tbuckley/cabot-search huggingface dataset:
Abstract 2893: PARP-1 regulates cell cycle by downregulating E2F-1 transcriptional activity in vitro and in vivo
Authors: Pablo Iglesias, Marcos Seoane, Isabel Castro-Piedras, Victor M. Arce, Jose A. Costoya
Journal: Cancer Research (2016)

Abstract Although PARP-1 has been traditionally related to DNA repair, in the last years an increasing number of studies have linked this polymerase to other cellular processes such as metabolism and cell mitosis. In this study we wanted to investigate the biological importance of the interaction between PARP-1 and the transcription factor E2F-1, and more specifically in scenarios where the activity, or hyperactivity, of E2F-1 is of critical importance such as embryonic development or oncogenesis. In this regard, we have found that the treatment either with enzymatic inhibitors of PARP-1 has an effect on the transcriptional activity of E2F-1 as well as the proliferative rate of treated cells. This effect is significantly increased with the treatment with gossypol, a specific inhibitor of PARP-1 protein-protein interactions occurring through the BRCT domain, as in the case of E2F-1. This effect is also observed in vivo since the severity of histological malformations in Rb-/- embryos is significantly reduced in Parp-1-/- Rb-/- embryos, which phenotype closely resembles that of E2f-1-/- Rb-/- mice. Finally, we also found that the deletion or inhibition of PARP-1 in an animal model of gliomagenesis helps the cell to block oncogenic stimuli derived from E2F-1 hyperactivity, by reactivating critical signalling pathways involved in oncogene-induced senescence. In summary, the importance of the relationship between PARP-1 and E2F-1 in different biological contexts leads us to believe that the search for ways of altering or disrupting this interaction could be a novel strategy for the development of molecules of therapeutic potential. Citation Format: Pablo Iglesias, Marcos Seoane, Isabel Castro-Piedras, Victor M. Arce, Jose A. Costoya. PARP-1 regulates cell cycle by downregulating E2F-1 transcriptional activity in vitro and in vivo. [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 2893.
La gestion des fièvres hémorragiques virales aux Pays-Bas
Authors: C.-M. Swaan, P.-J. Van Den Broek, S. Wijnands, J. E. Van Steenbergen
Journal: Eurosurveillance (2002)

Deux cas de fievre de Lassa ont ete rapportes aux Pays-Bas depuis que les fievres hemorragiques virales sont devenues des MDO en 1978. En 1980, un expatrie au Burkina Faso a presente une forme mineure, biologiquement confirmee apres sa sortie d’hospitalisation. Le second cas, survenu en 2000, est decede apres onze jours d’hospitalisation. Les difficultes rencontrees dans la prise en charge de ce cas et la recherche des personnes contacts exposees - une centaine - ont alors souligne l’importance d’etablir aux Pays-Bas des recommandations nationales.
Bringing complexity to sports injury prevention research: from simplification to explanation
Authors: Sheree Bekker, Alexander M Clark
Journal: British Journal of Sports Medicine (2016)

Sports injury prevention research takes being formulaic to the extreme. Countless papers begin by reminding that sports injuries remain a significant public health burden,1 and we are reassured that the proven efficacy of numerous interventions shows that sports injuries can be prevented.2 Despite this optimistic picture, and amidst the proliferation of consensus statements and guidelines, the effectiveness of sports injury prevention interventions remains disappointingly inconsistent. We trace these discrepancies to two approaches that have guided past work—simple and complicated—and then move to propose a potentially useful way forward, that of complexity.

The ‘simple’ perspective advocates that injury incidence can be reduced via a recipe-type approach. Simplicity casts sports injuries as straightforward occurrences for which an optimal intervention is sought, where interventions either ‘work’ or ‘do not work’. The Sequence of Prevention model,3 for example, consists of four steps: (1) establish the extent of the problem, (2) establish the aetiology and extent of the injury, (3) introduce preventative measures and …
Abstract 4254: Dynamic change of differentiation in spheroids derived from mixed small cell carcinoma/adenocarcinoma of the uterine cervix
Authors: Satoshi Kubota
Journal: Cancer Research (2016)

