tbuckley/cabot-search huggingface dataset:
Abstract 4875: HIVE Proteomics: Integrated, cloud-based RNA-Seq and proteomics analysis of prostate adenocarcinoma samples
Authors: Hayley Dingerdissen, Raja Mazumder
Journal: Cancer Research (2015)

Abstract Automated bottom-up proteomics workflows implemented with modern mass-spectrometry instrumentation can readily generate millions of peptide fragmentation spectra from cell-lines and clinically derived samples. The tandem mass-spectra promise to reveal wild-type and somatic mutations, insertions, and deletions and alternatively spliced isoforms translated to functional protein isoforms in tumor samples. However, the available reference proteomes represent a poor analysis substrate for the observation of protein evidence of genomic and transcript variation. The advent of cheap and fast RNA sequencing (RNA-Seq) provides an elegant solution to the lack of sample-specific reference proteomes. We anticipate that the falling cost of RNA-Seq will prompt an increasing number of proteomics labs to use contract next-gen sequencing (NGS) services to obtain RNA-Seq data to derive sample-specific reference proteomes. In contrast to public repositories of genomic variation, sample-specific RNA-Seq data captures transcribed rare, individual, cell-type, and sample-specific genomic variation. RNA-Seq-based transcripts also provide sample-specific information on observable proteins. Furthermore, paired RNA-Seq and proteomics data links gene expression and protein abundance, enabling the study of gene regulation linked to protein abundance dynamics. However, the analysis of multi-gigabyte paired mass-spectra and RNA-Seq datasets pose significant scientific and logistical challenges. Few proteomics labs have the personnel, archival data storage, computational resources, or informatics pipelines needed. The cloud-based genomics analysis platform High-performance Integrated Virtual Environment (HIVE) will provide turn-key integrated proteomics and RNA-Seq analyses to the wider proteomics community in a secure, trackable, sharable, and scalable computing platform. We will then use this integrated proteomics_RNA-Seq analysis pipeline to identify high-value mutations in prostate adenocarcinoma samples, thereby demonstrating the utility of the platform while also generating key data for future investigations. Citation Format: Hayley Dingerdissen, Raja Mazumder. HIVE Proteomics: Integrated, cloud-based RNA-Seq and proteomics analysis of prostate adenocarcinoma samples. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4875. doi:10.1158/1538-7445.AM2015-4875
147. Transcription Factor Binding Site in Plasmid Regulates Persistence of Transgene Expression in Mouse Liver
Authors: Chunbo Zhang, Leping Li, Dexi Liu
Journal: Molecular Therapy (2015)

Persistent expression of transgene is most desirable for treatment of genetic diseases. It is primarily controlled by genetic elements in the promoter region where transcription factors bind. The objective of this study is to assess the role of the transcription factor binding sites (TFBS) present in the most commonly used CMV and albumin promoters containing the promoter core sequence and several TFBS for ATF1, NFκB, SRF, AP1, Sp1, NF1α, CEBPA, HNF4α, and HNF1 in determining persistency of transgene expression in mice. Secreted embryonic alkaline phosphatase (SEAP) and interleukin 10 (IL-10) were used as a reporter to monitor transgene expression. Various deletion mutation plasmids at the promoter region were made to examine the function of each of the TFBS in regulating reporter gene expression. Similarly, a series of new plasmids containing only one TFBS inserted at the 5' end of the TATA-box region was made to assess its unique activity in affecting transgene expression. Our results showed that TFBSs are essential for effective transgene expression in mouse liver after a hydrodynamic tail vein gene delivery. Plasmid with a TATA-box with all TFBS deleted resulted in minimal level of gene product, 700-fold lower than the original plasmids. Reporter gene expression appears transient reaching the background level in less than 2 weeks. The more TFBS the plasmid has, the higher level of gene product was seen. Plasmid containing a single TFBS either NFκB, ATF1, CEBPA, HNF4α, or HNF1 exhibits persistent transgene expression for more than 2 months, at which animals injected with plasmids containing NFkB, ATF1, CEBPA, HNF4α, or HNF1 exhibited gene product level 60, 130, 1020, 2250, and 2076 folds higher than that of animals injected with plasmids without TFBS, respectively. Mechanism study employing real time PCR, Western Blotting, and ChIP reveals involvement of histone acetylation and the binding of acetylated histones to plasmid DNA sequences in TFBS-mediated enhancement in persistency of reporter gene expression. TFBSs for HNF4α appear most potent in recruiting H4AC and TBP proteins to the plasmids. Our results suggest that TFBSs for NFkB, ATF1, CEBPA, HNF4α, and HNF1 are important elements to include into the promoter for achieving longer-term gene expression. In addition, histone acetylation on plasmid is a probable pathway that TFBS regulate the duration of transgene expression.
Mucinous appendiceal tumors of uncertain malignant potential (UMP): Prognostic factors and implications for treatment and follow-up.
Authors: K. F. Fournier, R. Royal, L. A. Lambert, M. Taggart, S. Rafeeq, P. F. Mansfield
Journal: Journal of Clinical Oncology (2011)

