Search for the Pair Production of Dark Particles X with K_{L}

We present the first search for the pair production of dark particles X via K_{L}^{0}→XX with X decaying into two photons using the data collected by the KOTO experiment. No signal was observed in the mass range of 40-110 MeV/c^{2} and 210-240 MeV/c^{2}. This sets upper limits on the branching fractions as B(K_{L}^{0}→XX)<(1-4)×10^{-7} and B(K_{L}^{0}→XX)<(1-2)×10^{-6} at the 90% confidence level for the two mass regions, respectively.

Implementation of Bronchoscopic Lung Volume Reduction Using One-Way Endobronchial Valves: A Retrospective Single-Centre Cohort Study.

BACKGROUND: Bronchoscopic lung volume reduction (BLVR) using 1-way endobronchial valves (EBV) has become a guideline treatment in patients with advanced emphysema. Evidence from this minimally invasive treatment derives mainly from well-designed controlled trials conducted in high-volume specialized intervention centres. Little is known about real-life outcome data in hospitals setting up this novel treatment and which favourable conditions are required for a continuous successful program. OBJECTIVES: In this study, we aim to evaluate the eligibility rate for BLVR and whether the implementation of BLVR in our academic hospital is feasible and yields clinically significant outcomes. METHOD: A retrospective evaluation of patients treated with EBV between January 2016 and August 2019 was conducted. COPD assessment test (CAT), forced expiratory volume in 1 s (FEV1), residual volume (RV), and 6-min walking test (6MWT) were measured at baseline and 3 months after intervention. Paired sample t tests were performed to compare means before and after intervention. RESULTS: Of 350 subjects screened, 283 (81%) were not suitable for intervention mostly due to lack of a target lobe. The remaining 67 subjects (19%) underwent bronchoscopic assessment, and if suitable, valves were placed in the same session. In total, 55 subjects (16%) were treated with EBV of which 10 did not have complete follow-up: 6 subjects had their valves removed because of severe pneumothorax (n = 2) or lack of benefit (n = 4) and the remaining 4 had missing follow-up data. Finally, 45 patients had complete follow-up at 3 months and showed an average change ± SD in CAT -4 ± 6 points, FEV1 +190 ± 140 mL, RV -770 ± 790 mL, and +37 ± 65 m on the 6MWT (all p < 0.001). After 1-year follow-up, 34 (76%) subjects had their EBV in situ. CONCLUSION: Implementing BLVR with EBV is feasible and effective. Only 16% of screened patients were eligible, indicating that this intervention is only applicable in a small subset of highly selected subjects with advanced emphysema, and therefore a high volume of COPD patients is essential for a sustainable BLVR program.

Study of the K_{L}→π

The rare decay K_{L}→π^{0}νν[over ¯] was studied with the dataset taken at the J-PARC KOTO experiment in 2016, 2017, and 2018. With a single event sensitivity of (7.20±0.05_{stat}±0.66_{syst})×10^{-10}, three candidate events were observed in the signal region. After unveiling them, contaminations from K^{±} and scattered K_{L} decays were studied, and the total number of background events was estimated to be 1.22±0.26. We conclude that the number of observed events is statistically consistent with the background expectation. For this dataset, we set an upper limit of 4.9×10^{-9} on the branching fraction of K_{L}→π^{0}νν[over ¯] at the 90% confidence level.

Dual-Energy Computed Tomography Compared to Lung Perfusion Scintigraphy to Assess Pulmonary Perfusion in Patients Screened for Endoscopic Lung Volume Reduction.

BACKGROUND: Endoscopic lung volume reduction (ELVR) using one-way endobronchial valves is a technique to reduce hyperinflation in patients with severe emphysema by inducing collapse of a severely destroyed pulmonary lobe. Patient selection is mainly based on evaluation of emphysema severity on high-resolution computed tomography and evaluation of lung perfusion with perfusion scintigraphy. Dual-energy contrast-enhanced CT scans may be useful for perfusion assessment in emphysema but has not been compared against perfusion scintigraphy. AIMS: The aim of the study was to compare perfusion distribution assessed with dual-energy contrast-enhanced computed tomography and perfusion scintigraphy. MATERIAL AND METHODS: Forty consecutive patients with severe emphysema, who were screened for ELVR, were included. Perfusion was assessed with 99mTc perfusion scintigraphy and using the iodine map calculated from the dual-energy contrast-enhanced CT scans. Perfusion distribution was calculated as usually for the upper, middle, and lower thirds of both lungs with the planar technique and the iodine overlay. RESULTS: Perfusion distribution between the right and left lung showed good correlation (r = 0.8). The limits of agreement of the mean absolute difference in percentage perfusion per region of interest were 0.75-5.6%. The upper lobes showed more severe perfusion reduction than the lower lobes. Mean difference in measured pulmonary perfusion ranged from -2.8% to 2.3%. Lower limit of agreement ranged from -8.9% to 4.6% and upper limit was 3.3-10.0%. CONCLUSION: Quantification of perfusion distribution using planar 99mTc perfusion scintigraphy and iodine overlays calculated from dual-energy contrast-enhanced CTs correlates well with acceptable variability.

