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BACKGROUND: The repair of facial skin and soft tissue defects remains a clinical challenge. The author introduced a novel "table tennis racquet" random skin flap for wound repair after facial skin cancer excision and discussed its survival mechanisms. METHODS: A lateral mandibular neck skin flap shaped like a table tennis racquet with no well-known blood vessels at the narrow pedicle was designed in 31 cases to repair tissue defects. Among them, there were 8 cases of skin carcinoma in the frontotemporal area and 23 cases of skin carcinoma in the cheek. The flap area was 8.0 × 7.0 cm at maximum and 3.0 × 2.5 cm at minimum, with a pedicle width of 1.0-2.0 cm and a pedicle length of 2.0-6.0 cm. RESULTS: All 31 "table tennis racquet" random skin flaps survived, although there were 3 cases with delayed healing of distal flap bruising. All of them had an ideal local shape after repair with a concealed donor area and inconspicuous scars. CONCLUSIONS: This flap has a "table tennis racquet" shape with a pedicle without well-known blood vessels and has a length-to-width ratio that exceeds that of conventional random flaps, making it unconventional. Because of its long and narrow pedicle, it not only has a large rotation and coverage area but also can be designed away from the defect area, avoiding the defect of no donor tissue being localized near the defect. Overall, this approach is an ideal option for repairing tissue defects after enlarged excision of facial skin carcinoma.
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Neoplasias Faciais , Procedimentos de Cirurgia Plástica , Neoplasias Cutâneas , Retalhos Cirúrgicos , Humanos , Neoplasias Cutâneas/cirurgia , Neoplasias Cutâneas/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias Faciais/cirurgia , Idoso , Procedimentos de Cirurgia Plástica/métodos , Retalhos Cirúrgicos/irrigação sanguínea , Resultado do Tratamento , Transplante de Pele/métodos , Adulto , Cicatrização/fisiologia , Idoso de 80 Anos ou mais , Sobrevivência de EnxertoRESUMO
The oriental tobacco budworm Helicoverpa assulta (Lepidoptera: Noctuidae) is a specialist pest that may cause serious damages to important crops such as chili pepper and tobacco. Various man-made insecticides have been applied to control the infestation of this pest. To understand how this pest copes with insecticides, it is required to identify key players involved in insecticide transformation. In this study, a P450 gene of CYP6B subfamily was identified in the oriental tobacco budworm, and its expression pattern was revealed. Moreover, the activities of HassCYP6B6 against 12 insecticides were explored using recombinant enzymes produced in the facile Escherichia coli. Data from metabolic experiments showed that HassCYP6B6 was able to metabolize conventional insecticides including organophosporates (diazinon, malathion, phoxim), carbamate propoxur, and pyrethroid esfenvalerate, while no significant metabolism was observed towards new-type pesticides such as neonicotinoids (acetamiprid, imidacloprid), diamides (chlorantraniliprole, cyantraniliprole), macrocyclic lactone (emamectin benzoate, ivermectin), and metaflumizone. Structures of metabolites were proposed based on mass spectrometry analyses. The results demonstrate that HassCYP6B6 plays important roles in the transformation of multiple insecticides via substrate-dependent catalytic mechanisms including dehydrogenation, hydroxylation and oxidative desulfurization. The findings have important applied implications for the usage of insecticides.
