ox-LDL Promotes Bidirectional Regulation of Neuronal Apoptosis Through The PCSK9/LRP1 Signaling Pathway / 生物化学与生物物理进展

Obiective Alzheimer’s disease (AD) is a degenerative disease of the central nervous system (CNS) caused by a variety of risk factors. There are various pathological changes, but apoptosis of the neurological meridian cells is one of the most important pathological bases. Hyperlipidemia is a high-risk factor for the development of AD, which can lead to increased levels of oxidized low-density lipoprotein (ox-LDL) in brain tissues. PCSK9 is a protease closely related to lipid metabolism, but studies have shown that it may be related to the development of AD. LRP1 is abundantly expressed in neuronal cells, and it is an important transporter for the clearance of Aβ. There is now a large amount of literature confirming that PCSK9 can induce the degradation of LRP1. PI3K/AKT is an important signaling pathway in vivo, which plays an important role in apoptosis, and there is now a large amount of literature confirming that LRP1 activates the PI3K/AKT pathway, which has an anti-apoptotic effect. So can PCSK9 affect the PI3K/AKT pathway through LRP1 and thus regulate neuronal apoptosis? This deserves further investigation.The aim of this study was to explore the role of PCSK9 in mediating ox-LDL pro-apoptotic neuronal cell death and its mechanism, and then further elaborate the mechanism of hyperlipidemia leading to neurodegenerative diseases such as AD. MethodsFirstly, PC12 cells were treated with different concentrations of ox-LDL (0, 25, 50, 75 and 100 mg/L) for 24 h. Oil red O staining was used to detect lipid accumulation in PC12 cells, Hoechst33258 staining and flow cytometry to detect apoptosis in PC12 cells, ELISA to detect the content of Aβ secreted by PC12, Western blot to detect expression of SREBP2, PCSK9 and LRP1. Then PC12 cells were treated with 75 mg/L ox-LDL for different times (0, 6, 12, 24, 48 h), and Western blot were performed to detect the expression of SREBP2, PCSK9 and LRP1. Finally, after transfecting 100 nmol/L PCSK9 siRNA into PC12 cells for 48 h, PC12 cells were treated with 75 mg/L ox-LDL for 24 h, Hoechst33258 staining and flow cytometry to detect apoptosis rate of PC12 cells, and Western blot to detect PCSK9, LRP1, PI3K, AKT, P-PI3K , P-AKT, NF-κB, Bcl-2, Bax, Caspase-9 and Caspase-3 expression, and ELISA detected Aβ content secreted by PC12 cells. Resultsox-LDL increased lipid accumulation and promoted apoptosis and Aβ secretion in PC12 cells, as well as increasing the expression of SREBP2 and PCSK9 and decreasing the expression of LRP1 in PC12 cells. pCsk9 siRNA could be inhibited through the PI3K/AKT pathway and the NF-κB-Bcl-2/Bax-Caspase-9/3 pathway to inhibit ox-LDL-induced apoptosis in PC12 cells while increasing Aβ secretion in PC12 cells. Conclusionox-LDL plays a bidirectional regulatory role in ox-LDL-induced apoptosis of PC12 cells by inducing an increase in PCSK9 expression and a decrease in LRP1 expression in PC12 cells, which in turn affects different signaling pathways downstream.

Clinical features and imaging manifestations for intravascular large B-cell lymphoma / 中南大学学报(医学版)

Objective:Intravascular large B-cell lymphomas are a rare group of extranodal non-Hodgkin's lymphomas with no apparent specificity of symptoms and often a poor prognosis.This study aims to investigate the clinical features and imaging manifestations of intravascular large B-cell lymphoma,to improve the awareness of clinicians and imaging physicians and to reduce the underdiagnosis and misdiagnosis of this disease. Methods:Five patients with pathologically confirmed intravascular large B-cell lymphoma diagnosed between December 2011 and February 2022 at Xiangya Hospital of Central South University were retrospectively analyzed for clinical features and imaging manifestations. Results:The age range for the 5 patients in this paper was 44-72 years at an average of(55.4±11.2)years,2 were male and 3 were female.There were 4 patients with fever,3 patients with cough,3 patients with fatigue,and 2 patients with neurological symptoms.The primary sites of lesions were bilateral adrenal glands(2 cases),liver(1 case),central nervous system(1 case),lung(1 case).Imaging of the corresponding site was performed in 5 cases.When the primary site is the adrenal gland,it appears as bilateral adrenal masses or bilateral adrenal thickening with clear contours.When the primary site is the liver,it appears as a hypodense lesion in the right lobe of the liver with"vascular floating sign".When the primary site is the central nervous system,it appears as multiple tumor-like lesions in the frontal-parietal-occipital lobe,right temporal lobe and bilateral cerebellar hemispheres with multiple hemorrhages within the lesions.When the primary site is the lung,it appears as multiple ground glass shadows and solid changes in both lungs with localized lobular septal thickening.The final pathological diagnosis was intravascular large B-cell lymphoma in all 5 patients,one of whom had a good prognosis after chemotherapy,2 of whom died within 3 days of discharge,and two of whom were lost to follow-up. Conclusion:Intravascular large B-cell lymphoma can involve multiple tissues and organs,and its prognosis is often poor,and its imaging manifestations possess certain specificity.When this disease is highly suspected,a biopsy of the corresponding organ should be performed as soon as possible to clarify the diagnosis.