Energy transfer from adipocytes to cancer cells in breast cancer.

Limitations of the current therapeutic approach have raised the need for a novel therapeutic agent in breast cancer. Recently, interest in drugs targeting the tumor microenvironment (TME) had drawn attention in the treatment of breast cancer. Furthermore, recent studies have suggested the role of adipocytes, which are part of the TME, in tumor initiation, growth, and metastasis. In this study, we investigated the metabolic interaction between adipocytes and breast cancer cells and its potential as a new therapeutic target in breast cancer. Breast cancer cell lines and human breast cancer tissue samples were evaluated. Compared to cancer cells cultured alone, or the control group, those co-cultured with adipocytes showed lipid transfer from adipocytes to cancer cells and it was different according to the molecular subtype of breast cancer. Breast cancer cells affected the lipolysis of adipocytes and adipocytes affected the ß-oxidation of breast cancer cells. The key molecule of the process was fatty acid binding protein 4 (FABP4), which is combined with free fatty acid (FFA) and supports its migration to cancer cells. When FABP4 was suppressed, lipid transfer between adipocytes and cancer cells, lipolysis of adipocytes, and ß-oxidation of breast cancer cells were reduced. Furthermore, the expression of lipid metabolism-related proteins and lipolysis-related proteins in breast cancer with adipose stroma showed significantly different expression according to the region of breast cancer tissue. Taken together, we demonstrated the metabolic interaction between adipocytes and breast cancer cells. Breast cancer cells increase the lipolysis in adipocytes and produce a fatty acid, and fatty acid enters into cancer cells. Also, adipocytes contribute to the survival and growth of cancer cells through increased mitochondrial ß-oxidation by using fatty acid from adipocytes. The key molecule of the process is FABP4 and when FABP4 is suppressed, the metabolic interaction is reduced, suggesting its role as a potential therapeutic target.

iNKT cells prevent obesity-induced hepatic steatosis in mice in a C-C chemokine receptor 7-dependent manner.

Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis are characterized by an increase in hepatic triglyceride content with infiltration of immune cells, which can cause steatohepatitis and hepatic insulin resistance. C-C chemokine receptor 7 (CCR7) is primarily expressed in immune cells, and CCR7 deficiency leads to the development of multi-organ autoimmunity, chronic renal disease and autoimmune diabetes. Here, we investigated the effect of CCR7 on hepatic steatosis in a mouse model and its underlying mechanism. Our results demonstrated that body and liver weights were higher in the CCR7-/- mice than in the wild-type (WT) mice when they were fed a high-fat diet. Further, glucose tolerance and insulin sensitivity were markedly diminished in CCR7-/- mice. The number of invariant natural killer T (iNKT) cells was reduced in the livers of the CCR7-/- mice. Moreover, liver inflammation was detected in obese CCR7-/- mice, which was ameliorated by the adoptive transfer of hepatic mononuclear cells from WT mice, but not through the transfer of hepatic mononuclear cells from CD1d-/- or interleukin-10-deficient (IL-10-/-) mice. Overall, these results suggest that CCR7+ mononuclear cells in the liver could regulate obesity-induced hepatic steatosis via induction of IL-10-expressing iNKT cells.

Src-type tyrosine kinase p56lck is critical for thymic stromal lymphopoietin-induced allergic rhinitis.

