Digital Commons Network^™

Strain-Dependent Variation In The Early Transcriptional Response To Cns Injury Using A Cortical Explant System, David J. Graber, Brent T. Harris, William F. Hickey

Dartmouth Scholarship

While it is clear that inbred strains of mice have variations in immunological responsiveness, the influence of genetic background following tissue damage in the central nervous system is not fully understood. A cortical explant system was employed as a model for injury to determine whether the immediate transcriptional response to tissue resection revealed differences among three mouse strains. Immunological mRNAs were measured in cerebral cortex from SJL/J, C57BL/6J, and BALB/cJ mice using real time RT-PCR. Freshly isolated cortical tissue and cortical sections incubated in explant medium were examined. Levels of mRNA, normalized to β-actin, were compared using one way analysis …

The Use Of Targeted Charge-Reversal Nanoparticles (Tcrns) To Investigate Nuclear Delivery Of Fluorescent Agents To Cancer Cells: Implications For Novel Prostate And Breast Cancer Therapy, Mario Dance

Theses and Dissertations

Nanotechnology has recently emerged as a strong contributor toward research efforts to develop targeted systems of drug delivery in cancer therapy. Our work investigates the therapeutic potential of Targeted Charge-Reversal Nanoparticles (TCRNs), a novel nanoparticle with in vitro evidence of nuclear drug delivery. Using M12 prostate cancer cells, MDA-MB-231 breast cancer cells, and modified derivatives of these cell lines, we investigated the ability of Folic Acid-tagged TCRNs to deliver Nile Red and Dimethyl Indole Redfluorescent (DiR) fluorescent dyes to the nucleus of cells using confocal microscopy and in vivo biphontonic imaging using Xenogen® Technology. Confocal imaging with the SCP28 derivative …

Glutamatergic Plasticity In Medial Prefrontal Cortex And Ventral Tegmental Area Following Extended-Access Cocaine Self-Administration, Behnam Ghasemzadeh, Preethi Vasudevan, Chad Giles, Anthony Purgianto, Chad Seubert, John R. Mantsch

Biomedical Sciences Faculty Research and Publications

Glutamate signaling in prefrontal cortex and ventral tegmental area plays an important role in the molecular and behavioral plasticity associated with addiction to drugs of abuse. The current study investigated the expression and postsynaptic density redistribution of glutamate receptors and synaptic scaffolding proteins in dorsomedial and ventromedial prefrontal cortex and ventral tegmental area after cocaine self-administration. After 14 days of extended-access (6 h/day) cocaine self-administration, rats were exposed to one of three withdrawal regimen for 10 days. Animals either stayed in home cages (Home), returned to self-administration boxes with the levers withdrawn (Box), or underwent extinction training (Extinction). Extinction training …

Reciprocal Effects Of Oxidative Stress On Heme Oxygenase Expression And Activity Contributes To Reno-Vascular Abnormalities In Ec-Sod Knockout Mice, Tomoko Kawakami, Nitin Puri, Komal Sodhi, Lars Bellner, Toru Takahashi, Kiyoshi Morita, Rita Rezzani, Tim D. Oury, Nader G. Abraham

Biochemistry and Microbiology

Heme oxygenase (HO) system is one of the key regulators of cellular redox homeostasis which responds to oxidative stress (ROS) via HO-1 induction. However, recent reports have suggested an inhibitory effect of ROS on HO activity. In light of these conflicting reports, this study was designed to evaluate effects of chronic oxidative stress on HO system and its role in contributing towards patho-physiological abnormalities observed in extracellular superoxide dismutase (EC-SOD, SOD3) KO animals. Experiments were performed in WT and EC-SOD^(−/−) mice treated with and without HO inducer, cobalt protoporphyrin (CoPP). EC-SOD^(−/−) mice exhibited oxidative stress, renal histopathological abnormalities, …

Developmental Remodeling Of Relay Cells In The Dorsal Lateral Geniculate Nucleus (Dlgn) Of The Mouse And The Role Of Retinal Innervation, Rana El-Danaf

Theses and Dissertations

The dorsal lateral geniculate nucleus (dLGN) has become an important model for studying many aspects of visual system development. To date, studies have focused on the development of retinal projections and the role of activity in shaping the pattern of synaptic connections made with thalamocortical relay cells. By contrast, little is known about relay cells and the factors that regulate the growth and establishment of their dendritic architecture. In many systems, such growth seems consistent with the synaptotrophic hypothesis which states that synapse formation and dendritic growth work in a concerted fashion such that afferent input and the establishment of …

