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  1. Article ; Online: Reader Response: Long-term Effect of Regular Physical Activity and Exercise Habits in Patients With Early Parkinson Disease.

    Grippe, Talyta Cortez / Marras, Connie / Rafferty, Miriam / Lang, Anthony E

    Neurology

    2022  Volume 99, Issue 9, Page(s) 401–402

    MeSH term(s) Exercise ; Habits ; Humans ; Parkinson Disease
    Language English
    Publishing date 2022-06-03
    Publishing country United States
    Document type Journal Article ; Comment
    ZDB-ID 207147-2
    ISSN 1526-632X ; 0028-3878
    ISSN (online) 1526-632X
    ISSN 0028-3878
    DOI 10.1212/WNL.0000000000201127
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Chromatin, cancer and drug therapies.

    Cortez, Connie C / Jones, Peter A

    Mutation research

    2008  Volume 647, Issue 1-2, Page(s) 44–51

    Abstract: The structure and organization of chromatin have attracted a great deal of attention recently because of their implications for the field of epigenetics. DNA methylation and the post-translational modifications that occur on histones can specify ... ...

    Abstract The structure and organization of chromatin have attracted a great deal of attention recently because of their implications for the field of epigenetics. DNA methylation and the post-translational modifications that occur on histones can specify transcriptional competency. During cancer development, tumor suppressor genes become silenced by DNA hypermethylation and chromatin modifiers no longer perform in their usual manner. Current epigenetic therapy has been able to take advantage of the reversibility of these epimutations. Progress has been made in the treatment of hematological malignancies and some solid tumors. As the knowledge of how chromatin regulates gene expression is enhanced, improvements in the treatment of cancer can be made.
    MeSH term(s) Acetylation ; Amino Acid Sequence ; Chromatin/chemistry ; DNA Methylation/drug effects ; Epigenesis, Genetic/drug effects ; Histone Deacetylase Inhibitors ; Histones/metabolism ; Humans ; Neoplasms/drug therapy ; Neoplasms/genetics
    Chemical Substances Chromatin ; Histone Deacetylase Inhibitors ; Histones
    Language English
    Publishing date 2008-07-22
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 206607-5
    ISSN 1873-135X ; 0027-5107 ; 1383-5718 ; 0165-1110 ; 0165-1161 ; 0165-7992 ; 0921-8777 ; 0165-1218 ; 1383-5726 ; 0167-8817 ; 0921-8734 ; 1383-5742
    ISSN (online) 1873-135X
    ISSN 0027-5107 ; 1383-5718 ; 0165-1110 ; 0165-1161 ; 0165-7992 ; 0921-8777 ; 0165-1218 ; 1383-5726 ; 0167-8817 ; 0921-8734 ; 1383-5742
    DOI 10.1016/j.mrfmmm.2008.07.006
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: DNA methylation directly silences genes with non-CpG island promoters and establishes a nucleosome occupied promoter.

    Han, Han / Cortez, Connie C / Yang, Xiaojing / Nichols, Peter W / Jones, Peter A / Liang, Gangning

    Human molecular genetics

    2011  Volume 20, Issue 22, Page(s) 4299–4310

    Abstract: Despite the fact that 45% of all human gene promoters do not contain CpG islands, the role of DNA methylation in control of non-CpG island promoters is controversial and its relevance in normal and pathological processes is poorly understood. Among the ... ...