Abstract Small cell carcinoma of the uterine cervix (SCCC) occurs mainly in young women with poor prognosis. Clear treatment algorithm remains difficult to develop for its rarity. Herein, we report a case of SCCC with adenocarcinoma component, and analyzed the mechanism of differentiation using a spheroid culture method. CTOS (cancer tissue-originated spheroid) is a primary culture system by which highly purified and viable cancer cells are cultivated. The principle of this method is maintaining cell-cell contact throughout the preparation and culture process. CTOS preserves characters of original tumors, especially their differentiation status. We generated a panel of CTOSs from 9 SCCCs. The success rate of CTOS preparation in SCCC was 100%, indicating SCCC is one of the most suitable cancers for CTOS method. We focused on SCCCs with adenocarcinoma component. These admixed tumors have been reported in other organs, such as lung, ovary, stomach, and so on. However, the mechanism underlying mixed tumor remains unclear. One of the CTOSs retained the characteristics of mixed tumor in original tumor. Immunostaining revealed that CD99 was positive in the region of small cell carcinoma region, and CK7 in that of adenocarcinoma. CTOSs were sorted by CD99 and EpCAM (a possible stem cell marker) expression levels, and transplanted into NOD-Scid mice. Xenotumors derived from both CD99lowEpCAMlow cells and CD99lowEpCAMhigh cells showed mixed cell type in H&amp;E staining. Immunohistochemistry revealed that CD99 was positive in the region of small cell carcinoma, and CK7 in that of adenocarcinoma. On the other hand, CD99highEpCAMhigh cells-derived xenotumor consisted of only small cell carcinoma. The tumors were positive for CD99, but negative for CK7. Next, we searched for the key factor of differentiation. It has been reported that hypoxia induced adenocarcinoma in lung adenosquamous cell carcinoma. When CTOSs were incubated in hypoxia (3%O2), FACS analysis revealed that proportion of CD99low cells increased (20.6% in normoxia, 40.2% in hypoxia). Immunostaining of CTOSs showed similar results. Thus differentiation status of a mixed type SCCC showed dynamic change of differentiation in spheroids depending on culture conditions. The research can provide insight into the origin of mixed tumor of SCCC, and may be useful for developing treatment strategy. Citation Format: Satoshi Kubota. Dynamic change of differentiation in spheroids derived from mixed small cell carcinoma/adenocarcinoma of the uterine cervix. [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 4254.
Abstract 1860: MDM2 stabilizes and induces HIF-1α levels during reoxygenation of cancer cells
Authors: Thanigaivelan Kanagasabai, Rohin Chand, AmyAman Kaur, Sivanesan Dhandayuthapani, Olena Bracho, Appu Rathinavelu
Journal: Cancer Research (2016)

Abstract Hypoxia stimulates several pathways that are critical to cancer cell growth and survival, including activation of vascular endothelial growth factor (VEGF) transcription. Overexpression of VEGF and the extent of neo-angiogenesis are closely correlated with increase in tumor size and cancer metastases. The main regulator of hypoxia-induced angiogenesis is the hypoxia inducible factor (HIF)-1α which regulates the transcription of various target genes including VEGF. Stabilization of HIF-1α in cancer cells could enable tumor progression and results in poor survival. In this respect, the multifunctional mouse double minute 2 homolog (MDM2) oncoprotein has been gaining significant amount of attention. The MDM2 oncoprotein has been shown to exert both p53-dependent and p53-independent roles in oncogenesis. It is also well established that MDM2 gene amplification can occur in diverse human malignancies that include soft tissue sarcomas, neuroblastoma, cancers of the brain, breast, ovary, cervix, lung, colon, prostate, and bone. Mechanisms underlying induction and stabilization of HIF-1α in normoxic conditions are less clearly understood. Our present data indicated that the normoxic expression level of HIF-1α was significantly higher (p&amp;lt;0.0001) in LNCaP-MST as compared with LNCaP cells. When we treated the cells with the MDM2 inhibitor nutlin-3, the levels of HIF-1α was significantly down regulated. These results were further correlated with the differences in subcellular compartmentalization and degradation of HIF-1α. Findings from our lab shows the degradation rate of HIF-1α protein in both the nuclear and cytoplasmic compartments of LNCaP (non-transfected) and LNCaP-MST (MDM2 transfected) cells. In LNCaP cells, the degradation of HIF-1α protein occurs within 8 min in cytoplasmic (99%) and 10 min in nuclear compartments (75%). Whereas, in LNCaP-MST cells, the degradation rate of HIF-1α protein was slower even at 10 min of reoxygenation in both cytoplasmic (70%) and nuclear compartment (40%). Our results suggest that, MDM2 could play the role of master regulator in stabilizing HIF-1α even after reoxygenation. Further studies in this direction will shed more light on the in-depth mechanisms involved in the regulation of HIF-1α in MDM2 positive cancers. (This project was supported by The Royal Dames of Cancer Research Inc., Ft. Lauderdale, Florida). Citation Format: Thanigaivelan Kanagasabai, Rohin Chand, AmyAman Kaur, Sivanesan Dhandayuthapani, Olena Bracho, Appu Rathinavelu. MDM2 stabilizes and induces HIF-1α levels during reoxygenation of cancer 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 1860.
Protein Profiling in Myeloma In Vivo; Effects of Bortezomib in a Mouse Model of Myeloma.
Authors: Claire M. Edwards, Robert L. Caldwell, Andreia L. Bates, Jessica A. Fowler, James R. Edwards, Babatunde O. Oyajobi, Seint T. Lwin, Jianghong Zhang, Gregory R. Mundy
Journal: Blood (2007)
Synthetic Nucleic Acids and Treatment of Neurological Diseases
Authors: David R. Corey
Journal: JAMA Neurology (2016)

