tbuckley/cabot-search huggingface dataset:
Abstract 2294: Atypical nevi and risk of incident skin cancer in US men: a prospective study
Authors: WEN-QING LI, Eunyoung Cho, Alisa Goldstein, Yen-Tsung Huang, Martin Weinstock, Abrar Qureshi
Journal: Cancer Research (2017)

Abstract Background and Aims: Atypical nevi (AN) are a strong risk factor as well as a precursor of melanoma. However, most previous studies on the associations between atypical nevi (AN) and the risk of melanoma have been conducted in retrospective case-control settings and the few available prospective studies have been based on small sample sizes. Further, few studies have examined the associations between AN and risk of keratinocyte carcinomas (formerly called non-melanoma skin cancer). We prospectively examined the risk of incident melanoma, squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) associated with AN. Methods: In the Health Professionals Follow-up Study, information on AN was collected by self-report. Only those confirmed cases of AN by a supplementary questionnaire, the Atypical Nevus Screening Questionnaire (ANQ), were included in the analyses. Diagnosis of skin cancers was reported biennially and information on melanoma and SCC was pathologically confirmed. A total of 50193 men were included in our study, with 1239 confirmed cases of AN with information on diagnosis year. Cases of AN that were not confirmed or did not respond to the ANQ were excluded from the analyses. Time-dependent Cox-regression analyses were conducted for the associations between AN and risk of incident melanoma, SCC, and BCC respectively. Results: We identified 545 melanoma cases, 1721 SCC cases, and 13498 BCC cases during the follow-up (1986-2012). A history of AN was significantly associated with increased risk of incident melanoma (hazard ratio [HR]=3.50, 95% confidence interval [CI]: 2.13-5.76) overall and at different body sites (head and neck, trunk, or limbs). The risk of melanoma was particularly augmented with the increasing number of AN that were surgically removed (HR=1.26, 95% CI: 1.16-1.37 per AN) and for cases of AN with tissue re-excision from the nevus removal sites (HR=4.59, 95% CI: 1.70-12.41). A history of AN was also significantly associated with increased risk of BCC (HR=1.84, 95% CI: 1.60-2.10) and was only associated with risk of SCC at the trunk sites (HR=3.09, 95% CI: 1.24-7.72). Conclusions: A history of AN significantly increased the risk of subsequent melanoma in a prospective study of men. A history of AN may also be associated with increased risk of BCC overall and trunk SCC, which requires further studies to replicate. Citation Format: WEN-QING LI, Eunyoung Cho, Alisa Goldstein, Yen-Tsung Huang, Martin Weinstock, Abrar Qureshi. Atypical nevi and risk of incident skin cancer in US men: a prospective study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2294. doi:10.1158/1538-7445.AM2017-2294
Job-Exposure Matrices in Occupational Epidemiology
Authors: Shelia K. Hoar, Sc.D.
Journal: JNCI Journal of the National Cancer Institute (1982)

Job-Exposure Matrices in Occupational Epidemiology Get access Shelia K. Hoar, Sc.D. Shelia K. Hoar, Sc.D. Environmental Epidemiology Branch National Cancer Institute National Institutes of Health Public Health Service U. S. Department of Health and Human Services Landow Building, , Room 3C06 Bethesda, Maryland 20205 Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 69, Issue 6, December 1982, Pages 1419–1420, https://doi.org/10.1093/jnci/69.6.1419 Published: 01 December 1982
Abstract 4080: Cytochrome P450 enzyme activity is enhanced in hepatocytes grown using a perfused 3D cell culture drug screening system
Authors: James T. Shoemaker, Jelena Vukasinovic
Journal: Cancer Research (2017)

