bluuebunny/crossref_metadata_2025 huggingface dataset:
The interplay of Aurora kinase A, EGFR, and SRC pathways in regulating cancer resistance to targeted therapy
Authors:   , Ratushny Vladimir , Golemis Erica
Published: July 2024

The oncogenic kinase SRC, the mitotic regulator Aurora kinase A (AURKA), and the receptor tyrosine kinase epidermal growth factor receptor (EGFR) have each been shown to be involved in cancer development and progression. Increased activity of SRC promotes tumor invasion and metastasis, while overexpression of AURKA drives tumor aneuploidy and chromosomal instability. These actions nominate SRC and AURKA as valuable therapeutic targets for cancer and recently developed inhibitors for SRC and AURKA are at various stages of preclinical and clinical development. Therapeutic inhibitors of EGFR have shown limited success in the clinic because of innate or acquired resistance to these EGFR-targeted drugs, likely to occur through compensatory activation of cancer-promoting effectors downstream of EGFR. We nominated AURKA as a possible resistance mediator to EGFR inhibitors by conducting a small interfering RNA (siRNA) screening of a targeted siRNA library of EGFR interactors. We showed that inhibitors of EGFR synergize with inhibitors of Aurora kinase A to reduce colorectal and squamous cell carcinoma cell line proliferation, colony growth in soft agar, cell motility, increase cell death, and decrease tumor growth in an in vivo xenograft model. Dual inhibition of AURKA and EGFR significantly reduced the activity of SRC and other SRC-family kinases, nominating the SRC signaling pathway as a potential functional determinant of this drug synergy. There are many known cross-connections between the signaling networks of SRC and EGFR. These observations, coupled with the knowledge that SRC and AURKA share a common interaction partner, NEDD9, suggested that a potentially significant functional interaction between SRC and AURKA might exist. Investigating this possibility, we demonstrated a potent synergy between inhibitors of AURKA and inhibitors of SRC in multiple ovarian and colorectal cancer cell lines but not in normal ovarian epithelial cell lines. Combination of AURKA and SRC inhibitors selectively killed cancer cells that have undergone aberrant mitosis, and is associated with a post-mitotic reattachment defect. Combined inhibition of AURKA and SRC potentiates dasatinib-dependent SRC inactivation. Interestingly, we also observed a physical interaction and mutual cross-phosphorylation between SRC and AURKA, in vitro, that enhance SRC kinase activity. Together, these findings provide a scientific rationale for combining either EGFR or SRC inhibitors with inhibitors of AURKA in the clinic.
Neuroprotective and neuroregenerative strategies after contusion spinal cord injury
Authors:   , Sandrow-Feinberg Harra Rebecca , Houle John D
Published: July 2024

Spinal cord injury (SCI) results in a devastating and permanent injury to the central nervous system. Damage to the spinal cord interrupts transmission of ascending and descending information which creates sensory and motor deficits. The degree of impairment is dependent upon the level and severity of the injury. Cervical (C) contusion injuries are most common resulting in a bruising or compression of the cord. Due to the prevalence of this form of SCI the rodent model chosen was a severe unilateral cervical contusion SCI. A mid cervical injury was created with the Infinite Horizon impactor using a force of 200 Kdyne. The first study using a C4 injury investigated function after aspiration of the lesion site and apposition of one end of a pre-degenerated peripheral nerve graft during an acute (7 day) and chronic (28 day) situation. A change in injury level was requires for subsequent studies because of the remarkable spontaneous recovery after the two initial studies with a C4 injury. Results indicated that function atter the C4 injury was not further impaired with removal of the lesion site debris of either time point. Remaining studies used the C5 injury model to investigate the neuroprotective and/or neuroregenerative consequences of acute treatment with a modified anti-inflammatory agent, pegylated interferon-[beta] (PEG IFN-[beta]). This model also was used for development and for further study of a forced exercise rehabilitation strategy. Short term studies evaluated biochemical changes in spinal cord tissue in response to SCI, exercise or PEG IFN-[beta] alone. Exercise resulted in significantly increased levels of brain-derived neurotrophic factor and reduced inflammatory cell infiltration caudal to the injury. PEG IFN-[beta] treatment resulted in a decrease of some pro-inflammatory cytokines and an increased in some anti-inflammatory cytokines. Long term behavioral assessments revealed accelerated early recovery that plateaued by five weeks post SCI and exercise. Each therapeutic approach led to beneficial effects but in combination they did not act synergistically. These results suggest several possible strategies for neuroprotection and partial recovery after SCI though further studies are needed to achieve full recovery.
Immediate and long term effects of child sexual abuse
Authors:   , Blum Carol
Published: July 2024

The impact of child sexual abuse on psychological adjustment has been a concern of theorists and practitioners since the time of Sigmund Freud. This dissertation reviews literature on the immediate and long term effects of child sexual abuse and demonstrates that the experience impedes resolution of normal developmental tasks through the life span. Outcomes vary widely across individuals, with sexuality, affective experiences, behavior, interpersonal functioning, and self concept being the areas most frequently affected. Individual, familial, and environmental factors which influence the outcome are discussed in order to further understand the mechanisms of traumatic impact. The field of research on stress and coping is explored in an attempt to address the process of adaptation by sexual abuse victims.
The effect of neutral position foot orthoses on gait of children with down syndrome
Authors:   , Selby-Silverstein Lisa , Palisano Robert J
Published: July 2024

