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1.
Sci Transl Med ; 12(537)2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32238575

RESUMO

Tumors with high mutational burden (TMB) tend to be responsive to immune checkpoint blockade (ICB) because there are neoantigens available for targeting by reinvigorated T cells, whereas those with low TMB demonstrate limited clinical responses. To determine whether antigen-specific T cell responses can be elicited after treatment with ICB in cancers that have a low TMB, we conducted a clinical trial with ipilimumab in 30 patients with metastatic castration-resistant prostate cancer. We identified two distinct cohorts by survival and progression times: "favorable" (n = 9) and "unfavorable" (n = 10). Patients in the favorable cohort had high intratumoral CD8 T cell density and IFN-γ response gene signature and/or antigen-specific T cell responses. Two patients with a relatively low TMB had T cell responses against unique neoantigens. Moreover, six of nine patients in the favorable group are still alive at the time of analysis, with survival ranging from 33 to 54 months after treatment. All 10 patients in the unfavorable cohort have succumbed to their disease and had survival ranging from 0.6 to 10.3 months. Collectively, our data indicate that immunological correlates associated with effector T cell responses are observed in patients with metastatic prostate cancer who benefit from ICB.

2.
BMC Med ; 18(1): 2, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31902369

RESUMO

BACKGROUND: Heart failure (HF) has been recognized as a global pandemic with a high rate of hospitalization, morbidity, and mortality. Although numerous advances have been made, its representative molecular signatures remain largely unknown, especially the role of genes in HF progression. The aim of the present prospective follow-up study was to reveal potential biomarkers associated with the progression of heart failure. METHODS: We generated multi-level transcriptomic data from a cohort of left ventricular heart tissue collected from 21 HF patients and 9 healthy donors. By using Masson staining to calculate the fibrosis percentage for each sample, we applied lasso regression model to identify the genes associated with fibrosis as well as progression. The genes were further validated by immunohistochemistry (IHC) staining in the same cohort and qRT-PCR using another independent cohort (20 HF and 9 healthy donors). Enzyme-linked immunosorbent assay (ELISA) was used to measure the plasma level in a validation cohort (139 HF patients) for predicting HF progression. RESULTS: Based on the multi-level transcriptomic data, we examined differentially expressed genes [mRNAs, microRNAs, and long non-coding RNAs (lncRNAs)] in the study cohort. The follow-up functional annotation and regulatory network analyses revealed their potential roles in regulating extracellular matrix. We further identified several genes that were associated with fibrosis. By using the survival time before transplantation, COL1A1 was identified as a potential biomarker for HF progression and its upregulation was confirmed by both IHC and qRT-PCR. Furthermore, COL1A1 content ≥ 256.5 ng/ml in plasma was found to be associated with poor survival within 1 year of heart transplantation from heart failure [hazard ratio (HR) 7.4, 95% confidence interval (CI) 3.5 to 15.8, Log-rank p value < 1.0 × 10- 4]. CONCLUSIONS: Our results suggested that COL1A1 might be a plasma biomarker of HF and associated with HF progression, especially to predict the 1-year survival from HF onset to transplantation.

3.
Curr Protein Pept Sci ; 21(2): 114-123, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31322070

RESUMO

Mites and ticks are associated with many human diseases including allergic diseases and scabies. With the recent advances in the high throughput DNA sequencing technology, many mitochondrial nuclear genomes of these species have been sequenced and the resulting genomic resources will certainly provide novel insights for the future investigation of the functionally important proteins and peptides in these species. In this mini-review, the current situation of mite and tick genomes is described and the future perspectives for the application of the genomic resources are discussed, especially including the novel identification and structural analysis of allergens.

