tbuckley/cabot-search huggingface dataset:
AB0168 IL-6 Maybe A Crucial Role in Peripheral Arthritis of Non-Radiographic Axial Ankylosing Spondylitis by Toll-Like Receptor 2 and 4
Authors: S.Y. Lee
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> The blocking of IL-6 therapy is not effective treatment of ankylosing spondylitis (AS) in recent report, but the role of blocking IL-6 on peripheral joint in non-radiographic axial AS is unknown. <h3>Objectives</h3> we studied the blocking of IL-6 in peripheral arthritis of non-radiographic axial AS via Toll like receptors. <h3>Methods</h3> Synovial fibroblast (FLS) were obtained from knee of eight non-radiographic axial AS patients who were high BASDAI score (&gt;6), and six RA patients who were moderate DAS28 score (&gt;3.2). The expression of IL-6 was analyzed by real-time polymerase chain reaction and multiplex secretary protein analysis technology, Bio-plex assay, also the expression of toll like receptor (TLR) in FLS was detected by western blot. <h3>Results</h3> The expression of TLR 2 and TLR 4 were observed on AS and RA FLS. The administration of peptidoglycan for TLR 2 and LPS for TLR 4 increased the level of IL-6 in AS and RA FLS. The treatment of AS FLS with IL-6 inhibitor, tocilizumab, resulted in reduced expression of TLR 2 and TLR 4 in AS FLS and re-administration of peptidoglycan for TLR 2 and LPS for TLR 4 treatment did not increased the expression of IL-6, TLR 2 and TLR 4 in AS FLS. <h3>Conclusions</h3> Our results suggest that IL-6 maybe crucial role in peripheral arthritis of non-radiographic axial AS and blocking of IL-6 may ameliorate peripheral arthritis of AS by regulating TLR 2 and TLR 4, so inhibition of IL-6 maybe a potential therapeutic strategy in peripheral arthritis of non-radiographic axial AS. <h3>References</h3> Treatment of non-radiographic axial spondyloarthritis: it is only the beginning. Ann Rheum Dis June 2013 Vol 72 No 6 <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.3901
Abstract 3258: Development of novel ribonucleotide reductase inhibitors: A story from structural analysis to preclinical study
Authors: Bingsen Zhou, Leila Su, Yate-Ching Yuan, Shuya Hu, Yun Yen
Journal: Cancer Research (2011)

Abstract The goal of this project is to develop new class inhibitors for Ribonucleotide Reductase (RR), a key enzyme for DNA synthesis. These inhibitors are more effective than existing small molecule therapies, and can overcome resistance from Hydroxyurea (HU), the only FDA approved drug for targeting RR-based cancers. In addition, this new class of inhibitors will ameliorate the severe iron chelating side effects associated with 3-Aminopyridine-2-Carboxaldehyde Thiosemicarbazone (3-AP, Triapine®), a compound that is currently been testing in human phase II clinic trials. A lead compound, COH29 (US Patent No. 54435.8056.US01) with sub-micro molar range inhibition was developed through modification of a hit identified from screening a diverse compound library from NCI Developmental Therapeutics Program (DTP). COH29 demonstrated 90.2% inhibitory activity of recombinant human RRM2/RRM1 enzyme complex at 9 µM in vitro. Moreover, examine the cytotoxicity of COH29 in a NCI broad panel of 60 human cancer cell lines in vitro by 5 doses MTT cytotoxicity assay indicated COH29 show a good inhibition against cancer cells special to leukemia and ovarian cancer cells. Importantly, COH29 shows less toxicity to human normal fibroblast cells as compared to 3-AP. Results from computer modeling and biophysical measurements suggest that COH29 interferes with the radical transfer pathway at the interface between RRM1 and RRM2. This represents a unique binding mechanism that is completely different from existing known inhibitors. Biacore binding analysis, computer docking, as well as NMR Saturation Transfer Difference (STD) studies have been performed and identified COH29 binding is specific to RRM2. These studies further confirm a V-shaped binding pocket of RRM2 with COH29. Preliminary data suggest that COH29 represents a promising new class of RR inhibitors with the advantages of (a) a unique mechanism and target specificity that interferes with the radical transfer pathway at the RRM1-RRM2 interface, (b) greater potency than HU in the sub-µM range of IC50, and (c) avoiding iron chelating-related side effects compared to 3-AP. Therefore, our objectives are to optimize the properties of COH29 into a viable candidate as a future anticancer drug targeting over expressed RR based cancers. (This project was supported by NIH grant CA 127541) 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 3258. doi:10.1158/1538-7445.AM2011-3258
