Objective:To evaluate the efficacy and safety of azacytidine (AZA) combined with homoharringtonine (HHT) and low-dose cytarabine (LDAC) in the treatment of acute myeloid leukemia (AML) patients with 3+ 7 conventional regimen intolerance.Methods:A retrospective analysis was conducted on the clinical characteristics, efficacy, prognosis, and adverse events of 33 AML patients (15 initially diagnosed and 18 relapsed/refractory) admitted to the Second Xiangya Hospital of Central South University.Results:Among the 33 AML patients treated with this regimen, the median age was 55 years old, 9 patients had a moderate cytogenetic risk, and 18 patients had a high cytogenetic risk. Among the 33 patients, 3 were lost to follow-up and 1 had incomplete data. Among the remaining 29 patients who received AZA+ HHT+ LDAC treatment, the total complete response (CR) rate was 69.0%(20/29), and the total response rate (ORR) was 79.3%(23/29); The median progression free survival (PFS) was 7.0 months. Among the subgroup analysis, including age, gender, Eastern Cooperative Oncology Group (ECOG) score, disease classification, bone marrow progenitor cells, peripheral blood leukocytes, risk stratification, and epigenetic abnormalities, only CR rates and PFS differences were statistically significant among different ECOG scoring groups ( P=0.048; P=0.021). A total of 29 patients underwent 69 AZA+ HHT+ LDAC chemotherapy cycles. Retrospective grading was performed on 69 cycles based on common toxicity criteria for adverse events (CTC AE version 5.0). The most common grade Ⅲ-Ⅳ hematological adverse events were thrombocytopenia (54/69, 78.3%) and granulocytopenia (48/69, 69.6%). Common non hematological adverse events included nausea (19/69, 27.5%), infection (17/69, 24.6%), and hypokalemia (18/69, 26.1%). Conclusions:AZA combined with HHT and LDAC has a good therapeutic effect in the treatment of acute myeloid leukemia, and adverse reaction events are controllable.

PURPOSE: Survival of metastatic breast cancer (MBC) patient remains unknown and varies greatly from person to person. Thus, we aimed to construct a nomogram to quantify the survival probability of patients with MBC. MATERIALS AND METHODS: We had included 793 MBC patients and calculated trends of case fatality rate by Kaplan-Meier method and joinpoint regression. Six hundred thirty-four patients with MBC between January 2004 and July 2011 and 159 patients with MBC between August 2011 and July 2013 were assigned to training cohort and internal validation cohort, respectively. We constructed the nomogram based on the results of univariable and multivariable Cox regression analyses in the training cohort and validated the nomogram in the validation cohort. Concordance index and calibration curves were used to assess the effectiveness of nomogram. RESULTS: Case fatality rate of MBC was increasing (annual percentage change [APC], 21.6; 95% confidence interval [CI], 1.0 to 46.3; p < 0.05) in the first 18 months and then decreased (APC, -4.5; 95% CI, -8.2 to -0.7; p < 0.05). Metastasis-free interval, age, metastasis location, and hormone receptor status were independent prognostic factors and were included in the nomogram, which had a concordance index of 0.69 in the training cohort and 0.67 in the validation cohort. Calibration curves indicated good consistency between the two cohorts at 1 and 3 years. CONCLUSION: In conclusion, the fatality risk of MBC was increasing and reached the summit between 13th and 18th month after the detection of MBC. We have developed and validated a nomogram to predict the 1- and 3-year survival probability in MBC.
Breast Neoplasms* ; Breast* ; Calibration ; Cohort Studies ; Humans ; Methods ; Mortality ; Neoplasm Metastasis* ; Nomograms ; Risk Assessment*

