tbuckley/cabot-search huggingface dataset:
Comparison of the inhibition potentials of icotinib and erlotinib against human UDP-glucuronosyltransferase 1A1
Authors: Xuewei Cheng, Xia Lv, Hengyan Qu, Dandan Li, Mengmeng Hu, Wenzhi Guo, Guangbo Ge, Ruihua Dong
Journal: Acta Pharmaceutica Sinica B (2017)

UDP-glucuronosyltransferase 1A1 (UGT1A1) plays a key role in detoxification of many potentially harmful compounds and drugs. UGT1A1 inhibition may bring risks of drug–drug interactions (DDIs), hyperbilirubinemia and drug-induced liver injury. This study aimed to investigate and compare the inhibitory effects of icotinib and erlotinib against UGT1A1, as well as to evaluate their potential DDI risks via UGT1A1 inhibition. The results demonstrated that both icotinib and erlotinib are UGT1A1 inhibitors, but the inhibitory effect of icotinib on UGT1A1 is weaker than that of erlotinib. The IC50 values of icotinib and erlotinib against UGT1A1-mediated NCHN-O-glucuronidation in human liver microsomes (HLMs) were 5.15 and 0.68 μmol/L, respectively. Inhibition kinetic analyses demonstrated that both icotinib and erlotinib were non-competitive inhibitors against UGT1A1-mediated glucuronidation of NCHN in HLMs, with the Ki values of 8.55 and 1.23 μmol/L, respectively. Furthermore, their potential DDI risks via UGT1A1 inhibition were quantitatively predicted by the ratio of the areas under the concentration–time curve (AUC) of NCHN. These findings are helpful for the medicinal chemists to design and develop next generation tyrosine kinase inhibitors with improved safety, as well as to guide reasonable applications of icotinib and erlotinib in clinic, especially for avoiding their potential DDI risks via UGT1A1 inhibition.
Evaluation of Immune Mechanisms to Understand Idelalislib-Associated Diarrhea-Colitis
Authors: Richard R. Furman, Michael Hallek, Jeffrey P. Sharman, Peter Hillmen, Andrew D. Zelenetz, Ian W. Flinn, Wojciech Jurczak, Veerendra Munugalavadla, Yuanyuan Xiao, Lianqing Zheng, Arati V. Rao, Lyndah K. Dreiling, Gilles A. Salles, Susan M. O'Brien
Journal: Blood (2016)
FRI0595 Epidemiology and complications of hospitalized patients with adult onset still's disease in united states: a nationwide estimate
Authors: B Mehta, W Briggs, P Efthimiou
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> There is a dearth of epidemiological studies in the US and worldwide on Adult Onset Still9s Disease (AOSD). Currently, there is no consensus on its incidence and prevalence in different populations. Most studies report a majority of patients below the age of 35.[1] <h3>Objectives</h3> To describe the demographics, complications and mortality of hospitalized patients with AOSD in United States. <h3>Methods</h3> All adult (&gt;18 years) hospitalized patients in 2013 from a nationwide inpatient sample (NIS) database were captured. AOSD patients were identified using the ICD-9 code 714.2 that was in use in 2013. Patients also coded for Rheumatoid Arthritis, Lupus, Myositis, Polymyalgia Rheumatica, Ankylosing Spondylosis and Psoriatic Arthritis were excluded. This was done in order to truly capture patients with strictly AOSD. NIS is the largest all- payer inpatient care database in the United States with approximately 8 million hospitalizations each year. Discharge weights were used to enable nationwide estimates. Descriptive statistics were represented as means/medians for continuous and as frequencies and percentages for categorical variables. <h3>Results</h3> In 2013, 1410 US patients were coded with the ICD-9 code 714.2 and, after excluding concomitant rheumatic disease diagnoses as per protocol, 1265 AOSD patients were analyzed. AOSD patients had a mean age of 53.8 (SD - 18.1) years and a median age of 54 years. 70.4% were females. The racial/ethnic distribution showed that 61.6% white, 13.9% African American and 17.3% Hispanic patients were affected. 56.9% were hospitalized in urban teaching hospitals. The Mid-Atlantic census division had the highest number of patients – 240 (Figure). 35 (2.8%) of patients developed Macrophage Activating Syndrome (MAS). 30 (2.4%) patients had other severe complications of AOSD like disseminated intravascular coagulation (DIC) and thrombotic thrombocytopenic purpura (TTP). Median length of stay was 4 days and median hospital charges were $31,400 (Table). There were 35 inpatient deaths (mortality 2.8%): 71.4% of deaths were in females, 50% in Asians, and 71.4% were in patients in the 54- 67 age group. <h3>Conclusions</h3> In hospitalized American AOSD patients, the average age was higher than previously thought. This may indicate an aging population with a higher number of comorbidities that justify hospitalization. Mortality increased with age and was higher among women and Asians. To our knowledge, this is the largest epidemiological study of AOSD today in the USA. <h3>References</h3> Sakata N, Shimizu S, Hirano F, Fushimi K. Epidemiological study of adult-onset Still9s disease using a Japanese administrative database. Rheumatol Int 2016;36(10):1399–405 doi: 10.1007/s00296–016–3546–8. <h3>Disclosure of Interest</h3> None declared
NF-κB regulates GDF-15 to suppress macrophage surveillance during early tumor development
Authors: Nivedita M Ratnam, Jennifer M Peterson, Erin E Talbert, Katherine J Ladner, Priyani V Rajasekera, Carl R Schmidt, Mary E Dillhoff, Benjamin J Swanson, Ericka Haverick, Raleigh D Kladney, Terence M Williams, Gustavo W Leone, David J Wang, Denis C Guttridge
Journal: Journal of Clinical Investigation (2017)

