Lnc-TMEM132D-AS1 overexpression reduces sensitivity of non-small cell lung cancer cells to osimertinib / 南方医科大学学报

OBJECTIVE@#To screen the differentially expressed long non-coding RNAs (lncRNAs) in non-small cell lung cancer (NSCLC) cells with acquired resistance to osimertinib and explore their roles in drug resistance of the cells.@*METHODS@#The cell lines H1975_OR and HCC827_OR with acquired osimertinib resistance were derived from their osimertinib-sensitive parental NSCLC cell lines H1975 and HCC827, respectively, and their sensitivity to osimertinib was assessed with CCK-8 assay, clone formation assay and flow cytometry. RNA sequencing (RNA-seq) and real-time quantitative PCR (qPCR) were used to screen the differentially expressed lncRNAs in osimertinib-resistant cells. The role of the identified lncRNA in osimertinib resistance was explored using CCK-8, clone formation and Transwell assays, and its subcellular localization and downstream targets were analyzed by nucleoplasmic separation, bioinformatics analysis and qPCR.@*RESULTS@#The resistance index of H1975_OR and HCC827_OR cells to osimertinib was 598.70 and 428.82, respectively (P < 0.001), and the two cell lines showed significantly increased proliferation and colony-forming abilities with decreased apoptosis (P < 0.01). RNA-seq identified 34 differentially expressed lncRNAs in osimertinib-resistant cells, and among them lnc-TMEM132D-AS1 showed the highest increase of expression after acquired osimertinib resistance (P < 0.01). Analysis of the TCGA database suggested that the level of lnc-TMEM132D-AS1 was significantly higher in NSCLC than in adjacent tissues (P < 0.001), and its high expression was associated with a poor prognosis of the patients. In osimertinib-sensitive cells, overexpression of Lnc-TMEM132D-AS1 obviously promoted cell proliferation, colony formation and migration (P < 0.05), while Lnc-TMEM132D-AS1 knockdown partially restored osimertinib sensitivity of the resistant cells (P < 0.01). Lnc-TMEM132D-AS1 was localized mainly in the cytoplasm, and bioinformatics analysis suggested that hsa-miR-766-5p was its candidate target, and their expression levels were inversely correlated. The target mRNAs of hsa-miR-766-5p were mainly enriched in the Ras signaling pathway.@*CONCLUSION@#The expression of lnc-TMEM132D-AS1 is significantly upregulated in NSCLC cells with acquired osimertinib resistance, and may serve as a potential biomarker and therapeutic target for osimertinibresistant NSCLC.

A real world study on the relationship between drug resistance of targeted therapy and prognosis of HER-2-positive advanced breast cancer / 中华肿瘤杂志

Objective: To explore the effect of primary and acquired resistance to anti-human epidermal growth factor receptor 2 (HER-2) on the overall survival of patients with HER-2 positive advanced breast cancer. Methods: The clinical characteristics of HER-2 positive patients with advanced breast cancer admitted to Cancer Hospital of Chinese Academy of Medical Sciences from January 1998 to December 2018 were collected, and their neoadjuvant/adjuvant and advanced three-line chemotherapy were summarized. Among them, targeted drugs for HER-2 included trastuzumab, pertuzumab, T-DM1, RC48-ADC, lapatinib, pyrotinib, allitinib, sipatinib, seratinib. Based on the duration of benefit from anti HER-2 treatment, the patients were divided into two groups: primary anti HER-2 resistance group and acquired anti HER-2 resistance group. In this study, the overall survival (OS) was used as the main end point. Kaplan-Meier analysis and Cox proportional risk regression model were used to analyze the effects of different drug resistance mechanisms on the overall survival. Results: The whole group of 284 patients were included. The median age of recurrence and metastasis was 48 years old, 155 (54.6%) were hormone receptor (HR) positive and 129 (45.4%) were HR negative, 128 cases (45.1%) were premenopausal and 156 cases (54.9%) were postmenopausal, 277 cases (97.5%) had a score of 0-1 in ECoG PS and 7 cases (2.5%) had a score of more than 2 in the first diagnosis of relapse and metastasis. There were 103 cases (36.3%) in the primary drug resistance group and 181 cases (63.7%) in the secondary drug resistance group. The median overall survival time of the two groups was 24.9 months and 40.4 months, respectively, with statistical significance (P<0.001). Conclusion: Primary resistance to HER-2 is one of the factors of poor prognosis in HER-2 positive breast cancer, and its mechanism needs to be further explored.

miR-125a-5p promotes the resistance to gefitinib in non-small cell lung carcinoma cells by targetingAPAF1 / 中国肿瘤生物治疗杂志

