Pathology Commons^™

Human Dectin-1 Deficiency Impairs Macrophage-Mediated Defense Against Phaeohyphomycosis, Rebecca A. Drummond, Jigar V. Desai, Amy P. Hsu, Vasileios Oikonomou, Donald C. Vinh, Joshua A. Acklin, Michael S. Abers, Magdalena A. Walkiewicz, Sarah L. Anzick, Muthulekha Swamydas, Simon Vautier, Mukil Natarajan, Andrew J. Oler, Daisuke Yamanaka, Katrin D. Mayer-Barber, Yoichiro Iwakura, David Bianchi, Brian Driscoll, Ken Hauck, Ahnika Kline, Nicholas S.P. Viall, Christa S. Zerbe, Elise M.N. Ferré, Monica M. Schmitt, Tom Dimaggio, Stefania Pittaluga, John A. Butman, Adrian M. Zelazny, Yvonne R. Shea, Cesar A. Arias, Cameron Ashbaugh, Maryam Mahmood, Zelalem Temesgen, Alexander G. Theofiles, Masayuki Nigo, Varsha Moudgal, Karen C. Bloch, Sean G. Kelly, M. Suzanne Whitworth, Ganesh Rao, Cindy J. Whitener, Neema Mafi, Juan Gea-Banacloche, Lawrence C. Kenyon, William R. Miller, Katia Boggian, Andrea Gilbert, Matthew Sincock, Alexandra F. Freeman, John E. Bennett, Rodrigo Hasbun, Constantinos M. Mikelis, Kyung J. Kwon-Chung, Yasmine Belkaid, Gordon D. Brown, Jean K. Lim, Douglas B. Kuhns, Steven M. Holland, Michail S. Lionakis

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Subcutaneous phaeohyphomycosis typically affects immunocompetent individuals following traumatic inoculation. Severe or disseminated infection can occur in CARD9 deficiency or after transplantation, but the mechanisms protecting against phaeohyphomycosis remain unclear. We evaluated a patient with progressive, refractory Corynespora cassiicola phaeohyphomycosis and found that he carried biallelic deleterious mutations in CLEC7A encoding the CARD9-coupled, β-glucan-binding receptor, Dectin-1. The patient's PBMCs failed to produce TNF-α and IL-1β in response to β-glucan and/or C. cassiicola. To confirm the cellular and molecular requirements for immunity against C. cassiicola, we developed a mouse model of this infection. Mouse macrophages required Dectin-1 and CARD9 for IL-1β and …

The Role Of Decorin And Biglycan Signaling In Tumorigenesis, Valentina Diehl, Lisa Sophie Huber, Jonel Trebicka, Malgorzata Wygrecka, Renato V. Iozzo, Liliana Schaefer

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The complex and adaptive nature of malignant neoplasm constitute a major challenge for the development of effective anti-oncogenic therapies. Emerging evidence has uncovered the pivotal functions exerted by the small leucine-rich proteoglycans, decorin and biglycan, in affecting tumor growth and progression. In their soluble forms, decorin and biglycan act as powerful signaling molecules. By receptor-mediated signal transduction, both proteoglycans modulate key processes vital for tumor initiation and progression, such as autophagy, inflammation, cell-cycle, apoptosis, and angiogenesis. Despite of their structural homology, these two proteoglycans interact with distinct cell surface receptors and thus modulate distinct signaling pathways that ultimately affect cancer …

Metabolic Adaptation To The Chronic Loss Of Ca 2+ Signaling Induced By Ko Of Ip 3 Receptors Or The Mitochondrial Ca 2+ Uniporter, Michael P. Young, Zachary T Schug, David M. Booth, David I Yule, Katsuhiko Mikoshiba, György Hajnóczky, Suresh K Joseph

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Calcium signaling is essential for regulating many biological processes. Endoplasmic reticulum inositol trisphosphate receptors (IP3Rs) and the mitochondrial Ca2+ uniporter (MCU) are key proteins that regulate intracellular Ca2+ concentration. Mitochondrial Ca2+ accumulation activates Ca2+-sensitive dehydrogenases of the tricarboxylic acid (TCA) cycle that maintain the biosynthetic and bioenergetic needs of both normal and cancer cells. However, the interplay between calcium signaling and metabolism is not well understood. In this study, we used human cancer cell lines (HEK293 and HeLa) with stable KOs of all three IP3R isoforms (triple KO [TKO]) or MCU to examine metabolic and bioenergetic responses to the chronic …

