tbuckley/cabot-search huggingface dataset:
A9.2 Tenascin-C expression during knee joint regeneration in the red-spotted NEWT notophthalmus viridescens
Authors: Sony Adhi Susanto, Christiane Schönfeld, Matthias Geyer, Carina Schreiyäck, Uwe Lange, Mario Looso, Thomas Braun, Elena Neumann, Ulf Müller-Ladner
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> In mammals, tissue or organ damage often results in fibrotic scar formation, which in turn may impair proper organ function. Many urodele amphibians are capable of regenerating different tissues including lenses, heart, and spinal cord or even entire body parts like limbs or tails without any functional impairment. We previously established the red-spotted newt <i>Notophthalmus viridescens</i> as a model organism to study endogenous knee joint regeneration in adult vertebrates. After surgical removal of articular cartilage from the femur or after intra-articular collagenase injection, newts displayed osteoarthritis (OA)-like symptoms, including joint instability and luxation. However, after approximately 3 months the joint function was completely restored in the treated animals. To evaluate the underlying molecular mechanisms guiding this regenerative process, a cDNA approach was used in this study. <h3>Methods</h3> A cDNA array derived from regenerating newt myocardium containing 100000 normalised expressed sequence tags (ESTs) was carried out after surgically and collagenase-induced knee damage in newts to identify key players involved in knee joint regeneration. Several ESTs were found to be regulated during the regenerative process. By using public databases, several deregulated candidate genes were identified and selected for further analysis on mRNA (Real‑Time PCR) and protein level (immunohistochemistry). <h3>Results</h3> In the cDNA array, a number of genes was found to be deregulated during the course of knee joint regeneration, including several matricellular proteins like tenascin-C (TN-C), periostin and osteonectin/SPARC. Among them, TN-C showed the strongest upregulation during the regenerative process and was selected for further studies. On the mRNA level, a strong upregulation of TN-C mRNA was found in both models: While in the collagenase model TN-C was upregulated at 10 days and 40 days after OA induction, TN-C expression ceased in the surgically-induced OA model at day 40. In immunohistochemical analyses, TN-C expression was restricted to the periosteum 10 days after damage. As knee joint regeneration progressed, TN-C was also found in regenerating cartilage (40 days after damage). <h3>Conclusions</h3> TN-C is involved in the regenerative process after OA induction in the newt. <i>In vitro </i>siRNA knockdown of TN-C might help to identify the molecular pathways involved. Analysis of the selected candidate genes and identification of underlying pathways guiding regeneration might ease the development of new treatment modalities of OA in humans.
Risk factors associated with death or neurological deterioration among patients with Gram-negative postneurosurgical meningitis
Authors: A. Neuberger, B. Shofty, B. Bishop, M.E. Naffaa, T. Binawi, T. Babich, Z.H. Rappaport, M. Zaaroor, G. Sviri, D. Yahav, M. Paul
Journal: Clinical Microbiology and Infection (2016)
SC-12 * CD133 SURFACE EXPRESSION INDICATES ASYMMETRIC INHERITANCE OF SIGNALING RECEPTORS DURING GLIOBLASTOMA CANCER STEM CELL MITOSIS
Authors: M. Hitomi, S. Jarvis, V. Yogeswaran, K. Pfaff, J. Lathia
Journal: Neuro-Oncology (2014)

Asymmetric cell division, the mechanism by which stem cells generate progeny undergoing tissue specific differentiation and a self-renewing stem cell population, enables organogenesis, maintenance of tissue homeostasis, and tissue regeneration without depleting stem cell pools. Cancer stem cells (CSCs) have been identified in malignant cancers including glioblastoma (GBM) by virtue of their enhanced self-renewal capacity and ability to reconstitute an entire tumor with all types of cells found in the original tumor. CSCs also play pivotal roles in therapeutic resistance and are the focus of recent therapeutic development efforts. CSC maintenance is regulated by intrinsic stem cell transcription factors, as well as by multiple extrinsic factors in the tumor microenvironment. In addition to these factors, the mode of cell division plays a critical role in CSC maintenance as exemplified by normal stem cells. Previously, we demonstrated that asymmetric segregation of a CSC marker, CD133, at the time of mitosis correlated with fate determination of CSCs derived from clinical GBM patient samples. Utilizing quantitative immunofluorecsence, we detected that receptors for key signaling molecules critical for CSC maintenance were co-segregated with CD133. Inhibition of downstream signaling induced asymmetric cell death in one of the daughter cells. These data indicate that CD133 marks daughter cells with higher inheritance of molecules that facilitate self-renewal and that asymmetric cell division may benefit CSC survival by concentrating essential receptors to one daughter cell in addition to its potential role in increasing cellular heterogeneity of the tumor.
