tbuckley/cabot-search huggingface dataset:
Abstract 4049: Conserved region 2 of Human Papilloma Virus 18 protein E7 is required for E7 binding to centromere protein C
Authors: Aoi Tokuda, Shoko Takahashi, Masafumi Yoshimoto, Yuji Yaginuma
Journal: Cancer Research (2016)

Abstract The molecular genetics of cervical cancer have not been thoroughly elucidated, despite the fact that cervical cancer is responsible for the deaths of over 250,000 women annually worldwide. Infection with human papillomaviruses (HPVs) is linked to the pathogenesis of a variety of human diseases, including genital warts, laryngeal papillomas, and most notably, cervical cancer. Recently HPV infection was reported to be associated with head and neck cancers.High-risk human papillomaviruses (HPVs) are etiologically linked to human cervical and oral cancers. HPV infection leads to aneuploidy, a numerical chromosomal aberration caused by dysregulation of chromosomal segregation. We found that high-risk HPV18 and HPV58 E7 proteins bind to centromere protein C (CENP-C), a component of the kinetochore that is essential for proper chromosomal segregation. Low-risk HPV4, HPV6, and HPV11 E7s do not bind to CENP-C. The PxDLLCxE sequence in conserved region 2 (CR2) of HPV18 E7 is required for E7 binding to CENP-C. Our results indicate that differences in the ability of high- and low-risk HPV E7s to bind to CENP-C reflect the different oncogenic potentials of high- and low-risk type HPVs.We demonstrated that the E7 proteins from low-risk HPVs do not bind to CENP-C, and that the PxDLLCxE sequence in conserved region 2 of the HPV18 E7 protein is required for E7 binding to CENP-C. CENP-C is a component of the inner kinetochore, and as such, it plays an essential role in proper chromosome segregation, mitotic checkpoint function, and kinetochore assembly. Therefore, we hypothesize that differences in the capability of various E7s from low- and high-risk type HPVs to bind to CENP-C reflect the different oncogenic potential of high- and low-risk type HPVs. Citation Format: Aoi Tokuda, Shoko Takahashi, Masafumi Yoshimoto, Yuji Yaginuma. Conserved region 2 of Human Papilloma Virus 18 protein E7 is required for E7 binding to centromere protein C. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4049.
Abstract 3128: Detection of genetic and epigenetic DNA markers in urine for the early detection of primary and recurrent HCC
Authors: Surbhi Jain, Hie-Won Hann, Sitong Chen, Selena Y. Lin, Ting-Tsung Chang, Chi-Tan Hu, Wei Song, Ying-Hsiu Su
Journal: Cancer Research (2016)

Abstract The purpose of this study was to explore the potential of urine DNA biomarkers for the early detection of primary and recurrent hepatocellular carcinoma (HCC). HCC is an aggressive disease with a 5-year survival rate of 26% in early-stage cancers, and a mere 2% in later stages, with an approximate 50% recurrence rate in the first 2 years of treatment. The most commonly used screening biomarker for HCC is serum alpha-fetoprotein (AFP), which detects only 40-60% of cases. We have previously shown that urine contains fragmented, circulation-derived, cell-free DNA that can be used for detection of cancer-related DNA markers, if a tumor is present. In order to detect circulation-derived, cell-free DNA markers in urine, we have developed short amplicon (∼50 bp) PCR-based assays for the three most frequent hotspot mutations in TP53 (codon 249), TERT (-124, promoter), and CTNNB1 (hotspot in exon 3, codons 32-37), and for aberrant DNA methylation in GSTP1 (mGSTP1) and RASSF1A (mRASSF1A). This five marker panel has an area under the receiver operating curve of 0.94 (92.2% sensitivity at 80% specificity) in distinguishing primary HCC (n = 77) from non-HCC (n = 91) patients by a logistic regression-based combination algorithm. Furthermore, these 5 DNA markers scored 42 of the 45 (93.3%) AFP-negative (&amp;lt; 20 ng/mL) HCC urine samples “positive” in this study population. To validate the urine DNA test for the early detection of recurrent HCC, an on-going blinded study was conducted. Ten patients with treated HCC were monitored for recurrence of HCC with serum AFP and urine DNA markers. Urine samples were collected from these patients at visits with a hepatologist, barcoded, and tested for the five DNA markers. Of the 10 patients, 4 developed recurrence during the study. The HCC-specific urine DNA markers were detected in 3 out of these 4 patients six months prior to MRI diagnosis, and detected concurrent with MRI diagnosis in the other patient. In conclusion, HCC DNA markers can be detected in urine of patients with HCC by short-amplicon, PCR-based assays. Furthermore, we have demonstrated that the urine DNA test detected at least 40% more HCC in an open-labeled study as compared to serum AFP alone, and has the potential to become the first line of screening for HCC in high risk populations. Citation Format: Surbhi Jain, Hie-Won Hann, Sitong Chen, Selena Y. Lin, Ting-Tsung Chang, Chi-Tan Hu, Wei Song, Ying-Hsiu Su. Detection of genetic and epigenetic DNA markers in urine for the early detection of primary and recurrent HCC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3128.
Preliminary results for the advanced salivary gland carcinoma cohort of the phase 1b KEYNOTE-028 study of pembrolizumab.
Authors: Roger B. Cohen, Jean-Pierre Delord, Toshihiko Doi, Sarina Anne Piha-Paul, Stephen V. Liu, Jill Gilbert, Alain Patrick Algazi, Sara Cresta, Ruey-Long Hong, Christophe Le Tourneau, Daphne Day, Andrea Varga, Elena Elez, John M. Wallmark, Sanatan Saraf, Anne Morosky, Jonathan D. Cheng, Bhumsuk Keam
Journal: Journal of Clinical Oncology (2016)

