tbuckley/cabot-search huggingface dataset:
Abstract 5188: Epigenetic changes mediated by polycomb repressive complex 2 are associated with cisplatin acquired resistance in testicular germ cell tumor
Authors: Ratnakar Singh, Zeeshan Fazal, Emmanuel Bikorimana, Andrea Corbet, Jennifer Rodriguez, Alyssa Steege, Sarah J. Freemantle, Michael J. Spinella
Journal: Cancer Research (2019)

Abstract Testicular germ cell tumors (TGCTs) represent the most common carcinoma affecting young men. TGCTs serve as a paradigm of chemo-sensitive tumors as more than 80% of metastatic disease can be cured with cisplatin-based chemotherapy. However, therapy resistance can occur, which results in poor patient outcomes. The mechanisms of cisplatin resistant in these tumors remain largely undefined. To study the mechanism of cisplatin acquired resistance we generated several independent, acquired resistant clones of parental NT2/D1, 833K and 2102EP testicular cancer cells employing an in vitro protocol designed to mimic the standard-of-care cisplatin regimen used to treat TGCT patients. We further characterized 10 of these clonal lines and confirmed stable cisplatin resistance ranging from 5- to 30-fold. After confirming the cisplatin resistance, we performed RNA seq transcriptomic profiling, differential gene expression analysis, DAVID and GSEA. Remarkably, RNA-seq based transcriptional profiling revealed highly significant alterations shared between the majority of the resistant cells regardless of their parental cell of origin. This includes apparent amplification of chromosomal region 17q21-25 in 8 of 10 lines. Unexpectedly, 7 of 10 lines had a highly significant enrichment of genes regulated by H3K27 methylation and polycomb repressive complex 2 (PRC2). Transcription factor prediction analysis of genes differentially expressed between resistant and parental cells revealed that polycomb complex members were among the most highly ranked predicted transcription factors responsible for the gene expression changes. These include EZH2, SUZ12, JARID2 and BMI1. We will present our ongoing studies investigating the role of PRC2 and H3K27 methylation in mediating cisplatin resistance in these cells and in patient samples. Together our data suggests that repression of H3K27 methylation may be a mechanism of cisplatin acquired resistance in TGCTs and that restoration of PRC2 function could be a viable approach to overcome treatment failure. Citation Format: Ratnakar Singh, Zeeshan Fazal, Emmanuel Bikorimana, Andrea Corbet, Jennifer Rodriguez, Alyssa Steege, Sarah J. Freemantle, Michael J. Spinella. Epigenetic changes mediated by polycomb repressive complex 2 are associated with cisplatin acquired resistance in testicular germ cell tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5188.
Drugs Past Their Expiration Date
Journal: JAMA (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Denosumab vs Zoledronic Acid for Bone-Targeted Therapy in Multiple Myeloma
Authors: Rajshekhar Chakraborty, Navneet S. Majhail, Faiz Anwer
Journal: JAMA Oncology (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
IPH4102, a first-in-class anti-KIR3DL2 monoclonal antibody, in patients with relapsed or refractory cutaneous T-cell lymphoma: an international, first-in-human, open-label, phase 1 trial
Authors: Martine Bagot, Pierluigi Porcu, Anne Marie-Cardine, Maxime Battistella, Basem M William, Maarten Vermeer, Sean Whittaker, Federico Rotolo, Caroline Ram-Wolff, Michael S Khodadoust, Armand Bensussan, Carine Paturel, Cecile Bonnafous, Helene Sicard, Hatem A Azim, Youn H Kim
Journal: The Lancet Oncology (2019)
Abstract 2850: Characterization of cadherin 6 as a novel therapeutic target in metastatic ovarian carcinoma
Authors: Miranda Burdiel, Ruben Bartolomé, Marta Jaén, Ignacio Casal
Journal: Cancer Research (2019)

