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1.
Nature ; 623(7985): 157-166, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37853118

RESUMO

Immunotherapy failures can result from the highly suppressive tumour microenvironment that characterizes aggressive forms of cancer such as recurrent glioblastoma (rGBM)1,2. Here we report the results of a first-in-human phase I trial in 41 patients with rGBM who were injected with CAN-3110-an oncolytic herpes virus (oHSV)3. In contrast to other clinical oHSVs, CAN-3110 retains the viral neurovirulence ICP34.5 gene transcribed by a nestin promoter; nestin is overexpressed in GBM and other invasive tumours, but not in the adult brain or healthy differentiated tissue4. These modifications confer CAN-3110 with preferential tumour replication. No dose-limiting toxicities were encountered. Positive HSV1 serology was significantly associated with both improved survival and clearance of CAN-3110 from injected tumours. Survival after treatment, particularly in individuals seropositive for HSV1, was significantly associated with (1) changes in tumour/PBMC T cell counts and clonal diversity, (2) peripheral expansion/contraction of specific T cell clonotypes; and (3) tumour transcriptomic signatures of immune activation. These results provide human validation that intralesional oHSV treatment enhances anticancer immune responses even in immunosuppressive tumour microenvironments, particularly in individuals with cognate serology to the injected virus. This provides a biological rationale for use of this oncolytic modality in cancers that are otherwise unresponsive to immunotherapy (ClinicalTrials.gov: NCT03152318 ).


Assuntos
Neoplasias Encefálicas , Glioblastoma , Herpesvirus Humano 1 , Terapia Viral Oncolítica , Vírus Oncolíticos , Humanos , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Glioblastoma/imunologia , Glioblastoma/patologia , Nestina/genética , Terapia Viral Oncolítica/efeitos adversos , Vírus Oncolíticos/genética , Vírus Oncolíticos/imunologia , Vírus Oncolíticos/fisiologia , Reprodutibilidade dos Testes , Análise de Sobrevida , Linfócitos T/citologia , Linfócitos T/imunologia , Resultado do Tratamento , Microambiente Tumoral/imunologia , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 1/fisiologia
2.
Mol Cell ; 78(6): 1207-1223.e8, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32504554

RESUMO

Tumor interferon (IFN) signaling promotes PD-L1 expression to suppress T cell-mediated immunosurveillance. We identify the IFN-stimulated non-coding RNA 1 (INCR1) as a long noncoding RNA (lncRNA) transcribed from the PD-L1 locus and show that INCR1 controls IFNγ signaling in multiple tumor types. Silencing INCR1 decreases the expression of PD-L1, JAK2, and several other IFNγ-stimulated genes. INCR1 knockdown sensitizes tumor cells to cytotoxic T cell-mediated killing, improving CAR T cell therapy. We discover that PD-L1 and JAK2 transcripts are negatively regulated by binding to HNRNPH1, a nuclear ribonucleoprotein. The primary transcript of INCR1 binds HNRNPH1 to block its inhibitory effects on the neighboring genes PD-L1 and JAK2, enabling their expression. These findings introduce a mechanism of tumor IFNγ signaling regulation mediated by the lncRNA INCR1 and suggest a therapeutic target for cancer immunotherapy.


Assuntos
Antígeno B7-H1/genética , Interferon gama/metabolismo , RNA Longo não Codificante/genética , Idoso , Animais , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imunoterapia , Imunoterapia Adotiva/métodos , Interferon gama/genética , Interferons/genética , Interferons/metabolismo , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos NOD , Pessoa de Meia-Idade , Proteína 2 Ligante de Morte Celular Programada 1/genética , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linfócitos T Citotóxicos
3.
Rheumatology (Oxford) ; 61(3): 1276-1281, 2022 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-34255816

