Cell and Developmental Biology Commons^™

Clinical Features And Outcome Of Sporadic Colorectal Carcinoma In Young Patients: A Cross-Sectional Analysis From A Developing Country, Muhammad Nauman Zahir, Eisha Mahpara Azhar, Sobia Rafiq, Kulsoom Ghias, Munira Shabbir-Moosajee

Department of Biological & Biomedical Sciences

Background: Early onset colorectal carcinoma (CRC) is rare and has been hypothesized to be a biologically and clinically distinct entity personifying aggressive disease and worse survival.
Methods: Data for 131 patients was collected by retrospective chart review. Cox proportional hazard model was used to compute prevalence ratios and 95% confidence intervals.
Results: Early onset sporadic CRC accounted for 32% of all CRC treated in the specified time period. The mean age was 33.3 ± 7.9 years and the male to female ratio was 2 : 1. Colon and rectal cancers accounted for 55% and 45% of patients, respectively. 96% of …

Nel Positively Regulates The Genesis Of Retinal Ganglion Cells By Promoting Their Differentiation And Survival During Development, Chizu Nakamoto, Soh-Leh Kuan, Amy Findlay, Elaine Durward, Zhufeng Ouyang, Masaru Nakamoto, Ewa Zakrewska, Takuma Endo

Biology Faculty Publications

For correct functioning of the nervous system, the appropriate number and complement of neuronal cell types must be produced during development. However, the molecular mechanisms that regulate the production of individual classes of neurons are poorly understood. In this study, we investigate the function of the thrombospondin-1–like glycoprotein, Nel (neural epidermal growth factor [EGF]-like), in the generation of retinal ganglion cells (RGCs) in chicks. During eye development, Nel is strongly expressed in the presumptive retinal pigment epithelium and RGCs. Nel overexpression in the developing retina by in ovo electroporation increases the number of RGCs, whereas the number of displaced amacrine …

A Novel Function For 12-Lipoxygenase In C-Met And Integrin Β4 Axis Crosstalk, Elizabeth Tovar

Wayne State University Dissertations

Cancer cell metastasis is the single most threatening occurrence of tumor progression and predicts patient prognosis as well as survival. Invasion can be regulated by the Met receptor tyrosine kinase (c-Met), integrin beta4, and the lipid enzyme, 12-Lipoxygenase (12-LOX). Therefore we sought to determine if beta4, c-MET and 12-LOX comprise a signaling axis. c-Met is implicated in cancer cell dissemination through regulation of invasion in EMT where cell-cell junctions are disturbed to allow motility. Furthermore, beta4 promotes cellular adhesion to the extracellular matrix through hemidesmosomes. However, the homeostatic signaling functions of beta4's cytoplasmic tail can be hijacked by growth factor …

Non-Raft Ac2 Defines A Camp Signaling Compartment That Selectively Regulates Il-6 Expression In Airway Smooth Muscle Cells, Amy S. Bogard, Anna V. Birg, Rennolds S. Ostrom

Pharmacy Faculty Articles and Research

Adenylyl cyclase (AC) isoforms differ in their tissue distribution, cellular localization, regulation, and protein interactions. Most cell types express multiple AC isoforms. We hypothesized that cAMP produced by different AC isoforms regulates unique cellular responses in human bronchial smooth muscle cells (BSMC). Overexpression of AC2, AC3, or AC6 had distinct effects on forskolin (Fsk)-induced expression of a number of known cAMP-responsive genes. These data show that different AC isoforms can differentially regulate gene expression. Most notable, overexpression and activation of AC2 enhanced interleukin 6 (IL-6) expression, but overexpression of AC3 or AC6 had no effect. IL-6 production by BSMC was …

Cellular Coping Mechanisms To Hypoxia In The Longhorn Sculpin (Myoxocephalus Octodecemspinosus) Brain, Kelly Heino