<h3>Importance</h3> The ability to control gene expression with antisense oligonucleotides (ASOs) could provide a new treatment strategy for disease. <h3>Objective</h3> To review the use of ASOs for the treatment of neurological disorders. <h3>Evidence Review</h3> Articles were identified through a search of PubMed references from 2000 to 2016 for articles describing the use of ASOs to treat disease, with specific attention to neurological disease. We concentrated our review on articles pertaining to activation of frataxin expression (Friedreich’s ataxia) and production of active survival motor neuron 2 (<i>SMN2</i>, spinal muscular atrophy). <h3>Findings</h3> Many neurological diseases are caused by inappropriate expression of a protein. Mutations may reduce expression of a wild-type protein, and strategies to activate expression may provide therapeutic benefit. For other diseases, a mutant protein may be expressed too highly and methods that reduce mutant protein expression might form the basis for drug development. Synthetic ASOs can recognize cellular RNA and control gene expression. Antisense oligonucleotides are not a new concept, but successful clinical development has proceeded at a slow pace. Advances in ASO chemistry, biological understanding, and clinical design are making successful applications more likely. <h3>Conclusions and Relevance</h3> Both laboratory and clinical studies are demonstrating the potential of ASOs as a source of drugs to treat neurological disease.
Tremelimumab as second- or third-line treatment of unresectable malignant mesothelioma (MM): Results from the global, double-blind, placebo-controlled DETERMINE study.
Authors: Hedy L. Kindler, Arnaud Scherpereel, Luana Calabrò, Joachim Aerts, Susana Cedres Perez, Alessandra Bearz, Kristiaan Nackaerts, Dean Anthony Fennell, Dariusz Kowalski, Anne S. Tsao, Paul Taylor, Federica Grosso, Scott Joseph Antonia, Anna K. Nowak, Ramy A. Ibrahim, Maria Taboada, Martina Puglisi, Paul K. Stockman, Michele Maio
Journal: Journal of Clinical Oncology (2016)

