Pathology Commons^™

How Should Clinicians Weigh The Benefits And Harms Of Discussing Politicized Topics That Influence Their Individual Patients' Health?, Diana Alame, Robert D. Truog

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Health implications of politically charged phenomena are particularly difficult for physicians to discuss with their patients and communities. Addressing climate change and its associated health effects involves trade-offs between health and economic prosperity, necessitating that physicians weigh the potential benefits and risks of discussing climate change health effects. We argue that the potential benefits of physician communication and advocacy ultimately outweigh the potential risks. Therefore, physicians should be supported in their efforts to educate their patients and communities about climate change health effects. Furthermore, democratic deliberation could prove helpful in addressing disagreements among physicians within a practice about such politicized …

Idiopathic Nodular Glomerulosclerosis In A Chronic Marijuana User; A Case Report And Review Of The Literature, Mehri Mollaee, Tibor Fülöp, Sohil Abdul Salim, Seyed Mehrdad Hamrahian

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Background: Nodular glomerulosclerosis is a characteristic histological finding of diabetic nephropathy (DN) with thickened glomerular basement membrane (GBM) and hyalinized arterioles. Idiopathic nodular glomerulosclerosis (ING), a rare distinct clinicopathologic entity, is the term used to denote classic DN confirmed by light microscopy, immuno-fluorescence, and electron microscopy in the absence of diabetes mellitus (DM). ING has been linked to heavy tobacco smoking, chronic hypertension, obesity and insulin resistance. Its association with marijuana use is unknown. Case Presentation: We report a case of biopsy-proved ING in the absence of pre-existing history of DM and heavy smoking. This report addresses the possible accentuation …

Non-Hodgkin And Hodgkin Lymphomas Select For Overexpression Of Bclw., Clare M. Adams, Ramkrishna Mitra, Jerald Z. Gong, Md, Christine M. Eischen

Department of Cancer Biology Faculty Papers

Purpose: B-cell lymphomas must acquire resistance to apoptosis during their development. We recently discovered BCLW, an antiapoptotic BCL2 family member thought only to contribute to spermatogenesis, was overexpressed in diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma. To gain insight into the contribution of BCLW to B-cell lymphomas and its potential to confer resistance to BCL2 inhibitors, we investigated the expression of BCLW and the other antiapoptotic BCL2 family members in six different B-cell lymphomas. Experimental Design: We performed a large-scale gene expression analysis of datasets comprising approximately 2,300 lymphoma patient samples, including non-Hodgkin and Hodgkin lymphomas as well as …

Life After Being A Pathology Department Chair Ii: Lessons Learned., David N. Bailey, Mary F. Lipscomb, Fred Gorstein, David Wilkinson, Fred Sanfilippo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The 2016 Association of Pathology Chairs annual meeting featured a discussion group of Association of Pathology Chairs senior fellows (former chairs of academic departments of pathology who have remained active in Association of Pathology Chairs) that focused on how they decided to transition from the chair, how they prepared for such transition, and what they did after the transition. At the 2017 annual meeting, the senior fellows (encompassing 481 years of chair service) discussed lessons they learned from service as chair. These lessons included preparation for the chairship, what they would have done differently as chair, critical factors for success …

Developmental Lead And/Or Prenatal Stress Exposures Followed By Different Types Of Behavioral Experience Result In The Divergence Of Brain Epigenetic Profiles In A Sex, Brain Region, And Time-Dependent Manner: Implications For Neurotoxicology., Deborah A. Cory-Slechta, Marissa Sobolewski, Garima Varma, Jay S. Schneider

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Over a lifetime, early developmental exposures to neurocognitive risk factors, such as lead (Pb) exposures and prenatal stress (PS), will be followed by multiple varied behavioral experiences. Pb, PS and behavioral experience can each influence brain epigenetic profiles. Our recent studies show a greater level of complexity, however, as all three factors interact within each sex to generate differential adult variation in global post-translational histone modifications (PTHMs), which may result in fundamentally different consequences for life-long learning and behavioral function. We have reported that PTHM profiles differ by sex, brain region and time point of measurement following developmental exposures to …

