Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors

BACKGROUND Gastrointestinal stromal tumors(GISTs)are typical gastrointestinal tract neoplasms.Imatinib is the first-line therapy for GIST patients.Drug resistance limits the long-term effectiveness of imatinib.The regulatory effect of insulin-like growth factor 2(IGF2)has been confirmed in various cancers and is related to resistance to chemotherapy and a worse prognosis.AIM To further investigate the mechanism of IGF2 specific to GISTs.METHODS IGF2 was screened and analyzed using Gene Expression Omnibus(GEO:GSE225819)data.After IGF2 knockdown or overexpression by transfection,the phenotypes(proliferation,migration,invasion,apoptosis)of GIST cells were characterized by cell counting kit 8,Transwell,and flow cytometry assays.We used western blotting to evaluate pathway-associated and epithelial-mesenchymal transition(EMT)-associated proteins.We injected transfected cells into nude mice to establish a tumor xenograft model and observed the occurrence and metastasis of GIST.RESULTS Data from the GEO indicated that IGF2 expression is high in GISTs,associated with liver metastasis,and closely related to drug resistance.GIST cells with high expression of IGF2 had increased proliferation and migration,invasiveness and EMT.Knockdown of IGF2 significantly inhibited those activities.In addition,OEIGF2 promoted GIST metastasis in vivo in nude mice.IGF2 activated IGF1R signaling in GIST cells,and IGF2/IGF1R-mediated glycolysis was required for GIST with liver metastasis.GIST cells with IGF2 knockdown were sensitive to imatinib treatment when IGF2 overexpression significantly raised imatinib resistance.Moreover,2-deoxy-D-glucose(a glycolysis inhibitor)treatment reversed IGF2 overexpressionmediated imatinib resistance in GISTs.CONCLUSION IGF2 targeting of IGF1R signaling inhibited metastasis and decreased imatinib resistance by driving glycolysis in GISTs.

Review of Baduanjin and resistance exercise for the mental health of patients with hematologic malignancies

Patients with hematological tumors experience physical and psychological stress,and negative psychological states.Baduanjin,an emerging psychological rehabil-itation method combined with resistance exercise,has received widespread attention.This study reviews the current status of the application of Baduanjin combined with resistance exercise in improving the negative psychological state of patients with hematological tumors and discusses its problems and prospects.Through a literature review and comprehensive analysis,the application of Baduanjin and resistance exercise in the psychological rehabilitation of patients with hematological tumors was identified and evaluated.The results showed that Baduanjin with resistance exercise had a positive effect on improving negative psychological states of patients with hematological tumors,which can alleviate anxiety,depression,and other adverse emotions,and improve quality of life.However,there is a lack of unified and standardized exercise intervention programs for practical application,and patient participation and compliance must be improved.Baduanjin combined with resistance exercise can potentially improve the negative psychological status of patients with hematological tumors;however,it is still necessary to further standardize and improve the exercise program improving patient participation and compliance.Future studies should strengthen theoretical exploration and empirical research,providing more effective psychological rehabilitation strategies for patients with hematological tumors.

Analysis of Multi-Drug Resistant Organism Surveillance and Antimicrobial Resistance Early Warning in a Hospital in 2022

