Parallel Multiplier Designs for the Galois/Counter Mode of Operation

The Galois/Counter Mode of Operation (GCM), recently standardized by NIST, simultaneously authenticates and encrypts data at speeds not previously possible for both software and hardware implementations. In GCM, data integrity is achieved by chaining Galois field multiplication operations while a symmetric key block cipher such as the Advanced Encryption Standard (AES), is used to meet goals of confidentiality. Area optimization in a number of proposed high throughput GCM designs have been approached through implementing efficient composite Sboxes for AES. Not as much work has been done in reducing area requirements of the Galois multiplication operation in the GCM which consists of up to 30% of the overall area using a bruteforce approach. Current pipelined implementations of GCM also have large key change latencies which potentially reduce the average throughput expected under traditional internet traffic conditions. This thesis aims to address these issues by presenting area efficient parallel multiplier designs for the GCM and provide an approach for achieving low latency key changes. The widely known Karatsuba parallel multiplier (KA) and the recently proposed Fan-Hasan multiplier (FH) were designed for the GCM and implemented on ASIC and FPGA architectures. This is the first time these multipliers have been compared with a practical implementation, and the FH multiplier showed note worthy improvements over the KA multiplier in terms of delay with similar area requirements. Using the composite Sbox, ASIC designs of GCM implemented with subquadratic multipliers are shown to have an area savings of up to 18%, without affecting the throughput, against designs using the brute force Mastrovito multiplier. For low delay LUT Sbox designs in GCM, although the subquadratic multipliers are a part of the critical path, implementations with the FH multiplier showed the highest efficiency in terms of area resources and throughput over all other designs. FPGA results similarly showed a significant reduction in the number of slices using subquadratic multipliers, and the highest throughput to date for FPGA implementations of GCM was also achieved. The proposed reduced latency key change design, which supports all key types of AES, showed a 20% improvement in average throughput over other GCM designs that do not use the same techniques. The GCM implementations provided in this thesis provide some of the most area efficient, yet high throughput designs to date

Single-cell profiling of human dura and meningioma reveals cellular meningeal landscape and insights into meningioma immune response

BACKGROUND: Recent investigations of the meninges have highlighted the importance of the dura layer in central nervous system immune surveillance beyond a purely structural role. However, our understanding of the meninges largely stems from the use of pre-clinical models rather than human samples. METHODS: Single-cell RNA sequencing of seven non-tumor-associated human dura samples and six primary meningioma tumor samples (4 matched and 2 non-matched) was performed. Cell type identities, gene expression profiles, and T cell receptor expression were analyzed. Copy number variant (CNV) analysis was performed to identify putative tumor cells and analyze intratumoral CNV heterogeneity. Immunohistochemistry and imaging mass cytometry was performed on selected samples to validate protein expression and reveal spatial localization of select protein markers. RESULTS: In this study, we use single-cell RNA sequencing to perform the first characterization of both non-tumor-associated human dura and primary meningioma samples. First, we reveal a complex immune microenvironment in human dura that is transcriptionally distinct from that of meningioma. In addition, we characterize a functionally diverse and heterogenous landscape of non-immune cells including endothelial cells and fibroblasts. Through imaging mass cytometry, we highlight the spatial relationship among immune cell types and vasculature in non-tumor-associated dura. Utilizing T cell receptor sequencing, we show significant TCR overlap between matched dura and meningioma samples. Finally, we report copy number variant heterogeneity within our meningioma samples. CONCLUSIONS: Our comprehensive investigation of both the immune and non-immune cellular landscapes of human dura and meningioma at single-cell resolution builds upon previously published data in murine models and provides new insight into previously uncharacterized roles of human dura

Biomarker-defined clusters by level of Type 2 inflammatory involvement in severe asthma

Peer reviewedPostprin

A histologically proven case of lymphocytic interstitial pneumonia in a HIV infected adult with an undetectable viral load

Lymphocytic interstitial pneumonia (LIP) is on the spectrum of lymphoproliferative diseases that can affect the lungs. Although common in human immunodeficiency virus (HIV) infected children, it is rarely reported in adults. A 51-year-old HIV infected female patient presented with worsening dyspnea over five months. She had radiological findings of bilateral lung nodular infiltrates. Her CD4 count was 835 cells/uL and her HIV viral load was undetectable. Bronchoalveolar lavage did not yield any infectious pathogen. The pathology on an open lung biopsy revealed marked lymphocytic infiltrates and widening of alveolar septa consistent with the diagnosis of LIP. LIP is a rare entity in adults. Previously reported cases in HIV infected adults were associated with a high HIV viral load at the time of diagnosis. Here we present the first case of LIP in an HIV infected adult with an undetectable viral load

The changing anatomic position of squamous cell carcinoma of the lung – a new conundrum

