Search

Background: Coronavirus disease 2019 (COVID-19) pneumonia can have prolonged sequelae and lead to respiratory dysfunction, mainly because of impaired diffusion capacity for carbon monoxide (DLCO). The clinical factors associated with DLCO impairment, including blood biochemistry test parameters, remain unclear. Methods: Patients with COVID-19 pneumonia who underwent inpatient treatment between April 2020 and August 2021 were included in this study. A pulmonary function test was performed 3 months after onset, and the sequelae symptoms were investigated. Clinical factors, including blood test parameters and abnormal chest shadows on computed tomography, of COVID-19 pneumonia associated with DLCO impairment were investigated. Results: In total, 54 recovered patients participated in this study. Twenty-six patients (48%) and 12 patients (22%) had sequelae symptoms 2 and 3 months after, respectively. The main sequelae symptoms at 3 months were dyspnea and general malaise. Pulmonary function tests showed that 13 patients (24%) had both DLCO <80% predicted value (pred) and DLCO/alveolar volume (VA) <80% pred, and appeared to have DLCO impairment not attributable to an abnormal lung volume. Clinical factors associated with impaired DLCO were investigated in multivariable regression analysis. Ferritin level of >686.5 ng/mL (odds ratio: 11.08, 95% confidence interval [CI]: 1.84–66.59; p = 0.009) was most strongly associated with DLCO impairment. Conclusions: Decreased DLCO was the most common respiratory function impairment, and ferritin level was a significantly associated clinical factor. Serum ferritin level could be used as a predictor of DLCO impairment in cases of COVID-19 pneumonia. [ABSTRACT FROM AUTHOR]

Objectives: Semi-quantitative CT score is generally used for evaluating the disease status of Mycobacterium abscessus (Mab) Pulmonary disease (Mab-PD). However, its accuracy and clinical usefulness are limited, since the CT score is largely affected by coexisting lung disease. Hence, we hypothesized that numerical change in CT score during the observation period may be useful for evaluating disease activity of Mab-PD. Methods: Patients diagnosed with Mab-PD based on the official ATS/ERS/ESCMID/IDSA statement at Jikei University Hospital and Jikei Daisan Hospital between 2015 January 1 and 2021 July 31 were included (n = 32). We reviewed the medical records, and bacteriological and laboratory data of the patients. Chest CT was performed at diagnosis in all 32 cases. In 18 cases, chest CT images within 4 years before diagnosis were available. The numerical change in CT score between two time points was calculated and the association of the CT scores with sputum Gaffky score and serum CRP was examined. Results: CT score at diagnosis was not correlated with sputum Gaffky score nor serum CRP, while the difference of absolute value and change rate in CT score between at diagnosis and immediate past CT were well correlated with both sputum Gaffky score and serum CRP. Conclusions: Chronological change in CT score may more precisely reflect the disease activity of airway mycobacterial burden and systemic inflammation in Mab-PD at the timing of diagnosis. [ABSTRACT FROM AUTHOR]

Mastication interventions have previously been shown to alleviate acute stress. However, the relationship between masticatory performance and stress response among individuals remains unclear. This study aimed to examine the relationship between masticatory ability and stress response in young women by measuring the autonomic nerve function and salivary α-amylase activity during psychosocial stress. Eighty women (aged 20.0 ± 1.9 years) were divided into either a low or high masticatory performance group, and the Trier Social Stress Test was conducted. Moreover, the autonomic function was measured at rest, immediately before stress, immediately after stress, and 10 min after stress. The salivary α-amylase activity was also measured at rest, 5 min after stress, and 15 min after stress. The visual analog scale (VAS) was used for subjective stress evaluation. There was a significant increase in the autonomic balance of both groups immediately before stress loading, but whilst the high masticatory ability group showed a return to resting-state levels after stress loading, the low masticatory ability group showed elevated levels after stress loading. Salivary α-amylase activity significantly increased 5 min after stress loading in the low, but not high, masticatory ability group. Furthermore, the VAS scores for tension and confusion after stress were significantly higher in the low masticatory ability group than in the high masticatory ability group. Our findings suggest that high masticatory performance may contribute to alleviating psychosocial stress. This is the first study to clarify the relationship between habitual masticatory performance and psychosocial stress suppression in young women. [ABSTRACT FROM AUTHOR]

Waning humoral immunity after mRNA vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a significant problem for public health. Breakthrough infection in hospitals over several months after vaccination has not been fully characterized, especially against the delta (B.1.617.2) variant. Here, we describe an outbreak in our hospital in September of 2021, mainly through serological evaluation of the breakthrough infection. This retrospective observational study was done at an emergency and acute care hospital with 204 beds and 486 staff members where most staff members (92.6%) had had their second BNT162b2 vaccination by May of 2021. The peri-infection anti-spike RBD protein IgG (anti-S IgG) titers (lowest values between 11 days before and 7 days after onset or diagnosis) of serum samples from the breakthrough-infected persons were quantified. We also logarithmically estimated the anti-S IgG titers during the exposure period in September of uninfected staff members from their samples collected in May and December 2021. Whole-genome sequencing was done on obtained samples. In this outbreak, twelve persons (ten inpatients and two staff members) were diagnosed with SARS-CoV-2 infection by Loop-Mediated Isothermal Amplification (LAMP) or RT-PCR, eight of whom had been vaccinated twice. Peri-infection anti-S IgG titers could be determined in seven of the eight breakthrough cases, with a geometric mean titer (GMT) of 1,034 AU/ml (95% confidence interval [CI], 398 to 2,686). Among 289 uninfected staff members with data from the two sampling points, the GMT of the estimated anti-S IgG titers during the exposure period in 51 staff members, who were working at the outbreak ward and potentially exposed but uninfected, and 238 other unexposed staff members were 1,458 AU/ml (95% CI, 1,196 to 1,777) and 1,628 AU/ml (95% CI, 1,500 to 1,766), respectively. All viruses from the eight samples for which whole-genome sequencing was available were identified as delta variants. Of the infected persons, one remained asymptomatic throughout the course of treatment, and eleven had an illness of mild to moderate severity, including ten who received monoclonal antibody cocktail (Casirivimab/imdevimab) therapy. Measurement and estimation of anti-spike antibody levels after SARS-CoV-2 vaccination would be helpful for evaluating the risk of breakthrough infection and for determining the necessity of booster vaccination. [ABSTRACT FROM AUTHOR]

