tbuckley/cabot-search huggingface dataset:
PTU-139 Colonic histological abnormalities are non-specific and non-significant in bile acid malabsorption
Authors: O Orekoya, J McLaughlin, E Leitao, W Johns, P Paine
Journal: Gut (2012)

<h3>Introduction</h3> Bile acid malabsorption (BAM) is a common cause of chronic secretory diarrhoea via poorly characterised mechanisms. The aim of this study was to determine if histological abnormalities in colonic mucosa are linked to BAM in patients with chronic diarrhoea. <h3>Methods</h3> During a 6-year period 264 patients were investigated with SeHCAT for chronic diarrhoea and their retention values recorded (≤8% = positive result; ≥16% = negative result). Colonic biopsies and histological analysis were available in 150 (57%). The patients were categorised as: Group 1: terminal ileum Crohn9s disease, (pre or post resection) n=51. Group 2: Idiopathic BAM (including patients with diarrhoea predominant IBS) n=159. Group 3: BAM secondary to other gastrointestinal disease n=51; of which cholecystectomy (n=37), coeliac disease (n=1), chronic pancreatitis (n=1), bacterial overgrowth (n=2), diabetes (n=4) and other gastrointestinal surgeries (n=6). Group 4: terminal ileum disease plus cholecystectomy n=3. <h3>Results</h3> A histological abnormality was present in 29% (n=16/56) of the patients with positive SeHCAT, vs 23% (n=17/74) of the patients with negative SeHCAT (p=0.318, two-tailed Fisher9s exact test). Similarly, 30% (n=6/20) of the patients with equivocal SeHCAT results (8%–16% retention) had histological abnormalities. As expected, the highest prevalence of these abnormalities was noted in groups 1 and 4, the subjects with Crohn9s disease, regardless of the presence of BAM. Abnormalities were noted in descriptive terms and included colitis (n=4), chronic inflammation (n=5), cryptitis (n=4), mild non-specific inflammation (n=11), moderate non-specific inflammation (n=5), polyps (n=2), ulceration (n=6) and active inflammatory bowel disease (n=2). 30% (n=8/27) of positive SeHCAT with idiopathic BAM (group 2) had abnormalities on histology compared with 19% (n=10/52) who had negative SeHCAT in group 2, which was again a non-significant difference (p=0.397, two-tailed Fisher9s exact test). The 7% (n=2/28) of patient in group 3 with histological abnormalities also had negative SeHCAT results. <h3>Conclusion</h3> This retrospective study indicates that colonic histological abnormality is non-specific and coincidental to the presence of bile acid malabsorption in patients with chronic diarrhoea. It is unlikely to be relevant to the mechanism of diarrhoea which is probably non-inflammatory. This might be further studied in the future using faecal markers of inflammation in these patients. <h3>Competing interests</h3> None declared.
SP0187 Metabolic Syndrome in Patients with Psoriatic Disease
Authors: A. Ogdie
Journal: Annals of the Rheumatic Diseases (2013)

<h3></h3> Psoriasis and psoriatic arthritis have been linked to an increased prevalence of metabolic syndrome when compared to the general population. This session will review the evidence for the association between psoriatic disease and metabolic syndrome, biologic explanations for the epidemiologic association, and the relevance for clinical practice. The prevalence of metabolic syndrome in the Western European and United States ranges from 15-35% but has been found to be significantly elevated in patients with psoriasis compared to the general population in several studies. Metabolic syndrome is a combination of disorders that includes obesity, elevated fasting glucose, hypertension, and/or dyslipidemia (low high density lipoprotein and/or high triglycerides). This combination of disorders confers a significantly increased risk of major adverse cardiovascular events (MACE). It is possible that metabolic syndrome partially explains the increased risk of MACE reported in patients with psoriatic disease. The biologic basis for the link between psoriasis and metabolic syndrome is not entirely clear. Both psoriasis and obesity share increased levels of inflammatory cytokines which may promote insulin resistance, dyslipidemia and atherosclerosis. Shared genetic susceptibility loci have been identified but their impact is unclear. The individual disorders of metabolic syndrome should be identified and aggressively managed in patients with psoriatic disease. <h3>Disclosure of Interest</h3> None Declared
Abstract A12: AmotL2 linking hypoxia to invasion
Authors: Mahdi Mojallal, Yujuan Zheng, Sara Hultin, Lars Holmgren
Journal: Cancer Research (2011)

