tbuckley/cabot-search huggingface dataset:
Abstract 1168: Urothelial cell carcinomas harbor very frequent mutations in FGFR3-PI3K-AKT pathway and highest prevalence of mutations is related to low-grade tumors
Authors: Silvia Hernandez, Laia Agell, Silvia De Muga, Nuria Juanpere, Laura Lopez, Raquel Murillo, Marta Lorenzo, Sergio Serrano, Joaquim Bellmunt, Josep Lloreta
Journal: Cancer Research (2010)

Abstract More than 90% of bladder cancers are urothelial cell carcinomas. Superficial/papillary and invasive tumors progress via different molecular pathways. FGFR3 and PI3KCA mutations are more commonly found in superficial/papillary tumors. The PI3K-AKT pathway emerges as an alternative pathogenic mechanism linked to bladder cancer. We have analyzed the prevalence of mutations in FGFR3, PI3KCA, KRAS, BRAF and AKT1 genes in a set of 61 bladder tumors classified as TaG1 (n=10), TaG2 (n=19), TaG3 (n=8), T1G2 (n= 3), T1G3 (n= 11), T2G2 (n=1) and T2G3 (n=10). We focused on analyzing the hot spot mutation codons and surrounding regions. Mutation analysis of DNA from paraffin-embedded tumors was performed by direct sequencing of PCR products. Thirty-six (60%) tumors presented mutations, 22 cases with only one mutated gene, whereas 14 of 61 cases had mutations in two genes. The most frequently mutated gene was FGFR3 in 25 tumors, followed by PI3KCA in 16 tumors. The distribution and combinations of mutations was: FGFR3 (n= 16), PI3KCA (n= 3), AKT1 (n= 2), KRAS (n= 1), FGFR3-PI3KCA (n= 9), FGFR3-AKT1 (n= 1), and PI3KCA-KRAS (n= 4). No tumor showed BRAF mutations. According to tumor stage, 26 of 37 (70%) Ta tumors, 3 of 13 (23%) T1 tumors and 7 of 11 (63%) of T2 tumors harbored mutations. On the other hand, according to tumor grade, the distribution of mutations was: grade 1, 9 of 11 (82%); grade 2, 15 of 22 (68%); and grade 3, 12 of 28 (43%), with an overall rate of 27 mutations in 50 high grade tumors (54%). In grade 1, 100% of mutations were found in FGFR3 and/or PI3KCA, with FGFR3 mutations in 9 of 10 tumors. In grade 2, 11 of 15 mutated tumors (73%) showed alterations in FGFR3 and/or PI3KCA, and 4 tumors displayed mutations in AKT1 and KRAS (3 of them in combination with FGFR3 or PI3KCA). In grade 3, 8 of 12 mutated tumors (66%) showed mutations in FGFR3 and/or PI3KCA, and 4 tumors harbored mutations in AKT1 and KRAS (2 of them in combination with PI3KCA). Mutations in AKT1 and KRAS were found in grade 2 and 3, but not in grade 1 tumors. Percentage of mutations in the FGFR3-PI3K-AKT1 pathway is inversely proportional to grade, and it is more often associated with low grade tumors. Mutations in FGFR3 are often found alone in bladder tumors, whereas PI3KCA mutations are more frequent in combination with other mutated genes, such as FGFR3 or KRAS. FGFR3 and KRAS mutations seem to be mutually exclusive, but not PI3KCA and KRAS, nor FGFR3 and AKT1 mutations. 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 1168.
Abstract 1891: Tanshinone IIA is a novel agent for melanoma prevention and therapy
Authors: Zhibo Wang, Naiqiang Cui, Soldano Ferrone, Xianzhong Wu, Ronald Herberman, Wenjun Wang
Journal: Cancer Research (2010)

