Publications by authors named "Yuzhuo Wang"

221 Publications

Co-modification with MSC membrane and PDA prevents FeO-induced pulmonary toxicity in mice via AMPK-ULK1 axis.

Toxicol Lett 2021 Sep 10;351:145-154. Epub 2021 Sep 10.

Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, China. Electronic address:

FeO nanoparticles are widely used in the diagnosis and treatment of diseases due to their superparamagnetism, but their toxicity in vivo, which can result in apoptosis or autophagy, cannot be ignored. It has been reported that polydopamine (PDA) modification can reduce the toxicity of FeO and increase its biocompatibility. However, more research is warranted to further improve the modification method. We therefore developed a new method to coat [email protected] nanoparticles with the mesenchymal stem cell membrane (MSCM) and evaluated the toxicity of the modified particles in the lungs of mice. We found that the MSCM modification significantly reduced lung injury induced by FeO particles in mice. Compared with [email protected] nanoparticles, co-modification with MSCM and PDA significantly reduced autophagy and apoptosis in mouse lung tissue, and reduced activation of autophagy mediated by the AMPK-ULK1 pathway axis. Thus, co-modification with MSCM and PDA prevents FeO-induced pulmonary toxicity in mice by inhibiting autophagy, apoptosis, and oxidative stress.
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http://dx.doi.org/10.1016/j.toxlet.2021.09.003DOI Listing
September 2021

Circulating C-reactive protein increases lung cancer risk: Results from a prospective cohort of UK Biobank.

Int J Cancer 2021 Aug 27. Epub 2021 Aug 27.

Department of Epidemiology, School of Public Health, Southeast University, Nanjing, China.

Chronic inflammation has been associated with the development of lung cancer. In this study, we examined the association between C-reactive protein (CRP) and lung cancer in a prospective cohort study and used Mendelian randomization (MR) to clarify the causality. We included 420 977 participants from the UK Biobank (UKB) in the analyses; 1892 thereof were diagnosed with lung cancer during the follow-up. Hazards ratios (HRs) of CRP concentrations were estimated by Cox proportional hazard models and two approaches of MR analysis were performed. Besides, we added CRP concentrations to epidemiological model of lung cancer to evaluate its prediagnostic role through time-dependent receiver operating characteristic curve analysis. Elevated CRP levels were associated with a 22% increased lung cancer risk per 1 SD increase (HR = 1.22, 95% confidence interval [CI] = 1.18-1.26). Positive associations were observed in small cell lung cancer (HR = 1.21, 95% CI = 1.10-1.33), lung adenocarcinoma (HR = 1.17, 95% CI = 1.11-1.23) and lung squamous cell carcinoma (HR = 1.22, 95% CI = 1.14-1.31). No genetical association of circulating CRP levels and lung cancer risk was observed in MR analysis. When added to a risk model of lung cancer, CRP improved the performance of model as long as 8 years among current smokers (basic model: C-statistic = 0.78 [95% CI = 0.75-0.80]; CRP model: C-statistic = 0.79 [95% CI = 0.76-0.81]; P  = .003, P  = .014). Our results did not support the causal association of circulating CRP with lung cancer risk. However, circulating CRP could be a prediagnostic marker of lung cancer as long as 8 years in advance for current smokers.
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http://dx.doi.org/10.1002/ijc.33780DOI Listing
August 2021

Genome-wide gene-smoking interaction study identified novel susceptibility loci for non-small cell lung cancer in Chinese populations.

Carcinogenesis 2021 Jul 23. Epub 2021 Jul 23.

Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.

Gene-smoking interactions play important roles in the development of non-small cell lung cancer (NSCLC). To identify single nucleotide polymorphisms (SNPs) that modify the association of smoking behavior with NSCLC risk, we conducted a genome-wide gene-smoking interaction study in Chinese populations. The genome-wide interaction analysis between SNPs and smoking status (ever- versus never-smokers) was carried out using genome-wide association studies (GWAS) of NSCLC, which included 13,327 cases and 13,328 controls. Stratified analysis by histological subtypes was also conducted. We used a genome-wide significance threshold of 5×10 -8 for identifying significant gene-smoking interactions and 1×10 -6 for identifying suggestive results. Functional annotation was performed to identify potential functional SNPs and target genes. We identified three novel loci with significant or suggestive gene-smoking interaction. For NSCLC, the interaction between rs2746087 (20q11.23) and smoking status reached genome-wide significance threshold (OR = 0.63, 95%CI: 0.54-0.74, P = 3.31×10 -8), and the interaction between rs11912498 (22q12.1) and smoking status reached suggestive significance threshold (OR = 0.72, 95%CI: 0.63-0.82, P = 8.10×10 -7). Stratified analysis by histological subtypes identified suggestive interactions between rs459724 (5q11.2) and smoking status (OR = 0.61, 95%CI: 0.51-0.73, P = 7.55×10 -8) in the risk of lung squamous cell carcinoma. Functional annotation indicated that both classic and novel biological processes, including nicotine addiction and airway clearance, may modulate the susceptibility to NSCLC. These novel loci provide new insights into the biological mechanisms underlying NSCLC risk. Independent replication in large-scale studies is needed and experimental studies are warranted to functionally validate these associations.
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http://dx.doi.org/10.1093/carcin/bgab064DOI Listing
July 2021

Lipophilization and amylose inclusion complexation enhance the stability and release of catechin.

Carbohydr Polym 2021 Oct 26;269:118251. Epub 2021 May 26.

Department of Nutrition and Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China; Beijing Laboratory of Food Quality and Safety, China Agricultural University, Beijing 100083, China; Xinghua Industrial Research Centre for Food Science and Human Health, China Agricultural University, Shinaian West Road, Xinghua, Jiangsu 225700, China. Electronic address:

Catechin is a natural phenolic compound with various bioactivities. However, it is unstable under light and heat environments. Amylose can form a single helical hydrophobic cavity to encapsulate and protect bioactive compounds. In this work, we applied amylose inclusion complexes (IC) to encapsulate a lipophilized catechin, i.e., hexadecyl catechin (HC), to improve its photostability and thermal stability. The formation of amylose-HC IC was characterized using differential scanning calorimetry, X-ray diffraction, and Fourier transform infrared spectroscopy. The photostability and thermal stability studies showed that the retention of guest molecules in IC was 86.1% ± 5.1% and 87.4% ± 0.6%, respectively, which was significantly higher than that of the catechin, HC, and amylose-HC physical mixture groups. Moreover, the in vitro release profile of IC demonstrated a steady and complete release of catechin. The findings show the amylose encapsulation of catechin is a promising technique to preserve bioactive compounds in food.
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http://dx.doi.org/10.1016/j.carbpol.2021.118251DOI Listing
October 2021

Molecular events in neuroendocrine prostate cancer development.

