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  1. Article ; Online: Meta-analysis of the robustness of COVID-19 diagnostic kit performance during the early pandemic

    George J Netto / Chandrakumar Shanmugam / Michael Behring / Vishwas Luthra / Sixto M Leal / Sooryanarayana Varambally / Upender Manne

    BMJ Open, Vol 12, Iss

    2022  Volume 4

    Keywords Medicine ; R
    Language English
    Publishing date 2022-04-01T00:00:00Z
    Publisher BMJ Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Androgen Receptor Signaling Induces Cisplatin Resistance via Down-Regulating GULP1 Expression in Bladder Cancer

    Yuki Teramoto / Guiyang Jiang / Takuro Goto / Taichi Mizushima / Yujiro Nagata / George J. Netto / Hiroshi Miyamoto

    International Journal of Molecular Sciences, Vol 22, Iss 10030, p

    2021  Volume 10030

    Abstract: The underlying molecular mechanisms of resistance to cisplatin-based systemic chemotherapy in bladder cancer patients remain to be elucidated, while the link between androgen receptor (AR) activity and chemosensitivity in urothelial cancer has been ... ...

    Abstract The underlying molecular mechanisms of resistance to cisplatin-based systemic chemotherapy in bladder cancer patients remain to be elucidated, while the link between androgen receptor (AR) activity and chemosensitivity in urothelial cancer has been implicated. Our DNA microarray analysis in control vs. AR knockdown bladder cancer lines identified GULP1 as a potential target of AR signaling. We herein determined the relationship between AR activity and GULP1 expression in bladder cancer cells and then assessed the functional role of GULP1 in cisplatin sensitivity. Androgen treatment in AR-positive cells or AR overexpression in AR-negative cells considerably reduced the levels of GULP1 expression. Chromatin immunoprecipitation further showed direct interaction of AR with the promoter region of GULP1. Meanwhile, GULP1 knockdown sublines were significantly more resistant to cisplatin treatment compared with respective controls. GULP1 knockdown also resulted in a significant decrease in apoptosis, as well as a significant increase in G2/M phases, when treated with cisplatin. In addition, GULP1 was immunoreactive in 74% of muscle-invasive bladder cancers from patients who had subsequently undergone neoadjuvant chemotherapy, including 53% of responders showing moderate (2+)/strong (3+) expression vs. 23% of non-responders showing 2+/3+ expression ( P = 0.044). These findings indicate that GULP1 represents a key downstream effector of AR signaling in enhancing sensitivity to cisplatin treatment.
    Keywords androgen receptor ; chemoresistance ; cisplatin ; immunohistochemistry ; urothelial cancer ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 616
    Language English
    Publishing date 2021-09-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Molecular Diagnostics for Precision Medicine in Colorectal Cancer

    Guoli Chen / Zhaohai Yang / James R. Eshleman / George J. Netto / Ming-Tseh Lin

    BioMed Research International, Vol

    Current Status and Future Perspective

    2016  Volume 2016

    Abstract: Precision medicine, a concept that has recently emerged and has been widely discussed, emphasizes tailoring medical care to individuals largely based on information acquired from molecular diagnostic testing. As a vital aspect of precision cancer ... ...

    Abstract Precision medicine, a concept that has recently emerged and has been widely discussed, emphasizes tailoring medical care to individuals largely based on information acquired from molecular diagnostic testing. As a vital aspect of precision cancer medicine, targeted therapy has been proven to be efficacious and less toxic for cancer treatment. Colorectal cancer (CRC) is one of the most common cancers and among the leading causes for cancer related deaths in the United States and worldwide. By far, CRC has been one of the most successful examples in the field of precision cancer medicine, applying molecular tests to guide targeted therapy. In this review, we summarize the current guidelines for anti-EGFR therapy, revisit the roles of pathologists in an era of precision cancer medicine, demonstrate the transition from traditional “one test-one drug” assays to multiplex assays, especially by using next-generation sequencing platforms in the clinical diagnostic laboratories, and discuss the future perspectives of tumor heterogeneity associated with anti-EGFR resistance and immune checkpoint blockage therapy in CRC.
    Keywords Medicine ; R
    Subject code 616 ; 610
    Language English
    Publishing date 2016-01-01T00:00:00Z
    Publisher Hindawi Limited
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: ARID1A-deficient bladder cancer is dependent on PI3K signaling and sensitive to EZH2 and PI3K inhibitors

    Hasibur Rehman / Darshan S. Chandrashekar / Chakravarthi Balabhadrapatruni / Saroj Nepal / Sai Akshaya Hodigere Balasubramanya / Abigail K. Shelton / Kasey R. Skinner / Ai-Hong Ma / Ting Rao / Sumit Agarwal / Marie-Lisa Eich / Alyncia D. Robinson / Gurudatta Naik / Upender Manne / George J. Netto / C. Ryan Miller / Chong-xian Pan / Guru Sonpavde / Sooryanarayana Varambally /
    James E. Ferguson III

    JCI Insight, Vol 7, Iss

    2022  Volume 16

    Abstract: Metastatic urothelial carcinoma is generally incurable with current systemic therapies. Chromatin modifiers are frequently mutated in bladder cancer, with ARID1A-inactivating mutations present in about 20% of tumors. EZH2, a histone methyltransferase, ... ...

