tbuckley/cabot-search huggingface dataset:
Target-Driven Positive Selection at Hot Spots of Scorpion Toxins Uncovers Their Potential in Design of Insecticides
Authors: Limei Zhu, Steve Peigneur, Bin Gao, Shangfei Zhang, Jan Tytgat, Shunyi Zhu
Journal: Molecular Biology and Evolution (2016)

Positive selection sites (PSSs), a class of amino acid sites with an excess of nonsynonymous to synonymous substitutions, are indicators of adaptive molecular evolution and have been detected in many protein families involved in a diversity of biological processes by statistical approaches. However, few studies are conducted to evaluate their functional significance and the driving force behind the evolution (i.e., agent of selection). Scorpion α-toxins are a class of multigene family of peptide neurotoxins affecting voltage-gated Na+ (Nav) channels, whose members exhibit differential potency and preference for insect and mammalian Nav channels. In this study, we undertook a systematical molecular dissection of nearly all the PSSs newly characterized in the Mesobuthus α-toxin family and a two-residue insertion (19AlaPhe20) located within a positively selected loop via mutational analysis of α-like MeuNaTxα-5, one member affecting both insect and mammalian Nav channels. This allows to identify hot-spot residues on its functional face involved in interaction with the receptor site of Nav channels, which comprises two PSSs (Ile40 and Leu41) and the small insertion, both located on two spatially separated functional loops. Mutations at these hot-spots resulted in a remarkably decreased anti-mammalian activity in MeuNaTxα-5 with partially impaired or enhanced insecticide activity, suggesting the potential of PSSs in designing promising candidate insecticides from scorpion α-like toxins. Based on an experiment-guided toxin-channel complex model and high evolutionary variability in the receptor site of predators and prey of scorpions, we provide new evidence for target-driven adaptive evolution of scorpion toxins to deal with their targets' diversity.
Genetic Analysis as an Aid in Diagnosis for Patients With Midline Carcinomas of Uncertain Histologies
Authors: Robert J. Motzer, Eduardo Rodriguez, Victor E. Reuter, Felipe Samaneigo, Ethan Dmitrovsky, Dean F. Bajorin, David G. Pfister, Nasser Z. Parsa, R. S. K. Chaganti, George J. Bosl
Journal: JNCI Journal of the National Cancer Institute (1991)

The tumors of nine patients with carcinomas of uncertain histogenesis eight with poorly differentiated carcinomas involving primarily midline structures and one with a diagnosis of seminoma and atypical clinical features) were studied by cytogenetic and Southern blot analyses. Four of the eight patients with poorly differentiated carcinomas had abnormalities of chromosome 12 consistent with a diagnosis of germ cell tumor. These abnormalities comprised an i(12p) in two patients and a del(12q) in a third patient detected by cytogenetic analysis and multiple copies of 12p detected by Southern blot analysis in a fourth patient. Three of these four patients with a diagnosis of germ cell tumor established by genetic analysis achieved a complete response to cisplatin-based chemotherapy. The tumor biopsy of one patient showed a t(11; 22) (q24; q12), and this patient had chemotherapy directed to neuroepi-thelioma. Cytogenetic analysis was un-successful for the tumors of three patients; these tumors did not have multiple copies of 12p detected by Southern blot analysis. These patients did not respond to cisplatin-based chemotherapy. One patient with a diagnosis of extragonadal seminoma failed to respond to cisplatin-based chemotherapy and had a second tumor biopsy performed that demonstrated a t(8; 14) (q24; q32). This patient's diagnosis was changed to a non-Hodgkin's lymphoma. Thus, genetic analysis provided a diagnosis in six of nine patients. Cytogenetic and molecular analyses are useful clinical tools for the determination of histogenesis in some patients with poorly differentiated carcinomas of uncertain histology. [J Natl Cancer Inst 83:341–346, 1991]
AACR Begins Molecular Biology Conferences
Authors: L. Anderson
Journal: JNCI Journal of the National Cancer Institute (1988)

Journal Article AACR Begins Molecular Biology Conferences Get access Linda Anderson Linda Anderson Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 80, Issue 19, 7 December 1988, Pages 1517–1518, https://doi.org/10.1093/jnci/80.19.1517 Published: 07 December 1988
P17.07 * FENOFIBRATE AS A NOVEL THERAPEUTIC ADJUVANT FOR TARGETING GLIOMA STEM CELLS
Authors: E. Binello, I. M. Germano
Journal: Neuro-Oncology (2014)

