tbuckley/cabot-search huggingface dataset:
New ifosfamide analogs aiming less neurotoxicity and less nephrotoxicity
Authors: Thomas Storme, Alain Deroussent, Fabienne Munier, Lionel Mercier, Thierry Martens, Micheline Re, Jacques Royer, Philippe Bourget, Gilles Vassal, Angelo Paci
Journal: Cancer Research (2007)

5591   Ifosfamide (IFM) is an useful prodrug with cytochrome P450 metabolisation associated to both antitumor activity and toxicities such as urotoxicity, nephrotoxicity and neurotoxicity. Isophosphoramide mustard is the bisalkylating active metabolite and acrolein, the urotoxic one. Since acrolein toxicity is limited by systematic coadministration of mesna, the urotoxicity incidence has been lowered. Current evidence suggests that chloroacetaldehyde (CAA), a IFM metabolite from the side-chain oxidation is responsible for both neurotoxicity and nephrotoxicity (Kerbusch T,et. al.  Clin. Pharmacokinet.  2001 ,  40(1) , 41-62). To prevent CAA formation, side chain-methylated ifosfamide analogs ( i.e.   C  7 , C  9 -dimethyl-ifosfamide) have been enantioselectively synthesised in our laboratory (Paci A, et. al.  Bioorg. Med. Chem. Lett.   2001 ,  11(10) , 1347-1349). To confirm our hypothesis, two topics have to be evaluated: anticancer activity, through the liberation of alkylating nitrogen mustard, and reduced toxicogenic catabolism. First a mechanistic study by phosphorus Nuclear Magnetic Resonance ( 31 P-NMR) kinetic is efficient to estimate oxazaphosphorine mustards alkylating activity (Boal JH, et. al . J. Med. Chem.  1989 ,  32(8) , 1768-1773). The alkylating activity of the modified mustards generated by these new side chain-substituted IFM analogs in comparison to IFM mustard will be presented. Second, as metabolic and toxicologic studies, we developed a HPLC-MS/MS technique to evaluate  in vitro  biotransformation of the asymmetrically synthesised IFM analogs by human hepatic microsomes containing CYP3A4 and 2B6 (Storme T, et. al.  J. Chrom. B Biomed. Anal.   2005 ,  820(2),  251-259). In order to evaluate their cytotoxicities, co-culture of 9L glioblastoma cells and of induced rat microsomes was performed (Baldwin A, et. al.  Arch. Biochem. Biophys.  2003 ,  409(1),  197-206). These co-cultures experiences demontrate that these new analogs are more cytotoxic than IFM i.e. CI50 0.08 µM for analogs vs 0.5 µM for IFM. Cell cycle effect is under investigation. I n vitro  biotransformation of analogs showed an  N -deschloroethylation process as with IFM. Nevertheless, this metabolisation leads to chloroacetone, less reactive than CAA. Nephrotoxicity of chloroacetone will be compared with CAA on a rat model which is being developed.    These new dimethylated analogs of IFM are more cytotoxic than IFM metabolites. After these first tests, the most promising component will be selected to attempt  in vivo  studies of its anti-tumor activity and nephrotoxic side effect.
