Lee J.,Indiana University |
Yakubov B.,Indiana University |
Ivan C.,University of Houston |
Jones D.R.,Indiana University |
And 6 more authors.
Neoplasia (United States) | Year: 2016
Resistance to chemotherapy is a hallmark of pancreatic ductal adenocarcinoma (PDA) and has been partly attributed to the dense desmoplastic stroma, which forms a protective niche for cancer cells. Tissue transglutaminase (TG2), a Ca2+-dependent enzyme, is secreted by PDA cells and cross-links proteins in the tumor microenvironment (TME) through acyl-transfer between glutamine and lysine residues, promoting PDA growth. The objective of the current study was to determine whether secreted TG2 by PDA cells alters the response of pancreatic tumors to gemcitabine. Orthotopic pancreatic xenografts and co-culture of PDA and stromal cells were employed to determine the mechanisms by which TG2 alters tumor-stroma interactions and response to gemcitabine. Analysis of the pancreatic The Cancer Genome Atlas (TCGA) database demonstrated that increased TG2 expression levels correlate with worse overall survival (hazard ratio = 1.37). Stable TG2 knockdown in PDA cells led to decreased size of pancreatic xenografts and increased sensitivity to gemcitabine in vivo. However, TG2 downregulation did not increase cytotoxicity of gemcitabine in vitro. Additionally, multivessel density and gemcitabine uptake in pancreatic tumor tissue, as measured by mass spectrometry (MS-HPLC), were not significantly different in tumors expressing TG2 versus tumors in which TG2 was knocked down. Fibroblasts, stimulated by TG2 secreted by PDA cells, secrete laminin A1, which protects cancer cells from gemcitabine-induced cytotoxicity. In all, our results demonstrate that TG2 secreted in the pancreatic TME orchestrates the cross talk between cancer cells and stroma, impacting tumor growth and response to chemotherapy. Our study supports TG2 inhibition to increase the antitumor effects of gemcitabine in PDA. © 2016
Shinnick K.M.,Feinberg Cardiovascular Research Institute |
Shinnick K.M.,Robert rie Cancer Center |
Eklund E.A.,Robert rie Cancer Center |
Eklund E.A.,Jesse Brown Medical Center |
And 2 more authors.
Journal of Clinical Investigation | Year: 2010
HSCs maintain the circulating blood cell population. Defects in the orderly pattern of hematopoietic cell division and differentiation can lead to leukemia, myeloproliferative disorders, or marrow failure; however, the factors that control this pattern are incompletely understood. Geminin is an unstable regulatory protein that regulates the extent of DNA replication and is thought to coordinate cell division with cell differentiation. Here, we set out to determine the function of Geminin in hematopoiesis by deleting the Geminin gene (Gmnn) from mouse bone marrow cells. This severely perturbed the pattern of blood cell production in all 3 hematopoietic lineages (erythrocyte, megakaryocyte, and leukocyte). Red cell production was virtually abolished, while megakaryocyte production was greatly enhanced. Leukocyte production transiently decreased and then recovered. Stem and progenitor cell numbers were preserved, and Gmnn-/- HSCs successfully reconstituted hematopoiesis in irradiated mice. CD34+ Gmnn-/- leukocyte precursors displayed DNA overreplication and formed extremely small granulocyte and monocyte colonies in methylcellulose. While cultured Gmnn-/- megakaryocyte-erythrocyte precursors did not form erythroid colonies, they did form greater than normal numbers of megakaryocyte colonies. Gmnn-/- megakaryocytes and erythroblasts had normal DNA content. These data led us to postulate that Geminin regulates the relative production of erythrocytes and megakaryocytes from megakaryocyte-erythrocyte precursors by a replication-independent mechanism.
Gerami P.,Robert rie Comprehensive Cancer Center |
Gerami P.,Robert rie Cancer Center |
Busam K.,Sloan Kettering Cancer Center |
Cochran A.,University of California at Los Angeles |
And 19 more authors.