Domain Requirements For The Diverse Immune Regulatory Functions Of Foxp3, Wei-Ping Zeng, Vincent E. Sollars, Andrea Del Pilar Belalcazar

Biochemistry and Microbiology

Foxp3 is responsible for the major immunological features of Treg cells, including hypoproliferation in vitro, immune suppression of conventional T cells and resistance to Th2 cell differentiation. In addition to the Forkhead domain, the Foxp3 protein contains the N-terminal, zinc finger and leucine zipper domains. To understand how these domains contribute to Foxp3 functions, we systematically compared the roles of these domains in determining the 3 major immunological features of Treg cells. We designed a bridge-mediated mutagenesis method to generate Foxp3 mutants with complete deletion of each of the domains. CD4 T cells expressing the Foxp3 mutant with deletion of …

Biochemical And Functional Characterization Of The Ledgf/P75-Mecp2 Interaction In Tumor Cells, Lai Sum Leoh

Loma Linda University Electronic Theses, Dissertations & Projects

The lens epithelial derived growth factor p75 (LEDGF/p75) is a novel pro-survival and stress-inducible transcription co-activator that protects mammalian cells from various environmental stresses such as oxidative stress, heat shock, and serum starvation. This emerging cancer-related protein is highly expressed in prostate tumors and other tumor types and promotes resistance to chemotherapy in cancer cells. LEDGF/p75 is also involved in acquired immunodeficiency syndrome (AIDS) since it interacts with HIV-1 integrase to facilitate the integration and replication of the HIV virus in human cells. In addition, LEDGF/p75 has been shown to interact with MLL (mixed lineage leukemia)/menin transcription complex in leukemia …

Aging And Sympathetic Neurotransmission In Two Strains Of Rats That Differ In Longevity And Immune Profiles, Sam David Perez

Loma Linda University Electronic Theses, Dissertations & Projects

Age-related changes in sympathetic neurotransmission in immune organs may be associated with immunosenescence; however no causal relationship has been established. From previous studies in Fischer rats (F344), we have found that during middle age, sympathetic nerve activity (SNA) rises in the spleen followed by a decline in noradrenergic (NA) innervation. Also, increased sympathetic signaling via betaadrenergic receptor (β-AR) and reduced proliferation of lymphocytes are evident with increasing age. Although SNA progressively rises with age, effects of age on sympathetic factors may be different across rat strains. If causal relationships exist between sympathetic activity and immune function, they may be related …

Lateralization Of Emotion, Reaction Time, And Skin Conductance Responsiveness, Kimberley Erin Rose

Loma Linda University Electronic Theses, Dissertations & Projects

Bilateral presentations of brief (250 ms), unmasked emotional and neutral stimuli were examined in two experiments with primarily female samples. Reaction time and accuracy data were used to measure perception of emotion and skin conductance response (SCR) was used to measure experience of emotion. Both words and pictures were used to account for hemispheric differences in language and visuospatial dominance. Response time was faster to emotional pictures than words. Reaction time and speeded accuracy data did not support right hemisphere hypothesis (RHH) or valence hypothesis (VH) in the expected manner. Data suggested emotion caused greater interference under speeded conditions in …

Acute Fatty Liver Of Pregnancy: An Update On Mechanisms, Sathish Kumar Natarajan, Kavitha R. Thangaraj, Ashish Goel, C. E. Eapen, K. A. Balasubramanian, Anup Ramachandran

School of Veterinary and Biomedical Sciences: Faculty Publications

Acute fatty liver of pregnancy (AFLP), characterized by hepatic microvesicular steatosis, is a sudden catastrophic illness occurring almost exclusively in the third trimester of pregnancy. Defective fatty acid oxidation in the fetus has been shown to be associated with this disease. Since the placenta has the same genetic makeup as the fetus and as AFLP patients generally recover following delivery, we hypothesized that the placenta might be involved in pathogenesis of this disease. In an animal model of hepatic microvesicular steatosis (using sodium valproate), we found that microvesicular steatosis results in mitochondrial structural alterations and oxidative stress in subcellular organelles …

Autoimmune Responses To Atherosclerotic Lipids: A Study In Murine Models Of Atherosclerosis And Obesity, Hanjing Wu

