Liposome-mediated Functional Expression of Multiple Drug Resistance Gene in Human Bone Marrow CD34^+ Cells

Summary: The expression and functional activity of multiple drug resistance (MDR1) gene in human normal bone marrow CD34+ cells was observed. Human normal bone marrow CD34+ cells were enriched with magnetic cell sorting (MACS) system, and then liposome-mediated MDR1 gene was transferred into bone marrow CD34+ cells. Fluorescence-activated cell sorter was used to evaluate the expression and functional activity of P-glycoprotein (P-gp) encoded by MDR1 gene. It was found that the purity of bone marrow CD34+ cells was approximately (91±4.56) % and recovery rate was (72.3±2.36) % by MACS. The expression of P-gp in the transfected CD34+cells was obviously higher than that in non-transfected CD34+ cells. The amount of P-gp in non-transfected CD34+ cells was (11.2±2.2) %, but increased to (23.6±2.34) % 48 h after gene transfection (P<0.0l). The amount of P-gp was gradually decreased to the basic level one week later. The accumulation and extrusion assays showed that the overexpression of P-gp could efflux Rh-123 out of cells and there was low fluorescence within the transfected cells. The functional activity of P-gp could be inhibited by 10 μg/ml verapamil. It was suggested that the transient and highly effective expression and functional activity of P-gp could be obtained by liposome-mediated MRD1 transferring into human normal bone marrow CD34+ cells.

Suppression of P-gp induced multiple drug resistance in a drug resistant gastric cancer cell line by overexpression of Fas

AIM To observe the drug sensitizing effect andrelated mechanisms of fas gene transduction onhuman drug-resistant gastric cancer cellSGC7901/VCR(resistant to Vincristine).METHODS The cell cycle alteration wasobserved by FACS.The sensitivity of gastriccancer cells to apoptosis was determined by invitro apoptosis assay.The drug sensitization ofcells to several anti-tumor drugs was observedby MTT assay.Immunochemical method wasused to show expression of P-gp and Topo Ⅱ ingastric cancer cells.RESULTS Comparing to SGC7901 and pBK-SGC7901/VCR,fas-SGC7901/VCR showeddecreasing G2 cells and increasing S cells,theG2 phase fraction of pBK-SGC7901/VCR wasabout 3.0 times that of fas-SGC7901/VCR,but Sphase fraction of fas-SGC7901/VCR was about1.9 times that of pBK-SGC7901/VCR,indicatingS phase arrest of fas-SGC7901/VCR.FACS alsosuggested apoptosis of fas-SGC7901/VCR,fas-SGC7901/VCR was more sensitive to apoptosisinducing agent VM-26 than pBK-SGC7901/VCR.MTT assay showed increased sensitization offas-SGC7901/VCR to DDP,MMC and 5-FU,butsame sensitization to VCR according to pBK-SGC7901/VCR.SGC7901,pBK-SGC7901/ VCRand fas-SGC7901/VCR had positively stainedTopo Ⅱ equally.P-gp staining in pBK- SGC7901/VCR was stronger than in SG07901,but there was little staining of P-gp in fas.SGC7901/VCR.CONCLUSION fas gene transduction couldreverse the MDR of human drug-resistant gastriccancer cell SGC7901/VCR to a degree,possiblybecause of higher sensitization to apoptosis anddecreased expression of P-gp.

Novel mechanism of drug resistance to proteasome inhibitors in multiple myeloma

Multiple myeloma(MM) is a cancer caused by uncontrolled proliferation of antibody-secreting plasma cells in bone marrow, which represents the second most common hematological malignancy. MM is a highly heterogeneous disease and can be classified into a spectrum of subgroups based on their molecular and cytogenetic abnormalities. In the past decade, novel therapies, especially, the first-in-class proteasome inhibitor bortezomib, have been revolutionary for the treatment of MM patients. Despite these remarkable achievements, myeloma remains incurable with a high frequency of patients suffering from a relapse, due to drug resistance. Mutation in the proteasome β5-subunit(PSMB5) was found in a bortezomib-resistant cell line generated via long-term coculture with increasing concentrations of bortezomib in 2008, but their actual implication in drug resistance in the clinic has not been reported until recently. A recent study discovered four resistance-inducing PSMB5 mutations from a relapsed MM patient receiving prolonged bortezomib treatment. Analysis of the dynamic clonal evolution revealed that two subclones existed at the onset of disease, while the other two subclones were induced. Protein structural modeling and functional assays demonstrated that all four mutations impaired the binding of bortezomib to the 20 S proteasome, conferring different degrees of resistance. The authors further demonstrated two potential approaches to overcome drug resistance by using combination therapy for targeting proteolysis machinery independent of the 20 S proteasome.