    Abstract Despite the fact that 45% of all human gene promoters do not contain CpG islands, the role of DNA methylation in control of non-CpG island promoters is controversial and its relevance in normal and pathological processes is poorly understood. Among the few studies which investigate the correlation between DNA methylation and expression of genes with non-CpG island promoters, the majority do not support the view that DNA methylation directly leads to transcription silencing of these genes. Our reporter assays and gene reactivation by 5-aza-2'-deoxycytidine, a DNA demethylating agent, show that DNA methylation occurring at CpG poor LAMB3 promoter and RUNX3 promoter 1(RUNX3 P1) can directly lead to transcriptional silencing in cells competent to express these genes in vitro. Using Nucleosome Occupancy Methylome- Sequencing, NOMe-Seq, a single-molecule, high-resolution nucleosome positioning assay, we demonstrate that active, but not inactive, non-CpG island promoters display a nucleosome-depleted region (NDR) immediately upstream of the transcription start site (TSS). Furthermore, using NOMe-Seq and clonal analysis, we show that in RUNX3 expressing 623 melanoma cells, RUNX3 P1 has two distinct chromatin configurations: one is unmethylated with an NDR upstream of the TSS; another is methylated and nucleosome occupied, indicating that RUNX3 P1 is monoallelically methylated. Together, these results demonstrate that the epigenetic signatures comprising DNA methylation, histone marks and nucleosome occupancy of non-CpG island promoters are almost identical to CpG island promoters, suggesting that aberrant methylation patterns of non-CpG island promoters may also contribute to tumorigenesis and should therefore be included in analyses of cancer epigenetics.
    MeSH term(s) Cell Adhesion Molecules/genetics ; Cell Line, Tumor ; Cells, Cultured ; Chromatin Immunoprecipitation ; Core Binding Factor Alpha 3 Subunit/genetics ; CpG Islands/genetics ; DNA Methylation/drug effects ; DNA Methylation/genetics ; DNA Methylation/physiology ; Deoxycytidine/pharmacology ; Gene Silencing/physiology ; Humans ; Nucleosomes/metabolism ; Promoter Regions, Genetic/genetics ; Real-Time Polymerase Chain Reaction ; Kalinin
    Chemical Substances Cell Adhesion Molecules ; Core Binding Factor Alpha 3 Subunit ; Nucleosomes ; Deoxycytidine (0W860991D6)
    Language English
    Publishing date 2011-08-11
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1108742-0
    ISSN 1460-2083 ; 0964-6906
    ISSN (online) 1460-2083
    ISSN 0964-6906
    DOI 10.1093/hmg/ddr356
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: ERG overexpression and PTEN status predict capsular penetration in prostate carcinoma.

    Nagle, Raymond B / Algotar, Amit M / Cortez, Connie C / Smith, Katherine / Jones, Carol / Sathyanarayana, Ubaradka G / Yun, Steven / Riley, Janice / Nagy, Dea / Dittamore, Ryan / Dalkin, Bruce / Brosh, Laura / Pestano, Gary

    The Prostate

    2013  Volume 73, Issue 11, Page(s) 1233–1240

    Abstract: Background: This study examines the combined effect of two common genetic alterations, ERG and PTEN, in prostate carcinoma progression.: Methods: Prostate tissue from 90 patients having unilateral capsular penetrating lesions, and a contra-lateral ... ...

    Abstract Background: This study examines the combined effect of two common genetic alterations, ERG and PTEN, in prostate carcinoma progression.
    Methods: Prostate tissue from 90 patients having unilateral capsular penetrating lesions, and a contra-lateral organ confined second lesion, were examined by immunohistochemistry for the expression of the TMPRSS2:ERG transformation product ERG and the loss of expression of PTEN, a powerful phosphatase inhibiting the PI3 kinase pathway. Multivariate logistic regression was carried out to analyze the data.
    Results: After adjusting for Gleason score, the odds of having capsular penetration were 5.19 times higher (P = 0.015) for ERG+/PTEN- group as compared to the wild type (ERG-/PTEN+).
    Conclusions: This study presents the first evidence that ERG over expression and PTEN deletion is associated with greater risk of capsular penetration. Although further studies are needed, these results have the potential to change clinical assessment for prostate cancer.
    MeSH term(s) Aged ; Biomarkers, Tumor/biosynthesis ; Biomarkers, Tumor/genetics ; Follow-Up Studies ; Gene Deletion ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; Middle Aged ; Neoplasm Invasiveness/diagnosis ; Neoplasm Invasiveness/genetics ; PTEN Phosphohydrolase/biosynthesis ; PTEN Phosphohydrolase/genetics ; Predictive Value of Tests ; Prostatic Neoplasms/diagnosis ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/metabolism ; Trans-Activators/biosynthesis ; Trans-Activators/genetics ; Transcriptional Regulator ERG
    Chemical Substances Biomarkers, Tumor ; ERG protein, human ; Trans-Activators ; Transcriptional Regulator ERG ; PTEN Phosphohydrolase (EC 3.1.3.67) ; PTEN protein, human (EC 3.1.3.67)
    Language English
    Publishing date 2013-05-07
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 604707-5
    ISSN 1097-0045 ; 0270-4137
    ISSN (online) 1097-0045
    ISSN 0270-4137
    DOI 10.1002/pros.22675
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: DZNep is a global histone methylation inhibitor that reactivates developmental genes not silenced by DNA methylation.

