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1.
EBioMedicine ; 65: 103251, 2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33639401

RESUMO

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, LRT125A (phosphonull) and LRY47A (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.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33568749

RESUMO

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.

3.
Eur J Pharm Sci ; 158: 105690, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33359617

RESUMO

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.

4.
Int J Cancer ; 148(2): 469-480, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33038264

RESUMO

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.

5.
Gene ; 767: 145287, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-33181258

RESUMO

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 (Pbonferroni < 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.


Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Transtornos Respiratórios/genética , Asma/genética , Bancos de Espécimes Biológicos , Doença Crônica/epidemiologia , Bases de Dados Genéticas , Feminino , Humanos , Pulmão/fisiopatologia , Masculino , Polimorfismo de Nucleotídeo Único/genética , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/genética , Fumar/genética , Reino Unido
6.
Phys Rev Lett ; 125(21): 213602, 2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33275003

RESUMO

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.

7.
Sci Rep ; 10(1): 21297, 2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33277578

RESUMO

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.

8.
Int J Mol Sci ; 21(21)2020 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-33171818

RESUMO

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.

9.
Nat Commun ; 11(1): 6083, 2020 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-33247113

RESUMO

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.

10.
J Informetr ; 14(4): 101091, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33072184

RESUMO

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.

11.
Epigenomics ; 12(16): 1457-1476, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32938196

RESUMO

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.

12.
Front Genet ; 11: 679, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32754194

RESUMO

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 DAGLB (P = 3.70 × 10-18) and BTN3A2 (P = 3.20 × 10-5), respectively. Gene-based analyses identified DAGLB and FBXO43 as novel susceptibility genes for GC. DAGLB and FBXO43 were significantly overexpressed in GC tissues than in their adjacent tissues (P = 5.59 × 10-7 and P = 3.90 × 10-6, respectively), and high expression level of these two genes was associated with an unfavorable prognosis of GC patients (P = 1.30 × 10-7 and P = 7.60 × 10-3, 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.

13.
Epigenomics ; 12(13): 1123-1138, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32618200

RESUMO

Background: Castration-resistant prostate cancer (CRPC) is an incurable malignancy. Long noncoding RNAs (lncRNAs) play key roles in drug resistance. Materials & methods: LncRNA HORAS5 role in cabazitaxel resistance (i.e., cell-count, IC50 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. HORAS5 expression was queried in clinical database. Results: Cabazitaxel increased HORAS5 expression that upregulated BCL2A1, thereby protecting CRPC cells from cabazitaxel-induced apoptosis. BCL2A1 knockdown decreased cell-count and increased apoptosis in CRPC cells. HORAS5-targeting antisense oligonucleotide decreased cabazitaxel IC50. In CRPC clinical samples, HORAS5 expression increased upon taxane treatment. Conclusion: HORAS5 stimulates the expression of BCL2A1 thereby decreasing apoptosis and enhancing cabazitaxel resistance in CRPC cells.

14.
Opt Express ; 28(12): 17171-17187, 2020 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-32679930

RESUMO

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.

15.
Cells ; 9(6)2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32512818

RESUMO

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.

16.
Cancers (Basel) ; 12(6)2020 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-32545767

RESUMO

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 EHD1, ATM, FBXO10, SH2D2A, CDH5, MAGED1, and TP73 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 BAP1, SETD2, NF2, CDKN2A/B, LASTS1/2, PBRM1, and SMARCC1 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.

17.
Ecol Evol ; 10(10): 4352-4361, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32489602

RESUMO

Theaceae, an economically important angiosperm family, is widely distributed in tropical and subtropical forests in Asia. In China, Theaceae has particularly high abundances and endemism, comprising ~75% of the total genera and ~46% of the total species worldwide. Therefore, predicting the response of Theaceae species to climate change is vital. In this study, we collected distribution data for 200 wild Theaceae species in China, and predicted their distribution patterns under current and future climactic conditions by species distribution modeling (SDM). We revealed that Theaceae species richness is highest in southeastern China and on Hainan Island, reaching its highest value (137 species) in Fujian Province. According to the IUCN Red List criteria for assessing species threat levels under two dispersal assumptions (no dispersal and full dispersal), we evaluated the conservation status of all Theaceae species by calculating loss of suitable habitat under future climate scenarios. We predicted that nine additional species will become threatened due to climate change in the future; one species will be classified as critically endangered (CR), two as endangered (EN), and six as vulnerable (VU). Given their extinction risks associated with climate change, we recommended that these species be added to the Red List. Our investigation of migration patterns revealed regional differences in the number of emigrant, immigrant, and persistent species, indicating the need for targeted conservation strategies. Regions containing numerous emigrants are concentrated in Northern Taiwan and coastal regions of Zhejiang and Fujian provinces, while regions containing numerous immigrants include central Sichuan Province, the southeastern Tibet Autonomous Region, southwest Yunnan Province, northwest Sichuan Province, and the junction of Guangxi and Hunan provinces. Lastly, regions containing persistent species are widely distributed in southern China. Importantly, regions with high species turnover are located on the northern border of the entire Theaceae species distribution ranges owing to upwards migration; these regions are considered most sensitive to climate change and conservation planning should therefore be prioritized here. This study will contribute valuable information for reducing the negative impacts of climate change on Theaceae species, which will ultimately improve biodiversity conservation efficiency.