Nat Rev Urol 2021 Jul 21. Epub 2021 Jul 21.

Vancouver Prostate Centre, Vancouver, BC, Canada.

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer. NEPC arises de novo only rarely; the disease predominantly develops from adenocarcinoma in response to drug-induced androgen receptor signalling inhibition, although the mechanisms behind this transdifferentiation are a subject of debate. The survival of patients with NEPC is poor, and few effective treatment options are available. To improve clinical outcomes, understanding of the biology and molecular mechanisms regulating NEPC development is crucial. Various NEPC molecular drivers make temporal contributions during NEPC development, and despite the limited treatment options available, several novel targeted therapeutics are currently under research.
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http://dx.doi.org/10.1038/s41585-021-00490-0DOI Listing
July 2021

Air Pollution, Genetic Factors and the Risk of Lung Cancer: A Prospective Study in the UK Biobank.

Am J Respir Crit Care Med 2021 Jul 12. Epub 2021 Jul 12.

Nanjing Medical University School of Public Health, 572407, Department of Epidemiology, Center for Global Health, Nanjing, China.

Both genetic and environmental factors contribute to lung cancer, but the degree to which air pollution modifies the impact of genetic susceptibility on lung cancer remains unknown. To investigate whether air pollution and genetic factors jointly contribute to incident lung cancer. We analyzed data from 455,974 participants (53% women) without previous cancer at baseline in the UK Biobank. The concentrations of particulate matter (PM, PM and PM), nitrogen dioxide (NO), and nitrogen oxides (NO) were estimated by land-use regression models, and the association between air pollutants and incident lung cancer was investigated using a Cox proportional hazard model. Furthermore, we constructed a polygenic risk score and evaluated whether air pollutants modified the effect of genetic susceptibility on the development of lung cancer. The results showed significant associations between the risk of lung cancer and PM (hazard ratio [HR]: 1.63, 95% confidence interval [CI]: 1.33-2.01; per 5 μg/m), PM (1.53, 1.20-1.96; per 10 μg/m), NO (1.10, 1.05-1.15; per 10 μg/m), and NO (1.13, 1.07-1.18; per 20 μg/m). There were additive interactions between air pollutants and the genetic risk. Compared with participants with low genetic risk and low air pollution, those with high air pollution and high genetic risk had the highest risk of lung cancer (PM: HR: 1.71, 95% CI:1.45-2.02; PM: 1.77, 1.50-2.10; NO: 1.77, 1.42-2.22; NO: 1.67, 1.43-1.95). Long-term exposure to air pollution may increase the risk of lung cancer, especially in those with high genetic risk.
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http://dx.doi.org/10.1164/rccm.202011-4063OCDOI Listing
July 2021

Palladium/Xu-Phos-catalyzed asymmetric carboamination towards isoxazolidines and pyrrolidines.

Chem Sci 2021 May 5;12(23):8241-8245. Epub 2021 May 5.

Department of Chemistry, Fudan University 2005 Songhu Road Shanghai 200438 China

An efficient palladium-catalyzed enantioselective carboamination reaction of -Boc--homoallyl-hydroxylamines and -Boc-pent-4-enylamines with aryl or alkenyl bromides was developed, delivering various substituted isoxazolidines and pyrrolidines in good yields with up to 97% ee. The reaction features mild conditions, general substrate scope and scalability. The obtained products can be transformed into chiral 1,3-aminoalcohol derivatives without erosion of chirality. The newly identified Xu-Phos ligand bearing an -OPr group is responsible for the good yield and high enantioselectivity.
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http://dx.doi.org/10.1039/d1sc01337hDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208297PMC
May 2021

Establishment and characterization of a novel treatment-related neuroendocrine prostate cancer cell line KUCaP13.

Cancer Sci 2021 Jul 1;112(7):2781-2791. Epub 2021 Jun 1.

Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

The prevalence of neuroendocrine prostate cancer (NEPC) arising from adenocarcinoma (AC) upon potent androgen receptor (AR) pathway inhibition is increasing. Deeper understanding of NEPC biology and development of novel therapeutic agents are needed. However, research is hindered by the paucity of research models, especially cell lines developed from NEPC patients. We established a novel NEPC cell line, KUCaP13, from tissue of a patient initially diagnosed with AC which later recurred as NEPC. The cell line has been maintained permanently in vitro under regular cell culture conditions and is amenable to gene engineering with lentivirus. KUCaP13 cells lack the expression of AR and overexpress NEPC-associated genes, including SOX2, EZH2, AURKA, PEG10, POU3F2, ENO2, and FOXA2. Importantly, the cell line maintains the homozygous deletion of CHD1, which was confirmed in the primary AC of the index patient. Loss of heterozygosity of TP53 and PTEN, and an allelic loss of RB1 with a transcriptomic signature compatible with Rb pathway aberration were revealed. Knockdown of PEG10 using shRNA significantly suppressed growth in vivo. Introduction of luciferase allowed serial monitoring of cells implanted orthotopically or in the renal subcapsule. Although H3K27me was reduced by EZH2 inhibition, reversion to AC was not observed. KUCaP13 is the first patient-derived, treatment-related NEPC cell line with triple loss of tumor suppressors critical for NEPC development through lineage plasticity. It could be valuable in research to deepen the understanding of NEPC.
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http://dx.doi.org/10.1111/cas.14935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253279PMC
July 2021

A cross-tissue transcriptome-wide association study identifies novel susceptibility genes for lung cancer in Chinese populations.

Hum Mol Genet 2021 Aug;30(17):1666-1676

Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China.