RESUMO

OBJECTIVES: Up to 0.3% of Japanese have hypouricaemia. Most cases appear to result from a hereditary disease, renal hypouricaemia (RHUC), which causes exercise-induced acute kidney injury and urolithiasis. However, to what extent RHUC accounts for hypouricaemia is not known. We therefore investigated its frequency and evaluated its risks by genotyping a general Japanese population. METHODS: A cohort of 4993 Japanese was examined by genotyping the non-functional variants R90H (rs121907896) and W258X (rs121907892) of URAT1/SLC22A12, the two most common causative variants of RHUC in Japanese. RESULTS: Participants' fractional excretion of uric acid and risk allele frequencies markedly increased at lower serum uric acid (SUA) levels. Ten participants (0.200%) had an SUA level ≤2.0 mg/dl and nine had R90H or W258X and were likely to have RHUC. Logistic regression analysis revealed these URAT1 variants to be significantly and independently associated with the risk of hypouricaemia and mild hypouricaemia (SUA ≤3.0 mg/dl) as well as sex, age and BMI, but these URAT1 variants were the only risks in the hypouricaemia population (SUA ≤2.0 mg/dl). W258X was only a risk in males with SUA ≤3.0 mg/dl. CONCLUSION: Our study accurately reveals the prevalence of RHUC and provides genetic evidence for its definition (SUA ≤2.0 mg/dl). We also show that individuals with SUA ≤3.0 mg/dl, especially males, are prone to RHUC. Our findings will help to promote a better epidemiological understanding of RHUC as well as more accurate diagnosis, especially in males with mild hypouricaemia.


Assuntos
Transportadores de Ânions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Erros Inatos do Transporte Tubular Renal/genética , Cálculos Urinários/genética , Feminino , Variação Genética , Genótipo , Humanos , Japão/epidemiologia , Masculino , Erros Inatos do Transporte Tubular Renal/epidemiologia , Cálculos Urinários/epidemiologia
4.
Langmuir ; 38(18): 5464-5471, 2022 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-35436122

RESUMO

Artificial planar bilayer lipid membranes (BLMs) are simple models of cellular systems under physically and chemically controlled conditions, and they have been used to investigate membrane protein activity. Baculovirus-budded virus (BV) systems can express recombinant membrane proteins. In this study, aiming for membrane protein reconstitution, we examined the fusion of BVs containing recombinant membrane proteins into artificial planar BLMs on a Si microwell substrate. BV fusion with the BLMs depended on the pH of the solution, and it was enhanced at lower pH. Based on fluorescence recovery after photobleaching (FRAP) measurement, the fusion state of BVs was evaluated, and full fusion at low pH was confirmed. The fluorescent labeling the membrane proteins was also observed in the freestanding part of the BLMs as well as in the supported part. These results demonstrate the effectiveness of BLMs as a platform to examine detailed fusion dynamics of BVs. Furthermore, this study revealed that the fusion of BVs is a promising method for reconstituting membrane proteins to artificial freestanding BLMs for the development of biodevices with which we can examine membrane protein activity.


Assuntos
Dióxido de Silício , Envelope Viral , Baculoviridae/metabolismo , Bicamadas Lipídicas , Fusão de Membrana , Proteínas de Membrana , Proteínas Recombinantes/metabolismo
5.
Retina ; 42(6): 1199-1202, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34077167

RESUMO

PURPOSE: To evaluate the utility of extending the limbus-to-cannula distance to 6.0 mm during pars plana vitrectomy for highly myopic eyes. METHODS: Four eyes with axial lengths exceeding 31.0 mm, that underwent 25-gauge pars plana vitrectomy were retrospectively evaluated. Assuming that cannulas were inserted 3.5 mm and 6.0 mm from the corneal limbus, the distance from the cannula to the fovea (CF distance) was preoperatively evaluated using anterior segmental optical coherence tomography. Surgical complications were also investigated. RESULTS: The CF distance was shortened by 1.22 ± 0.05 mm and 1.22 ± 0.09 mm on the temporal and nasal sides, respectively, by inserting the cannula at 3.5 mm to 6.0 mm from the corneal limbus. As per the preoperatively measured CF distance, one of the cannulas was inserted 6.0 mm from the corneal limbus in three eyes. Their cannulas were confirmed to be inserted at the pars plana, and no surgical complications associated with this technique were observed. CONCLUSION: Extending the limbus-to-cannula distance to 6.0 mm during pars plana vitrectomy could be one of the options to reach the posterior pole in highly myopic eyes. A preoperatively measured CF distance can be a clinical criterion in determining the cannula position.