Macrophages are attracted to developing tumors and can participate in immune surveillance to eliminate neoplastic cells. In response, neoplastic cells utilize NF-κB to suppress this killing activity, but the mechanisms underlying their self-protection remain unclear. Here, we report that this dynamic interaction between tumor cells and macrophages is integrally linked by a soluble factor identified as growth and differentiation factor 15 (GDF-15). In vitro, tumor-derived GDF-15 signals in macrophages to suppress their proapoptotic activity by inhibiting TNF and nitric oxide (NO) production. In vivo, depletion of GDF-15 in Ras-driven tumor xenografts and in an orthotopic model of pancreatic cancer delayed tumor development. This delay correlated with increased infiltrating antitumor macrophages. Further, production of GDF-15 is directly regulated by NF-κB, and the colocalization of activated NF-κB and GDF-15 in epithelial ducts of human pancreatic adenocarcinoma supports the importance of this observation. Mechanistically, we found that GDF-15 suppresses macrophage activity by inhibiting TGF-β–activated kinase (TAK1) signaling to NF-κB, thereby blocking synthesis of TNF and NO. Based on these results, we propose that the NF-κB/GDF-15 regulatory axis is important for tumor cells in evading macrophage immune surveillance during the early stages of tumorigenesis.
Stop bombarding public with offers of bigger portions, say campaigners
Authors: Jacqui Wise
Journal: BMJ (2017)

The average consumer is asked 106 times a year whether he or she would like to upgrade to a larger drink or meal, buy a supersize bar of chocolate at the checkout, or add an unhealthy side order or topping, a report has found.1

The report, from the Royal Society for Public Health and the weight loss organisation Slimming World, said that the “drip-drip effect” of this verbal upselling means that the average person consumes an additional 330 calories a week—17 000 extra calories a year—potentially leading to weight gain of 5 …
AB1091 High acceptance rate in RA, as and PSA patients when being started on biosimilar TNF or being switched from the original TNF MAB (REMICADE, ENBREL) - a single center experience
Authors: H Kellner
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Biiosimilar TNF Mab (BioTNF) have become available in most of the European countries in the last few years. They are labeled to be used in the most common rheumatic diseases, like RA, AS and PsA. Controlled studies have shown comparable efficacy and safety of BioTNF and original TNF (Remicade, Enbrel). BioTNF are allowed to be used in TNF naive patients as well as in TNF pretreated patients (switchers). Prescriptions in different countries may vary due to local most often cost driven restrictions. So far, little is known about the awareness, acceptance and possible obstacles which may influence patients willingness to accept therapy with BioTNF instead using the original compounds <h3>Objectives</h3> The study was conducted and designed to get a deeper insight in what may influence patients decision making and willingness to accept treatment with BioTNF firsthand or accept switching. <h3>Methods</h3> Between February 2015 and December 2016 41 patients (BioINF n=29, BioETA n=12) were introduced to BioTNF therapy. 9 Patients (Bio-INF n=3, Bio-ETA n=6) received TNF therapy the first time, in 32 patients (Remicade n=23, ETA n=8) werde switched from the originator TNF compound to BioTNF. All patients received comprrehensive information on BioTNF in verbal and written form. A standardised questionaire was used to ask patients on their awareness, acceptance and about possible obstacles for the usage of BioiTNF Mab. <h3>Results</h3> 6 out of 9 TNF naive patients agreed after their first information on BioTNF to start therapy with BioINF (n=3) or BioETA (n=3). Another 2 patients accepted BioETA therapy on their second visite. Only one patients asked to be started on the originator TNF Remicade. In patients being ask to switch from Remicade to BioINF 19 patients accepted promptly to be switch and in patients with Enbrel therapy 6 out of 9. Finally only 1 patient on Remicade TNF therapy denied even after a third visit to be switched. Mayor concern to deny the use of BioTNF were possible lack of efficacy (30%), safety (32%) and missing longterm experience (35%). The main motivation to switch was patients believe to save money and that they were ask to switch to BioTNF Mab on short notice from their health care insurance company. <h3>Conclusions</h3> There is a high acceptance rate in patients with chronic inflammatory rheumatic disease to be started on or switched to BioTNF (&gt;90%). Their are little concerns in patients accepting BioTNF with regard to safety or efficacy of BioTNF. Patients are aware of BioTNF as a less costly way to treat their rheumatic condition. Physicians should be aware of this willingness and offer BioTNF therapy were it is appropriate. Using BioTNF is a cost saving way to use biologics in rheumatic therapy with equal efficacy and safety compared to the originiator compounds. <h3>Disclosure of Interest</h3> None declared
Abstract 10647: Importance of Volumetric Analysis as an Indicator of Left Ventricular Remodeling in Patients with Chronic Severe Mitral Regurgitation
Authors: Chun G Schiros, Donald Clark, James D Gladden, Himanshu Gupta, Steven G Lloyd, David C McGiffin, Thomas S Denney, Louis J Dell'Italia, Mustafa I Ahmed
Journal: Circulation (2011)

