Characterization of monocyte subsets through the course of AIDS pathogenesis and correlations with the development of SIV-Encephalitis

Thesis advisor: Kenneth C. WilliamsIndividuals infected with Human Immunodeficiency Virus (HIV) are susceptible to pathological abnormalities due to the infiltration of virus into different anatomical compartments. Monocytes are a heterogeneous population that undergoes changes in phenotype with HIV infection. It is hypothesized that changes in monocyte subsets observed through the course of infection will correlate with the development of SIV-Encephalitis (SIVE). 14 CD8+ T cell depleted rhesus macaques were infected with SIVmac251 and changes in 3 monocyte subsets, defined by their CD14 and CD16 surface expression as CD14+CD16-, CD14+CD16+, and CD14-CD16+, were tracked through the course of disease. The CD14+CD16- subset increased in the absolute number of cells and decreased in percentage of the total monocyte population. The CD14+CD16+ and CD14-CD16+ subsets increased in both absolute number and percentage. These changes have a biphasic dynamic that occurs during early infection and is pronounced in encephalitic animals. Several markers showed differential expression with infection and between subsets. Mac387, an early monocyte-macrophage marker, demonstrated a considerable decrease in expression. Concomitant with this change, CD68, CD163, CD44v6, CCR2, and CD64 increased expression in the total monocyte population, with the magnitude of these changes occurring in a subset-specific manner. In conclusion, monocyte subsets undergo changes with SIV infection that correspond to the development of encephalitis, highlighting the contribution of monocytes in neuroAIDS.Thesis (MS) — Boston College, 2010.Submitted to: Boston College. Graduate School of Arts and Sciences.Discipline: Biology

Parametric Power Spectral Density Analysis of Noise from Instrumentation in MALDI TOF Mass Spectrometry

Noise in mass spectrometry can interfere with identification of the biochemical substances in the sample. For example, the electric motors and circuits inside the mass spectrometer or in nearby equipment generate random noise that may distort the true shape of mass spectra. This paper presents a stochastic signal processing approach to analyzing noise from electrical noise sources (i.e., noise from instrumentation) in MALDI TOF mass spectrometry. Noise from instrumentation was hypothesized to be a mixture of thermal noise, 1/f noise, and electric or magnetic interference in the instrument. Parametric power spectral density estimation was conducted to derive the power distribution of noise from instrumentation with respect to frequencies. As expected, the experimental results show that noise from instrumentation contains 1/f noise and prominent periodic components in addition to thermal noise. These periodic components imply that the mass spectrometers used in this study may not be completely shielded from the internal or external electrical noise sources. However, according to a simulation study of human plasma mass spectra, noise from instrumentation does not seem to affect mass spectra significantly. In conclusion, analysis of noise from instrumentation using stochastic signal processing here provides an intuitive perspective on how to quantify noise in mass spectrometry through spectral modeling

LSF small molecule inhibitors phenocopy LSF-targeted siRNAs causing mitotic defects and senescence in cancer cells

The oncogene LSF has been proposed as a novel target with therapeutic potential for multiple cancers. LSF overexpression correlates with poor prognosis for both liver and colorectal cancers, for which there are currently limited therapeutic treatment options. In particular, molecularly targeted therapies for hepatocellular carcinoma targeting cellular receptors and kinases have yielded disappointing clinical results, providing an urgency for targeting distinct mechanisms. LSF small molecule inhibitors, Factor Quinolinone Inhibitors (FQIs), have exhibited robust anti-tumor activity in multiple pre-clinical models of hepatocellular carcinoma, with no observable toxicity. To understand how the inhibitors impact cancer cell proliferation, we characterized the cellular phenotypes that result from loss of LSF activity. Phenotypically, inhibition of LSF activity induced a mitotic delay with condensed, but unaligned, chromosomes. This mitotic disruption resulted in improper cellular division leading to multiple outcomes: multi-nucleation, apoptosis, and cellular senescence. The cellular phenotypes observed upon FQI1 treatment were due specifically to the loss of LSF activity, as siRNA specifically targeting LSF produced nearly identical phenotypes. Taken together, these findings confirm that LSF is a promising therapeutic target for cancer treatment.First author draf