Assuntos
Miopia , Vitrectomia , Cânula , Corpo Ciliar/cirurgia , Humanos , Miopia/cirurgia , Estudos Retrospectivos , Vitrectomia/métodos
6.
Ann Rheum Dis ; 79(5): 657-665, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32238385

RESUMO

OBJECTIVES: Genome-wide meta-analyses of clinically defined gout were performed to identify subtype-specific susceptibility loci. Evaluation using selection pressure analysis with these loci was also conducted to investigate genetic risks characteristic of the Japanese population over the last 2000-3000 years. METHODS: Two genome-wide association studies (GWASs) of 3053 clinically defined gout cases and 4554 controls from Japanese males were performed using the Japonica Array and Illumina Array platforms. About 7.2 million single-nucleotide polymorphisms were meta-analysed after imputation. Patients were then divided into four clinical subtypes (the renal underexcretion type, renal overload type, combined type and normal type), and meta-analyses were conducted in the same manner. Selection pressure analyses using singleton density score were also performed on each subtype. RESULTS: In addition to the eight loci we reported previously, two novel loci, PIBF1 and ACSM2B, were identified at a genome-wide significance level (p<5.0×10-8) from a GWAS meta-analysis of all gout patients, and other two novel intergenic loci, CD2-PTGFRN and SLC28A3-NTRK2, from normal type gout patients. Subtype-dependent patterns of Manhattan plots were observed with subtype GWASs of gout patients, indicating that these subtype-specific loci suggest differences in pathophysiology along patients' gout subtypes. Selection pressure analysis revealed significant enrichment of selection pressure on ABCG2 in addition to ALDH2 loci for all subtypes except for normal type gout. CONCLUSIONS: Our findings on subtype GWAS meta-analyses and selection pressure analysis of gout will assist elucidation of the subtype-dependent molecular targets and evolutionary involvement among genotype, phenotype and subtype-specific tailor-made medicine/prevention of gout and hyperuricaemia.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Aldeído-Desidrogenase Mitocondrial/genética , Predisposição Genética para Doença/etnologia , Estudo de Associação Genômica Ampla , Gota/genética , Proteínas de Neoplasias/genética , Estudos de Casos e Controles , Loci Gênicos , Genótipo , Gota/epidemiologia , Humanos , Incidência , Japão , Masculino , Fenótipo , Prognóstico , Valores de Referência , Medição de Risco , Índice de Gravidade de Doença
7.
Nano Lett ; 19(1): 461-470, 2019 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-30525693

RESUMO

Three-dimensional (3D) graphene architectures are of great interest as applications in flexible electronics and biointerfaces. In this study, we demonstrate the facile formation of predetermined 3D polymeric microstructures simply by transferring monolayer graphene. The graphene adheres to the surface of polymeric films via noncovalent π-π stacking bonding and induces a sloped internal strain, leading to the self-rolling of 3D microscale architectures. Micropatterns and varied thicknesses of the 2D films prior to the self-rolling allows for control over the resulting 3D geometries. The strain then present on the hexagonal unit cell of the graphene produces a nonlinear electrical conductivity across the device. The driving force behind the self-folding process arises from the reconfiguration of the molecules within the crystalline materials. We believe that this effective and versatile way of realizing a 3D graphene structure is potentially applicable to alternative 2D layered materials as well as other flexible polymeric templates.

8.
Ann Rheum Dis ; 78(10): 1430-1437, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31289104

RESUMO

OBJECTIVE: The first ever genome-wide association study (GWAS) of clinically defined gout cases and asymptomatic hyperuricaemia (AHUA) controls was performed to identify novel gout loci that aggravate AHUA into gout. METHODS: We carried out a GWAS of 945 clinically defined gout cases and 1003 AHUA controls followed by 2 replication studies. In total, 2860 gout cases and 3149 AHUA controls (all Japanese men) were analysed. We also compared the ORs for each locus in the present GWAS (gout vs AHUA) with those in the previous GWAS (gout vs normouricaemia). RESULTS: This new approach enabled us to identify two novel gout loci (rs7927466 of CNTN5 and rs9952962 of MIR302F) and one suggestive locus (rs12980365 of ZNF724) at the genome-wide significance level (p<5.0×10-8). The present study also identified the loci of ABCG2, ALDH2 and SLC2A9. One of them, rs671 of ALDH2, was identified as a gout locus by GWAS for the first time. Comparing ORs for each locus in the present versus the previous GWAS revealed three 'gout vs AHUA GWAS'-specific loci (CNTN5, MIR302F and ZNF724) to be clearly associated with mechanisms of gout development which distinctly differ from the known gout risk loci that basically elevate serum uric acid level. CONCLUSIONS: This meta-analysis is the first to reveal the loci associated with crystal-induced inflammation, the last step in gout development that aggravates AHUA into gout. Our findings should help to elucidate the molecular mechanisms of gout development and assist the prevention of gout attacks in high-risk AHUA individuals.


