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1.
Cell ; 173(2): 355-370.e14, 2018 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-29625052

RESUMO

We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in MET, RET, and PTPN11 associated with high gene expression. We nominated 47 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer.


Assuntos
Células Germinativas/metabolismo , Neoplasias/patologia , Variações do Número de Cópias de DNA , Bases de Dados Genéticas , Deleção de Genes , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Células Germinativas/citologia , Mutação em Linhagem Germinativa , Humanos , Perda de Heterozigosidade/genética , Mutação de Sentido Incorreto , Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Supressoras de Tumor/genética
2.
Genome Res ; 32(5): 916-929, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35301263

RESUMO

Genetic variants drive the evolution of traits and diseases. We previously modeled these variants as small displacements in fitness landscapes and estimated their functional impact by differentiating the evolutionary relationship between genotype and phenotype. Conversely, here we integrate these derivatives to identify genes steering specific traits. Over cancer cohorts, integration identified 460 likely tumor-driving genes. Many have literature and experimental support but had eluded prior genomic searches for positive selection in tumors. Beyond providing cancer insights, these results introduce a general calculus of evolution to quantify the genotype-phenotype relationship and discover genes associated with complex traits and diseases.


Assuntos
Cálculos , Neoplasias , Evolução Biológica , Aptidão Genética , Genótipo , Humanos , Modelos Genéticos , Neoplasias/genética , Fenótipo , Seleção Genética
3.
Nano Lett ; 23(11): 5391-5398, 2023 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-36971404

RESUMO

Since thermometry of human skin is critical information that provides important aspects of human health and physiology, accurate and continuous temperature measurement is required for the observation of physical abnormalities. However, conventional thermometers are uncomfortable because of their bulky and heavy features. In this work, we fabricated a thin, stretchable array-type temperature sensor using graphene-based materials. Furthermore, we controlled the degree of graphene oxide reduction and enhanced the temperature sensitivity. The sensor exhibited an excellent sensitivity of 2.085% °C-1. The overall device was designed in a wavy meander shape to provide stretchability for the device so that precise detection of skin temperature could be performed. Furthermore, polyimide film was coated to secure the chemical and mechanical stabilities of the device. The array-type sensor enabled spatial heat mapping with high resolution. Finally, we introduced some practical applications of skin temperature sensing, suggesting the possibility of skin thermography and healthcare monitoring.


Assuntos
Grafite , Temperatura Cutânea , Humanos , Temperatura , Termografia
4.
Korean J Physiol Pharmacol ; 28(3): 209-217, 2024 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-38682169

RESUMO

In addition to cellular damage, ischemia-reperfusion (IR) injury induces substantial damage to the mitochondria and endoplasmic reticulum. In this study, we sought to determine whether impaired mitochondrial function owing to IR could be restored by transplanting mitochondria into the heart under ex vivo IR states. Additionally, we aimed to provide preliminary results to inform therapeutic options for ischemic heart disease (IHD). Healthy mitochondria isolated from autologous gluteus maximus muscle were transplanted into the hearts of Sprague-Dawley rats damaged by IR using the Langendorff system, and the heart rate and oxygen consumption capacity of the mitochondria were measured to confirm whether heart function was restored. In addition, relative expression levels were measured to identify the genes related to IR injury. Mitochondrial oxygen consumption capacity was found to be lower in the IR group than in the group that underwent mitochondrial transplantation after IR injury (p < 0.05), and the control group showed a tendency toward increased oxygen consumption capacity compared with the IR group. Among the genes related to fatty acid metabolism, Cpt1b (p < 0.05) and Fads1 (p < 0.01) showed significant expression in the following order: IR group, IR + transplantation group, and control group. These results suggest that mitochondrial transplantation protects the heart from IR damage and may be feasible as a therapeutic option for IHD.

5.
J Clin Monit Comput ; 37(2): 669-677, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36463542

RESUMO

This study investigated the effects of pneumoperitoneum and the head-down tilt position on common carotid artery (CCA) blood flow in surgical patients. METHODS: This prospective observational study included 20 patients who underwent gynecological surgery. CCA blood flow was measured using Doppler ultrasound at four-time points: awake in the supine position [T1], 3 min after anesthesia induction in the supine position [T2], 3 min after pneumoperitoneum in the supine position [T3], and 3 min after pneumoperitoneum in the head-down tilt position [T4]. Hemodynamic and respiratory parameters were also recorded at each time point. Linear mixed-effect analyses were performed to compare CCA blood flow across the time points and assess its relationship with hemodynamic parameters. RESULTS: Compared with T1, CCA blood flow decreased significantly at T2 (345.4 [288.0-392.9] vs. 293.1 [253.0-342.6], P = 0.048). CCA blood flow were also significantly lower at T3 and T4 compared with T1 (345.4 [288.0-392.9] vs. 283.6 [258.8-307.6] and 287.1 [242.1-321.4], P = 0.005 and 0.016, respectively). CCA blood flow at T3 and T4 did not significantly differ from that at T2. Changes in CCA blood flow were significantly associated with changes in cardiac index and stroke volume index (P = 0.011 and 0.024, respectively). CONCLUSION: CCA blood flow was significantly decreased by anesthesia induction. Inducing pneumoperitoneum, with or without the head-down tilt position, did not further decrease CCA blood flow if the cardiac index remained unchanged. The cardiac index and stroke volume index were significantly associated with CCA blood flow. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov (NCT04233177, January 18, 2020).


