tbuckley/cabot-search huggingface dataset:
Abstract 662: Evaluation of the anti-cancer effects of the tumor selective vascular disruption agent BNC105 in preclinical renal cancer models
Authors: Tina C. Lavranos, Annabell F. Leske, Donna M. Beaumont, Jelena Gasic, Gabriel Kremmidiotis
Journal: Cancer Research (2011)

Abstract The disruption of blood vessels that feed tumors represents one of the most promising therapeutic strategies for treating cancer. BNC105 is a tubulin targeting dual acting vascular disruption agent with cytotoxic ability in solid tumors. A prodrug formulation, BNC105P, is under evaluation in phase II clinical trials for malignant mesothelioma and metastatic renal cell carcinoma as a 10min IV infusion. We have conducted a number of preclinical evaluations that provide a strong rationale for combining BNC105P treatment with agents that target mTOR signalling. BNC105 activity operates through the selective disruption of tumor blood vessels. Over 95% of blood flow is disrupted in tumors grown in xenograft animal models using human cancer cell lines representing a number of different cancer types, including breast, lung, colon, brain and mesothelioma. In the renal cancer setting we evaluated the anti-cancer effects of BNC105 in a Caki-1 xenograft model and a syngeneic murine renal cancer orthotopic model. Animals carrying Caki-1 solid tumors were treated with a single dose of BNC105P. Disruption of blood flow within the tumors was observed as early as 3 hr post-treatment. Similarly, blood flow disruption was seen in mice carrying solid tumors orthotopically inoculated in the kidney capsule using the RENCA mouse renal cancer cell line. Interestingly, BNC105P treatment also caused blood flow disruption in lung metastatic lesions seen in a number of the animals orthotopically inoculated with RENCA. The vasculature in non-cancerous portions of the kidney and all normal tissues examined, remained intact. Tumor re-vascularisation following BNC105P treatment was observed 2 days following administration. Immunohistochemical and Western blot analyses in BNC105P treated tumors revealed that a number of proteins involved in the mTOR signalling pathway exhibit expression changes consistent with activation of this pathway possibly a result of BNC105P induced tumor hypoxia. Up-regulation in phosphorylated mTOR, Hif1a and down-regulation of phosphorylated 4EBP1 were observed. The consequences of targeting mTOR in combination with BNC105P are currently under investigation in these preclinical models. 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 662. doi:10.1158/1538-7445.AM2011-662
Abstract 2255: Diagnostic and prognostic value of oncogenic human papillomavirus in patients with carcinoma of unknown primary of the neck
Authors: Ernst-Jan M. Speel, Jos M.J.A.A. Straetmans, Julia Vent, Zlatan Mujagic, Mieke Henfling, Annick Haesevoets, B Haidl, Christian U. Huebbers, Frans CS Ramaekers, Bernd Kremer, Jens P. Klussmann
Journal: Cancer Research (2011)

Abstract Objective. To date, there is no consensus on the optimal diagnostic and therapeutic strategy for patients with carcinoma of unknown primary (CUP) of the neck. These tumors are heterogeneous in their clinical and biological characteristics, and a pre-operative prognostic marker is desirable to optimize therapy and improve outcome and survival. Human papillomavirus (HPV) is an etiologic factor in a subgroup of head and neck squamous cell carcinomas and has been identified as a significant prognostic biomarker. We sought to determine if HPV also may add relevant information on the origin and prognosis of these tumors. Material and method. 47 patients (mean age 58.7 years; 40 men, 7 women) presenting with CUP of the neck between 1994 and 2008 in Cologne were examined by standard diagnostic procedures including radiological imaging of the head, neck, thorax and abdomen, positron emission tomography (PET), panendoscopy, curettage of the nasopharynx, bilateral tonsillectomy and blind probes of the base of tongue. All patients were surgically treated with neck dissection of the diseased neck as well as adjuvant chemoradiation. The mean follow up time was 34 months. Formaldehyde-fixed, paraffin-embedded tissue specimens of the 47 metastases were examined retrospectively by means of p16INK4A immunohistochemistry, HPV-specific PCR and fluorescence in situ hybridization. Results were correlated with clinical follow-up data. Results. Oncogenic HPV was present in 12/47 (26%) metastases (10 with HPV 16), which showed also