Suppression of androgen receptor signaling induces prostate cancer migration via activation of the CCL20-CCR6 axis.

The suppression of androgen receptor (AR) expression exacerbates the migration potential of prostate cancer. This study identified a previously unrecognized regulation of the AR-controlled pathway that promotes migration potential in prostate cancer cells. Prostate cancer cells that pass through a transwell membrane (mig cells) have a higher migration potential with a decreased AR expression than parental cells. In this study, we aimed to elucidate the mechanism of migration enhancement associated with the suppression of AR signaling. Expression of C-C motif ligand 20 (CCL20) is upregulated in mig cells, unlike in the parental cells. Knockdown of AR with small interfering RNA (siAR) in LNCaP and C4-2B cells increased CCL20 secretion and enhanced the migration of cancer cells. Mig cells, CCL20-treated cells, and siAR cells promoted cell migration with an enhancement of AKT phosphorylation and Snail expression, while the addition of a C-C chemokine receptor 6 (CCR6, the specific receptor of CCL20) inhibitor, anti-CCL20 antibody, and AKT inhibitor suppressed the activation of AKT and Snail. With 59 samples of prostate cancer tissue, CCL20 secretion was profuse in metastatic cases despite low AR expression levels. Snail expression was associated with the expression of CCL20 and CCR6. A xenograft study showed that the anti-CCL20 antibody significantly inhibited Snail expression, thereby suggesting a new therapeutic approach for castration-resistant prostate cancer with the inhibition of the axis between CCL20 and CCR6.

Centrilobular Emphysema Is Associated with Pectoralis Muscle Reduction in Current Smokers without Airflow Limitation.

BACKGROUND: Physiological and prognostic associations of centrilobular emphysema (CLE) and paraseptal emphysema (PSE) in smokers with and without chronic obstructive pulmonary disease (COPD) have been increasingly recognized, but the associations with extrapulmonary abnormalities, such as muscle wasting, osteoporosis, and cardiovascular diseases, remain unestablished. OBJECTIVES: The aim of the study was to investigate whether CLE was associated with extrapulmonary abnormalities independent of concomitant PSE in smokers without airflow limitation. METHODS: This retrospective study consecutively enrolled current smokers without airflow limitation who underwent lung cancer screening with computed tomography and spirometry. CLE and PSE were visually identified based on the Fleischner Society classification system. Cross-sectional areas of pectoralis muscles (PM) and adjacent subcutaneous adipose tissue (SAT), bone mineral density (BMD), and coronary artery calcification (CAC) were evaluated. RESULTS: Of 310 current smokers without airflow limitation, 83 (26.8%) had CLE. The PSE prevalence was higher (67.5% vs. 23.3%), and PM area, SAT area, and BMD were lower in smokers with CLE than in those without (PM area (mean), 34.5 versus 38.6 cm2; SAT area (mean), 29.3 versus 36.8 cm2; BMD (mean), 158.3 versus 178.4 Hounsfield unit), while CAC presence did not differ. In multivariable models, CLE was associated with lower PM area but not with SAT area or BMD, after adjusting for PSE presence, demographics, and forced expiratory volume in 1 s. CONCLUSIONS: The observed association between CLE and lower PM area suggests that susceptibility to skeletal muscle loss could be high in smokers with CLE even without COPD.

Usefulness of serum CCL2 as prognostic biomarker in prostate cancer: a long-term follow-up study.

