Identification of DNA sequence variants in the estrogen receptor pathway in breast cancer

Breast cancer is of public health importance with an increasing incidence over the past decade. Estrogen Receptor (ER) activity is critical for promoting majority of breast cancers. Inhibiting ER is one of the most successful targeted therapies in oncology. Studies have suggested that genomic variation in ER binding sites and ESR1 gene may be responsible for endocrine treatment response and cancer progression. We investigated the role of single nucleotide variants (SNVs) in the ER pathway in breast cancer, including clinically relevant mutations in ER gene and regulatory variants in ER binding sites. First, we developed a computational pipeline to identify SNVs in ER binding sites, using chromatin immunoprecipitation-sequencing (ChIP-seq) data from hormone responsive breast cancer cells and tumors. Analysis of ER ChIP-seq data from multiple MCF7 studies characterized a SNV within intron 2 of the IGF1R gene, rs62022087, predicted to increase the affinity for ER binding. By integrating 43 ER ChIP-seq data sets, multi-omics and clinical data, we identified SNVs regulating downstream target genes which may contribute to patients’ survival. Second, we used sensitive detection methods to detect mutations and identified high frequencies ESR1 mutations in primary tumors, metastatic lesions and cell-free DNA samples. This result may be due to higher sensitivity of our study in detecting mutations at very low allele frequency. Finally, we generated appropriate knock-in cell lines through CRISPR technology to study ER mutations. RNA-seq studies revealed ER mutations are can activate estrogen regulated genes in a ligand independent manner and also may induce/repress a set of novel targets. Cell adhesion assays demonstrated mutants are less adhesive to Collagen I which may be a marker of metastasis. Taken together, our findings indicate that SNVs in ER pathway are clinically important and may predict drug response in ER+ breast cancer. From the public health perspective, screening for these impactful variants will be soon part of the genetic testing as our knowledge of genome improves. This will eventually help initiatives to reduce public health burden by choosing the right treatment for breast cancer patients in personalized manner

The Role of Heuristics in Information Security Decision Making

Inadvertent human errors (e.g., clicking on phishing emails or falling for a spoofed website) have been the primary cause of security breaches in recent years. To understand the root cause of these errors and examine practical solutions for users to overcome them, we applied the theory of bounded rationality and explored the role of heuristics (i.e., short mental processes) in security decision making. Interviews with 27 participants revealed that users rely on various heuristics to simplify their decision making in the information security context. Specifically, users rely on experts’ comments (i.e., expertise heuristic), information at hand, such as recent events (i.e., availability heuristic), and security-representative visual cues (i.e., representativeness heuristic). Findings also showed the use of other heuristics, including affect, brand, and anchoring, to a lesser degree. The results have practical and theoretical significance. In particular, they extend the literature by integrating bounded rationality concepts and elaborating “how” users simplify their security decision making by relying on cognitive heuristics

Quantifying environmental risk factors for multiple sclerosis in discordant monozygotic twins: a case report

Relative contribution of genetic and environmental risk factors in complex disorders is widely explored through discordant identical twins. Multiple sclerosis is a demyelinating disease of the central nervous system in which the interplay of genetic and environmental risk factors define the disease pathogenicity. Robust epidemiological studies in different populations suggested that active levels of serum vitamin D and viral load implicate in MS pathogenicity and severity. In order to refine non-shared components of susceptibility factors in MS, we investigated the role of serum 25-hydroxyvitamin D and viral infection in a pair of identical twins remained discordant for MS during the course of 5 years follow up. Here we report serological finding regarding the viral load and serum 25-hydroxyvitamin D level in a pair of discordant monozygotic twins. Based on our observation, lower levels of serum 25-hydroxyvitamin D and higher anti-viral IgG titre was consistent with the disease statues in the affected sib

Targeted Mutation Detection in Advanced Breast Cancer Using MammaSeq Identifies RET as a Potential Contributor to Breast Cancer Metastasis