The purpose of this study was to determine if neutral position foot orthoses (NPFOs) immediately improved gait of children with Down Syndrome (DS) and excessively pronated feet. The subjects were 16 children with DS and 10 children without disabilities who were three to six years old. Using 3 dimensional motion analysis, a 3 dimensional force plate, a pressure plate and a tachometer, gait of children with DS wearing sneakers was compared to their gait wearing sneakers and NPFOs, and to gait of children without disabilities. Statistical analyses included two-way Analyses of Covariance, and Mann Whitney U tests and Wilcoxon Matched-Pairs tests of coefficients of variation. When the children wore NPFOs, foot angle was the only dependent variable that was significantly different; the feet became more medially rotated (p <.001). Descriptively, however, when NPFOs were worn, center of pressure moved 11% laterally under the feet reflecting increased supination. In addition, velocity during stance decreased 6%. Normalized peak ankle torque, phase peak ankle torque, and normalized sneaker print length were not significantly affected by NPFOs. Significant interaction effects indicated that individual children responded differently to NPFOs. In addition, foot angle, center of pressure, print length and stance velocity exhibited significantly less trial-to-trial variability (p <.001), and both ankle torque variables showed significantly more trial-to-trial variability (p <.001) when the children with DS wore NPFOs. Gait of children with DS differed significantly from gait of children without disabilities for 4 of the 6 variables tested and a fifth variable showed descriptive differences. Trial-to-trial variability data reflected differences in foot angle and phase peak ankle torque between the two groups of children. Some of the changes observed caused gait of children with DS to be more similar to and some caused gait to be less similar to gait of children without disabilities. The finding that individual children responded differently to NPFOs suggests that responses cannot be predicted and that gait assessment is needed to determine the effects of NPFOs in any particular child with DS. Additional research, including investigation of other variables and long-term study, is needed to determine the efficacy of NPFOs for children with DS.
The sustainable growth rate of a firm
Authors:   , Zantout Zaher Zouheir , Clark John
Published: July 2024

The present study synthesizes various elements of prior research and extends its content to develop a sustainable growth rate model for the firm. This model provides a conceptual framework for linking and examining commonly discussed strategic management factors and objectives. Specifically, the effects of the corporate income tax, asset turnover, fixed asset replacement requirements, corporate financial and dividend policies, inflation rates for the factor inputs and the output, and unexpected technological breakthroughs on the firm's sustainable growth rate are thoroughly treated. The developed model is shown to be the general case of many of the well publicized models, i.e., with additional restrictive assumptions, the developed model would simplify to many of these models. Moreover, it is more comprehensive in accounting for the factors that impact the growth potentials of a firm and has more realistic assumptions. Since there is lack of empirical evidence on the reliability and validity of the different known sustainable growth rate models and for the sake of further showing the power and reliability of the developed model as compared to other models, a sample of 81 rapidly growing companies during the period 1983-1987 is used. It is shown that the developed model is empirically more reliable and valid. Finally, to illustrate its usefulness, the developed sustainable growth rate model is applied in three different areas of strategic management: strategic investment and financing policy, strategic manufacturing management and technological forecasting, and strategic marketing management and pricing strategy. Accordingly, the proposed model is shown to be a powerful financial and strategic management tool. This dissertation concludes with a set of recommendations for future research.
Toughening mechanisms in discontinuous glass/polypropylene composites
Authors:   , Williams Eunethia Denise
Published: July 2024

There are five energy absorbing mechanisms for discontinuous fiber reinforced composites. These include fiber debonding, fiber pullout/bridging, fiber breakage, matrix cracking and matrix deformation. Because of the typically random orientation of fibers in these systems, it has been difficult to develop an experimental approach to determine which of these contributions dominate the measured in-plane toughness values. To address this issue, a specimen has been developed of one pultruded sheet of polypropylene-glass longitudinally centered in a compression molded polypropylene bar. Experimentally, interface strength was varied from weak to intermediate to strong adhesion through the addition of different sizings and maleic anhydride grafted polypropylene. The pullout contribution was determined through varying fiber length. Matrix contributions were determined by changing the molecular weight of the matrix and by changing the crystal structure from predominantly the alpha form to the beta form. Experiments of Izod testing have shown that impact strength is maximized in specimens with a weak interface at an optimum fiber length corresponding to the fiber length at which pullout predominates. In specimens with an intermediate strength interface, impact strength showed a maximum but was reduced. In specimens with a strong interface, impact strength was the lowest and fairly level. Experiments of tensile testing also showed maximum toughness in specimens with a weak interface with an optimum fiber length where pull out predominates. In specimens with a strong interface, tensile toughness was reduced. Examination of these specimens suggests that the impact strength is maximized by the density via the crystallinity of the resin. The density influences the volume contraction of the matrix around the fibers during cooling. This volume contraction creates a radial stress on the fibers that affects the frictional shear stress against which the fibers are pulled out during fracture. A higher density translates into a higher frictional stress and therefore a higher toughness. It was found that neither the crystal structure nor the matrix toughness altered the controlling effect of the matrix density on the impact strength. On the other hand, the tensile toughness was maximized by the yield stress of the matrix for the weak interface.
Properties and reactivity of immune complexes in rheumatoid synovial fluid
Authors:   , Passon Theodore J.
Published: July 2024

