Comparison of BCR::ABL (P210) mRNA levels detected by dPCR and qPCR methods in patients with chronic myeloid leukemia / 中华血液学杂志

Objective: To compare digital polymerase chain reaction (dPCR) and real-time quantitative PCR (qPCR) measurements of BCR::ABL (P210) mRNA expression in patients with chronic myeloid leukemia (CML) . Methods: In this non-interventional, cross-sectional study, BCR::ABL (P210) mRNA was simultaneously measured by dPCR and qPCR in peripheral blood samples collected from patients with CML who underwent tyrosine kinase inhibitor therapy and who achieved at least a complete cytogenetic response from September 2021 to February 2023 at Peking University People's Hospital. The difference, correlation, and agreement between the two methods were evaluated using the Wilcoxon signed-rank test, Spearman's correlation, and Bland-Altman analysis, respectively. Results: In total, 459 data pairs for BCR::ABL mRNA expression measured by dPCR and qPCR from 356 patients with CML were analyzed. There was a significant difference in BCR::ABL mRNA expression between the two methods (P<0.001). When analyzed by the depth of the molecular response (MR), a significant difference only existed for patients with ≥MR4.5 (P<0.001). No significant difference was observed for those who did not achieve a major MR (no MMR; P=0.922) or for those who achieved a major MR (MMR; P=0.723) or MR4 (P=0.099). There was a moderate correlation between the BCR::ABL mRNA expression between the two methods (r=0.761, P<0.001). However, the correlation gradually weakened or disappeared as the depth of the MR increased (no MMR: r=0.929, P<0.001; MMR: r=0.815, P<0.001; MR4: r=0.408, P<0.001; MR4.5: r=0.176, P=0.176). In addition, the agreement in BCR::ABL mRNA expression between the two methods in those with MR4.5 was weaker than other groups (no MMR: ▉= 0.042, P=0.846; MMR:▉=0.054, P=0.229; MR4:▉=-0.020, P=0.399; MR4.5:▉=-0.219, P<0.001) . Conclusions: dPCR is more accurate than qPCR for measuring BCR::ABL (P210) mRNA expression in patients with CML who achieve a stable deep MR.

Factors influencing severe cytopenia in chronic phase chronic myeloid leukemia patients receiving initial second generation tyrosine kinase inhibitors and its impact on treatment responses and outcomes / 中华血液学杂志

Objective: To explore the influencing covariates of severe neutrophils and/or thrombocytopenia and their effect on treatment response and outcome in patients with chronic-phase chronic myeloid leukemia (CP-CML) receiving initial second-generation tyrosine kinase inhibitors (2G-TKI) . Methods: Data from consecutive patients aged ≥18 years with newly diagnosed CP-CML who received initial 2G-TKI at Peking University People's Hospital from September 2008 to November 2021 were interrogated. Binary logistic regression models and Fine-Gray and Cox regression models were applied. Results: Data from 267 patients who received initial 2G-TKI, including nilotinib (n=239, 89.5% ) and dasatinib (n=28, 10.5% ) , were interrogated. The median age was 36 (range, 18-73) years, and 156 (58.4% ) patients were male. At a median treatment period of 1.0 (0.1-3.0) month, 43 (16.1% ) patients developed grade ≥3 neutrophils and/or thrombocytopenia and recovered within 1.0 (0.1-24.6) month. Male (OR=2.9, 95% CI 1.2-6.8; P=0.018) , age of ≥36 years (OR=3.2, 95% CI 1.4-7.2, P=0.005) , a spleen below a costal margin of ≥7 cm (OR=2.8, 95% CI 1.2-6.6, P=0.020) , and a hemoglobin (HGB) level of <100 g/L (OR=2.9, 95% CI 1.3-6.8, P=0.012) at diagnosis were significantly associated with grade ≥ 3 neutrophils and/or thrombocytopenia. Based on their regression coefficients, male, age of ≥36 years, a spleen below a costal margin of ≥7 cm, and an HGB level of <100 g/L were given 1 point to form a predictive system. All patients were divided into three risk subgroups, and the incidence of severe cytopenia significantly differed among the three groups (P < 0.001) . Grade ≥3 neutrophils and/or thrombocytopenia for >2 weeks was significantly associated with lower cumulative incidences of complete cytogenetic response (CCyR, HR=0.5, 95% CI 0.3-0.7, P<0.001) and major molecular response (MMR, HR=0.4, 95% CI 0.3-0.8, P=0.004) and was not significantly associated with failure, progression, and survival. Conclusion: Male, advanced age, a large spleen, and a low HGB level were significantly associated with severe cytopenia. The four covariates were used to establish a prediction model, in which the incidence of severe cytopenia among different risk groups was significantly different. Severe cytopenia for >2 weeks was a negative factor for responses but not for outcomes.

