Previous studies have revealed that patients with hypertrophic cardiomyopathy (HCM) exhibit differences in symptom severity and prognosis, indicating potential HCM subtypes among these patients. Here, 793 patients with HCM were recruited at an average follow-up of 32.78 ± 27.58 months to identify potential HCM subtypes by performing consensus clustering on the basis of their echocardiography features. Furthermore, we proposed a systematic method for illustrating the relationship between the phenotype and genotype of each HCM subtype by using machine learning modeling and interactome network detection techniques based on whole-exome sequencing data. Another independent cohort that consisted of 414 patients with HCM was recruited to replicate the findings. Consequently, two subtypes characterized by different clinical outcomes were identified in HCM. Patients with subtype 2 presented asymmetric septal hypertrophy associated with a stable course, while those with subtype 1 displayed left ventricular systolic dysfunction and aggressive progression. Machine learning modeling based on personal whole-exome data identified 46 genes with mutation burden that could accurately predict subtype propensities. Furthermore, the patients in another cohort predicted as subtype 1 by the 46-gene model presented increased left ventricular end-diastolic diameter and reduced left ventricular ejection fraction. By employing echocardiography and genetic screening for the 46 genes, HCM can be classified into two subtypes with distinct clinical outcomes.

Radiotherapy is widely used in the management of advanced colorectal cancer (CRC). However, the clinical efficacy is limited by the safe irradiated dose. Sensitizing tumor cells to radiotherapy via interrupting DNA repair is a promising approach to conquering the limitation. The BRCA1-BARD1 complex has been demonstrated to play a critical role in homologous recombination (HR) DSB repair, and its functions may be affected by HERC2 or BAP1. Accumulated evidence illustrates that the ubiquitination-deubiquitination balance is involved in these processes; however, the precise mechanism for the cross-talk among these proteins in HR repair following radiation hasn't been defined. Through activity-based profiling, we identified PT33 as an active entity for HR repair suppression. Subsequently, we revealed that BAP1 serves as a novel molecular target of PT33 via a CRISPR-based deubiquitinase screen. Mechanistically, pharmacological covalent inhibition of BAP1 with PT33 recruits HERC2 to compete with BARD1 for BRCA1 interaction, interrupting HR repair. Consequently, PT33 treatment can substantially enhance the sensitivity of CRC cells to radiotherapy in vitro and in vivo. Overall, these findings provide a mechanistic basis for PT33-induced HR suppression and may guide an effective strategy to improve therapeutic gain.

BACKGROUND: Familial hypercholesterolemia (FH) is a common autosomal dominant hereditary disease. Its early diagnosis and intervention significantly improve the patient's quality of life. However, there are few types of research on the FH pathogenic genes in China. METHODS: In this study, we recruited a family diagnosed with FH and used whole exome sequencing (WES) to analyze the proband variants. Intracellular cholesterol level, reactive oxygen species (ROS) level, and the expression of pyroptosis-related genes were detected after overexpression of wild-type or variant LDLR in L02 cells. RESULTS: A heterozygous missense variant predicted to be deleterious to LDLR (c.1879G > A, p.Ala627Thr) was identified in the proband. Mechanistically, intracellular cholesterol level, ROS level, and the expression of pyroptosis-related genes, nucleotide-binding oligomerization domain-like receptor family protein 3 (NLRP3) inflammasome and components (caspase 1, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and NLRP3), gasdermin D (GSDMD), interleukin (IL) -18, IL-1β was elevated in the variant LDLR group, which was attenuated by inhibition of ROS. CONCLUSIONS FH is associated with a variant (c.1879G>A, p.Ala627Thr) in the LDLR gene. Regarding the mechanism, the ROS/NLRP3-mediated pyroptosis in hepatic cells may contribute to the pathogenesis of the LDLR variant.

