Medical Specialties Commons^™

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 …

Response Of An Aggressive Periosteal Aneurysmal Bone Cyst (Abc) Of The Radius To Denosumab Therapy., Chantal Pauli, Bruno Fuchs, Christian Pfirrmann, Julia A. Bridge, Silvia Hofer, Beata Bode

Journal Articles: Pathology and Microbiology

Aneurysmal bone cyst (ABC), once considered a reactive lesion, has been proven to be a neoplasia characterized by rearrangements of the USP6-gene. Aggressive local growth and recurrences are common and therapeutic options may be limited due to the vicinity of crucial structures. We describe a case of a locally aggressive, multinucleated giant cell-containing lesion of the forearm of a 21-year old woman, treated with denosumab for recurrent, surgically uncontrollable disease. Under the influence of this RANKL inhibitor, the tumor showed a marked reduction of the content of the osteoclastic giant cells and an extensive metaplastic osteoid production leading to the …

Steady Increment Of Immature Platelet Fraction Is Suppressed By Irradiation In Single-Donor Platelet Components During Storage, Hong Hong, Wenbin Xiao, Robert W. Maitta

Faculty Scholarship

Circulating immature platelet fraction (IPF) reflects real-time thrombopoiesis and correlates with platelet recovery from thrombocytopenic presentations. To understand the dynamics of IPF in platelet transfusions, we quantified the %-IPF in single-donor platelet components (SDP) during prolonged storage. %-IPF significantly increased from baseline by day 5 post-donation. Absolute IPF counts (A-IPC) had similar significant increments. However, gamma-irradiation suppressed the increments of %-IPF and A-IPC by >50%. Ultrastructural analysis of SDP units at day 10 showed well preserved morphology of immature platelets. Our findings suggest that IPF might actively expand ex-vivo and may have a longer shelf life than their mature counterparts. …

Metabotropic Glutamate Receptor-1 Contributes To Progression In Triple Negative Breast Cancer, Malathi Banda, Cecilia L. Speyer, Sara N. Semma, Kingsley O. Osuala, Nicole Kounalakis, Keila E. Torres Torres, Nicola J. Barnard, Hyunjin J. Kim, Bonnie F. Sloane, Fred R. Miller, James S. Goydos, David H. Gorski

Department of Surgery

TNBC is an aggressive breast cancer subtype that does not express hormone receptors (estrogen and progesterone receptors, ER and PR) or amplified human epidermal growth factor receptor type 2 (HER2), and there currently exist no targeted therapies effective against it. Consequently, finding new molecular targets in triple negative breast cancer (TNBC) is critical to improving patient outcomes. Previously, we have detected the expression of metabotropic glutamate receptor-1 (gene: GRM1; protein: mGluR1) in TNBC and observed that targeting glutamatergic signaling inhibits TNBC growth both in vitro and in vivo. In this study, we explored how mGluR1 contributes to TNBC …

Gold(Iii)-Dithiocarbamato Peptidomimetics In The Forefront Of The Targeted Anticancer Therapy: Preclinical Studies Against Human Breast Neoplasia, Chiara Nardon, Sara M. Schmitt, Huanjie Yang, Jian Zuo, Delores Fregona, Q. Ping Dou

Oncology Faculty Publications

Since the serendipitous discovery of cisplatin, platinum-based drugs have become well-established antitumor agents, despite the fact that their clinical use is limited by many severe side-effects. In order to both improve the chemotherapeutic index and broaden the therapeutic spectrum of current drugs, our most recent anti-neoplastic agents, Au(III) complexes, were designed as carrier-mediated delivery systems exploiting peptide transporters, which are up-regulated in some cancers. Among all, we focused on two compounds and tested them on human MDA-MB-231 (resistant to cisplatin) breast cancer cell cultures and xenografts, discovering the proteasome as a major target both in vitro and in vivo. …

Can Newly Developed, Rapid Immunochromatographic Antigen Detection Tests Be Reliably Used For The Laboratory Diagnosis Of Influenza Virus Infections?, J. J. Dunn, C. C. Ginocchio

