tbuckley/cabot-search huggingface dataset:
Abstract 4127: Expression profiling of paired formalin-fixed, paraffin-embedded (FFPE) and fresh-frozen tissue samples on Ion Torrent PGMTM.
Authors: Jian Gu
Journal: Cancer Research (2013)

Abstract Archived formalin-fixed paraffin-embedded (FFPE) specimens represent excellent resources for biomarker discovery, but it has been a major challenge to study gene expression in these samples due to mRNA degradation and modification during fixation and processing. We have developed methods for small RNA and whole transcriptome analysis of FFPE samples on the Ion Torrent PGM™ System using Ion total RNA-Seq Kit v2 and RiboMinus Eukaryote System v2. Paired FFPE and fresh-frozen RNA samples from lung adenocarcinoma tissue were used in this study. Small RNA libraries were prepared using the Ion Total RNA-Seq kit v2 with modified protocol, followed by sequencing on PGM™ system. Results show that small RNA extracted from FFPE sample was successfully converted to small RNA library. Although percentage of reads mapped to miRBase was slightly lower when compared to fresh-frozen sample, the overall miRBase coverage and detection sensitivity were comparable. For whole transcriptome analysis, RiboMinus Eukaryote System v2 kit was used to deplete rRNA from FFPE samples, followed by library construction using the Ion Total RNA-Seq kit v2 with a modified protocol. Significant reduction in rRNA reads was observed after sequencing. High RefSeq correlations were observed between fresh-frozen and FFPE samples. In conclusion, a full spectrum of gene expression data, from both small RNA and whole transcriptome, were generated from FFPE samples using Ion Total RNA-Seq kit v2 with modified protocols. High correlations were observed between paired fresh-frozen and FFPE samples, demonstrating the reliability of the modified workflow for gene expression profiling on FFPE samples. This study provides feasibility for systematic gene expression analysis on FFPE samples from cancer and other diseases. Citation Format: Jian Gu. Expression profiling of paired formalin-fixed, paraffin-embedded (FFPE) and fresh-frozen tissue samples on Ion Torrent PGMTM. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4127. doi:10.1158/1538-7445.AM2013-4127
Abstract 3607: The effect of gefitinib on the expression of c-MYC and TSP-1 in cancer cells
Authors: Mitsuhiro Suenaga, Chuwa Tei, Shin-ichi Akiyama
Journal: Cancer Research (2010)

Abstract Gefitinib is a selective inhibitor of epidermal growth factor receptor tyrosine kinase, and is known to suppress tumor angiogenesis. We previously reported that gefitinib suppressed E2F-1 expression and telomerase activity in A431 and A549 cells. The expression of hTERT was increased by c-MYC, whereas we found that 5-FU decreased the expression of c-MYC and increased Thrombospondin-1 (TSP-1) expression. In the present study, we examined the effects of gefitinib on the expression of c-MYC and TSP-1 in human epidermmoid carcinoma A431 and lung adenocarcinoma A549 cells. Gefitinib suppressed the expression of c-MYC in both of two cell lines within 12 hours after gefitinib exposure, however, the expression of c-MYC mRNA was reduced only in A431 cells. A549 cells are known to have K-RAS mutation but A431 cells do not. We suppose that post-transcriptional inhibition or degradation of c-MYC had been induced by the treatment with gefitinib. MG132, a proteasome inhibitor, could inhibit the suppression of c-MYC expression by gefitinib exposure in both of these cells. Thus, the promotion of c-MYC degradation may be one of the mechanisms of the suppression of c-MYC expression by gefitinib exposure on these cells. On the other hand, in A549 cells, 5-20μM of gefitinib suppressed the expression of c-MYC after incubation for 96 hours too, while TSP-1 expression was increased by gefitinib. In A431 cells, 0.12-1.0μM of gefitinib affected the expression of c-MYC and TSP-1. As in A549 cells, TSP-1 expression was up-regulated but the expression of c-MYC was attenuated by gefitinib. Our findings suggest that the anti-angiogenic effects of gefitinib might be, at least in part, due to TSP-1 expression augmented by gefitinib. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3607.
Six Scientists Win 1989 Lasker Awards
Authors: D. Dortch
Journal: JNCI Journal of the National Cancer Institute (1989)

