RESUMO
Jaw1 (also known as IRAG2), a tail-anchored protein with 39 carboxyl (C)-terminal amino acids, is oriented to the lumen of the endoplasmic reticulum and outer nuclear membrane. We previously reported that Jaw1, as a member of the KASH protein family, plays a role in maintaining nuclear shape via its C-terminal region. Furthermore, we recently reported that Jaw1 functions as an augmentative effector of Ca2+ release from the endoplasmic reticulum by interacting with the inositol 1,4,5-trisphosphate receptors (IP3Rs). Intriguingly, the C-terminal region is partially cleaved, meaning that Jaw1 exists in the cell in at least two forms - uncleaved and cleaved. However, the mechanism of the cleavage event and its physiological significance remain to be determined. In this study, we demonstrate that the C-terminal region of Jaw1 is cleaved after its insertion by the signal peptidase complex (SPC). Particularly, our results indicate that the SPC with the catalytic subunit SEC11A, but not SEC11C, specifically cleaves Jaw1. Furthermore, using a mutant with a defect in the cleavage event, we demonstrate that the cleavage event enhances the augmentative effect of Jaw1 on the Ca2+ release ability of IP3Rs.
Assuntos
Sinalização do Cálcio , Cálcio , Receptores de Inositol 1,4,5-Trifosfato/genética , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Cálcio/metabolismo , Sinalização do Cálcio/fisiologia , Retículo Endoplasmático/metabolismo , Núcleo Celular/metabolismo , Inositol 1,4,5-Trifosfato/metabolismoRESUMO
Glycoside hydrolase (GH) family 13 is among the main families of enzymes acting on starch; recently, subfamily 47 of GH13 (GH13_47) has been established. The crystal structure and function of a GH13_47 enzyme from Bacteroides ovatus has only been reported to date. This enzyme has α-amylase activity, while the GH13_47 enzymes comprise approximately 800-900 amino acid residues which are almost double those of typical α-amylases. It is important to know how different the GH13_47 enzymes are from other α-amylases. Rhodothermus marinus JCM9785, a thermophilic bacterium, possesses a gene for the GH13_47 enzyme, which is designated here as RmGH13_47A. Its structure has been predicted to be composed of seven domains: N1, N2, N3, A, B, C, and D. We constructed a plasmid encoding Gly266-Glu886, which contains the N3, A, B, and C domains and expressed the protein in Escherichia coli. The enzyme hydrolyzed starch and pullulan by a neopullulanase-type action. Additionally, the enzyme acted on maltotetraose, and saccharides with α-1,6-glucosidic linkages were observed in the products. Following the replacement of the catalytic residue Asp563 with Ala, the crystal structure of the variant D563A in complex with the enzymatic products from maltotetraose was determined; as a result, electron density for an α-1,6-branched pentasaccharide was observed in the catalytic pocket, and Ile762 and Asp763 interacted with the branched chain of the pentasaccharide. These findings suggest that RmGH13_47A is an α-amylase that prefers α-1,6-branched parts of starch to produce oligosaccharides.