BACKGROUND: Thymic stromal lymphopoietin (TSLP) is a regulator of mast cell-mediated allergic inflammatory reactions, but the manner in which TSLP contributes to allergic rhinitis (AR) remains unclear. OBJECTIVE: Here, we sought to determine that TSLP plays a crucial role in AR by interacting with Src-type tyrosine kinase p56lck and STAT6 and promoting mast cells degranulation. METHODS: The effects of TSLP on mast cell degranulation and AR were analysed in human mast cell line (HMC-1 cells), ovalbumin (OVA)-induced AR animal model, and human subjects. Small interfering RNA experiments were performed in HMC-1 cells and OVA-induced AR model. Immune responses were analysed by enzyme-linked immunosorbent assay, Western blotting, immunoprecipitation, and histological studies. RESULTS: Thymic stromal lymphopoietin levels and mast cell-derived p56lck activation were elevated in human subjects with AR, and in AR mice, exogenous TSLP accelerated TH2-allergic inflammatory reactions by up-regulating p56lck and STAT6. On the other hand, depletion of TSLP, p56lck, and STAT6 ameliorated clinical symptoms in AR mice. The selective inhibitor of p56lck, damnacanthal, inhibits AR reactions. CONCLUSION: Collectively, these observations suggest a role for TSLP/p56lck/STAT6 in AR and offer insight into potential therapeutic strategies.

Reliability and validity of the Atopic Dermatitis Symptom Score (ADSS).

BACKGROUND: We have developed the Atopic Dermatitis Symptom Score (ADSS) by which patients or parents can easily assess and record AD symptoms on a daily basis in a smartphone application. The aim of this study was to evaluate the reliability and validity of the ADSS. METHODS: We enrolled 307 children and adolescents with AD. Parents or caregivers were asked to record daily symptoms of the patients (itching, sleep disturbance, erythema, dryness, oozing, and edema) using a scale of 0-4. Statistical analyses consisted of the test-retest reliability, concurrent validity, minimal clinically important difference (MCID), responsiveness, floor or ceiling effects, and screening accuracy. Receiver-operating characteristic analyses were conducted to evaluate the ADSS cutoff point for predicting severe AD (SCORing AD [SCORAD] ≥40). RESULTS: Test-retest reliability between daytime and night-time ADSS was good (intraclass correlation coefficient, 0.82 [95% CI: 0.70-0.90]). An increase in ADSS was significantly associated with an increase in SCORAD (r = 0.64, P < .0001) (concurrent validity). The MCID was 4.1 points for the ADSS. There was a significant association between changes in ADSS and SCORAD (r = 0.56, P < .0001), indicating good responsiveness. At the optimal ADSS cutoff value of 7.0, sensitivity, specificity, and positive and negative predictive values were 88.4%, 78.6%, 21.1%, and 99.1%, respectively (screening accuracy). CONCLUSIONS: The ADSS can be a useful tool for self-assessment of skin symptoms in children with AD.

Therapeutic effects of Artemisia scoparia Waldst. et Kitaib in a murine model of atopic dermatitis.

BACKGROUND: Artemisia scoparia Waldst. et Kitaib (AS) (Oriental wormwood, known as Bissuk in Korea) is a plant used in cosmetic and pharmaceutical treatments. However, the effect of AS on atopic dermatitis (AD) has not been described. AIM: To examine the inhibitory effect of AS on AD using a murine model. METHODS: We applied either AS, the butanol-extracted fraction of AS (Bu-OH) or 3,5-dicaffeoyl-epi-quinic acid (DEQA, a major component of Bu-OH) topically for 3 weeks to 2,4-dinitrofluorobenzene (DNFB)-induced skin lesions in BALB/c mice. RESULTS: AS, Bu-OH and DEQA suppressed the clinical symptoms of DNFB-induced skin lesions and he associated scratching behaviour. Numbers of inflammatory cells infiltrating skin lesions were significantly reduced by AS or Bu-OH application but not by DEQA. In addition, AS significantly suppressed serum levels of histamine and IgE, while Bu-OH significantly suppressed serum levels of histamine, IgE, thymic stromal lymphopoietin (TSLP), interleukin (IL)-4 and IL-6, and DEQA significantly suppressed serum levels of histamine, IgE, TSLP and IL-4 in DNFB-induced AD mice. In skin lesions, AS and Bu-OH significantly reduced inflammatory cytokines, whereas DEQA did not. AS, Bu-OH and DEQA all significantly suppressed caspase-1 activities. CONCLUSIONS: These results demonstrate the anti-AD effects of AS, Bu-OH and DEQA, and suggest that all three have therapeutic potential.

Exogenous administration of DLK1 ameliorates hepatic steatosis and regulates gluconeogenesis via activation of AMPK.

