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  • 1
    In: JCO Clinical Cancer Informatics, American Society of Clinical Oncology (ASCO), , No. 6 ( 2022-06)
    Abstract: Data quality and standardization remain a challenge when analyzing real-world clinical data. We built a clinical research database, using machine learning and natural learning processing, and investigated factors influencing testosterone recovery (T-recovery) in patients with localized prostate cancer (LPC) after initial androgen deprivation therapy (ADT). METHODS Medication and treatment-associated dates missing in structured tables were extracted from patient notes using ConceptMapper, an automated data extraction tool, standardized and curated in Sema4 clinical research database. ADT usage duration was evaluated, and T-recovery in patients with LPC was analyzed by the Kaplan-Meier method and multivariable Cox proportional hazards models. We assessed the prognostic value of post-ADT T-recovery with prostate-specific antigen progression-free survival and failure-free survival. RESULTS In total, 4,125 of 30,832 (13.4%) patients with prostate cancer had medication exclusively from notes with high precision and recall, F1 score ≥ 0.95. Association of dates with medication usage had a F1 score of 0.76. ADT duration estimation had higher accuracy combining information from notes to tables from electronic medical record (70% v 45%). Baseline testosterone was the strongest predictor of T-recovery in these patients. Patients with a baseline testosterone ≥ 300 ng/dL recovered in 9.79 versus 38 months for patients with baseline testosterone 〈 300 ng/dL ( P 〈 .0001). Shorter prostate-specific antigen progression-free interval was observed for patients with T-recovery (≥ 300 ng/dL) at 6 months after ADT cessation compared with patients without T-recovery ( 〈 300 ng/dL; 13.7 v 25.1 months; P = .055). CONCLUSION We augmented structured electronic medical record data with data extracted from notes and improved the accuracy of medication information for patients. ADT exposure and T-recovery in patients with LPC produced results consistent with the literature and clinical experience and illustrates the power of applying machine learning methods to enhance the quality of real-world evidence in answering clinically relevant questions.
    Type of Medium: Online Resource
    ISSN: 2473-4276
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
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  • 2
    Online Resource
    Online Resource
    American Chemical Society (ACS) ; 2010
    In:  Molecular Pharmaceutics Vol. 7, No. 2 ( 2010-04-05), p. 386-397
    In: Molecular Pharmaceutics, American Chemical Society (ACS), Vol. 7, No. 2 ( 2010-04-05), p. 386-397
    Type of Medium: Online Resource
    ISSN: 1543-8384 , 1543-8392
    Language: English
    Publisher: American Chemical Society (ACS)
    Publication Date: 2010
    detail.hit.zdb_id: 2132489-X
    SSG: 15,3
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  • 3
    In: Molecular Pharmaceutics, American Chemical Society (ACS), Vol. 8, No. 6 ( 2011-12-05), p. 2310-2319
    Type of Medium: Online Resource
    ISSN: 1543-8384 , 1543-8392
    Language: English
    Publisher: American Chemical Society (ACS)
    Publication Date: 2011
    detail.hit.zdb_id: 2132489-X
    SSG: 15,3
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  • 4
    In: Molecular Cancer, Springer Science and Business Media LLC, Vol. 10, No. 1 ( 2011-12)
    Abstract: Epithelial to mesenchymal transition (EMT) occurs during cancer cell invasion and malignant metastasis. Features of EMT include spindle-like cell morphology, loss of epithelial cellular markers and gain of mesenchymal phenotype. Activation of the RON receptor tyrosine kinase by macrophage-stimulating protein (MSP) has been implicated in cellular EMT program; however, the major signaling determinant(s) responsible for MSP-induced EMT is unknown. Results The study presented here demonstrates that RSK2, a downstream signaling protein of the Ras-Erk1/2 pathway, is the principal molecule that links MSP-activated RON signaling to complete EMT. Using MDCK cells expressing RON as a model, a spindle-shape based screen was conducted, which identifies RSK2 among various intracellular proteins as a potential signaling molecule responsible for MSP-induced EMT. MSP stimulation dissociated RSK2 with Erk1/2 and promoted RSK2 nuclear translocation. MSP strongly induced RSK2 phosphorylation in a dose-dependent manner. These effects relied on RON and Erk1/2 phosphorylation, which is significantly potentiated by transforming growth factor (TGF)-β1, an EMT-inducing cytokine. Specific RSK inhibitor SL0101 completely prevented MSP-induced RSK phosphorylation, which results in inhibition of MSP-induced spindle-like morphology and suppression of cell migration associated with EMT. In HT-29 cancer cells that barely express RSK2, forced RSK2 expression results in EMT-like phenotype upon MSP stimulation. Moreover, specific siRNA-mediated silencing of RSK2 but not RSK1 in L3.6pl pancreatic cancer cells significantly inhibited MSP-induced EMT-like phenotype and cell migration. Conclusions MSP-induced RSK2 activation is a critical determinant linking RON signaling to cellular EMT program. Inhibition of RSK2 activity may provide a therapeutic opportunity for blocking RON-mediated cancer cell migration and subsequent invasion.