Assuntos
Proteínas de Bactérias , Modelos Moleculares , Rhodothermus , alfa-Amilases , Rhodothermus/enzimologia , Rhodothermus/genética , alfa-Amilases/química , alfa-Amilases/metabolismo , alfa-Amilases/genética , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/genética , Glucanos/metabolismo , Glucanos/química , Especificidade por Substrato , Amido/metabolismo , Amido/química , Sequência de Aminoácidos , Oligossacarídeos/metabolismo , Oligossacarídeos/química , Domínio Catalítico , Ligação Proteica , Escherichia coli/genética , Escherichia coli/metabolismo , Hidrólise , Domínios e Motivos de Interação entre Proteínas , Cristalografia por Raios X , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/genética , Clonagem Molecular , Glicosídeo Hidrolases/química , Glicosídeo Hidrolases/metabolismo , Glicosídeo Hidrolases/genética , Sítios de Ligação , Conformação Proteica em alfa-Hélice , Maltose/análogos & derivadosRESUMO
OBJECTIVE: To assess safety of baricitinib in Japanese patients with rheumatoid arthritis in real-world clinical practice. METHODS: This all-case post-marketing surveillance study included patients initiating baricitinib for rheumatoid arthritis from September 2017 to April 2019. Treatment duration was recorded. Safety data were collected for up to 3 years from baricitinib initiation (up to 4 weeks post discontinuation in discontinuing patients). RESULTS: Safety analyses included 4720 patients; 2580 (54.7%) were ≥65 years old. Baricitinib persistence rate was 45.4% (3 year Kaplan-Meier analysis); the most common discontinuation reason was insufficient effectiveness (n = 1005, 21.3%). Serious adverse events occurred in 600 patients (incidence rate 10.42/100 patient-years; 95% confidence interval, 9.76-11.09). There were 39 deaths (incidence rate 0.43 [0.30-0.57]/100 patient-years). Incidence rate per 100 patient-years for adverse events of special interest were herpes zoster 4.68 (4.22-5.14), serious infection 3.05 (2.68-3.41), malignancy 1.09 (0.87-1.30), major adverse cardiovascular events 0.35 (0.23-0.48) and venous thromboembolism 0.25 (0.15-0.36). Incidence rates did not increase with prolonged exposure. CONCLUSIONS: No new safety concerns were identified during this 3 year post-marketing surveillance study of baricitinib in Japanese patients with rheumatoid arthritis. Patients and clinicians should be cognizant of herpes zoster and other serious infection risks during baricitinib treatment, especially in the first 6 months.
RESUMO
The trisaccharide 1-kestose, a major constituent of fructooligosaccharide, has strong prebiotic effects. We used high-performance liquid chromatography and 1H nuclear magnetic resonance spectroscopy to show that BiBftA, a ß-fructosyltransferase belonging to glycoside hydrolase family 68, from Beijerinckia indica subsp. indica catalyzes transfructosylation of sucrose to produce mostly 1-kestose and levan polysaccharides. We substituted His395 and Phe473 in BiBftA with Arg and Tyr, respectively, and analyzed the reactions of the mutant enzymes with 180 g/L sucrose. The ratio of the molar concentrations of glucose and 1-kestose in the reaction mixture with wild-type BiBftA was 100:8.1, whereas that in the reaction mixture with the variant H395R/F473Y was 100:45.5, indicating that H395R/F473Y predominantly accumulated 1-kestose from sucrose. The X-ray crystal structure of H395R/F473Y suggests that its catalytic pocket is unfavorable for binding of sucrose while favorable for transfructosylation.
Assuntos
Proteínas de Bactérias , Hexosiltransferases , Hexosiltransferases/genética , Hexosiltransferases/metabolismo , Sacarose/metabolismoRESUMO
OBJECTIVES: To assess the safety and effectiveness of baricitinib treatment for rheumatoid arthritis (RA) in real-world clinical practice. METHODS: This ongoing all-case post-marketing surveillance study (starting September 2017) includes all patients with RA treated with baricitinib in Japan. Safety and effectiveness (disease activity) were assessed for 24 weeks. RESULTS: Safety analyses to February 2021 included 4731 patients (initial baricitinib dose: 4 mg/day, n = 3058; 2 mg/day, n = 1661; other, n = 12); 1059 (22.38%) were ≥75 years and 3362 (71.06%) previously received biologic therapy. The overall observational period was 1863.14 patient-years; 1174 (24.82%) patients discontinued baricitinib before Week 24, mostly for lack of effectiveness (n = 478; 10.10%). Adverse events occurred in 1271 (26.87%) patients [serious: 203 (4.29%); death: 18 (0.38%)]. The incidence of herpes zoster, hepatic function disorder, and serious infection was 3.09%, 2.77%, and 1.90%, respectively. Malignancy occurred in 17 patients (0.36%) and major adverse cardiovascular events in seven patients (0.15%). Among patients with effectiveness data, at least 26.57% (Boolean) achieved remission at Week 24. CONCLUSIONS: This large nationwide surveillance study evaluated the safety and effectiveness of 24 weeks of baricitinib for RA in real-world clinical practice. Continued surveillance of long-term safety is ongoing.
