tbuckley/cabot-search huggingface dataset:
LNK/SH2B3 Loss of Function Promotes Atherosclerosis and Thrombosis
Authors: Wei Wang, Yang Tang, Ying Wang, Liana Tascau, Joanna Balcerek, Wei Tong, Ross L. Levine, Carrie Welch, Alan R. Tall, Nan Wang
Journal: Circulation Research (2016)

Rationale: Human genome-wide association studies have revealed novel genetic loci that are associated with coronary heart disease. One such locus resides in LNK/SH2B3 , which in mice is expressed in hematopoietic cells and suppresses thrombopoietin signaling via its receptor myeloproliferative leukemia virus oncogene. However, the mechanisms underlying the association of LNK single-nucleotide polymorphisms with coronary heart disease are poorly understood. Objective: To understand the functional effects of LNK single-nucleotide polymorphisms and explore the mechanisms whereby LNK loss of function impacts atherosclerosis and thrombosis. Methods and Results: Using human cord blood, we show that the common TT risk genotype (R262W) of LNK is associated with expansion of hematopoietic stem cells and enhanced megakaryopoiesis, demonstrating reduced LNK function and increased myeloproliferative leukemia virus oncogene signaling. In mice, hematopoietic Lnk deficiency leads to accelerated arterial thrombosis and atherosclerosis, but only in the setting of hypercholesterolemia. Hypercholesterolemia acts synergistically with LNK deficiency to increase interleukin 3/granulocyte-macrophage colony-stimulating factor receptor signaling in bone marrow myeloid progenitors, whereas in platelets cholesterol loading combines with Lnk deficiency to increase activation. Platelet LNK deficiency increases myeloproliferative leukemia virus oncogene signaling and AKT activation, whereas cholesterol loading decreases SHIP-1 phosphorylation, acting convergently to increase AKT and platelet activation. Together with increased myelopoiesis, platelet activation promotes prothrombotic and proatherogenic platelet/leukocyte aggregate formation. Conclusions: LNK (R262W) is a loss-of-function variant that promotes thrombopoietin/myeloproliferative leukemia virus oncogene signaling and platelet and leukocyte production. In mice, LNK deficiency is associated with both increased platelet production and activation. Hypercholesterolemia acts in platelets and hematopoietic progenitors to exacerbate thrombosis and atherosclerosis associated with LNK deficiency.
The IASLC Mesothelioma Staging Project: Proposals for Revisions of the N Descriptors in the Forthcoming Eighth Edition of the TNM Classification for Pleural Mesothelioma
Authors: David Rice, Kari Chansky, Anna Nowak, Harvey Pass, Hedy Kindler, Lynn Shemanski, Isabelle Opitz, Sergi Call, Seiki Hasegawa, Kemp Kernstine, Cansel Atinkaya, Federico Rea, Philippe Nafteux, Valerie W. Rusch, Peter Goldstraw, Ramón Rami-Porta, Hisao Asamura, David Ball, David Beer, Ricardo Beyruti, Vanessa Bolejack, Kari Chansky, John Crowley, Frank Detterbeck, Wilfried Ernst Erich Eberhardt, John Edwards, Françoise Galateau-Sallé, Dorothy Giroux, Fergus Gleeson, Patti Groome, James Huang, Catherine Kennedy, Jhingook Kim, Young Tae Kim, Laura Kingsbury, Haruhiko Kondo, Mark Krasnik, Kaoru Kubota, Antoon Lerut, Gustavo Lyons, Mirella Marino, Edith M. Marom, Jan van Meerbeeck, Alan Mitchell, Takashi Nakano, Andrew G. Nicholson, Anna Nowak, Michael Peake, Thomas Rice, Kenneth Rosenzweig, Enrico Ruffini, Valerie Rusch, Nagahiro Saijo, Paul Van Schil, Jean-Paul Sculier, Lynn Shemanski, Kelly Stratton, Kenji Suzuki, Yuji Tachimori, Charles F. Thomas, William Travis, Ming S. Tsao, Andrew