College of Graduate Studies: Theses & Dissertations

The loss of neurological function due to hypoxia remains to be a challenge in many species due to the lack of knowledge and understanding of cellular responses. To investigate cellular responses and survival strategies of the brain during hypoxia and post-hypoxia recovery in a moderate hypoxia-tolerant species, with the hopes of identifying possible therapeutic remedies, thirty Longhorn sculpin, Myoxocephalus octodecimspinosus, were challenged with acute hypoxia (40% O2 saturation for 1 h) and twelve additional sculpin were used as controls (~90% O₂ saturation). Fish were sampled at each of the following time points: control/normoxic conditions (T=0 h); hypoxic conditions …

Paracrine-Rescued Lobulogenesis In Chimeric Outgrowths Comprising Progesterone-Receptor-Null Mammary Epithelium And Redirected Wild-Type Testicular Cells, Robert D. Bruno, Corinne A. Boulanger, Sonia M. Rosenfield, Lisa H. Anderson, John P. Lydon, Gilbert H. Smith

School of Medical Diagnostics & Translational Sciences Publications

We have previously shown that non-mammary and tumorigenic cells can respond to the signals of the mammary niche and alter their cell fate to that of mammary epithelial progenitor cells. Here we tested the hypothesis that paracrine signals from mammary epithelial cells expressing progesterone receptor (PR) are dispensable for redirection of testicular cells, and that re-directed wild-type testicular-derived mammary cells can rescue lobulogenesis of PR-null mammary epithelium by paracrine signaling during pregnancy. We injected PR-null epithelial cells mixed with testicular cells from wild-type adult male mice into cleared fat-pads of recipient mice. The testicular cells were redirected in vivo to …

Dielectric Characterization Of Coastal Cartilage Chondrocytes, Michael W. Stacey, Ahmet C. Sabuncu, Ali Beskok

Bioelectrics Publications

BACKGROUND: Chondrocytes respond to biomechanical and bioelectrochemical stimuli by secreting appropriate extracellular matrix proteins that enable the tissue to withstand the large forces it experiences. Although biomechanical aspects of cartilage are well described, little is known of the bioelectrochemical responses. The focus of this study is to identify bioelectrical characteristics of human costal cartilage cells using dielectric spectroscopy.

METHODS: Dielectric spectroscopy allows non-invasive probing of biological cells. An in house computer program is developed to extract dielectric properties of human costal cartilage cells from raw cell suspension impedance data measured by a microfluidic device. The dielectric properties of chondrocytes are …

Basic Features Of A Cell Electroporation Model: Illustrative Behavior For Two Very Different Pulses, Reuben S. Son, Kyle C. Smith, Thiruvallur R. Gowrishankar, P. Thomas Vernier, James C. Weaver

Bioelectrics Publications

Science increasingly involves complex modeling. Here we describe a model for cell electroporation in which membrane properties are dynamically modified by poration. Spatial scales range from cell membrane thickness (5 nm) to a typical mammalian cell radius (10 μm), and can be used with idealized and experimental pulse waveforms. The model consists of traditional passive components and additional active components representing nonequilibrium processes. Model responses include measurable quantities: transmembrane voltage, membrane electrical conductance, and solute transport rates and amounts for the representative "long" and "short" pulses. The long pulse-1.5 kV/cm, 100 μs-evolves two pore subpopulations with a valley at ~5 …

Cellular Regulation Of Extension And Retraction Of Pseudopod-Like Blebs Produced By Nanosecond Pulsed Electric Field, Mikhail A. Rassokhin, Andrei G. Pakhomov

Bioelectrics Publications

Recently we described a new phenomenon of anodotropic pseudopod-like blebbing in U937 cells exposed to nanosecond pulsed electric field (nsPEF). In Ca²⁺ -free buffer such exposure initiates formation of pseudopod-like blebs (PLBs), protrusive cylindrical cell extensions that are distinct from apoptotic and necrotic blebs. PLBs nucleate predominantly on anode-facing cell pole and extend toward anode during nsPEF exposure. Bleb extension depends on actin polymerization and availability of actin monomers. Inhibition of intracellular Ca²⁺ , cell contractility, and RhoA produced no effect on PLB initiation. Meanwhile, inhibition of WASP by wiskostatin causes dose-dependent suppression of PLB growth. Soon after …