Glioma stem cells (GSC) are being increasingly recognized as the culprits behind the resistance of glioblastoma to standard therapy, including surgery, temozolomide and radiation therapy. Intensive research is currently underway to uncover novel and effective GSC targeting strategies Fenofibrate is an FDA-approved hypolipidemic agent in widespread clinical use. Recent evidence has supported a possible role for fenofibrate as an nti-cancer agent in various cancer pathologies, including glioblastoma. Our own previous work has demonstrated that fenofibrate reduces proliferation and induces apoptosis in human high-grade glioma cells. Here, we present our results on the effects of fenofibrate on GSC in the in vitro setting. We chose to examine invasion because this property is known as a hallmark obstacle in the successful treatment of glioblastoma and recent data has implicated GSC. We found that fenofibrate treatment at a dose of 25 microM significantly decreased GSC invasion in a standard Matrigel invasion assay. We then examined the effect of fenofibrate on stem-cell marker expression and chose CD133 and Oct4. CD133 remains one of the most commonly used GSC markers to date, while Oct4 is an embryonic stem cell marker linked to glioma grade. Results demonstrated that fenofibrate treatment at 25 microM significantly diminished expression of both CD133 and Oct4 as measured by flow cytometry and/or immunofluorescence staining. Finally, we investigated possible mechanisms and identified NF-kappaB and CyclinD1 as candidates. Inhibition of NF-kappaB reportedly decreases invasion in GSC and is a well-established property of fenofibrate in the inflammatory setting. Downregulation of Cyclin D1 has been found to correlate with attenuated invasion in human glioblastoma cells and may be observed with fenofibrate treatment of lymphoma cells. Using a panel of established human glioma cell lines, we found that fenofibrate treatment robustly diminished the expression of both NF-kappaB and Cyclin D1 in a dose-dependent and p53-independent manner. In conclusion, our data show that fenofibrate significantly attenuates both GSC invasion and expression of the CD133 and Oct4 stem-cell markers, in association with diminished NF-kappaB and Cyclin D1 signaling in glioma cells. Based on these results, we propose that fenofibrate should be considered a novel and direct GSC targeting agent. Its relatively low cost, minimal toxicity and availability make it an attractive agent for rapid translation to the clinical setting as an adjuvant treatment for glioblastoma.
AB0794 Development of a computerized animated activity questionnaire (aaq) to measure activity limitations in patients with hip and knee osteoarthritis.
Authors: W. F. Peter, H. C. de Vet, M. Boers, J. Harlaar, L. D. Roorda, R. W. Poolman, V. A. Scholtes, M. Steultjens, E. M. Roos, F. Guillemin, C. Rat, M. G. Benedetti, A. Escobar Martinez, C. B. Terwee
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Self-report questionnaires and performance-based tests correlate moderately in measuring activity limitations, indicating that they are measuring different aspects. Self-reports measures mainly the patients' perception which may lead to cross-cultural differences. Performance-based tests measure an artificial situation and might be a burden for patients, requires physical presence and is time- and money consuming. An alternative method is a computerized animated activity questionnaire (AAQ). Besides being a solution for the abovementioned disadvantages the AAQ do not need reading ability and translation for international use. <h3>Objectives</h3> To develop a computerized AAQ, a new method to assess activity limitations in patients with hip and knee osteoarthritis (OA). <h3>Methods</h3> First the construct to be measured is described. For content validity the ICF core set for hip and knee OA and self-report questionnaires were consulted. In addition two patient focus group sessions were performed to identify the most limited activities, included the different executions of those activities. Subsequently a specialized company videotaped the executions of the activities (performed by physical therapists as actors) using motion capture and transformed the videos into animations. A virtual environment was created in the animation in order to imitate a standard real life situation as much as possible. A computerized questionnaire was composed. <h3>Results</h3> Seventeen basic daily activities were selected. For each activity 3 to 5 levels of executions were filmed. Subsequently video animations were produced of all the levels of execution of the 17 activities. In the final AAQ patients are asked to choose the video that best matches their own performance. <h3>Conclusions</h3> A new Patient Reported Outcome method to measure activity limitations in patients with hip and knee OA was developed: the computerized AAQ. The AAQ shows animations of basic daily activities in virtual, real life situations. The AAQ can minimize the patients' perception, is less burdensome and save time/money. Furthermore no reading ability and translation is needed. On-going research focuses on assessing (cross-cultural) validity and reliability. <b>Funding</b> This project is funded by the EULAR Grant for research on Patient Reported Outcome. <h3>Disclosure of Interest</h3> None Declared
