Open Access Policy Articles

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The IUPUI Faculty Council adopted an open access policy on October 7th, 2014 (available from: https://openaccess.indianapolis.iu.edu/). This policy shows IU Indianapolis's commitment to disseminating the fruits of research and scholarship as widely as possible. Open access policies increase authors’ rights, readership and citation rates for scholarly articles. The opt out provision ensures that all faculty authors have the freedom to publish in the journal of their choice.

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Now showing 1 - 10 of 33411

The Association of Depression and Anxiety with Health-Related Quality of Life in Cancer Patients with Depression and/or Pain
(Wiley, 2010) Brown, Linda F.; Kroenke, Kurt; Theobald, Dale E.; Wu, Jingwei; Tu, Wanzhu; Psychology, School of Science
Objectives: Depression is known to be a major problem in cancer patients, and evidence is emerging about the importance of anxiety. Because the disorders are highly comorbid, we examined the relationship of anxiety and depression with health-related quality of life (HRQL) in cancer patients. Methods: Sample included 405 adult oncology patients participating in a randomized controlled trial of telecare management for pain and depression. This secondary cross-sectional analysis of baseline data examined independent and additive effects of anxiety and depression on HRQL, disability, and somatic symptom severity. Results: In 397 patients who screened positive for either pain or depression or both, 135 had comorbid anxiety and depression, 174 had depression but not anxiety, and 88 had neither. Differences existed across all nonphysical HRQL domains and were more pronounced incrementally across the three groups in the expected direction. In GLM modeling, anxiety and depression were each associated with all the domains when modeled separately (p<0.0001). When modeled together, anxiety and depression had independent and additive effects on the mental health domains of HRQL and on somatic symptom burden. In other domains (vitality, perceived disability, overall quality of life, and general health perceptions), only depression had an effect. Conclusion: Anxiety and depression have strong and independent associations with mental health domains and somatic symptom burden in cancer patients. However, depression has a more pervasive association with multiple other domains of HRQL. Paying attention to both anxiety and depression may be particularly important when addressing mental health needs and somatic symptom distress.
Association of Ideomotor Apraxia With Frontal Gray Matter Volume Loss in Corticobasal Syndrome
(American Medical Association, 2009) Huey, Edward D.; Pardini, Matteo; Cavanagh, Alyson; Wassermann, Eric M.; Kapogiannis, Dimitrios; Spina, Salvatore; Ghetti, Bernardino; Grafman, Jordan; Pathology and Laboratory Medicine, School of Medicine
Objective: To determine the brain areas associated with specific components of ideomotor apraxia (IMA) in corticobasal syndrome (CBS). Design: Case-control and cross-sectional study. Participants: Forty-eight patients with CBS and 14 control subjects. Intervention Administration of the Test of Oral and Limb Apraxia. Main outcome measures: Differences between patients with CBS and healthy controls and associations between areas of gray matter volume and IMA determined by voxel-based morphometry in patients with CBS. Results: Overall, IMA was associated with decreased gray matter volume in the left supplemental motor area, premotor cortex, and caudate nucleus of patients with CBS. The overall degree of apraxia was independent of the side of motor impairment. Praxis to imitation (vs command) was particularly impaired in the patients with CBS. Patients demonstrated equal impairment in transitive and intransitive praxis. Conclusions: In patients with CBS, IMA is associated with left posterior frontal cortical and subcortical volume loss. Despite showing left frontal volume loss associated with IMA, patients with CBS have particularly impaired imitation of gestures. These findings suggest either that the IMA of CBS affects a route of praxis that bypasses motor engrams or that motor engrams are affected but that they exist in areas other than the inferior parietal cortex.