Introduction To Fourth Special Issue On Electroporation-Based Technologies And Treatments, Damijan Miklavčič, Lluis M. Mir, P. Thomas Vernier

Bioelectrics Publications

This fourth special electroporation-based technologies and treatments issue of the Journal of Membrane Biology contains reports on recent developments in the field of electroporation by participants in the 7th International Workshop and Postgraduate Course on electroporation based technologies and treatments (EBTT 2013) held in Ljubljana, November 17–23, 2013. The 65 participants included faculty members, invited lecturers, special guests, and young scientists, and students from 16 countries. In addition to lectures on the fundamentals, this year’s sessions included talks on microbial inactivation by pulsed electric fields, modeling of intracellular electroporation, electroporation in food processing, and electrotransfer-facilitated DNA vaccination.

The Effect Of Lactic Acid On Mast Cell Function, Andrew J. Spence

Theses and Dissertations

This study shows for the first time the effect that L-(+)-lactic acid has on mast cell activation. Lactic acid is a byproduct of anaerobic glycolysis and is associated with inflammatory environments such as wounds, tumors and, asthma. In this study, pre-treatment with lactic acid altered cytokine production by bone marrow-derived mast cells (BMMC). Specifically, lactic acid enhanced cytokine secretion following IgE cross-linking, but decreased IL-33 mediated cytokine production. These effects were altered by genetic background, since C57BL/6 mast cells demonstrated the aforementioned result, but lactic acid had no effect on IgE-mediated cytokine production in 129/SvJ mast cells. The affected cytokines …

Mitochondrial Dynamics: Exploring A Novel Target Against Myocardial Ischemia-Reperfusion Injury, Yi Dong

Wayne State University Dissertations

Mitochondrial fusion and fission, collectively termed mitochondrial dynamics, are among the core mechanisms responsible for maintaining mitochondrial health and functional integrity. Dynamin-related protein 1 (DRP1) is a key regulator of mitochondrial fission. Recent studies suggest that i) mitochondrial dynamics, particularly, mitochondrial fission, serves as a mediator of cell fate in the setting of ischemia-reperfusion (IR) injury, and, ii) inhibition of DRP1 and mitochondrial fission provides cardioprotection against IR injury. However, the precise role of DRP1 translocation to mitochondria in the pathogenesis of myocardial ischemia-reperfusion injury has not been established.

Using an established model of hypoxia-reoxygenation (HR) in cultured HL-1 cardiomyocytes, …

Dj-1 And Atp13a2: Two Proteins Involved In Parkinson’S Disease, Josephat M Asiago

Open Access Dissertations

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease, affecting approximately 0.3% of the total U.S. population, and its prevalence increases with age. Two neuropathological hallmarks of PD are the loss of dopaminergic neurons in the substantia nigra pars compacta, a region in the midbrain involved in initiating and sustaining movement, and the presence of cytosolic inclusions called Lewy bodies (LBs) in various brain regions. LBs are enriched with fibrillar forms of the presynaptic protein &agr;-synuclein (aSyn). Two autosomal recessive genes implicated in familial PD are PARK9, encoding the P-type ATPase ATP13A2, a lysosomal ATPase; and …

Mechanisms Of Age-Related Inflammation And Cancer : The Synergistic Effect Of Oxidants And Calcium, Donald A. Mccarthy

Legacy Theses & Dissertations (2009 - 2024)

The accumulation of senescent cells during the process of aging has been implicated as causal in numerous age-related pathologies. Senescent cells adopt a secretory phenotype consisting of many factors including matrix remodeling enzymes, growth factors, cytokines, and chemokines. Their secretory nature is the primary reason that they are associated with disease, but it remains unclear why they become so inflammatory. Using primary human fibroblasts cultured to senescence, we mechanistically determined why senescent cells are such potent inducers of inflammation. Our findings indicate that the early production of the cytokine Interleukin 1-α (IL-1α) is central to this transition. We found that …

The Lipogenic Phenotype Of Her2/Neu-Positive Breast Cancer Cells, Jan Martin Baumann

Legacy Theses & Dissertations (2009 - 2024)

Recent work has shown that HER2/neu-positive breast cancer cells rely on a unique Warburg-like metabolism for survival and aggressive behavior. These cells are dependent on fatty acid (FA) synthesis, show markedly increased levels of stored fats and disruption of the synthetic process results in apoptosis. Supplementation of the growth media with physiological concentrations of saturated FAs induces cell death, whereas HER2-normal cells are not affected. This is particularly interesting in the context of new epidemiological data showing that a diet rich in saturated FAs is positively correlated with the development of HER2-negative disease, but not HER2/neu-positive disease.