Identification of TNFRSF1A as a novel regulator of carfilzomib resistance in multiple myeloma

Multiple myeloma(MM)is a hematological tumor with high mortality and recurrence rate.Carfilzomib is a new-generation proteasome inhibitor that is used as the first-line therapy for MM.However,the development of drug resistance is a pervasive obstacle to treating MM.Therefore,elucidating the drug resistance mechanisms is conducive to the formulation of novel therapeutic therapies.To elucidate the mechanisms of carfilzomib resistance,we retrieved the GSE78069 microarray dataset containing carfilzomib-resistant LP-1 MM cells and parental MM cells.Differential gene expression analyses revealed major alterations in the major histocompatibility complex(MHC)and cell adhesion molecules.The upregulation of the tumor necrosis factor(TNF)receptor superfamily member 1A(TNFRSF1A)gene was accompanied by the downregulation of MHC genes and cell adhesion molecules.Furthermore,to investigate the roles of these genes,we established a carfilzomib-resistant cell model and observed that carfilzomib resistance induced TNFRSF1A overexpression and TNFRSF1A silencing reversed carfilzomib resistance and reactivated the expression of cell adhesion molecules.Furthermore,TNFRSF1A silencing suppressed the tumorigenesis of MM cells in immunocompetent mice,indicating that TNFRSF1A may lead to carfilzomib resistance by dampening antitumor immunity.Furthermore,our results indicated that TNFRSF1A overexpression conferred carfilzomib resistance in MM cells and suppressed the expression of MHC genes and cell adhesion molecules.The suppression of MHC genes and cell adhesion molecules may impair the interaction between immune cells and cancer cells to impair antitumor immunity.Future studies are warranted to further investigate the signaling pathway underlying the regulatory role of TNFRSF1A in MM cells.

Enhanced anticancer effect of doxorubicin by TPGS-coated liposomes with Bcl-2 siRNA-corona for dual suppression of drug resistance

Multiple drug resistance(MDR)is a tough problem in developing hepatocellular carcinoma(HCC)therapy.Here,we developed TPGS-coated cationic liposomes with Bcl-2 siRNA corona to load doxorubicin(Dox)i.e.,Bcl-2 siRNA/Dox-TPGS-LPs,to enhance anticancer effect of Dox in HCC-MDR.TPGS i.e.,d-α-tocopheryl polyethylene glycol 1000 succinate,inhibited Pglycoprotein(P-gp)efflux pump and Bcl-2 siRNA suppressed anti-apoptotic Bcl-2 protein.The Bcl-2 siRNA loaded in the liposomal corona was observed under transmission electron microscopy.The stability and hemolysis evaluation demonstrated Bcl-2 siRNA/Dox-TPGSLPs had good biocompatibility and siRNA-corona could protect the liposomal core to avoid the attachment of fetal bovine serum.In drug-resistant cells,TPGS effectively prolonged intracellular Dox retention time and siRNA-corona did improve the internalization of Dox from liposomes.In vitro and in vivo anticancer effect of this dual-functional nanostructure was examined in HCC-MDR Bel7402/5-FU tumor model.MTT assay confirmed the IC50 value of Dox was 20–50 fold higher in Bel7402/5-FU MDR cells than that in sensitive Bel7402 cells.Bcl-2 siRNA corona successfully entered the cytosol of Bel7402/5-FU MDR cells to downregulate Bcl-2 protein levels in vitro and in vivo.Bcl-2 siRNA/Dox-TPGS-LPs showed superior to TPGS-(or siRNA-)linked Dox liposomes in cell apoptosis and cytotoxicity assay in Bel7402/5-FU MDR cells,and 7-fold greater effect than free Dox in tumor growth inhibition of Bel7402/5-FU xenograft nude mice.In conclusion,TPGS-coated cationic liposomes with Bcl-2 siRNA corona had the capacity to inhibit MDR dual-pathways and subsequently improved the anti-tumor activity of the chemotherapeutic agent co-delivered to a level that cannot be achieved by inhibiting a MDR single way.