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Inseticidas , Mariposas , Inseticidas/metabolismo , Animais , Mariposas/genética , Mariposas/metabolismo , Proteínas de Insetos/metabolismo , Proteínas de Insetos/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Sistema Enzimático do Citocromo P-450/genéticaRESUMO
Background/Objective: Reticulocyte hemoglobin content (MCHr) was recognized as a rapid and reliable marker for investigating iron deficiency (ID). We hypothesized that MCHr was associated with the risk of iron deficiency anemia in adults. Methods: This is a dual-center case-control study. A total of 806 patients and healthy individuals were recruited from Ruijin Hospital and Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine between January 2021 and December 2021. The participants were categorized into iron deficiency anemia (IDA) group (n = 302), non-IDA group (n = 366), and healthy control group (n = 138). According to the MCHr level, the participants were divided into two groups, i.e. normal MCHr (≥25 pg) and decreased MCHr (<25 pg) group. Multivariate logistic regression analysis and adjusted subgroup analysis were conducted to estimate the relative risk between MCHr and IDA, with confounding factors including age, sex, hemoglobin (Hb), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), Hematocrit (HCT), serum iron (Fe), ferritin (Ferrit), and total iron binding capacity (TIBC). Results: Compared with the non-IDA, the MCHr level with IDA decreased significantly. ROC curve analysis showed that MCHr had the largest area under the AUC curve. After comprehensive adjustment for confounding factors, individuals with normal level of MCHr exhibited a decreased risk of IDA (OR = 0.68 [0.60, 0.77], P < 0.01), while the risk of IDA was up to 5 times higher for those with decreased MCHr. Conclusion: Our findings supported the hypothesis that MCHr was associated with the risk of IDA in adults and could serve as an indicator of IDA severity. MCHr holds clinical value as an auxiliary diagnostic indicator, providing valuable insights into whether invasive examinations are warranted in the assessment of IDA.
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Pulmonary fibrosis (PF) is a progressive and fatal lung disease with high incidence and a lack of effective treatment, which is a severe public health problem. PF has caused a huge socio-economic burden, and its pathogenesis has become a research hotspot. SIRT1 is a nicotinamide adenosine dinucleotide (NAD)-dependent sirtuin essential in tumours, Epithelial mesenchymal transition (EMT), and anti-aging. Numerous studies have demonstrated after extensive research that it is crucial in preventing the progression of pulmonary fibrosis. This article reviews the biological roles and mechanisms of SIRT1 in regulating the progression of pulmonary fibrosis in terms of EMT, oxidative stress, inflammation, aging, autophagy, and discusses the potential of SIRT1 as a therapeutic target for pulmonary fibrosis, and provides a new perspective on therapeutic drugs and prognosis prospects.
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Neoplasias , Fibrose Pulmonar , Sirtuína 1 , Humanos , Transição Epitelial-Mesenquimal , Fibrose , Estresse Oxidativo , Sirtuína 1/genética , Sirtuína 1/metabolismoRESUMO
Background: Immunotherapy has greatly changed the treatment of advanced non-small cell lung cancer (NSCLC). Anoikis is a programmed cell death process associated with cancer. However, the correlation between anoikis-related genes and the tumor microenvironment (TME) features and immunotherapeutic outcome in NSCLC has not been fully explored. Methods: The bulk and single-cell transcriptome data of NSCLC were downloaded from TCGA and GEO databases. The distribution of anoikis-related genes on different cell types at the single-cell level was analyzed, and these genes specifically expressed by tumor cells and immunotherapy-related were further extracted. Next, the candidate gene CTNND1 was identified and its correlations with the TME features and immunotherapeutic outcome in NSCLC were explored in multiple public cohorts. Finally, an in-house cohort was used to determine the CTNND1 expression and immuno-correlation in NSCLC. Results: At single-cell atlas, we found that anoikis-related genes expressed specifically in tumor cells of NSCLC. By intersecting anoikis-related genes, immunotherapy-associated genes, and the genes expressed in tumor cells, we obtained a special biomarker CTNND1. In addition, cell-cell communication analysis revealed that CTNND1+ tumor cells communicated with immune subpopulations frequently. Moreover, we found that high expression of CTNND1 was related to immuno-suppressive status of NSCLC. The expression of CTNND1 and its immuno-correlation were also validated, and the results showed that CTNND1 was highly expressed in NSCLC tissues and tumors with high CTNND1 expression accompanied with low CD8+ T cells infiltration. Conclusions: Overall, our study reported that CTNND1 can be considered as a novel biomarker for the predication of immunotherapeutic responses and a potential target for NSCLC therapy.