Molecular Actions Of The Vitamin D Receptor In Breast Cancer, Erika Laporta

Legacy Theses & Dissertations (2009 - 2024)

1,25-Dihydroxyvitamin D (1,25D) exerts anti-cancer actions through the vitamin D receptor (VDR) but the specific targets that mediate these effects remain to be defined. In these studies, growth and genomic responses to 1,25D were evaluated in a cellular model system derived from mammary tumors generated in VDR knockout (KO) and wildtype (WT) mice. WT145 cells (derived from WT tumors) expressed VDR and were growth inhibited by 1,25D, whereas KO240 cells (derived from VDRKO tumors) lacked VDR and were not growth inhibited by 1,25D. KO240 cell clones stably expressing VDR (KOhVDR cells) were sensitized to 1,25D mediated growth arrest. Genomic profiling …

Computational Modeling-Driven Study Of Signaling Pathway Affecting Cleft Formation During Submandibular Salivary Gland Development, Shayoni Ray

Legacy Theses & Dissertations (2009 - 2024)

Branching morphogenesis is a conserved mechanism of mammalian organ development (salivary glands, lungs, mammary glands, pancreas, kidney, etc.), and has been a classic topic of study for generations of developmental biologists. During the process of tissue formation, several cellular and molecular and protein signaling events occur at successive stages enabling proper formation of tissue shape and structure. In order to provide a comprehensive understanding of the process of branching morphogenesis, we need a systems level approach to integrate multifactorial information. My overall global hypothesis is that multiple mathematical modeling approaches can be utilized to extract crucial cellular and tissue level …

Effect Of Long Term Rapamycin Treatment On Mtor Signalling Network In Colon And Liver Of C57bl/6 Mice, John Sorge

Wayne State University Theses

Many studies have investigated the effects of rapamycin on aging and cancer. However, the effects of long-term rapamycin supplementation on a cancer model have not been performed. This is the first study that investigates the effects of long-term supplementation of rapamycin in a cancer model. ACF analysis of colon tissues in mice showed no significant difference between controls and those supplemented with rapamycin. Factors such as energy balance, cellular environment, PI3K/Akt/mTOR pathway, and more have been assessed in this study. The duration of rapamycin supplementation seems to play an important role in the protection against cancer. Ultimately, this study suggests …

Characterization Of Adult Zebrafish Retinal Regeneration Following Two Different Damage Models, Jennifer Lee Thomas

Wayne State University Dissertations

Unlike mammals, zebrafish can regenerate all of their retinal neurons through Müller glial cells, which respond to retinal damage by re-entering the cell cycle to create clusters of progenitor cells. The progenitors continue to proliferate as they migrate to the site of damage, where they ultimately differentiate into new retinal neurons. In contrast, Müller glia of the mammalian retina respond to injury with reactive gliosis, which if persistent, can lead to loss of Müller cell function and devastating vision loss. Despite this, multiple lines of evidence suggest that mammalian Müller glial cells possess a latent ability to regenerate retinal neurons. …

Gbetagamma-Microtubule Mediated Mechanism Of Neuronal Differentiation, Jorge Anibal Sierra Fonseca

Open Access Theses & Dissertations

Neurodegeneration, a progressive loss of nerve cells (neurons), occurs in many neurological disorders, including Alzheimer's and Parkinson's diseases, as well as in the aging brain. Disruption of microtubules in neurons and the aggregation of proteins associated with them is the hallmark of neurodegeneration. Nevertheless, the cause of this disorder is largely unknown, and no effective drugs are available to treat the disease processes. Therefore, there is a need to understand the molecular mechanisms that drive the assembly and disassembly of microtubules during neurite outgrowth and differentiation. Evidence suggests that nerve growth factor (NGF) induces neurite outgrowth from PC12 cells by …

