Growth differentiation factor 15 predicts cardiovascular events in stable coronary artery disease / 老年心脏病学杂志（英文版）

BACKGROUND@#Growth differentiation factor 15 (GDF-15) has been explored as a potential biomarker for various inflammatory diseases and cardiovascular events. This study aimed to assess the predictive role of GDF-15 levels in cardiovascular events and all-cause mortality, considering traditional risk factors and other biomarkers.@*METHODS@#A prospective study was conducted and 3699 patients with stable coronary artery disease (CAD) were enrolled into the research. Baseline GDF-15 levels were measured. Median follow-up was 3.1 years during the study. We analyzed clinical variables and several biomarkers. Multivariable Cox regression analysis was performed to evaluate prognostic performance of GDF-15 levels in predicting myocardial infarction (MI), heart failure, stroke, cardiovascular death, and non-cardiovascular death.@*RESULTS@#Baseline GDF-15 levels for 3699 patients were grouped by quartile (≤ 1153, 1153-1888, 1888-3043, > 3043 ng/L). Higher GDF-15 levels were associated with older age, male gender, history of hypertension, and elevated levels of N-terminal pro B-type natriuretic peptide (NT-pro BNP), soluble suppression of tumorigenesis-2 (sST2), and creatine (each with P < 0.001). Adjusting for established risk factors and biomarkers in Cox proportional hazards models, a 1 standard deviation (SD) increase in GDF-15 was associated with elevated risk of clinical events [hazard ratio (HR) = 2.18, 95% confidence interval (CI): (1.52-3.11)], including: MI [HR = 2.83 95% CI: (1.03-7.74)], heart failure [HR = 2.71 95% CI: (1.18-6.23)], cardiovascular and non-cardiovascular death [HR = 2.48, 95% CI (1.49-4.11)] during the median follow up of 3.1 years.@*CONCLUSIONS@#Higher levels of GDF-15 consistently provides prognostic information for cardiovascular events and all cause death, independent of clinical risk factors and other biomarkers. GDF-15 could be considered as a valuable addition to future risk prediction model in secondary prevention for predicting clinical events in patient with stable CAD.

Early diagnosis of acute kidney injury in aged patients undergoing percutaneous coronary intervention / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

In aged patients, acute kidney injury (AKI) is a common clinical complication after percutaneous coronary intervention (PCI), highlighting the need for timely and certain diagnosis of this disease. A single centre, nested case-control study was conducted, which assessed the usefulness of urinary liver-type fatty acid-binding protein (uL-FABP), neutrophil gelatinase-associated lipocalin (uNGAL), and kidney injury molecule-1 (uKIM-1) for early detection of AKI. One hundred and thirty-two patients at or over 60 years old undergoing PCI were included. Serum creatinine (SCr) was measured before PCI, 24 and 48 h after PCI; uL-FABP, uNGAL, and uKIM-1 were measured before PCI, 6, 24, and 48 h after PCI. We identified 16 AKI patients and selected 32 control patients matched by admission time (<1 week), age (±5 years), and gender. In the receiver operating characteristic (ROC) curve analysis, the areas under the curve (AUCs) for the relative measurements of uL-FABP, uNGAL, and uKIM-1 were 0.809, 0.867, and 0.512 at 6 h after PCI, and 0.888, 0.840, and 0.676 at 24 h after PCI, respectively. AUC for the combination of uL-FABP and uNGAL was 0.899 at 6 h after PCI, and 0.917 at 24 h after PCI. Thus, measurement of uL-FABP and uNGAL levels at 6 and 24 h after PCI may be useful in detecting AKI in aged patients. Measurement of uKIM-1 levels provides inferior predictive power for early diagnosis of AKI.