Assuntos
Antirreumáticos , Artrite Reumatoide , Humanos , Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , População do Leste Asiático , Vigilância de Produtos Comercializados , Resultado do Tratamento , IdosoRESUMO
An α-glucosidase from Aspergillus sojae, AsojAgdL, exhibits strong transglucosylation activity to produce α-1,6-glucosidic linkages. The most remarkable structural feature of AsojAgdL is that residues 457-560 of AsojAgdL (designated the NC sequence) is not conserved in other glycoside hydrolase family 31 enzymes, and part of this NC sequence is proteolytically cleaved during its maturation. In this study, the enzyme was expressed in Pichia pastoris, and electrophoretic analysis indicated that the recombinant enzyme, rAsojAgdL, consisted of two polypeptide chains, as observed in the case of the enzyme produced in an Aspergillus strain. The crystal structure of rAsojAgdL was determined in complex with the substrate analog trehalose. Electron density corresponding to residues 496-515 of the NC sequence was not seen, and there were no α-helices or ß-strands except for a short α-helix in the structures of residues 457-495 and residues 516-560, both of which belong to the NC sequence. The residues 457-495 and the residues 516-560 both formed extra components of the catalytic domain. The residues 457-495 constituted the entrance of the catalytic pocket of rAsojAgdL, and Gly467, Asp468, Pro469, and Pro470 in the NC sequence were located within 4 Å of Trp400, a key residue involved in binding of the substrate. The results suggest that the proteolytic processing of the NC sequence is related to the formation of the catalytic pocket of AsojAgdL.
Assuntos
Aspergillus , alfa-Glucosidases , Aspergillus/genética , Aspergillus/metabolismo , Domínio Catalítico , Especificidade por Substrato , alfa-Glucosidases/química , alfa-Glucosidases/genética , alfa-Glucosidases/metabolismoRESUMO
The nodes of Ranvier are unmyelinated gaps in the axon, important for the efficient transmission of action potentials. Despite the identification of several glycoproteins involved in node formation and maintenance, glycans' structure and formation in the node remain unclear. Previously, we developed a recombinant lectin from the Clostridium botulinum neurotoxin complex, specific to the galactose and N-acetylgalactosamine terminal epitopes (Gg). Gg stained Neuro2a cells. Here, we show Gg punctuate staining in mouse brain cryosections. Thus, we hypothesized that Gg could help study glycans in the node of Ranvier. Lectin histochemistry on mouse brain cryosections confirmed that Gg binds specifically to the node of Ranvier in the central nervous system (CNS). Using a combination of lectin blotting, glycosidase treatment on tissue sections, and lectin histochemistry, Gg ligands were identified as α-galactose terminal glycoproteins in the perinodal extracellular matrix. Furthermore, we detected the spatiotemporal distribution of galactosylated glycans in the CNS node of Ranvier in mouse brain tissues at different postnatal times. Finally, we observed impaired clustering of galactosylated glycans in the nodes during demyelination and remyelination in cuprizone-induced demyelination and remyelination mouse model. In conclusion, Gg can serve as a novel brain imaging tool in glycobiology and report glycoprotein formation and alterations in the CNS node of Ranvier. Our findings might serve as a first step to establish the role of glycans in the node of Ranvier.
Assuntos
Doenças Desmielinizantes , Lectinas , Nós Neurofibrosos , Animais , Camundongos , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Sistema Nervoso Central/diagnóstico por imagem , Sistema Nervoso Central/metabolismo , Doenças Desmielinizantes/metabolismo , Galactose/metabolismo , Glicoproteínas/metabolismo , Lectinas/química , Neuroimagem , Polissacarídeos/química , Polissacarídeos/metabolismo , Nós Neurofibrosos/metabolismoRESUMO
The MicroLED probe enables optogenetic control of neural activity in spatially separated brain regions. Understanding its heat generation characteristics is important. In this study, we investigated the temperature rise (ΔT) characteristics in the brain tissue using a MicroLED probe. The ΔT strongly depended on the surrounding environment of the probe, including the differences between the air and the brain, and the area touching the brain tissue. Through animal experiments, we suggest an in situ temperature monitoring method using temperature dependence on electrical characteristics of the MicroLED. Finally, optical stimulation by MicroLEDs proved effective in controlling optogenetic neural activity in animal models.