    Type of Medium: Online Resource
    ISSN: 1476-4598
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2011
    detail.hit.zdb_id: 2091373-4
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  • 5
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 2010
    In:  Acta Pharmacologica Sinica Vol. 31, No. 9 ( 2010-9), p. 1181-1188
    In: Acta Pharmacologica Sinica, Springer Science and Business Media LLC, Vol. 31, No. 9 ( 2010-9), p. 1181-1188
    Type of Medium: Online Resource
    ISSN: 1671-4083 , 1745-7254
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2010
    detail.hit.zdb_id: 2088565-9
    SSG: 15,3
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  • 6
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 2011
    In:  Cancer Chemotherapy and Pharmacology Vol. 67, No. 5 ( 2011-5), p. 1073-1083
    In: Cancer Chemotherapy and Pharmacology, Springer Science and Business Media LLC, Vol. 67, No. 5 ( 2011-5), p. 1073-1083
    Type of Medium: Online Resource
    ISSN: 0344-5704 , 1432-0843
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2011
    detail.hit.zdb_id: 1458488-8
    SSG: 15,3
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  • 7
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. e17047-e17047
    Abstract: e17047 Background: The addition of docetaxel or a novel hormonal agent (NHA), such as abiraterone acetate or enzalutamide, has become standard of care for mHSPC, but prospective data for comparative efficacy remains limited. Clinical variables abstracted through natural language processing of free text from patient charts can provide real-world data to answer important clinical questions. Methods: Using an innovative data abstraction process, we retrospectively identified men with de novo mHSPC within deidentified charts from the Mount Sinai Health System treated with either docetaxel or a NHA between January 1, 2014 and April 30, 2019. Dates were chosen to reflect the timeline for which these therapeutic agents received regulatory approval for mHSPC, but also to allow sufficient clinical follow up after treatment initiation. Primary outcome of failure-free survival (FFS), defined as the time to next treatment, was assessed using the Kaplan-Meier method and multivariable Cox proportional hazards models. We additionally performed multivariable analysis to evaluate the prognostic significance of post-treatment PSA nadir on FFS. Results: A total of 94 de novo mHSPC patients that received either docetaxel or an NHA were identified using proprietary Sema4 data abstraction process: 52 received docetaxel, 42 received an NHA. Use of an upfront NHA in mHSPC was associated with a significantly longer FFS compared to docetaxel (20.7 vs. 10.1 months, p = 0.023). While NHAs were associated with a significantly longer FFS than docetaxel in patients with high metastatic burden of disease (25.12 vs. 9.63 months, p = 0.014), this was not observed in low-volume disease (20.71 vs. 26.5 months, p = 0.9). In multivariable model analysis adjusting for age, baseline PSA, and metastasis burden, docetaxel remains independently associated with worse FFS compared to NHA (HR 1.96, 95% CI 1.12−3.45, p = 0.019). Irrespective of docetaxel or NHA use, lower post-treatment PSA nadir levels were associated with improved FFS (58.95 vs. 11.57 vs. 9.4 months for PSA ≤0.2, 0.2-0.4, 〉 0.4ng/ml, respectively; p 〈 0.001). Conclusions: Clinical variables abstracted from deidentified clinical documentation can efficiently provide relevant and reliable data upon which clinical research can be based. Comparative analysis of real-world data demonstrates superior FFS in de novo mHSPC treated with a NHA as compared to docetaxel. The depth of PSA response holds prognostic value for mHSPC outcomes, regardless of treatment used.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
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  • 8
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. e15036-e15036
    Abstract: e15036 Background: Advances in tumor molecular profiling and bioinformatics are adding new insights to support real-world research. In this study, paired tumor NGS testing data was curated and analyzed from electronic medical records (EMR) to understand mutational and targeted therapy landscape. Methods: A database initiated in 2013 to collect data, including outcomes, on all patients referred to the molecular tumor board at the Avera Cancer Institute was curated and analyzed. A data pipeline that combined results from curated NGS data with curated EMR data from Avera was used to correlate targetable mutations to a corresponding therapy and assessed treatment patterns. Results: Data were from 1804 patients with 44 cancer types including breast (462; 26%), lung (338;19%), colorectal (198;11%), ovarian (168;9%), and uterine (100;5%). Overall, 83% of patients had a positive NGS result and 67% had a targetable mutation per NCCN guidelines. 32% of patients with a targetable mutation received targeted therapy per guideline. Overall, 381 patients with 28 tumor types received targeted therapies based on NGS results and targetable biomarkers. Of these, 288/381 (76%) were stage III-IV and 93/381 (24%) early stage/stage unknown. In non-small cell lung cancer, 76% of stage III-IV patients with mutations in EGFR (exon 19 deletion, L858, L861, S768, G719), MET (exon 14 skipping, amplification), BRAF V600 and ALK/ ROS1/ RET fusions received a targeted therapy per NCCN guidelines. In advanced breast cancer, 97% with ERBB2 amplification received targeted therapy (trastuzumab, pertuzumab, neratinib, lapatinib, tucatinib). 