HPD: an online integrated human pathway database enabling systems biology studies
(BioMed Central, 2009-10-08) Chowbina, Sudhir R.; Wu, Xiaogang; Zhang, Fan; Li, Peter M.; Pandey, Ragini; Kasamsetty, Harini N.; Chen, Jake Y.; Computer and Information Science, Purdue School of Science
Background: Pathway-oriented experimental and computational studies have led to a significant accumulation of biological knowledge concerning three major types of biological pathway events: molecular signaling events, gene regulation events, and metabolic reaction events. A pathway consists of a series of molecular pathway events that link molecular entities such as proteins, genes, and metabolites. There are approximately 300 biological pathway resources as of April 2009 according to the Pathguide database; however, these pathway databases generally have poor coverage or poor quality, and are difficult to integrate, due to syntactic-level and semantic-level data incompatibilities. Results: We developed the Human Pathway Database (HPD) by integrating heterogeneous human pathway data that are either curated at the NCI Pathway Interaction Database (PID), Reactome, BioCarta, KEGG or indexed from the Protein Lounge Web sites. Integration of pathway data at syntactic, semantic, and schematic levels was based on a unified pathway data model and data warehousing-based integration techniques. HPD provides a comprehensive online view that connects human proteins, genes, RNA transcripts, enzymes, signaling events, metabolic reaction events, and gene regulatory events. At the time of this writing HPD includes 999 human pathways and more than 59,341 human molecular entities. The HPD software provides both a user-friendly Web interface for online use and a robust relational database backend for advanced pathway querying. This pathway tool enables users to 1) search for human pathways from different resources by simply entering genes/proteins involved in pathways or words appearing in pathway names, 2) analyze pathway-protein association, 3) study pathway-pathway similarity, and 4) build integrated pathway networks. We demonstrated the usage and characteristics of the new HPD through three breast cancer case studies. Conclusion: HPD http://bio.informatics.iupui.edu/HPD is a new resource for searching, managing, and studying human biological pathways. Users of HPD can search against large collections of human biological pathways, compare related pathways and their molecular entity compositions, and build high-quality, expanded-scope disease pathway models. The current HPD software can help users address a wide range of pathway-related questions in human disease biology studies.
Reconstitution of amphiregulin-EGFR signaling in lung squamous cell carcinomas activates PTHrP gene expression and contributes to cancer-mediated diseases of the bone
(American Association for Cancer Research, 2009) Gilmore, Jennifer L.; Gonterman, Ryan M.; Menon, Keshav; Lorch, Gwendolen; Riese, David J., II; Robling, Alex; Foley, John; Anatomy, Cell Biology and Physiology, School of Medicine
Parathyroid hormone-related protein (PTHrP) is the causative factor of the paraneoplastic syndrome humoral hypercalcemia of malignancy (HHM) and it also contributes to osteolytic metastases, both of which are common complications of squamous carcinomas of the lung. Inhibition of autocrine epidermal growth factor receptor (EGFR) signaling has been shown to reduce plasma calcium and PTHrP concentrations in two lung squamous cell carcinoma xenograft models of HHM. The purpose of this study was to investigate the mechanism by which EGFR is activated and stimulates PTHrP gene expression in lung squamous carcinoma cell lines. Amphiregulin (AREG) was the only EGFR ligand that could be consistently detected in conditioned media from the SCC lines, and reduction of its expression either by siRNA or by precipitating antibody reduced PTHrP mRNA expression as effectively as EGFR-targeted inhibition. Using siRNA knockdown or inhibitors to upstream regulators of AREG shedding including TACE, Src/Lck, and G(i/o), also reduced PTHrP mRNA expression. We determined that blockade of autocrine AREG-EGFR signaling does not affect PTHrP mRNA stability. Of the three PTHrP promoters (P1, P2, and P3), P1 mRNA could be reduced by nearly 100% with an EGFR inhibitor, and both epidermal growth factor and AREG stimulated P1 mRNA by approximately 5-fold. Finally, ectopic expression of EGFR in a receptor-low but AREG-expressing cell line increased PTHrP mRNA levels in vitro, and induced the capability to cause HHM and rapid osteolytic growth in vivo. Taken together, we provide evidence that AREG stimulation of EGFR results in high levels of PTHrP gene expression, contributing to cancer-associated bone pathology.