    Miranda, Tina Branscombe / Cortez, Connie C / Yoo, Christine B / Liang, Gangning / Abe, Masanobu / Kelly, Theresa K / Marquez, Victor E / Jones, Peter A

    Molecular cancer therapeutics

    2009  Volume 8, Issue 6, Page(s) 1579–1588

    Abstract: DNA methylation, histone modifications, and nucleosomal occupancy collaborate to cause silencing of tumor-related genes in cancer. The development of drugs that target these processes is therefore important for cancer therapy. Inhibitors of DNA ... ...

    Abstract DNA methylation, histone modifications, and nucleosomal occupancy collaborate to cause silencing of tumor-related genes in cancer. The development of drugs that target these processes is therefore important for cancer therapy. Inhibitors of DNA methylation and histone deacetylation have been approved by the Food and Drug Administration for treatment of hematologic malignancies. However, drugs that target other mechanisms still need to be developed. Recently, 3-deazaneplanocin A (DZNep) was reported to selectively inhibit trimethylation of lysine 27 on histone H3 (H3K27me3) and lysine 20 on histone H4 (H4K20me3) as well as reactivate silenced genes in cancer cells. This finding opens the door to the pharmacologic inhibition of histone methylation. We therefore wanted to further study the mechanism of action of DZNep in cancer cells. Western blot analysis shows that DZNep globally inhibits histone methylation and is not selective. Two other drugs, sinefungin and adenosine dialdehyde, have similar effects as DZNep on H3K27me3. Intriguingly, chromatin immunoprecipitation of various histone modifications and microarray analysis show that DZNep acts through a different pathway than 5-aza-2'-deoxycytidine, a DNA methyltransferase inhibitor. These observations give us interesting insight into how chromatin structure affects gene expression. We also determined the kinetics of gene activation to understand if the induced changes were somatically heritable. We found that upon removal of DZNep, gene expression is reduced to its original state. This suggests that there is a homeostatic mechanism that returns the histone modifications to their "ground state" after DZNep treatment. Our data show the strong need for further development of histone methylation inhibitors.
    MeSH term(s) Adenosine/analogs & derivatives ; Adenosine/chemistry ; Adenosine/pharmacology ; Azacitidine/analogs & derivatives ; Azacitidine/chemistry ; Azacitidine/pharmacology ; Blotting, Western ; Cell Line ; Cell Line, Tumor ; DNA Methylation/drug effects ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Decitabine ; Enhancer of Zeste Homolog 2 Protein ; Enzyme Inhibitors/pharmacology ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic/drug effects ; Histones/metabolism ; Humans ; Keratin-7/genetics ; Keratin-7/metabolism ; Methylation/drug effects ; Molecular Structure ; Oligonucleotide Array Sequence Analysis ; Polycomb Repressive Complex 2 ; Reverse Transcriptase Polymerase Chain Reaction ; Transcription Factors/genetics ; Transcription Factors/metabolism
    Chemical Substances DNA-Binding Proteins ; Enzyme Inhibitors ; Histones ; KRT7 protein, human ; Keratin-7 ; Transcription Factors ; 3-deazaneplanocin (544SH4020S) ; Decitabine (776B62CQ27) ; EZH2 protein, human (EC 2.1.1.43) ; Enhancer of Zeste Homolog 2 Protein (EC 2.1.1.43) ; Polycomb Repressive Complex 2 (EC 2.1.1.43) ; Adenosine (K72T3FS567) ; Azacitidine (M801H13NRU) ; sinefungin (W2U467CIIL)
    Language English
    Publishing date 2009-06-09
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2063563-1
    ISSN 1538-8514 ; 1535-7163
    ISSN (online) 1538-8514
    ISSN 1535-7163
    DOI 10.1158/1535-7163.MCT-09-0013
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Perioperative thrombelastography serves as an important assessment tool of transfusion requirements during liver transplantation.