Abstract Cadherin 6 (CDH6) is a type II cadherin containing a RGD motif in a similar way to LI-cadherin (CDH17) and VE-cadherin (CDH5), which are able to activate α2β1 integrin signalling to promote lung and liver metastasis. CDH6 gene is frequently overexpressed in late stages of some types of ovarian carcinoma, clear cell renal carcinoma, renal papillary carcinoma and thyroid cancers. Therefore, as reported for CDH17 and CDH5, we hypothesized that CDH6 might be a potential therapeutic target for metastatic ovarian cancer. Indeed, an “in silico” analysis revealed a significant association between CDH6 expression, tumour stage and poor survival in renal and ovarian cancer patients. We confirmed a high CDH6 expression in ovarian cancer cell lines, although with significant differences in cell surface availability, as determined by flow cytometry. In addition, we noticed a variable α2β1 integrin expression in the same cell lines. Indeed, CDH6 RGD peptide caused β1 integrin activation in OVCAR3 cells but not in SKOV-3, suggesting the existence of alternative mechanisms. In this regard, as CDH6 has been reported to be a αIIbβ3 integrin ligand in platelets, we investigated and confirmed the expression of αIIbβ3 integrin in SKOV3 but not in OVCAR3 cells. Remarkably, CDH6 was able to activate αIIbβ3 integrin in SKOV3 cells. Moreover, silencing of CDH6 or β3 integrin triggered a significant loss of prometastatic traits in ovarian cells, such as cell adhesion, migration, invasion and proliferation. Signalling pathway analysis demonstrated that β3 integrin activation was triggering the phosphorylation of AKT and SRC, but not FAK, promoting cell invasion. Finally, treatment with monoclonal antibodies against the cadherin RGD motif inhibited the metastatic behaviour in ovarian cancer cell lines “in vitro”. Experiments with metastatic mouse models to confirm the inhibitory capacity of cadherin RGD-specific monoclonal antibodies are in progress. In summary, these findings suggest that CDH6 RGD motif could activate α2β1 or αIIbβ3 integrins, according to the cell context, and be targeted to avoid metastatic dissemination and cancer progression in those ovarian tumours overexpressing CDH6. Citation Format: Miranda Burdiel, Ruben Bartolomé, Marta Jaén, Ignacio Casal. Characterization of cadherin 6 as a novel therapeutic target in metastatic ovarian carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2850.
Prognostic and predictive value of topoisomerase II alpha in a randomized trial comparing CMF to CEF in premenopausal women with node positive breast cancer (NCIC CTG MA.5)
Authors: F. P. O’Malley, S. Chia, D. Tu, L. E. Shepherd, M. N. Levine, D. G. Huntsman, V. H. Bramwell, I. L. Andrulis, K. I. Pritchard
Journal: Journal of Clinical Oncology (2006)

533 Background: It has been suggested that Topoisomerase II alpha (TOP2A) status rather than Her-2/neu status may predict response to anthracycline chemotherapy in breast cancer. Methods: In MA.5, 710 premenopausal women with node positive breast cancer were randomized to receive adjuvant CEF (epirubicin 60 mg/m 2 &amp; 5-FU 500 mg/m 2 both IV, days 1 &amp; 8, and cyclophosphamide 75 mg/m 2 p.o. days 1 through 14); vs CMF (methotrexate 40 mg/m 2 &amp; 5-FU 600 mg/m 2 both IV days 1 &amp; 8 and cyclophosphamide 100 mg/m 2 p.o. days 1 through 14), all for six 28-day cycles. Tissue microarrays (TMAs) were constructed from paraffin embedded specimens from 447 (63%) of these patients. TOP2A was measured by fluorescence-in-situ hybridization (FISH), classifying tumors into 3 groups by TOP2A/CEP 17 ratios: amplified (Amp) if ratio ≥2; deleted (Del) if ratio &lt; 0.8; normal (N) if ratio 0.8 to 2. Cox models assessed interaction between treatment and TOP2A, adjusting for age, nodal status, ER, HER-2/neu status, grade, surgery and tumor size. Results: Thirty-one patients (6.9%) had tumours with Del TOP2A; 53 (11.9%) with Amp TOP2A; and 353 (81.2%) with N TOP2A. 5-year disease-free survival (DFS) was 48%, 51%, and 61% for patients with Del, Amp and N TOP2A respectively (p=0.22 adjusted global test). 