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1.
PLoS Genet ; 16(2): e1008572, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-32012149

RESUMEN

Cancer genomes with mutations in the exonuclease domain of Polymerase Epsilon (POLE) present with an extraordinarily high somatic mutation burden. In vitro studies have shown that distinct POLE mutants exhibit different polymerase activity. Yet, genome-wide mutation patterns and driver mutation formation arising from different POLE mutants remains unclear. Here, we curated somatic mutation calls from 7,345 colorectal cancer samples from published studies and publicly available databases. These include 44 POLE mutant samples including 9 with whole genome sequencing data available. The POLE mutant samples were categorized based on the specific POLE mutation present. Mutation spectrum, associations of somatic mutations with epigenomics features and co-occurrence with specific driver mutations were examined across different POLE mutants. We found that different POLE mutants exhibit distinct mutation spectrum with significantly higher relative frequency of C>T mutations in POLE V411L mutants. Our analysis showed that this increase frequency in C>T mutations is not dependent on DNA methylation and not associated with other genomic features and is thus specifically due to DNA sequence context alone. Notably, we found strong association of the TP53 R213* mutation specifically with POLE P286R mutants. This truncation mutation occurs within the TT[C>T]GA context. For C>T mutations, this sequence context is significantly more likely to be mutated in POLE P286R mutants compared with other POLE exonuclease domain mutants. This study refines our understanding of DNA polymerase fidelity and underscores genome-wide mutation spectrum and specific cancer driver mutation formation observed in POLE mutant cancers.


Asunto(s)
Carcinogénesis/genética , Neoplasias Colorrectales/genética , ADN Polimerasa II/metabolismo , Proteínas de Unión a Poli-ADP-Ribosa/metabolismo , Dominios Proteicos/genética , Proteína p53 Supresora de Tumor/genética , Islas de CpG/genética , Citosina/metabolismo , Metilación de ADN/genética , Análisis Mutacional de ADN/estadística & datos numéricos , ADN Polimerasa II/genética , Bases de Datos Genéticas/estadística & datos numéricos , Conjuntos de Datos como Asunto , Epigénesis Genética , Humanos , Mutación , Proteínas de Unión a Poli-ADP-Ribosa/genética , Secuenciación Completa del Genoma/estadística & datos numéricos
2.
Soft Matter ; 16(43): 9876-9881, 2020 Nov 21.
Artículo en Inglés | MEDLINE | ID: mdl-33006593

RESUMEN

Supramolecular gels have been widely reported on account of their unique superiority and application prospects. In this work, we constructed a novel supramolecular gel (HD-G) by using hydroxy-naphthaldehyde decorated with naphthalimide in DMSO solution, which exhibited excellent selectivity and ultrasensitive sensing properties toward CN- (the lowest detection limit is 1.82 × 10-10 M). The sensing mechanism of this supramolecular gel takes advantage of π-π stacking interactions and anion-π interactions, which is different from the other familiar methods.

3.
BMC Genomics ; 20(1): 464, 2019 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-31174470

RESUMEN

BACKGROUND: The WRKY gene family is one of the most important families in higher plants. As transcription factors, they actively respond to biotic and abiotic stress and are also involved in plant development. Chinese jujube (Ziziphus jujuba Mill.) is the largest type of dried fruit tree in China in terms of production, but its production is largely limited by phytoplasma infection, and the information about the role of WRKY genes under phytoplasma stress was still limited. RESULTS: We identified 54 ZjWRKYs in the jujube genome and classified them into three subgroups according to conserved WRKY domains and zinc-finger structure. 41 ZjWRKYs were distributed on 11 of 12 pseudo chromosomes in Chinese jujube. The majority of ZjWRKYs were highly expressed in the seven examined tissues, indicating that they play multiple roles in these vegetative and reproductive organs. Transcriptome data showed that most of the characterised ZjWRKYs were highly expressed at later stages of fruit development. RT-qPCR demonstrated that the expression of 23 ZjWRKYs changed following phytoplasma infection, suggesting that they are involved in signalling pathways that respond to phytoplasma stress. Then, STRING analysis and yeast two-hybrid screening proved that some ZjWRKY proteins were interacting with ZjMAPKK proteins, which were also involved in phytoplasma invasion. Moreover, their differential expressions were further confirmed in resistant and susceptible jujube varieties under phytoplasma stress. These results suggest that ZjWRKYs play significant roles in phytoplasma tolerance and should be crucial candidate genes for jujube-phytoplasma interaction. CONCLUSIONS: 54 ZjWRKYs in Chinese jujube were identified and classified into three subgroups. 41 ZjWRKYs were unevenly distributed along the chromosomes. The majority of ZjWRKYs were highly expressed in various tissues. Most of the ZjWRKYs were positive responses to phytoplasma invasion, and that provided candidate genes for the future studies of jujube-phytoplasma interaction.


