Molecular Evolution of Genetic Susceptibility to Hepatocellular Carcinoma

Background

Hepatocellular carcinoma (HCC) is a leading cancer-related cause of death worldwide. There are widespread global differences in HCC risk. Although the impact of geographic prevalence of specific causes of chronic liver disease on HCC is recognized, the contribution of the underlying genetic architecture to the risk of HCC remains undefined. Our aim was to characterize evolutionary trends in genetic susceptibility to HCC.

Methods

We examined the genetic risk associated with HCC risk alleles identified from genome-wide association studies and correlated these with geographic location and temporal and spatial patterns of human migration.

Results

A moderate increase in differentiation was noted for rs2596542 (F _st = 0.106) and rs17401966 (F _st = 0.116), single nucleotide polymorphisms (SNPs) associated with an increased risk of HCC in patients with chronic HCV and HBV, respectively. Both of these SNPs show a recent increase in allelic frequency with the most recent human migrations into East Asia, Oceania and the Americas. In contrast another SNP associated with an increased risk of HCC, rs9275572, showed a lack of differentiation (F _st = 0.09) with stable allelic expression across populations. The genetic risk score for HCC, based on the allelic frequency and risk odds ratio of five SNPs associated with increased risk of HCC, was greatest in populations from Africa and decreased with subsequent migration into Europe and Asia. However, a major increase was noted with the most recent migrations into Oceania and the Americas.

Conclusions

There are differences in directional differentiation of HCC risk alleles across human populations that can contribute to population-based differences in HCC prevalence.     

Multiple Left Internal Mammary Artery-to-Pulmonary Artery Fistulae 15 Years after Coronary Artery Bypass Grafting

Left internal mammary artery (LIMA)-to-pulmonary artery fistulae rarely develop after coronary artery bypass grafting. Fewer than 30 cases of these fistulae have been reported since 1947. Nevertheless, this entity should be considered as a cause of recurrent angina after bypass surgery, in the absence of other causes. We present the case of a 67-year-old man with cardiac symptoms in whom multiple LIMA-to-pulmonary artery fistulae were found, 15 years after he had undergone coronary artery bypass grafting. The diagnosis was confirmed by means of coronary angiography with selective catheterization of the LIMA and by computed tomographic angiography of the heart. The patient underwent reoperative 2-vessel coronary artery bypass grafting and ligation of multiple fistulae; 16 months postoperatively, he was asymptomatic and doing well. In addition to reporting this case, we discuss relevant diagnostic and treatment considerations.Key words: Arteriovenous malformations/physiopathology, coronary artery bypass/adverse effects, fistula/etiology, internal mammary-coronary artery anastomosis/adverse effects, mammary arteries/surgery, myocardial ischemia/etiology, pulmonary artery/surgery, vascular fistula/complications/etiology/surgeryAs a bypass-graft conduit to the left anterior descending coronary artery (LAD), the left internal mammary artery (LIMA) is the vessel of choice because of its proven longevity and long-term patency. The formation of a LIMA-to-pulmonary artery (PA) fistula after coronary artery bypass grafting (CABG) is a rare complication: fewer than 30 reports have appeared in the medical literature.¹ We report a case of multiple LIMA-to-PA fistulae that we found 15 years after a patient had undergone CABG.     

Malignant phyllodes tumor of the left atrium

Metastatic tumors to the heart usually involve right sided chambers. We report a rare case of malignant phyllodes tumor of breast with metastatic involvement of left atrium occurring through direct invasion from mediastinal micro-metastasis and presenting as a left atrial mass causing arrhythmia.     

Augmented mixed beta regression models for periodontal proportion data

Continuous (clustered) proportion data often arise in various domains of medicine and public health where the response variable of interest is a proportion (or percentage) quantifying disease status for the cluster units, ranging between zero and one. However, because of the presence of relatively disease‐free as well as heavily diseased subjects in any study, the proportion values can lie in the interval [0,1]. While beta regression can be adapted to assess covariate effects in these situations, its versatility is often challenged because of the presence/excess of zeros and ones because the beta support lies in the interval (0,1). To circumvent this, we augment the probabilities of zero and one with the beta density, controlling for the clustering effect. Our approach is Bayesian with the ability to borrow information across various stages of the complex model hierarchy and produces a computationally convenient framework amenable to available freeware. The marginal likelihood is tractable and can be used to develop Bayesian case‐deletion influence diagnostics based on q‐divergence measures. Both simulation studies and application to a real dataset from a clinical periodontology study quantify the gain in model fit and parameter estimation over other ad hoc alternatives and provide quantitative insight into assessing the true covariate effects on the proportion responses. Copyright © 2014 John Wiley & Sons, Ltd.     