5-year overall survival (OS) was 55%, 61% &amp; 75% for patients with Del, Amp, and N TOP2A (p=0.67 adjusted global test). HRs for DFS and OS by treatment and TOP2A are presented in the table . Conclusions: TOP2A status was a significant predictive factor for benefit from CEF treatment for OS. Although there was a trend for TOP2A status predicting improved DFS with CEF, the test for interaction was not significant. In adjusted analysis TOP2A did not reach significance as a prognostic factor for DFS or OS. (This study was supported by the Canadian Breast Cancer Research Alliance (CBCRA), the National Cancer Institute of Canada (NCIC) and the Canadian Cancer Society.) [Table: see text] [Table: see text]
Cumulative Effects of Cholesterol and other Risk Factors on Coronary Artery Calcification in Men and Women:
Authors: Christopher J. O’Donnell, Martin G. Larson, Michelle Kupka, Warren J. Manning, Daniel Levy, Melvin E. Clouse
Journal: Circulation (2001)

P92 Introduction: Coronary artery calcification (CAC) by electron beam computed tomography (EBCT) is associated with contemporaneous levels of traditional risk factors (RFs). The availability of repeated measures over 25 years allows a unique examination of relations of CAC with long-term RF levels in Framingham Heart Study subjects. Methods: Men and women free of symptomatic coronary disease underwent EBCT. Subjects were randomly sampled across quartiles of age and quintiles of Framingham coronary risk score. Longterm RFs were derived from 25-year averaged values. Logistic regression was used to relate long-term RFs to CAC. Results: In 167 men (35-76 yrs) and 160 women (35-77 yrs), age, long-term total cholesterol, and long-term systolic BP were related to Agatston CAC score ≥ 100 ( Table). In multivariable analyses, long-term total cholesterol was an independent predictor of CAC (p&lt;0.02). Conclusion: Long-term exposure to coronary disease RFs is associated with increased risk for subclinical CAC. These studies may provide insights into differences in RFs for clinical coronary events and for atherosclerosis. Table 1.
Abstract 1062: Development and characterization of patient-derived xenograft models for acute myeloid leukemia
Authors: Michelle Ulrich, Martha Anderson, Robert Thurman, Fu Li
Journal: Cancer Research (2019)

Abstract Drug development for acute myeloid leukemia (AML) remains challenging, in part, due to the lack of preclinical models that reflect the biology of AML patients. For example, while the majority of AML patients express both CD33 and CD123, only a small fraction of AML cell lines express CD123. Similarly, most AML cell lines have a differentiated phenotype, which may bias the evaluation towards certain types of AML. To address these challenges, we developed a dozen patient derived xenograft (PDX) models to aid preclinical development of AML drugs. Bone marrow samples from 32 AML patients were implanted intravenously into NSG mice. Thirteen of them led to successful expansion of human CD45+ cells in the bone marrow, as demonstrated by flow cytometry. Twelve of these established disease in a secondary passage. Using multicolor flow cytometry analysis, we found that expression of CD33 and CD123 were preserved from AML patients and engrafted disease in NSG mice. Moreover, RNA-sequencing analysis demonstrated that gene expression largely remained consistent between the first two passages. Detailed genetic analysis demonstrated the preservation AML-relevant mutations, such as FLT3-ITD mutations and IDH2 mutations in the PDX model. In summary, we have successfully established AML PDX models that reflect the antigen expression and molecular genetics of AML patients. These models may facilitate the future development of antibody-based therapeutics. Citation Format: Michelle Ulrich, Martha Anderson, Robert Thurman, Fu Li. Development and characterization of patient-derived xenograft models for acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1062.