5.
Food Sci Biotechnol ; 28(6): 1687-1692, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31807341

RESUMO

Melanosis is major problem of crustaceans during their rigor mortis storage. This study for the first time was designed to optimize the formula of preservatives to maintain the color feature of Pacific white shrimp using response surface methodology. A three-factors-three-levels Box-Behnken design was applied to evaluate the effect of chitosan, citric acid and l-cysteine on color features (L*, a*, b* and ΔE) of Pacific white shrimp. It was found that the increasing rate of ΔE was retarded by the higher concentrations of chitosan, citric acid and l-cysteine in a certain range. The optimal formula for inhibiting the increase of ΔE was 1.36% chitosan, 0.47% citric acid and 0.31% l-cysteine. Under the optimal pretreated conditions, the predicted ΔE of shrimp after 8 days of storage was 14.59, close to the measured values (14.49). These results indicated that the optimal combined preservatives could retard the decrease of lightness and the aggregation of ΔE and melanosis effectively, and might be a potential application for retarding melanosis and extending shelf life of Pacific white shrimp.

6.
Int J Endocrinol ; 2019: 9691345, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31737070

RESUMO

With the deepening of the researches on uric acid, especially in the study of metabolic diseases, uric acid has been found to be closely related to obesity, metabolic syndrome, nonalcoholic fatty liver disease, diabetes, and other metabolic diseases. Uric acid causes a series of pathophysiological changes through inflammation, oxidative stress, vascular endothelial injury, and so on and thus subsequently promotes the occurrence and development of diseases. This review confirmed the positive correlation between uric acid and diabetes mellitus and its chronic complications through the pathogenesis and clinical studies aspects.

7.
Biomed Pharmacother ; 120: 109503, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31590127

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a common and complex metabolic disorder. Despite the widespread concern, there are still few effective treatments except lifestyle interventions. Nuclear receptor subfamily 2 group E member 1 (Nr2e1) is a transcription factor which regulates many biological processes, including development, growth, and differentiation of nerve cells. However, its specific function in hepatocyte is still unknown. In the present study, we found that the expression of Nr2e1 decreased in the livers of high-fat diet-fed mice. We generated Nr2e1 knockout (KO) mice and studied whether Nr2e1 ablation was related to NAFLD. We found that typical pathological features of NAFLD, including insulin resistance, hepatic steatosis, and inflammation, were present in Nr2e1-KO mice or high-fat diet-induced mice models. In conclusion, Nr2e1 ablation promotes liver steatosis and systemic insulin resistance. Nr2e1 may play a protective role in the formation of NAFLD and may serve as a worthy therapeutic target for NAFLD.


Assuntos
Dieta Hiperlipídica , Glucose/metabolismo , Inflamação/etiologia , Fígado/metabolismo , Obesidade/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Fígado Gorduroso/induzido quimicamente , Regulação da Expressão Gênica/efeitos dos fármacos , Intolerância à Glucose , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos , Camundongos Knockout , Receptores Citoplasmáticos e Nucleares/genética
9.
Cell Chem Biol ; 26(10): 1407-1416.e5, 2019 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-31378710

RESUMO

A protein-fragment complementation assay (PCA) for detecting and localizing intracellular protein-protein interactions (PPIs) was built by bisection of miniSOG, a fluorescent flavoprotein derived from the light, oxygen, voltage (LOV)-2 domain of Arabidopsis phototropin. When brought together by interacting proteins, the fragments reconstitute a functional reporter that permits tagged protein complexes to be visualized by fluorescence light microscopy (LM), and then by standard as well as "multicolor" electron microscopy (EM) via the photooxidation of 3-3'-diaminobenzidine and its derivatives.

10.
PeerJ ; 7: e7209, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31304066

RESUMO

Mitochondrial dynamics is associated with mitochondrial function, which is associated with diabetes. Although an important indicator of the mitochondrial unfolded protein response, to the best of our knowledge, CLPP and its effects on mitochondrial dynamics in islet cells have not been studied to date. We analyzed the effects of CLPP on mitochondrial dynamics and mitochondrial function in the mice islet ß-cell line Min6 under high glucose and high fat conditions. Min6 cells were assigned to: Normal, HG, HG+NC, HG+siCLPP, HF, HF+NC and HF+ siCLPP groups. High glucose and high fat can promote the mRNA and protein expression of CLPP in mitochondria. The increase of mitochondrial fission, the decrese of mitochondrial fusion, and the damage of mintocondrial ultrastructure were significant in the siCLPP cell groups as compared to no-siCLPP treated groups. Meanwhile, mitochondrial functions of MIN6 cells treated with siCLPP were impaired, such as ATP decreased, ROS increased, mitochondrial membrane potential decreased. In addition, cell insulin secretion decreased and cell apoptosis rate increased in siCLPP groups. These results revealed that mitochondrial unfolded protein response geneCLPP alleviated high glucose and high fat-induced mitochondrial dynamics imbalance and mitochondrial dysfunction.