Abstract A critical requirement for assessing drug toxicity in vitro is cytochrome P450 (CYP) function that is physiologically representative. Due to low levels of CYP enzyme activity, cell lines such as HepG2 hepatocytes have largely been supplanted with primary cells derived from human donor tissue. While these cells retain CYP activity ex vivo, drug screening is limited to short-term assessments due to de-differentiation. This limits their efficacy in testing slow-clearing, large-molecule compounds such as antibody-based therapies and low-turnover drugs. Cell lines in monolayer cultures have been effective in assessing the safety of small molecule drugs, but the disparity between cell lines and in vivo tissue biology proves too substantial for current potential therapies. Three-dimensional (3D) cultures have been shown to be more physiologically relevant models of in vivo tissue. However, even they fail to fully mimic living tissue and suffer from the lack of active oxygen and nutrient transport. Lena Biosciences has developed a groundbreaking in vitro system that facilitates long-term survival of 3D cultures. Cells seeded in 3D hydrogels supported by a rigid scaffold are maintained in statistically independent wells in their own medium which floats atop a high-density blood-substitute in which medium is immiscible. Infusion and withdrawal of this blood-substitute introduces perfusion into a medium-throughput multiwell system without the need for separate pumps for each culture condition. Internal validation experiments using hepatocytes cultured in a 12-well system showed a two-fold improvement in cellular respiration (measured by alamarBlue assay) over cultures maintained in a standard multiwell plate when the blood-substitute was introduced, and a three-fold improvement when the cultures were perfused. Cell viability (measured by LDH release) was significantly improved when perfusion was introduced. CYP activity (assessed using both fluorescent and luminescent substrate-based assays) was also significantly higher in the perfused hepatocyte cultures. These data demonstrate the substantial advantages to growing cells in this novel perfused cell culture model. Scaling the system to include multiple cell types (primary or cell lines), would allow for simultaneous testing of target and off-target effects of potential small or large molecule therapies. Thus, this system serves as a major improvement over the current organ-on-a-chip solutions in the area of drug safety testing. Citation Format: James T. Shoemaker, Jelena Vukasinovic. Cytochrome P450 enzyme activity is enhanced in hepatocytes grown using a perfused 3D cell culture drug screening system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4080. doi:10.1158/1538-7445.AM2017-4080
Abstract 826: Nrf2 confers radioresistance by regulating cancer stem trait in lung cancer cells
Authors: Xiaoqing He, Alex Chi, Liying Wang, Yon Rojanasakul
Journal: Cancer Research (2017)

Abstract Lung cancer is the leading cause of cancer-related death accounting for more than 1.3 million deaths worldwide annually. Despite advances in treatment, the five-year survival rate is 2% if the cancer has metastasized to other organs. The major cause of poor prognosis of advanced lung cancer is multi-resistance to chemo/radio therapy. Therefore, it is crucial to understand the underlying mechanisms of chemo/radio resistance and develop therapeutic strategies to overcome the resistance. Transcription factor Nrf2 is a key regulator of cytoprotective genes which facilitate cellular defense against harmful insults. We found that Nrf2 and its downstream target NQO1 are highly upregulated in lung cancer patient tumor tissues as well as in lung cancer cell lines compared to adjacent normal tissues or normal cell lines. We hypothesized that the upregulated Nrf2 may be responsible for radio/chemo resistance and malignancy in lung cancer. RNA interference studies showed that knockdown of Nrf2 substantially increased the sensitivity of human lung cancer H460 and A549 cells to radiation-induced cell death. Knockdown of Nrf2 also decreased tumor sphere formation, suggesting its role in cancer stem cell (CSC) regulation which may be responsible for the radioresistance. Analyses of CSC markers including ALDH and Oct4 in control and Nrf2-knockdown H460 and A549 cells support this finding. Together, our results indicate an essential role of Nrf2 in the control and regulation of CSCs and radioresistance. Since CSCs are widely believed to be responsible for cancer chemoresistance and relapse, our novel finding on the role of Nrf2 in radiation resistance may aid in the design of novel therapeutic strategies for resistant cancers. Citation Format: Xiaoqing He, Alex Chi, Liying Wang, Yon Rojanasakul. Nrf2 confers radioresistance by regulating cancer stem trait in lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 826. doi:10.1158/1538-7445.AM2017-826
Strontium release from Sr2+-loaded bone cements and dispersion in healthy and osteoporotic rat bone
Authors: Marcus Rohnke, Stefanie Pfitzenreuter, Boris Mogwitz, Anja Henß, Jürgen Thomas, Dina Bieberstein, Thomas Gemming, Svenja K. Otto, Seemun Ray, Matthias Schumacher, Michael Gelinsky, Volker Alt
Journal: Journal of Controlled Release (2017)
Abstract 61: Zymelink drug conjugate platform: redefining the therapeutic window for ADCs
Authors: Stuart Barnscher, John Babcook, Jamie Rich, Geoff Winters, Graham Garnett, Andrea Hernandez, Vincent Fung, Kevin Yin, Kevin Hamblett, Rupert Davies
Journal: Cancer Research (2017)