Effects of PINK1 mediated mitophagy on senescence and function of rat bone marrow endothelial progenitor cells / 中国药理学通报

Aim To investigate the effects of PTEN-induced putative kinase1(PINK1)mediated mitophagy on senescence and function of rat bone marrow endothelial progenitor cells(EPCs)by using small interfering RNA(siRNA)technology to knock down the PINK1 gene in rat bone marrow EPCs.Methods EPCs from bone marrow in rats were isolated, cultured and identified.After counting, EPCs were randomlydivided into control group, negative control group(NC siRNA), and Pink1 transfection group(PINK1 siRNA).The expression of PINK1 mRNA and protein in cells in various groups were detected by qRT-PCR and Western blot.At the same time, different time points were chosen to simulate the aging process based on the best knock down time.The senescence of cells was detected by SA-β-galactosidase staining and p16 protein expression.The function of cell proliferation, migration and tubule formation was detected by CCK-8, Transwell chamber and in vitro angiogenesis kit.ROS level was detected by flow cytometry.The expressions of PINK1, Parkin, LC3, and p62 were detected by Western blot.Mitochondria and autophagosomes were observed by transmission electron microscope.Results 48 h after PINK1 siRNA transfected, PINK1 was effectively knocked down.Compared with control group, the positive rate of blue staining and the expression of p16 protein in PINK1 siRNA group increased significantly 48 h and 96 h after transfection.The function of cell proliferation, migration and tubule formation decreased significantly.The level of ROS increased significantly, while the expression of PINK1, Parkin and LC3 protein decreased significantly, and p62 protein expression increased significantly.Under the transmission electron microscope, the mitochondria swelled and denatured, and the number of autophagosomes decreased in the PINK1 siRNA group.Conclusions The down-regulation of PINK1 gene can aggravate the senescence of EPCs, and PINK1 mediated mitophagy may participate in the regulation of senescence and function of EPCs.

Combination of socio-demographic and clinical co-variates for predicting treatment responses and outcomes in patients with chronic myeloid leukemia in the chronic phase / 中华血液学杂志

Objective: To explore the impacts of socio-demographic and clinical co-variates on treatment responses and outcomes in patients with chronic myeloid leukemia in the chronic phase (CML-CP) receiving tyrosine kinase inhibitor (TKI) and identified the predictive models for them. Methods: Data of newly diagnosed adult patients with CML-CP receiving first-line TKI and having complete socio-demographic data and clinical information were reviewed. Cox model was used to identify the independent variables associated with complete cytogenetic response (CCyR) , major molecular response (MMR) , molecular response 4 (MR(4)) and molecular response 4.5 (MR(4.5)) , as well as failure-free survival (FFS) , progression-free survival (PFS) , overall survival (OS) and CML-related OS. Results: A total of 1414 CML-CP patients treated with first-line imatinib (n=1176) , nilotinib (n=170) or dasatinib (n=68) were reviewed. Median age was 40 (18-83) years and 873 patients (61.7% ) were males. Result of the multivariate analysis showed that lower educational level (P<0.001-0.070) and EUTOS long-term survival intermediate or high-risk (P<0.001-0.009) were significantly associated with lower cumulative incidences of CCyR, MMR, MR(4) and MR(4.5), as well as the inferior FFS, PFS, OS and CML-related OS. In addition, those who were males, from rural households, had white blood cells (WBC) ≥120×10(9)/L, hemoglobin (HGB) <115 g/L and treated with first-line imatinib had significantly lower cumulative incidences of cytogenetic and/or molecular responses. Being single, divorced or widowed, having, rural household registration, WBC≥120×10(9)/L, HGB<15 g/L, and comorbidity (ies) was significantly associated with inferior FFS, PFS, OS, and/or CML-related OS. Thereafter, the patients were classified into several subgroups using the socio-demographic characteristics and clinical variables by cytogenetic and molecular responses, treatment failure and disease progression, as well as overall survival and CML-related OS, respectively. There were significant differences in treatment responses and outcomes among the subgroups (P<0.001) . Conclusion: Except for clinical co-variates, socio-demographic co-variates significantly correlated with TKI treatment responses and outcomes in CML-CP patients. Models established by the combination of independent socio-demographic and clinical co-variates could effectively predict the responses and outcome.

