tbuckley/cabot-search huggingface dataset:
AB0772 Exploring Fatigue Patterns over Time in Early Osteoarthritis: Results from the CHECK Study
Authors: C. Bode, J. Botterman, L. Siemons, M. Van de Laar, J. Dekker
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Only a few studies have examined fatigue in Osteoarthritis, but all revealed fatigue as ubiquitously present and related to several physical and mental health aspects among OA patients. <h3>Objectives</h3> The goal of this study was to examine whether different groups of fatigue trajectories can be identified among middle-age patients with early symptomatic osteoarthritis (OA), to establish the level of fatigue severity within each of these fatigue groups, and to assess the role of age, gender and OA severity in relation to group classification. <h3>Methods</h3> Data on fatigue and patient characteristics were collected from the CHECK cohort. Growth mixture modeling (GMM) was applied in order to identify distinct fatigue groups as well as to take into account the influence of radiographic OA severity (Kellgren-Lawrence grading), age and gender on group classification. <h3>Results</h3> A stable, a U-shape, and an inverted U-shape trajectory were identified. The fatigue levels of the latter two groups (i.e. approximately two-thirds of the sample) were comparable to the Dutch cancer population. Females and younger OA patients experienced higher levels of fatigue within each group and females were more likely than males to exhibit the inverted U-shape fatigue pattern. The covariates were not related to the interindividual differences in fatigue change over time within each fatigue group. <h3>Conclusions</h3> Three different fatigue patterns were found among a sample of early OA patients. These patterns indicate that a large number of OA patients experience elevated levels of fatigue already at an early stage of OA. This finding asks for more attention regarding fatigue in OA research, and warrants tailored psychosocial interventions for patients with elevated levels of fatigue. <h3>Acknowledgements</h3> The CHECK study is financed by the Dutch Arthritis Foundation. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.5062
Janus kinase inhibition lessens inflammation and ameliorates disease in murine models of hemophagocytic lymphohistiocytosis
Authors: Rupali Das, Peng Guan, Leslee Sprague, Katherine Verbist, Paige Tedrick, Qi Angel An, Cheng Cheng, Makoto Kurachi, Ross Levine, E. John Wherry, Scott W. Canna, Edward M. Behrens, Kim E. Nichols
Journal: Blood (2016)
Abstract 2157: Cell cycle dependent regulation of c-Myb target gene specificity
Authors: Anita M. Quintana, Scott A. Ness
Journal: Cancer Research (2011)

Abstract The c-Myb transcription factor is a critical regulator of proliferation and stem cell differentiation, and mutated alleles of c-Myb are oncogenic, but little is known about changes in c-Myb activity during the cell cycle. Previous studies have shown that the specificity of c-Myb depends in part on its DNA binding domain, but also on protein-protein interaction motifs in the C-terminal regulatory domains of the protein. These interactions are likely subject to regulation by post-translational modifications and are modified in oncogenic derivatives of c-Myb, which regulate different sets of target genes than the normal c-Myb protein. The analysis of cell cycle regulated target genes provides an ideal means of following the regulation of c-Myb activity in different subsets of cells that are in distinct cell cycle phases. Using Chromatin Immunoprecipitation (ChIP) assays, we found that c-Myb associated with some target genes only in specific cell cycle stages. For example, with the Cyclin E1 gene promoter only in G2/M phase cells. However, we also found that the levels of c-Myb protein were dramatically affected by treating with some cell cycle blocking agents. To map the association of c-Myb with specific target genes during the cell cycle, we developed a novel Fix-Sort-ChIP approach, in which asynchronously growing cells were fixed with formaldehyde, stained with Hoechst 33342 and separated into different cell cycle fractions by flow sorting, then processed for ChIP assays. This approach showed that the specificity of c-Myb is dramatically different in small subpopulations of cells, for example cells in the G2/M phase of the cell cycle, than in the bulk population. The repositioning of c-Myb during the cell cycle is not due to changes in its expression and also occurs with ectopically expressed, epitope-tagged versions of c-Myb. The repositioning occurs in established cell lines, in primary human CD34+ hematopoietic progenitors and in primary human acute myeloid leukemia cells. Our results suggest that c-Myb specificity is actively regulated during the cell cycle, probably through changes in protein-protein interactions. This sheds new light on the dynamic nature of gene regulation during the cell cycle and on the importance of post-translational modifications and/or oncogenic mutations that can dramatically alter the activity and the specificity of transcription factors like c-Myb. 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 2157. doi:10.1158/1538-7445.AM2011-2157
Compartmentalization of Ascites and Edema in Patients with Hepatic Cirrhosis
Authors: Leroy Shear, Santiago Ching, George J. Gabuzda
Journal: New England Journal of Medicine (1970)

