Association Between Adequate Serum 25(OH)D Levels and Atherogenic Dyslipidemia in Young Adults.

AIM: This study aimed to investigate the association between vitamin D deficiency and novel biomarkers of atherogenic dyslipidemia among young adults. METHOD: A total of 976 young adults were recruited between 2011 and 2019. Their serum 25(OH)D levels were measured, and lipid profile markers, including low-density lipoprotein cholesterol (LDL-C), low-density lipoprotein triglyceride (LDL-TG), and small-dense low-density lipoprotein cholesterol (sdLDL-C), were assessed as novel biomarkers of atherogenic dyslipidemia. Multivariable linear regression was used to analyze the association between vitamin D levels and lipid profile markers. Odds ratios were calculated to assess the risk of atherogenic dyslipidemia in individuals with serum 25(OH)D levels below 30 ng/mL compared to those with levels above 30 ng/mL. Structural equation modeling (SEM) was employed to explore potential mediation pathways. RESULTS: The study found a significant association between vitamin D levels and lower levels of LDL-C, LDL-TG, sdLDL-C, non-high-density lipoprotein cholesterol (non-HDL-C), triglycerides, and total cholesterol. Individuals with serum 25(OH)D levels below 30 ng/mL exhibited significantly higher odds ratios for developing atherogenic dyslipidemia in a dose-response pattern compared to those with vitamin D levels above 30 ng/mL. Notably, structural equation modeling (SEM) analysis revealed that vitamin D did not affect atherogenic lipid markers through the mediation of insulin resistance markers or high-sensitivity C-reactive protein. CONCLUSION: This study provides evidence of an association between vitamin D deficiency and atherogenic dyslipidemia in young adults. It further highlights that individuals with serum 25(OH)D levels below 30 ng/mL are at a significantly higher risk of developing atherogenic dyslipidemia in a dose-response manner compared to those with higher vitamin D levels. These findings underscore the potential role of vitamin D in dyslipidemia management and emphasize the importance of maintaining sufficient vitamin D levels for cardiovascular health in young adults.

Glycative Stress, Glycated Hemoglobin, and Atherogenic Dyslipidemia in Patients with Hyperlipidemia.

(1) Background: Diabetes mellitus (DM) is a significant health problem and is associated with dyslipidemia; however, the association between glycative stress, in terms of glycated hemoglobin (HbA1c), and atherogenic dyslipidemia in hyperlipidemic patients with and without DM has rarely been reported. (2) Methods: We prospectively recruited 949 hyperlipidemic patients from the Lipid Clinic of the National Taiwan University Hospital. HbA1c and fasting serum lipids, including total cholesterol (TC), high- and low-density lipoprotein cholesterol (HDL-C and LDL-C), small dense LDL-C (sdLDL-C), very low-density lipoprotein cholesterol (VLDL-C), triglycerides, and advanced glycation end-products (AGEs), were measured. After fasting for 10-14 h, all subjects except those with DM underwent a standard oral glucose tolerance test (OGTT) with 75 g of glucose loading. All subjects were asked to discontinue the use of lipid-lowering agents for 8 weeks before recruitment. (3) Results: Patients with DM had a higher prevalence of hypertension and higher levels of triglyceride, TC/HDL-C ratio, AGEs, VLDL-C, and sdLDL-C. Among patients with higher HbA1c, the serum VLDL-C, AGEs, and TC/HDL-C ratio were significantly higher than those with lower HbA1c. After adjustment for covariates, multiple logistic regression analyses revealed different groups of dysglycemia with higher HbA1c had a higher odds ratio for TC/HDL-C ≥ 5, sdLDL-C ≥ 75th percentile, VLDL-C ≥ 75th percentile and AGEs ≥ 75th percentile. (4) Conclusions: A higher HbA1c was associated with a significant increase in the risk of atherogenic dyslipidemia and AGEs levels in patients with hyperlipidemia. The findings can be very promising in clinical application.

Association of Urinary Lead and Cadmium Levels, and Serum Lipids with Subclinical Arteriosclerosis: Evidence from Taiwan.

