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1.
Nanoscale ; 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31913398

RESUMO

The development of molecules with immune stimulatory properties is crucial for cancer immunotherapy. In this work, we combined two peptide-based molecules, tuftsin (TKPR) and Nap-GDFDFDY, to develop a novel self-assembling molecule Nap-GDFDFDYTKPR (Comp. 3), which has strong CD8+ T cell stimulatory properties. Comp. 3 could self-assemble into nanofibers and hydrogels, which significantly improved the stability of tuftsin against enzyme digestion. The nanofibers of Comp. 3 enhanced the phagocytic activity of macrophages, promoted the maturation of DCs, and stimulated the expression of cytokines. In addition, it demonstrated an excellent anti-tumor efficacy in vivo by eliciting a strong CD8+ T immune response. Taken together, our observations revealed a powerful immune stimulating nanomaterial that is a promising compound for cancer immunotherapy.

2.
Int J Biol Sci ; 16(1): 38-48, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31892844

RESUMO

Alternative pre-mRNA splicing plays important roles in co-transcriptional and post-transcriptional regulation of gene expression functioned during many developmental processes, such as spermatogenesis. The studies focusing on alternative splicing on spermatogenesis supported the notion that the development of testis is regulated by a higher level of alternative splicing than other tissues. Here, we aim to review the mechanisms underlying alternative splicing, particularly the splicing variants functioned in the process of spermatogenesis and the male infertility. There are five points regarding the alternative splicing including ⅰ) a brief introduction of alternative pre-mRNA splicing; ⅱ) the alternative splicing events in spermatogenesis-associated genes enriched in different stages of spermatogenesis; ⅲ) the mechanisms of alternative splicing regulation, such as splicing factors and m6A demethylation; ⅳ) the splice site recognition and alternative splicing, including the production and degradation of abnormal transcripts caused by gene variations and nonsense-mediated mRNA decay, respectively; ⅴ) abnormal alternative splicing correlated with male infertility. Taking together, this review highlights the impacts of alternative splicing and splicing variants in mammal spermatogenesis and provides new insights of the potential application of the alternative splicing into the therapy of male infertility.

4.
Eur J Immunol ; 2020 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-31954378

RESUMO

The B-cell CLL/lymphoma 6 (Bcl6) oncogenic repressor is a master regulator of humoral immunity and B-cell lymphomagenesis. Whereas much research has focused on its regulation and function of germinal center B cells and T cells, the role of Bcl6 in regulating the functions of innate immunity is not well defined. Here, we demonstrated that experimental autoimmune encephalomyelitis (EAE) is exacerbated in LysM Cre+/ - Bcl6fl/fl mice. Although other cells such as neutrophils might be involved in this conditional mutant mouse model, we found that the disease pathology is mainly associated with a biased M1 macrophage activity and an enhanced encephalitogenic CD4+ Th17 cell response. In addition, LPS-induced sepsis mice exhibited an enhanced M1 and inhibited M2 response, further confirming that Bcl6 has an important role in regulating macrophage polarization. Mechanistically, Bcl6 interacts with IκBζ and interferes its binding to the Il-6 (interleukin-6) promotor in macrophages, leading to a suppressed transcription of Il-6. These findings have demonstrated that Bcl6 exerts its regulatory function mainly by repressing Il-6 expression in macrophages. Thus, our study presents a novel role for Bcl6 in regulating immune response and inflammation. Interaction between Bcl6 and IκBζ in macrophages may provide a potential therapeutic target for autoimmune inflammatory disease. This article is protected by copyright. All rights reserved.