The population dynamics of mosquitoes in temperate regions are not as well understood as those in tropical and subtropical regions, despite concerns that vector-borne diseases may be prevalent in future climates. Aedes albopictus, a vector mosquito in temperate regions, undergoes egg diapause while overwintering. To assess the prevalence of mosquito-borne diseases in the future, this study aimed to simulate and predict mosquito population dynamics under estimated future climatic conditions. In this study, we tailored the physiology-based climate-driven mosquito population (PCMP) model for temperate mosquitoes to incorporate egg diapauses for overwintering. We also investigated how the incorporation of the effect of rainfall on larval carrying capacity (into a model) changes the population dynamics of this species under future climate conditions. The PCMP model was constructed to simulate mosquito population dynamics, and the parameters of egg diapause and rainfall effects were estimated for each model to fit the observed data in Tokyo. We applied the global climate model data to the PCMP model and observed an increase in the mosquito population under future climate conditions. By applying the PCMP models (with or without the rainfall effect on the carrying capacity of the A. albopictus), our projections indicated that mosquito population dynamics in the future could experience changes in the patterns of their active season and population abundance. According to our results, the peak population number simulated using the highest CO2 emission scenario, while incorporating the rainfall effect on the carrying capacity, was approximately 1.35 times larger than that predicted using the model that did not consider the rainfall effect. This implies that the inclusion of rainfall effects on mosquito population dynamics has a major impact on the risk assessments of mosquito-borne diseases in the future. [ABSTRACT FROM AUTHOR]

Objectives: Recently, incidence of Mycobacterium abscessus (Mab) pulmonary disease (Mab-PD) is increasing worldwide. We aimed to identify factors associated with severity of Mycobacterium abscessus (Mab) pulmonary disease (Mab-PD). Methods: All patients diagnosed as Mab-PD based on the official ATS/IDSA statement between 2017 January 1 and 2021 July 31 were included (n = 13). We reviewed medical records, bacteriological and laboratory data of the patients. Severity of lung lesions and esophageal diameters in chest CT were quantitatively evaluated. Gaffky score in the sputum was used as airway mycobacterial burden. We explored the factors associated with high CT score and high Gaffky score. Results: Maximum diameter of esophagus (MDE) in severe disease (CT score≧10) was greater than that in milder disease (CT score<10) (18.0±7.9mm, 9.3±3.1mm, respectively, p = 0.01), and MDE was well correlated with CT score (R = 0.69, p = 0.007). MDE in high mycobacterial burden group (Gaffky score ≧5) tended to be greater than that in low mycobacterial burden group (Gaffky score <5) (16.1±6.8mm, 10.1±5.5mm, respectively, p = 0.12), and MDE was well correlated with Gaffky score (R = 0.68, p = 0.009). Lung lesions were bilateral and predominant in middle or lower lobes. Conclusions: Esophageal dilatation was correlated with severity of Mab-PD and airway mycobacterial burden. Gastroesophageal reflux might be associated with Mab disease progression. [ABSTRACT FROM AUTHOR]

Triglyceride-rich lipoproteins (TRLs) are circulating reservoirs of fatty acids used as vital energy sources for peripheral tissues. Lipoprotein lipase (LPL) is a predominant enzyme mediating triglyceride (TG) lipolysis and TRL clearance to provide fatty acids to tissues in animals. Physiological and human genetic evidence support a primary role for LPL in hydrolyzing TRL TGs. We hypothesized that endothelial lipase (EL), another extracellular lipase that primarily hydrolyzes lipoprotein phospholipids may also contribute to TRL metabolism. To explore this, we studied the impact of genetic EL loss-of-function on TRL metabolism in humans and mice. Humans carrying a loss-of-function missense variant in LIPG, p.Asn396Ser (rs77960347), demonstrated elevated plasma TGs and elevated phospholipids in TRLs, among other lipoprotein classes. Mice with germline EL deficiency challenged with excess dietary TG through refeeding or a high-fat diet exhibited elevated TGs, delayed dietary TRL clearance, and impaired TRL TG lipolysis in vivo that was rescued by EL reconstitution in the liver. Lipidomic analyses of postprandial plasma from high-fat fed Lipg-/- mice demonstrated accumulation of phospholipids and TGs harboring long-chain polyunsaturated fatty acids (PUFAs), known substrates for EL lipolysis. In vitro and in vivo, EL and LPL together promoted greater TG lipolysis than either extracellular lipase alone. Our data positions EL as a key collaborator of LPL to mediate efficient lipolysis of TRLs in humans and mice. Author summary: Endothelial lipase (EL) plays a pivotal role in the breakdown of high-density lipoproteins (HDLs) by hydrolyzing phospholipids on HDL surfaces. Here we show through studies of humans and mice with genetic loss-of-function of EL activity that EL is also crucial in catabolizing triglyceride (TG)-rich lipoproteins, particularly in states of nutrient excess such as after refeeding or after feeding a high-fat diet. We demonstrate that EL collaborates with lipoprotein lipase (LPL), the predominant enzyme hydrolysing triglycerides, to promote the breakdown of triglycerides on lipoproteins. The mechanism for this may be due to an underappreciated ability of EL to hydrolyze TGs and cooperate with LPL to efficiently break down and clear these particles. Our data adds important insights into the mechanisms of circulating TG metabolism in mice and humans as informed by large-scale human genetics. [ABSTRACT FROM AUTHOR]