    Graff, Justin T / Cortez, Alexander R / Dhar, Vikrom K / Wakefield, Connor / Cuffy, Madison C / Shah, Shimul A / Goodman, Michael D

    Surgery open science

    2020  Volume 2, Issue 2, Page(s) 70–74

    Abstract: Background: Thrombelastography has become increasingly used in liver transplantation. The implications of thrombelastography at various stages of liver transplantation, however, remain poorly understood. Our goal was to examine thrombelastography-based ... ...

    Abstract Background: Thrombelastography has become increasingly used in liver transplantation. The implications of thrombelastography at various stages of liver transplantation, however, remain poorly understood. Our goal was to examine thrombelastography-based coagulopathy profiles in liver transplantation and determine whether preoperative thrombelastography is predictive of transfusion requirements perioperatively.
    Methods: A retrospective review of 364 liver transplantations from January 2013 to May 2017 at a single institution was performed. Patients were categorized as hypocoagulable or nonhypocoagulable based on their preoperative thrombelastography profile. The primary outcome was intraoperative transfusion requirements.
    Results: Of patients undergoing liver transplantation, 47% (
    Conclusion: Coagulation abnormalities are common among liver transplantation patients and can be identified using thrombelastography. Identification of a patient's coagulation state preoperatively aids in guiding transfusion during liver transplantation. This work serves to better direct clinicians during major surgery to improve perioperative resource utilization. Future prospective work should aim to identify specific thrombelastography values that may predict transfusion requirements.
    Language English
    Publishing date 2020-01-23
    Publishing country United States
    Document type Journal Article
    ISSN 2589-8450
    ISSN (online) 2589-8450
    DOI 10.1016/j.sopen.2019.12.004
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: RUNX3 methylation reveals that bladder tumors are older in patients with a history of smoking.

    Wolff, Erika M / Liang, Gangning / Cortez, Connie C / Tsai, Yvonne C / Castelao, J Esteban / Cortessis, Victoria K / Tsao-Wei, Denice D / Groshen, Susan / Jones, Peter A

    Cancer research

    2008  Volume 68, Issue 15, Page(s) 6208–6214

    Abstract: Exposure to tobacco smoke is associated with increased DNA methylation at certain genes in both lung and bladder tumors. We sought to identify interactions in bladder cancer between DNA methylation and a history of smoking, along with any possible effect ...