OBJECTIVE: Prostate-specific antigen is considered the most useful biomarker for prostate cancer, but not in all cases. In a previous study, we have shown that a risk classification combining prostate-specific antigen ≥100 ng/mL and chemokine (CC motif) ligand 2 ≥ 320 pg/mL can predict survivals. We investigated the long-term usefulness of serum chemokine (CC motif) ligand 2 as a complementary biomarker to prostate-specific antigen and developed a novel risk classification system. METHODS: Serum samples were collected from 379 patients who underwent prostate biopsy at Kanazawa University Hospital between 2007 and 2013, and 255 patients with histologically diagnosed prostate cancer were included in this study. We retrospectively examined the efficacy of serum chemokine (CC motif) ligand 2 as a prognostic biomarker. RESULTS: Patients with chemokine (CC motif) ligand 2 ≥ 320 pg/mL exhibited a significantly shorter overall survival, prostate cancer-specific survival and castration-resistant prostate cancer-free survival than those with chemokine (CC motif) ligand 2 < 320 pg/mL. Multivariate analysis was performed to determine whether chemokine (CC motif) ligand 2 was a useful prognostic factor. Independent significant predictors of worse overall survival were prostate-specific antigen ≥ 100 ng/mL, Gleason score ≥ 8 and chemokine (CC motif) ligand 2 ≥ 320 pg/dL. Prognostic predictors of prostate cancer-specific survival or cancer-free survival in multivariate analysis were prostate-specific antigen ≥ 100 ng/mL and Gleason score ≥ 8. A novel risk classification system was created to predict overall survival in patients based on the number of risk factors present (chemokine (CC motif) ligand 2 ≥ 320 pg/mL, prostate-specific antigen ≥ 100 ng/mL, Gleason score ≥ 8). Scores 2 or 3, 1 and 0 indicated Poor, Intermediate and Good risk groups, respectively. CONCLUSIONS: This study demonstrated the utility of serum chemokine (CC motif) ligand 2 level as a predictive biomarker of long-term overall survival in prostate cancer. A novel risk classification system that predicts long-term overall survival based on the combined indications of chemokine (CC motif) ligand 2 level, prostate-specific antigen level and Gleason score may be a useful prognostic tool for prostate cancer.

Clinical risk factors related to treatment failure in Mycobacterium abscessus lung disease.

The clinical importance of Mycobacterium abscessus subsp. abscessus (M. abscessus) lung disease has been increasing, but few studies have assessed the clinical characteristics associated with the treatment outcome. We retrospectively analyzed 75 consecutive patients with M. abscessus lung disease diagnosed at a tertiary hospital from January 2004 to April 2018. Among 52 patients with sufficient clinical data, 19 patients (42.2%) achieved treatment success. Compared with 26 (57.8%) patients in the treatment failure group, body mass index (BMI) (19.8 vs 17.5 kg/m2, P = 0.022), previous nontuberculous mycobacterial (NTM) lung disease (26.3% vs 61.5%, P = 0.034), the presence of cavitary lesions (31.6% vs 69.2%, P = 0.017), and the bronchiectasis score (3.0 vs 5.0, P = 0.003) were significantly different in the treatment success group. Multivariate analysis showed that age (adjusted hazard ratio (aHR), 0.94; 95% confidence interval (CI), 0.90 to 0.99; P = 0.010), the presence of cavitary lesions (aHR, 0.34; 95% CI, 0.12 to 0.94; P = 0.039), and previous NTM lung disease (aHR, 0.28; 95% CI, 0.09 to 0.86; P = 0.026) were negatively associated with treatment success. This is the first study to show that previous NTM lung disease might be a clinically important factor related to unfavorable treatment outcomes in M. abscessus lung disease patients. To increase our understanding the characteristics of M. abscessus lung disease, this factor should be independently analyzed in future research.

Identification of candidate genes involved in the etiology of sporadic Tourette syndrome by exome sequencing.