Reimaging biological barriers affecting distribution and extravasation of PEG/peptide- modified liposomes in xenograft SMMC7721 tumor
Authors: Hailing Tang, Mengjie Rui, Junhua Mai, Wei Guo, Yuhong Xu
Journal: Acta Pharmaceutica Sinica B (2019)

Liposomes, as one of the most successful nanotherapeutics, have a major impact on many biomedical areas. In this study, we performed laser scanning confocal microscope (LSCM) and immunohistochemistry (IHC) assays to investigate the intra-tumor transport and antitumor mechanism of GE11 peptide-conjugated active targeting liposomes (GE11-TLs) in SMMC7721 xenograft model. According to classification of individual cell types in high resolution images, biodistribution of macrophages, tumor cells, cells with high epidermal growth factor receptor (EGFR) expression and interstitial matrix in tumor microenvironment, in addition, their impacts on intra-tumor penetration of GE11-TLs were estimated. Type I collagen fibers and macrophage flooded in the whole SMMC7721 tumor xenografts. Tumor angiogenesis was of great heterogeneity from the periphery to the center region. However, the receptor-binding site barriers were supposed to be the leading cause of poor penetration of GE11-TLs. We anticipate these images can give a deep reconsideration for rational design of target nanoparticles for overcoming biological barriers to drug delivery.
Abstract 1248: Not BCL2 but BFL1 is overexpressed and have strong correlation with NF-kB pathway in diffuse large B-cell lymphoma
Authors: Chansub Lee, Hyojin Song, Seulki Song, Daeyoon Kim, Jihyun Park, Sungyoung Lee, Hongseok Yun, Sheehyun Kim, Sung-Soo Yoon, Youngil Koh
Journal: Cancer Research (2019)

Abstract Venetoclax, anti-apoptotic BCL2-selective inhibitor, has demonstrated efficacy in B-cell multiple lymphoid malignancies. However, several studies have shown that the other anti-apoptotic BCL2 family genes can increase the risk of venetoclax resistance. Accordingly, compounds targeting other BCL2 family are actively being developed. So it is necessary to find which BCL2 family genes is overexpressed in certain tumors. We profiled BCL2 family genes expression with RNA-seq across different types of lymphoid malignancies (follicular lymphoma, burkitt lymphoma, diffuse large b-cell lymphoma, multiple myeloma, and acute leukocyte leukemia). Log2-transformed TMM-normalized RPKM was used for expression levels. As is known, BCL2 and MCL1 was highly expressed in follicular lymphoma and multiple myeloma, respectively. Interestingly, we discovered BFL1, one of anti-apoptotic BCL2 family genes, is overexpressed in both activated B-cell (ABC) and germinal center B-cell (GCB) type diffuse large B cell lymphoma (DLBCL). It has been well known that BFL1 is a pro-survival NF-kB target gene and indeed NF-kB pathway is highly activated in ABC-DLBCL. Also recent studies have shown that activation of this pathway can occur in GCB-DLBCL. Using gene set enrichment analysis, we confirmed that high expression of BFL1 is associated with negative regulation of intrinsic apoptosis and activation of NF-kB in B-cell. Also we discovered that NF-kB pathway activation in correlation with BFL-1 is especially dominant in DLBCL compared to other lymphoid malignancies. Among NF-kB signal related molecules (TNF receptors or Toll-like receptors), CD40 expression significantly correlated with BFL1 expression. In contrast, BCL2, another important apoptosis related gene, showed a negative association with the NF-kB pathway in DLBCL. We could validate our observation using microarray data. In conclusion, BFL1, which may controls intrinsic apoptosis and have strong correlation with NF-kB, is overexpressed in DLCBL. We suggest not venetoclax but BFL1 inhibitor may exert clinical benefit in DLBCL. Citation Format: Chansub Lee, Hyojin Song, Seulki Song, Daeyoon Kim, Jihyun Park, Sungyoung Lee, Hongseok Yun, Sheehyun Kim, Sung-Soo Yoon, Youngil Koh. Not BCL2 but BFL1 is overexpressed and have strong correlation with NF-kB pathway in diffuse large B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1248.