372 Background: The diagnosis of UMP is used for dysplastic mucinous tumors that are difficult to classify as clearly benign or malignant. Given the rarity of this tumor, management of these patients is unclear. Methods: All patients with a pathologic diagnosis of an appendiceal mucinous UMP who underwent evaluation at a single institution between September 1993 and July 2009 were retrospectively reviewed. Patient demographics, operative findings, pathology, tumor markers, procedures performed, recurrence, overall survival, and disease-free survival were determined. Results: Of 688 patients with appendiceal neoplasms, 62 (9%) patients (pts) were identified as having UMP. Initial procedures included: appendectomy - 45, colectomy - 11, cytoreduction - 2, and other - 4. Median follow-up was 43.2 months (range 2-184 mos). Median overall survival (OS) was 11.5 years (range 2-184 mos). Median disease-free survival (DFS) has not been reached. There was a trend towards improved DFS in patients who are: female, &lt; 65 years of age, or have mucin confined to the appendix or its serosal surface. Clinicopathologic factors associated with a significantly worse overall DFS included elevated serum CEA (3.6 years, p = 0.0129) and CA-125 (4.16 years, p = 0.0288). DFS at 8 years follow-up in patients with a normal CEA was as follows: 100% if mucin confined to lumen of the appendix, 90% if mucin confined to serosa, and 69% if mucin was in an extra-appendiceal location. 15 patients developed recurrent disease and had an OS of 4.6 years after recurrence. Conclusions: Mucinous UMP tumors of the appendix have an overall favorable prognosis. In patients with a negative margin and mucin confined to the appendix or serosa, expectant management may be sufficient. Elevation of CEA or CA-125 may warrant closer monitoring or intervention. If confirmed in a larger cohort, these findings may have substantial implications for management of these patients. No significant financial relationships to disclose.
723. AAV Mediated Cancer Targeting: Systemic Trafficking to Tumor Is More Important Than Vector Tumor Cell Interaction
Authors: Yuan Lu, Damien Marsic, Chen Ling, Maria V. Guijario, Padraic P. Levings, Glyn D. Palmer, Anthony Dacanay, Rachael S. Watson-Levings, Viktoria Hyddmark, Margaret E. White, Sergei Zolotukhin, Steven C. Ghivizzani
Journal: Molecular Therapy (2016)

