tbuckley/cabot-search huggingface dataset:
Profil et évolution de la chimiosensibilité du paludisme d'importation à Plasmodium falciparum en France en 2000
Authors: P Ralaimazava, R Durand, N Godineau, A Keundjian, Z Jezic, B Pradines, O Bouchaud, J Le Bras
Journal: Eurosurveillance (2002)

En 2000, la chimiosensibilite du paludisme d’importation est restee stable en France. Tous pays d’infection confondus, la bi-resistance a la chloroquine et au cycloguanil n’a pas evolue de 1996 a 2000. La monotherapie par quinine ou mefloquine reste le traitement de premiere intention au paludisme a P. falciparum. Pour ces antipaludiques, la resistance est rare en Afrique et sans evolution au cours des 15 dernieres annees.
AB0227 Validation of Patient-Derived Disease Activity Score in Chinese Rheumatoid Arthritis Patients
Authors: M.-H.A. Leung, E. Choy, C.S. Lau
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background</h3> The current standard of care for rheumatoid arthritis (RA) is treat to remission or low activity state. This underlines the need of regular assessment of disease activity. Patient-derived Disease Activity Score (PDAS) is one of the tools that have been developed and validated to allow patients with RA to self-assess disease activity.<sup>1</sup> Two versions of PDAS are available: PDAS1 (with ESR) and PDAS2 (without ESR). The corresponding cut-off points of RA activity statuses had been reported.<sup>2</sup> PDAS was developed in English speaking patients. <h3>Objectives</h3> To explore the validity of PDAS in Chinese speaking RA patients. <h3>Methods</h3> 100 RA patients were recruited from rheumatology specialist clinic in Hong Kong. They were asked to complete in Chinese version of questionnaires before clinic which included functional status (Health Assessment Questionnaire)<sup>3</sup>, self assessed swollen and tender joint count, morning stiffness and global assessment. Standard disease activity score DAS28ESR and CDAI were assessed by Rheumatologists at these visits. Correlation with PDAS1 and 2 was done with Spearman rank test and categorical agreement by kappa statistics. The study was approved by local ethics committee. <h3>Results</h3> Patient characteristics are as follows: mean age 60 years (standard deviation SD 12), mean RA disease duration 14 years (SD 9), 90% female, 71% seropositive, 48% patients in remission or low disease activity while 52% in moderate or high disease activity. PDAS in Chinese patients showed equally high correlation with DAS28ESR and CDAI. Spearman rank correlation coefficients were similar to those in original PDAS derivation (in brackets) (all P&lt;0.0001): When comparing RA activity statuses ([remission or low] versus [moderate or high activity]) using kappa statistics, PDAS showed considerable agreement with DAS28ESR, noting that within this patient group, the agreement of DAS28ESR with CDAI itself was only 0.60: In particular for PDAS2, a formula without the need of blood test, has good sensitivity (96%) of picking up DAS28 remission or low activity, and good negative predictive value (89%) to signal moderate or high activity. <h3>Conclusions</h3> PDAS can be adapated to Chinese language speaking RA patients in routine clinical setting. PDAS2 is useful in two aspects: informing patients that they are well treated-to-target; and concuring with patients having moderate or high disease actiivity. <h3>References</h3> Choy EH et al. Arthritis Rheum. 2008 Feb 15;59(2):192–9 ACR 2012 Abstract 27063 Koh ET et al. J Rheumatol. 1998 Sep;25(9):1705–8 <h3>Disclosure of Interest</h3> None declared
David Oliver: Lies, damned lies, and the NHS
Authors: David Oliver
Journal: BMJ (2016)

My school maths teacher got us reading Darrell Huff’s seminal How to Lie with Statistics . The lessons have endured. In a similar vein was a wonderful recent column in the Observer by the statistician David Spiegelhalter on nine ways people misuse numbers to support their arguments.1 Three of these included recent examples from the NHS.
Abstract 906: Exosomes from mutant TP53 cancer cells polarize tumor associated macrophages
Authors: Tomer Cooks, Ioannis S. Pateras, Keval M. Patel, Tim Forshew, Vassilis G. Gorgoulis, Curtis C. Harris
Journal: Cancer Research (2016)