Compartmentalization of ascites and nonascitic fluid was demonstrated in cirrhotic patients treated with dietary sodium restriction, diuretic therapy or paracentesis. Disparity between ascitic and nonascitic fluid absorption rates, evident during spontaneous diuresis, was exaggerated by diuretic administration. Despite rapid diuresis maximum ascites absorption rate was 930 ml per 24 hours — close to the rate of intraperitoneal saline absorption by noncirrhotic human subjects. After paracentesis ascitic fluid re-formed at as much as three and a half times the maximum absorption rate. It began to form during the paracentesis procedure and continued at a gradually decreasing rate for three to four days. The ascites formed largely by a shift of nonascitic fluid to the peritoneal cavity. However, some patients also formed ascites from retained exogenous fluid; they gained weight, and mild dilutional hyponatremia developed. Compartmentalization of ascites and edema probably causes some complications that follow attempts to remove abnormal extracellular-fluid collections by paracentesis or diuresis.
277 LY2109761-LOADED MICROCAPSULES AS DRUG DELIVERY SYSTEM TO INHIBIT THE TGF-B1 PATHWAY IN HEPATOCELLULAR CARCINOMA
Authors: A. Mazzocca, F. Baldassarre, V. Vergaro, S. Leporatti, G. Ciccarella, S. Antonaci, G. Giannelli
Journal: Journal of Hepatology (2012)
A game theoretic approach to repeated foreign body ingestion
Authors: Sarah Diamond, Amnon Sonnenberg
Journal: Endoscopy (2015)

Between January 2010 and February 2014, a 39-year-old asthmatic woman with borderline personality disorder, post-traumatic stress disorder, and a history of childhood sexual trauma was admitted to our hospital system 61 times for foreign body ingestion. During these hospitalizations, she underwent 62 upper endoscopies. She also required two exploratory laparotomies for surgical retrieval of a pencil fragment and a battery that had become obstructed in the small bowel. She has swallowed pencils, portions of disposable razors, knitting needles, metal nail files, toothbrush handles, plastic pen fragments, hair barrettes, disposable cutlery, and AA batteries. All her admissions occurred late in the evening or on weekends. During the past 4-year time period, she also underwent at least 28 additional upper endoscopies at outside hospitals for intentional foreign body ingestion. The patient was assessed as being at high risk for repeated self-harm. She engaged in cognitive behavioral therapy, dialectical behavioral therapy, and electroconvulsive therapy, but her pattern of repetitive swallowing remained unchanged.
A pilot study of vascular endothelial growth factor inhibition with bevacizumab in patients with lymphedema following breast cancer treatment.
Authors: KD Miller, D Christmon, BP Schneider, A Storniolo, SE Clare, GW Sledge
Journal: Cancer Research (2009)