Meflin (Islr) expression has gained attention as a marker for mesenchymal stem cells, but its function remains largely unexplored. Here, we report the generation of Meflin-CreERT2 mice with CreERT2 inserted under the Meflin gene promoter to label Meflin-expressing cells genetically, thereby enabling their lineages to be traced. We found that in adult mice, Meflin-expressing lineage cells were present in adipose tissue stroma and had differentiated into mature adipocytes. These cells constituted Crown-like structures in the adipose tissue of mice after high-fat diet loading. Cold stimulation led to the differentiation of Meflin-expressing lineage cells into beige adipocytes. Thus, the Meflin-CreERT2 mouse line is a useful new tool for visualizing and tracking the lineage of Meflin-expressing cells. [ABSTRACT FROM AUTHOR]

Objectives: Anti-IL-17/23 biologics are increasingly used to treat psoriasis. We aimed to elucidate characteristics of drug-induced interstitial pneumonia (DIIP) caused by anti-IL-17/23 biologics. Methods: We retrospectively analyzed the clinical data of psoriasis patients treated with anti-IL-17/23 biologics. Chest CT was performed to evaluate DIIP. Serum KL-6 levels were measured before treatment (baseline) and during treatment. Results: A total of 603 psoriasis patients were treated with anti-IL-17/23 biologics with mean follow-up of 21.1 months. Six patients developed DIIP at mean 14 months after initiation of the therapy. Older age, higher baseline KL-6 value and more frequent pre-existing IPs were associated with development of DIIP by univariate analysis. At the onset of DIIP, elevated serum KL-6 levels with concomitantly increased ground glass opacity (GGO) in Chest CT were demonstrated. DIIP was improved by only cessation of causative agents in five patients but steroid therapy was needed in one patient. Conclusions: DIIP is a plausible complication of anti-IL-17/23 biologics. Age, baseline KL-6 level and underlying IP could be the risk factors for DIIP development. Serum KL-6 levels and chest CT are useful for not only predicting but also detecting DIIP caused by anti-IL-17/23 biologics. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a lethal disease characterized by a progressive increase in pulmonary artery pressure due to an increase in vessel tone and occlusion of vessels. The endogenous vasodilator prostacyclin and its analogs are used as therapeutic agents for PAH. However, their pharmacological effects on occlusive vascular remodeling have not been elucidated yet. Selexipag is a recently approved, orally available and selective prostacyclin receptor agonist with a non-prostanoid structure. In this study, we investigated the pharmacological effects of selexipag on the pathology of chronic severe PAH in Sprague-Dawley and Fischer rat models in which PAH was induced by a combination of injection with the vascular endothelial growth factor receptor antagonist Sugen 5416 and exposure to hypoxia (SuHx). Oral administration of selexipag for three weeks significantly improved right ventricular systolic pressure and right ventricular (RV) hypertrophy in Sprague-Dawley SuHx rats. Selexipag attenuated the proportion of lung vessels with occlusive lesions and the medial wall thickness of lung arteries, corresponding to decreased numbers of Ki-67-positive cells and a reduced expression of collagen type 1 in remodeled vessels. Administration of selexipag to Fischer rats with SuHx-induced PAH reduced RV hypertrophy and mortality caused by RV failure. These effects were probably based on the potent prostacyclin receptor agonistic effect of selexipag on pulmonary vessels. Selexipag has been approved and is used in the clinical treatment of PAH worldwide. It is thought that these beneficial effects of prostacyclin receptor agonists on multiple aspects of PAH pathology contribute to the clinical outcomes in patients with PAH. [ABSTRACT FROM AUTHOR]

The preoperative endocrine prognostic index (PEPI) predicts survival after neoadjuvant endocrine therapy (NAE) using aromatase inhibitors (AIs) for women with postmenopausal estrogen receptor (ER)-positive breast cancer irrespective of the human epidermal growth factor receptor 2 (HER2) status. Although the progesterone receptor (PgR) is also a prognostic factor for ER-positive breast cancer, the PgR status was not considered a prognostic factor in the original PEPI scoring system. In this study, we investigated the utility of a modified PEPI including the PgR status (PEPI-P) as a prognostic factor after NAE for postmenopausal patients with ER-positive and HER2-negative breast cancer. We enrolled 107 patients with invasive ER-positive and HER2-negative breast cancer treated with exemestane for ≥4 months as NAE. We initially assessed PEPI and compared survival between the groups. Additionally, we obtained an effective cutoff for PgR through survival analysis. Then, we assessed the survival significance of PEPI-P. A PgR staining rate of 50% was the most significant cutoff for predicting recurrence-free survival (RFS) and cancer-specific survival (CSS). PEPI was a significant prognostic factor; moreover, PEPI-P was the most significant prognostic indicator for RFS and CSS. PEPI-P is a potent prognostic indicator of survival after NAE using AIs for postmenopausal patients with ER-positive and HER2-negative breast cancer. This modified PEPI may be useful for therapeutic decision-making regarding postmenopausal ER-positive and HER2-negative breast cancer after NAE. [ABSTRACT FROM AUTHOR]