Abstract Introduction: TP53 mutants are involved in the pathogenesis of most solid tumors and are known to gain oncogenic functions distinct from their original wild-type form. The existence of such gain-of-function (GOF) activities is supported by ample evidence, however only in a cell-autonomous fashion. Since tumor-associated-macrophages (TAM) are also a hallmark of solid tumors typically correlated with poor prognosis, we investigated the link between mutations in the TP53 gene (mutp53) occurring in epithelial tumor cells and the formation of a surrounding TAM population in-situ. Methods: By designing a co-culture system we incubated human primary monocytes together with colorectal cancer (CRC) cells differing in their p53 status. Relevant macrophages markers were evaluated on RNA level and protein level. In addition, co-cultured macrophages were subjected to various functional assays (phagocytosis, migration, and invasion). In attempt to confirm clinical relevance, samples from a cohort of human CRC patients were analyzed using genomic and immunohistochemical methods. To identify the interaction between the tumor cells and the macrophages, we isolated exosomes from the CRC cells and subjected them to a Nanostring analysis to learn about their microRNAs composition. Results: In this study, we discovered that mutp53 exerts a non-cell-autonomous effect over neighboring macrophages by using specific microRNAs (miRs) which are shuttled through an exosomal transfer resulting with a phenotype change of the affected macrophages. Mutp53-specific exosomes containing cargoes such as miR-1246 were shown to be used by macrophages at the receiving end, thus promoting the formation of TAM subset also observed in surgical specimens resected from cancer patients. Conclusions: Altogether, these findings are consistent with a microenvironmental role for specific “hot-spot” p53 mutants tightening the interaction between the tumor cell and the immune compartment. Additionally, this study is the first to show a non-cell-autonomous role played by mutant p53 - the most common form of mutation found in human cancers. Deciphering the intricate regulation shared by the tumor cell and its surrounding macrophages may give rise to novel prognostic and diagnostic tools as well as to therapeutic approaches targeting TAM, specific tumor-promoting miRs and mutp53-specific subsets of exosomes. Citation Format: Tomer Cooks, Ioannis S. Pateras, Keval M. Patel, Tim Forshew, Vassilis G. Gorgoulis, Curtis C. Harris. Exosomes from mutant TP53 cancer cells polarize tumor associated macrophages. [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 906.
Successful Pregnancy In APL Patients Treated According to the AIDA Protocol.
Authors: Paola Carluccio, Alessandra Ricco, Domenico Pastore, Massimo Breccia, Maria Grazia Kropp, Eros Di Bona, Francesco Fabbiano, Felicetto Ferrara, Lorella Melillo, Francesco Lo-Coco, Giorgina Specchia
Journal: Blood (2010)
Abstract 2897: Recurrent transcriptome alterations across multiple cancer types
Authors: Bogumil Kaczkowski, Yuji Tanaka, Hideya Kawaji, Albin Sandelin, Robin Andersson, Masayoshi Itoh, Timo Lassmann, Yoshihide Hayashizaki, Piero Carninci, Alistair R.R. Forrest
Journal: Cancer Research (2016)

Abstract Genes that are frequently deregulated in cancer are clinically attractive as both potential pan-cancer diagnostic markers and therapeutic targets. Here we compared Cap Analysis of Gene Expression (CAGE) profiles from 225 cancer cell lines and 339 corresponding primary cell samples to identify transcripts that are recurrently deregulated in a broad range of cancer types. CAGE is a 5’ sequence tag technology that globally determines transcription start sites (TSS) in the genome and their expression levels. This allowed us to assess novel aspects of the cancer transcriptome. First, we identified (at promoter resolution) hundreds of protein coding and long non-coding transcripts that are commonly de-regulated in cancer cell lines. Next, we showed that promoters that overlap repetitive elements (especially SINE/Alu and LTR/ERV1 elements) are often upregulated in cancer. In particular, a specific repeat family, REP522 (largely palindromic, unclassified interspersed repeat of ∼1.8Kb in size), was strongly enriched for the most up-regulated promoters. To our knowledge this is the first report implicating REP522 activation in cancer. Then, taking advantage of the fact that CAGE data can be used to estimate the activity of enhancers from balanced bidirectional transcription we identified 90 enhancer RNA producing regions that are recurrently activated in cancer cell lines. With ENCODE ChIA-PET data, we linked 16 of the cancer-activated enhancers to promoters of known cancer related genes. Finally, to confirm that our results are relevant to clinical tumors we performed complementary analysis in RNA-seq data from 4,055 tumors and 563 normal tissues profiled by The Cancer Genome Atlas (TCGA) and we identified a core set of pan-cancer biomarkers (of both coding and non-coding transcripts) that are recurrently perturbed in both the FANTOM5 and TCGA datasets. In summary, our extensive transcriptome analysis identified a comprehensive set of candidate biomarkers with pan-cancer potential, and extended the perspective of enhancers and repetitive elements that are recurrently activated during carcinogenesis. Citation Format: Bogumil Kaczkowski, Yuji Tanaka, Hideya Kawaji, Albin Sandelin, Robin Andersson, Masayoshi Itoh, Timo Lassmann, Yoshihide Hayashizaki, Piero Carninci, Alistair R.R. Forrest, FANTOM5 Consortium. Recurrent transcriptome alterations across multiple cancer types. [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 2897.
Giant cell arteritis
Authors: Karina Lazarewicz, Pippa Watson
Journal: BMJ (2019)