Adding tumor specific ligands to enhance vector tumor cell interaction is the conventional concept to generate tumor targeting adeno-associated viral vector (AAV). However, it remains poorly proved whether high AAV tumor cell interaction contributes to high tumor localization in vivo following systemic delivery. Here, we conducted directed evolution selections on patient derived xenograft models using a complex AAV capsid library. Uniquely, we compared the pressure for AAV tumor cell interaction alone (intratumoral library injection) and multi-layer pressure including traveling to the tumor and infection (intravenous library injection). Distinct patterns of AAV capsid motifs were identified after intratumoral and intravenous screenings. Motifs isolated from intratumoral screenings were named tumor specific motifs and those isolated from intravenous screenings were named systematic trafficking motifs. AAVs with tumor specific motifs but not systemic trafficking motifs showed significantly increased tumor cell transduction in vitro, indicating enhanced vector target cell interaction after intratumoral-based selections. Interestingly, following systemic delivery, AAVs with systemic trafficking motifs mediated hundreds of folds higher transgene expression than those with tumor specific motifs and wild type AAV in vivo. The combination of both motifs further increases the tumor tropism but not the transduction efficiency in vivo. When analyzing the AAV genome biodistribution by quantifying the genome copy number, the systemic trafficking motifs greatly reduced the native AAV tropism, which potentiated higher accessibility of AAV to the tumor. In contrast, AAVs only bearing tumor specific motifs maintained native AAV tropism and failed to mediate increased genome localization in tumor. Furthermore, in two independent patient derived xenograft models and two different tumor types, our novel AAV vector armed with combined motifs all showed hundreds of folds increase in transduction efficiency with no detectable off-targeting expression. In conclusion, contradictory to the prevailing theory, our study demonstrated that the AAV tumor cell interaction did not contribute to increased tumor localization but just specificity in vivo. Therefore, targeting is not only depending on AAV tumor cell interaction but also, and more importantly, depending on the accessibility of AAV to the tumor cells following systemic delivery. Future cancer directed AAV vector design should take into account the complex processes during systemic delivery as well as the vector tumor cell interaction.
E1308: Phase II Trial of Induction Chemotherapy Followed by Reduced-Dose Radiation and Weekly Cetuximab in Patients With HPV-Associated Resectable Squamous Cell Carcinoma of the Oropharynx— ECOG-ACRIN Cancer Research Group
Authors: Shanthi Marur, Shuli Li, Anthony J. Cmelak, Maura L. Gillison, Weiqiang J. Zhao, Robert L. Ferris, William H. Westra, Jill Gilbert, Julie E. Bauman, Lynne I. Wagner, David R. Trevarthen, Jahagirdar Balkrishna, Barbara A. Murphy, Nishant Agrawal, A. Dimitrios Colevas, Christine H. Chung, Barbara Burtness
Journal: Journal of Clinical Oncology (2017)

Purpose Human papillomavirus (HPV)–associated oropharyngeal squamous cell carcinoma (OPSCC) is treatment-responsive. Definitive chemoradiation results in high cure rates but causes long-term toxicity and may represent overtreatment of some patients. This phase II trial evaluated whether complete clinical response (cCR) to induction chemotherapy (IC) could select patients with HPV-associated OPSCC for reduced radiation dose as a means of sparing late sequelae. Methods Patients with HPV16 and/or p16-positive, stage III-IV OPSCC received three cycles of IC with cisplatin, paclitaxel, and cetuximab. Patients with primary-site cCR to IC received intensity-modulated radiation therapy (IMRT) 54 Gy with weekly cetuximab; those with less than cCR to IC at the primary site or nodes received 69.3 Gy and cetuximab to those regions. The primary end point was 2-year progression-free survival. Results Of the 90 patients enrolled, 80 were evaluable. Their median age was 57 years (range, 35 to 73 years), with the majority having stage T1-3N0-N2b OPSCC and a history of ≤ 10 pack-years of cigarette smoking. Three cycles of IC were delivered to 77 of the 80 patients. Fifty-six patients (70%) achieved a primary-site cCR to IC and 51 patients continued to cetuximab with IMRT 54 Gy. After median follow-up of 35.4 months, 2-year progression-free survival and overall survival rates were 80% and 94%, respectively, for patients with primary-site cCR treated with 54 Gy of radiation (n = 51); 96% and 96%, respectively, for patients with &lt; T4, &lt; N2c, and ≤ 10 pack-year smoking history who were treated with ≤ 54 Gy of radiation (n = 27). At 12 months, significantly fewer patients treated with a radiation dose ≤ 54 Gy had difficulty swallowing solids (40% v 89%; P = .011) or had impaired nutrition (10% v 44%; P = .025). Conclusion For IC responders, reduced-dose IMRT with concurrent cetuximab is worthy of further study in favorable-risk patients with HPV-associated OPSCC. Radiation dose reduction resulted in significantly improved swallowing and nutritional status.
Detection of an Infant’s Duodenal Atresia by Milk Scan
Authors: Ha Wu, Zhiheng Huang, Min Ji, Yiwei Li, Ruifang Zhao
Journal: Clinical Nuclear Medicine (2016)