Turrisi, Johan Vansteenkiste, Hirokazu Watanabe, Yi-Long Wu, Paul Baas, Jeremy Erasmus, Seiki Hasegawa, Kouki Inai, Kemp Kernstine, Hedy Kindler, Lee Krug, Kristiaan Nackaerts, Harvey Pass, David Rice, Conrad Falkson, Pier Luigi Filosso, Giuseppe Giaccone, Kazuya Kondo, Marco Lucchi, Meinoshin Okumura, Eugene Blackstone, Hisao Asamura, Hasan Batirel, Andrea Bille, Ugo Pastorino, Sergi Call, Ayten K. Cangir, Susana Cedres, Joseph S. Friedberg, Francoise Galateau-Salle, Seiki Hasagawa, Kemp H. Kernstine, Hedy Kindler, Brian McCaughan, Philippe Nafteux, Kristiaan Nackaerts, Johan Vansteenkiste, Takashi Nakano, Anna Nowak, Cansel Atinkaya Ozturk, Harvey Pass, Marc de Perrot, Federico Rea, David C. Rice, Robert Rintoul, Enrico Ruffini, Valerie Rusch, Lorenzo Spaggiari, Domenico Galetta, K.N. Syrigos, Charles Thomas, Jan van Meerbeeck, Walter Weder, Isabelle Opitz, Masahiro Yoshimura
Journal: Journal of Thoracic Oncology (2016)
P1284 : Establishment of an interdisciplinary online expert-forum (INXFO) specialized in HIV and hepatitis in Germany – up-date 2014
Authors: N. Hanhoff, P. Braun, P. Ingiliz, T. Kümmerle, S. Preis, J. Rockstroh, E. Wolf, C. Wyen, L. Meemken
Journal: Journal of Hepatology (2015)
Abstract 3040: A novel methoxyflavanone from a Chinese medicinal herb (Perilla frutescens) induces G2/M cell cycle arrest and apoptosis in A549 human lung adenocarcinoma cells
Authors: Amer Ali Abd El Hafeez Mohamed, Takashi Fujimura, Rikiya Kamei, Noriko Hirakawa, Kenji Baba, Miyako Nakano, Kazuhisa Ono, Seiji Kawamoto
Journal: Cancer Research (2016)

Abstract Background: Perilla frutescens is a common traditional Chinese medicinal herb used for a variety of diseases, e.g. allergic asthma, cough and intestinal disorders. Flavonoids isolated from P. frutescens such as rosmarinic acid, caffeic acid and apigenin have been reported to inhibit proliferation of a variety of cancer cell lines. We recently identified a novel methoxyflavanone named PDMF (Perilla-derived methoxyflavanone) from P. frutescens as a candidate for anti-allergic drug. The objective of the study is to investigate antitumor potency of PDMF on A549 human lung adenocarcinoma and to elucidate its carcinostatic mechanisms. Methods: Effect of PDMF on cell proliferation and viability of A549 cells were assessed by BrdU incorporation assay and trypan blue dye exclusion test. Cell cycle and apoptosis analyses were carried out by flow cytometry. To elucidate antitumor mechanisms of PDMF, expression and activation status of cell cycle/apoptosis regulators (p53/p21/BAX/caspases) were thoroughly analyzed by immunoblotting. Results: Stimulation with PDMF not only triggered G2/M cell cycle arrest but also induced apoptosis of A549 cells in a dose-dependent manner. Mechanistically, PDMF stimulation significantly induced protein levels of p53 and its phosphorylated active forms (pSer15) accompanied by induction of p21 and BAX. We also found that proapoptotic caspase molecules (caspase 3, 8, and 9) were all activated upon stimulation with PDMF. Conclusion: These results suggest that this Perilla-derived methoxyflavanone represents a useful cancer-preventive phytochemical that triggers G2/M arrest, apoptosis, and activation of p53 pathway. Citation Format: Amer Ali Abd El Hafeez Mohamed, Takashi Fujimura, Rikiya Kamei, Noriko Hirakawa, Kenji Baba, Miyako Nakano, Kazuhisa Ono, Seiji Kawamoto. A novel methoxyflavanone from a Chinese medicinal herb (Perilla frutescens) induces G2/M cell cycle arrest and apoptosis in A549 human lung adenocarcinoma cells. [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 3040.
