Mining Genomic Variants And Causal Pathways Linking Hdl And Triglycerides To Coronary Disease

Blood lipids are important biomarkers of risk of coronary heart disease (CHD), the leading cause of death in the world. Myriad data support a causal role of low-density lipoprotein cholesterol (LDL-C) in increasing risk of CHD. Long-standing epidemiology suggests that high-density lipoprotein cholesterol (HDL-C) may protect from disease while high triglycerides (TGs) increase CHD risk. However, the causality of HDL-C and TG to CHD remains controversial. New genetic methodologies have allowed a better look into causal pathways underlying relationships between these traits and disease. Using a combination of approaches for interrogating rare genetic variation in humans, we investigated how HDL and TG may relate to CHD. First, through sequencing and exome-wide genotyping of subjects with extremely high HDL-C, we identified the first homozygote for a loss-of-function (LOF) variant in SCARB1, which encodes scavenger receptor class BI (SR-BI), a hepatic receptor for HDL-C. Despite markedly elevated HDL-C, carriers of this variant had an increased risk of CHD. These findings suggest that HDL functionality in driving cholesterol removal through SR-BI (the reverse cholesterol transport hypothesis) is protective from CHD in humans. Next, we functionally examined one of the first novel loci from genome-wide association studies (GWAS) for HDL-C, GALNT2. Through discovery of humans with genetic GALNT2 LOF and additional studies in rodents and nonhuman primates, we showed that GALNT2 LOF lowers HDL-C across mammals. We also identify one physiological mechanism linking GALNT2 to HDL-C through its enzymatic function. Thirdly, we studied the mechanism of protection of the APOC3 A43T variant recently reported to lower TGs and CHD risk from exome sequencing. Studies in human carriers and animal models suggest that A43T accelerates renal clearance of circulating ApoC-III, thus hindering its function in delaying TG-rich lipoprotein turnover. These data establish ApoC-III clearance mechanisms as potential therapeutic targets for TG lowering. Finally, we adapted a targeted sequencing approach to increase discovery of causal rare coding and noncoding variants at candidate loci influencing HDL-C and TGs. Collectively, this work provides a sampling of approaches for leveraging the spectrum of genomic methods to identify clinically relevant variants impacting HDL, TG and CHD risk

Isolated Splenic Metastasis from Rectal Carcinoma: A Rare Occurrence

The presence of isolated splenic metastasis in rectal carcinoma is uncommon and usually presents as an asymptomatic mass, noted incidentally on imaging. Splenectomy is usually performed with the goal of curing metastatic disease. It is unclear if adjuvant chemotherapy affords any benefit, and the prognosis is unknown. The case of a young woman is reported, in whom an isolated metastatic lesion in the spleen was discovered 9 months after adjuvant chemotherapy for stage III rectal adenocarcinoma. The patient has remained disease-free for nearly 5 years following splenectomy and chemotherapy. To our knowledge, this is the fourth reported case in the English literature of an isolated splenic metastatic lesion from rectal cancer. We discuss the unique presentation, the importance of post-treatment surveillance, and the implementation of multi-modality treatment strategies in this young patient

A Protocol for a Pan-Canadian Prospective Observational Study on Active Surveillance or Surgery for Very Low Risk Papillary Thyroid Cancer

BackgroundThe traditional management of papillary thyroid cancer (PTC) is thyroidectomy (total or partial removal of the thyroid). Active surveillance (AS) may be considered as an alternative option for small, low risk PTC. AS involves close follow-up (including regularly scheduled clinical and radiological assessments), with the intention of intervening with surgery for disease progression or patient preference.MethodsThis is a protocol for a prospective, observational, long-term follow-up multi-centre Canadian cohort study. Consenting eligible adults with small, low risk PTC (< 2cm in maximal diameter, confined to the thyroid, and not immediately adjacent to critical structures in the neck) are offered the choice of AS or surgery for management of PTC. Patient participants are free to choose either option (AS or surgery) and the disease management course is thus not assigned by the investigators. Surgery is provided as usual care by a surgeon in an institution of the patient’s choice. Our primary objective is to determine the rate of ‘failure’ of disease management in respective AS and surgical arms as defined by: i) AS arm – surgery for progression of PTC, and ii) surgical arm - surgery or other treatment for disease persistence or progression after completing initial treatment. Secondary outcomes include long-term thyroid oncologic and treatment outcomes, as well as patient-reported outcomes.DiscussionThe results from this study will provide long-term clinical and patient reported outcome evidence regarding active surveillance or immediate surgery for management of small, low risk PTC. This will inform future clinical trials in disease management of small, low risk papillary thyroid cancer.Registration detailsThis prospective observational cohort study is registered on clinicaltrials.gov (NCT04624477), but it should not be considered a clinical trial as there is no assigned intervention and patients are free to choose either AS or surgery

Design and development of Cu‐Al‐Mn‐Ni shape memory alloy coated optical fibre sensor for condition‐based monitoring of physical systems

Abstract Online fault detection, isolation and recovery using smart sensors play an important role in intelligent manufacturing system. Fibre optic sensors are very interesting for condition monitoring applications due to the advantage of this technology. Here, the experimental demonstration of Cu‐based shape memory alloy (SMA) coated optical fibre for temperature‐based sensing applications is reported. The benefit of Cu‐based SMA coated optical fibre over conventional metallic coating has been evaluated in the study. For consistent coating, an in situ fixture with a rotary drive setup has been designed and developed. Thermo optic test bench has been developed to study the actuation characteristics of the SMA coated optical fibre for varying current and voltage. Experiments were performed to investigate the light intensity in the SMA coated optical fibre at different actuation conditions. The displacement that takes place in the optical fibre due to the external temperature stimuli will create proportional intensity and wavelength shifts. The maximum average displacement of 4.9 mm has been achieved for Cu‐Al‐Mn‐Ni coated optical fibre. Results show variation in the optical fibre signal due to heating and cooling of the fibre from the applied electrical stimulus on Cu‐based SMA coating in the form of austenite to martensite transformation