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m6A is the most prevalent internal modification of eukaryotic mRNA, and plays a crucial role in tumorigenesis and various other biological processes. Lung cancer is a common primary malignant tumor of the lungs, which involves multiple factors in its occurrence and progression. Currently, only the demethylases FTO and ALKBH5 have been identified as associated with m6A modification. These demethylases play a crucial role in regulating the growth and invasion of lung cancer cells by removing methyl groups, thereby influencing stability and translation efficiency of mRNA. Furthermore, they participate in essential biological signaling pathways, making them potential targets for intervention in lung cancer treatment. Here we provides an overview of the involvement of m6A demethylase in lung cancer, as well as their potential application in the diagnosis, prognosis and treatment of the disease.
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Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Prognóstico , RNA Mensageiro/genéticaRESUMO
We present a dedicated end-station for solution phase high repetition rate (MHz) picosecond hard x-ray spectroscopy at beamline 15-2 of the Stanford Synchrotron Radiation Lightsource. A high-power ultrafast ytterbium-doped fiber laser is used to photoexcite the samples at a repetition rate of 640 kHz, while the data acquisition operates at the 1.28 MHz repetition rate of the storage ring recording data in an alternating on-off mode. The time-resolved x-ray measurements are enabled via gating the x-ray detectors with the 20 mA/70 ps camshaft bunch of SPEAR3, a mode available during the routine operations of the Stanford Synchrotron Radiation Lightsource. As a benchmark study, aiming to demonstrate the advantageous capabilities of this end-station, we have conducted picosecond Fe K-edge x-ray absorption spectroscopy on aqueous [FeII(phen)3]2+, a prototypical spin crossover complex that undergoes light-induced excited spin state trapping forming an electronic excited state with a 0.6-0.7 ns lifetime. In addition, we report transient Fe Kß main line and valence-to-core x-ray emission spectra, showing a unique detection sensitivity and an excellent agreement with model spectra and density functional theory calculations, respectively. Notably, the achieved signal-to-noise ratio, the overall performance, and the routine availability of the developed end-station have enabled a systematic time-resolved science program using the monochromatic beam at the Stanford Synchrotron Radiation Lightsource.
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Administration of CHK1-targeted anticancer therapies is associated with an increased cumulative risk of cardiac complications, which is further amplified when combined with gemcitabine. However, the underlying mechanisms remain elusive. In this study, we generated hiPSC-CMs and murine models to elucidate the mechanisms underlying CHK1 inhibition combined with gemcitabine-induced cardiotoxicity and identify potential targets for cardioprotection. Mice were intraperitoneally injected with 25 mg/kg CHK1 inhibitor AZD7762 and 20 mg/kg gemcitabine for 3 weeks. hiPSC-CMs and NMCMs were incubated with 0.5 uM AZD7762 and 0.1 uM gemcitabine for 24 h. Both pharmacological inhibition or genetic deletion of CHK1 and administration of gemcitabine induced mtROS overproduction and pyroptosis in cardiomyocytes by disrupting mitochondrial respiration, ultimately causing heart atrophy and cardiac dysfunction in mice. These toxic effects were further exacerbated with combination administration. Using mitochondria-targeting sequence-directed vectors to overexpress CHK1 in cardiomyocyte (CM) mitochondria, we identified the localization of CHK1 in CM mitochondria and its crucial role in maintaining mitochondrial redox homeostasis for the first time. Mitochondrial CHK1 function loss mediated the cardiotoxicity induced by AZD7762 and CHK1-knockout. Mechanistically, mitochondrial CHK1 directly phosphorylates SIRT3 and promotes its expression within mitochondria. On the contrary, both AZD7762 or CHK1-knockout and gemcitabine decreased mitochondrial SIRT3 abundance, thus resulting in respiration dysfunction. Further hiPSC-CMs and mice experiments demonstrated that SIRT3 overexpression maintained mitochondrial function while alleviating CM pyroptosis, and thereby improving mice cardiac function. In summary, our results suggest that targeting SIRT3 could represent a novel therapeutic approach for clinical prevention and treatment of cardiotoxicity induced by CHK1 inhibition and gemcitabine.