p16INK4A overexpression. In 42% of CUP patients the primary tumor was discovered during follow-up. A significant correlation between HPV positivity and later detection of the primary tumor in the oropharynx was found (p=0.038). Moreover, patients with a p16INK4A- (13/47) or HPV-positive tumor had a more favorable overall 5-year survival rate then p16INK4A- and HPV-negative tumors (69% vs 33%, p=0.05; 65% vs 37%, p=0.093; respectively). Conclusion. HPV is present in a quarter of neck metastases of CUP patients and the presence of oncogenic HPV and p16INK4A expression can serve to locate the primary tumor in the oropharynx. In addition, both biomarkers are indicators of a favorable prognosis. 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 2255. doi:10.1158/1538-7445.AM2011-2255
SAT0424 Serum Tweak as a Biomarker for Disease Activity of Systemic Lupus Erythematosus
Authors: S.-K. Kim, J.-Y. Choe
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Biomarkers related with disease susceptibility, diagnosis, and organ involvement in systemic lupus erythematosus (SLE) has been found to be closely related with the presence of antibodies to dsDNA, C1q, and monocyte chemotactic protein-1 (MCP-1). Recently, the variable cytokines and chemokines including interferon γ-induced protein-10 (IP-10), TNF-like weak inducer of apoptosis (TWEAK), and MCP-1 have been suggested as potent effectors or indicators for disease activity and/or renal involvement in SLE. <h3>Objectives</h3> This study investigated to identify optimal serum and urine biomarkers related with disease activity in female patients with SLE. <h3>Methods</h3> Seventy SLE patients and sixty-one healthy controls were consecutively enrolled. IP-10, TWEAK, and MCP-1 in both serum and urine were measured using enzyme-linked immunosorbent assay. Statistical analysis was performed by Mann-Whitney U test, Spearman correlation analysis, multivariate regression analysis, and logistic regression analysis. <h3>Results</h3> Both serum and urine TWEAK, IP-10, and MCP-1 levels in either low and high SLEDAI groups of SLE were markedly higher than those in healthy controls. Serum TWEAK levels was positively associated with serum IP and serum MCP-1 levels (p&lt;0.001 of both). There were significant differences of serum TWEAK levels, SLEDAI score, and urine protein/creatinine between non-renal and renal involvement of SLE (p=0.034, p&lt;0.001, and p&lt;0.001, respectively). Serum TWEAK levels was found to be a crucial determinant to high SLEDAI activity and renal involvement (p=0.044, OR =1.006, 95% CIs 1.000 - 1.011 and p=0.046, OR =1.005, 95% CIs 1.000 - 1.019, respectively). <h3>Conclusions</h3> This study demonstrated that serum TWEAK levels might be a potent biomarker to reflect disease activity and renal involvement in SLE patients. <h3>References</h3> Liu CC, et al. Best Pract Res Clin Rheumatol 2009;23:507-23. Narumi S, et al. Cytokine 2000;12:1561-5. Schwartz N, et al. J Autoimmun 2006;27:242-50. <h3>Disclosure of Interest</h3> None declared
Abstract 5595: ALK mutant-driven cell lines develop crizotinib resistance by secondary mutations and ALK-independent means
Authors: Andrew L. Faber, Lori J. Johnson, James E. Thomas
Journal: Cancer Research (2012)

Abstract The clinical success of crizotinib against mutant ALK-expressing cancers has generated great interest; however, the emergence of drug resistance is limiting its durability in some patients. In NSCLC, crizotinib resistance is linked to secondary mutations within EML4-ALK at amino acids L1196M, C1156Y, L1152R. A mutation at amino acid F1174L reduced the sensitivity to criozotinib in a patient with an inflammatory myofibroblastic tumor harboring a RANBP2-ALK translocation. The goal of our studies was to evaluate mechanisms of crizotinib resistance in a range of ALK-mutant expressing cell lines. Cells from ALCL (Karpas299), NSCLC (NCI-H3122 and NCI-H2228) or neuroblastoma (SKNSH and KELLY) developed resistance to crizotinib after being exposed to incremental increases in the compound over several weeks. NPM-ALK expressing Karpas299 cells independently acquired point mutations in ALK at amino acids N1178H and I1171N. As the concentration of drug was increased, cells that harbored the NPM-ALK N1178H mutation also expressed a mutation at G1269A. Each mutation enhanced the temperature dependent auto-phosphorylation activity of the kinase and diminished the inhibitory effect of crizotinib on downstream ALK signaling. Mutations in Karpas299 cells were also accompanied by up regulation