ALTERED GROUND REACTION FORCE DURING COUNTER MOVEMENT JUMPS IN PREVIOUSLY INJURED PROFESSIONAL FOOTBALL PLAYERS
Authors: Ruben Argemi, Julio Elverdin, Pablo Ortega Gallo
Journal: British Journal of Sports Medicine (2017)

Background Sports injuries produce changes in movement characteristics, which can be measured qualitatively and quantitatively in the ground reaction force. Objective To characterize the strength curve of a counter movement jump (CMJ) in professional footballers who were suffering from sports injuries. Design Case-control study. Setting Professional footballers of Club Atlético Boca Juniors. Participants 32 players suffering from sports-related ankle, knee and muscle injuries, who were tested during the first week that they were able to jump, and 52 as control group, who were tested during preventive medical controls. Main Outcome Measurements We analysed 5 stages of the force curve during CMJ: 1. Starting movement, 2. Start of eccentric contraction, 3. Eccentric contraction, 4. Peak eccentric, 5. Peak concentric, and rate of force development (RFD). In areas 1, 2 and 3 asymmetry was examined qualitatively (curve shape ), in zones 4 and 5, quantitatively (&gt;5%). Results All of injured players showed asymmetry versus 48% in control group (p&lt;0.05), 85% of injured players showed deficits in zone 4 (16.5% in peak force vs 11,6% in control; p&lt;0.05). Asymmetry of RFD in players with ankle and knee injuries was 26% and 14%, respectively, while those with psoas injuries presented inverted asymmetry(less force in non injury leg). Players with ankle injuries showed asymmetry in zones 1–4 and knee injuries in zones 1–5 (73% and 85% of the cases, respectively). Players treated surgically for knee injuries (ACL and menisci) demonstrated asymmetry in zones 4 and 5 in 100% of the cases. Players with adductor and hamstring injuries displayed asymmetry in zones 4 and 2–3, respectively (100% of cases for both). All players were symmetrical at return to sports. Conclusions The force plate is a device that allows the characterization of function in sports injuries during the rehabilitation process, and help establish parameters for the return of the athlete to a normal athletic life.
Neoadjuvant Treatment With Trastuzumab and FOLFOX Induces a Complete Pathologic Response in a Metastatic<i>ERBB2</i>(HER2)-Amplified Duodenal Cancer
Authors: Ahmad Hamad, Aatur D. Singhi, Nathan Bahary, Kevin McGrath, Rula Amarin, Herbert J. Zeh, Amer H. Zureikat
Journal: Journal of the National Comprehensive Cancer Network (2017)

Overexpression of HER2 protein and amplification of the ERBB2 gene has been observed in various adenocarcinomas, providing a therapeutic target that can be used to extend the survival of a select cohort of patients. Anti-HER2 therapy has been successfully applied to gastric and colorectal cancers, but its use and potential benefit in small intestinal carcinomas is not well characterized. We applied anti-HER2 therapy to an ERBB2-amplified advanced duodenal adenocarcinoma, adding trastuzumab to FOLFOX in the neoadjuvant setting. A 61-year-old woman with an advanced duodenal cancer harboring an ERBB2 amplification received preoperative trastuzumab and FOLFOX. Restaging revealed significant tumor downstaging with no metastasis. After multidisciplinary assessment, she underwent pancreaticoduodenectomy. Final pathologic analysis revealed no residual invasive adenocarcinoma, consistent with a complete neoadjuvant treatment response. This case report emphasizes the need for further molecular characterization of small bowel cancers; genetic alterations may provide therapeutic targets to improve the prognosis of these rare and aggressive malignancies.
PTH-100 The effect of gastric helicobacter pylori infection on the intestinal microbiome of ibd patients
Authors: N Quraishi, N Bhala, R Cooney, S Pathmakanthan, J McNamara, S Gosh, I Henderson, T Iqbal, A Rossiter
Journal: Gut (2017)

Introduction   Helicobacter pylori  is a Gram-negative bacterium, which infects over 50% of the population worldwide. However, only a subset of these infections result in gastrointestinal diseases, such as peptic ulceration (10%) and gastric cancer (2%). Several epidemiological studies have revealed that people who carry  H. pylori  are at a decreased risk of developing IBD. However, a mechanistic understanding of the association between  H. pylori  infection and IBD is still unknown. Unlike any other microbial species, once  H. pylori  colonises its gastric niche, it is able to dominate the gastric microbiome, representing 90%–95% of the total microbial population. Therefore, we hypothesised that the presence of  H. pylori  in the upper gastrointestinal (GI) tract prevents the colonisation of the lower GI tract with microbial species associated with the pathogenesis of IBD.  