Objective:To determine the clinical distribution of multi-drug resistant organism(MDRO)in Jiangyan Hospital and the monitoring and warning of drug-resistance bacteria to provide an important basis for guiding the application of broad-spectrum antibiotics in clinical treatment and reducing the occurrence of nosocomial infection.Methods:Retrospective screening and analysis were conducted on the pathogenic strains of hospitalized patients in our hospital in 2022.Results:A total of 2,769 strains of pathogenic bacteria and 390 strains of MDRO were detected and isolated in our hospital in 2022;the detection rate of MDRO was 14.08%.A total of 516 strains(18.64%)Klebsiella pneumoniae(KP)and 62 strains(12.02%)of carbapenem-resistant Klebsiella pneumoniae(CR-KP)were detected;436 strains(15.75%)of Escherichia coli(ECO)were detected,including 8 strains(1.83%)of CR-ECO;342 strains(12.35%)of Pseudomonas aeruginosa(PA)and 116 strains(33.92%)of CR-PA were detected;there were 194 strains(7.01%)of Acinetobacter baumannii(AB),among which 125 strains(64.43%)were CR-AB;there were 291 strains(10.51%)of Staphylococcus aureus,among which 79 strains(27.15%)of methicillin-resistant Staphylococcus aureus(MRSA)were detected;78 strains(2.82%)of Enterococcus faecalis were detected,and vancomycin-resistant enterococcus(VRE)was not detected.The first five MDROs were CR-AB,CR-PA,MRSA,CR-KP,and CR-ECO.The top five departments with the highest MDRO detection rate in 2022 were the ICU(37.44%),the Pulmonology Department(ward 13;31.03%),the Department of Rehabilitation(ward 5;6.67%),the Department of Neurosurgery(ward 11;4.62%),and the Department of General Surgery(ward 10;3.59 The resistance rate of antibacterial drugs is divided into four levels for early warning:30%to 40%,41%to 50%,51%to 75%,and 75%or more.Conclusion:Our hospital should strengthen the monitoring of antimicrobial resistance warning related to MDRO and the abuse of antimicrobial drugs.Based on the results of drug sensitivity and antimicrobial resistance warning,the use of antibiotics should be standardized in clinical practice to reduce nosocomial infection。

The Role and Mechanism of Unfolded Protein Response Pathway in Tumor Drug Resistance

In the process of tumor proliferation and metastasis,tumor cells encounter hypoxia,low glucose,acidosis,and other stressful environments.These conditions prompt tumor cells to generate endoplasmic reticulum stress(ERS).As a signal mechanism that mitigates ERS in eukaryotic cells,the unfolded protein response(UPR)pathway can activate cells and tissues,regulating pathological activities in various cells,and maintaining ER homeostasis.It forms the most crucial adaptive and defensive mechanism for cells.However,under the continuous influence of chemotherapy drugs,the quantity of unfolded proteins and erroneous proteins produced by tumor cells significantly increases,surpassing the normal regulatory range of UPR.Consequently,ERS fails to function properly,fostering tumor cell proliferation and the development of drug resistance.This review delves into the study of three UPR pathways(PERK,IRE1,and ATF6),elucidating the mechanisms of drug resistance and research progress in the signal transduction pathway of UPR related to cancers.It provides a profound understanding of the role and relationship between UPR and anti-tumor drugs,offering a new direction for effective clinical treatment.

Expression and significance of multi-drug resistance-associated protein 3 in different tumor cell lines

Objective To investigate the expression and meaning of MRP3 in different tumor cells. MethodsThe monoclonal antibody against MRP3 was used to identify the expression of MRP3 by flow cytometer in seven tumor cells and human embryo kidney cell lines 293T.And RT-PCR was used to detect the mRNA of MRP3 in eight cell lines. ResultsThe mRNA of MRP3 was expressed in three pancreatic carcinoma cell lines.MRP3 protein was observed in BxPC-3 and AsPC-1 cells. ConclusionMRP3 may express in different tumor in tissue-specific manner.BxPC-3 and AsPC-1 may serve as cellular models for in vitro studies on multidrug resistance of pancreatic carcinoma.

The Roles of Four Multi-drug Resistance Proteins in Hepatocellular Carcinoma Multidrug Resistance

