33 results on '"Parilla M"'
Search Results
2. 207 - RNA/HnRNPK and BRD4/BET Mediate 5-Azacytidine (5-AZA) Action and Resistance in MDS/AML
- Author
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Cheng, J., Chen, L., Li, Y., Cloe, A., Parilla, M., Beau, M.L., Larson, R., and Vardiman, J.
- Published
- 2017
- Full Text
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3. Actividad antioxidante de pigmentos antociánicos
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Kuskoski, E. Marta, primary, Asuero, Agustín G., additional, García-Parilla, M. Carmen, additional, Troncoso, Ana M., additional, and Fett, Roseane, additional
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- 2004
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4. Expect the unexpected: endocarditis caused by Legionella feeleii.
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Moran A, Otero Espinal DE, Parilla M, Beavis KG, Mullane KM, and Tesic V
- Abstract
We report a fatal case of Legionella feeleii endocarditis in a post-lung transplant patient. The diagnosis was delayed, as routine microbiological testing of nonrespiratory specimens does not account for extrapulmonary Legionella, and urine antigen testing only reliably detects Legionella pneumophila serogroup 1. This case also illustrates the utility of molecular sequencing for blood culture-negative endocarditis., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
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- 2024
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5. An update on genetic aberrations in T-cell neoplasms.
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Parilla M, Quesada AE, Medeiros LJ, and Thakral B
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- Humans, T-Lymphocytes pathology, Mutation, Lymphoma diagnosis, Lymphoma genetics, Lymphoma pathology, Lymphoma, B-Cell pathology, Leukemia pathology
- Abstract
T-cell neoplasms are a highly heterogeneous group of leukaemias and lymphomas that represent 10-15% of all lymphoid neoplasms. Traditionally, our understanding of T-cell leukaemias and lymphomas has lagged behind that of B-cell neoplasms, in part due to their rarity. However, recent advances in our understanding of T-cell differentiation, based on gene expression and mutation profiling and other high throughput methods, have better elucidated the pathogenetic mechanisms of T-cell leukaemias and lymphomas. In this review, we provide an overview of many of the molecular abnormalities that occur in various types of T-cell leukaemia and lymphoma. Much of this knowledge has been used to refine diagnostic criteria that has been included in the fifth edition of the World Health Organization. This knowledge is also being used to improve prognostication and identify novel therapeutic targets, and we expect this progress will continue, eventually resulting in improved outcomes for patients with T-cell leukaemias and lymphomas., (Copyright © 2023 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)
- Published
- 2023
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6. Triple-Negative Primary Myelofibrosis: A Bone Marrow Pathology Group Study.
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Al-Ghamdi YA, Lake J, Bagg A, Thakral B, Wang SA, Bueso-Ramos C, Masarova L, Verstovsek S, Rogers HJ, Hsi ED, Gralewski JH, Chabot-Richards D, George TI, Rets A, Hasserjian RP, Weinberg OK, Parilla M, Arber DA, Padilla O, Orazi A, and Tam W
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- Humans, Bone Marrow pathology, Mutation, Prognosis, Janus Kinase 2 genetics, Transcription Factors genetics, Primary Myelofibrosis genetics, Primary Myelofibrosis pathology, Myeloproliferative Disorders genetics
- Abstract
Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm driven by canonical gene mutations in JAK2, CALR, or MPL in >80% of the cases. PMF that lacks these canonical alterations is termed triple-negative PMF (TN-PMF). The pathologic and genetic characteristics of TN-PMF compared with those of conventional PMF with canonical driver mutations (DM-PMF) have not been well studied. We aimed to identify clinicopathologic and molecular genetic differences between patients with TN-PMF (n = 56) and DM-PMF (n = 89), all of whom fulfilled the 2016 World Health Organization diagnostic criteria for PMF. Compared with the control group, patients in the TN-PMF group were more likely to have thrombocytopenia and less likely to have organomegaly. The bone marrow in patients with TN-PMF showed fewer granulocytic elements and more frequent dyserythropoiesis. Cytogenetic analysis showed a higher incidence of trisomy 8. Targeted next-generation sequencing revealed a lower frequency of ASXL1 mutations but enrichment of ASXL1/SRSF2 comutations. Our findings demonstrated several clinicopathologic and molecular differences between TN-PMF and DM-PMF. These findings, particularly the observed mutation profile characterized by a higher frequency of ASXL1 and SRSF2 comutation, suggest that at least a subset of TN-PMF may be pathogenetically different from DM-PMF, with potential prognostic implications., (Copyright © 2022 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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7. Toward a More Just System of Care in Molecular Pathology.
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Lilley CM, Delille M, Mirza KM, and Parilla M
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- Humans, United States, Minority Groups, Health Policy, Pathology, Molecular, Delivery of Health Care
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Policy Points American health care policy must be critically assessed to establish the role it plays in sustaining and alleviating the health disparities that currently exist in molecular genetic testing. It is critical to understand the economic and sociocultural influences that drive patients to undergo or forgo molecular testing, especially in marginalized patient populations. A multipronged solution with actions necessary from multiple stakeholders is required to reduce the cost of health care, rebalance regional disparities, encourage physician engagement, reduce data bias, and earn patients' trust., Context: The health status of a population is greatly influenced by both biological processes and external factors. For years, minority and low socioeconomic patient populations have faced worse outcomes and poorer health in the United States. Experts have worked extensively to understand the issues and find solutions to alleviate this disproportionate burden of disease. As a result, there have been some improvements and successes, but wide gaps still exist. Diagnostic molecular genetic testing and so-called personalized medicine are just now being integrated into the current American health care system. The way in which these tests are integrated can either exacerbate or reduce health disparities., Methods: We provide case scenarios-loosely based on real-life patients-so that nonexperts can see the impacts of complex policy decisions and unintentional biases in technology without needing to understand all the intricacies. We use data to explain these findings from an extensive literature search examining both peer-reviewed and gray literature., Findings: Access to diagnostic molecular genetic testing is not equitable or sufficient, owing to at least five major factors: (1) cost to the patient, (2) location, (3) lack of provider buy-in, (4) data-set bias, and (5) lack of public trust., Conclusions: Molecular genetic pathology can be made more equitable with the concerted efforts of multiple stakeholders. Confronting the five major factors identified here may help us usher in a new era of precision medicine without its discriminatory counterpart., (© 2022 The Authors. The Milbank Quarterly published by Wiley Periodicals LLC on behalf of The Milbank Memorial Fund.)
- Published
- 2022
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8. Recurrent Loss of Heterozygosity in Pancreatic Neuroendocrine Tumors.