    Abstract Metastatic urothelial carcinoma is generally incurable with current systemic therapies. Chromatin modifiers are frequently mutated in bladder cancer, with ARID1A-inactivating mutations present in about 20% of tumors. EZH2, a histone methyltransferase, acts as an oncogene that functionally opposes ARID1A. In addition, PI3K signaling is activated in more than 20% of bladder cancers. Using a combination of in vitro and in vivo data, including patient-derived xenografts, we show that ARID1A-mutant tumors were more sensitive to EZH2 inhibition than ARID1A WT tumors. Mechanistic studies revealed that (a) ARID1A deficiency results in a dependency on PI3K/AKT/mTOR signaling via upregulation of a noncanonical PI3K regulatory subunit, PIK3R3, and downregulation of MAPK signaling and (b) EZH2 inhibitor sensitivity is due to upregulation of PIK3IP1, a protein inhibitor of PI3K signaling. We show that PIK3IP1 inhibited PI3K signaling by inducing proteasomal degradation of PIK3R3. Furthermore, ARID1A-deficient bladder cancer was sensitive to combination therapies with EZH2 and PI3K inhibitors in a synergistic manner. Thus, our studies suggest that bladder cancers with ARID1A mutations can be treated with inhibitors of EZH2 and/or PI3K and revealed mechanistic insights into the role of noncanonical PI3K constituents in bladder cancer biology.
    Keywords Oncology ; Medicine ; R
    Subject code 616
    Language English
    Publishing date 2022-08-01T00:00:00Z
    Publisher American Society for Clinical investigation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Expression of Nectin-4 and PD-L1 in Upper Tract Urothelial Carcinoma

    Eisuke Tomiyama / Kazutoshi Fujita / Maria Del Carmen Rodriguez Pena / Diana Taheri / Eri Banno / Taigo Kato / Koji Hatano / Atsunari Kawashima / Takeshi Ujike / Motohide Uemura / Tetsuya Takao / Seiji Yamaguchi / Hiroaki Fushimi / Kazuhiro Yoshimura / Hirotsugu Uemura / George J. Netto / Norio Nonomura

    International Journal of Molecular Sciences, Vol 21, Iss 5390, p

    2020  Volume 5390

    Abstract: Enfortumab vedotin is a novel antibody–drug conjugate targeting Nectin-4, which is highly expressed in urothelial carcinoma. However, the expression status of Nectin-4 in upper tract urothelial carcinoma (UTUC) remains unclear. The relationship between ... ...

    Abstract Enfortumab vedotin is a novel antibody–drug conjugate targeting Nectin-4, which is highly expressed in urothelial carcinoma. However, the expression status of Nectin-4 in upper tract urothelial carcinoma (UTUC) remains unclear. The relationship between Nectin-4 and Programmed Death Ligand 1 (PD-L1) in UTUC is also ambiguous. We performed immunohistochemical analysis of 99 UTUC tissue microarray to assess the expression of Nectin-4 and PD-L1 in UTUC. Nectin-4-positivity was detected in 65 (65.7%) samples, and PD-L1 was detected in 24 (24.2%) samples. There was no correlation between the expression of Nectin-4 and PD-L1. Patients with strong Nectin-4-expressing tumors had a significantly higher risk of progression ( p = 0.031) and cancer-specific mortality ( p = 0.036). Strong Nectin-4 expression was also an independent predictor of disease progression in the high-risk group (pT3 ≤ or presence of lymphovascular invasion or lymph node metastasis) (Hazard ratio, 3.32 [95% confidence interval, 1.20–7.98; p = 0.027]). In conclusion, we demonstrated that Nectin-4 expression rate in UTUC was 65.7% and independent of PD-L1 expression. Strong Nectin-4 expression was associated with worse progression-free survival in high-risk UTUC. These findings suggested that enfortumab vedotin may be effective in a broad range of patients with UTUC, regardless of PD-L1 expression.
    Keywords Nectin-4 ; Programmed Death Ligand 1 ; upper tract urothelial carcinoma ; enfortumab vedotin ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 616
    Language English
    Publishing date 2020-07-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Global 5-Hydroxymethylcytosine Levels Are Profoundly Reduced in Multiple Genitourinary Malignancies.