The lack of any reported breast cancer specific diagnostic NGS tests inspired the development of MammaSeq, an amplicon based NGS panel built specifically for use in advanced breast cancer. In a pilot study to define the clinical utility of the panel, 46 solid tumor samples, plus an additional 14 samples of circulating-free DNA (cfDNA) from patients with advanced breast cancer were sequenced and analyzed using the OncoKB precision oncology database. We identified 26 clinically actionable variants (levels 1-3) annotated by the OncoKB precision oncology database, distributed across 20 out of 46 solid tumor cases (40%), and 4 clinically actionable mutations distributed across 4 samples in the 14 cfDNA sample cohort (29%). The mutation allele (MAF) frequencies of ESR1-D538G and FOXA1-Y175C mutations correlated with CA.27.29 levels in patient-matched blood, indicating that MAF may be a reliable marker for disease burden. Interestingly, 4 of the mutations found in metastatic samples occurred in the gene RET, an oncogenic receptor tyrosine kinase. In an orthogonal study, the lab has recently identified RET as one of the most recurrently upregulated genes in breast cancer brain metastases. Interestingly, the ligand for RET is the family of glial-cell derived neurotrophic factors (GDNF), a growth factor secreted by glial cells of the central nervous system. This lead to the hypothesis that RET overexpression facilitates breast cancer brain metastasis in response to the high levels of GDNF, while RET activating point mutations increase metastatic capacity without specific organ tropism. While the effect of GDNF treatment on proliferation in 2D was limited, in ultra-low attachment (ULA) plates we saw a significant increase in anchorage independent growth of MCF-7 cells. To determine if GDNF acts as a chemoattractant for RET positive BrCa cells, we utilized a transwell migration assay, with GDNF as the sole chemoattractant. When RET was overexpressed, there was a visual increase in cell migration. Together, these studies demonstrate the clinical feasibility of using MammaSeq to detect clinically actionable mutations in breast cancer patients, and provides provisional data supporting the investigation of RET signaling as a potentially targetable mediator of breast cancer brain metastasis

Biallelic loss of LDB3 leads to a lethal pediatric dilated cardiomyopathy

Autosomal dominant variants in LDB3 (also known as ZASP), encoding the PDZ-LIM domain-binding factor, have been linked to a late onset phenotype of cardiomyopathy and myofibrillar myopathy in humans. However, despite knockout mice displaying a much more severe phenotype with premature death, bi-allelic variants in LDB3 have not yet been reported. Here we identify biallelic loss-of-function variants in five unrelated cardiomyopathy families by next-generation sequencing. In the first family, we identified compound heterozygous LOF variants in LDB3 in a fetus with bilateral talipes and mild left cardiac ventricular enlargement. Ultra-structural examination revealed highly irregular Z-disc formation, and RNA analysis demonstrated little/no expression of LDB3 protein with a functional C-terminal LIM domain in muscle tissue from the affected fetus. In a second family, a homozygous LDB3 nonsense variant was identified in a young girl with severe early-onset dilated cardiomyopathy with left ventricular non-compaction; the same homozygous nonsense variant was identified in a third unrelated female infant with dilated cardiomyopathy. We further identified homozygous LDB3 frameshift variants in two unrelated probands diagnosed with cardiomegaly and severely reduced left ventricular ejection fraction. Our findings demonstrate that recessive LDB3 variants can lead to an early-onset severe human phenotype of cardiomyopathy and myopathy, reminiscent of the knockout mouse phenotype, and supporting a loss of function mechanism

