冻融胚胎移植术后第9和11天β-HCG水平对单胎妊娠临床结局的预测价值

目的探讨冻融胚胎移植术后第9和11天血清β-人绒毛膜促性腺激素(β-HCG)水平对单胎妊娠临床结局的预测价值。方法回顾性分析2012年12月-2018年8月于广州医科大学附属第六医院生殖中心行冻融胚胎移植术并获得单胎妊娠的342例患者的临床资料,按不同的妊娠结局将患者分为异位妊娠组、早期流产组和活产组,比较各组移植后第9和11天血清β-HCG的差异,绘制ROC曲线计算不同妊娠结局的β-HCG界值。结果各组移植后第9和11天β-HCG比较,差异有统计学意义(P<0.05),在冻融胚胎移植周期中,移植后第9天预测单胎宫内妊娠/异位妊娠和单胎活产/非活产的β-HCG最佳阈值分别为27.5和32.5 IU/L;移植后第11天预测单胎宫内妊娠/异位妊娠和单胎活产/非活产的β-HCG最佳阈值分别为77.5和119.0 IU/L。结论冻融胚胎移植术后第9和11天测定血清β-HCG水平能有效预测单胎异位妊娠、单胎早期流产及单胎活产等不同体外受精妊娠结局。

Blue rubber bleb nevus syndrome:A case report and literature review

Blue rubber bleb nevus syndrome(BRBNS)is a rare disease characterized by multiple venous malformations and hemangiomas in the skin and visceral organs.The lesions often involve the cutaneous and gastrointestinal systems.Other organs can also be involved,such as the central nervous system,liver,and muscles.The most common symptoms are gastrointestinal bleeding and secondary iron deficiency anemia.The syndrome may also present with severe complications such as rupture,intestinal torsion,and intussusception,and can even cause death.Cutaneous malformations are usually asymptomatic and do not require treatment.The treatment of gastrointestinal lesions is determined by the extent of intestinal involvement and severity of the disease.Most patients respond to supportive therapy,such as iron supplementation and blood transfusion.For more significant hemorrhages or severe complications,surgical resection,endoscopic sclerosis,and laser photocoagulation have been proposed.Here we present a case of BRBNS in a 45-year-old woman involving 16sites including the scalp,eyelid,orbit,lip,tongue,face,back,upper and lower limbs,buttocks,root of neck,clavicle area,superior mediastinum,glottis,esophagus,colon,and anus,with secondary severe anemia.In addition,we summarize the epidemiology,clinical manifestations,diagnosis,differential diagnosis and therapies of this disease by analyzing all previously reported cases to enhance the awareness of this syndrome.

High expression of anti-apoptotic protein Bcl-2 is a good prognostic factor in colorectal cancer: Result of a metaanalysis

AIM To systematically evaluate the prognostic-predictive capability of Bcl-2 in colorectal cancer(CRC).METHODS A systematic literature search was conducted using Pub Med,Web of Science and EMBASE databases. Any eligible study must meet the following criteria:(1) bcl-2 expression was evaluated in human CRC tissues by immunohistochemistry;(2) assessment of the relationships between bcl-2 expression and overall survival(OS),disease free survival(DFS),recurrent free survival(RFS) or clinic-pathological characteristics of CRC was included;(3) sufficient information was provided to estimate the hazard ratio(HR) or odds ratio and their 95% confidence intervals(CIs); and(4) the study was published in English. The impact of Bcl-2 expression on survival of CRC patients were evaluated through this meta-analysis.RESULTS A total of 40 eligible articles involving 7658 patients were enrolled in our final analysis. We drew the conclusion that Bcl-2 high expression was significantly correlated with favorable OS(pooled HR = 0.69,95%CI: 0.55-0.87,P = 0.002) and better DFS/RFS(pooled HR = 0.65,95%CI: 0.50-0.85,P = 0.001). Additionally,the subgroup analysis suggested that Bcl-2 overexpression was significantly associated withprognosis(OS) especially in patients came from Europe and America but not Asian and patients who did not receive any adjuvant therapy before surgery. Finally,our present results indicated that expression of bcl-2 protein was associated with high differentiation grade and A/B Ducks' stage. CONCLUSION Bcl-2 high expression was significantly correlated with favorable OS and better DFS/RFS. Hence,we propose that Bcl-2 may be a valuable prognostic-predictive marker in CRC.