Tourette Syndrome (TS) is a neurodevelopmental disorder characterized by chronic motor and vocal tics. Although there is a large genetic contribution, the genetic architecture of TS remains unclear. Exome sequencing has successfully revealed the contribution of de novo mutations in sporadic cases with neuropsychiatric disorders such as autism and schizophrenia. Here, using exome sequencing, we investigated de novo mutations in individuals with sporadic TS to identify novel risk loci and elucidate the genetic background of TS. Exome analysis was conducted for sporadic TS cases: nine trio families and one quartet family with concordant twins were investigated. Missense mutations were evaluated using functional prediction algorithms, and their population frequencies were calculated based on three public databases. Gene expression patterns in the brain were analyzed using the BrainSpan Developmental Transcriptome. Thirty de novo mutations, including four synonymous and four missense mutations, were identified. Among the missense mutations, one in the rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR)-coding gene (rs140964083: G > A, found in one proband) was predicted to be hazardous. In the three public databases analyzed, variants in the same SNP locus were absent, and variants in the same gene were either absent or present at an extremely low frequency (3/5,008), indicating the rarity of hazardous RICTOR mutations in the general population. The de novo variant of RICTOR may be implicated in the development of sporadic TS, and RICTOR is a novel candidate factor for TS etiology.

Evaluation of polygenic risks for narcolepsy and essential hypersomnia.

In humans, narcolepsy is a sleep disorder that is characterized by sleepiness, cataplexy and rapid eye movement (REM) sleep abnormalities. Essential hypersomnia (EHS) is another type of sleep disorder that is characterized by excessive daytime sleepiness without cataplexy. A human leukocyte antigen (HLA) class II allele, HLA-DQB1*06:02, is a major genetic factor for narcolepsy. Almost all narcoleptic patients are carriers of this HLA allele, while 30-50% of EHS patients and 12% of all healthy individuals in Japan carry this allele. The pathogenesis of narcolepsy and EHS is thought to be partially shared. To evaluate the contribution of common single-nucleotide polymorphisms (SNPs) to narcolepsy onset and to assess the common genetic background of narcolepsy and EHS, we conducted a polygenic analysis that included 393 narcoleptic patients, 38 EHS patients with HLA-DQB1*06:02, 119 EHS patients without HLA-DQB1*06:02 and 1582 healthy individuals. We also included 376 individuals with panic disorder and 213 individuals with autism to confirm whether the results were biased. Polygenic risks in narcolepsy were estimated to explain 58.1% (PHLA-DQB1*06:02=2.30 × 10-48, Pwhole genome without HLA-DQB1*06:02=6.73 × 10-2) including HLA-DQB1*06:02 effects and 1.3% (Pwhole genome without HLA-DQB1*06:02=2.43 × 10-2) excluding HLA-DQB1*06:02 effects. The results also indicated that small-effect SNPs contributed to the development of narcolepsy. Reported susceptibility SNPs for narcolepsy in the Japanese population, CPT1B (carnitine palmitoyltransferase 1B), TRA@ (T-cell receptor alpha) and P2RY11 (purinergic receptor P2Y, G-protein coupled, 11), were found to explain 0.8% of narcolepsy onset (Pwhole genome without HLA-DQB1*06:02=9.74 × 10-2). EHS patients with HLA-DQB1*06:02 were estimated to have higher shared genetic background to narcoleptic patients than EHS patients without HLA-DQB1*06:02 even when the effects of HLA-DQB1*06:02 were excluded (EHS with HLA-DQB1*06:02: 40.4%, PHLA-DQB1*06:02=7.02 × 10-14, Pwhole genome without HLA-DQB1*06:02=1.34 × 10-1, EHS without HLA-DQB1*06:02: 0.4%, Pwhole genome without HLA-DQB1*06:02=3.06 × 10-1). Meanwhile, the polygenic risks for narcolepsy could not explain the onset of panic disorder and autism, suggesting that our results were reasonable.

Long-term effect of a name change for schizophrenia on reducing stigma.