The roles of multi-drug resistance protein 1 （MDR1）, multi-drug resistance related protein 1 （MRP1）, lung resistance protein （LRP） and breast cancer resistance protein （BCRP） in the multi-drug resistance （MDR） of hepatocellular carcinoma （HCC） were studied. By exposing HepG2 cell line to progressively increased concentrations of adriamycin （ADM）, HepG2 multi-drug resistant subline （HepG2/ADM） was induced. The MDR index of HepG2/ADM was detected by using MTT. The expressions of the four MDR proteins in the three cell lines （L02, HepG2, HepG2/ADM） were investigated at mRNA and protein levels by real-time RT-PCR and Western blot respectively. Our results showed that when the ADM concentration was under 100 pg/L, HepG2 could easily be induced to be drug-resistant. The IC50 of the HepG2/ADM to ADM was 282 times that of HepG2. The expression of MDR1 and BCRP mRNA in HepG2/ADM cells were 400 and 9 times that of HepG2 cells respectively while there was no difference in the mRNA expressions of MRPl and LRE There was no difference between HepG2 and L02 cells in the mRNA expressions of the four genes. At the protein level, the expressions of MDRI, BCRP and LRP but MRPl in HepG2/ADM were significantly higher than those of HepG2 and L02. Between HepG2 and L02, there was no difference in the expressions of four genes at the protein level. HepG2/ADM is a good model for the study of MDR. The four genes are probably the normally expressed gene in liver. The expressions of MDRl and BCRP could be up-regulated by anti-cancer agents in vitro. The MDR of HCC was mainly due to the up-regulation of MDR1 and BCRP but MRP1 and LRE These findings suggest they may serve as targets for the reversal of MDR of HCC.

Relationship between Methylation Status of Multi-drug Resistance Protein(MRP) and Multi-drug Resistance in Lung Cancer Cell Lines

Objective： To study the relationship between the methylation status of multi-drug resistance protein （MRP） gene and the expression of its mRNA and protein in lung cancer cell lines. Methods： Human embryo lung cell line WI-38, lung adenocarcinoma cell line SPCA-1 and its drug-resistant cells induced by different concentrations of doxorubicin were treated with restriction endonuclease Eco47III. The methylation status of MRP was examined by PCR, and the expressions of its mRNA and protein were evaluated by in situ hybridization and immunohistochemistry. Results： MRP gene promoter region of WI-38 cells was in hypermethylation status, but the promoter region of MRP in SPCA-1 cells and their resistant derivatives induced by different concentrations of doxorubicin were in hypomethylation status. There were significant differences in the expression of MRP mRNA among WI-38 cell line, SPCA-1 cells and their drug-resistant derivatives induced by different concentration of doxorubicin. Consistently, MRP immunostaining presented similar significant differences. Conclusion： The promoter region of MRP in SPCA-1 lung adenocarcinoma cells was in hypomethylation status. The hypomethylation status of 5＇ regulatory region of MRP promoter is an important structural basis that can increase the activity of transcription and results in the development of drug resistance in lung cancer.

Tumor microenvironment involvement in colorectal cancer progression via Wnt/β-catenin pathway:Providing understanding of the complex mechanisms of chemoresistance

Colorectal cancer(CRC)continues to be one of the main causes of death from cancer because patients progress unfavorably due to resistance to current therapies.Dysregulation of the Wnt/β-catenin pathway plays a fundamental role in the genesis and progression of several types of cancer,including CRC.In many subtypes of CRC,hyperactivation of theβ-catenin pathway is associated with mutations of the adenomatous polyposis coli gene.However,it can also be associated with other causes.In recent years,studies of the tumor microenvironment(TME)have demonstrated its importance in the development and progression of CRC.In this tumor nest,several cell types,structures,and biomolecules interact with neoplastic cells to pave the way for the spread of the disease.Cross-communications between tumor cells and the TME are then established primarily through paracrine factors,which trigger the activation of numerous signaling pathways.Crucial advances in the field of oncology have been made in the last decade.This Minireview aims to actualize what is known about the central role of the Wnt/β-catenin pathway in CRC chemoresistance and aggressiveness,focusing on crosscommunication between CRC cells and the TME.Through this analysis,our main objective was to increase the understanding of this complex disease considering a more global context.Since many treatments for advanced CRC fail due to mechanisms involving chemoresistance,the data here exposed and analyzed are of great interest for the development of novel and effective therapies.