Exploring the mechanism of action of Danggui Shaoyao San in the treatment of polycystic ovary syndrome based on integrated pharmacology and molecular docking

Background:We used integrated pharmacology and molecular docking to investigate the mechanism of action of Danggui Shaoyao San(DSS)in the treatment of polycystic ovary syndrome(PCOS),and to provide a basis for subsequent systematic studies.Methods:The Integrative Pharmacology-based Research Platform of Traditional Chinese Medicine(TCMIP)V2.0 was used for target prediction of the drugs within DSS.Relevant targets for PCOS were retrieved in the human gene database(GeneCards)and imported within TCMIP V2.0.Relying on the“Chinese medicine association network mining”module in the TCMIP V2.0 platform,the“drug target-disease target”interaction network is constructed.We continue to enrich and analyze the potential targets of the above drugs for disease intervention through the TCMIP V2.0 platform,draw a multidimensional network map of“Chinese herbal medicine–chemical composition–disease–potential target–pathway”and validate the intersection of chemical composition and drug with disease by molecular docking.Results:There are 88 potential targets and 28 potential core targets among the action targets of DSS and PCOS.Combined with protein-protein interaction network analysis,the potential core targets of disease and drug intersection are estrogen receptor 1 androgen receptor.The binding energies obtained by molecular docking were all≤-5.0 kJ/moL,indicating that the potentially active chemical components have good binding activity to the intersection targets.Conclusion:DSS has the potential to be a multi-target and multi-pathway treatment for PCOS.

Molecular mechanism of Herba Eupatorii in treating COVID-19 based on network pharmacology and molecular docking

Objective:To explore the therapeutic target and molecular mechanism of Herba Eupatorii in the intervention of COVID-19(coronavirus disease 2019)by network pharmacology.Methods:TCMSP(Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform)and TCMIP V2.0(Integrative Pharmacology-based Research Platform of Traditional Chinese Medicine)databases were used to search the active ingredients and corresponding drug targets of Herba Eupatorii.Related targets of COVID-19 were searched in Genecards,pharmGKB,CTD,Drugbank and TTD databases.After the intersection targets were selected using VENNY 2.1 online platform,the PPI(protein-protein interaction)network was downloaded into STRING database,and the data were analyzed and sorted out using Cytoscape software to obtain the potential key targets for the treatment of COVID-19 by Herba Eupatorii.At the same time,using the data of active ingredients and intersection targets,a network of"TCM-active ingredients-key targets"was constructed in Cytoscape software to screen out chemical molecules with potential therapeutic effects.GO(Gene Ontology)functional enrichment analysis and KEGG(Kyoto Encyclopedia of Genes)pathway enrichment analysis of key target proteins were performed by R software.AutoDock Vina program was used for molecular docking of the top 5 active ingredients and key targets to calculate the minimum binding energy.Results:There were 26 active ingredients,160 targets,and 1969 pathogenic genes of COVID-19,among which 59 genes were intersection targets of drugs and diseases.After PPI network screening,the key target proteins were AKT1(RAC-alpha serine/threonine-protein kinase),JUN(transcription factor AP-1),TP53(cellular tumor antigen p53),ACTB(actin beta)and EGFR(epidermal growth factor receptor).Through the network of"TCM-Active Ingredients-Key Targets",Luteolin,Eupatolin,Stigmasterol,Eupatoriopicrin and Dammaradienyl acetate were identified as the active ingredients with potential therapeutic effects in the treatment of COVID-19.After R software was used for GO enrichment analysis,1978 GO items were obtained(P<0.05),including 1870 BP items,26 CC items and 82 MF items.149 pathways were obtained by KEGG enrichment analysis(P<0.05).It mainly involves IL-17(interleukin-17)signaling pathway,TNF(tumor necrosis factor)signaling pathway,C-type lectin receptor signaling pathway,PI3K-Akt(phosphatidylinositol 3 kinase-protein kinase B)signaling pathway,and T Cell receptor signaling pathway,etc.The molecular docking results showed that the active ingredients had good binding activity with key targets.Conclusion:Through the potential chemical constituents of Luteolin,Eupatolin,Stigmasterol,Eupatoriopicrin and Dammaradienyl acetate,Herba Eupatorii may act on AKT1,JUN,TP53,ACTB,EGFR and other targets.Involvement in IL-17 signaling pathway,TNF signaling pathway,C-Type Lectin receptor signaling pathway,PI3K-Akt signaling pathway,T Cell receptor signaling pathway and other pathways play an anti-inflammatory and antiviral roles in intervening in the occurrence and development of COVID-19.