Background: The timing of surgery for patients with severe chronic mitral regurgitation (MR) remains controversial. Despite current guideline recommendations, postoperative left ventricular (LV) dy...
Unsupervised primaquine for the treatment of Plasmodium vivax malaria relapses in southern Papua: A hospital-based cohort study
Authors: Nicholas M. Douglas, Jeanne Rini Poespoprodjo, Dewi Patriani, Michael J. Malloy, Enny Kenangalem, Paulus Sugiarto, Julie A. Simpson, Yati Soenarto, Nicholas M. Anstey, Ric N. Price
Journal: PLoS Medicine (2017)

Primaquine is the only licensed drug for eradicating Plasmodium vivax hypnozoites and, therefore, preventing relapses of vivax malaria. It is a vital component of global malaria elimination efforts. Primaquine is efficacious when supervised in clinical trials, but its effectiveness in real-world settings is unknown. We aimed to determine whether unsupervised primaquine was effective for preventing re-presentation to hospital with vivax malaria in southern Papua, Indonesia.Routinely-collected hospital surveillance data were used to undertake a pragmatic comparison of the risk of re-presentation to hospital with vivax malaria in patients prescribed dihydroartemisinin-piperaquine (DHP) combined with primaquine versus those patients prescribed DHP alone. The omission of primaquine was predominantly due to 3 stock outages. Individual clinical, pharmacy, and laboratory data were merged using individual hospital identification numbers and the date of presentation to hospital. Between April 2004 and December 2013, there were 86,797 documented episodes of vivax malaria, of which 62,492 (72.0%) were included in the analysis. The risk of re-presentation with vivax malaria within 1 year was 33.8% (95% confidence Interval [CI] 33.1%-34.5%) after initial monoinfection with P. vivax and 29.2% (95% CI 28.1%-30.4%) after mixed-species infection. The risk of re-presentation with P. vivax malaria was higher in children 1 to <5 years of age (49.6% [95% CI 48.4%-50.9%]) compared to patients 15 years of age or older (24.2% [95% CI 23.4-24.9%]); Adjusted Hazard Ratio (AHR) = 2.23 (95% CI 2.15-2.31), p < 0.001. Overall, the risk of re-presentation was 37.2% (95% CI 35.6%-38.8%) in patients who were prescribed no primaquine compared to 31.6% (95% CI 30.9%-32.3%) in those prescribed either a low (≥1.5 mg/kg and <5 mg/kg) or high (≥5 mg/kg) dose of primaquine (AHR = 0.90 [95% CI 0.86-0.95, p < 0.001]). Limiting the comparison to high dose versus no primaquine in the period during and 12 months before and after a large stock outage resulted in minimal change in the estimated clinical effectiveness of primaquine (AHR 0.91, 95% CI 0.85-0.97, p = 0.003). Our pragmatic study avoided the clinical influences associated with prospective study involvement but was subject to attrition bias caused by passive follow-up.Unsupervised primaquine for vivax malaria, prescribed according to the current World Health Organization guidelines, was associated with a minimal reduction in the risk of clinical recurrence within 1 year in Papua, Indonesia. New strategies for the effective radical cure of vivax malaria are needed in resource-poor settings.
Oral Cancer and Mouthwash Use
Authors: R. G. Newcombe, Ph.D., T. M. Arendorf, B.D.S., M. Med. Sci.
Journal: JNCI Journal of the National Cancer Institute (1983)