A number of studies suggest that the formation of antigen-antibody complexes (i.e., immune complexes (IC)) in synovial fluid and synovial tissue are involved in maintaining the chronic inflammatory synovitis in joints of patients with rheumatoid arthritis (RA). The exact mechanism of this involvment is not well understood and has, for the most part, been limited to studies of the interaction of IC with the complement system. In the present study, we have examined the properties of IC in rheumatoid synovial fluid via density gradient centrifugation and Sepharose CL-6B chromatography and studied their interaction with circulating mononuclear cells. Three different fractions of IC were identified. The largest molecular weight form, fraction I (>1000KD) was predominately composed of IgG and IgM and contained both IgM-RF and IgG-RF. All three fractions of IC can bind Clq and stimulate human mononuclear cell prostaglandin E (PGE) production. Fraction I, IC bound Clq most readily while fraction III IC were the most effective stimulators of mononuclear cell PGE production. IC stimulation of mononuclear cell PGE production was inhibited by Staphylococcus protein A suggesting mediation via activation of Fc receptors. We also present preliminary evidence that IC fraction III exhibit a differential reactivity towards normal and RA mononuclear cells. Exposure of normal mononuclear cells to these complexes resulted in greater PGE production when compared to RA mononuclear cells. We further present preliminary evidence which suggests that IC Fraction III can induce normal and RA mononuclear cell IL-1 (MCF) activity. These data suggest that synovial fluid from RA patients contains IgG-IgG-RF IC which appears to be particularly reactive in stimulating normal mononuclear cell PGE production when compared to RA mononuclear cells. The results obtained from these observations could potentially enhance our understanding of the complex interaction between immune events and cartilage destruction associated with RA.
Using a structural determinants approach to investigate gender differences in organizational commitment
Authors:   , Moore Daniel Patrick , Parasuraman Saroj
Published: July 2024

The purpose of this research was to investigate gender differences in organizational commitment (OC), based on a conceptual model that integrated Kanter's (1977a) theory of the structural determinants of organizational behavior with the unidimensional approach (Fishbein, 1967; Calder & Ross, 1973; Fishbein & Azjen, 1975) towards attitude formation. The model posited that: (i) men and women would experience different levels of positional opportunity and power, (ii) these differences would affect their expectations of attaining valued work outcomes, (iii) and in turn would influence the commitment to the organization. Thus, the model proposed that the relationship between gender and OC would be mediated by opportunity and power, as well as expectations. Furthermore, the model proposed that intention to stay would be influenced by the interaction effect of OC and the perception of suitable alternatives. This study was based on survey research, using a cross-sectional and correlational design. The respondents occupied managerial and professional positions in a variety of organizations in such businesses as manufacturing, education, banking, and health care. The results of the study confirmed 5 of the 12 hypotheses. The hypotheses that gender would be negatively related to opportunity, power, and suitable alternatives were not supported. With the exception of the gender-opportunity, gender-power, gender-suitable alternatives, and OC-suitable alternatives linkages, all of the remaining direct relationships hypothesized received moderate to strong support. Specifically, the results confirmed the following hypothesized linkages: that opportunity and power were positively related to the expectations of attaining valued work outcomes, expectations were positively related to OC, and OC was positively related to intent to stay. Clearly, when employees perceive their positions as empowering and as providing an opportunity for advancement, they express positive feelings towards their organization. Several limitations must be considerd when interpreting these results. First, respondents were highly educated managerial and professional employees. Secondly, the reliance on survey data and the cross sectional design of the study complicates the task of distinguishing correlations between variables from truly causal relationships. Lastly, the similarity in design and scale of measurement for many of the study variables may overstate the relations among these variables. (Abstract shortened with permission of author.).
The publications of U.S. industrial scientists
Authors:   , Halperin Michael Robert
Published: July 2024

This study examines the relationship between the volume of scientific and technical publications (papers) by industrial scientists, and the characteristics of the corporations in which they work. Specifically the study examines: (1) the relationship between several key financial characteristics of U.S. industrial firms and the production of scientific papers; (2) the relationship between the amount of scientific papers published by industrial scientists, and the publication of patents; (3) the relationship between the quality of the scientists employed by U.S. industrial firms and the firms' output of scientific publications. Data from 225 U.S. corporations are collected for the years 1975 through 1983. The corporations chosen for the study all have a history of consistent expenditure of funds for research and development. There is a substantial correlation between patenting and the publication of scientific papers for the group of 225 U.S. corporations in this study although there is considerable industry variation in the relationship. Large firms in the study, as measured by their annual sales, produce proportionately fewer scientific papers than do small firms. Although R&D expenditures and the publication of scientific papers are highly correlated, there appears to be no pattern between R&D and paper publication over time. R&D "productivity" (the annual number of papers published divided by constant dollar annual R&D expenditures) has remained fairly constant between 1975 and 1983. The number of elite scientists in a corporation is more highly correlated with the publication of scientific papers than with the publication of patents.
Defining sexual boundaries between children and adults
Authors:   , DiSimone-Weiss Rosalie Theresa-Ann , McGuffin Patrick W.
Published: July 2024