Abstract Hypoxia has been shown to be a bad prognostic marker correlating with metastasis and poor survival. Furthermore, in response to antiangiogenic therapy hypoxic tumor cells become invasive and form metastasis. Malignant tumor cells undergo epithelial-mesenchymal transition (EMT) and become depolarized. A protein important for apicobasal polarity during tumor progression is Crumbs3 (crb3). Silencing of Crumbs3 disrupts epithelial cell polarity and possibly promotes metastasis. AmotL2, a gene regulated by hypoxia, associates to the Crb3/Pals/Patj polarity complex via its PDZ-binding motif (unpublished data). Here we show that AmotL2 disrupts apicobasal polarity resulting in the development of an invasive phenotype. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A12.
Incidental Finding of Accessory Spleen on Bone Scintigraphy
Authors: M. CASTELLANI, E. RESCHINI, A. BRUNO, R. BENTI, G. MAROTTA, P. GERUNDINI
Journal: Clinical Nuclear Medicine (1996)

The case of a 42-year-old woman with hereditary spherocytosis whose spleen was removed in infancy is reported. A bone scan, which was performed during the staging of a hepatocellular carcinoma showed a mass concentrating MDP laterally to the upper pole of the left kidney. CT and US raised the suspicion of a renal mass. Dynamic scintigraphy with DTPA showed the mass to be highly vascular, but probably not of renal origin. The surgically removed mass was a calcified accessory spleen. The history of splenectomy in infancy made the preoperative diagnosis almost impossible, but the nuclear medicine procedures were more accurate than the radiological procedures in the diagnosis towards an extrarenal mass that was well perfused and calcified.
Operative Techniques in Early-Stage Lung Cancer
Authors: Thomas A. D'Amico
Journal: Journal of the National Comprehensive Cancer Network (2010)

Lung cancer is the most common cause of death by malignancy, responsible for more deaths than the next 4 causes combined and predicted to account for nearly 220,000 new cancer diagnoses and 160,000 deaths in 2009. The cornerstone of therapy for early-stage lung cancer is lobectomy and mediastinal lymph node dissection. Although lobectomy is considered the standard procedure, segmentectomy may be appropriate for selected patients. Conventional approaches to resection may be used, including posterolateral and muscle-sparing thoracotomy. However, minimally invasive lobectomy and segmentectomy procedures are now commonly used with superior outcomes.
Abstract 4612: Analysis of transcriptional regulation by progesterone receptor in ER-positive breast cancer cells by ChIP-Seq
Authors: Fan Yang, Sven Bilke, Marbin Pineda, Bob Walker, Jack Zhu, Paul Meltzer
Journal: Cancer Research (2010)

Abstract Breast cancer is among the most common malignancies in women. It is well established that progesterone receptor (PR) is a major determinant in the development and progression of breast tumor, as well as in diagnosis and treatment of breast cancer. However, it is still not fully understood how PR affects downstream signaling pathways and cross talks with other intracellular signal transduction pathways. To better define the role played by PR in estrogen receptor (ER)-dependent gene regulation, we have used chromatin immunoprecipitation coupled with next generation sequencing (ChIP-Seq) to examine the in vivo DNA binding by PR. Whole-Genome ChIP-Seq analysis has identified large number of PR binding sites in T-47D breast cancer cells, which are ER-positive and PR-positive. PR binding sites were detected in proximal promoter regions as well as distal regions, with most located in non-proximal regions. The comparison of PR and ER binding sites revealed that a significant of portion of the PR binding sites overlaps with the ER binding sites, indicating a close relationship between PR and ER in ER-dependent gene regulation. The PR motifs were found to be among the most enriched sequence motifs within the PR binding sites. Further analysis using the chromosome conformation capture assay revealed that progesterone induces changes to the chromatin structures of known PR-regulated genes. The ChIP-Seq data, together with the expression profiling and other results, indicate that PR may cooperate with ER and play an important role in ER-dependent gene regulation, mammary epithelial differentiation and breast cancer development. 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 4612.
Abstract 4690: Inhibition of PI3K-AKT signaling causes a FOXO-dependent induction of receptor tyrosine kinase expression and phosphorylation in cancer
Authors: Sarat Chandarlapaty, Ayana Sawai, Vanessa Rodrik-Outmezguine, Maurizio Scaltriti, Violeta Serra, Jose Baselga, Neal Rosen
Journal: Cancer Research (2011)