    Enrico Munari / Alcides Chaux / Ajay M Vaghasia / Diana Taheri / Sarah Karram / Stephania M Bezerra / Nilda Gonzalez Roibon / William G Nelson / Srinivasan Yegnasubramanian / George J Netto / Michael C Haffner

    PLoS ONE, Vol 11, Iss 1, p e

    2016  Volume 0146302

    Abstract: Solid tumors are characterized by a plethora of epigenetic changes. In particular, patterns methylation of cytosines at the 5-position (5mC) in the context of CpGs are frequently altered in tumors. Recent evidence suggests that 5mC can get converted to 5- ...

    Abstract Solid tumors are characterized by a plethora of epigenetic changes. In particular, patterns methylation of cytosines at the 5-position (5mC) in the context of CpGs are frequently altered in tumors. Recent evidence suggests that 5mC can get converted to 5-hydroxylmethylcytosine (5hmC) in an enzymatic process involving ten eleven translocation (TET) protein family members, and this process appears to be important in facilitating plasticity of cytosine methylation. Here we evaluated the global levels of 5hmC using a validated immunohistochemical staining method in a large series of clear cell renal cell carcinoma (n = 111), urothelial cell carcinoma (n = 55) and testicular germ cell tumors (n = 84) and matched adjacent benign tissues. Whereas tumor-adjacent benign tissues were mostly characterized by high levels of 5hmC, renal cell carcinoma and urothelial cell carcinoma showed dramatically reduced staining for 5hmC. 5hmC levels were low in both primary tumors and metastases of clear cell renal cell carcinoma and showed no association with disease outcomes. In normal testis, robust 5hmC staining was only observed in stroma and Sertoli cells. Seminoma showed greatly reduced 5hmC immunolabeling, whereas differentiated teratoma, embryonal and yolk sack tumors exhibited high 5hmC levels. The substantial tumor specific loss of 5hmC, particularly in clear cell renal cell carcinoma and urothelial cell carcinoma, suggests that alterations in pathways involved in establishing and maintaining 5hmC levels might be very common in cancer and could potentially be exploited for diagnosis and treatment.
    Keywords Medicine ; R ; Science ; Q
    Subject code 616
    Language English
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Clinical Validation of the 2005 ISUP Gleason Grading System in a Cohort of Intermediate and High Risk Men Undergoing Radical Prostatectomy.

    Sheila F Faraj / Stephania M Bezerra / Kasra Yousefi / Helen Fedor / Stephanie Glavaris / Misop Han / Alan W Partin / Elizabeth Humphreys / Jeffrey Tosoian / Michael H Johnson / Elai Davicioni / Bruce J Trock / Edward M Schaeffer / Ashley E Ross / George J Netto

    PLoS ONE, Vol 11, Iss 1, p e

    2016  Volume 0146189

    Abstract: In 2005, the International Society of Urological Pathology (ISUP) introduced several modifications to the original Gleason system that were intended to enhance the prognostic power of Gleason score (GS). The objective of this study was to clinically ... ...

    Abstract In 2005, the International Society of Urological Pathology (ISUP) introduced several modifications to the original Gleason system that were intended to enhance the prognostic power of Gleason score (GS). The objective of this study was to clinically validate the 2005 ISUP Gleason grading system for its ability to detect metastasis. We queried our institutional RP database for men with NCCN clinically localized intermediate to high-risk disease undergoing radical prostatectomy (RP) between 1992 and 2010 with no additional treatment until the time of metastatic progression. A case-cohort design was utilized. A total of 333 available RP samples were re-reviewed and GS was reassigned per the 2005 ISUP Gleason system. Cumulative incidence of metastasis was 0%, 8.4%, 24.5% and 44.4% among specimens that were downgraded, unchanged, had one point GS increase and two point GS increase, respectively. The hazard ratio for metastasis raised in GS 8 and 9 compared to GS 7 from 2.77 and 5.91 to 3.49 and 9.31, respectively. The survival c-index of GS increased from 0.70 to 0.80 when samples were re-graded at 5 years post RP. The c-index of the reassigned GS was higher than the original GS (0.77 vs 0.64) for predicting PCSM at 10 years post RP. The regraded GS improved the prediction of metastasis and PCSM. This validates the updated Gleason grading system using an unambiguous clinical endpoint and highlights the need for reassignment of Gleason grading according to 2005 ISUP system when considering comparisons of novel biomarkers to clinicopathological variables in archival cohorts.
    Keywords Medicine ; R ; Science ; Q
    Subject code 001
    Language English
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: AIM1 is an actin-binding protein that suppresses cell migration and micrometastatic dissemination

    Michael C. Haffner / David M. Esopi / Alcides Chaux / Meltem Gürel / Susmita Ghosh / Ajay M. Vaghasia / Harrison Tsai / Kunhwa Kim / Nicole Castagna / Hong Lam / Jessica Hicks / Nicolas Wyhs / Debika Biswal Shinohara / Paula J. Hurley / Brian W. Simons / Edward M. Schaeffer / Tamara L. Lotan / William B. Isaacs / George J. Netto /
    Angelo M. De Marzo / William G. Nelson / Steven S. An / Srinivasan Yegnasubramanian

    Nature Communications, Vol 8, Iss 1, Pp 1-

    2017  Volume 17

    Abstract: Invasion of malignant cells involves changes in cytoskeleton dynamics. Here the authors identify absent in melanoma 1 as an actin binding protein and show that it regulates cytoskeletal remodeling and cell migration in prostate epithelial cells, acting ... ...