Research progress of heat-clearing and dampness-removing method to improve the inflammatory microenvironment of gout

Gout is a metabolic bone and joint disease caused by purine metabolism disorder.The disturbance of inflammatory microenvironment caused by monosodium urate(MSU)deposition is an important pathological mechanism of gout occurrence and development.In the understanding of Traditional Chinese medicine(TCM),the interaction of"dampness","heat"and"stasis"is the main pathogenesis of gout,and the method of clearing heat and removing dampness is the main treatment method of TCM for gout.In recent years,studies have found that heat-clearing and dampness-removing method can improve the TCM symptom score of gout patients,especially in the body tiredness,dry mouth and dry throat,short yellow urine,thirsty,etc.,which are the characteristics of dampness and heat syndrome,this may be related to the fact that the TCM heat-clearing and dampness-removing method in the treatment of gout removes the appearance of dampness and heat,improves the inflammatory microenvironment of gout and restores the normal metabolic function of human body.This paper deeply explores the specific mechanism of TCM heat-clearing and dampness-removing method to improve the inflammatory microenvironment of gout,which can provide new ideas for the diagnosis and treatment of clinical gout.

Research progress on regulation of immune microenvironment of breast cancer by Traditional Chinese medicine

Breast cancer is the most common malignant tumor in women,and the current treatment mainly includes surgery,radiotherapy and chemotherapy.With the development of cell biology,molecular biology and immunology,breast cancer has entered the era of immunotherapy.Through multi-level and multi-way regulation of relevant genes and proteins,TCM regulates the immune microenvironment,and has great advantages in inhibiting tumor progression,alleviating surgical complications,improving immune system function,alleviating the damage to the body caused by surgery,radiotherapy and chemotherapy,and reducing the recurrence rate etc,provides ideas for the comprehensive treatment of breast cancer.This paper discusses the understanding of breast cancer in Traditional Chinese medicine,the influence of immune microenvironment on the occurrence and development of breast cancer,and the regulation of immune microenvironment in breast cancer by traditional Chinese medicine,in order to provide theoretical basis for the diagnosis and treatment of breast cancer with traditional Chinese medicine.

Coronavirus Disease 2019(COVID-19)vaccines and menstrual cycle length

People all across the world are getting vaccinated against the virus as Coronavirus Disease 2019(COVID-19)spreads.The possibility of adverse reactions to COVID-19 vaccinations has always been a source of concern[1-4].It is also unclear whether COVID-19 immunizations impact female vaccinators’menstrual cycles.Unfortunately,menstrual cycle outcomes were not collected in clinical studies of the current COVID-19 vaccines[1-4].The menstrual cycle of a woman runs from the first day of her menstruation to the first day of her next cycle.Many factors,including nutrition,sleep,and exercise,as well as illness,travel,and stress,are known to influence the length of the menstrual cycle[5].COVID-19 vaccines have caused a variety of side effects in people,including pain at the injection site,nausea,aches,fever,and fatigue.

Tetrandrine citrate eliminates imatinib-resistant chronic myeloid leukemia cells in vitro and in vivo by inhibiting Bcr-Abl/β-catenin axis

Objective:To evaluate the effects of tetrandrine citrate, a novel tetrandrine salt with high water solubility, on the growth of imatinib (IM)-resistant chronic myeloid leukemia (CML) in vitro and in vivo, and reveal action molecular mechanisms. Methods:Cell viability in vitro was measured using methyl thiazolyl tetrazolium (MTT) assay. CML cell growth in vivo was assessed using a xenograft model in nude mice. Bcr-Abl and β-catenin protein levels were determined using Western blotting. Bcr-Abl messenger RNA (mRNA) was measured by reverse transcription polymerase chain reaction (RT-PCR). Flow cytometry (FCM) was used to determine cell cycle status. Results:Tetrandrine citrate inhibited the growth of IM-resistant K562 cells, primary leukemia cells, and primitive CD34 + leukemia cells, and their inhibition concentration that inhibited 50% of target cells (IC 50 ) ranged from 1.20 to 2.97 μg/ml. In contrast, tetrandrine citrate did not affect normal blood cells under the same conditions, and IC 50 values were about 10.12-13.11 μg/ml. Oral administration of tetrandrine citrate caused complete regression of IM-resistant K562 xeno-grafts in nude mice without overt toxicity. Western blot results revealed that treatment of IM-resistant K562 cells with tetrandrine citrate resulted in a significant decrease of both p210 Bcr-Abl and β-catenin proteins, but IM did not affect the Bcr-Abl protein levels. Proteasome inhibitor, MG132, did not prevent tetrandrine-mediated decrease of the p210 Bcr-Abl protein. RT-PCR results showed that tetrandrine treatment caused a decrease of Bcr-Abl mRNA. FCM analysis indicated that tetrandrine induced gap 1 (G 1 ) arrest in CML cells. Conclusions:Tetrandrine citrate is a novel orally active tetrandrine salt with potent anti-tumor activity against IM-resistant K562 cells and CML cells. Tetrandrine citrate-induced growth inhibition of leukemia cells may be involved in the depletion of p210 Bcr-Abl mRNA and β-catenin protein.