Asunto(s)
Familia de Multigenes , Phytoplasma , Proteínas de Plantas/genética , Factores de Transcripción/genética , Ziziphus/genética , Secuencias de Aminoácidos , Mapeo Cromosómico , Genoma de Planta , Filogenia , Proteínas de Plantas/química , Proteínas de Plantas/clasificación , Proteínas de Plantas/fisiología , Factores de Transcripción/química , Factores de Transcripción/clasificación , Factores de Transcripción/fisiología , Transcriptoma , Ziziphus/microbiología
4.
Am J Hum Genet ; 98(2): 256-74, 2016 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-26833333

RESUMEN

Comprehensive identification of somatic structural variations (SVs) and understanding their mutational mechanisms in cancer might contribute to understanding biological differences and help to identify new therapeutic targets. Unfortunately, characterization of complex SVs across the whole genome and the mutational mechanisms underlying esophageal squamous cell carcinoma (ESCC) is largely unclear. To define a comprehensive catalog of somatic SVs, affected target genes, and their underlying mechanisms in ESCC, we re-analyzed whole-genome sequencing (WGS) data from 31 ESCCs using Meerkat algorithm to predict somatic SVs and Patchwork to determine copy-number changes. We found deletions and translocations with NHEJ and alt-EJ signature as the dominant SV types, and 16% of deletions were complex deletions. SVs frequently led to disruption of cancer-associated genes (e.g., CDKN2A and NOTCH1) with different mutational mechanisms. Moreover, chromothripsis, kataegis, and breakage-fusion-bridge (BFB) were identified as contributing to locally mis-arranged chromosomes that occurred in 55% of ESCCs. These genomic catastrophes led to amplification of oncogene through chromothripsis-derived double-minute chromosome formation (e.g., FGFR1 and LETM2) or BFB-affected chromosomes (e.g., CCND1, EGFR, ERBB2, MMPs, and MYC), with approximately 30% of ESCCs harboring BFB-derived CCND1 amplification. Furthermore, analyses of copy-number alterations reveal high frequency of whole-genome duplication (WGD) and recurrent focal amplification of CDCA7 that might act as a potential oncogene in ESCC. Our findings reveal molecular defects such as chromothripsis and BFB in malignant transformation of ESCCs and demonstrate diverse models of SVs-derived target genes in ESCCs. These genome-wide SV profiles and their underlying mechanisms provide preventive, diagnostic, and therapeutic implications for ESCCs.


Asunto(s)
Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Estudios de Asociación Genética/métodos , Variación Genética , Línea Celular , Ciclina D1/genética , Variaciones en el Número de Copia de ADN , Receptores ErbB/genética , Carcinoma de Células Escamosas de Esófago , Eliminación de Gen , Reordenamiento Génico , Genes p16 , Genoma Humano , Genómica , Humanos , Hibridación Fluorescente in Situ , Receptor ErbB-2/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Receptor Notch1/genética , Reproducibilidad de los Resultados , Análisis de Secuencia de ARN , Translocación Genética
5.
Carcinogenesis ; 39(5): 708-718, 2018 05 03.
Artículo en Inglés | MEDLINE | ID: mdl-29546405