St-Producing E. Coli Oppose Carcinogen-Induced Colorectal Tumorigenesis In Mice., Peng Li, Jieru E. Lin, Adam E. Snook, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

There is a geographic inequality in the incidence of colorectal cancer, lowest in developing countries, and greatest in developed countries. This disparity suggests an environmental contribution to cancer resistance in endemic populations. Enterotoxigenic bacteria associated with diarrheal disease are prevalent in developing countries, including enterotoxigenic E. coli (ETEC) producing heat-stable enterotoxins (STs). STs are peptides that are structurally homologous to paracrine hormones that regulate the intestinal guanylyl cyclase C (GUCY2C) receptor. Beyond secretion, GUCY2C is a tumor suppressor universally silenced by loss of expression of its paracrine hormone during carcinogenesis. Thus, the geographic imbalance in colorectal cancer, in part, may …

Strain Specific Effects Of Low Level Lead Exposure On Associative Learning And Memory In Rats., Megha Verma, J. S. Schneider

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Exposure to lead (Pb) remains a significant public health concern. Lead exposure in early life impairs the normal development of numerous cognitive and neurobehavioral processes. Previous work has shown that the effects of developmental Pb exposure on gene expression patterns in the brain are modulated by various factors including the developmental timing of the exposure, level of exposure, sex, and genetic background. Using gene microarray profiling, we previously reported a significant strain-specific effect of Pb exposure on the hippocampal transcriptome, with the greatest number of differentially expressed transcripts in Long Evans (LE) rats and the fewest in Sprague Dawley (SD) …

Posttranscriptional Upregulation Of Idh1 By Hur Establishes A Powerful Survival Phenotype In Pancreatic Cancer Cells., Mahsa Zarei, Shruti Lal, Seth J. Parker, Avinoam Nevler, Ali Vaziri-Gohar, Katerina Dukleska, Nicole C. Mambelli-Lisboa, Cynthia Moffat, Fernando F Blanco, Saswati N. Chand, Masaya Jimbo, Joseph A. Cozzitorto, Wei Jiang, Charles J. Yeo, Eric R. Londin, Erin L. Seifert, Christian M. Metallo, Jonathan R. Brody, Jordan M. Winter

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Cancer aggressiveness may result from the selective pressure of a harsh nutrient-deprived microenvironment. Here we illustrate how such conditions promote chemotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Glucose or glutamine withdrawal resulted in a 5- to 10-fold protective effect with chemotherapy treatment. PDAC xenografts were less sensitive to gemcitabine in hypoglycemic mice compared with hyperglycemic mice. Consistent with this observation, patients receiving adjuvant gemcitabine (n = 107) with elevated serum glucose levels (HgbA1C > 6.5%) exhibited improved survival. We identified enhanced antioxidant defense as a driver of chemoresistance in this setting. ROS levels were doubled in vitro by either nutrient withdrawal …

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 …

Macrophage Type 2 Differentiation In A Patient With Laryngeal Squamous Cell Carcinoma And Metastatic Prostate Adenocarcinoma To The Cervical Lymph Nodes., Michael C. Topf, Madalina Tuluc, Larry A. Harshyne, Adam J. Luginbuhl

Department of Otolaryngology - Head and Neck Surgery Faculty Papers

BACKGROUND: The tumor microenvironment often polarizes infiltrating macrophages towards a type 2, or M2 phenotype, that is characterized by expression of various cysteine-rich, scavenger receptors, including CD163. The primary function of M2 macrophages is to facilitate wound healing. As such, they are capable of providing metabolic support to a growing tumor, neovascularization, as well as protection from cytotoxic T cells. The tumor microenvironment contains a milieu of secreted factors and vesicles, which in certain circumstances can gain access to lymphatic vessels that drain to local lymph nodes.