PARANOID REACTION
Authors: G. H. Stevenson, S. R. Montgomery
Journal: American Journal of Psychiatry (1932)

There appears to be a clinical sub-entity in the psychogenic or "reaction to environment" group of psychoses, in which the chief symptoms are persecutory delusions, with or without hallucinations, and without obvious personality or intellectual changes, occurrring in highly moral women, and becoming apparent during the fifth and sixth decades after a long prodromal period, the change from normal to psychopathic being so gradual that relatives have found difficulty in fixing the date of onset and persons who have but slight contact with the patient are not aware that the individual is suffering from a psychosis. A close study of many cases admitted to our mental hospitals over a period years has convinced us that there is a specific etiological factor, among others common to the group as a whole. This so-called specific factor we believe to be an overt or imagined sinful act on the part of the patient, which is not sinful to the patient, however, as she either projects the blame on others or denies that it would have been consciously desired by her. The situation is thus not dealt with adequately and honestly, and a state of emotional unrest is produced. As a quietus to conscience a persecutory delusional trend is developed slowly and progressively until a well-marked psychosis results. If our deductions are correct, we feel that mental hygiene instruction to the laity can utilize the concrete suggestion of greater honesty with ourselves in dealing with problems relating to temptation, sin and conscience.
Abstract 4094: Pancreatic cancers epigenetically silence <i>ZFHX1B,</i> hypomethylate and overexpress miR-200a/−200b, in association with elevated circulating miR-200a and miR-200b levels
Authors: Ang Li, Noriyuki Omura, Seung-Mo Hong, Audrey Vincent, Kimberly Walter, Margaret Griffith, Michael Borges, Michael Goggins
Journal: Cancer Research (2010)

Abstract Aberrant DNA methylation and miRNA expression play important roles in the pathogenesis of pancreatic cancer. While interrogating differentially methylated CpG islands in pancreatic cancer we identified two members of miR-200 family, miR-200a and miR-200b that were hypomethylated and overexpressed in pancreatic cancer. We also identified prevalent hypermethylation and silencing of one of their downstream targets, ZFHX1B (SIP1, ZEB2), whose protein product suppresses E-cadherin expression and contributes to epithelial mesenchymal transition. In a panel of 23 pancreatic cell lines we observed a reciprocal correlation between miR-200, ZFHX1B and E-cadherin expression with pancreatic cancer associated fibroblasts showing the opposite expression pattern to most pancreatic cancers. In Panc-1cells, which express ZFHX1B, have low E-cadherin expression and do not express miR-200a or miR-200b, exogenous expression of miR-200a and miR-200b down regulated ZFHX1B mRNA and increased E-cadherin expression. However, most pancreatic cancers express miR-200a and miR-200b, but this expression does not affect ZFHX1B expression as the ZFHX1B promoter is silenced by hypermethylation, and in these cancers E-cadherin is generally expressed at or above normal levels. Both miR-200a and miR-200b were significantly elevated in the sera of pancreatic cancer and chronic pancreatitis patients compared to healthy controls (p&amp;lt;0.0001), yielding receiver operating characteristic curve areas of 0.861 and 0.85, respectively. In conclusion, most pancreatic cancers display hypomethylation and overexpression of miR-200a and miR-200b, silencing of ZFHX1B by promoter methylation and retain expression of E-cadherin. The elevated serum levels of miR-200a and miR-200b in most patients with pancreatic cancer could have diagnostic utility. 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 4094.