Abstract LB-242: Oncosomes: Large bioactive particles secreted by prostate cancer cells
Authors: Dolores Di Vizio, Matteo Morello, Brendan McNeish, Peter Schow, Michael P. Lisanti, Marsha A. Moses, Michael R. Freeman
Journal: Cancer Research (2010)

Abstract Purpose of the study: Human prostate tumor cells were recently shown by our group to secrete large (0.5-10 m diameter) bioactive microvesicles capable of activating signal transduction and inducing proliferation and migration in cells in the tumor microenvironment (Di Vizio, et al. Cancer Res. 2009 69: 5601-9). These secreted particles, termed oncosomes, were shown to be vehicles for numerous signaling proteins involved in cell growth and motility. They also contain the membrane protein caveolin-1 (Cav-1), a mediator of prostate cancer (PCa) metastasis and a circulating PCa biomarker. The purpose of this study was to develop the tools to identify, isolate, sort and characterize PCa-derived oncosomes. Experimental procedures: Secreted particles from PCa cells were ultracentrifuged at 100,000xg and the pelleted material processed on a Moflo High-Speed Cell Sorter (Beckman-Coulter) and analyzed using Summit V4.3 software (Dako Colorado, Inc.). 1, 3 and 10 m bead standards (Spherotech Inc.) were used to set size gates. To avoid capturing aggregated material, forward scatter and pulse width were set at a linear scale and only single events were gated and analyzed. Sorted particles were visualized by confocal and electron microscopy. Results: Using the above procedure, we were able to retrieve intact particles of 1-10 m in diameter secreted by LNCaP cells overexpressing the oncoprotein MyrAkt1. The nontumorigenic prostate stromal cell line WPMY-1 secreted &amp;gt; 10-fold fewer particles in this size range. We confirmed that these were membrane-derived particles by showing that they contained MyrAkt1, which localizes to the plasma membrane. Particles in a similar size range were also sorted after purification from LNCaP cells stably expressing a Cav-1/GFP fusion protein. Sorted particles visualized microscopically appeared to be surrounded by a lipid bilayer and to have intrinsic structure that made them resistant to collapse. Particles isolated by these methods evoked degradation of FITC-labeled collagen and contained active MMP9 and MMP2, two key proteases involved in tumor cell invasion. Conclusions: The specific type of large bioactive particle we have isolated has not been previously described in any tumor system. Studies are ongoing to detect these particles in animal models of cancer and in human patients. 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 LB-242.
Abstract 3081: Loss of Shoca-2 expression in colorectal cancer correlates with metastasis as Shoca-2 represses EGF-regulated STAT3 activation via recruitment of PP1beta
Authors: Sébastien Loeffler, Michal Kovac, Saulius Zuklys, Marcel Keller, Daniel Hess, Salvatore Piscuoglio, Luigi Terraciano, Karl Heinimann, Georg Holländer
Journal: Cancer Research (2010)

Abstract Objective: We sought to define in colorectal cancer (CRC) the function of Shoca-2 (a.k.a. SH2D4A), an until now uncharacterized SH2 domain-containing protein. Methods: Tandem affinity purification, immunoprecipitation, site-specific mutagenesis, shRNA expression targeting and gene expression analysis were used to characterize binding partners of human Shoca-2 and identify the signaling pathway(s) where this adapter protein is involved. To assess Shoca-2 function on cell growth, colony formation assays and cell cycle analyses were carried out. CRC biopsies were analyzed by immunohistochemistry and molecular genetic methods for the presence of Shoca-2. Results: Here we demonstrate that Shoca-2 forms a complex with EGFR and STAT3. In response to EGF signaling, a Shoca-2/STAT3 dimer dissociates from EGFR and recruits the serine/threonine phosphatase PP1beta to the complex. Consequently, STAT3 activity is repressed and the EGF signaling pathway ceases to be activated. A lack of Shoca-2 expression secondary to a genomic loss of the locus is frequently observed in metastatic colorectal cancer and correlates with an increase in phosphorylated STAT3 in these cells. Conversely, the ectopic expression of wild type Shoca-2 but not of a mutant form defective in its ability to bind to PP1beta suppresses STAT3-dependent tumor cell growth. Conclusion: Our results identify Shoca-2 as a tumor suppressor that acts upon EGF stimulation as an adaptor protein to target STAT3 for dephosphorylation. 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 3081.