Risk factors of stroke-associated pneumonia for patients with mild to moderate acute ischemic stroke / 中国康复理论与实践

ObjectiveTo explore the risk factors of stroke-associated pneumonia (SAP) for patients with mild to moderate acute ischemic stroke (AIS). MethodsFrom October, 2016 to December, 2019, 321 patients with mild to moderate AIS in Beijing Bo'ai Hospital were collected and divided into SAP group (n = 71) and non-SAP group (n = 250) according to whether they were complicated with SAP. Gender, age, time from symptom onset to admission, systolic pressure, diastolic pressure, scores of National Institutes of Health Stroke Scale (NIHSS) at admission, and medical history were recorded. Laboratory indexes including the count of white blood cell and platelet, levels of D-dimer, hypersensitive C-reactive protein (hs-CRP) and α-hydroxybutyrate dehydrogenase (α-HBDH) were measured. ResultsUnivariate analysis showed that age, NIHSS score, history of hypertension, atrial fibrillation, prior cerebral infarction, the count of white blood cell and platelet, the levels of D-dimer, hs-CRP and α-HBDH were the influencing factors of SAP (P < 0.2). Multivariate Logistic regression showed that age > 70 years old (OR = 7.121, 95%CI 3.493 to 14.514, P < 0.001), NIHSS score > 4 (5 to 10, OR = 4.861, 95% CI 2.412 to 9.797, P < 0.001), the count of platelet > 300×109/L (OR = 6.978, 95% CI 1.864 to 26.128, P = 0.004), and the level of D-dimer > 1.0 mg/L (OR = 3.036, 95% CI, 1.518 to 6.071, P = 0.002) were the risk factors of SAP. The model fitted the original data well (HL = 1.509，P = 0.680) and appeared a good prediction (AUC = 0.847, 95% CI 0.796 to 0.898, P < 0.001). ConclusionAge > 70 years old, NIHSS score > 4 (5 to 10), the count of platelet > 300×109/L and the level of D-dimer > 1.0 mg/L were the risk factors of SAP for patients with mild to moderate AIS.

Compound from Magnolia officinalis Ameliorates White Matter Injury by Promoting Oligodendrocyte Maturation in Chronic Cerebral Ischemia Models / 神经科学通报·英文版

Chronic cerebral hypoperfusion leads to white matter injury (WMI), which subsequently causes neurodegeneration and even cognitive impairment. However, due to the lack of treatment specifically for WMI, novel recognized and effective therapeutic strategies are urgently needed. In this study, we found that honokiol and magnolol, two compounds derived from Magnolia officinalis, significantly facilitated the differentiation of primary oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes, with a more prominent effect of the former compound. Moreover, our results demonstrated that honokiol treatment improved myelin injury, induced mature oligodendrocyte protein expression, attenuated cognitive decline, promoted oligodendrocyte regeneration, and inhibited astrocytic activation in the bilateral carotid artery stenosis model. Mechanistically, honokiol increased the phosphorylation of serine/threonine kinase (Akt) and mammalian target of rapamycin (mTOR) by activating cannabinoid receptor 1 during OPC differentiation. Collectively, our study indicates that honokiol might serve as a potential treatment for WMI in chronic cerebral ischemia.