Abstract Antibody drug conjugates (ADCs) combine the specificity of monoclonal antibodies with potent antineoplastic small molecules, and promise efficacy without the systemic toxicity of chemotherapy. Despite this tremendous potential, most clinical ADCs have failed to provide sufficient therapeutic benefit before the onset of off-target dose-limiting platform toxicities. Here we report the development of proprietary protease cleavable N-acyl sulfonamide linked hemiasterlin and auristatin payloads, Zymelink, that allow the generation of an efficacious ADC platform with improved tolerability. Both Zymelink drug-linkers were conjugated via maleimides to endogenous cysteines. As Zymelink drug-linkers are more polar than maleimide valine citrulline monomethyl auristatin E drug-linker, the resulting ADCs can be produced with potential advantages in PK, efficacy and safety. The resulting ADCs exhibit potent in vitro cytotoxicity. A trastuzumab-based ADC prepared with Zymelink drug-linker and demonstrated at least equivalent efficacy compared to a trastuzumab-based ADC prepared with MMAE, promoting durable complete regressions in a patient-derived xenograft model. Zymelink hemiasterlin and auristatin ADCs were tolerated at 5-6 fold higher doses compared to a MMAE ADC in cynomolgus monkeys. The maximum tolerated dose of the MMAE ADC was just 3 mg/kg based on severe neutropenia. Zymelink hemiasterlin ADC was tolerated at 15 mg/kg with no evidence of neutropenia or elevations in transaminases. Zymelink auristatin ADC was tolerated at 18 mg/kg based on increased levels of transaminases at 24 mg/kg. Moreover, Zymelink ADCs exhibited greater serum exposure at equivalent doses. These results suggest Zymelink ADCs have a greatly expanded therapeutic window compared to MMAE conjugates. Citation Format: Stuart Barnscher, John Babcook, Jamie Rich, Geoff Winters, Graham Garnett, Andrea Hernandez, Vincent Fung, Kevin Yin, Kevin Hamblett, Rupert Davies. Zymelink drug conjugate platform: redefining the therapeutic window for ADCs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 61. doi:10.1158/1538-7445.AM2017-61
Abstract 924: Dedifferentiation into polyploid blastomere-like cancer stem cells via formation of polyploid giant cancer cells
Authors: Na Niu, Jinsong Liu
Journal: Cancer Research (2017)

Abstract We have recently shown that polyploid giant cancer cells (PGCCs) are capable of tumor initiation and acquisition of embryonic-like stemness and thus represent a novel type of cancer stem cells. However, two important questions remain to be answered from this surprising finding: (1) how PGCCs acquire such stemness; (2) on which stage of normal development PGCCs correspond to. Here, we tracked the fate of single PGCCs induced via mitotic failure by paclitaxel. Morphologically, early spheroids derived from PGCCs were indistinguishable from human embryos at the polyploid blastomere, compaction, morula, and blastocyst-like stages by scanning electron microscopy. PGCCs showed time- and space-dependent activation of expression of the embryonic stem cell markers OCT4, NANOG, SOX2, and SSEA-1 and lacked expression of Xist. PGCCs also showed time-dependent activation of expression of the germ layer-specific markers alpha-fetoprotein, smooth muscle actin, and β3-tubulin and were capable of redifferentiation into three germ layers in vitro. PGCCs-derived daughter cells showed attenuated invasive ability and increased resistance to paclitaxel. PGCCs-derived spheroids grew into a wide spectrum of human neoplasms, including malignant dysgerminoma and embryonic carcinoma, poorly differentiated or well-differentiated carcinomas, and benign squamous tissue. We also observed PGCCs in ovarian cancer from patients treated with chemotherapy. Thus, our data demonstrated that PGCCs acquired novel cancer stem cell properties and capability to redifferentiate into different tumors including the germ cell tumors, which are at the topmost developmental hierarchy. Our studies, for the first time, link PGCCs to the polyploid blastomere-like cancer stem cells and thus offer a new paradigm for the origin of cancer. Citation Format: Na Niu, Jinsong Liu. Dedifferentiation into polyploid blastomere-like cancer stem cells via formation of polyploid giant cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 924. doi:10.1158/1538-7445.AM2017-924
Abstract 2099: In vitro characterization of the effect of nazartinib against non-small cell lung cancer activating clinically relevant EGFR mutants
Authors: Keita Masuzawa, Hiroyuki Yasuda, Toshiyuki Hirano, Shigenari Nukaga, Hanako Hasegawa, Junko Hamamoto, Katsuhiko Naoki, Kenzo Soejima, Tomoko Betsuyaku
Journal: Cancer Research (2017)