Abstract Background: Tanshinone IIA (TIIA) is a non-toxic natural compound isolated from traditional Chinese herb, Salvia Miltiorrhiza that has been used for prevention and therapy of a wide array of diseases such as vascular diseases and cancers in other countries. It has been documented outside the United States that TIIA has the biological functions of being pro-differentiation, anti-oxidant, anti-inflammation, anti-carcinogenesis and anti-tumor. However, TIIA has not been studied for melanoma prevention and therapy up to date. Methods: Purified standard substance of TIIA has been use for this pilot study. Human adult epidermal melanocyte HEMa-LP and primary human melanoma cell MEL526 were used. Western blot, flow cytometry, ELISA and immunofluorescence techniques were employed to probe the biomarkers interested pre and post treatment of TIIA. Results: TIIA inhibited MEL526 proliferation and induced MEL526 apoptosis at 20 µM that is below far away from TIIA plasma therapeutic concentrations in vivo. TIIA inhibited MEL526 cell motility at concentrations of 2.5µM or 5µM. TIIA (1.25 µM, 2.5 µM and 5 µM) prevented melanocyte epigenetic transdifferentiation to malignant melanoma cell induced by MEL526 conditioned cell culture medium, while TIIA is not toxic to normal melanocytes at those concentrations. TIIA induced transformed-HEMa-LP cell apoptosis at the above concentrations addressed. TIIA consistently down-regulated, at various ratios of drug concentration/cell density, the expression of melanoma stem cell biomarker CD133, and the expression of chondroitin sulfate proteoglycan 4 that is associated positively with melanocytic malignant transformation/progression and melanoma stem cell biomarker expression. STAT5-mediated up-regulation of Foxp3 has been documented in regulatory T cell differentiation and function, but not in melanocyte; and the higher expression level of STAT5a predicts the lower degree of atypia of nevi. In this study it was fund that TIIA increased the expression of STAT5a in MEL526 while the expression of Foxp3, a cancer suppressor gene, was up-regulated. TIIA inhibited the activation EFGR, which activation promotes carcinogenesis and progression of skin cancers. It was not found that TIIA regulated other biomarkers tested such as HLA Class I and B7H1 antigens. In addition, it was found that TIIA promoted human PBMC to produce IFNγ. Conclusion: TIIA is a potential novel agent used for melanoma prevention and therapy. However, further studies of TIIA are needed to prove the biological function and mechanisms in vivo. 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 1891.
ME-11 * REDUCTION OF NFkB IN THE IN THE TUMOR MICROENVIRONMENT ALTERS THE NEURAL EXTRACELLULAR MATRIX AND REDUCES GLIOBLASTOMA GROWTH AND DISPERSION
Authors: A. Kwiatkowska, M. Nandhu, C. Hecker, M. Viapiano
Journal: Neuro-Oncology (2014)

Identifying major support mechanisms in the neural microenvironment could have significant impact against growth and invasion of malignant gliomas. The NFkB pathway is a major signaling hub that drives tumor progression and at the same time regulates the inflammatory responses of normal tissues. Here we show that animals with a stunted NFkB response exhibit reduced reactivity against intracranial gliomas, which surprisingly reduces tumor growth and invasion. NFkB-deficient mice (RelA + /- TNFR1-/-) were injected intracranially with mouse GL261 glioblastoma cells to analyze tumor phenotype. Histological and MRI analyses showed significantly smaller tumors in RelA + /- mice compared to control littermates. Interestingly, immunohistochemical studies indicated that tumors in RelA + /- mice had vascularization and infiltration of microglia/macrophages comparable to controls, but significant reduction of M2 microglia/macrophage polarization and GFAP-positive astroglia. The lower reactivity of RelA + /- astroglia was also evident following intracranial implantation of highly invasive mouse glioblastoma cells (Mut4; GFAP-Cre:Nf1loxP/+ Trp53-/+ PTENloxP/+), suggesting that the astrocyte compartment played a major role in tumor growth or invasion. To test this hypothesis we prepared cultures of brain slices, where astrocytes and their secreted ECM are the major components challenging glioma cells. Interestingly, glioblastoma cells were significantly less invasive in brain slices from NFkB-deficient mice compared to wild-type tissue. Further analysis of RelA-/–astrocytes demonstrated reduced migration towards glioblastoma cells, increased expression of neural chondroitin sulfate proteoglycans and reduced expression of the metalloproteases that cleave these inhibitory ECM proteins, lending support to the reduced tumor progression observed in vivo. Taken together, these results strongly suggest that activation of NFkB in the neural microenvironment underlies the reactive glial response that promotes tumor growth and invasion. In particular, our results highlight astroglial NFkB signaling as a driver of glioma malignancy that should be considered for long-term targeted strategies.
The Acquisition of Herpes Simplex Virus during Pregnancy
Authors: Zane A. Brown, Stacy Selke, Judy Zeh, Jerome Kopelman, Arthur Maslow, Rhoda L. Ashley, D. Heather Watts, Sylvia Berry, Millie Herd, Lawrence Corey
Journal: New England Journal of Medicine (1997)

The acquisition of genital herpes during pregnancy has been associated with spontaneous abortion, prematurity, and congenital and neonatal herpes. The frequency of seroconversion, maternal symptoms of the disease, and the timing of its greatest effect on the outcome of pregnancy have not been systematically studied.
Accelerated Fetal Growth Prior to Diagnosis of Gestational Diabetes Mellitus: A Prospective Cohort Study of Nulliparous Women
Authors: Ulla Sovio, Helen R. Murphy, Gordon C.S. Smith
Journal: Diabetes Care (2016)

