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1.
Biochim Biophys Acta Rev Cancer ; 1879(5): 189143, 2024 Jun 25.
Article in English | MEDLINE | ID: mdl-38936517

ABSTRACT

Transposable elements (TEs), comprising nearly 50% of the human genome, have transitioned from being perceived as "genomic junk" to key players in cancer progression. Contemporary research links TE regulatory disruptions with cancer development, underscoring their therapeutic potential. Advances in long-read sequencing, computational analytics, single-cell sequencing, proteomics, and CRISPR-Cas9 technologies have enriched our understanding of TEs' clinical implications, notably their impact on genome architecture, gene regulation, and evolutionary processes. In cancer, TEs, including long interspersed element-1 (LINE-1), Alus, and long terminal repeat (LTR) elements, demonstrate altered patterns, influencing both tumorigenic and tumor-suppressive mechanisms. TE-derived nucleic acids and tumor antigens play critical roles in tumor immunity, bridging innate and adaptive responses. Given their central role in oncology, TE-targeted therapies, particularly through reverse transcriptase inhibitors and epigenetic modulators, represent a novel avenue in cancer treatment. Combining these TE-focused strategies with existing chemotherapy or immunotherapy regimens could enhance efficacy and offer a new dimension in cancer treatment. This review delves into recent TE detection advancements, explores their multifaceted roles in tumorigenesis and immune regulation, discusses emerging diagnostic and therapeutic approaches centered on TEs, and anticipates future directions in cancer research.

2.
FEMS Microbiol Lett ; 3712024 Jan 09.
Article in English | MEDLINE | ID: mdl-38740525

ABSTRACT

Enterococcus raffinosus, named by Collins et al. in 1989, is a cocci-shaped bacterium that typically appears in pairs or short chains. As a Gram-positive and non-motile bacterium, it grows at 10°C-45°C, exhibiting negative peroxidase activity [1]. It is a normal flora in the oropharynx and gastrointestinal tract of domestic cats [2] and can also be isolated from human rectal swabs [3], it belongs to the same genus Enterococcus as Enterococcus faecalis and Enterococcus faecium. Enterococcus faecalis and Enterococcus faecium constitute 90% of clinically isolated strains. However, the incidence of other enterococci, excluding E. faecalis and E. faecium, is on the rise [4]. In this case report, a patient with pediatric urinary tract infections caused by E. raffinosus was presented, and a summary of relevant literature was provided.


Subject(s)
Anti-Bacterial Agents , Enterococcus , Gram-Positive Bacterial Infections , Urinary Tract Infections , Humans , Urinary Tract Infections/microbiology , Urinary Tract Infections/drug therapy , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Enterococcus/drug effects , Enterococcus/isolation & purification , Gram-Positive Bacterial Infections/microbiology , Gram-Positive Bacterial Infections/drug therapy , Male , Remission, Spontaneous , Child
3.
Cell Res ; 34(1): 58-75, 2024 01.
Article in English | MEDLINE | ID: mdl-38168642

ABSTRACT

Triple-negative breast cancer (TNBC) is an aggressive disease characterized by remarkable intratumor heterogeneity (ITH), which poses therapeutic challenges. However, the clinical relevance and key determinant of ITH in TNBC are poorly understood. Here, we comprehensively characterized ITH levels using multi-omics data across our center's cohort (n = 260), The Cancer Genome Atlas cohort (n = 134), and four immunotherapy-treated cohorts (n = 109). Our results revealed that high ITH was associated with poor patient survival and immunotherapy resistance. Importantly, we identified zinc finger protein 689 (ZNF689) deficiency as a crucial determinant of ITH formation. Mechanistically, the ZNF689-TRIM28 complex was found to directly bind to the promoter of long interspersed element-1 (LINE-1), inducing H3K9me3-mediated transcriptional silencing. ZNF689 deficiency reactivated LINE-1 retrotransposition to exacerbate genomic instability, which fostered ITH. Single-cell RNA sequencing, spatially resolved transcriptomics and flow cytometry analysis confirmed that ZNF689 deficiency-induced ITH inhibited antigen presentation and T-cell activation, conferring immunotherapy resistance. Pharmacological inhibition of LINE-1 significantly reduced ITH, enhanced antitumor immunity, and eventually sensitized ZNF689-deficient tumors to immunotherapy in vivo. Consistently, ZNF689 expression positively correlated with favorable prognosis and immunotherapy response in clinical samples. Altogether, our study uncovers a previously unrecognized mechanism underlying ZNF689 deficiency-induced ITH and suggests LINE-1 inhibition combined with immunotherapy as a novel treatment strategy for TNBC.