8% of advanced breast cancer patients with PIK3CA mutation received alpelisib, with all patients receiving the drug since 2019. 38% advanced breast cancer patients with BRCA1/2 mutation received Olaparib. In ovarian cancer, 48% of advanced stage patients received targeted therapy for BRCA 1/2, ATM, CDK12, CHEK2, ERBB2, FANCL, KRAS, ALK, BRAF alterations. Olaparib was used in 70% of advanced prostate cancer patients with BRCA1/2 mutations. Dabrafenib combined with Trametinib were most preferred for BRAF V600 mutation in melanoma and colorectal tumors respectively. Off label use of targeted therapy was observed in about 6% of advanced patients; examples include trametinib for KRAS/NRAS mutation [non-small cell lung cancer, colorectal, pancreatic, ovarian], PARP inhibitors for BRCA1/2, ATM mutations [urothelial, peritoneal] , anti-ERBB2 inhibitors for ERBB2 in-frame, missense, exon 20 insertion mutations [lung and breast]. Conclusions: These study results demonstrate that automated data mining can provide insights into the genomic and therapeutic landscape of a real-world patient population. Across all tumor types, most patients are being given appropriate targeted therapies as per guidelines. Off-label use of targeted therapy was also observed.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 9
    In: Molecular Cancer, Springer Science and Business Media LLC, Vol. 10, No. 1 ( 2011-12)
    Abstract: Overexpression of the RON receptor tyrosine kinase contributes to epithelial cell transformation, malignant progression, and acquired drug resistance. RON also has been considered as a potential target for therapeutic intervention. This study determines biochemical features and inhibitory activity of a mouse monoclonal antibody (mAb) Zt/f2 in experimental cancer therapy. Results Zt/f2 is a mouse IgG2a mAb that is highly specific and sensitive to human RON and its oncogenic variants such as RON160 (ED 50 = 2.3 nmol/L). Receptor binding studies revealed that Zt/f2 interacts with an epitope(s) located in a 49 amino acid sequence coded by exon 11 in the RON β-chain extracellular sequences. This sequence is critical in regulating RON maturation and phosphorylation. Zt/f2 did not compete with ligand macrophage-stimulating protein for binding to RON; however, its engagement effectively induced RON internalization, which diminishes RON expression and impairs downstream signaling activation. These biochemical features provide the cellular basis for the use of Zt/f2 to inhibit tumor growth in animal model. Repeated administration of Zt/f2 as a single agent into Balb/c mice results in partial inhibition of tumor growth caused by transformed NIH-3T3 cells expressing oncogenic RON160. Colon cancer HT-29 cell-mediated tumor growth in athymic nude mice also was attenuated following Zt/f2 treatment. In both cases, ~50% inhibition of tumor growth as measured by tumor volume was achieved. Moreover, Zt/f2 in combination with 5-fluorouracil showed an enhanced inhibition effect of ~80% on HT-29 cell-mediated tumor growth in vivo . Conclusions Zt/f2 is a potential therapeutic mAb capable of inhibiting RON-mediated oncogenesis by colon cancer cells in animal models. The inhibitory effect of Zt/f2 in vivo in combination with chemoagent 5-fluorouracil could represent a novel strategy for future colon cancer therapy.
    Type of Medium: Online Resource
    ISSN: 1476-4598
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2011
    detail.hit.zdb_id: 2091373-4
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  • 10
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2015
    In:  Molecular Cancer Research Vol. 13, No. 3 ( 2015-03-01), p. 483-492
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 13, No. 3 ( 2015-03-01), p. 483-492
    Abstract: RhoGDI2 (ARHGDIB) suppresses metastasis in a variety of cancers but the mechanism is unclear, thus hampering development of human therapeutics. RhoGDI2 is a guanine nucleotide dissociation inhibitor (GDI) for the Rho family of GTPases thought to primarily bind to Rac1; however, Rac1 activation was not decreased by RhoGDI2 expression in bladder cancer cells. To better understand the GTPase-binding partners for RhoGDI2, a mass spectrometry–based proteomic approach was used in bladder cancer cells. As expected, endogenous RhoGDI2 coimmunoprecipitates with Rac1 and unexpectedly also with RhoC. Further analysis demonstrated that RhoGDI2 negatively regulates RhoC, as knockdown of RhoGDI2 increased RhoC activation in response to serum stimulation. Conversely, overexpression of RhoGDI2 decreased RhoC activation. RhoC promoted bladder cancer cell growth and invasion, as knockdown increased cell doubling time, decreased invasion through Matrigel, and decreased colony formation in soft agar. Importantly, RhoC knockdown reduced in vivo lung colonization by bladder cancer cells following tail vein injection in immunocompromised mice. Finally, unbiased transcriptome analysis revealed a set of genes regulated by RhoGDI2 overexpression and RhoC knockdown in bladder cancer cells. Implications: RhoGDI2 suppresses bladder cancer metastatic colonization via negative regulation of RhoC activity, providing a rationale for the development of therapeutics that target RhoC signaling. Mol Cancer Res; 13(3); 483–92. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2097884-4
    SSG: 12
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