OBJECTIVE To determine whether fetal overgrowth precedes the diagnosis of gestational diabetes mellitus (GDM) and to quantify the interrelationships among fetal overgrowth, GDM, and maternal obesity. RESEARCH DESIGN AND METHODS We conducted a prospective cohort study of unselected nulliparous women and performed ultrasonic measurement of the fetal abdominal circumference (AC) and head circumference (HC) at 20 and 28 weeks of gestational age (wkGA). Exposures were diagnosis of GDM ≥28 wkGA and maternal obesity. The risk of AC &amp;gt;90th and HC-to-AC ratio &amp;lt;10th percentile was modeled using log-binomial regression, adjusted for maternal characteristics. RESULTS Of 4,069 women, 171 (4.2%) were diagnosed with GDM at ≥28 wkGA. There was no association between fetal biometry at 20 wkGA and subsequent maternal diagnosis of GDM. However, at 28 wkGA, there was an increased risk of AC &amp;gt;90th percentile (adjusted relative risk 2.05 [95% CI 1.37–3.07]) and HC-to-AC ratio &amp;lt;10th percentile (1.97 [1.30–2.99]). Maternal obesity showed similar associations at 28 wkGA (2.04 [1.62–2.56] and 1.46 [1.12–1.90], respectively). The combination of GDM and obesity was associated with an approximately fivefold risk of AC &amp;gt;90th (4.52 [2.98–6.85]) and approximately threefold risk of HC-to-AC ratio &amp;lt;10th percentile (2.80 [1.64–4.78]) at 28 wkGA. Fetal AC &amp;gt;90th percentile at 28 weeks was associated with an approximately fourfold risk of being large for gestational age at birth. CONCLUSIONS Diagnosis of GDM is preceded by excessive growth of the fetal AC between 20 and 28 wkGA, and its effects on fetal growth are additive with the effects of maternal obesity.
Abstract 4642: Combined glycolytic inhibition and anti-vascular treatment in retinoblastoma: Novel strategy for tumor control avoids chemotherapy
Authors: Timothy G. Murray, Steve Houston, Christina Decatur, Yolanda Pina, Ted Lampidis
Journal: Cancer Research (2012)

Abstract Purpose: The purpose of this study was to evaluate the combination treatment of glycolytic inhibitors and anti-angiogenic agents on tumor burden and hypoxia in advanced retinoblastoma using the LHbetaTag murine transgenic retinoblastoma model. Methods: Under IACUC protocol, thirty advanced LHbetaTag mice (16 weeks of age) were divided into 5 groups (n=6 per group) and treated with periocular injections of (a) saline, (b) 2-deoxy-glucose (2-DG), (c) anecortave acetate (AA) or (d) 2-DG plus AA (one day post AA treatment) or (e) 2-DG plus AA (one week post AA treatment). Eyes were enucleated at 21 weeks and tumor sections were analyzed for tumor burden and intra-tumoral hypoxia. Results: Combined treatment with 2-DG and AA (both 2-DG one day and one week post AA treatment) showed significant reduction in tumor burden compared to saline control (61% and 56% respectively, p &amp;lt;.001). Eyes treated with 2-DG one day post AA injection showed a significant tumor burden reduction as compared to 2-DG alone or 2-DG plus AA injected after one week (p&amp;lt;01). Further, intra-tumoral hypoxia was eliminated in 2-DG treated eyes at one day post AA injection and was significantly reduced in 2-DG eyes treated one week after AA injection (p&amp;lt;.0001). Conclusion: Combination focal therapy with glycolytic inhibitors and angiogenic inhibitors significantly enhanced tumor control and reduced tumor hypoxia. Treatment timing greatly impacted the effect of combined treatment. Combination therapy with 2-DG and AA was as effective as current chemotherapy regimens in the treatment of LHbetaTag murine transgenic retinoblastoma and may potentially serve as an alternative treatment strategy for advanced pediatric retinoblastoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4642. doi:1538-7445.AM2012-4642
PTU-071 Cause of Death in the Exeter Inflammatory Bowel Disease (IBD) Population
Authors: E Wesley, B Beddoes, A Forbes, M Clarke, T K Daneshmend, T Ahmad
Journal: Gut (2013)