Abstract Abstract #6142 Purpose: Lymphedema is a significant long-term complication of primary therapy for breast cancer but little is known regarding its etiology and persistence other than relation to the number of lymph nodes (LN) removed. We suggest the following model: Mechanical disruption of normal lymphatic drainage leads to increased back pressure on lymphatic vessels producing an increase in interstitial fluid pressure (IFP). The increased in IFP triggers local production of VEGF-C to stimulate compensatory lymphangiogenesis. As VEGF-A (and to a lesser extent –C) also increases vascular permeability, the consequent increase in interstitial fluid and edema predominate. Anecdotally, several patients (pts) with metastatic disease treated with bevacizumab monotherapy noted improvement in long-standing lymphedema. This pilot study was conducted to explore these observations prospectively.&amp;#x2028; Methods: We used an existing biospecimen bank to conduct a case-control study to compare VEGF-A, -C, -D and VEGFR-3 serum concentrations in breast cancer pts with and without lymphedema (matched for age and LN status). In a separate pilot trial, pts with significant unilateral lymphedema receive bevacizumab, 15 mg/kg every 3 weeks. Baseline assessments include arm volume, interstitial fluid pressure (IFP), extracellular fluid volume by lymphometer (ECF), quality of life (QOL) and plasma VEGF-C, -D, and R-3. IFP is measured serially for 24 hours after the first treatment; arm volume, ECF, QOL, and plasma VEGF-C/D/R-3 are assessed at 3 and 6 weeks.&amp;#x2028; Results: Samples were available for 16 pts with chronic lymphedema and 24 matched controls. Median VEGF-C levels were significantly increased in pts with lymphedema (6895 pg/ml vs. 5349 pg/ml, p=0.001). Median VEGF-A levels were slightly higher in pts with lymphedema (375 pg/ml vs.250 pg/ml, p=NS). Eight pts have been enrolled in the pilot trial thus far. Median duration of lymphedema was 4.4 years (2.2-16.6) Median time since surgery was 7.1 years (3.4-17.6); median time since radiation (n=7) was 4.4 years (2.3-7.9). Complete IFP data is available in 5 pts. Baseline IFP was significantly higher in the affected compared to unaffected arm (9.04 vs. -2.07 mmHg; p=0.0017). Median IFP in the affected arm decreased an average of 42.6% 24 hours after bevacizumab infusion (11.1 vs. 6.9 mmHg; p=0.09). Total arm circumference decreased by an average of 2.8 cm three weeks after initial treatment.&amp;#x2028; Conclusions: Preliminary data supports the hypothesis that VEGF plays a central role in the development and persistence of lymphedema after local therapy for breast cancer. Inhibiting VEGF acutely decreases IFP and may be an effective treatment. Treatment and accrual to the pilot trial continues; full data will be available by December 2008. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6142.
Abstract 1413: Rapamycin inhibits lymph node metastasis in an orthotopic model of head and neck squamous cell carcinoma: A possible role for a suppression of VEGFR-3 expression
Authors: Oleksandr Ekshyyan, Tara N. Moore-Medlin, Matthew C. Raley, Kunal Sonavane, Michael A. Brodt, Xiaohua Rong, Fleurette Abreo, Jonathan S. Alexander, Cherie-Ann O. Nathan
Journal: Cancer Research (2012)

Abstract Background: Tumor cell dissemination to cervical lymph nodes via the lymphatic system represents the first step in the metastasis of head and neck squamous cell carcinoma (HNSCC) and is the most significant prognostic factor for tumor recurrence decreasing survival by 50%. The anti-lymphangiogenic properties of mTOR inhibitors are not yet well understood nor have the effects of rapalogues’ on tumor-associated lymphangiogenesis been investigated in HNSCC. Methods: The lymphatic suppressing effects of rapamycin were evaluated in vitro using lymphatic endothelial cell lines (SV-LEC; HMEC-1a). An orthotopic model of HNSCC was used to evaluate anti-lymphangiogenic effects of rapamycin in vivo. OSC-19 cells were injected into the basolateral tongue of SCID mice. After 5 days mice were given daily IP injections of vehicle (control group) or rapamycin at 5 mg/kg. On day 21 after OSC-19 administration mice were sacrificed and tongues, cervical lymph nodes and serum collected. The incidence of cervical lymph node metastasis, the number of tumor-free and tumor-associated lymphatic vessels in mouse lingual tissue, and expression of pro-lymphangiogenic markers were assessed. Results: We found that LEC proliferation was significantly reduced by rapamycin. LEC growth inhibition by rapamycin was linked with decreased expression of VEGFR-3 in both LECs, and in some HNSCC cell lines. Rapamycin significantly lowered the fraction of tumor-associated lymphatic vessels in mouse tongues (p=0.0167) and decreased the number of metastasis-positive lymph nodes (p=0.04). Rapamycin also significantly attenuated the extent of metastatic tumor cell spread within the lymph nodes (p&amp;lt;0.0001). Conclusion: The results of this study demonstrate anti-lymphangiogenic properties of mTOR inhibitors in HNSCC. These findings provide preclinical data showing that rapalogues exert anti-lymphatic effects in head and neck cancer via suppressing ofVEGFR-3 expression. 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 1413. doi:1538-7445.AM2012-1413
DETECTION OF CIRCULATING TUMOR DNA IN EARLY AND LATE STAGE HUMAN MALIGNANCIES
Authors: C. Bettegowda, M. Sausen, R. Leary, I. Kinde, N. Agrawal, B. Bartlett, H. Wang, B. Luber, K. Kinzler, B. Vogelstein, N. Papadopoulos
Journal: Neuro-Oncology (2014)