6017 Background: Patients (pts) with treatment-refractory salivary gland cancer have limited treatment options. The PD-1 pathway is upregulated in many tumors leading to immune response suppression. Pembrolizumab (pembro), an anti–PD-1 antibody, blocks interaction between PD-1 and PD-L1 and PD-L2. The nonrandomized KEYNOTE-028 (NCT02054806) trial evaluated the safety and efficacy of pembro in 20 advanced solid tumor cohorts. Results from the salivary gland carcinoma cohort are presented. Methods: Key inclusion criteria included advanced (unresectable and/or metastatic) salivary gland carcinoma excluding sarcomas and mesenchymal tumors, failure of systemic therapy, ECOG PS 0-1, and PD-L1 expression in ≥ 1% of tumor or stroma cells by IHC. Pts received pembro 10 mg/kg every 2 wk for up to 24 mo or until confirmed progression, intolerable toxicity, death or withdrawal of consent. Response assessed every 8 wk for the first 6 mo and every 12 wk thereafter. The primary end point was ORR per RECIST v1.1 by investigator review. Results: As of Dec 10, 2015, 26 pts were enrolled in this cohort. Median age was 57.0 y; 88.5% were male; 73.1% had an ECOG PS of 1; 73.1% had received prior therapy for metastatic disease. At data cutoff, median follow-up duration was 61.9 wk (range, 8.7-88.4). Treatment-related adverse events (TRAEs) occurred in 22 (84.6%) pts; TRAEs in ≥ 15% of pts were diarrhea (n = 4), decreased appetite (n = 4), pruritus (n = 4), and fatigue (n = 8). 3 (11.5%) pts had grade 3-5 TRAEs which resulted in 1 death (interstitial lung disease); 2 (7.7%) pts discontinued pembro because of a TRAE (grade 2 arthritis; grade 3 hepatitis). Confirmed ORR was 11.5% (PR, n = 3; 95% CI, 2.4-30.2); median duration of response was 17.0 wk (range, 15.1-53.4+). Pts achieving PR had adenocarcinoma (n = 2) and high-grade serous carcinoma (n = 1). Stable disease rate was 46.2% (n = 12; 95% CI, 26.6-66.6). The 6-mo OS rate was 70.4%; the 6-mo PFS rate was 20.7%. At data cutoff, 2 pts were on treatment. Conclusions: In this heavily pretreated population, pembro showed promising antitumor activity. Clinical benefit of pembrolizumab in advanced salivary gland carcinoma will be further investigated in the phase 2 KEYNOTE-158 trial (NCT02628067). Clinical trial information: NCT02054806.
Problems of junior doctors in Poland: scientific insight
Authors: Filip A Dabrowski, Anna Oleksiak, Anna Sladowska
Journal: BMJ (2016)

Bettany reports the June demonstration by junior doctors in Poland against poor wages, quality of training, and a lack of regulation of working hours.1

