Association of Next Generation Sequencing Based Genotypic Profiling with MICM Characteristics in NPM1 Mutated Acute Myeloid Leukemia / 中国实验血液学杂志

OBJECTIVE@#To explain the clinicobiological heterogeneity of NPM1 mutated (NPM1mut) acute myeloid leukemia (AML) by analyzing the association between next-generation sequencing (NGS) profiles and MICM characteristics in patients with this AML subtype.@*METHODS@#Data of 238 NPM1mut patients with available NGS information on 112 genes related to blood disease was collected, and χ2 test and nonparametric test were used to analyze the distribution association between NGS-detecting mutations and conventional MICM parameters.@*RESULTS@#In entire NPM1mut cohort, totaling 240 NPM1 mutation events were identified, of whom 10 (10/240, 4.2%) were missense mutations, which did not involve any W288 or W290 locus and were found exclusively in NPM1mut/FLT3-ITD- group. All but one of these missense mutations (9/10, 90%) were accompanied by AML subtype-defining recurrent cytogenetic or molecular abnormalities, of which 7 cases were in the low risk and 2 in the high risk. NPM1mut occurred solely as an insertion/deletion (indel) type in the NPM1mut/FLT3-ITD+ group. The incidence of favorable plus unfavorable karyotypes in NPM1mut/FLT3-ITD- group was higher than in NPM1mut/FLT3-ITD+ group (6.4% vs. 0, P=0.031). The positive rates of CD34 and CD7 in NPM1mut/FLT3-ITD+ group were significantly higher than in NPM1mut/FLT3-ITD- group (CD34: 47.9% vs. 20.6%, P<0.001; CD7: 61.5% vs. 29.9%, P<0.001). Logistic analysis showed that FLT3-ITD independently predicted for CD34+ and CD7+ [odds ratio (OR)=5.29, 95%CI: 2.64-10.60, P<0.001; OR=3.47, 95%CI: 1.79-6.73, P<0.001; respectively]. Ras-pathway mutations independently predicted for HLA-DR+ (OR=4.05, 95%CI: 1.70-9.63, P=0.002), and KRAS mutation for MPO- (OR=0.18, 95%CI: 0.05-0.62, P=0.007). TET2/IDH1 mutations independently predicted for CD34- and CD7- (OR=0.26, 95%CI: 0.11-0.62, P=0.002; OR=0.30, 95%CI: 0.14-0.62, P=0.001; respectively), and MPO+ (OR=3.52, 95%CI: 1.48-8.38, P=0.004). DNMT3A-R882 independently predicted for CD7+ and HLA-DR+ (OR=3.59, 95%CI: 1.80-7.16, P<0.001; OR=13.41, 95%CI: 4.56-39.45, P<0.001; respectively), and DNMT3A mutation for MPO-(OR=0.35, 95%CI: 1.48-8.38, P=0.004).@*CONCLUSION@#Co-existing FLT3-ITD in NPM1mut AML independently predicts for CD34+ and CD7+, co-existing Ras-pathway mutation for HLA-DR+ and MPO-, co-existing TET2/IDH1 mutation for CD34-, CD7-, and MPO+, and co-existing DNMT3A mutation for HLA-DR+, CD7+, and MPO-, thereby providing a new mechanism explanation for the immunophenotypic heterogeneity of these AML patients.

The Mutated Gene Sequenced by NGS and the Correlation of Their Coexistent Mutual Exclusiveness in NPM1 Mutated Acute Myeloid Leukemia / 中国实验血液学杂志

OBJECTIVE@#To analyze the clinicobiological heterogeneity of NPM1 mutated (NPM1@*METHODS@#The NGS data based on 112 genes related to blood disease in 238 newly diagnosed patients with NPM1@*RESULTS@#Among all the patients, at least one co-mutation was detected out. The median number per case of the mutated genes, including NPM1@*CONCLUSION@#Prognoses of AML involving less common NPM1 missense mutations should be stated on a case by case basis. The mutational landscape and co-occurrence and mutual exclusivity correlations of NPM1

