Cholangiocarcinoma 2020: the next horizon in mechanisms and management.

Cholangiocarcinoma (CCA) includes a cluster of highly heterogeneous biliary malignant tumours that can arise at any point of the biliary tree. Their incidence is increasing globally, currently accounting for ~15% of all primary liver cancers and ~3% of gastrointestinal malignancies. The silent presentation of these tumours combined with their highly aggressive nature and refractoriness to chemotherapy contribute to their alarming mortality, representing ~2% of all cancer-related deaths worldwide yearly.

Function of Torsin AAA+ ATPases in Pseudorabies Virus Nuclear Egress.

Newly assembled herpesvirus nucleocapsids traverse the intact nuclear envelope by a vesicle-mediated nucleo-cytoplasmic transport for final virion maturation in the cytoplasm. For this, they bud at the inner nuclear membrane resulting in primary enveloped particles in the perinuclear space (PNS) followed by fusion of the primary envelope with the outer nuclear membrane (ONM). While the conserved viral nuclear egress complex orchestrates the first steps, effectors of fusion of the primary virion envelope with the ONM are still mostly enigmatic but might include cellular proteins like SUN2 or ESCRT-III components.

Development of a pulsatile cadaver-based simulation for training of open abdominal vascular surgery skills.

Objective: Developing competence in open aortic surgery is increasingly challenging in vascular surgery training programs. Although static cadaver models provide an opportunity for dissection and exposure, the lack of pulsatility limits further education in managing blood vessels. We developed an affordable pulsatile cadaver simulation model to improve training in open abdominal aortic surgery with the primary objective of determining whether it incorporated the fidelity required to teach critical surgical techniques.

Replication of Newly Identified Genetic Associations Between Abdominal Aortic Aneurysm and SMYD2, LINC00540, PCIF1/MMP9/ZNF335, and ERG.

Objective: A recently published genome wide association study of abdominal aortic aneurysms (AAA), based on pooled case control data of European ancestry, identified four new loci for AAA: SMYD2 (top single nucleotide polymorphism [SNP] rs1795061), LINC00540 (rs9316871), PCIF1/MMP9/ZNF335 (rs3827066), and ERG (rs2836411). Of the four, rs1795061 and rs2836411 showed significant heterogeneity across studies and the p value for rs9316871 did not reach the genome wide significance threshold until discovery and replication data were pooled together in that study. The objective of this study was to replicate these newly identified genetic associations for AAA in a US based prospective cohort study, the Atherosclerosis Risk in Communities (ARIC) Study, and a Greece based case control study.

Effect of beam configuration with inaccurate or incomplete small field output factors on the accuracy of treatment planning dose calculation.

Purpose: To evaluate the effect of beam configuration with inaccurate or incomplete small field output factors on the accuracy of dose calculations in treatment planning systems.

Methods: Output factors were measured using various detectors and for a range of field sizes. Three types of treatment machines were configured in two treatment planning systems.

DYT1 Dystonia Patient-Derived Fibroblasts Have Increased Deformability and Susceptibility to Damage by Mechanical Forces.

DYT1 dystonia is a neurological movement disorder that is caused by a loss-of-function mutation in the / gene, which encodes torsinA, a conserved luminal ATPases-associated with various cellular activities (AAA+) protein. TorsinA is required for the assembly of functional linker of nucleoskeleton and cytoskeleton (LINC) complexes, and consequently the mechanical integration of the nucleus and the cytoskeleton. Despite the potential implications of altered mechanobiology in dystonia pathogenesis, the role of torsinA in regulating cellular mechanical phenotype, or mechanotype, in DYT1 dystonia remains unknown.

The Association of Aromatic Amino Acids with Incident Hip Fracture, aBMD, and Body Composition from the Cardiovascular Health Study.

In 5187 persons from the Cardiovascular Health Study, there was no significant association of dietary intakes of aromatic amino acids (AAA) with areal BMD of the hip or body composition. However, those who had the lowest dietary intakes of AAA were at increased risk for incident hip fractures. Prior studies of the association of protein intake with osteoporosis are conflicting and have not directly examined the relationship of aromatic amino acids (AAA) with fractures, areal bone mineral density (aBMD), and body composition.

Inhibitory Effects of Green Tea Polyphenols on Microbial Metabolism of Aromatic Amino Acids in Humans Revealed by Metabolomic Analysis.

The bioactivities and potential health benefits of green tea polyphenols (GTP) have been extensively investigated, but the metabolic impact of chronic GTP intake on humans is not well defined. In this study, fecal and urine samples from postmenopausal female subjects taking a GTP supplement or placebo for 12 months were compared by liquid chromatography-mass spectrometry-based metabolomic analysis. The GTP-derived and GTP-responsive metabolites were identified and characterized by structural elucidation and quantitative analysis of the metabolites contributing to the separation of control and treatment samples in the multivariate models.

Association of Life's Simple 7 with reduced clinically manifest abdominal aortic aneurysm: The ARIC study.