Assuntos
Contactinas/genética , Gota/genética , Hiperuricemia/genética , MicroRNAs/genética , Dedos de Zinco/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Adulto , Aldeído-Desidrogenase Mitocondrial/genética , Doenças Assintomáticas , Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Proteínas Facilitadoras de Transporte de Glucose/genética , Gota/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Fatores de Risco , Ácido Úrico/sangue
9.
Langmuir ; 35(36): 11725-11734, 2019 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-31407907

RESUMO

The lateral diffusion of lipids is a key factor when functionalizing artificial planar bilayer lipid membranes (BLMs). Fluorescence recovery after photobleaching (FRAP) is an established method for evaluating the fluidity of BLMs by the quantitative determination of the diffusion coefficient. However, a BLM with a uniform diffusion coefficient is usually assumed for analysis. In addition, when the BLM to be evaluated is small, the spread of a bleached circle caused by lateral diffusion during the bleaching process and the divergence of the laser used for bleaching interfere with the quantitative analysis. In this study, a numerical calculation was adopted to make it possible to analyze the continuous BLM between freestanding and supported areas, where the diffusion coefficients change depending on the presence or absence of an interaction with the substrate. A quantitative evaluation independent of such bleaching conditions as the bleaching diameter was also ensured by incorporating the spreading effect of the bleached circle in the calculation, which was employed to analyze a freestanding BLM with a diameter of only a few micrometers. By comparing calculations and experiments on FRAP recovery curves, we found that there are multiple diffusion elements and high diffusion barriers at the boundary between the freestanding and supported areas in a BLM over a SiO2/Si microwell substrate.

10.
J Pineal Res ; 67(3): e12594, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31286565

RESUMO

Astronauts experience osteoporosis-like loss of bone mass because of microgravity conditions during space flight. To prevent bone loss, they need a riskless and antiresorptive drug. Melatonin is reported to suppress osteoclast function. However, no studies have examined the effects of melatonin on bone metabolism under microgravity conditions. We used goldfish scales as a bone model of coexisting osteoclasts and osteoblasts and demonstrated that mRNA expression level of acetylserotonin O-methyltransferase, an enzyme essential for melatonin synthesis, decreased significantly under microgravity. During space flight, microgravity stimulated osteoclastic activity and significantly increased gene expression for osteoclast differentiation and activation. Melatonin treatment significantly stimulated Calcitonin (an osteoclast-inhibiting hormone) mRNA expression and decreased the mRNA expression of receptor activator of nuclear factor κB ligand (a promoter of osteoclastogenesis), which coincided with suppressed gene expression levels for osteoclast functions. This is the first study to report the inhibitory effect of melatonin on osteoclastic activation by microgravity. We also observed a novel action pathway of melatonin on osteoclasts via an increase in CALCITONIN secretion. Melatonin could be the source of a potential novel drug to prevent bone loss during space flight.


Assuntos
Reabsorção Óssea/prevenção & controle , Melatonina/uso terapêutico , Voo Espacial , Animais , Densidade Óssea/efeitos dos fármacos , Calcitonina/metabolismo , Diferenciação Celular/efeitos dos fármacos , Carpa Dourada , Imuno-Histoquímica , NF-kappa B/metabolismo , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , RNA Mensageiro/metabolismo , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Ausência de Peso/efeitos adversos
11.
Heart Vessels ; 34(7): 1203-1211, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30680493

RESUMO

A highly conductive textile was woven from nano-fibers coated with the PEDOT-PSS polymer. The aim of this study was to assess the usefulness of textile electrodes for ECG recording as a smart garment. Electrode textile pads and lead wires were sewn to the lining of sportswear and their tolerability to repeated washings were tested up to 150 times. The electrical conductivity of the textile electrode remained functional for up to 50 machine washes. To assess the level of motion artifacts or noise during the daily monitoring of ECG, a single lead ECG with conventional or textile electrodes was recorded during supine rest, seated rest, upright trunk rotation (i.e., twisting), and stepping movement in 66 healthy adults. A Holter system was used for data storage and analysis. ECG patterns of P, QRS, and T waves were comparable between the conventional and textile electrodes. However, the signal-to-artifact-and/or-noise ratio (SAR) during twisting was larger in the textile electrodes than in the conventional electrodes. No skin irritation was seen in the textile electrodes. The single lead textile electrodes embedded in an inner garment were usable for continuous and/or repeated ECG monitoring in daily life except during vigorous trunk movement.