Role of exosomes in metastasis and therapeutic resistance in esophageal cancer

Esophageal cancer(EC)has a high incidence and mortality rate and is emerging as one of the most common health problems globally.Owing to the lack of sensitive detection methods,uncontrollable rapid metastasis,and pervasive treatment resistance,EC is often diagnosed in advanced stages and is susceptible to local recurrence.Exosomes are important components of intercellular communication and the exosome-mediated crosstalk between the cancer and surrounding cells within the tumor microenvironment plays a crucial role in the metastasis,progression,and therapeutic resistance of EC.Considering the critical role of exosomes in tumor pathogenesis,this review focused on elucidating the impact of exosomes on EC metastasis and therapeutic resistance.Here,we summarized the relevant signaling pathways involved in these processes.In addition,we discussed the potential clinical applications of exosomes for the early diagnosis,prognosis,and treatment of EC.

Analysis of Pathogen Distribution and Drug Resistance of Nosocomial Infections Accompanied in Patients with Malignant Tumor

Objective： To investigate the pathogen distribution and drug resistance of nosocomial infections accompanied in patients with malignant tumor. Methods： The pathogen culture and drug-sensitivity data of 107 specimens isolated from malignant tumor patients accompanied with nosocomial infection were retrospectively analyzed. Results： Among 118 strains of pathogens isolated from 107 specimens, 77 were gram-negative bacillus（65.3%）, 26 were gram-positive coccus（65.3%）, and 15 were fungus（12.7%）. Eleven specimens were revealed to have combined infection of bacterium and fungus. Gram-negative bacillus showed high sensitivity to amikacin, ciprofloxacin, and tienam. Gram-positive cocci were highly sensitive to tienam and vancomycin. The bacteria were resistant to other antibiotics in different degrees, Vancomycin-resistant staphylococcus was not detected, Candida was sensitive to antifungals. Conclusion： Conditional pathogenic bacteria were mainly responsible for nosocomial infections in malignant tumor patients with considerable drug resistance. This shows that bacterial tests and the rational use of antibiotics should be emphasized in clinical practice to prevent the formation of drug resistant strains and further endogenous infections.

Functional Activity of Circulating Phagocytes as Potential Pretreatment Marker of Tumor Drug Resistance

The aim of this work was a study of the functional activity of neutrophils and peripheral blood monocytes in rats with the transplanted Walker carcinosarcoma as potential predictors of the sensitivity of this tumor to doxorubicin treatment. This study provides an evidence that such indices of the functional activity of circulating phagocytes of the tumor-bearing rats as the quantity and the phagocytosis intensity of monocytes, as well as the intensity of ROS production by monocytes and neutrophils, may reflect the degree of sensitivity of the tumor to doxorubicin. So it was shown that the growth of the resistant tumor caused a significant increase of the number of circulating phagocytic cells and the intensity of phagocytosis by more than 100% (p < 0.001) compared with the corresponding indices of intact rats and rats with the parental variant of the tumor. The ability of blood mono-cytes and neutrophils of rats with a resistant tumor to produce ROS was also significantly different from that in intact rats and animals with the parental carcinosarcoma variant. The predictive value of these indices is especially important in the dynamic monitoring of the development of tumor drug resistance during long-term cancer chemotherapy. Considering the standard 2 - 3 week interval between the courses of cancer therapy and the short lifetime of circulating phagocytes, an assessment of the indices of their functional activity before each subsequent course can be considered as a pretreatment assessment. Meanwhile, further studies are needed to determine the spectrum of malignant neoplasms for which the degree of tumor drug resistance correlates with the functional activity of circulating phagocytes.