Abstract 1391: Gene expression profiling for cancer classification in circulating tumor cells
Authors: Harris S. Soifer, Ranelle C. Salunga, Tristan G. Harris, Jose Ramirez, Priyadarshini Gogoi, Yixin Wang, Saedeh Sepehri, Kalyan Handique, Catherine A. Schnabel
Journal: Cancer Research (2016)

Abstract Background: Enumeration and molecular characterization of circulating tumor cells (CTCs) offer a non-invasive method for tumor analysis, particularly in cases where the biopsy is difficult to obtain or has been exhausted by conventional diagnostic methods. The 92-gene assay (CancerTYPE ID®, bioTheranostics, Inc.) is a clinically-validated cancer classifier based on the collective expression of 87 informative genes, many of which are involved in lineage commitment and signal transduction. The objective of this study was to determine the feasibility of a blood-based application using differential gene expression. Methods: Technical feasibility studies for cancer cell enrichment and RNA viability were conducted by purifying cancer cell lines that were spiked into donor blood using a microfluidic chip (Celsee PREP™100 system, Celsee Diagnostics) followed by immunodepletion of leukocytes. Quantitative RT-PCR and immunoflourescence were performed on cells harvested at different steps of the purification workflow. Quantitative RT-PCR on individual genes specific to each lineage compartment was used to estimate cell types and cell numbers that were co-purified by the workflow. Gene expression was evaluated by the 92-gene assay. Results: An integrated workflow was established that allows for the molecular characterization of cancer cells purified from blood. Cell enrichment on the microfluidic chip followed by purification using immunodepletion resulted in efficient recovery (&amp;gt; 80% of input cells) and viable RNA from cancer cells spiked into whole blood. A key result of this study was the demonstration that the level of cancer-specific gene expression in purified samples was similar to the level of expression from an equivalent number of unspiked cancer cells suggests that significant cell loss does not occur during the purification workflow. A comparison of gene expression profiles from purified and mixed cell populations allowed for the identification of subsets of genes that are differentially expressed in cancer cells compared with leukocytes. Conclusion: A functional workflow with viable RNA and efficient recovery of cancer cells that are within the technical specifications of the 92-gene assay was established. Findings from this feasibility study are fundamental to the potential for CTC-based cancer classification. Citation Format: Harris S. Soifer, Ranelle C. Salunga, Tristan G. Harris, Jose Ramirez, Priyadarshini Gogoi, Yixin Wang, Saedeh Sepehri, Kalyan Handique, Catherine A. Schnabel. Gene expression profiling for cancer classification in circulating tumor cells. [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 1391.
Abstract 5161: Development of cutaneous basal cell carcinomas from cutaneous actinic keratoses
Authors: W Clark Lambert, Claude E. Gagna, Muriel W. Lambert
Journal: Cancer Research (2016)

Abstract Actinic keratoses (AKs) are extremely common proliferations of epidermal keratinocytes which show cytological atypia and impaired ability to mature as the cells that comprise them migrate from the basal layer of the epidermis to higher levels of the epidermis. A small percentage of AKs are well known to progress to cutaneous squamous cell carcinomas (SCCs). However, progression of AKs to cutaneous basal cell carcinomas (BCCs) has not been convincingly documented despite several attempts, even though BCCs are significantly more common than SCCs in the general US and European populations. Documented cases have been dismissed as actinic keratoses that have simply occurred superimposed upon basal cell carcinomas due to chance occurrence of two common sun induced skin lesions at the same sites. In a university based referral dermatopathology service, one of us (WCL) observed 21 cases of AKs progressing to BCCs during a 29 year period (January 1, 1985 to December 31, 2013) of continuous observation in which 115,898 cases of AKs, 10,188 cases of BCCs and 4,809 cases of SCCs were diagnosed. Only cases in which a continuous progression of cells from those showing changes typical of AKs to those showing changes typical of BCCs was observed were included. During the same interval 308 cases of AKs progressing to SCCs were diagnosed. To further test the hypothesis that AKs can progress to BCCs, cases of AKs that progressed to BCCs were further examined to determine those in which neither the AK nor the BCC occupied the entire skin surface (i.e., length of the epidermal basement membrane) present in the specimen. Of the 21 cases, 13 met this criterion. All were shave biopsies of sun damaged skin. For each biopsy, the proportion of the surface covered by the AK, the proportion occupied by the BCC, and the proportion of the surface overlapped by both lesions were measured and the proportion of overlap was compared to the proportion of overlap expected due to chance. Statistical analysis showed that the observed overlap exceeded the expected overlap by 32 per cent with p &amp;lt; 0.05. We conclude that progression of AKs to BCCs, while not as common as progression of AKs to SCCs, does occur in a small proportion of cases. Citation Format: W Clark Lambert, Claude E. Gagna, Muriel W. Lambert. Development of cutaneous basal cell carcinomas from cutaneous actinic keratoses. [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 5161.