Correlation between Cyclin A Gene Expression in Adult Patients with Acute Leukemia and Drug Resistance

In order to investigate the relationship between the expression of cyclin A and drug resistance in adult patients with acute leukemia (AL), the mRNA expression of cyclin A, mdr1, TopⅡ α , bcl-2 was detected in 64 adult patients with AL and 20 normal controls by semi-reverse transcription polymerse chain reaction (semi-RT-PCR). It was found that the cyclin A and TopⅡ α mRNA expression levels in drug resistant group were significantly lower than in sensitive group ( P <0.01). Under the same experimental condition no cyclin A mRNA expression was detectable in all normal controls. The mdr1 and bcl-2 mRNA expression levels in resistant group were significantly higher than in sensitive group ( P <0.01). cyclin A and TopⅡ α gene expression levels were closely correlated ( r s =+0.794, P=0.000, n =64) in all AL patients, but cyclin A was not correlated with mdr1 and bcl-2 gene expression levels. In drug resistant group there was a negative correlation between the gene expression levels of cyclin A and mdr1 ( r s =-0.337, P=0.029 ). The 10 AL patients with positive lower expression of both cyclin A and TopⅡ α were all resistant to drugs. Logistic regression of Binary analysis showed the correlation between the lower expression of cyclin A and drug resistance. It was concluded that lower expression of cyclin A gene might be an unfavorable prognostic factor for patients with AL, and detection of both cyclin A and TopⅡ α gene expression would predict drug resistance in AL patients.

Mechanism of drug resistance and reversal with ligustra-zine and cyclosporin A in cisplatin--inducedhuman epithelial ovarian cancer resistant cell line 3Ao/cDDP

Objective: To investigate the mechanism of resistance and reversal effect of ligustrazine and cyclosporin A in cisplatin--induced multidrug resistance ovarian cancer cell line 3Ao/cDDP. Methods: Using the corresponding dose calculated from clinical chemotherapy at 30 mg cisplatin per cycle, we established 3Ao/cDDP with 3Ao exposed at regular intervals and repeatedly to high-level concentration of cisplatin at 10 mg/ml for 24 hours each time. Expressions of LRP, MRP, P-gp, GSTp and TopoII were quantitatively detected with FCM. For drug resistance reversal, cyclosporin A and ligustrazine were administered singly or in combination at the maximal dose without cytotoxicity. Inhibition rates were determined by MTT assay. Results: 3Ao/cDDP was established after 4.5 months, with resistance factor 1.6 which was similar to clinical resistance degree. Low expression levels of MRP and P-gp were found in both 3Ao and 3Ao/cDDP (P>0.05), and LRP and GSTp expression levels in 3Ao/cDDP were significantly higher than those in 3Ao (P<0.005 and P<0.05, respectively), and TopoII in 3Ao/cDDP was significantly lower vs 3Ao (P<0.05). The inhibition rate of cDDP was 20.807±0.015%, cDDP plus ligustrazine 27.421±0.07% (P>0.05 vs cDDP), cDDP plus cyclosporin A 49.635±0.021% (P<0.01 vs cDDP), and cDDP plus ligustrazine and cyclosporin A 58.861±0.014% (P<0.01 vs cDDP). Conclusions: 3Ao/cDDP, induced by cisplatin and established by imitating the characteristics of clinical chemotherapy for epithelial ovarian cancer, was an ideal model for investigation of cisplatin resistance in vitro. Cisplatin resistance in 3Ao/cDDP could be accounted for by higher LRP, GSTp and lower TopoII expression and was not associated with MRP or P-gp. Ligustrazine had no significant reversal effect on cisplatin resistance, but cyclosporin A could reverse the resistance effectively.