Clinical Performance Of The Point-Of-Care Cobas Liat For Detection Of Sars-Cov-2 In 20 Minutes: A Multicenter Study., Glen Hansen, Jamie Marino, Zi-Xuan Wang, Kathleen G Beavis, John Rodrigo, Kylie Labog, Lars F Westblade, Run Jin, Nedra Love, Karen Ding, Sachin Garg, Alan Huang, Joanna Sickler, Nam K Tran

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Highly accurate testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the point of care (POC) is an unmet diagnostic need in emergency care and time-sensitive outpatient care settings. Reverse transcription-PCR (RT-PCR) technology is the gold standard for SARS-CoV-2 diagnostics. We performed a multisite U.S. study comparing the clinical performance of the first U.S. Food and Drug Administration (FDA)-authorized POC RT-PCR for detection of SARS-CoV-2 in 20 min, the cobas Liat SARS-CoV-2 and influenza A/B nucleic acid test, to the most widely used RT-PCR laboratory test, the cobas 68/8800 SARS-CoV-2 test. Clinical nasopharyngeal swab specimens from 444 patients with …

Genomic Characterization Of Malignant Progression In Neoplastic Pancreatic Cysts, Michaël Noë, Noushin Niknafs, Catherine G Fischer, Wenzel M Hackeng, Violeta Beleva Guthrie, Waki Hosoda, Marija Debeljak, Eniko Papp, Vilmos Adleff, James R White, Claudio Luchini, Antonio Pea, Aldo Scarpa, Giovanni Butturini, Giuseppe Zamboni, Paola Castelli, Seung-Mo Hong, Shinichi Yachida, Nobuyoshi Hiraoka, Anthony J Gill, Jaswinder S Samra, G Johan A Offerhaus, Anne Hoorens, Joanne Verheij, Casper Jansen, N Volkan Adsay, Wei Jiang, Jordan Winter, Jorge Albores-Saavedra, Benoit Terris, Elizabeth D Thompson, Nicholas J Roberts, Ralph H Hruban, Rachel Karchin, Robert B Scharpf, Lodewijk A A Brosens, Victor E Velculescu, Laura D Wood

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are non-invasive neoplasms that are often observed in association with invasive pancreatic cancers, but their origins and evolutionary relationships are poorly understood. In this study, we analyze 148 samples from IPMNs, MCNs, and small associated invasive carcinomas from 18 patients using whole exome or targeted sequencing. Using evolutionary analyses, we establish that both IPMNs and MCNs are direct precursors to pancreatic cancer. Mutations in SMAD4 and TGFBR2 are frequently restricted to invasive carcinoma, while RNF43 alterations are largely in non-invasive lesions. Genomic analyses suggest an average window of over three …

Catabolic Degradation Of Endothelial Vegfa Via Autophagy, Thomas Neill, Carolyn Chen, Simone Buraschi, Renato V. Iozzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Extracellular matrix-evoked angiostasis and autophagy within the tumor microenvironment represent two critical, but unconnected, functions of the small leucine-rich proteoglycan, decorin. Acting as a partial agonist of vascular endothelial growth factor 2 (VEGFR2), soluble decorin signals via the energy sensing protein, AMP-activated protein kinase (AMPK), in the autophagic degradation of intracellular vascular endothelial growth factor A (VEGFA). Here, we discovered that soluble decorin evokes intracellular catabolism of endothelial VEGFA that is mechanistically independent of mTOR, but requires an autophagic regulator, paternally expressed gene 3 (PEG3). We found that administration of autophagic inhibitors such as chloroquine or bafilomycin A1, or depletion …

Multiple Mitochondrial Thioesterases Have Distinct Tissue And Substrate Specificity And Coa Regulation, Suggesting Unique Functional Roles., Carmen Bekeova, Lauren Anderson-Pullinger, Kevin Boye, Felix Boos, Yana Sharpadskaya, Johannes M Herrmann, Erin L. Seifert