To optimize cardiovascular health, the American Heart Association (AHA) has recommended 'Life's Simple 7 (LS7)'. We tested the hypothesis that greater adherence to the LS7 cardiovascular risk metric is associated with reduced risk of developing abdominal aortic aneurysm (AAA). A total of 14,375 black and white participants aged 45-64 years at the baseline visit of the Atherosclerosis Risk in Communities (ARIC) study cohort were included in this analysis.

Adherence to the Dietary Approaches to Stop Hypertension Dietary Pattern and Risk of Abdominal Aortic Aneurysm: Results From the ARIC Study.

Background The role of a healthy dietary pattern in the prevention of abdominal aortic aneurysms ( AAA ) is unknown. We aimed to evaluate the relationship between adherence to a Dietary Approaches To Stop Hypertension-style dietary pattern and the risk of incident AAA s. Methods and Results Dietary intake was assessed via a 66-item food frequency questionnaire at baseline (1987-1989) and at visit 3 (1993-1995) in 13 496 participants enrolled in the ARIC (Atherosclerosis Risk in Communities) study without clinical AAA (mean age, 54 years).

Chronic kidney disease measures and the risk of abdominal aortic aneurysm.

Background And Aims: Despite its strong link to cardiovascular outcomes, the association of chronic kidney disease (CKD) with abdominal aortic aneurysm (AAA) has not been explicitly and comprehensively investigated.

Methods: In 10,724 participants in the Atherosclerosis Risk in Communities Study (aged 53-75 years during 1996-1998), we evaluated the associations of two key CKD measures - estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (ACR) - with incident AAA (AAA diagnosis in outpatient, hospitalization discharge, or death records). Additionally, we performed a cross-sectional analysis for the CKD measures and ultrasound-based abdominal aortic diameter in 4258 participants during 2011-2013.

The Association of Biomarkers of Inflammation and Extracellular Matrix Degradation With the Risk of Abdominal Aortic Aneurysm: The ARIC Study.

Animal and human laboratory studies suggest that the pathogenesis of abdominal aortic aneurysms (AAAs) involves inflammation and degradation and remodeling of the extracellular matrix. This study prospectively assessed the association between biomarkers for these mechanisms and the presence of AAA during 24 years of follow-up in the Atherosclerosis Risk in Communities (ARIC) study. The ARIC prospectively identified clinically diagnosed AAAs in 15 792 men and women from baseline in 1987 to 1989 to 2011 using hospital discharge codes and death records.

Evaluation of the relationship between plasma lipids and abdominal aortic aneurysm: A Mendelian randomization study.

Studies have reported that higher circulating levels of total cholesterol (TC), low-density lipoprotein (LDL) cholesterol and lower of high-density lipoprotein (HDL) cholesterol may be associated with increased risk of abdominal aortic aneurysm (AAA). Whether dyslipidemia causes AAA is still unclear and is potentially testable using a Mendelian randomization (MR) approach. We investigated the associations between blood lipids and AAA using two-sample MR analysis with SNP-lipids association estimates from a published genome-wide association study of blood lipids (n = 188,577) and SNP-AAA association estimates from European Americans (EAs) of the Atherosclerosis Risk in Communities (ARIC) study (n = 8,793).

Cellphone Legislation and Self-Reported Behaviors Among Subgroups of Adolescent U.S. Drivers.

Purpose: The relationship between cellphone use while driving legislation and self-reported adolescent driver behavior is poorly understood, especially across demographic subgroups. This study investigated the relationship between statewide cellphone legislation and cellphone use behaviors across adolescent driver subgroups, including age (16/17 vs. 18), sex, race/ethnicity (white non-Hispanic and others), and rurality (urban or rural).

Association of carotid atherosclerosis and stiffness with abdominal aortic aneurysm: The atherosclerosis risk in communities (ARIC) study.

Background And Aims: Individuals with atherosclerosis and stiffness often have increased abdominal aortic diameters, but prospective evidence linking them to the risk of abdominal aortic aneurysm (AAA) is limited.

Methods: We prospectively examined the relationship of carotid atherosclerosis and stiffness with future risk of AAA in ARIC. At Visits 1 (1987-89) or 2 (1990-1992), we assessed carotid atherosclerosis (represented by greater carotid intima-media thickness [cIMT] or presence of atherosclerotic plaque) and lower carotid distensibility (reflected by a higher carotid Beta Index).

Markers of vitamin D metabolism and incidence of clinically diagnosed abdominal aortic aneurysm: The Atherosclerosis Risk in Communities Study.

Little is known about whether markers of vitamin D metabolism are associated with the development of abdominal aortic aneurysm (AAA), though these markers have been linked to other cardiovascular diseases. We tested the hypotheses that risk of AAA is higher among individuals with low serum concentrations of 25-hydroxy vitamin D [25(OH)D], and among those with elevated concentrations of calcium, fibroblast growth factor 23 (FGF23), phosphorus, and parathyroid hormone (PTH) using data from a cohort of black and white individuals with long-term follow-up. Markers of vitamin D metabolism were measured using serum collected in 1990-1992 from ARIC study participants (mean ± SD age 56.