11.
Medicine (Baltimore) ; 98(29): e16498, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31335716

RESUMO

RATIONALE: Relapse is the main cause of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Unfortunately, there are no efficient methods to prevent relapse after allo-HSCT. Chimeric antigen receptor T (CAR-T) cells have achieved favorable outcomes in the treatment of refractory/relapsed acute lymphoblastic leukemia (ALL) because of their strong anti-leukemia activity. However, it is unclear whether the CAR-T cells constructed using viral systems can be used as preventive infusions to prevent relapse after haploidentical HSCT. PATIENT CONCERNS: Two patients with ALL with high risk received haploidentical HSCT. DIAGNOSES: Two patients were diagnosed with ALL with high risk. INTERVENTIONS: Patients received preventive infusion of donor-derived CAR-T cells constructed using viral systems on day 60 after haploidentical HSCT. OUTCOMES: The CAR-T cells were continually detected, and no graft versus host disease developed. The two patients survived with disease-free for 1 year and 6 months, respectively. LESSONS: Preventive infusion of donor-derived CAR-T cells after haploidentical HSCT may be safe and that immunosuppressors may not affect the proliferation of CAR-T cells.


Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Imunoterapia Adotiva/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos Quiméricos/uso terapêutico , Transplante Haploidêntico , Adulto , Pré-Escolar , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imunossupressores/uso terapêutico , Masculino , Doadores de Tecidos
12.
Acta Pharmacol Sin ; 40(12): 1532-1543, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31165783

RESUMO

Obesity induces accumulation of adipose tissue macrophages (ATMs) and ATM-driven inflammatory responses that promote the development of glucose and lipid metabolism disorders. ClC-3 chloride channel/antiporter, encoded by the Clcn3, is critical for some basic cellular functions. Our previous work has shown significant alleviation of type 2 diabetes in Clcn3 knockout (Clcn3-/-) mice. In the present study we investigated the role of Clcn3 in high-fat diet (HFD)-induced obesity and ATM inflammation. To establish the mouse obesity model, both Clcn3-/- mice and wild-type mice were fed a HFD for 4 or 16 weeks. The metabolic parameters were assessed and the abdominal total adipose tissue was scanned using computed tomography. Their epididymal fat pad tissue and adipose tissue stromal vascular fraction (SVF) cells were isolated for analyses. We found that the HFD-fed Clcn3-/- mice displayed a significant decrease in obesity-induced body weight gain and abdominal visceral fat accumulation as well as an improvement of glucose and lipid metabolism as compared with HFD-fed wild-type mice. Furthermore, the Clcn3 deficiency significantly attenuated HFD-induced ATM accumulation, HFD-increased F4/80+ CD11c+ CD206- SVF cells as well as HFD-activated TLR-4/NF-κB signaling in epididymal fat tissue. In cultured human THP-1 macrophages, adenovirus-mediated transfer of Clcn3 specific shRNA inhibited, whereas adenovirus-mediated cDNA overexpression of Clcn3 enhanced lipopolysaccharide-induced activation of NF-κB and TLR-4. These results demonstrate a novel role for Clcn3 in HFD-induced obesity and ATM inflammation.