Subject(s)
Triple Negative Breast Neoplasms , Humans , Immunotherapy , Triple Negative Breast Neoplasms/immunology , Triple Negative Breast Neoplasms/pathology , Triple Negative Breast Neoplasms/therapy , Transcription Factors/metabolism , Apoptosis Regulatory Proteins/metabolism , Drug Resistance, Neoplasm/genetics
4.
Nat Chem ; 16(1): 122-131, 2024 Jan.
Article in English | MEDLINE | ID: mdl-37710046

ABSTRACT

Biomarker discovery is essential for the understanding, diagnosis, targeted therapy and prognosis assessment of malignant diseases. However, it remains a huge challenge due to the lack of sensitive methods to identify disease-specific rare molecules. Here we present MORAC, molecular recognition based on affinity and catalysis, which enables the effective identification of candidate biomarkers with low abundance. MORAC relies on a class of DNAzymes, each cleaving a sole RNA linkage embedded in their DNA chain upon specifically sensing a complex system with no prior knowledge of the system's molecular content. We show that signal amplification from catalysis ensures the DNAzymes high sensitivity (for target probing); meanwhile, a simple RNA-to-DNA mutation can shut down their RNA cleavage ability and turn them into a pure affinity tool (for target pulldown). Using MORAC, we identify previously unknown, low-abundance candidate biomarkers with clear clinical value, including apolipoprotein L6 in breast cancer and seryl-tRNA synthetase 1 in polyps preceding colon cancer.


Subject(s)
Biosensing Techniques , DNA, Catalytic , DNA, Catalytic/genetics , DNA , RNA , Biomarkers
5.
Aging (Albany NY) ; 14(18): 7328-7347, 2022 09 29.
Article in English | MEDLINE | ID: mdl-36178365

ABSTRACT

There is considerable heterogeneity in the genomic drivers of lung adenocarcinoma, which has a dismal prognosis. Bioinformatics analysis was performed on lung adenocarcinoma (LUAD) datasets to establish a multi-autophagy gene model to predict patient prognosis. LUAD data were downloaded from The Cancer Genome Atlas (TCGA) database as a training set to construct a LUAD prognostic model. According to the risk score, a Kaplan-Meier cumulative curve was plotted to evaluate the prognostic value. Furthermore, a nomogram was established to predict the three-year and five-year survival of patients with LUAD based on their prognostic characteristics. Two genes (ITGB1 and EIF2AK3) were identified in the autophagy-related prognostic model, and the multivariate Cox proportional risk model showed that risk score was an independent predictor of prognosis in LUAD patients (HR=3.3, 95%CI= 2.3 to 4.6, P< 0.0001). The Kaplan-Meier cumulative curve showed that low-risk patients had significantly better overall (P<0.0001). The validation dataset GSE68465 further confirmed the nomogram's robust ability to assess the prognosis of LUAD patients. A prognosis model of autophagy-related genes based on a LUAD dataset was constructed and exhibited diagnostic value in the prognosis of LUAD patients. Moreover, real-time qPCR confirmed the expression patterns of EIF2AK3 and ITGB1 in LUAD cell lines. Two key autophagy-related genes have been suggested as prognostic markers for lung adenocarcinoma.