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Parilla M, Chapel D, Hechtman JF, Wanjari P, El Jabbour T, Sharma A, Ritterhouse L, Segal J, Vanderbilt C, Klimstra DS, Setia N, and Tang L
- Subjects
- DNA Copy Number Variations, High-Throughput Nucleotide Sequencing, Humans, Loss of Heterozygosity, Neuroendocrine Tumors pathology, Pancreatic Neoplasms genetics, Pancreatic Neoplasms pathology
- Abstract
Chromosomal aneuploidies are prognostic markers across a wide variety of tumor types, and recent literature suggests that pancreatic neuroendocrine tumors are no different. In this study 214 patients with grade 1, 2, or 3 pancreatic neuroendocrine tumors had their tissue examined for chromosomal copy number alterations using next-generation sequencing. Univariate and multivariate statistical analyses were performed with all-cause mortality and disease-specific mortality as the end comparators. As such, the cohort stratified into 3 different clinically relevant chromosomal subgroups: an indolent subgroup characterized by loss of chromosome 11 in relative isolation, an aggressive subgroup characterized by losses of chromosomes 1, 2, 3, 6, 10, 11, 16, and 22 and with no loss of chromosomes 4, 5, 7, 12, 14, 17, 19, and 20, and finally a heterogeneous third group with a subset of cases that behave even more aggressively than the aforementioned., Competing Interests: Conflicts of Interest and Source of Funding: D.C. work is supported by the Ovarian Cancer Research Alliance [Ann Schreiber Mentored Investigator Award; grant number 650320]. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2022
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9. ATM Germline-Mutated Gastroesophageal Junction Adenocarcinomas: Clinical Descriptors, Molecular Characteristics, and Potential Therapeutic Implications.
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El Jabbour T, Misyura M, Cowzer D, Zimmermann M, Rimkunas V, Marra A, Derakhshan F, Selenica P, Parilla M, Setton JS, Ceyhan-Birsoy O, Kemel Y, Catchings A, Ranganathan M, Ku GY, Janjigian YY, Zinda M, Koehler M, Stadler Z, Shia J, Reis-Filho JS, and Mandelker D
- Subjects
- Ataxia Telangiectasia Mutated Proteins genetics, Esophagogastric Junction metabolism, Esophagogastric Junction pathology, Germ Cells metabolism, Germ Cells pathology, Humans, Adenocarcinoma genetics, Adenocarcinoma pathology, Esophageal Neoplasms genetics, Esophageal Neoplasms pathology, Stomach Neoplasms metabolism
- Abstract
Background: Gastroesophageal junction (GEJ) adenocarcinoma is a rare cancer associated with poor prognosis. The genetic factors conferring predisposition to GEJ adenocarcinoma have yet to be identified., Methods: We analyzed germline testing results from 23 381 cancer patients undergoing tumor-normal sequencing, of which 312 individuals had GEJ adenocarcinoma. Genomic profiles and clinico-pathologic features were analyzed for the GEJ adenocarcinomas. Silencing of ATM and ATR was performed using validated short-interfering RNA species in GEJ, esophageal, and gastric adenocarcinoma cell lines. All statistical tests were 2-sided., Results: Pathogenic or likely pathogenic ATM variants were identified in 18 of 312 patients (5.8%), and bi-allelic inactivation of ATM through loss of heterozygosity of the wild-type allele was detected in all (16 of 16) samples with sufficient tumor content. Germline ATM-mutated GEJ adenocarcinomas largely lacked somatic mutations in TP53, were more likely to harbor MDM2 amplification, and harbored statistically significantly fewer somatic single nucleotide variants (2.0 mutations/Mb vs 7.9 mutations/Mb; P < .001). A statistically significantly higher proportion of germline ATM-mutated than ATM-wild-type GEJ adenocarcinoma patients underwent a curative resection (10 [100%] vs 92 [86.8%], P = .04; Fisher's exact test.), A synthetic lethal interaction between short-interfering RNA silencing of ATM and ATR was observed in the models analyzed., Conclusions: Our results indicate that germline pathogenic variants in ATM drive oncogenesis in GEJ adenocarcinoma and might result in a distinct clinical phenotype. Given the high prevalence of germline ATM-mutated GEJ adenocarcinomas, genetic testing for individuals with GEJ adenocarcinomas may be considered to better inform prognostication, treatment decisions, and future cancer risk., (© The Author(s) 2022. Published by Oxford University Press.)
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- 2022
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10. Epigenetic Dysregulation of 5-hydroxymethylcytosine in Well-Differentiated Pancreatic Neuroendocrine Tumors.
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Sharma AE, Olivas A, Parilla M, Yassan L, Wang H, Zhang SS, Weber C, Keutgen XM, Hart J, Krausz T, and Setia N
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- 5-Methylcytosine analogs & derivatives, Epigenesis, Genetic, Female, Humans, Mitotic Index, Neuroendocrine Tumors metabolism, Pancreatic Neoplasms metabolism
- Abstract
Dysregulation of epigenetic mechanisms, reflected by loss of expression of 5-hydroxymethylcytosine (5-hmC) is being increasingly recognized as a marker of aggressive behavior in several neoplasms; however, the role of such epigenetic modifiers in pancreatic neuroendocrine tumors (PanNETs) has not been studied. Annotated cohort of 60 PanNETs was evaluated for 5-hmC expression using immunohistochemistry. Univariable and multivariable analyses were performed. To determine intratumor heterogeneity of 5-hmC expression, 26 additional synchronous metastatic deposits of PanNETs from 8 patients were evaluated for 5-hmC expression. 5-hmC level showed significant association with the presence of distant metastases (P=0.02), female sex (P=0.04), and Ki-67 proliferation index (P=0.002). A multivariate model created using the stepwise logistic regression analysis showed the presence of nodal metastases (odds ratio=6.15), lymphovascular invasion (odds ratio=4.07) and lack of 5-hmC expression (odds ratio=5.34) were predictive of the risk of distant metastasis in PanNETs with a c-statistic of 0.845. Epigenetic intratumoral heterogeneity of 5-hmC expression was seen in 37.5% cases (3/8). Our work provides evidence that epigenetic regulators are involved in the pathobiology of PanNETs and immunohistochemical analysis of 5-hmC may be able to refine prognostic evaluation of these tumors., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2022
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11. Benign vs malignant pancreatic lesions: Molecular insights to an ongoing debate.