Although dozens of susceptibility loci have been identified for lung cancer in genome-wide association studies (GWASs), the susceptibility genes and underlying mechanisms remain unclear. In this study, we conducted a cross-tissue transcriptome-wide association study (TWAS) with UTMOST based on summary statistics from 13 327 lung cancer cases and 13 328 controls and the genetic-expression matrix over 44 human tissues in the Genotype-Tissue Expression (GTEx) project. After further evaluating the associations in each tissue, we revealed 6 susceptibility genes in known loci and identified 12 novel ones. Among those, five novel genes, including DCAF16 (Pcross-tissue = 2.57 × 10-5, PLung = 2.89 × 10-5), CBL (Pcross-tissue = 5.08 × 10-7, PLung = 1.82 × 10-4), ATR (Pcross-tissue = 1.45 × 10-5, PLung = 9.68 × 10-5), GYPE (Pcross-tissue = 1.45 × 10-5, PLung = 2.17 × 10-3) and PARD3 (Pcross-tissue = 5.79 × 10-6, PLung = 4.05 × 10-3), were significantly associated with the risk of lung cancer in both cross-tissue and lung tissue models. Further colocalization analysis indicated that rs7667864 (C > A) and rs2298650 (G > T) drove the GWAS association signals at 4p15.31-32 (OR = 1.09, 95%CI: 1.04-1.12, PGWAS = 5.54 × 10-5) and 11q23.3 (OR = 1.08, 95%CI: 1.04-1.13, PGWAS = 5.55 × 10-5), as well as the expression of DCAF16 (βGTEx = 0.24, PGTEx = 9.81 × 10-15; βNJLCC = 0.29, PNJLCC = 3.84 × 10-8) and CBL (βGTEx = -0.17, PGTEx = 2.82 × 10-8; βNJLCC = -0.32, PNJLCC = 2.61 × 10-7) in lung tissue. Functional annotations and phenotype assays supported the carcinogenic effect of these novel susceptibility genes in lung carcinogenesis.
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http://dx.doi.org/10.1093/hmg/ddab119DOI Listing
August 2021

Relationships between sleep traits and lung cancer risk: a prospective cohort study in UK Biobank.

Sleep 2021 Sep;44(9)

Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.

Study Objectives: To prospectively investigate the association between sleep traits and lung cancer risk, accounting for the interactions with genetic predisposition of lung cancer.

Methods: We included 469 691 individuals free of lung cancer at recruitment from UK Biobank, measuring sleep behaviors with a standardized questionnaire and identifying incident lung cancer cases through linkage to national cancer and death registries. We estimated multivariable-adjusted hazard ratios (HRs) for lung cancer (2177 incident cases) across four sleep traits (sleep duration, chronotype, insomnia, and snoring) and examined the interaction and joint effects with a lung cancer polygenic risk score.

Results: A U-shaped association was observed for sleep duration and lung cancer risk, with an 18% higher risk (95% confidence interval [CI]: 1.07 to 1.30) for short sleepers and a 17% higher risk (95% CI: 1.02 to 1.34) for long sleepers compared with normal sleepers (7-8 h/day). Evening preference was associated with elevated lung cancer risk compared with morning preference (HR: 1.25; 95% CI: 1.07 to 1.46), but no association was found for insomnia or snoring. Compared with participants with favorable sleep traits and low genetic risk, those with both unfavorable sleep duration (<7 hours or >8 hours) or evening preference and high genetic risk showed the greatest lung cancer risk (HRsleep duration: 1.83; 95% CI: 1.47 to 2.27; HRchronotype: 1.85; 95% CI: 1.34 to 2.56).

Conclusions: Both unfavorable sleep duration and evening chronotype were associated with increased lung cancer incidence, especially for those with low to moderate genetic risk. These results indicate that sleep behaviors as modifiable risk factors may have potential implications for lung cancer risk.
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http://dx.doi.org/10.1093/sleep/zsab089DOI Listing
September 2021

The evolutionarily conserved long non-coding RNA LINC00261 drives neuroendocrine prostate cancer proliferation and metastasis via distinct nuclear and cytoplasmic mechanisms.

Mol Oncol 2021 Jul 26;15(7):1921-1941. Epub 2021 Apr 26.

Cancer Research Group-School of Life Health and Chemical Sciences, The Open University, Milton Keynes, UK.

Metastatic neuroendocrine prostate cancer (NEPC) is a highly aggressive disease, whose incidence is rising. Long noncoding RNAs (lncRNAs) represent a large family of disease- and tissue-specific transcripts, most of which are still functionally uncharacterized. Thus, we set out to identify the highly conserved lncRNAs that play a central role in NEPC pathogenesis. To this end, we performed transcriptomic analyses of donor-matched patient-derived xenograft models (PDXs) with immunohistologic features of prostate adenocarcinoma (AR /PSA ) or NEPC (AR /SYN /CHGA ) and through differential expression analyses identified lncRNAs that were upregulated upon neuroendocrine transdifferentiation. These genes were prioritized for functional assessment based on the level of conservation in vertebrates. Here, LINC00261 emerged as the top gene with over 3229-fold upregulation in NEPC. Consistently, LINC00261 expression was significantly upregulated in NEPC specimens in multiple patient cohorts. Knockdown of LINC00261 in PC-3 cells dramatically attenuated its proliferative and metastatic abilities, which are explained by parallel downregulation of CBX2 and FOXA2 through distinct molecular mechanisms. In the cell cytoplasm, LINC00261 binds to and sequesters miR-8485 from targeting the CBX2 mRNA, while inside the nucleus, LINC00261 functions as a transcriptional scaffold to induce SMAD-driven expression of the FOXA2 gene. For the first time, these results demonstrate hyperactivation of the LINC00261-CBX2-FOXA2 axes in NEPC to drive proliferation and metastasis, and that LINC00261 may be utilized as a therapeutic target and a biomarker for this incurable disease.
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http://dx.doi.org/10.1002/1878-0261.12954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253100PMC
July 2021

Long non-coding RNAs in the doxorubicin resistance of cancer cells.

Cancer Lett 2021 Jun 22;508:104-114. Epub 2021 Mar 22.

Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea; KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address:

Chemotherapy is the main treatment used for cancer patients failing surgery. Doxorubicin (DOX) is a well-known chemotherapeutic agent capable of suppressing proliferation in cancer cells and triggering apoptosis via inhibiting topoisomerase II activity and producing DNA breaks. This activity of DOX restrains mitosis and cell cycle progression. However, frequent application of DOX results in the emergence of resistance in the cancer cells. It seems that genetic and epigenetic factors can provide DOX resistance of cancer cells. Long non-coding RNAs (lncRNAs) are a subcategory of non-coding RNAs with role in the regulation of several cellular processes such as proliferation, migration, differentiation and apoptosis. LncRNA dysregulation has been associated with chemoresistance, and this profile occurs upon DOX treatment of cancer. In the present review, we focus on the role of lncRNAs in mediating DOX resistance and discuss the molecular pathways and mechanisms. LncRNAs can drive DOX resistance via activating pathways such as NF-κB, PI3K/Akt, Wnt, and FOXC2. Some lncRNAs can activate protective autophagy in response to the stress caused by DOX, which mediates resistance. In contrast, there are other lncRNAs involved in the sensitivity of cancer cells to DOX, such as GAS5, PTCSC3 and FENDRR. Some anti-tumor agents such as polydatin can regulate the expression of lncRNAs, enhancing DOX sensitivity. Overall, lncRNAs are potential players in DOX resistance, and their identification and targeting are of importance in chemosensitivity. Furthermore, these findings can be translated into clinical for treatment of cancer patients.
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http://dx.doi.org/10.1016/j.canlet.2021.03.018DOI Listing
June 2021

A noncanonical AR addiction drives enzalutamide resistance in prostate cancer.

Nat Commun 2021 03 9;12(1):1521. Epub 2021 Mar 9.

Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.

Resistance to next-generation anti-androgen enzalutamide (ENZ) constitutes a major challenge for the treatment of castration-resistant prostate cancer (CRPC). By performing genome-wide ChIP-seq profiling in ENZ-resistant CRPC cells we identify a set of androgen receptor (AR) binding sites with increased AR binding intensity (ARBS-gained). While ARBS-gained loci lack the canonical androgen response elements (ARE) and pioneer factor FOXA1 binding motifs, they are highly enriched with CpG islands and the binding sites of unmethylated CpG dinucleotide-binding protein CXXC5 and the partner TET2. RNA-seq analysis reveals that both CXXC5 and its regulated genes including ID1 are upregulated in ENZ-resistant cell lines and these results are further confirmed in patient-derived xenografts (PDXs) and patient specimens. Consistent with the finding that ARBS-gained loci are highly enriched with H3K27ac modification, ENZ-resistant PCa cells, organoids, xenografts and PDXs are hyper-sensitive to NEO2734, a dual inhibitor of BET and CBP/p300 proteins. These results not only reveal a noncanonical AR function in acquisition of ENZ resistance, but also posit a treatment strategy to target this vulnerability in ENZ-resistant CRPC.
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http://dx.doi.org/10.1038/s41467-021-21860-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943793PMC
March 2021

Androgen receptor (AR) antagonism triggers acute succinate-mediated adaptive responses to reactivate AR signaling.

EMBO Mol Med 2021 May 11;13(5):e13427. Epub 2021 Mar 11.

Vancouver Prostate Centre, Vancouver, BC, Canada.

Treatment-induced adaptive pathways converge to support androgen receptor (AR) reactivation and emergence of castration-resistant prostate cancer (PCa) after AR pathway inhibition (ARPI). We set out to explore poorly defined acute adaptive responses that orchestrate shifts in energy metabolism after ARPI and identified rapid changes in succinate dehydrogenase (SDH), a TCA cycle enzyme with well-known tumor suppressor activity. We show that AR directly regulates transcription of its catalytic subunits (SDHA, SDHB) via androgen response elements (AREs). ARPI acutely suppresses SDH activity, leading to accumulation of the oncometabolite, succinate. Succinate triggers calcium ions release from intracellular stores, which in turn phospho-activates the AR-cochaperone, Hsp27 via p-CaMKK2/p-AMPK/p-p38 axis to enhance AR protein stabilization and activity. Activation of this pathway was seen in tissue microarray analysis on prostatectomy tissues and patient-derived xenografts. This adaptive response is blocked by co-targeting AR with Hsp27 under both in vitro and in vivo studies, sensitizing PCa cells to ARPI treatments.
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http://dx.doi.org/10.15252/emmm.202013427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103094PMC
May 2021

The role of LR-TIMAP/PP1c complex in the occurrence and development of no-reflow.

EBioMedicine 2021 Mar 24;65:103251. Epub 2021 Feb 24.

Thoracic Surgery Laboratory, the First College of Clinical Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221006, China; Department of Thoracic Surgery, Affifiliated Hospital of Xuzhou Medical University, 99 West Huaihai Road, Xuzhou, Jiangsu 221006, China. Electronic address:

Background: The presence of no-reflow can increase the risk of major adverse cardiac events and is widely regarded as an important sign of serious prognosis. Previous studies show that laminin receptor (LR) is closely related to the morphology and function of microvessels. However, whether LR is involved in the occurrence and development of no-reflow is still unknown.

Methods: In vivo, positron emission tomography (PET) perfusion imaging was performed to detect the effects of intramyocardial gene (LR-AAV and LR-siRNA-AAV) delivery treatment on the degree of no-reflow. In vitro, LC-MS/MS analysis was conducted to identify the LR phosphorylation sites of human cardiac microvascular endothelial cells (HCMECs) treated with oxygen-glucose deprivation (OGD) for 4 h. Western blot analyses were used to evaluate the phosphorylation levels of LR at residues Tyr47 (phospho-Tyr47-LR/pY47-LR) and Thr125 (phospho-Thr125-LR/pT125-LR) and their effects on the phosphorylation of VE-cadherin residue Ser665 (phospho-Ser665-VE-cad).

Findings: LR over-expression, LR (phosphonull) and LR (phosphonull) treatments were found to reduce the level of phospho-Ser665-VE-cad, and subsequently maintain adherent junctions and endothelial barrier integrity in hypoxic environments. Mechanistically, TIMAP/PP1c can combine with LR on the cell membrane to form a novel LR-TIMAP/PP1c complex. The level of pY47-LR determined the stability of LR-TIMAP/PP1c complex. The binding of TIMAP/PP1c on LR activated the protein phosphatase activity of PP1c and regulated the level of pT125-LR.