BACKGROUND: Exposure to lead and cadmium has been linked to changes in lipid metabolism and the development of arteriosclerosis, but the role of lipoprotein profiles in this relationship is not well understood, including the potential role of novel lipid biomarkers. METHODS: In this study, we enrolled 736 young Taiwanese subjects aged 12 to 30 years to assess the correlation between urine levels of lead and cadmium, lipoprotein profiles, and carotid intima-media thickness (CIMT). RESULTS: Higher levels of lead and cadmium were significantly associated with higher levels of low-density lipoprotein cholesterol (LDL-C), small dense LDL-C (sdLDL-C), LDL-triglyceride (LDL-TG), and CIMT. Participants with higher levels of lead and cadmium had the highest mean values of CIMT, LDL-C, sdLDL-C, and LDL-TG. In a structural equation model, lead had a direct and indirect association with CIMT through LDL-C and sdLDL-C, whereas cadmium had a direct association with CIMT and an indirect association through LDL-C. CONCLUSION: Our results suggest higher levels of lead and cadmium are associated with abnormal lipid profiles and increased CIMT. These heavy metals could have additive effects on lipids and CIMT, and the relationship between them may be mediated by lipoprotein levels. Further research is needed to determine the causal relationship.

Surface plasmon-enhanced fluorescence and surface-enhanced Raman scattering dual-readout chip constructed with silver nanowires: Label-free clinical detection of direct-bilirubin.

It has been found that the direct/total bilirubin ratio (D/T-BIL) is related to the survival rate of COVID-19 pneumonia. The presence of an excessive amount of bilirubin in human blood also causes liver and neurological damage, leading to death. Therefore, upon considering the adverse impact of the presence of excessive bilirubin in human blood, it has become highly imperative to detect bilirubin in a fast and label-free manner. Herein, we designed and constructed a random-crossed-woodpile nanostructure from silver nanowires to form a 3-dimensional plasmonic hotspot-rich (3D-PHS) nanostructure and successfully used it to detect direct bilirubin (D-BIL) in human blood in a label-free manner. The 3D-PHS nanochip provides rich spatial hot spots that are simultaneously responsive to SERS and SPEF effects and consequently, successfully used to measure and characterize D-BIL with a detection limit of ∼10 nM, requiring only 10µL of human serum for rapid screening, which is the first time D-BIL has been detected in a clinically relevant range. This demonstrates a simple, label-free, pretreatment-free potential biosensing technology that can be used in health care units, and further, in the efficient detection of point-of-care testing with a portable spectrometer.

Association between Vitamin D Deficiency and High Serum Levels of Small Dense LDL in Middle-Aged Adults.

Recent studies suggested a potential link between vitamin D deficiency and cardiovascular risk factors, including dyslipidemia. This study aimed to investigate the association between serum 25(OH)D levels and atherogenic lipid profiles, specifically, that of small dense low-density lipoprotein-cholesterol (sdLDL-C). From 2009 to 2011, a total of 715 individuals aged 35-65 without evident cardiovascular disease (CVD) were enrolled. Their levels of serum 25(OH)D and lipid profiles were measured. Vitamin D deficiency was found to be more common in females, smokers, alcohol drinkers, individuals at a younger age, and those who do not exercise regularly. The analysis of lipid profiles revealed that high sdLDL-C levels were associated with low serum vitamin D levels and were more common among cigarette smokers; alcohol drinkers; individuals with hypertension; individuals with high BMI; and those with high levels of fasting blood glucose, triglycerides, LDL-C, and VLDL-C. The use of multivariate logistic regression verified a strong negative correlation between low vitamin D status (serum 25(OH)D < 15 ng/mL) and the three identified biomarkers of atherogenic dyslipidemia: high serum levels of sdLDL-C, triglycerides, and VLDL-C. This study provides strong evidence that vitamin D deficiency is associated with atherogenic dyslipidemia, and in particular, high sdLDL-C levels in middle-aged adults without CVD.

Positive Association Between Small Dense Low-Density Lipoprotein Cholesterol Concentration and Biomarkers of Inflammation, Thrombosis, and Prediabetes in Non-Diabetic Adults.