Anti-and non-tumor necrosis factor-α-targeted therapies effects on insulin resistance in rheumatoid arthritis,psoriatic arthritis and ankylosing spondylitis

In addition toβ-cell failure with inadequate insulin secretion,the crucial mechanism leading to establishment of diabetes mellitus(DM)is the resistance of target cells to insulin,i.e.insulin resistance(IR),indicating a requirement of beyond-normal insulin concentrations to maintain euglycemic status and an ineffective strength of transduction signaling from the receptor,downstream to the substrates of insulin action.IR is a common feature of most metabolic disorders,particularly type II DM as well as some cases of type I DM.A variety of human inammatory disorders with increased levels of proinflammatory cytokines,including tumor necrosis factor(TNF)-α,interleukin(IL)-6 and IL-1β,have been reported to be associated with an increased risk of IR.Autoimmunemediated arthritis conditions,including rheumatoid arthritis(RA),psoriatic arthritis(PsA)and ankylosing spondylitis(AS),with the involvement of proinflammatory cytokines as their central pathogenesis,have been demonstrated to be associated with IR,especially during the active disease state.There is an increasing trend towards using biologic agents and small molecule-targeted drugs to treat such disorders.In this review,we focus on the effects of anti-TNF-α-and non-TNF-α-targeted therapies on IR in patients with RA,PsA and AS.Anti-TNF-αtherapy,IL-1 blockade,IL-6 antagonist,Janus kinase inhibitor and phosphodiesterase type 4 blocker can reduce IR and improve diabetic hyper-glycemia in autoimmune-mediated arthritis.

Direct and Residual Microbicidal Efficacy of Various Antiseptics against Multi-Drug Resistant Bacteria

Background: Infections in ICU’s patients are known to often originate from the colonization of wounds by the patient’s endogenous microbiota, and to eventually lead to secondary sepsis. Aim: to compare in vitro the direct and residual effects after different exposure times of 4% chlorhexidine, and of 0.1% and 0.04% polyhexanide (in gel and solution forms), on ATCC-microorganisms, and too, on bacterial strains obtained from ICU patients. Methods: We used wild multi-drug resistant strains recently obtained from the wounds of patients hospitalized at ICU and reference strains from the American Type Culture Collection (ATCC). Chlorhexidine 4% was studied as a reference solution. The direct and residual effects of the 0.1% and 0.04% polyhexanide, in gel and solution forms, were analyzed using cotton germ carriers. To evaluate the direct effect, we exposed the strains to the antiseptic. To assess the residual effect, the germ-carriers were impregnated with antiseptic and were allowed to dry before we contaminated them. We inoculated the germ carriers in a culture medium with an inhibitor of antiseptic effect to count the number of surviving microorganisms. Findings: 0.1% Polyhexanide solution proved a direct and residual efficacy after 24 hours equivalent to 4% chlorhexidine. Is very important to highlight that this great efficacy did not change according to whether they were ATCC or multidrug-resistant strains. Conclusions: 0.1% polyhexanide demonstrated a great direct and residual efficacy (like 4% chlorhexidine), against multi-drug resistant strains isolated from ICU’s patients. Moreover, due to its few cytotoxicity against keratinocytes and fibroblasts can be an optimal antiseptic for burns, wounds or ulcers.

Molecular characterization of antimicrobial multi-drug resistance in non-typhoidal Salmonellae from chicken and clam in Mangalore, India

Salmonella enterica has been documented as one of the leading causes of salmonellosis throughout the world and is most commonly associated with the consumption of contaminated food products. Thus, this research was aimed at studying the antimicrobial susceptibility pattern and detection of quinolone resistance in Salmonella spp isolated from food of animal origin. Thirty-six Salmonella isolates comprising 8 from poultry and 28 from seafood（clams） were identified, serotyped and characterized for their antimicrobial susceptibility against 10 different antibiotics. Plasmid DNA was isolated from all the isolates by alkaline lysis, quinolone resistant non-typhoidal S. Weltevreden were examined for mutation in the DNA gyrase coding gene. Among the 36 Salmonella isolates, 20 were S. weltevreden（8 from poultry and 12 from seafood） and 16 were S. Typhimurium（from seafood）. All the isolates showed multiple resistance to nalidixic acid, tetracycline, co-trimoxazole and nitrofurantoin, but, interestingly, the isolates were 100% susceptible to ampicillin, chloramphenicol and gentamicin. Resistant isolates from the study carried the genes responsible for resistance to respective antibiotics. The strain S130 isolated in the study showed single point mutation,Asp87Gly, at position 87 in quinolone resistance determining region. It revealed mutation in quinolone resistance determining region as a cause for quinolone resistance in non-typhoidal Salmonellae. The occurrence of genes accountable for plasmid mediated resistance to quinolones（viz., qnrA, qnrB and qnrS） in plasmid of non-typhoidal Salmonellae isolates provides evidence for plasmid mediated quinolone resistance.