Regulation of circadian blood pressure: from mice to astronauts
(Wolters Kluwer, 2010) Agarwal, Rajiv; Medicine, School of Medicine
Purpose of review: Circadian variation is commonly seen in healthy people; aberration in these biological rhythms is an early sign of disease. Impaired circadian variation of blood pressure (BP) has been shown to be associated with greater target organ damage and with an elevated risk of cardiovascular events independent of the BP load. The purpose of this review is to examine the physiology of circadian BP variation and propose a tripartite model that explains the regulation of circadian BP. Recent findings: The time-keeper in mammals resides centrally in the suprachiasmatic nucleus. Apart from this central clock, molecular clocks exist in most peripheral tissues including vascular tissue and the kidney. These molecular clocks regulate sodium balance, sympathetic function and vascular tone. A physiological model is proposed that integrates our understanding of molecular clocks in mice with the circadian BP variation among humans. The master regulator in this proposed model is the sleep-activity cycle. The equivalents of peripheral clocks are endothelial and adrenergic functions. Thus, in the proposed model, the variation in circadian BP is dependent upon three major factors: physical activity, autonomic function, and sodium sensitivity. Summary: The integrated consideration of physical activity, autonomic function, and sodium sensitivity appears to explain the physiology of circadian BP variation and the pathophysiology of disrupted BP rhythms in various conditions and disease states. Our understanding of molecular clocks in mice may help to explain the provenance of blunted circadian BP variation even among astronauts.
Downregulation of Kv4.2 channels mediated by NR2B-containing NMDA receptors in cultured hippocampal neurons
(Elsevier, 2010) Lei, Zhigang; Deng, Ping; Li, Yan; Xu, Zao C.; Anatomy, Cell Biology and Physiology, School of Medicine
Somatodendritic Kv4.2 channels mediate transient A-type potassium currents (IA), and play critical roles in controlling neuronal excitability and modulating synaptic plasticity. Our studies have shown a NMDA receptor-dependent downregulation of Kv4.2 and IA. NMDA receptors are heteromeric complexes of NR1 combined with NR2A-NR2D, mainly NR2A and NR2B. Here, we investigate NR2B receptor-mediated modulation of Kv4.2 and IA in cultured hippocampal neurons. Application of glutamate caused a reduction in total Kv4.2 protein levels and Kv4.2 clusters, and produced a hyperpolarized shift in the inactivation curve of IA. The effects of glutamate on Kv4.2 and IA were inhibited by pretreatment of NR2B-selective antagonists. NR2B-containing NMDA receptors are believed to be located predominantly extrasynaptically. Like application of glutamate, selective activation of extrasynaptic NMDA receptors caused a reduction in total Kv4.2 protein levels and Kv4.2 clusters, which was also blocked by NR2B-selective antagonists. In contrast, specific stimulation of synaptic NMDA receptors had no effect on Kv4.2. In addition, the influx of Ca2+ was essential for extrasynaptic modulation of Kv4.2. Calpain inhibitors prevented the reduction of total Kv4.2 protein levels following activation of extrasynaptic NMDA receptors. These results demonstrate that the glutamate-induced downregulation of Kv4.2 and IA is mediated by NR2B-containing NMDA receptors and is linked to proteolysis by calpain, which might contribute to the development of neuronal hyperexcitability and neurodegenerative diseases.
PU.1 regulates TCR expression by modulating GATA-3 activity
(Oxford University Press, 2009) Chang, Hua-Chen; Han, Ling; Jabeen, Rukhsana; Carotta, Sebastian; Nutt, Stephen L.; Kaplan, Mark H.; Pediatrics, School of Medicine
The Ets transcription factor PU.1 is a master regulator for the development of multiple lineages during hematopoiesis. The expression pattern of PU.1 is dynamically regulated during early T lineage development in the thymus. We previously revealed that PU.1 delineates heterogeneity of effector Th2 populations. In this study, we further define the function of PU.1 on the Th2 phenotype using mice that specifically lack PU.1 in T cells using an lck-Cre transgene with a conditional Sfpi1 allele (Sfpi1(lck-/-)). Although deletion of PU.1 by the lck-Cre transgene does not affect T cell development, Sfpi1(lck-/-) T cells have a lower activation threshold than wild-type T cells. When TCR engagement is limiting, Sfpi1(lck-/-) T cells cultured in Th2 polarizing conditions secrete higher levels of Th2 cytokines and have greater cytokine homogeneity than wild-type cells. We show that PU.1 modulates the levels of TCR expression in CD4(+) T cells by regulating the DNA-binding activity of GATA-3 and limiting GATA-3 regulation of TCR gene expression. GATA-3-dependent regulation of TCR expression is also observed in Th1 and Th2 cells. In CD4(+) T cells, PU.1 expression segregates into subpopulations of cells that have lower levels of surface TCR, suggesting that PU.1 contributes to the heterogeneity of TCR expression. Thus, we have identified a mechanism whereby increased GATA-3 function in the absence of the antagonizing activity of PU.1 leads to increased TCR expression, a reduced activation threshold, and increased homogeneity in Th2 populations.