RESUMEN

Synchronous colorectal cancers (syCRCs), which present two or more lesions at diagnosis, are rare and pose a great challenge for clinical management. Although some predisposing factors associated with syCRCs have been studied with limited accession, the full repertoire of genomic events among the lesions within an individual and the causes of syCRCs remain unclear. We performed whole-exome sequencing of 40 surgical tumour samples of paired lesions from 20 patients to characterize the genetic alterations. Lesions from same patient showed distinct landscapes of somatic aberrations and shared few mutations, which suggests that they originate and develop independently, although they shared the similar genetic background. Canonical genes, such as APC, KRAS, TP53 and PIK3CA, were frequently mutated in the syCRCs, and most of them show different mutation profile compared with solitary colorectal cancer. We identified a recurrent somatic alteration (K15fs) in RPL22 in 25% of the syCRCs. Functional analysis indicated that mutated RPL22 may suppress cell apoptosis and promote the epithelial-mesenchymal transition (EMT). Potential drug targets were identified in several signalling pathways, and they present great discrepancy between lesions from the same patient. Our data show that the syCRCs within the same patient present great genetic heterogeneity, and they may be driven by distinct molecular events and develop independently. The discrepancy of potential drug targets and mutation burden in lesions from one patient provides valuable information in clinical management for patients with syCRCs.


Asunto(s)
Neoplasias Colorrectales/genética , Apoptosis/genética , Variaciones en el Número de Copia de ADN/genética , Transición Epitelial-Mesenquimal/genética , Exoma/genética , Heterogeneidad Genética , Predisposición Genética a la Enfermedad/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Mutación/genética , Transducción de Señal/genética
6.
Soft Matter ; 14(42): 8529-8536, 2018 Oct 31.
Artículo en Inglés | MEDLINE | ID: mdl-30338770

RESUMEN

Here, a novel pseudorotaxanes-type crosslinker of a supramolecular polymer network (WP5-PN) has been constructed from a host water-soluble pillar[5]arene (WP5) and a guest naphthalene dimethylamine derivative (PN) via a stepwise process involving multiple non-covalent interactions. The obtained supramolecular polymers were able to transform into a supramolecular polymer gel (WP5-PN-G) and show AIE properties in DMSO-H2O binary solution. Interestingly, due to the dynamic and reversible nature of non-covalent interactions, the resultant supramolecular polymer gels exhibited external stimuli-responsiveness to different parameters, such as temperature, acid-base, competitive guest and mechanical stress. Moreover, WP5-PN-G showed fluorescent response for Fe3+ and Cu2+, while its xerogel showed excellent recyclable separation properties for these metal ions with adsorption rates up to 98.07% and 95.38%, respectively. Moreover, by rational introduction of these metal ions into the WP5-PN-G, corresponding metal ion coordinated metallogels, such as WP5-PN-FeG and WP5-PN-CuG were obtained. These metallogels could selectively and sensitively sense F- and CN-, respectively. The detection limits of these metallogels for F- and CN- were about 1 × 10-8 M. The WP5-PN-G has potential applications in multi-analytes detection and separation as well as fluorescent display materials.

7.
BMC Genomics ; 18(1): 855, 2017 Nov 09.
Artículo en Inglés | MEDLINE | ID: mdl-29121856

RESUMEN

BACKGROUND: Chinese jujube (Ziziphus jujuba Mill.) is one of the most important members in the Rhamnaceae family. The whole genome sequence and more than 30,000 proteins of Chinese jujube have been obtained in 2014. Mitogen-activated protein kinase cascades are universal signal transduction modules in plants, which is rapidly activated under various biotic and abiotic stresses. To date, there has been no comprehensive analysis of the MAPK and MAPKK gene family in Chinese jujube at the whole genome level. RESULTS: By performing a series of bioinformatics analysis, ten MAPK and five MAPKK genes were identified from the genome database of Chinese jujube, and then compared with the homologous genes from Arabidopsis. Phylogenetic analysis showed that ZjMAPKs was classified into four known groups, including A, B, C and D. ZjMAPKs contains five members of the TEY phosphorylation site and five members with the TDY motif. The ZjMAPKK family was subsequently divided into three groups, A, B and D. The gene structure, conserved motifs, functional annotation and chromosome distribution of ZjMAPKs and ZjMAPKKs were also predicted. ZjMAPKs and ZjMAPKKs were distributed on nine pseudo-chromosomes of Chinese jujube. Subsequently, expression analysis of ZjMAPK and ZjMAPKK genes using reverse transcription PCR and quantitative real-time PCR was carried out. The majority of ZjMAPK and ZjMAPKK genes were expressed in all tested organs/tissues with considerable differences in transcript levels indicating that they might be constitutively expressed. Moreover, ZjMKK5 was specific expressed in early development stage of jujube flower bud, indicating it plays some roles in reproductive organs development. The transcript expression of most ZjMAPK and ZjMAPKK genes was down-regulated in response to plant growth regulators, darkness treatment and phytoplasma infection. CONCLUSIONS: We identified ten ZjMAPK and five ZjMAPKK genes from the genome database of Chinese jujube, the research results shown that ZjMPKs and ZjMKKs have the different expression patterns, indicating that they might play different roles in response to various treatments. The results provide valuable information for the further elucidation of physiological functions and biological roles of jujube MAPKs and MAPKKs.