Abstract 3401: Vemurafenib-induced RhoB expression leads to melanoma cell resistance.
Authors: Audrey Delmas, Julia Cherier, Claire Medale-Giamarchi, Anne Pradines, Gilles Favre
Journal: Cancer Research (2013)

Abstract Most of melanoma harbour mutations leading to the constitutive activation of the Ras/Raf/MEK/ERK mitogen-activated protein kinase (MAPK) pathway (i.e: activating mutations of BRAF, NRAS, c-KIT). Addiction of melanoma to the MAPK pathways led to the development of inhibitors targeting either mutant BRAF, such as Vemurafenib (PLX4032), or MEK. Melanoma treatment recently met a breakthrough with the clinical evaluation of Vemurafenib that demonstrated an unprecedented 80% response rate among patients with BRAF V600E melanomas treated with Vemurafenib, but rapidly limited by drug resistance, which still requires to be elucidated. The MAPK pathway regulates the expression of many genes which can mediate therapeutic response but also resistance, such as RhoGTPases. We analysed the mRNA expression of the RhoGTPases in two BRAF mutated melanoma cell lines, WM266-4 and A375, in response to inhibition of the MAPK pathway by PLX4032. We observed that the mRNA of RhoB was increased by PLX4032 treatment. This result was confirmed in many other BRAF mutated melanoma cell lines by inhibition of the MAPK pathway with BRAF inhibitors (PLX4032 or SB-590885) as well as MEK inhibitors (AZD6244 or AS703026). MEK inhibitors (AZD6244 or AS703026) upregulate RhoB in BRAF wild-type melanoma cells harbouring N-Ras, K-Ras or c-KIT mutation suggesting that inhibiting MAPK pathway is critical for RhoB expression modulation. It is noteworthy that this modulation is cell type dependent, while it was not found in BRAF mutated non-melanoma cells as colon carcinoma cells (Colo205 and RKO). To investigate the role of RhoB induction in cellular responses to BRAF and MEK inhibitors, the RhoB induction was suppressed using RNA interference. The cells treated with siRNA targeting RhoB, WM266-4 and A375 cells, were more sensitive to PLX4032 and AZD6244. Moreover the blockade of RhoB induction led to a significant increase of PLX4032-induced apoptosis as shown by the increase of the subG1 population and PARP cleavage. Our findings show that RhoB upregulation is involved in PLX4032 response and both inhibitions of MAPK pathway and RhoB expression trigger cell death and should prompt a search for agents. Indeed co-targeting MAPK and RhoB pathways, could lead to a synthetic lethality and prevent resistance to either BRAF or MEK inhibitors. Ongoing work focuses on confirming this role in tumour-xenografted mouse models. Citation Format: Audrey Delmas, Julia Cherier, Claire Medale-Giamarchi, Anne Pradines, Gilles Favre. Vemurafenib-induced RhoB expression leads to melanoma cell resistance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3401. doi:10.1158/1538-7445.AM2013-3401
Retroperitoneal Pheochromocytoma With Thorax and Bilateral Neck Chemodectoma in Patients With Multiorgan Sarcoidosis
Authors: Jolanta Kunikowska, Laretta Grabowska, Sadegh Toutounchi, Andrzej Cieszanowski, Magdalena Witkowska
Journal: Clinical Nuclear Medicine (2014)

A 37-year-old man with multiorgan sarcoidosis, hypertension, and abdominal mass on CT was referred to the nuclear medicine department. PET/CT with 68Ga DOTATATE demonstrated an increased uptake in the abdominal mass and in the mediastinum, neck (bilaterally), and right jugular foramen; low uptake was observed in hilar and groin lymph nodes. MRI revealed abnormal focal lesions, showing increased signal on T2-weighted fat-saturated images, marked contrast enhancement on T1-weighted gradient-echo images, and restricted diffusion in the same locations as on PET/CT. Patients underwent surgery of abdominal mass and right neck tumors, with histologic diagnosis consistent with extra-adrenal pheochromocytoma and neck chemodectoma.