Journal Articles

Five years ago, the Point-Counterpoint series was launched. The initial article asked about the role of rapid immunochromatographic antigen testing in diagnosis of influenza A virus 2009 H1N1 infection (1). Since that article, major changes have been made not only in immunochromatographic antigen detection (IAD) test for the influenza viruses but there also has been rapid development of commercially available nucleic acid amplification tests (NAATs) for influenza virus detection as well. Further, a novel variant of influenza A, H7N9, has emerged in Asia and H5N1 is also re-emergent. In this initial article, the editor of this series, Peter Gilligan, identified …

Sinusoidal Obstruction Syndrome (Hepatic Veno-Occlusive Disease), C. Q. Fan, J. M. Crawford

Journal Articles

Hepatic sinusoidal obstruction syndrome (SOS) is an obliterative venulitis of the terminal hepatic venules, which in its more severe forms imparts a high risk of mortality. SOS, also known as veno-occlusive disease (VOD), occurs as a result of cytoreductive therapy prior to hematopoietic stem cell transplantation (HSCT), following oxaliplatin-containing adjuvant or neoadjuvant chemotherapy for colorectal carcinoma metastatic to the liver and treated by partial hepatectomy, in patients taking pyrrolizidine alkaloid-containing herbal remedies, and in other particular settings such as the autosomal recessive condition of veno-occlusive disease with immunodeficiency (VODI). A central pathogenic event is toxic destruction of hepatic sinusoidal endothelial …

Is Aggressive Digital Papillary Adenocarcinoma Really Aggressive Digital Papillary Adenocarcinoma?, S. Chen, M. Asgari

Journal Articles

No abstract provided.

Papillary Adenocarcinoma In Situ Of The Skin: Report Of Four Cases, S. Chen, M. Asgari

Journal Articles

Although rare isolated cases of adenocarcinoma in situ of skin have been reported in the literature, adenocarcinoma in situ of skin as a concept and as a diagnostic category has not been established in the field of dermatopathology. In this work, four cases of papillary adenocarcinoma in situ of the skin are presented. In addition, the notion that lesions previously reported in the medical literature under the term of "papillary eccrine adenoma" are actually adenocarcinoma in situ is discussed.

Brain Region-Specific Alterations In The Gene Expression Of Cytokines, Immune Cell Markers And Cholinergic System Components During Peripheral Endotoxin-Induced Inflammation, H. A. Silverman, M. Dancho, A. Regnier-Golanov, M. Nasim, M. Ochani, P. S. Olofsson, M. Ahmed, E. J. Miller, S. S. Chavan, E. Golanov, C. Metz, K. J. Tracey, V. A. Pavlov

Journal Articles

Inflammatory conditions characterized by excessive peripheral immune responses are associated with diverse alterations in brain function, and brain-derived neural pathways regulate peripheral inflammation. Important aspects of this bidirectional peripheral immune - brain communication, including the impact of peripheral inflammation on brain region-specific cytokine responses, and brain cholinergic signaling (which plays a role in controlling peripheral cytokine levels) remain unclear. To provide insight, we studied gene expression of cytokines, immune cell markers and brain cholinergic system components in the cortex, cerebellum, brainstem, hippocampus, hypothalamus, striatum, and thalamus in mice following an intraperitoneal lipopolysaccharide injection. Endotoxemia was accompanied by elevated serum levels …

Septic Arthritis Of A Native Knee Joint Due To Corynebacterium Striatum, L. F. Westblade, F. Shams, S. Duong, O. Tariq, A. Bulbin, W. Zhen, S. Sakaria, B. A. Ford, C. A. D. Burnham, C. C. Ginocchio, +1 Additional Author

Journal Articles

We report a case of septic arthritis of a native knee joint due to Corynebacterium striatum, a rare and unusual cause of septic arthritis of native joints. The isolate was identified by a combination of phenotypic, mass spectrometric, and nucleic acid-based assays and exhibited high-level resistance to most antimicrobials.