Asunto(s)
Genómica , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Proteínas Quinasas Activadas por Mitógenos/genética , Ziziphus/enzimología , Ziziphus/genética , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Secuencia Conservada , Genoma de Planta/genética , Quinasas de Proteína Quinasa Activadas por Mitógenos/química , Proteínas Quinasas Activadas por Mitógenos/química , Filogenia , Alineación de Secuencia
8.
Ecol Evol ; 14(7): e11653, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38983705

RESUMEN

Cirsium japonicum contains a variety of medicinal components with good clinical efficacy. With the rapid changes in global climate, it is increasingly important to study the distribution of species habitats and the factors influencing their adaptability. Utilizing the MaxEnt model, we forecasted the present and future distribution regions of suitable habitats for C. japonicum under various climate scenarios. The outcome showed that under the current climate, the total suitable area of C. japonicum is 2,303,624 km2 and the highly suitable area is 79,117 km2. The distribution of C. japonicum is significantly influenced by key environmental factors such as temperature annual range, precipitation of the driest month, and precipitation of the wettest month. In light of future climate change, the suitable habitat for C. japonicum is anticipated to progressively relocate toward the western and northern regions, leading to an expansion in the total suitable area. These findings offer valuable insights into the conservation, sustainable utilization, and standardized cultivation of wild C. japonicum resources.

9.
Ecol Evol ; 14(1): e10848, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38264336

RESUMEN

Many kinds of medicinal ingredients occur in Cirsium lineare that have good clinical efficacy, conferring on this species its high medicinal development value. However, with a rapidly changing global climate, it is increasingly imperative to study the factors affecting the habitat distribution and survival of species. We predicted the current and future distribution areas of suitable habitats for C. lineare, analyzed the importance of environmental variables in influencing habitat shifts, and described the alterations to suitable habitats of C. lineare in different periods (modern, 2050s, and 2070s) and scenarios (RCP2.6, RCP4.5, and RCP8.5). The results show that, under the current climate, the total suitable area of C. lineare is about 2,220,900 km2, of which the highly suitable portion amounts to ca. 292,600 km2. The minimum temperature of the coldest month, annual precipitation, and mean daily temperature range are the chief environmental variables affecting the distribution of habitat for C. lineare. In the same period, with rising greenhouse gas emission concentrations, the total suitable area will increase. In general, under future climate change, the suitable habitat for C. lineare will gradually migrate to the west and north, and its total suitable area will also expand. The results of this experiment can be used for the conservation and management of the wild resources of C. lineare. We can choose suitable growth areas to protect the medicinal resources of C. lineare through in situ conservation and artificial breeding.

10.
Zhonghua Yi Xue Za Zhi ; 93(20): 1583-4, 2013 May 28.
Artículo en Zh | MEDLINE | ID: mdl-24028730

RESUMEN

OBJECTIVE: To evaluate the feasibility and clinical results of subsequent retroperitoneoscopic surgery for patients with previous ipsilateral retroperitoneal surgery through frank incision. METHODS: A total of 10 patents were selected for subsequent laparoscopic surgery through retroperitoneal approach. Among them, there were recurrent renal cysts (n = 4) including a history of open surgery (n = 1) and retroperitoneal surgery (n = 3) and nonfunctional kidneys (n = 6) including open nephropyelopolasty (n = 3), retroperitoneoscopic nephropyelopolasty (n = 1) and retroperitoneoscopic ureterolithotomy (n = 2). The mean surgical duration was (12-85) 38.6 months. All patients underwent retroperitoneoscopy. Decortication was performed for renal cysts and nephrectomy for nonfunctional kidneys. RESULTS: All operations were successfully performed with a mean surgical duration of 97 (40-185) minutes and a mean volume of blood loss 125 (20-460) ml. Among 4 cases with intraoperative peritoneal rupture, one case had renal cyst on ventral side. After enlargement, the procedure was performed through peritoneal cavity. The mean postoperative hospital stay was 5.6 (3-9) days. Nine patients received a mean follow-up period of 21.5 (3-47) months. All symptoms were relieved without any occurrence of postoperative complications. CONCLUSION: For patients with previous ipsilateral retroperitoneal surgery, retroperitoneoscopy may be feasible for properly selected cases.