8502 Background: MM is an asbestos-induced cancer with increasing global incidence. 1st-line treatment is pemetrexed + platinum; there are no approved 2nd-line therapies. CTLA-4 is a co-inhibitory receptor expressed on activated T cells. Tremelimumab (T) is a selective human IgG2 mAb inhibitor of CTLA-4 that promotes T-cell activation. Single-arm Phase 2 trials of T using 2 different doses and schedules achieved responses and durable disease control in MM pts.1,2 DETERMINE (NCT01843374) evaluated T vs placebo (P) in pts with unresectable pleural or peritoneal MM. Methods: Eligible pts who progressed after 1–2 lines of prior therapy were randomized 2:1 to receive T (10 mg/kg q4w for 7 doses, then q12w) or P, and stratified by EORTC status, line of therapy and anatomic site. Primary endpoint was overall survival (OS). Secondary endpoints included progression free survival, objective response rate and duration, durable disease control rate and safety. Results: From May 2013 to December 2014, 571 pts were randomized (382 to T, 189 to P; median age 66 yrs [range 28–87]; male 76%; EORTC status low/high risk: 58%/42%; pleural 95%; epithelioid histology 83%; 2nd/3rd line: 63%/37%). 380 received T, 189 P (median 3.0 [range 1–13] doses for both arms). 81% have died. There was no statistically significant difference in OS, T vs P (median 7.7 vs 7.3 mos; HR = 0.92, 95% CI: 0.76–1.12, p = 0.408). Subsequent anticancer treatment was low (T 24%, P 31%). Most frequent Grade ≥ 3 treatment-emergent AEs (T 65%/P 48%): dyspnea (9%/14%), diarrhea (15%/1%) and colitis (7%/0%). Most frequent AEs (any grade) included: diarrhea (47%/19%), dyspnea (32%/37%), decreased appetite (29%/24%), fatigue (24%/32%), nausea (28%/20%), constipation (17%/28%), pruritus (27%/8%) and rash (21%/7%). Conclusions: T monotherapy did not demonstrate superiority to P for the primary endpoint OS in 2nd/3rd-line MM. Preliminary safety data are consistent with the known safety profile of T. Other endpoint data will be presented. An ongoing Phase 2 study (NIBIT-MESO-1) evaluates T in combination with durvalumab in 1st/2nd-line MM. 1. Calabrò et al. Lancet Resp Med 2015; 2. Calabrò et al. Lancet Oncol 2013 Clinical trial information: NCT01843374.
Congenital heart disease in adults
Authors: Bejal Pandya, Shay Cullen, Fiona Walker
Journal: BMJ (2016)

#### What you need to know

Heart disease is the most common birth defect, affecting nine in 1000 babies born in the United Kingdom. The spectrum of the underlying lesions ranges from a simple septal defect to more complex structural abnormalities. Most of those born with cardiac defects lead active lives and survive well into late adulthood. These adults with congenital heart disease have often had previous surgical corrections or percutaneous catheter treatments and are left with residual structural defects, valve lesions, or ventricular dysfunction. Most therefore require lifelong specialist congenital cardiology follow-up to identify when re-interventions are necessary. Those with highly complex disease are usually reviewed annually, with the frequency of follow-up determined by clinical status and severity of any residual problems.

NHS England has recently completed a review on the care of patients with congenital heart disease.1 Specialist centres have been evaluated against agreed standards and designated or commissioned accordingly, in order to provide varying levels of care across a geographical network. This review provides practical advice for non-specialists to help understand the longer term problems associated with congenital heart disease and how these are managed.

#### Sources and selection criteria

We carried out an electronic search through PubMed and Medline using the terms “ACHD” [adults with congenital heart disease] and “GUCH” [grown ups with congenital heart disease]. We also used personal archives, our experience, and relevant guidelines from the European Society of cardiology, American college …
Prediction of depressive disorder following myocardial infarction; Data from the Myocardial Infarction and Depression - Intervention Trial (MIND-IT)
Authors: van Jochum Melle, de Peter Jonge, AM Kuyper, A Honig, AH Schene, HJ Crijns, van den Maarten Berg, Johan Ormel
Journal: Journal of the American College of Cardiology (2005)
Efficacy of cetuximab immediately after bevacizumab: A phase III multicenter trial comparing two different sequences of cetuximab and FOLFOX in K-Ras WT metastatic colorectal cancer patients refractory FOLFIRI/bevacizumab.
Authors: Stefano Cascinu, Alberto Zaniboni, Sara Lonardi, Gerardo Rosati, Guglielmo Nasti, Monica Giordano, Domenico C. Corsi, Francesco Ferraú, Rosario Vincenz Iaffaioli, Paolo Marchetti, Massimo Aglietta, Domenico Bilancia, Monica Ronzoni, Irene Claudia Floriani, Roberto Labianca
Journal: Journal of Clinical Oncology (2016)

