPI groups. The clinical characteristics including age, gender, body mass index, hypertension, dyslipidemia, diabetes mellitus, and smoking history were also reviewed. Results There were 38 incomplete MB cases and 13 complete MB cases in the normal MPI group,and 5 and 18 in the abnormal MPI group (χ2=18.134,P=0.000). The MB length in the normal and abnormal MPI group were (14.7±3.7) mm and (15.5±4.5) mm (t=0.804,P=0.424). However, the systolic stenosis degree of MCA showed significant difference (χ2=17.839,P=0.000). The clinical characteristics were not significantly differentt between the normal and abnormal MPI groups (P>0.05). Conclusions The MB type and the systolic stenosis degree of MCA can affect myocardial perfusion.Patients with complete MB and the moderate-to-severe systolic stenosis degree of MCA are more susceptible to myocardial ischemia. However, the MB length is not correlated with myocardial ischemia.

Activation of alpha 7 nicotinic acetylcholine receptor protects mice from radiation-induced intestinal injury and mortality.

Radiation-induced gastrointestinal syndrome occurs when the body is exposed to a high dose of radiation. Currently, safe and effective radioprotectants are not available. Apoptosis was reported to play a primary role in radiation-induced injury. Recent evidence suggests that stimulation of α7 nicotinic acetylcholine receptor (α7nAChR) prevents cell death by inhibition of apoptosis. In this study, we demonstrated that a single dose of PNU282987 (100 µg/kg, i.p.), a selective α7nAChR agonist, protected mice from intestinal injury and significantly improved survival when administered prior to lethal 8 Gy total body irradiation. In vitro, PNU282987 protected against 8 Gy radiation-induced cell death in human umbilical venous endothelial cells by inhibiting apoptosis. We conclude that activation of α7nAChR may provide a new therapeutic pathway for the treatment of radiation-induced damage and mortality.