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A frequency-dependent dielectric constant characterizes the dielectric response of a medium and also represents the time scale of system's collective dynamics. Although it is valuable not only academically but also practically for developing advanced devices, getting the value of a solution at the interface with a solid or electrode surface is challenging both experimentally and computationally. Here, we propose a computational method that imitates the dielectric spectroscopy and AC impedance measurement. It combines a time-dependent voltage applied molecular dynamics simulation with an equivalent circuit representation of a system composed of a solution confined between two identical electrodes. It gives the frequency-dependent dielectric constants of the bulk solution and the interface simultaneously. Unlike the conventional method, it does not require computation of a dipole autocorrelation function and its Fourier transformation. Application of the method on a system of water confined between polarizable Pt electrodes gives the static dielectric constant and the relaxation time of the bulk water in good agreement with previous simulation results and experimental values. In addition, it gives a much smaller static dielectric constant at the interface, consistent with previous observations. The outline of the dielectric dispersion curve of the interface seems similar to that of the bulk, but the relaxation time is several times faster.
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BACKGROUND: HER2 signaling might be involved in the regulation of immune cell activation in the tumor microenvironment (TME) of gastric cancer (GC). However, the relationship between HER2 status and immune cell condition in the HER2-positive GC TME is not clearly understood. METHODS: To investigate the effect of HER2 signaling on the activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which contributes to immune cell activation in the GC TME, we evaluated the associations among the expressions of HER2, cGAS-STING, and the number of CD8+ tumor-infiltrating lymphocytes (TIL) by considering HER2 heterogeneity in HER2-positive GC tissues. We also examined the effect of HER2 signaling on the activation of STING signaling in vitro using human HER2-positive GC cell lines. RESULTS: The expression of HER2 is highly heterogeneous in HER2-positive GC tissues, and we found that the number of CD8+ TIL in HER2 high areas was significantly lower than that in HER2 low areas in HER2-positive GC tissues. Intriguingly, the tumor cell-intrinsic expression of STING, but not cGAS, was also significantly lower in the HER2 high areas than the HER2 low areas in HER2-positive GC tissues. Moreover, in vitro experiments, we demonstrated that the blockade of HER2 signaling increased the expression of STING and its target genes, including IFNB1, CXCL9/10/11, and CCL5, in HER2-positive GC cell lines. CONCLUSIONS: Our results suggest that HER2 signaling might suppress immune cell activation in the GC TME by inhibiting STING signaling in tumor cells in HER2-positive GC.
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Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Regulación hacia Abajo , Linfocitos T CD8-positivos , Nucleotidiltransferasas/genética , Nucleotidiltransferasas/metabolismo , Interferones/genética , Interferones/metabolismo , Microambiente TumoralRESUMEN
Itching due to atopic dermatitis causes sleep disorders in children, but its pathology is unknown. The aim of this study is to investigate nocturnal scratching as an indirect index of itching during sleep and its relationship with depth of sleep in children with atopic dermatitis. Nocturnal scratching was measured in a total of 20 children with atopic dermatitis, using a smartwatch installed with the application Itch Tracker. Depth of sleep was analysed using polysomnography. The severity of atopic dermatitis was scored using Eczema Area and Severity Index (EASI) and Patient-Oriented Eczema Measure (POEM). The number and time of nocturnal scratching measured by Itch Tracker had a significantly positive correlation with EASI scores, whereas POEM scores were not correlated with EASI scores. Mean sleep efficiency was 90.0% and scratching episodes (n = 67) started mainly during the awake stage or light sleep stages. In the scratching episodes that started during sleep stages (n = 34), the sleep stage changed to a lighter one or to the awake stage in 35.5% of episodes. Itch Tracker is applicable to measure nocturnal scratching in children. Nocturnal scratching can deteriorate quality of sleep by changing the sleep stage to a lighter one or to the awake stage.