OBJECTIVE：To study the spectrum-effect relationship of HPLC finger print of different polar parts of Ampelopsis grossedentata with its in vivo anti-inflammatory effect. METHODS ：A. grossedentata was reflux extracted with 70％ ethanol，then extracted with petroleum ether ，chloroform，ethyl acetate and water saturated n-butanol；or it was directly decocted with water and then concentrated to obtain different polar parts. The xylene-induced mice ear swelling model was established ；using dexamethasone as positive control ，anti-inflammatory activity of different polar parts of A. grossedentata was investigated. Fingerprints of different polar parts of A. grossedentata were established by HPLC. The determination was performed on Poroshell 120 EC-C18 column with mobile phase consisted of acetonitrile- 0.1％ phosphoric acid solution （gradient elution ）at the flow rate of 1 mL/min. The column temperature was 25 ℃. The detection wavelength was set at 365 nm，and sample size was 5 μL. The grey ralational analysis method was used to analyze the spectrum-effect relationship of HPLC fingerprint common peaks of different polar parts of A. grossedentata with its anti-inflammatory effect. The correlation coefficient and correlation degree were calculated and ranked. RESULTS：Anti-inflammatory experiment showed that the anti-inflammatory effects of 70％ ethanol extraction part ，ethyl acetate extraction part and water extraction part were the most significant （inhibitory rates of ear swelling were 54.07％，30.54％， 30.45％）. Five common peaks were determined in HPLC fingerprints of different polar parts from A. grossedentata . The spectrum-effect analysis results showed that the correlation of5 common peaks were higher than 0.6；among them ，peak 3 and peak 2 （dihydromyricetin） had the strongest anti- inflammatory effect ，and their correlation degrees were both mail：123745789@qq.com greater than 0.8. CONCLUSIONS ： The anti-inflammatory effect of A. grossedentata on xylene-induced ear swelling in mice is the result of multi-comp onent synergy ； unknown substance of peak 3 and dihydromyricetin may be the main active components of A. grossedentata .

Objective:To investigate the assisted pregnancy clinical effect of autologous peripheral blood mononuclear cells (PBMCs) combined with low molecular weight heparin (LMWH) on patients with intrauterine adhesion separation.Methods:Nine patients with intrauterine adhesion separation were treated with intrauterine perfusion of PBMCs 48 hours before transplantation. The low molecular weight heparin 3 200 IU injected daily subcutaneously were carried out on the day of transplantation. Measurement of endometrial thickness and observation of pregnant outcome were perfomed.Results:After 9 patients were injected into the uterine cavity with autologous PBMCs. It was found that, compared to the previous, the thickness of the endometrium was increased, and the morphology of the endometrium was improved in 6 cases. After transplantation, 7 cases of the patients were clinically pregnant, 1 of the patients was biochemically pregnant, and 1 of the patients was not pregnant; among the 7 clinical pregnancy cases, 1 case was intrauterine compound pregnancy (operation on the affected side of fallopian tube pregnancy had been performed), another 2 cases had embryo termination at the 7-8th week of gestation by B-scan ultrasonography analysis. However, 3 cases of clinical pregnancy in 4 patients with repeated implantation failure. At present, 2 cases were in live labor, and the other three cases were in normal continuous pregnancy.Conclusions:Intrauterine perfusion of human PBMCs combined with low molecular weight heparin is beneficial to the improvement of endometrial receptivity and the pregnancy outcome of some patients after the separation of intrauterine adhesions.