In a surgical operation requiring endoscopy, it is essential to obtain a clear endoscopic view. However, it is often disturbed by the contamination on the lens during the surgery. No device can clean the lens surface simply and completely. Many surgeons are hampered by the impaired view and the distraction by the repeated cleaning of the lens. Therefore, we developed a novel endoscope cleaning device to address this problem. The device was made of 3D-printed rubber-like plastic. It contains a syringe filled with saline and an aspiration system. It would be used intraoperatively to wash the lens surface in a few seconds with rapid flow of water and air. The cleaning ability of the device was evaluated using mayonnaise with adenosine triphosphate (ATP) as a model contaminant. The gauze-wiping maneuver was selected as control. After each maneuver, the clarity of the endoscopic view was evaluated, and residual contaminants were assessed quantitatively with ATP assay. The cleaning device obtained a crisp and clear view and eliminated the contaminant on the lens every time after a single cleaning maneuver. The gauze-wiping maneuver required for the lens to be wiped at least three times to obtain a clear view, and even then, some contaminants remained. Repeated contamination and cleaning using gauze led to accumulation of contaminants on the lens, which resulted in difficulty in cleaning the lens as the operation proceeded. The cleaning device did not show such accumulation. Our novel cleaning device with air and water flow has been shown to wash out the lens contaminants completely and immediately in a simple manner. It is expected to improve the safety and cost-effectiveness of endoscopic surgery. [ABSTRACT FROM AUTHOR]

Background: Hoarding disorder (HD) is a disease concept newly presented in DSM-5. As far as we know, no studies have examined the structural changes relevant to hoarding by applying the diagnostic criteria of HD in DSM-5. In the present study, we aimed to find abnormalities in gray matter (GM) structures of patients with HD. Methods: Seventeen patients who met the DSM-5 criteria for HD, 17 obsessive-compulsive disorder (OCD) patients, and 17 healthy controls (HCs) participated in this study. All participants underwent MRI scanning of the brain by a 3.0-Tesla MRI scanner. In a voxel-based morphometric procedure, preprocessed GM structural images were used to compare the three groups. Thereafter we investigated the correlation between the clinical data (age of onset, symptomatic severity) and GM volume. Results: The HD group showed a significantly increased GM volume compared to the OCD and healthy control groups (p<0.05) in both Brodmann area (BA)10 and BA11. There was no significant difference between OCD and healthy control groups. No significant correlation between the clinical data including age of onset, symptom severity score, and GM volume was observed in HD and OCD groups. Conclusions: The results might help to explain the inconsistency of previous studies. As with OCD, HD is considered to have cognitive dysfunction as its basis. This result is convincing after considering the clinical features of HD and suggested that structural abnormalities in the prefrontal regions might relate to the pathophysiology of HD. [ABSTRACT FROM AUTHOR]

Hyperoxic lung injury is pathologically characterized by alveolar edema, interlobular septal edema, hyaline membrane disease, lung inflammation, and alveolar hemorrhage. Although the precise mechanism by which hyperoxia causes lung injury is not well defined, oxidative stress, epithelial cell death, and proinflammatory cytokines are thought to be involved. Probucol—a commercially available drug for treating hypercholesterolemia—has been suggested to have antioxidant and antiapoptotic effects. This study aimed to assess whether probucol could attenuate hyperoxic lung injury in mice. Mice were exposed to 95% O2 for 72 h, with or without pre-treatment with 130 μg/kg probucol intratracheally. Probucol treatment significantly decreased both the number of inflammatory cells in the bronchoalveolar lavage fluid and the degree of lung injury in hyperoxia-exposed mice. Probucol treatment reduced the number of cells positive for 8-hydroxyl-2′-deoxyguanosine or terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and suppressed NF-κB activation, Bax expression, and caspase-9 activation in lung tissues from hyperoxia-exposed mice. These results suggest that probucol can reduce oxidative DNA damage, apoptotic cell death, and inflammation in lung tissues. Intratracheal administration of probucol may be a novel treatment for lung diseases induced by oxidative stress, such as hyperoxic lung injury and acute respiratory distress syndrome. [ABSTRACT FROM AUTHOR]

To specify critical factors responsible for Pseudomonas aeruginosa penetration through the Caco-2 cell epithelial barrier, we analyzed transposon insertion mutants that demonstrated a dramatic reduction in penetration activity relative to P. aeruginosa PAO1 strain. From these strains, mutations could be grouped into five classes, specifically flagellin-associated genes, pili-associated genes, heat-shock protein genes, genes related to the glycolytic pathway, and biosynthesis-related genes. Of these mutants, we here focused on the serA mutant, as the association between this gene and penetration activity is yet unknown. Inactivation of the serA gene caused significant repression of bacterial penetration through Caco-2 cell monolayers with decreased swimming and swarming motilities, bacterial adherence, and fly mortality rate, as well as repression of ExoS secretion; however, twitching motility was not affected. Furthermore, L-serine, which is known to inhibit the D-3-phosphoglycerate dehydrogenase activity of the SerA protein, caused significant reductions in penetration through Caco-2 cell monolayers, swarming and swimming motilities, bacterial adherence to Caco-2 cells, and virulence in flies in the wild-type P. aeruginosa PAO1 strain. Together, these results suggest that serA is associated with bacterial motility and adherence, which are mediated by flagella that play a key role in the penetration of P. aeruginosa through Caco-2 cell monolayers. Oral administration of L-serine to compromised hosts might have the potential to interfere with bacterial translocation and prevent septicemia caused by P. aeruginosa through inhibition of serA function. [ABSTRACT FROM AUTHOR]

Background: Patients with idiopathic interstitial pneumonias sometimes have a few features of connective tissue disease (CTD) and yet do not fulfil the diagnostic criteria for any specific CTD. Objective: This study was conducted to elucidate the characteristics, prognosis, and disease behavior in patients with interstitial lung disease (ILD) associated with systemic sclerosis (SSc)-related autoantibodies. Methods: We retrospectively analyzed medical records of 72 ILD patients: 40 patients with SSc (SSc-ILD) and 32 patients with SSc-related autoantibody-positive ILD but not with CTD (ScAb-ILD), indicating lung-dominant CTD with SSc-related autoantibody. Results: Patients with SSc-ILD were predominantly females and non-smokers, and most had nonspecific interstitial pneumonia confirmed by high-resolution computed tomography (HRCT) and pathological analysis. However, about half of the patients with ScAb-ILD were male and current or ex-smokers. On HRCT analysis, honeycombing was more predominant in patients with ScAb-ILD than with SSc-ILD. Pathological analysis showed the severity of vascular intimal or medial thickening in the SSc-ILD patients to be significantly higher than that in the ScAb-ILD patients. Survival curves showed that the patients with ScAb-ILD had a significantly poorer outcome than those with SSc-ILD. Conclusion: Data from this study suggest that lung-dominant CTD with SSc-related autoantibody is a different disease entity from SSc-ILD. [ABSTRACT FROM AUTHOR]