- Author
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Aldyab M, El Jabbour T, Parilla M, and Lee H
- Abstract
Several benign conditions such as chronic pancreatitis, autoimmune pancreatitis, and paraduodenal pancreatitis can present as mass lesions and may mimic pancreatic ductal adenocarcinoma (PDAC) clinically and radiologically. Thorough histologic examination with attention to certain morphologic features can assist in deciphering neoplastic from reactive, however small biopsies often remain a challenge. Variable histologic patterns in conventional PDAC may also confound the diagnosis of PDAC. Uncommon subtypes of pancreatic carcinoma such as adenosquamous and squamous cell carcinoma, colloid carcinoma, medullary carcinoma, hepatoid carcinoma and signet ring cell carcinoma necessitate excluding metastasis from other sites prior to rendering the diagnosis of pancreatic carcinoma. The use of immunohistochemical staining and molecular markers can aid in separating benign from malignant and PDAC from metastasis. PDAC expresses a few non-specific epithelial and mucin immunomarkers such as CK7, CK19, MUC1, MUC4 and MUC5AC. However, the only immunohistochemical marker that is specific for PDAC in the right clinical context is SMAD4. Loss of SMAD4 within atypical glands and ducts supports the diagnosis of PDAC in a limited sample. Unfortunately, this finding is seen only in 50% of PDAC cases. The identification of certain mutations can help support a diagnosis of PDAC when benign conditions are in the differential. At the molecular level, KRAS oncogene mutations are seen in approximately 93% of PDACs. Subsequent neoplastic progression is driven by additional mutations of tumor suppressor genes, such as CDKN2A , TP53 , and SMAD4 . Molecular markers can also provide an insight to the prognosis. For instance, the loss of SMAD4 is associated with a poor outcome whereas mutations in MLL , MLL2 , MLL3 , and ARID1A are associated with improved survival., Competing Interests: Conflict-of-interest statement: There is no conflict of interest associated with any of the senior author or other coauthors contributed their efforts in this manuscript., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)
- Published
- 2021
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12. BAP1-Mutated Clear Cell Renal Cell Carcinoma.
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Gallan AJ, Parilla M, Segal J, Ritterhouse L, and Antic T
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- Aged, Carcinoma, Renal Cell diagnosis, Humans, Kidney Neoplasms diagnosis, Kidney Neoplasms genetics, Male, Middle Aged, Nuclear Proteins genetics, Phenotype, Prognosis, Transcription Factors metabolism, Tumor Suppressor Proteins genetics, Ubiquitin Thiolesterase genetics, Carcinoma, Renal Cell pathology, Gene Expression Regulation, Neoplastic genetics, Kidney Neoplasms pathology, Mutation genetics, Tumor Suppressor Proteins metabolism, Ubiquitin Thiolesterase metabolism
- Abstract
Objectives: While aberrations in the VHL gene and chromosome 3p resulting in clear cell renal cell carcinoma (CCRCC) are well established, we know that additional mutations in chromatin remodeling genes PBRM1, SETD2, and BRCA1-associated protein 1 (BAP1) contribute to pathogenesis in some cases. Given the known aggressive clinical behavior of BAP1-mutated CCRCC, we sought to define the pathologic phenotype of BAP1-mutated CCRCC., Methods: We identified 14 cases of molecularly proven BAP1-mutated CCRCC and investigated their clinicopathologic features., Results: BAP1-mutated CCRCC frequently showed papillary, tubulopapillary, or expanded nested architecture; demonstrated granular to diffusely eosinophilic cytoplasm with prominent eosinophilic globules; and contained high-grade nuclei. This morphology demonstrates significant overlap with Xp11 translocation renal cell carcinoma (RCC). Immunohistochemistry notably demonstrates loss of BAP1 expression in almost all tumors, in addition to strong p504S expression. A conventional CCRCC component was frequently present adjacent to the characteristic BAP1 areas and showed retained BAP1 expression and only patchy p504S. Approximately two-thirds of BAP1-mutated CCRCCs were stage pT3, renal vein invasion was common, and 50% developed metastases., Conclusions: Herein, we describe the histologic and immunohistochemical findings in BAP1-mutated CCRCC, which has important implications for utilization of molecular testing, prognosis, future therapeutics, and distinction from other RCC subtypes such as Xp11 translocation RCC., (© American Society for Clinical Pathology, 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2021
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13. A Tale of 2 Morphologies: Diagnostic Pitfalls in TFEB -Associated Renal Cell Carcinomas, Including a Novel NEAT1-TFEB Fusion.
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Sharma AE, Parilla M, Wanjari P, Segal JP, and Antic T
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- Adult, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors genetics, Biopsy, Carcinoma, Renal Cell genetics, Carcinoma, Renal Cell pathology, Carcinoma, Renal Cell surgery, Clathrin Heavy Chains genetics, Diagnosis, Differential, Female, Humans, Kidney pathology, Kidney surgery, Kidney Neoplasms genetics, Kidney Neoplasms pathology, Kidney Neoplasms surgery, Middle Aged, Nephrectomy, Perivascular Epithelioid Cell Neoplasms diagnosis, RNA, Long Noncoding genetics, RNA-Seq, Translocation, Genetic, Treatment Outcome, Biomarkers, Tumor genetics, Carcinoma, Renal Cell diagnosis, Kidney Neoplasms diagnosis, Oncogene Proteins, Fusion genetics
- Abstract
Aims: Translocation-associated renal cell carcinomas (RCCs) have been extensively subcharacterized in recent years, such that each is largely recognized by the 2016 World Health Organization as categorical neoplastic entities in the genitourinary tract. Those belonging to the t (6;11) family of tumors classically have a fusion between TFEB and MALAT1/α, and display a particular histomorphology. Specifically, they show a biphasic population of both small and large epithelioid cells, the smaller component of which surrounds basement membrane-type material. Despite this apt description, the tumors have variable morphology and mimic other RCCs including those with TFE3 translocations. Therefore, a high degree of suspicion is required to make the correct diagnosis., Methods: The 2 cases described in this article were of strikingly different appearance, and initially considered consistent with other non-translocation-associated renal tumors. These included clear cell RCC (CCRCC), perivascular epithelioid cell tumor (PEComa), and other eosinophilic RCCs (mainly papillary RCC type 2)., Results: Using RNA sequencing techniques, they were found to harbor distinct pathogenic rearrangements involving the TFEB gene, namely, fusions with CLTC and NEAT1 (the latter partnering heretofore never reported)., Conclusions: These alterations manifested in 2 notably dissimilar lesions, underscoring the importance of including this family of carcinomas in the differential of any renal neoplasm that does not display immunophenotypic characteristics consistent with its morphology.
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- 2021
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14. Uterine Tumor Resembling Ovarian Sex Cord Stromal Tumor (UTROSCT): A Series of 3 Cases With Extensive Rhabdoid Differentiation, Malignant Behavior, and ESR1-NCOA2 Fusions.