Subject(s)
Adenocarcinoma of Lung , Lung Neoplasms , Adenocarcinoma of Lung/pathology , Autophagy/genetics , Biomarkers, Tumor/genetics , Gene Expression Regulation, Neoplastic , Humans , Lung Neoplasms/pathology , Prognosis , Proportional Hazards Models
6.
Front Psychol ; 13: 941943, 2022.
Article in English | MEDLINE | ID: mdl-35898976

ABSTRACT

Teachers' work engagement is considered an essential component in instruction. Accordingly, the emphasis should be over physical and mental predictors of this construct. In this line, this study investigates the relationship between Chinese English as a Foreign Language (EFL) teachers' individual self-efficacy, collective efficacy, and work engagement. To this end, 300 Chinese instructors (males = 96, females = 204) from different colleges and universities participated in this study. The questionnaires were distributed among teachers with different educational levels and experiences. Linear multiple regression was used as a measure for data analysis. The findings showed the significant correlations between teachers' work engagement, self-efficacy, and collective efficacy. Comparing the predictability power, teachers' self-efficacy (B = 0.57) proved to have a higher index compared to their index of collective efficacy competence (B = 0.22). This study concluded that self-efficacious teachers and teachers who believe in collective efficacy are more engaged in the EFL contexts. Moreover, the study has some pedagogical implications and suggestions for different teacher educators, administrators, and advisors.

7.
Cell Res ; 32(5): 477-490, 2022 05.
Article in English | MEDLINE | ID: mdl-35105939

ABSTRACT

Metabolic reprogramming is a hallmark of cancer. However, systematic characterizations of metabolites in triple-negative breast cancer (TNBC) are still lacking. Our study profiled the polar metabolome and lipidome in 330 TNBC samples and 149 paired normal breast tissues to construct a large metabolomic atlas of TNBC. Combining with previously established transcriptomic and genomic data of the same cohort, we conducted a comprehensive analysis linking TNBC metabolome to genomics. Our study classified TNBCs into three distinct metabolomic subgroups: C1, characterized by the enrichment of ceramides and fatty acids; C2, featured with the upregulation of metabolites related to oxidation reaction and glycosyl transfer; and C3, having the lowest level of metabolic dysregulation. Based on this newly developed metabolomic dataset, we refined previous TNBC transcriptomic subtypes and identified some crucial subtype-specific metabolites as potential therapeutic targets. The transcriptomic luminal androgen receptor (LAR) subtype overlapped with metabolomic C1 subtype. Experiments on patient-derived organoid and xenograft models indicate that targeting sphingosine-1-phosphate (S1P), an intermediate of the ceramide pathway, is a promising therapy for LAR tumors. Moreover, the transcriptomic basal-like immune-suppressed (BLIS) subtype contained two prognostic metabolomic subgroups (C2 and C3), which could be distinguished through machine-learning methods. We show that N-acetyl-aspartyl-glutamate is a crucial tumor-promoting metabolite and potential therapeutic target for high-risk BLIS tumors. Together, our study reveals the clinical significance of TNBC metabolomics, which can not only optimize the transcriptomic subtyping system, but also suggest novel therapeutic targets. This metabolomic dataset can serve as a useful public resource to promote precision treatment of TNBC.


Subject(s)
Triple Negative Breast Neoplasms , Biomarkers, Tumor/genetics , Humans , Metabolomics , Precision Medicine , Transcriptome , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/pathology
8.
Public Transp ; 14(1): 191-261, 2022.
Article in English | MEDLINE | ID: mdl-38625193

ABSTRACT

Network-based systems are at the core of our everyday life. Whether it is electronic networking, electricity grids or transportation, users expect the networks to function properly and provide a feeling of safety and security. However, there may be disturbances. In this paper, we consider disturbances in the context of public transportation. The focus in this respect is on public transport planning and operations. To classify and cope with disturbances, one can find many ideas, including robustness, resilience, vulnerability, disruption mitigation or delay management. We survey related streams of literature and put them into perspective. As a major insight we show that different strands of literature exist that may benefit from becoming better connected and intertwined. Together with recent advances in information technology and solution methods, more integrated problem settings incorporating robustness and disturbances can play a major role in future planning and operations.