The sound produced by a dental air turbine handpiece (dental drill) can markedly influence the sound environment in a dental clinic. Indeed, many patients report that the sound of a dental drill elicits an unpleasant feeling. Although several manufacturers have attempted to reduce the sound pressure levels produced by dental drills during idling based on ISO 14457, the sound emitted by such drills under active drilling conditions may negatively influence the dental clinic sound environment. The physical metrics related to the unpleasant impressions associated with dental drill sounds have not been determined. In the present study, psychological measurements of dental drill sounds were conducted with the aim of facilitating improvement of the sound environment at dental clinics. Specifically, we examined the impressions elicited by the sounds of 12 types of dental drills in idling and drilling conditions using a semantic differential. The analysis revealed that the impressions of dental drill sounds varied considerably between idling and drilling conditions and among the examined drills. This finding suggests that measuring the sound of a dental drill in idling conditions alone may be insufficient for evaluating the effects of the sound. We related the results of the psychological evaluations to those of measurements of the physical metrics of equivalent continuous A-weighted sound pressure levels (LAeq) and sharpness. Factor analysis indicated that impressions of the dental drill sounds consisted of two factors: “metallic and unpleasant” and “powerful”. LAeq had a strong relationship with “powerful impression”, calculated sharpness was positively related to “metallic impression”, and “unpleasant impression” was predicted by the combination of both LAeq and calculated sharpness. The present analyses indicate that, in addition to a reduction in sound pressure level, refining the frequency components of dental drill sounds is important for creating a comfortable sound environment in dental clinics. [ABSTRACT FROM AUTHOR]

One standard treatment option for advanced-stage cancer is surgical resection of malignant tumors following by adjuvant chemotherapy and chemoradiotherapy. Additionally, neoadjuvant chemotherapy may be applied if required. During the time course of treatments, patients are generally followed by computed tomography (CT) surveillance, and by tumor marker diagnosis. However, currently, early evidence of recurrence and/or metastasis of tumors with a clinically relevant biomarker remains a major therapeutic challenge. In particular, there has been no validated biomarker for predicting treatment outcomes in therapeutic settings. Recently, we have looked at glycoforms of serum α1-acid glycoprotein (AGP) by using a crossed affinoimmunoelectrophoresis with two lectins and an anti-AGP antibody. The primary glycan structures of AGP were also analyzed by a mass spectrometer and a novel software in a large number of patients with various cancers. Accordingly, the relative abundance of α1,3fucosylated glycans in AGP (FUCAGP) was found to be significantly high in cancer patients as compared with the healthy controls. Further, strikingly elevated levels of FUCAGP were found in patients with poor prognosis but not in patients with good prognosis. In the current study, levels of FUCAGP in serum samples from various cancer patients were analyzed and 17 patients including 13 who had undergone chemotherapy were followed for several years post operation. FUCAGP level determined diligently by using a mass spectrometer was found to change along with disease prognosis as well as with responses to treatments, in particular, to various chemotherapies. Therefore, FUCAGP levels measured during following-up of the patients after operation appeared to be clinically relevant biomarker of treatment intervention. [ABSTRACT FROM AUTHOR]

Objective: Enhancing immunologic responses, including human leukocyte antigen (HLA) class I expression on tumor cells and recognition and elimination of tumor cells by tumor-specific cytotoxic T lymphocyte (CTL), is considered a novel concept of radiotherapy. The present study examined patients who underwent preoperative hyperthermo-chemoradiotherapy (HCRT) for locally advanced rectal cancer to assess the correlation between HLA class I expression and clinical outcome. Materials and Methods: Seventy-eight patients with locally advanced rectal adenocarcinoma who received preoperative HCRT were enrolled. The median age of the patients was 64 years (range, 33–85 years) and 4, 18, and 56 patients had clinical stage I, II and III disease, respectively. Formalin-fixed and paraffin-embedded tissues excised before and after HCRT were subjected to immunohistochemical analysis with an anti-HLA class I-A, B, C antibody. HLA class I expression was graded according to tumor cell positivity. Results: In pre-HCRT, the number of specimens categorized as Grade 0 and 1 were 19 (24%) and 58 (74%), respectively. Only 1 patient (1%) showed Grade 2 expression. However, 6 (8%), 27 (35%), 7 (9%), and 12 (15%) post-HCRT specimens were graded as Grade 0, 1, 2, and 3, respectively. There was a significant increase in HLA class I expression in post-HCRT specimens (p<0.01). However, neither pre- nor post-HCRT HLA class I expression affected overall survival and distant metastasis-free survival in clinical stage III patients. Univariate analysis revealed that Post-HCRT HLA class I expression showed a significant negative relationship with LC (p<0.05). Nevertheless, multivariate analysis showed that there was no correlation between HLA class I expression and clinical outcome. Conclusion: HCRT increased HLA class I expression in rectal cancer patients. However, multivariate analysis failed to show any correlation between the level of HLA class I expression and prognosis. [ABSTRACT FROM AUTHOR]