Objective:To preliminarily study the characteristics of ventricular synchronicity in patients of idiopathic pulmonary arterial hypertension (IPAH) with different heart function.
Methods:Our research included in 2 groups:IPAH group, n=40 patients intermittently collected in our hospital from 2010-10 to 2014-12 and Control group, n=23 normal subjects from the same period of time. Tissue Doppler echocardiography was conducted to compare interventricular systolic and diastolic time to peak (Ts and Te), their differences (Te-Ts) and (Te-Ts) of left ventricle (LV), right ventricle (RV), interventricular septum (IVS) between 2 groups.
Results:Ts and Te of RV were longer than Ts and Te of LV and IVS in both groups, P<0.05. Compared with Control group, by heart function reducing, IPAH group showed different Ts and Te of LV and IVS, P<0.05 and Ts was gradually prolonged, Te was gradually shorter;while Te of RV became longer firs tand then became shorter thereafter. In IPAH group, the patients with heart function grade IV had the longer Ts of LV and IVS than those with heart functionII, III;the patients with heart function IV had the shorter Te of LV, RV and IVS than those with heart function II, III, all P<0.05. In IPAH group with different heart function, Te between RV-IVS and RV-LV were different from Control group, all P<0.05;Te between LV-IVS in heart function IV patients had the largest difference from Control group, P<0.05. Compared with Control group, IPAH group had gradually decreased Te-Ts of LV and IVS by heart function reducing asgrade II>III>IV, all differences had statistic meaning.
Conclusion:IPAH patients with different right heart function may have interventricular systolic and diastolic de-synchronicity;by reduced heart function, interventricular Te-Ts could be specifically shortened.

This study was designed to detect the impact of Valerian Ligusticum Pill (VLP) on cerebral ischemia reperfusion injury in rats, and explore the mechanism of angiogenesis. Sixty SD male rats were randomly divided into five groups, including sham operation group, model group, VLP-low (30mg·kg^-1) group, VLP-high (50mg·kg^-1) group and nimodipine (10mg·kg^-1) group. The ischemia reperfusion injury model was induced by occlusion of middle cerebral artery with suture embolus, reperfusion after 30 minutes' ischemia. When the rats were awake, the first neurological function scores was determined with modified neurological severity score (mNSS). The rats were given VLP (30mg·kg^-1, 50mg·kg^-1) and nimodipine (10mg·kg^-1) through intragastric administration at 2 mL, once a day for a total of 7 days, while an equal amount of distilled water was used in the sham operation group and model control group. After 7 days, the rats were given second neurological function scores, and improvement of neurological function=[the first score]-[the second score]. The rats were sacrificed to investigate the infarction volume percentage with 2,3,5-triphenyl tetrazolium chloride method; do the qualitative and half quantitative analyses for protein vascular endothelial growth factor receptor 2 (VEGFR2) in the tissue of cortex infarction around by Western blot; detect the new blood vessels of cortex infarction around by ki67/lectin immunofluorescence double staining method. Results suggest that VLP could significantly improve the neurological function, reduce the percentage of infarct volume, increase the expression of VEGFR2 and number of new blood vessels in the cortex infarction around compared with model group. In conclusion, VLP may relive the acute cerebral ischemia reperfusion injury in rats by inducing angiogenesis.

OBJECTIVETo investigate the association between exposure to the famine during early life and elevated resting heart rate (RHR) in adulthood.

METHODFrom June 2006 to October 2007, the employees of kailuan group who took part in the health examination were selected. Of those, 18 619 cases who was born during October 1, 1956 to September 30, 1964 in Hebei province were finally included in the analysis based on the inclusion and exclusion criteria. All the subjects were received questionnaire survey, smoking and drinking, physical examination, Lab examination and the measurement of RHR. The subjects of famine exposure group (3 190 cases) were born from October 1, 1959 to September 30, 1961, semi-exposure group (3 851 cases) were born from October 1, 1958 to September 30, 1959 and from October 1, 1961 to September 30, 1962, control group (11 578 cases) were born from October 1, 1956 to September 30, 1958 and from October 1, 1962 to September 30, 1964. The RHR and the detection rate of elevated RHR were compared among the three groups. The Multivariate logistic regression model was used to analyze the association between of exposure to famine during early life and elevated RHR in adulthood.

RESULTSThe RHR level was higher in famine exposure group and semi-exposed group than control group, which were (74.34 ± 9.71), (74.41 ± 9.48) and (73.90 ± 9.45) beat per minute (bpm) (P values were 0.003 and 0.020, respectively). In all of the subjects. The results of multivariate logistic regression showed that exposure of famine during early life increased the risk of elevated RHR in adulthood after adjustment for age, gender and other confounders (OR = 1.10, 95% CI: 1.01-1.21). In men, exposure of famine during early life also increased the risk of elevated RHR in adulthood (OR = 1.15, 95% CI: 1.04-1.28); In women, there was no association between the famine exposure and elevated RHR (OR = 0.92, 95% CI: 0.74-1.14).