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Dermatitis Atópica , Eccema , Humanos , Niño , Dermatitis Atópica/complicaciones , Dermatitis Atópica/diagnóstico , Calidad del Sueño , Índice de Severidad de la Enfermedad , Prurito/diagnóstico , Prurito/etiología , SueñoRESUMEN
PURPOSE: Both obstructive sleep apnea (OSA) and the common cold are disorders of the upper respiratory tract, and may be associated. However, studies on the association between OSA and upper respiratory tract infections (URTI) in children are scarce. The aim of this study was to investigate possible associations between snoring, the severity of OSA, and URTI in elementary school children. METHODS: This was a cross-sectional study in a community cohort of elementary school children (first and second graders) in Japan. Information on sleep habits, history of URTI, and OSA risk was obtained from a parental questionnaire. Children underwent overnight tracheal sound recordings from which apnea-hypopnea index was estimated. Multivariable logistic analysis was employed to define the association between snoring, OSA, and URTI ≥ 3 episodes over six months. RESULTS: Of the 922 potential enrollees, 653 children and their parents (71%) agreed to participate in the study. Multivariable-adjusted ORs for URTI were 1.73 (95%CI: 1.16 to 2.59) in children who snored 1 to 4 nights per week and 2.82 (95%CI: 1.26 to 6.28) in snoring ≥ 5 nights per week compared with never snoring (reference). Likewise, subjectively reported louder snoring, as well as objectively defined louder sound levels, were significantly associated with URTI. In addition, OR for URTI in children with an estimated apnea-hypopnea index ≥ 2.0 events/hour was 2.65 (95%CI: 1.32 to 5.31) compared to children with apnea-hypopnea index less than 1.0 events/hour (reference). CONCLUSIONS: Snoring and severity of OSA as measured by nocturnal tracheal sound recordings were associated with increased susceptibility to URTI in elementary school children.
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Lung function deterioration is significantly associated with poor prognosis in patients with chronic obstructive pulmonary disease (COPD). We previously reported that CC chemokine ligand 17/thymus and activation-regulated chemokine (CCL17/TARC) could be a predictive factor of lung function decline in patients with COPD. However, the role of CCL17 in the pathogenesis of COPD is unclear. Here we examined the role of CCL17 in lung inflammation using mouse COPD models. Exposure to cigarette smoking induced CCL17 production in bronchial epithelial cells and accumulation of alveolar macrophages in the lungs. Intranasal administration of recombinant CCL17 further enhanced cigarette smoke-induced macrophage accumulation and also aggravated elastase-induced pulmonary emphysema. We confirmed that cigarette smoke (CS) extract as well as hydrogen peroxide upregulated CCL17 in BAES-2B cells. Of note, macrophages of both M1 and M2 surface markers were accumulated by cigarette smoke. Both alveolar macrophage accumulation via exposure to cigarette smoking and emphysematous changes induced by elastase administration were significantly reduced in CCL17-deficient mice. We further demonstrated that CCL17 strongly induced the expression of CC chemokine ligand 2 (CCL2), a chemoattractant for macrophages, in RAW264.7 cells, and its production was inhibited by knockdown of CCR4, the receptor of CCL17. Collectively, the present results demonstrate that CCL17 is produced by lung epithelial cells upon CS exposure. Furthermore, CCL17 is involved in CS-induced accumulation of alveolar macrophages and development of elastase-induced pulmonary emphysema, possibly through CCL17-induced production of CCL2 by macrophages. Our findings may provide a new insight into the pathogenesis of COPD.
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Enfermedad Pulmonar Obstructiva Crónica , Enfisema Pulmonar , Animales , Modelos Animales de Enfermedad , Humanos , Ligandos , Pulmón/patología , Ratones , Enfermedad Pulmonar Obstructiva Crónica/patología , Enfisema Pulmonar/metabolismoRESUMEN
The structure and electronic properties of a molecule at an electrochemical interface are changed by interactions with the electrode surface and the electrolyte solution, which can be significantly modulated by an applied voltage. We present an efficient self-consistent quantum mechanics/molecular mechanics (QM/MM) approach to study a physisorbed molecule at a metal electrode-electrolyte interface under the constant-voltage condition. The approach employs a classical polarizable double electrode model, which enables us to study the QM/MM system in the constant-voltage ensemble. A mean-field embedding approximation is further introduced in order to overcome the difficulties associated with statistical sampling of the electrolyte configurations. The results of applying the method to a test system indicate that the adsorbed molecule is no less or slightly more polarized at the interface than in the bulk electrolyte solution. The geometry of the horizontally adsorbed molecule is modulated by their electrostatic interactions with the polarizable electrode surfaces and also the interactions with cations attracted toward the interface when the adsorbate is reduced. We also demonstrate that the approach can be used to quantitatively evaluate the reorganization energy of a one electron reduction reaction of a molecule in an electrochemical cell.