Antibacterial effect of Allium sativum cloves and Zingiber officinale rhizomes against multiple-drug resistant clinical pathogens

Objective:To evaluate the antibacterial properties ot Allium sativum(garlic) cloves and Zingiber officinale(ginger) rhizomes against multi-drug resistant clinical pathogens causing nosocomial infection.Methods:The cloves of garlic and rhizomes of ginger were extracted with 95%(v/v) ethanol.The ethanolic extracts were subjected to antibacterial sensitivity test against clinical pathogens.Results:Anti-bacterial potentials of the extracts of two crude garlic cloves and ginger rhizomes were tested against five gram negative and two gram positive multi-drug resistant bacteria isolates.All the bacterial isolates were susceptible to crude extracts of both plants extracts.Except Enterobacter sp.and Klebsiella sp.,all other isolates were susceptible when subjected to ethanolic extracts of garlic and ginger.The highest inhibition zone was observed with garlic(19.4S mm) against Pseudomonas aeruginosa(P.aeruginosa).The minimal inhibitory concentration was as low as 67.00 μg/mL against P.aeruginosa.Conclusions:Natural spices of garlic and ginger possess effective anti-bacterial activity against multi-drug clinical pathogens and can be used for prevention of drug resistant microbial diseases and further evaluation is necessary.

Overcoming drug resistance by targeting protein homeostasis in multiple myeloma

Multiple myeloma(MM)is a plasma cell disorder typically characterized by abundant synthesis of clonal immunoglobulin or free light chains.Although incurable,a deeper understanding of MM pathobiology has fueled major therapeutical advances over the past two decades,significantly improving patient outcomes.Proteasome inhibitors,immunomodulatory drugs,and monoclonal antibodies are among the most effective anti-MM drugs,targeting not only the cancerous cells,but also the bone marrow microenvironment.However,de novo resistance has been reported,and acquired resistance is inevitable for most patients over time,leading to relapsed/refractory disease and poor outcomes.Sustained protein synthesis coupled with impaired/insufficient proteolytic mechanisms makes MM cells exquisitely sensitive to perturbations in protein homeostasis,offering us the opportunity to target this intrinsic vulnerability for therapeutic purposes.This review highlights the scientific rationale for the clinical use of FDA-approved and investigational agents targeting protein homeostasis in MM.

Prediction of multiple drug resistance phenotype in cancer cell lines using gene expression profiles and phylogenetic trees

When microarray gene expression data are used to predict multiple drug resistance(MDR)phenotypes for anticancer drugs,the normalization strategy and the quality of the selected signature genes are usually the main causes of inconsistency among different experiments.A stable statistical drug response prediction model is urgently required in oncology.In this study,the microarray gene expression data of multiple cancer cell lines with MDR was analyzed.For each probe-set,the expression value was defined as present/absent(1/0)and was classified into a gene set defined with protein domain organization(PDO).After employing the gene content method of phylogenetic analysis,a phylogenetic model(cell tree)for MDR phenotype prediction was built at the PDO gene set level.The results indicate that classification of cancer cell lines is predominantly affected by both the histopa-thological features and the MDR phenotype(paclitaxel and vinblastine).When applying this model to predict the MDR phenotype of independent samples,the phylogenetic model performs better than signature gene models.Although the utility of our procedure is limited due to sample heterogeneity,it still has potential application in MDR research,especially for hematological tumors or established cell lines.

The Role of 1q21 Gain on the Prognosis of Multiple Myeloma

Multiple myeloma(MM)is a clonal expansion of malignant plasma cells,and comprises approximately 10%of hematologic malignancies.Although various therapeutic agents and strategies,such as immunomodulatory agents,proteasome inhibitors,monoclonal antibodies and hematopoietic stem cell transplantation(HSCT)have been evaluated,MM remains largely incurable.It is therefore important to further explore the risk factors for disease progression,and to design trials aimed at improving the patient outcomes.Previous studies have considered the presence of a gain in 1q21 as a risk factor for a poorer overall survival.Gain of 1q21 is one of the most common chromosomal aberrations in MM,being detected by fluorescence in situ hybridization in 36%to 47%of newly-diagnosed patients,as well as 52%and 62%patients with relapsed MM.Although a series of reports identified 1q21 gain in MM as a significant and independent poor prognostic factor,other studies failed to demonstrate any prognostic value.Thus,the prognostic value of 1q21 gain in MM remains controversial.We reviewed the current knowledge about 1q21 gain and its value for the clinical management of MM.