AIMS: Recent studies suggest elevated levels of small dense low-density lipoprotein cholesterol (sdLDL-C) can predict the risk of incident coronary heart disease (CHD), even in individuals considered to be at low risk for cardiovascular disease(CVD) based on their LDL-C levels. This study aims to prospectively investigate the association between sdLDL-C concentration and traditional and nontraditional CHD risk markers to explore the underlying roles of sdLDL-C in atherogenic processes. METHODS: Between 2009 and 2011, 594 healthy volunteers aged 35-65 years were recruited as control subjects in a study of work-related risk factors and acute CHD. All participants fasted for 12-14 h, and venous blood samples were collected in the morning to measure serum lipid profiles and other CHD-related markers. A standard oral glucose tolerance test was performed on all participants to assess their subclinical diabetes and prediabetes status. RESULTS: There were significantly positive associations between sdLDL-C concentration and traditional (age, smoking and alcohol drinking habit, blood pressure, body mass index (BMI), serum lipid profiles, and diabetes status) and nontraditional risk factors (complete blood counts, (CBC), fibrinogen, high-sensitivity C-reactive protein, and subclinical diabetes status) for CVD. After adjusting for confounding variables which include age, gender, BMI, hypertension, household income, and smoking and alcohol drinking habits, all atherosclerotic risk markers except D-dimer were significantly and positively associated with sdLDL-C. CONCLUSIONS: Our data indicated sdLDL-C is strongly associated with atherosclerotic risk markers, such as inflammation, thrombosis, hematological markers, and prediabetes. This study supports the hypothesis that sdLDL-C is a promising CVD risk biomarker.

Opioids for Chronic Noncancer Pain: A Systematic Review and Meta-analysis.

Importance: Harms and benefits of opioids for chronic noncancer pain remain unclear. Objective: To systematically review randomized clinical trials (RCTs) of opioids for chronic noncancer pain. Data Sources and Study Selection: The databases of CENTRAL, CINAHL, EMBASE, MEDLINE, AMED, and PsycINFO were searched from inception to April 2018 for RCTs of opioids for chronic noncancer pain vs any nonopioid control. Data Extraction and Synthesis: Paired reviewers independently extracted data. The analyses used random-effects models and the Grading of Recommendations Assessment, Development and Evaluation to rate the quality of the evidence. Main Outcomes and Measures: The primary outcomes were pain intensity (score range, 0-10 cm on a visual analog scale for pain; lower is better and the minimally important difference [MID] is 1 cm), physical functioning (score range, 0-100 points on the 36-item Short Form physical component score [SF-36 PCS]; higher is better and the MID is 5 points), and incidence of vomiting. Results: Ninety-six RCTs including 26 169 participants (61% female; median age, 58 years [interquartile range, 51-61 years]) were included. Of the included studies, there were 25 trials of neuropathic pain, 32 trials of nociceptive pain, 33 trials of central sensitization (pain present in the absence of tissue damage), and 6 trials of mixed types of pain. Compared with placebo, opioid use was associated with reduced pain (weighted mean difference [WMD], -0.69 cm [95% CI, -0.82 to -0.56 cm] on a 10-cm visual analog scale for pain; modeled risk difference for achieving the MID, 11.9% [95% CI, 9.7% to 14.1%]), improved physical functioning (WMD, 2.04 points [95% CI, 1.41 to 2.68 points] on the 100-point SF-36 PCS; modeled risk difference for achieving the MID, 8.5% [95% CI, 5.9% to 11.2%]), and increased vomiting (5.9% with opioids vs 2.3% with placebo for trials that excluded patients with adverse events during a run-in period). Low- to moderate-quality evidence suggested similar associations of opioids with improvements in pain and physical functioning compared with nonsteroidal anti-inflammatory drugs (pain: WMD, -0.60 cm [95% CI, -1.54 to 0.34 cm]; physical functioning: WMD, -0.90 points [95% CI, -2.69 to 0.89 points]), tricyclic antidepressants (pain: WMD, -0.13 cm [95% CI, -0.99 to 0.74 cm]; physical functioning: WMD, -5.31 points [95% CI, -13.77 to 3.14 points]), and anticonvulsants (pain: WMD, -0.90 cm [95% CI, -1.65 to -0.14 cm]; physical functioning: WMD, 0.45 points [95% CI, -5.77 to 6.66 points]). Conclusions and Relevance: In this meta-analysis of RCTs of patients with chronic noncancer pain, evidence from high-quality studies showed that opioid use was associated with statistically significant but small improvements in pain and physical functioning, and increased risk of vomiting compared with placebo. Comparisons of opioids with nonopioid alternatives suggested that the benefit for pain and functioning may be similar, although the evidence was from studies of only low to moderate quality.