5.
Eur J Pharm Sci ; : 105216, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31945451

RESUMO

With the purpose of overcoming the serious hepatotoxicity of antituberculosis drug isoniazid (INH), a cocrystallization strategy based on complementary advantages was implemented by choosing the hepatoprotective nutraceutical quercetin (QCT) as the cocrystal former. The strategy plays the solubility advantage of INH to improve the bioavailability of the insoluble QCT, thereby significantly enhancing the QCT's hepatoprotective effects. The optimized protective effects of QCT, in turn, feed back to INH to reduce its hepatotoxicity. Along this line, a novel INH-QCT cocrystal was successfully prepared and structurally characterized. The systematic evaluation results of the in vitro/vivo revealed that, due to the advantage of INH's solubility, the dissolution efficiency of QCT from the cocrystal was increased 51.67-fold compared with that of coarse quercetin, and the oral bioavailability of the cocrystal in rats was enhanced by 28.91 times. As a result, the INH-QCT cocrystal almost removed INH induced serious hepatotoxicity, which has been demonstrated by the hepatotoxicity studies in rats. These findings present new opportunities for the advantageous solid forms of low-toxic antituberculosis drugs, and open new avenues against toxic side effects of drugs through the cocrystallization mean.

6.
Bone ; : 115226, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31945472

RESUMO

OBJECTIVE: This multicenter study aimed to evaluate the association between volumetric bone mineral density (vBMD) and abdominal aortic calcification (AAC) in a Chinese population. METHODS: Quantitative computed tomography (QCT) and Agatston score (AS) were used to measure vBMD and AAC, respectively, in 3457 participants during 2013-2017. The association between vBMD and AAC was assessed using multivariate regression analysis, adjusted for age, residence, education, body mass index, and other cardiovascular risk factors. RESULTS: The mean age of women and men was 61.4 and 62.7 years, respectively. In total, 30.4% of women and 37.7% of men were found to have AAC. After full adjustment, higher vBMD was associated with lower AAC score (ß, -0.095; 95% confidence interval [CI], -0.167 to -0.024; P = 0.0087) and lower AAC prevalence (odds ratio [OR], 0.873; 95% CI, 0.824 to 0.924; P < 0.0001) in men. Inverse trends were also observed in the association of vBMD quartile with AAC severity (lowest vs highest quartile; ß = 0.235; 95% CI, 0.011 to 0.459; Ptrend < 0.0001) and AAC prevalence (lowest vs highest quartile; OR = 1.329; 95% CI, 1.087 to 1.625; Ptrend < 0.0001) in men. However, no significant result was obtained in women, except for the association between quartiles of vBMD and AAC score. CONCLUSIONS: In our study, vBMD was inversely associated with AAC among men independent of age and shared risk factors. However, the association was not significant among women.

7.
Sensors (Basel) ; 20(2)2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31947594

RESUMO

This paper introduces a new method to measure whole cycle length change non-destructively and continuously using a digital image analysis system. The macroscale length changes of mortars containing different shrinkage-reducing admixture (SRA) dosages (0%, 1%, 2% and 5% by cement weight) were first determined using a complementary metal oxide semiconductor (CMOS) image sensor under alternating dry and wet curing conditions. After that, the length change was calculated using developed digital image processing technology (DIPT) software. After that, several significant conclusions could be drawn by combining with the results of systematic tests of the macroscopic and microscale physical properties of the cement mortar using X-ray diffraction, scanning electron microscopy, mercury intrusion porosimetry (MIP) and nuclear magnetic resonance (NMR) methods. The test results indicated that SRAs exhibited significant effects on the shrinkage inhibition of cement mortars, whereas the shrinkage reduction behaviour was also affected by varying the curing conditions. The MIP and NMR analyses demonstrated that SRAs reduced the irreversible shrinkage of the cement mortars by decreasing the volume percentage of the 3-50 nm pores and promoting the conversion of calcium silicate hydrate gel from an oligomeric to a high polymerization state thereby improving the volume stability of cement mortars.