Duodenal membranous atresia is a rare congenital disease. Here, we present a case of 6-month-old girl referred to us for repeated vomiting since birth. Milk scan was performed, and the results revealed a typical “double-bubble” sign. In addition, only very little activity was shown in the small intestine even at the end of the scintigraphy. These results led to the diagnosis of duodenal atresia, which was subsequently confirmed by gastroenterography and laparotomy. Our case demonstrated the potential value of milk scan in the diagnosis of this congenital disorder.
Using BV6 to enhance radiosensitivity in non-small cell lung cancer cell lines.
Authors: A. Torossian, W. Li, B. Li, N. Giacalone, B. Lu
Journal: Journal of Clinical Oncology (2011)

e13508 Background: Radiation therapy for non-small cell lung cancer (NSCLC) profoundly relies on the efficient function of the apoptosis pathway. Overexpression of cIAP1 and XIAP, members of the inhibitors of apoptosis (IAP) family, is associated with resistance to therapy. We studied the ability of BV6, an IAP antagonist, to sensitize NSCLC cell lines to radiation therapy. Methods: Following treatment of NSCLC cell lines HCC193 and H460 with BV6, cell survival was measured using MTS assays. Immunoblotting for cleaved caspase 3, cIAP1, and XIAP was used to establish the role of apoptosis in the mechanism of action of BV6. The radiosensitizing effect of BV6 was studied using clonogenic survival assays. The pathway of apoptosis in the cell lines was studied with western blot analysis for cleaved caspase 8 and 9, in addition to ELISA analysis for TNF-α. Results: Sensitivity to BV6 induced apoptosis was established in both cell lines in a concentration and time dependent manner; HCC193, however, was more sensitive than H460. Based on the relative sensitivities of the cell lines, higher concentrations (HCC193- 1µM; H460- 5µM) and longer incubation periods (HCC193- 24 hours; H460- 48 hours) were used to study BV6 in H460 than in HCC193. Treatment with BV6 was found to decrease levels of cIAP1 and XIAP expression. BV6 was found to significantly enhance radiosensitivity in both cell lines (HCC193-DER=1.38; H460- DER=1.42). Radiation and BV6 combination treatment was found to synergistically increase apoptosis in the HCC193 and H460 cell lines. The radiosensitivity associated with BV6 induced apoptosis was found to occur through the extrinsic apoptotic pathway in HCC193, while that of H460 was through the intrinsic apoptotic pathway. Conclusions: BV6, an IAP antagonist, was found to significantly enhance radiosensitivity in two NSCLC cell lines, one of which was relatively insensitive to BV6. Further investigation of BV6 and other IAP antagonists and their potential use in the clinical setting for increasing the therapeutic ratio of radiation therapy in lung cancer is warranted.
Unrelated Cord Blood Transplantation in Patients with Hematologic Malignancies in Brazil – A Sociedade Brasileira De Transplantes De Medula Ossea and Eurocord Collaborative Study.
Authors: Celso Arrais Rodrigues, Daniela Setubal, Carmem Bonfim, Samir Kanaan Nabhan, Vergílio Antônio Renzi Colturato, Marcos Augusto Mauad, Mair Pedro de Souza, Alexandre Mello de Azevedo, Nelson Hamerschlak, Adriana Seber, Henrique Bittencourt, Matheus Vescovi Gonçalves, Claudio Galvao de Castro, Frederico L. Dulley, Carmino Antonio De Souza, Wagnara Chaves, Jose Zanis Neto, Ricardo Pasquini, Eliane Gluckman, Vanderson Rocha, Luis Fernando Bouzas
Journal: Blood (2009)
Low Incidence of GVHD and Treatment-Related Morbidity (TRM) with Intermediate Doses of Continuous Infusion IV Busulfan and Daily Fludarabine with Individualized Doses of Alemtuzamab for Matched Related (MRD) and Unrelated (MUD) Transplant Pts with High-Risk Hematologic Malignancies.
Authors: Thomas Shea, Jonathan Serody, Don Gabriel, Terrance Comeau, Anastasia Ivanova, Dominic Moore, Robert Irons, Whitley Julia, Sharf Andrew, Cherie Dunphy, Brecher Mark
Journal: Blood (2007)
Implications of telomeres and telomerase in endometrial pathology
Authors: D.K. Hapangama, A. Kamal, G. Saretzki
Journal: Human Reproduction Update (2016)