BACKGROUND/OBJECTIVES: Activation of Notch signaling pathologically enhances lipogenesis and gluconeogenesis in the liver causing non-alcoholic fatty liver disease (NAFLD) and diabetes. Delta-like 1 homolog (DLK1), an imprinted gene that can modulate adipogenesis and muscle development in mice, was found as an inhibitory regulator of Notch signaling. Therefore, we investigated the metabolic effect of exogenous DLK1 in vitro and in vivo. SUBJECTS/METHODS: A soluble DLK1 peptide was generated with fusion between a human Fc fragment and extracellular domain of DLK1. Male db/db mice were randomly assigned to two groups: vehicle treated and DLK1-treated group (25 mg kg(-1), intraperitoneal injection, twice a week for 4 weeks). Primary mice hepatocytes and HepG2 cells were used for in vitro experiments. RESULTS: After 4 weeks of DLK1 administration, hepatic triglyceride content and lipid droplets in liver tissues, as well as serum levels of liver enzymes, were markedly decreased in db/db mice. DLK1 treatment induced phosphorylation of AMPK and ACC and suppressed nuclear expression of SREBP-1c in the mouse liver or hepatocytes, indicating regulation of fatty acid oxidation and synthesis pathways. Furthermore, DLK1-treated mice showed significantly lower levels of fasting and random glucose, with improved glucose and insulin tolerance compared with the vehicle-treated group. Macrophage infiltration and proinflammatory cytokine levels in the epididymal fat were decreased in DLK1-treated db/db mice. Moreover, DLK1 suppressed glucose production from hepatocytes, which was blocked after co-administration of an AMPK inhibitor, compound C. DLK1-treated hepatocytes and mouse liver tissues showed lower PEPCK and G6Pase expression. DLK1 triggered AKT phosphorylation followed by cytosolic translocation of FOXO1 from the nucleus in hepatocytes. CONCLUSIONS: The present study demonstrated that exogenous administration of DLK1 reduced hepatic steatosis and hyperglycemia via AMPK activation in the liver. This result suggests that DLK1 may be a novel therapeutic approach for treating NAFLD and diabetes.

The circulating sphingosine-1-phosphate level predicts incident fracture in postmenopausal women: a 3.5-year follow-up observation study.

UNLABELLED: A high level of circulating sphingosine-1-phosphate (S1P) is associated with a high incidence of osteoporotic fracture and a high rate of an insufficient response to bisphosphonate therapy. INTRODUCTION: Sphingosine-1-phosphate (S1P) is a significant regulator of bone metabolism. Recently, we found that a high plasma S1P level is associated with low bone mineral density (BMD), high levels of bone resorption markers (BRMs), and a high risk of prevalent vertebral fracture in postmenopausal women. We investigated the possibility that S1P is a predictor of incident fracture. METHODS: A total of 248 postmenopausal women participated in this longitudinal study and were followed up for a mean duration of 3.5 years (untreated [n = 76] or treated with bisphosphonate or hormone replacement therapy [n = 172]). The baseline plasma S1P level and prevalent and incident fracture occurrence were assessed. RESULTS: A high S1P level was significantly associated with a higher rate of prevalent fracture after adjusting for femoral neck (FN) BMD, BRM, and potential confounders (odds ratio = 2.05; 95 % confidence interval [CI] = 1.03-4.00). Incident fractures occurred more frequently in the highest S1P tertile (T3) than in the lower two tertiles (T1-2) after adjusting for confounders, including baseline FN BMD, prevalent fracture, antiosteoporotic medication, annualized changes in FN BMD, BRM, and potential confounders (hazard ratio = 5.52; 95 % CI = 1.04-56.54). Insufficient response to bisphosphonate therapy occurred more frequently in T3 than T1-2 (odds ratio = 4.43; 95 % CI = 1.02-21.25). CONCLUSIONS: The plasma S1P level may be a potential predictor of fracture occurrence and an insufficient response to bisphosphonate therapy in postmenopausal women.

Correlates of family involvement before and during medical visits among older adults with high-risk diabetes.