The Centre for Studies and Analyses and the Commission for the Young Doctors of the Polish Medical Chamber conducted a survey among 2691 doctors under 35 in a specialist training system in Poland. Some 69% of respondents had …
Abstract 3621: High efficiency detection of low frequency alleles in cell-free DNA
Authors: Kamran Shazand, Jing Ning, Anthony Popkie, Egon Ranghini, John Paul Jerome
Journal: Cancer Research (2016)

Abstract Cancer is a genetic disease, caused by a variety of alterations to a cell's genome. One specific type of alteration associated with cancer is point mutations, and Next-generation sequencing (NGS) is a key tool to identify those mutations. Unlike inherited mutations, cancer mutations can be found at very low frequencies, mainly because of tumor heterogeneity and their dilution in the germline background. Cell-free DNA (cfDNA) derived from blood plasma, is a promising material for cancer research and diagnosis, and can be readily obtained via non-invasive procedures. However, the amount of tumor DNA and, hence, the amount of rare allele in the cfDNA are typically very low. Sensitive methods are therefore needed for the detection of somatic, cancer-associated mutations in cfDNA isolated from liquid biopsies to support both discovery and clinical decision making in oncology. To overcome these challenges, we developed at Rubicon Genomics an NGS library preparation kit, namely ThruPLEX® Plasma-seq, optimized specifically for cfDNA at input levels from less than 1 ng to 30 ng. We designed experiments to determine the lower limit of SNV detection under these assay conditions. Six individual ThruPLEX® Plasma-seq libraries generated from 10 ng cfDNA were enriched with the Agilent SureSelect XT2 reagents and ClearSeq Comprehensive Cancer panel (151 genes). After sequencing to &amp;gt;500X coverage, SNP calling was performed using Agilent SureCall software to identify the SNPs specific to each sample. In a second step, the cfDNA isolated from two of these plasma samples with known SNP differences were mixed to generate various spike-in frequencies (10%, 5%, 2% and 0.5%) prior to preparing libraries and enrichment. This is to simulate low allele frequency, and to determine the sensitivity of ThruPLEX® Plasma-seq under the outlined assay conditions. Our results showed that it was possible to detect specific alleles down to an actual 0.6% with the theoretical 0.5% spike-in ratio. The percent of on­target bases was over 45%. The sensitivity (SNPs detected/total SNPs analyzed) of our test was above 97% for 10%, 5%, and 2% frequencies and 70% for 0.5%. This is a demonstration of ThruPLEX® Plasma-seq to produce libraries with high enough complexity to detect low frequency alleles from limited amounts of cfDNA from plasma. Citation Format: Kamran Shazand, Jing Ning, Anthony Popkie, Egon Ranghini, John Paul Jerome. High efficiency detection of low frequency alleles in cell-free DNA. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3621.
ECG Challenge: June 23/30, 2015
Authors: Philip Podrid
Journal: Circulation (2015)

ECG Challenge 2232A 76-year-old man with a history of hypertension for which he is taking lisinopril, metoprolol, and diltiazem presents to his primary care physician for a routine physical examination.He reports fatigue and occasional lightheadedness.His physical examination is unremarkable except for a slow pulse, which prompts an ECG.
Abstract 2516: TRIM8 modulates stem-like cells in glioblastoma
Authors: Changming Zhang, Mukherjee Subhas, Tucker-Burden Carol, Monica Chau, Jun Kong, Daniel Brat
Journal: Cancer Research (2016)

Abstract Glioblastoma stem-like cells (GSC) contribute to rapid growth and clinical recurrence of these fatal tumors and are highly resistant to therapy. STAT3 is known to contribute to maintenance and proliferation of GSC. Here we report a novel protein known as Tri-partite Motif containing protein 8 (TRIM8) that modifies tumor growth through STAT3. TRIM8, previously referred to as “glioblastoma expressed ring finger protein” is expressed at equal levels in glioblastoma and normal brain samples, despite showing hemizygous deletion in 87% of cases in TCGA data. To uncover mechanisms, we knocked down TRIM8 in glioblastoma-derived neurospheres using sh-RNA and found that this reduced the levels of phosphorylated STAT3 (p-STAT3), C-MYC and SOX2. Overexpression of TRIM8 resulted in higher expression of p-STAT3, C-MYC, SOX2 and CD133. We also found that specifically blocking STAT3 in neurospheres by pharmacological inhibition reduced the expression of TRIM8. Conversely, upregulation of STAT3 induced by IL-6 results in increased expression of TRIM8. Together, our results indicate that TRIM8 could potentially regulate GSC by forming a positive feedback loop with STAT3. Citation Format: Changming Zhang, Mukherjee Subhas, Tucker-Burden Carol, Monica Chau, Jun Kong, Daniel Brat. TRIM8 modulates stem-like cells in glioblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2516.
The effect of monosialylganglioside mix modifying the PEGylated liposomal epirubicin on the accelerated blood clearance phenomenon
Authors: Ting Zhang, Songlei Zhou, Le Kang, Xiang Luo, Yang Liu, Yanzhi Song, Xinrong Liu, Yihui Deng
Journal: Asian Journal of Pharmaceutical Sciences (2016)