Safety and efficacy of short-term dual antiplatelet therapy combined with intensive rosuvastatin in acute ischemic stroke

Abstract Objective: To investigate the safety and efficacy of short-term (7-day) Dual Antiplatelet Therapy (DAPT) with intensive rosuvastatin in Acute Ischemic Stroke (AIS). Methods: In this study, patients with AIS in the emergency department of the hospital from October 2016 to December 2019 were registered and divided into the control group (Single Antiplatelet Therapy [SAPT] + rosuvastatin) and the study group (7-day DAPT + intensive rosuvastatin) according to the therapy regimens. The generalized linear model was used to compare the National Institute of Health Stroke Scale (NIHSS) scores between the two groups during the 21-day treatment. A Cox regression model was used to compare recurrent ischemic stroke, bleeding events, Statin-Induced Liver Injury (SILI), and Statin-Associated Myopathy (SAM) between the two groups during the 90-day follow-up. Results: Comparison of NIHSS scores after 21-day treatment: NIHSS scores in the study group decreased significantly, 0.273-times as much as that in the control group (Odds Ratio [OR] 0.273; 95% Confidence Interval [95% CI] 0.208-0.359; p < 0.001). Comparison of recurrent ischemic stroke during the 90-day follow-up: The therapy of the study group reduced the risk of recurrent stroke by 65% (7.76% vs. 22.82%, Hazard Ratio [HR] 0.350; 95% CI 0.167-0.730; p = 0.005). Comparison of bleeding events: There was no statistical difference between the two groups (7.79% vs. 6.71%, HR = 1.076; 95% CI 0.424-2.732; p = 0.878). No cases of SILI and SAM were found. Conclusions: Short-term DAPT with intensive rosuvastatin effectively relieved the clinical symptoms and significantly reduced the recurrent stroke for patients with mild-to-moderate AIS within 90 days, without increasing bleeding events, SILI and SAM.

Changes and predictive value of plasma histone H4 levels in patients with septic cardiomyopathy / 中华急诊医学杂志

Objective:To observe the changes of serum histone H4 level and its predictive value in patients with septic cardiomyopathy.Methods:A prospective study was conducted. A total of 147 patients with sepsis and septic shock were collected in emergency department. The general data were recorded. Transthoracic echocardiography and plasma histone H4 were conducted within 24 hours and 7 days after admission.The scores of sequential organ failure assessment(SOFA), acute physiology and chronic health evaluationⅡ(APACHEⅡ), and nutritional risk screening 2002 (NRS2002) were evaluated within 24 hours. According to whether septic cardiomyopathy occurred, the patients were divided into two groups, and dynamic changes of histone H4 on the first and seventh day of the two groups were observed. The factors influencing the occurrence of septic cardiomyopathy were analyzed by multivariate logistic regression. The prediction ability of serum histone H4 on septic cardiomyopathy was evaluated by receiver operating curve (ROC).Results:The incidence of septic cardiomyopathy was 28.6% (42 / 147). The level of histone H4 in septic cardiomyopathy group was higher than that in non septic cardiomyopathy group ( Z = 4.449, P < 0.001), and dynamic detection showed that the level of histone H4 on the seventh day was lower than that on admission ( Z=3.057, P=0.002). Multivariate logistic regression showed that the high serum histone H4 level [Odd Ratio( OR)=1.337, 95% confidence interval (95% CI) was 1.173-1.522, P < 0.001], SOFA ( OR= 1.474, 95% CI 1.227-1.769, P < 0.001), older age ( OR = 1.074, 95% CI 1.019-1.132, P = 0.008) were independent risk factors for septic cardiomyopathy. The area of ROC curve for serum histone H4 to predict septic cardiomyopathy was 0.729 ( P < 0.001), the predictive cut-off value was 10.81 ng/ml, which yielded a sensitivity 0.524 and a specificity of 0.914. Conclusions:The level of histone H4 showed dynamic change in septic cardiomyopathy, and high serum histone H4 level has a good predictive value for the occurrence of septic cardiomyopathy.

Relationship between sleep quality and slow-flow in patients with acute coronary syndrome during percutaneous coronary intervention and its impact on clinical prognosis / 中国医师杂志