CASE PRESENTATION: We report a 59-year-old male with recurrent T4 squamous cell carcinoma …

Cyclin D1 Restrains Oncogene-Induced Autophagy By Regulating The Ampk-Lkb1 Signaling Axis., Mathew C. Casimiro, Gabriele Disante, Agnese Di Rocco, Emanuele Loro, Claudia Pupo, Timothy G. Pestell, Sara Bisetto, Marco A. Velasco-Velázquez, Xuanmao Jiao, Zhiping Li, Christine M. Kusminski, Erin L. Seifert, Chenguang Wang, Daniel Ly, Bin Zheng, Che-Hung Shen, Philipp E. Scherer, Richard Pestell

Department of Cancer Biology Faculty Papers

Autophagy activated after DNA damage or other stresses mitigates cellular damage by removing damaged proteins, lipids, and organelles. Activation of the master metabolic kinase AMPK enhances autophagy. Here we report that cyclin D1 restrains autophagy by modulating the activation of AMPK. In cell models of human breast cancer or in a cyclin D1-deficient model, we observed a cyclin D1-mediated reduction in AMPK activation. Mechanistic investigations showed that cyclin D1 inhibited mitochondrial function, promoted glycolysis, and reduced activation of AMPK (pT172), possibly through a mechanism that involves cyclin D1-Cdk4/Cdk6 phosphorylation of LKB1. Our findings suggest how AMPK activation by cyclin D1 …

Intracellular Ca 2+ Sensing: Role In Calcium Homeostasis And Signaling, Rafaela Bagur, György Hajnóczky

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Ca²⁺ is a ubiquitous intracellular messenger that controls diverse cellular functions but can become toxic and cause cell death. Selective control of specific targets depends on spatiotemporal patterning of the calcium signal and decoding it by multiple, tunable, and often strategically positioned Ca²⁺-sensing elements. Ca²⁺ is detected by specialized motifs on proteins that have been biochemically characterized decades ago. However, the field of Ca²⁺ sensing has been reenergized by recent progress in fluorescent technology, genetics, and cryo-EM. These approaches exposed local Ca²⁺-sensing mechanisms inside organelles and at the organellar interfaces, revealed how Ca …

Intratumoral Heterogeneity Analysis Reveals Hidden Associations Between Protein Expression Losses And Patient Survival In Clear Cell Renal Cell Carcinoma., Wei Jiang, Essel Dulaimi, Karthik Devarajan, Theodore Parsons, Qiong Wang, Raymond O'Neill, Charalambos C. Solomides, Stephen C. Peiper, Joseph R. Testa, Robert Uzzo, Haifeng Yang

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Intratumoral heterogeneity (ITH) is a prominent feature of kidney cancer. It is not known whether it has utility in finding associations between protein expression and clinical parameters. We used ITH that is detected by immunohistochemistry (IHC) to aid the association analysis between the loss of SWI/SNF components and clinical parameters.160 ccRCC tumors (40 per tumor stage) were used to generate tissue microarray (TMA). Four foci from different regions of each tumor were selected. IHC was performed against PBRM1, ARID1A, SETD2, SMARCA4, and SMARCA2. Statistical analyses were performed to correlate biomarker losses with patho-clinical parameters. Categorical variables were compared between groups …

The Nephrotoxicity Of Vancomycin., Edward J. Filippone, Walter K. Kraft, John L. Farber

Department of Medicine Faculty Papers

No abstract provided.