AB0371 In RA patients with very strongly positive serology there is a striking discordance in presentation between those with very strongly positive ACPA levels associated with negative or low-positive rf levels and those with very strongly positive RF levels
Authors: S. Poore, D. Hutchinson
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> RA has been viewed for many years as a heterogeneous collection of rheumatic diseases. Previously rheumatoid factor (RF) positive and negative patients were regarded as distinct clinical subtypes. Additionally, within seropositive RA those with very strongly positive RF levels were also thought to have a characteristic disease process. The addition of anti-citrullinated protein antibody (ACPA) testing has led to a distinction between ACPA positive and negative patients. However, no studies have compared the clinical presentation of RA patients with very strongly positive ACPA levels associated with a negative or low-positive RF levels with those RA patients with a very strongly positive RF. <h3>Objectives</h3> To assess the clinical presentation and demographics of RA patients with very strongly positive ACPA levels (&gt;170 IU) in the presence of a negative or low-positive RF (≤30 IU) compared to patients with a very strongly positive RF (&gt;300 IU). <h3>Methods</h3> The study included 64 RA patients with a disease duration 170 IU) was present in 22 patients, this group will be referred to as the discordant antibody group. 42 had very strongly positive RF levels (arbitrarily 10 fold higher than the upper normal range 0-30, i.e. &gt;300 IU). Data was collected through analysis of clinic letters and a serologically blinded telephone questionnaire. Patients with a personal or family history of psoriasis were excluded. <h3>Results</h3> <i>Demographics:</i> There was a significantly increased prevalence of females in the discordant antibody group (82% vs. 45%) p=0.005 <i>Clinical features:</i> Palindromic rheumatism was significantly more likely to precede the diagnosis of RA in the discordant antibody group (8 of 22 (36%)) compared to the strongly positive RF group (1 of 42 (2%)) p=0.0009. An asymmetrical onset was significantly more likely in the discordant antibodies group (15 of 22 (68%) vs. 14 of 42 (33%)) p=0.008. There was a significantly increased prevalence of large joint<sup>†</sup> involvement in the discordant antibody group (16 of 22 (72%) vs. 15 of 42 (35%)) p=0.005.The presence of nodules and PMR presentation did not differ significantly between the two groups p=0.22. <sup>†</sup> Large and small joints were defined according to 2010 ACR-EULAR criteria. <h3>Conclusions</h3> Patients with very strongly positive ACPA levels associated with a negative or low-positive RF levels were significantly more likely to be female and to have a palindromic type presentation. Large joint and an asymmetrical presentation were also significantly more prevalent in this group and further studies are required to determine whether this group are a new and distinct subtype of RA. <h3>Disclosure of Interest</h3> None Declared
THE EFFECT OF LOSARTAN ON DIASTOLIC FUNCTION, EXERCISE CAPACITY AND SYMPTOMS IN HYPERTROPHIC CARDIOMYOPATHY
Authors: Anna Axelsson, Kasper Iversen, Niels Vejlstrup, Carolyn Ho, Ole Havndrup, Morten K. Jensen, Henning Bundgaard
Journal: Journal of the American College of Cardiology (2015)
Abstract 887: Long-term prognostic role of functional limitations among women with breast cancer
Authors: Dejana Braithwaite, William Satariano, Robert A. Hiatt, Martha Slattery, Bette Caan
Journal: Cancer Research (2010)

Abstract Background: Functional limitations have been associated with poor survival among women with breast cancer within the first year of diagnosis. The long-term prognostic role of these difficulties in the completion of tasks of everyday life remains unknown. Methods: We studied a cohort of 2270 women diagnosed with breast cancer between 1997 and 2000, who provided information on functional limitations of body functions involving endurance, strength, muscular range of motion and small muscle dexterity at enrollment. The median follow up was 8.7 years (range 0-10 years). We investigated the association of functional limitations with survival from all causes, breast cancer and competing (non-breast cancer) causes in delayed entry Cox regression models. All statistical tests were two-sided. Results: Proportionately more patients with limitations were older, less educated and obese (p&amp;lt;.0001 for each) versus those without these difficulties. The age-adjusted hazard ratio for functional limitations as a 13-level variable of 1.08 (95%CI 1.05-1.14) suggests that there was an 8% increase in risk of death with each additional limitation. In multivariate models, functional limitations were associated with a statistically significant risk of death from all causes [hazard ratio (HR)=1.40, 95% confidence interval (CI) 1.03-1.92] and from competing causes (HR=2.60, 95%CI 1.69-3.98) but not breast cancer (HR=.90, 95%CI .64 −1.26). Conclusion: Women with breast cancer and functional limitations present after initial breast cancer treatment have a greater likelihood of dying of competing causes than breast cancer. Intervening to improve physical function among women with breast cancer may lead to improvements in life expectancy. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. 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 887.