<h3>Introduction</h3> Recent meta-analyses of population based IBD mortality studies have shown no increase in standardised mortality ratio for ulcerative colitis (UC)<sup>1</sup>, but a small increase for Crohn’s disease (CD)<sup>2</sup>. 26–50% of deaths in CD patients were related to the underlying IBD diagnosis<sup>2</sup>. The aims of this study were to investigate the death cause distribution in a well defined IBD population and to establish the proportion of deaths related to the underlying diagnosis or treatment. <h3>Methods</h3> Retrospective case note review to establish cause of death of all patients on the Exeter IBD database who died in the 9yr period until 31.12.2011. Cases were reviewed by 2 clinicians to establish cause of death and ascertain whether it was related to the underlying diagnosis or treatment. <h3>Results</h3> 143 deaths, 82 male. 87 had UC, 46 CD and 10 IBD unclassified. Mean age at diagnosis was 58 (11 – 94). Mean duration of disease at time of death was 17 years (0–61). The median age of death was 72.5 and 79 years for CD and UC respectively (<i>P</i> = 0.001, 95% CI –13 - –3 years). The underlying disease or treatment was implicated in the cause of death in 35/143 (23%) patients and was more common in CD compared to UC patients (37 vs. 18%, <i>P</i> = 0.03). There was no change over time in the proportion of related deaths. 13/143 (9%) had a diagnosis of colorectal cancer at the time of death; in 8 this was the primary cause of death. 8 had Primary Sclerosing Cholangitis, all of whom died of related complications. 8 patients had a haematological malignancy including 3 patients with colonic lymphomas, 1 with chronic myeloid leukaemia, 2 with non-Hodgkin’s lymphoma and 1 with peripheral T cell lymphoma. Half of these patients had previously been prescribed thiopurines. 10 died during emergency admission for acute IBD. 3 had coexisting enteric infection. 2 died from perforations (gastric and ileal). 7 died of post-operative complications of IBD surgery (3 emergency cases, 4 elective). 94/143 (66%) died of conditions unrelated to IBD (including 23 cardiac, 21 respiratory causes). 38 (27%) died of cancer. A cause of death could not be established for 14 patients. <h3>Conclusion</h3> CD patients died at a younger age compared with UC patients and were more likely to die from a complication of IBD or treatment. The proportion of IBD related deaths has not changed within the time period of this study. <h3>Disclosure of Interest</h3> None Declared <h3>References</h3> Jess, T <i>et al. Am J Gastro</i><i></i><b>102</b>, 609–617 (2007). Duricova, D. <i>et al. IBD</i><b>16</b>, 347–353 (2010).
SP0120 Trap deficiency, autoimmunity and other mendelian variants of lupus
Authors: Y. Crow
Journal: Annals of the Rheumatic Diseases (2013)

Our studies of the Mendelian interferonopathy Aicardi-Goutières syndrome (AGS), and the related disorder familial chilblain lupus, have highlighted the role of cell-intrinsic nucleic acid detection in the causation of autoimmunity, and emphasised the importance of type I interferon (IFN) in the pathogenesis of systemic lupus erythematosus (SLE). This experience has prompted us to consider the identification and analysis of single-gene disorders predisposing to the development of SLE as a tractable approach to understanding the pathogenesis of lupus; such “experiments of nature” representing the equivalent of genetically engineered animal models of disease – in the human context<sup>1</sup>. In line with this research strategy, we became interested in the immuno-osseous dysplasia spondyloenchondrodysplasia (SPENCD). Although regarded primarily as a skeletal dysplasia, SPENCD patients have been reported to show immune dysfunction, with a particular susceptibility to the development of SLE. We confirmed a very high frequency of autoimmune phenotypes, including lupus, in SPENCD patients, and subsequently identified biallelic mutations in the <i>ACP5</i> gene, encoding tartrate resistant acid phosphatase (TRAP), as causative of the disease<sup>2</sup>. Considering both the importance of the cytokine IFN-alpha (IFN-α) in the pathogenesis of SLE, and the clinical overlap of SPENCD with AGS, we then went on to demonstrate increased type I IFN activity, and increased expression of type I IFN-stimulated genes, a so-called IFN signature, in cells from affected individuals. In an accompanying paper, Lausch et al implicated osteopontin, a known substrate of TRAP with a recognized role in both IFN-αproduction in plasmacytoid dendritic cells and type I IFN production in lupus, as relevant to the pathology of SPENCD<sup>3</sup>. Together with deficiency of early components of the classical complement pathway and mutations in <i>TREX1</i>, TRAP deficiency now represents a third monogenic disorder associated with the development of SLE also demonstrating an up-regulation of type I interferon activity. Thus, our findings identify a previously unrecognised link between TRAP and type I interferon, and further emphasise the importance of the type I interferon response to autoimmunity<sup>4</sup>. <h3>References</h3> Crow YJ. Lupus: how much “complexity” is really (just) genetic heterogeneity? Arthritis Rheum 2011;63:3661-4. Briggs TA, et al. Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature. Nat Genet 2011;43: 127-31. Lausch E et al. Genetic deficiency of tartrate-resistant acid phosphatase associated with skeletal dysplasia, cerebral calcifications and autoimmunity. Nat Genet 2011;43:132-7. Crow YJ. Type I interferonopathies: a novel set of inborn errors of immunity. Ann N Y Acad Sci. 2011;1238:91-8. <h3>Disclosure of Interest</h3> None Declared
Abstract 3231: Comprehensive profiling of actionab.
Authors: Yulei Wang, Richard Bourgon, Shan Lu, Yibing Yan, Yinghui Guan, Lisa Ryner, Rajesh Partel, Mark Lackner, Lukas Amler
Journal: Cancer Research (2013)