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Quinase 1 do Ponto de Checagem , Células-Tronco Pluripotentes Induzidas , Sirtuína 3 , Animais , Camundongos , Cardiotoxicidade/metabolismo , Gencitabina , Homeostase , Células-Tronco Pluripotentes Induzidas/metabolismo , Mitocôndrias/metabolismo , Miócitos Cardíacos , Oxirredução , Sirtuína 3/genética , Quinase 1 do Ponto de Checagem/metabolismoRESUMO
Skin, as an exposed tissue, often suffers damage after exposure to radiotherapy and accidental events, which may lead to the formation of chronic refractory wounds. However, effective treatment options are usually limited for severe radiation-induced skin injury (RSI). Platelet-rich plasma (PRP) has been identified to promote wound healing, but whether a new generation of blood-derived biomaterial, injectable platelet-rich fibrin (i-PRF), is effective in repairing RSI remains unclear. In this study, blood was drawn from humans and Sprague-Dawley rats to prepare PRP and i-PRF, and the regenerative functions of PRP and i-PRF were investigated by exposing the dorsal skin of SD rats to local radiation (45 Gy) and exposing HDF-α cells and human umbilical vein endothelial cells (HUVECs) cells to X-rays (10 Gy). The healing effect of i-PRF on RSI was analysed by tube formation assay, cell migration and apoptosis assays, ROS assay, wound healing assay, histological characterisation and immunostaining. The results showed that exposure to high doses of radiation reduced cell viability, increased ROS levels and induced cell apoptosis, thereby causing dorsal trauma of rats. However, both PRP and i-PRF could resisted RSI, and they were capable of reducing inflammation and promoting angiogenesis and vascular regeneration. i-PRF has a higher concentration of platelets and platelet-derived growth factors, which has a more convenient preparation method and better repair effect and possesses a good application prospect for the repair of RSI.
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Fibrina Rica em Plaquetas , Plasma Rico em Plaquetas , Lesões por Radiação , Humanos , Ratos , Animais , Cicatrização , Espécies Reativas de Oxigênio/metabolismo , Proliferação de Células , Ratos Sprague-Dawley , Células Endoteliais da Veia Umbilical HumanaRESUMO
PURPOSE: To compare the cost-benefit of active surveillance (AS) against immediate fine needle aspiration (FNA) of sonographically suspicious subcentimeter thyroid nodules. MATERIALS AND METHODS: A Markov model was constructed to compare the cost-benefit of 3 strategies from the point of discovery until death: (a) Surveillance of all nodules, (b) Surveillance of nodules with positive cytology, and (c) Surgery of nodules with positive cytology. The reference case was a 40-year-old woman with a sonographically suspicious subcentimeter thyroid nodule. Transition probabilities, costs, and health state utilities were derived from the literature. Sensitivity analyses were performed to evaluate model uncertainty. Willingness-to-pay threshold was set at $100,000/quality-adjusted life year. RESULTS: Surveillance of nodules with positive cytology dominated in the reference scenario and was cost-beneficial over Surveillance of all nodules, independent of the utility of AS. Surveillance of all nodules was cost-beneficial only at a life expectancy of <2.6 years or surveillance duration of <4 years. CONCLUSIONS: While current guidelines recommend AS of sonographically suspicious subcentimeter nodules, the results of this study suggest that immediate FNA (Surveillance of nodules with positive cytology) is more cost-beneficial than AS (Surveillance of all nodules). Patients with positive cytology on FNA may subsequently opt for AS (Surveillance of nodules with positive cytology) or surgery (Surgery of nodules with positive cytology) according to their level of comfort (ie, utility) with AS.