Asunto(s)
Laparoscopía/métodos , Procedimientos Quirúrgicos Urológicos/métodos , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nefrectomía/métodos , Reoperación , Resultado del Tratamiento
11.
Adv Sci (Weinh) ; 10(31): e2303230, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37743226

RESUMEN

Bladder carcinoma (BC) recurrence is a major clinical challenge, and targeting the tumor microenvironment (TME) is a promising therapy. However, the relationship between individual TME components, particularly cancer-associated fibroblasts (CAFs), and tumor recurrence is unclear. Here, TME heterogeneity in primary and recurrent BC is investigated using single-cell RNA sequence profiling of 62 460 cells. Two cancer stem cell (CSC) subtypes are identified in recurrent BC. An inflammatory CAF subtype, ICAM1+ iCAFs, specifically associated with BC recurrence is also identified. iCAFs are found to secrete FGF2, which acts on the CD44 receptor of rCSC-M, thereby maintaining tumor stemness and epithelial-mesenchymal transition. Additionally, THBS1+ monocytes, a group of myeloid-derived suppressor cells (MDSCs), are enriched in recurrent BC and interacted with CAFs. ICAM1+ iCAFs are found to secrete CCL2, which binds to CCR2 in MDSCs. Moreover, elevated STAT3, NFKB2, VEGFA, and CTGF levels in iCAFs reshape the TME in recurrent tumors. CCL2 inhibition in an in situ BC mouse model suppressed tumor growth, decreased MDSCs and Tregs, and fostered tumor immune suppression. The study results highlight the role of iCAFs in TME cell-cell crosstalk during recurrent BC. The identification of pivotal signaling factors driving BC relapse is promising for the development of novel therapies.


Asunto(s)
Fibroblastos Asociados al Cáncer , Neoplasias de la Vejiga Urinaria , Animales , Ratones , Fibroblastos Asociados al Cáncer/metabolismo , Microambiente Tumoral , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/patología , Monocitos , Enfermedad Crónica
12.
J Natl Cancer Cent ; 3(1): 56-64, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-39036316

RESUMEN

Background: Tumour mutational burden (TMB) has emerged as a predictive marker for responsiveness to immune checkpoint inhibitors (ICI) in multiple tumour types. It can be calculated from somatic mutations detected from whole exome or targeted panel sequencing data. As mutations are unevenly distributed across the cancer genome, the clinical implications from TMB calculated using different genomic regions are not clear. Methods: Pan-cancer data of 10,179 samples were collected from The Cancer Genome Atlas cohort and 6,831 cancer patients with either ICI or non-ICI treatment outcomes were derived from published papers. TMB was calculated as the count of non-synonymous mutations and normalised by the size of genomic regions. Dirichlet method, linear regression and Poisson calibration models are used to unify TMB from different gene panels. Results: We found that panels based on cancer genes usually overestimate TMB compared to whole exome, potentially leading to misclassification of patients to receive ICI. The overestimation is caused by positive selection for mutations in cancer genes and cannot be completely addressed by the removal of mutational hotspots. We compared different approaches to address this discrepancy and developed a generalised statistical model capable of interconverting TMB derived from whole exome and different panel sequencing data, enabling TMB correction for patient stratification for ICI treatment. We show that in a cohort of lung cancer patients treated with ICI, when using a TMB cutoff of 10 mut/Mb, our corrected TMB outperforms the original panel-based TMB. Conclusion: Cancer gene-based panels usually overestimate TMB, and these findings will be valuable for unifying TMB calculations across cancer gene panels in clinical practice.

