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1.
G3 (Bethesda) ; 11(1)2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33561234

RESUMO

The development of hair follicles (HFs) is dependent on interactions between epithelial cells and dermal fibroblasts, which may play an important role in maintaining the structure of HFs during their development and maturation. Wnt family member 10 (WNT10A) is a hub gene during HF development and maturation that may regulate the proliferation of dermal fibroblasts and epithelial cells through microRNAs (miRNAs) and messenger RNAs (mRNAs) to maintain the structural stability of HFs. In the present study, we confirmed that WNT10A is the target gene of chi-miR-130b-3p by real-time quantitative PCR, western blotting, and a dual-luciferase reporter gene assay. We successfully cultured fetal epithelial cells and dermal fibroblasts using the tissue block attachment method, and Cell Counting Kit-8 (CCK8) results showed that chi-miR-130b-3p regulates epithelial cell and dermal fibroblast proliferation by targeting WNT10A.

2.
Neuropharmacology ; 187: 108488, 2021 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-33556384

RESUMO

Neonatal hypoxic-ischemic encephalopathy (NHIE) is one of the most prevalent causes of death during the perinatal period. The lack of exposure to oxytocin is associated with NHIE-mediated severe brain injury. However, the underlying mechanism is not fully understood. This study combined immunohistochemistry with electrophysiological recordings of hippocampal CA1 neurons to investigate the role of oxytocin in an in vitro model of hypoxic-ischemic (HI) injury (oxygen and glucose deprivation, OGD) in postnatal day 7-10 rats. Immunohistochemical analysis showed that oxytocin largely reduced the relative intensity of TOPRO-3 staining following OGD in the hippocampal CA1 region. Whole-cell patch-clamp recording revealed that the OGD-induced onset time of anoxic depolarization (AD) was significantly delayed by oxytocin. This protective effect of oxytocin was blocked by pretreatment with [d(CH2)51, Tyr (Me)2, Thr4, Orn8, des-Gly-NH29] vasotocin (dVOT, an oxytocin receptor antagonist) or bicuculline (a GABAA receptor antagonist). Interestingly, oxytocin enhanced inhibitory postsynaptic currents in CA1 pyramidal neurons, which were abolished by tetrodotoxin or dVOT. In contrast, oxytocin had no effect on excitatory postsynaptic currents but induced an inward current in 86% of the pyramidal neurons tested. Taken together, these results demonstrate that oxytocin receptor signaling plays a critical role in attenuating neonatal neural death by facilitating GABAergic transmission, which may help to regulate the excitatory-inhibitory balance in local neuronal networks in NHIE patients.

3.
Mol Cancer ; 20(1): 36, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33608029

RESUMO

Early detection is crucial to improve breast cancer (BC) patients' outcomes and survival. Mammogram and ultrasound adopting the Breast Imaging Reporting and Data System (BI-RADS) categorization are widely used for BC early detection, while suffering high false-positive rate leading to unnecessary biopsy, especially in BI-RADS category-4 patients. Plasma cell-free DNA (cfDNA) carrying on DNA methylation information has emerged as a non-invasive approach for cancer detection. Here we present a prospective multi-center study with whole-genome bisulfite sequencing data to address the clinical utility of cfDNA methylation markers from 203 female patients with breast lesions suspected for malignancy. The cfDNA is enriched with hypo-methylated genomic regions. A practical computational framework was devised to excavate optimal cfDNA-rich DNA methylation markers, which significantly improved the early diagnosis of BI-RADS category-4 patients (AUC from 0.78-0.79 to 0.93-0.94). As a proof-of-concept study, we performed the first blood-based whole-genome DNA methylation study for detecting early-stage breast cancer from benign tumors at single-base resolution, which suggests that combining the liquid biopsy with the traditional diagnostic imaging can improve the current clinical practice, by reducing the false-positive rate and avoiding unnecessary harms.