Multi-Drug Resistance Pattern of Lactose Non-Fermenting <i>Escherichia coli</i>as Causative Agent of Urine Tract Infections in Luanda, Angola

This prospective study was carried out to assess the sensitivity and resistance pattern of lactose non-fermenting Escherichia coli from July 2018 to December 2018 in the Laboratory of Microbiology at Luanda Medical Center, Angola. Out of 1170 patient, a total of 120 urine specimens infected with Escherichia coli (>105 CFU/ml) were collected according to the routine protocol of urinalysis. Among these 120 isolates, 25 (21%) isolates were determined as “atypical”, lactose non-fermenting E. colis trains. The twenty-five lactose non-fermenting Escherichia coli strains isolated from urine samples in Luanda Medical Center were declared as Multiple Drugs-Resistant strains with high resistance to Cefalexine (100%), Cefuroxime (100%), Ceftriaxone (92%), Gentamycin (92%), Ciprofloxacin (72%) and Amoxiciclin/Clavulanic (80%). The alarming resistance level to the first-choice drugs for the treatment of urinary tract infections caused by non-fermentative lactose E. coli was observed.

New avenues for the treatment of immunotherapy-resistant pancreatic cancer

Pancreatic cancer(PC)is characterized by its extremely aggressive nature and ranks 14th in the number of new cancer cases worldwide.However,due to its complexity,it ranks 7th in the list of the most lethal cancers worldwide.The pathogenesis of PC involves several complex processes,including familial genetic factors associated with risk factors such as obesity,diabetes mellitus,chronic pancreatitis,and smoking.Mutations in genes such as KRAS,TP53,and SMAD4 are linked to the appearance of malignant cells that generate pancreatic lesions and,consequently,cancer.In this context,some therapies are used for PC,one of which is immunotherapy,which is extremely promising in various other types of cancer but has shown little response in the treatment of PC due to various resistance mechanisms that contribute to a drop in immunotherapy efficiency.It is therefore clear that the tumor microenvironment(TME)has a huge impact on the resistance process,since cellular and non-cellular elements create an immunosuppressive environment,characterized by a dense desmoplastic stroma with cancerassociated fibroblasts,pancreatic stellate cells,extracellular matrix,and immunosuppressive cells.Linked to this are genetic mutations in TP53 and immunosuppressive factors that act on T cells,resulting in a shortage of CD8+T cells and limited expression of activation markers such as interferon-gamma.In this way,finding new strategies that make it possible to manipulate resistance mechanisms is necessary.Thus,techniques such as the use of TME modulators that block receptors and stromal molecules that generate resistance,the use of genetic manipulation in specific regions,such as microRNAs,the modulation of extrinsic and intrinsic factors associated with T cells,and,above all,therapeutic models that combine these modulation techniques constitute the promising future of PC therapy.Thus,this study aims to elucidate the main mechanisms of resistance to immunotherapy in PC and new ways of manipulating this process,resulting in a more efficient therapy for cancer patients and,consequently,a reduction in the lethality of this aggressive cancer.