Six Scientists Win 1989 Lasker Awards Debbie Dortch Debbie Dortch Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 81, Issue 19, 4 October 1989, Pages 1447–1448, https://doi.org/10.1093/jnci/81.19.1447 Published: 04 October 1989
Activity and tolerability of afatinib (BIBW 2992) and cetuximab in NSCLC patients with acquired resistance to erlotinib or gefitinib.
Authors: Y. Y. Janjigian, H. J. Groen, L. Horn, E. F. Smit, Y. Fu, F. Wang, M. Shahidi, L. J. Denis, W. Pao, V. A. Miller
Journal: Journal of Clinical Oncology (2011)

7525^ Background: Despite initial responses to reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, (erlotinib or gefitinib), all non-small cell lung cancer (NSCLC) patients with EGFR-sensitizing mutations experience disease progression. This "acquired resistance" (AR) is associated with a second site exon 20 EGFR T790M mutation (M) in >50% of cases. No therapy, including the anti-EGFR antibody cetuximab plus erlotinib, has proven effective in treating AR (Janjigian YY. Clin Cancer Res; Epub Jan 2011). Preclinical data suggest afatinib, a potent ErbB family blocker, is active in T790M M cell lines such as H1975. Combined EGFR targeting with afatinib and cetuximab has induced near complete responses in T790M transgenic murine models. This study assesses safety and preliminary efficacy of this combination in NSCLC. Methods: NSCLC patients with clinically defined AR (Jackman D. J Clin Oncol 2010;28:357) received oral afatinib 40 mg daily with escalating dose cohorts of biweekly cetuximab at 250 and 500 mg/m2. Patients receiving the recommended Phase II dose (RP2D) were evaluated for objective response. Acquisition of tumor tissue after emergence of AR was mandated. Results: Of 26 treated patients, 22 received the predefined maximum dose (RP2D: afatinib 40 mg + cetuximab 500 mg/m2). Median time on erlotinib or gefitinib at study entry was 2.4 years. No dose-limiting toxicity was observed. Common adverse events were grade 1/2 rash (35/46%) and diarrhea (50/19%), respectively, and three patients (11.5%) had grade 3 rash. Disease control was observed in all patients enrolled at RP2D (tumor size reduction up to 76%; treatment duration up to 5+ months so far). Confirmed partial responses (PRs) were seen in 8/22 evaluable patients (36%, 95% confidence interval [CI]: 0.17–0.59), including 4/13 (29%) confirmed PRs in T790M+NSCLC. Enrollment has now begun in an 80-patient expansion cohort. Conclusions: Combined EGFR targeting with afatinib and cetuximab is tolerable at RP2D. Owing to encouraging clinical activity in AR to prior erlotinib or gefitinib, the study has been expanded. Elucidating mechanisms underlying regression in T790M+ and T790M– patients is critical.
Abstract O.31: Tenascin-C can be a Novel Prognostic Biomarker For Kawasaki Disease
Authors: Kyoko Imanaka-Yoshida, Yoshiaki Okuma, Takeji Matsushita, Michiaki HIroe, Kei Takahashi
Journal: Circulation (2015)

Tenascin-C (TNC) is an extracellular matrix glycoprotein sparsely detected in normal but highly expressed in pathological condition associated with inflammation in variety of tissues. By taking advantage of its specific expression, TNC is applicable as a biomarker and a molecular imaging target for diagnosis of disease activity for ventricular remodeling. In blood vessels, the expression of TNC in normal is generally low but strong expression is linked with several pathological conditions such as pulmonary artery hypertension, coronary atherosclerotic intima, and aortic aneurysm/ dissection. We hypothesized that TNC could be useful for evaluating disease activity of Kawasaki Disease(KD). We measured serum level of TNC of 174 patients with KD using ELSA and found that the TNC level was significantly higher than that of the controls, and the initial treatment with intravenous immunoglobulin decreased the level. Combination of serum TNC and Kobayashi score increased the accuracy to identify cases at a high risk of unresponsiveness to high-dose intravenous immunoglobulin. Immunohistochemical analysis of autopsied cases showed that TNC was strongly expressed in coronary vascular lesion at acute stage of KD patients as well as in the Candida albicans-induced murine model of vasculitis/aneurysm. Biomechanical analysis demonstrated that vascular flexibility was reduced in TNC knockout mice. A combination of inflammation and mechanical stress to aorta induced dissecting aneurysm in TNC knockout mice. In vitro, TNC enhanced macrophage migration and cytokine synthesis, meanwhile TNC synthesis was up-regulated by various pro-inflammatory cytokines. These results suggest that TNC is expressed in vascular lesion of KD reflecting active inflammation, which has diverse functions to modulate not only inflammatory response but also regulate vascular remodeling and aneurysm formation. TNC could be a key molecule in pathophysiology and a promising biomarker of KD.
Abstract 5105: Towards a multiparametric biomarker panel for pancreatic cancer detection
Authors: Shalini Makawita, Chris Smith, Ihor Batruch, Felix Rueckert, Eleftherios P. Diamandis
Journal: Cancer Research (2011)