5.
Drug Deliv ; 28(1): 206-217, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33472443

RESUMO

Corneal neovascularization (CNV) is the major cause of blindness after eye injury; however, only several drugs can be applied and the invasive administration ways (i.e., intravitreal injection and subconjunctival injection) are used. Resveratrol is a highly effective anti-VEGF agent against CNV. However, its applications are limited due to its strong hydrophobicity and instability. Here, we developed a resveratrol-loaded ocular lamellar crystalline gel (ROLG) for high inhibition of CNV. ROLGs were composed of resveratrol, glyceryl monooleate (GMO), ethanol, and water, and their lamellar crystalline structures were identified by polarizing light microscopy and small-angle X-ray scattering. High drug loading (4.4 mg/g) of ROLGs was achieved due to the hydrogen bonding between GMO and resveratrol. Resveratrol showed sustained release with 67% accumulative release in 7 h, which was attributed to the slow erosion of gels. Resveratrol in ROLGs had a high corneal permeation 3 times higher than resveratrol in hyaluronic acid suspensions (RHSs). ROLGs were administered to rats only once a day because of their strong retention on the cornea surface. ROLGs were safe due to the very little contact of ethanol in ROLGs to the cornea. CNV post-rat corneal alkaline injury was highly inhibited by ROLGs, resulting from the attenuation of corneal VEGF expression and then corneal healing was improved. The ROLG was a promising ocular medicine for the prevention of CNV.

6.
Am J Hum Genet ; 108(2): 337-345, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33434492

RESUMO

Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is associated with congenital absence of the uterus, cervix, and the upper part of the vagina; it is a sex-limited trait. Disrupted development of the Müllerian ducts (MD)/Wölffian ducts (WD) through multifactorial mechanisms has been proposed to underlie MRKHS. In this study, exome sequencing (ES) was performed on a Chinese discovery cohort (442 affected subjects and 941 female control subjects) and a replication MRKHS cohort (150 affected subjects of mixed ethnicity from North America, South America, and Europe). Phenotypic follow-up of the female reproductive system was performed on an additional cohort of PAX8-associated congenital hypothyroidism (CH) (n = 5, Chinese). By analyzing 19 candidate genes essential for MD/WD development, we identified 12 likely gene-disrupting (LGD) variants in 7 genes: PAX8 (n = 4), BMP4 (n = 2), BMP7 (n = 2), TBX6 (n = 1), HOXA10 (n = 1), EMX2 (n = 1), and WNT9B (n = 1), while LGD variants in these genes were not detected in control samples (p = 1.27E-06). Interestingly, a sex-limited penetrance with paternal inheritance was observed in multiple families. One additional PAX8 LGD variant from the replication cohort and two missense variants from both cohorts were revealed to cause loss-of-function of the protein. From the PAX8-associated CH cohort, we identified one individual presenting a syndromic condition characterized by CH and MRKHS (CH-MRKHS). Our study demonstrates the comprehensive utilization of knowledge from developmental biology toward elucidating genetic perturbations, i.e., rare pathogenic alleles involving the same loci, contributing to human birth defects.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/genética , Anormalidades Congênitas/genética , Ductos Paramesonéfricos/anormalidades , Ductos Paramesonéfricos/crescimento & desenvolvimento , Mutação , Ductos Mesonéfricos/crescimento & desenvolvimento , Adulto , Proteína Morfogenética Óssea 4/genética , Proteína Morfogenética Óssea 7/genética , Códon sem Sentido , Feminino , Estudos de Associação Genética , Pleiotropia Genética , Proteínas Homeobox A10/genética , Proteínas de Homeodomínio/genética , Humanos , Fator de Transcrição PAX8/genética , Herança Paterna , Penetrância , Proteínas com Domínio T/genética , Fatores de Transcrição/genética , Proteínas Wnt/genética , Ductos Mesonéfricos/anormalidades
7.
PLoS One ; 15(12): e0243507, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33351808

RESUMO

OBJECTIVE: Mature hair follicles represent an important stage of hair follicle development, which determines the stability of hair follicle structure and its ability to enter the hair cycle. Here, we used weighted gene co-expression network analysis (WGCNA) to identify hub genes of mature skin and hair follicles in Inner Mongolian cashmere goats. METHODS: We used transcriptome sequencing data for the skin of Inner Mongolian cashmere goats from fetal days 45-135 days, and divided the co expressed genes into different modules by WGCNA. Characteristic values were used to screen out modules that were highly expressed in mature skin follicles. Module hub genes were then selected based on the correlation coefficients between the gene and module eigenvalue, gene connectivity, and Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. The results were confirmed by quantitative polymerase chain reaction (qPCR). RESULTS: Ten modules were successfully defined, of which one, with a total of 3166 genes, was selected as a specific module through sample and gene expression pattern analyses. A total of 584 candidate hub genes in the module were screened by the correlation coefficients between the genes and module eigenvalue and gene connectivity. Finally, GO/KEGG functional enrichment analyses detected WNT10A as a key gene in the development and maturation of skin hair follicles in fetal Inner Mongolian cashmere goats. qPCR showed that the expression trends of 13 genes from seven fetal skin samples were consistent with the sequencing results, indicating that the sequencing results were reliable.n.