Assuntos
Encéfalo , Optogenética , Animais , Optogenética/métodos , Encéfalo/diagnóstico por imagemRESUMO
BACKGROUND AND AIM: Although an inverse relationship between current smoking and the development of ulcerative colitis (UC) has been shown in North America and Europe, evidence is limited in Asian countries, where the incidence of UC is rapidly increasing. This Japanese case-control study examined the association between active and passive smoking and risk of UC. METHODS: A self-administered questionnaire was used to obtain information on smoking and potential confounding factors in 384 cases with a diagnosis of UC within the past 4 years and 665 controls. RESULTS: Compared with having never smoked, having ever smoked was associated with an increased risk of UC (adjusted odds ratio [OR] = 1.70, 95% confidence interval [CI]: 1.23-2.37). No association was observed between current smoking and risk of UC, but former smokers had a significant elevation in risk (adjusted OR = 2.40, 95% CI: 1.67-3.45). There was a positive dose-response relationship with pack-years smoked (P for trend = 0.006). Among never smokers, passive smoking exposure at home was significantly associated with an increased risk of UC (adjusted OR = 1.90, 95% CI: 1.30-2.79). A significant dose-response gradient was also observed between pack-years of passive smoking at home and risk of UC (P for trend = 0.0003). CONCLUSIONS: We confirmed that former smoking elevated the risk of UC, whereas an inverse association between current smoking and the risk of UC did not reach a statistically significant level. Passive smoking may be associated with an increased risk of UC.
Assuntos
Colite Ulcerativa , Poluição por Fumaça de Tabaco , Estudos de Casos e Controles , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/epidemiologia , Colite Ulcerativa/etiologia , Humanos , Japão/epidemiologia , Fatores de Risco , Poluição por Fumaça de Tabaco/efeitos adversosRESUMO
Fructooligosaccharide is a mixture of mostly the trisaccharide 1-kestose (GF2), tetrasaccharide nystose (GF3), and fructosyl nystose (GF4). Enzymes that hydrolyze GF3 may be useful for preparing GF2 from the fructooligosaccharide mixture. A ß-fructofuranosidase belonging to glycoside hydrolase family 32 (GH32) from the honeybee gut bacterium Frischella perrara (FperFFase) was expressed in Escherichia coli and purified. The time course of the hydrolysis of 60 mM sucrose, GF2, and GF3 by FperFFase was analyzed, showing that the hydrolytic activity of FperFFase for trisaccharide GF2 was lower than those for disaccharide sucrose and tetrasaccharide GF3. The crystal structure of FperFFase and its structure in complex with fructose were determined. FperFFase was found to be structurally homologous to bifidobacterial ß-fructofuranosidases even though bifidobacterial enzymes preferably hydrolyze GF2 and the amino acid residues interacting with fructose at subsite - 1 are mostly conserved between them. A proline residue was inserted between Asp298 and Ser299 using site-directed mutagenesis, and the activity of the variant 298P299 was measured. The ratio of activities for 60 mM GF2/GF3 by wild-type FperFFase was 35.5%, while that of 298P299 was 23.6%, indicating that the structure of the loop comprising Trp297-Asp298-Ser299 correlated with the substrate preference of FperFFase. The crystal structure also shows that a loop consisting of residues 117-127 is likely to contribute to the substrate binding of FperFFase. The results obtained herein suggest that FperFFase is potentially useful for the manufacture of GF2. KEY POINTS: ⢠Frischella ß-fructofuranosidase hydrolyzed nystose more efficiently than 1-kestose. ⢠Trp297-Asp298-Ser299 was shown to be correlated with the substrate preference. ⢠Loop consisting of residues 117-127 appears to contribute to the substrate binding.