BACKGROUND: A name change for schizophrenia was first implemented in Japan for reducing stigma in 2002; however, little is known of its long-term impact. METHODS: Total 259 students from 20 universities answered an anonymous self-administered questionnaire about their mental health-related experiences, and stigma scales including feasible knowledge and negative stereotypes for four specific diseases, including schizophrenia (old and new names), depression, and diabetes mellitus. We also asked to choose the old and new names of schizophrenia and dementia among ten names for mental and physical illnesses and conditions. RESULTS: The participants had more feasible knowledge and fewer negative stereotypes for the new name of schizophrenia than the old name, but were still significantly worse than for depression and diabetes mellitus (p < 0.01). Direct contact experiences with those who have mental health problems were associated with feasible knowledge for schizophrenia but not negative stereotypes (ß = 0.13, p = 0.020). The rate of correct responses for the old and new names of schizophrenia was significantly lower than that of dementia (41 vs. 87%, p < 0.001). Mental health-related experience from media was associated with the recognition of name change for schizophrenia (p = 0.008), which was associated with less feasible knowledge for new name of schizophrenia. DISCUSSION: The name change of schizophrenia has reduced stigma since 12 years have passed. More effective campaigns, educational curricula, and policy making are needed to reduce stigma toward schizophrenia.

Centrilobular emphysema and airway dysanapsis: factors associated with low respiratory function in younger smokers.

Background: Low respiratory function in young adulthood is one of the important factors in the trajectory leading to the future development of COPD, but its morphological characteristics are not well characterised. Methods: We retrospectively enrolled 172 subjects aged 40-49 years with ≥10 pack-years smoking history who underwent lung cancer screening by computed tomography (CT) and spirometry at two Japanese hospitals. Emphysema was visually assessed according to the Fleischner Society guidelines and classified into two types: centrilobular emphysema (CLE) and paraseptal emphysema (PSE). Airway dysanapsis was assessed with the airway/lung ratio (ALR), which was calculated by the geometric mean of the lumen diameters of the 14 branching segments divided by the cube root of total lung volume on a CT scan. Results: Among the subjects, CLE and PSE were observed in 20.9% and 30.8%, respectively. The mean ALR was 0.04 and did not differ between those with and without each type of emphysema. Multivariable regression analysis models adjusted for age, sex, body mass index and smoking status indicated that CLE and a low ALR were independently associated with lower forced expiratory volume in 1 s (FEV1)/forced vital capacity (estimate -1.64 (95% CI -2.68- -0.60) and 6.73 (95% CI 4.24-9.24), respectively) and FEV1 % pred (estimate -2.81 (95% CI -5.10- -0.52) and 10.9 (95% CI 5.36-16.4), respectively). Conclusions: CLE and airway dysanapsis on CT were independently associated with low respiratory function in younger smokers.

A reference equation for lung volume on computed tomography in Japanese middle-aged and elderly adults.

BACKGROUND: Effective use of lung volume data measured on computed tomography (CT) requires reference values for specific populations. This study examined whether an equation previously generated for multiple ethnic groups in the United States, including Asians predominantly composed of Chinese people, in the Multi-Ethnic Study of Atherosclerosis (MESA) could be used for Japanese people and, if necessary, to optimize this equation. Moreover, the equation was used to characterize patients with chronic obstructive pulmonary disease (COPD) and lung hyperexpansion. METHODS: This study included a lung cancer screening CT cohort of asymptomatic never smokers aged ≥40 years from two institutions (n = 364 and 419) to validate and optimize the MESA equation and a COPD cohort (n = 199) to test its applicability. RESULTS: In all asymptomatic never smokers, the variance explained by the predicted values (R2) based on the original MESA equation was 0.60. The original equation was optimized to minimize the root mean squared error (RMSE) by adjusting the scaling factor but not the age, sex, height, or body mass index terms of the equation. The RMSE changed from 714 ml in the original equation to 637 ml in the optimized equation. In the COPD cohort, lung hyperexpansion, defined based on the 95th percentile of the ratio of measured lung volume to predicted lung volume in never smokers (122 %), was observed in 60 (30 %) patients and was associated with centrilobular emphysema and air trapping on inspiratory/expiratory CT. CONCLUSIONS: The MESA equation was optimized for Japanese middle-aged and elderly adults.