Expression Of Blimp-1 In Dendritic Cells Modulates The Innate Inflammatory Response In Dextran Sodium Sulfate-Induced Colitis, S. J. Kim, J. Goldstein, K. Dorso, M. Merad, L. Mayer, J. M. Crawford, P. K. Gregersen, B. Diamond

Journal Articles

A single nucleotide polymorphism of PRDM1, the gene encoding Blimp-1, is strongly associated with inflammatory bowel disease. Here, we demonstrate that Blimp-1 in CD103(+) dendritic cells (DCs) critically contributes to the regulation of macrophage homeostasis in the colon. Dextran sodium sulfate (DSS)-exposed Blimp-1(cko) mice with a deletion of Blimp-1 in CD103(+) DCs and CD11c(hi) macrophages exhibited severe inflammatory symptoms, pronounced weight loss, high mortality, robust infiltration of neutrophils in epithelial regions of the colon, an increased expression of proinflammatory cytokines and a significant decrease in CD103(+) DCs in the colon compared with DSS exposed wild-type (WT) mice. Purified colonic macrophages …

Schwannoma Of The Cervical Esophagus, M. Ferrante, A. Khan, C. Fan, F. Z. Jelloul

Journal Articles

Esophageal schwannoma is a rare tumor first described in 1967 by Chaterlin and Fissore. These tumors are most commonly found incidentally or from diagnostic work up of dysphagia or dyspnea. This entity cannot be diagnosed on clinical or radiographic basis alone. Histology demonstrates palisading spindle cells, few if any mitotic figures, and a peripheral cuff of lymphoid cells. Immunohistochemically, tumor cells stain positive for S100, a characteristic marker of Schwann cells. Once diagnosed, surgical enucleation is the typical treatment method employed.

Aggressive Renal Angiomyolipoma Of The Lipomatous Variant With Inferior Vena Cava Thrombus: A Case Report And Review Of The Literature, C. Fox, S. S. Salami, D. M. Moreira, G. S. Landis, D. Chan, O. Yaskiv, M. A. Vira

Journal Articles

Two variants of renal angiomyolipoma (AML)—classic and epithelioid—have been described. Although the epithelioid variant has been reported to demonstrate an aggressive clinical behavior, classic AML is usually benign. Herein, we report a case of a 42-year-old asymptomatic woman with a lipomatous variant of renal AML associated with an inferior vena cava thrombus managed with radical nephrectomy and caval thrombectomy.

Mantle Cell Lymphoma With In Situ Or Mantle Zone Growth Pattern: A Study Of Five Cases And Review Of Literature, P. Hsu, T. Yang, S. Sheikh-Fayyaz, J. Brody, J. Bandovic, S. Roy, J. Laser, J. E. Kolitz, C. Devoe, X. Zhang

Journal Articles

We present two rare cases of in situ mantle cell lymphoma ("in situ MCL") and three cases of MCL with mantle zone growth pattern (MCL-MZGP). The patients include four males and one female, with a median age of 66 years (range, 52 to 86 years). Two present with isolated lymphadenopathy and three with multiple lymphadenopathy. At presentation, the complete blood count (CBC) and serum lactate dehydrogenase (LDH) are normal in all cases. Histologic examination reveals an in situ pattern in two cases and a mantle zone growth pattern in three cases. The staging bone marrow biopsies show minimal involvement by …

Risk Factors For Gi Adverse Events In A Phase Iii Randomized Trial Of Bevacizumab In First-Line Therapy Of Advanced Ovarian Cancer: A Gynecologic Oncology Group Study, R. A. Burger, M. F. Brady, M. A. Bookman, B. J. Monk, J. L. Walker, H. D. Homesley, J. Fowler, S. C. Rubin, N. Katsumata, S. X. Liang, +4 Additional Authors