AB0092 Angiogenic and angiostatic mediators in spondyloarthritis
Authors: L. Riente, I. Puxeddu, M. Tronchetti, A. Delle Sedie, S. Bombardieri, P. Migliorini
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> The spondyloarthritis (SpA), including ankylosing spondylitis (AS) psoriatic arthritis, reactive arthritis, arthritis associated with inflammatory bowel disease and “undifferentiated” SpA (uSpA), are characterised by inflammatory back pain (IBP), sacroiliitis, peripheral arthritis, and enthesitis together with an association with HLA B27. Undifferentiated SpA is a diagnosis of exclusion, and can include patients with IBP who may have early ankylosing spondylitis but do not yet fulfil the classification criteria for AS. Angiogenesis, the formation of new capillaries from pre-existing vessels, isan early event in inflammatory joint diseases. <h3>Objectives</h3> The aim of our study is to investigate the regulation of pro-angiogenic mediators and their endogenous inhibitors in uSpA and AS. <h3>Methods</h3> Forty one adult patients with uSpA and 9 patients with definitive diagnosis of AS (according to the 1984 modified New York criteria) were studied. Vascular Endothelial Growth Factor (VEGF), Fibroblast Growth Factor (FGF-2) and their inhibitors Endostatin (ES) and Thrombospondin-1 (TSP-1) were measured in the sera of these patients and of 39 healthy subjects by enzyme immunoassays. <h3>Results</h3> The serum levels of VEGF but not FGF-2 resulted significantly higher in the uSpA group than in the control subjects (P=0.0052). ES and TSP-1 were significantly higher in both uSpA (P&lt;0.0001; P&lt;0.0001, respectively) and AS (P=0.0014; P=0.0310, respectively) compared to the controls. <h3>Conclusions</h3> Our results suggest that a disregulation of circulating angiogenic and angiostatic mediators takes place both in uSpA than in AS. Further investigations on angiogenic and angiostatic mediators in a larger number of patients with different subtypes of SpA would be useful to understand better their role in the pathophysiology of this group of disorders. <h3>Disclosure of Interest</h3> None Declared
A PET-MRI Case of Corticocerebellar Diaschisis After Stroke
Authors: Valentina Garibotto, Maria I. Vargas, Karl-Olof Lovblad, Osman Ratib
Journal: Clinical Nuclear Medicine (2011)

We report a case of a 46-year-old man who underwent a hybrid PET-MRI study 3 months after an acute ischemic stroke of the left middle cerebral artery territory. The FDG PET images show a severe hypometabolism occurring in the cortical and subcortical ischemic territory, as well as in functionally connected but intact areas, such as the homolateral pons and the contralateral cerebellar hemisphere. The MRI images show T2 hyperintensity in the pyramidal and frontopontine tract, associated with fiber degeneration, and no significant cerebellar atrophy. Hybrid PET-MRI imaging can measure various correlates (fiber degeneration and metabolic disconnection) of the diaschisis phenomenon.
NO RACIAL DIFFERENCES IN THE ASSOCIATION OF CARDIORESPIRATORY FITNESS WITH INCIDENT ATRIAL FIBRILLATION: RESULTS FROM THE HENRY FORD EXERCISE TESTING PROJECT (THE FIT PROJECT)
Authors: Waqas Qureshi, Michael Blaha, Steven Keteyian, Clinton Brawner, Mouaz Al-Mallah
Journal: Journal of the American College of Cardiology (2015)