Discussion on design of clinical trial scheme for doctor-patient co-construction of traditional Chinese medicine and Western medicine under concept of narrative medicine / 中国中药杂志

With the continuous improvement of modern medical technology, medical practice has become more and more procedural. The medical process is often dominated by doctors, while the value orientation of patients is often ignored, lacking effective communication between doctors and patients. In response to this phenomenon, Charon R proposed the concept of narrative medicine, which has been recognized by all walks of life. In recent years, the value of medical humanism has attracted more attention, and the research on narrative medicine at home and abroad is increasing gradually. But at present, most of the research on narrative medicine is in terms of theory, lacking clinical research. How to make narrative medicine applied in the real world is the focus of current research. Following the concept of narrative medicine, and taking the study on doctor-patient parallel medical record to evaluate the real clinical efficacy of traditional Chinese medicine(TCM) and Western medicine(WM) in the treatment of digestive diseases as an example, this study is to explore the design contents and key points of the clinical trial scheme of doctor-patient co-construction of TCM and WM under narrative medicine, and discuss the activity form and clinical efficacy evaluation method under narrative medicine. Clinical trial design includes four aspects: medicine, ethics, statistics and trial management. This study explored the design of the doctor-patient co-construction clinical trial scheme under narrative medicine from both theoretical and practical aspects, providing reference for the design and research of future doctor-patient co-construction scheme, and expecting to establish a better efficacy evaluation method of TCM and WM.

Efficacy of Shensong Yangxin Capsules in treating bradycardia combined with premature beat: a systematic review and Meta-analysis of randomized clinical trials / 中国中药杂志

To analyze the efficacy and safety of Shensong Yangxin Capsules in treatment of bradycardia combined with premature beat. Databases, such as CNKI, VIP, WanFang, SinoMed, PubMed, Cochrane Library, ClinicalTrials were retrieved by computers for relevant randomized controlled trials of Shensong Yangxin Capsules in treatment of bradycardia combined with premature beat. Two researchers independently screened out the literatures, extracted data according to the inclusion criteria, and applied the Risk of Bias assessment tool in assessing the methodological quality. The Cochrane systematic evaluation software RevMan 5.3 was used for data analysis. Totally 9 randomized controlled trials including 706 subjects were included. The intervention measure was the single administration with Shensong Yangxin Capsules, and the control measure was the blank control. The results showed that Shensong Yangxin Capsules had an obvious effect on average heart rate(MD=6.59, 95%CI[3.87, 9.31], I~2=90%), premature beat efficacy(RR=1.72, 95%CI[1.53, 1.93], I~2=0%), heart rate efficacy(RR=1.74, 95%CI[1.40, 2.17], I~2=47%), and objective efficacy(RR=1.50, 95%CI[1.31, 1.70], I~2=31%). Eight studies reported safety events, with no significant adverse reaction. In conclusion, the single administration with Shensong Yangxin Capsules may have a certain effect in improving heart rate, controlling premature beats and alleviating clinical symptoms in patients with bradycardia combined with premature beat, with no obvious adverse reaction. Shensong Yangxin Capsules can be used in clinic. This potential conclusion needs to be confirmed in future trials using rigorous methodology.

Efficacy and safety of Wenxin Granules in treatment of chronic heart failure with atrial fibrillation: a systematic review / 中国中药杂志