Child sexual abuse is a widespread problem with potential serious psychological and physical sequelae. The majority of the perpetrators of this abuse are known by the victim, and are often a member of the victim's household. Child sexual abuse most commonly occurs as a gradual progression from behaviors that are difficult to distinguish from normal caretaking or expressions of affection, to behaviors that are more physiologically invasive. This study begins to address intrafamilial abuse by surveying the opinions of professionals-child psychologists, child psychiatrists and pediatricians-regarding when selected behaviors, related to nudity, cosleeping and kissing on the lips become inappropriate. An interaction between child and parent gender was found for all investigated behaviors. The age at which behaviors related to nudity and cosleeping were said to become inappropriate was younger for different-gender parent and child than for same-gender parent and child. The opposite was found for kissing. Examination of respondent characteristics found that those professionals who are younger, do not have a psychodynamic orientation, or are from the western states generally respond that the investigated behaviors become inappropriate at later ages than those who do not have these characteristics. In addition, although psychologists and psychiatrists were not found to significantly differ in their responses, pediatricians generally responded with a significantly older age cut-off than did either of the other two professions.
Material specific memory changes following anterior temporal lobectomy as predicted by the intracarotid amobarbital test
Authors:   , Donofrio Nancy , Williams Joseph M
Published: July 2024

Temporal Lobe Epilepsy often remains refractory to drug therapy, at which time anterior temporal lobectomy (ATL) may be considered. Left anterior temporal lobectomy (LATL) has been shown to produce deficits in verbal memory, while right anterior temporal lobectomy (RATL) produces deficits in visuospatial memory. The Intracarotid Amobarbital Test (IAT) provides a unique opportunity to assess each hemisphere's contribution to memory function through the production of a reversible lesion. The IAT has been used routinely to predict global memory deficit following unilateral ATL. However, greater predictive power may be obtained by examining the relationship between material-specific components of IAT memory and post-surgical memory. This study tested the hypothesis that unilateral material-specific memory scores on the IAT can predict material-specific memory deficits following unilateral ATL, with both verbal and visuospatial memory. 70 left hemisphere language dominant patients undergoing ATL (42 RATL; 28 LATL) completed the California Verbal Learning Test and the Graduate Hospital Facial Memory Test pre- and post-operatively. IAT material-specific difference scores and absolute hemisphere scores were used to predict post-operative neuropsychological changes. Results indicated reliable changes in verbal and visuospatial memory following unilateral ATL. In the verbal domain, LATL patients declined post-operatively, while the RATL patients improved. In the visuospatial domain, RATL patients declined postoperatively, while LATL patients improved. The IAT total memory asymmetry score and verbal memory asymmetry score significantly predicted changes in verbal memory following ATL, even after controlling for the variance associated with WAIS-R FSIQ, education, and age at first neurological risk for epilepsy. A larger asymmetry between left and right injection memory scores was associated with less of a decline on verbal memory measures post-operatively. Additionally, IAT memory performance following the ipsilateral injection, relying primarily on the non-epileptic hemisphere, predicted changes in verbal memory following ATL. Better performance using the non-epileptic hemisphere was associated with less of a decline on the verbal memory measures post-operatively, providing evidence for the hippocampal reserve theory of memory in ATL. Interestingly, IAT performance does not significantly contribute to the prediction of changes in visuospatial memory following ATL.
Horizontal two-phase flow of gases and non-Newtonian liquids
Authors:   , Shu Ming-tsai
Published: July 2024

The goal of the research reported here is to develop methods whereby pressure drop, void fraction, and flow pattern for horizontal two-phase flow of gases and non-Newtonian liquids can be predicted simply from knowledge of fluid properties, flow rates, and pipe size. The scope of investigation includes experimental work on two-phase flow patterns of annular, intermittent, and stratified flow, as well as the transitions among these patterns. Experimental tests have been performed using several Newtonian and pseudoplastic liquids to cover a wide range of viscosity and pseudoplasticity. The experimental work has also been complemented by the development of analytical models for each flow pattern, in which predictive equations account quantitatively for the shear-dependent viscosity of the liquid phase. For pressure drop and holdup, models obtained by modifying existing correlations for Newtonian liquids yield good agreement between theory and experiment for annular flow and for stratified wavy flow. Pseudoplasticity of the liquid, entrainment of liquid droplets in the gas, and aeration of dispersed bubbles in the liquid are predicted to reduce both pressure drop and holdup significantly and experimental results tend to confirm these trends. Pseudoplasticity also affect flow pattern transition. In particular, shear-thinning increases the void fraction of the two-phase mixture and thus causes the transition to annular flow to occur at higher gas velocities than for Newtonian liquids of comparable zero-shear viscosity. This effect can be predicted from a correlation developed in this work. Another feature of this study is the experimental development of a capacitance sensor for void fraction measurement of two-phase flow in cylindrical channels. Theoretical prediction of the device's behavior is also presented.
Pre-clinical evaluation of 2'-O-methyl antisense oligonucleotides as potential therapeutics for Duchenne muscular dystrophy and spinal muscular atrophy
Authors:   , Williams Jason H. , Lutz Gordon J
Published: July 2024