of a drug efflux transporter, BCRP, whose heightened expression level was dependent on the presence of the compound. In contrast no additional mutations were discovered in ALK in crizotinib resistant NCI-H3122 and NCI-H2228 (EML4-ALK) or SKNSH and KELLY (ALK F1174L) cell lines. Instead both NCI-H3122 and NCI-H2228 resistant cell lines displayed increased levels of phospho-HER2 and HER3 and activation of AKT and ERK that may be due to autocrine secretion of a growth factor. NSCLC resistant lines also displayed an apparent change in phenotype with a mesenchymal-to-epithelial transition. SKNSH and KELLY are inherently less sensitive to crizotinib. We found that these cells may survive exposure to high levels of the compound by altering RET expression. Our observations represent potential mechanisms of resistance demonstrated in a small number of cell lines. It will be important to align these results with emerging data from drug-resistant patients to understand the multiple mechanisms by which resistance might develop. 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 5595. doi:1538-7445.AM2012-5595
ANNULUS ASSESSMENT PRIOR TO TRANSCATHETER AORTIC VALVE REPLACEMENT: ANNULUS DIMENSIONS MAY NOT BE LARGEST IN MID-SYSTOLE
Authors: Omar K. Khalique, Nicolas Bettinger, Nadira Hamid, Susheel Kodali, Rebecca Hahn, Jonathon White, Ramin Hastings, Juan Terre, Tulio Palmerini, Tamim Nazif, Torsten Vahl, Isaac George, Martin Leon
Journal: Journal of the American College of Cardiology (2016)
FRI0573-HPR Effects of Relaxation Techniques in Total Knee Arthroplasty Patients during Their Hospital Stay
Authors: H. Guney, N. Vardar Yagli, O. Caglar, I. Yuksel
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Surgical techniques and treatment methods of the arthroplasty have been improved and the results after total knee arthroplasty (TKA) are generally good. However, some patients have suboptimal postoperative results with respect to pain and physical functioning and may not be satisfied with the results of their TKA. Psychological symptoms were found to be associated with these suboptimal results. <h3>Objectives</h3> To determine weather relaxation techniques had beneficial effects on pain, sleeping quality, functional status and physiological symptoms in TKA patients during their hospital stay. <h3>Methods</h3> Forty-seven patients who underwent unilateral TKA were randomized as relaxation techniques (RT) group (n=24) and control group (n=23). RT group was received physiotherapy treatment and 8 sessions (2 times a day, for four days after surgery) of relaxation exercises. Control group received only physiotherapy treatment. Intensity of pain and quality of sleeping were measured with visual analog scale (VAS). Early functional levels were assessed with the Iowa Level of Assistance Scale (ILAS). The measurements were done first four days after surgery. Depression and anxiety levels were detected with the use of Hospital Anxiety and Depression scale (HADS). Repeated measurements of ANOVA were used to analyze differences between groups for pain, ILAS and quality of sleeping. Student t test was used to analyze depression and anxiety levels between groups. <h3>Results</h3> The difference in sleeping quality results were significant between RT group and control group (F<sub>(3,135)</sub>=6.539, p=0.001). Sleeping quality results were better in RT group compared to control group in postoperative day 1 (p&lt;0.001), day 2 (p&lt;0.001) and day 3 (p&lt;0.001). On postoperative day four there was no difference in sleeping quality between groups (p=0.062). HADS depression (p=0.002) and HADS anxiety (p=0.014) scores were lower in RT group compared to control group. There were no differences in pain levels (F<sub>(3,135)</sub>=0.988, p=0.401) and in ILAS scores (F<sub>(3,135)</sub>=2.234, p=0.076) between groups. <h3>Conclusions</h3> Relaxation techniques can be applied to TKA patients during their hospital stay. RT enhances sleeping quality and lessens depression and anxiety symptoms in TKA patients. <h3>References</h3> Duivenvoorden T, Vissers MM, Verhaar JA, Busschbach JJ, Gosens T, Bloem RM, Bierma-Zeinstra SM, Reijman M. Anxiety and depressive symptoms before and after total hip and knee arthroplasty: a prospective multicentre study. Osteoarthritis Cartilage. 2013 Dec;21(12):1834-40. Taibi DM, Vitiello MV. Yoga for osteoarthritis: nursing and research considerations. J Gerontol Nurs. 2012 Jul;38(7):26-35 <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.4381
Lipid absorption and metabolism.