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A precise understanding of the interfacial structure and dynamics is essential for the optimal design of various electrochemical devices. Herein, we propose a method for classical molecular dynamics simulations to deal with electrochemical interfaces with polarizable electrodes under the open circuit condition. Less attention has been given to electrochemical circuit conditions in computation despite being often essential for a proper assessment, especially comparison between different models. The present method is based on the chemical potential equalization principle, as is a method developed previously to deal with systems under the closed circuit condition. These two methods can be interconverted through the Legendre transformation so that the difference in the circuit conditions can be compared on the same footing. Furthermore, the electrode polarization effect can be correctly studied by comparing the present method with conventional simulations with the electrodes represented by fixed charges, since both of the methods describe systems under the open circuit condition. The method is applied to a parallel-plate capacitor composed of platinum electrodes and an aqueous electrolyte solution. The electrode polarization effects have an impact on the interfacial structure of the electrolyte solution. We found that the difference in circuit conditions significantly affects the dynamics of the electrolyte solution. The electric field at the charged electrode surface is poorly screened by the nonequilibrium solution structure in the open circuit condition, which accelerates the motion of the electrolyte solution.
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BACKGROUND: Upper extremity deep vein thrombosis (UEDVT) is relatively rare but cannot be negligible because it can cause fatal complications. Although it is reported that the occurrence rate of UEDVT has increased due to central venous catheter (CVC), cancer, and surgical invasion, there is still limited information for esophagectomy. The aim of this study was to evaluate the clinical factors, including CVC placement and thromboprophylaxis approach, as well as retrosternal space's width as a predictive factor for UEDVT in patients receiving esophagectomy. METHODS: This study included 66 patients who underwent esophagectomy with retrosternal reconstruction using a gastric tube. All patients routinely underwent contrast-enhanced computed tomography (CT) on the 4th postoperative day. Low-molecular-weight-heparin (LMWH) was routinely administered by the 2nd postoperative day. To evaluate retrosternal space's width, (a) The distance from sternum to brachiocephalic artery and (b) the distance from sternum to vertebra were measured by preoperative CT, and the ratio of (a) to (b) was defined as the width of retrosternal space. RESULTS: Among all patients, 11 (16.7%) suffered from UEDVT, and none was preoperatively received CVC placement, while 7 were inserted in non-UEDVT cases. Retrosternal space's width in patients with UEDVT was significantly smaller than that in patients without UEDVT (0.17 vs. 0.26; P < 0.0001). A cutoff value of the width was 0.21, which has high sensitivity (87%) and specificity (82%) for UEDVT prediction, respectively. CONCLUSION: The existence of CVC may not affect the development of UEDVT, but preoperative evaluation of retrosternal ratio may predict the occurrence of UEDVT.
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Trombosis Venosa Profunda de la Extremidad Superior , Tromboembolia Venosa , Anticoagulantes , Esofagectomía/efectos adversos , Heparina de Bajo-Peso-Molecular , Humanos , Incidencia , Factores de Riesgo , Extremidad Superior , Trombosis Venosa Profunda de la Extremidad Superior/tratamiento farmacológico , Trombosis Venosa Profunda de la Extremidad Superior/epidemiología , Trombosis Venosa Profunda de la Extremidad Superior/etiología , Tromboembolia Venosa/complicaciones , Tromboembolia Venosa/tratamiento farmacológicoRESUMEN
AT-rich interactive domain 1A (ARID1A), which is a tumor suppressor gene, is frequently mutated in Epstein-Barr virus-positive gastric cancer [EBV (+) GC]. While most ARID1A mutations in GC are truncating mutations, leading to loss of ARID1A protein expression, epigenetic modifications appear to contribute to ARID1A deficiency in EBV (+) GC harboring wild-type ARID1A. Based on the significant role of epigenetic modifications in EBV (+) GC that contributes to ARID1A deficiency, the methylation status of ARID1A was evaluated in EBV-infected cells and GC patients using a publicly available microarray and the Cancer Genome Atlas (TCGA) database. EBV-encoded miRNAs that potentially target ARID1A were identified as an additional epigenetic modulator by computational prediction. In vitro experiments were conducted to evaluate how EBV-encoded miRNAs affected ARID1A mRNA and protein levels. In clinical GC samples, the expression of predicted miRNAs and ARID1A and the mutation status of ARID1A was evaluated. As results, ARID1A was not hypermethylated in EBV (+) GC samples or EBV-infected GC cells. EBV infection did not alter ARID1A mRNA levels, suggesting that ARID1A protein deficiency was caused by post-transcriptional gene silencing in ARID1A-WT EBV (+) GC. Overexpression of miR-BART11-3p and miR-BART12, which were identified as miRNAs that potentially bind ARID1A, suppressed ARID1A protein expression in MKN7 and NCI-N87 cells. Highly expressed miR-BART11-3p and miR-BART12 were correlated with decreased ARID1A levels in GC tumors which did not harbor ARID1A mutations. The present findings revealed that ARID1A expression was epigenetically regulated by miR-BART11-3p and miR-BART12 in EBV (+) GC.