Drug Discovery Research in India: Current State and Future Prospects

Indian civilization developed a strong system of traditional medicine and was one of the first nations to develop a synthetic drug. In the postindependence era, Indian pharmaceutical industry developed a strong base for production of generic drugs. Challenges for the future are to give its traditional medicine a strong scientific base and develop research and clinical capability to consistently produce new drugs based on advances in modern biological sciences.Indian civilization is one of the few in the world that developed a full-fledged system of traditional medicine. The approach of Indian traditional medicine, e.g., the ayurvedic system, is herbal based in general and is more effective for chronic diseases and prevention. Although modern medicine has found its own niche in India, traditional formulations are still widely used, and more and more scientifically validated formulations are appearing in the market. In recent times, many plants used in Indian system of medicine have been analyzed by modern analytical methods and active components have been isolated. Significant amount of medicinal chemistry efforts are going on around these molecules in an attempt to develop more potent leads. These include curcumin from turmeric,¹ Bacosides from Brahmi (Bacopa monnieri),² and Forskolin from Coleus forskohlii. The first modern synthetic drug to be developed in India was Urea Stibamine in 1922 by UN Brahmachari against visceral leishmaniasis.³ Visceral leishmaniasis was a severe health burden during the early part of the 20th century, and it was a life saving drug for a large section of the population. Historically, it was the second drug developed against an infectious disease after Salversan (against Syphillis) and well before penicillin or sulfa drugs. It is still in use in many countries in a modified form.     

Weighted burden analysis of exome-sequenced late-onset Alzheimer's cases and controls provides further evidence for a role for PSEN1 and suggests involvement of the PI3K/Akt/GSK-3β and WNT signalling pathways

Previous studies have implicated common and rare genetic variants as risk factors for late-onset Alzheimer's disease (LOAD). Here, weighted burden analysis was applied to over 10,000 exome-sequenced subjects from the Alzheimer's Disease Sequencing Project. Analyses were carried out to investigate whether rare variants predicted to have a functional effect within a gene were more commonly seen in cases or in controls. Confirmatory results were obtained for TREM2, ABCA7, and SORL1. Additional support was provided for PSEN1 (p = 0.0002), which previously had been only weakly implicated in LOAD. There was suggestive evidence that functional variants in PIK3R1, WNT7A, C1R, and EXOC5 might increase risk and that variants in TIAF1 and/or NDRG2 might have a protective effect. Overall, there was strong evidence (p = 5 × 10⁻⁶) that variants in tyrosine phosphatase genes reduce the risk of developing LOAD. Because PIK3R1 variants are expected to impair PI3K/Akt/GSK-3β signalling while variants in tyrosine phosphatase genes would enhance it, these findings are in line with those from animal models, suggesting that this pathway is protective against Alzheimer's disease.     

Percutaneous coronary intervention in octogenarians: 10-year experience from a primary percutaneous coronary intervention centre with off-site cardiothoracic support