9.
Mitochondrial DNA B Resour ; 6(3): 1253-1255, 2021 Mar 26.
Article in English | MEDLINE | ID: mdl-33829100

ABSTRACT

Phaius hainanensis C. Z. Tang et S. J. Cheng is a species with extremely small populations and is endemic to China. Genetic data of this orchid species is minimal. With the aim to identify appropriate chloroplast markers for the use in conservation biology studies, the plastome of P. hainanenisis was assembled. The plastome of P. hainanensis is 158,314 bp in length and contains a large single copy region of 86,700 bp in length, a small single copy region of 18,452 bp, and a pair of inverted repeats of 26,581 bp. The annotation predicted 114 unique genes, including 80 protein-coding, 30 tRNAs, and four rRNAs. Seventeen genes contained a single intron and two genes (clpP and ycf3) have two introns. The GC content of P. hainanensis is 36.9%. Phylogenetic analysis indicated P. hainanensis is closely related to P. tancarvilleae, and it also supported that Phaius and Calanthe are sister groups. The plastome data reported in this study will contribute to further studies of phylogeny and conservation of Phaius species.

10.
Medicine (Baltimore) ; 100(14): e25375, 2021 Apr 09.
Article in English | MEDLINE | ID: mdl-33832123

ABSTRACT

RATIONALE: Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV) is a rare congenital malformation in neonates that results in severe respiratory distress and pulmonary hypertension. ACD/MPV is caused by mutations in the FOXF1 gene. Herein, a new case of a girl with ACD/MPV carrying a novel pathogenic variant of FOXF1 was reported. PATIENT CONCERNS: A 3-month-old Chinese girl was admitted to the hospital presenting a complaint of cyanosis for 10 days and respiratory distress for 2 days. The history of foreign body inhalation was denied. DIAGNOSES: Blood routine, liver and kidney function, electrolytes, type B natriuretic peptide, electrocardiogram, cardiac computed tomography (CT), and echocardiography were done after admission. Dysplasia of the alveolar and the left upper pulmonary vein was displayed through cardiac CT. Echocardiography showed atrial septal defect, tricuspid valve malformation, and pulmonary hypertension. Sequence analysis of FOXF1 from genomic deoxyribonucleic acid (DNA) revealed that the patient was heterozygous for a novel missense variant (c.418 C>T, p.Pro140Gly). Furthermore, genetic analysis of both parents confirmed the de novo occurrence of the variant. Conservation analysis showed that the locus was highly conserved across species. Then, ACD/MPV was a clinical diagnosis. INTERVENTIONS: After admission, nasal catheter oxygen inhalation, cefazoxime sodium, furosemide diuretic, milrinone lactate, and Bosentan were given to the patient. OUTCOMES: After 6 days of hospitalization, the patient's condition did not improved, the parents gave up treatment and discharged. The patient died half a month after discharge. LESSONS: ACD/MPV is a rare congenital malformation with a poor prognosis. A new de novo mutation of FOXF1 was found in our case. Non-invasive methods such as DNA sequencing and FOXF1 analysis are helpful in the clinical diagnosis of ACD/MPV especially in early infants with respiratory distress and pulmonary hypertension.


Subject(s)
Forkhead Transcription Factors/genetics , Persistent Fetal Circulation Syndrome/diagnosis , Persistent Fetal Circulation Syndrome/genetics , Pulmonary Alveoli/abnormalities , Pulmonary Veins/abnormalities , Echocardiography/methods , Fatal Outcome , Female , Heart Septal Defects, Atrial/diagnostic imaging , Heart Septal Defects, Atrial/genetics , Heterozygote , Humans , Hypertension, Pulmonary/diagnostic imaging , Hypertension, Pulmonary/genetics , Infant , Mutation, Missense , Oxygen Inhalation Therapy/methods , Persistent Fetal Circulation Syndrome/drug therapy , Sequence Analysis/methods , Treatment Failure , Tricuspid Valve/abnormalities , Tricuspid Valve/diagnostic imaging
11.
Oncogene ; 40(12): 2323-2334, 2021 03.
Article in English | MEDLINE | ID: mdl-33654196