AIMS: To examine the characteristics of patients with diabetes who regularly receive help from a supporter in preparing for and attending medical visits, and the association between this help and clinical risk factors for diabetes complications. METHODS: We linked survey data about family involvement for patients in the Veterans Health Administration system with poorly controlled Type 2 diabetes (n = 588; mean 67 years; 97% male) with health record data on blood pressure, glycaemic control and prescription-fill gaps. We used multivariable regression to assess whether supporter presence and, among patients with supporters, supporter role (visit preparation, accompaniment to medical visit or no involvement) were associated with concurrent trends in clinical risk factors over 2 years, adjusting for sociodemographic and health characteristics. RESULTS: Most patients (78%) had a main health supporter; of these, more had regular support for preparing for appointments (69%) than were regularly accompanied to them (45%). Patients with preparation help only were younger and more educated than accompanied patients. Support presence and type was not significantly associated with clinical risk factors. CONCLUSIONS: Family help preparing for appointments was common among these patients with high-risk diabetes. In its current form, family support for medical visits may not affect clinical factors in the short term. Supporters helping patients engage in medical visits may need training and assistance to have an impact on the clinical trajectory of patients with diabetes.

Profiling of rectal cancers MRI in pathological complete remission states after neoadjuvant concurrent chemoradiation therapy.

AIM: To fully characterise the magnetic resonance imaging (MRI) traits of rectal cancers in a large sample of patients, each experiencing pathological complete remission (pCR) after neoadjuvant concurrent chemoradiation therapy (CCRT). MATERIALS AND METHODS: A total of 120 patients (77 male, 43 female; median age, 59.5 years; range, 32-81 years) with rectal cancers in CCRT-induced pCR states who underwent pre- and post-CCRT MRI and eventual surgery between July, 2005 and September, 2014 were retrospectively reviewed. In most (n=100), diffusion-weighted imaging was also performed. Tumour volume, tumour regression grade (TRG), T-stage, mesorectal fascia (MRF) status, and T2 signal intensity (T2-SI) were analysed. Paired t-test and McNemar's test were applied for statistical comparisons. RESULTS: Tumour volume declined sharply after CCRT (pre-CCRT, 21.5 ± 22.4 cm(3); post-CCRT, 6.6 ± 8.4 cm(3); p<0.001). TRG distribution was as follows: G1 (clinical CR), 3; G2, 38; G3, 78; G4, 1; and G5 (marked progression), 0. Downstaging of T-stage (34%,16/47) and MRF status (19.7%,13/66) did occur; but on post-CCRT MRI, 25.8% (31/120) remained at T3 ≥ 5 mm or T4 stage, and 44.2% (53/120) were MRF-positive. A majority (88.3%, 106/120) of patients displayed intermediate T2-SI prior to CCRT. Most converted to dark T2-SI after CCRT, with 12.5% (15/120) unchanged. On post-CCRT MRI, 11% (11/100) of patients showed diffusion restriction. CONCLUSION: MRI findings in CCRT-induced pCR-status rectal cancers were highly variable. Tumour volume and T2-SI mostly decreased; however, such lesions occasionally presented with unexpected atypical features, such as large residual volume and/or intermediate T2-SI.

Low skeletal muscle mass associates with low femoral neck strength, especially in older Korean women: the Fourth Korea National Health and Nutrition Examination Survey (KNHANES IV).

SUMMARY: Data gathered from a nationally representative cohort demonstrated that subject with low skeletal muscle mass had consistently low femoral neck composite strength indices for compression, bending, and impact, especially in older women, supporting the highly integrated nature of skeletal muscle and bone. INTRODUCTION: Skeletal muscle and bone interact mechanically and functionally. The present study was performed to investigate the association between muscle mass and femoral neck composite strength indices using a nationally representative cohort. METHODS: This is a population-based, cross-sectional study from Korea National Health and Nutrition Examination Surveys, including 1,275 Koreans (674 women and 601 men) aged 50 years or older. Femoral neck axis length and width were measured by hip DXA scans and were combined with BMD, body weight, and height to create composite indices of femoral neck strength relative to load in three different failure modes: compression, bending, and impact. Presarcopenia was defined as an appendicular skeletal muscle mass (ASM) divided by body weight that was less than 1 SD below the sex-specific mean for young adults. RESULTS: After adjusting for confounders, women with presarcopenia had consistently lower indices for compression strength (CSI), bending strength (BSI), and impact strength (ISI) than women without this condition. Men with presarcopenia had a lower ISI value than men without presarcopenia. Multiple regression analyses revealed that lower relative skeletal muscle mass (ASM/weight) associated significantly with lower values for all three femoral neck composite indices in women and with lower CSI and ISI in men. CONCLUSIONS: These findings provide the first clinical evidence for the notion that age-related low muscle mass may increase the risk of osteoporotic hip fractures by decreasing femoral neck strength relative to load, especially in older women, and support the highly integrated nature of skeletal muscle and bone.