    Abstract Exposure to tobacco smoke is associated with increased DNA methylation at certain genes in both lung and bladder tumors. We sought to identify interactions in bladder cancer between DNA methylation and a history of smoking, along with any possible effect of aging. We measured DNA methylation in 342 transitional cell carcinoma tumors at BCL2, PTGS2 (COX2), DAPK, CDH1 (ECAD), EDNRB, RASSF1A, RUNX3, TERT, and TIMP3. The prevalence of methylation at RUNX3, a polycomb target gene, increased as a function of age at diagnosis (P = 0.031) and a history of smoking (P = 0.015). RUNX3 methylation also preceded methylation at the other eight genes (P < 0.001). It has been proposed that DNA methylation patterns constitute a "molecular clock" and can be used to determine the "age" of normal tissues (i.e., the number of times the cells have divided). Because RUNX3 methylation increases with age, is not present in normal urothelium, and occurs early in tumorigenesis, it can be used for the first time as a molecular clock to determine the age of a bladder tumor. Doing so reveals that tumors from smokers are "older" than tumors from nonsmokers (P = 0.009) due to tumors in smokers either initiating earlier or undergoing more rapid cell divisions. Because RUNX3 methylation is acquired early on in tumorigenesis, then its detection in biopsy or urine specimens could provide a marker to screen cigarette smokers long before any symptoms of bladder cancer are present.
    MeSH term(s) Adult ; Aged ; Base Sequence ; Core Binding Factor Alpha 3 Subunit/genetics ; DNA Methylation ; DNA Primers ; Female ; Humans ; Male ; Middle Aged ; Smoking/genetics ; Urinary Bladder Neoplasms/genetics ; Urinary Bladder Neoplasms/pathology
    Chemical Substances Core Binding Factor Alpha 3 Subunit ; DNA Primers ; Runx3 protein, human
    Language English
    Publishing date 2008-08-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-07-6616
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  8. Article: Identification of DNMT1 (DNA methyltransferase 1) hypomorphs in somatic knockouts suggests an essential role for DNMT1 in cell survival.

    Egger, Gerda / Jeong, Shinwu / Escobar, Sonia G / Cortez, Connie C / Li, Tony W H / Saito, Yoshimasa / Yoo, Christine B / Jones, Peter A / Liang, Gangning

    Proceedings of the National Academy of Sciences of the United States of America

    2006  Volume 103, Issue 38, Page(s) 14080–14085

    Abstract: ... but preserved the catalytic C-terminal domain, was present at different levels in all DNMT1 single-knockout and ...

    Abstract Previous studies have shown that DNA methyltransferase (Dnmt) 1 is required for maintenance of bulk DNA methylation and is essential for mouse development. However, somatic disruption of DNMT1 in the human cancer cell line HCT116 was not lethal and caused only minor decreases in methylation. Here, we report the identification of a truncated DNMT1 protein, which was generated by the disruption of DNMT1 in HCT116 cells. The truncated protein, which had parts of the regulatory N-terminal domain deleted but preserved the catalytic C-terminal domain, was present at different levels in all DNMT1 single-knockout and DNMT1/DNMT3b double-knockout cell lines tested and retained hemimethylase activity. DNMT1 RNAi resulted in decreased cell viability in WT and knockout cells and further loss of DNA methylation in DNMT1 knockout cells. Furthermore, we observed a delay in methylation after replication and an increase in hemimethylation of specific CpG sites in cells expressing the truncated protein. Remethylation studies after drug-induced hypomethylation suggest a putative role of DNMT1 in the de novo methylation of a subtelomeric repeat, D4Z4, which is lost in cells lacking full-length DNMT1. Our data suggest that DNMT1 might be essential for maintenance of DNA methylation, proliferation, and survival of cancer cells.
    MeSH term(s) Animals ; Azacitidine/analogs & derivatives ; Azacitidine/metabolism ; Cell Line ; Cell Survival ; DNA (Cytosine-5-)-Methyltransferase 1 ; DNA (Cytosine-5-)-Methyltransferases/genetics ; DNA (Cytosine-5-)-Methyltransferases/metabolism ; DNA Methylation ; DNA Modification Methylases/antagonists & inhibitors ; Enzyme Inhibitors/metabolism ; Genetic Engineering ; Humans ; Mice ; RNA Interference
    Chemical Substances Enzyme Inhibitors ; decitabine (776B62CQ27) ; DNA Modification Methylases (EC 2.1.1.-) ; DNA (Cytosine-5-)-Methyltransferase 1 (EC 2.1.1.37) ; DNA (Cytosine-5-)-Methyltransferases (EC 2.1.1.37) ; DNMT1 protein, human (EC 2.1.1.37) ; Dnmt1 protein, mouse (EC 2.1.1.37) ; Azacitidine (M801H13NRU)
    Language English
    Publishing date 2006-09-19
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.0604602103
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  9. Article ; Online: Do Internal or External Characteristics More Reliably Predict Burnout in Resident Physicians: A Multi-institutional Study.