Abstract 3224: Preclinical PKPD modeling and human dose projection of PF-04691502, a PI3K/mTOR dual inhibitor
Authors: Kenneth T. Luu, Eric Zhang, Shubha Bagrodia, Jing Yuan
Journal: Cancer Research (2010)

Abstract PF-04691502 is a potent dual inhibitor of PI3K and mTOR, which are involved in regulating cell growth, proliferation and survival. The main objective of this work was to develop a preclinical pharmacokinetic-pharmacodynamic (PKPD) model for the compound and project the human efficacious dose. The PK of PF-04691502 in mouse obtained following oral dosing was described by a linear 2-compartment model which was used to drive two separate PD models: 1) an exponential growth model describing the tumor growth inhibition (TGI) and 2) an indirect-response model describing changes in intratumoral pAKT-S473/AKT in the U87MG xenograft mouse model. Based on the PK model, the half-life calculated from the linear elimination constant (k = 0.306 hr−1) was 2.3 hr and the plasma-compartment volume of distribution was 8.72 L/kg. The inter-compartmental distribution rate constants were 0.282 hr−1 and 0.212 hr−1 for k12 and k21, respectively. The model estimated in-vivo potency (IC50) for pAKT-S473/AKT suppression was 38.3 nM which was within the range of the IC50 (23 nM) for TGI (as parameterized by the model). The Imax estimated from the model was 0.975 (or 97.5%), which indicated nearly complete suppression of pAKT-S473/AKT production rate by PF-04691502. Based on the PKPD model and the scaled human PK, a clinical dose of 10 mg QD was determined to be adequate for maintaining the level of pAKT-S473/AKT below 50% of baseline. At steady-state PK this dose yielded a range of 50-80% human pAKT-S473/AKT suppression over the 24 hr dosing interval. In conclusion, PF-04691502 was determined to have a robust PKPD relationship in the preclinical animal model and was projected to have a clinically achievable efficacious dose of approximately 10 mg QD. 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 3224.
P3-05-09: Comparison of Clinical Features and Patterns of Recurrence in Triple Negative Breast Cancers in Relation to Other Breast Cancers.
Authors: de Oliveira C Tosello, EM Barbosa, de Andrade J Costa, EC Lyra, MC Felzener, Zveibil D Krutman, SHG Grosso, Goes de Oliveira R Sampaio, Góes JC Sampaio
Journal: Cancer Research (2011)

Abstract Background : Breast cancer is an heterogeneous disease that have several and different biological characteristics and clinical behaviours. Of these, triple negative breast cancer represents 10–17%.This kind of tumor is characterized by estrogen, progesterone and HER2 receptor negativity and they are very aggressive, associated with poor prognosis, younger patients, high incidence of metastases and shorter relapse free survival. Triple negative breast tumours are more likely to experience local recurrence and distant relapse than other breast tumors, and require a more aggressive intervention. PURPOSE : To compare the incidence of metastases, clinical features and outcome among patients with triple negative breast cancer and women with other types of breast cancer. METHODS : This is a retrospective cohort analysis from 3893 patients with invasive breast cancer, diagnosed between January 2000 and April 2011 and attended at Brazilian Institute of Cancer Control (IBCC) in Sao Paulo, Brazil. Five hundred of these tumors were triple negative. We made a correlation of clinical variables such as age, tumor stage (TNM) and analysis of last follow-ups, such as metastases, disease free survival, death for tumor, death for other reasons, lost of follow-up, hygiene and diet regime (RHD) and local recurrence. Results: The median follow-up for the cohort was 4,29 years. The mean age at diagnosis in triple negative group was 54,8 and for the others group was 57,1 years. Subgroup analysis of tumor grade showed that the triple negative breast tumors were diagnosed later (Stage II and III; p:&amp;lt;0,0001). There was no difference in the appearance of the two types of tumors, when considering diagnose age. The incidence of metastases, death for tumor and free survival in triple negative tumors, respectively; 25,6%, 13,8% and 57,2% (p:&amp;lt;0,0001) demonstrates the aggressiveness of this kind of tumor. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-05-09.