Assuntos
Cabras/genética , Folículo Piloso/embriologia , Animais , China , Desenvolvimento Fetal/genética , Feto/metabolismo , Perfilação da Expressão Gênica/métodos , Ontologia Genética , Redes Reguladoras de Genes/genética , Genoma/genética , Cabras/embriologia , Folículo Piloso/metabolismo , RNA Mensageiro/genética , Pele/metabolismo , Transcriptoma/genética
8.
ACS Biomater Sci Eng ; 6(10): 5720-5733, 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33320565

RESUMO

A biomaterial scaffold is a promising tool employed to drive tissue regeneration. This technology has been successfully applied in human tissue rebuilding, particularly for the skin. Meanwhile, there is still room for further improvement, such as maintaining sufficient functionality of a biomaterial scaffold. Here, we developed a new decellularization method to generate a complete anatomical skin biomatrix scaffold with a preserved extracellular matrix (ECM) architecture. We performed proteomic and bioinformatic analyses of the skin scaffold maps of humans, pigs, and rats and systematically analyzed the interaction between ECM proteins and different cell types in the skin microenvironment. These interactions served to quantify the structure and function of the skin's Matrisome comprising core ECM components and ECM-associated soluble signaling molecules required for the regulation of epidermal development. We primarily found that the properties of the skin ECM were species-specific. For example, the composition and function of the ECM of the human skin were more similar to those of pigs compared with those of rats. However, the skin ECM of the pig was significantly deficient in its enzyme systems and immune regulatory factors compared with that of humans. These findings provide a new understanding of the role of the skin ECM niche as well as an attractive strategy that can apply tissue engineering principles to skin biomatrix scaffold materials, which promises to accelerate and enhance tissue regeneration.

9.
Orphanet J Rare Dis ; 15(1): 288, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33054853

RESUMO

BACKGROUND: Isolated macrodactyly is a severe congenital hand anomaly with functional and physiological impact. Known causative genes include PIK3CA, AKT1 and PTEN. The aim of this study is to gain insights into the genetics basis of isolated macrodactyly. RESULTS: We enrolled 24 patients with isolated macrodactyly. Four of them were diagnosed with Proteus syndrome based on skin presentations characteristic to this disease. Targeted next-generation sequencing was performed using patients' blood and affected tissues. Overall, 20 patients carry mosaic PIK3CA pathogenic variants, i.e. p.His1047Arg (N = 7), p.Glu542Lys (N = 6), p.Glu545Lys (N = 2), p.His1047Leu (N = 2), p.Glu453Lys (N = 1), p.Gln546Lys (N = 1) and p.His1047Tyr (N = 1). Four patients who met the diagnostic criteria of Proteus syndrome carry mosaic AKT1 p.Glu17Lys variant. Variant allele frequencies of these mosaic variants obtained through next-generation sequencing range from 10 to 33%. In genotype-phenotype correlation analysis of patients with PIK3CA variant, we found that patients with the macrodactyly of the lower limbs tend to carry PIK3CA variants located in the helical domain (P = 0.005). CONCLUSIONS: Mosaic PIK3CA and AKT1 variants can be found in all of our samples with isolated macrodactyly. Insights into phenotypic and genetic spectrum of isolated macrodactyly may be helpful in perusing a more precise and effective management of isolated macrodactyly.