CONCLUSIONExposure of famine during early life increases the risk of elevated RHR in adulthood. This negative effect existed mainly in the male.

Adult ; Alcohol Drinking ; China ; Female ; Heart Rate ; Human Development ; Humans ; Logistic Models ; Male ; Risk Factors ; Smoking ; Starvation

Objective To investigate the correlation between the degree of liver fibrosis and Aspartate aminotransferase-to-Platelet Ratio Index ( APRI ) in children with biliary atresia ( BA ) , and evaluate the clinical significance of liver fibrosis in biliary atresia.Methods A total of 97 patients with diagnosed BA were recruited between January 2010 and June 2013.AST, PLT and APRI were determined one week before laparotomy.The severity of hepatic tibrosis was.Judged by Metavir system the correlation among AST, PLT, APRI and severity of liver fibrosis were evaluated, and their diagnostic value for degree of liver fibrosis was analyzed by ROC.Results Sera AST levels and PLT counts of BA patients were found to be positively(r=0.367, P<0.01) and negatively(r=-0.403, P<0.01) correlated with Metavir scores of liver fibrosis, respectively.There existed positive correlation between APRI and the severity of hepatic fibrosis (r=0.541, P<0.01).The area under ROC curve of APRI to diagnose none or mild fibrosis and moderately severe fibrosis was 0.78, with sensitivity of 77.9%and specificity of 62.1%at the optimal cut-off value of 0.75; the area under ROC curve of APRI to diagnose moderately severe fibrosis with liver cirrhosis arrived 0.85, with sensitivity of 75.0% and specificity of 89.4% at the optimal cut-off value of 1.77.The accuracy of none or mild fibrosis, moderate fibrosis and cirrhosis diagnosed by APRI were 73.2%, 64.9%, 87.6%, respectively.Conclusion APRI can be used as a non-invasive parameter to assess the severity of hepatic fibrosis with BA.

Objective To investigate the association between exposure to the famine during early life and elevated resting heart rate(RHR)in adulthood. Method From June 2006 to October 2007, the employees of kailuan group who took part in the health examination were selected. Of those, 18 619 cases who was born during October 1 ,1956 to September 30,1964 in Hebei province were finally included in the analysis based on the inclusion and exclusion criteria. All the subjects were received questionnaire survey, smoking and drinking, physical examination, Lab examination and the measurement of RHR. The subjects of famine exposure group(3 190 cases) were born from October 1 ,1959 to September 30, 1961,semi?exposure group( 3 851 cases) were born from October 1,1958 to September 30, 1959 and from October 1, 1961 to September 30, 1962 ,control group(11 578 cases) were born from October 1, 1956 to September 30, 1958 and from October 1, 1962 to September 30, 1964. The RHR and the detection rate of elevated RHR were compared among the three groups. The Multivariate logistic regression model was used to analyze the association between of exposure to famine during early life and elevated RHR in adulthood. Results The RHR level was higher in famine exposure group and semi?exposed group than control group, which were (74.34 ± 9.71),(74.41 ± 9.48)and(73.90 ± 9.45)beat per minute(bpm)(P values were 0.003 and 0.020, respectively).In all of the subjects. The results of multivariate logistic regression showed that exposure of famine during early life increased the risk of elevated RHR in adulthood after adjustment for age,gender and other confounders (OR=1.10, 95%CI:1.01-1.21). In men, exposure of famine during early life also increased the risk of elevated RHR in adulthood(OR=1.15, 95%CI:1.04-1.28);In women, there was no association between the famine exposure and elevated RHR (OR=0.92,95%CI:0.74-1.14). Conclusion Exposure of famine during early life increases the risk of elevated RHR in adulthood. This negative effect existed mainly in the male.