Leber’s Hereditary Optic Neuropathy (LHON) is one of the commonest mitochondrial diseases. It causes total blindness, and predominantly affects young males. For the disease to develop, it is necessary for an individual to carry one of the primary mtDNA mutations 11778G>A, 14484T>C or 3460G>A. However these mutations are not sufficient to cause disease, and they do not explain the characteristic features of LHON such as the higher prevalence in males, incomplete penetrance, and relatively later age of onset. In order to explore the roles of nuclear encoded mitochondrial proteins in development of LHON, we applied a proteomic approach to samples from affected and unaffected individuals from 3 pedigrees and from 5 unrelated controls. Two-dimensional electrophoresis followed by MS/MS analysis in the mitochondrial lysate identified 17 proteins which were differentially expressed between LHON cases and unrelated controls, and 24 proteins which were differentially expressed between unaffected relatives and unrelated controls. The proteomic data were successfully validated by western blot analysis of 3 selected proteins. All of the proteins identified in the study were mitochondrial proteins and most of them were down regulated in 11778G>A mutant fibroblasts. These proteins included: subunits of OXPHOS enzyme complexes, proteins involved in intermediary metabolic processes, nucleoid related proteins, chaperones, cristae remodelling proteins and an anti-oxidant enzyme. The protein profiles of both the affected and unaffected 11778G>A carriers shared many features which differed from those of unrelated control group, revealing similar proteomic responses to 11778G>A mutation in both affected and unaffected individuals. Differentially expressed proteins revealed two broad groups: a cluster of bioenergetic pathway proteins and a cluster involved in protein quality control system. Defects in these systems are likely to impede the function of retinal ganglion cells, and may lead to the development of LHON in synergy with the primary mtDNA mutation. [ABSTRACT FROM AUTHOR]

Tumors formed by a highly metastatic human lung cancer cell line are characterized by activated signaling via vascular endothelial growth factor (VEGF)-C through its receptor (VEGFR-3) and aggressive lymph node metastasis. In this study, we examined how these highly metastatic cancers acquired aggressive lymph node metastasis. Compared with their lower metastatic counterparts, the highly metastatic tumors formed by this cell line expressed higher amounts of interleukin (IL)-1α, with similarly augmented expression of IL-1α and IL-1β by tumor stromal cells and of VEGF-A and VEGF-C by tumor-associated macrophages. These tumor-associated macrophages were mainly of the M2 type. Administration of a macrophage-targeting drug suppressed the production of these potent angiogenic and lymphangiogenic factors, resulting in decreased tumor growth, angiogenesis, lymphangiogenesis, and lymph node metastasis. In Matrigel plug assays, the highly metastatic cells formed tumors that were extensively infiltrated by M2-type macrophages and exhibited enhanced angiogenesis and lymphangiogenesis. All of these responses were suppressed by the IL-1 receptor (IL-1R) antagonist anakinra. Thus, the IL-1α-driven inflammatory activation of angiogenesis and lymphangiogenesis seems to provide a highly metastatic tumor microenvironment favorable for lymph node metastasis through cross-talk with macrophages. Accordingly, the IL-1R/M2-type macrophage axis may be a good therapeutic target for patients with this form of lung cancer. [ABSTRACT FROM AUTHOR]

Blood group-related glycans determining ABO and Lewis blood groups are known to function as attachment factors for most of the norovirus (NoV) strains. To identify binding specificity of each NoV, recombinant norovirus-like particles (VLPs) and human saliva samples with different ABO, Lewis phenotypes and secretor status have been commonly applied. When binding specificities of VLPs prepared from 16 different genotypes of NoVs in GI and GII genogroups were characterized in samples of human gastric mucosa compared to human saliva based on blood group phenotypes, considerable differences were observed for several strains. Novel binding specificities determined by an ELISA using preparations from human gastric mucosa were also ascertained by immunohistochemical analyses using human jejunal mucosa, widely believed to be susceptible to NoV infection. Further, A, B and O(H) blood group substances prepared from porcine and squid tissues were found to be effective for preventing ABO blood group-specific binding of VLPs to both saliva and mucosa samples. Therefore, these blood group substances might have potential for the prevention and treatment of NoV infection. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) play key roles in regulation of cellular processes in response to changes in environment. In this study, we examined alterations in miRNA profiles in peripheral blood from 25 male medical students two months and two days before the National Examination for Medical Practitioners. Blood obtained one month after the examination were used as baseline controls. Levels of seven miRNAs (miR-16, -20b, -26b, -29a, -126, -144 and -144*) were significantly elevated during the pre-examination period in association with significant down-regulation of their target mRNAs (WNT4, CCM2, MAK, and FGFR1 mRNAs) two days before the examination. State anxiety assessed two months before the examination was positively and negatively correlated with miR-16 and its target WNT4 mRNA levels, respectively. Fold changes in miR-16 levels from two days before to one month after the examination were inversely correlated with those in WNT4 mRNA levels over the same time points. We also confirmed the interaction between miR-16 and WNT4 3′UTR in HEK293T cells overexpressing FLAG-tagged WNT4 3′UTR and miR-16. Thus, a distinct group of miRNAs in periheral blood may participate in the integrated response to chronic academic stress in healthy young men. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease caused by selective loss of motor neurons. In the ALS motor neurons, TAR DNA-binding protein of 43 kDa (TDP-43) is dislocated from the nucleus to cytoplasm and forms inclusions, suggesting that loss of a nuclear function of TDP-43 may underlie the pathogenesis of ALS. TDP-43 functions in RNA metabolism include regulation of transcription, mRNA stability, and alternative splicing of pre-mRNA. However, a function of TDP-43 in tissue affected with ALS has not been elucidated. We sought to identify the molecular indicators reflecting on a TDP- 43 function. Using exon array analysis, we observed a remarkable alteration of splicing in the polymerase delta interacting protein 3 (POLDIP3) as a result of the depletion of TDP-43 expression in two types of cultured cells. In the cells treated with TDP-43 siRNA, wild-type POLDIP3 (variant-1) decreased and POLDIP3 lacking exon 3 (variant-2) increased. The RNA binding ability of TDP-43 was necessary for inclusion of POLDIP3 exon 3. Moreover, we found an increment of POLDIP3 variant-2 mRNA in motor cortex, spinal cord and spinal motor neurons collected by laser capture microdissection with ALS. Our results suggest a loss of TDP-43 function in tissues affected with ALS, supporting the hypothesis that a loss of function of TDP-43 underlies the pathogenesis of ALS. [ABSTRACT FROM AUTHOR]