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Proteínas de Unión al ADN/genética , Infecciones por Virus de Epstein-Barr/genética , Herpesvirus Humano 4/genética , MicroARNs/metabolismo , Neoplasias Gástricas/genética , Factores de Transcripción/genética , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Biología Computacional , Metilación de ADN , Proteínas de Unión al ADN/deficiencia , Conjuntos de Datos como Asunto , Epigénesis Genética , Infecciones por Virus de Epstein-Barr/patología , Infecciones por Virus de Epstein-Barr/cirugía , Infecciones por Virus de Epstein-Barr/virología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/genética , Interacciones Huésped-Patógeno/genética , Humanos , Masculino , MicroARNs/agonistas , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Regiones Promotoras Genéticas/genética , Interferencia de ARN/efectos de los fármacos , Estudios Retrospectivos , Estómago/patología , Estómago/cirugía , Estómago/virología , Neoplasias Gástricas/patología , Neoplasias Gástricas/cirugía , Neoplasias Gástricas/virología , Factores de Transcripción/deficienciaRESUMEN
The aim of scaffold hopping (SH) is to find compounds consisting of different scaffolds from those in already known active compounds, giving an opportunity for unexplored regions of chemical space. We previously demonstrated the usefulness of pharmacophore graphs (PhGs) for this purpose through proof-of-concept virtual screening experiments. PhGs consist of nodes and edges corresponding to pharmacophoric features (PFs) and their topological distances. Although PhGs were effective in SH, they are hard to interpret as they are complete graphs. Herein, we introduce an intuitive representation of a molecule, termed as sparse pharmacophore graphs (SPhG) by keeping the topological distances among PFs as much as possible while reducing the number of edges in the graphs. Several benchmark calculations quantitatively confirmed the sparseness of the graphs and the preservation of topological distances among pharmacophoric points. As proof-of-concept applications, virtual screening (VS) trials for SH were conducted using active and inactive compounds from ChEMBL and PubChem databases for three biological targets: thrombin, tyrosine kinase ABL1, and κ-opioid receptor. The performances of VS were comparable with using fully connected PhGs. Furthermore, highly ranked SPhGs were interpretable for the three biological targets, in particular for thrombin, for which selected SPhGs were in agreement with the structure-based interpretation.
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Diseño de Fármacos , Receptores de DrogaRESUMEN
Chemical reaction dynamics in solution are closely related to solvation dynamics, and understanding solvent responses remains a crucial issue in chemistry and chemical biology. In this study, we experimentally and computationally investigated the solvation dynamics along different solvation coordinates of the same molecule: the electronically excited state and ground state of the p-aminophenylthiyl radical generated by the photodissociation of bis(p-aminophenyl)disulfide. Time profiles of the peak shifts from the transient absorption and emission spectra after photodissociation were extracted to discuss the solvent reorganization process in various ionic liquids (ILs) with different viscosities. The absorption peak position of the radical followed common solvation dynamics, shifting to a lower energy with time due to reorganization of the surrounding solvent molecules in response to the charge redistribution and molecular volume change caused by photodissociation. On the other hand, the emission band of the radical did not show a meaningful spectral shift with time. It was also found that the solvation time in the ground state was not strongly dependent on the solvent viscosity. These experimental results deviate from the conventional dynamic Stokes shift theory. To discuss the experimental results, non-equilibrium molecular dynamics simulations were conducted. The spectral shift obtained by MD simulations indicated the existence of a large solvation energy change and solvation dynamics around the radical after the photodissociation. On the other hand, the electronic excitation of the radical brought about a relatively smaller solvation energy change, especially at the long delay time after the photodissociation. These differences might be one of the reasons for the unique experimentally observed solvation dynamics.