Assuntos
Oligossacarídeos , beta-Frutofuranosidase , Animais , Abelhas , Frutose , Gammaproteobacteria , Oligossacarídeos/metabolismo , Sacarose , Trissacarídeos/metabolismo , beta-Frutofuranosidase/metabolismoRESUMO
(1) Background: A mouth-free interface is required for functional electrical stimulation (FES) in people with spinal cord injuries. We developed a novel system for clenching the human metacarpophalangeal (MP) joint using an earphone-type ear canal movement sensor. Experiments to control joint angle and joint stiffness were performed using the developed system. (2) Methods: The proposed FES used an equilibrium point control signal and stiffness control signal: electrical agonist-antagonist ratio and electrical agonist-antagonist sum. An angle sensor was used to acquire the joint angle, and system identification was utilized to measure joint stiffness using the external force of a robot arm. Each experiment included six and five subjects, respectively. (3) Results: While the joint angle could be controlled well by clenching with some hysteresis and delay in three subjects, it could not be controlled relatively well after hyperextension in the other subjects, which revealed a calibration problem and a change in the characteristics of the human MP joint caused by hyperextension. The joint stiffness increased with the clenching amplitude in five subjects. In addition, the results indicated that viscosity can be controlled. (4) Conclusions: The developed system can control joint angle and stiffness. In future research, we will develop a method to show that this system can control the equilibrium point and stiffness simultaneously.
Assuntos
Meato Acústico Externo , Traumatismos da Medula Espinal , Estimulação Elétrica , Humanos , Articulação Metacarpofalângica , Movimento/fisiologiaRESUMO
INTRODUCTION: According to the guidelines, the dosage for mandibular wisdom tooth extraction (MWTE) varies within the administration period. There is a 24-fold difference between the minimum and maximum doses. If an appropriate antimicrobial can be administered without increasing incidence of surgical site infection (SSI), it may lead to a global action plan on antimicrobial resistance (AMR). Therefore, we prospectively surveyed incidence of SSI post-operatively and use of oral antibiotics (OA) for MWTE. METHODS: Subjects were patients who underwent MWTE in our dental outpatient clinic from May 2019 to April 2020. Two groups were formed depending on type of administration period they received: 24 h and 48 h after surgery. The following information was collected: (1) patient factors (age, gender, body mass index, presence/absence of preoperative medication, diagnosis, impacted wisdom tooth status; (2) surgical factors (operative time, presence/absence of closure, presence/absence of hemostat, doctor career, type and frequency of painkiller); (3) relationship between administration period of OA and SSI occurrence; and (4) details of SSI. RESULTS: Three hundred forty subjects were analyzed, all of which used amoxicillin. There were 106 cases in 24 h group and 234 cases in 48 h group. The total incidence of SSI was 1.1% (4/340 cases), with 0.9% (1/106 cases) in 24 h group and 1.3% (3/234 cases) in 48 h group; there was no difference between the two groups. CONCLUSION: Our study suggests that amoxicillin (250 mg/dose every 8 h x 3 doses beginning 1 h before surgery) might be sufficient in preventing SSI in Japanese dental patients without SSI risk factors.