Current status of blood pressure control in patients with coronary heart disease / 中国应用生理学杂志

OBJECTIVE@#To evaluate the level of blood pressure control in patients with coronary heart disease (CHD) of China in order to provide guidance for the prevention and treatment of CHD.@*METHODS@#The patients with CHD were retrospectively collected from 2011~2014 in PLA General Hospital and Hainan Branch Hospital. Then analyzed the difference of blood pressure compliance rate between different surgical methods percutaneous coronary intervention (PCI), coronary artery bypass grafting(CABG), secondary preventive drugs(aspirin, clopidogrel, nitrates, trimetazidine, nicorandil, hypotensor, hypoglycemic, lipid-lowering drugs) and lifestyle(smoking, drinking, exercise).@*RESULTS@#①Effects of surgical methods on blood pressure:Male's systolic blood pressure (SBP) and diastolic blood pressure(DBP) in the CABG group were lower in the PCI group and control group, and female's DBP in the CABG group were lower in the PCI group. ②Usage rate of secondary prevention drugs:usage rate of trimetazidine, calcium antagonist, β-blockers, angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor antagonist (ARB) in hypertension group were higher than in normal blood pressure group. ③ Lifestyle condition:compliance rate of blood pressure in the smoking group was lower than that in the non smoking group. And there was no significant difference in blood pressure compliance rate among whether drinking and doing exercise or not.@*CONCLUSIONS@#Blood pressure control in patients with CHD was still not satisfied. Compared with PCI, CABG may be more beneficial in the control of blood pressure in patients with CHD. Smoking cessation and improving the usage rate of secondary preventive drugs are still the main means of blood pressure control.

Application and Exploration of Big Data Mining in Clinical Medicine / 中华医学杂志(英文版)

<p><b>OBJECTIVE</b>To review theories and technologies of big data mining and their application in clinical medicine.</p><p><b>DATA SOURCES</b>Literatures published in English or Chinese regarding theories and technologies of big data mining and the concrete applications of data mining technology in clinical medicine were obtained from PubMed and Chinese Hospital Knowledge Database from 1975 to 2015.</p><p><b>STUDY SELECTION</b>Original articles regarding big data mining theory/technology and big data mining's application in the medical field were selected.</p><p><b>RESULTS</b>This review characterized the basic theories and technologies of big data mining including fuzzy theory, rough set theory, cloud theory, Dempster-Shafer theory, artificial neural network, genetic algorithm, inductive learning theory, Bayesian network, decision tree, pattern recognition, high-performance computing, and statistical analysis. The application of big data mining in clinical medicine was analyzed in the fields of disease risk assessment, clinical decision support, prediction of disease development, guidance of rational use of drugs, medical management, and evidence-based medicine.</p><p><b>CONCLUSION</b>Big data mining has the potential to play an important role in clinical medicine.</p>

Aneurysm resection and vascular reconstruction for true aneurysm at the initial segment of splenic artery / 华中科技大学学报（医学）（英德文版）

The aneurysms at the initial segment of splenic artery are rare. This paper aimed to investigate the methods to treat the true aneurysm at the initial segment of splenic artery by aneurysmectomy plus vascular reconstruction. Retrospectively reviewed were 11 cases of true aneurysm at the initial segment of splenic artery who were treated in our hospital from January 2000 to June 2013. All cases were diagnosed by color ultrasonography, computer tomography (CT) and angiography. Upon resection of the aneurysm, the auto-vein transplantation was performed in situ between the hepatic artery and the distal part of the splenic artery in 1 case; the artificial vessel bypass was done between the infra-renal aorta and distal portion of the splenic artery in 7 cases; the splenectomy was done in 2 cases; the splenectomy in combination with ligation of multiple small aneurysms were performed in 1 case. All cases were cured and discharged from the hospital 10-14 days after operation. A 1-14 year follow-up showed that 9 cases survived, and 2 cases died, including 1 case who died of acute myocardial infarction 2 years after aorta-splenic artery bypass operation and 1 case who died of acute cerebral hemorrhage 5 years after aneurysm resection and the splenectomy. Among 6 cases receiving aorta-splenic artery bypass, 1 gradually developed stenosis at anatomosed site, which eventually progressed to complete occlusion 2 years to 6 years after operation, without suffering from splenic infarction because the spleen was supplied by the short gastric vessel and its collaterals. The other 5 cases receiving aorta-splenic artery bypass and 1 case undergoing autologous vascular transplantation did not develop stricture or pseudoaneurysm at the stoma. Our study showed that the aneurysmectomy plus vascular reconstruction is a better treatment for aneurysm at the initial segment of splenic artery.