ABSTRACT

Progression of triple-negative breast cancer (TNBC) constitutes a major unresolved clinical challenge, and effective targeted therapies are lacking. Because microtubule dynamics play pivotal roles in breast cancer metastasis, we performed RNA sequencing on 245 samples from TNBC patients to characterize the landscape of microtubule-associated proteins (MAPs). Here, our transcriptome analyses revealed that low expression of one MAP, tektin4, indicated poor patient outcomes. Tektin4 loss led to a marked increase in TNBC migration, invasion, and metastasis and a decrease in microtubule stability. Mechanistically, we identified a novel microtubule-associated complex containing tektin4 and histone deacetylase 6 (HDAC6). Tektin4 loss increased the interaction between HDAC6 and α-tubulin, thus decreasing microtubule stability through HDAC6-mediated tubulin deacetylation. Significantly, we found that tektin4 loss sensitized TNBC cells, xenograft models, and patient-derived organoid models to the HDAC6-selective inhibitor ACY1215. Furthermore, tektin4 expression levels were positively correlated with microtubule stability levels in clinical samples. Together, our findings uncover a metastasis suppressor function of tektin4 and support clinical development of HDAC6 inhibition as a new therapeutic strategy for tektin4-deficient TNBC patients.


Subject(s)
Histone Deacetylase 6/genetics , Histone Deacetylase Inhibitors/pharmacology , Microtubule Proteins/genetics , Triple Negative Breast Neoplasms/genetics , Tubulin/genetics , Acetylation/drug effects , Animals , Cell Movement/drug effects , Cell Proliferation/drug effects , Disease Models, Animal , Gene Expression Regulation, Neoplastic/drug effects , Heterografts , Humans , Hydroxamic Acids/pharmacology , Mice , Neoplasm Metastasis , Pyrimidines/pharmacology , Sequence Analysis, RNA , Triple Negative Breast Neoplasms/pathology , Exome Sequencing
12.
Breast Cancer Res Treat ; 185(2): 371-380, 2021 Jan.
Article in English | MEDLINE | ID: mdl-32975708

ABSTRACT

PURPOSE: Resistance to paclitaxel remains a major challenge in treating breast cancer. Our preclinical study suggested that TEKT4 germline variations in breast cancer are associated with paclitaxel resistance and increase vinorelbine sensitivity. This clinical trial compared the efficacy of paclitaxel and vinorelbine in breast cancer neoadjuvant chemotherapy. METHODS: In this open-label, single-center, phase II trial, female patients with human epidermal growth factor receptor 2 (HER2)-negative, stage IIB-IIIC breast cancer harboring TEKT4 germline variations were randomly assigned to the paclitaxel plus epirubicin (PE) or vinorelbine plus epirubicin (NE). The primary endpoint was the pathologic complete response (pCR) rate, and the secondary endpoints were the objective response rate (ORR) and safety. Targeted sequencing of a panel comprising 484 breast-related genes was performed to identify pCR-associated somatic mutations in each group. RESULTS: 91 Patients were assigned to PE (46 patients) or NE (45 patients). NE numerically increased the pCR rate (22.2% versus 8.7%, P = 0.074). The ORRs for NE and PE were 82.2% and 76.1%, respectively. Interestingly, NE (15.4%) showed a significantly higher pCR rate than PE (0%) in the hormone receptor (HR)-positive subgroup (P = 0.044). Both regimens were well tolerated, with grade 3 and 4 toxicities reported at the expected levels. The biomarker analysis showed that UNC13D mutation predicted the pCR rate in NE (P = 0.011). CONCLUSIONS: Although the primary endpoint was not met, NE might bring clinical benefit to HR-positive patients or patients simultaneously carrying UNC13D mutations.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Breast Neoplasms , Epirubicin , Neoadjuvant Therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Cyclophosphamide/therapeutic use , Epirubicin/therapeutic use , Female , Humans , Membrane Proteins , Paclitaxel/adverse effects , Receptor, ErbB-2/genetics , Trastuzumab/therapeutic use , Treatment Outcome , Vinorelbine/therapeutic use
13.
Mitochondrial DNA B Resour ; 5(3): 3612-3613, 2020 Oct 21.
Article in English | MEDLINE | ID: mdl-33367030