13.
Eur J Drug Metab Pharmacokinet ; 37(3): 225-31, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22562361

RESUMEN

The aim of this study was to determine transepithelial transport characteristics of rosuvastatin and effect of ursolic acid (P-gp potential inhibitor) and ko143 (ABC transporters selective inhibitor) on its transport in Caco-2 monolayers. A reliable Caco-2 cell monolayers model was established. The TEER value was used to inspect integrity of cell model. Apparent permeability coefficients (Papp(BL-AP) and Papp(AP-BL)) were used to analyze transepithelial transport of rosuvastatin. Uptake of rosuvastatin was time- and concentration-dependent in Caco-2 cell. The ko143 but not ursolic acid had effect on the uptake of rosuvastatin in Caco-2 cell monolayer model and affected apparent permeability coefficient and apparent permeability of rosuvastatin. Active transport and passive diffusion absorption existed in transepithelial transport of rosuvastatin in Caco-2 cell model. Ursolic acid had no effect on transport of rosuvastatin in Caco-2 cell monolayer. The result indicated that ursolic acid may not cause effect on intestinal absorption of rosuvastatin.


Asunto(s)
Fluorobencenos/farmacocinética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Pirimidinas/farmacocinética , Sulfonamidas/farmacocinética , Triterpenos/farmacología , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Transportadoras de Casetes de Unión a ATP/fisiología , Transporte Biológico/efectos de los fármacos , Células CACO-2 , Humanos , Proteínas de Neoplasias/fisiología , Rosuvastatina Cálcica , Ácido Ursólico
14.
Genome Med ; 14(1): 124, 2022 Oct 31.
Artículo en Inglés | MEDLINE | ID: mdl-36316687

RESUMEN

BACKGROUND: Ganciclovir (GCV) is widely used in solid organ and haematopoietic stem cell transplant patients for prophylaxis and treatment of cytomegalovirus. It has long been considered a mutagen and carcinogen. However, the contribution of GCV to cancer incidence and other factors that influence its mutagenicity remains unknown. METHODS: This retrospective cohort study analysed genomics data for 121,771 patients who had undergone targeted sequencing compiled by the Genomics Evidence Neoplasia Information Exchange (GENIE) or Foundation Medicine (FM). A statistical approach was developed to identify patients with GCV-associated mutational signature (GCVsig) from targeted sequenced data of tumour samples. Cell line exposure models were further used to quantify mutation burden and DNA damage caused by GCV and other antiviral and immunosuppressive drugs. RESULTS: Mutational profiles from 22 of 121,771 patient samples in the GENIE and FM cohorts showed evidence of GCVsig. A diverse range of cancers was represented. All patients with detailed clinical history available had previously undergone solid organ transplantation and received GCV and mycophenolate treatment. RAS hotspot mutations associated with GCVsig were present in 9 of the 22 samples, with all samples harbouring multiple GCV-associated protein-altering mutations in cancer driver genes. In vitro testing in cell lines showed that elevated DNA damage response and GCVsig are uniquely associated with GCV but not acyclovir, a structurally similar antiviral. Combination treatment of GCV with the immunosuppressant, mycophenolate mofetil (MMF), increased the misincorporation of GCV in genomic DNA and mutations attributed to GCVsig in cell lines and organoids. CONCLUSIONS: In summary, GCV can cause a diverse range of cancers. Its mutagenicity may be potentiated by other therapies, such as mycophenolate, commonly co-prescribed with GCV for post-transplant patients. Further investigation of the optimal use of these drugs could help reduce GCV-associated mutagenesis in post-transplant patients.


Asunto(s)
Infecciones por Citomegalovirus , Ganciclovir , Neoplasias , Humanos , Antivirales/efectos adversos , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/prevención & control , Ganciclovir/efectos adversos , Inmunosupresores/efectos adversos , Mutación , Neoplasias/inducido químicamente , Neoplasias/genética , Estudios Retrospectivos
15.
Sci Adv ; 7(45): eabg4398, 2021 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-34730999

RESUMEN

Multiple mutational signatures have been associated with DNA mismatch repair (MMR)­deficient cancers, but the mechanisms underlying their origin remain unclear. Here, using mutation data from cancer genomes, we identify a previously unknown function of MMR that is able to protect genomes from 5-methylcytosine (5mC) deamination­induced somatic mutations in a replication-independent manner. Cancers with deficiency of MMR proteins MSH2/MSH6 (MutSα) exhibit mutational signature contributions distinct from those that are deficient in MLH1/PMS2 (MutLα). This disparity arises from unrepaired 5mC deamination­induced mismatches rather than replicative DNA polymerase errors. In cancers with biallelic loss of MBD4 DNA glycosylase, repair of 5mC deamination damage is strongly associated with H3K36me3 chromatin, implicating MutSα as the essential factor in its repair. We thus uncover a noncanonical role of MMR in the protection against 5mC deamination­induced mutation in human cancers.