Aneurysm resection and vascular reconstruction for true aneurysm at the initial segment of splenic artery / 华中科技大学学报（医学）（英德文版）

The aneurysms at the initial segment of splenic artery are rare. This paper aimed to investigate the methods to treat the true aneurysm at the initial segment of splenic artery by aneurysmectomy plus vascular reconstruction. Retrospectively reviewed were 11 cases of true aneurysm at the initial segment of splenic artery who were treated in our hospital from January 2000 to June 2013. All cases were diagnosed by color ultrasonography, computer tomography (CT) and angiography. Upon resection of the aneurysm, the auto-vein transplantation was performed in situ between the hepatic artery and the distal part of the splenic artery in 1 case; the artificial vessel bypass was done between the infra-renal aorta and distal portion of the splenic artery in 7 cases; the splenectomy was done in 2 cases; the splenectomy in combination with ligation of multiple small aneurysms were performed in 1 case. All cases were cured and discharged from the hospital 10-14 days after operation. A 1-14 year follow-up showed that 9 cases survived, and 2 cases died, including 1 case who died of acute myocardial infarction 2 years after aorta-splenic artery bypass operation and 1 case who died of acute cerebral hemorrhage 5 years after aneurysm resection and the splenectomy. Among 6 cases receiving aorta-splenic artery bypass, 1 gradually developed stenosis at anatomosed site, which eventually progressed to complete occlusion 2 years to 6 years after operation, without suffering from splenic infarction because the spleen was supplied by the short gastric vessel and its collaterals. The other 5 cases receiving aorta-splenic artery bypass and 1 case undergoing autologous vascular transplantation did not develop stricture or pseudoaneurysm at the stoma. Our study showed that the aneurysmectomy plus vascular reconstruction is a better treatment for aneurysm at the initial segment of splenic artery.

The protective role of interleukin-6 monoclonal antibody on experimental autoimmune myocarditis and its mechanism / 中国应用生理学杂志

<p><b>OBJECTIVE</b>To investigate the therapeutic effect of IL-6 mAb on experimental autoimmune myocarditis (EAM) in rats, and search the mechanism of the role of IL-6, helper T cells 17 (Th17) and regulative T cells (Treg) in EAM pathogenesis.</p><p><b>METHODS</b>Thirty-four Lewis rats were divided into three groups randomly, i.e. control group (n = 6), EAM group (n = 12), and IL-6 mAb intervention group (n = 16). Rats in EAM group and IL-6 mAb intervention group were injected intracutaneously with myosin to establish EAM model. Rats in IL-6 mAb intervention group were injected intraperitoneally with 1 mg IL-6 mAb on 1st, 7th to 20th day after cardiac myosin immune injection. Myocardial inflammation was examined by HE stain, Masson stain, and TdT assay (TUNEL reaction) on 21st and 84th day after IL-6 mAb therapy in order to assess the therapeutic role. Spleen cells were analyzed by flow cytometry to illustrate Th17 and Treg cells? number and function. The serum concentration of IL-6, IL-10, IL-17, and TGF-beta in each group was measured by ELISA, concentration of STAT3, RORgammat, and Foxp3 mRNA in each group was determined with RT-PCR. Spleen cells derived from EAM were stimulated by IL-6 mAb in vitro, and the concentration of IL-10, IL-17 and TGF-beta was measured by ELISA.</p><p><b>RESULTS</b>Inflammation score, fibrosis score, and apoptosis index in IL-6 mAb intervention group were significantly decreased as compared with those in EAM group (P < 0.01). The number of Th17 and Treg cells in EAM group on the 21st day (experimental acute peak stage) were increased, and those in intervention group on the 21st day were significantly inhibited (P < 0.01). The concentration of serum IL-6, IL-10, IL-17 and TGF-beta in intervention group on the 21st day was decreased dramatically in comparison with that in EAM group on the same day (P < 0.01). The levels of peripheral blood STAT3, RORgammat, Foxp3 mRNA in intervention group on the 21st day was decreased significantly as compared with that in EAM group (P < 0.01). The expression of IL-10, IL-17 and TGF-beta was increased significantly (P < 0.01) by stimulation of IL-6 mAb on spleen cells derived from EAM in vitro.</p><p><b>CONCLUSIONS</b>IL-6 mAb could neutralize IL-6, and ameliorate myocarditis and reduce heart autoimmune responses. IL-6 mAb has significantly protective effects on EAM by suppressing Th17 and Treg cells.</p>