BACKGROUND: The development of minimally-invasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital PCR-based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. In particular we studied the plasma of 14 medulloblastoma, 13 WHO grade 2-3 glioma and 14 WHO grade IV astrocytoma cases for levels of ctDNA. METHODS: The basis of our approach is to differentiate DNA shed by normal cells from DNA derived from tumor cells. In order to distinguish the two populations of cell-free DNA, we first identify a tumor-specific alteration. We then query for that exact mutation in matching plasma from the same patient to generate a personalized tumor biomarker. Only DNA derived from the tumor will harbor the genetic alteration. We initially use targeted, exomic, or whole genome sequencing to identify sequence or structural alterations in tumor tissues of 410 individuals. DNA was extracted from less than 5 ml of plasma in each case. The majority of plasma samples were queried for levels of ctDNA using a high fidelity next-generation sequencing approach coined Safe-SeqS. RESULTS: We found that at least one tumor-specific mutant molecule could be identified in <5 mL of plasma in >75% of patients with advanced ovarian, colorectal, bladder, gastroesophoageal, pancreatic, breast, melanoma, hepatocellular and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. Approximately 40% of medulloblastoma and 10% of low or high grade glioma cases had detectable levels of ctDNA. In patients with localized non-CNS tumors, ctDNA was detected in 73%, 57%, 48% and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor (EGFR) blockade in 24 colorectal cancer patients who objectively responded to therapy but who subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase (MAPK) pathway. CONCLUSIONS: Taken together, these data suggest that ctDNA is a sensitive, specific and robust biomarker that can be used for a variety of clinical and research purposes in patients with several multiple different types of cancer. For individuals with CNS neoplasms, alternate strategies may need to be developed in order to detect cell-free tumor derived DNA at levels that are clinically meaningful. ABSTRACT CATEGORY: Neuropathology & Tumor Biomarkers.
P61 Karel Styblo comes to town: staff perspectives on TB cohort review
Authors: C. Anderson, S. Tamne, J. White, I. Abubakar, S. Anderson, S. Dart, J. DeKoningh, M. Lipman
Journal: Thorax (2011)

Since its creation by Dr Karel Styblo, the cohort review (CR) principle of systematically analysing treatment outcome of every notified TB case and contact investigation in a brief, timely, structured manner, has been implemented widely outside of the UK—with impressive results. In 2010, North Central London (NCL) TB service adopted the concept, trained staff members and put in practice CR. Given the resource implications that our service faced already, plus the potential for its introduction to result in an increased staff workload, we undertook a survey of how CR was perceived and the impact it had on those involved in its use. After four rounds of CR (12 months from introduction), an anonymous on-line survey was sent to NCL staff members plus external participants and observers who had attended at least one review. The survey explored participant9s personal and institutional response to the organisation, impact and outcome of CR9s introduction. It was sent to 88 individuals. 72 (82%) completed the 10 min online questionnaire. Over 95% felt that CR identified gaps in service, most frequently: collaboration with other TB services (69%), patient care (63%), collaboration with allied services (51%) and service organisation (45%). Just over a third felt that CR highlighted training needs, especially for contact tracing. 70% reported changes to their way of working—in particular altering practice in response to apparent weaknesses in their approach to contact tracing. 86% felt that CR led to improvement in the speed of interventions, better data quality and enhanced professional relations. A small number of staff noted negative consequences which largely reflected increase in initial work load. Cohort review has enhanced our service provision. It is well received by local staff as well as external participants &amp; observers. Our data are encouraging; and we hope will assist in promoting roll out to other parts of the country.
The Value of Breast Ultrasound in <i>BRCA</i>1 and <i>BRCA</i>2 Mutation Carriers.
Authors: K. Bosse, M. Graeser, K. Rhiem, A. Gossmann, M. Hackenbroch, M. Warm, P. Mallmann, R. Schmutzler
Journal: Cancer Research (2009)

