Predicting Breast Cancer Response to Neoadjuvant Chemotherapy Using Pretreatment Diffuse Optical Spectroscopic-Texture Analysis

Purpose: Diffuse optical spectroscopy (DOS) has been demonstrated capable of monitoring response to neoadjuvant chemotherapy (NAC) in locally advanced breast cancer (LABC) patients. In this study, we evaluate texture features of pre-treatment DOS functional maps for predicting LABC response to NAC. Methods: LABC patients (n = 37) underwent DOS-breast imaging before starting neoadjuvant chemotherapy. Breast-tissue parametric maps were constructed and texture analyses were performed based on grey level co-occurrence matrices (GLCM) for feature extraction. Ground-truth labels as responders (R) or non-responders (NR) were assigned to patients based on Miller-Payne pathological response criteria. The capability of DOS-textural features computed on volumetric tumour data before the start of treatment (i.e. “pre-treatment”) to predict patient responses to NAC was evaluated using a leave-one-out validation scheme at subject level. Data were analysed using a logistic regression, naïve Bayes, and k-nearest neighbour (k-NN) classifiers. Results: Data indicated that textural characteristics of pre-treatment DOS parametric maps can differentiate between treatment response outcomes. The HbO2-homogeneity resulted in the highest accuracy amongst univariate parameters in predicting response to chemotherapy: sensitivity (%Sn) and specificity (%Sp) were 86.5 and 89.0%, respectively and accuracy was 87.8%. The highest predictors using multivariate (binary) combination features were the Hb-Contrast + HbO2-Homogeneity which resulted in a %Sn/%Sp = 78.0/81.0% and an accuracy of 79.5%. Conclusions: This study demonstrated that pre-treatment tumour DOS-texture features can predict breast cancer response to NAC and potentially guide treatments

Genomic epidemiology reveals multiple introductions of Zika virus into the United States

Zika virus (ZIKV) is causing an unprecedented epidemic linked to severe congenital abnormalities. In July 2016, mosquito-borne ZIKV transmission was reported in the continental United States; since then, hundreds of locally acquired infections have been reported in Florida. To gain insights into the timing, source, and likely route(s) of ZIKV introduction, we tracked the virus from its first detection in Florida by sequencing ZIKV genomes from infected patients and Aedes aegypti mosquitoes. We show that at least 4 introductions, but potentially as many as 40, contributed to the outbreak in Florida and that local transmission is likely to have started in the spring of 2016-several months before its initial detection. By analysing surveillance and genetic data, we show that ZIKV moved among transmission zones in Miami. Our analyses show that most introductions were linked to the Caribbean, a finding corroborated by the high incidence rates and traffic volumes from the region into the Miami area. Our study provides an understanding of how ZIKV initiates transmission in new regions

Investigating treatments for adipose stem cells to maximize trophic factor production for cartilage regeneration

Osteoarthritis is a leading cause of disability in the United States. Current methods of treatment aim to replace cartilage as opposed to regenerating tissue. There is interest in using stem cells as a source of growth factors to stimulate cartilage cells to produce extracellular matrix and an environment conducive to cartilage regeneration. The purpose of this study is to assess the effect of chemical and biological stimulation and a 3 dimensional structural environment on mRNA levels of adipose-derived stem cells in vitro and on cartilage regeneration in vivo. Adispose-derived stem cells (ASCs) were isolated from rats, microencapsulated, and treated with chondrogenic media. Chondrogenic media (CM) increased mRNA levels of many genes involved in chondrogenesis, including comp, acan, colX, and tgfb3, and decreased levels of the angiogenic factors fgf2 and vegfa. Microencapsulation increased mRNA levels of pthlh and tgfb3, and there was little difference on mRNA levels between calcium and barium crosslinks. The chemical components, ascorbic acid 2-phosphate (AA2P) and dexamethasone (Dex), and biological components, growth factors TGF-B1 and BMP-6, or chondrogenic media were assessed for their effect on ASC gene profile. Removing growth factors reduced mRNA levels of all genes assessed, whereas removing Dex and AA2P had variable effects on mRNA levels. ASCs were microencapsulated and preconditioned with CM prior to transplantation in a 2 mm cartilage defect in rats. The in vivo results displayed moderate cartilage infiltration into the defect. These data suggest that microencapsulation and treatment with CM can alter the gene profile to be conducive to cartilage regeneration and may regenerate cartilage in vivo.Undergraduat