Interpretation: This study demonstrates that low level of phospho-LR reduces no-reflow area through stabilizing the LR-TIMAP/PP1c complex and promoting the stability of adherens junctions, and may help identify new therapeutic targets for the treatment of no-reflow.
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http://dx.doi.org/10.1016/j.ebiom.2021.103251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921471PMC
March 2021

ZRSR2 overexpression is a frequent and early event in castration-resistant prostate cancer development.

Prostate Cancer Prostatic Dis 2021 Sep 10;24(3):775-785. Epub 2021 Feb 10.

Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.

Background: Androgen deprivation therapy (ADT) remains the leading systemic therapy for locally advanced and metastatic prostate cancers (PCa). While a majority of PCa patients initially respond to ADT, the durability of response is variable and most patients will eventually develop incurable castration-resistant prostate cancer (CRPC). Our research objective is to identify potential early driver genes responsible for CRPC development.

Methods: We have developed a unique panel of hormone-naïve PCa (HNPC) patient-derived xenograft (PDX) models at the Living Tumor Laboratory. The PDXs provide a unique platform for driver gene discovery as they allow for the analysis of differentially expressed genes via transcriptomic profiling at various time points after mouse host castration. In the present study, we focused on genes with expression changes shortly after castration but before CRPC has fully developed. These are likely to be potential early drivers of CRPC development. Such genes were further validated for their clinical relevance using data from PCa patient databases. ZRSR2 was identified as a top gene candidate and selected for further functional studies.

Results: ZRSR2 is significantly upregulated in our PDX models during the early phases of CRPC development after mouse host castration and remains consistently high in fully developed CRPC PDX models. Moreover, high ZRSR2 expression is also observed in clinical CRPC samples. Importantly, elevated ZRSR2 in PCa samples is correlated with poor patient treatment outcomes. ZRSR2 knockdown reduced PCa cell proliferation and delayed cell cycle progression at least partially through inhibition of the Cyclin D1 (CCND1) pathway.

Conclusion: Using our unique HNPC PDX models that develop into CRPC after host castration, we identified ZRSR2 as a potential early driver of CRPC development.
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http://dx.doi.org/10.1038/s41391-021-00322-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384624PMC
September 2021

Preparation and Characterization of Protein-loaded PFC Nanoemulsions for the Treatment of Heart Diseases by Pulmonary Administration.

Eur J Pharm Sci 2021 Mar 24;158:105690. Epub 2020 Dec 24.

Department of Thoracic Cardiovascular Surgery, Affiliated Hospital of Xuzhou Medical University, China. Electronic address:

In the treatment of heart disease, strategies for the targeted delivery of protein therapeutics to the heart by inhalation are still immature. Perfluorocarbons (PFCs) are inert chemicals with good biocompatibility, and unique physico-chemical properties that have recently led to their applications in numerous fields. In this study, we combined the advantages of protein-phospholipid complexes and PFC emulsions and then synthesized protein-loaded PFC nanoemulsions (PNEs) to test whether, after inhalation, these nanoemulsions could deliver therapeutic proteins to the heart. After preparing protein-phospholipid complexes by lyophilization, we obtained PNEs by extrusion. The particle size and surface charge of PNEs were about 140 nm and -50 mV, respectively. In vitro results showed that the PNEs had a fine particle fraction of 35% and exhibited sustained protein release. Translocation studies were done using three types of pulmonary epithelial cells, and ~7% translocation was observed in the Calu-3 cell line. Further, they were easily absorbed by cells and had therapeutic effects in culture. In vivo results showed that the PNEs successfully delivered proteins to the myocardial tissue of rats and reduced ischemic myocardial injury caused by acute myocardial infarction (AMI). This study suggests that inhalation of PNEs is a new potential strategy to deliver proteins to cardiac tissues for treating heart diseases.
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http://dx.doi.org/10.1016/j.ejps.2020.105690DOI Listing
March 2021

Geological methane emissions and wildfire risk in the degraded permafrost area of the Xiao Xing'an Mountains, China.

Sci Rep 2020 12 4;10(1):21297. Epub 2020 Dec 4.

Institute of Cold Regions Science and Engineering, Northeast Forestry University, Harbin, 150040, China.

With global warming, the carbon pool in the degradation zone of permafrost around the Arctic will gradually be disturbed and may enter the atmosphere in the form of released methane gas, becoming an important factor of environmental change in permafrost areas. We selected the northwestern section of the Xiao Xing'an Mountains in China as the study area, located in the degradation zone on the southern margin of the permafrost region in Eurasia, and set up multiple study monitoring areas equipped with methane concentration sensors, air temperature sensors, pore water pressure sensors and soil temperature sensors for long-term monitoring of data changes using the high-density electrical method, ground penetrating radar and on-site drilling to survey the distribution of frozen soil and geological conditions in the study area, combined with remote sensing images of Sentinel-2 L1C and unmanned aerial vehicle photographs and three-dimensional image reconstruction, analysis of fire activities and related geological environmental factors. The results show that since 2004, the permafrost thickness of the marsh wetland in the study area has gradually reduced and the degradation rate obviously accelerated; the organic matter and methane hydrate (metastable methane hydrate and stable methane hydrate) stored in the permafrost under the marsh wetland are gradually entering the atmosphere in the form of methane gas. Methane emissions show seasonal changes, and the annual methane emissions can be divided into three main stages, including a high-concentration short-term emission stage (March to May), a higher-concentration long-term stable emission stage (June to August) and a higher-concentration short-term emission stage (September to November); there is a certain correlation between the change in atmospheric methane concentration and the change in atmospheric pressure and pore water pressure. From March to May every year (high-concentration short-term emission stage), with snow melting, the air humidity reaches an annual low value, and the surface methane concentration reaches an annual high value. The high concentration of methane gas entering the surface in this stage is expected to increase the risk of wildfire in the permafrost degradation area in two ways (increasing the regional air temperature and self-combustion), which may be an important factor that leads to a seasonal wildfire frequency difference in the permafrost zone of Northeast China and Southeast Siberia, with the peak in spring and autumn and the monthly maximum in spring. The increase in the frequency of wildfires is projected to further generate positive feedback on climate change by affecting soil microorganisms and soil structure. Southeastern Siberia and northeastern China, which are on the southern boundary of the permafrost region of Eurasia, need to be targeted to establish fire warning and management mechanisms to effectively reduce the risk of wildfires.
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http://dx.doi.org/10.1038/s41598-020-78170-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718274PMC
December 2020

Geometric Control of Collective Spontaneous Emission.