Reversing drug resistance in the ovarian carcinoma cell line SKOV3/mdr1 in vitro by antisense oligodeoxynucleotides

Objective To investigate the effect of multidrug resistance gene 1 (mdr1) antisense oligodeoxynucleotides (ODNs) on reversing multidrug resistance in the drug resistant ovarian carcinoma cell line SKOV3/mdr1. Methods The ovarian carcinoma cell line SKOV3 transducted with a human multidrug resistance gene (mdr1) served as the drug resistant model (SKOV3/mdr1). The mdr1 antisense ODNs was transfected into SKOV3/mdr1 cells while mediated by lipofectamine. Reverse transcription-polymerase chain reaction (RT-PCR) was used to measure the expression and the amount of the mdr1 mRNA in the cells. The positive rate and function of the mdr1 gene product P-glycoprotein (Pgp) in the mdr1 antisense ODNs treated SKOV3/mdr1 cells were determined by flow cytometry and rhodamine 123 efflux. Drug resistance in the SKOV3/mdr1 cell line was observed by MTT assay and cell colony culture. Results The mdr1 mRNA level was decreased to about 60% of that of β-actin after mdr1 antisense ODNs treatment. The Pgp positive rate of mdr1 antisense ODNs treated SKOV3/mdr1 cells decreased from 100% to 52.6% (P<0.01). The intracellular rhodamine 123 retention was increased from 9.1% to 33.8% (P<0.01). The chemoresistance to taxol decreased to 58% of SKOV3/mdr1 with mdr1 antisense ODN treatment. Compared with SKOV3/mdr1 cells in the control group, under a certain range of drug concentrations, the number of drug resistance colonies in mdr1 antisense ODNs treated SKOV3/mdr1 cells for taxol and doxorubicin decreased by 8.6±0.8 fold and 3.1±0.6 fold, respectively. Some non-specific functions during oligodeoxyncleotide treatment was also detected. Conclusion mdr1 expression in the SKOV1/mdr1 cell line was partially inhibited after mdr1 antisense ODNs treatment at the mRNA and protein level, increasing the chemotherapy sensitivity of this drug resistant ovarian carcinoma cell line.

Drug resistance and minimal residual disease in multiple myeloma

Great progress has been made in improving survival in multiple myeloma(MM)patients over the last 30 years.New drugs have been introduced and complete responses are frequently seen.However,the majority of MM patients do experience a relapse at a variable time after treatment,and ultimately the disease becomes drug-resistant following therapies.Recently,minimal residual disease(MRD)detection has been introduced in clinical trials utilizing novel therapeutic agents to measure the depth of response.MRD can be considered as a surrogate for both progression-free and overall survival.In this perspective,the persistence of a residual therapy-resistant myeloma plasma cell clone can be associated with inferior survivals.The present review gives an overview of drug resistance in MM,i.e.,mutation ofβ5 subunit of the proteasome;upregulation of pumps of efflux;heat shock protein induction for proteasome inhibitors;downregulation of CRBN expression;deregulation of IRF4 expression;mutation of CRBN,IKZF1,and IKZF3 for immunomodulatory drugs and decreased target expression;complement protein increase;sBCMA increase;and BCMA down expression for monoclonal antibodies.Multicolor flow cytometry,or next-generation flow,and next-generation sequencing are currently the techniques available to measure MRD with sensitivity at 10-5.Sustained MRD negativity is related to prolonged survival,and it is evaluated in all recent clinical trials as a surrogate of drug efficacy.