Abstract Pancreatic cancer is one of the most highly lethal of all solid malignancies for which serological biomarkers to aid in the detection and clinical management of patients are urgently needed. To date, the lack of a single highly specific and sensitive marker for pancreatic cancer detection has led to a growing consensus in the field towards the development of panels of biomarkers, where-by the combinatorial assessment of multiple biomarkers will likely result in increased sensitivity and specificity. In this respect, we previously characterized the conditioned media of six pancreatic cancer cell lines (MIA-PaCa2, BxPc3, PANC1, Su.86.86, CAPAN1, CFPAC1) and the normal human pancreatic ductal epithelial cell line HPDE, as well as six pancreatic juice samples from pancreatic ductal adenocarcinoma patients using strong cation exchange followed by reverse-phase coupled online to an LTQ-Orbitrap mass spectrometer. This resulted in the identification of 3810 non-redundant proteins in the cell lines and 648 proteins in the pancreatic juice. All proteins were identified with 2 or more peptides. Through subsequent bioinformatic analyses which included hierarchical clustering, label-free protein quantification between the cancer and normal cell lines, cellular localization, tissue specificity and integration of the proteomes from the multiple biological fluids, a list of candidate pancreatic cancer biomarkers was generated. Preliminary verification of selected candidates using enzyme-linked immunosorbent assays (ELISAs) in a screening set of plasma samples from pancreatic cancer patients and healthy age-sex matched controls (n=40) show five proteins (designated PANC1, PANC2, PANC3, PANC4 and PANC5) to be significantly increased in pancreatic cancer plasma (p=0.0011, p&amp;lt;0.0001, p&amp;lt;0.0001, p&amp;lt;0.0001 and p=0.0098, respectively). Individually, these proteins did not exhibit improved area under the curve (AUC) in comparison to CA19.9 levels measured in the same samples; however the combination of the five proteins with CA19.9 showed improved AUC to CA19.9 alone (CA19.9 alone AUC = 0.97; all proteins with CA19.9 AUC = 1.0). These data suggest that this novel panel warrants further evaluation as a pancreatic cancer diagnostic tool. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5105. doi:10.1158/1538-7445.AM2011-5105
Abstract 5165: Pathway oriented phospho-proteomics analysis with reverse phase protein array (RPPA) technology in cell growth and cancer therapy.
Authors: Takeomi Inoue, Naoko Iwata, Eiji Nishiwaki, Yasuyuki Kirii
Journal: Cancer Research (2013)