ABSTRACT

Paphiopedilum spicerianum (H. G. Reichenbach) Pfitzer is an endangered and threatened orchid species in China. The genetic and molecular data of this orchid species is deficient. With the aim to identify appropriate chloroplast markers for the use in a conservation biology study, the complete chloroplast genome of P. spicerianum was reported. We found that the chloroplast genome of P. spicerianum is 157,292 bp in length, containing a large single-copy region of 87,252 bp, a small single-copy region of 1828 bp, and a pair of inverted repeats of 34,106 bp. Genome annotation predicted 105 unique genes, including 71 protein-coding genes, 30 tRNAs, and four rRNAs. Fourteen genes contained one intron and two genes (clpP and ycf3) had two introns. The GC content of the P. spicerianum was 35.8%. Phylogenetic analysis indicated P. spicerianum was closely related to P. purpuratum.

14.
Front Pediatr ; 8: 524, 2020.
Article in English | MEDLINE | ID: mdl-33014928

ABSTRACT

Introduction: Congenital descending aorta-right atrial tunnel is a rare congenital heart defect. Herein, a new case successfully treated by transcatheter closure using a new type of ventricular septal defect occluder from the aortic side was reported. Case Presentation: An 11-month-old Chinese girl presenting with a cardiac murmur was suspected with partial anomalous pulmonary venous connection as assessed by echocardiography. Descending aorta-right atrial tunnel was confirmed by computed tomography angiography and cardiac catheterization. Subsequently, transcatheter closure was performed successfully using a new type of ventricular septal defect occluder from the aortic side. The cardiac murmur disappeared after the intervention, and echocardiography did not reveal any abnormal flow inside the right atrium. At 6 months, the patient had no murmur, and no residual shunt was found using the echocardiogram. Conclusion: Descending aorta-right atrial tunnel is a rare anomaly. Transcatheter closure was successful in our case. Long-term follow-up is needed to assess any progressive growth of the residual tunnel.

15.
Theranostics ; 10(24): 10940-10956, 2020.
Article in English | MEDLINE | ID: mdl-33042263

ABSTRACT

Background: Taxanes are frontline chemotherapeutic drugs for patients with triple-negative breast cancer (TNBC); however, chemoresistance reduces their effectiveness. We hypothesized that the molecular profiling of tumor samples before and after neoadjuvant chemotherapy (NAC) would help identify genes associated with drug resistance. Methods: We sequenced 10 samples by RNA-seq from 8 NAC patients with TNBC: 3 patients with a pathologic complete response (pCR) and the other 5 with non-pCR. Differentially expressed genes that predicted chemotherapy response were selected for in vitro functional screening via a small-scale siRNAs pool. The clinical and functional significance of the gene of interest in TNBC was further investigated in vitro and in vivo, and biochemical assays and imaging analysis were applied to study the mechanisms. Results: Synaptotagmin-like 4 (SYTL4), a Rab effector in vesicle transport, was identified as a leading functional candidate. High SYTL4 expression indicated a poor prognosis in multiple TNBC cohorts, specifically in taxane-treated TNBCs. SYTL4 was identified as a novel chemoresistant gene as validated in TNBC cells, a mouse model and patient-derived organoids. Mechanistically, downregulating SYTL4 stabilized the microtubule network and slowed down microtubule growth rate. Furthermore, SYTL4 colocalized with microtubules and interacted with microtubules through its middle region containing the linker and C2A domain. Finally, we found that SYTL4 was able to bind microtubules and inhibit the in vitro microtubule polymerization. Conclusion: SYTL4 is a novel chemoresistant gene in TNBC and its upregulation indicates poor prognosis in taxane-treated TNBC. Further, SYTL4 directly binds microtubules and decreases microtubule stability.