Assuntos
Dente Serotino , Infecção da Ferida Cirúrgica , Amoxicilina/uso terapêutico , Antibacterianos/uso terapêutico , Antibioticoprofilaxia , Humanos , Japão/epidemiologia , Dente Serotino/cirurgia , Estudos Prospectivos , Infecção da Ferida Cirúrgica/epidemiologia , Infecção da Ferida Cirúrgica/prevenção & controleRESUMO
This study used data from a large-scale multicenter medical information database in Japan to estimate the incidence rate of herpes zoster (HZ) and to examine the relationship between hypertension, dyslipidemia, and diabetes mellitus (DM), and the risk of HZ among patients with rheumatoid arthritis (RA). The research dataset consisted of 221,196 records of potential target patients with RA extracted between April 1, 2008 and August 31, 2017 from the Medical Data Vision database. To assess the association between hypertension, dyslipidemia, and DM and the risk of HZ, a case-control study was set up. Records of 101,498 study subjects met the inclusion criteria. During the observation period, 2566 patients developed HZ and the overall incidence rate was 5.2 (95% confidence interval: 5.0-5.4 per 1000 patient-years). Hypertension, dyslipidemia, and DM were significantly associated with an increased risk of HZ after adjustment for sex, age, hospital size, and use of anti-rheumatic drugs. When mutual adjustment was made for hypertension, dyslipidemia, and DM, the positive associations between hypertension and dyslipidemia and the risk of HZ remained significant; however, the positive association with DM completely disappeared. RA patients with hypertension or dyslipidemia may be at higher risk of HZ.
Assuntos
Artrite Reumatoide/epidemiologia , Herpes Zoster/epidemiologia , Hipertensão/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Causalidade , Bases de Dados Factuais , Diabetes Mellitus/epidemiologia , Dislipidemias , Feminino , Humanos , Incidência , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de RiscoRESUMO
OBJECTIVES: To evaluate the incidence of infection in patients with active rheumatoid arthritis (RA) treated with baricitinib, an oral selective Janus kinase (JAK)1 and JAK2 inhibitor. METHODS: Infections are summarised from an integrated database (8 phase 3/2/1b clinical trials and 1 long-term extension (LTE)) with data to 1 April 2017. The 'all-bari-RA' analysis set included patients who received any baricitinib dose. Placebo comparison was based on six studies with 4 mg and placebo to week 24, including four trials with 2 mg (placebo-controlled set). Dose-response assessment was based on four studies with 2 mg and 4 mg, including LTE data (2-4 mg extended set). RESULTS: There were 3492 patients who received baricitinib for 7860 patient-years (PY) of exposure (median 2.6 years, maximum 6.1 years). Treatment-emergent infections were higher for baricitinib versus placebo (exposure-adjusted incidence rate (IR)/100 PY: placebo 75.9, 2 mg 84.0 (p not significant), 4 mg 88.4 (p≤0.001)). The IR of serious infection was similar for baricitinib versus placebo and stable over time (all-bari-RA IR 3.0/100 PY). There were 11 cases of tuberculosis (all-bari-RA IR 0.1/100 PY); all occurred with 4 mg in endemic regions. Herpes zoster (HZ) IR/100 PY was higher for baricitinib versus placebo (placebo 1.0, 2 mg 3.1 (p not significant), 4 mg 4.3 (p≤0.01)); rates remained elevated and stable over time (all-bari-RA 3.3). Opportunistic infections, including multidermatomal HZ, were infrequent in the baricitinib programme (all-bari-RA IR 0.5/100 PY). CONCLUSIONS: Increased rates of treatment-emergent infections including HZ were observed in patients with RA treated with baricitinib, consistent with baricitinib's immunomodulatory mode of action.
Assuntos
Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Azetidinas/efeitos adversos , Hospedeiro Imunocomprometido , Infecções/imunologia , Sulfonamidas/efeitos adversos , Método Duplo-Cego , Humanos , Incidência , Infecções/epidemiologia , Purinas , Pirazóis , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos RetrospectivosRESUMO
BACKGROUND: Successful local therapy for oligometastases may lead to longer survival. The purpose of this multicentre retrospective study was to investigate factors affecting the local control (LC) of pulmonary oligometastases treated by stereotactic body radiotherapy (SBRT) and to investigate the impact of LC on survival. METHODS: The inclusion criteria included 1 to 5 metastases, the primary lesion and other extrathoracic metastases were controlled before SBRT, and the biological effective dose (BED10) of the SBRT was 75 Gy or more. The Cox proportional hazards model was used for analyses. RESULTS: Data of 1378 patients with 1547 tumours from 68 institutions were analysed. The median follow-up period was 24.2 months. The one-year, 3-year and 5-year LC rates were 92.1, 81.3 and 78.6%, respectively, and the 1-year, 3-year and 5-year overall survival rates were 90.1, 60.3 and 45.5%, respectively. Multivariate analysis for LC showed that increased maximum tumour diameter (p = 0.011), type A dose calculation algorithm (p = 0.005), shorter overall treatment time of SBRT (p = 0.035) and colorectal primary origin (p < 0.001 excluding oesophagus origin) were significantly associated with a lower LC rate. In the survival analysis, local failure (p < 0.001), worse performance status (1 vs. 0, p = 0.013; 2-3 vs. 0, p < 0.001), oesophageal primary origin (vs. colorectal origin, p = 0.038), squamous cell carcinoma (vs. adenocarcinoma, p = 0.006) and increased maximum tumour diameter (p < 0.001) showed significant relationships with shorter survival. CONCLUSIONS: Several factors of oligometastases and SBRT affected LC. LC of pulmonary oligometastases by SBRT showed a significant survival benefit compared to patients with local failure.