Effects of multidrug resistance, antisense RNA on the chemosensitivity of hepatocellular carcinoma cells

BACKGROUND: Multidrug resistance is a major obstacle in cancer chemotherapy. We examined whether the antisense RNA of multidrug resistance gene 1 (mdr1) could reverse multidrug resistance in the human hepatocellular carcinoma (HCC) cell line SMMC7721/ADM. METHODS: The recombinant adenoviruses pAdEasy- GFP-ASmdr1 product was produced by the adenoviral vector AdEasy system, which can express antisense RNA against the mdr1 gene. Following that, the recombinant adenovirus was transfected into the P-glycoprotein- producing multidrug resistance cell line, SMMC7721/ADM human HCC cells resistant to adriamycin (ADM) and daunorubicin (DNR). In order to investigate the reversal of multidrug resistance phenotype, we measured the expression of mdr1 mRNA by RT-PCR and the production of P-glycoprotein by flow cytometry. The sensitivities for ADM and DNR SMMC7721/ADM cells were examined by [3-(4, 5-dimethylthi-azol-2-yl)-2,5 diphenyl-terazolium bromide] (MTT) analysis. RESULTS: The low-level expression of mdr1 mRNA and P-glycoprotein production were observed in parental sensitive cells SMMC/7721 in addition to the overexpressionof mdr1 mRNA and P-glycoprotein in SMMC7721/ADM cells. The transfection of antisense-RNA into SMMC7721/ ADM cells resulted in decreases of mdr1 mRNA and P-glycoprotein, but increase of drug sensitivities. The sensitivities of transfected SMMC7721/ADM cells to ADM and DNR in IC50 reduced by 31.25% and 62.96% respectively. CONCLUSIONS: Mdr1 antisense RNA can increase the sensitivities of SMMC7721/ADM cells to anticancer drug by decreasing the expression of the mdr1 gene and inhibiting P-glycoprotein expression. This strategy may be applicable to cancer patients with P-glycoportein mediated multidrug resistance.

Effects of Taxotere on invasive potential and multidrug resistance phenotype in pancreatic carcinoma cell line SUIT-2

INTRODUCTIONDevelopment of drug-resistance to chemotherapyand subsequent metastasis of tumor are primarilyresponsible for treatment failure and the death fromcancer. There have been many previous studies onthe relationship between expression of multidrugresistance (MDR) phenotype P-glycoprotein (P-gp)and the malignant properties of tumors, but theresults are often conflicting[1-8]. The difference intumor types or MDR phenotype induced by specificagents might account for this discrepancy. Taxotere(TXT), a member of the family of taxanes, hasantitumor activity through its effect of promotingthe polymerization of tubulin[9,10].

Comparison of extended spectrum β-lactamasesproducing Escherichia coli with non-ESBLsproducing E.coli:drug-resistance and virulence

The virulent factors of Escherichia coil （E.cofi） play an important role in the process of pathopoiesis. The study aimed to compare drug-resistant genes and virulence genes between extended spectrum β-1actamases （ESBLs）-producing E.coli and non-ESBLs-producing E.cofi to provide a reference for physicians in management of hospital infection. From October 2010 to August 2011,96 drug-resistant strains of E. coli isolated were collected from the specimens in Qingdao Municipal Hospital, Qingdao, China. These bacteria strains were divided into a ESBLs-producing group and a non-ESBLs-producing group. Drug sensitivity tests were performed using the Kirby-Bauer （K-B） method. Disinfectant gene, qacEAl-sull and 8 virulence genes （CNF2, hlyA, eaeA, VT1, est, bfpA, elt, and CNF1） were tested by polymerase chain reaction （PCR）. Among the 96 E.coli isolates, the ESBLs-producing E.coli comprised 46 （47.9%） strains and the non-ESBLs-producing E.cofi consisted of 50 （52.1%） strains. The detection rates of multiple drug-resistant strain, qacEAl-sull, CNF2, hlyA, eaeA,VT1, est, bfpA, elt, and CNF1 in 46 ESBLs-producing E.coli isolates were 89.1%, 76.1%, 6.5%, 69.6%, 69.6%, 89.1%, 10.9%, 26.1%, 8.7%, and 19.6%, respectively. In the non-ESBLs-producing E.cofi strains, the positive rates of multiple drug-resistant strain, qacEAl-sull, CNF2, hlyA, eaeA, VT1, est, bfpA, elt, and CNF1 were 62.0%, 80.0%, 16.0%, 28.0%, 64.0%, 38.0%, 6.0%, 34.0%, 10.0%, and 24.0%, respectively. The difference in the detection rates of multiple drug-resistant strain, hlyA and VT1 between the ESBLs-producing E.cofi strains and the non-ESBLs-producing E.cofi strains was statistically significant （P〈0.05）. The positive rate of multiple drug-resistant strains is higher in the ESBLs-producing strains than in the non-ESBLs-producing strains. The expression of some virulence genes hlyA and VT1 varies between the ESBLs-producing strains and the non-ESBLs-producing strains. Increased awareness of clinicians and enhanced testing by laboratories are required to reduce treatment failures and prevent the spread of multiple drug-resistant strains.