BACKGROUND:The anterior cruciate ligament has unique nonlinear mechanical properties under a complex physiological loading environment.Elastin is an important contributor to the mechanical properties of the anterior cruciate ligament,but its mechanical response to the anterior cruciate ligament under axial tension is not clear. OBJECTIVE:To quantitatively analyze the effect of elastin on the tensile mechanical response of the anterior cruciate ligament. METHODS:Elastase solution and control buffer were prepared.The porcine anterior cruciate ligament samples were prepared into small-size samples and randomly soaked in 0,0.1,1.0,2.0,5.0,and 10.0 U/mL elastase solution for 6 hours,and other small samples of the same size were soaked in 2 U/mL elastase solution for 0,1,3,6,9,and 12 hours.To determine suitable soaking conditions for elastin-targeted enzymes and verify the digestive effect,histological staining was used to compare the effects of enzyme treatment on tissue structure and composition.The ligament samples were randomly divided into elastase-treated group and PBS group,and immersed in 2 U/mL elastase solution and PBS buffer for 6 hours,respectively.A mechanical tensile test was performed before and after immersion. RESULTS AND CONCLUSION:(1)The biochemical results showed that being treated in 2 U/mL elastase solution for 6 hours could reduce the elastin content by 31.1%,and had no significant effect on other mechanical-related components in the tissue.(2)The histological results showed that elastase was able to penetrate the tissue,and the loose degree of tissue increased after treatment.(3)In the mechanical results before and after treatment,the mechanical properties of the PBS group decreased significantly,only the low-tension elastic modulus increased significantly and the initial length increased significantly in the elastase-treated group.(4)The intergroup comparison results showed that there was no significant difference between the two groups in pre-treatment,but the low-tension elastic modulus,initial slopes,saturated slopes,and initial length of the elastase-treated group after treatment were significantly higher than those in the PBS group.(5)These results suggest that elastin degradation significantly affects the biomechanical properties of the anterior cruciate ligament and further complements our understanding of the structure-function relationship of the anterior cruciate ligament.

Objective:To investigate the application value of artificial neural network in laparoscopic surgery training.Methods:The prospective cohort study was conducted. A total of 158 trainees from the First Hospital Affiliated to Army Medical University between Semptember and November, 2019 who had no experience in laparoscopic technology were selected for laparoscopic surgery training, including 52 graduate students of surgery from grade 2019, 2018 and 2017, 58 surgeons receiving standardized residency training, 12 interns and 36 refresher physicians. The 158 trainees were divided into two groups using the random number table. Trainees trained by artificial neural network laparoscopic simulator were allocated into artificial neural network group, and trainees trained by box laparoscopic simulator were allocated into general laparoscopic simulator group. Trainees in both groups were trained using the laparoscopic simulator for 10 hours (5-day continuous training, 2 hours per day) on fundamentals of laparoscopic surgery. Observation indicators: (1) comparison of operation grades on laparoscopic simulator before and after training in the two groups; (2) comparison of improvement of the operation grades on laparoscopic simulator after training between the two groups. Measurement data with normal distribution were represented as Mean± SD, comparison within groups was analyzed using the paired t test and comparison between groups was analyzed using the independent sample t test. Measurement data with skewed distribution were represented as M (range). Results:A total of 158 trainees were selected for eligibility, including 140 males and 18 females, aged from 23 to 34 years, with a median age of 27 years. Of the 158 trainees, 79 were in the artificial neural network group and 79 were in the general laparoscopic simulator group. (1) Comparison of operation grades on laparoscopic simulator before and after training in the two groups: operation grades of the nails transferring, pattern cutting, ligation, sewing knots in vivo and sewing knots in vitro for the artificial neural network group before training were 51.2±4.9, 45.6±3.7, 43.0±3.6, 42.1±3.1, and 39.6±3.1, respectively. The above indicators for the artificial neural network group after training were 78.6±3.0, 76.4±3.9, 79.9±2.5, 78.3±3.5, and 84.1±3.8, respectively. There were significant differences in the above indicators for the artificial neural network group before and after training ( t=-42.490, -56.256, -80.373, -70.802, -79.742, P<0.05). The above indicators for the general laparoscopic simulator group before training were 50.1±2.9, 45.4±3.9, 42.7±3.0, 42.3±3.4, and 39.2±4.7, respectively. The above indicators for the general laparoscopic simulator group after training were 70.4±5.0, 69.8±4.0, 72.3±3.3, 72.3±3.5, and 72.8±3.2, respectively. There were significant differences in the above indicators for the general laparoscopic simulator group before and after training ( t=-28.942, -42.436, -58.357, -52.322, -53.098, P<0.05). (2) Comparison of improvement of the operation grades on laparoscopic simulator after training between the two groups: improvement of the operation grades in the nails transferring, pattern cutting, ligation, sewing knots in vivo and sewing knots in vitro for the artificial neural network group after training were 27.4±5.7, 30.8±5.0, 36.9±4.1, 36.2±4.5 and 39.5±5.4, respectively. The above indicators for the general laparoscopic simulator group after training were 20.3±6.2, 24.4±5.1, 29.6±4.5, 29.9±5.1 and 33.5±5.6, respectively. There were significant differences in the above indicators between the two groups ( t=7.597, 7.946, 10.638, 8.200, 6.969, P<0.05). Conclusion:The introduction of artificial neural network in laparoscopic surgery training can improve the training effects.