Journal Articles

Purpose To evaluate risk factors for GI adverse events (AEs) within a phase III trial of bevacizumab in first-line ovarian cancer therapy. Patients and Methods Women with previously untreated advanced disease after surgery were randomly allocated to six cycles of platinum-taxane chemotherapy plus placebo cycles (C)2 to C22 (R1); chemotherapy plus bevacizumab C2 to C6 plus placebo C7 to C22 (R2); or chemotherapy plus bevacizumab C2 to C22 (R3). Patients were evaluated for history or on-study development of potential risk factors for GI AEs defined as grade 2 perforation, fistula, necrosis, or hemorrhage. Results Of 1,873 patients enrolled, 1,759 (94%) …

Academic Pathology: A New Journal, J. M. Crawford

Journal Articles

No abstract provided.

The Business Of Genomic Testing: A Survey Of Early Adopters, J. M. Crawford, L. Bry, J. Pfeifer, S. K. Caughron, S. Black-Schaffer, J. A. Kant, J. H. Kaufman

Journal Articles

Purpose: The practice of "genomic" (or "personalized") medicine requires the availability of appropriate diagnostic testing. Our study objective was to identify the reasons for health systems to bring next-generation Sequencing into their clinical laboratories and to understand the process by which such decisions were made. Such information may be of value to other health systems seeking to provide next-generation sequencing-testing to their patient populations. Methods: A standardized open-ended interview was conducted With the laboratory medical directors and/or department of pathology chairs of 13 different academic institutions in 10 different states. Results: Genomic testing for cancer dominated the institutional decision making, …

Tblr1 As An Androgen Receptor (Ar) Coactivator Selectively Activates Ar Target Genes To Inhibit Prostate Cancer Growth, G. Daniels, Y. Li, L. L. Gellert, A. Zhou, J. Melamed, X. Wu, X. Zhang, D. Zhang, D. Meruelo, S. K. Logan, R. Basch, P. Lee

Journal Articles

Androgen receptor (AR), a steroid hormone receptor, is critical for prostate cancer growth. However, activation of AR by androgens can also lead to growth suppression and differentiation. Transcriptional cofactors play an important role in this switch between proliferative and anti-proliferative AR target gene programs. Transducin beta-like-related protein 1 (TBLR1), a core component of the nuclear receptor corepressor complex, shows both corepressor and coactivator activities on nuclear receptors, but little is known about its effects on AR and prostate cancer. We characterized TBLR1 as a coactivator of AR in prostate cancer cells and determined that the activation is dependent on both …

Headaches And Hemiparesis In An Immunocompetent Inmate, Andrea Gilbert Jelinek, Christine Fuller, Ahmet Baykal, Kimberly Stogner-Underwood, Hope Richard, Knarik Arkun

Pathology Publications

This is a case of a 22 year-old African American male inmate with no significant past medical history who regularly cleaned moldy bathrooms and showers during his incarceration. The patient presented with progressive development of left-sided weakness, dizziness, headaches, and vomiting over a two month period. In summary, we report this case to boost awareness of the potential for CNS phaeohyphomycosis infection to present as a clinical and radioimaging mimic of high grade glioma. Our patient, a previously healthy adult, is one of less than a dozen cases of cerebral phaeohyphomycosis due to Bipolaris documented in the literature, and is …

The Role Of Pdgf C And Its Splice Variant In Breast Cancer, Alyssa Bottrell

Wayne State University Dissertations

The PDGF family consists of four members; while PDGF A and B are secreted as active dimers, PDGF C and D are secreted as latent dimers that undergo serine protease-mediated extracellular proteolytic activation. Gene expression analysis of breast cancer cell lines showed that PDGF C expression is associated with Basal B subtype breast cancer cells which have cancer stem cell-like characteristics. Furthermore, PDGF C expression is associated with triple-negative (estrogen receptor-, progesterone receptor- and HER2/neu-negative) breast cancer cells, a challenging type of breast cancer to treat. During the course of our study, we discovered a splice variant of PDGF C …