Autophagy-related mechanisms for treatment of multiple myeloma

Multiple myeloma(MM)is a type of hematological cancer that occurs when B cells become malignant.Various drugs such as proteasome inhibitors,immunomodulators,and compounds that cause DNA damage can be used in the treatment of MM.Autophagy,a type 2 cell death mechanism,plays a crucial role in determining the fate of B cells,either promoting their survival or inducing cell death.Therefore,autophagy can either facilitate the progression or hinder the treatment of MM disease.In this review,autophagy mechanisms that may be effective in MM cells were covered and evaluated within the contexts of unfolded protein response(UPR),bone marrow microenvironment(BMME),drug resistance,hypoxia,DNA repair and transcriptional regulation,and apoptosis.The genes that are effective in each mechanism and research efforts on this subject were discussed in detail.Signaling pathways targeted by new drugs to benefit from autophagy in MM disease were covered.The efficacy of drugs that regulate autophagy in MM was examined,and clinical trials on this subject were included.Consequently,among the autophagy mechanisms that are effective in MM,the most suitable ones to be used in the treatment were expressed.The importance of 3D models and microfluidic systems for the discovery of new drugs for autophagy and personalized treatment was emphasized.Ultimately,this review aims to provide a comprehensive overview of MM disease,encompassing autophagy mechanisms,drugs,clinical studies,and further studies.

2015—2022年天水市肺结核患者耐药情况及利福平耐药特征分析

目的:分析2015—2022年甘肃省天水市肺结核患者耐药情况及利福平耐药特征,为优化耐药结核病卫生政策提供科学依据。方法:采用回顾性研究方法,从“中国疾病预防控制信息系统”子系统“结核病管理信息系统”中收集2015—2022年天水市肺结核患者实验室检测结果、耐药筛查和耐药结核病诊断信息等资料,分析患者病原学阳性率、药物敏感性试验结果和耐药诊断时间等。结果:2015—2022年,天水市共登记活动性肺结核患者8458例,除外结核性胸膜炎的肺结核患者为7895例,病原学阳性率为28.32%(2236/7895),且从2015年的11.33%(177/1562)上升至2022年的61.30%(236/385),呈明显上升趋势(χ_(趋势)^(2)=1014.480,P=0.000);天水市应耐药筛查肺结核患者2360例,实际耐药筛查率为85.00%(2006/2360),从2015年的54.80%(97/177)上升至2022年的93.39%(240/257),呈明显上升趋势(χ_(趋势)^(2)=397.292,P=0.000);天水市耐药检出率为98.90%(1984/2006),利福平耐药检出率为15.73%(312/1984),从2015年的10.42%(10/96)上升至2017年的28.57%(62/217),再下降至2022年的11.34%(27/238),呈先上升后下降趋势(χ_(趋势)^(2)=27.248,P=0.000)。312例利福平耐药患者中,男性[198例(63.46%)]多于女性[114例(36.54%)];年龄相对集中在20~29岁[85例(27.24%)]和40~49岁[66例(21.15%)],且老年患者(60~83岁)比例从2016年的9.52%(2/21)上升至2022年的25.93%(7/27),呈明显上升趋势(χ_(趋势)^(2)=4.801,P=0.028);职业以农民为主[213例(68.27%)];痰涂片结果以涂阳患者居多[215例(68.91%)],但痰涂片阳性率从2015年的100.00%(10/10)下降至2022年的59.26%(16/27),呈下降趋势(χ_(趋势)^(2)=17.664,P=0.000)。耐药谱前3位依次为利福平+异烟肼+乙胺丁醇[26.92%(84/312)]、利福平[26.28%(82/312)]和利福平+异烟肼[23.40%(73/312)]。耐药患者诊断时间中位数(四分位数)从2016年的145(91,196)d逐年下降至2019年的21(12,39)d。结论:2015—2022年天水市肺结核患者病原学阳性率和耐药筛查率均呈逐年上升趋势,利福平耐药检出率波动较大,耐药诊断时间明显缩短,建议加大老年肺结核患者利福平耐药筛查力度,以减少耐药肺结核的传播。