A Systems Approach to Tissue Remodeling
(ASME, 2009) Kassab, Ghassan S.; Surgery, School of Medicine
Remodeling of tissue in response to physical stress is a very complex process. The changes in the stimulus (cause) and response (effect) must be measured and the results must be organized into mathematical forms that are suitable for predictions and applications. An experiment where the stimulus (pressure, flow, shear stress, etc.) can be changed approximately as a step function (a step plus a perturbation) and the response (structure, material properties, function, etc.), which can be measured over time, can be simulated by indicial response functions (IRFs). The IRF is a mathematical expression of the ratio of the change in a particular feature of the system in response to a unit step change in stimulus. The IRF approach provides a quantitative description of the remodeling process, simplifies the interpretation of data, and greatly increases the potential of using the experimental data for prediction of the outcome for future experiments. The objective of this review is to provide an overview of the IRF approach including some exemplary systems. The goal is to illustrate how the indicial expressions make it possible to integrate biological complexity by convolution. The time courses of stimuli represent half of the convolution while the time course of changes in response represents the second half of the convolution. The IRF approach provides an understanding of the physiological problems with mathematical accuracy and may be conducive to new findings.
Continuing Psychosocial Care Needs in Children with New-Onset Epilepsy and Their Parents
(Wolters Kluwer, 2009) Shore, Cheryl P.; Buelow, Janice M.; Austin, Joan K.; Johnson, Cynthia S.; School of Nursing
Children with new-onset epilepsy and their parents have many psychosocial care needs, including concerns and fears and needs for information and support. No prospective studies address psychosocial care needs at 12 and 24 months after seizure onset. It is unknown if psychosocial care needs are associated with children's attitudes toward having epilepsy or with parental responses to their child's epilepsy. Our study addresses this knowledge gap. Members of 143 families took part in the study. Children were 8 to 14 years old and had at least two seizures. Parents and children completed Psychosocial Care Need Scales at 3, 6, 12, and 24 months after the first seizure. Children also completed the Child Attitude Toward Illness Scale, and parents completed the Parent Response to Child Illness scale. Data were analyzed using descriptive statistics and correlations. Although psychosocial care needs were highest at the 3-month data collection for both parents and children, some worries and concerns and needs for information and support persisted for 24 months. In children, more psychosocial care needs were associated with more negative attitudes toward having epilepsy. In parents, high psychosocial care needs were associated with a more negative impact on family life. A substantial number of parents and children have unmet psychosocial care needs that are associated with more negative child attitudes and a negative impact on family life, even 24 months after the onset of seizures. Nurses should assess both children and parents for these needs at every encounter with the healthcare system to address their needs.
Inducible pluripotent stem cells: Not quite ready for prime time?
(Wolters Kluwer, 2010) Robbins, Reiesha D.; Prasain, Nutan; Maier, Bernhard F.; Yoder, Mervin C.; Mirmira, Raghavendra G.; Pediatrics, School of Medicine
Purpose of review: Inducible pluripotent stem (iPS) cells derived from somatic cells represent a novel renewable source of tissue precursors. The potential of iPS cells is considered to be at least equivalent to that of human embryonic stem cells, facilitating the treatment or cure of diseases such as diabetes mellitus, spinal cord injuries, cardiovascular disease, and neurodegenerative diseases, but with the potential added benefit of evading the adaptive immune response that otherwise limits allogeneic cell-based therapies. This review discusses recent advances in pluripotency induction and the use of iPS cells to produce differentiated cells, while highlighting roadblocks to the widespread use of this technology in the clinical arena. Recent findings: Whereas ethical and safety issues surrounding the use of human embryonic stem cells for the treatment of disease continue to be debated, use of iPS cells may be viewed as a more widely acceptable compromise. Since the first descriptions of inducible pluripotency from somatic cells, multiple laboratories have collectively made tremendous strides both in developing alternative, more clinically acceptable, induction strategies and in demonstrating the proof-of-principle that iPS cells can be differentiated into a variety of cell types to reverse mouse models of human disease. Summary: Although the prospect of using patient-specific iPS cells has much appeal from an ethical and immunologic perspective, the limitations of the technology from the standpoint of reprogramming efficiency and therapeutic safety necessitate much more in-depth research before the initiation of human clinical trials.

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