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Acyl-CoA thioesterases (Acots) hydrolyze fatty acyl-CoA esters. Acots in the mitochondrial matrix are poised to mitigate β-oxidation overload and maintain CoA availability. Several Acots associate with mitochondria, but whether they all localize to the matrix, are redundant, or have different roles is unresolved. Here, we compared the suborganellar localization, activity, expression, and regulation among mitochondrial Acots (Acot2, -7, -9, and -13) in mitochondria from multiple mouse tissues and from a model of Acot2 depletion. Acot7, -9, and -13 localized to the matrix, joining Acot2 that was previously shown to localize there. Mitochondria from heart, skeletal muscle, brown adipose tissue, and …

A Physiologically-Based Pharmacokinetic Model For Targeting Calcitriol-Conjugated Quantum Dots To Inflammatory Breast Cancer Cells., James Forder, Mallory Smith, Margot Wagner, Rachel J. Schaefer, Jonathan Gorky, Kenneth L. Van Golen, Anja Nohe, Prasad Dhurjati

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Quantum dots (QDs) conjugated with 1,25 dihydroxyvitamin D3 (calcitriol) and Mucin-1 (MUC-1) antibodies (SM3) have been found to target inflammatory breast cancer (IBC) tumors and reduce proliferation, migration, and differentiation of these tumors in mice. A physiologically-based pharmacokinetic model has been constructed and optimized to match experimental data for multiple QDs: control QDs, QDs conjugated with calcitriol, and QDs conjugated with both calcitriol and SM3 MUC1 antibodies. The model predicts continuous QD concentration for key tissues in mice distinguished by IBC stage (healthy, early-stage, and late-stage). Experimental and clinical efforts in QD treatment of IBC can be augmented by in …

Comparison Of Two Commercial Matrix-Assisted Laser Desorption/Ionization-Time Of Flight Mass Spectrometry (Maldi-Tof Ms) Systems For Identification Of Nontuberculous Mycobacteria., Barbara A. Brown-Elliott, Thomas R. Fritsche, Brooke J. Olson, Sruthi Vasireddy, Ravikiran Vasireddy, Elena Iakhiaeva, Diana Alame, Richard J. Wallace, John A. Branda

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Objectives: This multi-center study’s aim was to assess the performance of two commercially-available matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) systems in identifying a challenge collection of clinically-relevant nontuberculous mycobacteria (NTM).

Methods: NTM clinical isolates (N=244) belonging to 23 species/subspecies were identified by gene sequencing and analyzed using the Bruker Biotyper with Mycobacterial Library v5.0.0 and the bioMérieux VITEK MS with v3.0 database.

Results: Using the Bruker or bioMérieux systems, 92% or 95% of NTM strains, respectively, were identified at least to the complex/group level; 62% and 57%, respectively, were identified to the highest taxonomic level. Differentiation between members …

Gm1 Ganglioside Modifies Α-Synuclein Toxicity And Is Neuroprotective In A Rat Α-Synuclein Model Of Parkinson's Disease., Jay S. Schneider, Radha Aras, Courtney K. Williams, James B. Koprich, Jonathan M. Brotchie, Vikrant Singh

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

While GM1 may interact with α-synuclein in vitro to inhibit aggregation, the ability of GM1 to protect against α-synuclein toxicity in vivo has not been investigated. We used targeted adeno-associated viral vector (AAV) overexpression of human mutant α-synuclein (A53T) in the rat substantia nigra (SN) to produce degeneration of SN dopamine neurons, loss of striatal dopamine levels, and behavioral impairment. Some animals received daily GM1 ganglioside administration for 6 weeks, beginning 24 hours after AAV-A53T administration or delayed start GM1 administration for 5 weeks beginning 3 weeks after AAV-A53T administration. Both types of GM1 administration protected against loss of SN …

Potential Role Of Csf Cytokine Profiles In Discriminating Infectious From Non-Infectious Cns Disorders., Danielle Fortuna, D. Craig Hooper, Amity L. Roberts, Larry A. Harshyne, Michelle Nagurney, Mark T. Curtis