Assuntos
Tecido Adiposo Branco/metabolismo , Canais de Cloreto/genética , Inflamação/metabolismo , Macrófagos/metabolismo , Obesidade/metabolismo , Tecido Adiposo Branco/patologia , Animais , Linhagem Celular , Dieta Hiperlipídica , Humanos , Camundongos Knockout , NF-kappa B/metabolismo , Obesidade/genética , Receptor 4 Toll-Like/metabolismo
13.
Onco Targets Ther ; 12: 2431-2438, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31040688

RESUMO

Background: Radiofrequency ablation (RFA) is one of the definitive treatment modalities for liver cancer and has been increasingly used in the scenario of small-sized liver cancer. It is generally believed that RFA is minimally invasive and associated with a favorable safety profile in liver cancer patients. However, this interventional technique is subject to some morbidity in high-risk patients, such as those with complicating cirrhosis or a liver cancer located at a refractory segment. Methods: Herein, we report the case of a middle-aged woman who developed acute liver failure with a complicating respiratory failure after RFA of recurrent intrahepatic cholangiocarcinoma. Results: A diagnosis of hepatopulmonary syndrome was established. The patient was hospitalized in the intensive care unit for mechanical ventilation. Finally, the patient recovered from an eventful clinical course and survived free of recurrence until the last follow-up visit at 1 year after the discharge. Conclusion: Our case report warns that hepatopulmonary syndrome, a less common morbidity secondary to liver cancer RFA, should require timely identification and appropriate management due to its life-threatening outcome.

14.
Front Psychol ; 10: 363, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30846959

RESUMO

This study examined the unique and interactive effects of various career-specific parenting practices (i.e., parental career support, interference, and lack of engagement) on Chinese high school students' career decision-making self-efficacy (CDSE) as well as the mediating role of autonomy in such associations. Based on data from 641 Chinese high school students (47.6% male; mean age = 15.28 years old, SD = 0.49) in 2016, two moderated mediating effects were identified. Higher level of parental career engagement strengthened the positive association between parental career support and adolescents' autonomy, which in turn, was associated positively with adolescents' CDSE. Parental career interference related negatively with adolescents' CDSE via autonomy when lack of parental career engagement was low, but related positively with adolescents' CDSE via autonomy when lack of parental career engagement was high. These findings advance our understanding of the underlying processes between career-specific parenting practices and adolescents' CDSE. Implications for practices were discussed.

15.
ACS Chem Neurosci ; 10(5): 2385-2396, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30785256

RESUMO

Painful diabetic neuropathy (PDN) is among the common complications in diabetes mellitus (DM), with its underlying mechanisms largely unknown. Synapsin II is primarily expressed in the spinal dorsal horn, and its upregulation mediates a superfluous release of glutamate and a deficiency of GABAergic interneuron synaptic transmission, which is directly implicated in the facilitation of pain signals in the hyperalgesic nociceptive response. Recently, synapsin II has been revealed to be associated with the modulation of neurite outgrowth, whereas the process of this neuronal structural neuroplasticity following neuronal hyperexcitability still remains unclear. In this study, we found that under conditions of elevated glucose, TNF-α induced the activation of mTOR, mediating the upregulation of synapsin II and neurite outgrowth in dorsal horn neurons. In vivo, we demonstrated that mTOR and synapsin II were upregulated and coexpressed in the spinal dorsal horn neurons in rats with streptozotocin (STZ)-induced diabetes. Furthermore, the intrathecal administration of the mTOR inhibitor rapamycin or synapsin II shRNA significantly diminished the expression of synapsin II, effectively mitigating hyperalgesia in PDN rats. We are the first to discover that in STZ-induced diabetic rats the activation of mTOR mediates the upregulation of synapsin II and neurite outgrowth, both contributing to hyperalgesia. These findings may benefit the clinical therapy of PDN by provision of a novel target.