Dissertations and Theses (Open Access)

Atherosclerosis is a chronic, complex arterial disease characterized by intimal lipid accumulation and inflammation. A unique lipid-binding molecule, namely cluster of differentiation 1d (CD1d), may impact atherosclerosis. Structurally, CD1d acts as a nonpolymorphic cell-surface receptor, resembling the major histocompatibility complex-I (MHC-I). While MHC-I restricts peptide antigen presentation to T cells, CD1d presents lipid antigens to T cells named CD1d-restrictedd T cells. Although increased expression of CD1d has been found in human plaques, the exact nature of CD1d-recognized lipids in atherosclerosis remains to be determined. Three groups of lipids may undergo oxidation in atherosclerosis producing atherogenic lipids: phospholipids, fatty acids, and …

A Single Phenylalanine Residue In The Main Intracellular Loop Of Α1 Γ-Aminobutyric Acid Type A And Glycine Receptors Influences Their Sensitivity To Propofol, Gustavo Moraga-Cid, Gonzalo E. Yevenes, Günther Schmalzing, Robert W. Peoples, Luis G. Aguayo

Biomedical Sciences Faculty Research and Publications

Background: The intravenous anesthetic propofol acts as a positive allosteric modulator of glycine (GlyRs) and γ-aminobutyric acid type A (GABA_ARs) receptors. Although the role of transmembrane residues is recognized, little is known about the involvement of other regions in the modulatory effects of propofol. Therefore, the influence of the large intracellular loop in propofol sensitivity of both receptors was explored. Methods: The large intracellular loop of α₁ GlyRs and α₁β₂ GABA_ARs was screened using alanine replacement. Sensitivity to propofol was studied using patch-clamp recording in HEK293 cells transiently transfected with …

Relationship Of Adipokines With Insulin Sensitivity In African Americans., Maria P Martinez Cantarin, Scott W Keith, Stephanie Deloach, Yonghong Huan, Bonita Falkner

Department of Medicine Faculty Papers

INTRODUCTION: Cytokines produced by adipose tissue, including adiponectin, have been associated with metabolic abnormalities. The purpose of this study was to examine the relationship of insulin sensitivity measured by euglycemic hyperinsulinemic insulin clamp with plasma adiponectin and other adipokines in young adult African Americans.

METHODS: Participants were healthy African Americans. Anthropometric measures, blood pressure, an oral glucose tolerance test and an euglycemic hyperinsulinemic insulin clamp were performed. Insulin sensitivity measurements were adjusted for percentage of fat mass. Plasma concentrations of adiponectin, plasminogen activator inhibitor-1 (PAI-1) and interleukin-6 (IL-6) were assayed on plasma from fasting blood samples. Pearson correlation coefficients and …

Sirolimus-Induced Pneumonitis Complicated By Pentamidine-Induced Phospholipidosis In A Renal Transplant Recipient: A Case Report., E J Filippone, J M Carson, R A Beckford, B C Jaffe, E Newman, B K Awsare, C Doria, J L Farber

Department of Medicine Faculty Papers

The proliferation signal inhibitors (PSIs)-sirolimus, everolimus, and temsirolimus-have been associated with a noninfectious pneumonitis characterized by lymphocytic alveolitis and bronciolitis obliterans with organizing pneumonia (BOOP). This condition usually occurs within the first year. Herein we presented a case of a deceased donor renal transplant with interstitial pneumonitis developing 6 years after a switch from tacrolimus to sirolimus due to chronic graft dysfunction. After the addition of intravenous pentamidine due to the suspicion of Pneumocystis pneumonia, there was marked clinical deterioration requiring intubation. Open lung biopsy revealed sirolimus-induced pulmonary toxicity (BOOP) with the additional finding of a drug-induced phospholipidosis (DIPL) that …

Step-Wise Loss Of Bacterial Flagellar Torsion Confers Progressive Phagocytic Evasion, Rustin R. Lovewell, Ryan M. Collins, Julie L. Acker, George A. O'Toole, Matthew J. Wargo, Brent Berwin, Craig R. Roy