Objective:To investigate the relationship between sleep quality and slow-flow in patients with acute coronary syndrome during percutaneous coronary intervention(PCI) and its impact on clinical prognosis.Methods:200 patients with ACS hospitalized in the cardiology department of Guangzhou First People's Hospital from January 2017 to October 2018 were selected. The Pittsburgh Sleep Quality Index (PSQI) was measured before elective PCI, and the sleep breathing of patients was monitored by micro motion sensitive mattress sleep monitoring system (MSMSMS). The patients were divided into normal sleep group (68 cases, PSQI≤7 points) and sleep disorder group (132 cases, PSQI>7 points). The levels of plasma endothelin-1 (ET-1) and nitric oxide (NO) were measured. The " slow-flow" that took place during PCI were also recorded. Major cardiac adverse events (MACE) of patients took placed during 12 months follow-up periods were recorded and compared between two groups.Results:Compared with normal sleep group, patients in sleep disorder group had higher ratio of sleep apnea-hypopnea syndrome (SAHS), hypoxemia and lower deep sleep (25.00% vs 10.29%, 25.76% vs 11.76%, 66.67% vs 48.53%, all P<0.05); lower level of NO and higher level of ET-1 [(28.65±3.26)μmol/L vs (30.24±4.08)μmol/L; (21.17±3.08)pg/ml vs (18.90±2.95)pg/ml, P<0.05]; more slow-flow events took place during PCI in sleep disorder group than normal sleep group (16.67 vs 5.88%, P<0.05); After 12 months of follow-up, Kaplan-Meier survival analysis showed patients of the two groups had significantly different cumulative non-events survival rates (19.70% vs 7.35%, Log rank=5.06, P=0.025). Conclusions:Sleep disorder increase the slow-flow phenomenon during PCI in patients with ACS and affect the clinical prognosis.

Prenatal genetic diagnosis of the fetuses with isolated corpus callosum abnormality / 中华妇产科杂志

Objective:To explore the application value of chromosome karyotype analysis, chromosomal microarray analysis (CMA) and whole exome sequencing (WES) in prenatal diagnosis of isolated corpus callosum abnormality (CCA) fetus.Methods:Fetuses diagnosed with isolated CCA by ultrasound and MRI and receiving invasive prenatal diagnosis in Guangzhou Women and Children′s Medical Center and Qingyuan People′s Hospital from January 2010 to April 2021 were selected. Karyotype analysis and/or CMA [or copy number variation sequencing (CNV-seq)] were performed on all fetal samples, and WES was performed on fetal samples and their parents whose karyotype analysis and/or CMA (or CNV-seq) results were not abnormal.Results:Among 65 fetuses with isolated CCA, 38 cases underwent karyotype analysis, and 3 cases were detected with abnormal karyotypes, with a detection rate of 8% (3/38). A total of 49 fetuses with isolated CCA underwent CMA (or CNV-seq) detection, and 6 cases of pathogenic CNV were detected, the detection rate was 12% (6/49). Among them, the karyotype analysis results were abnormal, and the detection rate of further CMA detection was 1/1. The karyotype results were normal, and the detection rate of further CMA (or CNV-seq) detection was 14% (3/21). The detection rate of CMA as the first-line detection technique was 7% (2/27). A total of 25 fetuses with isolated CCA with negative results of karyotyping and/or CMA were tested by WES, and 9 cases (36%, 9/25) were detected with pathogenic genes. The gradient genetic diagnosis of chromosomal karyotyping, CMA and WES resulted in a definite genetic diagnosis of 26% (17/65) of isolated CCA fetuses.Conclusions:Prenatal genetic diagnosis of isolated CCA fetuses is of great clinical significance. The detection rate of CMA is higher than that of traditional karyotyping. CMA detection could be used as a first-line detection technique for fetuses with isolated CCA. WES could increase the pathogenicity detection rate of fetuses with isolated CCA when karyotype analysis and/or CMA test results are negative.

Impact of nonsteroidal anti-inflammatory drugs on efficacy of anti-PD-1 therapy for primary liver cancer / 南方医科大学学报

OBJECTIVE@#To assess the impact of nonsteroidal anti-inflammatory drugs (NSAIDs) on clinical outcomes of patients receiving anti-PD-1 immunotherapy for hepatocellular carcinoma.@*METHODS@#We conducted a retrospective study among 215 patients with primary liver cancer receiving immunotherapy between June, 2018 and October, 2020. The patients with balanced baseline characteristics were selected based on propensity matching scores, and among them 33 patients who used NSAIDs were matched at the ratio of 1∶3 with 78 patients who did not use NSAIDs. We compared the overall survival (OS), progression-free survival (PFS), and disease control rate (DCR) between the two groups.@*RESULTS@#There was no significant difference in OS between the patients using NSAIDs (29.7%) and those who did not use NSAIDs (70.2%). Univariate and multivariate analyses did not show an a correlation of NSAIDs use with DCR (univariate analysis: OR=0.602, 95% CI: 0.299-1.213, P=0.156; multivariate analysis: OR=0.693, 95% CI: 0.330-1.458, P=0.334), PFS (univariate analysis: HR=1.230, 95% CI: 0.789-1.916, P=0.361; multivariate analysis: HR=1.151, 95% CI: 0.732-1.810, P=9.544), or OS (univariate analysis: HR=0.552, 95% CI: 0.208-1.463, P=0.232; multivariate analysis: HR=1.085, 95% CI: 0.685-1.717, P=0.729).@*CONCLUSION@#Our results show no favorable effect of NSAIDs on the efficacy of immunotherapy in patients with advanced primary liver cancer, but this finding still needs to be verified by future prospective studies of large cohorts.