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Current laboratory testing of cerebrospinal fluid (CSF) does not consistently discriminate between different central nervous system (CNS) disease states. Rapidly distinguishing CNS infections from other brain and spinal cord disorders that share a similar clinical presentation is critical. New approaches focusing on aspects of disease biology, such as immune response profiles that can have stimulus-specific attributes, may be helpful. We undertook this preliminary proof-of-concept study using multiplex ELISA to measure CSF cytokine levels in various CNS disorders (infections, autoimmune/demyelinating diseases, lymphomas, and gliomas) to determine the potential utility of cytokine patterns in differentiating CNS infections from other CNS diseases. Both …

Metabolic Reprogramming Of Murine Cardiomyocytes During Autophagy Requires The Extracellular Nutrient Sensor Decorin., Maria A. Gubbiotti, Erin L. Seifert, Ulrich Rodeck, Jan B. Hoek, Renato V. Iozzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The extracellular matrix is a master regulator of tissue homeostasis in health and disease. Here we examined how the small, leucine-rich, extracellular matrix proteoglycan decorin regulates cardiomyocyte metabolism during fasting in vivo. First, we validated in Dcn^-/- mice that decorin plays an essential role in autophagy induced by fasting. High-Throughput metabolomics analyses of cardiac tissue in Dcn^-/- mice subjected to fasting revealed striking differences in the hexosamine biosynthetic pathway resulting in aberrant cardiac O-β-N-Acetylglycosylation as compared with WT mice. Functionally, Dcn^-/- mice maintained cardiac function at a level comparable with nonfasted animals whereas fasted WT mice showed …

Cellular Network Modeling And Single Cell Gene Expression Analysis Reveals Novel Hepatic Stellate Cell Phenotypes Controlling Liver Regeneration Dynamics, Daniel Cook, Sirisha Achanta, Jan B. Hoek, Babatunde A. Ogunnaike, Rajanikanth Vadigepalli

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Background: Recent results from single cell gene and protein regulation studies are starting to uncover the previously underappreciated fact that individual cells within a population exhibit high variability in the expression of mRNA and proteins (i.e., molecular variability). By combining cellular network modeling, and high-throughput gene expression measurements in single cells, we seek to reconcile the high molecular variability in single cells with the relatively low variability in tissue-scale gene and protein expression and the highly coordinated functional responses of tissues to physiological challenges. In this study, we focus on relating the dynamic changes in distributions of hepatic stellate cell …

Different Behavioral Experiences Produce Distinctive Parallel Changes In, And Correlate With, Frontal Cortex And Hippocampal Global Post-Translational Histone Levels., Marissa Sobolewski, Garima Singh, Jay S. Schneider, Deborah A. Cory-Slechta

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

While it is clear that behavioral experience modulates epigenetic profiles, it is less evident how the nature of that experience influences outcomes and whether epigenetic/genetic "biomarkers" could be extracted to classify different types of behavioral experience. To begin to address this question, male and female mice were subjected to either a Fixed Interval (FI) schedule of food reward, or a single episode of forced swim followed by restraint stress, or no explicit behavioral experience after which global expression levels of two activating (H3K9ac and H3K4me3) and two repressive (H3K9me2 and H3k27me3) post-translational histone modifications (PTHMs), were measured in hippocampus (HIPP) …

Spsnet: Subpopulation-Sensitive Network-Based Analysis Of Heterogeneous Gene Expression Data., Abha Belorkar, Rajanikanth Vadigepalli, Limsoon Wong

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Transcriptomic datasets often contain undeclared heterogeneity arising from biological variation such as diversity of disease subtypes, treatment subgroups, time-series gene expression, nested experimental conditions, as well as technical variation due to batch effects, platform differences in integrated meta-analyses, etc. However, current analysis approaches are primarily designed to handle comparisons between experimental conditions represented by homogeneous samples, thus precluding the discovery of underlying subphenotypes. Unsupervised methods for subtype identification are typically based on individual gene level analysis, which often result in irreproducible gene signatures for potential subtypes. Emerging methods to study heterogeneity have been largely developed in the context of …