8.
Cells ; 9(1)2020 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-31947947

RESUMO

Metabolic reprogramming universally occurs in cancer. Mitochondria act as the hubs of bioenergetics and metabolism. The morphodynamics of mitochondria, comprised of fusion and fission processes, are closely associated with mitochondrial functions and are often dysregulated in cancer. In this study, we aim to investigate the mitochondrial morphodynamics and its functional consequences in human liver cancer. We observed excessive activation of mitochondrial fusion in tumor tissues from hepatocellular carcinoma (HCC) patients and in vitro cultured tumor organoids from cholangiocarcinoma (CCA). The knockdown of the fusion regulator genes, OPA1 (Optic atrophy 1) or MFN1 (Mitofusin 1), inhibited the fusion process in HCC cell lines and CCA tumor organoids. This resulted in inhibition of cell growth in vitro and tumor formation in vivo, after tumor cell engraftment in mice. This inhibitory effect is associated with the induction of cell apoptosis, but not related to cell cycle arrest. Genome-wide transcriptomic profiling revealed that the inhibition of fusion predominately affected cellular metabolic pathways. This was further confirmed by the blocking of mitochondrial fusion which attenuated oxygen consumption and cellular ATP production of tumor cells. In conclusion, increased mitochondrial fusion in liver cancer alters metabolism and fuels tumor cell growth.

9.
Elife ; 92020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31951198

RESUMO

DNA double strand breaks (DSBs) have detrimental effects on cell survival and genomic stability, and are related to cancer and other human diseases. In this study, we identified microtubule-depolymerizing kinesin Kif2C as a protein associated with DSB-mimicking DNA templates and known DSB repair proteins in Xenopus egg extracts and mammalian cells. The recruitment of Kif2C to DNA damage sites was dependent on both PARP and ATM activities. Kif2C knockdown or knockout led to accumulation of endogenous DNA damage, DNA damage hypersensitivity, and reduced DSB repair via both NHEJ and HR. Interestingly, Kif2C depletion, or inhibition of its microtubule depolymerase activity, reduced the mobility of DSBs, impaired the formation of DNA damage foci, and decreased the occurrence of foci fusion and resolution. Taken together, our study established Kif2C as a new player of the DNA damage response, and presented a new mechanism that governs DSB dynamics and repair.

10.
Nat Chem Biol ; 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31932723

RESUMO

In plants, lineage-specific metabolites can be created by activities derived from the catalytic promiscuity of ancestral proteins, although examples of recruiting detoxification systems to biosynthetic pathways are scarce. The ubiquitous glyoxalase (GLX) system scavenges the cytotoxic methylglyoxal, in which GLXI isomerizes the α-hydroxy carbonyl in the methylglyoxal-glutathione adduct for subsequent hydrolysis. We show that GLXIs across kingdoms are more promiscuous than recognized previously and can act as aromatases without cofactors. In cotton, a specialized GLXI variant, SPG, has lost its GSH-binding sites and organelle-targeting signal, and evolved to aromatize cyclic sesquiterpenes bearing α-hydroxyketones to synthesize defense compounds in the cytosol. Notably, SPG is able to transform acetylated deoxynivalenol, the prevalent mycotoxin contaminating cereals and foods. We propose that detoxification enzymes are a valuable source of new catalytic functions and SPG, a standalone enzyme catalyzing complex reactions, has potential for toxin degradation, crop engineering and design of novel aromatics.

11.
Artigo em Inglês | MEDLINE | ID: mdl-31932880

RESUMO

PURPOSE: The aim of the present study was to investigate the risk factors associated with central lymph node metastasis (CLNM) in papillary thyroid microcarcinoma (PTMC). METHODS: A total of 553 patients with PTMC confirmed by histological examination, who underwent thyroidectomy and central neck dissection (CND), were enrolled. The clinicopathological and ultrasonographic features from the patients were analyzed retrospectively. RESULTS: PTMC patient age, Hashimoto thyroiditis (HT), tumor location, extrathyroidal extension (ETE), microcalcification and higher E values were correlated with the incidence of CLNM. Multivariate logistic regression analysis showed that age, HT, tumor location, ETE and Emax were related to the extent of CLNM. Chi-squared automatic interaction detection (CHAID) classification tree model showed that patients with tumor in upper/lower third combined ETE had a high risk of CLNM. Furthermore, cN0 PTMC patients with age ≤ 45 years and ETE had more extensive CLNM. CONCLUSION: Our observations could be helpful for the assessment of prognostic factors of PTMC patients with CLNM.