XELOX doublet regimen versus EOX triplet regimen as first-line treatment for advanced gastric cancer:An open-labeled,multicenter,randomized,prospective phase III trial(EXELOX)

Background:There is no consensus on whether triplet regimen is better than doublet regimen in the first-line treatment of advanced gastric cancer(AGC).We aimed to compare the efficacy and safety of oxaliplatin plus capecitabine(XELOX)and epirubicin,oxaliplatin,plus capecitabine(EOX)regimens in treating AGC.Methods:This phase III trial enrolled previously untreated patients with AGC whowere randomly assigned to receive the XELOXor EOXregimen.The primary endpoint was non-inferiority in progression-free survival(PFS)for XELOX as compared with EOX on an intention-to-treat basis.Results:Between April 10,2015 andAugust 20,2020,448AGCpatientswere randomized to receive XELOX(n=222)or EOX(n=226).The median PFS(mPFS)was 5.0 months(95%confidence interval[CI]=4.5-6.0 months)in the XELOX arm and 5.5 months(95%CI=5.0-6.0 months)in the EOX arm(hazard ratio[HR]=0.989,95%CI=0.812-1.203;P_(non-inferiority)=0.003).There was no significant difference inmedian overall survival(mOS)(12.0 vs.12.0months,P=0.384)or objective response rate(37.4%vs.45.1%,P=0.291)between the two groups.In patients with poorly differentiated adenocarcinoma and liver metastasis,the EOX arm had a significantly longer mOS(P=0.021)and a trend of longer mPFS(P=0.073)than the XELOX arm.The rate of grade 3/4 adverse events(AEs)was 42.2%(90/213)in the XELOX arm and 72.5%(156/215)in the EOX arm(P=0.001).The global health-related quality of life(QoL)score was significantly higher in the XELOX arm than in the EOX arm during chemotherapy.Conclusions:This non-inferiority trial demonstrated that the doublet regimen was as effective as the triplet regimen and had a better safety profile and QoL as a first-line treatment for AGC patients.However,the triplet regimen might have a survival advantage in patients with poorly differentiated adenocarcinoma and liver metastasis.

Over-expression of the AtGA2ox8 gene decreases the biomass accumulation and lignification in rapeseed (Brassica napus L.)

Gibberellin 2-oxidase (GA 2-oxidase) plays very important roles in plant growth and development. In this study, the AtGA2ox8 gene, derived from Arabidopsis (Arabidopsis thaliana), was transformed and over-expressed in rapeseed (Brassica napus L.) to assess the role of AtGA2ox8 in biomass accumulation and lignification in plants. The transgenic plants, identified by resistant selection, polymerase chain reaction (PCR) and reverse-transcription PCR (RT-PCR) analyses, and green fluorescence examination, showed growth retardation, flowering delay, and dwarf stature. The fresh weight and dry weight in transgenic lines were about 21% and 29% lower than those in wild type (WT), respectively, and the fresh to dry weight ratios were higher than that of WT. Quantitative measurements demonstrated that the lignin content in transgenic lines decreased by 10%-20%, and histochemical staining results also showed reduced lignification in transgenic lines. Quantitative real-time PCR analysis indicated that the transcript levels of lignin biosynthetic genes in transgenic lines were markedly decreased and were consistent with the reduced lignification. These results suggest that the reduced biomass accumulation and lignification in the AtGA2ox8 over-expression rapeseed might be due to altered lignin biosynthetic gene expression.