Abstract Hyperactivation of the PI3K-AKT-mTOR pathway is a common mechanism for oncogenic signaling in tumors and multiple inhibitors of this pathway are now in clinical development. As the PI3K-AKT-mTOR pathway is known to be tightly regulated by negative feedback, we hypothesized that these drugs might relieve feedback inhibition, reactivate upstream signaling and limit their antitumor effects. We tested the effects of inhibitors of PI3K and AKT kinase on receptor tyrosine kinase signaling in a panel of cell lines derived from multiple tumor types. PI3K-AKT pathway inhibition resulted in increased expression and phosphorylation of a common set of receptor tyrosine kinases, including IGF-1R and insulin receptor and HER3. Induction of RTK expression was dependent on activation of members of the Forkhead transcription factor family in response to AKT inhibition. We found that depletion of FOXO proteins blocked the rise in HER3, IGF-1R, and insulin receptor protein and phosphorylation caused by AKT inhibition. Expression of a constitutively activated form of one of the FOXO proteins resulted in increased expression of these receptors. Moreover, immunoprecipitation of FOXO proteins revealed that they are preferentially associated with the promoters of these receptors upon AKT inhibition. To determine the consequences of induction of these RTKs, we utilized HER kinase inhibitors to block activation of the receptors. In multiple xenograft tumor models, PI3K-AKT inhibition resulted in potent RTK induction in vivo and combined inhibition of the HER kinases and AKT resulted in improved antitumor effects with tumor regressions observed in several cases. We conclude that the PI3K-AKT pathway feedback regulates RTK expression through a FOXO-dependent induction of RTK transcripts. This reactivation of upstream RTK signaling is likely to attenuate the effects of AKT inhibition. Blockade of feedback-upregulated RTKs may significantly improve the antitumor effects of PI3K-AKT inhibitors and is a potential combination strategy for PI3K-AKT driven cancers. 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 4690. doi:10.1158/1538-7445.AM2011-4690
Abstract 5351: Prevalence and function of p53 mutations among children with adrenocortical carcinoma (ADCC)
Authors: Jonathan D. Wasserman, Ana Novokmet, Claudia Eichler-Jonsson, David Malkin
Journal: Cancer Research (2011)

Abstract Adrenocortical carcinoma (ACC) is a rare tumor in children, affecting 0.4 per million children worldwide. Incidence in adults is approximately 5-fold higher and may represent a distinct genetic and biologic entity. Mortality rates among patients with ACC are high and treatment options are limited. Previous studies have suggested that a majority of children who develop ACC possess germline mutations in the p53 tumor suppressor gene. In this study we sought to characterize the prevalence and mutational spectrum of p53 among a large multi-center cohort of children with ACC. We further compared the specific mutations found in these children with mutations found in individuals with the Li-Fraumeni syndrome, a familial cancer predisposition syndrome which is strongly associated with germline p53 mutation. Among 58 independent pedigrees assessed for p53 mutation, 29 (50%) carried a heterozygous mutation in p53. No mutation was identified more than once among this cohort. This is in contrast to families with the LFS, where 6 “hotspot” mutations are disproportionately over-represented, combined accounting for 20% of patients with identified p53 mutations. Missense mutations were noted in 28/29 individuals, with a single intragenic deletion identified in the remaining individual. Mutations were found predominantly within the DNA-binding domain (26/29 (90%)). One mutation was identified in the trans-activation domain and two in the oligomerization domain. In the course of this analysis, we identified several novel p53 mutations among children with ACC. These mutations were functionally characterized in vitro based on the ability of mutant p53 to activate transcription of known p53 target genes including those involved in DNA damage repair, cell-cycle arrest and apoptosis. Dominant-negative activity of these mutations was also assessed. Several of the novel mutations demonstrated either full p53 function or partial loss-of-function. The association of these seemingly milder mutations with adrenal tumorigenesis suggests that adrenal tissues may be more sensitive to partial decrease in p53 function than other LFS-affected tissues and that other predisposing or disease-modifying genetic alterations may exist to propel these cells towards a transformed fate. Further efforts to identify disease modifying loci, as well as pathogenic loci in children with wild-type p53 genes are underway via genome-wide analysis. 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 5351. doi:10.1158/1538-7445.AM2011-5351
Abstract 2713: Helicobacter pylori increases the risk of colorectal polyps in African Americans
Authors: Marwah Zahaf, Laiyemo Adeyinka, Mehdi Nouraie, Hassan Brim, Duane Smoot, Edward Lee, Hassan Ashktorab
Journal: Cancer Research (2010)