Body mass index and in-hospital mortality in anorexia nervosa: data from the Japanese Diagnosis Procedure Combination database.

One of the main purposes of admission for anorexia nervosa is to manage acute medical conditions related to this condition. Factors associated with in-hospital mortality in anorexia nervosa remain unclear. This study describes the clinical features of anorexia nervosa patients requiring hospitalization in Japan. We analyzed the association between in-hospital mortality and body mass index upon admission using a currently available, nationwide hospital-based database. We identified 669 eligible patients with anorexia nervosa (BMI ≤ 16.5) from 229 hospitals between July and December, 2010. More than 90 % of the patients were female and 100 patients were admitted involuntarily. The average body mass index was 13.1, and the in-hospital mortality rate was 0.7 %. Five patients who died had a BMI under 11, indicating that patients with an extremely low BMI may be likely to die, despite admission.

Role of Positive Biopsy Core Ratio in Prostate Cancer Patients.

BACKGROUND/AIM: The percentage of positive cores (PPC) is increasingly recognized as a prognostic factor in prostate cancer. However, the usefulness of PPC for patients undergoing androgen deprivation therapy (ADT) and high-risk group has not been adequately studied. PATIENTS AND METHODS: A retrospective analysis was conducted of 255 patients who underwent prostate biopsy (all-case group). We examined the efficacy of PPC as a prognostic biomarker. RESULTS: Eighty-nine patients were treated with ADT alone (ADT group), and 107 patients were classified as high-risk (high-risk group). The median duration of follow-up was 112.4 months, 85.3 months, and 110.0 months for the all-case, ADT, and high-risk groups, respectively. Patients with PPC >60% had significantly shorter prostate cancer-specific survival (CSS) and castration-resistant prostate cancer-free survival (CFS) in the all-case and ADT groups. In the high-risk group, patients with PPC >60% had shorter CFS but no difference in CSS. Multivariate analysis showed that significant independent predictors of prostate CSS were the presence of metastasis at diagnosis and PPC >60% in the all-case and ADT groups. CONCLUSION: PPC may be a prognostic factor in ADT treated and high-risk prostate patients.

Novel α-Trifluoromethyl Chalcone Exerts Antitumor Effects Against Prostate Cancer Cells.

BACKGROUND/AIM: Despite treating advanced prostate cancer (PCa) with androgen deprivation therapy, it eventually progresses to castration-resistant PCa. Subsequently, taxanes are administered, but when PCa becomes resistant to taxanes, another treatment is needed, which has not yet been established. We previously synthesized a novel α-trifluoromethyl chalcone, YS71, and reported its antitumor effects against PCa cells. In this study, we confirmed its efficacy against androgen-sensitive, androgen-independent, and taxane-resistant PCa cells. MATERIALS AND METHODS: The PCa cell lines used were LNCaP, PC-3, DU145, PC-3-TxR (paclitaxel-resistant), PC-3-TxR/CxR (paclitaxel- and cabazitaxel-resistant), DU145-TxR, and DU145-TxR/CxR. The antiproliferative effects of YS71 were evaluated using proliferation assay. The reverse transcriptase transcription-polymerase chain reaction and western blot were performed to determine the expression level of androgen receptor (AR), whereas luciferase assay was performed to determine the AR activity. Furthermore, TUNEL assay and western blot were performed to investigate the mechanism of the antiproliferative effect. RESULTS: YS71 exerted a dose-dependent antitumor effect, inhibited AR activity, and induced apoptosis in all PCa cells in a dose-dependent manner. Western blot showed that YS71 increased the levels of apoptosis-related proteins, cleaved caspase-3, and cleaved PARP, and decreased the levels of the antiapoptotic proteins, Bcl-xL and Bcl-2. In addition, microarray analysis revealed that YS71 decreased several cancer-related genes. CONCLUSION: YS71 exhibits antitumor activity by inducing apoptosis in PCa cells, including taxane-resistant cells. It could be a potential future therapeutic option for hormone- and chemotherapy-resistant PCa.