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BACKGROUND: Artery-first approach pancreatoduodenectomy (AFA-PD) is an important technique for treating pancreatic ductal adenocarcinoma (PDAC). However, it remains unknown whether performing complete lymphadenectomy around the entire superior mesenteric artery (SMA) is associated with better outcomes. In this retrospective study, we aimed to investigate whether this approach improved overall and recurrence-free survival in patients with PDAC. METHODS: We identified 88 patients with T3 PDAC who underwent PD at St. Marianna University School of Medicine, Kawasaki, Japan, between April 2005 and October 2017. Two groups were defined: an "AFA-PD group" (n = 45) who had undergone AFA-PD in addition to complete lymphadenectomy around the entire SMA, and a "conventional PD group" (n = 43) in whom complete lymphadenectomy had not been performed (conventional group). Univariate and multivariate survival analyses were performed to identify risk factors for overall and disease-free survival. RESULTS: The AFA-PD group had a longer median survival time (40.3 vs. 22.6 months; p = 0.0140) and a higher 5-year survival rate (40.3% vs. 5.9%, p = 0.005) than the conventional PD group. Multivariate analysis showed that AFA-PD with complete lymphadenectomy around the entire SMA was an independent factor for improved overall survival (p = 0.022). Recurrences around the SMA were significantly less frequent in the AFA-PD group than in the conventional group (22.2% vs. 44.2%, p = 0.041). CONCLUSIONS: AFA-PD with complete lymphadenectomy around the entire SMA can prevent recurrences around the SMA and may prolong overall survival in patients with PDAC.
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Neoplasias Pancreáticas , Pancreaticoduodenectomía , Humanos , Japón/epidemiología , Escisión del Ganglio Linfático , Arteria Mesentérica Superior/cirugía , Recurrencia Local de Neoplasia , Neoplasias Pancreáticas/cirugía , Estudios RetrospectivosRESUMEN
A proper understanding and description of the electronic response of the electrode surfaces in electrochemical systems are quite important because the interactions between the electrode surface and electrolyte give rise to unique and useful interfacial properties. Atomistic modeling of the electrodes requires not only an accurate description of the electronic response under a constant-potential condition but also computational efficiency in order to deal with systems large enough to investigate the interfacial electrolyte structures. We thus develop a self-consistent-charge density functional tight binding based method to model a pair of electrodes in electrochemical cells under the constant-potential condition. The method is more efficient than the (ab initio) density functional theory calculations so that it can treat systems as large as those studied in classical atomistic simulations. It can also describe the electronic response of electrodes quantum mechanically and more accurately than the classical counterparts. The constant-potential condition is introduced through a Legendre transformation of the electronic energy with respect to the difference in the number of electrons in the two electrodes and their electrochemical potential difference, through which the Kohn-Sham equations for each electrode are variationally derived. The method is applied to platinum electrodes faced parallel to each other under an applied voltage. The electronic response to the voltage and a charged particle is compared with the result of a classical constant-potential method based on the chemical potential equalization principle.
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Recombination dynamics of geminate p-aminophenylthiyl (PAPT) radicals produced from the photodissociation of bis(p-aminophenyl) disulfide in ionic liquids (ILs) were investigated by transient absorption spectroscopy. ILs with various cationic species were used to examine the effect of viscosity and polarity on recombination dynamics. Experimentally obtained recombination yields and dynamics were found to be virtually independent of the cation species, despite the viscosity range of the solvent ILs being extensive, spanning from a few tens of mPa s to several hundred mPa s. We applied a theoretical analysis model based on the diffusion equation to the time profiles of the experimentally determined recombination yields of geminate PAPT radicals. The square well potential was incorporated into the diffusion equation to consider the concerted dynamics of solvent cage formation and recombination. A long-time asymptotic expression for the survival probability of the photodissociated products was derived and used to simulate the experimentally obtained time profile of the recombination yield. The time profiles in the range of 20-1000 ps and the final yield were successfully simulated by the asymptotic expression of the square well potential model. The optimized parameters used for the fit, including the mutual diffusion coefficient of the radical pairs, cage radius of the potential well, and well depth, were discussed in terms of the diffusion coefficient conventional theory and the potential mean force estimated from the molecular dynamics simulation for the photodissociation reaction in ILs.