Abstract Background: H. Pylori infection have linked to colorectal polyps, mainly through hypergastrinemia and its trophic effect on colon mucosa. African Americans were under represented despite both common diseases are more prevalent in them. Aim: The aim of this study was to investigate whether H. Pylori infection has a role in development of colorectal polyps in Africans Americans. Methods: Retrospectively, Africans Americans (n=1262) greater than 40 years old who underwent bidirectional gastrointestinal endoscopy on the same day were enrolled. The pre-procedure indication and post-procedure diagnosis were recorded (n=1262). H. Pylori status was assessed by immunohistochemistry on gastric specimens. Colorectal polyps were confirmed by histological examination of biopsies from complete colonoscopy. Multivariable logistic regression was used to assess the independent risk factors of polyp occurrence. Results: Colorectal polyps (regardless polyp pathology) were more prevalent in H. Pylori-infected subjects (43%; 160/368) compared to (34%; 302/894) uninfected subjects (OR=1.5; 95 %CI=1.2-1.9). Furthermore, there was a trend toward larger polyp size ≥ 1cm in H. Pylori positive patients (P=0.07). There was no difference in histopathology or location of polyps in regard to H. Pylori status. Among the participants, 21 (2%) were defined with baseline above average risk for colorectal polyps justifying colonoscopy and of those; the polyps were detected in 62% (OR; 95%CI=2.9; 1.2-7.1). Age and male gender were independent risk factors for colorectal polyps. Conclusion: H. Pylori increases the risk of developing colorectal polyps and may increase the chances for having a larger size polyp in Africans Americans. These findings suggest that H. Pylori might have a role in the initiation and/or promotion of polyps. Further studies are needed to explore its mechanisms. 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 2713.
Abstract 5403: Akt inhibitor MK-2206 combined with Dasatinib synergistically inhibits the growth of sarcoma cells
Authors: Christopher L. Cubitt, Jillaina L. Menth, Jana L. Dawson, Daniel M. Sullivan
Journal: Cancer Research (2010)