Antisense Oligonucleotides (AO) with 2'-O-Methyl (2OMe) modifications can circumvent dystrophin mutations via exon skipping and correct aberrant SMN2 splicing and are hopeful drugs for Duchenne Muscular Dystrophy (DMD) and Spinal Muscular Atrophy (SMA). However, the efficacy of these compounds when delivered locally or systemically in animal models for DMD is limited by their inefficient delivery to nuclei of various cell types. Furthermore, viability of 2OMe AO correction of SMN2 in a mouse model for SMA has yet to be established. In attempt to improve the delivery efficiency of 2OMe AO in skeletal muscle, we evaluated copolymers composed of cationic poly(ethylene imine) (PEI) and polyethylene glycol (PEG) by performing localized injections into hind limb muscles of a dystrophic (mdx) mouse. We found that PEGylated low MW PEI2K formulations improved transfection efficiency over naked AO as evidenced by a high number of dystrophin positive fibers widely distributed throughout the muscle. Repeated injection of AO complexed to nanogold-conjugated PEI2K-PEG copolymer increased dystrophin expression to 20%, the mark determined to be functionally relevant for improvement of dystrophic muscle. Thus, PEGylated PEI2K copolymers are efficient carriers for local delivery of 2OMe AOs and warrant further development as potential therapeutics for treatment of DMD. We subsequently evaluated correction of SMN2 splicing in a mouse model for SMA using a 2OMe AO sequence established to effectively increase Survival of Motor Neuron (SMN) protein in SMA patient fibroblasts. Injections into the cerebrospinal fluid (CSF) over the first 10 days of life increased functional SMN in brain and spinal cord to 35-55% as compared to wild-type control. 2OMe AO treated mice were significantly heavier as compared to un-injected SMA control mice suggesting this compound may extend lifespan if treatment is continued. Overall, this study shows that 2OMe AOs are effective compounds for the correction of splice defects and the production of functional protein in animal models for DMD and SMA. In addition, the delivery efficiency of 2OMe AOs in skeletal muscle of the mdx mouse is greatly increased when complexed with PEGylated PEI2K copolymers. The results from this thesis provide an important step in the preclinical development of 2OMe AOs as effective therapeutics for DMD and SMA.
Multi-robot navigation in a maze
Authors:   , Lebaudy Andres
Published: July 2024

We consider path planning for multiple mobile robots navigating in a rectangular maze divided into cells of equal size. Some cells contain permanent obstacles and some are empty and available for a robot to move into. All robots are synchronized and each robot is allowed to move into an empty cell adjacent to the one that it presently occupies. The objective is to determine a set of collision-free paths that lead each robot from a specified initial location to a specified goal location in minimum time. Two general approaches are investigated: centralized planning and distributed planning. Using centralized-planning, a single processor with full knowledge of the maze topology and of the initial and goal locations of the robots determines the time-optimal paths using standard graph search techniques. The central planners provide optimal solutions (whenever one exists) but they are computationally prohibitive-the complexity of the graph search grows exponentially in the number of navigating robots. In the distributed-planning version, minimum-length paths are first computed for each robot independently (i.e., under the assumption that each robot navigates the maze alone). The individually-optimal paths are then modified locally to produce collision-free paths. Our modifications are based on limiting the robots' visible neighborhood-robots adjust their independently-planned paths when they "see" other robots in their vicinity and realize the threat of collision. In the limit, robots are totally "blind" and they learn about the existence of other robots by colliding with them. Our study provides new near-optimal on-line algorithms for safe navigation of limited-vision robots. We also provide exact expressions for the mean path lengths within mazes of arbitrary architectures.
Studies directed towards the synthesis of Polyhydroxylated Indolizidines (Pt.1) ; Tandem Nitroaldol/Diels-Alder reactions of Nitroethylene derivatives (Pt.2)
Authors:   , Shah-Patel Sharmila , Wade Peter A
Published: July 2024