11.
Signal Transduct Target Ther ; 5(1): 240, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33060566

RESUMO

The COVID-19 pandemic has emerged as a global health emergency due to its association with severe pneumonia and relative high mortality. However, the molecular characteristics and pathological features underlying COVID-19 pneumonia remain largely unknown. To characterize molecular mechanisms underlying COVID-19 pathogenesis in the lung tissue using a proteomic approach, fresh lung tissues were obtained from newly deceased patients with COVID-19 pneumonia. After virus inactivation, a quantitative proteomic approach combined with bioinformatics analysis was used to detect proteomic changes in the SARS-CoV-2-infected lung tissues. We identified significant differentially expressed proteins involved in a variety of fundamental biological processes including cellular metabolism, blood coagulation, immune response, angiogenesis, and cell microenvironment regulation. Several inflammatory factors were upregulated, which was possibly caused by the activation of NF-κB signaling. Extensive dysregulation of the lung proteome in response to SARS-CoV-2 infection was discovered. Our results systematically outlined the molecular pathological features in terms of the lung response to SARS-CoV-2 infection, and provided the scientific basis for the therapeutic target that is urgently needed to control the COVID-19 pandemic.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/genética , Lesão Pulmonar/genética , Pneumonia Viral/genética , Proteoma/genética , Proteômica/métodos , Síndrome Respiratória Aguda Grave/genética , Idoso , Autopsia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Citocinas/genética , Citocinas/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ontologia Genética , Humanos , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Lesão Pulmonar/virologia , Masculino , Redes e Vias Metabólicas , Anotação de Sequência Molecular , NF-kappa B/genética , NF-kappa B/metabolismo , Pandemias , Pneumonia Viral/metabolismo , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Proteoma/metabolismo , Síndrome Respiratória Aguda Grave/metabolismo , Síndrome Respiratória Aguda Grave/patologia , Síndrome Respiratória Aguda Grave/virologia , Índice de Gravidade de Doença , Transdução de Sinais
12.
Aging (Albany NY) ; 12(19): 19022-19044, 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33044945

RESUMO

RNA modifications modulate most steps of gene expression. However, little is known about its role in neuroblastoma (NBL) and the inhibitors targeting it. We analyzed the RNA-seq (n=122) and CNV data (n=78) from NBL patients in Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database. The NBL sub-clusters (cluster1/2) were identified via consensus clustering for expression of RNA modification regulators (RNA-MRs). Cox regression, principle component analysis and chi-square analysis were used to compare differences of survival, transcriptome, and clinicopathology between clusters. Cluster1 showed significantly poor prognosis, of which RNA-MRs' expression and CNV alteration were closely related to pathologic stage. RNA-MRs and functional related prognostic genes were obtained using spearman correlation analysis, and queried in CMap and L1000 FWD database to obtain 88 inhibitors. The effects of 5 inhibitors on RNA-MRs were confirmed in SH-SY5Y cells. The RNA-MRs exhibited two complementary regulation functions: one conducted by TET2 and related to translation and glycolysis; another conducted by ALYREF, NSUN2 and ADARB1 and related to cell cycle and DNA repair. The perturbed proteomic profile of HDAC inhibitors was different from that of others, thus drug combination overcame drug resistance and was potential for NBL therapy with RNA-MRs as therapeutic targets.

13.
Int J Nanomedicine ; 15: 7979-7993, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116513

RESUMO

Background: Both magnetic nanoparticles (MNPs) and exosomes derived from bone mesenchymal stem cells (BMSC-Exos) have been reported to improve wound healing. In this study, novel exosomes (mag-BMSC-Exos) would be fabricated from BMSCs with the stimulation of MNPs and a static magnetic field (SMF) to further enhance wound repair. Methods: Mag-BMSC-Exos, namely, exosomes derived from BMSCs preconditioned with Fe3O4 nanoparticles and a SMF, together with BMSC-Exos were both first isolated by ultracentrifugation, respectively. Afterwards, we conducted in vitro experiments, including scratch wound assays, transwell assays, and tube formation assays, and established an in vivo wound healing model. The miRNA expression profiles were compared between BMSC-Exos and mag-BMSC-Exos to detect the potential mechanism of improving wound healing. At last, the function of exosomal miR-21-5p during wound healing was confirmed by utilizing a series of gain- and loss-of-function experiments in vitro. Results: The optimal working magnetic condition was 50 µg/mL Fe3O4 nanoparticles combined with 100 mT SMF. In vitro, mag-BMSC-Exo administration promoted proliferation, migration and angiogenesis to a greater extent than BMSC-Exo administration. Local transplantation of mag-BMSC-Exos into rat skin wounds resulted in accelerated wound closure, narrower scar widths and enhanced angiogenesis compared with BMSC-Exo transplantation. Notably, miR-21-5p was found to be highly enriched in mag-BMSC-Exos and served as a critical mediator in mag-BMSC-Exo-induced regulatory effects through inhibition of SPRY2 and activation of the PI3K/AKT and ERK1/2 signaling pathways. Conclusion: Mag-BMSC-Exos can further enhance wound healing than BMSC-Exos by improving angiogenesis and fibroblast function, and miR-21-5p upregulation in mag-BMSC-Exos might be the potential mechanism. This work offers an effective and promising protocol to improve wound healing in clinic.