Subject(s)
Drug Resistance, Neoplasm/genetics , Neoplasm Recurrence, Local/epidemiology , Paclitaxel/pharmacology , Triple Negative Breast Neoplasms/therapy , Vesicular Transport Proteins/genetics , Adolescent , Adult , Animals , Breast/pathology , Breast/surgery , Cell Line, Tumor , Chemotherapy, Adjuvant/methods , Disease-Free Survival , Down-Regulation , Female , Gene Expression Regulation, Neoplastic , Gene Knockdown Techniques , Humans , Intravital Microscopy , Mastectomy , Mice , Microtubules/metabolism , Middle Aged , Neoadjuvant Therapy/methods , Neoplasm Recurrence, Local/genetics , Organoids , Paclitaxel/therapeutic use , Prognosis , Protein Multimerization/genetics , RNA-Seq , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/mortality , Triple Negative Breast Neoplasms/pathology , Tubulin/metabolism , Tumor Cells, Cultured , Vesicular Transport Proteins/metabolism , Young Adult
16.
Mol Cancer ; 19(1): 87, 2020 05 11.
Article in English | MEDLINE | ID: mdl-32393270

ABSTRACT

BACKGROUND: Estrogen receptor-positive (ER+) breast cancers represent approximately two-thirds of all breast cancers and have a sustained risk of late disease recurrence. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have shown significant efficacy in ER+ breast cancer. However, their effects are still limited by drug resistance. In this study, we aim to explore the role of long noncoding RNA TROJAN in ER+ breast cancer. METHODS: The expression level of TROJAN in breast cancer tissue and cell lines was determined by quantitative real-time PCR. In vitro and in vivo assays as well as patient derived organoid were preformed to explore the phenotype of TROJAN in ER+ breast cancer. The TROJAN-NKRF-CDK2 axis were screened and validated by RNA pull-down, mass spectrometry, RNA immunoprecipitation, microarray, dual-luciferase reporter and chromatin immunoprecipitation assays. RESULTS: Herein, we showed that TROJAN was highly expressed in ER+ breast cancer. TROJAN promoted cell proliferation and resistance to a CDK4/6 inhibitor and was associated with poor survival in ER+ breast cancer. TROJAN can bind to NKRF and inhibit its interaction with RELA, upregulating the expression of CDK2. The inhibition of TROJAN abolished the activity of CDK2, reversing the resistance to CDK4/6 inhibitor. A TROJAN antisense oligonucleotide sensitized breast cancer cells and organoid to the CDK4/6 inhibitor palbociclib both in vitro and in vivo. CONCLUSIONS: TROJAN promotes ER+ breast cancer proliferation and is a potential target for reversing CDK4/6 inhibitor resistance.


Subject(s)
Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Cyclin-Dependent Kinase 2/genetics , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Drug Resistance, Neoplasm , RNA, Long Noncoding/genetics , Receptors, Estrogen/metabolism , Animals , Apoptosis , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cell Proliferation , Cyclin-Dependent Kinase 2/metabolism , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Female , Gene Expression Regulation, Neoplastic , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Piperazines/pharmacology , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
17.
J Pharmacol Sci ; 143(3): 238-241, 2020 Jul.
Article in English | MEDLINE | ID: mdl-32265105

ABSTRACT

Resveratrol has been extensively studied as the anti-cancer agent. A variety of resveratrol analogues have been developed with structural modification to improve its bioactivity. In this work, resveratrol analogues, compound 1-4, were designed and synthesized with the Stille-Heck reaction. These results showed compound 1-4 had better anticancer effect than that of parent resveratrol. Especially compound 1 ((E)-4,4'-(ethene-1,2-diyl)bis(3-methylphenol)) displayed the excellent cytotoxicity and high selectivity. The mechanism research indicated compound 1 inhibited cell proliferation by binary paths of cell cycle arrest in S phase regulated by cyclin A1/A2 and apoptosis induction mediated by Bax/Bcl2 in a prooxidant manner.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis/drug effects , Cell Cycle Checkpoints/drug effects , Neoplasms/pathology , Resveratrol/analogs & derivatives , Resveratrol/pharmacology , Apoptosis/genetics , Cell Proliferation/drug effects , Cell Proliferation/genetics , HeLa Cells , Humans , MCF-7 Cells , Organic Chemistry Phenomena , Proto-Oncogene Proteins c-bcl-2/metabolism , Resveratrol/chemical synthesis , Resveratrol/chemistry , Structure-Activity Relationship , bcl-2-Associated X Protein/metabolism
18.
BMC Chem ; 14(1): 13, 2020 Dec.
Article in English | MEDLINE | ID: mdl-32099972