Predominance of triple wild-type and IGF2R mutations in mucosal melanomas.

BACKGROUND: Primary mucosal melanoma (MM) is a rare subtype of melanoma that arises from melanocytes in the mucosa. MM has not been well profiled for mutations and its etiology is not well understood, rendering current treatment strategies unsuccessful. Hence, we investigated mutational landscape for MM to understand its etiology and to clarify mutations that are potentially relevant for MM treatment. METHODS: Forty one MM and 48 cutaneous melanoma (CM) tissues were profiled for mutations using targeted deep next-generation sequencing (NGS) for 89 cancer-related genes. A total of 997 mutations within exons were analyzed for their mutational spectrum and prevalence of mutation, and 685 non-synonymous variants were investigated to identify mutations in individual genes and pathways. PD-L1 expression from 21 MM and 18 CM were assessed by immunohistochemistry. RESULTS: Mutational spectrum analysis revealed a lower frequency of UV-induced DNA damage in MM than in CM (p = 0.001), while tobacco exposure was indicated as a potential etiologic factor for MM. In accordance with low UV damage signatures, MM demonstrated an overall lower number of mutations compared to CM (6.5 mutations/Mb vs 14.8 mutations/Mb, p = 0.001), and less PD-L1 expression (p = 0.003). Compared to CM, which showed frequent mutations in known driver genes (BRAF 50.0%, NRAS 29.2%), MM displayed lower mutation frequencies (BRAF; 12.2%, p < 0.001, NRAS; 17.1%), and was significantly more enriched for triple wild-type (no mutations in BRAF, RAS, or NF1, 70.7% vs 25.0%, p < 0.001), IGF2R mutation (31.7% vs 6.3%, p = 0.002), and KIT mutation (9.8% vs 0%, p = 0.042). Of clinical relevance, presence of DCC mutations was significantly associated with poorer overall survival in MM (log-rank test, p = 0.02). Furthermore, mutational spectrum analysis distinguished primary anorectal MM from CM metastasized to the bowel (spectrum analysis p < 0.001, number of mutations p = 0.002). CONCLUSIONS: These findings demonstrated a potential etiologic factor and driver mutation for MM and strongly suggested that MM initiation or progression involves distinct molecular-mechanisms from CM. This study also identified mutational signatures that are clinically relevant for MM treatment.

The Epigenomic Landscape of Pituitary Adenomas Reveals Specific Alterations and Differentiates Among Acromegaly, Cushing's Disease and Endocrine-Inactive Subtypes.

Purpose: Pituitary adenomas are one of the most common benign neoplasms of the central nervous system. Although emerging evidence suggests roles for both genetic and epigenetic factors in tumorigenesis, the degree to which these factors contribute to disease remains poorly understood.Experimental Design: A multiplatform analysis was performed to identify the genomic and epigenomic underpinnings of disease among the three major subtypes of surgically resected pituitary adenomas in 48 patients: growth hormone (GH)-secreting (n = 17), adrenocorticotropic hormone (ACTH)-secreting (n = 13, including 3 silent-ACTH adenomas), and endocrine-inactive (n = 18). Whole-exome sequencing was used to profile the somatic mutational landscape, whole-transcriptome sequencing was used to identify disease-specific patterns of gene expression, and array-based DNA methylation profiling was used to examine genome-wide patterns of DNA methylation.Results: Recurrent single-nucleotide and small indel somatic mutations were infrequent among the three adenoma subtypes. However, somatic copy-number alterations (SCNA) were identified in all three pituitary adenoma subtypes. Methylation analysis revealed adenoma subtype-specific DNA methylation profiles, with GH-secreting adenomas being dominated by hypomethylated sites. Likewise, gene-expression patterns revealed adenoma subtype-specific profiles. Integrating DNA methylation and gene-expression data revealed that hypomethylation of promoter regions are related with increased expression of GH1 and SSTR5 genes in GH-secreting adenomas and POMC gene in ACTH-secreting adenomas. Finally, multispectral IHC staining of immune-related proteins showed abundant expression of PD-L1 among all three adenoma subtypes.Conclusions: Taken together, these data stress the contribution of epigenomic alterations to disease-specific etiology among adenoma subtypes and highlight potential targets for future immunotherapy-based treatments. This article reveals novel insights into the epigenomics underlying pituitary adenomas and highlights how differences in epigenomic states are related to important transcriptome alterations that define adenoma subtypes. Clin Cancer Res; 24(17); 4126-36. ©2018 AACR.