Assuntos
Exossomos/efeitos dos fármacos , Exossomos/metabolismo , Campos Magnéticos , Nanopartículas de Magnetita , Células-Tronco Mesenquimais/citologia , MicroRNAs/genética , Regulação para Cima , Cicatrização , Animais , Fibroblastos/citologia , Fibroblastos/metabolismo , Sistema de Sinalização das MAP Quinases , Proteínas do Tecido Nervoso/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Ratos
14.
Stem Cell Res Ther ; 11(1): 415, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32967725

RESUMO

Millions suffer from skin diseases. Functional interfollicular epidermal stem cells are needed in skin therapy or drug screening in vitro. We obtained functional interfollicular epidermal stem cells with intact stemness and cell junctions by treating them with Wnt3a. Moreover, epidermal stem cell-derived extracellular vesicles were useful in epidermal cell growth. Finally, functional epidermal 3D organoids with polarity were cultured using Wnt3a and the supernatant derived from interfollicular epidermal stem cells and fresh medium in a 1:1 ratio. These results provide novel directions for the improvement of skin organoids and their potential in clinical application.

15.
Orphanet J Rare Dis ; 15(1): 250, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32933559

RESUMO

BACKGROUND: We previously reported a novel clinically distinguishable subtype of congenital scoliosis (CS), namely, TBX6-associated congenital scoliosis (TACS). We further developed the TBX6-associated CS risk score (TACScore), a multivariate phenotype-based model to predict TACS according to the patient's clinical manifestations. In this study, we aimed to evaluate whether using the TACScore as a screening method prior to performing whole-exome sequencing (WES) is more cost-effective than using WES as the first-line genetic test for CS. METHODS: We retrospectively collected the molecular data of 416 CS patients in the Deciphering disorders Involving Scoliosis and COmorbidities (DISCO) study. A decision tree was constructed to estimate the cost and the diagnostic time required for the two alternative strategies (TACScore versus WES). Bootstrapping simulations and sensitivity analyses were performed to examine the distributions and robustness of the estimates. The economic evaluation considered both the health care payer and the personal budget perspectives. RESULTS: From the health care payer perspective, the strategy of using the TACScore as the primary screening method resulted in an average cost of $1074.2 (95%CI: $1044.8 to $1103.5) and an average diagnostic duration of 38.7d (95%CI: 37.8d to 39.6d) to obtain a molecular diagnosis for each patient. In contrast, the corresponding values were $1169.6 (95%CI: $1166.9 to $1172.2) and 41.4d (95%CI: 41.1d to 41.7d) taking WES as the first-line test (P < 0.001). From the personal budget perspective, patients who were predicted to be positive by the TACScore received a result with an average cost of $715.1 (95%CI: $594.5 to $835.7) and an average diagnostic duration of 30.4d (95%CI: 26.3d to 34.6d). Comparatively, the strategy of WES as the first-line test was estimated to have significantly longer diagnostic time with an average of 44.0d (95%CI: 43.2d to 44.9d), and more expensive with an average of $1193.4 (95%CI: $1185.5 to $1201.3) (P < 0.001). In 100% of the bootstrapping simulations, the TACScore strategy was significantly less costly and more time-saving than WES. The sensitivity analyses revealed that the TACScore strategy remained cost-effective even when the cost per WES decreased to $8.8. CONCLUSIONS: This retrospective study provides clinicians with economic evidence to integrate the TACScore into clinical practice. The TACScore can be considered a cost-effective tool when it serves as a screening test prior to performing WES.

16.
Front Oncol ; 10: 1301, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32903496

RESUMO

Breast cancer is a major disease with high morbidity and mortality in women worldwide. Increased use of imaging biomarkers has been shown to add more information with clinical utility in the detection and evaluation of breast cancer. To date, numerous studies related to PET-based imaging in breast cancer have been published. Here, we review available studies on the clinical utility of different PET-based molecular imaging methods in breast cancer diagnosis, staging, distant-metastasis detection, therapeutic and prognostic prediction, and evaluation of therapeutic responses. For primary breast cancer, PET/MRI performed similarly to MRI but better than PET/CT. PET/CT and PET/MRI both have higher sensitivity than MRI in the detection of axillary and extra-axillary nodal metastases. For distant metastases, PET/CT has better performance in the detection of lung metastasis, while PET/MRI performs better in the liver and bone. Additionally, PET/CT is superior in terms of monitoring local recurrence. The progress in novel radiotracers and PET radiomics presents opportunities to reclassify tumors by combining their fine anatomical features with molecular characteristics and develop a beneficial pathway from bench to bedside to predict the treatment response and prognosis of breast cancer. However, further investigation is still needed before application of these modalities in clinical practice. In conclusion, PET-based imaging is not suitable for early-stage breast cancer, but it adds value in identifying regional nodal disease and distant metastases as an adjuvant to standard diagnostic imaging. Recent advances in imaging techniques would further widen the comprehensive and convergent applications of PET approaches in the clinical management of breast cancer.