American Journal of Surgical Pathology | Year: 2014
Predicting clinical behavior of atypical Spitz tumors remains problematic. In this study, we assessed interobserver agreement of diagnosis by 13 expert dermatopathologists for atypical Spitz tumors (n=75). We determined which histomorphologic features were most heavily weighted for their diagnostic significance by the experts and also which histomorphologic features had a statistically significant correlation with clinical outcome. There was a low interobserver agreement among the experts in categorizing lesions as malignant versus nonmalignant (κ=0.30). The histomorphologic features that were given the most diagnostic significance by the experts were: consumption of the epidermis, atypical mitoses, high-grade cytologic atypia, and mitotic rate. Conversely, the histomorphologic features that most correlated with disease progression were: frequent mitoses, deep mitoses, asymmetry, high-grade cytologic atypia, and ulceration. The presence and/or pattern of pagetoid spread, consumption of the epidermis, and lymphoid aggregates demonstrated no association with clinical behavior. The results support the assertion that there is a lack of consensus in the assessment of atypical Spitz tumors by expert dermatopathologists. Importantly, many features used to distinguish conventional melanoma from nevi were not useful in predicting the behavior of atypical Spitz tumors. This study may provide some guidance regarding histologic assessment of these enigmatic tumors. Copyright © 2014 by Lippincott Williams & Wilkins.
Wong S.J.,Medical College of Wisconsin |
Campbell B.,Medical College of Wisconsin |
Massey B.,Medical College of Wisconsin |
Lynch D.P.,Marquette University |
And 12 more authors.
Oral Oncology | Year: 2013
Background Photodynamic therapy with aminolevulinic acid (ALA PDT) for oral leukoplakia has shown promising effects in regression of oral leukoplakia. Although ALA has been extensively studied and is an ideal photosensitizer, the optimal light dose for treatment of oral leukoplakia has not been determined. We conducted a phase I study to determine MTD and DLT of PDT in patients treated with ALA for leukoplakia. Methods Patients with histologically confirmed oral leukoplakia received a single treatment of ALA PDT in cohorts with escalating doses of light (585 nm). Clinical, histologic, and biologic markers were assessed. Results Analysis of 11 participants is reported. No significant toxicity from ALA PDT was observed in patients who received ALA with a light dose of up to 4 J/cm2. One participant experienced transient grade 3 transaminase elevation due to ALA. One participant had a partial clinical response 3 months after treatment. Biologic mucosal risk markers showed no significant associations. Determination of MTD could not be accomplished within a feasible timeframe for completion of the study. Conclusions ALA PDT could be safely administered with a light dose up to 4 J/cm2 and demonstrated activity. Larger studies are needed to fully elucidate the MTD and efficacy of ALA-PDT. © 2013 Elsevier Ltd. All rights reserved.
Yelamos O.,Northwestern University |
Arva N.C.,Ann And Robert H Lurie Childrens Hospital Of Chicago |
Obregon R.,Northwestern University |
Yazdan P.,Northwestern University |
And 5 more authors.
