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Triple-negative breast cancer (TNBC) is a nasty disease with extremely high malignancy and poor prognosis. Annexin A3 (ANXA3) is a potential prognosis biomarker, displaying an excellent correlation of ANXA3 overexpression with patients' poor prognosis. Silencing the expression of ANXA3 effectively inhibits the proliferation and metastasis of TNBC, suggesting that ANXA3 can be a promising therapeutic target to treat TNBC. Herein, we report a first-in-class ANXA3-targeted small molecule (R)-SL18, which demonstrated excellent anti-proliferative and anti-invasive activities to TNBC cells. (R)-SL18 directly bound to ANXA3 and increased its ubiquitination, thereby inducing ANXA3 degradation with moderate family selectivity. Importantly, (R)-SL18 showed a safe and effective therapeutic potency in a high ANXA3-expressing TNBC patient-derived xenograft model. Furthermore, (R)-SL18 could reduce the β-catenin level, and accordingly inhibit the Wnt/β-catenin signaling pathway in TNBC cells. Collectively, our data suggested that targeting degradation of ANXA3 by (R)-SL18 possesses the potential to treat TNBC.
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Objective To explore the value of UF-5000 urinary sediment analyzer in assistant examination of urinary tract infections by comparing the results of bacteria and white blood cells for UF-5000 with those of routine laboratory methods.Methods A total of 1 021 clean mid-stage urine samples suspected urinary tract infection were collected from the inpatients and outpatients of the Guangdong Provincial People's Hospital from October to December 2017.All specimens were detected by UF-5000 to evaluate the repeatability,linearity,carrying contamination rate,stability and efficiency of review flag by the instrument.Urine bacterial culture and clinical diagnosis were used as reference standards to calculate the coincidence rate of bacterial test results with purified bacteria,coincidence rate with bacterial culture,and agreement rate with cultured colonies.The urinary fungal culture and clinical diagnosis were used as reference standards to calculate the coincidence rate,sensitivity and specificity of the fungal test.Based on the results of bacterial culture and clinical diagnosis,UF-5000 was used to detect the efficacy of white blood cells and bacteria for the diagnosis of UTI.The results of UF-5000 detection,the results of urinary dry chemistry analyzer UC-3500,and the results of bacterial smear microscopy were compared with the results of urinary bacterial culture to determine the sensitivity,specificity and sensitivity of each method,and the coincidence rate of with the culture method.Statistical analysis was performed using variance analysis,Wilcoxon rank sum test,coincidence rate test (Kappa test),and receiver operating characteristic curve (ROC curve).Results UF-5000 was used to detect bacteria and white blood cells,UC-3500 was used to detect neutrophil esterase and nitrite with good repeatability,which met the EP5-A requirements;the linear relationship between bacteria was very good in the range of 0-10 000/ml,R=0.999;the contamination rate of UF-5000 was 0.00％ for bacteria,0.01％ for white blood cells.The rate of UC-3500 was qualified;the bacteria was stable for 2 hours at room temperature and 6 hours at 4 ℃,and the white blood cells were stable for 4 hours at room temperature and 4 hours at 4 ℃.Compared with UF-1000i,the review flag rate of UF-5000 reduced about 77.8％.The coincidence rate of detection and purification of UF-5000 bacteria was 100.0％(16/16),that of Gram-negative bacteria (G-) was 94.0％ (110/117),that of Gram-positive bacteria (G+) was 82.2％(37/45).The agreement rate of compared with bacterial colonies was 95.1％(216/227),and that of fungi culture was 77.1％ (749/972),that of sensitivity was 81.9％(118/144),and that of specificity was 76.2％(631/828).UF-5000,UC-3500,and bacterial smear microscopy showed that the ability of bacterial infection of urinary tract was compared with the results of traditional bacterial culture.The UF-5000 urinary tract infection flag (UTI) had the highest agreement rate,reaching 84.1％ (180/214).The sensitivity was 70.3％ (52/74),the specificity was 91.4％ (128/140);the coincidence rate of UC-3500 was 73.8％ (158/214),the sensitivity was 25.7％ (19/74),and the specificity was 99.3％ (139/140);the consistency of bacterial smear microscopy was 66.4％ (142/214),the sensitivity was 82.4％ (61/74),and the specificity was 57.9％ (81/140).Conclusion The total number of bacteria and white blood cell counted by UF-5000,the flag of bacterial and the UTI information,have partial clinical significance in the rapid detection of urinary tract infection.