重症监护病房多重耐药菌感染分布情况及影响因素分析

目的分析重症监护病房(ICU)患者多重耐药菌(MDRO)感染的分布情况及其危险因素,并提出相关的预防和控制措施。方法本研究以2021年7月至2022年12月汕头市某三级甲等医院ICU收治的1407例患者为对象,回顾性收集其住院期间是否发生MDRO感染,分析MDRO感染发生率和分布情况,并分为MDRO感染组和非MDRO感染组进行比较,采用多因素logistic回归筛选MDRO感染的相关危险因素。结果ICU共有1407例住院患者均接受细菌培养及耐药菌株检测,其中男性患者为880例,女性患者为527例;MDRO感染发生率为18.69%(263/1407)。ICU中MDRO感染菌株主要涉及大肠埃希菌、金黄色葡萄球菌和肺炎克雷伯菌等。多因素分析结果显示,合并心血管病(OR=1.453,95%CI 1.006~2.079)、广谱抗生素使用时长≥1周(OR=1.900,95%CI 1.377~2.620)、使用≥2联抗生素(OR=1.913,95%CI 1.378~2.655)、留置血管内导管(OR=2.456,95%CI 1.416~3.241)与MDRO感染风险增高有关(P<0.05)。结论ICU患者中MDRO的感染发生率相对其他普通病区仍处于较高水平,应针对MDRO感染的特点和相关的高危因素及时采取预防和控制措施,有效降低MDRO的感染发生率。

2020—2022年某医院主要细菌耐药情况分析

目的通过分析福建中医药大学附属第二人民医院2020年1月—2022年12月常见细菌的耐药性,了解医院的细菌耐药情况,为临床提供合理使用抗菌药物的参考依据。方法通过回顾性分析方法对2020年1月—2022年12月福建中医药大学附属第二人民医院患者标本分离的病原菌株进行统计,从病原菌标本分布、病原菌种类及耐药等方面进行分析。结果2020—2022年分离的菌株共计12009株,呼吸道标本(包括痰、肺泡灌洗液)最多。前5位为大肠埃希菌2139株(17.81%)、肺炎克雷伯菌1342株(11.17%)、铜绿假单胞菌1094株(9.11%)、金黄色葡萄球菌为主793株(6.60%)、鲍曼不动杆菌541株(4.50%)。耐碳青霉烯类肺炎克雷伯菌(Carbapenemresistant K.pneumoniae,CR-KP)和耐碳青霉烯类铜绿假单胞菌(Carbapenemresistant Pseudomonas aeruginosa,CR-PA)2022年比2020年明显升高,差异有统计学意义(P<0.01)。其余3种耐甲氧西林金黄色葡萄球菌(Methicillin-resistant S.aureus,MRSA)、耐碳青霉烯类大肠埃希菌(Carbapenemresistant Escherichia coli,CR-EC)、耐碳青霉烯类鲍曼不动杆菌(Carbapenemresistant Acinetobacter baumannii,CRAB)3年间检出率差异无统计学意义(P>0.05)。鲍曼不动杆菌对大多数常用抗菌药物耐药率>50%。结论福建中医药大学附属第二人民医院主要以革兰阴性杆菌为主,鲍曼不动杆菌对大多数常用抗菌药物耐药率>50%,CR-KP(耐碳青霉烯类肺炎克雷伯菌)和CR-PA(耐碳青霉烯类铜绿假单胞菌)的耐药率呈增高趋势,建议临床密切关注病原菌耐药情况的变化,减少多重耐药菌的产生。