Abstract The number of effective drugs available for the treatment of soft tissue and bone sarcomas is limited to a small group of antineoplastic agents. Previously, we have identified synergistic anti-tumor activities of the Akt inhibitor, Triciribine, when combined with the Src family inhibitor Dasatinib. The goal of this study was to determine the effectiveness of MK-2206, a newly developed inhibitor of Akt, when combined with Dasatinib in a panel of nine sarcoma cell lines. CT-Blue cell viability experiments were performed to test dilutions of MK-2206 alone and in combination with Dasatinib at a 1:1 constant molar ratio. IC50s for MK-2206 alone ranged from 3 to 12.5 µM in the nine cell lines (Table). Using CI analyses (effective dose levels of 0.7, 0.9 &amp; 0.95), a synergistic or strongly synergistic reduction in cell viability (CI &amp;lt;0.7 or &amp;lt;0.3 respectively) was observed in all cell lines. Synergy was observed over a wide dose range and remained synergistic when as little as 0.8 µM of each drug was combined. Table. IC50s and Chou and Talalay Combination Index (CI) Synergy Analysis. Inhibitory concentration of MK-2206 required for 50% reduction in viable cells after 72 hour treatment (IC50). CI values represent the level of synergy resulting from concurrent MK-2206 plus Dasatinib treatment. +/− symbols indicate calculated CI range (+++, synergism; ++++, strong synergism).Cell lineSarcoma typeIC50 (M)Combination Index (CI)meanSEMnmeanSEMnSynergyU2-OSosteo12.5E-6809.5E-9120.400.103+++MNNG HOSosteo9.3E-61.2E-6110.210.202++++A-673Ewing9.6E-6963.4E-9120.440.173+++RD-ESEwing8.5E-61.0E-6100.180.032++++SK-ES-1Ewing3.0E-6371.3E-9120.230.084++++SK-LMS-1leiomyo8.2E-6936.4E-9110.320.033+++SK-UT-1leiomyo6.6E-6889.7E-9110.260.153++++SW-872lipo9.0E-61.1E-6120.480.205+++HT-1080fibro11.7E-6694.9E-9110.540.203+++ In Caspase 3/7 activation assays, MK-2206 induced apoptosis in most cell lines at low µM concentrations. Concurrent MK-2206 plus Dasatinib treatment synergistically enhanced apoptosis during the first 24 hrs of treatment in 4 of 9 cell lines. Ongoing experiments are underway to identify the effects of drug sequencing on cell viability and find mechanisms that can account for the synergistic interactions. However, results of current experiments indicate that a MK-2206, Dasatinib combination may be an effective treatment regimen for sarcoma patients. MK-2206 was provided by Merck &amp; Co. Inc. Funded by the Pediatric Cancer Foundation. 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 5403.
A1.31 HLA-B27 over-expression in rats alters central and peripheral monocyte populations
Authors: C Ansalone, C Milling, CS Goodyear
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background and objectives</h3> HLA-B27 expression is associated with spondyloarthropathy (SpA) and transgenic rats expressing human HLA-B27 and b2-microglobulin (B27 rats) display systemic inflammation and bone loss, which resembles human SpA. We have previously shown that these rats lack a dendritic cell population. However, the myeloid compartment has not been fully characterised. Here, we aimed to characterise monocyte and pre-osteoclast subsets in the bone marrow and blood of B27 rats, and examined the potential of different monocyte/pre-osteoclast subsets to generate mature osteoclasts. <h3>Materials and methods</h3> 14–16 week old control (B7) and B27 rats were bled and plasma CCL2 levels were measured by ELISA. Monocytes subsets were analysed and quantified in both the bone marrow and blood of B27, B7 and non-transgenic animals, by evaluation of surface markers (CD172a, CD43, and CD11b) and intracellular uptake of fluorescent M-CSF and CCL2 by flow cytometry. Monocyte populations were FACS sorted and cultured in pro-osteoclastogenic medium for 7 days to evaluate osteoclastogenic potential. Cultures were stained with tartrate-resistant acid phosphatase (TRAP) and mature osteoclasts (TRAP<sup>+</sup> and ≥3 nuclei) were quantified by light microscopy. <h3>Results</h3> A previously unidentified CD172a<sup>+</sup> CD43<sup>lo</sup> CD11b<sup>-</sup> population of monocytes was observed in the bone marrow. These are <i>bona fide</i> monocytes, expressing CD115 and CCR2, as determined by uptake of fluorescent M-CSF and CCL2 respectively. Interestingly, this new monocyte population was significantly increased in B27 rats. Assessment of the osteoclastogenic potential of bone marrow monocyte subsets revealed that CD172a<sup>+</sup> CD43<sup>lo</sup> CD11b<sup>-</sup>, but not CD172a<sup>+</sup> CD43<sup>lo</sup> CD11b<sup>+</sup> monocytes,can differentiate into mature osteoclasts. Furthermore, although CD172a<sup>+</sup> CD43<sup>lo</sup> CD11b<sup>-</sup> have osteoclastogenic potential, optimal osteoclastogenesis was observed only when all CD43<sup>lo</sup> (CD172a<sup>+</sup> CD43<sup>lo</sup> CD11b<sup>-</sup> and CD172a<sup>+</sup> CD43<sup>lo</sup> CD11b<sup>+</sup>) were present. No differences in osteoclastogenesis were observed between B27 and controls rats. Finally, evaluation of circulating monocytes demonstrated that all blood monocytes express CD11b and that the CD43<sup>lo</sup>CD11b<sup>+</sup> population was increased in B27 rats. This corresponded with an increase in CCL2 plasma levels in the B27 rats. <h3>Conclusions</h3> We have identified a previously unreported CD11b<sup>-</sup>monocyte population in the bone marrow of rats, which can differentiate into mature osteoclasts. Along with the numbers of total CD43<sup>lo</sup> monocytes, this population is significantly increased in the bone marrow and blood of rats over-expressing HLA-B27. The increase in these populations in the B27 rats may contribute to enhanced inflammation and bone loss.