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Neoplasias da Glândula Tireoide , Nódulo da Glândula Tireoide , Feminino , Humanos , Adulto , Nódulo da Glândula Tireoide/diagnóstico por imagem , Nódulo da Glândula Tireoide/terapia , Biópsia por Agulha Fina/métodos , Análise de Custo-Efetividade , Conduta Expectante , Análise Custo-BenefícioRESUMO
Osteosarcoma (OS) is a primary malignant bone tumor that most commonly affects children, adolescents, and young adults. Here, we comprehensively analyze genomic, epigenomic and transcriptomic data from 121 OS patients. Somatic mutations are diverse within the cohort, and only TP53 is significantly mutated. Through unsupervised integrative clustering of the multi-omics data, we classify OS into four subtypes with distinct molecular features and clinical prognosis: (1) Immune activated (S-IA), (2) Immune suppressed (S-IS), (3) Homologous recombination deficiency dominant (S-HRD), and (4) MYC driven (S-MD). MYC amplification with HR proficiency tumors is identified with a high oxidative phosphorylation signature resulting in resistance to neoadjuvant chemotherapy. Potential therapeutic targets are identified for each subtype, including platinum-based chemotherapy, immune checkpoint inhibitors, anti-VEGFR, anti-MYC and PARPi-based synthetic lethal strategies. Our comprehensive integrated characterization provides a valuable resource that deepens our understanding of the disease, and may guide future clinical strategies for the precision treatment of OS.
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Neoplasias Ósseas , Osteossarcoma , Adulto Jovem , Adolescente , Criança , Humanos , Osteossarcoma/genética , Osteossarcoma/terapia , Genômica/métodos , Transcriptoma , Platina , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genéticaRESUMO
RNA polymerase II (Pol II) apparatuses are compartmentalized into transcriptional clusters. Whether protein factors control these clusters remains unknown. In this study, we find that the ATPase-associated with diverse cellular activities (AAA + ) ATPase RUVBL2 co-occupies promoters with Pol II and various transcription factors. RUVBL2 interacts with unphosphorylated Pol II in chromatin to promote RPB1 carboxy-terminal domain (CTD) clustering and transcription initiation. Rapid depletion of RUVBL2 leads to a decrease in the number of Pol II clusters and inhibits nascent RNA synthesis, and tethering RUVBL2 to an active promoter enhances Pol II clustering at the promoter. We also identify target genes that are directly linked to the RUVBL2-Pol II axis. Many of these genes are hallmarks of cancers and encode proteins with diverse cellular functions. Our results demonstrate an emerging activity for RUVBL2 in regulating Pol II cluster formation in the nucleus.
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RNA Polimerase II , Fatores de Transcrição , Adenosina Trifosfatases/metabolismo , Cromatina/genética , Análise por Conglomerados , RNA , RNA Polimerase II/genética , RNA Polimerase II/metabolismo , Fatores de Transcrição/metabolismo , Transcrição GênicaRESUMO
Hippo, an evolutionarily conserved kinase cascade reaction in organisms, can respond to a set of signals, such as mechanical signals and cell metabolism, to maintain cell growth, differentiation, tissue/organ development, and homeostasis. In the past ten years, Hippo has controlled the development of tissues and organs by regulating the process of cell proliferation, especially in the field of cardiac regeneration after myocardial infarction. This suggests that Hippo signaling is closely linked to cardiovascular disease. Atherosclerosis is the most common disease of the cardiovascular system. It is characterised by chronic inflammation of the vascular wall, mainly involving dysfunction of endothelial cells, smooth muscle cells, and macrophages. Oxidized Low density lipoprotein (LDL) damages the barrier function of endothelial cells, which enter the middle membrane of the vascular wall, accelerate the formation of foam cells, and promote the occurrence and development of atherosclerosis. Autophagy is associated with the development of atherosclerosis. However, the mechanism of Hippo regulation of atherosclerosis has not meant to be clarified. In view of the pivotal role of this signaling pathway in maintaining cell growth, proliferation, and differentiation, the imbalance of Hippo is related to atherosclerosis and related diseases. In this review, we emphasized Hippo as a hub for regulating atherosclerosis and discussed its potential targets in pathophysiology, human diseases, and related pharmacology.