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Bennett JA, Lastra RR, Barroeta JE, Parilla M, Galbo F, Wanjari P, Young RH, Krausz T, and Oliva E
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- Adult, Endometrial Stromal Tumors genetics, Female, Humans, Middle Aged, Oncogene Fusion, Sex Cord-Gonadal Stromal Tumors genetics, Sex Cord-Gonadal Stromal Tumors pathology, Endometrial Stromal Tumors pathology, Nuclear Receptor Coactivator 2 genetics, Uterine Neoplasms genetics, Uterine Neoplasms pathology
- Abstract
ESR1 and GREB1 fusions have recently been described in uterine tumor resembling ovarian sex cord tumor (UTROSCT). Thus far, recurrences have been documented in a subset of those harboring GREB1 fusions, but not in those with ESR1 rearrangements. Here we describe the clinicopathologic features of 3 recurrent UTROSCTs with striking rhabdoid morphology (an unusual feature of these tumors overall) and ESR1-NCOA2 fusions. The patients were 32, 37, and 54 years at initial diagnosis and first recurrence occurred at 7, 9, and 32 years. The primary tumors (available in two cases) were centered in the myometrium and showed infiltrative borders. They predominantly grew in sheets and cords, but also had a pseudopapillary appearance. Cells were uniformly epithelioid with eccentric nuclei, prominent nucleoli, abundant eosinophilic globular/glassy (rhabdoid) cytoplasm, and infrequent mitoses (≤4/10 high-power fields [HPFs]). Recurrences were morphologically identical to the primary tumors, but demonstrated brisk mitotic activity (≥16/10 HPFs). The third tumor (with only recurrences available) had multiple patterns, including diffuse, corded, trabecular, and a focal retiform growth. Rhabdoid cells were conspicuous, but only comprised ~50% of the tumor, and mitoses numbered up to 2/10 HPFs. All tumors were strongly and diffusely positive for WT1, CAM5.2, ER, and PR, but negative for inhibin. Diffuse calretinin and desmin expression, as well as focal melan-A positivity, was noted in one tumor, but was negative in the others. In all 3 tumors, INI-1 and BRG-1 were retained, and ESR1-NCOA2 fusions were detected by targeted RNA sequencing. This study is the first to highlight an association between UTROSCTs with extensive rhabdoid differentiation, ESR1-NCOA2 fusions, and aggressive behavior. UTROSCTs are considered neoplasms of uncertain malignant potential, but have a benign course in most cases. Thus, it is important to be aware of these specific features and recommend long-term follow-up due to their propensity for late recurrences.
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- 2020
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15. Red cell morphology in sickle cell disease.
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Parilla M and Gurbuxani S
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- Humans, Anemia, Sickle Cell blood, Anemia, Sickle Cell diagnosis, Erythrocytes pathology, Erythrocytes, Abnormal pathology
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- 2020
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16. Eosinophilic Renal Cell Tumors With a TSC and MTOR Gene Mutations Are Morphologically and Immunohistochemically Heterogenous: Clinicopathologic and Molecular Study.
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Tjota M, Chen H, Parilla M, Wanjari P, Segal J, and Antic T
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- Adolescent, Adult, Aged, Biomarkers, Tumor metabolism, Carcinoma, Renal Cell genetics, Carcinoma, Renal Cell metabolism, Carcinoma, Renal Cell pathology, Eosinophilia etiology, Eosinophilia pathology, Female, Follow-Up Studies, High-Throughput Nucleotide Sequencing, Humans, Immunohistochemistry, Kidney Neoplasms genetics, Kidney Neoplasms metabolism, Kidney Neoplasms pathology, Male, Middle Aged, Mutation, Prognosis, Retrospective Studies, Young Adult, Biomarkers, Tumor genetics, Carcinoma, Renal Cell diagnosis, Eosinophils pathology, Kidney Neoplasms diagnosis, TOR Serine-Threonine Kinases genetics, Tuberous Sclerosis Complex 1 Protein genetics, Tuberous Sclerosis Complex 2 Protein genetics
- Abstract
Eosinophilic renal neoplasms have a wide spectrum of histologic presentations, and several studies have demonstrated a subtype of renal cell carcinomas (RCCs) associated with the tuberous sclerosis complex (TSC)/mammalian target of rapamycin pathway. A review of our institutional archives led to the identification of 18 cases of renal eosinophilic tumors with unusual morphology. Immunohistochemical analysis demonstrated that these could be separated into 3 groups: group 1 had solid architecture and morphology similar to chromophobe RCC but was negative for CK20 and vimentin, and had weak focal staining for CK7 and P504S; group 2 had solid architecture and morphology similar to either renal oncocytoma or chromophobe RCC, eosinophilic variant and had diffuse staining of CK7 and P504S, absent to weak staining of CK20, and negative staining for vimentin; and group 3 had solid, cystic and papillary architecture and was negative for CK7, except for 1 case, along with moderate to strong staining of CK20, P504S, and vimentin. The cases were then sent for next-generation sequencing to determine whether molecular pathogenic variants were present. In group 1, all 3 cases had mutations in TSC2. In group 2, pathogenic variants were identified in 3 genes: TSC1, TSC2, and MTOR. In group 3, genetic alterations and pathogenic variants were identified in TSC1 and TSC2. Our results support TSC/MTOR-associated neoplasms as a distinct group that exhibits heterogenous morphology and immunohistochemical staining.
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- 2020
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17. Follicular Thyroid Neoplasms: Comparison of Clinicopathologic and Molecular Features of Atypical Adenomas and Follicular Thyroid Carcinomas.
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Cracolici V, Ritterhouse LL, Segal JP, Puranik R, Wanjari P, Kadri S, Parilla M, and Cipriani NA
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- Adenocarcinoma, Follicular genetics, Adenocarcinoma, Follicular pathology, Adenoma genetics, Adenoma pathology, Adolescent, Adult, Aged, Aged, 80 and over, Diagnosis, Differential, Female, Humans, Male, Middle Aged, Mutation, Neoplasm Metastasis, Thyroid Neoplasms genetics, Thyroid Neoplasms pathology, Young Adult, Adenocarcinoma, Follicular diagnosis, Adenoma diagnosis, Biomarkers, Tumor genetics, Telomerase genetics, Thyroid Neoplasms diagnosis
- Abstract
In follicular thyroid neoplasms without invasion, a diagnosis of atypical adenoma (AA) (follicular tumor of uncertain malignant potential) may be rendered if atypical features (indefinite capsular/vascular invasion, necrosis, solid growth, increased mitoses) are present. This study compares clinical, histologic, and molecular features of patients with AAs (n=31), nonmetastatic follicular thyroid carcinoma (nmFTC) (n=18), and metastatic follicular thyroid carcinoma (mFTC) (n=38). Patients with mFTC were older. Mitotic activity in areas of solid growth was greatest in mFTC (P=0.05). Oncocytic tumors tended to show solid growth (P=0.04). The presence or frequency of capsular and/or vascular invasion was not different between nmFTC and mFTC. TERT promoter mutations were higher in patients with mFTC (50%) than nmFTC (25%) and AA (10%) (P=0.02). TERT promoter mutation was associated with necrosis (P=0.01) and solid growth plus increased mitoses (P=0.03). Necrosis and TERT promoter mutations were identified in all groups, most frequently in mFTC. The combination of solid growth with increased mitoses, necrosis, and TERT promoter mutation was only seen in follicular carcinomas. Poorly differentiated features, vascular invasion, and TERT promoter mutation correlated with metastasis in FTC. Given the low frequency of necrosis and TERT promoter mutation in AAs, close clinical follow-up is recommended in patients with these findings, especially if additional atypical features (such as solid growth plus mitoses) are present.
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- 2020
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18. An Evaluation of CD61 Immunohistochemistry in Identification of Vascular Invasion in Follicular Thyroid Neoplasms.