Abstract OBJECTIVE: BRCA1/2 mutations carriers face a lifetime risk for breast cancer of 60 to 80%. Typically, tumor incidence is high at young age and tumor growth rates are significantly elevated. On ultrasound investigation the malignancies often mimic fibroadenomas with round shape, circumscribed margins and a homogeneous internal structure leading to a BIRADS 3 classification. On this background we evaluated the efficacy of ultrasound for the early detection of breast cancer in this high risk group.METHODS: Between 01/1997-07/2008 223 BRCA1/2 mutation carriers participated in a breast cancer screening program which included semi-annual ultrasound (US) and annual mammography (MG) and MR imaging (MRI).Screening procedures started from age 25, MG at age 30. As patients consecutively joint the study women underwent 5 (median) screening rounds with a range of 1 to 22 appointments, totaling 1855 rounds of screening. All three imaging modalities were coded according to the American College of Radiology (BI-RADS classification).RESULTS: We detected 15 primary and 14 secondary contralateral BRCA-associated tumors in 27 patients. Age at diagnosis ranged from 29 to 66 years (median 41 years). BI-RADS classification IV and V enabled the detection of 9 (32%) cancers by mammography, 21 (87,5%) by US and 27 (96%) by MRI scan. Specificity added up to 100%. Three (11%) tumors were detected by the semi-annual ultrasound screen and two patients presented with interval carcinomas (16 and 8 mm in diameter) between two screening appointments. Thus, the proportion of interval cancers was 7%.CONCLUSION: Semi-annual sonography as a supplementary examination enabled us to reveal 3 additional invasive cancers (two stage pT1b, one stage pT1c). Due to the specific tumor morphology and the considerably elevated tumor doubling time mutation carriers may benefit from the addition of semi-annual ultrasound as a highly sensitive and cost-effective method. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4004.
OC-089 Epigenetic Control of GI Inflammation Via the Methyl-Binding Protein MBD2
Authors: G-R Jones, P Cook, L Webb, A MacDonald
Journal: Gut (2013)

<h3>Introduction</h3> Methyl-CpG binding protein domain protein-2 (Mbd2) is a transcriptional co-repressor that binds to methylated DNA. Mbd2 can recruit a nucleosome remodelling complex which contains chromatin remodelling and histone deacetylase properties. Mbd2 deficient mice are viable and fertile. However, they display a dysregulated immune phenotype with an aberrant T cell cytokine response<i></i> and susceptibility to intestinal helminth infection (1). This immunological phenotype has not been explored in the GI tract. <h3>Aim</h3> To assess the impact of Mbd2 deficiency on the activation status and cytokine production of naïve <i>Mbd2-/-</i> leucocytes isolated from murine small intestine (SI) and large intestine (LI) lamina propria (LP). <h3>Methods</h3> All mice were bred in specific-pathogen free facilities at the University of Edinburgh. <i>Mbd2-/-</i> mice were produced as described previously (1). Single cell suspension of SI and LI LP were isolated as previously described, n = 4 in each group, minimum 2 experiments (2). Controls were wildtype (WT) age and sex matched littermates. Cells were first stained with LiveDead blue (Life Technologies), FcR-Block and subsequently; CD11c, Ly6C, CD80, B220, CD11b, MHC(II), Ly6G, CD103, F4/80, CD40 and CD45. 4hr incubation with PMA/ionomycin/GolgiStop (BD bioscience) was performed for intracellular cytokine analysis with IFNgamma, IL-4, IL-13, IL-17 and TNFalpha. Samples were acquired using an LSRII and analysed with FlowJo (TreeStar), student t test was used with Prism (GraphPad) in statistical analyses. <h3>Results</h3> <i>Mbd2-/-</i> mice showed significantly greater IFNgamma, TNFalpha and IL-17 but not IL-13 or IL-4 production in CD4+ and CD8+ lymphocytes isolated from SI and LI LP compared to WT controls. In addition surface activation markers CD80 and CD86 were significantly greater in <i>Mbd2-/-</i> CD103+CD11b+CD11c+ Dendritic cells and CD11b+CD11c+F4/80 macrophages from SI LP. <h3>Conclusion</h3> These results show for the first time that epigenetic processes can regulate both antigen presenting cell activation status and T cell production of potentially damaging inflammatory cytokines at the mucosal-environmental barrier. They also identify methyl-binding proteins and/or genes that they regulate as exciting new targets for therapeutic modulation of GI inflammation. <h3>Disclosure of Interest</h3> None Declared <h3>References</h3> Hutchins ASA <i>et al.</i> Cutting edge: a critical role for gene silencing in preventing excessive type 1 immunity. J Immunol.2005 175(9):5606–5610. Little MC <i>et al.</i> The characterization of intraepithelial lymphocytes, lamina propria leukocytes, and isolated lymphoid follicles in the large intestine of mice infected with the intestinal nematode parasite Trichuris muris. J Immunol. Am Assoc Immnol; 2005; 175(10):6713–6722.