Authors: A Kuksis, N A Shaikh, A G Hoffman
Journal: Environmental Health Perspectives (1979)

Metabolic processes occurring within the mucosal cell are critical in determining results of interactions between environmental agents and the alimentary tract. The absorption, metabolism, and transport of lipids affects most those agents which are lipid soluble. The understanding of the process involved in lipid absorption and transport is therefore important for both appreciation of the mechanism of uptake of these toxins and for an effective interference with it. Most of the detailed mechanisms of lipid absorption and transport have been proposed from in vitro studies with soluble cell-free systems. The present review integrates these results with recent in vivo and in vitro findings with intact animal tissues and isolated mucosal cells. While there is much general agreement occasional startling differences are also observed, which may have a bearing on the mechanism of normal fat absorption and on the understanding of the transport of the fat-soluble toxins across the mucosal villus cell.
Abstract 3964: Inference of robust tumor phylogenetic markers from multi-sample data
Authors: Ayshwarya Subramanian, Russell Schwartz, Stanley Shackney
Journal: Cancer Research (2012)

Abstract Computational cancer phylogenetics can play an important role in delineating possible tumor progression pathways and identifying molecular subtypes and mechanisms of action. We previously developed a pipeline for constructing tumor phylogenies from recurring cell types computationally inferred from whole genome copy number data. The accuracy and detail of these tumor phylogenies, however, depends on the identification of accurate and high-resolution molecular markers of progression, i.e., reproducible regions of copy number variation that can be used to robustly differentiate different subtypes and stages of progression. Here we present a new method for the problem using hidden Markov models (HMMs) to derive robust, high resolution progression markers from sets of tumor samples. We demonstrate our method on a publicly available array comparative genome hybridization (aCGH) dataset (NCBI GEO GSE16672, Navin et al., 2010) from sectioned primary ductal breast tumors. Our method uses an HMM, a class of probabilistic models, to classify sets of aCGH data into a partitioning of samples into normal (diploid) or amplified at each copy number probe. It differs from other similar HMM methods primarily in seeking a parsimonious set of combinations of amplification states able to explain all aCGH profiles simultaneously in order to identify robust markers of progression across samples. The model learns frequencies with which different combinations of amplifications are observed across the samples by modeling individual probes as Gaussian random variables with either normal or tetraploid means, with data more consistent with tetraploid being classified as amplified and those more consistent with diploid classified as normal. To handle a combinatorial explosion in combinations of amplification states with increasing numbers of samples, the method introduces a Gibbs sampling algorithm to learn a parsimonious model of the most frequently occurring combinations of amplification states. We applied our methods to a previously constructed set of inferred cell types derived from the Navin et al. data (Tolliver et al., 2010) and to a comparison set of 9 random samples from the raw aCGH data. We validated our model relative to manual labeling of amplicons on the same data. In both experiments, the HMM method was able to pick up significantly larger numbers of robustly amplified segments per chromosome than did prior methods or manual analysis. The resulting segments can be directly fed into downstream analysis routines for phylogeny inference or other predictions. In future work, the HMM method may be improved by fine-tuning the underlying model for copy number variation. 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 3964. doi:1538-7445.AM2012-3964
Abstract P5-11-13: Tamoxifen and Ovarian Function
Authors: M Berliere, F Dalenc, N Piquard, I Leconte, L Fellah, J-F Baurain, C Galant, F Duhoux, J-P. Machiels
Journal: Cancer Research (2010)