Assuntos
Eletrocardiografia Ambulatorial , Poliestirenos/química , Processamento de Sinais Assistido por Computador , Têxteis , Tiofenos/química , Dispositivos Eletrônicos Vestíveis , Adulto , Estudos Transversais , Eletrocardiografia/instrumentação , Eletrodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão Sinal-Ruído , Soluções , Tensão Superficial , Adulto Jovem
12.
Ophthalmology ; 125(12): 1929-1936, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30126649

RESUMO

PURPOSE: To report the incidence of, risk factors for, and characteristics of paracentral acute middle maculopathy (PAMM) after 25-gauge pars plana vitrectomy for proliferative diabetic retinopathy (PDR). DESIGN: Retrospective, consecutive, interventional case series. PARTICIPANTS: Five hundred thirty eyes of 427 patients who underwent primary vitrectomy for PDR from 2013 through 2016. METHODS: The patients underwent measurement of best-corrected visual acuity (BCVA), fundus photography, and OCT before and within 2 weeks after vitrectomy. A generalized linear mixed-effects model was used to evaluate risk factors for development of PAMM. MAIN OUTCOME MEASURES: The incidence, associated risk factors, and clinical characteristics of PAMM following vitrectomy, including the change in BCVA in eyes with PAMM and the distribution of PAMM as determined by en face OCT. RESULTS: Four hundred ninety-six eyes of 395 patients who met the eligibility criteria were evaluated. The incidence of PAMM was 3.8% (15/395) for patients and 3.6% (18/496) for eyes. Multivariate analysis showed the significant risk factors for PAMM development to be younger age (mean age, 49 years in patients and 59 years in control participants; odds ratio [OR] 0.94; 95% confidence interval [CI], 0.89-0.99; P = 0.021) and female gender (66.7% of patients and 31.3% of control participants; OR, 4.48; 95% CI, 1.57-12.6; P = 0.005). The PAMM was distributed on either side of the causative arterioles. In 14 of the 18 eyes (78%), PAMM was located within a 3-mm diameter of the fovea. In 10 eyes (56%), PAMM measured 1 disc diameter or more, and in 5 eyes (28%), PAMM measured one third disc diameter or less. No emboli were found in any eyes; however, multiple segmental arterial constrictions were confirmed during vitrectomy in 1 eye. The BCVA decreased more than 2 lines in 2 eyes (5%). CONCLUSIONS: Paracentral acute middle maculopathy can develop after pars plana vitrectomy for PDR, especially in patients who are younger and female. Impaired blood flow in arterioles, which leads to tissue hypoxia, was associated with development of PAMM.


Assuntos
Retinopatia Diabética/cirurgia , Doenças Retinianas/epidemiologia , Vitrectomia/efeitos adversos , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Retinopatia Diabética/diagnóstico por imagem , Feminino , Humanos , Incidência , Fotocoagulação a Laser , Masculino , Pessoa de Meia-Idade , Doenças Retinianas/diagnóstico por imagem , Doenças Retinianas/cirurgia , Estudos Retrospectivos , Fatores de Risco , Microscopia com Lâmpada de Fenda , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia
13.
Phys Chem Chem Phys ; 20(2): 889-897, 2018 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-29239423

RESUMO

We demonstrate the synthesis of unique heterostructures consisting of SnS and WS2 (or SnS and MoS2) by two-step chemical vapor deposition (CVD). After the first CVD growth of triangular WS2 (MoS2) grains, the second CVD step was performed to grow square SnS grains on the same substrate. We found that these SnS grains can be grown at very low temperature with the substrate temperature of 200 °C. Most of the SnS grains nucleated from the side edges of WS2 (MoS2) grains, resulting in the formation of partly stacked heterostructures with a large overlapping area. The SnS grains showed doped p-type transfer character with a hole mobility of 15 cm2 V-1 s-1, while the WS2 and MoS2 grains displayed n-type character with a high on/off ratio of >106. The SnS-WS2 and SnS-MoS2 heterostructures exhibited clear rectifying behavior, signifying the formation of p-n junctions at their interfaces. This heterostructure growth combined with the low temperature SnS growth will provide a promising means to exploit two-dimensional heterostructures by avoiding possible damage to the first material.