Establishment and evaluation of clinical diagnostic scoring system for septic cardiomyopathy / 中华危重病急救医学

Objective:To establish a clinical diagnostic scoring system for septic cardiomyopathy (SCM) and evaluate its diagnostic efficacy.Methods:A prospective cohort study was performed. Patients with sepsis and septic shock admitted to the department of emergency of China Rehabilitation Research Center were enrolled from January 2019 to December 2020. The baseline information, medical history, heart rate (HR), mean arterial pressure (MAP), body temperature and respiratory rate (RR) on admission were recorded. Laboratory indexes such as white blood cell count (WBC), hypersensitivity C-reactive protein (hs-CRP), N-terminal pro-brain natriuretic peptide (NT-proBNP), and blood lactic acid (Lac) were measured. Transthoracic echocardiography was conducted within 24 hours and on the 7th after admission. Sequential organ failure assessment (SOFA) score, acute physiology and chronic health evaluationⅡ(APACHEⅡ), and nutritional risk screening 2002 scale (NRS2002) were also assessed. The patients were divided into two groups according to whether SCM occurred or not. The risk factors of SCM were screened by univariate and multivariate Logistic regression. The cut-off value of continuous index was determined by receiver operator characteristic curve (ROC curve) and discretized concerning clinical data. The regression coefficient β was used to establish the corresponding score, and the clinical diagnostic score system of SCM was established. The diagnostic value of the model was evaluated by ROC curve.Results:In total, 147 patients were enrolled in the study and the incidence of SCM was 28.6% (42/147). Univariate Logistic regression analysis showed the risk factors of SCM included: ① continuous indicators: age, NT-proBNP, RR, MAP, Lac, NRS2002, SOFA, APACHEⅡ; ② discrete indicators: shock, use of vasoactive drugs, history of coronary heart disease, acute kidney injury (AKI). Multivariate Logistic regression analysis after discretization of above continuous index showed that age≥87 years old, NT-proBNP≥3 000 ng/L, RR≥30 times/min, Lac≥3 mmol/L and SOFA≥10 points were independent risk factors for SCM [age ≥87 years: odds ratio ( OR) = 3.491, 95% confidence interval (95% CI) was 1.371-8.893, P = 0.009; NT-proBNP≥3 000 ng/L: OR = 2.708, 95% CI was 1.093-6.711, P = 0.031; RR≥30 times/min: OR = 3.404, 95% CI was 1.356-8.541, P = 0.009; Lac≥3 mmol/L: OR = 3.572, 95% CI was 1.460-8.739, P = 0.005; SOFA≥10 points: OR = 8.693, 95% CI was 2.541-29.742, P = 0.001]. The clinical diagnostic score system of SCM was established successfully, which was composed of age≥87 years old (1 point), NT-proBNP ≥ 3 000 ng/L(1 point), RR≥30 times/min (1 point), Lac≥3.0 mmol/L (1 point), SOFA≥10 points (2 points), and the total score was 6 points. ROC curve analysis showed the cut-off value of the scoring system for diagnosing SCM was 3 points, the area under ROC curve (AUC) was 0.833, 95% CI was 0.755-0.910, P < 0.001, with the sensitivity of 71.4%, and specificity of 86.7%. Conclusion:The clinical diagnostic scoring system has good diagnostic efficacy for SCM and contributes to early identification of SCM for clinicians.