Pharmacological Effect and Mechanism of Andrographolide： A Review / 中国实验方剂学杂志

Andrographolide， a diterpene lactone， is the important material basis for the pharmacological effect of the Chinese medicinal Andrographis paniculata （Burm.f.）Nees. Modern pharmacological research has shown that andrographolide has many pharmacological activities such as anti-inflammation， bacteriostat， anti-virus， anti-tumor， protecting liver， promoting the function of gallbladder， and protecting the cardiovascular system and nervous system. It has significant anti-inflammatory activity which involves multiple targets. To be specific， it can inhibit nuclear factor-κB （NF-κB）， signal transduction and activator of transcription 3 （STAT3）， and other signaling pathways， reduce the synthesis and release of downstream inflammatory mediators， and regulate oxidative stress and immune response to achieve anti-inflammatory effect on various inflammatory diseases. At the same time， it suppresses a variety of tumor cells by inhibiting tumor cell proliferation， blocking cell cycle， and inducing tumor cell apoptosis. Its anti-tumor mechanism involves cellular signaling pathways such as Notch， phosphatidylinositol 3-kinase/protein kinase B （PI3K/Akt）， NF-κB， and secreted glycoprotein/β-catenin （Wnt/β-catenin）. In addition， it can also alleviate diabetes by regulating glucose metabolism. According to related research， it often exerts pharmacological effects through multiple pathways and multiple targets， but the specific targets are unclear. Therefore， this article summarizes the relevant studies on the pharmacological effects and mechanisms of andrographolide in the past three years and puts forward the future research directions， which is expected to serve as a reference for the further in-depth research and development and utilization of andrographolide.

Anti-tumor Effect of Shikonin： A Review / 中国实验方剂学杂志

The incidence and mortality of cancer are increasing year by year， seriously threatening human health. At present， the chemotherapy-based treatment of cancer can prolong the survival time of patients， but its severe side effects and adverse reactions often lead to poor prognosis. Therefore， searching for anti-cancer drugs with high efficiency and low toxicity has become the focus of clinical attention from all over the world. The effective components of Chinese medicine have the advantages of mild side effect and multi-target regulation， and their anti-tumor activities are highly favored by many researchers. Shikonin， a naphthoquinone compound， is the main effective component of Arnebiae Radix， with anti-tumor， anti-inflammatory， antioxidant， and other pharmacological effect. Studies have shown that shikonin possesses significant anti-tumor activities against a variety of tumor cells， and it can inhibit the development of many cancers， such as breast cancer， lung cancer， liver cancer， cervical cancer， ovarian cancer， colon cancer， and prostate cancer. The anti-tumor mechanism of shikonin is mainly related to multi-pathway and multi-target inhibition of tumor cell proliferation， the promotion of reactive oxygen species （ROS） production， induction of tumor cell apoptosis， cell cycle arrest， and tumor cell autophagy， and the inhibition of tumor cell migration and invasion. In addition， shikonin can increase the sensitivity of tumor cells to anti-tumor drugs and reverse the drug resistance of tumor cells. The signaling pathways involved in the anti-tumor effect of shikonin include phosphatidylinositol 3-kinase/protein kinase B （PI3K/Akt）， PI3K/Akt/mammalian target of rapamycin （mTOR）， mitogen-activated protein kinase （MAPK）， pyruvate kinase M2/signal transducer and activator of transcription protein 3 （PKM2/STAT3）， and Kelch-like epichlorohydrin-related protein 1/nuclear factor E2-related factor 2 （Keap1/Nrf2）. The anti-tumor effects are mainly achieved through the regulation of the PI3K/Akt signaling pathway. Based on the relevant literature on the anti-tumor effect and mechanism of shikonin in China and abroad， the present study reviewed the research progress in the past three years to provide useful references for the further study of the anti-tumor effect of shikonin and the research and development of new antineoplastic drugs.