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Cracolici V, Parilla M, Henriksen KJ, and Cipriani NA
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- Adolescent, Adult, Aged, Aged, 80 and over, Blood Platelets metabolism, Female, Humans, Immunohistochemistry, Male, Middle Aged, Neoplasm Invasiveness pathology, Neoplastic Cells, Circulating pathology, Young Adult, Adenocarcinoma, Follicular pathology, Adenoma pathology, Biomarkers, Tumor analysis, Integrin beta3 analysis, Thyroid Neoplasms pathology
- Abstract
The identification of vascular invasion in follicular thyroid neoplasms is essential for categorizing lesions as benign (follicular adenomas) or malignant (follicular thyroid carcinomas). Among the histologic criteria diagnostic of true vascular invasion is tumor-cell associated thrombosis, including fibrin deposition and platelet clumping. This study aims to evaluate whether an immunohistochemical stain for the platelet-associated protein CD61 could assist in identifying tumor-associated thromboses and thereby confirm vascular invasion in follicular thyroid neoplasms. Histologic review and CD61 immunostaining of 19 atypical follicular adenomas, 13 non-metastatic follicular thyroid carcinomas, and 11 metastatic follicular thyroid carcinomas was performed. Linear arrays or clustered groups of CD61-expressing intravascular platelets were present in 51% of cases overall, including 54% of follicular thyroid carcinomas and 47% of follicular adenomas, mostly within intracapsular or peritumoral vessels. In three follicular thyroid carcinomas (all with distant metastases), CD61-expressing platelets were present in association with intravascular tumor cells. This finding was not present in adenomas. CD61 staining alone did not distinguish between atypical follicular adenomas, non-metastatic carcinomas, and metastatic carcinomas. When present in association with intravascular tumor cells, however, CD61-expressing platelets may serve as a marker for vascular invasion and aid in the diagnosis of follicular thyroid carcinoma.
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- 2020
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19. Beyond the Variants: Mutational Patterns in Next-Generation Sequencing Data for Cancer Precision Medicine.
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Parilla M and Ritterhouse LL
- Abstract
Massively parallel sequencing, also referred to as "next-generation sequencing" (NGS) provides not only information about simple, single nucleotide alterations, but it can also provide information on complex variations, such as insertions and deletions, copy number alterations, and structural variants. In addition to identifying individual alterations, genome-wide biomarkers can be discerned from somatic cancer NGS data, broadly termed mutational patterns and signatures. This review will focus on several of the most common genome-wide biomarkers such as tumor mutational burden, microsatellite instability, homologous recombination deficiency, and mutational signatures., (Copyright © 2020 Parilla and Ritterhouse.)
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- 2020
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20. Clinical Validation and Implementation of a Measurable Residual Disease Assay for NPM1 in Acute Myeloid Leukemia by Error-Corrected Next-Generation Sequencing.
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Ritterhouse LL, Parilla M, Zhen CJ, Wurst MN, Puranik R, Henderson CM, Joudeh NZ, Hartley MJ, Haridas R, Wanjari P, Furtado LV, Kadri S, and Segal JP
- Subjects
- Biomarkers, Tumor blood, Biomarkers, Tumor genetics, Humans, Leukemia, Myeloid, Acute diagnosis, Limit of Detection, Mutation, Neoplasm, Residual genetics, Nuclear Proteins blood, Nucleophosmin, Recurrence, Sensitivity and Specificity, Sequence Analysis, DNA, High-Throughput Nucleotide Sequencing methods, Leukemia, Myeloid, Acute genetics, Neoplasm, Residual diagnosis, Nuclear Proteins genetics
- Abstract
Background: Nucleophosmin 1 (NPM1) is one of the most commonly mutated genes in acute myeloid leukemia, with mutations observed in approximately 30% of all adult cases. The persistence of NPM1 mutations following chemotherapy is associated with a greater risk of relapse as well as a lower rate of survival, making NPM1 measurable residual disease (MRD) an informative clinical target., Methods: Herein, we have developed a straightforward unique molecular identifier (UMI)-based amplicon next-generation sequencing method for the detection of NPM1-mutated MRD that addresses some of the limitations present in other assays., Results: The NPM1 assay allowed for accurate counting of individual mutant and wild-type molecules down to 0.01% variant allelic frequency. In silico contamination experiments highlighted the ability of this UMI methodology to maximize specificity through dramatic reductions in sequencing/demultiplexing bleed-through error., Conclusion: Performance and clinical utility of the NPM1 MRD assay are established via both validation experiments and analyses of live performance over 1.5 years of routine clinical service.
- Published
- 2019
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21. Kikuchi-Fujimoto Disease in Children: An Important Diagnostic Consideration for Cervical Lymphadenitis.
- Author
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Batton E, Alali M, Hageman JR, Parilla M, and Yu KOA
- Subjects
- Adolescent, Child, Histiocytic Necrotizing Lymphadenitis etiology, Histiocytic Necrotizing Lymphadenitis physiopathology, Humans, Male, Diagnosis, Differential, Histiocytic Necrotizing Lymphadenitis diagnosis
- Abstract
Kikuchi-Fujimoto disease (KFD), or histiocytic necrotizing lymphadenitis, is a rare, benign, and self-limited disease that causes lymphadenopathy and has a characteristic histological appearance. The etiology of this disease is unknown, but a possible infectious trigger has been hypothesized. In the adult population this disease is more common in females; however, in the pediatric population it is more common in males. Descriptions in the pediatric literature are lacking, particularly in the United States. The authors report three cases of pediatric KFD that presented at the same institution in a 9-month time period. All three patients were male and of non-Asian descent who were diagnosed with KFD by histopathologic specimen after presenting with unilateral cervical lymphadenitis. Each patient had additional laboratory evidence of a possible bacterial infection at the time of diagnosis. These three cases highlight the importance of considering KFD early when a pediatric patient presents with unilateral cervical lymphadenitis. The authors discuss the epidemiology, etiology, clinical manifestations, diagnostic approaches, and treatment of KFD. [Pediatr Ann. 2019;48(10):e406-e411.]., (Copyright 2019, SLACK Incorporated.)