ABSTRACT

With the improvement and advance in cancer diagnosis and treatment, the cancer is still a major cause of morbidity and mortality throughout the world. Obviously, new breakthroughs in therapies remain be urgent needed. In this work, we designed and synthesized the compound 1-4, namely resveratrol analogues with methylation of hydroxy distyrene, to further explore its new anti-cancer potential. Encouragingly, compound 1 ((E)-4,4'-(ethene-1,2-diyl)bis(3,5-dimethylphenol)) exhibited cytotoxicity superior to resveratrol in MCF 7 cells. More importantly, the compound 1 showed greater toxicity to tumor cells than that to normal cells, which proved that it could selectively kill tumor cells. The favorable results encouraged us to explore the inhibitory mechanism of compound 1 on MCF 7 cells. The research finding indicated the compound 1 inhibited tumor cell proliferation by both arresting cell cycle in S phase and apoptosis via a prooxidant manner. In addition, the results further verified compound 1 caused cell cycle arrest in S phase and apoptosis by down-regulation of the cycling A1/cycling A2 expression and the rise of Bax/Bcl-2 ratio in a p21-dependant pathway in MCF 7 cells. Therefore, these results are helpful for the effective design of anticancer reagents and the better understanding of their mechanism of action.

19.
Nanoscale ; 11(36): 17010-17017, 2019 Sep 19.
Article in English | MEDLINE | ID: mdl-31498345

ABSTRACT

The search for metal-free catalysts for oxygen reduction reactions (ORRs) in energy storage and conversion devices, such as fuel cells and metal-air batteries, is highly desirable but challenging. Here, we have designed and synthesized controllable 3D nitrogen and phosphorous co-doped holey graphene foams (N,P-HGFs) as a high-efficiency ORR catalyst through structural regulation and electronic engineering. The obtained catalyst shows a half-wave potential of 0.865 V in alkaline electrolytes. It is found that Zn-air batteries with the N,P-HGFs-1000 air electrode exhibit excellent discharge performance and durability. Our study suggests that the remarkable ORR performance of N,P co-doped graphene is mainly due to the graphite N-C-P structure, where an enhanced charge density and increased HOMO energy level are confirmed by both experimental results and theoretical density-functional theory calculations.

20.
Cancer Manag Res ; 10: 4381-4391, 2018.
Article in English | MEDLINE | ID: mdl-30349371

ABSTRACT

BACKGROUND: Occult breast cancer (OBC) is a rare type of breast cancer that has not been well studied. The clinicopathological characteristics and treatment recommendations for OBC are based on a limited number of retrospective studies and thus remain controversial. PATIENTS AND METHODS: We identified 479 OBC patients and 115,739 non-OBC patients from 2004 to 2014 in and the Surveillance, Epidemiology, and End Results (SEER) database. The clinicopathological characteristics and survival outcomes were compared between OBC and non-OBC patients. We used the propensity score 1:1 matching analysis to evaluate OBC vs non-OBC comparison using balanced groups with respect to the observed covariates. We further divided the OBC population into four groups based on different treatment strategies. Univariable and multivariable analyses were used to calculate and compare the four treatment outcomes within the OBC population. RESULTS: OBC patients were older, exhibited a more advanced stage, a higher rate of negative estrogen receptor and progesterone receptor status, a higher rate of HER2-positive status, and a higher rate of ≥10 positive lymph nodes, and were less likely to undergo surgical treatment than non-OBC patients. After adjustments for clinicopathological factors, the OBC patients exhibited a significantly better survival than the non-OBC patients (P<0.001). This result was confirmed in a 1:1 matched case-control analysis. Within the four OBC treatment groups, we observed no difference in survival among the mastectomy group, the breast-conserving surgery (BCS) group, and the axillary lymph node dissection (ALND)-only group. The multivariable analysis revealed that the sentinel lymph node dissection-only group had the worst prognosis (P<0.001). Conclusion: OBC has unique clinicopathological characteristics and a favorable prognosis compared with non-OBC. BCS plus ALND and radiotherapy showed a survival benefit that was similar to that of mastectomy for OBC patients.

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