12.
Accid Anal Prev ; 136: 105299, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31945594

RESUMO

The connected and automated vehicle (CAV) technologies have made great progresses. It has been commonly accepted that CV or AV technologies would reduce human errors in driving and benefit traffic safety. However, the answer of how many crashes can be prevented because of CV or AV technologies has not reached a consistent conclusion. In order to quantitatively answer this question, this study used meta-analysis to evaluate the safety effectiveness of nine common and important CV or AV technologies, and tested the safety effectiveness of these technologies for six countries. First, 73 studies about the safety impact of CV or AV technologies were filtered out from 826 CAV-related papers or reports. Second, the safety impacts of these technologies with regard to assistant types and triggering times have been compared. It shows AV technologies can play a more significant role than CV technologies, and the technologies with closer triggering time to collision time have greater safety effectiveness. Third, in the meta-analysis, the random effect model was used to evaluate the safety effectiveness, and the funnel plots and trim-and-fill method were used to evaluate and adjust publication bias, so as to objectively evaluate the safety effectiveness of each technology. Then, according to the crash data of six countries, the comprehensive safety effectiveness and compilation of safety effectiveness of the above technologies were calculated. The results show that if all of technologies were implemented in the six countries, the average number of crashes could be reduced by 3.40 million, among which the India would reduce the most (54.24%). Additionally, different countries should develop different development strategies, e.g., USA should prioritize the development of the lane change warning and intersection warning, the UK should prioritize applications related to intersection warning and rear-end warning. Overall, this study provides comprehensive and quantitative understating of the safety effectiveness of CA or AV technologies and would contribute to government, vehicle companies, and agencies in deciding the development priority of CA or AV technologies.

13.
Eur J Med Chem ; 189: 112028, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31945665

RESUMO

Extrahepatic cytochrome P450 1B1 (CYP1B1), which is highly expressed in various tumors, is an attractive and potential target for cancer prevention, therapy, and reversal of drug resistance. CYP1B1 inhibition is the current predominant therapeutic paradigm to treating CYP1B1-mediated malignancy, but therapeutic effect has little success. Herein, we reported CYP1B1 degradation in place of CYP1B1 inhibition for reversing drug resistance toward docetaxel in CYP1B1-overexpressing prostate cancer cell line DU145 using a PROTAC strategy. Replacing chlorine atom of a CYP1B1 selective inhibitor we found previously with ethynyl, we got the resulting α-naphthoflavone derivative 5 which kept strong inhibition against CYP1B1 (IC50 = 0.4 ± 0.2 nM) and high selectivity. Coupling of 5 with thalidomide derivatives of varying chain lengths afforded conjugates 6A-Dvia click reaction. In vitro cell-based assay indicated that 6C was more effective in eliminating drug resistance of CYP1B1-overexpressed DU145 cells compared with other analogues. Western blotting analysis showed CYP1B1 degradation was one main reason for the reversal of drug resistance to docetaxel and the effect was obtained in a concentration-dependent manner. This work is the first attempt to overcome CYP1B1-mediated drug resistance via CYP1B1 degradation instead of CYP1B1 inhibition, which could provide a new direction toward eliminating drug resistance.

14.
Chin J Nat Med ; 18(1): 57-69, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31955824

RESUMO

Diterpenoid lactones (DLs), a group of furan-containing compounds found in Dioscorea bulbifera L. (DB), have been reported to be associated with hepatotoxicity. Different hepatotoxicities of these DLs have been observed in vitro, but reasonable explanations for the differential hepatotoxicity have not been provided. Herein, the present study aimed to confirm the potential factors that contribute to varied hepatotoxicity of four representative DLs (diosbulbins A, B, C, F). In vitro toxic effects were evaluated in various cell models and the interactions between DLs and CYP3A4 at the atomic level were simulated by molecular docking. Results showed that DLs exhibited varied cytotoxicities, and that CYP3A4 played a modulatory role in this process. Moreover, structural variation may cause different affinities between DLs and CYP3A4, which was positively correlated with the observation of cytotoxicity. In addition, analysis of the glutathione (GSH) conjugates indicated that reactive intermediates were formed by metabolic oxidation that occurred on the furan moiety of DLs, whereas, GSH consumption analysis reflected the consistency between the reactive metabolites and the hepatotoxicity. Collectively, our findings illustrated that the metabolic regulation played a crucial role in generating the varied hepatotoxicity of DLs.