This systematic review aims to evaluate the efficacy and safety of Wenxin Granules in the treatment of chronic heart failure with atrial fibrillation. Databases,such as CNKI,Wan Fang Date,VIP,PubMed,Cochrane Library,were electronically retrieved for relevant randomized controlled trials of Wenxin Granules in the treatment of chronic heart failure with atrial fibrillation. Two researchers independently screened out the literatures,extracted data according to the inclusion criteria,and conducted a quality assessment by the risk bias assessment tool in the Cochrane evaluation manual. Cochrane systematic evaluation software Rev Man 5. 3 was used for data analysis. Totally 11 randomized controlled trials,including 941 subjects. The intervention measures were the conventional treatment recommended by the guidelines combined with Wenxin Granules; and the control measures were the conventional treatment recommended by the guidelines alone. The results showed that compared with conventional treatment alone,Wenxin Granules combined with conventional treatment can better reduce the BNP level in patients with heart failure with atrial fibrillation( MD =-258. 18,95% CI[-464. 06,-52. 30],P= 0. 01) or NT-proBNP level,better improve left ventricular ejection fraction( MD = 6. 72,95%CI[4. 61,8. 84],P<0. 000 01),I~2= 65%,And the ventricular rate decreased more significantly( MD =-11. 66,95% CI[-15. 79,-7. 54],P<0. 000 01),and the cardiac function was improved more efficiently( RR = 1. 20,95%CI [1. 11,1. 31],P<0. 000 1),I~2= 23%.In conclusion,compared with the single administration of conventional Western medicine,the combined administration of Wenxin Granules has better effects in reducing the level of BNP or NT-proBNP,slowing down the ventricular rate,and improving the left ventricular ejection fraction,with fewer adverse reactions. However,due to the small sample size and the low quality of literatures included in this systematic review,it is shall be carefully applied in clinic. More rigorous randomized controlled trials shall be conducted to determine the efficacy of Wenxin Granules in improving cardiac function in the treatment of chronic heart failure with atrial fibrillation.

Babaodan Capsules for viral hepatitis: systematic review of clinical efficacy and safety and Meta-analysis of randomized clinical trials / 中国中药杂志

To systemically analyze the efficacy and safety of Babaodan Capsules in treatment of viral hepatitis. Databases such as CNKI,Wan Fang Date,VIP,Sino Med,PubMed,and Cochrane Library were electronically searched for relevant randomized controlled trials about Babaodan Capsules in the treatment of viral hepatitis,from database establishment to November 11,2018. Two researchers independently screened the literature and extracted data according to the inclusion criteria. GRADE system was used to evaluate evidence quality,and we used the Cochrane Rev Man 5. 3 software for Meta-analysis. Six randomized controlled trials including 520 subjects were included. Babaodan Capsules combined with conventional treatment were used as intervention measures,and the conventional treatment was used as the control measures. The results showed Babaodan Capsules combined with conventional treatment had better efficacy on reducing the total bilirubin( MD =-16. 25,95% CI[-19. 86,-12. 63]),alanine aminotransferase( MD =-26. 62,95% CI[-41. 18,-12. 06]),total bile acid( MD=-46. 02,95%CI[-49. 18,-42. 85]) and improving clinical efficiency( RR = 1. 34,95%CI[1. 13,1. 59]) than conventional treatment alone. In addition,Babaodan Capsules combined with conventional treatment can delay the progression of liver fibrosis to some extent. Qualitative analysis showed that the combined treatment regimen was more effective in relieving clinical symptoms. There was no significant difference between the two regimens in increasing albumin and prothrombin activity. Babaodan Capsules combined with conventional treatment showed no adverse reactions. In summary,for patients with viral hepatitis,the combination of Babaodan Capsules and conventional treatment has more advantages in reducing total bilirubin,alanine aminotransferase and total bile acid and is more effective in improving clinical symptoms as compared with conventional Western medicine,with no serious adverse reactions. Its clinical application with syndrome differentiation method can be considered. However,due to the limited number and quality of the original researches,more multi-center,high-quality randomized controlled trials are needed for further verification.

Research Related to Neural Protection of Hypoxic and Hyperoxic Preconditioning after Spinal Cord Injury (review) / 中国康复理论与实践

Repeated acute intermittent hypoxia promotes the expression of growth factors and neurotrophic factors, as well as the key molecules for neural protection and plasticity. Hypoxic preconditioning may improve the survival rate of transplant-ed stem cells and protect the neural function. Meanwhile, acute intermittent hypoxia can be an approach to improve re-spiratory function after spinal cord injury. Hyperbaric oxygen may improve the neural tolerance to hypoxia and isch-emia, to protect the structure of cells and tissues, and promote the neuranagenesis. It is important to study the role of hy-poxic and hyperoxic preconditioning in spinal cord injury.