16.
FASEB J ; 33(1): 532-544, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29989844

RESUMO

Polydatin, also called piceid, is a stilbenoid glucoside of a resveratrol derivative. It derives mainly from the root and rhizome of Polygonum cuspidatum Sieb. et Zucc. Although the role of P. cuspidatum root in angiogenesis has been reported, the active chemical or chemicals responsible for such function is not known. Here, polydatin was proposed to bind VEGF, which therefore altered the functions of VEGF in angiogenesis. Several lines of evidence supported the pharmaceutical effects of polydatin in VEGF-induced angiogenesis. In human umbilical vein endothelial cells, polydatin inhibited VEGF-stimulated cell proliferation, cell migration, and tube formation. Moreover, polydatin showed suppressive effects on the subintestinal vessel formation in zebrafish embryos. In signaling cascades, polydatin application attenuated VEGF-induced phosphorylations of VEGF receptor 2 and JNK. Moreover, the VEGF-induced phosphorylations of Akt, eNOS, and Erk were significantly decreased in the presence of polydatin. In parallel, the formation of reactive oxygen species, triggered by VEGF, was markedly decreased under polydatin application. Thus, our results supported the angiogenic roles of polydatin, as well as its signaling mechanism in blocking VEGF-mediated responses. The current study provides support for the possible development of polydatin as a potential therapeutic agent for treatment and prevention of angiogenesis-related diseases.-Hu, W.-H., Wang, H.-Y., Kong, X.-P., Xiong, Q.-P., Poon, K. K.-M., Xu, L., Duan, R., Chan, G. K.-L., Dong, T. T.-X., Tsim, K. W.-K. Polydatin suppresses VEGF-induced angiogenesis through binding with VEGF and inhibiting its receptor signaling.


Assuntos
Inibidores da Angiogênese/farmacologia , Movimento Celular , Proliferação de Células , Glucosídeos/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Estilbenos/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Células Endoteliais da Veia Umbilical Humana , Humanos , Fosforilação , Transdução de Sinais , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Peixe-Zebra
17.
J Agric Food Chem ; 67(4): 1127-1137, 2019 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-30525561

RESUMO

Resveratrol is a polyphenol commonly found in plants and food health products, such as grape and red wine, and was identified for its binding to vascular endothelial growth factor (VEGF) by using HerboChips screening. The binding, therefore, resulted in alterations of VEGF binding to its receptor and revealed the roles of VEGF in angiogenesis. Several lines of evidence gave support to the inhibitory activities of resveratrol in VEGF-triggered angiogenesis. In human umbilical vein endothelial cells (HUVECs), compared with a VEGF-induced group, resveratrol, at a high concentration, suppressed VEGF-mediated endothelial cell proliferation, cell migration, cell invasion, and tube formation by 80 ± 9.01%, 140 ± 3.78%, 110 ± 7.51%, and 120 ± 10.26%, respectively. Moreover, resveratrol inhibited the subintestinal vessel formation in zebrafish embryo. In signaling cascades, application of resveratrol in HUVECs reduced the VEGF-triggered VEGF receptor 2 phosphorylation and c-Jun N-terminal kinase phosphorylation. Moreover, the VEGF-mediated phosphorylations of endothelial nitric oxide synthase, protein kinase B, and extracellular signal-regulated kinase were obviously decreased by (3 ± 0.37)-, (2 ± 0.27)- and (6 ± 0.23)-fold, respectively, in the presence of resveratrol at high concentration. Parallelly, the VEGF-induced reactive oxygen species formation was significantly decreased by 50 ± 7.88% to 120 ± 14.82% under resveratrol treatment. Thus, our results provided support to the antiangiogenic roles of resveratrol, as well as its related signaling mechanisms, in attenuating the VEGF-mediated responses. The present results supported possible development of resveratrol, which should be considered as a therapeutic agent in terms of prevention and clinical treatment of diseases related to angiogenesis.


Assuntos
Inibidores da Angiogênese/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Resveratrol/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Fosforilação/efeitos dos fármacos , Receptores de Fatores de Crescimento do Endotélio Vascular/química , Receptores de Fatores de Crescimento do Endotélio Vascular/genética , Resveratrol/química , Resveratrol/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/química , Peixe-Zebra
18.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 49(5): 759-764, 2018 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-30378340

RESUMO

OBJECTIVE: To determine the prevalence and associated factors of cognitive impairments in the community-dwelling elderly aged 60 years or older in Chengdu of Sichuan province. METHODS: A random cluster sampling strategy was adopted to select 621 community-dwelling elderly. Face-to-face interviews were conducted to assess the cognitive status of the participants. 2 tests and logistic regression analyses were performed to identify factors associated with cognitive impairments. RESULTS: About 40.9% of the participants had cognitive impairments. Those attended primary schools had a lower risk of cognitive impairments [odds ratio OR)=0.369, P<0.001] compared with the illiterate ones. Older age OR=1.505 for 70-79 years, P=0.042; OR=3.069 for ≥80 years, P<0.001), cerebrovascular disease OR=2.159, P=0.003) and smoking OR=2.388, P<0.001) were risk factors of cognitive impairments. Men had lower risk OR=0.489, P=0.005) of cognitive impairments than women. CONCLUSION: The prevalence of cognitive impairments in community-dwelling elderly in Chengdu is high in comparison with those in other cities. Illiteracy, older age (over 70 years), women, smoking, and cerebrovascular disease are risk factors of cognitive impairments.