Concurrent Non-Ketotic Hyperglycinemia And Propionic Acidemia In An Eight Year Old Boy, Paul Kruszka, Brian Kirmse, Dina Zand, Kristina Cusmano-Ozog, Elaine Spector, John Hove, Kimberly A. Chapman

Pathology Faculty Publications

This is the first reported case of a patient with both non-ketotic hyperglycinemia and propionic acidemia. At 2 years of age, the patient was diagnosed with non-ketotic hyperglycinemia by elevated glycine levels and mutations in the GLDC gene (paternal allele: c.1576_1577insC delT and c.1580delGinsCAA; p.S527Tfs*13, and maternal allele: c.1819G>A; p.G607S). At 8 years of age after having been placed on ketogenic diet, he became lethargic and had severe metabolic acidosis with ketonuria. Urine organic acid analysis and plasma acylcarnitine profile were consistent with propionic acidemia. He was found to have an apparently homozygous mutation in the PCCB gene: c.49C …

Refusal To Autopsy: A Societal Practice In Pakistan Context, Laila Akber Cassum

School of Nursing & Midwifery

Autopsies or post-mortem examinations have become a common practice in Western medicine for verifying the cause of death, and to obtain additional scientific information on certain diseases. In monotheistic religions autopsies present several ethical questions even though the advantages attributed to post-mortems in the West are well acknowledged by people living in this modern world. In Islamic Republic of Pakistan where Islam is the prevailing religion followed by the Muslims, Pakistani society have diverse perception, assumptions and hypothesis on the concept of autopsy. This presumption is due to presence of diverse objections raised in religious and sociocultural context. In our …

The Heart Weight–Body Weight Coefficient In Kenyans Aged 14 Years And Above, Mbayah Etabale

Master of Medicine in Anatomic Pathology

Background: The heart size has traditionally been assessed using absolute reference weights. But the heart weight (HW) has been shown to depend on one’s body size hence a better measure is the ratio of the HW to the body weight (BW) – the HW-BW coefficient. Initially noted to be 0.43% and 0.40% in males and females respectively, recent studies have shown an increase of up to 0.51%. Objective: To determine the HW-BW coefficient in Kenyans aged 14 years and above. Methods: One hundred and four deceased Kenyans aged 14 years and above, with no heart or chronic lung disease, were …

Residual Disease And Hpv Persistence After Cryotherapy For Cervical Intraepithelial Neoplasia Grade 2/3 In Hiv Positive Women In Kenya, Hugo De Vuyst, Nelly R. Mugo, Silvia Franceschi, Kevin Mckenzie, Vanessa Tenet, Julia Njoroge, Farzana S. Rana, Samah R. Sakr, Peter J.F. Snijders, Michael Chung

Pathology, East Africa

Objective: To assess residual cervical intraepithelial neoplasia (CIN) 2/3 disease and clearance of high-risk (hr) human papillomavirus (HPV) infections at 6 months after cryotherapy among HIV-positive women.

Design: Follow-up study.

Methods: 79 HIV-positive women received cryotherapy for CIN2/3 in Nairobi, Kenya, and underwent conventional cytology 6 months later. Biopsies were performed on high grade cytological lesions and hrHPV was assessed before (cervical cells and biopsy) and after cryotherapy (cells).

Results: At 6 months after cryotherapy CIN2/3 had been eliminated in 61 women (77.2%; 95% Confidence Interval, (CI):66.4–85.9). 18 women (22.8%) had residual CIN2/3, and all these women had hrHPV at …

Epidemiology Of Malaria In A Village In The Rufiji River Delta, Tanzania: Declining Transmission Over 25 Years Revealed By Different Parasitological Metrics, Anna Färnert, Victor Yman, Manijeh Vafa Homann, Grace Wandell, Leah Mhoja, Marita Johansson, Salome Jesaja, Johanna Sandlund, Kazuyuki Tanabe, Ulf Hammar, Matteo Bottai, Zul Premji, Anders Björkman, Ingegerd Rooth

Pathology, East Africa

Background: Assessments of the epidemiology of malaria over time are needed to understand changes in transmission and guide control and elimination strategies.