Part I. The synthesis of polyhydroxylated indolizidines using 4-oxygenated 4,5-dihydroisoxazole (DHI) intermediates derived from carbohydrate precursors was investigated. To begin a bicyclic DHI ring was constructed by nitrosative cyclization of a ribofuranoside which contained an iodo group located [gamma] to a tosyl group. Reaction of the ribofuranoside with a mixture of excess sodium nitrite and n-propyl nitrite in DMSO afforded displacement of iodine by nitrite, nitrosation, and cyclization of oxime anion with displacement of the tosyl group. The optically active bicyclic DHI was obtained in 43% yield. In order to furnish the additional three carbons needed for the targeted indolizidines, the nitro group of the bicyclic DHI was displaced by an acetylide derived from an O-protected propargyl alcohol derivative. Catalytic hydrogenation of the alkyne group followed by hydride reduction of the DHI ring afforded exclusively one isomer of the [gamma]-amino alcohol, the precursor to 1-deoxy-8a-epicastanospermine. Removal of the acetal moiety of the [gamma]-amino alcohol with trifluoroacetic acid was possible. The resulting triol was acetylated furnishing the triacetate in 35% yield for which the structure could be readily established. Part II. A general one-pot procedure for the in-situ generation of nitroethylene derivatives and their use as dienophiles in the Diels-Alder reaction was developed. The nitroethylene derivatives which were generated include (1-nitroethenyl)sulfonyl benzene, ethyl 2-nitropropenoate, and (1-nitroethenyl)phenyl methanone. Generation involved condensation of formalin with the appropriate nitromethane derivative. When generation was conducted in the presence of diene and acetic acid, cycloadducts substituted with sulfone, ester, and ketone groups were obtained. Dienes used included cyclopentadiene, 2,3-dimethyl-1,3-butadiene, isoprene, and 1,3-cyclohexadiene. Synthetic transformations of [alpha]-nitrosulfone cycloadducts involving sulfone group replacement by carbon nucleophiles were also carried out. Several [beta],[gamma]-unsaturated [alpha]-nitrosulfones were prepared. The dianion of phenylsulfonylnitromethane, generated using excess LDA, afforded the non-conjugated [beta],[gamma]-unsaturated [alpha]-nitrosulfones, upon treatment with aldehydes followed by acetic acid. Bis (nitrosulfone) byproducts were also detected in these reactions, apparently arising from Michael condensation of phenylsulfonylnitromethane with [alpha],[beta]-unsaturated [alpha]-nitrosulfone intermediates.
Entry inhibitors targeting HIV-1 Env gp120 as AIDS microbicide candidates
Authors:   , McFadden Karyn , Chaiken Irwin
Published: July 2024

Topical microbicides that can be used to prevent the spread of HIV-1 are urgently needed by women in the developing world. A recent clinical study has demonstrated that specifically targeting the virus reduces the rate of infection although the development of resistance mutations remains an important issue. Novel drugs are needed that can inactivate or block the virus and that are not part of the normal treatment regiment for the disease. This has brought a new emphasis on compounds that can block the initial attachment and entry of the virus. Entry occurs when the viral glycoprotein gp120 interacts with CD4 and a co-receptor resulting in the fusion of the viral and host cell membranes. One interesting inhibitor lead that targets this process is 12p1, a small peptide that binds to gp120 and blocks its interaction with both CD4 and the co-receptor but with low efficacy. We used several strategies to improve the potency of 12p1 and assessed the most promising compound for breadth of inhibition and safety. We initially modified 12p1 by creating a recombinant protein with 12p1 fused to the C-terminal domain of the small gp120 targeting lectin, cyanovirin-N. The chimera retained the high affinity binding and antiviral potentcy of cyanovirin-N as well as the dual antagonism of the 12p1 domain. We also analyzed the potential of a high potency peptide triazole derivative of 12p1, HNG-156, to act as a microbicide candidate. We found that HNG-156 can neutralize HIV-1 from subtypes A, B, C and D with no detectable toxicity. It can be combined with tenofovir or other entry inhibitors and appears to act synergistically with cyanovirin-N and other sugar binding compounds. Overall, we have improved the potency of the parent 12p1 and demonstrated that a peptide triazole derivative can be used as a safe and effective microbicide candidate to stop HIV-1.
Characterization of anthrolysin O, the Bacillus anthracis cholesterol-dependent cytolysin
Authors:   , Shannon Jeffrey G. , Rest Richard F
Published: July 2024

We characterized the expression of a putative toxin of B. anthracis, a member of the cholesterol-dependent cytolysin (CDC) family, which includes listeriolysin O (LLO), perfringolysin O (PFO) and streptolysin O (SLO). We have named the cytotoxin 'anthrolysin O' (ALO). Although B. anthracis expresses minimal hemolytic activity in clinical settings, we show that Sterne strain 7702 expresses hemolytic activity when grown in BHI broth, or in other rich bacteriologic media, but secretes barely detectable amounts of hemolysin when grown in Luria-Bertani (LB) broth. Glucose supplementation of LB broth increases the amount of secreted hemolytic activity. Expression of hemolytic activity is maximal during mid- to late-log phase and decreases in stationary phase. These observations are supported, in part, by semi-quantitative reverse transcriptase PCR of alo mRNA. Hemolytic activity in growth supernatants was increased in the presence of reducing agent, and almost totally inhibited in a dose-dependent manner by cholesterol-both activities characteristic of a CDC toxin. A mutant of Sterne strain 7702, strain UT231, in which the alo gene was deleted and replaced by a kanamycin cassette, secreted barely detectable hemolytic activity into growth medium. When strain UT231 was complimented in trans with native alo on a low copy number plasmid (strain UT231(pUTE554)), it regained the ability to secrete hemolytic activity, indicating that ALO is the major hemolysin secreted by this strain of B. anthracis in rich media in vitro. To further support the alo gene product being a hemolysin, recombinant B. anthracis ALO (rALO) purified from E. coli was extremely active against washed human erythrocytes, with complete hemolysis detected at ~30 molecules of rALO per erythrocyte. We have gone on to examine the interaction of the UT231 strain with mouse and human macrophage-like cell lines. These experiments demonstrate that ALO does not appear to be required for escape of B. anthracis from these cells.
Steroid hormone withdrawal alters the GABA-A receptor pharmacological profile
Authors:   , Hsu Fu-Chun Robert , Smith Sheryl S.
Published: July 2024