The research progress on the basic characteristics and metabolic regulation of α1-acid glycoprotein / 药学实践杂志

Metabolic homeostasis is a basic function necessary for the survival of the organism. α1-acid glycoprotein (AGP) is an acute phase protein with a glycosylation degree of up to 45%. It has high affinity and low capacity. Although the biological role of AGP is not fully understood, it has been proven that it can regulate immunity and metabolism, and play an important role in transporting drugs and maintaining capillary barrier function. In this review, the structural characteristics, biochemical characteristics and the regulation of AGP expression were reviewed, with emphasis on the regulatory role of AGP in metabolism, suggesting that AGP may be a potential key factor in metabolic pathways, which provides a new research direction for metabolic diseases.

The effect of HMS-01 on stably expressed hERG channel currents in HEK293 cells detected with the manualpatch clamp method / 药学实践杂志

Objective To test the cardiac toxicity of new compound HMS-01 and evaluate the safety profile for clinical trials. Methods Manualpatch clamp method was used to measure human Ether-a-go-go-Related Gene (hERG) potassium channel currents with different concentrations of HMS-01. Cisapride was selected as the positive control drug. HMS-01 was diluted to the concentration of 0.3, 1, 3, 10 and 30 µmol/L and applied to the cells. The changes in electrical currents were recorded and the inhibition rate was calculated. Results At the highest concentration of 30µmol/L, the inhibitory rate of HMS-01 on hERG channel was less than 30%. There was no obvious inhibitory effect compared with cisapride. Conclusion Compared with the cisapride, HMS-01 has no obvious inhibitory effect on hERG channel and has no cardiotoxicity.

The Predict Significance of ALDH Activity to the Relapse of t(8;21) Acute Myeloid Leukemia Patients at Complete Remission / 中国实验血液学杂志

OBJECTIVE@#To investigate the predict significance of the high aldehyde dehydrogenase activity (ALDH@*METHODS@#Bone marrow samples of 23 t(8;21) AML patients diagnosis and achieved complete remission in our hospital from April 2015 to June 2016 were collected, then flow cytometry method was used to detect the activity of ALDH, relationship between it and relapse was analyzed.@*RESULTS@#All the patients were followed up for a median of 32 (2-52) months. The median percentage of CD34@*CONCLUSION@#The percentage of CD34

Effect of Danggui Buxuetang on Functional Activity of Endothelial Progenitor Cells Exposed to Shear Stress / 中国实验方剂学杂志

Objective:To investigate the effect of Danggui Buxuetang（DGBX）on the functional activity of rat endothelial progenitor cells（EPCs）exposed to different luminar shear stress （SS）. Method:EPCs isolated from rat bone marrow were incubated on a parallel plate flow chamber at a steady SS of 0， 0.12， 1.2， 2.4 Pa for 6 h，then the cells exposed to different SS were randomly divided into 8 groups： control group （perfused with serum free medium），simvastatin group（0.1 μmol·L^-1simvastatin），3 DGBX groups（low，medium，high-dose DGBX）and 3 inhibitor groups（3 DGBX groups with LY294002）. After 12 h，the samples were collected for the detection of cell proliferation ，migration，tubule formation ，the secretion of nitric oxide （NO） ，and the expressions of endothelial nitric oxide synthase（eNOS） mRNA and protein kinase B（Akt），respectively. Result:Compared with the control group，simvastatin and DGBX（high-dose）could both promote the functional activities and NO secretion，and up-regulate the expressions of eNOS mRNA and Akt protein in EPCs exposed to different SS（<italic>P</italic><0.05），while DGBX（mid-dose）could do these only at 0 Pa. However，LY294002 could inhibit all effects of DGBX on EPCs. Conclusion:SS seems to play an important role in the effect of DGBX on EPCs，and DGBX could promote the functional activity of EPCs exposed to SS by up-regulating the expressions of NO/eNOS/Akt.