Berbamine inhibits proliferation and induces apoptosis of KU812 cells by increasing Smad3 activity

Objective: The cytotoxic effect of berbamine on chronic myeloid leukemia (CML) cell line KU812 was evaluated,and the mechanisms of its action were explored.Methods: The effect of berbamine on the KU812 cell growth was determined by methyl thiazolyl tetrazolium (MTT) assay.Flow cytometry was used to profile cell cycle alteration upon berbamine treatment.Reverse transcription polymerase chain reaction (RT-PCR) was carried out to determine the transcripts of transforming growth factor-β (TGF-β) receptors (TβRs),Smad3,c-Myc,cyclin D1,p21Cip1(p21),and p27Kip1(p27).Changes in the protein levels of total Smad3,phosphorylated Smad3,the downstream targets of Smad3,and specific apoptosis-related factors were evaluated by Western blotting.Results: Berbamine inhibited KU812 cell proliferation in a doseand time-dependent manner,and the half maximal inhibitory concentration (IC50) values for treatments of 24,48,and 72 h were 5.83,3.43,and 0.75 μg/ml,respectively.Berbamine induced G1 arrest as well as apoptosis in KU812 cells.Transcriptions of Smad3 and p21 were up-regulated,while those of TβRI,TβRII,c-Myc,cyclin D1 and p27 were not changed significantly.The protein levels of both total Smad3 and phosphorylated Smad3 were both up-regulated after berbamine treatment,together with decreased c-Myc and cyclin D1 and increased p21.Meanwhile,the levels of the anti-apoptotic proteins,such as Bcl-2 and Bcl-xL,were decreased,whereas pro-apoptotic Bax was increased.Conclusions: Berbamine suppresses KU812 cell proliferation through induction of cell cycle arrest in G1 and apoptosis.It activates Smad3 without additional stimulation of TGF-β,and alters the levels of the Smad3 downstream targets,including c-Myc,cyclin D1 and p21.Our findings suggest that berbamine is a promising drug in the treatment of advanced stage patients with CML.

Light Regulation of Gibberellins Metabolism in Seedling Development

Light affects many aspects of plant development, including seed germination, stem elongation, and floral initiation. How photoreceptors control photomorphogenic processes is not yet fully understood. Because phytohormones are chemical regulators of plant development, it may not be surprising that light affects, directly or indirectly, cellular levels and signaling processes of various phytohormones, such as auxin, gibberellins （GA）, cytokinin, ethylene, abscisic acid （ABA）, and brassinosteroids （BR）. Among those phytohormones, light regulation of GA metabolism has probably attracted more attention among photoblologists and it is arguably the most extensively studied plant hormone at present with respect to its role in photomorphogenesis. It has become Increasingly clear that phytochromes and cryptochromes are the major photoreceptors mediating light regulation of GA homeostasis. This short article attempts to examine some recent developments in our understanding of how light and photoreceptors regulate GA blosynthesis and catabolism during seedling development. It is not our intention to carry out a comprehensive review of the field, and readers are referred to recent review articles for a more complete view of this area of study （Kamiya and Garcia-Martinez 1999; Hedden and Phillips 2000; Garcla-Martinez and GI12001; Olszewski et al. 2002; Halliday and Fankhauser 2003; Sun and Gubler 2004）.

Blue-Light-Independent Activity of Arabidopsis Cryptochromes in the Regulation of Steady-State Levels of Protein and mRNA Expression

Cryptochromes are blue-light receptors that mediate blue-light inhibition of hypocotyl elongation and bluelight stimulation of floral initiation in Arabidopsis. In addition to their blue-light-dependent functions, cryptochromes are also involved in blue-light-independent regulation of the circadian clock, cotyledon unfolding, and hypocotyl inhibition. However, the molecular mechanism associated with the blue-light-independent function of cryptochromes remains unclear. We reported here a comparative proteomics study of the light regulation of protein expression. We showed that, as expected, the protein expression of many metabolic enzymes changed in response to both blue light and red light. Surprisingly, some light-regulated protein expression changes are impaired in the cry1cry2 mutant in both blue light and red light. This result suggests that, in addition to mediating blue-light-dependent regulation of protein expression, cryptochromes are also involved in the blue-light-independent regulation of gene expression. Consistent with this hypothesis, the cry1cry2 mutant exhibited reduced changes of mRNA expression in response to not only blue light, but also red light, although the cryptochrome effects on the red-light-dependent gene expression changes are generally less pronounced. These results support a hypothesis that, in addition to their blue-light-specific functions, cryptochromes also play roles in the control of gene expression mediated by the red/far-red-light receptor phytochromes.

Authors' response

For the Letter to the Editor "Emerging role of berbamine as an anti-cancer agent in systemic malignancies besides chronic myeloid leukemia",we are pleased with the interest in our article (Liang et al.,2011),and appreciate the insightful comments made by Dr.Kapoor (2012).He systemically reviewed application of berbamine as an anti-cancer agent during the past few years and found that berbamine also shows anti-cancer activity for other systemic malignancies besides chronic myeloid leukemia.Extensive scrutiny of its molecular targets and mechanism of action in the past few decades has provided important insights.