Eukaryotic chromosomal ends are linear and are protected by nucleoprotein complexes known as telomeres. The complex structural anatomy and the diverse functions of telomeres as well as the unique reverse transcriptase enzyme, telomerase that maintains telomeres are under intensive scientific scrutiny. Both are involved in many human diseases including cancer, but also in ageing and chronic disease such as diabetes. Their intricate involvement in many cellular processes and pathways is being dynamically deciphered in many organs including the endometrium. This review summarizes our current knowledge on the topic of telomeres and telomerase and their potential role in providing plausible explanations for endometrial aberrations related to common gynaecological pathologies. This review outlines the recent major findings in telomere and telomerase functions in the context of endometrial biology. It highlights the contemporary discoveries in hormonal regulation, normal endometrial regeneration, stem cells and common gynaecological diseases such as endometriosis, infertility, recurrent reproductive failure and endometrial cancer (EC). The authors carried out systematic PubMed (Medline) and Ovid searches using the key words: telomerase, telomeres, telomere length, human telomerase reverse transcriptase, telomeric RNA component, with endometrium, hormonal regulation, endometrial stem/progenitor cells, endometrial regeneration, endometriosis, recurrent miscarriage, infertility, endometrial hyperplasia, EC and uterine cancer. Publications used in this review date from 1995 until 31st June 2016. The human endometrium is a unique somatic organ, which displays dynamic telomerase activity (TA) related to the menstrual cycle. Telomerase is implicated in almost all endometrial pathologies and appears to be crucial to endometrial stem cells. In particular, it is vital for normal endometrial regeneration, providing a distinct route to formulate possible curative, non-hormonal therapies to treat chronic endometrial conditions. Furthermore, our current understanding of telomere maintenance in EC is incomplete. Data derived from other malignancies on the role of telomerase in carcinogenesis cannot be extrapolated to EC because unlike in other cancers, TA is already present in proliferating healthy endometrial cells. Since telomerase is pivotal to endometrial regeneration, further studies elucidating the role of telomeres, telomerase, their associated proteins and their regulation in normal endometrial regeneration as well as their role in endometrial pathologies are essential. This approach may allow future development of novel treatment strategies that are not only non-hormonal but also potentially curative.
Abstract LB-093: Activation of the FGFR1 signaling pathway by the epstein-barr virus-encoded LMP1 promotes aerobic glycolysis and transformation of human nasopharyngeal epithelial cells
Authors: Kwok Fung Lo, Christopher W Dawson, Lawrence S Young, Kwok Wai Lo
Journal: Cancer Research (2015)

Abstract Undifferentiated nasopharyngeal carcinoma (NPC) is closely associated with Epstein-Barr virus (EBV) latent infection. The EBV-encoded latent membrane protein 1 (LMP1) oncogene is believed to be important in NPC pathogenesis by virtue of its ability to activate multiple cell signaling pathways to induce proliferation, transformation, angiogenesis and invasiveness as well as modulation of energy metabolism. In this study, we report that LMP1 increases cell uptake of glucose and glutamine, enhances LDHA activity and lactate production, but reduces pyruvate kinase activity and pyruvate concentration. LMP1 also increases the phosphorylation of PKM2, LDHA and FGFR1 as well as expression of PDHK1, FGFR1, c-Myc and HIF-1α regardless of oxygen availability. This suggests that LMP1 promotes aerobic glycolysis. In addition to FGFR1, LMP1 also upregulates FGF2, the FGFR1 ligand, setting up a constitutive activation loop of FGFR1 signaling to promote aerobic glycolysis. FGFR1 inhibitors also abolish LMP1-mediated cellular transformation (proliferation and anchorage-independent growth) as well as cell migration and invasion in nasopharyngeal epithelial cells. Immunohistochemical staining revealed that a high level of phosphorylated FGFR1 is common in primary NPC specimens, and that this correlated with the expression of LMP1. Inhibition of FGFR1 activity in NPC cells results in the suppression of cell proliferation and anchorage-independent growth. Our current findings demonstrate that LMP1-mediated FGFR1 activation contributes to growth and transformation of epithelial cells, thereby implicating FGF2/FGFR1 signaling activation in the EBV-driven pathogenesis of NPC. Citation Format: Kwok Fung Lo, Christopher W Dawson, Lawrence S Young, Kwok Wai Lo. Activation of the FGFR1 signaling pathway by the epstein-barr virus-encoded LMP1 promotes aerobic glycolysis and transformation of human nasopharyngeal epithelial cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-093. doi:10.1158/1538-7445.AM2015-LB-093