Primary brain calcification: an international study reporting novel variants and associated phenotypes.

Primary familial brain calcification (PFBC) is a rare cerebral microvascular calcifying disorder with a wide spectrum of motor, cognitive, and neuropsychiatric symptoms. It is typically inherited as an autosomal-dominant trait with four causative genes identified so far: SLC20A2, PDGFRB, PDGFB, and XPR1. Our study aimed at screening the coding regions of these genes in a series of 177 unrelated probands that fulfilled the diagnostic criteria for primary brain calcification regardless of their family history. Sequence variants were classified as pathogenic, likely pathogenic, or of uncertain significance (VUS), based on the ACMG-AMP recommendations. We identified 45 probands (25.4%) carrying either pathogenic or likely pathogenic variants (n = 34, 19.2%) or VUS (n = 11, 6.2%). SLC20A2 provided the highest contribution (16.9%), followed by XPR1 and PDGFB (3.4% each), and PDGFRB (1.7%). A total of 81.5% of carriers were symptomatic and the most recurrent symptoms were parkinsonism, cognitive impairment, and psychiatric disturbances (52.3%, 40.9%, and 38.6% of symptomatic individuals, respectively), with a wide range of age at onset (from childhood to 81 years). While the pathogenic and likely pathogenic variants identified in this study can be used for genetic counseling, the VUS will require additional evidence, such as recurrence in unrelated patients, in order to be classified as pathogenic.

MiR-200a Regulates CDK4/6 Inhibitor Effect by Targeting CDK6 in Metastatic Melanoma.

The CDK4/6 pathway is frequently dysregulated in cutaneous melanoma. Recently, CDK4/6 inhibitors have shown promising clinical activity against several cancer types, including melanoma. Here, we show that microRNA-200a decreases CDK6 expression and thus reduces the response of CDK4/6 inhibitor in highly proliferative metastatic melanoma. Down-regulation of microRNA-200a expression in melanoma cells is associated with disease progression and a higher number of lymph node metastases. Furthermore, microRNA-200a expression is epigenetically modulated by both DNA methylation at the promoter region and chromatin accessibility of an upstream genomic region with enhancer activity. Mechanistically, overexpression of miR-200a in metastatic melanoma cells induces cell cycle arrest by targeting CDK6 and decreases the levels of phosphorylated-Rb1 and E2F-downstream targets, diminishing cell proliferation; these effects are recovered by CDK6 overexpression. Conversely, low microRNA-200a expression in metastatic melanoma cells results in higher levels of CDK6 and a more significant response to CDK4/6 inhibitors. We propose that microRNA-200a functions as a "cell cycle brake" that is lost during melanoma progression to metastasis and provides the ability to identify melanomas that are highly proliferative and more prompted to respond to CDK4/6 inhibitors.

Epigenetic Regulation of KPC1 Ubiquitin Ligase Affects the NF-κB Pathway in Melanoma.

Purpose: Abnormal activation of the NF-κB pathway induces a more aggressive phenotype of cutaneous melanoma. Understanding the mechanisms involved in melanoma NF-κB activation may identify novel targets for this pathway. KPC1, an E3 ubiquitin ligase, is a regulator of the NF-κB pathway. The objective of this study was to investigate the mechanisms regulating KPC1 expression and its clinical impact in melanoma.Experimental Design: The clinical impact of KPC1 expression and its epigenetic regulation were assessed in large cohorts of clinically well-annotated melanoma tissues (tissue microarrays; n = 137, JWCI cohort; n = 40) and The Cancer Genome Atlas database (TCGA cohort, n = 370). Using melanoma cell lines, we investigated the functional interactions between KPC1 and NF-κB, and the epigenetic regulations of KPC1, including DNA methylation and miRNA expression.Results: We verified that KPC1 suppresses melanoma proliferation by processing NF-κB1 p105 into p50, thereby modulating NF-κB target gene expression. Concordantly, KPC1 expression was downregulated in American Joint Committee on Cancer stage IV melanoma compared with early stages (stage I/II P = 0.013, stage III P = 0.004), and low KPC1 expression was significantly associated with poor overall survival in stage IV melanoma (n = 137; HR 1.810; P = 0.006). Furthermore, our data showed that high miR-155-5p expression, which is controlled by DNA methylation at its promoter region (TCGA; Pearson's r -0.455; P < 0.001), is significantly associated with KPC1 downregulation (JWCI; P = 0.028, TCGA; P = 0.003).Conclusions: This study revealed novel epigenetic regulation of KPC1 associated with NF-κB pathway activation, promoting metastatic melanoma progression. These findings suggest the potential utility of KPC1 and its epigenetic regulation as theranostic targets. Clin Cancer Res; 23(16); 4831-42. ©2017 AACR.