Assuntos
Neoplasias Pulmonares/secundário , Radiocirurgia/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Adulto JovemRESUMO
An enzyme belonging to glycoside hydrolase family 68 (GH68) from Beijerinckia indica subsp. indica NBRC 3744 was expressed in Escherichia coli. Biochemical characterization showed that the enzyme was identified to be a ß-fructosyltransferase (BiBftA). Crystallization of a full-length BiBftA was initially attempted, but no crystals were obtained. We constructed a variant in which 5 residues (Pro199-Gly203) and 13 residues (Leu522-Gln534) in potentially flexible regions were deleted, and we successfully crystallized this variant BiBftA. BiBftA is composed of a five-bladed ß-propeller fold as in other GH68 enzymes. The structure of BiBftA in complex with fructose unexpectedly indicated that one ß-fructofuranose (ß-Fruf) molecule and one ß-fructopyranose molecule bind to the catalytic pocket. The orientation of ß-Fruf at subsite -1 is tilted from the orientation observed in most GH68 enzymes, presenting a second structure of a GH68 enzyme in complex with the tilted binding mode of ß-Fruf.
Assuntos
Beijerinckiaceae/enzimologia , Frutose/metabolismo , Glicosídeo Hidrolases/química , Glicosídeo Hidrolases/metabolismo , Sequência de Aminoácidos , Cristalografia por Raios X , Glicosídeo Hidrolases/genética , Modelos Moleculares , Mutagênese , Conformação Proteica , Relação Estrutura-AtividadeRESUMO
Objectives: Baricitinib is a selective oral inhibitor of JAK1/JAK2 for patients with moderately-to-severely active rheumatoid arthritis (RA). Baricitinib's safety profile in Japanese patients was evaluated using six studies (five Ph2/Ph3 trials, one long-term extension study through 01 September 2016) from an integrated database (nine RA studies).Methods: Incidence rates (IRs) or exposure-adjusted IRs (EAIRs) of adverse events (AEs) per 100 patient-years (PY) were calculated using data which included RA patients exposed to any baricitinib dose.Results: Five hundred and fourteen Japanese patients received baricitinib for 851.5 total PY of exposure (median 1.7 years, maximum 3.2). The EAIR of treatment-emergent AEs was 57.4/100PY. There were no deaths; 31 patients had serious infections (IR: 3.6/100PY), 55 herpes zoster (6.5), 0 tuberculosis, 10 malignancies (1.1) including two lymphomas, two major cardiovascular AEs (0.3), one gastrointestinal perforation (0.1), and four deep vein thrombosis (0.5). In Japanese patients, herpes zoster was more frequent than that of patients overall in the integrated database, but the events were considered manageable.Conclusion: In this analysis, baricitinib had acceptable safety profile in Japanese RA patients in the context of demonstrated efficacy. Aside from herpes zoster, baricitinib safety was not notably different between Japanese RA patients and those RA patients in the integrated database.Trial registration: NCT01185353, NCT00902486, NCT01469013, NCT01710358, NCT01721044, NCT01721057, NCT01711359, and NCT01885078 at https://clinicaltrials.gov/.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Azetidinas/administração & dosagem , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Sulfonamidas/administração & dosagem , Administração Oral , Artrite Reumatoide/metabolismo , Azetidinas/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Humanos , Incidência , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Purinas , Pirazóis , Sulfonamidas/efeitos adversos , Resultado do TratamentoRESUMO