16.
Eur J Cancer ; 157: 94-107, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34492588

RESUMEN

AIM: High immune cell infiltration of the tumour microenvironment is generally associated with a good prognosis in solid cancers. However, a subset of patients with colorectal cancer (CRC) tumours with high immune cell infiltration have a poor outcome. These tumours have a high level of T cell infiltration and are also characterised by increased expression of programmed death-ligand 1 (PD-L1). As these tumours comprise both microsatellite instability and microsatellite stable subtypes, the mechanism underlying this phenotype is unknown. METHODS: Using RNA-seq data from The Cancer Genome Atlas, we quantified transposable element (TE) expression and developed a TE expression score that is predictive of prognosis and immune infiltration independent of microsatellite instability status and tumour staging in CRC. RESULTS: Tumours with the highest TE expression score showed increased immune cell infiltration with upregulation of interferon (IFN) signalling pathways and downstream activation of IFN-simulated genes. As expected, cell lines treated with DNA methyltransferase inhibitor mimicked patient tumours with increased TE expression and IFN signalling. However, surprisingly, unlike high TE expressing CRC, there is little evidence for the activation of JAK-STAT signalling and PD-L1 expression in DNA methyltransferase inhibitor-treated cells. Single-cell RNA-seq analysis of CRC samples showed that PD-L1 expression is mainly confined to tumour-associated macrophages and T cells, suggesting that TE mediated IFN signalling is triggering expression of PD-L1 in immune cells rather than in tumour cells. CONCLUSIONS: Our study uncovers a novel mechanism of TE driven immune evasion and highlights TE expression as an important factor for patient prognosis in CRC.


Asunto(s)
Neoplasias Colorrectales/genética , Neoplasias Colorrectales/inmunología , Elementos Transponibles de ADN/fisiología , Escape del Tumor/inmunología , Antígeno B7-H1/fisiología , Línea Celular Tumoral , Metilación de ADN , Humanos , Inmunidad Innata , Factores de Transcripción STAT/fisiología
17.
Arch Orthop Trauma Surg ; 130(9): 1177-83, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20364263

RESUMEN

INTRODUCTION: The treatment of displaced acetabular fractures with formal open reduction and internal fixation has gained general acceptance. However, extensile exposure can lead to complications. Two-dimensional fluoroscopy-based computerized navigation for placement of percutaneous screw across non-displaced acetabular fractures has attracted interest by making use of stored patient-specific imaging data to provide real-time guidance in multiple image planes during implant placement. The purpose of the present study was to document early treatment results and complications associated with this new technique and evaluate its clinical application to displaced acetabular fractures amenable to closed or limited open reduction. MATERIALS AND METHODS: Eighteen adult patients with 12 non-displaced and 8 displaced acetabular fractures were treated with percutaneous screw fixation under the guidance of a fluoroscopy-based navigation system. There were 14 men and four women with a mean age of 42.1 years (range 19-54 years). According to the AO and Orthopaedic Trauma Association Classification, there were nine 62-A3, five 62-B1, three 62-B2, and three 62-B3. The mean follow-up was 21 months (range 12-28 months). The mean time from injury to surgery was 4 days (range 2-7 days). RESULTS: A total of 30 acetabular screws were inserted, including 21 anterior column screws and 9 posterior column screws. The average operation time was 24.6 min (range 16-47 min) from the image acquisition to wound closure. The average fluoroscopic time was 28.4 s (range 11-58 s). Compared to the final position of the screw, the average deviated distance of wire tip was 2.5 mm (range 1.1-3.6 mm) and the average trajectory difference was 2.45 degrees (range 1.5 degrees -4.6 degrees ). Maximal gap displacement averaged 10 mm (range 2-22 mm) preoperatively and 3 mm (range 0-5 mm) postoperatively; while maximal step displacement averaged 4 mm (range 1-10 mm) preoperatively and 2 mm (range 0-4 mm) postoperatively. One patient sustained a transient femoral nerve palsy and resolved 2 months after the operation. No superficial or deep infection occurred. Using the rating system of D'Aubigne and Postel, 13 patients had excellent results, 4 patients had good results, and 1 patient had a fair result. CONCLUSION: Percutaneous screw fixation of acetabular fractures with 2D fluoroscopy-based navigation could be applied not only to non-displaced fractures but also to displaced fractures amenable to closed or limited open reduction.