Application of whole exome sequencing technology in fetuses with congenital structural abnormalities / 中华医学遗传学杂志

OBJECTIVE@#To investigate the application value of whole exome sequencing technology in fetuses with congenital structural abnormalities.@*METHODS@#The chromosomal abnormalities of 1147 families were analyzed. According to the follow-up results, the data of fetuses with new phenotypes in late pregnancy or after birth were reanalyzed. Subgroups were divided according to the organs involved and whether single malformation or not. The gene regulatory network map was drawn by using string database and Cytoscape software. Fisher exact probability method was used to compare the difference of the diagnostic rate of pathogenic genes among the groups.@*RESULTS@#A total of 160 fetal cases received positive molecular diagnosed, involving 178 variant sites of 125 pathogenic genes, including 8 cases (4.9%, 8/163) by data reanalysis, and the overall positive diagnosis rate was 13.9%. Diagnostic rate was highest in the group of skeletal malformation (31.5%, 39/124) and lowest in that with thoracic malformation (0, 0/32). The gene clusters of fetal edema and intrauterine growth restriction were independent, and were not associated with the major structural malformations. The probability of each parent carrying the same recessive gene variant was 0.03 (39/1146) and 0.08 (4/53) with positive family history.@*CONCLUSION@#For fetuses with congenital structural abnormalities that are negative for conventional genetic tests, 13.9% of phenotypic associated pathogenic/likely pathogenic genetic variants can be detected by whole exome sequencing technology. Its application value for prenatal diagnosis varies in fetus with different organs involved. Reanalysis of sequencing data for cases with new phenotypes in late pregnancy or after birth can further improve the molecular diagnosis rate. Further investigations are needed to explore the related genetic mechanisms.

Prediction of Short- and Long-term Death in Patients with Acute Ischemic Stroke Using Various Scoring Systems / 中国康复理论与实践

Objective:To compare the prediction of Ischemic Stroke Predictive Risk Score (iScore), Preadmission Comorbidities, Level of Consciousness, Age, and Neurologic Deficit (PLAN), Acute Stroke Registry and Analysis of Lausanne (ASTRAL) and Totaled Health Risks in Vascular Events (THRIVE) for short- and long-term death for patients with acute ischemic stroke (AIS). Methods:From August, 2015 to June, 2018, 323 AIS patients in emergency ward were included, and followed up 30 days, three months and a year after including. Receiver operating characteristic (ROC) curve was used to analyze the predictive effects of iScore, PLAN, ASTRAL and THRIVE. Results:The all-cause mortality 30 days, three months and a year after including was 12.4% (40/323), 17.3% (56/323) and 25.7% (83/323), respectively. The area under curve (AUC) from more to less arranged as iScore, PLAN, ASTRAL and THRIVES. There was significant difference of AUC between iScore and THRIVE (Z > 1.990, P < 0.05), but not among the others (Z < 1.943, P > 0.05). Conclusion:iScore, PLAN, ASTRAL and THRIVE may predict short- and long-term death of AIS patients in the emergency well, and iScore is the best. However, the procedure of iScore is complex, it is recommended to use PLAN and ASTRAL for emergency.

Analysis of families with fetal congenital abnormalities but negative prenatal diagnosis by whole exome sequencing / 中华妇产科杂志

Objective:To evaluate the value of whole exome sequencing (WES) in prenatal clinical application.Methods:A total of 1 152 cases of congenital abnormal [including structural malformation, nuchal translucency (NT) thickening and intrauterine growth restriction] with traditional prenatal diagnosis [including G-band karyotype analysis and chromosome microarray analysis (CMA)] negative were analyzed. The congenital abnormal fetuses were divided into retrospective group and prospective group according to the time of WES detection, that is whether the pregnancy termination or not. According to the specific location of fetal malformation and their family history, the cohort was divided into subgroups. The clinical prognosis of all fetuses were followed up, and the effect of WES test results on pregnancy decision-making and clinical intervention were analyzed. According to the follow-up results, the data of fetuses with new phenotypes in the third trimester or after birth were re-analyzed.Results:Among 1 152 families who received WES, 5 families were excluded because of nonbiological parents. Among the remaining 1 147 families, 152 fetuses obtained positive diagnosis (13.3%,152/1 147), including 74 fetuses in the retrospective group (16.1%,74/460) and 78 fetuses in the prospective group (11.4%,78/687). In fetuses with negative CMA and G-band karyotype analysis results but new phenotypes in the third trimester or after birth, the positive rate by WES data re-analysis was 4.9% (8/163). A total of 34 (21.3%, 34/160) fetuses were directly affected by the corresponding positive molecular diagnosis. Among 68 cases of live births with diagnostic variation grade 4, 29 cases (42.7%, 29/68) received appropriate medical intervention through rapid review of WES results.Conclusions:WES could increase the detection rate of abnormal fetuses with negative G-banding karyotype analysis and CMA by 13.3%. Prenatal WES could guide pregnancy decision-making and early clinical intervention. It might be an effective strategy to pay attention to the special follow-up of the third trimester and postnatal fetus and to re-analyze the WES data.