OBJECTIVETo examine the trends in patient characteristics and clinical outcomes over a ten-year period and to analyse the predictors of mortality in octogenarians undergoing percutaneous coronary intervention (PCI) in our centre.METHODSA total of 782 consecutive octogenarians (aged 80 and above) were identified from a prospectively collected PCI database within our non-surgical, medium volume centre between 1st January 2007 and 31st December 2016. This represented 10.9% of all PCI procedures performed in our centre during this period. We evaluated the demographic and procedural characteristics of the cohort with respect to clinical outcomes (all-cause in-hospital and 1-year mortality, in-hospital complication rates, duration of hospital admission, coronary disease angiographic complexity and major co-morbidities). The cohort was further stratified into three chronological tertiles (January 2007 to July 2012, 261 cases; August 2012 to May 2015, 261 cases; June 2015 to December 2016, 260 cases) to assess for differences over time. Predictors of mortality were identified through a multivariate regression analysis.RESULTSThe number of octogenarians undergoing PCI increased nearly ten-fold over the studied period. Despite this, there were no significant differences in clinical outcomes or patient characteristics, except for the increased use of trans-radial vascular access [11.9% in first tertile vs. 73.2% in third tertile (P < 0.0001)]. The all-cause in-hospital (5.8% vs. 4.6% vs. 3.8%, P = 0.578) and 1-year mortality (12.4% vs. 12.5% vs. 14.4%, P = 0.746) remained constant in all three tertiles respectively. Six independent predictors of mortality were identified - increasing age [HR = 1.12 (1.03−1.22), P = 0.008], cardiogenic shock [HR = 16.40 (4.04–66.65), P < 0.0001], severe left ventricular impairment [HR = 3.52 (1.69−7.33), P = 0.001], peripheral vascular disease [HR = 2.73 (1.22−6.13), P = 0.015], diabetes [HR = 2.59 (1.30−5.17), P = 0.007] and low creatinine clearance [HR = 0.98 (0.96−1.00), P = 0.031]. CONCLUSIONThis contemporary observational study provides a useful insight into the real-world practice of PCI in octogenarians.

Although age is a major cardiovascular risk factor which has a marked impact on the prevalence of coronary artery disease (CAD) and cardiovascular mortality,^[1] there is a recognised reluctance in offering percutaneous coronary intervention (PCI) to octogenarians (≥ 80 years old),^[2] despite its proven benefit in this age group.^[3–5] As a result, an increasing number of octogenarians undergoing PCI is observed, reaching almost 10% of all PCI procedures performed in United Kingdom in the period 2008–2012.^[6]Despite the increasing demand for PCI in the octogenarians, this patient population remains under-represented in randomised trials or only a highly selected group is investigated.^[7,8] Emerging evidence shows that the survival advantage of invasive compared with non-invasive management appears to extend to patients with non-ST elevation myocardial infarction (NSTEMI) who are octogenarians,^[4,9] although predictably, mortality rates are higher in patients undergoing primary PCI for STEMI.^[10]In the absence of robust randomised clinical data on PCI treatment strategies for the octogenarians, observational studies remain valuable in providing insights to outcome and mortality trends. As a result, we aimed to evaluate the characteristics of our “real world” octogenarian patient population presenting over a ten-year period to a PCI centre with off-site cardiothoracic support in terms of demographics, the procedural and clinical outcomes, and any potential predictors of mortality.     

Pathologic evidence of retinoblastoma seeds supported by field emission scanning electron microscopy and Raman spectroscopy

Purpose:The aim of this study was to examine the pathology of retinoblastoma (RB) seeds with supportive evidence by field emission scanning electron microscopy and Raman spectroscopy.Methods:This study was a laboratory-based observational study. Enucleated eyeballs received in the ocular pathology department of a tertiary eye care center in northeast India were included in the cohort after obtaining written informed consent during the surgery. The study was carried out for 6 years (2015–2020). Most of the eyeballs were Group-E RBs. Standard eyeballs sectioning were done by bread loaf techniques. Gross documentations included RB seeds seen in the smallest calotte done with utmost care. Seeds were documented also in permanent sections. Scanning electron microscopy and Raman spectroscopy were carried out in an index case.Results:Out of the total 59 cases, 35 RB cases had different seedings. The mean age at enucleation was 2.9 years. RB seeds were seen in vitreous (n = 19), subretinal plus vitreous (n = 7), anterior chamber (n = 1), over crystalline lens (n = 3), retinal surface (n = 1), retinal pigment epithelium (RPE; n = 2), subretinal (n = 1), calcified seeds (n = 2). Other characteristics were dusts (n = 7), clouds (n = 11), spheres (n = 4), and unspecified type (n = 13). Histopathological high-risk factors showed significant choroidal (n = 22) and optic nerve (n = 15) involvement. Few cases had extraocular spread. Undifferentiated tumor (n = 24) was seen with higher evidence of necrosis (n = 23). Raman spectra differentiated the seeds from the normal tissue on the basis of lipid and protein content.Conclusion:This study highlights the different types of RB seeds with high-risk factors. The morphology of those seeds showed the difference between vitreous and subretinal seeds under advanced microscopic observations.