Method  To test this, we collected stool samples from IBD patients (comprising Ulcerative Colitis and Crohn’s disease patients) and determined their  H. pylori  status using a stool antigen test. We then characterised the intestinal microbiota of  H. pylori  positive (n=9) and negative IBD patients (n=18), by amplifying the V4 hyper-variable region of the 16S rRNA gene from faecal DNA. To determine the predominant phyla, these products were sequenced using the Illumina MiSeq and data analysis was performed using the QIIME pipeline and GreenGenes database.  Results  Interestingly, bacterial community structure revealed that there is a strong trend towards a decrease of Proteobacteria and an increase of Bacteroidetes in  H. pylori  positive IBD patients. Of note, IBD is generally characterised by an increase in Proteobacteria and a decrease in Bacteroidetes. Furthermore, using PICRUSt to investigate the functional composition of the metagenomes, we found that the  H. pylori  positive IBD patients displayed significant functional differences, including decreased bacterial motility and chemotaxis (p=  Conclusion  Our preliminary data suggests that the presence of  H. pylori  infection may promote a less pathogenic intestinal microbiome in patients with established IBD. This data provides the rationale to extend our studies with increased patient numbers and healthy controls to determine the mechanistic basis for the negative association of  H. pylori  infection and IBD.  Disclosure of Interest  None Declared
Effects of a Brief Educational Program on Optimization of Fluoroscopy to Minimize Radiation Exposure During Endoscopic Retrograde Cholangiopancreatography
Authors: Monique T Barakat, Nirav C Thosani, Robert J Huang, Abhishek Choudhary, Rajan Kochar, Shivangi Kothari, Subhas Banerjee
Journal: Clinical Gastroenterology and Hepatology (2017)
Dasatinib Compared with Imatinib In Newly Diagnosed Chronic Myelogenous Leukemia In Chronic Phase (CML-CP):Results of Japanese Subset Analysis In DASISION Trial.
Authors: Michinori Ogura, Hirohisa Nakamae, Shin Fujisawa, Kenichi Ishizawa, Masafumi Taniwaki, Atae Utsunomiya, Kosei Matsue, Kazuo Tamura, Kensuke Usuki, Mitsune Tanimoto, Yoji Ishida, Hideki Akiyama, Rika Sakai, Masanobu Kasai, Masayuki Hino, Kyoji Ueda, Taku Seriu, M. Brigid Bradley-Garelik, Chao Zhu
Journal: Blood (2010)
Abstract 19140: Prediction of Inotrope Initiation in Patients With Advanced Heart Failure
Authors: Ulrich P Jorde, Nadav Nahumi, Jason Han, Jimmy Duong, Shing Lee, Kerry A Morrison, Sunu S Thomas, Paolo Colombo, Melana Yuzefpolskaya, Arthur R Garan, Nir Uriel
Journal: Circulation (2013)

Introduction: It is now widely accepted that the need for inotropic therapy initiation in advanced heart failure (INTERMACS Class 3) in otherwise suitable patients constitutes the closing point of the ideal time window to initiate long term mechanical circulatory support. In this study, we sought to predict this time point. Hypothesis: Maximal exercise testing in conjunction with echocardiographic parameters can be used to objectively stratify a pts risk for inotrope dependence. Methods: We conducted a prospective study of pts in various stages of HF. Cardiopulmonary exercise testing and echocardiograms were performed at baseline, and the pts were followed for 48 months. The primary endpoint was inotrope initiation; secondary endpoints included LVAD implantation, heart transplantation, and death. Results: One hundred and thirty-five pts were enrolled. The mean pt age was 53 ± 13 years, 74% were male, and 34% had ischemic cardiomyopathy. The cohort was 15%, 40%, 45%, and NYHA Class I, II, and III respectively. Pts were followed for a median duration of 31 months (IQR: 16-46). Since enrollment, 19 pts (14.1%) have been initiated on inotrope therapy. Univariate predictors of inotrope dependence that were entered into the multivariable Cox model are: left ventricular ejection fraction, peak oxygen consumption, and heart rate reserve &gt;45%. The derived score predicts inotrope initiation within one year with a sensitivity of 78.6% and specificity of 73.7% (ROC curve AUC=0.82). Probability of inotrope initiation was well stratified by scoring quartiles. Conclusion: A simple score comprised of left ventricular ejection fraction, peak oxygen consumption, and heart rate reserve &gt;45% can help predict HF deterioration. Validation of a successful model which predicts time to inotrope use would be beneficial for appropriate timing of mechanical circulatory support.