PEGylated liposomes are potential candidates to improve the pharmacokinetic characteristics of encapsulated drugs, to extend their circulation half-life and facilitate their passive accumulation at tumour sites. However, PEG-modified liposomes can induce accelerated blood clearance (ABC) upon repeated administration, and the extent of ABC phenomenon on the cytotoxic drugs-containing PEGylated liposomes is related to the dose of the cytotoxic drugs. In this study, EPI served as a model cytotoxic drug, a hydrophilic surfactant molecule, monosialylganglioside (GM1) was chosen and modified on the liposomes together with PEG. It was shown that upon mixed modification, when GM1 contents reached 10% or 15% mol, the ABC phenomenon of the PEGylated liposomal EPI significantly reduced. We also found that GM1 played an important role in abrogating the ABC phenomenon in both the induction phase and the effectuation phase. The results suggested that GM1 incorporation unfortunately did not avoid occurrence of ABC phenomenon completely, but GM1 modification on PEGylated liposomes may provide a significant improvement in clinical practice of PEGylated liposomes. Further study must be necessary.
Abstract A21: Inhibition of USP7 for the treatment of multiple myeloma and other malignancies.
Authors: Benjamin Nicholson, Matthew P. Kodrasov, James P. LaRocque, Michael J. Eddins, Suresh Kumar, Dharminder Chauhan, Kenneth C. Anderson, Michael R. Mattern
Journal: Clinical Cancer Research (2015)

Abstract The conjugation and deconjugation of ubiquitin controls the stability, localization and activity of many cellular proteins. Deconjugation of ubiquitin is performed by a family of ~80 deubiquitylating enzymes (DUBs) including USP7 which specifically removes ubiquitin from HDM2, Foxp3, claspin and other therapeutically relevant substrates. Importantly, USP7 is overexpressed in human multiple myeloma cells and the expression level of USP7 inversely correlates with prognosis in multiple myeloma patients. Previously, we reported the discovery and characterization of P0005091 a USP7 inhibitor which exhibited anti-tumor activity in in vitro and in vivo models of multiple myeloma. Additionally, we reported that P0005091 inhibits USP47 a closely related DUB which is an emerging oncology target in its own right. Furthermore, a structural analog of P0005091, P0022077 has recently been reported by another research group to inhibit neuroblastoma growth in an orthotopic mouse model suggesting that in addition to hematological tumors, solid tumors may be treatable via inhibition of USP7. To obtain additional starting points for a USP7 or a USP7/USP47 specific drug discovery program we recently performed a new screening campaign. By utilizing a biophysical assay platform we were able to exclude compounds that bind to the active site of USP7 thus increasing the possibility of identifying allosteric modifiers of USP7 activity. Hits from this screen are currently the subject of hit to lead optimization and will be evaluated in biophysical and biochemical assays as well as in vitro and in vivo models of hematological malignancies. Data will be presented describing these results. Citation Format: Benjamin Nicholson, Matthew P. Kodrasov, James P. LaRocque, Michael J. Eddins, Suresh Kumar, Dharminder Chauhan, Kenneth C. Anderson, Michael R. Mattern. Inhibition of USP7 for the treatment of multiple myeloma and other malignancies. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr A21.
Abstract 5077: The insulin-like growth factor-2 (IGF-2): A potential therapeutic target for triple-negative breast cancer metastasis
Authors: Nalo Hamilton, Diana Marquez-Garban, Richard Pietras
Journal: Cancer Research (2016)