Abstract Comprehensive characterization of genetic profiles in clinically actionable genes in each tumor promises to facilitate personalized approaches to cancer treatment. However, development of systematic genetic profiling of cancers in the clinical setting is facing unique technical challenges. More than 90% of tumor samples available for clinical sequencing are formalin-fixed and paraffin-embedded (FFPE). These samples are not only limited by quantities, the DNA quality in these samples is often compromised due to different degree of degradation, cross-links and chemical modifications. Targeted sequencing, in which genomic regions of interests are selectively enriched before sequencing to achieve high coverage and sensitivity, can potentially provide a cost-effective and efficient solution for clinical sequencing. However, very few studies have been reported on the development of methodology that is applicable and robust in analyzing “real-world” clinical FFPE samples. Here we report the development of a novel methodology that integrates microfluidic multiplex PCR-based target enrichment with massively parallel sequencing for high-throughput, high-content targeted sequencing of clinically actionable cancer genes in FFPE tumor tissues. This method enables amplifying 963 regions from 88 common cancer genes in 48 samples and simultaneously sequencing 48 pooled barcoded samples in a single sequencing reaction. Using this method, we sequenced 40 cancer cell lines and a well-defined Latin square study with dilution series of 8 known somatic mutations, to comprehensively assess the sensitivity, specificity, reproducibility in both target enrichment and variant detection. Furthermore, using paired fresh frozen/FFPE tissues obtained from 16 cancer patients, we developed and optimized a FFPE protocol that yields high-quality genetic profiles highly concordant to those derived from parallel fresh frozen samples. To demonstrate the clinical utility of this method, we sequenced a cohort of 73 FFPE tumor samples from endometrial cancer patients. Many clinically actionable mutations were identified in these patients’ samples and confirmed using orthogonal validations. Our results demonstrated the feasibility and clinical utility of our method in clinical sequencing, setting the stage for ultimately translating this method in clinical setting to inform and guide cancer treatment. Citation Format: Yulei Wang, Richard Bourgon, Shan Lu, Yibing Yan, Yinghui Guan, Lisa Ryner, Rajesh Partel, Mark Lackner, Lukas Amler. Comprehensive profiling of actionab. [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 3231. doi:10.1158/1538-7445.AM2013-3231
Immune monitoring technology primer: whole exome sequencing for neoantigen discovery and precision oncology
Authors: Pia Kvistborg, Raphael Clynes, Wenru Song, Jianda Yuan
Journal: Journal for ImmunoTherapy of Cancer (2016)

ᅟ ᅟ * Abbreviations: DNA : deoxyribonucleic acid FFPE : formalin-fixed, paraffin-embedded (tissue) MHC : major histocompatibility complex NGS : next-generation sequencing NSCLC : non-small cell lung cancer PBMCs : peripheral blood mononuclear cells RNA : ribonucleic acid sSNV : somatic single nucleotide variant TILs : tumor infiltrating lymphocytes TMSA : tumor mutation specific antigen TSNA : tumor specific neoantigens
How the friends and family test is conveyed to the public should be reconsidered
Authors: R. Davis
Journal: BMJ (2013)

In July 2013 the first data from the friends and family test (FFT) became publicly available on NHS Choices.1 Hospitals are given an FFT score and ranked “best,” “OK,” or “worst.”

There are several problems about how these data are currently conveyed to the public.

Firstly, no details are provided on how the FFT score is calculated, in particular that …
Authors’ reply: Station data and modelled climate data in Africa
Authors: S Ng, B J Cowling
Journal: Eurosurveillance (2014)

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