Role of heuristics and biases in information security decision making

Inadvertent and Irrational human errors (e.g., clicking on phishing emails) have been the primary cause of security breaches in recent years. It has been estimated that these errors are a source of approximately 84% of all breaches in 2017 (Sher-Jan, 2018). To understand the root cause of these errors and examine practical solutions for personal users, I applied the theory of bounded rationality (Simon, 1972, 2000). In the second chapter, I examined the role of several factors (i.e., objective knowledge, subjective knowledge, and default security level) on how secure a decision made by a personal user is (i.e., security level of user’s decision). I discovered that the default security level has the most significant influence on the security level of a user’s decision. Furthermore, the results illustrated that subjective security knowledge mediates the impact of objective security knowledge on security decisions. In Chapter 3, I explored the role of heuristics (i.e., short mental processes) in security decision making. Interviews conducted reveal that users rely on various heuristics to simplify their decision making. Specifically, users rely on experts’ comments (i.e., expertise heuristic), information at hand, such as recent events (i.e., availability heuristic), and security-representative visual cues (i.e., representativeness heuristic). Findings also showed the use of other heuristics, including affect, brand, and anchoring, to a lesser degree. In Chapter 4, I examined the impact of several nudging strategies by using the most prevalent heuristic cues discovered in Chapter 3 and the construal level (i.e., level of abstraction) of messages on users’ security decisions. Using the security level of settings and password entropy as measures of the overall degree of security, users made more secure decisions in the presence of any of the heuristic cues irrespective of the construal level compared to the baseline group (i.e., no-message group). Additionally, with respect to the security level of settings, low-level construal availability, low-level construal representativeness, and high-level construal expertise had the highest impact. For password entropy, low-level construal availability and low-level construal representativeness were also the most effective combination. However, there was no significant difference between high-level and low-level construal expertise conditions.Business, Sauder School ofManagement Information Systems, Division ofGraduat

Co-occurrence of multiple sclerosis and Thomsen’s myotonia: a report of two cases

Multiple sclerosis (MS) is a common demyelinating disease of the central nervous system in which an abnormal immune system response results in damage to the myelin sheaths surrounding nerves. The etiology of MS remains elusive, although it has been suggested to be influenced by both genetic and environmental factors. Here, we report two exceptional cases of patients affected by both MS and Thomsen’s myotonia. Electromyography and MRI scans confirmed the presence of both diseases in the referred cases. Although the mechanisms underlying the co-occurrence of MS and Thomsen’s disease are unclear, we have endeavored to offer plausible explanations for it

Role of Feedback in Improving Novice Users’ Security Performance Using Construal Level and Valance Framing

For novice non-organizational users (NNOUs)- individuals who are not subject to security guidelines of a firm and who possess no or minimal information security training, feedback messages are among the only feasible solutions that can guide them towards better security performance. However, it is not clear which combinations of feedback messages are the most effective for such users as existing findings are scarce and, in the case of actual performance, non-existent. Utilizing an app developed for this study and drawing on Prospect Theory and Construal-Level Theory, we conducted a 2×2×2 (framing valence: positive/negative × framing type: attribute/goal × construal level: high/low) between-subjects design study to assess the effect of feedback messages on users’ security settings selection. Our findings suggest that messages which are low-level, negative, and framed around user goals are most effective. Our findings extend the literature and provide insight into developing adaptive feedback mechanisms

The role of non-HLA single nucleotide polymorphisms in multiple sclerosis susceptibility.

Multiple sclerosis (MS) is the most common neurological disease of the central nervous system affecting young adults. While the etiology of the disease is still unknown, epidemiological and genetics studies have shown a significant inherited component involved in MS pathogenesis. Single nucleotide polymorphisms (SNPs) associated with MS have been recently evaluated by two main groups of high-throughput genotyping analyses: candidate gene approaches and genome-wide association studies (GWAS). Although both types of studies have identified polymorphisms in the human leukocyte antigen (HLA) region as the strongest susceptibility loci for MS, recent investigations have identified a broad spectrum of non-HLA genes prominently associated with MS. This review will focus on recent findings in non-HLA genes as well as their SNPs which have shown high linkage to MS as a genetic-based disorder. Understanding of non-HLA polymorphisms will help elucidate the signalling aberrations involved in MS development and may help to identify novel, personalized approaches to therapy