Abstract Purpose: Multiple EGFR-TKIs are available and under development to treat patients with lung cancer harboring EGFR mutations. Nazartinib is one of the 3rd generation EGFR-TKIs targeting EGFR T790M as well as common mutations such as L858R and exon 19 deletions. Today, there is no clear guideline regarding which EGFR-TKIs should be used for which mutations. The purpose of this study is to clarify which EGFR-TKIs including nazartinib are best for each EGFR mutation, especially exon 20 insertion mutations using in vitro modeling. Experimental design: We evaluated drug sensitivity and downstream signaling of human lung cancer cell lines (PC9, H3255, H1975, PC9ER, BID007) and Ba/F3 cells harboring multiple types of EGFR mutations for 1st- (erlotinib), 2nd- (afatinib) and 3rd- (osimertinib and nazartinib) generation EGFR-TKIs by MTS assay and western blotting. An in vitro model of mutation specificity was created by calculating the ratio of IC50 values between mutated and wild type EGFRs. Results: The model of mutation specificity identified a wide therapeutic window of each EGFR-TKIs for exon 19 deletions and L858R. On the other hand, osimertinib and nazartinib have wide therapeutic window for T790M positive mutations in human cell lines and Ba/F3 cells. In human cell lines and Ba/F3 cells harboring exon 19 deletions or L858R, afatinib dramatically inhibited the phosphorylation of EGFR, AKT, and ERK. Afatinib and 3rd generation EGFR-TKIs, osimertinib and nazartinib, effectively inhibited the phosphorylation of EGFR, AKT, and ERK in T790M positive cells. For EGFR exon 20 insertion mutations, althogh afatinib, osimertinib and nazartinib effectively inhibited the phosphorylation of EGFR, AKT, and ERK in several exon 20 insertion mutations, osimertinib and nazartinib were potent and presented a wide therapeutic window. Conclusion: Nazartinib as well as osimertinib has wide therapeutic windows for exon 19 deletions, L858R, T790M and some exon 20 insertions . Citation Format: Keita Masuzawa, Hiroyuki Yasuda, Toshiyuki Hirano, Shigenari Nukaga, Hanako Hasegawa, Junko Hamamoto, Katsuhiko Naoki, Kenzo Soejima, Tomoko Betsuyaku. In vitro characterization of the effect of nazartinib against non-small cell lung cancer activating clinically relevant EGFR mutants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2099. doi:10.1158/1538-7445.AM2017-2099
Abstract LB-169: Targeted tumor prevention in Li-Fraumeni syndrome
Authors: Alice Soragni, Nhan Phan, David Eisenberg
Journal: Cancer Research (2017)