Novel Influences Of Il-10 On Cns Inflammation Revealed By Integrated Analyses Of Cytokine Networks And Microglial Morphology., Warren D. Anderson, Andrew D. Greenhalgh, Aditya Takwale, Samuel David, Rajanikanth Vadigepalli

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Coordinated interactions between cytokine signaling and morphological dynamics of microglial cells regulate neuroinflammation in CNS injury and disease. We found that pro-inflammatory cytokine gene expression in vivo showed a pronounced recovery following systemic LPS. We performed a novel multivariate analysis of microglial morphology and identified changes in specific morphological properties of microglia that matched the expression dynamics of pro-inflammatory cytokine TNFα. The adaptive recovery kinetics of TNFα expression and microglial soma size showed comparable profiles and dependence on anti-inflammatory cytokine IL-10 expression. The recovery of cytokine variations and microglial morphology responses to inflammation were negatively regulated by IL-10. Our novel …

Microscopic Examination Of Findings Encountered During Cadaver Dissection: Malignant, Benign Or Anatomic Variation?, Maria Cicioni, Vandi Ly, Guiyun Zhang, Bruce Fenderson

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Pathologic findings encountered during cadaver dissection provide an opportunity for integrating the preclinical basic sciences and encouraging critical thinking. The objective of this study was to determine whether it is possible to make a pathologic diagnosis of an unknown mass from an embalmed cadaver. Diagnoses would have to be based solely on gross and microscopic appearance of tissue, without clinical histories of the cadaveric donors. The tissue samples we removed from each mass were surprisingly well preserved and showed minimal autolysis. Indeed, some of the histological detail was as clear as may be found in any textbook. We were able …

Desmin Common Mutation Is Associated With Multi-Systemic Disease Manifestations And Depletion Of Mitochondria And Mitochondrial Dna., Elizabeth M. Mccormick, Lawrence C. Kenyon, Marni J. Falk

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Desmin (DES) is a major muscle scaffolding protein that also functions to anchor mitochondria. Pathogenic DES mutations, however, have not previously been recognized as a cause of multi-systemic mitochondrial disease. Here, we describe a 45-year-old man who presented to The Children's Hospital of Philadelphia Mitochondrial-Genetics Diagnostic Clinic for evaluation of progressive cardiac, neuromuscular, gastrointestinal, and mood disorders. Muscle biopsy at age 45 was remarkable for cytoplasmic bodies, as well as ragged red fibers and SDH positive/COX negative fibers that were suggestive of a mitochondrial myopathy. Muscle also showed significant reductions in mitochondrial content (16% of control mean for citrate synthase …

Targeting Fibroblast Activation Protein In Tumor Stroma With Chimeric Antigen Receptor T Cells Can Inhibit Tumor Growth And Augment Host Immunity Without Severe Toxicity., Liang-Chuan S. Wang, Albert Lo, John Scholler, Jing Sun, Rajrupa S. Majumdar, Veena Kapoor, Michael Antzis, Cody E. Cotner, Laura A. Johnson, Amy C. Durham, Charalambos C. Solomides, Md, Carl H. June, Ellen Puré, Steven M. Albelda

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The majority of chimeric antigen receptor (CAR) T-cell research has focused on attacking cancer cells. Here, we show that targeting the tumor-promoting, nontransformed stromal cells using CAR T cells may offer several advantages. We developed a retroviral CAR construct specific for the mouse fibroblast activation protein (FAP), comprising a single-chain Fv FAP [monoclonal antibody (mAb) 73.3] with the CD8α hinge and transmembrane regions, and the human CD3ζ and 4-1BB activation domains. The transduced muFAP-CAR mouse T cells secreted IFN-γ and killed FAP-expressing 3T3 target cells specifically. Adoptively transferred 73.3-FAP-CAR mouse T cells selectively reduced FAP(hi) stromal cells and inhibited the …

Proline-Rich Tyrosine Kinase 2 (Pyk2) Regulates Igf-I-Induced Cell Motility And Invasion Of Urothelial Carcinoma Cells, Marco Genua, Shi-Qiong Xu, Simone Buraschi, Stephen C. Peiper, Leonard G. Gomella, Antonio Belfiore, Renato V. Iozzo, Andrea Morrione