Prediction of Serum 25-Hydroxyvitamin D for Outcome of Acute Ischemic Stroke in Emergency / 中国康复理论与实践

Objective:To explore the change of serum 25-hydroxyvitamin D [25(OH)D] and prediction for outcome of acute ischemic stroke in emergency. Methods:From October, 2017 to September, 2019, 224 patients with acute ischemic stroke in emergency and 240 healthy controls were detected serum 25(OH)D within 24 hours after enrollment. The patients were assessed with National Institute of Health Stroke Scale (NIHSS) and Nutritional Risk Screening 2002 (NRS2002), and measured biochemics within 24 hours after admission. They were assessed with modified Rankin Scale (mRS) 180 days after stroke, and divided into favourable group (mRS ≤ 2, n = 106) and unfavourable group (mRS > 2, n = 118). The factors related with the outcome were analyzed with Logistic regression, and the prediction of 25(OH)D for the outcome were analyzed with receiver operator characteristic (ROC) curve. Results:Serum 25(OH)D was less in the patients than in the controls (Z = 4.296, P < 0.001), and less in the unfavourable group than in the favourable group (Z = 5.876, P < 0.001). Serum 25(OH)D (OR = 0.925, P < 0.05) was related with the outcome even controlling the impacts of age, sex, nutritional risk, infarct volume, scores of NIHSS, etc. The area under curve for serum 25(OH)D predicting outcome was 0.795 (P < 0.001). The cut-off point of prediction was 13.17 ng/ml, with the Yoden index of 0.548, which yielded a sensitivity of 0.746 and a specificity of 0.802. Conclusion:Serum 25-hydroxyvitamin D may predict the outcome 180 days after acute ischemic stroke, which may help for risk stratification in emergency.

Development of a UHPLC-MS/MS method for the quantification of ilaprazole enantiomers in rat plasma and its pharmacokinetic application / 药物分析学报

In Korea and China, ilaprazole is a widely used proton pump inhibitor in the treatment of gastric ulcers. In this study, a specific and sensitive LC-MS/MS method has been developed and validated for the quantification of ilaprazole enantiomers in the rat plasma, using R-lansoprazole as the internal standard. The enantioseparation was achieved on a CHIRALPAK AS-RH column (4.6 mm × 150 mm, i.d. 5μm), with a mobile phase composed of 10 mM ammonium acetate aqueous solution and acetonitrile (60:40, V/V), at a flow-rate of 0.5 mL/min. The method was validated over the concentration range of 0.5-300 ng/mL for both, R- and S -ilaprazole. The lower limit of quantification was 0.5 ng/mL for both enantiomers. The relative standard deviation (RSD) of intra- and inter-day precision of R-ilaprazole and S-ilaprazole was less than 10.9％, and the relative error accuracy (RE) ranged from -0.5％-2.0％. Finally, the method was successfully evaluated in rats in a stereoselective pharmacokinetic study of the ilaprazole racemate.

Upregulation of miR-489-3p and miR-630 inhibits oxaliplatin uptake in renal cell carcinoma by targeting OCT2

Renal cell carcinoma (RCC) is one of the most common malignant tumors affecting the urogenital system, accounting for 90% of renal malignancies. Traditional chemotherapy options are often the front-line choice of regimen in the treatment of patients with RCC, but responses may be modest or limited due to resistance of the tumor to anticarcinogen. Downregulated expression of organic cation transporter OCT2 is a possible mechanism underlying oxaliplatin resistance in RCC treatment. In this study, we observed that miR-489-3p and miR-630 suppress OCT2 expression by directly binding to the OCT2 3'-UTR. Meanwhile, 786-O-OCT2-miRNAs stable expression cell models, we found that miRNAs could repress the classic substrate 1-methyl-4-phenylpyridinium (MPP), fluorogenic substrate ,-dimethyl-4-(2-pyridin-4-ylethenyl) aniline (ASP), and oxaliplatin uptake by OCT2 both and in xenografts. In 33 clinical samples, miR-489-3p and miR-630 were significantly upregulated in RCC, negatively correlating with the OCT2 expression level compared to that in adjacent normal tissues, using tissue microarray analysis and qPCR validation. The increased binding of c-Myc to the promoter of pri-miR-630, responsible for the upregulation of miR-630 in RCC, was further evidenced by chromatin immunoprecipitation and dual-luciferase reporter assay. Overall, this study indicated that miR-489-3p and miR-630 function as oncotherapy-obstructing microRNAs by directly targeting OCT2 in RCC.