Phys Rev Lett 2020 Nov;125(21):213602

ICFO-Institut de Ciencies Fotoniques, The Barcelona Institute of Science and Technology, 08860 Castelldefels, Barcelona, Spain and ICREA-Institució Catalana de Recerca i Estudis Avançats, 08015 Barcelona, Spain.

Dipole spin-wave states of atomic ensembles with wave vector k(ω) mismatched from the dispersion relation of light are difficult to access by far-field excitation but may support rich phenomena beyond the traditional phase-matched scenario in quantum optics. We propose and demonstrate an optical technique to efficiently access these states. In particular, subnanosecond laser pulses shaped by a home-developed wideband modulation method are applied to shift the spin wave in k space with state-dependent geometric phase patterning, in an error-resilient fashion and on timescales much faster than spontaneous emission. We verify this control through the redirection, switch off, and recall of collectively enhanced emission from a ^{87}Rb gas with ∼75% single-step efficiency. Our work represents a first step toward efficient control of electric dipole spin waves for studying many-body dissipative dynamics of excited gases, as well as for numerous quantum optical applications.
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http://dx.doi.org/10.1103/PhysRevLett.125.213602DOI Listing
November 2020

Tumor evolutionary trajectories during the acquisition of invasiveness in early stage lung adenocarcinoma.

Nat Commun 2020 11 27;11(1):6083. Epub 2020 Nov 27.

Department of Thoracic Surgery, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, 21009, Nanjing, P.R. China.

The evolutionary trajectories of early lung adenocarcinoma (LUAD) have not been fully elucidated. We hypothesize that genomic analysis between pre-invasive and invasive components will facilitate the description of LUAD evolutionary patterns. We micro-dissect malignant pulmonary nodules (MPNs) into paired pre-invasive and invasive components for panel-genomic sequencing and recognize three evolutionary trajectories. Evolutionary mode 1 (EM1) demonstrates none of the common driver events between paired components, but another two modes, EM2A and EM2B, exhibit critical private alterations restricted to pre-invasive and invasive components, respectively. When ancestral clones harbor EGFR mutations, truncal mutation abundance significantly decrease after the acquisition of invasiveness, which may be associated with the intratumoral accumulation of infiltrated B cells. Harboring EGFR mutations is critical to the selective pressure and further impacts the prognosis. Our findings extend the understanding of evolutionary trajectories during invasiveness acquisition in early LUAD.
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http://dx.doi.org/10.1038/s41467-020-19855-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695730PMC
November 2020

Integrated gene-based and pathway analyses using UK Biobank data identify novel genes for chronic respiratory diseases.

Gene 2021 Jan 10;767:145287. Epub 2020 Nov 10.

Department of Epidemiology and Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing 211166, China. Electronic address:

Background: Chronic respiratory diseases have become a non-negligible cause of death globally. Although smoking and environmental exposures are primary risk factors for chronic respiratory diseases, genetic factors also play an important role in determining individual's susceptibility to diseases. Here we performed integrated gene-based and pathway analyses to systematically illuminate the heritable characteristics of chronic respiratory diseases.

Methods: UK (United Kingdom) Biobank is a very large, population-based prospective study with over 500,000 participants, established to allow detailed investigations of the genetic and nongenetic determinants of the diseases. Utilizing the GWAS-summarized data downloaded from UK Biobank, we conducted gene-based analysis to obtain associations of susceptibility genes with asthma, chronic obstructive pulmonary disease(COPD) and pneumonia using FUSION and MAGMA software. Across the identified susceptibility regions, functional annotation integrating multiple functional data sources was performed to explore potential regulatory mechanisms with INQUISIT algorithm. To further detect the biological process involved in the development of chronic respiratory diseases, we undertook pathway enrichment analysis with the R package (clusterProfiler).

Results: A total of 195 susceptibility genes were identified significantly associated with chronic respiratory diseases (P < 0.05), and 24/195 located out of known susceptibility regions (e.g. WDPCP in 2p15). Within the identified susceptibility regions, functional annotation revealed an aggregation of credible variants in promoter-like and enhancer-like histone modification regions and such regulatory mechanisms were specific to lung tissues. Furthermore, 110 genes with INQUISIT score ≥1 may influence diseases susceptibility through exerting effects on coding sequences, proximal promoter and distal enhancer regulations. Pathway enrichment results showed that these genes were enriched in immune-related processes and nicotinic acetylcholine receptors pathways.

Conclusions: This study implemented an integrated gene-based and pathway strategy to explore the underlying biological mechanisms and our findings may serve as promising targets for future clinical treatments of chronic respiratory diseases.
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http://dx.doi.org/10.1016/j.gene.2020.145287DOI Listing
January 2021

Lactic Acid and an Acidic Tumor Microenvironment suppress Anticancer Immunity.

Int J Mol Sci 2020 Nov 7;21(21). Epub 2020 Nov 7.

Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada.

Immune evasion and altered metabolism, where glucose utilization is diverted to increased lactic acid production, are two fundamental hallmarks of cancer. Although lactic acid has long been considered a waste product of this alteration, it is now well accepted that increased lactic acid production and the resultant acidification of the tumor microenvironment (TME) promotes multiple critical oncogenic processes including angiogenesis, tissue invasion/metastasis, and drug resistance. We and others have hypothesized that excess lactic acid in the TME is responsible for suppressing anticancer immunity. Recent studies support this hypothesis and provide mechanistic evidence explaining how lactic acid and the acidic TME impede immune cell functions. In this review, we consider lactic acid's role as a critical immunoregulatory molecule involved in suppressing immune effector cell proliferation and inducing immune cell de-differentiation. This results in the inhibition of antitumor immune responses and the activation of potent, negative regulators of innate and adaptive immune cells. We also consider the role of an acidic TME in suppressing anticancer immunity. Finally, we provide insights to help translate this new knowledge into impactful anticancer immune therapies.
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http://dx.doi.org/10.3390/ijms21218363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664620PMC
November 2020

Using the full-text content of academic articles to identify and evaluate algorithm entities in the domain of natural language processing.