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BACKGROUND: Proximal gastrectomy is a widely performed procedure that has become more common with an increasing number of proximal gastric cancer cases. Several types of reconstructive procedures after proximal gastrectomy have been developed, and it remains controversial which procedure is the most advantageous with regard to the preservation of postoperative gastric stump function and nutritional status. In the present study, we retrospectively analyzed reconstructive procedures in a consecutive case series for proximal gastrectomy, primarily focusing on postoperative body weight maintenance, nutritional status, and gastric remnant functional preservation. METHODS: We enrolled 69 patients who had undergone proximal gastrectomy for gastric cancer in our institute between 2005 and 2020. Short-term complications, preservation of gastric remnant functions, nutritional status, and post-operative weight changes were compared. RESULTS: After proximal gastrectomy, the numbers of patients who underwent direct esophago-gastrostomy, jejunal interposition, double tract reconstruction, and the double flap technique were 9, 10, 14, and 36, respectively. The patients in whom the double flap technique was performed suffered no reflux esophagitis after surgery. Prevalence of gastric residual at 12 months after surgery was lowest in the double flap technique group. Moreover, the double flap technique group had a better tendency regarding post-operative changes of serum albumin ratios. Furthermore, the post-operative body weight change ratio of the double flap technique group was smallest among all groups and was significantly better than that of the double tract group. CONCLUSIONS: The double flap technique after proximal gastrectomy was considered the most effective technique for reconstruction which leads to better bodyweight maintenance, and results in less reflux esophagitis.
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Muñón Gástrico , Laparoscopía , Neoplasias Gástricas , Gastrectomía , Humanos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/prevención & control , Estudios Retrospectivos , Neoplasias Gástricas/cirugía , Colgajos Quirúrgicos , Resultado del TratamientoRESUMEN
BACKGROUND: The deterioration of pulmonary function, such as FEV1-decline, is strongly associated with poor prognosis in patients with chronic obstructive pulmonary disease (COPD). However, few investigations shed light on useful biomarkers for predicting the decline of pulmonary function. We evaluated whether thymus and activation-regulated chemokine (TARC), a Th2 inflammation marker, could predict rapid FEV1-decline in COPD patients. METHODS: We recruited 161 patients with stable COPD and performed pulmonary function test once every six months. At the time of registration, blood tests, including serum levels of TARC were performed. We assessed the correlation between changes in parameters of pulmonary function tests and serum levels of TARC. The rapid-decline in pulmonary function was determined using 25th percentile of change in FEV1 or FEV1 percent predicted (%FEV1) per year. RESULTS: In the FEV1-rapid-decline group, the frequency of exacerbations, the degree of emphysema, and serum levels of TARC was higher than in the non-rapid-decline group. When using %FEV1 as a classifier instead of FEV1, age, the frequency of exacerbations, the degree of emphysema and serum levels of TARC in the rapid-decline group was significantly greater than those in the non-rapid-decline group. In univariate logistic regression analysis, TARC was the significant predictive factor for rapid-decline group. In multivariate analysis adjusted for emphysema, serum levels of TARC are independently significant predicting factors for the rapid-decline group. CONCLUSIONS: TARC is an independent predictive biomarker for the rapid-decline in FEV1. Measuring serum TARC levels may help the management of COPD patients by predicting the risk of FEV1 decline.
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Biomarcadores , Quimiocina CCL17/sangre , Enfermedad Pulmonar Obstructiva Crónica/sangre , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Quimiocinas/sangre , Femenino , Humanos , Mediadores de Inflamación/metabolismo , Masculino , Pronóstico , Enfermedad Pulmonar Obstructiva Crónica/etiología , Curva ROC , Pruebas de Función Respiratoria , Índice de Severidad de la Enfermedad , Células Th2/inmunología , Células Th2/metabolismoRESUMEN
The Tn antigen is the most prevalent tumor-associated carbohydrate antigen. It interacts with macrophage galactose-specific lectin(MGL)on dendric cells and macrophages, driving immune inhibitory signals. Colorectal cancer(CRC)exhibiting deficient mismatch repair(dMMR)is characterized by tumor-infiltrating lymphocytes(TILs), the expression of immune checkpoint molecules, and immune evasion. We recently reported that Tn antigen expression was associated with dMMR and that dMMR CRCs with strong Tn antigen expression demonstrated CD8+ T cell exclusion and a lack of PD-L1 expression. Our findings suggest that the immune cold subset of dMMR CRCs with strong Tn antigen may be effectively treated with immune checkpoint blockade therapy or cellular immunotherapy targeting Tn antigens.