@#[Abstract] Objective:ToinvestigatetheroleofmiR-125a-5pininducingthegefitinib(Gef)-resistance of non-small cell lung carcinoma (NSCLC) cells and its possible mechanism. Methods: Human NSCLC drug-resistant cell line A549/GR and NSCLC cell line A549 were chosen for this study. miR-125a-5p mimic, miR-125a-5p inhibitor, pcDNA3.1-APAF1 and empty vector pcDNA3.1 were transfected into A549/GR cells. The expression level of miR-125a-5p in cell lines was detected by qPCR. MTT, Transwell and Flow cytometry were used to detect the effects of Gef on proliferation, migration and apoptosis of cell lines, respectively. The targeting relationship between miR-125a-5p and APAF1 (apoptotic peptidase activating factor 1) was verified by Dual-luciferase reporter gene system. In addition, the expression of APAF1 protein in A549/GR cells was detected by Western blotting. The expression levels of caspase-3 and caspase-9 were assessed by colorimetry. Results: Expression level of miR-125a-5p was upregulated significantly in Gefresistant A549/GR cells (P<0.01). AndtheinfluencesofGefonA549/GRcellswereenhancedby knockdown of miR-125a-5p, including inhibiting cell proliferation and migration (all P<0.05) and inducing apoptosis (P<0.01). Dual luciferase reporter gene assay confirmed that miR-125a-5p targeted APAF1 and negatively regulated its expression. Furthermore, by targetedly downregulating APAF1, miR-125a-5p alleviated the inhibition of proliferation and migration (all P<0.05) and promotion of apoptosis (P<0.05) of A549/GR cells caused by Gef, and attenuated Gef-induced upregulation of apoptosis-related proteins caspase-3 and caspase-9 (all P<0.05). Conclusion: miR-125a-5p promotes Gef-resistance of A549/GR cells, and the underlying mechanisms are promotion of proliferation, migration and inhibition of apoptosis of non-small cell lung cancer cells by targetingAPAF1.

Role of STAT3 in Resistance of Non-small Cell Lung Cancer / 中国肺癌杂志

The inflammatory state of tumor microenvironment play an important role in non-small cell lung cancer (NSCLC) drug resistance. As the key signal pathway connecting inflammation and tumor, activated signal transduction and transcriptional activation factor 3 (STAT3) leads togenetic abnormal expression, gene silencing, genomic instability, etc. in tumor cells, and induces therapeutic resistance. STAT3 has thepotential to be a new target for reversal of resistance. In this review, we summarize the progress of STAT3 in acquired drug resistance of NSCLC, explore the possibility of STAT3 as a new target to reverse drug resistance, and provide basic theories for the new clinical treatment strategy of acquired drug resistance in NSCLC.
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Advances in drug resistance mechanism of immunological checkpoint inhibitors and post-drug resistant therapeutic strategy / 实用肿瘤学杂志

Immune-checkpoint blockers(ICBs)have been well received in a variety of tumors,and the quality of patient life has improved significantly.However,the reasons why not all patients treated with ICBs benefit from lesion control,symptom improvement,and survival time.Many patients are resistant to the first time when they have been using ICBs for a period of time.This is a clinical challenge.This review lists possible causes of primary drug resistance and acquired resistance to ICBs.The primary resistance is associated with several mechanisms,including tumor microenvironment,cancer cells themselves and other related factors.The acquired resistance includes nonclassical immunoprecipitation molecules secondary overexpression,abnormalities of antigen presenting signal pathway and dysfunction of T cell activation killer.Finally,we have described a variety of possible new combination of treatment,including combined radiotherapy and chemotherapy,and combined targeted therapy with other measures.

MDR - TB Current Status.

Drug resistant tuberculosis has been reported since the early days of the introduction of chemotherapy, but recently multi-drug resistant tuberculosis (MDR-TB) has been an area of growing concern and is posing a threat to control of tuberculosis. A review of 63 surveys conducted between 1985 and 1994 suggested that primary and acquired MDR-TB was between 0-10.8% and 0-48% respectively. However, the qualities of these studies were variable due to the lack of proper representativeness and size of population sampled, as well as lack of standardized laboratory methods in some of them. In 1994, WHO-IUATLD carried out a surveillance which concluded that the problem is global; the median prevalence of primary and acquired multi drug resistance was 1.4% (0-14.4%) and 13% (0-54.4%) respectively. A second WHO-IUATLD global project on drug surveillance carried out in 1996-1999 in 58 countries, found that the median prevalence of primary and acquired multi-drug resistance was 1% (0-14%) and 9% (0 - 48%) respectively. Current estimates report, the prevalence of primary and acquired multidrug resistance in India as 3.4% and 25% respectively.. It must be emphasized that optimal treatment of MDR-TB alone will not curb the epidemic. Efforts must be focused on the effective use of first line drugs in every new patient so as to prevent the ultimate emergence of multidrug resistance. The use of reserve drugs to cure multi-drug resistant tuberculosis and to reduce further transmission should be considered, but only as part of well structured programmes of tuberculosis control.