J Informetr 2020 Nov 11;14(4):101091. Epub 2020 Oct 11.

Department of Information Management, Nanjing University of Science and Technology, Nanjing, 210094, China.

In the era of big data, the advancement, improvement, and application of algorithms in academic research have played an important role in promoting the development of different disciplines. Academic papers in various disciplines, especially computer science, contain a large number of algorithms. Identifying the algorithms from the full-text content of papers can determine popular or classical algorithms in a specific field and help scholars gain a comprehensive understanding of the algorithms and even the field. To this end, this article takes the field of natural language processing (NLP) as an example and identifies algorithms from academic papers in the field. A dictionary of algorithms is constructed by manually annotating the contents of papers, and sentences containing algorithms in the dictionary are extracted through dictionary-based matching. The number of articles mentioning an algorithm is used as an indicator to analyze the influence of that algorithm. Our results reveal the algorithm with the highest influence in NLP papers and show that classification algorithms represent the largest proportion among the high-impact algorithms. In addition, the evolution of the influence of algorithms reflects the changes in research tasks and topics in the field, and the changes in the influence of different algorithms show different trends. As a preliminary exploration, this paper conducts an analysis of the impact of algorithms mentioned in the academic text, and the results can be used as training data for the automatic extraction of large-scale algorithms in the future. The methodology in this paper is domain-independent and can be applied to other domains.
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http://dx.doi.org/10.1016/j.joi.2020.101091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548120PMC
November 2020

GRB10 sustains AR activity by interacting with PP2A in prostate cancer cells.

Int J Cancer 2021 01 21;148(2):469-480. Epub 2020 Oct 21.

Vancouver Prostate Centre, Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.

Prostate cancer (PCa) progression is driven by androgen receptor (AR) signaling. Unfortunately, androgen-deprivation therapy and the use of even more potent AR pathway inhibitors (ARPIs) cannot bring about a cure. ARPI resistance (ie, castration-resistant PCa, CRPC) will inevitably develop. Previously, we demonstrated that GRB10 is an AR transcriptionally repressed gene that functionally contributes to CRPC development and ARPI resistance. GRB10 expression is elevated prior to CRPC development in our patient-derived xenograft models and is significantly upregulated in clinical CRPC samples. Here, we analyzed transcriptomic data from GRB10 knockdown in PCa cells and found that AR signaling is downregulated. While the mRNA expression of AR target genes decreased upon GRB10 knockdown, AR expression was not affected at the mRNA or protein level. We further found that phosphorylation of AR serine 81 (S81), which is critical for AR transcriptional activity, is decreased by GRB10 knockdown and increased by its overexpression. Luciferase assay using GRB10-knockdown cells also indicate reduced AR activity. Immunoprecipitation coupled with mass spectrometry revealed an interaction between GRB10 and the PP2A complex, which is a known phosphatase of AR. Further validations and analyses showed that GRB10 binds to the PP2Ac catalytic subunit with its PH domain. Mechanistically, GRB10 knockdown increased PP2Ac protein stability, which in turn decreased AR S81 phosphorylation and reduced AR activity. Our findings indicate a reciprocal feedback between GRB10 and AR signaling, implying the importance of GRB10 in PCa progression.
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http://dx.doi.org/10.1002/ijc.33335DOI Listing
January 2021

EZH2 inhibition: a promising strategy to prevent cancer immune editing.

Epigenomics 2020 08 17;12(16):1457-1476. Epub 2020 Sep 17.

Cancer Research Group, School of Life Health & Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK.

Immunotherapies are revolutionizing the clinical management of a wide range of cancers. However, intrinsic or acquired unresponsiveness to immunotherapies does occur due to the dynamic cancer immunoediting which ultimately leads to immune escape. The evolutionarily conserved histone modifier enhancer of zeste 2 (EZH2) is aberrantly overexpressed in a number of human cancers. Accumulating studies indicate that EZH2 is a main driver of cancer cells' immunoediting and mediate immune escape through downregulating immune recognition and activation, upregulating immune checkpoints and creating an immunosuppressive tumor microenvironment. In this review, we overviewed the roles of EZH2 in cancer immunoediting, the preclinical and clinical studies of current pharmacologic EZH2 inhibitors and the prospects for EZH2 inhibitor and immunotherapy combination for cancer treatment.
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http://dx.doi.org/10.2217/epi-2020-0186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607396PMC
August 2020

Integration of GWAS and eQTL Analysis to Identify Risk Loci and Susceptibility Genes for Gastric Cancer.

Front Genet 2020 10;11:679. Epub 2020 Jul 10.

Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.

Genome-wide association studies (GWAS) have identified several susceptibility loci for gastric cancer (GC), but the majority of identified single-nucleotide polymorphisms (SNPs) fall within the non-coding region and are likely to exert their biological function by modulating gene expression. To systematically estimate expression-associated SNPs (eSNPs) that confer genetic predisposition to GC, we evaluated the associations of 314,203 stomach tissue-specific eSNPs with GC risk in three GWAS datasets (2,631 cases and 4,373 controls). Subsequently, we conducted a gene-based analysis to calculate the cumulative effect of eSNPs through sequence kernel association combined test and Sherlock integrative analysis. At the SNP-level, we identified two novel variants (rs836545 at 7p22.1 and rs1892252 at 6p22.2) associated with GC risk. The risk allele carriers of rs836545-T and rs1892252-G exhibited higher expression levels of ( = 3.70 × 10) and ( = 3.20 × 10), respectively. Gene-based analyses identified and as novel susceptibility genes for GC. and were significantly overexpressed in GC tissues than in their adjacent tissues ( = 5.59 × 10 and = 3.90 × 10, respectively), and high expression level of these two genes was associated with an unfavorable prognosis of GC patients ( = 1.30 × 10 and = 7.60 × 10, respectively). Co-expression genes with these two novel genes in normal stomach tissues were significantly enriched in several cancer-related pathways, including P53, MAPK and TGF-beta pathways. In summary, our findings confirm the importance of eSNPs in dissecting the genetic basis of GC, and the identified eSNPs and relevant genes will provide new insight into the genetic and biological basis for the mechanism of GC development.
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http://dx.doi.org/10.3389/fgene.2020.00679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366424PMC
July 2020

Precise pulse shaping for quantum control of strong optical transitions.