632 Background: FOLFOX/FOLFIRI are effective as first-line treatment but FOLFOX might be more effective in second line. The optimal first-line in RAS wild type mCRC is still unclear even after 2 trials comparing chemotherapy with bevacizumab or cetuximab. While bevacizumab seems to loose efficacy across treatment lines, cetuximab has a similar activity across all treatment lines. It might be a better choice for the third-line in the view of an optimal sequence strategy. We designed a phase III randomised trial to compare two different treatment sequences of cetuximab and FOLFOX in mCRC patients refractory to FOLFIRI/bevacizumab first-line. Methods: Pts were randomized to receive Irinotecan/Cetuximab as 2 nd line followed by FOLFOX-4 as 3 rd line (Arm A) or the inverse sequence. Primary endpoint was progression free survival (PFS); secondary endpoints were overall survival and toxicity. 101 events were required in order to detect an hazard ratio of 0.57, translating in an increase of median PFS from 4 to 7 months (two-sided type I error 5%, power 80%). Results: 110 mCC pts were enrolled in this trial: 64 pts were males and 46 females with a mean age of 61 years. Efficacy results are reported in the table. Treatment was well tolerated with a low number of serious adverse reactions (2 in each treatment arm). Conclusions: Cetuximab is less effective immediately after bevacizumab. This is in accordance with data suggesting that EGFR inhibition is not active after VEGF blockade. The sequence of biological agents seems to be more relevant than the first-line choice. In RAS wild type patients progressing after a first line bevacizumab based therapy cetuximab should be given as first line or third line. Clinical trial information: NCT01030042. [Table: see text]
Abstract LB-014: Targeting insulin receptor splicing as a therapeutic intervention for pediatric rhabdomyosarcoma
Authors: Dawn S. Chandler, Chelsea Brown, Hemant Bid, Thomas Bebee, Daniel F. Comiskey, Frank Rigo, Peter J. Houghton
Journal: Cancer Research (2016)

Abstract The insulin receptor (IN-R) alternatively spliced variant A, encoding a receptor lacking exon 11, is the predominant isoform expressed in both pediatric sarcoma cells and vascular endothelial cells. Exon 11 of the IN-R gene is composed of 36 nucleotides that encode 12-amino acids that reside at the carboxyl terminus of the alpha subunit. Though only a small change in the protein composition, deletion of these 12 amino acids results in a receptor that has increased binding affinity for the IGF-2 growth factor and is exquisitely capable of responding to autocrine and paracrine signaling. Cells expressing both the IN-R A variant and the IGF-2 growth factor are therefore programmed for growth and angiogenesis, two essential steps in tumorigenesis. Furthermore, the IGF-2 can maintain angiogenesis through IN-R A when the IGF-1 receptor is blocked. We also demonstrate that hypoxia induces IN-R alternative splicing. This finding is particularly intriguing since recent studies have shown that adaptation to hypoxic environments is a hallmark of the neoplastic phenotype. We therefore hypothesize that the expression of splicing factors is altered by hypoxia leading to the generation of the IN-R A isoform, which contributes to cancer progression beyond the micrometastatic stage. To characterize sequence elements and RNA binding proteins in the regulation of IN-R alternative splicing, we have designed a hypoxia-induced splicing system that recapitulates the IN-R splicing seen in tumors. We have shown that sequence elements flanking the regulated exon are important for the hypoxia-induced splicing changes. Furthermore, have performed an antisense oligonucleotide (ASO) walk to target these splicing enhancer and repressor sequences to interfere with IN-R splicing. We have successfully targeted the CUGBP1 negative regulator of splicing that resides in intron 10 to increase the IN-R B full-length isoform. We have shown that an ASO used to drive production of the IN-R B isoform in a rhabdomyosarcoma (RMS) cell line, which normally expresses the IN-R A isoform, affects cancer cell behavior to induce reduced motility and cell migration. We therefore postulate that modulation of the splicing of the IN-R, alone or in conjunction with IGF-1R blocking antibodies, could be used as a therapeutic intervention in pediatric RMS cells. Citation Format: Dawn S. Chandler, Chelsea Brown, Hemant Bid, Thomas Bebee, Daniel F. Comiskey, Frank Rigo, Peter J. Houghton. Targeting insulin receptor splicing as a therapeutic intervention for pediatric rhabdomyosarcoma. [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 LB-014.