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The insulin-like growth factor receptor I (IGF-IR) plays an essential role in transformation by promoting cell growth and protecting cancer cells from apoptosis. We have recently demonstrated that the IGF-IR is overexpressed in invasive bladder cancer tissues and promotes motility and invasion of urothelial carcinoma cells. These effects require IGF-I-induced Akt- and MAPK-dependent activation of paxillin. The latter co-localizes with focal adhesion kinases (FAK) at dynamic focal adhesions and is critical for promoting motility of urothelial cancer cells. FAK and its homolog Proline-rich tyrosine kinase 2 (Pyk2) modulate paxillin activation; however, their role in regulating IGF-IR-dependent signaling and motility in …

P16/Rb Correlations In Oropharyngeal Squamous Cell Carcinoma (Oscc), Madalina Tuluc, Voichita Bar-Ad, David Cognetti

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The objective of this study is to explore the patterns of Rb expression in p16 positive and negative OSCC, in relation to patient's smoking history.

Aberrant Expression Of Cd56 On Granulocytes And Monocytes In Myeloproliferative Neoplasm And Myelodysplastic Syndrome, Ping Gong, Md, Fernanco Metrebian, Md, Alina Dulau-Florea, Md, Zi-Xuan Wang, Phd, Renu Bajaj, Phd, Stephen C Peiper, Jerald Z. Gong, Md

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Conclusions:

Aberrant CD56 expression on granulocytes is seen in all aubtypes MPN and high grade MDS. CD56 expression in MPN correlated with bone marrow morphology, BCR/ABL transcript, and bone marrow engraftment study following treatment. Identification of abnormal CD56+ granulocytes and monocytes is helpful in both the initial diagnosis and long-term follow up of patients with MPN and MDS.

Loss Of Retinoblastoma (Rb) Tumor Suppressor Expression In Breast Cancer Correlates With Better Response To Neoadjuvant Chemotherapy, Jeanne Mcfalls, Md, Jessica Kline, Ba, Gordon Schwartz, Md, Mba, Facs, Angieszka Witkiewicz, Md

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Conclusions:

Loss of RB tumor suppressor staining in pre-treatment breast cancer biopsies can be used prior to initiation of neoadjuvant chemotherapy to predict good tumor response. This association between RB loss and good neoadjuvant response holds regardless of ER status and across various chemotherapy regimens. Assessment of RB status in the pre-treatment biopsy could be useful clinical tool to define patients who are most likely to benefit from neoadjuvant chemotherapy.

Expression Of Stem Cell Marker Aldh1 In Cervical Intraepithelial Neoplasia, Ping Gong, Juan Palazzo, Md

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Conclusions:

Cervical dysplasia show positive staining for ALDH1 compared to normal cervical mucosa.

ALDH1 positive cells distribution parallels the dysplastic cells in cervical dysplasia.

CSC, as detected by ALDH1 expression, may play a role in the progression of cervical intraepithelial neoplasia and carcinogenesis.

P53 Expression In Oropharyngeal Squamous Cell Carcinoma In Increased In Hpv Positive Smokers, Madalina Tuluc, Voichita Bar-Ad, Zi-Xuan Wang, Joseph Curry

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Background and Objectives

High risk HPV is associated with oropharyngeal SCC (OSCC) and is responsible for the increasing incidence of this cancer type among younger patients.

Patients with HPV positive oropharyngeal SCC have a better prognosis when compared with HPV negative, tobacco induced SCC.

HPV E6 inactivates p53 leading to low expression of p53; tobacco induced oropharyngeal SCC is characterized by p53 overexpression, resistance to treatment and poor prognosis. However, in many cases of HPV OSCC, there is a history of current or remote smoking, making this disease a multifactorial process. We expect that smoking will influence the level of …

Decorin-Mediated Inhibition Of Colorectal Cancer Growth And Migration Is Associated With E-Cadherin In Vitro And In Mice., Xiuli Bi, Nicole M Pohl, Zhibin Qian, George R Yang, Yuan Gou, Grace Guzman, Andre Kajdacsy-Balla, Renato V Iozzo, Wancai Yang