Opt Express 2020 Jun;28(12):17171-17187

Advances of quantum control technology have led to nearly perfect single-qubit control of nuclear spins and atomic hyperfine ground states. In contrast, quantum control of strong optical transitions, even for free atoms, are far from being perfect. Developments of such quantum control appears to be limited by available laser technology for generating isolated, sub-nanosecond optical waveforms with 10's of GHz programming bandwidth. Here we propose a simple and robust method for the desired pulse shaping, based on precisely stacking multiple delayed picosecond pulses. Our proof-of-principal demonstration leads to arbitrarily shapeable optical waveforms with 30 GHz bandwidth and 100 ps duration. We confirm the stability of the waveforms by interfacing the pulses with laser-cooled atoms, resulting in "super-resolved" spectroscopic signals. This pulse shaping method may open exciting perspectives in quantum optics, and for fast laser cooling and atom interferometry with mode-locked lasers.
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http://dx.doi.org/10.1364/OE.389700DOI Listing
June 2020

LncRNA promotes taxane resistance in castration-resistant prostate cancer via a BCL2A1-dependent mechanism.

Epigenomics 2020 07 3;12(13):1123-1138. Epub 2020 Jul 3.

School of Life, Health & Chemical Sciences, The Open University, Walton Hall, Milton Keynes, Buckinghamshire, MK7 6AA, UK.

Castration-resistant prostate cancer (CRPC) is an incurable malignancy. Long noncoding RNAs (lncRNAs) play key roles in drug resistance. LncRNA role in cabazitaxel resistance (i.e., cell-count, IC and caspase activity) was studied via lentiviral-mediated overexpression and siRNA-based knockdown. Genes expression was analyzed with RNA-sequencing, reverse transcription quantitative PCR (RT-qPCR) and western blot. expression was queried in clinical database. Cabazitaxel increased expression that upregulated , thereby protecting CRPC cells from cabazitaxel-induced apoptosis. knockdown decreased cell-count and increased apoptosis in CRPC cells. -targeting antisense oligonucleotide decreased cabazitaxel IC. In CRPC clinical samples, expression increased upon taxane treatment. stimulates the expression of BCL2A1 thereby decreasing apoptosis and enhancing cabazitaxel resistance in CRPC cells.
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http://dx.doi.org/10.2217/epi-2019-0316DOI Listing
July 2020

Well-Differentiated Papillary Mesothelioma of the Peritoneum Is Genetically Distinct from Malignant Mesothelioma.

Cancers (Basel) 2020 Jun 13;12(6). Epub 2020 Jun 13.

Department of Pathology, Vancouver General Hospital, Vancouver, BC V5Z 1M9, Canada.

Well-differentiated papillary mesothelioma (WDPM) is an uncommon mesothelial proliferation that is most commonly encountered as an incidental finding in the peritoneal cavity. There is controversy in the literature about whether WDPM is a neoplasm or a reactive process and, if neoplastic, whether it is a variant or precursor of epithelial malignant mesothelioma or is a different entity. Using whole exome sequencing of five WDPMs of the peritoneum, we have identified distinct mutations in , , , , , , and shared by WDPM cases but not reported in malignant mesotheliomas. Furthermore, we show that WDPM is strongly enriched with C > A transversion substitution mutations, a pattern that is also not found in malignant mesotheliomas. The WDPMs lacked the alterations involving , , , , , , and that are frequently found in malignant mesotheliomas. We conclude that WDPMs are neoplasms that are genetically distinct from malignant mesotheliomas and, based on observed mutations, do not appear to be precursors of malignant mesotheliomas.
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http://dx.doi.org/10.3390/cancers12061568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352777PMC
June 2020

Conditionally Reprogrammed Cells from Patient-Derived Xenograft to Model Neuroendocrine Prostate Cancer Development.

Cells 2020 06 4;9(6). Epub 2020 Jun 4.

Vancouver Prostate Centre, Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC V6H 3Z6, Canada.

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer. It develops mainly via NE transdifferentiation of prostate adenocarcinoma in response to androgen receptor (AR)-inhibition therapy. The study of NEPC development has been hampered by a lack of clinically relevant models. We previously established a unique and first-in-field patient-derived xenograft (PDX) model of adenocarcinoma (LTL331)-to-NEPC (LTL331R) transdifferentiation. In this study, we applied conditional reprogramming (CR) culture to establish a LTL331 PDX-derived cancer cell line named LTL331_CR_Cell. These cells retain the same genomic mutations as the LTL331 parental tumor. They can be continuously propagated in vitro and can be genetically manipulated. Androgen deprivation treatment on LTL331_CR_Cells had no effect on cell proliferation. Transcriptomic analyses comparing the LTL331_CR_Cell to its parental tumor revealed a profound downregulation of the androgen response pathway and an upregulation of stem and basal cell marker genes. The transcriptome of LTL331_CR_Cells partially resembles that of post-castrated LTL331 xenografts in mice. Notably, when grafted under the renal capsules of male NOD/SCID mice, LTL331_CR_Cells spontaneously gave rise to NEPC tumors. This is evidenced by the histological expression of the NE marker CD56 and the loss of adenocarcinoma markers such as PSA. Transcriptomic analyses of the newly developed NEPC tumors further demonstrate marked enrichment of NEPC signature genes and loss of AR signaling genes. This study provides a novel research tool derived from a unique PDX model. It allows for the investigation of mechanisms underlying NEPC development by enabling gene manipulations ex vivo and subsequent functional evaluations in vivo.
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http://dx.doi.org/10.3390/cells9061398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349646PMC
June 2020
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