American Journal of Surgical Pathology | Year: 2015
Differentiating proliferative nodules (PNs) from melanomas arising in congenital nevi (CN) is a considerable challenge for dermatopathologists. Most of the specimens dermatopathologists assess that deal with this differential diagnosis involve proliferations of melanocytes arising in the dermis. In this study, we compare the clinical, histologic, and molecular findings of these 2 conditions. In our database, we found 22 examples of PNs arising in the dermis of CN and 2 cases of lethal melanomas arising from the dermis/epidermis of CN of children. Importantly, we found that among dermal melanocytic proliferations arising from CN in children, PNs are far more common than lethal melanomas. Clinically, multiplicity of lesions favored a diagnosis of PNs, whereas ulceration was infrequent in PNs compared with lethal melanomas. Histologically, PNs showed several distinct patterns including expansile nodules of epithelioid melanocytes with mitotic counts lower than that seen in the melanomas (1.67 vs. 12.5 mitoses/mm 2), a small round blue cell pattern often highly mitotically active, neurocristic-like, blue nevus-like, a nevoid melanoma-like pattern, or an undifferentiated spindle cell pattern. The lethal melanomas both featured expansile nodules of epithelioid melanocytes with high mitotic counts (range, 5 to 20 mitoses/mm 2) and an ulcerated overlying epidermis. At the molecular level, the PNs showed mostly whole chromosomal copy number aberrations, which in some cases were accompanied by rare partial chromosomal aberrations, whereas both lethal melanomas showed highly elevated copy number aberrations involving 6p25 without gains of the long arm of chromosome 6. Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
Martinez-Escala M.E.,Northwestern University |
Sidiropoulos M.,Northwestern University |
Deonizio J.,Northwestern University |
Gerami P.,Northwestern University |
And 3 more authors.
British Journal of Dermatology | Year: 2015
Background T cells with a γδ phenotype have been associated with aggressive lymphomas. Yet, inflammatory skin disorders and low-grade lymphoproliferative disorders have rarely been described with a predominant γδ T-cell infiltrate. Objectives To review our experience and determine the clinical relevance of the γδ T-cell phenotype in lymphomatoid papulosis (LyP) and pityriasis lichenoides (PL). Methods A retrospective dermatopathology file review looking for LyP and PL characterized by a γδ T-cell phenotype was performed. Clinical manifestations and course, histological features and molecular data were analyzed. Results Six of 16 cases of LyP and four of 23 cases diagnosed as PL during a 5-year period (2009-14) were identified. The median follow-up for the whole group was 16 months (range 3-64), showing an indolent clinical course in all cases. Conclusions The detection of a predominantly γδ T-cell phenotype in papular lymphoid-rich infiltrates in the absence of other lesions is not associated with a clinically aggressive course. γδ T-cell-rich variants of LyP and PL may reflect a spectrum of related conditions. This is a single academic centre retrospective chart review of a relatively small sample. © 2014 British Association of Dermatologists.
Deonizio J.M.D.,Northwestern University |
Rosen S.T.,Northwestern University |
Rosen S.T.,Robert rie Cancer Center |
Guitart J.,Northwestern University |
Guitart J.,Robert rie Cancer Center
Pathology Case Reviews | Year: 2012
An 81-year-old white woman with a past medical history significant for coronary artery disease and a cerebrovascular accident presented with a large ulcerated tumor on her left ankle of 3 months duration. A skin biopsy was reported as diffuse large B-cell lymphoma. The histology revealed a diffuse infiltrate composed of a monotonous population of large round lymphocytes with features of centroblasts and immunoblasts. Immunostaining showed that the tumor cells were positive for CD20, MUM-1, FOX-P1, IgM, and BCL2 but negative for CD30. Immunostaining for Ki-67 showed that the tumor cells had a high proliferative index. The lesion was treated with radiotherapy, but the patient died 8 months later. There are 3 main types of primary cutaneous B-cell lymphoma: primary cutaneous marginal zone lymphoma, primary cutaneous follicle center lymphoma, and primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL-LT). Primary cutaneous marginal zone lymphoma and primary cutaneous follicle center lymphoma are indolent lymphomas with a 5-year disease-specific survival greater than 95%, whereas PCLBCL-LT represents a more aggressive type of disease with a 5-year disease-specific survival of approximately 50%. PCLBCL-LT has a phenotype similar to the "activated" subtype of nodal diffuse large B-cell lymphoma, which is thought to be a reason for the poor prognosis. The treatment of patients with PCLBCL-LT should be aggressive and polychemotherapy is indicated in most cases. © 2012 Lippincott Williams & Wilkins, Inc.