A Trend in Acquired Drug Resistances of Tuberculosis Patients Registered in Health Centers from 1981 to 2004 / 결핵및호흡기질환

BACKGROUND: The drug resistance rate in tuberculosis patients with history of chemotherapy is an important indicator of for evaluation of appropriateness of treatment regimens and compliance of patients. This study examined the long-term changes in the drug resistance rates among TB patients failed in treatment or reactivated. METHODS: The results of drug susceptibility testing data from patients registered in health centers from 1981 to 2004 were analyzed. RESULTS: The rate of resistance to isoniazid decreased from 90% to 20%, and the resistance to ethambutol decreased from 45% to 6%. The rate of resistance to rifampicin varied from 13% to 28% and the resistance to pyrazinamide was 5% to 10%. Multidrug resistance was about 2-3% lower than any rifampicin resistance rates. The second-line drug resistance was ranged from 1% to 3%. There was no difference between patients' genders. Patient numbers per 100,000 population increased with age. The regional distribution was even at 4-6 patients per 100,000 population, and drug resistance rates were significantly lower in big city areas than in small towns and rural areas. CONCLUSION: The rates of resistance of Mycobacterium tuberculosis isolated from TB patients with history of chemotherapy to isoniazid, rifampin, ethambutol, and isoniazid plus rifampin were significantly decreased during over two decades.

Expression and Functional Significance of Lung Resistance Protein in Pancreatic Adenocarcinoma Cell / 中国普外基础与临床杂志

Objective To detect the expression of lung resistance protein (LRP) and investigate its significance in pancreatic carcinoma cell lines (SW1990, PCT-2, PCT-3, PCT-4, Aspc-1, Capan-1, Mia-PaCa-2 and Panc-1). Methods Reverse transcription PCR (RT-PCR) and immunocytochemistry (ICC) were carried out to investigate the expression of LRP. Results LRP mRNA was absent in PCT-2 cell line by RT-PCR. Mild to moderate expression level was found in other pancreatic carcinoma cell lines. PCT-4, Aspc-1 and Panc-1 presented the highest LRP mRNA expression level, in contrast, SW1990, PCT-3, Capan-1 and Mia-PaCa-2 showed moderate LRP mRNA expression. The median value was 0.56?0.33. LRP was further validated by ICC. Absent to weak protein expression of LRP was found in PCT-2 and PCT-3. Overexpressed LRP was present in SW1990, Capan-1 and Aspc-1, furthermore, the highest expression of LRP was found in Panc-1, Mia-PaCa-2 and PCT-4 cell lines. Conclusion All these data showed that LRP might play an important role in multidrug resistance of pancreatic carcinoma.

Epidemiological characteristics of patients with drug-resistant tuberculosis / 결핵

BACKGROUND: There is increasing concern in many countries about the problem of drug-resistant tuberculosis. Prevalence of primary drug-resistant tuberculosis is the optimal epidemiological indicator for long term monitoring of national tuberculosis control program. Our purpose was The purpose of our study is to assess clinical characteristics and socioeconomic status of patients with drug-resistant tuberculosis. METHODS: We studied 68 cases with durg-resistant Mycobacterium tuberculosis infection diagnosed at the Ewha Womans University Mokdong Hospital from March, 1995 to February, 2000. RESULTS: Patients with primary drug-resistant tuberculosis(PDR) were younger(39.6±16.3 years vs. 48.2±16.5 years; p<0.05), had more population of less than more were under the age of 40 years aged-group(62.9% vs. 36.4%; p<0.05) and were more highly educated than those with acquired drug-resistant tuberculosis(ADR)(38.9% vs. 11.1%; p<0.05). In patients with ADR, the rates of familial history of tuberculosis and living in a rented house residence in a rented house were increased higher than compared with to those of patients with PDR. Patients with ADR had more involved lobes(2.0±0.8 vs. 1.4±0.7; p<0.01) and longer treatment duration than those with PDR(18.3±7.2 months vs. 10.6±6.3 months; p<0.05). Patients with ADR showed larger numbers of resistant were resistant to more number of drugs, lower hospitalization rate and higher rate of self-interruption of medication than those with PDR. In patients with PDR, mono-drug resistance was increased, whereas poly-and multi-drug resistances were decreased compared with those with ADR. Resistance to isoniazid was the highest among antituberculosis drugs, and resistance to isoniazid in patients with ADR was higher than that in patients with PDR(90.9% vs. 71.4%; p<0.05). CONCLUSIONS: Patients with ADR were more likely to include more population be of lower socioeconomic class, and patients with PDR seem seemed to be young and socially active population. For control of drug-resistant Mycobacterium tuberculosis infection, proper isolation and prevention of patient with drug-resistant tuberculosis are needed.