Inhibitory Eefects of the novel tyrosine kinase inhibitor BGJ398 against human leukemic cell line KG-1 cells / 中华血液学杂志

Objective: To explore the effects and possible mechanisms of the novel pan-FGFR inhibitor BGJ398 on KG-1 cells in vitro. Methods: Effects of BGJ398 on cells proliferation were detected by CCK-8, the apoptosis was assessed by Annexin V-FITC. Reverse transcriptionquantitative polymerase chain reaction (q-PCR) analysis was used to detect the expression of apoptosis-related genes B cell lymphoma-2 (Bcl-2) and caspase-3. Western blotting analysis was performed to explore the proteins expression levels of Bcl-2, caspase-3 and the expression of p-AKT, p-S6K, p-ERK and FGFR1. Results: BGJ398 effectively inhibited cell proliferation by dose-dependent manners. BGJ398(1.4 µmol/L) induced apoptosis of KG-1 cells by 36.4%, compared with 4.5% in the control group(P<0.001). Treatment with BGJ398 at 1.4 µmol/L led to significant increases in the expression levels of caspase-3, and decreases in the expression of Bcl-2 (P<0.005). In accordance with these results, Western blot analysis further confirmed the increased expression of Bcl-2 protein along with elevated caspase-3 activity. In addition, BGJ398 markedly down-regulated FGFR1OP2-FGFR1 fusion protein, p-AKT and p-S6K expression, but not p-ERK expression. Conclusion: Novel pan-FGFR inhibitor BGJ398 substantially suppressed KG-1 cell growth and induced apoptosis by inhibiting the expression of FGFR1, p-AKT, p-S6K and regulating apoptosis-related proteins.

Systematic reviews of ganciclovir combined with traditional Chinese medicine for herpes simplex keratitis / 国际眼科杂志(Guoji Yanke Zazhi)

·AIM: To evaluate the efficacy and safety of ganciclovir combined with traditional Chinese medicine ( TCM ) in treatment of herpes simplex keratitis (HSK). ·METHODS: All randomized controlled trials ( RCTs) of ganciclovir combined with TCM for HSK were searched in CNKI, VIP, Wanfang, PubMed, Cochrane Library and EMbase database. The clinical endpoints of the total effective rate, relapse rate, heal time, and adverse reaction rate were collected to assess the drugs' efficacy and safety. The improved Jadad Scale was used to evaluate the methodological quality of included literatures. The RevMan5. 3 software and Stata 12. 0 were applied for meta-analysis. ·RESULTS: We finally included 15 RCTs involving 1 285 patients. As for the total effective rate, relapse rate and heal time, significant differences were noted between ganciclovir combined with TCM group and ganciclovir alone group. For the total effective rate, RR and 95% CI were 1. 23 ( 1. 15 ~ 1. 31 ) according to the number of patients and 1. 18(1. 02-1. 38) according to the number of diseased eyes. For relapse rate, RR and 95% CI were 0. 25 (0. 17-0. 36). For heal time, MD and 95% CI were -7. 58 (-10. 89 to - 4. 26 ). No statistic difference of adverse reaction rate between the two groups was observed [RR=0.53, 95% CI(0. 23-1. 22)]. The side effects in the two groups were mild and could be relieved by themselves. ·CONCLUSION: The ganciclovir combined with TCM can improve the total efficacy, reduce the relapse rate, and shorten the course of treatment for HSK with good safety.