Assuntos
Laparoscopia , Pneumoperitônio , Humanos , Decúbito Inclinado com Rebaixamento da Cabeça/fisiologia , Hemodinâmica/fisiologia , Artéria Carótida Primitiva , Anestesia Geral
6.
J Shoulder Elbow Surg ; 31(8): 1628-1639, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35337954

RESUMO

BACKGROUND: Recombinant human parathyroid hormone (rhPTH) promotes tendon-to-bone healing in humans and animals with rotator cuff tear (RCT). However, problems regarding repeated systemic rhPTH injections in humans exist. This study was conducted to evaluate the effect of topical rhPTH administration using 3-dimensionally (3D) printed nanofiber sheets on tendon-to-bone healing in a rabbit RCT model compared to that of direct topical rhPTH administration. METHODS: Eighty rabbits were randomly assigned to 5 groups (n = 16 each). To create the chronic RCT model, we induced complete supraspinatus tendon tears in both shoulders and left them untreated for 6 weeks. All transected tendons were repaired in a transosseous manner with saline injection in group A, hyaluronic acid (HA) injection in group B, 3D-printed nanofiber sheet fixation in group C, rhPTH and HA injection in group D, and 3D-printed rhPTH- and HA-soaked nanofiber sheet fixation in group E. Genetic (messenger RNA expression evaluation) and histologic evaluations (hematoxylin and eosin and Masson trichrome staining) were performed in half of the rabbits at 4 weeks postrepair. Genetic, histologic, and biomechanical evaluations (mode of tear and load to failure) were performed in the remaining rabbits at 12 weeks. RESULTS: For genetic evaluation, group E showed a higher collagen type I alpha 1 expression level than did the other groups (P = .008) at 4 weeks. However, its expression level was downregulated, and there was no difference at 12 weeks. For histologic evaluation, group E showed greater collagen fiber continuity, denser collagen fibers, and more mature tendon-to-bone junction than did the other groups (P = .001, P = .001, and P = .003, respectively) at 12 weeks. For biomechanical evaluation, group E showed a higher load-to-failure rate than did the other groups (P < .001) at 12 weeks. CONCLUSION: Three-dimensionally printed rhPTH-soaked nanofiber sheet fixation can promote tendon-to-bone healing of chronic RCT.


Assuntos
Nanofibras , Lesões do Manguito Rotador , Animais , Humanos , Coelhos , Fenômenos Biomecânicos , Colágeno/farmacologia , Modelos Animais de Doenças , Ácido Hialurônico , Nanofibras/uso terapêutico , Hormônio Paratireóideo/farmacologia , Impressão Tridimensional , Lesões do Manguito Rotador/patologia , Lesões do Manguito Rotador/cirurgia , Ruptura/cirurgia , Tendões/cirurgia , Cicatrização
7.
Alzheimers Dement ; 17(5): 831-846, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33576571

RESUMO

The strongest genetic risk factor for idiopathic late-onset Alzheimer's disease (LOAD) is apolipoprotein E (APOE) ɛ4, while the APOE ɛ2 allele is protective. However, there are paradoxical APOE ɛ4 carriers who remain disease-free and APOE ɛ2 carriers with LOAD. We compared exomes of healthy APOE ɛ4 carriers and APOE ɛ2 Alzheimer's disease (AD) patients, prioritizing coding variants based on their predicted functional impact, and identified 216 genes with differential mutational load between these two populations. These candidate genes were significantly dysregulated in LOAD brains, and many modulated tau- or ß42-induced neurodegeneration in Drosophila. Variants in these genes were associated with AD risk, even in APOE ɛ3 homozygotes, showing robust predictive power for risk stratification. Network analyses revealed involvement of candidate genes in brain cell type-specific pathways including synaptic biology, dendritic spine pruning and inflammation. These potential modifiers of LOAD may constitute novel biomarkers, provide potential therapeutic intervention avenues, and support applying this approach as larger whole exome sequencing cohorts become available.