    Abstract Invasion of malignant cells involves changes in cytoskeleton dynamics. Here the authors identify absent in melanoma 1 as an actin binding protein and show that it regulates cytoskeletal remodeling and cell migration in prostate epithelial cells, acting as a metastatic suppressor in cancer cells.
    Keywords Science ; Q
    Language English
    Publishing date 2017-07-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Correction

    Simeon U Springer / Chung-Hsin Chen / Maria Del Carmen Rodriguez Pena / Lu Li / Christopher Douville / Yuxuan Wang / Joshua David Cohen / Diana Taheri / Natalie Silliman / Joy Schaefer / Janine Ptak / Lisa Dobbyn / Maria Papoli / Isaac Kinde / Bahman Afsari / Aline C Tregnago / Stephania M Bezerra / Christopher VandenBussche / Kazutoshi Fujita /
    Dilek Ertoy / Isabela W Cunha / Lijia Yu / Trinity J Bivalacqua / Arthur P Grollman / Luis A Diaz / Rachel Karchin / Ludmila Danilova / Chao-Yuan Huang / Chia-Tung Shun / Robert J Turesky / Byeong Hwa Yun / Thomas A Rosenquist / Yeong-Shiau Pu / Ralph H Hruban / Cristian Tomasetti / Nickolas Papadopoulos / Ken W Kinzler / Bert Vogelstein / Kathleen G Dickman / George J Netto

    eLife, Vol

    Non-invasive detection of urothelial cancer through the analysis of driver gene mutations and aneuploidy

    2018  Volume 7

    Keywords Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2018-11-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Non-invasive detection of urothelial cancer through the analysis of driver gene mutations and aneuploidy

    Simeon U Springer / Chung-Hsin Chen / Maria Del Carmen Rodriguez Pena / Lu Li / Christopher Douville / Yuxuan Wang / Joshua David Cohen / Diana Taheri / Natalie Silliman / Joy Schaefer / Janine Ptak / Lisa Dobbyn / Maria Papoli / Isaac Kinde / Bahman Afsari / Aline C Tregnago / Stephania M Bezerra / Christopher VandenBussche / Kazutoshi Fujita /
    Dilek Ertoy / Isabela W Cunha / Lijia Yu / Trinity J Bivalacqua / Arthur P Grollman / Luis A Diaz / Rachel Karchin / Ludmila Danilova / Chao-Yuan Huang / Chia-Tung Shun / Robert J Turesky / Byeong Hwa Yun / Thomas A Rosenquist / Yeong-Shiau Pu / Ralph H Hruban / Cristian Tomasetti / Nickolas Papadopoulos / Ken W Kinzler / Bert Vogelstein / Kathleen G Dickman / George J Netto

    eLife, Vol

    2018  Volume 7

    Abstract: Current non-invasive approaches for detection of urothelial cancers are suboptimal. We developed a test to detect urothelial neoplasms using DNA recovered from cells shed into urine. UroSEEK incorporates massive parallel sequencing assays for mutations ... ...

    Abstract Current non-invasive approaches for detection of urothelial cancers are suboptimal. We developed a test to detect urothelial neoplasms using DNA recovered from cells shed into urine. UroSEEK incorporates massive parallel sequencing assays for mutations in 11 genes and copy number changes on 39 chromosome arms. In 570 patients at risk for bladder cancer (BC), UroSEEK was positive in 83% of those who developed BC. Combined with cytology, UroSEEK detected 95% of patients who developed BC. Of 56 patients with upper tract urothelial cancer, 75% tested positive by UroSEEK, including 79% of those with non-invasive tumors. UroSEEK detected genetic abnormalities in 68% of urines obtained from BC patients under surveillance who demonstrated clinical evidence of recurrence. The advantages of UroSEEK over cytology were evident in low-grade BCs; UroSEEK detected 67% of cases whereas cytology detected none. These results establish the foundation for a new non-invasive approach for detection of urothelial cancer.
    Keywords liquid biopsy ; cancer ; urine ; bladder ; renal pelvis ; ureter ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 616 ; 610
    Language English
    Publishing date 2018-03-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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