Genome-wide chromatin accessibility, DNA methylation and gene expression analysis of histone deacetylase inhibition in triple-negative breast cancer.

Triple-negative breast cancer (TNBC), especially the subset with a basal phenotype, represents the most aggressive subtype of breast cancer. Unlike other solid tumors, TNBCs harbor a low number of driver mutations. Conversely, we and others have demonstrated a significant impact of epigenetic alterations, including DNA methylation and histone post-translational modifications, affecting TNBCs. Due to the promising results in pre-clinical studies, histone deacetylase inhibitors (HDACi) are currently being tested in several clinical trials for breast cancer and other solid tumors. However, the genome-wide epigenetic and transcriptomic implications of HDAC inhibition are still poorly understood. Here, we provide detailed information about the design of a multi-platform dataset that describes the epigenomic and transcriptomic effects of HDACi. This dataset includes genome-wide chromatin accessibility (assessed by ATAC-Sequencing), DNA methylation (assessed by Illumina HM450K BeadChip) and gene expression (assessed by RNA-Sequencing) analyses before and after HDACi treatment of HCC1806 and MDA-MB-231, two human TNBC cell lines with basal-like phenotype.

Association of short-term exposure to fine particulate matter and nitrogen dioxide with acute cardiovascular effects.

This study evaluated whether exposure to fine particulate matter (PM2.5) and nitrogen dioxide (NO2) is associated with cardiovascular effects by examining a panel of 89 healthy subjects in Taipei, Taiwan. The subjects received two health examinations approximately 8months apart in 2013. Brachial-ankle pulse wave velocity (baPWV), a physiological indicator of arterial stiffness, and high-sensitivity C-reactive protein (hsCRP), a biomarker of vascular inflammations, were measured during each examination. Two exposure assessment methods were used for estimating the subjects' exposure to PM2.5 and NO2. The first method involved constructing daily land use regression (LUR) models according to measurements collected at ambient air quality monitoring stations. The second method required combining the LUR estimates with indoor monitoring data at the workplace of the subjects. Linear mixed models were used to examine the association between the exposure estimates and health outcomes. The results showed that a 10-µg/m(3) increase in PM2.5 concentration at a 1-day lag was associated with 2.1% (95% confidence interval: 0.7%-3.6%) and 2.4% (0.8%-4.0%) increases in baPWV based on the two exposure assessment methods, whereas no significant association was observed for NO2. The significant effects of PM2.5 remained in the two-pollutant models. By contrast, NO2, but not PM2.5, was significantly associated with increased hsCRP levels (16.0%-37.3% in single-pollutant models and 26.4%-44.6% in two-pollutant models, per 10-ppb increase in NO2). In conclusion, arterial stiffness might be more sensitive to short-term PM2.5 exposure than is inflammation.

Association of Psychosocial Work Hazards With Depression and Suboptimal Health in Executive Employees.

OBJECTIVES: This study aims to investigate whether psychosocial work-related hazards, measured by workplace justice and employment insecurity, are associated with depression and suboptimal health status in Taiwan's executive-level employees. METHODS: There were 365 executives who have received a series of cardiovascular health examinations, blood sampling, and self-reported questionnaires, which included the psychosocial work-related hazards and the CES-D scale. Suboptimal health status was defined as the presence of dyslipidemia or prediabetes. RESULTS: Executive-level employees perceived lower workplace justice and higher employment insecurity and had a significantly higher risk of depression (CES-D scores ≥16 or ≥23). However, workplace justice was identified as a significant determinant factor that was negative for dyslipidemia but protective for prediabetes. CONCLUSION: This study supports the fact that psychosocial work-related hazards can independently contribute to the risk of developing depression, prediabetes, and dyslipemia in executives.