Dartmouth Scholarship

Phagocytosis of bacteria by innate immune cells is a primary method of bacterial clearance during infection. However, the mechanisms by which the host cell recognizes bacteria and consequentially initiates phagocytosis are largely unclear. Previous studies of the bacterium Pseudomonas aeruginosa have indicated that bacterial flagella and flagellar motility play an important role in colonization of the host and, importantly, that loss of flagellar motility enables phagocytic evasion. Here we use molecular, cellular, and genetic methods to provide the first formal evidence that phagocytic cells recognize bacterial motility rather than flagella and initiate phagocytosis in response to this motility. We demonstrate …

Spiking Patterns And Their Functional Implications In The Antennal Lobe Of The Tobacco Hornworm Manduca Sexta, Hong Lei, Carolina E. Reisenman, Caroline H. Wilson, Prasad Gabbur, John G. Hildebrand

Health Sciences and Kinesiology Faculty Articles

Bursting as well as tonic firing patterns have been described in various sensory systems. In the olfactory system, spontaneous bursts have been observed in neurons distributed across several synaptic levels, from the periphery, to the olfactory bulb (OB) and to the olfactory cortex. Several in vitro studies indicate that spontaneous firing patterns may be viewed as “fingerprints” of different types of neurons that exhibit distinct functions in the OB. It is still not known, however, if and how neuronal burstiness is correlated with the coding of natural olfactory stimuli. We thus conducted an in vivo study to probe this question …

A Model Of Intracellular Θ Phase Precession Dependent On Intrinsic Subthreshold Membrane Currents., L Stan Leung

Physiology and Pharmacology Publications

A hippocampal place cell fires at an increasingly earlier phase in relation to the extracellular theta rhythm as a rodent moves through the place field. The present report presents a compartment model of a CA1 pyramidal cell that explains the increase in amplitude and the phase precession of intracellular theta oscillations, with the assumption that the cell receives an asymmetric ramp depolarization (<10 >mV) in the place field and rhythmic inhibitory and/or excitatory synaptic driving. Intracellular subthreshold membrane potential oscillations (MPOs) increase in amplitude and frequency, and show phase precession within the place field. Theta phase precession and MPO power …

Potential Applications Of Curcumin And Its Novel Synthetic Analogs And Nanotechnology-Based Formulations In Cancer Prevention And Therapy., Murielle Mimeault, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

Curcumin has attracted great attention in the therapeutic arsenal in clinical oncology due to its chemopreventive, antitumoral, radiosensibilizing and chemosensibilizing activities against various types of aggressive and recurrent cancers. These malignancies include leukemias, lymphomas, multiple myeloma, brain cancer, melanoma and skin, lung, prostate, breast, ovarian, liver, gastrointestinal, pancreatic and colorectal epithelial cancers. Curcumin mediates its anti-proliferative, anti-invasive and apoptotic effects on cancer cells, including cancer stem/progenitor cells and their progenies, through multiple molecular mechanisms. The oncogenic pathways inhibited by curcumin encompass the members of epidermal growth factor receptors (EGFR and erbB2), sonic hedgehog (SHH)/GLIs and Wnt/β-catenin and downstream signaling elements …

Monoclonal Antibodies Recognizing The Non-Tandem Repeat Regions Of The Human Mucin Muc4 In Pancreatic Cancer., Maneesh Jain, Ganesh Venkatraman, Nicolas Moniaux, Sukhwinder Kaur, Sushil Kumar, Subhankar Chakraborty, Grish C. Varshney, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

The MUC4 mucin is a high molecular weight, membrane-bound, and highly glycosylated protein. It is a multi-domain protein that is putatively cleaved into a large mucin-like subunit (MUC4α) and a C-terminal growth-factor like subunit (MUC4β). MUC4 plays critical roles in physiological and pathological conditions and is aberrantly overexpressed in several cancers, including those of the pancreas, cervix, breast and lung. It is also a potential biomarker for the diagnosis, prognosis and progression of several malignancies. Further, MUC4 plays diverse functional roles in cancer initiation and progression as evident from its involvement in oncogenic transformation, proliferation, inhibition of apoptosis, motility and …

A Conserved Tissue-Specific Homeodomain-Less Isoform Of Meis1 Is Downregulated In Colorectal Cancer., Richard C Crist, Jacquelyn J Roth, Scott A Waldman, Arthur M Buchberg