Effect of Stemona tuberosa Alkaloids on Apoptosis of SMMC-7721 Cells and Expression of Bcl-2， Bax， and Cleaved Caspase-3 / 中国实验方剂学杂志

Objective:To investigate the effect of<italic> Stemona tuberosa</italic> alkaloids on the apoptosis of human hepatoma SMMC-7721 cells and the expression of apoptosis-related proteins including B lymphocytoma-2 （Bcl-2）， Bcl-2-associated X protein （Bax）， and cleaved cysteinyl aspartate-specific protease-3 （cleaved Caspase-3）. Method:SMMC-7721 cells were routinely cultured， passaged， and treated with various concentrations （50， 75， 112， 167， and 250 mg·L^-1） of <italic>S. tuberosa </italic>alkaloids， while those in the blank control group were only treated with 10% fetal bovine serum. The cell proliferation was determined by tetrazolium bromide （MTT） colorimetry and colony assay and the cell apoptosis by Hoechst 33258 staining. The protein expression levels of Bcl-2， Bax， and cleaved Caspase-3 were detected by Western blot. Result:<italic>S. tuberosa</italic> alkaloids inhibited the proliferation of SMMC-7721 cells， and the inhibition rate was significantly increased in comparison with that in the blank control group （<italic>P</italic><0.01）， with the half maximal inhibitory concentrations （IC₅₀） at 24 h， 48 h， and 72 h being （173.36±8.75）， （112.14±16.50）， and （96.41±2.60）mg·L^-1， respectively. The cell colony-inhibitory activity was significantly increased in a dose-dependent manner （<italic>P</italic><0.01）. Compared with the blank control group， <italic>S. tuberosa</italic> alkaloids promoted the apoptosis of SMMC-7721 cells， manifested as increased number of apoptotic cells and elevated apoptotic rate （<italic>P</italic><0.01）. The typical morphological changes such as brightly blue-fluorescent condensed nuclei， cytoplasmic shrinking， and karyopyknosis were found under the upright fluorescence microscope. As revealed by comparison with the blank control group， the expression of Bcl-2 was significantly down-regulated （<italic>P</italic><0.01）， while the protein expression levels of pro-apoptotic protein Bax and cleaved Caspase-3 in the 75， 112， 167， and 250 mg·L^-1 <italic>S. tuberosa</italic> alkaloids groups were significantly up-regulated （<italic>P</italic><0.01）. Conclusion:<italic>S. tuberosa </italic>alkaloids inhibit the proliferation of SMMC-7721 cells and promote their apoptosis possibly by inhibiting Bcl-2 protein expression and promoting Bax and cleaved Caspase-3 protein expression.

Research Progress on Pharmacological Effect and Mechanism of Polydatin / 中国实验方剂学杂志

Polydatin， a polyphenolic compound， is the main active component of Chinese medicine Polygoni Cuspidati Rhizoma et Radix and has a variety of pharmacological activities. In recent years， there are more studies on the pharmacological effects and mechanisms of polydatin. Modern pharmacological studies show that polydatin has protective effects on the nervous system， cardio-cerebral vascular system， and respiratory system， and also has significant effects on the liver， kidney， lung， and other organs. Its effect of regulating blood glucose and blood lipid on atherosclerosis is significant， and the anti-fibrosis effect is significant on the liver and kidney. Polydatin can inhibit many types of tumor cells， suppress proliferation and induce apoptosis of tumor cells. Polydatin can also resist inflammation and radiation， protect bone marrow， and promote wound healing. Based on the literature on the pharmacological effects of polydatin， the authors found that the single pharmacological mechanism of polydatin is often regulated by multi-target proteins and multiple pathways， but the most of action targets are unclear， which needs to be further investigated. This study summarized the research progress on the pharmacological action and mechanism of polydatin in the past five years and put forward some suggestions on its present research situation and future research direction to broaden the research ideas of researchers and speed up the identification of the targets of its pharmacological effect. This study is expected to provide a scientific theoretical basis for the further development and utilization of polydatin.