OBJECTIVETo assess the association of neural development-related genes LIS1and TSNAX with bipolar disorder in a Chinese Han population.

METHODSThree hundred and eight five patients (including 188 males and 197 females) from Guangzhou Brain Hospital with bipolar disorder meeting the Diagnostic and Statistic Manual of Bipolar Disorder (BDI) (Fourth Edition) criteria and 475 healthy controls from the local community were recruited. Ten single nucleotide polymorphisms (SNPs) of the LIS1 and TSNAX genes were genotyped by GoldenGate genotyping assay on an Illumina Beadstation 500 machine. Association analyses of SNPs and haplotypes were performed with Plink 1.07 software.

RESULTSAnalysis of the total sample has failed to find any association of SNP or haplotype of the two genes with BDI (P> 0.05). When patients were divided into subgroups with or without psychotic symptom, no significant association of the two genes was found with psychotic BDI or non-psychotic BDI (P> 0.05). No significant association was found between any SNP and haplotype of two genes and female BDI or male BDI, nor were significant association found between age of onset and LIS1 and TSNAX gene polymorphisms.

CONCLUSIONOur results indicated that LIS1 and TSNAX genes are not associated with susceptibility to bipolar I disorder in Chinese Han population.

1-Alkyl-2-acetylglycerophosphocholine Esterase ; genetics ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Asian Continental Ancestry Group ; ethnology ; genetics ; Bipolar Disorder ; ethnology ; genetics ; Case-Control Studies ; DNA-Binding Proteins ; genetics ; Female ; Genetic Predisposition to Disease ; Genotype ; Humans ; Male ; Microtubule-Associated Proteins ; genetics ; Middle Aged ; Polymorphism, Single Nucleotide ; Young Adult