08.10 Serum lipid and fatty acid profiles are altered in patients with polymyositis or dermatomyositis
Authors: Joan Raouf, Helena Idborg, Petter Olsson, Helene Alexanderson, Maryam Dastmalchi, Per-Johan Jakobsson, Ingrid E Lundberg, Marina Korotkova
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Polymyositis (PM) and dermatomyositis (DM) are chronic autoimmune diseases, characterised by muscle fatigue and low muscle endurance. Conventional treatment includes high doses of glucocorticoids and immunosuppressive drugs; however, few patients recover muscle function. We recently reported that immunosuppressive treatment affected the expression of genes related to lipid/fatty acid (FA) metabolism, suggesting altered lipid/FA-profiles in PM/DM patients. <h3>Objectives</h3> To analyse lipid and FA profiles in sera from patients with polymyositis or dermatomyositis in comparison to healthy individuals and relation to immunosuppressive treatment. <h3>Methods</h3> Serum samples were obtained from 13 patients with established PM or DM and 12 healthy individuals. The second cohort consisted of eight untreated patients diagnosed with definite PM or DM with available follow-up serum sample after eight months of immunosuppressive treatment. Functional Index 2 (muscle function) was assessed in the second cohort. Serum lipids were extracted by using liquid-liquid extraction. FA composition of total serum lipids was determined by gas chromatography provided with flame ionisation detector (GC-FID). FA composition of several lipid classes, e.g. triacylglycerols, phospholipids, sphingolipids, and lysophospholipids was analysed by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). <h3>Results</h3> The FA composition of total serum lipids was altered in myositis patients compared to healthy individuals; the levels of C16:0 acid was significantly higher in myositis patients whereas the levels of C20:4 (n-6) acid was significantly lower. The levels of serum lipid species within phosphatidylcholine (PC), lysophosphatidylcholine (LPC) and triacylglycerol (TG) were significantly changed in myositis patients compared to healthy individuals. Immunosuppressive treatment resulted in increased levels of C20:2 (n-6) acid and C20:5 (n-3) acid as well as changed serum PC, PE and LPC profiles in myositis patients. Furthermore, a positive correlation was observed between the Functional index and the levels of PC(38:4) in serum from patients after treatment. <h3>Conclusions</h3> FA composition of total serum lipids is altered in myositis patients compared to healthy controls. Immunosuppressive treatment resulted in changed FA composition of serum PC, PE, and LPC. These findings indicate that FA metabolism might be deregulated in PM and DM patients contributing to muscle inflammatory responses and loss of muscle function.