15.
Chin J Nat Med ; 18(1): 75-80, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31955826

RESUMO

Purpurolides D-F (1-3), three new polyoxygenated bergamotanes bearing a 6/4/5/5 tetracyclic ring system, were isolated from the endophytic fungus Penicillium purpurogenum IMM 003. Their structures were unambiguously elucidated based on extensive spectroscopic data analyses, 13C NMR chemical shifts calculations coupled with the DP4+ probability method, and the calculated and experimental electronic circular dichroism (ECD) spectra. Compounds 1-3 showed significant inhibitory activity against pancreatic lipase (PL). The result highlights that the presence of 3-hydroxylated decanoic acid moiety at C-14 is important for increasing the inhibition potency against PL.

16.
J Cell Physiol ; 235(2): 1405-1416, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31347176

RESUMO

Breast cancer patients with high expression of aldehyde dehydrogenases (ALDHs) cell population have higher tolerability to chemotherapy since the cells posses a characteristic of breast cancer stem cells (BCSCs) that are resistant to conventional chemotherapy. In this study, we found that the ALDH-positive cells were higher in CD44+ CD24- and CD44+ CD24- ESA+ BCSCs than that in both BT549 and MDA-MB-231 cell lines but microRNA-7 (miR-7) level was lower in CD44+ CD24- and CD44+ CD24- ESA+ BCSCs than that in MDA-MB-231 cells. Moreover, miR-7 overexpression in MDA-MB-231 cells decreased ALDH1A3 activity by miR-7 directly binding to the 3'-untranslated region of ALDH1A3; while the ALDH1A3 expression was downregulated in MDA-MB-231 cells, the expressions of CD44 and Epithelium Specific Antigen (ESA) were reduced along with decreasing the BCSC subpopulation. Significantly, enforced expression of miR-7 in CD44+ CD24- ESA+ BCSC markedly inhibited the BCSC-driven xenograft growth in mice by decreasing an expression of ALDH1A3. Collectively, the findings demonstrate the miR-7 inhibits breast cancer growth via suppressing ALDH1A3 activity concomitant with decreasing BCSC subpopulation. This approach may be considered for an investigation on clinical treatment of breast cancers.

17.
Pancreas ; 49(1): 96-104, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31856084

RESUMO

OBJECTIVE: Long noncoding RNAs (lncRNAs) have received increasing attention as potential regulators of several biological processes. However, the precise effects of lncRNAs in acute pancreatitis (AP) have seldom been studied. This study aimed to describe the microarray-based differential expression profile of messenger RNA (mRNAs) and lncRNAs in AP and identify candidate biomarkers for the diagnosis, prognosis, and treatment of AP. METHODS: A rat model of AP was generated with retrograde pancreatic ductal injection of sodium taurocholate, and the pancreas was harvested for microarray detection. The biological functions of differentially expressed mRNAs noted from microarray data were assessed by bioinformatics analysis. A coding-noncoding gene coexpression network was built for the most promising mRNAs, from which 10 lncRNAs were selected for subsequent validation by real-time quantitative reverse transcription polymerase chain reaction. RESULTS: There were 1156 lncRNAs and 3022 mRNAs distinctively dysregulated in rats with AP relative to the controls. The significantly enriched Gene Ontology term associated with upregulated mRNAs was immune system process. Kyoto Encyclopedia of Genes and Genomes functional analysis demonstrated that the upregulated transcripts were highly enriched in natural killer cell-mediated cytotoxicity. CONCLUSIONS: Further research is needed to establish lncRNAs uc.308-, BC158811, BC166549, BC166474, and BC161988 as diagnostic and therapeutic targets.