ObjectiveTo study the effect of apigenin on the proliferation and apoptosis of human colon cancer CL187 cells and the underlying mechanisms. MethodHuman colorectal cancer CL187 cells were treated with different concentrations of apigenin （0， 30， 45， 60 mg·L^-1） according to the results of the preliminary experiment. The proliferation of CL187 cells was detected by methyl thiazolyl tetrazolium （MTT） and colony formation assays， and the apoptosis was observed via Hoechst 33258 staining. Real-time fluorescence quantitative PCR was conducted to determine the mRNA levels of cysteine protease-3 （Caspase-3）， B-cell lymphoma-2 （Bcl-2）， and Bcl-2-associated X protein （Bax） in the CL187 cells treated with apigenin. Western blot was employed to measure the protein levels of Caspase-3， Bcl-2， and Bax associated with apoptosis， protein kinase B （Akt） and phosphorylated Akt （p-Akt） in phosphatidylinositol 3-kinase/protein kinase B （PI3K/Akt） pathway， and extracellular signal-regulated kinases 1/2 （ERK1/2）， p-ERK1/2， c-Jun N-terminal kinase （JNK）， p-JNK， p38 mitogen-activated protein kinase （MAPK）， and p-p38 MAPK protein in MAPK pathway. ResultCompared with the blank group， the apigenin groups had low cell survival rates and high inhibition rates on cell proliferation （P<0.01）. Apigenin decreased the cell clone number and clone formation rate， and increased the inhibition rate on clone formation （P<0.01）. After CL187 cells were treated with different concentrations of apigenin for 48 h， typical apoptosis characteristics such as nuclear pyknosis， chromatin condensation， and enhanced fluorescence reaction were observed. Compared with blank group， 45， 60 mg·L^-1 apigenin treatments down-regulated the mRNA level of anti-apoptotic gene Bcl-2 （P<0.01） and all the apigenin treatments up-regulated those of the pro-apoptotic genes Bax and Caspase-3 （P<0.05， P<0.01）. Similarly， apigenin treatments down-regulated the protein level of Bcl-2 （P<0.05， P<0.01） and up-regulated those of Caspase-3 （P<0.05， P<0.01） and Bax （P<0.01， 45， 60 mg·L^-1）. The blank group had higher protein level of Akt than the 60 mg·L^-1 apigenin group （P<0.01）， higher protein levels of p-Akt， ERK1/2， and p-ERK1/2 than the 45， 60 mg·L^-1 apigenin groups （P<0.01）， and higher protein levels of JNK and p-JNK than the apigenin groups （P<0.05， P<0.01）. Compared with blank group， 60 mg·L^-1 apigenin up-regulated the protein level of p38 MAPK （P<0.05）， and all the apigenin groups up-regulated that of p-p38 MAPK （P<0.01）. Furthermore， apigenin lowered the p-Akt/Akt ratio （P<0.05， P<0.01） and p-ERK1/2/ERK1/2 ratio （P<0.01）， while it increased the p-JNK/JNK ratio （45， 60 mg·L^-1； P<0.05， P<0.01） and p-p38 MAPK/p38 MAPK ratio （P<0.05， P<0.01）. ConclusionApigenin can inhibit the proliferation and promote the apoptosis of CL187 cells by inhibiting the PI3K/Akt signaling pathway and regulating the expression of proteins in the MAPK signaling pathway.