Our recent study demonstrated that higher expression of N-myc downregulated gene 1 (NDRG1) is closely correlated with poor prognosis in gastric cancer patients. In this study, we asked whether NDRG1 has pivotal roles in malignant progression including metastasis of gastric cancer cells. By gene expression microarray analysis expression of NDRG1 showed the higher increase among a total of 3691 up-regulated genes in a highly metastatic gastric cancer cell line (58As1) than their parental low metastatic counterpart (HSC-58). The highly metastatic cell lines showed decreased expression of E-cadherin, together with enhanced expression of vimentin and Snail. This decreased expression of E-cadherin was restored by Snail knockdown in highly metastatic cell lines. We next established stable NDRG1 knockdown cell lines (As1/Sic50 and As1/Sic54) from the highly metastatic cell line, and both of these cell lines showed enhanced expression of E-cadherin and decreased expression of vimentin and Snail. And also, E-cadherin promoter-driven luciferase activity was found to be increased by NDRG1 knockdown in the highly metastatic cell line. NDRG1 knockdown in gastric cancer cell showed suppressed invasion of cancer cells into surround tissues, suppressed metastasis to the peritoneum and decreased ascites accumulation in mice with significantly improved survival rates. This is the first study to demonstrate that NDRG1 plays its pivotal role in the malignant progression of gastric cancer through epithelial mesenchymal transition. [ABSTRACT FROM AUTHOR]

Non-small-cell lung cancer harboring epidermal growth factor receptor (EGFR) mutations attains a meaningful response to EGFR-tyrosine kinase inhibitors (TKIs). However, acquired resistance to EGFR-TKIs could affect long-term outcome in almost all patients. To identify the potential mechanisms of resistance, we established cell lines resistant to EGFR-TKIs from the human lung cancer cell lines PC9 and11-18, which harbored activating EGFR mutations. One erlotinib-resistant cell line from PC9 and two erlotinib-resistant cell lines and two gefitinib-resistant cell lines from 11-18 were independently established. Almost complete loss of mutant delE746-A750 EGFR gene was observed in the erlotinib-resistant cells isolated from PC9, and partial loss of the mutant L858R EGFR gene copy was specifically observed in the erlotinib- and gefitinib-resistant cells from 11-18. However, constitutive activation of EGFR downstream signaling, PI3K/Akt, was observed even after loss of the mutated EGFR gene in all resistant cell lines even in the presence of the drug. In the erlotinib-resistant cells from PC9, constitutive PI3K/Akt activation was effectively inhibited by lapatinib (a dual TKI of EGFR and HER2) or BIBW2992 (pan-TKI of EGFR family proteins). Furthermore, erlotinib with either HER2 or HER3 knockdown by their cognate siRNAs also inhibited PI3K/Akt activation. Transfection of activating mutant EGFR complementary DNA restored drug sensitivity in the erlotinibresistant cell line. Our study indicates that loss of addiction to mutant EGFR resulted in gain of addiction to both HER2/HER3 and PI3K/Akt signaling to acquire EGFR-TKI resistance. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a severe neuropsychiatric disorder which has complex pathobiology with profound influences of genetic factors in its development. Although the numerous autism susceptible genes were identified, the etiology of autism is not fully explained. Using DNA microarray, we examined gene expression profiling in peripheral blood from 21 individuals in each of the four groups; young adults with ASD, age- and gender-matched healthy subjects (ASD control), healthy mothers having children with ASD (asdMO), and asdMO control. There was no blood relationship between ASD and asdMO. Comparing the ASD group with control, 19 genes were found to be significantly changed. These genes were mainly involved in cell morphology, cellular assembly and organization, and nerve system development and function. In addition, the asdMO group possessed a unique gene expression signature shown as significant alterations of protein synthesis despite of their nonautistic diagnostic status. Moreover, an ASD-associated gene expression signature was commonly observed in both individuals with ASD and asdMO. This unique gene expression profiling detected in peripheral leukocytes from affected subjects with ASD and unaffected mothers having ASD children suggest that a genetic predisposition to ASD may be detectable even in peripheral cells. Altered expression of several autism candidate genes such as FMR-1 and MECP2, could be detected in leukocytes. Taken together, these findings suggest that the ASD-associated genes identified in leukocytes are informative to explore the genetic, epigenetic, and environmental background of ASD and might become potential tools to assess the crucial factors related to the clinical onset of the disorder. [ABSTRACT FROM AUTHOR]

Background: Expression of the tumor suppressor p16INK4a increases during aging and replicative senescence. Methodology/Principal Findings: Here, we report that the microRNA miR-24 suppresses p16 expression in human diploid fibroblasts and cervical carcinoma cells. Increased p16 expression with replicative senescence was associated with decreased levels of miR-24, a microRNA that was predicted to associate with the p16 mRNA coding and 3'-untranslated regions. Ectopic miR-24 overexpression reduced p16 protein but not p16 mRNA levels. Conversely, introduction of antisense (AS)-miR-24 blocked miR-24 expression and markedly enhanced p16 protein levels, p16 translation, and the production of EGFP-p16 reporter bearing the miR-24 target recognition sites. Conclusions/Significance: Together, our results suggest that miR-24 represses the initiation and elongation phases of p16 translation. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD), the most common cause of dementia, is associated with aging, and it leads to neuron death. Deposits of amyloid β and aberrantly phosphorylated tau protein are known as pathological hallmarks of AD, but the underlying mechanisms have not yet been revealed. A high-throughput gene expression analysis previously showed that differentially expressed genes accompanying the progression of AD were more down-regulated than up-regulated in the later stages of AD. This suggested that the molecular networks and their constituent modules collapsed along with AD progression. In this study, by using gene expression profiles and protein interaction networks (PINs), we identified the PINs expressed in three brain regions: the entorhinal cortex (EC), hippocampus (HIP) and superior frontal gyrus (SFG). Dividing the expressed PINs into modules, we examined the stability of the modules with AD progression and with normal aging. We found that in the AD modules, the constituent proteins, interactions and cellular functions were not maintained between consecutive stages through all brain regions. Interestingly, the modules were collapsed with AD progression, specifically in the EC region. By identifying the modules that were affected by AD pathology, we found the transcriptional regulation-associated modules that interact with the proteasome-associated module via UCHL5 hub protein, which is a deubiquitinating enzyme. Considering PINs as a system made of network modules, we found that the modules relevant to the transcriptional regulation are disrupted in the EC region, which affects the ubiquitin-proteasome system. [ABSTRACT FROM AUTHOR]