Computational Modeling Of Allosteric Regulation In The Hsp90 Chaperones: A Statistical Ensemble Analysis Of Protein Structure Networks And Allosteric Communications, Kristin Blacklock, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

A fundamental role of the Hsp90 chaperone in regulating functional activity of diverse protein clients is essential for the integrity of signaling networks. In this work we have combined biophysical simulations of the Hsp90 crystal structures with the protein structure network analysis to characterize the statistical ensemble of allosteric interaction networks and communication pathways in the Hsp90 chaperones. We have found that principal structurally stable communities could be preserved during dynamic changes in the conformational ensemble. The dominant contribution of the inter-domain rigidity to the interaction networks has emerged as a common factor responsible for the thermodynamic stability of the …

Allosteric Regulation Of The Hsp90 Dynamics And Stability By Client Recruiter Cochaperones: Protein Structure Network Modeling, Kristin Blacklock, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

The fundamental role of the Hsp90 chaperone in supporting functional activity of diverse protein clients is anchored by specific cochaperones. A family of immune sensing client proteins is delivered to the Hsp90 system with the aid of cochaperones Sgt1 and Rar1 that act cooperatively with Hsp90 to form allosterically regulated dynamic complexes. In this work, functional dynamics and protein structure network modeling are combined to dissect molecular mechanisms of Hsp90 regulation by the client recruiter cochaperones. Dynamic signatures of the Hsp90-cochaperone complexes are manifested in differential modulation of the conformational mobility in the Hsp90 lid motif. Consistent with the experiments, …

Analysis Of The Role Of Two Autophagy Pathway Related Genes, Becn1 And Tsc1, In Murine Mammary Gland Development And Differentiation, Amber N. Hale

Theses and Dissertations--Biology

The mammary gland is a dynamic organ that undergoes the majority of its development in the postnatal period in four stages; mature virgin, pregnancy, lactation, and involution. Every stage relies on tightly regulated cellular proliferation, programmed cell death, and tissue remodeling mechanisms. Misregulation of autophagy, an intracellular catabolic process to maintain energy stores, has long been associated with mammary tumorigenesis and other pathologies. We hypothesize that appropriate regulation and execution of autophagy are necessary for proper development of the mammary ductal tree and maintenance of the secretory epithelia during late pregnancy and lactation. To test this hypothesis we examined the …

Calpain 5: A Non-Classical Calpain Highly Expressed In The Cns And Localized To Mitochondria And Nuclear Pml Bodies, Ranjana Singh

Theses and Dissertations--Neuroscience

Calpain 5 (CAPN5) is a non-classical member of the calpain family. It lacks the EF-hand motif characteristic of the classical calpains, calpain 1 and 2, but retains catalytic and Ca²⁺ binding non EF domains. Tra-3, an ortholog of CAPN5, is involved in necrotic cell death in C.elegans; although specific role of CAPN5 has not been investigated in the mammalian CNS. I compared relative mRNA levels of calpains in rat CNS, which revealed that CAPN5 is the second most highly expressed calpain. We examined relative levels of CAPN5 from late embryonic day 18 to postnatal day 90 and …

Mechanisms Of Cyclooxygenase-2-Dependent Human Aortic Smooth Muscle Cell Phenotypic Modulation, Oreoluwa O. Adedoyin

Theses and Dissertations--Pharmacy

Abdominal aortic aneurysm (AAA) is a disease of the aorta characterized by pathological remodeling and progressive weakening of the vessel resulting in the increased risk of rupture and sudden death. In a mouse model of the disease induced by chronic Angiotensin II (AngII) infusion, progression of AAAs is associated with reduced differentiation of smooth muscle cells (SMCs) at the site of lesion development. In the mouse model, the effectiveness of cyclooxygenase-2 (COX-2) inhibition for attenuating AAA progression is associated with maintenance of a differentiated SMC phenotype. However, the safety of COX-2 inhibitors is currently in question due to the increased …