Abstract Introduction: Triple-negative breast cancers (TNBC) occur in 15-17% of patients, yet this subtype accounts for almost half of all breast cancer (BC) deaths. This breast cancer sub-type often occur in younger and African American (AA) women. TNBCs cannot be treated with current chemotherapies. Although initially responsive to chemotherapy, TNBCs tend to relapse and metastasize early. As there are no specific treatments for TNBCs, we aim to identify the therapeutic potential of insulin-like growth factor- 2 (IGF-2) in TNBC management. Methods: Using immunohistochemistry archival breast tissue from women with metastatic TNBC was evaluated and scored for IGF-2 expression. To assess the ability of IGF-2 to stimulate cell proliferation and migration we used commercially available TNBC cell lines validated to be ER-alpha-negative (ER-), progesterone receptor-negative (PR-) and Her2 overexperssion-negative (HER2). Results: We have found IGF-2 to be highly expressed archival breast tissue of women with metastatic TNBC. Using TNBC cell lines MDA-MB-231, HCC 38, HCC 1806 and HCC 1937, our in vitro studies demonstrate the ability of IGF-2 to stimulate TNBC proliferation and migration (P = 0.05). Further, the combination of NVP-AEW541, an insulin-like growth factor-1 receptor (IGF-1R) inhibitor, and BMS-754807, an inhibitor of IGF-1R and the insulin receptor (IR), cause a significant (P &amp;lt; 0.05) reduction in TNBC proliferation and migration. Investigation into the cellular characteristics of the TNBC cell lines used, suggest that BRCA1 mutations increase cell susceptibility to IGF-1R inhibitors. Conclusion: Our data indicate that IGF-2 plays a role in TNBC metastasis, an action that can be inhibited by targeting multiple IGF-2 mediated receptors. Citation Format: Nalo Hamilton, Diana Marquez-Garban, Richard Pietras. The insulin-like growth factor-2 (IGF-2): A potential therapeutic target for triple-negative breast cancer metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5077.
Abstract 3411: Role of mucin gene variations in microRNA binding sites in modulating colorectal cancer susceptibility and clinical outcomes
Authors: Petra Bendova, Veronika Vymetalkova, Barbara Pardini, Fabio Rosa, Cornelia di Gaetano, Ludmila Vodickova, Tomas Buchler, Alessio Naccarati, Pavel Vodicka
Journal: Cancer Research (2016)

Abstract Mucins, high molecular weight glycoproteins predominantly expressed at the epithelial surface of tissues, provide protection for colon surface under normal physiological conditions. Mucinous colorectal carcinoma is generally defined as having greater than 50% of the tumor area with a mucinous differentiation by histologic examination. MiRNAs have recently emerged as important regulators for altered mucin expression during malignant development. MiRNAs are short non-coding RNAs that regulate gene expression by binding to the 3’untranslated regions (3’UTR) of target mRNA thereby hampering protein translation or inducing mRNA destabilization. Aberrant miRNA expression and/or function are frequently observed in colorectal cancer (CRC). Polymorphisms in miRNA binding sites may affect miRNA binding to target genes, resulting in differential mRNA and protein expression and susceptibility to common diseases. We hypothesize that variations in mucin genes may modulate signaling response affecting cancer susceptibility, cancer survival and efficacy of chemotherapy. Thirteen polymorphisms in nine mucin genes (MUC6, MUC7, MUC13, MUC14, MUC15, MUC17, MUC20, MUC21 and MUC24) were analyzed in DNA samples of 1111 cases and 1469 controls from the Czech Republic. Investigated variants were also studied in association with clinical outcome in all patients provided with detailed information on follow up. Genetic variations in mucin genes were associated with clinical outcome. In particular, CRC patients carrying the CC genotype for rs886403 in MUC21 gene displayed a shorter survival and higher recurrence risk (HR 1.69; 95% CI 1.13-2.46; p = 0.01 and EFS: HR 1.99; 95% CI 1.38-2.84; p = 0.0002, resp.). The observed association was strikingly pronounced in colon cancer patients while individuals with rectal cancer and carrying variant CC genotype of rs4729655 in MUC17 displayed better overall survival (HR 0.27; 95% CI 0.14-0.54; p = 0.0002). Expanding our knowledge on mucin involvement in CRC may help us better understand the etiopathogenesis of this disease and thereby contribute to the development of new treatment strategies. The present results identified plausible candidate SNPs potentially affecting miRNAs that target mucin genes in relation to CRC patients’ survival. Work supported by IGA MZ: NT 15-26535A Citation Format: Petra Bendova, Veronika Vymetalkova, Barbara Pardini, Fabio Rosa, Cornelia di Gaetano, Ludmila Vodickova, Tomas Buchler, Alessio Naccarati, Pavel Vodicka. Role of mucin gene variations in microRNA binding sites in modulating colorectal cancer susceptibility and clinical outcomes. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3411.