Preparing anti-SARS-CoV-2 agent EIDD-2801 by a practical and scalable approach, and quick evaluation

EIDD-2801 is an orally bioavailable prodrug, which will be applied for emergency use authorization from the U.S. Food and Drug Administration for the treatment of COVID-19. To investigate the optimal parameters, EIDD-2801 was optimized

Efficacy and safety of salmeterol/fluticasone compared with montelukast alone (or add-on therapy to fluticasone) in the treatment of bronchial asthma in children and adolescents: a systematic review and meta-analysis / 中华医学杂志(英文版)

BACKGROUND@#Despite the recommendation of inhaled corticosteroids (ICSs) plus long-acting beta 2-agonist (LABA) and leukotriene receptor antagonist (LTRA) or ICS/LTRA as stepwise approaches in asthmatic children, there is a lack of published systematic review comparing the efficacy and safety of the two therapies in children and adolescents aged 4 to 18 years. This study aimed to compare the safety and efficacy of salmeterol/fluticasone (SFC) vs. montelukast (MON), or combination of montelukast and fluticasone (MFC) in children and adolescents aged 4 to 18 years with bronchial asthma.@*METHODS@#A systematic search was conducted in MEDLINE, EMBASE, the Cochrane Library, China BioMedical Literature Database, Chinese National Knowledge Infrastructure, VIP Database for Chinese Technical Periodical, and Wanfang for randomized controlled trials (RCTs) published from inception to May 24, 2021. Interventions are as follows: SFC vs. MON, or combination of MFC, with no limitation of dosage or duration. Primary and secondary outcome measures were as follows: the primary outcome of interest was the risk of asthma exacerbation. Secondary outcomes included risk of hospitalization, pulmonary function, asthma control level, quality of life, and adverse events (AEs). A random-effects (I2 ≥ 50%) or fixed-effects model (I2 < 50%) was used to calculate pooled effect estimates, comparing the outcomes between the intervention and control groups where feasible.@*RESULTS@#Of the 1006 articles identified, 21 studies met the inclusion criteria with 2643 individuals; two were at low risk of bias. As no primary outcomes were similar after an identical treatment duration in the included studies, meta-analysis could not be performed. However, more studies favored SFC, instead of MON, owing to a lower risk of asthma exacerbation in the SFC group. As for secondary outcome, SFC showed a significant improvement of peak expiratory flow (PEF)%pred after 4 weeks compared with MFC (mean difference [MD]: 5.45; 95% confidence interval [CI]: 1.57-9.34; I2 = 95%; P = 0.006). As for asthma control level, SFC also showed a higher full-controlled level (risk ratio [RR]: 1.51; 95% CI: 1.24-1.85; I2 = 0; P < 0.001) and higher childhood asthma control test score after 4 weeks of treatment (MD: 2.30; 95% CI: 1.39-3.21; I2 = 72%; P < 0.001) compared with MFC.@*CONCLUSIONS@#SFC may be more effective than MFC for the treatment of asthma in children and adolescents, especially in improving asthma control level. However, there is insufficient evidence to make firm conclusive statements on the use of SFC or MON in children and adolescents aged 4 to 18 years with asthma. Further research is needed, particularly a combination of good-quality long-term prospective studies and well-designed RCTs.@*PROSPERO REGISTRATION NUMBER@#CRD42019133156.

Analysis of the efficacy and influencing factors of nilotinib or dasatinib as second- or third-line treatment in patients with chronic myeloid leukemia in the chronic phase and accelerated phase / 中华血液学杂志