Efficacy and Safety Of Bendamustine In Combination With Rituximab For Elderly Patients With Previously Untreated B-Cell Chronic Lymphocytic Leukemia. A Retrospective Multicenter Study
Authors: Luca Laurenti, Barbara Vannata, Idanna Innocenti, Francesco Autore, Francesco Ghio, Nadia Cecconi, Vincenzo Pitini, Patrizia Mondello, Maria Rosa Lanza Cariccio, Alessandro Gozzetti, Giovanni D'Arena, Roberta Murru, Nicola Piccirillo, Giuseppe Leone, Simona Sica
Journal: Blood (2013)
Abstract 3580: Topoisomerase II mediated DNA damage generates unique classes of genome rearrangements
Authors: Matthew Gilbertson, Radhika Patel, Karin C. Nitiss, John L. Nitiss
Journal: Cancer Research (2016)

Abstract Topoisomerase 2 (Top2) is the target of active anti-cancer agents such as etoposide and doxorubicin. These drugs interfere with the Top2 catalytic cycle and lead to trapping of the enzyme as a covalent protein: DNA complex. This trapped covalent complex is a unique DNA lesion that includes DNA strand breaks and covalent protein adducts at the site of the breaks. While Top2 mediated DNA damage is the major mechanism for tumor cell killing, it is also responsible for drug-induced translocations that can lead to secondary malignancies. We have developed several novel systems for assessing Top2-mediated genome instability using yeast as a model system. We developed repair proficient yeast strains that accumulate high levels of etoposide and other Top2 targeting drugs. We selected for loss-of-function mutations in the yeast CAN1 gene that arise following etoposide treatment, and examined the induced mutations by DNA sequencing. We identified a unique spectrum of mutations generated by etoposide in yeast. One novel class of mutational events induced by etoposide is relatively large deletions (&amp;gt;300 bp) and tandem duplications. Most of these etoposide-induced events are flanked by 4-8 nucleotide direct repeats. To further characterize the mechanism of Top2 induced genome instability, we took advantage of a novel Top2 allele isolated in our laboratory. This Top2 allele, termed top2AR, exhibits elevated levels of drug independent DNA cleavage in vitro, and inviability when combined with yeast mutants defective in DNA double strand break repair. We found a similar spectrum of large deletions and tandem duplications flanked by 4-8 nucleotide direct repeats. Interestingly, we also found that the recovery of large deletions and insertions was enhanced in yeast cells lacking Tdp1, a gene that participates in the repair of protein:DNA covalent complexes. Our results illustrate a novel type of genome rearrangement that is mediated by covalent Top2 DNA damage. It is noteworthy that the deletions and insertions flanked by short direct repeats have not been previously observed with other classes of DNA damaging agents. We suggest that the unique properties of these lesions may also contribute to oncogenic translocations induced by etoposide and other Top2 targeting drugs. We are currently using next-generation sequencing of etoposide treated yeast cells and cells carrying the top2AR allele to obtain a more complete picture of the types of alterations induced by Top2 mediated DNA damage. Citation Format: Matthew Gilbertson, Radhika Patel, Karin C. Nitiss, John L. Nitiss. Topoisomerase II mediated DNA damage generates unique classes of genome rearrangements. [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 3580.