Impact of obsessive-compulsive symptoms in Tourette's syndrome on neuropsychological performance.

AIM: Although inconsistencies in neuropsychological impairments in Tourette's syndrome (TS) have been discussed with respect to comorbid disorders, such as obsessive-compulsive disorder, few studies have focused on the specific dimensions of obsessive-compulsive symptoms (OCS) related to TS, such as aggression and symmetry. The aim of this study was to explore the impact of specific TS-related OCS on neuropsychological performance. METHODS: A series of neuropsychological tasks examining attention and executive functioning were performed in groups of 33 TS participants and 18 healthy controls. The neuropsychological performance of TS with Aggression OCS (n = 11) were compared to TS without Aggression OCS (n = 22) and controls by using MANCOVA controlling for age. In the same way as Aggression, we compared the performance of three groups by Symmetry: TS with Symmetry OCS (n = 14), TS without Symmetry OCS (n = 19) and controls. RESULTS: TS participants with Aggression OCS tended to make more perseverative errors than those without. Global OCS severity and tic severity did not correlate with any neuropsychological performances. No significant differences were detected between TS participants with and without Symmetry OCS. CONCLUSION: Neuropsychological deficits in TS might be affected not by global OCS severity but by specific TS-related OCS.

Appropriate Patient Status for Ra-223 Treatment in the Treatment Sequence for Castration-resistant Prostate Cancer.

BACKGROUND/AIM: Radium (Ra)-223 is widely used for treating castration-resistant prostate cancer (CRPC) with bone metastasis based on evidence of increased survival and decreased skeletal-related events. However, the timing of Ra-223 use in the treatment sequence of CRPC remains controversial. Therefore, this study aimed to explore the appropriate patient status for Ra-223 use in the CRPC treatment sequence by examining patients treated with Ra-223 from the time of CRPC diagnosis until death. PATIENTS AND METHODS: The medical records of 67 CRPC patients with bone metastasis who were treated with Ra-223 at two institutes were retrospectively analysed. The impact of 13 factors from the time of CRPC diagnosis until death was analysed using univariate and multivariate Cox hazard ratio models to evaluate the appropriate patient status for Ra-223 treatment. RESULTS: The median survival time following CRPC diagnosis for all the patient groups was 3.82 years. Univariate analysis identified a higher-than-normal alkaline phosphatase (ALP) level, bone scan indexes ≥2, and prostate-specific antigen (PSA) doubling time <3 months before Ra-223 treatment as predominant adverse prognostic factors. Ra-223 therapy discontinuation was not a significant factor. The survival of CRPC patients with these factors was significantly worse than that of patients without these factors. In the multivariate analysis, a higher-than-normal ALP level at the start of treatment was identified as a poor prognostic factor for mortality. CONCLUSION: The appropriate patient status for Ra-223 use includes low bone metastasis burden and well-controlled PSA levels.

Ra-223 and Ethinylestradiol Combination Therapy in Castration-resistant Prostate Cancer.

BACKGROUND/AIM: Ra-223 is a therapeutic agent for bone metastatic castration-resistant prostate cancer (mCRPC). We examined the efficacy of a treatment method using Ra-223 together with ethinylestradiol (EE). PATIENTS AND METHODS: Patients who received Ra-223 three or more times were included and two groups (with or without EE) were compared retrospectively. RESULTS: Eighteen patients were treated with Ra-223 and EE concomitantly (EstRadium therapy) and 13 patients were treated with Ra-223 alone or Ra-223 and agents other than EE (non-EstRadium therapy). The number of patients with decreased serum prostate-specific antigen level was significantly higher in the EstRadium therapy group than in the non-EstRadium therapy group (p=0.029). CONCLUSION: The combination of Ra-223 and EE, compared to Ra-223 alone, is an effective treatment option for bone mCRPC patients, in terms of PSA response.