Abstract 5531: Preparation and cellular delivery of doxorubicin nanoemulsion for cancer therapy
Authors: Sarala Pamujula, Dakshina Murthy Devanga Chinta, Ashley King, Vimal Kishore, Tarun K. Mandal
Journal: Cancer Research (2010)

Abstract Purpose: The aim of this study is to formulate a novel nanoemulsion of doxorubicin to enhance the therapeutic efficacy of the drug. Method: Four different multiple emulsions (W1/O/W2) were prepared (A, B, C, and D) by homogenization of a mixture of aqueous and oil phases. The resultant primary emulsions were later pass through a high pressure homogenization to further reduce the globules size to nanometer range. The formulation A is a control nanoemulsion, consisted of only deionized water as W1 phase. The W1 phase of the other three formulations (B, C, and D) consisted of aqueous solution of BSA (as an emulsion stabilizer), doxorubicin, and a mixture of BSA and doxorubicin, respectively. For all four formulations, the oil phase (O) consisted of a 2:1 mixture of soyabean oil and Span 80, and the outer aqueous phase (W2) consisted of prolaxamer P-85 and Vitamin E TPGS. The nanoemulsions were evaluated for stability, polydispersity index, size, and viscosity. Anticancer efficacy of these formulations was evaluated by Alamar Blue Assay and Colony Forming Assay using MCF-7 cells as a model malignant breast cancer cell line. Results: The stability of nanoemulsions was found to be significantly better for the formulations containing BSA. Presence of BSA or doxorubicin resulted in a significant increase in viscosity from 2.09 to 10.6 cP. Cell culture studies showed that doxorubicin nanoemulsions had higher localization in cytoplasm as compared to the nucleus. In regard to cellular uptake (intracellular quantification of doxorubicin), the following results were obtained at 2h, 24h, 48h, and 120h post-incubation, respectively: 42%, 30%, 37%, and 22% with doxorubicin solution; 12%, 19%, 21%, 33% with formulation C; and 0.25%, 6%, 10%, 19% with formulation D. The results of Alamar Blue Assay showed IC50 values of 0.97μM (solution), 1.62μM (formulation C) and 1.91μM (formulation D). The results of Colony Forming Assay (12days-post-treatment with equivalent to 0.86 μM doxorubicin) showed 74% (solution), 86% (formulation C) and 92.6% (formulation D) growth inhibitions. Conclusions: The presence of BSA within the aqueous phase enhances the stability of nanoemulsions. In comparison to doxorubicin solution, the nanoemulsions produce higher anticancer efficacy. This exploratory study will be followed by more detailed studies to confirm this preliminary finding. Acknowledgements: This work was funded in part by the NASA grant # NCC3-946-S4, Louisiana Board of Regents RC/EEP (2007-10), NIH grant# 5P20CA118768-02, and Louisiana Cancer Research Consortium. We are thankful to Dr. Thomas Wiese of the College of Pharmacy, XULA, for providing the Cell culture lab facilities. 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 5531.
DISCHARGE ST2 PREDICTS HEART FAILURE READMISSIONS IN PATIENTS WITH ACUTE DECOMPENSATED HEART FAILURE
Authors: Javier Amione-Guerra, Andrea Cordero-Reyes, Ahmed Soliman, Arvind Bhimaraj, Barry Trachtenberg, Guha Ashrith, Mohamed El-Beheary, John Baird, Vijay Nambi, Jerry Estep
Journal: Journal of the American College of Cardiology (2016)
A Prognostic Score for Advanced Hodgkin's Disease
Authors: Dirk Hasenclever, Volker Diehl, James O. Armitage, David Assouline, Magnus Björkholm, Ercole Brusamolino, George P. Canellos, Patrice Carde, Derek Crowther, David Cunningham, Houchingue Eghbali, Christophe Ferm, Richard I. Fisher, John H. Glick, Bengt Glimelius, Paolo G. Gobbi, Harald Holte, Sandra J. Horning, T. Andrew Lister, Dan L. Longo, Franco Mandelli, Aaron Polliack, Stephen J. Proctor, Lena Specht, John W. Sweetenham, Gillian Vaughan Hudson
Journal: New England Journal of Medicine (1998)

Two thirds of patients with advanced Hodgkin's disease are cured with current approaches to treatment. Prediction of the outcome is important to avoid overtreating some patients and to identify others in whom standard treatment is likely to fail.Data were collected from 25 centers and study groups on a total of 5141 patients treated with combination chemotherapy for advanced Hodgkin's disease, with or without radiotherapy. The data included the outcome and 19 demographic and clinical characteristics at diagnosis. The end point was freedom from progression of disease. Complete data were available for 1618 patients; the final Cox model was fitted to these data. Data from an additional 2643 patients were used for partial validation.The prognostic score was defined as the number of adverse prognostic factors present at diagnosis. Seven factors had similar independent prognostic effects: a serum albumin level of less than 4 g per deciliter, a hemoglobin level of less than 10.5 g per deciliter, male sex, an age of 45 years or older, stage IV disease (according to the Ann Arbor classification), leukocytosis (a white-cell count of at least 15,000 per cubic millimeter), and lymphocytopenia (a lymphocyte count of less than 600 per cubic millimeter, a count that was less than 8 percent of the white-cell count, or both). The score predicted the rate of freedom from progression of disease as follows: 0, or no factors (7 percent of the patients), 84 percent; 1 (22 percent of the patients), 77 percent; 2 (29 percent of the patients), 67 percent; 3 (23 percent of the patients), 60 percent; 4 (12 percent of the patients), 51 percent; and 5 or higher (7 percent of the patients), 42 percent.The prognostic score we developed may be useful in designing clinical trials for the treatment of advanced Hodgkin's disease and in making individual therapeutic decisions, but a distinct group of patients at very high risk could not be identified on the basis of routinely documented demographic and clinical characteristics.