14.
Wilderness Environ Med ; 29(2): 159-165, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29530472

RESUMO

INTRODUCTION: The 23rd World Scout Jamboree (WSJ) was a 10-day summer camp held in Japan in 2015 under hot and humid conditions. The attendees comprised 33,628 people from 155 countries and territories. The aim of this study was to examine the provision of medical services under such conditions and to identify preventive factors for major diseases among long-term campers. METHODS: Data were obtained from WSJ medical center records and examined to clarify the effects of age, sex, and period on visit frequencies and rates. RESULTS: Medical records from 3215 patients were examined. Daytime temperatures were 31.5±3.2°C and relative humidity was 61±13% (mean±SD). The initial visit rates among scouts and adults were 72.2 and 77.2 per 1000 persons, respectively. No significant age difference was observed in the initial visit rate; however, it was significantly higher among female patients than male patients. Significant differences were also seen in the adjusted odds ratios by age, sex, and period for disease distributions of initial visit frequencies. In addition, a higher initial visit frequency for heat strain-related diseases was seen among the scouts. Initial visit frequencies for heatstroke and/or dehydration increased just after opening day and persisted until closing day. CONCLUSIONS: Our findings suggest the importance of taking effective countermeasures against heat strain, fatigue, and unsanitary conditions at the WSJ. Medical services staff should take attendees' age, sex, and period into consideration to prevent heat strain-related diseases during such camps under hot and humid conditions.


Assuntos
Acampamento , Serviços de Saúde/estatística & dados numéricos , Temperatura Alta/efeitos adversos , Umidade/efeitos adversos , Adolescente , Adulto , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Adulto Jovem
15.
Ann Rheum Dis ; 76(5): 869-877, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-27899376

RESUMO

OBJECTIVE: A genome-wide association study (GWAS) of gout and its subtypes was performed to identify novel gout loci, including those that are subtype-specific. METHODS: Putative causal association signals from a GWAS of 945 clinically defined gout cases and 1213 controls from Japanese males were replicated with 1396 cases and 1268 controls using a custom chip of 1961 single nucleotide polymorphisms (SNPs). We also first conducted GWASs of gout subtypes. Replication with Caucasian and New Zealand Polynesian samples was done to further validate the loci identified in this study. RESULTS: In addition to the five loci we reported previously, further susceptibility loci were identified at a genome-wide significance level (p<5.0×10-8): urate transporter genes (SLC22A12 and SLC17A1) and HIST1H2BF-HIST1H4E for all gout cases, and NIPAL1 and FAM35A for the renal underexcretion gout subtype. While NIPAL1 encodes a magnesium transporter, functional analysis did not detect urate transport via NIPAL1, suggesting an indirect association with urate handling. Localisation analysis in the human kidney revealed expression of NIPAL1 and FAM35A mainly in the distal tubules, which suggests the involvement of the distal nephron in urate handling in humans. Clinically ascertained male patients with gout and controls of Caucasian and Polynesian ancestries were also genotyped, and FAM35A was associated with gout in all cases. A meta-analysis of the three populations revealed FAM35A to be associated with gout at a genome-wide level of significance (p meta =3.58×10-8). CONCLUSIONS: Our findings including novel gout risk loci provide further understanding of the molecular pathogenesis of gout and lead to a novel concept for the therapeutic target of gout/hyperuricaemia.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Gota/genética , Adulto , Idoso , Povo Asiático/genética , Estudos de Casos e Controles , Proteínas de Transporte de Cátions/genética , Proteínas de Ciclo Celular , Proteínas de Ligação a DNA , Loci Gênicos , Genótipo , Gota/classificação , Histonas/genética , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Havaiano Nativo ou Outro Ilhéu do Pacífico/genética , Transportadores de Ânions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Polimorfismo de Nucleotídeo Único , Proteínas/genética , Proteínas Cotransportadoras de Sódio-Fosfato Tipo I/genética , População Branca/genética
16.
Circ J ; 81(3): 361-367, 2017 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-28090071

RESUMO

BACKGROUND: The relationship between time of onset of acute myocardial infarction (MI) and long-term clinical outcome has not been completely understood. We hypothesized that morning onset acute MI may be associated with adverse cardiac events.Methods and Results:This study involved 663 patients who underwent primary percutaneous coronary intervention (PCI). The main outcome measures were cardiac death, recurrent acute coronary syndrome (ACS), and re-hospitalization for heart failure. Major adverse cardiac events (MACE) were defined as a composite of individual adverse outcomes. Morning onset acute MI occurred in 212 patients (32.0%); they had higher rates of recurrent ACS (13% vs. 8%, P=0.03) and MACE (21% vs. 14%, P=0.012) than the patients with other times of onset. The PCI rate for progressive lesions was also higher than for patients with other times of onset (23% vs. 14%, P=0.013). On multivariate Cox regression analysis, morning onset was an independent predictor of recurrent ACS, MACE, and PCI for progressive lesions, with adjusted hazard ratios of 1.34 (95% CI: 1.06-2.92, P=0.030), 1.51 (95% CI: 1.02-2.23, P=0.038), and 1.58 (95% CI: 1.03-2.42, P=0.037), respectively. CONCLUSIONS: Morning onset may be associated with increased risk of recurrent ACS and coronary atherosclerosis progression.