Safety of First-Line Letrozole Compared with Lapatinib Plus Letrozole in Patients with Postmenopausal Hormone Receptor Positive Metastatic Breast Cancer: EGF30008 Study.
Authors: J. Ro, J. Pippen, X. Pivot, A. Manikhas, L. Fehrenbacher, A. Makris, A. Florance, J. Maltzman, L. O'Rourke, S. Johnson
Journal: Cancer Research (2009)

Abstract Background: EGF30008 was a double-blind, placebo-controlled phase III study which evaluated the benefit of adding lapatinib (L) to letrozole (Let) alone in patient (pts) with hormone receptor positive (HR+), metastatic breast cancer. Median progression-free survival (PFS) in pts with HER2+ tumors was significantly increased from 3 to 8.2 mos with dual therapy (HR [95% CI] =0.71 [0.53, 0.96], P=.019). Safety data presented at the 2008 San Antonio Breast Cancer Symposium demonstrated that the combination of L+Let was manageable and predictable, with no unexpected toxicity.Methods: 1286 pts were randomized 1:1 to treatment with Let versus L+Let. Safety data were collected from start of study drug until 30 days after discontinuation. The safety population was based on the actual treatment received (Let n=623; L+Let n=655). Updated adverse events (AEs) associated with L were evaluated at both pt and event level as a function of time on study. AEs were categorized into 4 groups: diarrhea, rash, cardiac, and hepatobiliary events. Multiple AE terms were classified within these groups.Results: Safety data through 03Feb09 are reported (additional 8 mos data beyond trial reporting). Let group: median exposure of Let=37.57 weeks (range 0.9-251.1). L+Let group: median exposure of Let= 40.43 (range 0.1-248.6) and median exposure of L=40.14 weeks (range 0.3-248.6). Overall, there were 537 AE events (86%) in the Let alone group, and 629 (96%) in the L+Let group. Incidence, counts, and time to first occurrence of AEs associated with HER1 and HER2 inhibition are summarized below. Let (n=623)L+Let (n=655)Rash Pts with AE, n95 (15%)328 (50%)- Max Grade 30.012 (4%)- Max Grade 40.00.0AEs (n events)123638- Leading to study withdrawal1 (&amp;lt;1%)11 (2%)Median time to 1st onset, days7720Diarrhea Pts with AE, n127 (20%)419 (64%)- Max Grade 36 (5%)59 (14%)- Max Grade 40.02 (&amp;lt;1%)AEs (n events)1721026- Leading to study withdrawal2 (1%)22 (2%)Median time to 1st onset, days6114Hepatobiliary Pts with AE, n50 (8%)102 (16%)- Max Grade 39 (18%)33 (32%)- Max Grade 43 (6%)4 (4%)AEs (n events)103405- Leading to study drug withdrawal3 (3%)13 (3%)Median time to 1st onset12463LVEF decreases Pts with AE, n18 (3%)34 (5%)- Grade 32 (11%)8 (18%)- Grade 40.01 (3%)AEs (n events)1941- Leading to study drug withdrawal4 (21%)8 (20%)Median time to 1st onset, days323165 Graphs of AEs as a function of time as well as details on pts with multiple events will also be provided.Conclusion: Relatively few AEs were grade 3/4 or led to study drug discontinuation. Incidence, severity, and recovery of each toxicity as a function of time will be presented. The safety profile of L+Let remains consistent with the 8 additional months of data since initial reporting of study results. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5094.