EFFECT OF ASCORBIC ACID ON DNA SYNTHESIS,INTRACELLULAR ACCUMULATION OF ADM AND ADM RESISTANCE OF TUMOR CELL LINES

Objective: To determine the effect of ascorbic acid (AA) on DNA synthesis, intracellular accumulation of ADM and ADM resistance of tumor cell lines. Methods: K562, K562/ADM and KB cell lines were used to study the effect of ascorbic acid on DNA synthesis, intracellular accumulation of ADM and ADM resistance by fluid scintillometry, MTT method, spectrofluorophotometry and immunocytochemistry. Results: Results showed that AA was capable of inhibiting DNA synthesis of K562 and K562/ADM in a dosedependence fashion, but not KB cell line, and significantly reducing ADM sensitivity in K562 and KB cell lines, as well as potentiating obviously ADM resistance in K562/ADM cell line. Conclusion: These effects of AA may be closely correlated with significant elevation of intracellular accumulation of ADM in KB cell line, and significant reduction of that in K562 and K562/ADM cell lines but possibly not correlated with the expression of Pglycoprotein.

Systemic therapy in gastrointestinal stromal tumors

Gastrointestinal stromal tumors(GISTs)are the most common type of soft tissue sarcoma in the gastrointestinal tract.Most GISTs have been attributed to activated gain-of-function mutations in either KIT or platelet-derived growth factor receptorα,making these molecular features essential targets for therapeutic interventions.Although surgery is the standard treatment for localized GISTs,patients often experience relapse and disease progression even after surgery.In recent years,targeted therapy has significantly improved the prognosis of patients with advanced GISTs.Imatinib mesylate,a KIT inhibitor,is the first-line treatment for advanced GISTs and has revolutionized the treatment of this disease.However,drug resistance remains a major issue with imatinib treatment,as a significant majority of patients become resistant to imatinib either after initiation or after 2–3 years of treatment.Consequently,novel tyrosine kinase inhibitors such as sunitinib,regorafenib,ripretinib,and avapritinib have been introduced to address drug resistance.Immunotherapy has emerged as a potential approach for the treatment of advanced GISTs.This review comprehensively summarizes the pathogenesis of GISTs and the development of targeted therapies and immunotherapies,provides an overview of the emergence of drug resistance in advanced GISTs,and discusses the challenges and prospects associated with the treatment of GISTs.

Reversal of Multi-Drug Resistance by Vector-Based-ShRNA-Mdr1 In Vitro and In Vivo

In order to investigate the effects of vector-based hairpin small interference RNA （shRNA） on the reversal of multi-drug resistance （mdr） of A2780/Taxol cells, a novel vector pEGFP-HI/mdrl containing mdrl-shRNA targeting at position 2943-2963 of mdrl was designed and synthesized. Subsequently, A2780/Taxol cells were transfected with pEGFP-H1/rndrl, and the expression ofmdrl mRNA and P-gp was detected by using RT-PCR and Western blot respectively. MTT was used to measure the 50% inhibition concentration （IC50） of Taxol to A2780/Taxol cells. The results showed that at the 24th and 48th h after transfection, the expression of mdrl mRNA was decreased to （52.1±1.0）% and （0.01±1.7）%, and that of P-gp decreased to （88.3±2.1）% and 0%, respectively. At the 48th h after transfection, the relative reversal rate of A2780/Taxol cells to Taxol was 69.54%. In vivo, the nude mice xenografts were injected with pEGFP-H1/mdrl, and then administrated Taxol. The tumor volume in pEGFP-H1/mdrl-transfected group was significantly reduced as compared with that in blank control group or pEGFP-Hl-transfected group （807.20±103.16 vs 1563.78±210.54 or 1480.78±241.24 mm^3, both P〈0.01）. These results suggested that transfection of pEGFP-HI/mdrl could efficiently down-regulate the expression of mdrl mRNA and P-gp in A2780/Taxol cells, and effectively restore the sensitivity of A2780/Taxol ceils to Taxol both in vitro and in vivo.

Subpopulation cooperation renders drug resistance of hepatobiliary tumor organoids

Hepatobiliary tumors are of high grade of heterogeneity, which is recognized as a key contributor to drug resistance and poor disease prognosis. However, the intrinsic mechanism between heterogeneity and drug response in hepatobiliary tumor is still largely unknown. Using tumor organoid models, Wang and her colleagues have found that cooperation among distinct subpopulations might be a key mechanism for drug resistance in hepatobiliary tumor.