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Aterosclerose , Células Endoteliais , Aterosclerose/metabolismo , Células Endoteliais/metabolismo , Células Espumosas/metabolismo , Humanos , Macrófagos/metabolismo , Transdução de SinaisRESUMO
The normal development of follicles determines the reproductive performance of females. Granulosa cells (GC) play crucial roles in follicular maturation. Numerous studies have shown that miRNAs are involved in the regulation of GC. According to our previous sequencing data, gga-miR-146b-3p was differentially expressed in normal and atretic chicken follicles. In this study, we verified that gga-miR-146b-3p attenuated proliferation and autophagy but promoted apoptosis in chicken GC. Threonine kinase1 (AKT1), a key member of the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway, was predicted to be a target gene of gga-miR-146b-3p via bioinformatic analysis. Dual-luciferase reporter gene assays were used to determine target relationships. Moreover, knockout of AKT1 decelerated proliferation and autophagy while accelerating the apoptosis of GC. However, overexpression of AKT1 reversed these results. In summary, our results demonstrated that gga-miR-146b-3p repressed the proliferation and autophagy of chicken GC while up-regulating apoptosis by targeting AKT1 through the PI3K/AKT signaling pathway. These findings may provide great insights for further exploration of the molecular regulation of gga-miR-146b-3p and AKT1 on the functions of GC during folliculogenesis.
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Galinhas , MicroRNAs , Animais , Apoptose/genética , Autofagia/genética , Proliferação de Células/genética , Galinhas/genética , Galinhas/metabolismo , Feminino , Células da Granulosa/metabolismo , MicroRNAs/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
BACKGROUND: Mutations in DNA mismatch repair (MMR) genes associated with thyroid carcinoma (TC) have rarely been reported, especially in East Asian populations. METHODS: We examined tumor tissue from a cohort of 241 patients diagnosed with TC between 2008 and 2020. MMR proteins were detected using tissue microarray-based immunohistochemistry in order to identify MMR-protein-deficient (MMR-D) and MMR-protein-intact (MMR-I) tumors. We retrospectively summarized the clinicopathologic characteristics of patients with MMR-D TC, measured the expression of PD-L1, and recorded overall survival (OS) and other clinical outcomes. RESULTS: In our cohort, there were 18 (7.5%) MMR-D (MLH1, MSH2, MSH6, and PMS2) patients, including 12 with papillary TC (PTC) (6.7%), 2 with poorly differentiated TC (PDTC) (4.7%), and 4 with anaplastic TC (ATC) (22.2%). Half of them (9/18) showed a specific deletion in MSH6, and 6 of them also carried variants in the MSH6 and PMS2 gene. Survival was significantly better in patients with MMR-D ATC than in those with MMR-I tumors (p = 0.033). Four of the 18 MMR-D patients (22%) were found to be PD-L1 positive. Their OS was much shorter than that of PD-L1-negative patients. CONCLUSIONS: MMR-D and PD-L1 positivity appear to be associated with clinicopathological characteristics and prognosis in TC. The results indicate that MMR status may have important prognostic significance in TC. Therefore, immune checkpoint inhibitors that target the PD-1/PD-L1 pathway may be a treatment option for TCs.
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Antígeno B7-H1 , Neoplasias da Glândula Tireoide , Antígeno B7-H1/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Humanos , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/genéticaRESUMO
Matrix stiffness and fibrous structure provided by the native extracellular matrix have been increasingly appreciated as important cues in regulating cell behaviors. Recapitulating these physical cues for cell fate regulation remains a challenge due to the inherent difficulties in making mimetic hydrogels with well-defined compositions, tunable stiffness, and structures. Here, we present two series of fibrous and porous hydrogels with tunable stiffness based on genetically engineered resilin-silk-like and resilin-like protein polymers. Using these hydrogels as substrates, the mechanoresponses of bone marrow mesenchymal stem cells to stiffness and fibrous structure were systematically studied. For both hydrogel series, increasing compression modulus from 8.5 to 14.5 and 23 kPa consistently promoted cell proliferation and differentiation. Nonetheless, the promoting effects were more pronounced on the fibrous gels than their porous counterparts at all three stiffness levels. More interestingly, even the softest fibrous gel (8.5 kPa) allowed the stem cells to exhibit higher endothelial differentiation capability than the toughest porous gel (23 kPa). The predominant role of fibrous structure on the synergistic regulation of endothelial differentiation was further explored. It was found that the stiffness signal activated Yes-associated protein (YAP), the main regulator of endothelial differentiation, via spreading of focal adhesions, whereas fibrous structure reinforced YAP activation by promoting the maturation of focal adhesions and associated F-actin alignment. Therefore, our results shed light on the interplay of physical cues in regulating stem cells and may guide the fabrication of designer proteinaceous matrices toward regenerative medicine.