Preoperative and intraoperative infection workup in apparently aseptic revision shoulder arthroplasty.

The possibility of infection should be considered in every revision shoulder arthroplasty even in the absence of clinical symptoms and signs of infection because indolent infection is prevalent. Detection of infection in apparently aseptic failed arthroplasties poses a diagnostic challenge as the conventional principles and criteria used for hip and knee arthroplasty are not generally applicable. Propionibacterium acnes and Staphylococcus epidermidis are among the infectious organisms most commonly identified in such situations. Serum inflammatory markers are essential but are often unreliable as they have poor sensitivity in the shoulder. Preoperative shoulder joint aspiration culture is an important step but is subject to high false-negative rates. Lower cutoff values of synovial fluid analysis are used for detection of periprosthetic infection than for native joint infection as demonstrated in the knee literature. Intraoperatively, frozen section should be considered when a diagnosis of infection has not been established even in the presence of clinical suspicion. Gram stain is currently not recommended because of its low sensitivity and negative predictive value. Intraoperative culture is critical and should be performed whenever there is clinical suspicion of infection. Unexpected positive intraoperative cultures are not uncommon, and 6% to 25% of them appear to represent true infection as demonstrated with positive follow-up cultures or subsequent development of infection. In revision shoulder arthroplasty, determining the presence of infection can be difficult. A standardized approach is needed to determine the best course of treatment in this particular clinical setting.

The clinical usefulness of initial serum procalcitonin as an aggravation predictor in a hepatobiliary tract infection at emergency department.

BACKGROUND AND OBJECTIVES: The ability to predict future clinical deterioration early in patients who present to an emergency care center with a hepatobiliary tract infection is difficult. We studied the clinical usefulness of the initial serum levels of procalcitonin in a hepatobiliary tract infection as an indicator for predicting aggravation in the early stages. METHODS: Of the patients who presented with the clinical symptoms of a hepatobiliary tract infection, 99 were diagnosed with a hepatobiliary tract infection by imaging studies and subsequently enrolled in the study. Laboratory tests were obtained in the early stage of disease after presentation to an emergency care center. We assessed and compared the serum levels of many early inflammatory markers (white blood cell [WBC] counts, C-reactive protein and procalcitonin) between patients whose symptoms were initially stable upon arrival to an emergency care center but then deteriorated to, those whose symptoms remained consistently stable. Thus, we examined if the above serum markers are useful in predicting the possibility of future symptom aggravation. RESULTS: Of a total of 99 patients, 27 were assigned to the symptom aggravation group. The serum levels of WBC counts and C-reactive protein in the aggravation group were elevated. However, the median value (interquartile range) of procalcitonin was relatively increased at 2.28 (0.41-7.84 ng/ml), demonstrating a significant difference. CONCLUSIONS: In conclusion, initial serum levels of procalcitonin might be used as an indicator for aggravation in patients with hepatobiliary tract infection at the emergency department, even though there is hemodynamic stability.

Whole-genome analysis of a patient with early-stage small-cell lung cancer.

We performed whole-genome sequencing (WGS) of a case of early-stage small-cell lung cancer (SCLC) to analyze the genomic features. WGS revealed a lot of single-nucleotide variations (SNVs), small insertion/deletions and chromosomal abnormality. Chromosomes 4p, 5q, 13q, 15q, 17p and 22q contained many block deletions. Especially, copy loss was observed in tumor suppressor genes RB1 and TP53, and copy gain in oncogene hTERT. Somatic mutations were found in TP53 and CREBBP. Novel nonsynonymous (ns) SNVs in C6ORF103 and SLC5A4 genes were also found. Sanger sequencing of the SLC5A4 gene in 23 independent SCLC samples showed another nsSNV in the SLC5A4 gene, indicating that nsSNVs in the SLC5A4 gene are recurrent in SCLC. WGS of an early-stage SCLC identified novel recurrent mutations and validated known variations, including copy number variations. These findings provide insight into the genomic landscape contributing to SCLC development.

Potential relationship between the canonical Wnt signalling pathway and expression of the vitamin D receptor in alopecia.