Validation of the Estimation of Low-density Lipoprotein Cholesterol by the Modified Friedewald Equation in Ethnic Chinese Adults Living in Taiwan.

OBJECTIVE: The Friedewald equation has been used as the standard formula for the estimation of very low-density lipoprotein cholesterol (VLDL-C) to calculate the serum levels of low-density lipoprotein cholesterol (LDL-C). However, the usefulness of this formula in non-Caucasians has been challenged in recent years. The aim of this study was to assess the validity of the conventional and modified Friedewald equation in an ethnic Chinese adult population. METHODS: We prospectively recruited 938 subjects from the Lipid Clinic of the National Taiwan University Hospital. The fasting lipids, including cholesterol, high-density lipoprotein cholesterol, LDL-C, VLDL-C, and triglycerides (TGs), of each participant were measured and we constructed a prediction model for the estimation of LDL-C by the modified Friedewald equation. RESULTS: The constant values, used to estimate the VLDL-C concentration, were different in the Friedewald equation in the subgroups exhibiting different cardiovascular characteristics, ranging from 4.45 to 6.63, if we calculated the equation by a direct LDL-C measurement. According to the results of a stepwise multiple linear regression analysis excluding the TG levels ≥400 mg/dL, an equation for the individual constant Y estimation was as follows: Constant Y = 4.39 + (-0.59) if the age ≥50 years + 0.98 if men + TG group (2.06 if the TG levels were between 150-399 mg/dL; 1.07 if the TG levels were between 100-149 mg/dL) + (-0.49) if the cholesterol levels ≥240 mg/dL + the body mass index (BMI) group (0.8 if BMI ≥27 kg/m(2); 0.48 if BMI =24-27 kg/m(2)). CONCLUSION: This modified Friedewald formula provides a new and simple equation for calculating the LDL-C levels in ethnic Chinese people.

The CASC15 Long Intergenic Noncoding RNA Locus Is Involved in Melanoma Progression and Phenotype Switching.

In recent years, considerable advances have been made in the characterization of protein-coding alterations involved in the pathogenesis of melanoma. However, despite their growing implication in cancer, little is known about the role of long noncoding RNAs in melanoma progression. We hypothesized that copy number alterations (CNAs) of intergenic nonprotein-coding domains could help identify long intergenic noncoding RNAs (lincRNAs) associated with metastatic cutaneous melanoma. Among several candidates, our approach uncovered the chromosome 6p22.3 CASC15 (cancer susceptibility candidate 15) lincRNA locus as a frequently gained genomic segment in metastatic melanoma tumors and cell lines. The locus was actively transcribed in metastatic melanoma cells, and upregulation of CASC15 expression was associated with metastatic progression to brain metastasis in a mouse xenograft model. In clinical specimens, CASC15 levels increased during melanoma progression and were independent predictors of disease recurrence in a cohort of 141 patients with AJCC (American Joint Committee on Cancer) stage III lymph node metastasis. Moreover, small interfering RNA (siRNA) knockdown experiments revealed that CASC15 regulates melanoma cell phenotype switching between proliferative and invasive states. Accordingly, CASC15 levels correlated with known gene signatures corresponding to melanoma proliferative and invasive phenotypes. These findings support a key role for CASC15 in metastatic melanoma.

Reporting of IMMPACT-recommended core outcome domains among trials assessing opioids for chronic non-cancer pain.

The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) has recommended that trialists evaluating treatments for chronic pain should consider reporting 9 patient-important outcome domains. We examined the extent to which clinical trials evaluating the effect of opioids for chronic non-cancer pain (CNCP) report outcome domains recommended by IMMPACT. We systematically searched electronic databases for English-language studies that randomized patients with CNCP to receive an opioid or a non-opioid control. In duplicate and independently, reviewers established the eligibility of each identified study and recorded all reported outcome domains from eligible trials. We conducted a priori regression analyses to explore factors that may be associated with IMMPACT-recommended outcome domains. Among 156 eligible trials, reporting of IMMPACT-recommended outcome domains was highly variable, ranging from 99% for pain to 7% for interpersonal functioning. Recently published trials were more likely to report the effect of treatment on physical functioning, emotional functioning, role functioning, sleep and fatigue, and participant disposition. Trials for which the corresponding author was from North America were more likely to report treatment effects on physical functioning and participant ratings of improvement and satisfaction with treatment. Trials published in higher impact journals were more likely to report treatment effects on emotional function, but less likely to report participant ratings of improvement and satisfaction with treatment. Most IMMPACT domains showed an increased rate of reporting over time, although many patient-important outcome domains remained unreported by over half of all trials evaluating the effects of opioids for CNCP.