A CPW-Fed Rectangular Ring Monopole Antenna for WLAN Applications

We present a simple coplanar waveguide- (CPW-) fed rectangular ring monopole antenna designed for dual-band wireless local area network (WLAN) applications. The antenna is based on a simple structure composed of a CPW feed line and a rectangular ring. Dual-band WLAN operation can be achieved by controlling the distance between the rectangular ring and the ground plane of the CPW feed line, as well as the horizontal vertical lengths of the rectangular ring. Simulated and measured data show that the antenna has a compact size of 21.4×59.4 mm2, an impedance bandwidths of 2.21–2.70 GHz and 5.04–6.03 GHz, and a reflection coefficient of less than −10 dB. The antenna also exhibits an almost omnidirectional radiation pattern. This simple compact antenna with favorable frequency characteristics therefore is attractive for applications in dual-band WLAN

WNT11 is a direct target of early growth response protein 1

WNT11 is a member of the non-canonical Wnt family and plays a crucial role in tumor progression. However, the regulatory mechanisms underlying WNT11 expression are unclear. Tumor necrosis factor-alpha (TNF alpha) is a major inflammatory cytokine produced in the tumor microenvironment and contributes to processes associated with tumor progression, such as tumor invasion and metastasis. By using site-directed mutagenesis and introducing a serial deletion in the 5'-regulatory region of WNT11, we observed that TNF alpha activates the early growth response 1 (EGR1)-binding sequence (EBS) in the proximal region of WNT11 and that the transcription factor EGR1 is necessary for the TNF alpha-induced transcription of WNT11. EGR1 bound directly to the EBSs within the proximal 5'-regulatory region of WNT11 and ectopic expression of EGR1 stimulated WNT11 promoter activity, whereas the knockdown of EGR1 expression by RNA interference reduced TNF alpha-induced WNT11 expression in T47D breast cancer cells. We also observed that mitogen-activated protein kinases (MAPK), extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 kinase mediated TNF alpha-induced transcription of WNT11 via EGR1. Our results suggest that EGR1 directly targets WNT11 in response to TNF alpha stimulation in breast cancer cells

Effectiveness of a Comprehensive Stress Management Program to Reduce Work-Related Stress in a Medium-Sized Enterprise

OBJECTIVES: To assess the effectiveness of a comprehensive workplace stress management program consisting of participatory action-oriented training (PAOT) and individual management. METHODS: A comprehensive workplace stress management program was conducted in a medium-sized enterprise. The baseline survey was conducted in September 2011, using the Korean Occupational Stress Scale (KOSS) and Worker’s Stress Response Inventory (WSRI). After implementing both organizational and individual level interventions, the follow up evaluation was conducted in November 2011. RESULTS: Most of the workers participated in the organizational level PAOT and made Team-based improvement plans. Based on the stress survey, 24 workers were interviewed by a researcher. After the organizational and individual level interventions, there was a reduction of several adverse psychosocial factors and stress responses. In the case of blue-collar workers, psychosocial factors such as the physical environment, job demands, organizational system, lack of rewards, and occupational climate were significantly improved; in the case of white-collar workers, the occupational climate was improved. CONCLUSIONS: In light of these results, we concluded that the comprehensive stress management program was effective in reducing work-related stress in a short-term period. A persistent long-term follow up is necessary to determine whether the observed effects are maintained over time. Both team-based improvement activities and individual interviews have to be sustainable and complementary to each other under the long-term plan

High performance carbon nanotubes thin film transistors by selective ferric chloride doping