### What you need to know

Giant cell arteritis (GCA) is an inflammatory disease that affects medium and large blood vessels, classically the extracranial branches of the external carotid arteries. Inflammation in the wall of the affected artery may cause headache, scalp tenderness, jaw and tongue pain, and visual disturbances, but can also present with systemic or other less common symptoms, so that diagnosis can be challenging. It is a rare disease affecting 2.2 per 10 000 patient-years in the UK.1 Consequences can be serious if the diagnosis is delayed, and may include visual loss, stroke, and aortic aneurysm. Many patients with GCA first present to their general practitioner or local emergency department. The most common presenting symptom of GCA is headache (76%)1 but given its relative rarity, other causes of headache are much more common in these settings. Glucocorticosteroids are the mainstay of treatment, but at high doses and for prolonged periods of time are associated with substantial side effects. In April 2019, the National Institute for Health and Care Excellence (NICE) licensed tocilizumab for patients with refractory or relapsing disease.2 This article provides a practical update for non-specialists with particular emphasis on making a diagnosis and initial management. It also discusses the new NICE …
Risk of venous thromboembolism in hospitalised cancer patients in England—a cohort study
Authors: Sonia Ratib, Alex J. Walker, Tim R. Card, Matthew J. Grainge
Journal: Journal of Hematology & Oncology (2016)

Venous thromboembolism (VTE) is a well-recognised and life-threatening complication in patients with cancer. However, the precise risk of VTE in hospitalised cancer patients in England has not been previously reported. We conducted a cohort study using linked Hospital Episodes Statistics and Office for National Statistics mortality data. We determined the risk of VTE separately for 24 cancer sites following first hospitalisation for cancer (index date) and how this varied by age, proximity from hospital admission, administration of chemotherapy and calendar time. Between 1998 and 2012, 3,558,660 patients were hospitalised for cancer. The cancer sites with the highest risk of VTE during initial hospitalisation for cancer were pancreatic (4.9 %), ovarian (4 %) and liver (3.8 %). The three cancer sites with the highest risk of first VTE event within 6 months from discharge were pancreatic (3.7 %), oesophagus (3 %) and stomach (2.8 %). For most cancers, the risk of VTE within 6 months from discharge was higher amongst patients who underwent chemotherapy compared to those who did not. The impact of age on risk of VTE varied considerably between cancer sites. The risk of VTE amongst patients hospitalised for cancer varies greatly by cancer site, age, proximity from hospital admission, and chemotherapy administration.
Abstract 2954: MAP-kinase pathway activation facilitates survival of persistent FGFR1-amplified lung cancer cells upon FGFR inhibition
Authors: Florian Malchers, Meryem Seda Ercanoglu, Roman Kurt Thomas
Journal: Cancer Research (2016)