- Published
- 2019
- Full Text
- View/download PDF
22. Genetic Underpinnings of Renal Cell Carcinoma With Leiomyomatous Stroma.
- Author
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Parilla M, Alikhan M, Al-Kawaaz M, Patil S, Kadri S, Ritterhouse LL, Segal J, Fitzpatrick C, and Antic T
- Subjects
- Adult, Aged, Biomarkers, Tumor analysis, Carcinoma, Renal Cell chemistry, Carcinoma, Renal Cell pathology, Chicago, Female, Genetic Predisposition to Disease, Humans, Kidney Neoplasms chemistry, Kidney Neoplasms pathology, Leiomyoma chemistry, Leiomyoma pathology, Male, Middle Aged, Phenotype, Stromal Cells chemistry, Biomarkers, Tumor genetics, Carcinoma, Renal Cell genetics, Kidney Neoplasms genetics, Leiomyoma genetics, Stromal Cells pathology
- Abstract
Renal cell carcinoma (RCC) with leiomyomatous stroma is a provisional category of RCC in the 2016 World Health Organization Classification of Tumors of the Urinary System. Microscopic examination of hematoxylin and eosin-stained sections reveals this entity to be well-circumscribed with tubulopapillary growth of cells with clear cytoplasm in a background of leiomyomatous stroma. Herein we describe the genetic features of 15 University of Chicago Medical Center archived cases with hematoxylin and eosin histology matching the provisional diagnosis. Immunohistochemical (IHC) stains revealed 1/15 of these tumors to be clear cell renal cell carcinoma (ccRCC) and 6/15 to be clear cell papillary renal cell carcinoma (ccpRCC), demonstrating the morphologic overlap with these discrete known entities. Interestingly 3/6 of the ccpRCCs had chromosome 18 gain suggesting there may be novel specific genetic changes in ccpRCC with leiomyomatous stroma. Of the remaining 8 tumors with IHC staining patterns that do not fit either ccRCC or ccpRCC only 3 of these had mutations in the recently described TCEB1 gene with concurrent monosomy of chromosome 8. These 3 cases had a somewhat unique IHC pattern that possibly could separate them from the 5 other non-ccRCC/non-ccpRCC cases. This descriptive study, although small, demonstrates the difficulty in applying the current World Health Organization provisional criteria at a single institution with suggestion of an immunohistochemcial panel that may assist in the diagnosis of TCEB1-mutated RCC with leiomyomatous stroma.
- Published
- 2019
- Full Text
- View/download PDF
23. Integrating a Large Next-Generation Sequencing Panel into the Clinical Diagnosis of Gliomas Provides a Comprehensive Platform for Classification from FFPE Tissue or Smear Preparations.
- Author
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Parilla M, Kadri S, Patil SA, Fitzpatrick C, Ritterhouse L, Segal J, Collins J, and Pytel P
- Subjects
- Adult, Brain Neoplasms diagnosis, Cohort Studies, Female, Glioma diagnosis, Humans, Male, Middle Aged, Mutation genetics, Retrospective Studies, Biomarkers, Tumor genetics, Brain Neoplasms classification, Brain Neoplasms genetics, Glioma classification, Glioma genetics, High-Throughput Nucleotide Sequencing methods
- Abstract
The 2016 WHO classification of brain tumors represents a major step towards the integration of molecular data into pathologic diagnoses. Our institution has included massively parallel sequencing technology in the diagnostic work-up of all gliomas since January 2016. The utilized platform successfully identifies copy number variations, individual gene mutations, small insertions and deletions, and selected gene fusions. Herein, we retrospectively review the first 51 glial tumor samples run for clinical purposes using the UCM-OncoPlus platform, a 1213 gene targeted hybrid-capture next generation sequencing (NGS) panel. NGS paired with histomorphology and clinical data allowed for reliable, comprehensive, and cost-effective classification of all the analyzed gliomas (51/51) with minimal tissue required and without the need for additional testing. In addition to detecting all diagnostically relevant mutations according to the 2016 WHO system, our data suggest a large NGS-based platform may improve the accuracy of classifying gliomas beyond the 2016 WHO system, to provide truly personalized diagnostics. Furthermore, this methodology assists in classifying histologically challenging or clinically unusual cases. And, finally, the versatile nature of this testing methodology allows for near effortless expansion as new therapeutic targets and prognostic markers are discovered., (© 2019 American Association of Neuropathologists, Inc. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
24. Plasma exchange for heparin-induced thrombocytopenia in patients on extracorporeal circuits: A challenging case and a survey of the field.
- Author
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Cho JH, Parilla M, Treml A, and Wool GD
- Subjects
- Cardiopulmonary Bypass, Extracorporeal Circulation, Heart-Assist Devices, Hemolysis, Humans, Surveys and Questionnaires, Thrombocytopenia chemically induced, Thrombocytopenia complications, Thrombosis etiology, Heparin adverse effects, Plasma Exchange instrumentation, Plasma Exchange methods, Thrombocytopenia therapy
- Abstract
Current management of heparin-induced thrombocytopenia (HIT) involves prompt discontinuation of all heparin products and concomitant initiation of a direct thrombin or anti-Xa inhibitor for anticoagulation. In the setting of HIT complicated by an urgent need for cardiopulmonary bypass (CPB), the safety and the efficacy of short-term heparin-based anticoagulation after therapeutic plasma exchange (TPE) have been previously demonstrated. Patients with HIT requiring TPE are frequently on extracorporeal circuits (either CPB, extracorporeal membrane oxygenation [ECMO] or external ventricular assist devices [VADs]). Performing TPE in parallel with these circuits involves additional consideration for circuit size, anticoagulant/citrate management, as well as flow rates, and risk of air embolus. We report a case of a patient with HIT on external biventricular assist device (BiVAD) requiring urgent CPB who experienced thrombotic and hemolytic complications related to anticoagulation management around apheresis line placement for TPE. We also present results from a national survey of academic apheresis services regarding specific practices in managing patients with HIT on extracorporeal circuits who require TPE. In addition, we demonstrate the utility of TPE in patients with HIT on extracorporeal circuits and the risks of this procedure and the need to develop practice guidelines., (© 2018 Wiley Periodicals, Inc.)
- Published
- 2019
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25. Genomic Alterations in Undifferentiated Malignant Tumors with Rhabdoid Phenotype and Loss of BRG1 Immunoexpression Identified by Fine Needle Aspirates.
- Author
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Mei L, Alikhan M, Mujacic I, Parilla M, and Antic T
- Subjects
- Aged, Biomarkers, Tumor deficiency, Biopsy, Fine-Needle, DNA Helicases deficiency, DNA Mutational Analysis, Fatal Outcome, Female, Genetic Predisposition to Disease, Humans, Immunohistochemistry, Lung Neoplasms enzymology, Lung Neoplasms pathology, Lung Neoplasms therapy, Male, Middle Aged, Nuclear Proteins deficiency, Phenotype, Predictive Value of Tests, Retrospective Studies, Rhabdoid Tumor enzymology, Rhabdoid Tumor pathology, Rhabdoid Tumor therapy, Submandibular Gland Neoplasms enzymology, Submandibular Gland Neoplasms pathology, Submandibular Gland Neoplasms therapy, Transcription Factors deficiency, Treatment Outcome, Tumor Suppressor Protein p53 genetics, Biomarkers, Tumor genetics, Cell Differentiation, DNA Helicases genetics, Lung Neoplasms genetics, Mutation, Nuclear Proteins genetics, Rhabdoid Tumor genetics, Submandibular Gland Neoplasms genetics, Transcription Factors genetics
- Abstract
Objective: Evidence shows that the switch/sucrose nonfermenting chromatin remodeling complex plays a critical role in DNA repair, cancer progression and dedifferentiation. BRG1 is one of its key catalytic subunits. While the loss of BRG1 expression by immunocytochemistry has been identified in a subset of malignancies arising in various sites with undifferentiated/rhabdoid morphology and poor prognosis, the underlying basis for its loss is unclear., Methods: A retrospective search was conducted in our cytopathology archive for undifferentiated malignant tumors with rhabdoid phenotype and BRG1 loss. Clinical information was obtained from electronic medical records. Next-generation sequencing was performed following macro-dissection of paraffin-embedded cellblock tissue., Results: Three cases were identified; all presented with widely metastatic disease with no previously diagnosed primary malignancy, and subsequently died within 6 months of initial presentation. Cytologically, the aspirates showed dyshesive and undifferentiated cells with rhabdoid features. Extensive immunocytochemical workup demonstrated immunoreactivity with vimentin only and could not establish a specific lineage. BRG1 expression was absent, while INI1 expression was retained. Two cases harbored deleterious mutations in BRG1/SMARCA4. Pathogenic mutations in TP53 were identified in all tumors., Conclusions: BRG1 deficiency reflects underlying mutation in SMARCA4 gene in some but not all cases, suggesting that additional mechanisms may be causing BRG1 silencing. Pathogenic mutations in TP53 in all tumors are consistent with their highly aggressive nature. Recognizing the cytomorphology of this group of neoplasms and confirming their BRG1-deficient status by immunocytochemistry not only has prognostic implications, but may also impart potentially therapeutic value in the near future., (© 2019 S. Karger AG, Basel.)