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Hidrogéis , Células-Tronco Mesenquimais , Diferenciação Celular , Matriz Extracelular/metabolismo , Hidrogéis/química , Células-TroncoRESUMO
Adult mammals have limited potential for cardiac regeneration after injury. In contrast, neonatal mouse heart, up to 7 days post birth, can completely regenerate after injury. Therefore, identifying the key factors promoting the proliferation of endogenous cardiomyocytes (CMs) is a critical step in the development of cardiac regeneration therapies. In our previous study, we predicted that mitogen-activated protein kinase (MAPK) interacting serine/threonine-protein kinase 2 (MNK2) has the potential of promoting regeneration by using phosphoproteomics and iGPS algorithm. Here, we aimed to clarify the role of MNK2 in cardiac regeneration and explore the underlying mechanism. In vitro, MNK2 overexpression promoted, and MNK2 knockdown suppressed cardiomyocyte proliferation. In vivo, inhibition of MNK2 in CMs impaired myocardial regeneration in neonatal mice. In adult myocardial infarcted mice, MNK2 overexpression in CMs in the infarct border zone activated cardiomyocyte proliferation and improved cardiac repair. In CMs, MNK2 binded to eIF4E and regulated its phosphorylation level. Knockdown of eukaryotic translation initiation factor (eIF4E) impaired the proliferation-promoting effect of MNK2 in CMs. MNK2-eIF4E axis stimulated CMs proliferation by activating cyclin D1. Our study demonstrated that MNK2 kinase played a critical role in cardiac regeneration. Over-expression of MNK2 promoted cardiomyocyte proliferation in vitro and in vivo, at least partly, by activating the eIF4E-cyclin D1 axis. This investigation identified a novel target for heart regenerative therapy.
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Fator de Iniciação 4E em Eucariotos , Infarto do Miocárdio , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Ciclina D1/metabolismo , Fator de Iniciação 4E em Eucariotos/metabolismo , Mamíferos/metabolismo , Camundongos , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , FosforilaçãoRESUMO
BACKGROUND: The management of thyroid nodules ≥ 4 cm is controversial due to conflicting evidence on the prevalence of malignancy and diagnostic accuracy of fine-needle aspiration cytology (FNAC). Some literature recommends routine excision of large thyroid nodules due to high cytology false negative rates (FNR). We aim to investigate the diagnostic accuracy of FNAC, prevalence of malignancy in large (≥ 4 cm) thyroid nodules compared to nodules < 4 cm, and the clinical and ultrasound characteristics of those large nodules with false negative cytology. METHODS: This was a retrospective case-log review in a tertiary referral hospital. All thyroid nodules subjected to Ultrasound (US)-guided FNAC by the Interventional Radiology department between December 2011 and November 2017 were included. Data on patient demographics, thyroid US features, cytology findings, and surgical histology were collected and analyzed. Sensitivity, specificity, and FNR were calculated based on FNAC results and final post-operative histology. Factors associated with a false negative result were analyzed using univariate and multivariate analyses. RESULTS: A total of 4982 nodules were studied, including 4419 < 4 cm and 563 ≥ 4 cm. Malignancy rates were similar in both groups. For nodules ≥ 4 cm, FNAC sensitivity was 40%, specificity 100%, and FNR 6.6% compared to 4.2% in nodules < 4 cm. Within malignant nodules, there was a significantly higher proportion of follicular and Hurthle cell carcinomas in nodules ≥ 4 cm. Amongst nodules ≥ 4 cm, multivariate analysis revealed male gender to be an independent predictor of FNR (OR 3.32; 95% CI 1.29-8.59). CONCLUSION: Larger nodules ≥ 4 cm have a similar malignancy rate as nodules < 4 cm, and FNAC FNR is low at 6.6%. Management of large thyroid nodules should be individualized based on their clinical, sonographic and cytological features rather than routine surgery.