Variations in photodynamic diagnosis for bladder cancer due to the quality of endoscopic equipment.

BACKGROUND: Photodynamic diagnosis (PDD)-assisted transurethral resection of bladder tumor (TURBT) has different treatment outcomes across institutions, as seen in conventional TURBT. We retrospectively compared the difference in quality between the two types of endoscopic equipment used for PDD-assisted TURBT in our institution. METHODS: This study enrolled 205 consecutive patients who underwent PDD-assisted TURBT. Patients were divided into two groups according to the endoscopic equipment used for PDD-assisted TURBT: Group A using the conventionally used endoscopic system and Aladuck LS-DLED and Group S using the Storz PDD system. Cystoscopy findings of white light (WL), fluorescence light (FL), and combination (positive if either WL or FL was positive) were recorded, and diagnostic quality of PDD was compared between both groups. RESULTS: Group A had 105 cases and 336 specimens, while Group S had 100 cases and 361 specimens, with no significant differences between patient characteristics. The tumor sensitivities of WL, FL, and combination in Group A was 71.9%, 77.1%, 90.5%, respectively, while in Group S, these were 71.5%, 92.2%, 96.1%, respectively. Group S had significantly higher sensitivity of FL and combination than Group A, as well as higher detection of carcinoma in situ lesions. CONCLUSION: Both endoscopic systems had improved sensitivity with PDD-assistance versus WL only, with Group S having higher sensitivity. Differences in the quality of endoscopic equipment may influence the differences in treatment results with PDD-assisted TURBT across institutions.

Early chronic obstructive pulmonary disease: Associations of two spirometry criteria with clinical features.

BACKGROUND: Two spirometry criteria have been proposed for early chronic obstructive pulmonary disease (COPD) in young smokers: 1) forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) < the lower limit of normal (LLN), and 2) FEV1 decline ≥60 ml/year. These criteria have yet to be validated. This study explored clinical factors associated with these two spirometry criteria. METHODS: This retrospective study analysed medical check-up data from 13,010 consecutive subjects aged <50 years who underwent current and 3 previous spirometry tests in Japan. Current ≥10 pack-year smokers were the main focus of analysis; those meeting one or more spirometry criteria were diagnosed with early COPD. Early COPD was categorized into three subtypes: FEV1/FVC < LLN and FEV1 decline <60 ml/year (type 1), FEV1/FVC ≥ LLN and FEV1 decline ≥60 ml/year (type 2), and FEV1/FVC < LLN and FEV1 decline ≥60 ml/year (type 3). RESULTS: Of the 1579 current ≥ 10 pack-year smokers, 488 (30.9%) met the early COPD criteria. Multivariate multinomial logistic models adjusted for age, sex, height, body mass index (BMI) and smoking history indicated that past BMI increase and low exercise were associated with higher type 2 early COPD incidence (odds ratio (OR) [95% confidence interval (CI)] = 4.30 [3.10, 6.04], and 0.80 [0.69, 0.93], respectively) but not with higher type 1 incidence. A history of asthma was associated with higher type 3 incidence (OR [95% CI] = 1.98 [1.18, 3.07]). CONCLUSIONS: The 3 types of spirometry-based early COPD have different clinical factors. Their trajectories should be explored in longitudinal studies.

Serum CCL2 Is a Prognostic Biomarker for Non-Metastatic Castration-Sensitive Prostate Cancer.