18.
Neoplasia ; 22(6): 253-262, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32403054

RESUMO

Neuroendocrine prostate cancer (NEPC) is the most virulent form of prostate cancer. Importantly, our recent work examining metastatic biopsy samples demonstrates NEPC is increasing in frequency. In contrast to prostate adenocarcinomas that express a luminal gene expression program, NEPC tumors express a neuronal gene expression program. Despite this distinction, the diagnosis of NEPC is often challenging, demonstrating an urgent need to identify new biomarkers and therapeutic targets. Our prior work demonstrated that the histone demethylase LSD1 (KDM1A) is important for survival of prostate adenocarcinomas, but little was known about LSD1's role in NEPC. Recently, a neural-specific transcript variant of LSD1-LSD1+8a-was discovered and demonstrated to activate neuronal gene expression in neural cells. The splicing factor SRRM4 was previously shown to promote LSD1+8a splicing in neuronal cells, and SRRM4 promotes NEPC differentiation and cell survival. Therefore, we sought to determine if LSD1+8a might play a role in NEPC and whether LSD1+8a splicing was linked to SRRM4. To investigate a potential role for LSD1+8a in NEPC, we examined a panel of prostate adenocarcinoma and NEPC patient-derived xenografts and metastatic biopsies. LSD1+8a was expressed exclusively in NEPC samples and correlated significantly with elevated expression of SRRM4. Using SRRM4-overexpressing cell lines, we determined that SRRM4 mediates alternative splicing of LSD1+8a. Finally, using gain of function studies, we confirmed that LSD1+8a and SRRM4 co-regulate target genes distinct from canonical LSD1. Our findings suggest further study of the interplay between SRRM4 and LSD1+8a and mechanisms by which LSD1+8a regulates gene expression in NEPC is warranted.

19.
Eur Urol ; 78(6): 834-844, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32451180

RESUMO

BACKGROUND: Activating mutations in AKT1 and PIK3CA are undercharacterised in metastatic castration-resistant prostate cancer (mCRPC), but are linked to activation of phosphatidylinositol 3-kinase (PI3K) signalling and sensitivity to pathway inhibitors in other cancers. OBJECTIVE: To determine the prevalence, genomic context, and clinical associations of AKT1/PIK3CA activating mutations in mCRPC. DESIGN, SETTING, AND PARTICIPANTS: We analysed targeted cell-free DNA (cfDNA) sequencing data from 599 metastatic prostate cancer patients with circulating tumour DNA (ctDNA) content above 2%. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: In patients with AKT1/PIK3CA mutations, cfDNA was subjected to PTEN intron sequencing and matched diagnostic tumour tissue was analysed when possible. RESULTS AND LIMITATIONS: Of the patients, 6.0% (36/599) harboured somatic clonal activating mutation(s) in AKT1 or PIK3CA. Mutant allele-specific imbalance was common. Clonal mutations in mCRPC ctDNA were typically detected in pretreatment primary tissue and were consistent across serial ctDNA collections. AKT1/PIK3CA-mutant mCRPC had fewer androgen receptor (AR) gene copies than AKT1/PIK3CA wild-type mCRPC (median 4.7 vs 10.3, p = 0.003). AKT1 mutations were mutually exclusive with PTEN alterations. Patients with and without AKT1/PIK3CA mutations showed similar clinical outcomes with standard of care treatments. A heavily pretreated mCRPC patient with an AKT1 mutation experienced a 50% decline in prostate-specific antigen with Akt inhibitor (ipatasertib) monotherapy. Ipatasertib also had a marked antitumour effect in a patient-derived xenograft harbouring an AKT1 mutation. Limitations include the inability to assess AKT1/PIK3CA correlatives in ctDNA-negative patients. CONCLUSIONS: AKT1/PIK3CA activating mutations are relatively common and delineate a distinct mCRPC molecular subtype with low-level AR copy gain. Clonal prevalence and evidence of mutant allele selection propose PI3K pathway dependency in selected patients. The use of cfDNA screening enables prospective clinical trials to test PI3K pathway inhibitors in this population. PATIENT SUMMARY: Of advanced prostate cancer cases, 6% have activating mutations in the genes AKT1 or PIK3CA. These mutations can be identified using a blood test and may help select patients suitable for clinical trials of phosphatidylinositol 3-kinase inhibitors.

20.
Gene ; 744: 144608, 2020 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-32234541

RESUMO

Prostate cancer (PCa) is the third most common malignancy worldwide. Novel and effective therapeutic targets are needed for PCa. The purpose of this study was to discover novel therapeutic targets for PCa by performing advanced analysis on PCa RNA sequencing (RNAseq) data from The Cancer Genome Atlas (TCGA). Weighted correlation-network analysis (WGCNA) was performed on the RNAseq data of tumor samples, and the module most relevant to the Gleason score was identified. Combining differential gene-expression analysis and survival analysis, we narrowed down potential therapeutic target genes and found that PKMYT1 might be one. Subsequently, functional studies (i.e., cell-proliferation assays, cell cycle analysis, and colony-formation assays) demonstrated that knockdown of PKMYT1 significantly inhibited the growth of PCa cells. Further investigation illustrated that PKMYT1 promoted the growth of PCa cells through targeting CCNB1 and CCNE1 expression. In addition, fostamatinib, an inhibitor of PKMYT1, effectively inhibited the proliferation of PCa cells. Taken together, our results suggest that PKMYT1 is a gene associated with malignancy of PCa and is a novel therapeutic target.


Assuntos
Neoplasias da Próstata/enzimologia , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Ciclina B1/genética , Ciclina B1/metabolismo , Ciclina E/genética , Ciclina E/metabolismo , Humanos , Masculino , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Oxazinas/uso terapêutico , Prognóstico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Piridinas/uso terapêutico
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