Methods: A longitudinal population study was established in 1985 in Nyamisati village in the Rufiji River Delta, Tanzania. A physician and research team lived in the village 1984–2000. Parasite prevalence by microscopy and two PCR methods, spleen rates and haemoglobin levels were measured in repeated cross-sectional surveys between 1985 and 2010. Passive surveillance of malaria cases was maintained until end 1999. Bed nets were distributed after the surveys 1993, 1999 and 2010.

Results: In 1985, overall parasite prevalence …

Androgen Receptor Expression And Associated Clinico-Pathologic Features In Primary Breast Cancer From Kenya, Joshua Kibera Chege

Master of Medicine in Anatomic Pathology

Introduction: Breast cancer is a heterogeneous group of diseases classified into various subtypes according to clinical, histological and molecular features as well as by the expression of prognostic and predictive biomarkers. New biomarkers are being studied which may be therapeutic targets in various breast cancer subtypes particularly triple-negative breast cancer. Recent studies show that androgen receptor (AR) expression can be used as a prognostic marker and there is evidence that anti-androgen therapy may be beneficial in oestrogen receptor negative breast cancer. Retrospective studies show that patients with breast cancers co-expressing androgen receptor and oestrogen receptor have a favourable prognosis and …

The Prevalence Of Malaria And Assessment Of The Uptake Of Malaria Prevention Measures In Blood Donors In Two Regional Blood Transfusion Centres In Kenya, Valerie Magutu

Master of Medicine in Clinical Pathology

Transfusion transmitted malaria is one of the most common transfusion transmissible infections and is a threat to blood safety and malaria control in Sub-Saharan African countries where malaria is endemic. The majority of healthy adults living in malaria endemic areas have some degree of immunity to the disease and an asymptomatic low-level parasitaemia is known to exist in a subset of this population. Blood donors recruited from the population are screened using a donor-selection criteria that includes age, weight, self-declared well-being and measurement of vital signs but not history of recent malaria infection or treatment. The Kenya National Blood Transfusion …

P90/Cip2a Regulates Lung Cancer Cell Proliferation And Cell Apoptosis Via The Akt Signaling Pathway, Ningjing Lei

Open Access Theses & Dissertations

Cancerous inhibitor of PP2A (CIP2A) is an intracellular endogenous protein phosphatase 2A (PP2A) inhibitor with oncogenic activities. Initially identified as a tumor-associated antigen (TAA) in gastric and liver cancer patients, CIP2A was overexpressed in a variety of cancer types. And the overexpression of CIP2A in cancer cell is associated with increased cell proliferation and decreased cell apoptosis. However, the mechanism of CIP2A in cancer progression is still poorly understood. Here, we reported the evidence that CIP2A can regulate AKT phosphorylation at S473 under growth factor stimulation and our results also showed that CIP2A might regulate cell proliferation and cell apoptosis …

Β-Lactamase Production And Antimicrobial Susceptibility Pattern Of Moraxella Catarrhalis Isolates: Report From Pakistan, Sadia Omer Sheikh, Naima Fasih, Seema Irfan, Afia Zafar

Department of Pathology and Laboratory Medicine

Objective: To assess the frequency of β-lactamase production and antimicrobial resistance in Moraxella catarrhalis isolated from clinical specimens in Pakistan. Methods: This cross sectional study (January to December 2010) was conducted in clinical microbiology laboratory of Aga Khan University Hospital. A total of 97 clinical respiratory specimens growing Moraxella catarrhalis were included. Frequency of β-lactamase production and antimicrobial resistance rates against ampicillin, erythromycin, ciprofloxacin and tetracycline were noted by performing minimum inhibitory concentration (MIC). MICs were calculated as MIC50 and MIC90.
Results: β-Lactamase production was detected in 84% of isolates, which correlated well with high MIC of …