ObjectiveTo analyze the clinical application hotspots， development trends， compatibility characteristics， application rules， and formulation mechanisms of the Chinese marine drug pair Haliotidis Concha-Oystreae Concha in order to provide references for its clinical medication and further research. MethodBy means of various modern literature databases such as China National Knowledge Infrastructure （CNKI）， modern clinical prescriptions containing Haliotidis Concha-Oystreae Concha， as well as the clinical application hotspots， were retrieved， followed by visualized analysis of hotspots and development trends of their clinical applications using Citespace. The drug composition， efficacy and indications， and drug dosages in the prescriptions were statistically analyzed. Additionally， various statistical software including SPSS Modeler 18.0 were employed to analyze the indications， syndromes， and formulation rules of Haliotidis Concha-Oystreae Concha. ResultThe visualized analysis included 90 articles， revealing a gradual decrease in publications in this field in recent years. Key clinical application keywords were identified as hypertension， collateral deficiency producing wind， insomnia， etc. Eighty clinical prescriptions were retrieved， involving 121 drugs. Frequency analysis of compatibility demonstrated that the top 10 drugs were Uncariae Ramulus cum Uncis， Gastrodiae Rhizoma， Os Draconis， Achyranthis Bidentatae Radix， Paeoniae Radix Alba， Chrysanthemi Flos， Scutellariae Radix， Gardeniae Frucuts， Glycyrrhizae Radix et Rhizoma， and Polygoni Multiflori Caulis. Association rule analysis showed that core combinations included "Uncariae Ramulus cum Uncis-Achyranthis Bidentatae Radix" and "Os Draconis-Pheretima-Chuanxiong Rhizoma". Through factor reliability analysis， new drug combinations were derived， such as "Gastrodiae Rhizoma-Polygoni Multiflori Caulis-Eucommiae Cortex-Taxilli Herba-Leonuri Herba"， "Achyranthis Bidentatae Radix-Uncariae Ramulus cum Uncis"， "Scutellariae Radix-Glycyrrhizae Radix et Rhizoma-Margarita-Prunellae Spica"， "Os Draconis-Pheretima-Bombyx Batryticatus"， "Chrysanthemi Flos-Chuanxiong Rhizoma"， "Poria-Acori Tatarinowii Rhizoma"， and "Paeoniae Radix Alba-Gardeniae Fructus-Sclerotium Poriae Pararadicis". The Haliotidis Concha-Oystreae Concha drug pair was mainly used to treat diseases with liver Yang hyperactivity syndrome， with hypertension accounting for 40.00%， migraines for 30.00%， and dizziness for 15.00%. In the treatment of liver Yang hyperactivity syndrome， the main categories of compatible drugs were liver-pacifying and wind-extinguishing ones （19.86%）， blood-activating and stasis-resolving ones （12.13%）， and spirit-calming ones （10.08%）. High-frequency drugs in the prescriptions function to reduce blood pressure through multiple pathways， such as increasing nitric oxide （NO） levels， downregulating angiotensin Ⅱ （Ang Ⅱ）， and inhibiting angiotensin-converting enzyme （ACE）. ConclusionThrough comprehensive analysis of the results， the Haliotidis Concha-Oystreae Concha drug pair is commonly used for hypertension with liver Yang hyperactivity syndrome， and is often combined with deficiency-tonifying， liver-pacifying and wind-extinguishing， heat-clearing， and spirit-calming drugs， aiming to simultaneously extinguish wind， relieve spasms， and pacify the liver to subdue Yang， while also clearing heat to relax bowels， stabilizing the mind， and enhancing the liver-pacifying and Yang-subduing effects of this drug pair.

Zedoary tumeric (Curcumae Rhizoma, Ezhu in Chinese) has a long history of application and has great potential in the treatment of liver cancer. The antiliver cancer effect of zedoary tumeric depends on the combined action of multiple pharmacodynamic substances. In order to clarify the specific mechanism of zedoary tumeric against liver cancer, this paper first analyzes the mechanism of its single pharmacodynamic substance against liver cancer, and then verifies the joint anti liver cancer mechanism of its “pharmacodynamic group”. By searching the research on the antihepatoma effect of active components of zedoary tumeric in recent years, we found that pharmacodynamic substances, including curcumol, zedoarondiol, curcumenol, curzerenone, curdione, curcumin, germacrone, β-elemene, can act on multi-target and multi-channel to play an antihepatoma role. For example, curcumin can regulate miR, GLO1, CD133, VEGF, YAP, LIN28B, GPR81, HCAR-1, P53 and PI3K/Akt/mTOR, HSP70/TLR4 and NF-κB. Wnt/TGF/EMT, Nrf2/Keap1, JAK/STAT and other pathways play an antihepatoma role. Network pharmacological analysis showed that the core targets of the “pharmacodynamic group” for anti-life cancer are AKT1, EGFR, MAPK8, etc, and the core pathways are neuroactive live receiver interaction, nitrogen metabolism, HIF-1 signaling pathway, etc. At the same time, by comparing and analyzing the relationship between the specific mechanisms of pharmacodynamic substance and “pharmacodynamic group”, it is found that they have great reference significance in target, pathway, biological function, determination of core pharmacodynamic components, formation of core target protein interaction, in-depth research of single pharmacodynamic substance, increasing curative effect and so on. By analyzing the internal mechanism of zedoary tumeric pharmacodynamic substance and “pharmacodynamic group” in the treatment of liver cancer, this paper intends to provide some ideas and references for the deeper pharmacological research of zedoary tumeric and the relationship between pharmacodynamic substance and “pharmacodynamic group”.