17.
Mol Genet Genomic Med ; 8(10): e1453, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32815649

RESUMO

BACKGROUND: Congenital scoliosis (CS) is a spinal deformity due to vertebral malformations. Although insufficiency of TBX6 dosage contributes to a substantial proportion of CS, the molecular etiology for the majority of CS remains largely unknown. TBX6-mediated genes involved in the process of somitogenesis represent promising candidates. METHODS: Individuals affected with CS and without a positive genetic finding were referred to this study. Proband-only exome sequencing (ES) were performed on the recruited individuals, followed by analysis of TBX6-mediated candidate genes, namely MEOX1, MEOX2, MESP2, MYOD1, MYF5, RIPPLY1, and RIPPLY2. RESULTS: A total of 584 patients with CS of unknown molecular etiology were recruited. After ES analysis, protein-truncating variants in RIPPLY1 and MYF5 were identified from two individuals, respectively. In addition, we identified five deleterious missense variants (MYOD1, n = 4; RIPPLY2, n = 1) in TBX6-mediated genes. We observed a significant mutational burden of MYOD1 in CS (p = 0.032) compared with the in-house controls (n = 1854). Moreover, a potential oligogenic disease-causing mode was proposed based on the observed mutational co-existence of MYOD1/MEOX1 and MYOD1/RIPPLY1. CONCLUSION: Our study characterized the mutational spectrum of TBX6-mediated genes, prioritized core candidate genes/variants, and provided insight into a potential oligogenic disease-causing mode in CS.

18.
Adv Healthc Mater ; 9(14): e2000318, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32548975

RESUMO

3D-printed porous titanium-aluminum-vanadium (Ti6Al4V, pTi) scaffolds offer surgeons a good option for the reconstruction of large bone defects, especially at the load-bearing sites. However, poor osteogenesis limits its application in clinic. In this study, a new magnetic coating is successfully fabricated by codepositing of Fe3 O4 nanoparticles and polydopamine (PDA) on the surface of 3D-printed pTi scaffolds, which enhances cell attachment, proliferation, and osteogenic differentiation of hBMSCs in vitro and new bone formation of rabbit femoral bone defects in vivo with/without a static magnetic field (SMF). Furthermore, through proteomic analysis, the enhanced osteogenic effect of the magnetic Fe3 O4 /PDA coating with the SMF is found to be related to upregulate the TGFß-Smads signaling pathway. Therefore, this work provides a simple protocol to improve the osteogenesis of 3D-printed porous pTi scaffolds, which will help their application in clinic.

20.
Med Oncol ; 37(6): 56, 2020 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-32424617

RESUMO

Colorectal neuroendocrine tumors (NETs) are rare neoplasms and studies on colorectal NETs are relatively few compared to other tumors. To better understand the pathogenesis of this tumor, we performed whole-genome sequencing and follow-up verification using Sanger sequencing of the colorectal NETs and paired para-tumor tissue. We analyzed the features of the gene mutation spectrum and mutation signature patterns, and analyzed the four pathways that were altered by gene mutation in pancreatic neuroendocrine tumors, including DNA damage and repair, chromatin remodeling, telomere maintenance and mTOR signaling activation. We found that PARP4 which is related to the DNA damage and repair pathway; TSC2, which is related to the mTOR signaling activation pathway; and SLX1A, which is related to telomere maintenance, were mutated in colorectal NETs. Our data analyzed characteristics of gene mutation in colorectal NETs at the whole-genome level, and may help to better understand the pathogenesis of colorectal NETs and may be helpful for potential tumor therapy in the future.


Assuntos
Neoplasias Colorretais/genética , Mutação , Tumores Neuroendócrinos/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Neoplasias Colorretais/patologia , Análise Mutacional de DNA/métodos , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/patologia , Transdução de Sinais , Sequenciamento Completo do Genoma/métodos
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