Abstract Li-Fraumeni syndrome (LFS) is a rare, dominant cancer predisposition disorder. The majority of LFS cases are brought about by germline p53 mutations. Individuals affected develop a spectrum of cancers occurring since childhood or early adulthood (Mai et al, 2012). Tumors associated with LFS include but are not limited to sarcomas, lymphomas and leukemias, breast cancers, brain tumors, etc (Olivier et al, 2010; Mai et al, 2012). p53 is a tumor suppressor gene that regulates many cellular processes and prevents cancer formation, growth and dissemination. When inactivated by mutation, it not only loses its tumor suppressive function, but also acquires oncogenic properties. Mutations of p53 promote destabilization of its three-dimensional structure, which can cause p53 to partially unfold, aggregate and accumulate in cells (Xu et al, 2011). We developed a peptide, ReACp53, to arrest p53 clumping and accumulation, chaperone p53 to a functional state and promote its degradation, hence arresting tumor proliferation (Soragni et al, 2016). ReACp53 can also target p63 and p73 (Zheng et al, 2016). It has shown good tolerability and a favorable safety profile in vivo. In LFS patients and LFS animal models, p53 is undetectable in normal tissues. However, the protein starts to accumulate in tumors and pre-cancerous lesions (Lang et al, 2004; Soragni et al, unpublished data). As p53 accumulation is correlated with aggregation (Xu et al, 2011; Soragni et al, 2016), we postulated that, by periodically administering ReACp53, we could target this initial event early on, and prevent p53 accumulation and/or push the p53 aggregates-ridden cells into apoptosis (Soragni et al, 2016). Here, we tested ReACp53 as a tumor preventive agent, by administering it twice a week from weaning to LFS mice carrying the aggregation-prone R172H mutation (R175H in humans). ReACp53 delayed cancer onset resulting in a significant increase in overall survival (OS). The homozygous cohort (n=16/group) showed a 50% increase in median survival in ReACp53-treated mice (median OS 15.79 vs 23.93 weeks for vehicle vs ReACp53, p=0.005; HR=2.6). Heterozygous mice (n=8/group) showed a 36% increase in OS with a median of 58.86 vs 80.50 weeks for vehicle vs ReACp53 (p=0.03, HR=2.6). No long-term side effect was observed upon ReACp53 administration. The tumor spectrum reported differed between the two groups. Activation of a functional p53 response in mouse cells and LFS patient cells treated with ReACp53 is undergoing. Overall, our study supports ReACp53 therapy as a potential approach to tumor prevention in LFS. Citation Format: Alice Soragni, Nhan Phan, David Eisenberg. Targeted tumor prevention in Li-Fraumeni syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-169. doi:10.1158/1538-7445.AM2017-LB-169
Abstract 19135: Impact of New Cardiac Conduction Disturbances After TAVI on Myocardial Contractility and Mortality
Authors: Zisis Dimitriadis, Smita Scholtz, Werner Scholtz, Marcus Wiemer, Cornelia Piper, Stephan Ensminger, Henrik Fox, Dieter Horstkotte, Lothar Faber
Journal: Circulation (2015)

Introduction: Our study aimed to evaluate the impact of procedure-related cardiac conduction disturbances (CCD) on myocardial performance (standard and speckle-tracking-based LV function parameters) after transfemoral aortic valve implantation (TAVI TF). Hypothesis: New cardiac conduction disturbances after TAVI impair LV function and morphology as well as survival. Methods: Between 2010 and 2013, 168 patients (pts.) underwent TAVI TF using the Core Valve at our institution. 95 of them with complete follow-up (mean follow up 264± 241 days) were evaluated with respect to the presence of new CCD and their effect on myocardial performance. Results: Aortic valve orifice and mean gradient significantly improved (from 0.7 ± 0.2 to 1.8 ± 0.4 cm 2 , p&lt;0.001 and from 42.4 ± 17.7 to 8.3 ± 4.0 mmHg, p&lt;0.001, respectively). After TAVI, 37.9% of pts. presented with new CCDs. Pts. without additional CCDs showed an improvement of left ventricular systolic and diastolic function (LVEF from 43.7 ± 16.5% to 48 ± 16.2%, p= 0.004; E/A-ratio from 1.4 ± 1.0 to 1.0 ± 0.9, p= 0.006), whereas pts. with procedure-related CCDs had a mild LVEF deterioration (from 51.8 ± 13.9% to 47.3 ± 8.5%, p=0.16). Comparison of the changes between groups without and with CCDs revealed significant differences (Table 1). However, on Kaplan Meier analysis survival was not significantly different between both groups (p=0.73). Conclusions: Procedure-related conductions abnormalities after TAVI impair LV function, however in our pt. cohort with no impact on overall survival.