ASYMPTOMATIC EXTRACRANIAL CAROTID ATHEROSCLEROSIS AND RISK FOR CEREBROVASCULAR EVENTS IN PATIENTS WITH NON-VALVULAR ATRIAL FIBRILLATION: THE ARAPACIS STUDY
Authors: Stefania Basili, Lorenzo Loffredo, Daniele Pastori, Marco Proietti, Alessio Farcomeni, Annarita Vestri, Pasquale Pignatelli, Gino Roberto Corazza, Francesco Perticone, Francesco Violi
Journal: Journal of the American College of Cardiology (2016)
THE MYOCARDIAL CONTRACTION FRACTION (MCF) IS ASSOCIATED WITH NYHA CLASS AS WELL AS DELAYED ENHANCEMENT BY CARDIAC MRI IN HYPERTROPHIC CARDIOMYOPATHY AND PREDICTS SUDDEN CARDIAC DEATH
Authors: Mathew S. Maurer, Jonathan Ginns, Barry Maron, Iacopo Olivotto, John Lesser, Christiane Gruner, Andrew Crean, Harry Rakowski, Ethan Rowin, Massimo Lombardi, Paolo Spirito, Elena Biagini, Camillo Autore, Warren Manning, Benedetta Tomberli, Martin Maron, Raymond Chan
Journal: Journal of the American College of Cardiology (2016)
THE PROGNOSTIC VALUE OF EXERCISE ECG TEST AND CARDIAC COMPUTED TOMOGRAPHY CORONARY ANGIOGRAPHY FOR CARDIOVASCULAR EVENTS IN PATIENT PRESENTING WITH CHEST PAIN
Authors: Jong-Hwa Ahn, Jeong Rang Park, Kye Hwan Kim, Jin-Sin Koh, Seok-Jae Hwang, Yongwhi Park, Young Hoon Jung, Choong Hwan Kwak, Jin-Yong Hwang
Journal: Journal of the American College of Cardiology (2015)
GW25-e0793 Detailed Coronary Angiographic Analysis and Predictors of Significant Coronary Artery Disease in Chinese Men and Women with Chest Pain
Authors: Bai Hongyuan, Ni Yajuan, Zhang Songlin, Wang Tingzhong, Wei Feng, Song Bingxue, Zhang Xuedan, Du Yuan, Dong Xin, Ma Aiqun
Journal: Journal of the American College of Cardiology (2014)
Redox Status Contributes to Tamoxifen-Resistant Growth of Breast Cancer.
Authors: R. Penney, J. Slingerland, D. Roy
Journal: Cancer Research (2009)

Abstract The emergence of tamoxifen resistance is a major problem in the treatment of breast cancer. Tamoxifen-resistant growth coincides with a high intracellular oxidant state, and tamoxifen is known to increase intracellular oxidants in breast cancer cells. We postulate that the conversion of breast tumors to a tamoxifen-resistant phenotype is associated with a progressive shift towards a pro-oxidant environment of cells as a result of chronic antiestrogen treatment therapy. In this study, we present data that show that modifying the redox state of thioredoxin (Trx) changes the sensitivity of cells to tamoxifen, and that these changes occur through Trx-Jab1-p27 interactions. The use of ebselen on tamoxifen-resistant LCC2 breast cancer cells increased thioredoxin expression and decreased DNA synthesis in tamoxifen-treated cells. In thioredoxin reductase 2 (TrxR2)-overexpressed cells, tamoxifen inhibited in vitro tumor formation as measured by growth of colonies, and also inhibited DNA synthesis. Probing Trx in a Jab1 immunoprecipitation showed that Jab1 interacts with Trx, and that overexpression of TrxR2 results in higher Jab1-Trx interaction. Similarly, using a p27 immunoprecipitation, we found that Jab1 interacts with p27, and p27 interacts with Trx. When we knock down Jab1, we show a decrease in both colony growth and DNA synthesis in tamoxifen-treated cells. These data support our hypothesis that altering the redox status of breast cancer contributes to the restoration of tamoxifen sensitivity, and that this restoration occurs through a Trx/Jab1/p27 mechanism. The data indicate that overexpressing TrxR2 and reducing oxidized Trx increases Jab1/Trx binding, restores the inhibitory effects of p27, and restores tamoxifen sensitivity to previously resistant breast cancer cells. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5134.