Assuntos
Síndrome Coronariana Aguda , Doença da Artéria Coronariana , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Síndrome Coronariana Aguda/complicações , Síndrome Coronariana Aguda/mortalidade , Síndrome Coronariana Aguda/fisiopatologia , Síndrome Coronariana Aguda/cirurgia , Idoso , Idoso de 80 Anos ou mais , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/mortalidade , Doença da Artéria Coronariana/fisiopatologia , Doença da Artéria Coronariana/cirurgia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Infarto do Miocárdio com Supradesnível do Segmento ST/complicações , Infarto do Miocárdio com Supradesnível do Segmento ST/mortalidade , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia
17.
Graefes Arch Clin Exp Ophthalmol ; 255(4): 665-671, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27770210

RESUMO

PURPOSE: The purpose of this study was to compare ocular and systemic parameters between proliferative diabetic retinopathy (PDR) cases with postoperative vitreous hemorrhage (PVH) and those without PVH after 25-gauge vitrectomy, and to investigate the predictors of PVH. METHODS: The medical records of 106 eyes of 78 consecutive patients who underwent primary 25-gauge vitrectomy were reviewed. RESULTS: The incidences of early and late PVH were found to be 18.9 % (20/106 eyes) and 17.9 % (19/106 eyes) respectively. On multiple logistic regression analysis, intraoperative bleeding from new vessels on the disc was identified as the most important factor, with the greatest odds ratio, for the development of early PVH (odds ratio = 3.395, P = 0.134), while the HbA1c level was identified as the most important significant factor, with the greatest odds ratio, for the development of late PVH (odds ratio = 1.403, P = 0.014). CONCLUSIONS: Early PVH tends to occur in severe PDR cases, while late PVH tends to occur in cases with poor diabetic control.


Assuntos
Retinopatia Diabética/cirurgia , Hemorragia Pós-Operatória/diagnóstico , Vitrectomia/efeitos adversos , Hemorragia Vítrea/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Hemorragia Pós-Operatória/etiologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Acuidade Visual , Hemorragia Vítrea/etiologia
18.
J Biol Chem ; 290(3): 1485-95, 2015 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-25429107

RESUMO

The ubiquitin-like interferon (IFN)-stimulated gene 15 (ISG15) and its specific E1, E2, and E3 enzymes are transcriptionally induced by type I IFNs. ISG15 conjugates newly synthesized proteins. ISG15 linkage to proteins appears to be an important downstream IFN signaling event that discriminates cellular and pathogenic proteins synthesized during IFN stimulation from existing proteins. This eliminates potentially pathogenic proteins as the cell attempts to return to normal homeostasis after IFN "stressed" conditions. However, the molecular events that occur in this process are not well known. Here, we show that the C-terminal LRLRGG of ISG15 interacts with the binder of ubiquitin zinc finger (BUZ) domain of histone deacetylase 6 (HDAC6). Because HDAC6 is involved in the autophagic clearance of ubiquitinated aggregates during which SQSTM1/p62 plays a major role as a cargo adapter, we also were able to confirm that p62 binds to ISG15 protein and its conjugated proteins upon forced expression. Both HDAC6 and p62 co-localized with ISG15 in an insoluble fraction of the cytosol, and this co-localization was magnified by the proteasome inhibitor MG132. In addition, ISG15 was degraded via the lysosome. Overexpression of ISG15, which leads to an increased conjugation level of the cellular proteome, enhanced autophagic degradation independently of IFN signaling transduction. These results thus indicate that ISG15 conjugation marks proteins for interaction with HDAC6 and p62 upon forced stressful conditions likely as a step toward autophagic clearance.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Autofagia , Citocinas/metabolismo , Histona Desacetilases/metabolismo , Ubiquitinas/metabolismo , Citosol/metabolismo , DNA Complementar/metabolismo , Doxiciclina/química , Células HEK293 , Desacetilase 6 de Histona , Homeostase , Humanos , Imunidade Inata , Leupeptinas/química , Lisossomos/metabolismo , Microscopia de Fluorescência , Inibidores de Proteassoma/metabolismo , Processamento de Proteína Pós-Traducional , Estrutura Terciária de Proteína , Proteoma/metabolismo , Proteína Sequestossoma-1 , Transdução de Sinais
19.
Ann Rheum Dis ; 75(4): 652-9, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25646370