A novel mutation P112H in the TARDBP gene associated with frontotemporal lobar degeneration without motor neuron disease and abundant neuritic amyloid plaques.

INTRODUCTION: Although TDP-43 is the main constituent of the ubiquitinated cytoplasmic inclusions in the most common forms of frontotemporal lobar degeneration, TARDBP mutations are not a common cause of familial frontotemporal dementia, especially in the absence of motor neuron disease. RESULTS: We describe a pedigree presenting with a complex autosomal dominant disease, with a heterogeneous clinical phenotype, comprising unspecified dementia, parkinsonism, frontotemporal dementia and motor neuron disease. Genetic analyses identified a novel P112H TARDBP double variation located in exon 3 coding for the first RNA recognition motif of the protein (RRM1). This double mutation is probably pathogenic based on neuropathological findings, in silico prediction analysis and exome sequencing. The two autopsied siblings described here presented with frontotemporal dementia involving multiple cognitive domains and behavior but lacking symptoms of motor neuron disease throughout the disease course. The siblings presented with strikingly similar, although atypical, neuropathological features, including an unclassifiable TDP-43 inclusion pattern, a high burden of tau-negative ß-amyloid neuritic plaques with an AD-like biochemical profile, and an unclassifiable 4-repeat tauopathy. The co-occurrence of multiple protein inclusions points to a pathogenic mechanism that facilitates misfolded protein interaction and aggregation or a loss of TDP-43 function that somehow impairs protein clearance. CONCLUSIONS: TARDBP mutation screening should be considered in familial frontotemporal dementia cases, even without signs or symptoms of motor neuron disease, especially when other more frequent causes of genetic frontotemporal dementia (i.e. GRN, C9ORF72, MAPT) have been excluded and when family history is complex and includes parkinsonism, motor neuron disease and frontotemporal dementia. Further investigations in this family may provide insight into the physiological functions of TARDBP.

Association between perfluoroalkyl substances and reproductive hormones in adolescents and young adults.

BACKGROUND: Few studies have explored the association between perfluoroalkyl substances (PFAS) and reproductive hormones in adolescents and young adults. OBJECTIVES: This study aimed to investigate the association of PFAS with reproductive hormones in adolescents and young adults. METHODS: We recruited 540 subjects aged 12-30 years from a 1992 to 2000 mass urine screening population and established a cohort from 2006 to 2008 via invitations by mail or/and telephone. Serum PFAS levels were analyzed with a Waters ACQUITY UPLC system coupled with a Waters Quattro Premier XE triple quadrupole mass spectrometer. Serum reproductive hormone levels were measured by immunoluminometric assay with an Architect random access assay system. PFAS levels were divided into different percentiles according to their detection limits in the multiple regression models to analyze associations between reproductive hormone levels and exposure with PFAS. RESULTS: The adjusted mean serum level of sex hormone-binding globulin (SHBG) decreased significantly in association with the <50th, 50-75, 75-90 and >90th percentile categories of perfluorooctanoic acid (PFOA) compared with a reference category for the females in the 12-17-year-old group. The follicle-stimulating hormone (FSH) levels were significantly decreased in association with the different percentile categories of perfluorooctane sulfonate (PFOS) in the male 12-17-year-old group and the different percentile categories of perfluoroundecanoic acid (PFUA) in the female 12-17-year-old group. The serum FSH levels in the females aged 12-17 were also decreased in association with the different percentile categories of PFUA. On the other hand, there was a significantly negative association between the different percentile categories of PFOS and the serum testosterone level among the female 12-17-year-old group. CONCLUSIONS: We found that the serum concentrations of PFOA, PFOS, and PFUA were negatively associated with the serum levels of SHBG, FSH, and testosterone in the young Taiwanese population and that these effects were the strongest in the females aged 12-17. Further studies are needed to determine whether these associations are causal.