Single wall carbon nanotubes (SWNT) have been a significant research topic as active layers for thin film transistors (TFTs) due to their high charge carrier mobility beyond that of crystalline silicon. In this study, we report an effective approach to achieve a very high field-effect mobility and on/off ratio for solution processed semiconducting SWNT TFTs, by selective doping through contact with a thin ferric chloride (FeCl3) dopant layer. The semiconducting layer is formed by a double spin coating of the highly purified (>99%) high pressure carbon mono oxide (HiPCO) SWNT sorted by wrapping of poly (3-dodecylthiophene-2,5-diyl) (P3DDT). In order to achieve effective hole injection from the top Au source electrode without increasing the off-state drain current, less purified (98-99%) SWNTs produced by the plasma discharge process sorted by wrapping of poly (9,9-di-n-dodecylfluorene) (PFDD) are formed on the top of HiPCO film. Significantly improved TFT performance is achieved by the insertion of a few nanometers of a FeCl3 dopant layer at the semiconductor-contact interface. A significant high hole field-effect of 48.35 +/- 3.11 cm(2)V(-1)s(-1) (bare: 6.18 +/- 0.87 cm(2)V(-1)s(-1)) with a reasonable on/off current ratio of 10(5), and low off current of similar to 80 pA, are obtained by controlling the concentration of FeCl3 dopant (thickness = 1.5 nm) at the contact. Mobility is improved further at 2.5 nm thickness of the FeCl3 dopant layer resulting in a hole mobility of 177 +/- 13.2 cm(2) V(-1)s(-1), an on/off ratio of 7.4 x 10(3), and off state current of 1.2 x 10(-9) A

Aurora A Functional Single Nucleotide Polymorphism (SNP) Correlates With Clinical Outcome in Patients With Advanced Solid Tumors Treated With Alisertib, an Investigational Aurora A Kinase Inhibitor

BACKGROUND: Alisertib (MLN8237) is an investigational, oral, selective Aurora A kinase inhibitor. Aurora A contains two functional single nucleotide polymorphisms (SNPs; codon 31 [F/I] and codon 57 [V/I]) that lead to functional changes. This study investigated the prognostic and predictive significance of these SNPs. METHODS: This study evaluated associations between Aurora A SNPs and overall survival (OS) in The Cancer Genome Atlas (TCGA) database. The Aurora A SNPs were also evaluated as predictive biomarkers for clinical outcomes to alisertib in two phase 2 studies (NCT01045421 and NCT01091428). Aurora A SNP genotyping was obtained from 85 patients with advanced solid tumors receiving single-agent alisertib and 122 patients with advanced recurrent ovarian cancer treated with alisertib plus weekly paclitaxel (n=62) or paclitaxel alone (n=60). Whole blood was collected prior to treatment and genotypes were analyzed by PCR. FINDINGS: TCGA data suggested prognostic significance for codon 57 SNP; solid tumor patients with VV and VI alleles had significantly reduced OS versus those with II alleles (HR 1.9 [VI] and 1.8 [VV]; p<0.0001). In NCT01045421, patients carrying the VV alleles at codon 57 (n=53, 62%) had significantly longer progression-free survival (PFS) than patients carrying IV or II alleles (n=32, 38%; HR 0.5; p=0.0195). In NCT01091428, patients with the VV alleles at codon 57 who received alisertib plus paclitaxel (n=47, 39%) had a trend towards improved PFS (7.5months) vs paclitaxel alone (n=32, 26%; 3.8months; HR 0.618; p=0.0593). In the paclitaxel alone arm, patients with the VV alleles had reduced PFS vs modified intent-to-treat (mITT) patients (3.8 vs 5.1months), consistent with the TCGA study identifying the VV alleles as a poor prognostic biomarker. No significant associations were identified for codon 31 SNP from the same data set. INTERPRETATION: These findings suggest that Aurora A SNP at codon 57 may predict disease outcome and response to alisertib in patients with solid tumors. Further investigation is warranted