Abstract One recurrent alteration of squamous cell lung cancer is the amplified region of the 8p12-p11 locus. The tyrosine kinase fibroblast growth factor receptor 1 (FGFR1) seems to be one of the most prominent targets of this amplification. Thus, small molecules inhibiting FGFRs have been employed to treat FGFR1-amplified squamous cell lung cancer. However, only about 16% of such FGFR1-amplified tumors respond to single agent inhibitor therapy. Several tumors exhibited insufficient tumor shrinkage, compatible with the existence of persistence of inhibitor-resistant tumor cells in the tumor. To investigate the mechanism of FGFR-inhibitor persistence we studied the lung cancer cell lines DMS114 and H1581. Both cell lines demonstrate GI50 values in the nanomolar range upon three different FGFR-inhibitors. However, both cell lines exhibit sustained cell viability within 0.5 to 5 μM inhibitor treatment, indicating a subpopulation of persistent cells. We therefore isolated these persistent cells by treating with a high dose of FGFR inhibitors. After 8 to 12 weeks the cells were completely resistant against all FGFR inhibitors tested. Genetic identity with the original cell line was confirmed by fingerprinting. We found that while parental cell lines showed depleted pERK signals, persistent cells were marked by a constant pERK level upon treatment. In H1581 cells, reactivation of the mitogen-activated protein kinase (MAPK) pathway was demonstrated by an active RAS-pulldown assay. Whole exome sequencing (WES) revealed high and focal NRAS amplification and DUSP6 depletion, leading to MAPK-pathway reactivation. Furthermore, retroviral overexpression of wild type RAS-isoforms induced FGFR-inhibitor resistance in parental H1581 cells. In DMS114 we observed MET and IGF-1R activation as possible mechanisms of persistence. Furthermore, co-inhibition of FGFR and MEK was a highly effective combination therapy to treat FGFR-inhibitor persistent cells. This study associates the MAPK-pathway as a key pathway for FGFR-dependent cell lines. Furthermore, these results suggest a beneficial FGFR / MEK combination treatment to avoid the outgrowth of FGFR-inhibitor persistent cells. Citation Format: Florian Malchers, Meryem Seda Ercanoglu, Roman Kurt Thomas. MAP-kinase pathway activation facilitates survival of persistent FGFR1-amplified lung cancer cells upon FGFR inhibition. [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 2954.
Abstract 3715: Benzimidazolone sulphonamides - potent, selective and drug-like inhibitors of poly(ADP Ribose) Glycohydrolase (PARG)
Authors: Allan Jordan, Ben Acton, Nicola Hamilton, James Hitchin, Colin Hutton, Dominic James, Cliff Jones, Stuart Jones, Alison McGonagle, Helen Small, Kate Smith, Alex Stowell, Julie Tucker, Ian Waddell, Bohdan Waszkowycz, Donald Ogilvie
Journal: Cancer Research (2016)

Abstract In recent years, many proteins involved in DNA repair, such as ATR, ATM and PARP, have received considerable attention as potential points of therapeutic intervention in cancer. Indeed, these efforts have recently delivered several agents into clinical evaluation or FDA regulatory approval. However, the DNA repair protein poly(ADP ribose) glycohydrolase (PARG), which plays an equally critical role in DNA single stand break repair, to successful drug discovery efforts. Through our innovative collaboration with AstraZeneca, we have discovered a novel PARG-binding pharmacophore and have employed this information to discover drug-like chemotypes, facilitating the development of potent and selective inhibitors. This poster will describe our emerging results in this area, where a novel benzimidazolone sulphonamide scaffold has been shown potently to inhibit PARG in both biochemical and cellular assays with potencies of 40 nM and 60 nM respectively. Moreover, these agents display pharmacology consistent with the anticipated mode of action, appropriate drug-like properties and are selective against PARP1 and the close glycohydrolase homologue ARH3. The medicinal chemistry optimisation of this scaffold will be described, alongside the recent biological results obtained. Ultimately, this work has helped deliver tool compounds which may help to elucidate the true pharmacology and roles of PARG in cancer and other disease settings. Citation Format: Allan Jordan, Ben Acton, Nicola Hamilton, James Hitchin, Colin Hutton, Dominic James, Cliff Jones, Stuart Jones, Alison McGonagle, Helen Small, Kate Smith, Alex Stowell, Julie Tucker, Ian Waddell, Bohdan Waszkowycz, Donald Ogilvie. Benzimidazolone sulphonamides - potent, selective and drug-like inhibitors of poly(ADP Ribose) Glycohydrolase (PARG). [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 3715.
Abstract 3231: Identification of CD245 as myosin 18A, a receptor for surfactant A: A novel pathway for activating human NK lymphocytes effector function
Authors: Jérôme Giustiniani, Adèle de Masson, Anne Marie-Cardine, Jean-David Bouaziz, Christian Garbar, Martine Bagot, Yacine Merrouche, Armand Bensussan
Journal: Cancer Research (2016)