Meflin (Islr) expression has gained attention as a marker for mesenchymal stem cells, but its function remains largely unexplored. Here, we report the generation of Meflin-CreERT2 mice with CreERT2 inserted under the Meflin gene promoter to label Meflin-expressing cells genetically, thereby enabling their lineages to be traced. We found that in adult mice, Meflin-expressing lineage cells were present in adipose tissue stroma and had differentiated into mature adipocytes. These cells constituted Crown-like structures in the adipose tissue of mice after high-fat diet loading. Cold stimulation led to the differentiation of Meflin-expressing lineage cells into beige adipocytes. Thus, the Meflin-CreERT2 mouse line is a useful new tool for visualizing and tracking the lineage of Meflin-expressing cells., Competing Interests: The authors have declared that no competing interests exist.

Pulmonary arterial hypertension (PAH) is a lethal disease characterized by a progressive increase in pulmonary artery pressure due to an increase in vessel tone and occlusion of vessels. The endogenous vasodilator prostacyclin and its analogs are used as therapeutic agents for PAH. However, their pharmacological effects on occlusive vascular remodeling have not been elucidated yet. Selexipag is a recently approved, orally available and selective prostacyclin receptor agonist with a non-prostanoid structure. In this study, we investigated the pharmacological effects of selexipag on the pathology of chronic severe PAH in Sprague-Dawley and Fischer rat models in which PAH was induced by a combination of injection with the vascular endothelial growth factor receptor antagonist Sugen 5416 and exposure to hypoxia (SuHx). Oral administration of selexipag for three weeks significantly improved right ventricular systolic pressure and right ventricular (RV) hypertrophy in Sprague-Dawley SuHx rats. Selexipag attenuated the proportion of lung vessels with occlusive lesions and the medial wall thickness of lung arteries, corresponding to decreased numbers of Ki-67-positive cells and a reduced expression of collagen type 1 in remodeled vessels. Administration of selexipag to Fischer rats with SuHx-induced PAH reduced RV hypertrophy and mortality caused by RV failure. These effects were probably based on the potent prostacyclin receptor agonistic effect of selexipag on pulmonary vessels. Selexipag has been approved and is used in the clinical treatment of PAH worldwide. It is thought that these beneficial effects of prostacyclin receptor agonists on multiple aspects of PAH pathology contribute to the clinical outcomes in patients with PAH., Competing Interests: All authors are employed by Nippon Shinyaku Co., Ltd. The funders had no role in study design, data collection and analysis, or preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

To discover susceptibility genes of late-onset Alzheimer's disease (LOAD), we conducted a 3-stage genome-wide association study (GWAS) using three populations: Japanese from the Japanese Genetic Consortium for Alzheimer Disease (JGSCAD), Koreans, and Caucasians from the Alzheimer Disease Genetic Consortium (ADGC). In Stage 1, we evaluated data for 5,877,918 genotyped and imputed SNPs in Japanese cases (n = 1,008) and controls (n = 1,016). Genome-wide significance was observed with 12 SNPs in the APOE region. Seven SNPs from other distinct regions with p-values <2×10(-5) were genotyped in a second Japanese sample (885 cases, 985 controls), and evidence of association was confirmed for one SORL1 SNP (rs3781834, P = 7.33×10(-7) in the combined sample). Subsequent analysis combining results for several SORL1 SNPs in the Japanese, Korean (339 cases, 1,129 controls) and Caucasians (11,840 AD cases, 10,931 controls) revealed genome wide significance with rs11218343 (P = 1.77×10(-9)) and rs3781834 (P = 1.04×10(-8)). SNPs in previously established AD loci in Caucasians showed strong evidence of association in Japanese including rs3851179 near PICALM (P = 1.71×10(-5)) and rs744373 near BIN1 (P = 1.39×10(-4)). The associated allele for each of these SNPs was the same as in Caucasians. These data demonstrate for the first time genome-wide significance of LOAD with SORL1 and confirm the role of other known loci for LOAD in Japanese. Our study highlights the importance of examining associations in multiple ethnic populations.

Background: Expression of the tumor suppressor p16(INK4a) increases during aging and replicative senescence., Methodology/principal Findings: Here, we report that the microRNA miR-24 suppresses p16 expression in human diploid fibroblasts and cervical carcinoma cells. Increased p16 expression with replicative senescence was associated with decreased levels of miR-24, a microRNA that was predicted to associate with the p16 mRNA coding and 3'-untranslated regions. Ectopic miR-24 overexpression reduced p16 protein but not p16 mRNA levels. Conversely, introduction of antisense (AS)-miR-24 blocked miR-24 expression and markedly enhanced p16 protein levels, p16 translation, and the production of EGFP-p16 reporter bearing the miR-24 target recognition sites., Conclusions/significance: Together, our results suggest that miR-24 represses the initiation and elongation phases of p16 translation.