Mutation of CALR Gene in Patients with Chronic Myeloproliferative Neoplasm and Its Clinical Significance / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To analyze the CARL gene mutation in the patients with chronic myeloproliferative neoplasm(MPN) and to explore the clinical significance of CALR mutation.</p><p><b>METHODS</b>The peripheral blood of patients was collected and the genomic DNA was exacted, the 9 exon of CALR gene and the fragment of human thrombopoetic receptor(MPL) gene were amplified by PCR, the mutation of CALR and MPL genes was detected by using the direct sequencing, the JAK2 V617F mutation was detected by using allele spicific PCR.</p><p><b>RESULTS</b>The CALR mutations were detected in 13 patients out of 55 MPN patients (23.6%). The frequency of CALR mutation was 22.7% (10/44) in 44 essential thrombocythemia(ET) patients. A total of 3 types of CALR mutation were identified (type I c.1092_1143del52bp, n=5; type II c.1154_1155insTTGTC, n=4; type III c.1094_1139del46bp, n=1). CALR mutations occurred at a frequency of 27.2% in primary myelofibrosis (PMF), including type I (n=2) and type II (n=1). The incidence of JAK2 V617F was 58.1%(32/55), that in ET and PMF was 59.1%(26/44) and 54.5% (6/11), respectively. The mutations of MPL W515 were not detectable in all cases, and the simultaneous mutation of CARL and MPL W515 was not detected. The median age of patients with CALR mutation was significantly younger than that of patients with JAK2 mutations (48 vs 64 years of old, P<0.05). The levels of hemoglobin and leukocytes in patients with CARL mutations were significantly lower (P<0.05) but the level of plateletes was higher than that in patients with JAK2 V617F mutations (P<0.05). Deep venous thrombosis occurred in 4 of 35 ET patients with the JAK2 V617F mutation (n=4), but did not occurr in the patients with CALR mutation. Karyotype abnormality was detected in only one case among 48 patients by chromosome karyotype analysis.</p><p><b>CONCLUSION</b>The incidence of CALR mutation is high in ET and PMF patients without JAK2 V617F and MPL W515K mutations, which is associated with younger median age, lower leucocyte and hemoglobin levels, higher platelet counts, and rare thrombocytosis, compared with the patients with JAK2 V617F mutation.</p>

Detection of ASXL1 Mutation and CALR Mutation Coexistance in Patients with Ph Negative Myeloproliferative Neoplasm and Its Clinical Gignificance / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To explore the coexistence of ASXL1 and CALR gene mutations in patients with essential thrombocytheima (ET) and with primary myelofibrosis(PMF), and to compare the differences of clinical characteristics between ET and PMF patients carrying ASXL1 and CALR mutations, and ET and PMF patients carrying solitary gene mutation, and ET and PMF patients without any mutations.</p><p><b>METHODS</b>The mutations of ASXL1 gene at exon 12, CALR gene at exon 9 and MPL gene at exon 10 in 263 essential ET patients and 29 PMF patients were detected by PCR amplification followed by direct sequencing of genomic DNA. The JAK2V617F mutations were used by allele specific PCR detection.</p><p><b>RESULTS</b>72.6%(212/292)of patients harbored at least one mutation. The incidences of ASXL1 and CALR mutations were 5.8% and 30.5%, respectively. The frequencies of JAK2V617F and MPL mutations were 39.0% and 2.4%, respectively. 5.1%(15/292) of patients had double mutations, including ASXL1 and CALR(n=11), ASXL1 and JAK2V617F(n=2), MPL and CALR(n=1) and ASXL1 and MPL(n=1). The frequency of concurrent ASXL1 and CALR mutations was found to be high. Significant difference was found on hemoglobin levels and platelet counts between CALR and ASXL1 mutations and single mutation (P<0.05),however, the difference on leukocyte counts and median age was not found. Compared with negative patients, the presence of ASXL1 and CALR mutations was found to be significantly correlative with lower hemoglobin level (P=0.045), lower leukocyte count (P=0.002) and with higher platelet counts(P=0.001), but the difference of median age was not found.</p><p><b>CONCLUSION</b>The frequency of concurrent ASXL1 and CALR mutations is higher in ET patients. The coexistence of ASXL1 and CALR gene mutations significantly associated with lower hemoglobin level and higher platelet count.</p>