AB0099 Taxol alleviates collagen-induced arthritis in mice by inhibiting the formation of microvessels
Authors: J Xu, Z Feng, J Zhu, S Chen, X Chen, J Li
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Angiogenesis is one of the critical features in rheumatoid arthritis (RA). Uncontrolled neovascularization could help the infiltration of inflammatory cells and lead to synovial hyperplasia and bone destruction further. Precious studies have demonstrated that the medicine taxol (PTX) has anti-angiogenesis effects. <h3>Objectives</h3> To evaluate the inhibitory effects of PTX on angiogenesis in a collagen-induced arthritis (CIA) mouse model. <h3>Methods</h3> A total of 50 mice were used to induce a CIA mouse model with collagen II (CII) and complete Freund9s adjuvant (CFA). Twenty-four with obvious arthritis syndrome were randomly divided into four groups: CIA model group, PTX 1.5 mg/kg group, PTX 1.0 mg/kg group, PTX 0.5 mg/kg group. In addition, 6 normal mice was regarded as the control group. PTX was administered by intraperitoneal injection in the PTX treatment groups 8 times every other day. Arthritis index scores, tissue pathology scores after HE staining and synovium microvessel density (MVD) analysis after immunohistochemical (IHC) staining were performed. Immunohistochemistry and ELISA were used to detect the expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-α (HIF-1α). Additionally, the correlation between MVD and pathological scores, level of VEGF and HIF-1α in the synovium were also evaluated. <h3>Results</h3> After PTX treatment, the three intervention group arthritis index scores (1.33±0.52, 2.00±0.63, 3.33±1.03) declined when compared with the CIA group (5.67±1.03, p&lt;0.001, p&lt;0.001, p=0.016). The total histological scores in the three PTX treatment groups (2.50±0.66, 3.89±0.86, 3.89±0.86) were lower than those in the CIA group (7.67±0.79, p&lt;0.001, p&lt;0.001, p=0.007). Similarly, PTX significantly alleviated the scores for synovitis, pannus formation and bone destruction. Compared with the CIA group (110.32±5.06/mm<sup>2</sup>), the MVD of the three intervention groups decreased in dose-dependent manner (17.05±1.97/mm<sup>2</sup>, 34.73±2.36/mm<sup>2</sup>, 57.55±2.72/mm<sup>2</sup>; p&lt;0.001, respectively). In addition, the expression of VEGF and HIF-1α in synovial tissues and serum also decreased significantly after PTX treatment. Further analysis showed that MVD and pathological scores and levels of VEGF and HIF-1α in the synovium were positively correlated (r=0.921, r=0.944, r=0.889, r=0.969, r=0.933; p&lt;0.001, respectively). <h3>Conclusions</h3> PTX may alleviate CIA by suppressing angiogenesis, providing new insights into the treatment of RA. VEGF and HIF-1α may be the target for PTX suppression of microvessel formation. <h3>References</h3> Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. The Lancet 2016. Park KS, Park MJ, Cho ML, et al. Type II collagen oral tolerance; mechanism and role in collagen-induced arthritis and rheumatoid arthritis. Mod Rheumatol 2009;19:581–9. <h3>Disclosure of Interest</h3> None declared
Abstract 1666: Developing healthcare data scientists using Veterans Health Administration (VHA) data resources: The NCI/VA Big Data Scientist Training Enhancement Program (BD-STEP)
Authors: Sarah G. Elder, Michelle Berny-Lang
Journal: Cancer Research (2019)

Abstract Due to advances in molecular profiling and medical imaging and the increased adoption of electronic health records (EHRs), the growth in oncology-related data has surpassed the development of a workforce capable of analyzing these data. This marks a missed opportunity in cancer research to gain insights toward better prediction of disease risk and therapeutic response. The Big Data Scientist Training Enhancement Program (BD-STEP), jointly managed by the National Cancer Institute and the Veterans Health Administration, addresses this gap by training the next generation of healthcare data scientists using the VA’s healthcare data infrastructure. Post-doctoral fellows from science and engineering backgrounds are paired with VA medical centers across the country, where they are immersed in the clinical environment as they pursue high-impact clinical research questions through data science. They enrich their data science skills using VA data resources, including clinical data from the VA healthcare system, genomic data from the Million Veterans Program (MVP), and treatment and diagnosis data from the VA Central Cancer Registry. Prospective fellows, data science experts, and healthcare researchers are encouraged to learn more about the program, its training opportunities, and existing projects using VA healthcare data. Citation Format: Sarah G. Elder, Michelle Berny-Lang. Developing healthcare data scientists using Veterans Health Administration (VHA) data resources: The NCI/VA Big Data Scientist Training Enhancement Program (BD-STEP) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1666.