Objective: To explore the efficacy and prognosis of nilotinib or dasatinib as second- or third-line treatment in patients with chronic myeloid leukemia (CML) in the chronic phase (CP) and accelerated phase (AP) . Methods: From January 2008 to November 2018, the data of CML patients who failed first- or second-line tyrosine kinase inhibitor (TKI) -therapy received nilotinib or dasatinib as second-line and third-line therapy were retrospectively reviewed. Results: A total of 226 patients receiving nilotinib or dastinib as second-line (n=183) and third-line (n=43) therapy were included in this study. With a median follow-up of 21 (range, 1-135) months, the cumulative rates of complete hematological response (CHR) , complete cytogenetic response (CCyR) and major molecular response (MMR) were 80.4%, 56.3%and 38.3%, respectively in those receiving TKI as second-line TKI therapy. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 78.7%and 93.1%, respectively. Multivariate analyses showed that Sokal high risk, female gender, the best response achieved <CHR on the first-line TKI-therapy, the interval from diagnosis to switching to second-line TKI ≥18 months, AP or hematologic failure, or non-specific mutation of BCR-ABL kinase domain before second-line TKI therapy, developing severe hematologic toxicity during the second-line TKI therapy were variables associated with poor responses or outcomes on second-line TKI therapy. With a median follow-up of 6 (range, 3-129) months, the cumulative CHR, CCyR and MMR were 95.7%, 29.3%, and 18.6%, respectively in those receiving the third-line TKI therapy. The 2-year PFS and OS rates were 66.8% and 93.8%, respectively. The patients with an interval from diagnosis to starting TKI ≥6 months, achieving no cytogenetic response on the second-line TKI, the interval from diagnosis to starting second-line TKI ≥60 months, and progression to AP before the third-line TKI therapy had lower probabilities of responses and unfavorable outcomes. Conclusions: The efficacy of dasatinib and nilotinib as second- or third-line TKI-therapy were active in the CML patients with TKI-resistance. The best response achieved on previous TKI-therapy, the disease phase before switching TKI, and the severe hematologic toxicity developing on the current TKI-therapy were associated with the responses and outcomes.

Perioperative protection for right heart in patients with apical displacement of tricuspid valve leaflets / 中国胸心血管外科临床杂志

@#The apical displacement of tricuspid valve leaflets complicated with significantly enlarged, thin and fibrotic wall of the right ventricle is prone to dysfunction of right heart. Therefore, the myocardial protection for the right ventricle is important. Based on the pathological changes, an algorithm of perioperative myocardial protection strategy is summarized. Firstly, we should clearly know that the right ventricular myocardium with severe lesions is much different from the unimpaired myocardium, because it is now on the margin of failure; secondly, right heart protection should be regarded as a systematic project, which runs through preoperative, intraoperative and postoperative periods, and requires close collaboration among surgeons, perfusionists, anesthesiologists and ICU physicians. In this article, we try to introduce the systematic project of the right heart protection, in order to improve the outcome of this population.

Establishment and evaluation of a TaqMan RT-qPCR method for tissue quantification of oncolytic virus M1 in vivo / 中国病理生理杂志

AIM:To establish a TaqMan RT-qPCR method for surveiling the spread of oncolytic virus M1 in tissue,helping control the dosage and assessing the safety of virus. METHODS:A TaqMan-based one-step RT-qPCR method for the detection and quantification of oncolytic virus M1 in the tissues was established. The virus load and distri-bution in the tissues of SD rats,cynomolgus monkeys and nude mice were also investigated. RESULTS:A pair of specific primers(Q3)and the standard viral RNA for SYBR Green RT-qPCR were screened and selected with the best specificity and amplification efficiency. By optimizing the experiment conditions,we found that the annealing temperature above 62℃reduced matrix effect but affected the amplification efficiency. So we established a one-step TaqMan RT-qPCR method and redesigned a pair of Q3 short primers(Q3S). Using the one-step TaqMan RT-qPCR and Q3S primer,the stan-dard RNA with low copy numbers was specifically detected under the background of mixed matrix RNA of SD rats or cyno-molgus monkeys. Furthermore,the method was verified to be suitable for detecting tissue distribution of M1 virus in the mice,SD rats and cynomolgus monkeys. CONCLUSION:The TaqMan-based one-step RT-qPCR constructed with Q3S primer can be used for M1 virus quantification in various tissue samples of different animals with better specificity and sen-sitivity,and may be further applied to the detection of clinical samples.

Curcumin inhibits Toll-like receptor 4/high mobility group box 1 pathway to protect lipopolysaccharide-induced acute lung injury / 中国胸心血管外科临床杂志