Purpose: Prostate-specific antigen (PSA) is a useful prostate cancer (PC) biomarker, but some cases reported that PSA does not correlate with the Gleason score. Serum chemokine (CC motif) ligand 2 (CCL2) has been reported to be a potential complementary PSA biomarker, but it remains unclear whether it can be applied to non-metastatic castration-sensitive prostate cancer (nmCSPC) or each section of the stages. Serum CCL2's usefulness was investigated as a prognostic nmCSPC biomarker in this study. Methods: Serum samples were collected from 379 patients who underwent prostate biopsy at Kanazawa University Hospital from 2007 to 2013. A total of 230 patients with nmCSPC were included in this study of the 255 patients with histologically diagnosed prostate cancer. The serum CCL2 efficacy as a prognostic nmCSPC biomarker was investigated retrospectively. Results: An independent significant predictor of worse OS was CCL2 ≥ 280 pg/dL and CRP ≥ 0.5 mg/dL in multivariate analysis. Gleason score ≥ 8 and CCL2 ≥ 280 pg/dL were independent significant predictors of CRPC-free survival (CFS) worsening in multivariate analysis. Serum CCL2 was a predictive biomarker for OS and CFS in nmCSPC. Furthermore, CCL2 ≥ 280 pg/mL patients had significantly worse visceral metastasis-free survival than those with CCL2 < 280 pg/mL. Conclusion: This study is the first to demonstrate serum CCL2 utility as a biomarker to predict OS and CFS in nmCSPC.

The prevalence and physiological impacts of centrilobular and paraseptal emphysema on computed tomography in smokers with preserved ratio impaired spirometry.

Centrilobular emphysema (CLE) and paraseptal emphysema (PSE) are observed in smokers with preserved ratio impaired spirometry (PRISm, defined as the ratio of forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) ≥0.7 and FEV1 <80%), but their prevalence and physiological impacts remain unestablished. This multicentre study aimed to investigate its prevalence and to test whether emphysema subtypes are differently associated with physiological impairments in smokers with PRISm. Both never- and ever-smokers aged ≥40 years who underwent computed tomography (CT) for lung cancer screening and spirometry were retrospectively and consecutively enrolled at three hospitals and a clinic. Emphysema subtypes were visually classified according to the Fleischner system. Air-trapping was assessed as the ratio of FVC to total lung capacity on CT (TLCCT). In 1046 never-smokers and 772 smokers with ≥10 pack-years, the prevalence of PRISm was 8.2% and 11.3%, respectively. The prevalence of PSE and CLE in smokers with PRISm was comparable to that in smokers with normal spirometry (PSE 43.7% versus 36.2%, p=1.00; CLE 46.0% versus 31.8%, p=0.21), but higher than that in never-smokers with PRISm (PSE 43.7% versus 1.2%, p<0.01; CLE 46% versus 4.7%, p<0.01) and lower than that in smokers with airflow limitation (PSE 43.7% versus 71.0%, p<0.01; CLE 46% versus 79.3%, p<0.01). The presence of CLE, but not PSE, was independently associated with reduced FVC/TLCCT in smokers with PRISm. Both PSE and CLE were common, but only CLE was associated with air-trapping in smokers with PRISm, suggesting different physiological roles of these emphysema subtypes.

A genome-wide CNV association study on panic disorder in a Japanese population.

Family and twin studies have indicated that genetic factors have an important role in panic disorder (PD), whereas its pathogenesis has remained elusive. We conducted a genome-wide copy number variation (CNV) association study to elucidate the involvement of structural variants in the etiology of PD. The participants were 2055 genetically unrelated Japanese people (535 PD cases and 1520 controls). CNVs were detected using Genome-Wide Human SNP array 6.0, determined by Birdsuite and confirmed by PennCNV. They were classified as rare CNVs (found in <1% of the total sample) or common CNVs (found in ≥5%). PLINK was used to perform global burden analysis for rare CNVs and association analysis for common CNVs. The sample yielded 2039 rare CNVs and 79 common CNVs. Significant increases in the rare CNV burden in PD cases were not found. Common duplications in 16p11.2 showed Bonferroni-corrected P-values <0.05. Individuals with PD did not exhibit an increased genome-wide rare CNV burden. Common duplications were associated with PD and found in the pericentromeric region of 16p11.2, which had been reported to be rich in low copy repeats and to harbor developmental disorders, neuropsychiatric disorders and dysmorphic features.