Analysis of changes in percentage of phenotype CD4 + CD45RA + and CD4+ CD45RO + in peripheral blood and effect of immunomodulation in aged male patients with chronic cardiac insufficiency / 中国应用生理学杂志

<p><b>OBJECTIVE</b>Autoimmunity participates in chronic heart failure (CCI), it is CD4+ T lymphocytes that mainly induces myocardial infiltration and the progression of the disease. The purpose of this research is to assess changes of CD4+, CD8+ T lymphocyte subset, and phenotype of primary T cell (CD4+ CD45RA+) and memory T cells (CD4+ CD45RO+) in peripheral blood in aged male patients with CCI. And to investigate the immunomodulatory effects on subsets of CD4+, CD8+ and phenotype of CD4+ CD45RA+ and CD4+ CD45RO+ and the possible therapeutic mechanism.</p><p><b>METHODS</b>The participant were 155 aged men among whom 94 cases were diagnosed as CCI and heart function of the rest 41 cases were normal. All patients underwent echocardiography examination and were collected peripheral blood before and after treatment. Serum N terminal pro-brain natriuretic peptide (NT-proBNP) levels were detected by heterogeneous immunoassay. Serum C reactive protein (CRP) were measured by immunoturbidimetry assay. T lymphocytes in peripheral blood were separated and determined distribution of CD4+, CD8+, CD4+ CD45RA+, CD4+ CD45RO+ using flow cytometry. Participants were divided into 3 groups: the CCI intervention group, who received regular therapy and thymopentin (20 mg intramuscular injection, once every other day for 3 month; n = 60) , the CCI control group, who received regular therapy (n = 54) and 41 healthy individual older than 57 years of age, who served as normal controls.</p><p><b>RESULTS</b>Compared with the control group, left ventricular ejection fraction (LVEF) and CD4+ CD45RO+ levels decreased, left ventricular end diastolic diameter (LVEDD), NT-proBNP, CRP, CD4+, CD4+ CD45RA+, CD4+/CD8+, CD4+ CD45RA+/CD4+ CD45RO+ levels were obviously higher in CCI group. Distribution of CD8+ was not significantly changed. The level of NT-proBNP, CRP, CD4+/CD8+, CD4+ CD45RA+/CD4+ CD45 RO+ was negatively correlated with LVEF. LVEF could be much improved via decreasing distribution of CD4+/CD8+, CD4+ CD45RA+/CD4+ CD45RO in CCI intervention group than in CCI control group.</p><p><b>CONCLUSION</b>The changes of CD4+/CD8+ and CD4+ CD45RA+/CD4+ CD45RO+ suggest that CD4+ T lymphocyte subset and its phenotype play an important role in the process of CCI. The regulation of CD4+ T lymphocyte and its phenotype may be one of the strategy in the treatment of CCI.</p>

Study of L-NAME treatment on experimental autoimmune myocarditis / 中国应用生理学杂志

<p><b>OBJECTIVE</b>To observe the therapeutic effect of N-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NOS, on experimental autoimmune myocarditis (EAM) in Balb/C mice and discuss the therapeutic mechanism induced by apoptosis.</p><p><b>METHODS</b>Thirty male Balb/C mice were divided into normal control group, model control group and experimental group randomly (n = 10). Model control group and experimental group were created into EAM by injection of porcine cardiac myosin subcutaneously in double groin and axilla and pertussis toxin intraperitoneally on day 0 and 7 respectively. Model control group was intraperitoneally administered 5 mg/(kg x day) of physiological saline after infective myosin and pertussis toxin. Experimental group was intraperitoneally given 5 mg/(kg x day) of L-NAME on day 1-21. The hearts and blood were processed after sacrificed on day 21. Cardiac inflammation score was measured by HE staining. Heart weight / body weight (HW/BW), serum nitric oxide (NO) level, activity of induced nitric oxide synthase (iNOS) and mRNA expression of iNOS in heart were measured in each group. Degree of heart apoptosis were evaluated by cardiac apoptotic index through TUNEL, immunohistochemical examination and real time PCR of Caspase-3, Caspase-8 and Caspase-9.</p><p><b>RESULTS</b>Compared with normal control group, cardiac inflammation score, HW/BW level of NO and activity of iNOS, mRNA expression of iNOS, the levels of mRNA and protein of Caspase-3, Caspase-8 and Caspase-9 and cardiac apoptotic index were significantly higher (P < 0.01) in model control group, and those of model control group were higher than those of experimental group (P < 0.01). HW/BW was only a little elevation in model control group compared with that in the experiment group (P < 0.05).</p><p><b>CONCLUSION</b>The development of EAM is related with the NO catalyzed by iNOS. L-NAME protects cardiac myocyte via suppressing the activity of iNOS and further decreased production of NO in EAM. The mechanism might be that L-NAME alleviated myocardial inflammation through inhibited the apoptosis of cardiac myocyte.</p>