Piperine is a kind of amide alkaloids presenting in Piper nigrum L.，which has the pharmacological action such as protecting cardiovascular system ，regulating glucose and lipid metabolism ，anti-tumor，improving nervous system diseases ， anti-inflammation and so on. This paper summarized the pharmacological action and mechanisms of piperine in recent years and found that piperine ，as the main active ingredient of P. nigrum ，could protect the cardiovascular system by reducing inflammation and oxidative stress ；improve mitochondrial function through anti-inflammatory and antioxidant effects ，thereby regulate glucose and lipid metabolism ；play an anti-tumor role by mediating the signaling pathways of Wnt/β-catenin，NF-κB/Nrf-2/KeAP-1/HO-1， PI3K/Akt，TGF-β1/Smad2/ERK1/2；improve neurological diseases by inhibiting autophagy ，relieving inflammation ，improving antioxidant，inhibiting neuronal apoptosis and regulating the expression of related proteins in neurons ；play an anti-inflammatory effect by inhibiting the activity of NF-κB and other signaling pathways and reducing the expression of inflammation-related proteins. However，the mechanism of action of piperine is not perfect ，and most of the studies have been confined to the pharmacological level or a certain signaling pathway and a certain target ，without being able to elucidate the interconnection between the relevant signaling pathway and the specific target from a holistic perspective. In the follow-up ，the specific targets of piperine can be identified and clinical trials can be carried out to provide support for the clinical application of piperine.

ObjectiveTo investigate the effect of Stemona tuberosa alkaloids （STA） on apoptosis and phosphatidylinositol 3-kinase/protein kinase B （PI3K/Akt） and c-Jun N-terminal kinase/p38 mitogen-activated protein kinase （JNK/p38 MAPK） signaling pathways in human lung cancer A549 cells. MethodA549 cells were classified into blank group and STA groups （100， 150， 200， 250， 300 mg⋅L^-1）. Thiazole blue （MTT） assay and colony formation assay were used to evaluate the proliferation of A549 cells. Apoptosis was observed based on Hoechst 33258 staining， flow cytometry， and Annexin V-FITC/PI staining. Western blot was employed to detect the expression of apoptosis-related proteins cysteine-aspartic acid protease-3 （Caspase-3）， B-cell lymphoma-2 （Bcl-2）-associated X protein （Bax）， and Bcl-2， and the expression of PI3K， phosphorylated （p）-PI3K， Akt， p-Akt， JNK， p-JNK， p38 MAPK， and p-p38 MAPK. ResultCompared with the blank group， STA groups （150， 200， 250， 300 mg⋅L^-1） demonstrated the increase in inhibition rate of cell proliferation （P<0.01） and cell clone inhibition rate， and decrease in cell clone formation rate （P<0.01）. In comparison with the blank group， STA groups showed typical characteristics of apoptosis， such as chromatin condensation and enhanced fluorescence reaction. The apoptosis rate of STA groups was significantly higher than that of the blank group （P<0.01）. Compared with the blank group， STA （150， 200， 250， 300 mg⋅L^-1） significantly up-regulated the protein expression of Caspase-3 and Bax （P<0.05， P<0.01） and down-regulated the expression of Bcl-2 protein （P<0.01）. Compared with the blank group， STA had no significant influence on the total protein expression of PI3K， Akt， JNK， and p38 MAPK. However， STA （150， 200， 250， 300 mg⋅L^-1） significantly decreased the levels of p-PI3K and p-Akt （P<0.05， P<0.01） and increased the level of p-p38 MAPK （P<0.05， P<0.01）. Compared with the blank group， STA （200， 250， 300 mg⋅L^-1） significantly raised the level of p-JNK （P<0.05， P<0.01）. ConclusionSTA can inhibit the proliferation and induce the apoptosis of A549 cells by inhibiting PI3K/Akt signaling pathway and activating JNK/p38 MAPK signaling pathway.