Assuntos
Doença de Alzheimer/genética , Apolipoproteína E2/genética , Apolipoproteína E4/genética , Encéfalo/patologia , Fenótipo , Animais , Drosophila , Heterozigoto , Homozigoto , Humanos , Mutação/genética
8.
Korean J Physiol Pharmacol ; 25(2): 167-175, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33602887

RESUMO

Far-infrared rays (FIR) are known to have various effects on atoms and molecular structures within cells owing to their radiation and vibration frequencies. The present study examined the effects of FIR on gene expression related to glucose transport through microarray analysis in rat skeletal muscle cells, as well as on mitochondrial biogenesis, at high and low glucose conditions. FIR were emitted from a bio-active material coated fabric (BMCF). L6 cells were treated with 30% BMCF for 24 h in medium containing 25 or 5.5 mM glucose, and changes in the expression of glucose transporter genes were determined. The expression of GLUT3 (Slc2a3) increased 2.0-fold (p < 0.05) under 5.5 mM glucose and 30% BMCF. In addition, mitochondrial oxygen consumption and membrane potential (ΔΨm) increased 1.5- and 3.4-fold (p < 0.05 and p < 0.001), respectively, but no significant change in expression of Pgc-1a, a regulator of mitochondrial biogenesis, was observed in 24 h. To analyze the relationship between GLUT3 expression and mitochondrial biogenesis under FIR, GLUT3 was down-modulated by siRNA for 72 h. As a result, the ΔΨm of the GLUT3 siRNA-treated cells increased 3.0-fold (p < 0.001), whereas that of the control group increased 4.6-fold (p < 0.001). Moreover, Pgc-1a expression increased upon 30% BMCF treatment for 72 h; an effect that was more pronounced in the presence of GLUT3. These results suggest that FIR may hold therapeutic potential for improving glucose metabolism and mitochondrial function in metabolic diseases associated with insufficient glucose supply, such as type 2 diabetes.

9.
Molecules ; 25(6)2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32244969

RESUMO

Alnus sibirica extracts (ASex) have long been used in Oriental medicine to treat various conditions. To provide a scientific basis for this application and the underlying mechanism, we investigated the anti-inflammatory effects of ASex in vitro and in vivo. The in vitro model was established using human dermal fibroblasts (HDFs) treated with inflammatory stimulants (lipopolysaccharide, tumor necrosis factor-alpha, interferon-gamma). Lactate dehydrogenase and reverse transcription-polymerase chain reaction showed that ASex inhibited the increased expression of acute-phase inflammatory cytokines. The in vivo model was established by inducing skin inflammation in NC/Nga mice via the repeated application of house dust mite (HDM) ointment to the ears and back of the mice for eight weeks. HDM application increased the severity of skin lesions, eosinophil/mast cell infiltration, and serum immunoglobulin E levels, which were all significantly decreased by ASex treatment, demonstrating the same degree of protection as hydrocortisone. Overall, ASex showed excellent anti-inflammatory effects both in vitro and in vivo, suggesting its potential as an excellent candidate drug to reduce skin inflammation.


Assuntos
Alnus/química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Animais , Biópsia , Cromatografia Líquida de Alta Pressão , Citocinas/sangue , Citocinas/genética , Citocinas/metabolismo , Derme/citologia , Derme/efeitos dos fármacos , Derme/metabolismo , Modelos Animais de Doenças , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Imunoglobulina E/sangue , Mediadores da Inflamação/metabolismo , Camundongos
10.
Molecules ; 24(16)2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31398908

RESUMO

The effects of Alnus sibirica (AS) extracts on cytokine expression induced by inflammatory stimulants were examined in human dermal fibroblasts (HDFs) and RAW264.7 cells. The anti-oxidative effect and effect on cell viability of AS extracts were evaluated, and four extracts with the highest anti-oxidative effects were selected. HDFs and RAW264.7 cells were treated with inflammatory stimulants, and the expression of cytokines involved in acute (IL-6 and IL-10) and chronic (IL-18) inflammation, the initiation of the immune response (IL-33), and non-specific immune responses (IL-1ß, IL-8, and TNF-α) were determined using a reverse-transcription polymerase chain reaction. LPS increased the expression of all the cytokines, except for IL-18; however, AS extracts, particularly AS2 and AS4, reduced this increase, and TNF-α treatment markedly increased the expression of cytokines related to non-specific immune responses. IFN-γ treatment induced no significant changes, except for increased IL-33 expression in HDFs. AS extracts inhibited the increase in the expression of IL-33 and other cytokines in HDFs. Thus, the exposure of HDFs and RAW264.7 cells to inflammatory stimulants increased the expression of cytokines related to all the inflammatory processes. HDFs are involved not only in simple tissue regeneration but also in inflammatory reactions in the skin. AS2 and AS4 may offer effective therapy for related conditions.


Assuntos
Alnus/química , Citocinas/genética , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Extratos Vegetais/farmacologia , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Humanos , Interferon gama/metabolismo , Interferon gama/farmacologia , Lipopolissacarídeos , Camundongos , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Células RAW 264.7 , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
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