Asunto(s)
Acetábulo/lesiones , Fijación Interna de Fracturas/métodos , Fracturas Óseas/diagnóstico por imagen , Fracturas Óseas/cirugía , Cirugía Asistida por Computador/métodos , Acetábulo/diagnóstico por imagen , Acetábulo/cirugía , Adulto , Tornillos Óseos , Estudios de Cohortes , Femenino , Fluoroscopía , Estudios de Seguimiento , Fijación Interna de Fracturas/instrumentación , Curación de Fractura/fisiología , Humanos , Luxaciones Articulares/diagnóstico por imagen , Luxaciones Articulares/cirugía , Masculino , Persona de Mediana Edad , Procedimientos Quirúrgicos Mínimamente Invasivos/instrumentación , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Radiografía Intervencional , Medición de Riesgo , Resultado del Tratamiento , Adulto Joven
18.
Zhongguo Gu Shang ; 33(4): 375-8, 2020 Apr 25.
Artículo en Zh | MEDLINE | ID: mdl-32351095

RESUMEN

OBJECTIVE: To observe the clinical effect of elastic intramedullary nail in minimally invasive treatment of floating knee injury in children. METHODS: From January 2009 to September 2017, 11 children with floating knee injury were treated with one-off open reduction and elastic intramedullary nail or external fixator fixation, including 7 males and 4 females, aged 5.0 to 11.0 years, with an average age of 8.3 years. The treatment results were evaluated according to karlstrom's standard. RESULTS: Eleven patients were followed up for 8 to 48 months, with an average of 28 months. All the fractures healed at one time, and there were no complications such as nonunion, malunion and serious dysfunction of knee joint. The length of the affected limb in 2 cases was 1.2 to 1.5 cm longer than that in the opposite side without shortening. According to Karlstrom scoring standard, 8 cases were excellent, 1 case was good and 2 cases were middle. CONCLUSION: Elastic intramedullary nail minimally invasive treatment of floating knee injury in children is a safe and effective treatment, which can effectively reduce the fracture and promote bone healing, which is conducive to early functional recovery.


Asunto(s)
Fijación Intramedular de Fracturas , Traumatismos de la Rodilla , Clavos Ortopédicos , Niño , Preescolar , Fijadores Externos , Femenino , Fijación de Fractura , Curación de Fractura , Humanos , Fijadores Internos , Traumatismos de la Rodilla/cirugía , Masculino , Resultado del Tratamiento
19.
Molecules ; 14(10): 3952-63, 2009 Oct 09.
Artículo en Inglés | MEDLINE | ID: mdl-19924041

RESUMEN

An efficient and practical method for the synthesis of indolyl-nitroalkane derivatives catalyzed by N-bromosuccinimide is described. The generality of this method was demonstrated by synthesizing an array of diverse 3-substituted indole derivatives by the reaction of different beta-nitrostyrenes with various substituted indoles. Simple reaction conditions accompanied by good yields of indolyl-nitroalkanes are the merits of this methodology.


Asunto(s)
Alcanos/síntesis química , Bromosuccinimida/química , Alcaloides Indólicos/síntesis química , Indoles/síntesis química , Catálisis
20.
Zhonghua Yi Xue Za Zhi ; 89(48): 3417-9, 2009 Dec 29.
Artículo en Zh | MEDLINE | ID: mdl-20223117

RESUMEN

OBJECTIVE: To discuss the causes of common complications of ureteroscopy and how to prevent them. METHODS: A total of 768 cases of common complications of ureteroscopy were retrospectively analyzed from February 2004 to February 2009. RESULTS: The intra-operative complications were failed entry (n = 6, 0.78%), ureterostoma injury and ureterostoma submucosa pseudocana (n = 12, 1.56%), ureteral perforation (n = 16, 2.08%), stone displacement (n = 13, 1.87%) and ureteral mucosa evulsion (n = 3, 0.39%). And the post-operative complications were lumbago or renal colic (n = 11, 1.43%), infection (n = 9, 1.17%)and severe hematuria (n = 5, 0.65%). CONCLUSION: Skillful operative techniques and strict indications are key to reducing complications of ureteroscopy.


Asunto(s)
Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/prevención & control , Ureteroscopía/efectos adversos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto Joven
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