Antibody Targeting of Antigen to Endogenous Immune Surveillance Pathways for the Induction of Tolerance

The overall goal of my thesis is to develop molecules to induce antigen-specic tolerance by co-opting endogenous tolerance mechanisms. To do this I developed antibody fragments that target the apoptotic pathway or the liver, and characterized the ensuing immune responses.In Chapter 1, I introduce the eld of immune tolerance. I discuss the mechanisms that the immune system employs to maintain tolerance to self, and avoid autoimmunity. I discuss the current standards of care in immunosuppression used to treat autoimmunity, allergy, transplantation, and prevention of anti-drug antibodies. Finally, I introduce emerging strategies that are in development to achieve antigen-specic tolerance. In Chapter 2, I expand upon a previously developed technique in the laboratory to target apoptotic erythrocytes for immune tolerance. I conduct phage display on mouse erythrocytes using a human antibody fragment phage library, and characterize the resulting erythrocyte-binding antibody fragments. I target antigen to erythrocytes and determine that delivery to this pathways yields profound and lasting T cell dysfunction, both in transgenic and endogenous T cells. I further characterize the mechanism of tolerance induction as occurring in the spleen, and for CD8 T cells by Batf3+ dendritic cells. In Chapter 3, I develop a method of targeting liver sinusoidal endothelial cells for their inherent tolerogenic properties. I conduct phage display on liver sinusoidal endothelial cell C-type lectin (LSECtin), for its specicity to LSECs in the liver. I characterize the Fabs from phage display, and determine that they are rapidly and specically internalized by LSECs. I target antigen to LSECtin, and determine that this pathway reduces presentation to T cells. I use protein engineering strategies to enhance antigen presentation by developing cathepsin-cleavable linkers and endosomal escape peptides. Finally, I encapsulate antigen in polymerosomes decorated with anti-LSECtin Fab, and enhance presentation by LSECs. In Chapter 4, I discuss the conclusions and future directions of this work. Furthermore, I discuss the limitations to the eld of antigen-specic tolerance, and oer potential strategies to overcome these limitations

Assessing Suicide Risk in Veterans: The Role of Military Culture as a Risk Factor

ABSTRACT Purpose: The purpose of this article is to investigate whether ‘military culture’ has been specifically considered as a suicide risk for veterans, and whether the suicide risk assessment tools available, meet the needs of veterans. Method: A PubMed literature search was conducted with search terms suicide, risk factors, veterans, risk assessment tools, military culture, brotherhood. Results: A lack of evidence-based research to address the unique circumstances of military culture as a risk factor for suicide. Conclusion: Current risk assessment protocols may be improved, with more research on military culture and its role in suicide risk

ADHD and Long-Term Treatment with Stimulants

ABSTRACT Attention-deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed mental disorders in the United States. Amphetamine-based stimulants such as dexamphetamine, mixed amphetamines, and lisdexamfetamine remain the most frequently prescribed medications for ADHD in children. ADHD is a chronic disorder, and many children continue stimulant therapy into adulthood. Knowing whether children requiring long-term treatment are at risk for developing substance use disorders as adults is imperative. Further research is needed to evaluate if there is evidence to suggest whether long-term treatment with amphetamine-derived stimulants leads to substance use disorders in children with ADHD. Keywords: ADHD treatments; stimulants; amphetamines; long-term effects; substance use disorde