The steroid hormone progesterone (P) is readily converted to 3[alpha]-OH-5[alpha]-pregnan-20-one (3[alpha], 5[alpha]-THP) in the brains of males and females. 3[alpha], 5[alpha]-THP, like benzodiazepines (BDZs), can mediate sedative effects to decrease anxiety and seizure susceptibility by potentiating the function of GABA, the major inhibitory neurotransmitter in the brain. Clinical symptoms of pre-menstrual syndrome (PMS) such as anxiety is strongly correlated with abrupt declines in circulating levels of P as well as its GABA-modulatory metabolite, 3[alpha], 5[alpha]-THP. However, we understand little of the changes in GABAA receptor (GABA-R) pharmacology after P withdrawal. One goal of this research was to characterize GABA-mediated function after P withdrawal using electrophysiological means. Towards this end, a multiple P-withdrawal paradigm was designed to mimic PMS and post-partum syndrome in a rat model. The hypothesis tested electrophysiologically was that withdrawal from elevated circulating levels of the female sex steroid P may change electrophysiological parameters of the GABA-R. Twenty-four hours after removal of a three-week s.c. P capsule implant (24 hours P withdrawal), the pharmacological profile of GABA-R was changed; there was a 70-100% reduction in the ability of lorazepam (LZM), a BDZ agonist, to potentiate GABA-evoked Cl- current in acutely isolated hippocampal CA1 neurons. This effect was a result of withdrawal from 3[alpha], 5[alpha]-THP rather than P, as blockade of 3[alpha], 5[alpha]-THP formation with indomethacin during chronic P treatment prevented the BDZ insensitivity. To test the hypothesis that decreases in total integrated GABA-gated current observed in the isolated CA1 pyramidal cells would be manifested as reduced GABA inhibition at the circuit level, the paired-pulse inhibition (PPI) paradigm was used to evaluate the GABA-R-mediated effects in hippocampal slices. In order to test the hypothesis that [alpha]4-subunit up-regulation may produce the observed changes in GABA-R pharmacology, antisense oligonucleotide administration was used to suppress expression of the [alpha]4 subunit of GABA-R induced by P withdrawal. The results indicate that treatment prevented most withdrawal effects such as LZM insensitivity, the altered pharmacological profile, the decreased PPI, and the decreased GABA current decay time constant in isolated neurons. (Abstract shortened by UMI.).
Identifying determinants of juvenile decertification decisions
Authors:   , Towers Karin , Heilbrun Kirk
Published: July 2024

In recent years, public concern about the prevalence and violence of juvenile crime has increased. With increased concern over violent juvenile crime has come increased pressure to send more juvenile offenders into the adult system for processing and punishment. Currently, all state and federal jurisdictions possess some form of statutory provision allowing juveniles thought to be beyond the reach of rehabilitation and deserving of harsher treatment to be prosecuted as adults in the criminal courts. The present study examines how Pennsylvania juveniles charged initially in adult court under the provisions of a relatively new statute, Act 33, are either retained there or decertified to the jurisdiction of the juvenile court. Eighty-nine adolescents from the Philadelphia area comprised the main group of interest. Participants had been referred by the Defender Association of Philadelphia to the Forensic Psychology Clinic at MCP Hahnemann University for a mental health evaluation relevant to a defense motion for decertification. Information was collected for each participant in the following areas: demographic and historical information, level of academic functioning, mental and emotional functioning, amenability to treatment recommendation, and psychopathy rating. Results of logistic analyses revealed that Psychopathy Checklist - Youth Version score contributed more significantly to predictive capacity regarding decertification decision than any other variable examined in this study, accounting for 29% of the variance. Other significant predictor variables included history of prior person-related offense charge, and history of prior property-related offense charge. Practical and policy implications are discussed, and directions for future study are suggested.
Glutamine Utilization in Cancer Cells
Authors:   , Qie Shuo , Sang Nianli
Published: July 2024