Abstract A number of molecularly targeted drugs have been successfully launched as anti-cancer agents, and intensive efforts are underway to discover new targets and their modifiers. Nevertheless, many compounds selected by enzyme screening methodology demonstrated unexpected effects in intact cells or animal models. Since recent efforts from signaling pathway analysis have revealed that complexity of signaling networks, homeostatic controls and off-target effects can lead to unexpected cellular/in vivo consequences, profiling the effects of drug candidates on a wide range of intracellular signaling pathways is becoming an attractive strategy. Many proteomics approaches, especially in the area of phospho-proteomics, have been developed, and their applications are rapidly growing for the purpose of cellular signal profiling. Among these approaches, reverse phase protein array (RPPA) is one of the most powerful technologies because of its high sensitivity and reliability. We have developed a signal transduction oriented RPPA system that focuses on phospho-protein profiles in samples. Thus far, our system utilizes approximately 180 phospho-protein specific antibodies and can profile the phosphorylation status of more than 100 Gene Ontology processes covering more than 10 components in each process. Our current studies on modification of cellular signals induced by tyrosine kinase inhibitors (TKIs) in several cancer cell types are elucidating novel mechanisms for TKI actions. For example, our studies on Erlotinib and Gefitinib treated cells have resulted in very similar profiles as EGF-stimulated cancer cells. However, several differences in the signaling profiles between them may suggest differences of efficacy and toxicity. Independently, we have developed a nearly comprehensive in vitro kinase inhibitor profiling system, and we already have complete inhibition profiles for nine kinase inhibitors such as Erlotinib or Gefitinib. This allows us to combine in vitro profiling results with pathway intervention profiles to build a database integrating kinase-inhibition-potencies and cellular-signaling-profiles. Our aim is to expand this database to obtain new information to guide strategies for effective targeting in drug discovery. In this presentation, we present the novel targeting discovery strategy based on this database analysis. Citation Format: Takeomi Inoue, Naoko Iwata, Eiji Nishiwaki, Yasuyuki Kirii. Pathway oriented phospho-proteomics analysis with reverse phase protein array (RPPA) technology in cell growth and cancer therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5165. doi:10.1158/1538-7445.AM2013-5165
AB0938 Clinical features and prevalence of psoriatic arthritis in patients with cutaneous psoriasis referred from the primary care
Authors: J.L. Fernandez-Sueiro, S. Pértega Diaz, J. Pinto Tasende, E. González, J. Fernández Lopez, N. Oreiro, F. de Toro, F. Blanco
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> The prevalence of psoriatic arthritis in patients with psoriasis goes from 6-42%, these differences may be due to the studied population, the definition of the disease and the estimation based on questionnaires. <h3>Objectives</h3> To estimate the prevalence of PsA in patients with cutaneous psoriasis referred from the primary care <h3>Methods</h3> Cross sectional study evaluating patients referred from the primary care with a diagnosis of cutaneous psoriasis without arthritis. Patients were evaluated in the following way: personal and family history, criteria for IBP, spinal and peripheral pain (VAS), peripheral joint count: tender and swollen (78/76), metrology (cervical rotation (CR), occiput to wall distance (OW), lateral lumbar flexion (LLF), modified Schober (mS)). MASES. SF12, DLQI, PASI, BSA. Peripheral and axial x-rays. ESR, CRP, anti CCP and HLA-B27. Case definition was made according to clinical judgement. A descriptive analysis of the variables was performed. <h3>Results</h3> 122 patients were studied. The medium age was 53,06±16,42 years. 57,4% were female, time of psoriasis duration was 23,4±15,1 years. 72,1% had type I psoriasis. 29,8% nail involvement, 1,6% dactylitis. IBP 12,3%. Nocturnal and overall spinal pain past week 1,76±2,88 and 2,13±3,04, peripheral VAS 2,65±3,3. TJC 0,57±3,11, SJC 0,01±0,09. mS 4,46±0,89, OW 0,11±0,85, LLF 16,25±3,99, CR &lt;70°: 5%, enthesitis 10,7%, PASI 0,21±0,98, BSA &lt;10%: 95,9%, DLQI 1,64±2,55 SF12 physical 50±8,7, SF12 mental 45,5±11,3, ESR ≤20 72,1%, CRP &lt;0,8: 83% anti-CCP ≤25: 97,2%. Negative FR: 90,1%. Negative HLA-B27: 90,3%. Peripheral erosions: 19%, at least grade II unilateral sacroiliitis: 15,5%. According to clinical criteria 12 patients had PsA 9,8% (95%IC: 4,1%–15,5%). These patients had: nail involvement: 25%, dactylitis 8,3%. Nocturnal and overall spinal pain past week 3,25±3,57 and 4,17±3,35, peripheral VAS 6,33±3,31, TJC 4,50±9,04, SJC 0,00, mS 4,48±1,03, OW 0,00, LLF 14,92±4,42. CR &lt;70°: 8,3%, enthesitis 41,7%, PASI 0,33±1,15, BSA &lt;10%: 100%, DLQI 1,42±1,56 SF12 physical 43,09±11,39, SF12 mental 39,28±12,11, ESR ≤20 70%, CRP &lt;0,8: 80%, anti-CCP ≤25: 100%. Negative FR 91,7%. Negative HLA-B27 91,7%. Peripheral erosions 18,2%, sacroiliitis grade II unilateral or higher 45,5% <h3>Conclusions</h3> In this cross sectional study applying clinical judgment as gold standard for the diagnosis of PsA, the prevalence of PsA in patients with cutaneous psoriasis referred from the primary care was of 9,8%. Funded with a grant from: Instituto de Salud Carlos III, FIS PI080789 <h3>Disclosure of Interest</h3> None Declared
BRCA somatic mutations and epigenetic BRCA modifications in serous ovarian cancer
Authors: M. Moschetta, A. George, S.B. Kaye, S. Banerjee
Journal: Annals of Oncology (2016)