RESUMO

OBJECTIVE: Gout, caused by hyperuricaemia, is a multifactorial disease. Although genome-wide association studies (GWASs) of gout have been reported, they included self-reported gout cases in which clinical information was insufficient. Therefore, the relationship between genetic variation and clinical subtypes of gout remains unclear. Here, we first performed a GWAS of clinically defined gout cases only. METHODS: A GWAS was conducted with 945 patients with clinically defined gout and 1213 controls in a Japanese male population, followed by replication study of 1048 clinically defined cases and 1334 controls. RESULTS: Five gout susceptibility loci were identified at the genome-wide significance level (p<5.0×10(-8)), which contained well-known urate transporter genes (ABCG2 and SLC2A9) and additional genes: rs1260326 (p=1.9×10(-12); OR=1.36) of GCKR (a gene for glucose and lipid metabolism), rs2188380 (p=1.6×10(-23); OR=1.75) of MYL2-CUX2 (genes associated with cholesterol and diabetes mellitus) and rs4073582 (p=6.4×10(-9); OR=1.66) of CNIH-2 (a gene for regulation of glutamate signalling). The latter two are identified as novel gout loci. Furthermore, among the identified single-nucleotide polymorphisms (SNPs), we demonstrated that the SNPs of ABCG2 and SLC2A9 were differentially associated with types of gout and clinical parameters underlying specific subtypes (renal underexcretion type and renal overload type). The effect of the risk allele of each SNP on clinical parameters showed significant linear relationships with the ratio of the case-control ORs for two distinct types of gout (r=0.96 [p=4.8×10(-4)] for urate clearance and r=0.96 [p=5.0×10(-4)] for urinary urate excretion). CONCLUSIONS: Our findings provide clues to better understand the pathogenesis of gout and will be useful for development of companion diagnostics.


Assuntos
Gota/genética , Hiperuricemia/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Idoso , Povo Asiático/genética , Miosinas Cardíacas/genética , Estudos de Casos e Controles , Proteínas do Ovo/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Proteínas Facilitadoras de Transporte de Glucose/genética , Gota/etiologia , Gota/urina , Humanos , Hiperuricemia/complicações , Hiperuricemia/urina , Japão , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Cadeias Leves de Miosina/genética , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Ácido Úrico/urina
20.
Surg Today ; 46(3): 309-12, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25904560

RESUMO

PURPOSE: To compare the safety of emergent laparoscopic cholecystectomy for acute acalculous cholecystitis (AAC) with surgery for acute calculous cholecystitis (ACC). METHODS: We retrospectively reviewed the perioperative records of 111 patients who underwent emergent laparoscopic cholecystectomy for acute cholecystitis under the care of the Department of Digestive Surgery, Kawasaki Medical School, Kurashiki, between January 2010 and April 2014. Patients were divided into the AAC group (27 patients) and the ACC group (84 patients), and their perioperative outcomes were compared. RESULTS: Patients in the AAC group had significantly higher disease severity and American Society of Anesthesiologists physical status scores (p = 0.001 and 0.037, respectively), lower blood hemoglobin and albumin concentrations (p = 0.0005 and 0.017, respectively), and lower hematocrit and platelet count (p < 0.0001 and 0.040, respectively) than those in the ACC group. When we compared perioperative outcomes, we also found that patients in the AAC group were more likely to have received a blood transfusion (p = 0.002) and to have required conversion to open surgery (p = 0.008). There were no significant differences in morbidity, mortality or length of hospital stay. CONCLUSIONS: Early laparoscopic cholecystectomy is safe in acute acalculous as well as acute calculous cholecystitis.


Assuntos
Colecistite Acalculosa/cirurgia , Colecistectomia Laparoscópica , Colecistite Aguda/cirurgia , Idoso , Idoso de 80 Anos ou mais , Colecistectomia Laparoscópica/métodos , Estudos de Coortes , Emergências , Feminino , Humanos , Masculino , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do Tratamento
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