Khan S.A.,Lynn Sage Breast Center |
Mangat A.,Lynn Sage Breast Center |
Rivers A.,Beaumont Hospital |
Revesz E.,Lynn Sage Breast Center |
And 2 more authors.
Annals of Surgical Oncology | Year: 2011
Background: Pathologic nipple discharge (PND) is diagnosed clinically and managed by diagnostic duct excision (DDE). Mammary ductoscopy in the office setting may change this standard. We performed a prospective study to assess the utility of office ductoscopy for surgical selection in women with nipple discharge. Methods: Women with nipple discharge meeting at least 2 of 3 criteria of PND (spontaneous, single duct, bloody or serous) underwent office ductoscopy. Those showing papillomatous lesions underwent DDE in the operating room (surgical group, n = 38); if no lesion was present, women were followed clinically (observation group, n = 21). Results: A papillomatous lesion was identified in 79% of women with 3-criteria PND and in 21% with 2 criteria (P = .001). DDE yielded a proliferative lesion in 35 of 38 women (92%). Of the 38, 27 (71%) had papillomata, 2 (5%) had florid hyperplasia, and 6 (16%) had ductal carcinoma in situ (DCIS) on final pathology. Also, 11 women with papilloma and 1 with DCIS presented with 2-criteria PND. Ductoscopy findings were a better predictor of the presence of intraductal neoplasia (area under curve [AUC] 0.9, 95% confidence interval [95% CI] 0.8-0.98) compared with 3-criteria PND (AUC 0.7, 95% CI 0.6-0.8). The 21 women in the observation group did not develop signs of malignancy or need biopsy during a 48-month follow-up period. Conclusions: Our findings suggest that office ductoscopy provides accurate surgical selection of women with nipple discharge and should be considered for women with 2 criteria of PND, and those with negative ductoscopy can be safely observed. These findings need confirmation in a larger study with longer follow-up. © 2011 Society of Surgical Oncology.
Gadd S.,Northwestern University |
Gadd S.,Robert rie Cancer Center |
Sredni S.T.,Northwestern University |
Sredni S.T.,Robert rie Cancer Center |
And 4 more authors.
Laboratory Investigation | Year: 2010
Rhabdoid tumors (RT) are aggressive tumors characterized by genetic loss of SMARCB1 (SNF5, INI-1), a component of the SWI/SNF chromatin remodeling complex. No effective treatment is currently available. This study seeks to shed light on the SMARCB1-mediated pathogenesis of RT and to discover potential therapeutic targets. Global gene expression of 10 RT was compared with 12 cellular mesoblastic nephromas, 16 clear cell sarcomas of the kidney, and 15 Wilms tumors. In all, 114 top genes were differentially expressed in RT (P>0.001, fold change <2 or 0.5). Among these were downregulation of SMARCB1 and genes previously associated with SMARCB1 (ATP1B1, PTN, DOCK4, NQO1, PLOD1, PTP4A2, PTPRK); 28/114 top differentially expressed genes were involved with neural or neural crest development and were all sharply downregulated. This was confirmed by Gene Set Enrichment Analysis (GSEA). Neural and neural crest stem cell marker proteins SOX10, ID3, CD133, and Musashi were negative by immunohistochemistry, whereas Nestin was positive. Decreased expression of CDKN1A, CDKN1B, CDKN1C, CDKN2A, and CCND1 was identified, while MYC-C was upregulated. GSEA of independent gene sets associated with bivalent histone modification and polycomb group targets in embryonic stem cells showed significant negative enrichment in RT. Several differentially expressed genes were associated with tumor suppression, invasion, and metastasis, including SPP1 (osteopontin), COL18A1 (endostatin), PTPRK, and DOCK4. We conclude that RTs arise within early progenitor cells during a critical developmental window in which loss of SMARCB1 directly results in repression of neural development, loss of cyclin-dependent kinase inhibition, and trithorax/polycomb dysregulation. © 2010 USCAP, Inc All rights reserved.