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Neoplasias Colorrectales , Reparación de la Incompatibilidad de ADN , Antígenos de Carbohidratos Asociados a Tumores , Antígeno B7-H1 , Neoplasias Colorrectales/terapia , Humanos , Inmunoterapia , Linfocitos Infiltrantes de TumorRESUMEN
The patient was a 66-year-old male who had undergone an operation for lung cancer and solitary brain metastases. Follow- up PET-CT after 1 year detected FDG accumulation in the stomach. We performed esophagogastroscopy and found an approximately 20 mm-sized Type 2 tumor on the greater curvature of the upper stomach. A pathological diagnosis of lung adenocarcinoma metastasis in the stomach was made. Laparoscopic surgery was performed on the metastatic lesion to prevent bleeding and perforation, and resection was achieved with minimal invasion. The current development of chemotherapy, including immunotherapy, has contributed to the improved prognosis of cancer patients, including those with lung metastasis in the stomach. Considering these backgrounds, preventive surgical resection under laparoscopy may be an effective approach for improving prognosis and preventing acute life-threatening adverse events. We report this case along with a literature review.
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Laparoscopía , Neoplasias Pulmonares , Neoplasias Gástricas , Anciano , Gastrectomía , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/cirugía , Masculino , Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/cirugíaRESUMEN
Smoking is a major risk factor for chronic obstructive pulmonary disease (COPD). Smoking susceptibility is important for the onset and development of COPD. We previously reported an association between serum iron concentrations and pulmonary function in male smokers. However, the mechanism governing smoking susceptibility in relation to iron deficiency is unclear; this study aimed to elucidate this mechanism. C57BL/6 male mice were fed an iron-deficient or normal diet and then exposed to cigarette smoke. BAL, histological analysis, and pulmonary function tests were performed after cigarette smoke exposure. Human alveolar type II epithelial A549 cells were treated with an iron chelator. Subsequently, A549 cells were exposed to cigarette smoke extract. In mice exposed to cigarette smoke for 2 weeks, the concentration of alveolar macrophages in the BAL fluid recovered from iron-deficient mice was significantly higher than that in normal diet mice. IL-6 and MCP-1 (monocyte chemotactic protein 1) concentrations in the BAL fluid increased significantly from baseline in iron-deficient mice, but not in normal diet mice. In mice exposed to cigarette smoke for 8 weeks, the pathological mean linear intercepts, physiological total lung capacity, and functional residual capacity in the lungs of iron-deficient mice were significantly greater than in normal diet mice. Phosphorylation of NF-κB was enhanced in the lungs of iron-deficient mice exposed to cigarette smoke and in the iron-chelating A549 cells exposed to cigarette smoke extract. Iron deficiency exaggerated cigarette smoke-induced pulmonary inflammation, suggesting that it may accelerate COPD development.
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Enfisema/etiología , Deficiencias de Hierro , Fumar/efectos adversos , Células A549 , Animales , Líquido del Lavado Bronquioalveolar , Dieta , Suplementos Dietéticos , Modelos Animales de Enfermedad , Enfisema/sangre , Recuento de Eritrocitos , Humanos , Inflamación/sangre , Inflamación/complicaciones , Inflamación/patología , Iones , Hierro/sangre , Quelantes del Hierro/farmacología , Pulmón/patología , Masculino , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Fosforilación/efectos de los fármacosRESUMEN
The primary goal of ligand-based virtual screening is to identify active compounds consisting of a core scaffold that is not found in the current active compound pool. Scaffold hopping is the term used for this purpose. In the present study, topological representations of pharmacophore features on chemical graphs were investigated for scaffold hopping. Pharmacophore graphs (PhGs), which consist of pharmacophore features as nodes and their topological distances as edges, were used as a representation of important information on compounds being active. We investigated ranking methods for prioritizing PhGs for scaffold hopping. The proposed method, NScaffold, which ranks PhGs based on the number of scaffolds covered by the PhGs, outperforms other conventional methods. As a demonstrative case, using a thrombin inhibitor data set, we interpreted the highest-ranked PhGs by NScaffold from the protein-ligand interaction point of view. It resulted that the NScaffold method successfully retrieved three known important interactions, showing the potential for identifying scaffold-hopped compounds with interpretable PhGs.