Dephosphorylation Of Iqg1 By Cdc14 Temporally Regulates Actin Ring Formation, Daniel Patrick Miller

Masters Theses

"Cytokinesis is the final step in cell division when the cell separates the cytoplasm by contracting a ring composed of filamentous actin (F-actin) and type II myosin. Iqg1, an IQGAP family member, is an essential scaffolding protein in budding yeast (S. cerevisiae) required for actin recruitment to, and contraction of, the actomyosin ring. Actin is recruited by the calponin homology domain (CHD) in anaphase after Iqg1 is localized to the bud neck. Consensus sites for the cyclin-dependent kinase (CDK) Cdc28 were identified flanking the CHD. This led us to the hypothesis that phosphorylation of Iqg1 by Cdc28 negatively regulates actin …

Functional Genomic And Proteomic Analysis Of Highly Drug Resistant Chronic Myeloid Leukemia, Derrick Matthew Oaxaca

Open Access Theses & Dissertations

Chronic Myeloid Leukemia (CML) has served as a model for how cancer can be selectively targeted with advanced forms of chemotherapies known as kinase inhibitors. Such new therapies have significantly altered the field of oncology and have led to monumental increases in both survival rates and quality of life for cancer patients. However, approximately one-third of CML patients will go on to develop drug resistance against major kinase inhibitors. Along with this, other cancers are showing increased incidences of drug resistance. Understanding how these cancers, such as CML, overcome drug sensitivity is of major importance within the clinic. To predict …

Cxcr2 Macromolecular Complex In Pancreatic Cancer: A Potential Therapeutic Target In Tumor Growth, Shuo Wang

Wayne State University Dissertations

The signaling mediated by the chemokine receptor CXC chemokine receptor 2 (CXCR2) plays an important role in promoting the progression of many cancers, including pancreatic cancer, one of the most lethal human malignancies. CXCR2 possesses a consensus PSD-95/DlgA/ZO-1 (PDZ) motif at its carboxyl termini, which might interact with potential PDZ scaffold/adaptor proteins. We have previously reported that CXCR2 PDZ motif-mediated protein interaction is an important regulator for neutrophil functions. Here, using a series of biochemical assays, we demonstrate that CXCR2 is physically coupled to its downstream effector phospholipase C-β3 (PLC-β3) that is mediated by PDZ scaffold protein Na(+)/H(+) exchange regulatory …

Combating Resistance To Epidermal Growth Factor Recpetor Inhibitors In Triple Negative Breast Cancer, Julie Marie Madden

Wayne State University Dissertations

Triple negative breast cancer (TNBC) patients suffer from a highly malignant and aggressive cancer that lacks an effective targeted therapeutic. Although many TNBCs, both in vitro and in vivo, have increased expression of epidermal growth factor receptor (EGFR), EGFR targeted inhibitors, such as gefitinib (GEF), have yet to demonstrate efficacy. Using mass spectrometry to identify pathways that remain activated in the presence of GEF, we found that components of the mTOR signaling pathway remain phosphorylated. While inhibiting mTOR with temsirolimus (TEM) decreased mTOR signaling, EGFR signaling pathways remained activated and the TNBC cell lines continued to proliferate. However, dual treatment …

Regulation Of Inositol Biosynthesis And Cellular Consequences Of Inositol Depletion: Implications For The Mechanism Of Action Of Valproate, Rania M. Deranieh

Wayne State University Dissertations

Inositol is a six-carbon cyclitol that is ubiquitous in biological systems. It is a precursor for the synthesis of numerous biologically important compounds, including inositol phosphates and phosphoinositides that are essential for cell function and viability. Inositol compounds play a role in membrane formation, gene regulation, signaling, regulation of ion channels, and membrane trafficking. Furthermore, inositol regulates hundreds of genes, including those involved in the biosynthesis of inositol and phospholipids. While transcriptional regulation of inositol biosynthesis has been extensively studied and well characterized, regulation of inositol biosynthesis at the enzymatic level has not been addressed. The current study shows that …