P132 Effects of resveratrol and a novel resveratrol-salicylate hybrid molecule on activation of human CD4+ T-cells
Authors: K Goldhahn, J Breitenbach, F Aldawsari, C Velazques-Martinez, B Kloesch, K Schmetterer, G Steiner
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Career situation of first and presenting author</h3> Student for a master or a PhD. <h3>Introduction</h3> T-cells are assumed to be crucially involved in the pathogenesis of systemic autoimmune diseases such as rheumatoid arthritis (RA). Consequently, substances modulating T-cell activation may have therapeutic benefit in RA and related rheumatic diseases. Resveratrol is a natural occuring polyphenol mainly produced in plants. The beneficial effects of resveratrol are due to its anti-inflammatory, anti-carcinogenic and anti-oxidant activities. <h3>Objectives</h3> To compare the effects of resveratrol and a novel resveratrol-salicylate hybrid molecule termed C-10 (Aldawsari FS <i>et al</i>, 2016) on human CD4<sup>+</sup> T-cells. <h3>Methods</h3> CD4<sup>+</sup> T-cells were isolated from healthy donors and pre-incubated with different concentrations of resveratrol or C-10 before being stimulated with anti-CD3/anti-CD28 antibodies. After 24 hour and 72 hour, respectively, cell culture supernatants were harvested and IL-2, IFN-γ and TNF-α release was quantified by ELISA. Proliferation rate was measured by thymidine incorporation. In addition, the up-regulation of the early activation markers CD25, CD69, CD71 and CD98 was analyzed and phosphorylation of signal transduction molecules were determined by western blot and/or flow cytometry. <h3>Results</h3> Inhibition of IL-2, IFN-γ and particularly TNF-α release was significantly more effective when the cells were treated with C-10 as compared to resveratrol. Moreover, the proliferation rate was significantly more decreased in the presence of C-10. The expression of CD25, CD69, CD71 and CD98hc was reduced to a similar degree by both compounds. Furthermore, phosphorylation of Akt and STAT-5 was substantially attenuated by C-10 and to a lesser degree also by resveratrol. All T cell subsets investigated (Th1, Th2, Th17) were affected at a similar degree but the most pronounced effect was seen in naïve T cells. <h3>Conclusions</h3> Our data demonstrate that C-10 suppressed cytokine secretion and proliferation more effectively than resveratrol. Both compounds influence the phosphorylation of important signalling molecules. The effect exerted on STAT-5 activation may be the key mechanism for inhibition of T cell activation. Thus, the resveratrol-salicylate hybrid molecule C-10 might be considered a candidate drug for treatment of RA and other T-cell driven autoimmune diseases. <h3>Reference</h3> Aldawsari FS, Aguiar RP, Wiirzler LA, Aguayo-Ortiz R, Aljuhani N, Cuman RK, Medina-Franco JL, Siraki AG, Velázquez-Martínez CA. Anti-inflammatory and antioxidant properties of a novel resveratrol-salicylate hybrid analog. <i>Bioorg Med Chem Lett.</i> 2016 Mar 1;26(5):1411–5. <h3>Disclosure of Interest</h3> None declared.
DNA Repair Dysfunction in Pancreatic Cancer: A Clinically Relevant Subtype for Drug Development
Authors: Talia Golan, Milind Javle
Journal: Journal of the National Comprehensive Cancer Network (2017)

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, with a 5-year survival rate of ≤7% across all stages. The limited success of conventional therapies for PDAC is at least partially attributable to its genetic heterogeneity. Precision targeting of known PDAC subtypes may positively affect the outcome of this disease. An important actionable subtype in this cancer is associated with DNA repair dysfunction, including cases with germline BRCA mutations. This subtype can be targeted by inhibitors of poly(ADP-ribose) polymerase (PARP). BRCA mutation–associated PDAC may be the first biomarker-driven subtype in this disease that can be successfully targeted. However, DNA repair defects can extend beyond the narrow spectrum of BRCA1/2 mutations in PDAC and are present in a large proportion of patients with familial PDAC. This review describes the subgroup of patients with PDAC with aberrant DNA repair and discusses diagnostic and therapeutic options.