Abstract 75: CellMiner, a systems pharmacological web-application for the NCI-60 cancerous cell-lines: Updates, data integration, and translationally relevant results
Authors: William C. Reinhold, Margot Sunshine, Sudir Varma, James Doroshow, Yves Pommier
Journal: Cancer Research (2016)

Abstract Understanding the influences of molecular alterations on pharmacological responses in the omic sense is at the fore of the effort to make oncology more effective and specific. At present, however, this remains a field in its infancy. The NCI-60 cancerous cell lines provide a premier set of databases for systems molecular pharmacological studies. This is due to the availability of both the robust, high-quality activity profiles generated by the Developmental Therapeutics Program (https://dtp.cancer.gov), and the panoply of molecular and phenotypic information available. The CellMiner web-application (http://discover.nci.nih.gov/cellminer) provides the user access to both of these. Activity data is available for 20,861 compounds, including 159 Food and Drug Administration (FDA)-approved, 85 clinical trial, and 443 known mechanism-of-action drugs. The molecular data includes transcript expression for 25,772 genes, genetic variants for 16,568 genes, transcript expression for 360 microRNAs, protein levels for 94 genes, DNA copy number (from aCGH) for 23,413 genes, and soon DNA methylation levels for 17,559 genes. “Cell line signatures” are provided for each of these data types, facilitating their comparison. It also provides “Pattern comparisons” for any input pattern of interest to 87,419 activity, molecular and phenotypic patterns (For CellMiner 1.7). Here we present our CellMiner updates, examples of data integration, and translationally relevant results. Citation Format: William C. Reinhold, Margot Sunshine, Sudir Varma, James Doroshow, Yves Pommier. CellMiner, a systems pharmacological web-application for the NCI-60 cancerous cell-lines: Updates, data integration, and translationally relevant results. [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 75.
Consolidation cystectomy after induction chemotherapy in node-positive urothelial bladder cancer.
Authors: Hristos Z. Kaimakliotis, Jose A. Pedrosa, M. Francesca Monn, Paul Gellhaus, Richard Bihrle, K. Clint Cary, Timothy A. Masterson, Richard Foster, Liang Cheng, Noah M. Hahn, Michael O. Koch
Journal: Journal of Clinical Oncology (2014)

e15520 Background: Induction chemotherapy in urothelial bladder cancer (UC) with node involvement allows for an opportunity to treat metastatic disease followed by consolidation cystectomy. We sought to compare the efficacy of cisplatin (CCC) and non-cisplatin combination chemotherapy (NCCC) induction regimens in patients that underwent consolidation cystectomy. Methods: We conducted a retrospective analysis of UC patients between 1990 - 2013 undergoing consolidation cystectomy after induction chemotherapy for clinical node involvement, with CCC or NCCC (carboplatin). Clinical node involvement was defined as biopsy proven or if >1.5cm on cross-sectional imaging at diagnosis. Pearson chi-square test was used to assess response to regimen, Kaplan-Meier methodology and log rank test for overall survival (OS), and Cox proportional hazards regression to evaluate characteristics associated with mortality. Results: Patient characteristics and clinicopathologic outcomes are shown in the Table below. Median OS for CCC and NCCC was 21.5 and 12.4 months, respectively (p<0.001). On multivariate analysis controlling for age, sex, preoperative creatinine >1.5mg/dL and Charlson Comorbidity Index (CCI) >3, NCCC was associated with a 2.5 times increased risk of death (95% CI 1.1-5.9, p=0.047). Conclusions: Clinical node involvement is an ominous finding in UC, and induction chemotherapy offers the chance for response in metastatic disease with an attempt at surgical treatment. Although few patients have a clinical response with pathologic down-staging of involved nodes, induction therapy with CCC appears to confer a survival advantage over NCCC regimens, even when controlling for renal function and comorbidities. If renal function and comorbidities permit, CCC should be the regimen of choice for induction chemotherapy in clinical node positive UC patients. Characteristics Cisplatin based (n=40) Non-Cisplatin based (n=16) p-value Age (median) 61 66 0.64 Male 32 (80%) 13 (81.2%) 0.91 Caucasian 40 (100%) 13 (81.2%) 0.01 Biopsy proven N+ 16 (40%) 1 (6.3%) 0.02 Cr >1.5mg/dL 3 (7.5%) 8 (50%) <0.001 CCI >3 17 (42.5%) 10 (62.5%) 0.17 <pT2N0Mx 10 (25.0%) 1 (6.3%) 0.11 5-year OS 32% 0 <0.001 Median OS (months) 21.5 12.4 <0.001