@#Objective    To investigate the protective effect and mechanism of curcumin on lipopolysaccharide (LPS)-induced acute lung injury. Methods    Totally 24 SD rats were randomly divided into a control group, a LPS group and a LPS+curcumin group (n=8 in each group). The degree of lung injury (oxygen partial pressure, wet/dry ratio, pathological scores) and inflammatory levels [tumor necrosis factor (TNF)-α, interleukin (IL)-6, monocyte chemotactic protein (MCP)-1, Toll-like receptor 4 (TLR4), mobility group box 1 protein (HMGB1) expression] of the lung were detected in different groups. Results    Oxygen partial pressure was significantly lower in the LPS group than that in the control group (P<0.05), while wet/dry ratio, pathological scores and expression levels of TNF-α, IL-6, MCP-1, TLR4 and HMGB1 were significantly higher in the LPS group than those in the control group (P<0.05). Compared with the LPS group, curcumin significantly reduced wet/dry ratio, pathological scores and expression levels of TNF-α, IL-6, MCP-1, TLR4 and HMGB1 in the LPS+curcumin group (P<0.05), while it significantly improved oxygen partial pressure (P<0.05). Conclusion    Curcumin might protect LPS-induced acute lung injury through inhibition of TLR4-HMGB1-inflammation pathway.

Pharmacokinetics of HMS-01 in rats / 药学实践杂志

Objective To study the pharmacokinetics of HMS-01 in rats and provide support for subsequent study. Methods A sensitive and specific method for the determination of HMS-01 in plasma and other biological samples was established by LC-MS/MS. The pharmacokinetics of HMS-01 in rats was studied by the established method. The pharmacokinetics of one dose of single intragastric administration and one dose of single intravenous administration in SD rats were studied, and the basic pharmacokinetic parameters were obtained. Results After intravenous injection of 1 mg/kg HMS-01, the area under the plasma concentration-time curve AUC0-t of male and female rats was 221 ng·h/ml and 409 ng·h/ml, respectively. The average clearance rates were 4.53 L/h·kg and 2.41 L/h·kg, respectively. The average plasma elimination half-lives were 0.786 h and 1.27 h, and the apparent distribution volume was 5.13 L/kg and 3.82 L/kg, respectively. After intragastric administration of 30 mg/kg HMS-01, the peak time of plasma concentration in rats was 1.17 h, the peak concentration of Cmax was 1 243 ng/ml, and the elimination half-life t1/2 was 2.00 h. The AUC0-t of male and female rats was 2 271 and 8 529 ng·h/ml respectively, and their bioavailability was 34.3% and 69.5% respectively. Conclusion The pharmacokinetics of HMS-01 in rats has significant gender differences. It is well absorbed orally, and the bioavailability of HMS-01 in females is much higher than that in males.

Philadelphia chromosome-negative myeloid neoplasms in patients with Philadelphia chromosome-positive chronic myeloid leukemia during tyrosine kinase inhibtor-therapy / 中华血液学杂志

Objective: To compare the clinical features between the 2 cohorts developing myelodysplastic syndrome or acute myeIogenous Ieukemia in Philadelphia chromosome-negative cells (Ph(-) MDS/AML) and maintaining disease stable in the patients with Philadelphia chromosome-positive chronic myeloid Ieukemia (Ph(+) CML) who had clonal chromosomal abnormalities in Philadelphia chromosome-negative metaphases (CCA/Ph(-)) during tyrosine kinase inhibtor (TKI) - therapy. Methods: We retrospectively analyzed Ph(+) CML patients who developed CCA/Ph(-) during TKI-therapy from May 2001 to December 2017. Results: Data of CCA/Ph(-) 63 patients, including 7 progressing to Ph(-) MDS/AML and 56 remaining disease stable were collected. Compared with those with stable disease, patients with Ph(-)MDS/AML had lower hemoglobin (P=0.007) and platelet (P=0.006) counts, and higher proportion of peripheral blasts (P<0.001) when the first time CCA/Ph(-) was detected, and more mosonomy 7 abnormality (5/7, 71.4%) when MDS or AML was diagnosed; meanwhile, trisomy 8 (32/56, 57.1%) was more common in those with stable disease. Outcome of the patients with Ph(-) MDS/AML were poor. However, most of those with CCA/Ph(-) and stable disease had optimal response on TKI-therapy. Conclusions: A few patients with Ph(+) CML developed CCA/Ph(-) during TKI-therapy, most of them had stable disease, but very few patients developed Ph(-) MDS/AML with more common occurrence of monosomy 7 or unknown cytopenia. Our data suggested the significance of monitoring of peripheral blood smear, bone marrow morphology and cytogenetic analysis once monosomy 7 or unknown cytopenia occurred.