    Mullins, C Haddon / Gleason, Frank / Wood, Tara / Baker, Samantha J / Cortez, Alexander R / Lovasik, Brendan / Sandhu, Gurjit / Cooper, Amanda / Hildreth, Amy N / Simmons, Jon D / Delman, Keith A / Lindeman, Brenessa

    Journal of surgical education

    2020  Volume 77, Issue 6, Page(s) e86–e93

    Abstract: ... Affective Mindfulness Scale, 2-Item Connor-Davidson Resilience Scale, Utrecht Work Engagement Scale, and Job ...

    Abstract Introduction: Surgical residents have been shown to experience high rates of burnout. Whether this is influenced predominately by intrinsic characteristics, external factors, or is multifactorial has not been well studied. The aim of this study was to explore the relationship between these elements and burnout. We hypothesized that residents with higher emotional intelligence scores, greater resilience and mindfulness, and better work environments would experience lower rates of burnout.
    Methods: General surgery residents at 7 sites in the US were invited to complete an electronic survey in 2019 that included the 2-item Maslach Burnout Inventory, Brief Emotional Intelligence Scale, Revised Cognitive and Affective Mindfulness Scale, 2-Item Connor-Davidson Resilience Scale, Utrecht Work Engagement Scale, and Job Resources scale of the Job Demands-Resources Questionnaire. Individual constructs were assessed for association with burnout, using multivariable logistic regression models. Residents' scores were evaluated in aggregate, in groups according to demographic characteristics, and by site.
    Results: Of 284 residents, 164 completed the survey (response rate 58%). A total of 71% of respondents were at high risk for burnout, with sites ranging from 57% to 85% (p = 0.49). Burnout rates demonstrated no significant difference across gender, PGY level, and respondent age. On bivariate model, no demographic variables were found to be associated with burnout, but the internal characteristics of emotional intelligence, resilience and mindfulness, and the external characteristics of work engagement and job resources were each found to be protective against burnout (p < 0.001 for all). However, multivariable models examining internal and external characteristics found that no internal characteristics were associated with burnout, while job resources (coeff. -1.0, p-value <0.001) and work engagement (coeff. -0.76, p-value 0.032) were significantly protective factors. Rates of engagement overall were high, particularly with respect to work "dedication."
    Conclusions: A majority of residents at multiple institutions were at high risk for burnout during the study period. Improved work engagement and job resources were found to be more strongly associated with decreased burnout rates when compared to internal characteristics. Although surgical residents appear to already be highly engaged in their work, programs should continue to explore ways to increase job resources, and further research should be aimed at elucidating the mediating effect of internal characteristics on these external factors.
    MeSH term(s) Burnout, Professional/epidemiology ; Emotional Intelligence ; Humans ; Internship and Residency ; Mindfulness ; Physicians ; Surveys and Questionnaires
    Language English
    Publishing date 2020-10-17
    Publishing country United States
    Document type Journal Article ; Multicenter Study
    ZDB-ID 2277538-9
    ISSN 1878-7452 ; 1931-7204
    ISSN (online) 1878-7452
    ISSN 1931-7204
    DOI 10.1016/j.jsurg.2020.09.024
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  10. Article ; Online: Novel dual-color immunohistochemical methods for detecting ERG-PTEN and ERG-SPINK1 status in prostate carcinoma.