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Background and purpose: MORC2 (microrchidia family CW-type zinc finger 2, MORC2) is a newly identified chromatin remodeling protein that plays key roles in DNA-based biological processes including gene transcription and DNA damage repair. However, its functional role in breast cancer development and progression re-mains unknown. ALDH1A3 (aldehyde dehydrogenase 1 family member A3), a member of the aldehyde dehydrogenases (ALDH) superfamily, is a putative breast cancer stem cell marker, but its regulatory mechanism in breast cancer is poor-ly characterized. This study aimed to investigate the effects of knockdown of endogenous MORC2 on the expression levels of ALDH1A3 and the breast cancer stem-like phenotype in MCF-7 cells. Methods: Human breast cancer MCF-7 cells were infected with negative control short hairpin RNAs (shNC) and specific shRNAs targeting human MORC2 (shMORC2), followed by selection with puromycin to generate stable MORC2 gene knockdown cell lines. Western blot and real-time fluorescent quantitative polymerase chain reaction (RTFQ-PCR) were used to examine the protein and mRNA levels of ALDH1A3 in MCF-7 cells stably expressing shNC and shMORC2. Microsphere formation and fluo-rescence-activated cell sorting (FACS) assays were used to analyze the effects of knockdown of MORC2 on the breast cancer stem-like phenotype. Results: Western blot and RTFQ-PCR analyses revealed that the protein and mRNA levels of ALDH1A3 were significantly down-regulated in shMORC2 expressing cells as compared with shNC -transfected control cells. Moreover, mammosphere formation assay showed that knockdown of endogenous MORC2 in MCF-7 cells significantly reduced the ability of cells to form microspheres. Consistently, FACS assays demonstrated that shMORC2-transfected cells had a lower proportion of ALDH-positive stem cells as compared with shNC expressing cells. In contrast, knockdown of MORC2 did not significantly affect the CD44+CD24- stem cell population. Conclusion:MORC2 promotes a breast cancer stem-like phenotype through, at least in part, regulating ALDH1A3 expression.
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Cancer stem cells (CSCs), a subpopulation of cancer cells with ability of initiating tumorigenesis, exist in many kinds of tumors including breast cancer. Cancer stem cells contribute to treatment resistance and relapse. Conventional treatments only kill differentiated cancer cells, but spare CSCs. Combining conventional treatments with therapeutic drugs targeting to CSCs will eradicate cancer cells more efficiently. Studying the molecular mechanisms of CSCs regulation is essential for developing new therapeutic strategies. Growing evidences showed CSCs are regulated by non-coding RNA (ncRNA) including microRNAs and long non-coding RNAs (lncRNAs), and histone-modifiers, such as let-7, miR-93, miR-100, HOTAIR, Bmi-1 and EZH2. Herein we review the roles of microRNAs, lncRNAs and histone-modifiers especially Polycomb family proteins in regulating breast cancer stem cells (BCSCs).
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Humans , Breast Neoplasms , Genetics , Metabolism , Pathology , Histones , Metabolism , Neoplastic Stem Cells , Metabolism , RNA, Untranslated , Genetics , MetabolismABSTRACT
Objective To explore the isolation and antimicrobial susceptibility of Mycoplasma from urogenital tract,and provide the basis for rational clinical treatment.Methods Urogenital tract specimens from 57 904 outpa-tients in a hospital between 2008 and 2014 were performedUreaplasma urealyticum (Uu)and Mycoplasma hominis (Mh)culture,identification,and antimicrobial susceptibility testing.Results Of 57 904 patients with urogenital in-fection,21 614 (37.33%)had positive culture for Mycoplasma,isolation rate of Mycoplasma in female and male were 42.14% (18 917/44 889)and 20.72% (2 697/13 015 )respectively;Mycoplasma was mainly isolated from population of 21 -40 years old;Uu≥104 CFU/mL and Mh<104 CFU/mL mixed infection was common(69.35%). The resistance of Mycoplasma to doxycycline,josamycin,and tetracycline were all low(<10%);resistance rates of Mh to doxycycline,erythromycin,clarithromycin,and roxithromycin were all significantly higher than Uu (all P <0.05).Conclusion Mycoplasma infection/carriage rate in female outpatients is significantly higher than male outpa-tients,antimicrobial profile of Uu is different from Mh,josamycin and doxycycline can be as the first choice for treatment of non-gonococcal urethritis (cervicitis)caused by Mycoplasma.