Metabolic transformation forms the biochemical foundation for oncogenic transformation. In addition to being utilized for protein translation, glutamine (Gln) can serve as carbon and nitrogen sources to fulfill energetic and biosynthetic needs for proliferating cells. However, during progression, solid tumors frequently develop an ischemic condition, resulting in low Gln levels. A better understanding of tumor cells' adaptive strategy to Gln-deprivation may provide new therapeutic targets. Being the first and rate limiting step for Gln utilization, glutaminolysis is catalyzed by glutaminase (GLS). It has been hypothesized that oncogenes may coordinate glutaminolysis with cell proliferation. In Chapter 2, we used breast cancer cells as a model and studied whether ErbB2 signaling regulates Gln utilization in breast cancer cells. Our results indicate that ErbB2 activation enhances GLS1 expression, and NF-[kappa]B signaling pathway mediates this regulation. Furthermore, we identified the enhanced GLS1 expression promotes cell proliferation of ErbB2-positive breast cancer cells. In Chapter 3, we studied the global gene expression reprogramming of tumor cells upon Gln-deprivation using cDNA microarray combined with ingenuity pathway analysis. Our data show that acute Gln-deprivation leads to G 2/M cell cycle arrest and eventually apoptosis. In comparison, the adapted MM01 cells show a slow growing phenotype and a distinctive profile of gene expression reprogramming, including ATF4 activation and the upregulation of stress responsive genes, such as Stanniocalcin 2 (STC2). In Chapters 4 and 5, we studied the role of STC2 in tumor cells' adaptation to Gln-deprivation. Our data show that STC2 upregulation switches tumor cells' priority from proliferation to survival upon Gln-deprivation. The activation of eIF2[alpha]-ATF4 pathway is implicated in STC2 upregulation upon Gln-deprivation. STC2 promoter region possesses ATF4 binding site, and ATF4 directly interacts with this site. Neither secretion nor stability of STC2 is affected by Gln-deprivation. Finally, our data show inhibition of GLS activity is sufficient to trigger eIF2[alpha]-ATF4 activation and STC2 upregulation, indicating lack of Gln utilization, not Gln itself, triggers the eIF2[alpha]-ATF4-STC2 pathway, which switches cells' priority from proliferation to survival. Taken together, our data indicate that Gln utilization and adaptive mechanisms to Gln-deprivation can be explored as novel therapeutic targets for cancer treatment.
The isolation of mutagenic trace organic chemicals from potable water samples by continuous liquid-liquid extraction
Authors:   , Lippincott Robert L. , Suffet Irwin H.
Published: July 2024

The development of methods for the quantitative assessment of the health risk associated with the exposure to hazardous organic chemicals in drinking water is an ongoing effort of many federal and state environmental departments. Such estimates are based on the quantitation of individual organic compounds. The approach considered in this research is the determination of the genotoxic effect of organic extracts of drinking water samples using the Ames Salmonella bioassay. Contaminants in drinking water samples are present at nanogram/L to microgram/L levels. While these levels can not cause acute effects, exposure to such levels over a lifetime may have a detrimental impact on human health. A 2 L/hr and a 10 L/hr continuous liquid-liquid extractor (CLLE) were optimized to extract organic material from water into dichloromethane in a reproducible manner. The CLLE collected time based composites as a stand alone unit sampling raw and finished drinking water sources. The extractor isolated mutagenic substances from raw and finished drinking water, and instrumental analysis was able to identify compounds at the part per trillion level in the drinking water. The 10 L/hr CLLE had a sufficient flow rate to evaluate temporal and spacial variability of organic compounds in potable water. This research has explored the use of conventional capillary GC, GC/MS, multidimensional gas chromatography, microbore HPLC, and LC/MS, for analysis of the CLLE extracts. The CLLE extracts showed Ames activity which ranged from 40 to 645 revertants per liter of finished water. The detected mutagenic activity is a direct result of the chlorine disinfection process used in water treatment. The two tester strains, TA100 and TA98, indicate that the majority of the mutagenic activity was due to base pair insertion mutagens. Order of magnitude decreases in detection levels for organic compounds by GC/MS are achieved when comparing the CLLE method to USEPA method 625. HPLC analysis of the CLLE extracts isolated four discrete fractions. The testing of each fraction for mutagenic activity is possible due to the milligram quantities of residue isolated by CLLE. Several nonionic surfactants and plasticizers were identified by LC/MS.
Coping with mammography
Authors:   , Bildner Cheryl
Published: July 2024

Breast cancer is the second most common form of cancer and a leading cause of cancer deaths among women in the United States (National Cancer Institute, 1996). Mammography is the principle instrument in the detection and diagnosis of breast cancer. Since mammography is crucial in early detection of breast cancer, measures should be taken to reduce the aversiveness of this procedure and make mammography fully accessible to all. In this investigation, problem-solving ability, information, and informational coping style were examined to determine the effects on patient anxiety, for women undergoing their first screening mammogram. A repeated measures analysis was conducted on 52 participants. Results found that information coping style and type of information delivered to participants had no effect on participant anxiety. Additionally, a series of correlations were conducted between social problem-solving ability and anxiety, and information coping style and anxiety. Significant inverse relationships were found between social problem-solving ability and level of anxiety. No relationship was found between information coping style and anxiety. Social problem-solving ability was also found to be a significant predictor of participant anxiety. Furthermore, age of first mammogram recipients was found to be affected by educational level and socioeconomic status. The clinical implications, limitations of this investigation, and directions for future research will be discussed.