18.
J Dairy Sci ; 103(1): 840-845, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31733844

RESUMO

This study investigated the antimicrobial susceptibility of methicillin-resistant Staphylococcus aureus (MRSA) isolated from cases of subclinical bovine mastitis in China, as well as resistance mechanisms and virulence genes encoding adhesins and toxins. We determined antimicrobial susceptibility using the disk diffusion method, and analyzed resistance, adhesin, and toxin genes using PCR. We confirmed MRSA in 73 of 498 (14.7%) Staph. aureus isolates recovered from subclinical mastitic milk samples. All isolates were positive for mecA. The MRSA isolates showed high resistance to penicillin (100.0%), gentamicin (100.0%), and tetracycline (98.6%). All MRSA isolates harbored resistance genes blaZ (penicillin), aacA/aphD (gentamicin), and tetM (alone or in combination with tetK, tetracycline). Moreover, all isolates carried the adhesin genes fnbpA, clfA, clfB, cna, sdrE, and map/eap, and most carried sdrC (98.6%), sdrD (95.9%), bbp (94.5%), and ebpS (80.8%). The toxin genes seh, hla, and hld were present in all isolates, and most isolates carried sea (71.2%), seg (84.9%), sei (82.2%), lukE-lukD (97.3%), and hlg (72.6%). These findings of high-level resistance to antimicrobials commonly used in dairy cattle should lead to calls for antibiogram analysis before antimicrobial therapy. The high frequency of adhesin and toxin genes in MRSA indicates their potential virulence in bovine mastitis in China.

19.
Cardiovasc Pathol ; 44: 107159, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31743871

RESUMO

Trastuzumab-mediated cardiotoxicity poses a significant challenge in the treatment of human epidermal growth factor receptor 2-positive breast cancer. To understand the underlying mechanisms, we conducted experiments to determine ultrastructural changes of rabbit cardiac tissue under different experimental conditions, including differing doses of trastuzumab and supplementation with oral sodium selenite, an antioxidant. Histopathology revealed lymphocyte and macrophage infiltration in myocardium of rabbits receiving four doses of trastuzumab. Transmission electron microscopy showed substantial changes with trastuzumab, including edema with separation of myofibril bundles and rupture of sarcomeres. Within mitochondria, edema resulted in disorganization of the cristae. Some mitochondria exhibited eccentric projections of their membranes with disruption of both inner and outer membranes. These changes were seen to a lesser extent in rabbits who received oral sodium selenite prior to trastuzumab. Selenium is integral to functioning of mitochondrial glutathione peroxidases, important antioxidants that also maintain membrane integrity. If mitochondria are disrupted as part of trastuzumab cardiac toxicity, selenium supplementation might be an important therapeutic or preventive consideration. Larger studies to explore this hypothesis are warranted.

20.
J Cell Physiol ; 235(3): 2183-2194, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31489631

RESUMO

New York esophageal squamous cell carcinoma 1 (NY-ESO-1) is aberrantly expressed in multiple myeloma (MM) patients, however, its role remains largely unknown. The present study aimed to investigate the effect of NY-ESO-1 knockdown on MM impact and provide evidence for targeting treatment of MM. Human MM U266 cells were infected with lentivirus-based small hairpin RNA-targeting NY-ESO-1 (LV-shNY-ESO-1). Cellular proliferation, colony-forming, migration, and invasion assays were employed. The expressions of cell cycle and epithelial-mesenchymal transition (EMT)-related molecules, MM growth, and mouse osteolytic lesions were evaluated. The results showed that the LV-shNY-ESO-1-U266 cells had a lower expression of NY-ESO-1 and a higher expressions of p21 and E-cadherin, and a weaker abilities of colony formation, drug-resistant to adriamycin, migration, and invasion than those of the control cells. Importantly, the knockdown of NY-ESO-1 inhibited significantly the U266 cell-induced MM growth and osteolytic lesions along with increasing the expressions of E-cadherin, p21, and p53 in mice challenged with LV-shNY-ESO-1-U266 cells. Collectively, our findings demonstrate that knockdown of NY-ESO-1 suppressed the U266 cell-induced MM growth and osteolytic lesions by inhibition of the MMs cell cycle and EMT. The NY-ESO-1 knockdown may be considered for future clinical trials in MM.

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