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A strain of Prototheca species isolated from a case of meningitis was identified by routine morphologic and biochemical methods as well as amplification of the related genes, in which the 28S large-subunit (LSU) region of ribosomal RNA (rRNA) gene and intergenic space (ITS) were amplified with universal fungal primers. The small-subunit (SSU) rRNA gene was amplified with eukaryote-specific primers and Prototheca genus-specific primers. Then, compared the sequences with the ones posted on BLAST (www. ncbi. nlm. nih. gov/BLAST). The organism choice giving the closest match, up to 99%, was considered the most likely correct identification. It was found that this strain of fungus grew well at 25 ℃ or 37 ℃. Smooth,moist colonies with white color were observed on Sabouraud Dextrose Agar (SDA) and Potato Dextrose Agar (PDA). Microscopically, globular or ovoid cells, a number of round, ovoid shaped endospores could be observed. No hypha, ascus or blastic conidia was found upon cultivation on SDA. Based on the morphological characteristics, this isolate could be identified as Prototheca species. The identity with Prototheca wickerhamii was 2.9 % as demonstrated by the API 20C AUX system. Sequence analysis showed that the ITS gene was proved to be a complex structural region which was not suitable for the identification of Prototheca species, but the LSU and SSU rDNA regions showed 94% and 99.9% sequence identities with Prototheca zopfii var. hydrocarbonea (P. zopfii var. hydrocarbonea) respectively, indicating that the SSU rRNA gene sequence might be more reliable on than the LSU rRNA gene sequence for identification of Prototheca species.
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OBJECTIVE To investigate the infection status and drug resistance of Mycoplasma strains isolated from genitourinary tract. METHODS The IST kit produced by Bio-Merieux was used to culture the Mycoplasma strains and to do drug susceptibility test. RESULTS The Mycoplasma infection ratio was 41.0%,with Ureaplasma urealyticum(Uu) 71.9%,Mycoplasma hominis(Mh) 2.3%,and mixed infection 25.8%,respectively.The drug susceptibility test showed that drug resistance ratios were as follows: to erythromycin 58.7%,ciprofloxacin 50.0%,ofloxacin 41.3%,pristinamycin 3.3%,josamycin 5.4% and doxycycline 7.6%. CONCLUSIONS Mycoplasma infection in genitourinary tract is mainly due to Uu infection.We should rationally choose and use antibiotics according to the drug susceptibility,and josamycin is very effective.
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OBJECTIVE To determine pathogens and drug resistance of lower respiratory tract infection in patients receiving mechanical ventilation in ICU and to provide the reference for clinical prevention and treatment.(METHODS) The ages,underlying diseases,pathogens distribution and resistance rate of Gram-negative bacteria of 110 cases patients receiving mechanical ventilation and being complicated lower respiratory tract infection in ICU were investigated.RESULTS Totally 110 strains of pathogens were isolated by bacterial culturing.The ratio of the Gram-negative bacteria to total bacteria isolated was 72.7%(80 strains) and of the Gram-positive bacteria was(18.2%)(19 strains),of the fungi was 10%(11 strains),among them the Pseudomonas aeruginosa contributed the majority,and ESBLs accounted for 38.8%,MRSA contributed 31.6% in Staphylococcus.Multidrug-(resistance) of Gram-negative bacteria to antimicrobial agents was serious.CONCLUSIONS Gram-negative bacteria are the majority of the pathogens,isolated from patients with lower respiratory tract infection in ICU receiving mechanical ventilation.It is suggested that there be urgent need for surveillance of bacterial resistance and rational use of antimicrobial(agents) during clinical therapy.