- Published
- 2019
- Full Text
- View/download PDF
26. Are Sporadic Eosinophilic Solid and Cystic Renal Cell Carcinomas Characterized by Somatic Tuberous Sclerosis Gene Mutations?
- Author
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Parilla M, Kadri S, Patil SA, Ritterhouse L, Segal J, Henriksen KJ, and Antic T
- Subjects
- Adult, Aged, Biopsy, Carcinoma, Renal Cell pathology, DNA Mutational Analysis methods, Eosinophilia pathology, Female, Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing, Humans, Kidney Neoplasms pathology, Neoplasms, Cystic, Mucinous, and Serous pathology, Phenotype, Biomarkers, Tumor genetics, Carcinoma, Renal Cell genetics, Eosinophilia genetics, Kidney Neoplasms genetics, Mutation, Neoplasms, Cystic, Mucinous, and Serous genetics, Tuberous Sclerosis Complex 2 Protein genetics
- Abstract
Eosinophilic solid and cystic renal cell carcinomas (ESC RCC) is a rare, unique tumor type not yet included in the World Health Organization classification of renal neoplasia. Separately, RCCs found in patients with tuberous sclerosis complex (TSC) have recently been categorized into 3 morphologic groups: RCC with a tubulopapillary architecture separated by smooth muscle stroma, chromophobe-like, and eosinophilic-microcytic type. The third classification has been identified in ∼11% of TSC-associated RCC and have histology identical to ESC RCCs. The sporadic form of ESC RCC, not associated with TSC, have only been characterized on the cytogenetic level and the full molecular underpinnings have yet to be examined. Using next-generation sequencing we present 2 cases of sporadic ESC RCC in patients without clinical features of tuberous sclerosis, which demonstrate pathogenic somatic TSC2 gene mutations. These mutations are without other alterations in any other genes associated with RCC, suggesting that sporadic ESC RCC may be characterized by somatic tuberous sclerosis gene mutations (TSC2).
- Published
- 2018
- Full Text
- View/download PDF
27. The thin line between CML and CMML.
- Author
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Parilla M and Venkataraman G
- Subjects
- Female, Humans, Middle Aged, Fusion Proteins, bcr-abl blood, Fusion Proteins, bcr-abl genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive blood, Leukemia, Myelogenous, Chronic, BCR-ABL Positive diagnosis, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Leukemia, Myelomonocytic, Chronic blood, Leukemia, Myelomonocytic, Chronic diagnosis, Leukemia, Myelomonocytic, Chronic genetics, Leukemia, Myelomonocytic, Chronic pathology
- Published
- 2017
- Full Text
- View/download PDF
28. The Effects of Disease Models of Nuclear Actin Polymerization on the Nucleus.
- Author
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Serebryannyy LA, Yuen M, Parilla M, Cooper ST, and de Lanerolle P
- Abstract
Actin plays a crucial role in regulating multiple processes within the nucleus, including transcription and chromatin organization. However, the polymerization state of nuclear actin remains controversial, and there is no evidence for persistent actin filaments in a normal interphase nucleus. Further, several disease pathologies are characterized by polymerization of nuclear actin into stable filaments or rods. These include filaments that stain with phalloidin, resulting from point mutations in skeletal α-actin, detected in the human skeletal disease intranuclear rod myopathy, and cofilin/actin rods that form in response to cellular stressors like heatshock. To further elucidate the effects of these pathological actin structures, we examined the nucleus in both cell culture models as well as isolated human tissues. We find these actin structures alter the distribution of both RNA polymerase II and chromatin. Our data suggest that nuclear actin filaments result in disruption of nuclear organization, which may contribute to the disease pathology.
- Published
- 2016
- Full Text
- View/download PDF
29. Persistent nuclear actin filaments inhibit transcription by RNA polymerase II.
- Author
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Serebryannyy LA, Parilla M, Annibale P, Cruz CM, Laster K, Gratton E, Kudryashov D, Kosak ST, Gottardi CJ, and de Lanerolle P
- Subjects
- Actins metabolism, Animals, COS Cells, Cell Proliferation, Chlorocebus aethiops, Cross-Linking Reagents metabolism, HeLa Cells, Humans, Polymerization, Protein Transport, RNA, Messenger genetics, RNA, Messenger metabolism, Actin Cytoskeleton metabolism, Cell Nucleus metabolism, RNA Polymerase II metabolism, Transcription, Genetic
- Abstract
Actin is abundant in the nucleus and it is clear that nuclear actin has important functions. However, mystery surrounds the absence of classical actin filaments in the nucleus. To address this question, we investigated how polymerizing nuclear actin into persistent nuclear actin filaments affected transcription by RNA polymerase II. Nuclear filaments impaired nuclear actin dynamics by polymerizing and sequestering nuclear actin. Polymerizing actin into stable nuclear filaments disrupted the interaction of actin with RNA polymerase II and correlated with impaired RNA polymerase II localization, dynamics, gene recruitment, and reduced global transcription and cell proliferation. Polymerizing and crosslinking nuclear actin in vitro similarly disrupted the actin-RNA-polymerase-II interaction and inhibited transcription. These data rationalize the general absence of stable actin filaments in mammalian somatic nuclei. They also suggest a dynamic pool of nuclear actin is required for the proper localization and activity of RNA polymerase II., Competing Interests: The authors declare no competing or financial interests., (© 2016. Published by The Company of Biologists Ltd.)
- Published
- 2016
- Full Text
- View/download PDF
30. Transgenic Drosophila for Investigating DUX4 and FRG1, Two Genes Associated with Facioscapulohumeral Muscular Dystrophy (FSHD).