Department of Microbiology and Immunology Faculty Papers

Colorectal cancer is one of the most common cancers in developed nations and is the result of both environmental and genetic factors. Many of the genetic lesions observed in colorectal cancer alter expression of homeobox genes, which encode homeodomain transcription factors. The MEIS1 homeobox gene is known to be involved in several hematological malignancies and solid tumors and recent evidence suggests that expression of the MEIS1 transcript is altered in colorectal cancer. Despite this potential connection, little is known about the role of the gene in the intestines. We probed murine gastrointestinal tissue samples with an N-terminal Meis1 antibody, revealing …

Slob, A Slowpoke Channel Binding Protein, Regulates Insulin Pathway Signaling And Metabolism In Drosophila., Amanda L. Sheldon, Jiaming Zhang, Hong Fei, Irwin B Levitan

Department of Neuroscience Faculty Papers

There is ample evidence that ion channel modulation by accessory proteins within a macromolecular complex can regulate channel activity and thereby impact neuronal excitability. However, the downstream consequences of ion channel modulation remain largely undetermined. The Drosophila melanogaster large conductance calcium-activated potassium channel SLOWPOKE (SLO) undergoes modulation via its binding partner SLO-binding protein (SLOB). Regulation of SLO by SLOB influences the voltage dependence of SLO activation and modulates synaptic transmission. SLO and SLOB are expressed especially prominently in median neurosecretory cells (mNSCs) in the pars intercerebralis (PI) region of the brain; these cells also express and secrete Drosophila insulin like …

Role Of Autophagy In Radiosensitization Of Breast Tumor Cells, Molly L. Bristol

Theses and Dissertations

In MCF-7 breast tumor cells, ionizing radiation promoted autophagy that was cytoprotective; pharmacological or genetic interference with autophagy induced by radiation resulted in growth suppression and/or cell killing (primarily by apoptosis). The hormonally active form of vitamin D, 1,25D3, also promoted autophagy in irradiated MCF-7 cells, sensitized the cells to radiation and suppressed the proliferative recovery that occurs after radiation alone. 1,25D3 also enhanced radiosensitivity and promoted autophagy in MCF7 cells that overexpress Her-2/neu as well as in p53 mutant Hs578t breast tumor cells. In contrast, 1,25D3 failed to alter radiosensitivity or promote autophagy in the BT474 breast tumor cell …

The Effects Of Hypothermia On Status Epilepticus-Induced Acquired Epilepsy, Kristin Phillips

Theses and Dissertations

Status epilepticus (SE) is a type of neurological injury characterized by continuous seizure activity and can lead to molecular and pathophysiological alterations leading to plasticity changes. SE can lead to the development of AE by the process of epileptogenesis, which is a phenomenon that describes the transformation of normal brain tissue into a hyperexcitable neuronal population. It has been demonstrated both in vivo and in vitro that calcium (Ca2+) dynamics are severely altered during and after SE, and these changes play a major role in the progression of epileptogenesis. It has also been reported that preventing the rise in intracellular …

Brain Activation And Connectivity In Non-Disabled Multiple Sclerosis Patients, Rene A. Colorado

Dissertations and Theses (Open Access)

Multiple sclerosis (MS) is the most common demyelinating disease affecting the central nervous system. There is no cure for MS and current therapies have limited efficacy. While the majority of individuals with MS develop significant clinical disability, a subset experiences a disease course with minimal impairment even in the presence of significant apparent tissue damage on magnetic resonance imaging (MRI). The current studies combined functional MRI and diffusion tensor imaging (DTI) to elucidate brain mechanisms associated with lack of clinical disability in patients with MS. Recent evidence has implicated cortical reorganization as a mechanism to limit the clinical manifestation of …

A Role For Mir-296 In The Regulation Of Lipoapoptosis By Targeting Puma., Sophie C. Cazanave, Justin L. Mott, Nafisa A. Elmi, Steven F. Bronk, Howard C. Masuoka, Michael R. Charlton, Gregory J. Gores

Journal Articles: Biochemistry & Molecular Biology

Saturated free fatty acids (FFA) induce hepatocyte lipoapoptosis, a key mediator of liver injury in nonalcoholic fatty liver disease (NAFLD). Lipoapoptosis involves the upregulation of the BH3-only protein PUMA, a potent pro-apoptotic protein. Given that dysregulation of hepatic microRNA expression has been observed in NAFLD, we examined the role of miRNA in regulating PUMA expression during lipotoxicity. By in silico analysis, we identified two putative binding sites for miR-296-5p within the 3' untranslated region (UTR) of PUMA mRNA. Enforced miR-296-5p levels efficiently reduced PUMA protein expression in Huh-7 cells, while antagonism of miR-296-5p function increased PUMA cellular levels. Reporter gene …