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Previous studies have shown that decorin expression is significantly reduced in colorectal cancer tissues and cancer cells, and genetic deletion of the decorin gene is sufficient to cause intestinal tumor formation in mice, resulting from a downregulation of p21, p27(kip1) and E-cadherin and an upregulation of β-catenin signaling [Bi,X. et al. (2008) Genetic deficiency of decorin causes intestinal tumor formation through disruption of intestinal cell maturation. Carcinogenesis, 29, 1435-1440]. However, the regulation of E-cadherin by decorin and its implication in cancer formation and metastasis is largely unknown. Using a decorin knockout mouse model (Dcn(-/-) mice) and manipulated expression of decorin …

Lung Carcinoma In The Era Of Personalized Medicine: The Role Of Cytology., Maureen F Zakowski, Marluce Bibbo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

In 2004, three groups working independently [1–3] , almost simultaneously, reported remarkable findings: that activating mutations in the epidermal growth factor receptor (EGFR) were common in certain lung carcinomas and that these mutations correlated with the response of those lung tumors to therapy with gefitinib and erlotinib, both EGFR tyrosine kinase inhibitors (TKIs). This was the first time driver mutations in lung cancer that responded to targeted therapy had been identified, marking the beginning of a new era of personalized medicine in lung cancer. Prior to the discovery of these mutations, patients had been treated with EGFR TKIs but predicting …

The Variable Presentations Of Anaplastic Spindle Cell Squamous Carcinoma Associated With Tall Cell Variant Of Papillary Thyroid Carcinoma., Pallavi P Gopal, Kathleen T Montone, Zubair Baloch, Madalina Tuluc, Virginia Livolsi

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: In 1976, Hawk and Hazard described the tall cell variant (TCV) of papillary thyroid carcinoma (PTC). While the lesions they described had cytologic features of papillary carcinoma, they showed more aggressive behavior with a greater propensity for extrathyroid extension and lymphovascular invasion than classic PTC. In 1991, Bronner and LiVolsi described a series of patients with TCV that progressed to spindle cell squamous carcinoma (SCSC), a unique form of anaplastic thyroid carcinoma. This study describes the variable clinical and pathologic presentations in 31 patients with anaplastic SCSC arising in association with TCV.

METHODS: The surgical pathology archives as well …

Prognostic Significance Of High-Grade Dysplasia In Colorectal Adenomas., A D Toll, D Fabius, T Hyslop, E Pequignot, A J Dimarino, A Infantolino, J P Palazzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Aim  Colonoscopy to detect and remove polyps has contributed to a reduction in colorectal carcinoma. Three-year follow up is recommended for patients considered to be at high risk (at least three adenomas, adenoma ≥ 1 cm, villous or high-grade features). Our study focused on patients diagnosed with high-grade dysplasia with regard to initial management and follow up. Method  A search of patients who had had endoscopic removal of a high-grade adenoma was carried out. Patients with the following were excluded: follow up of < 1 year, polyposis syndromes, prior colon cancer and a diagnosis of adenocarcinoma within 6 months following initial diagnosis. Results  Eighty-three patients treated between 1999 and 2007 for high-grade dysplasia (HGD) in a colorectal adenoma were identified. Over a median follow-up period of 4 years, 53 (64%) developed further adenomatous polyps. Among these, 7% had an adenoma with HGD or an adenocarcinoma. In all these patients, the initial high-grade adenoma was > 1 cm in diameter. Initial follow-up colonoscopy was performed on average 7 months following the initial diagnosis. …

Expression Of Aldehyde Dehydrogenase In Dysplastic Lesions Arising From Inflammatory Bowel Disease, Adam D. Toll, Bruce M. Boman, Juan P. Palazzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Conclusion: Our study demonstrates ALDH1 is significantly expressed in dysplatic lesions arising from IBD. ALDH1-expression in cancer stem cells suggest an important causative role in the progression to cancer in IBD. Although we found high sensitivity for dysplasia, the specificity was poor. In addition to neoplasia, ALDH1-expressing stem cells proliferate in response to chronic inflammation, accounting for the cases of inflammatory atypia with positive ALDHI1 expression.