We intend to develop earphone-type wearable devices to measure occlusal force by measuring ear canal movement using an ear sensor that we developed. The proposed device can measure occlusal force during eating. In this work, we simultaneously measured the ear canal movement (ear sensor value), the surface electromyography (EMG) of the masseter muscle and the occlusal force six times from five subjects as a basic study toward occlusal force meter development. Using the results, we investigated the correlation coefficient between the ear sensor value and the occlusal force, and the partial correlation coefficient between ear sensor values. Additionally, we investigated the average of the partial correlation coefficient and the absolute value of the average for each subject. The absolute value results indicated strong correlation, with correlation coefficients exceeding 0.9514 for all subjects. The subjects showed a lowest partial correlation coefficient of 0.6161 and a highest value of 0.8286. This was also indicative of correlation. We then estimated the occlusal force via a single regression analysis for each subject. Evaluation of the proposed method via the cross-validation method indicated that the root-mean-square error when comparing actual values with estimates for the five subjects ranged from 0.0338 to 0.0969.
Assuntos
Meato Acústico Externo/fisiologia , Eletromiografia/métodos , Potenciais de Ação , Adulto , Força de Mordida , Feminino , Humanos , Masculino , Músculo Masseter/fisiologia , Movimento , Dispositivos Eletrônicos Vestíveis , Adulto JovemRESUMO
The cause of hyperpigmentation, such as solar lentigo and seborrheic keratosis, is the excessive accumulation of melanin pigments in the epidermal basal layer. Melanin pigments are synthesized in the melanosomes, which are specific organelles produced by melanocytes in the basal layer. Melanosomes containing melanin pigments are transported to the neighboring keratinocytes. However, the behavior of melanosomes after being transported to the keratinocytes has been poorly understood. In this study, we focused on a lysosomal protease cathepsin V (CTSV) to clarify the mechanism underlying melanosome degradation in the keratinocytes. Using immunohistochemical observation, we found that CTSV was highly expressed across the entire epidermis in normal skin; however, CTSV expression levels were lower in the basal layer than those in the stratum corneum side in the hyperpigmented region. Moreover, we found that melanosome degradation was suppressed in CTSV knockdown cells. These results indicated that CTSV is involved in melanosome degradation.
Assuntos
Catepsinas/metabolismo , Cisteína Endopeptidases/metabolismo , Epiderme/patologia , Queratinócitos/metabolismo , Lisossomos/metabolismo , Melanossomas/metabolismo , Linhagem Celular , Epiderme/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Humanos , Hiperpigmentação/metabolismo , Hiperpigmentação/patologia , Queratinócitos/patologia , MasculinoRESUMO
We have carried out research and development on an earphone-type respiratory rate measuring device, earable POCER. The name earable POCER is a combination of "earable", which is a word coined from "wearable" and "ear", and "POCER", which is an acronym for "point-of-care ear sensor for respiratory rate measurement". The earable POCER calculates respiratory frequency, based on the measurement values over one minute, through the simple attachment of an ear sensor to one ear of the measured subject and displays these on a tablet terminal. The earable POCER irradiates infrared light using a light-emitting diode (LED) loaded on an ear sensor to the epidermis within the ear canal and, by receiving that reflected light with a phototransistor, it measures movement of the ear canal based on respiration. In an evaluation experiment, eight healthy subjects first breathed through the nose 12 times per minute, then 16 times per minute, and finally 20 times per minute, in accordance with the flashing of a timing instruction LED. The results of these evaluation tests showed that the accuracy of the respiratory frequency was 100% for nose breathing 12 times per minute, 93.8% at 16 times, and 93.8% at 20 times.