- Author
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Jones TI, Parilla M, and Jones PL
- Subjects
- Amino Acid Sequence, Animals, Animals, Genetically Modified, Cell Nucleus metabolism, Conserved Sequence, Drosophila Proteins chemistry, Drosophila Proteins metabolism, Epistasis, Genetic, Female, Germ Cells metabolism, Humans, Imaginal Discs metabolism, Male, Models, Biological, Molecular Sequence Data, Muscle, Skeletal abnormalities, Muscle, Skeletal metabolism, Phenotype, Drosophila Proteins genetics, Drosophila melanogaster genetics, Genes, Insect, Muscular Dystrophy, Facioscapulohumeral genetics
- Abstract
Facioscapulohumeral muscular dystrophy (FSHD) is typically an adult onset dominant myopathy. Epigenetic changes in the chromosome 4q35 region linked to both forms of FSHD lead to a relaxation of repression and increased somatic expression of DUX4-fl (DUX4-full length), the pathogenic alternative splicing isoform of the DUX4 gene. DUX4-fl encodes a transcription factor expressed in healthy testis and pluripotent stem cells; however, in FSHD, increased levels of DUX4-fl in myogenic cells lead to aberrant regulation of target genes. DUX4-fl has proven difficult to study in vivo; thus, little is known about its normal and pathogenic roles. The endogenous expression of DUX4-fl in FSHD-derived human muscle and myogenic cells is extremely low, exogenous expression of DUX4-fl in somatic cells rapidly induces cytotoxicity, and, due in part to the lack of conservation beyond primate lineages, viable animal models based on DUX4-fl have been difficult to generate. By contrast, the FRG1 (FSHD region gene 1), which is linked to FSHD, is evolutionarily conserved from invertebrates to humans, and has been studied in several model organisms. FRG1 expression is critical for the development of musculature and vasculature, and overexpression of FRG1 produces a myopathic phenotype, yet the normal and pathological functions of FRG1 are not well understood. Interestingly, DUX4 and FRG1 were recently linked when the latter was identified as a direct transcriptional target of DUX4-FL. To better understand the pathways affected in FSHD by DUX4-fl and FRG1, we generated transgenic lines of Drosophila expressing either gene under control of the UAS/GAL4 binary system. Utilizing these lines, we generated screenable phenotypes recapitulating certain known consequences of DUX4-fl or FRG1 overexpression. These transgenic Drosophila lines provide resources to dissect the pathways affected by DUX4-fl or FRG1 in a genetically tractable organism and may provide insight into both muscle development and pathogenic mechanisms in FSHD.
- Published
- 2016
- Full Text
- View/download PDF
31. Histone recognition and nuclear receptor co-activator functions of Drosophila cara mitad, a homolog of the N-terminal portion of mammalian MLL2 and MLL3.
- Author
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Chauhan C, Zraly CB, Parilla M, Diaz MO, and Dingwall AK
- Subjects
- Animals, Chromatin Immunoprecipitation, Drosophila genetics, Genes, Essential genetics, Histone-Lysine N-Methyltransferase metabolism, Histones metabolism, Immunoprecipitation, Methylation, Reverse Transcriptase Polymerase Chain Reaction, Drosophila metabolism, Drosophila Proteins genetics, Drosophila Proteins metabolism, Evolution, Molecular, Gene Expression Regulation genetics, Histone-Lysine N-Methyltransferase genetics, Myeloid-Lymphoid Leukemia Protein genetics, Nuclear Receptor Coactivators genetics, Nuclear Receptor Coactivators metabolism
- Abstract
MLL2 and MLL3 histone lysine methyltransferases are conserved components of COMPASS-like co-activator complexes. In vertebrates, the paralogous MLL2 and MLL3 contain multiple domains required for epigenetic reading and writing of the histone code involved in hormone-stimulated gene programming, including receptor-binding motifs, SET methyltransferase, HMG and PHD domains. The genes encoding MLL2 and MLL3 arose from a common ancestor. Phylogenetic analyses reveal that the ancestral gene underwent a fission event in some Brachycera dipterans, including Drosophila species, creating two independent genes corresponding to the N- and C-terminal portions. In Drosophila, the C-terminal SET domain is encoded by trithorax-related (trr), which is required for hormone-dependent gene activation. We identified the cara mitad (cmi) gene, which encodes the previously undiscovered N-terminal region consisting of PHD and HMG domains and receptor-binding motifs. The cmi gene is essential and its functions are dosage sensitive. CMI associates with TRR, as well as the EcR-USP receptor, and is required for hormone-dependent transcription. Unexpectedly, although the CMI and MLL2 PHDf3 domains could bind histone H3, neither showed preference for trimethylated lysine 4. Genetic tests reveal that cmi is required for proper global trimethylation of H3K4 and that hormone-stimulated transcription requires chromatin binding by CMI, methylation of H3K4 by TRR and demethylation of H3K27 by the demethylase UTX. The evolutionary split of MLL2 into two distinct genes in Drosophila provides important insight into distinct epigenetic functions of conserved readers and writers of the histone code.
- Published
- 2012
- Full Text
- View/download PDF
32. Release of the nonribosomal proteins from the mammalian native 40 S ribosomal subunit by aurintricarboxylic acid.
- Author
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Ayuso-Parilla M, Hirsch CA, and Henshaw EC
- Subjects
- Animals, Benzoates pharmacology, Blood Proteins metabolism, Carbon Isotopes, Cell Fractionation, Cell Line, Centrifugation, Density Gradient, Hemoglobins biosynthesis, Neoplasm Proteins metabolism, Peptide Chain Initiation, Translational drug effects, Peptide Chain Termination, Translational, Phenols pharmacology, Potassium Chloride pharmacology, Protein Binding, Protein Biosynthesis, Rabbits, Reticulocytes drug effects, Ribosomes drug effects, Tritium, Cyclohexanecarboxylic Acids pharmacology, Peptide Initiation Factors, Reticulocytes metabolism, Ribosomes metabolism
- Published
- 1973
33. The ribosome cycle in mammalian protein synthesis. 3. Evidence that the nonribosomal proteins bound to the native smaller subunit are initiation factors.
- Author
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Ayuso-Parilla M, Henshaw EC, and Hirsch CA
- Subjects
- Adenine metabolism, Animals, Carbon Isotopes, Cell Line, Cell-Free System, Centrifugation, Density Gradient, Culture Media, Formates metabolism, Models, Biological, Neoplasm Proteins biosynthesis, Peptide Chain Initiation, Translational, Peptide Chain Termination, Translational, Poly U pharmacology, Potassium Chloride pharmacology, Protein Binding, RNA, Neoplasm biosynthesis, RNA, Transfer metabolism, Ribosomes drug effects, Tritium, Carcinoma, Ehrlich Tumor metabolism, Cytoplasm metabolism, Neoplasm Proteins metabolism, Peptide Initiation Factors, Ribosomes metabolism
- Published
- 1973
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