Mct1 In Invasive Ductal Carcinoma: Monocarboxylate Metabolism And Aggressive Breast Cancer., Jennifer M. Johnson, Paolo Cotzia, Roberto Fratamico, Lekha Mikkilineni, Jason Chen, Daniele Colombo, Mehri Mollaee, Diana Whitaker-Menezes, Marina Domingo-Vidal, Zhao Lin, Tingting Zhan, Madalina Tuluc, Juan P. Palazzo, Ruth C. Birbe, Ubaldo E. Martinez-Outshoorn

Department of Medical Oncology Faculty Papers

Introduction: Monocarboxylate transporter 1 (MCT1) is an importer of monocarboxylates such as lactate and pyruvate and a marker of mitochondrial metabolism. MCT1 is highly expressed in a subgroup of cancer cells to allow for catabolite uptake from the tumor microenvironment to support mitochondrial metabolism. We studied the protein expression of MCT1 in a broad group of breast invasive ductal carcinoma specimens to determine its association with breast cancer subtypes and outcomes. Methods: MCT1 expression was evaluated by immunohistochemistry on tissue micro-arrays (TMA) obtained through our tumor bank. Two hundred and fifty-seven cases were analyzed: 180 cases were estrogen receptor and/or …

Gene Expression Profiles Among Murine Strains Segregate With Distinct Differences In The Progression Of Radiation-Induced Lung Disease., Isabel L. Jackson, Fitsum Baye, Chirayu Pankaj Goswami, Barry P. Katz, Andrew Zodda, Radmila Pavlovic, Ganga Gurung, Don Winans, Zeljko Vujaskovic

Jefferson Hospital Staff Papers and Presentations

Molecular mechanisms underlying development of acute pneumonitis and/or late fibrosis following thoracic irradiation remain poorly understood. Here, we hypothesize that heterogeneity in disease progression and phenotypic expression of radiation-induced lung disease (RILD) across murine strains presents an opportunity to better elucidate mechanisms driving tissue response toward pneumonitis and/or fibrosis. Distinct differences in disease progression were observed in age- and sex-matched CBA/J, C57L/J and C57BL/6J mice over 1 year after graded doses of whole-thorax lung irradiation (WTLI). Separately, comparison of gene expression profiles in lung tissue 24 h post-exposure demonstrated >5000 genes to be differentially expressed (P<0.01; >twofold change) between strains …

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 …

Camp Signaling Enhances Hiv-1 Long Terminal Repeat (Ltr)-Directed Transcription And Viral Replication In Bone Marrow Progenitor Cells., Anupam Banerjee, Luna Li, Vanessa Pirrone, Fred C. Krebs, Brian Wigdahl, Michael R. Nonnemacher

Kimmel Cancer Center Papers, Presentations, and Grand Rounds

CD34⁺ hematopoietic progenitor cells have been shown to be susceptible to HIV-1 infection, possibly due to a low-level expression of CXCR4, a coreceptor for HIV-1 entry. Given these observations, we have explored the impact of forskolin on cell surface expression of CXCR4 in a cell line model (TF-1). The elevation of intracellular cyclic adenosine monophosphate (cAMP) by forskolin through adenylyl cyclase (AC) resulted in transcriptional upregulation of CXCR4 with a concomitant increase in replication of the CXCR4-utilizing HIV-1 strain IIIB. Transient expression analyses also demonstrated an increase in CXCR4-, CCR5-, and CXCR4-/CCR5-utilizing HIV-1 (LAI, YU2, and 89.6, respectively) promoter …

Proteoglycan Neofunctions: Regulation Of Inflammation And Autophagy In Cancer Biology., Liliana Schaefer, Claudia Tredup, Maria A. Gubbiotti, Renato V. Iozzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Inflammation and autophagy have emerged as prominent issues in the context of proteoglycan signaling. In particular, two small, leucine-rich proteoglycans, biglycan and decorin, play pivotal roles in the regulation of these vital cellular pathways and, as such, are intrinsically involved in cancer initiation and progression. In this minireview, we will address novel functions of biglycan and decorin in inflammation and autophagy, and analyze new emerging signaling events triggered by these proteoglycans, which directly or indirectly modulate these processes. We will critically discuss the dual role of proteoglycan-driven inflammation and autophagy in tumor biology, and delineate the potential mechanisms through which …