Abstract 2928: Regulation of MST1 and MST2 by mTOR and androgen receptor signaling in prostate cancer
Authors: Filiz Kisaayak Collak, Daniel Luthringer, Hyung L. Kim, Leland Chung, Bekir Cinar
Journal: Cancer Research (2011)

Abstract The serine/threonine kinases MST1 and MST2 (hippo in Drosophila) were originally identified as pro-apoptotic proteins. In addition to their pro-apoptotic functions, evidence suggests that deficiency in MST1 and MST2 and their downstream effectors has been linked to developmental defects, tissue overgrowth, and cancer, including prostate cancer (PCa). However, the molecular mechanism that may modulate MST1 or MST2 signaling in PCa cells remains unknown. Here we investigate the impact of androgen receptor (AR) and PI3K-AKT-mTOR signaling on MST1 or MST2. We used biochemical, mutagenesis, histochemical, and pharmacological approaches to carry out this investigation. First, we demonstrate that AR and MST1 co-localize and form protein complexes in cell nuclei. Androgen further stimulates the interaction between the two proteins and reduces MST1 kinase activity in LNCaP PCa cells, suggesting that AR may sequester MST1 in an inactive form. Second, we showed that MST1 at Threonine120 (T120) was exclusively phosphorylated in cell nuclei, whereas MST2 at Threonine117 (T117), corresponding to MST1-T120, was phosphorylated only in the cytoplasm, although MST1 and MST2 were found in both locations. Similar phosphorylation patterns were also observed in prostate cancer tissue samples. Third, we have found that the T120 is not a physiologic target of AKT kinase in vivo, because the inhibition of AKT activity by a specific PI3K inhibitor, LY294002, had no effect on the phosphorylation of MST1 at the T120 site, but it did inhibit MST1-T117 phosphorylation. Furthermore, attenuation of mTOR activity by Ku0063794, a specific mTOR1 and mTOR2 inhibitor, abolished MST2-T117 phosphorylation, but without having an effect on the levels of phospho-MST1-Thr120. Lastly, the use of combined LY294002 and Ku0063794 compounds synergistically inhibited PCa cell growth, relative to a single compound. Our data suggest that AR and mTOR pathway signaling may oppose MST1 and MST2 in discrete cell locations. Thus, understanding the functional relationship between these signal networks in the context of cell proliferation and cell death may have important therapeutic implications in prostate cancer. 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 2928. doi:10.1158/1538-7445.AM2011-2928
PF-00299804 (PF299) in Asian patients (pts) with non-small cell lung cancer (NSCLC) refractory to chemotherapy (CT) and erlotinib (E) or gefitinib (G): A phase (P) I/II study.