Establishment of human cardiac C protein induced experimental autoimmune myocarditis model in rat / 中华心血管病杂志

<p><b>OBJECTIVE</b>To construct the recombinant plasmid of human cardiac C protein (CCP) peptide with immunogenicity and to express, purification and renature fusion protein. The fusion protein was injected to Lewis rats to establish experimental autoimmune myocarditis (EAM) model.</p><p><b>METHODS</b>Total RNA was extracted from human heart and used as the template for reverse transcriptase-directed cDNA synthesis. The cDNA was then amplified by polymerase chain reaction (PCR) using oligonucleotide primers specific for CCP peptide with immunogenicity. Subsequently, the purified CCP peptide gene was cloned into PEASY-T1 vector and the ligated product was identified by PCR and DNA sequence analysis. Then the CCP target gene of positive clone was inserted into the pQE30, a prokaryotic expression vector, and the inserting plasmid was transformed into Escherichia coli. host M15. The positive clone extracted from the bacterium liquid was sieved by insertional inactivation sieve method and identified by PCR of bacterium liquid, CCP immunological peptide was purified and renatured in semipermeable membrane. EAM model in Lewis rats was induced by injection of mixture of 100 µg CCP fusion protein immunological peptide and 2.5 g/L completed Freund adjuvant from two double foot pad and subsequent abdominal injection of 0.5 µg pertussis toxin. Two, four, six, and eight weeks after immunization, hemodynamic evaluation was made and hearts underwent histological examination.</p><p><b>RESULTS</b>The DNA sequence analysis for cloning vector extraction revealed that the CCP target gene was cloned into pQE30 exactly. The DNA of 1000 bp length was obtained by PCR examination of bacterium liquid with transformation of express recombinants which were consistent with the expected size. Purified fusion protein in vertical slab gel electrophoresis showed 35 000 as expected. The recombinant CCP fusion protein existed in inclusion bodies of E. coli and amounted to 80% - 90% of the total protein. Hemodynamic and histological evaluations showed typical acute inflammatory responses at 2 weeks, subacute inflammatory and fibrosis changes at 4 weeks after injection, and signs of chronic dilated cardiomyopathy at 6 weeks post injection.</p><p><b>CONCLUSION</b>Combination of gene clone technique and histidine tag protein purification technique can be used to synthesize human cardiac C protein to induce EAM model in Lewis rat.</p>

Experimental study of MMP-2 inhibitor treatment of experimental autoimmune myocarditis in Lewis rats / 中国应用生理学杂志

<p><b>OBJECTIVE</b>To investigate the inhibitor of matrix metalloproteinase-2 (MMP-2) (2R)-2-[5-[4-[ ethyl-methylamino] phenyl [thiophene-2-sulfonylamino]-3-methylbutyric acid (TISAM) therapeutic effect on experimental autoimmune myocarditis (EAM) in Lewis rats.</p><p><b>METHODS</b>Treatment protocol of oral administration of 5 mg/kg TISAM once a day for 14 days was performed on EAM Lewis rats. EAM Lewis rats were divided into 3 groups: treatment in early, middle and later stage respectively (n = 20). After experiment at the designate time point, the rats were euthanatized and hearts were harvested. Cardiac inflammatory score, fibrosis score and content, and infiltration of macrophages and T lyminflammatory score, fibrosis score and content, and infiltration of macrophages and T lymphocytes, message RNA (mRNA) expression of matrix metalloproteinase (MMP)-2 and MMP-9 and protein activity of gelatinase were determined.</p><p><b>RESULTS</b>TISAM treatment in early phase was invalid (treatment started from the creation of the model), treatment in middle and later phase was effective (treatment started from 7 and 14 day after the creation of the model).</p><p><b>CONCLUSION</b>Inhibitor of MMP-2 can block ventricular remodeling in middle stage in EAM Lewis rats. The mechanism maybe alleviate the inflammatory cell cardiac infiltration, decrease the mRNA expression of MMP-2 at transcript level and downregulate gelatinase activity at protein level.</p>