Abstract Natural Killer (NK) cells were identified over 40 years ago as a subset of lymphocytes able to spontaneously kill tumor cells in the absence of pre-stimulation. Present in most mammalian and avian species, NK cells play a critical role in the anti-tumor and anti-infectious immunity and in reproduction. NK cell cytotoxicity is tightly controlled by a balance between signals delivered through the engagement of activating and inhibitory receptors. Beside these receptors, costimulatory molecules co-exist at the surface of activated NK cells to potentiate NK cells functions. 4-1BB (CD137) is a costimulatory receptor expressed on T, B and NK cells whose expression is triggered by engagement of the Fc receptors on the NK cell surface, as during antibody-dependent cell cytotoxicity (ADCC). Consequently the engagement of CD137 increases cetuximab-, rituximab-, and trastuzumab-dependent NK cell cytotoxic function in different cancer models. We previously described CD245 as an unidentified structure on the surface of human peripheral blood lymphocytes that was recognized by the monoclonal antibodies DY12 and DY35. We also reported that CD245 on NK lymphocytes was associated with tyrosine phosphatase activities. We found that CD245 is the unconventional myosin 18A, which is a receptor for the surfactant protein A (SP-A). We characterized the molecular and functional properties of CD245 and identified a novel co-activation pathway that potentiates the NK cell cytotoxicity. Stimulation by specific antibodies or its physiological ligand SP-A is able to increase NK cell degranulation and lymphokine-activated killer activity towards tumor B cells and EBV-infected B cells, respectively. We also found that myosin 18A stimulation is able to induce CD137 expression at the NK cell surface and that the myosin 18A-induced NK cell cytotoxicity toward CD137L-expressing tumor cells is dependent on the CD137/CD137L interaction. Thus, CD245 could represent a novel and promising target in cancer immunotherapy. Citation Format: Jérôme Giustiniani, Adèle de Masson, Anne Marie-Cardine, Jean-David Bouaziz, Christian Garbar, Martine Bagot, Yacine Merrouche, Armand Bensussan. Identification of CD245 as myosin 18A, a receptor for surfactant A: A novel pathway for activating human NK lymphocytes effector function. [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 3231.
The effect of change in PSA velocity on overall survival (OS) in men with biochemically recurrent prostate cancer (BRPC) treated with nonhormonal agents: Combined analysis of four phase 2 trials.
Authors: Daniel L. Suzman, Marianna Zahurak, Michael Anthony Carducci, Mario A. Eisenberger, Emmanuel S. Antonarakis
Journal: Journal of Clinical Oncology (2014)

121 Background: A number of phase 2 trials in men with BRPC have assessed the impact of non-hormonal agents on PSA kinetics. We have previously demonstrated that changes in PSA kinetics are correlated with metastasis-free survival; however, it is unknown whether these changes may also correlate with overall survival (OS). Methods: We performed a combined retrospective analysis of 146 men with BRPC treated on phase 2 trials using one of four investigational drugs: lenalidomide (n=60), marimastat (n=39), ATN-224 (n=22), and imatinib (n=25). We examined factors influencing OS, including within-subject changes in PSA kinetics (PSA slope, PSA doubling time, and PSA velocity) before and 6 months after treatment initiation. Results: After a median follow up of 77 months, 47 men had died. In univariate Cox regression analysis, four factors were associated with OS: prior androgen deprivation therapy (ADT), prior local radiotherapy, baseline PSA velocity, and change in PSA velocity after therapy. In a landmark multivariable model, stratified by study, which also controlled for age and Gleason score (&lt;7 vs ≥7): prior radiotherapy, baseline PSA velocity, and increase in PSA velocity remained independent predictors of OS (Table). Median OS for men with an increase in PSA velocity on treatment was 9.1 years vs 12.3 years for men with a decrease in PSA velocity (HR 1.95; 95%CI 1.07–3.57; P=0.03). Conclusions: This hypothesis-generating study suggests that within-subject changes in PSA velocity after initiation of non-hormonal therapy may correlate with OS in men with BRPC. If validated in prospective trials using OS as the primary endpoint, change in PSA velocity may represent a reasonable intermediate endpoint for screening new agents in these patients. [Table: see text]