Abstract Background: to study and compare ovarian function (clinical and biological data) among premenopausal breast cancer patients receiving tamoxifen alone (group I) or tamoxifen following chemotherapy (group II), because some studies suggest that amenorrhea is an insufficient parameter to define menopausal status. Material and methods: between 1999 and 2003, 138 premenopausal patients, treated for early breast cancer, were included: 68 patients in the group of tamoxifen alone and 70 patients in de group of tamoxifen administered after chemotherapy (6 cycles of FEC 100 on day 1 every 3 weeks -5 fluorouracil 500 mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2- or 4 cycles of EC on day 1 every 3 weeks -epiadriamycine 75 mg/m2, cyclophosphamide 500 mg/m2-). All patients had a confirmed premenopausal status (biological data) at the entry of the study. The median age in group I was 44.5 (36 to 48) and 42 in group II (35 to 47.5). In group I, all were stage I and in group II, 34 were stage I and 36 were stage II. They were followed prospectively every 3 months for 3 years: date about menses, physical examination and blood tests (LH, FSH, 17-bêta-estradiol). Vaginal echography was added every 6 months. After 3 years, prospective evaluation was closed. Retrospective evaluation of all data was performed in 2009. Results: three patients were out of study in the group I and 2 were out of study in the group II. According to clinical data, patients were devided in 4 subgroups: a: regular menses (≥10 cycles/year) b: spaniomenorrhea (5 to 9 cycles/year) c: severe spaniomenorrhea (1 to 4 cycles/year) d: complete amenorrhea. The number of patients in each subgroup is respectively: - For group I (65 patients): 3 (4%), 19 (29%), 38 (58%) and 5 (8%). - For group II (68 patients): 2 (3%), 21 (30%), 38 (55%) and 7 (10%). The most interesting parameter to be studied wass the estradiol levels. Median values of estrogen levels For patients of subgroup a, tamoxifen mimicked an ovulatory cycle such as observed in patients receiving citrate of clomifen. For patients of subgroup b, the variations corresponded to nearly a normal ovulatory cycle. For patients of subgroups c and d, tamoxifen induced low levels of estradiol, LH and FSH, and very few variations. Estrogen levels did not to seem have an impact on disease free survival rate after 3 years of follow-up (100% in group I and 98.6% in group II and after 5 years (98.5% and 97%). In the two groups I and II, estrogen levels from patients of subgroups a and b were significantly higher than in subgroups c and d (p &amp;lt; 0.001). Conclusion: amenorrhea is an insufficient parameter to define menopausal status of patients receiving tamoxifen. Low estradiol level must be coupled to other biological parameters to characterize endocrine status. These data are very important in the choice of endocrine therapy. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-11-13.
GE-34 * THE MUTATIONAL LANDSCAPE AND TEMPORAL AND SPATIAL CLONAL EVOLUTION TO PROGRESSION IN 351 LOW-GRADE GLIOMAS
Authors: H. Suzuki, K. Aoki, F. Ohka, K. Motomura, M. Fujii, M. Sanada, H. Nakamura, M. Mizoguchi, T. Abe, Y. Muragaki, T. Wakabayashi, S. Ogawa, A. Natsume
Journal: Neuro-Oncology (2014)

Low grade gliomas (LGGs) are common infiltrative brain tumors in adults. Although LGGs typically show slower tumor progression and generally better clinical outcomes than high-grade gliomas, their clinical course is invariably indolent and deadly. In contrast to high-grade tumors, our knowledge about the genetic lesions and clonal evolution in LGG is still incomplete. In this study, we investigated relevant gene mutations and their role in clonal evolution using high-throughput genomics. Analysis of whole exome sequencing (WES) data from 52 LGGs identified significantly mutated genes included not only previously known mutational genes, including IDH1/2, TP53, ATRX, CIC, FUBP1 and NOTCH1, as well as multiple components of the PI3K pathway and the SWI/SNF complex. We further analyzed significant mutated genes in 351 LGGs by targeted deep sequencing. WES of multi-regional/time-point sampling from 14 cases further revealed complexity of intratumor heterogeneity and patterns of clonal evolution. According to the observed variant allele frequencies (VAFs), mutations of IDH1/2 and 1p19q co-deletion were thought to exist in the major clone, representing truncal mutations in most cases. In contrast, mutations in TP53, ATRX, CIC and FUBP1 were more often identified in one or more phylogenic branches in different subclones and involved in parallel evolution, where different mutations of the same genes were found at different time points in different locations. Collectively, our findings revealed two major, mutually exclusive patterns in clonal evolution in IDH-mutated LGGs; in some cases IDH1/2 mutations and 1p19q co-deletions were trunchal events, followed by CIC, FUBP1, NOTCH1 and other mutations in subsequent phylogenic branches. In other cases, the IDH1/2 mutations predated TP53, ATRX and other gene mutations.