Diagnostic value of detection of peripheral blood human telomerase reverse transcriptase mRNA and four tumor markers in patients with gastric cancer / 肿瘤研究与临床

Objective To evaluation the value of single and combined detection of peripheral blood human telomerase reverse transcriptase (hTERT) mRNA and tumor markers carcinoembryonic antigen (CEA), carbohydrate antigen 72-4 (CA72-4), CA19-9 and CA125 in the diagnosis of gastric cancer. Methods A total of 48 patients diagnosed with gastric cancer from June 2017 to October 2018 in Baotou Tumor Hospital were enrolled in the study group. Fifty healthy subjects were selected as healthy control group. The peripheral venous blood samples were collected from all subjects. After the synthesis of hTERT cDNA by reverse transcription, real-time fluorescence quantitative polymerase chain reaction (RT-PCR) was used for the amplification of hTERT gene fragment. The tumor markers CEA, CA72-4, CA19-9 and CA125 were quantitatively detected by electrochemiluminescence instrument. The sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio and negative likelihood ratio of individual markers or joint detection were calculated. The sensitivity and specificity of joint testing items were compared. Results There were statistically significant differences in the positive rates of hTERT mRNA (P< 0.01), CEA (P=0.002), CA72-4 (P=0.003), and CA19-9 (P=0.017) between the gastric cancer group and the healthy control group, while the positive rates of CA125 were not significantly different between the two groups (P> 0.05). The expression of hTERT mRNA was correlated with TMN stage, lymph node metastasis and distant metastasis (all P< 0.05), but was not correlated with age, sex, tumor location, invasion degree and differentiation degree (all P>0.05). The results of diagnostic indices showed that the hTERT mRNA had high sensitivity (84.8％), specificity (82.7％), accuracy (83.7％), positive predictive value (81.2％) and positive likelihood ratio (4.90). CA72-4 also had high specificity (61.2％), accuracy (64.3％), and positive predictive value (45.8％), which were second only to the hTERT mRNA. The diagnostic performance of CA125 combined with CEA, CA72-4, CA19-9 and peripheral blood hTERT mRNA was not significantly different from the latter four combined detection (P>0.05). The sensitivity and specificity of combined detection of traditional tumor markers CEA, CA72-4 and CA19-9 were 62.5％and 80.0％. The sensitivity and specificity of combined detection of hTERT mRNA, CEA, CA72-4 and CA19-9 could be change to 90.0％ and 67.5％. The difference in sensitivity between the two combined detection groups was statistically significant (P= 0.019), and the difference in specificity was not statistically significant (P> 0.05). Conclusion The comprehensive evaluation index of peripheral blood hTERT mRNA is better than the traditional gastric tumor markers, and it is expected to become a new marker for the diagnosis of gastric cancer.

Epigenetics-based regulation of uptake drug transporter expression is a new approach for cancer drug resistance intervention / 医学研究生学报

Drug resistance is a key factor for poor clinical efficacy of chemotherapy. One of the important reasons for drug resistance is the abnormal expression of drug metabolizing enzymes and drug transporters, which results in the decrease of drug concentration in cancer cells. In this paper, the mechanism of abnormal uptake transporter expression in tumors is analyzed from aspects of drug metabolism enzymes and transporters and tumor drug resistance, drug epigenetics and drug resistance, and potential targets of renal cancer drug resistance, such as OCT2. It is proposed that the regulation of uptake drug transporter expression in tumors by epigenetic mechanism is a new way to reverse drug resistance in tumors.

2018 DMPK research progress in China / 药学学报

This paper summarizes research progresses of Chinese scholars in the field of drug metabolism and pharmacokinetics (DMPK) in 2018. Chinese scholars focused on drug metabolizing enzymes and transporters, and carried out studies on the mechanisms of drug metabolism and transport of active molecules. Topics of research included regulatory mechanisms of drug metabolizing enzymes or transporters, and their implications in drug development and disease etiology or progression. Here, we summarized studies on drug toxicity based on drug metabolism or transport, rational drug use in the clinic, drug metabolism mediated by intestinal flora, metabolism of traditional Chinese medicines, and new technologies or models in DMPK. In recent years, the research focus of drug metabolism in China has transformed from serving for new drug discovery and rational use, to innovation driven and mechanism oriented research. The domestic research topics and technology utilization are gradually aligning with the international conventions.