The significant activity of poly(ADP-ribose)polymerase (PARP) inhibitors in the treatment of germline BRCA mutation-associated ovarian cancer, which represents ∼15% of HGS cases, has recently led to European Medicines Agency and food and drug administration approval of olaparib. Accumulating evidence suggests that PARP inhibitors may have a wider application in the treatment of sporadic ovarian cancers. Up to 50% of HGS ovarian cancer patients may exhibit homologous recombination deficiency (HRD) through mechanisms including germline BRCA mutations, somatic BRCA mutations, and BRCA promoter methylation. In this review, we discuss the role of somatic BRCA mutations and BRCA methylation in ovarian cancer. There is accumulating evidence for routine somatic BRCA mutation testing, but the relevance of BRCA epigenetic modifications is less clear. We explore the challenges that need to be addressed if the full potential of these markers of HRD is to be utilised in clinical practice.
Cell proliferation not associated with carcinogenesis in rodents and humans.
Authors: J M Ward, H Uno, Y Kurata, C M Weghorst, J J Jang
Journal: Environmental Health Perspectives (1993)

Cell proliferation has often been found to be associated with carcinogenesis in rodents and humans at different stages of the multistage carcinogenesis process. The multistage process includes initiation, promotion, and progression phases. At each phase, increasing the normal level of cell turnover of target cells may enhance carcinogenesis. However, we present evidence that normal levels of cell turnover, or increasing the rate of cell turnover at these different stages, do not necessarily lead to enhanced carcinogenesis. In normal tissues, the length of the cell cycle depends on the age of the host and varies from tissue to tissue. Tissues with normal short cell cycles, such as intestine and bone marrow, do not show a high rate of spontaneous tumors in most species. Cells with higher turnover should be more susceptible to carcinogens at the initiation stage of carcinogenesis if cell proliferation per se causes cancer and if these cells or their progeny survive. Cancer in humans is more often associated with specific etiological factors rather than with the natural proliferative rate of specific tissues. For many tissues of humans and rodents, age-related diseases develop in a progressive, irreversible manner. Often, naturally occurring chronic degenerative and inflammatory changes in a tissue (e.g., kidney, liver, heart, reproductive tract) lead to chronic regeneration of the damaged tissue. Yet, cancer is rarely found in these tissues. In rodent carcinogenesis experiments, chronic toxic lesions, accompanied by increases in normal levels of cell turnover, have sometimes been observed in target organs of nongenotoxic carcinogens. More often, however, organ-specific nongenotoxic toxins are not carcinogens. These toxins include compounds toxic for the liver, kidney, and nasal cavity. In 19 inhalation bioassays conducted by the National Toxicology Program, 5/5 nasal carcinogens and 12/14 nasal noncarcinogens caused nasal lesions usually associated with chronic cell proliferation. Although cell proliferation may contribute to multistage carcinogenesis, cell proliferation is not necessarily a tumor promoter or cocarcinogen.
Abstract LB-320: Inhibition of TGFß1 improves the therapeutic efficacy of non-immunologic tumor cell based vaccine
Authors: Pu Liu, Jade Jaffar, Elizabeth Swisher, Karl Erik Hellstrom, Ingegerd Hellström
Journal: Cancer Research (2010)

Abstract Background and objectives of the study: Many cancers, including ovarian cancer, over-express transforming growth factor-beta (TGF-ß), which helps them evade immune control through a variety of mechanisms. We investigated whether the efficacy of tumor cells to induce an immune response, when used intact or as part of a dendritic cell (DC)-based vaccine can be enhanced by inhibiting their production of TGFß1 via anti-sense. Methodology: The TGFß1 expression by two ovarian cancer cell lines was silenced by transfection with a non-replicating lentivirus shRNA. Autologous PBMC were co-cultivated, in the presense of IL-2, with Mitomycin-C (MMC) treated cancer cells or mature dendritic DC that had been pulsed with tumor lysates. The in vitro sensitized lymphoid cells were evaluated by ELISPOT for production of IFN-γ and by flow cytometry. Preliminary data: Quanitative ELISA showed that TGFß1 production in the two ovarian cancer lines was signficantly inhibited by transfection with shRNA. In vitro sensitization of autologous PBMC with either tumor cells where the TGFß1 gene had been silenced or with DC that had been pulsed with homogenates of tumor cells with a silencd TGFß1 gene induced a stronger IFNγ release and increased the frequency of NK cells and DC while it decreased the population of Treg cells. We are presently investigating the anti-tumor response in a mouse melanoma model after vaccination with murine bone-marrow derived DC which have benn pulsed with TGFß silenced tumor lysates. Conclusions: The production, by many tumors, of TGFß1 interferes with their ability to induce an anti-tumor response. This is true both when intact tumor cells and DC pulsed with tumor homogenate are used as immunogen. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-320.