    Bhalla, Ritu / Kunju, Lakshmi P / Tomlins, Scott A / Christopherson, Kelly / Cortez, Connie / Carskadon, Shannon / Siddiqui, Javed / Park, Kyung / Mosquera, Juan Miguel / Pestano, Gary A / Rubin, Mark A / Chinnaiyan, Arul M / Palanisamy, Nallasivam

    Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc

    2013  Volume 26, Issue 6, Page(s) 835–848

    Abstract: Identification of new molecular markers has led to the molecular classification of prostate cancer based on driving genetic lesions. The translation of these discoveries for clinical use necessitates the development of simple, reliable and rapid ... ...

    Abstract Identification of new molecular markers has led to the molecular classification of prostate cancer based on driving genetic lesions. The translation of these discoveries for clinical use necessitates the development of simple, reliable and rapid detection systems to screen patients for specific molecular aberrations. We developed two dual-color immunohistochemistry-based assays for the simultaneous assessment of ERG-PTEN and ERG-SPINK1 in prostate cancer. A total of 232 cases from 184 localized and 48 metastatic prostate cancers were evaluated for ERG-PTEN and 284 cases from 228 localized and 56 metastatic prostate cancers were evaluated for ERG-SPINK1. Of the 232 cases evaluated for ERG-PTEN, 81 (35%) ERG-positive and 77 (33%) PTEN-deleted cases were identified. Of the 81 ERG-positive cases, PTEN loss was confirmed in 35 (15%) cases by fluorescence in situ hybridization (FISH). PTEN status was concordant in 203 cases (sensitivity 90% and specificity 87%; P<0.0001) by both immunohistochemisty and FISH; however, immunohistochemisty could not distinguish between heterozygous and homozygous deletion status of PTEN. Of the 284 cases evaluated for ERG-SPINK1, 111 (39%) cases were positive for ERG. In the remaining 173 ERG-negative cases, SPINK1 was positive in 26 (9%) cases. SPINK1 expression was found to be mutually exclusive with ERG expression; however, we identified two cases, of which one showed concomitant expression of ERG and SPINK1 in the same tumor foci, and in the second case ERG and SPINK1 were seen in two independent foci of the same tumor nodule. Unlike the homogenous ERG staining in cancer tissues, heterogeneous SPINK1 staining was observed in the majority of the cases. Further studies are required to understand the molecular heterogeneity of cases with concomitant ERG-SPINK1 expression. Automated dual ERG-PTEN and ERG-SPINK1 immunohistochemisty assays are simple, reliable and portable across study sites for the simultaneous assessment of these proteins in prostate cancer.
    MeSH term(s) Biomarkers, Tumor/analysis ; Biomarkers, Tumor/genetics ; Carcinoma/chemistry ; Carcinoma/secondary ; Carrier Proteins/analysis ; Gene Deletion ; Heterozygote ; Homozygote ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Male ; Oncogene Proteins, Fusion/analysis ; Oncogene Proteins, Fusion/genetics ; PTEN Phosphohydrolase/analysis ; PTEN Phosphohydrolase/genetics ; Predictive Value of Tests ; Prostatic Neoplasms/chemistry ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/pathology ; Tissue Array Analysis ; Trans-Activators/analysis ; Transcriptional Regulator ERG ; Trypsin Inhibitor, Kazal Pancreatic
    Chemical Substances Biomarkers, Tumor ; Carrier Proteins ; ERG protein, human ; Oncogene Proteins, Fusion ; SPINK1 protein, human ; Trans-Activators ; Transcriptional Regulator ERG ; Trypsin Inhibitor, Kazal Pancreatic (50936-63-5) ; PTEN Phosphohydrolase (EC 3.1.3.67) ; PTEN protein, human (EC 3.1.3.67)
    Language English
    Publishing date 2013-01-25
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 645073-8
    ISSN 1530-0285 ; 0893-3952
    ISSN (online) 1530-0285
    ISSN 0893-3952
    DOI 10.1038/modpathol.2012.234
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