Diabetes-related factors and abdominal aortic aneurysm events: the Atherosclerotic Risk in Communities Study.

Purpose: To test the hypothesis that diabetes-related factors (metabolic syndrome [MetS], glucose, insulin, and leptin) are inversely associated with abdominal aortic aneurysm (AAA) risk.

Methods: We followed 13,736 participants, aged 45-64 years, without prior AAA surgery at baseline (1987-1989), for AAA occurrence through 2011. Hazard ratios (HRs) and their 95% confidence intervals (CIs) of AAA were calculated using Cox regression.

Lipoprotein(a) and abdominal aortic aneurysm risk: The Atherosclerosis Risk in Communities study.

Background And Aims: No prospective study has investigated whether elevated lipoprotein(a) concentrations are associated with an increased risk of abdominal aortic aneurysm (AAA). We aimed to prospectively investigate this association.

Methods: In 1987-1989, the Atherosclerosis Risk in Communities study measured plasma lipoprotein(a) in 13,683 participants aged 45-64 years, without a history of AAA surgery.

Prospective study of lung function and abdominal aortic aneurysm risk: The Atherosclerosis Risk in Communities study.

Background And Aims: No prospective study has investigated whether individuals with respiratory impairments, including chronic obstructive pulmonary disease (COPD) and restrictive lung disease (RLD), are at increased risk of abdominal aortic aneurysm (AAA). We aimed to prospectively investigate whether those respiratory impairments are associated with increased AAA risk.

Methods: In 1987-1989, the Atherosclerosis Risk in Communities (ARIC) study followed 14,269 participants aged 45-64 years, without a history of AAA surgery, through 2011.

Features of the Chaperone Cellular Network Revealed through Systematic Interaction Mapping.

A comprehensive view of molecular chaperone function in the cell was obtained through a systematic global integrative network approach based on physical (protein-protein) and genetic (gene-gene or epistatic) interaction mapping. This allowed us to decipher interactions involving all core chaperones (67) and cochaperones (15) of Saccharomyces cerevisiae. Our analysis revealed the presence of a large chaperone functional supercomplex, which we named the naturally joined (NAJ) chaperone complex, encompassing Hsp40, Hsp70, Hsp90, AAA+, CCT, and small Hsps.

Evaluation of dose calculation accuracy of treatment planning systems at hip prosthesis interfaces.

There are an increasing number of radiation therapy patients with hip prosthesis. The common method of minimizing treatment planning inaccuracies is to avoid radiation beams to transit through the prosthesis. However, the beams often exit through them, especially when the patient has a double-prosthesis.

TorsinA controls TAN line assembly and the retrograde flow of dorsal perinuclear actin cables during rearward nuclear movement.

The nucleus is positioned toward the rear of most migratory cells. In fibroblasts and myoblasts polarizing for migration, retrograde actin flow moves the nucleus rearward, resulting in the orientation of the centrosome in the direction of migration. In this study, we report that the nuclear envelope-localized AAA+ (ATPase associated with various cellular activities) torsinA (TA) and its activator, the inner nuclear membrane protein lamina-associated polypeptide 1 (LAP1), are required for rearward nuclear movement during centrosome orientation in migrating fibroblasts.

Lifetime Risk and Risk Factors for Abdominal Aortic Aneurysm in a 24-Year Prospective Study: The ARIC Study (Atherosclerosis Risk in Communities).

Objective: Abdominal aortic aneurysm (AAA) is an important vascular disease in older adults, but data on lifetime risk of AAA are sparse. We examined lifetime risk of AAA in a community-based cohort and prospectively assessed the association between midlife cardiovascular risk factors and AAAs.

Approach And Results: In ARIC study (Atherosclerosis Risk in Communities), 15 792 participants were recruited at visit 1 in 1987 to 1989 and followed up through 2013.

Variations in Abdominal Aortic Aneurysm Care: A Report From the International Consortium of Vascular Registries.

Background: This project by the ICVR (International Consortium of Vascular Registries), a collaboration of 11 vascular surgical quality registries, was designed to evaluate international variation in the contemporary management of abdominal aortic aneurysm (AAA) with relation to recommended treatment guidelines from the Society for Vascular Surgery and the European Society for Vascular Surgery.

Methods: Registry data for open and endovascular AAA repair (EVAR) during 2010 to 2013 were collected from 11 countries. Variations in patient selection and treatment were compared across countries and across centers within countries.

LINCing defective nuclear-cytoskeletal coupling and DYT1 dystonia.

Mechanical forces generated by nuclear-cytoskeletal coupling through the LINC (linker of nucleoskeleton and cytoskeleton) complex, an evolutionarily conserved molecular bridge in the nuclear envelope (NE), are critical for the execution of wholesale nuclear positioning events in migrating and dividing cells, chromosome dynamics during meiosis, and mechanotransduction. LINC complexes consist of outer (KASH (, and homology)) and inner (SUN ()) nuclear membrane proteins. KASH proteins interact with the cytoskeleton in the cytoplasm and SUN proteins in the perinuclear space of the NE.