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Neoplasias da Glândula Tireoide , Nódulo da Glândula Tireoide , Biópsia por Agulha Fina , Humanos , Masculino , Estudos Retrospectivos , Sensibilidade e Especificidade , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/cirurgia , Nódulo da Glândula Tireoide/diagnóstico por imagem , Nódulo da Glândula Tireoide/cirurgiaRESUMO
Background The neonatal heart maintains its entire regeneration capacity within days after birth. Using quantitative phosphoproteomics technology, we identified that SGK3 (serine/threonine-protein kinase 3) in the neonatal heart is highly expressed and activated after myocardial infarction. This study aimed to uncover the function and related mechanisms of SGK3 on cardiomyocyte proliferation and cardiac repair after apical resection or ischemia/reperfusion injury. Methods and Results The effect of SGK3 on proliferation and oxygen glucose deprivation/reoxygenation- induced apoptosis in isolated cardiomyocytes was evaluated using cardiomyocyte-specific SGK3 overexpression or knockdown adenovirus5 vector. In vivo, gain- and loss-of-function experiments using cardiomyocyte-specific adeno-associated virus 9 were performed to determine the effect of SGK3 in cardiomyocyte proliferation and cardiac repair after apical resection or ischemia/reperfusion injury. In vitro, overexpression of SGK3 enhanced, whereas knockdown of SGK3 decreased, the cardiomyocyte proliferation ratio. In vivo, inhibiting the expression of SGK3 shortened the time window of cardiac regeneration after apical resection in neonatal mice, and overexpression of SGK3 significantly promoted myocardial repair and cardiac function recovery after ischemia/reperfusion injury in adult mice. Mechanistically, SGK3 promoted cardiomyocyte regeneration and myocardial repair after cardiac injury by inhibiting GSK-3ß (glycogen synthase kinase-3ß) activity and upregulating ß-catenin expression. SGK3 also upregulated the expression of cell cycle promoting genes G1/S-specific cyclin-D1, c-myc (cellular-myelocytomatosis viral oncogene), and cdc20 (cell division cycle 20), but downregulated the expression of cell cycle negative regulators cyclin kinase inhibitor P 21 and cyclin kinase inhibitor P 27. Conclusions Our study reveals a key role of SGK3 on cardiac repair after apical resection or ischemia/reperfusion injury, which may reopen a novel therapeutic option for myocardial infarction.
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Glicogênio Sintase Quinase 3 beta/genética , Infarto do Miocárdio , Traumatismo por Reperfusão , Animais , Apoptose , Camundongos , Infarto do Miocárdio/genética , Miócitos Cardíacos , Proteínas Serina-Treonina Quinases/genética , Serina/química , Treonina/química , beta Catenina/genéticaRESUMO
The cotton bollworm, Helicoverpa armigera, is a polyphagous pest threatening many economically important crops worldwide. Until recently, synthetic pyrethroids remain in wide use for controlling pest insects including the cotton bollworm. Understanding the metabolic mechanism of pyrethroids in a given pest can provide significant implication for a smart choice of insecticides, and such information is useful for the development of novel selective and safe insecticides. In this study, we used complexes of recombinant H. armigera cytochrome P450 CYP9A and NADPH-dependent cytochrome P450 reductase to investigate the capacity of three CYP9A paralogs in the transformation of seven structurally different pyrethroids by metabolism assays. The results showed that the three paralogous CYP9As were able to metabolize multiple pyrethroids. Interestingly, all the three CYP9As transformed pyrethrin-resembling pyrethroids (e.g. bioallethrin) more efficiently than the heavily modified ones (e.g. bifenthrin). These findings suggest that herbivorous insects can cope with synthetic insecticides using their physiological systems that initially evolved to survive exposure to the defensive chemicals in their host plants, adding support to the pre-adaptation hypothesis.