Authors: K. Park, D. S. Heo, B. Cho, D. Kim, M. Ahn, S. Lee, R. D. Millham, A. Campbell, H. Zhang, J. Kim
Journal: Journal of Clinical Oncology (2010)

7599 Background: PF299 is an oral, irreversible, small molecule inhibitor of the human epidermal growth factor receptor (HER)-1, -2, and -4 tyrosine kinases. Trials in Western pts identified a recommended phase II dose (RP2D) of PF299 45 mg once daily (QD) and reported antitumor activity in NSCLC. We present a P1/2, multicenter, open-label study of Korean pts with KRAS wild-type NSCLC (adenocarcinoma histology) refractory to platinum-based CT and E or G. Methods: In the P1 dose-finding study portion, 12 pts received PF299, starting with 30 mg QD, to identify the RP2D and evaluate safety. Following P1, pts were enrolled in a Fleming single-stage P2 study and received the PF299 RP2D, 45 mg QD. Endpoints included progression-free survival rate at 4 months (PFS4m; primary), overall survival rate at 6 months (OS6m), objective response rate (ORR), safety, pharmacodynamic (PD) biomarkers (HER-1/-2 extracellular domain), serum and tumor KRAS and HER-1 genetic analyses, and patient-reported outcomes (PROs) measured by EORTC QLQ-C30/LC13. Results: In P2, 30 pts of 42 planned have enrolled to date, of whom 87% had received ≥3 prior CT regimens. Preliminary data show PFS4m, 35%; OS6m, 87%; ORR, 8%; and clinical benefit rate (partial response or stable disease ≥ 24 weeks), 20%. Preliminary PRO data indicate health-related quality of life (HRQOL; e.g. symptoms, functioning, global QOL) was not adversely impacted by PF299. Detailed analysis of PRO data on key NSCLC symptoms (cough, dyspnea, pain) will be conducted. Most treatment-related adverse events (TRAEs) were grade 1/2. Common TRAEs were diarrhea (69%; grade 3, 4%), rash (50%; 4%), and dermatitis acneiform (42%; 4%). No pts discontinued due to TRAEs. TRAEs, mainly diarrhea and rash, led to dose reductions/interruptions in 5 pts. Final efficacy, safety, PRO, and PD data and genetic analyses will be reported. Conclusions: Preliminary data consistent with Western trials show that in heavily treated Asian pts with NSCLC after E or G failure, PF299 is well tolerated and has antitumor activity without adversely impacting pts' HRQOL. These results support the ongoing global P3 trial in pts with refractory NSCLC. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer, Pfizer Korea Bristol-Myers Squibb, GlaxoSmithKline, Lilly, Merck Serono, Pfizer Pfizer AstraZeneca, Lilly, Roche AstraZeneca, Pfizer, Roche, sanofi-aventis
AB0711 Natriuretic Peptide Levels and the Correlation of Oxidative Stress in Patients with Ankylosing Spondylitis
Authors: M. Calis, E. Sonbahar, H. Talay Calis, C. Yazici, F. Ulku Demir, S. Mistik
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Recently, studies are focused on finding the relation between Natriuretric Peptide and the immune system. <h3>Objectives</h3> The aim of the present study is assessing the role of serum levels of natriuretic peptides and the correlation of oxidative stress in patients with ankylosing spondylitis <h3>Methods</h3> This study has been carried out in patients with ankylosing spondylitis (AS). 45 patients with AS and 20 healthy controls were enrolled. Serum levels of pro atrial natriuretic peptide (proANP), brain natriuretic peptide (BNP), N terminal pro C type natriuretic peptide (NTproCNP) who were from natriuretic peptide (NP) family and myeloperoxidase (MPO) activity, serum levels of total lipid hydroperoxides (LHP), neopterin, total oxidant status (TOS), total antioxidant status (TAOS), tumour necrosis factor alpha (TNF-α), advanced oxidation protein products (AOPP) and thiol levels were assayed. <h3>Results</h3> There was no significant difference in neopterin, TNF-α, TOS, TAOS, proANP and NTproCNP concentration between patients with AS and healthy controls. ESR, CRP, AOPP, MPO, LHP and BNP levels were significantly higher in patients with AS than in controls. Thiol, albumin levels were significantly lower in patients with AS than in controls. There was statistically significant difference between acut phase response markers, ESR and CRP levels of active group and inactive group. AOPP and MPO levels were significantly higher in active group than in inactive group and control group. LHP and thiol levels were statistically significant different in active and inactive group than in control group. NTproCNP, AOPP and LHP levels were significantly higher in patients who were active status than in remission status. Thiol, albumin levels were significantly lower in patients who were active status than in remission status. Serum AOPP levels correlated with BASDAI and BASFI scores, CRP and ESR levels in patients with AS. <h3>Conclusions</h3> These results indicate that serum AOPP and proANP levels may reflect clinical activity of disease and may be helpful for monitoring patients with AS. The higher levels of MPO activity showed us enhanced production of ROS by activated neutrophils play a role in the pathogenesis of AS patients. It is thought that NPs related to the oxidative stres in patients with AS and may play an important role of the pathogenesis. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.1064