Effects of matrix metalloproteinase-9 inhibitor in Lewis rats with experimental autoimmune myocarditis / 中华心血管病杂志

<p><b>OBJECTIVE</b>To investigate the effects of matrix metalloproteinase-9 (MMP-9) inhibitor minocyclin hydrochloride in Lewis rats with experimental autoimmune myocarditis (EAM).</p><p><b>METHODS</b>EAM was induced by injection of cardiac C protein emulsified in completed Freund adjuvant in double footpad and intraperitoneal injection of pertussis toxin on 6- to 8-week old Lewis rats. Sixty EAM Lewis rats were divided into 3 groups (early, middle and late intervention groups, n = 20 each: 10 minocyclin treated and 10 control rats). In early intervention group, rats in treatment group received intraperitoneal injection of minocyclin hydrochloride from 1(st) to 21(st) day after immunization; in middle intervention group, rats were treated from 8(th) to 28(th) day after immunization and in late intervention group, rats were treated from 15(th) to 35(th) day after immunization (50 mg/kg body weight, once daily). Control rats received intraperitoneal injection of same volumetric physiological saline at corresponding time periods. At the end of intervention, rats were euthanatized and hearts were harvested. Paraffin sections were used for hematoxylin and eosin stain to determine the inflammatory score, for picrosirius stain to determine fibrosis score and collagen content, and for immunohistological stain to determine macrophages and T lymphocytes. Real time PCR was used to detect mRNA expression of myocardial MMP-2 and MMP-9. Cryostat sections were used for in situ zymography to detect protein activity of gelatinase.</p><p><b>RESULTS</b>Inflammatory score in cardiac paraffin slides, number of cardiac macrophages and T lymphocytes, cardiac interstitial fibrosis score and content, expression of MMP-2, 9 mRNA and activity of gelatinase in treatment group were all significantly lower than in control group for early and middle intervention groups (inflammatory score: early control group vs. treatment group: 3.03 ± 1.35 vs.1.51 ± 0.36, P < 0.05, middle control group vs. treatment group: 3.75 ± 0.29 vs. 2.11 ± 0.82, P < 0.01; cardiac interstitial fibrosis score, early control group vs. treatment group: 2.75 ± 0.29 vs.1.51 ± 0.35, P < 0.01, middle control group vs. treatment group: 2.50 ± 0.41 vs. 1.61 ± 0.42, P < 0.05; gelatinase, early control group vs. treatment group: 162 367 ± 5095 vs. 62 366 ± 2131, P < 0.01, middle control group vs. treatment group: 184 256 ± 5427 vs. 113 197 ± 4809, P < 0.01) while these parameters were similar between minocyclin-treated and control rats in late intervention group (all P > 0.05).</p><p><b>CONCLUSIONS</b>MMP-9 plays an important role in the pathogenesis of autoimmune myocarditis. Inhibition of MMP-9 in early and middle stage could significantly attenuate inflammatory responses and myocardial fibrosis in this experimental EAM model.</p>

Treatment strategies in acute myeloid leukemia / 中华医学杂志(英文版)

<p><b>OBJECTIVE</b>To summarize the risk stratification and current treatment strategies for acute myeloid leukemia (AML) and discuss the role of emerging novel agents that might be applied in future clinical trials.</p><p><b>DATA SOURCES</b>The data in this article were collected from PubMed database with relevant English articles published from 1991 to 2009.</p><p><b>STUDY SELECTION</b>Articles regarding the risk stratification and therapeutic options of AML, as well as the characteristics of leukemic stem cells were selected.</p><p><b>RESULTS</b>AML is a heterogeneous disease with variable clinical outcome dependent on several prognostic factors, including age, cytogenetics and molecular markers. The advances in the understanding of AML pathogenesis and development will generate potential novel agents that might improve the treatment results of standard chemotherapy.</p><p><b>CONCLUSION</b>Deeper insight into the multiple transforming events of AML may aid us in designing combinations of small molecule inhibitors based on the individual patient characteristics.</p>