Abstract 322: Triple combination array analysis detects the Collagen type1 alpha1 (COL1A1) gene as a new tumor related gene in hepatocellular carcinoma
Authors: Hayashi Masamichi, Shuji Nomoto, Yukiyasu Okamura, Mitsuhiro Hishida, Yoko Nishikawa, Tsutomu Fujii, Hiroyuki Sugimoto, Shin Takeda, Akimasa Nakao
Journal: Cancer Research (2011)

Abstract Background: Epigenetics is one of the most important mechanisms for inactivating tumor suppressor genes or tumor-related genes in various human cancers. Hepatocellular carcinoma (HCC) is one type of human cancer in which epigenetic gene suppression is frequently found. To effectively detect a tumor-related, we performed triple combination array analysis, which consists of an expression array, a single nucleotide polymorphism (SNP) array, and a methylation array of the same surgical HCC specimen. Methods: Triple array analysis of one HCC sample from a 68-year-old female patient was performed. Gene expression profiles were determined using Affymetrix HGU133A and B Gene-Chips using RNA. The SNP chip array was conducted using the standard protocol for Affymetrix Gene Chip Mapping 500K arrays. Methylation array analysis used an Illumina Infinium HumanMethylation27 Beadchip Kit. The gene encoding Collagen type1 alpha1 (COL1A1) was identified and verified using HCC cell lines and 48 primary HCC tissues from patients who had undergone hepatectomy at our hospital. Results: Expression array analysis revealed that COL1A1 gene expression was decreased in tumor tissues (Log2 Ratio -1.1). In addition, SNP array analysis showed that the COL1A1 locus, 17q21, did not show a chromosomal deletion. Importantly, the methylation value (0-1.0) in the tumor tissue was higher (0.557) than that of the adjacent normal tissue (0.008). We hypothesized that the expression of this gene was suppressed by promoter hypermethylation. The suppressed expression of the COL1A1 gene in HCC cell lines was reactivated after 5-aza-2′-deoxycytidine (5-aza-dC) treatment. Sequence analysis identified hypermethylated CpG sites in the COL1A1 promoter region. In 48 HCC samples, 21 cases (44%) also showed COL1A1 gene promoter hypermethylation. The expression values of methylated cases, examined by real-time RT-PCR, were significantly downregulated (p=0.004) compared with unmethylated cases. Downregulation of the gene's expression was significantly correlated with pathological fc positive (p=0.026) and liver damage scores (p=0.011). Conclusion: Triple combination array analysis successfully revealed that the COL1A1 gene acts as a tumor suppressor gene in HCC via promoter hypermethylation. 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 322. doi:10.1158/1538-7445.AM2011-322
Septic Shock — Evaluating Another Failed Treatment
Authors: Richard P. Wenzel, Michael B. Edmond
Journal: New England Journal of Medicine (2012)

Sepsis, severe sepsis, and septic shock are progressively severe stages of the host's systemic inflammatory response to infection.1 The latter stages carry increasing rates of end-organ failure and death. The spectrum of the sepsis syndrome remains a leading cause of death in the United States, and early intervention with appropriate antibiotics (matching the antibiogram susceptibilities to the drugs administered) saves lives. Specific to septic shock, a large retrospective cohort study involving 2731 adults in 14 critical care units showed an absolute decrease of 7.6 percentage points in the survival rate for each hour of delay in antimicrobial administration from the . . .
Ivory Vertebra on 18F-Sodium Fluoride Scan
Authors: Jorge Daniel Oldan, Samuel Kuzminski, Olga James
Journal: Clinical Nuclear Medicine (2014)

We report a case of ivory vertebra on 18F-sodium fluoride. A prostate cancer patient had a 18F-sodium fluoride PET scan to evaluate overall spread of disease. In addition to other findings of metastatic disease, the patient had an ivory vertebra.