BACKGROUND: Vitamin D receptor (VDR) is expressed in dermal papilla cells and in the epidermis of the hair follicle. Patients with alopecia areata (AA) and alopecia universalis (AU) have VDR mutations. AIMS: We investigated expression of VDR in isolated hair follicles and epidermal keratinocytes from patients with AA or AU, and assessed changes in the expression of Wnt signalling regulation factors to determine the relationship between the occurrence of AA or AU and decreased expression of VDR. METHODS: Immunohistochemistry was performed for canonical Wnt signalling molecules, VDR, and proliferation and differentiation markers in the skin tissue of patients with AA or AU. After VDR small interfering RNA or Dickkopf-1 (DKK1) treatment of follicle dermal papilla (DP) cells, expression of VDR and Wnt signalling molecules was determined. DKK1 was used to treated keratinocytes and DP cells in a transwell coculture system. Western blotting analysis was performed to assay for VDR and ß-catenin. RESULTS: Expression of Wnt/ß-catenin signals and VDR was decreased in AA or AU lesions compared with nonlesional skin. Inhibition of Wnt/ß-catenin signals and VDR influenced differentiation and proliferation of epidermis and hair follicles. In the transwell coculture system, DKK1 reduced the expression of VDR and ß-catenin in cells in a dose-dependent manner. CONCLUSIONS: This study demonstrates that the decreased expression of VDR in AA and AU lesions is related to decreased expression of Wnt/ß-catenin signals, which inhibits proliferation and differentiation of hair follicles and epidermal cells.

The in vitro apoptotic effects of A248 and A1659, newly synthetic histone deacetylase inhibitors in oral cancer cells.

OBJECTIVES: Histone deacetylase (HDAC) inhibitors represent potential therapeutic agents against various cancers. In this study, we attempt to identify whether newly synthesized HDAC inhibitors, A248 and A1659, can be effective anti-cancer drug candidates for oral cancer. MATERIALS AND METHODS: The anti-cancer activities of A248 and A1659 in MC-3 and HN22 human oral cancer cells were evaluated by 3-(4,5-dimethylthiazol-20yl)-(3-carboxymethoxyphenyl)-2-(4-sulphophenyl)-2H-tetrazolium (MTS) assay, 4'-6-diamidino-2-phenylindole (DAPI) staining, Western blot analysis, immunocytochemistry, and small interference RNA (siRNA) technology. RESULTS: A248 and A1659 enhanced histone acetylation and decreased the viability of MC-3 and HN22 cells. A248 and A1659 also induced apoptosis, as evidenced by altered nuclear features and poly(ADP-ribose)polymerase (PARP) cleavage. A248 and A1659 markedly decreased Sp1 expression in a concentration- or time-dependent manner and blocked nuclear translocation of Sp1 protein from the cytosol, which contributed to an increase in p27 expression and a decrease in cyclin D1 expression. Furthermore, the knockdown of Sp1 protein with siRNA caused marked alteration of p27 and cyclin D1 expression to induce apoptosis. The most popular HDAC inhibitor, trichostatin A (TSA) also induced apoptosis and reduced the expression level of Sp1 protein. CONCLUSION: These results suggest that A248 and A1659, two new HDAC inhibitors, may be attractive therapeutic drug candidates for targeting Sp1 in human oral cancer cells.

Do measures of social support and social distress share general factors associated with suicidal ideation and attempts?

INTRODUCTION: Aspects of social relationships have variably been associated with suicidal ideation (SI) and suicide attempts (SAs). This study assessed whether social support and social distress measures have general factors versus measure-specific factors that are associated with suicide risk. METHODS: Adults (N = 455, 60.0% female), admitted to psychiatric inpatient units following a recent suicide attempt or active SI, completed assessments of social support (emotional support, instrumental support, friendship, perceived support from significant others, friends, family) and social distress (loneliness, perceived rejection, perceived burdensomeness, thwarted belongingness). Bifactor modeling examined general and specific factors of social support and distress in relation to SI (week prior to hospitalization, via the Beck Scale for SI) and SAs (past 30 days, via the Columbia Suicide Severity Rating Scale). RESULTS: SI was significantly associated with the general social support (B = -1.51), the general social distress (B = 1.67), and the specific perceived burdensomeness (B = 1.57) factors. SAs were significantly associated with the specific Perceived Rejection (OR = 1.05) and Thwarted Belongingness (OR = 0.91) factors. CONCLUSION: General social support and social distress were associated with SI but not recent SAs. Specific social distress factors were also related to SI and SAs controlling for general social distress, suggesting areas for future interventions.