04.20 Oxidative stress alters cellular bioenergetics in inflammatory arthritis
Authors: Monika Biniecka, Emese Balogh, Aisling Kennedy, Chin T Ng, Douglas J Veale, Ursula Fearon
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Hypoxia and oxidative stress are involved in mediating angiogenic processes in the inflamed synovial tissue. In this study we examine the expression of angiogenic markers in inflammatory arthritis and the effects of tumour necrosis factor alpha inhibitors (TNFi) on angiogenesis in relationship to synovial hypoxia <i>in vivo</i> and oxidative stress<i>. In vitro</i> oxidative stress-induced angiogenic responses are also investigated. <h3>Materials and methods</h3> 44 IA patients pre/post-TNFi underwent knee joint arthroscopy and <i>in vivo</i> oxygen levels (tpO<sub>2</sub>) were measured. Expression of angiogenic growth factors in paired serum, synovial fluid and synovial tissue was accessed by ELISA and immunohistochemistry. Pro-angiogenic processes, mitochondrial function and metabolism were assessed in RA Synovial Fibroblast Cells (RASFCs) and Human Microvascular Endothelial Cells (HMVECs) under normoxia or 3% hypoxia in the presence of oxidative stress inducer - 4-HNE using the tube formation and invasion assays and the XFe Extracellular Flux Seahorse Analyzer. <h3>Results</h3> VEGF and Ang2 were expressed in the joint synovial fluid and Ang1 and PDGF-B were expressed at a systemic level. The highest synovial tissue (ST) VEGF, Ang2 and Tie2 positivity was observed in vascular region compared to lining and sublining layers (all p&lt;0.05). Significant reduction in synovial vascularity and ST Ang2/Tie2 expression, paralleled by an increase in <i>in vivo</i> tpO<sub>2</sub> was found after TNFi (all p&lt;0.05). ST oxidative stress expression (8-oxo-dG and 4-HNE) was colocalized with VEGF, Ang2 and Tie2 and showed an association pre/post anti TNF-α therapy. <i>In vitro</i> 4-HNE promoted RASFCs secretion of pro-angiogenic mediators, ROS production, and cell proliferation (all p&lt;0.05). In HMVECs 4-HNE elevated angiogenic tube-formation and cell invasiveness (all p&lt;0.05), effects that were further potentiated by 3% hypoxia. Furthermore, 4-HNE significantly increases glycolytic activity of RASFC and HMVECs with concomitant attenuation of mitochondrial respiration. <h3>Conclusions</h3> Differential local and systemic expression of angiogenic factors may indicate a constant remodelling of synovial vasculature. Reduced levels of Ang2 and Tie2 following TNFi demonstrate a relationship between angiogenesis, hypoxia and TNFα pathway. Redox signalling can alter angiogenic responses of synovial cells. Oxidative stress alters cellular bioenergetics by promoting switch to glycolysis mitochondrial respiration supporting cellular invasion and dysregulated angiogenesis.
Regulating cancer associated fibroblasts with losartan-loaded injectable peptide hydrogel to potentiate chemotherapy in inhibiting growth and lung metastasis of triple negative breast cancer
Authors: Chunhua Hu, Xiaoyu Liu, Wei Ran, Jia Meng, Yihui Zhai, Pengcheng Zhang, Qi Yin, Haijun Yu, Zhiwen Zhang, Yaping Li
Journal: Biomaterials (2017)
Abstract 20276: Variants in the CDNK2B Gene on Chromosome 9p21 are Associated with Coronary Artery Disease Events in African American High Risk Families
Authors: Rasika A Mathias, Brian Kral, Bhoom Suktitipat, Hilma Holm, Lisa Yanek, Ingo Ruczinski, Dhananjay Vaidya, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Kari Stefansson, Arshed Quyyumi, Riyaz Patel, Maziar Zafari, Viola Vaccarino, Svati Shah, Christopher Granger, Jeffrey Gulcher, Lewis Becker, Diane Becker
Journal: Circulation (2010)

Background: A 58kb region on chromosome 9p21.3 region has consistently shown strong association with coronary artery disease (CAD) in multiple genome-wide association studies in populations of European and East Asian ancestry. In this study we sought to further characterize the role of genetic variants in 9p21.3 with incident CAD in African American individuals with a strong genetic predisposition for CAD. Methods and Results: Apparently healthy African American siblings (N=548) of patients with documented CAD <60 years of age were genotyped and followed for incident CAD for up to 17 years. There were 35 total CAD events (sudden death (n=1); MI (n=9); unstable or stable angina with revascularization (n=17); unstable or stable angina with no revascularization (n=8)) in African Americans at an average follow-up of 8.1 ±3 years range 5 to 17 years). Tests for association of 99 SNPs across the 9p21.3 region in a GEE logistic framework under an additive model, adjusting for multiple traditional risk factors fo...