Assuntos
Disfunção Cognitiva/epidemiologia , Idoso , Transtornos Cerebrovasculares , China/epidemiologia , Escolaridade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Prevalência , Fatores de Risco , Fumar
19.
Plant Mol Biol Report ; 36(3): 518-529, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30100671

RESUMO

Peanut (Arachis hypogaea), a major source of vegetable oil in many Asian countries, has become an integral part of human diet globally due to its high nutritional properties and option to consume in different forms. In order to meet the demand of vegetable oil, many peanut breeding programs of China have intensified their efforts in increasing oil content in newly bred varieties for reducing the import of edible oils in China. In this context, transcriptome sequencing data generated on 49 peanut cultivars were analyzed to identify candidate genes and develop molecular markers for seed oil content across multiple environments. Transcriptome analysis identified 5458 differentially expressed genes (DEGs) including 2243 positive DEGs and 3215 negative DEGs involved in oil synthesis process. Genome-wide association study identified 48 significant insertion/deletion (InDel) markers associated with seed oil content across five environments. A comparative genomics and transcriptomics analysis detected a total of 147 common gene clusters located in 17 chromosomes. Interestingly, an InDel cluster associated with seed oil content on A03 chromosome was detected in three different environments. Candidate genes identified on A03 form a haplotype, in which variable alleles were found to be different in oil content in an independent population. This locus is important for understanding the genetic control of peanut oil content and may be useful for marker-assisted selection in peanut breeding programs.

20.
Theranostics ; 8(15): 4226-4237, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30128049

RESUMO

A fundamental goal of many surgeries is nerve preservation, as inadvertent injury can lead to patient morbidity including numbness, pain, localized paralysis and incontinence. Nerve identification during surgery relies on multiple parameters including anatomy, texture, color and relationship to surrounding structures using white light illumination. We propose that fluorescent labeling of nerves can enhance the contrast between nerves and adjacent tissue during surgery which may lead to improved outcomes. Methods: Nerve binding peptide sequences including HNP401 were identified by phage display using selective binding to dissected nerve tissue. Peptide dye conjugates including FAM-HNP401 and structural variants were synthesized and screened for nerve binding after topical application on fresh rodent and human tissue and in-vivo after systemic IV administration into both mice and rats. Nerve to muscle contrast was quantified by measuring fluorescent intensity after topical or systemic administration of peptide dye conjugate. Results: Peptide dye conjugate FAM-HNP401 showed selective binding to human sural nerve with 10.9x fluorescence signal intensity (1374.44 ± 425.96) compared to a previously identified peptide FAM-NP41 (126.17 ± 61.03). FAM-HNP401 showed nerve-to-muscle contrast of 3.03 ± 0.57. FAM-HNP401 binds and highlight multiple human peripheral nerves including lower leg sural, upper arm medial antebrachial as well as autonomic nerves isolated from human prostate. Conclusion: Phage display has identified a novel peptide that selectively binds to ex-vivo human nerves and in-vivo using rodent models. FAM-HNP401 or an optimized variant could be translated for use in a clinical setting for intraoperative identification of human nerves to improve visualization and potentially decrease the incidence of intra-surgical nerve injury.


Assuntos
Imagem Molecular/métodos , Neuroimagem/métodos , Imagem Óptica/métodos , Coloração e Rotulagem/métodos , Cirurgia Assistida por Computador/métodos , Administração Intravenosa , Animais , Corantes Fluorescentes/administração & dosagem , Corantes Fluorescentes/metabolismo , Humanos , Camundongos , Peptídeos/administração & dosagem , Peptídeos/metabolismo , Ligação Proteica , Ratos
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