Rip1-Dependent And Independent Effects Of Necrostatin-1 In Necrosis And T Cell Activation., Youngsik Cho, Thomas Mcquade, Haibing Zhang, Jianke Zhang, Francis Ka-Ming Chan

Department of Microbiology and Immunology Faculty Papers

BACKGROUND: Programmed necrosis/necroptosis is an emerging form of cell death that plays important roles in mammalian development and the immune system. The pro-necrotic kinases in the receptor interacting protein (RIP) family are crucial mediators of programmed necrosis. Recent advances in necrosis research have been greatly aided by the identification of chemical inhibitors that block programmed necrosis. Necrostatin-1 (Nec-1) and its derivatives were previously shown to target the pro-necrotic kinase RIP1/RIPK1. The protective effect conferred by Nec-1 and its derivatives in many experimental model systems was often attributed to the inhibition of RIP1 function.

METHODOLOGY/PRINCIPAL FINDINGS: We compared the effect of …

Glutaredoxin 2 Prevents H2o2-Induced Cell Apoptosis By Protecting Complex I Activity In The Mitochondria, Hongli Wu, Kuiyi Xing, Marjorie F. Lou

School of Veterinary and Biomedical Sciences: Faculty Publications

Glutaredoxin 2 (Grx2) belongs to the oxidoreductase family and is an isozyme of glutaredoxin 1 (Grx1) present in the mitochondria, however its function is not well understood. The purpose of this study is to evaluate the potential anti-apoptotic function of Grx2 by examining its ability to protect complex I in the mitochondrial electron transport system using human lens epithelial cells as a model. We found that cells treated with 200 μM hydrogen peroxide (H2O2) for 24 h exhibited decreased viability and became apoptotic with corresponding Bax up-regulation, Bcl-2 down-regulation, caspase 3 activation and mitochondrial cytochrome c leakage. Grx2 over-expression (OE) …

The Role Of The Androgen Receptor Cofactor P44/Wdr77 In Astrocyte Activation, Bryce H. Vincent

Dissertations and Theses (Open Access)

Astrogliosis is induced by neuronal damage and is also a pathological feature of the major aging-related neurodegenerative disorders. The mechanisms that control the cascade of astrogliosis have not been well established. In a previous study, we identified a novel androgen receptor (AR)-interacting protein (p44/WDR77) and found that it plays a critical role in the control of proliferation and differentiation of prostate epithelial cells. In the present study, we found that deletion of the p44 gene in the mouse brain caused accelerated aging with dramatic astrogliosis. The p44/WDR77 is expressed in astrocytes and loss of p44/WDR77 expression in astrocytes leads to …

Echogenic Liposomes For Nitric Oxide Delivery And Breast Cancer Treatment, Soo Yeon Lee Female

Dissertations and Theses (Open Access)

Liposomes, also known as nontoxic, biodegradable, and non-immunogenic therapeutic delivery vehicles, have been proposed as a carrier for drugs and antitumor agents in cancer chemotherapy. Echogenic liposomes (ELIP) have the potential to entrap air or bioactive gas to enhance acoustic reflectivity in ultrasound and are used as a contrast agent. The innovative part of this study is based on a novel concept to encapsulate nitric oxide (NO) gas into ELIP, deliver it to breast cancer cells, and control its release via direct ultrasound exposure. Studies on the effect of NO in tumor biology have shown that a high levels of …

The Mechanism Of Tumorigenesis In The Immortalized Human Pancreatic Cell Lines: Cell Culture Models Of Human Pancreatic Cancer, Zhe Chang

Dissertations and Theses (Open Access)

The mechanism of tumorigenesis in the immortalized human pancreatic cell lines: cell culture models of human pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal cancer in the world. The most common genetic lesions identified in PDAC include activation of K-ras (90%) and Her2 (70%), loss of p16 (95%) and p14 (40%), inactivation p53 (50-75%) and Smad4 (55%). However, the role of these signature gene alterations in PDAC is still not well understood, especially, how these genetic lesions individually or in combination contribute mechanistically to human pancreatic oncogenesis is still elusive. Moreover, a cell culture transformation model with sequential …