Background: Traditionally, squamous cell carcinoma (SCC) of the lung is a central rather than a peripheral form of lung cancer. Rates of SCC in the lung periphery are typically sited in the 15–30% range. Recently, we observed that a significant portion of newly diagnosed SCC was located on a periphery. A comprehensive review of the tumor data at our facility, a busy teaching hospital with a large cohort of cancer patients, was undertaken to assess whether there had been a substantive change in the traditional epidemiologic distributions of the lung cancer, specifically with respect to SCC. Given the differences in cell biology and carcinogenesis of central versus peripheral SCC, a potential epidemiologic shift might suggest a change in tumor biology. Methods: From May 12, 2012 through May 13, 2013, all histopathologically confirmed diagnoses of SCC of the lung were retrospectively reviewed. Each patient's lesion was then classified as peripheral or central based on CT evidence. Results: A total of 56 patients were diagnosed with SCC. Of these, 55% (n=31) had peripheral and 45% (n=25) had central SCC. Twenty-nine patients did not have any prior history of malignancy. Of this subset of patients, 62% (n=18) had peripheral SCC, and 38% (n=11) had central SCC. Conclusion: Our findings appear to correlate with our initial observation that, within our institution, there has been a substantive shift in the traditional distribution of SCC with the majority of these cancers now being diagnosed in the lung periphery as opposed to the more central locations

Clinical remission in severe asthma with Biologic Therapy: an analysis from the UK Severe Asthma Registry

BACKGROUND: Novel biologic therapies have revolutionised the management of severe asthma with more ambitious treatment aims. Here we analyse the definition of clinical remission as a suggested treatment goal and consider the characteristics associated with clinical remission in a large, real-world severe asthma cohort.METHODS: This was a retrospective analysis of severe asthma patients registered in the UK Severe Asthma Registry (UKSAR) who met strict national access criteria for biologics. Patients had a pre-biologics baseline assessment and annual review. The primary definition of clinical remission applied included Asthma Control Questionnaire (ACQ)-5 &lt;1.5 and no oral corticosteroids for disease control and forced expiratory volume in 1 s above lower limit of normal or no more than 100 mL less than baseline.RESULTS: 18.3% of patients achieved the primary definition of remission. The adjusted odds of remission on biologic therapy were 7.44 (95% CI 1.73-31.95)-fold higher in patients with type 2 (T2)-high biomarkers. The adjusted odds of remission were lower in patients who were female (OR 0.61, 95% CI 0.45-0.93), obese (OR 0.49, 95% CI 0.24-0.65) or had ACQ-5 ≥1.5 (OR 0.19, 95% CI 0.12-0.31) pre-biologic therapy. The likelihood of remission reduced by 14% (95% CI 0.76-0.97) for every 10-year increase in disease duration. 12-21% of the cohort attained clinical remission depending on the definition applied; most of those who did not achieve remission failed to meet multiple criteria.CONCLUSIONS: 18.3% of patients achieved the primary definition of clinical remission. Remission was more likely in T2-high biomarker patients with shorter duration of disease and less comorbidity. Further research on the optimum time to commence biologics in severe asthma is required.</p

Immunologic targeting of FOXP3 in inflammatory breast cancer cells.

The forkhead transcription factor FOXP3 is necessary for induction of regulatory T lymphocytes (Tregs) and their immunosuppressive function. We have previously demonstrated that targeting Tregs by vaccination of mice with murine FOXP3 mRNA-transfected dendritic cells (DCs) elicits FOXP3-specific T cell responses and enhances tumor immunity. It is clear that FOXP3 expression is not restricted to T-cell lineage and herein, using RT-PCR, flow cytometry, and western immunoblot we demonstrate for the first time that FOXP3 is expressed in inflammatory breast cancer (IBC) cells, SUM149 (triple negative, ErbB1-activated) and SUM190 (ErbB2-overexpressing). Importantly, FOXP3-specific T cells generated in vitro using human FOXP3 RNA-transfected DCs as stimulators efficiently lyse SUM149 cells. Interestingly, an isogenic model (rSUM149) derived from SUM149 with an enhanced anti-apoptotic phenotype was resistant to FOXP3-specific T cell mediated lysis. The MHC class I cellular processing mechanism was intact in both cell lines at the protein and transcription levels suggesting that the resistance to cytolysis by rSUM149 cells was not related to MHC class I expression or to the MHC class I antigen processing machinery in these cells. Our data suggest that FOXP3 may be an effective tumor target in IBC cells however increased anti-apoptotic signaling can lead to immune evasion

Sex-Dependent Differences in Physical Exercise-Mediated Cognitive Recovery Following Middle Cerebral Artery Occlusion in Aged Rats

Stroke remains a leading cause of death and disability in the United States. No current treatments exist to promote cognitive recovery in survivors of stroke. A previous study from our laboratory determined that an acute bout of forced treadmill exercise was able to promote cognitive recovery in 3 month old male rats after middle cerebral artery occlusion (MCAo). In this study, we tested the hypothesis that 6 days of intense acute bout of forced treadmill exercise (physical exercise – PE) promotes cognitive recovery in 11–14 month old male rats. We determined that PE was able to ameliorate cognitive deficits as determined by contextual fear conditioning. Additionally, we also tested the hypothesis that PE promotes cognitive recovery in 11–13 month old reproductive senescent female rats. In contrast to males, the same intensity of exercise that decrease cognitive deficits in males was not able to promote cognitive recovery in female rats. Additionally, we determined that exercise did not lessen infarct volume in both male and female rats. There are many factors that contribute to higher stroke mortality and morbidities in women and thus, future studies will investigate the effects of PE in aged female rats to identify sex differences