Oral Cancer and Mouthwash Use Get access R. G. Newcombe, Ph.D., R. G. Newcombe, Ph.D. Lecturer Department of Medical Statistics University of Wales Welsh National School of Medicine Health ParkCardiff, CF4 4XN, Wales Search for other works by this author on: Oxford Academic PubMed Google Scholar T. M. Arendorf, B.D.S., M. Med. Sci. T. M. Arendorf, B.D.S., M. Med. Sci. Researrh Fellow Oral Medicine and Oral Pathology Welsh National School of Medicine Health ParkCardiff, CF4 4XN, Wales Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 71, Issue 6, December 1983, Pages 1103–1104, https://doi.org/10.1093/jnci/71.6.1103 Published: 01 December 1983
Abstract 62: Preserved Cerebral Microcirculation After Cardiac Arrest in an Asphyxial Rat Model
Authors: Niels Secher, Frederik B Hansen, Else Tønnesen, Leif østergaard, Asger Granfeldt
Journal: Circulation (2014)

Introduction: Cardiac arrest (CA) carries a dismal prognosis, mainly due to neurological injury. Studies have reported dysfunction of the sublingual microcirculation following cardiac arrest. The objective of the study was to investigate if this microcirculatory dysfunction is also present in the brain after cardiac arrest. Methods: Anesthetized, intubated, and ventilated, male Sprague-Dawley rats were randomized into two CA groups and two control groups and observed for 120 min or 360 min following return of spontaneous circulation (CA120min (n=8), Control120min (n=8), CA360min (n=8), and Control360min (n=8)). After ten minutes of ashpyxial induced CA animals were resuscitated using adrenalin and manual CPR. At the end of the observation period, cerebral microcirculation was evaluated by side stream dark field microscopy through a parietal craniotomy, and plasma samples were drawn for endothelial adhesion molecule and inflammatory marker analyses. Animals were monitored with invasive blood pressure, ECG and arterial blood gas samples throughout the study. Results: At the end of the observation period mean arterial pressure decreased significantly in the cardiac arrest groups being 55±12mmHg in the CA120min group and 51±9mmHg in the CA360min group compared to 85±8mmHg in the control groups, whereas PaCO2 was kept in the normal range and did not differ between groups. There was no difference between groups for total vessel density, perfused vessel density, proportion of perfused vessels, or microvascular flow index measured in the cerebral cortex. Plasma samples drawn 360 min after return of spontaneous circulation showed a significant increase in E-selectin, L-selectin, I-CAM1, IL-1β, IL-6, IL-10 and elastase compared to controls. Between the CA groups E-selectin and elastase showed an increase from 120 to 360 min after resuscitation (p&lt;0.007). Conclusion: Despite a significantly lower mean arterial pressure and elevated levels of soluble endothelial adhesion molecules and inflammatory cytokines, side stream dark field revealed no changes in the cerebral microcirculation in the early post resuscitation period.
Tiotropium in Early-Stage Chronic Obstructive Pulmonary Disease
Authors: Yumin Zhou, Nan-shan Zhong, Xiaochen Li, Shuyun Chen, Jinping Zheng, Dongxing Zhao, Weimin Yao, Rongchang Zhi, Liping Wei, Bingwen He, Xiangyan Zhang, Changli Yang, Ying Li, Fenglei Li, Juan Du, Jianping Gui, Bin Hu, Chunxue Bai, Ping Huang, Gang Chen, Yongjian Xu, Changzheng Wang, Biao Liang, Yinhuan Li, Guoping Hu, Hui Tan, Xianwei Ye, Xitao Ma, Yan Chen, Xiwei Hu, Jia Tian, Xiaodan Zhu, Zhe Shi, Xiufang Du, Minjing Li, Shengming Liu, Ronghuan Yu, Jianping Zhao, Qianli Ma, Canmao Xie, Xiongbin Li, Tao Chen, Yingxiang Lin, Lizhen Zeng, Changxiu Ye, Weishu Ye, Xiangwen Luo, Lingshan Zeng, Shuqing Yu, Wei-jie Guan, Pixin Ran
Journal: New England Journal of Medicine (2017)

Patients with mild or moderate chronic obstructive pulmonary disease (COPD) rarely receive medications, because they have few symptoms. We hypothesized that long-term use of tiotropium would improve lung function and ameliorate the decline in lung function in patients with mild or moderate COPD.
Government pledges strong research links with EU after Brexit
Authors: Anne Gulland
Journal: BMJ (2017)

UK scientists have cautiously welcomed the government’s pledge to maintain close links with European research institutions after Brexit.

A paper from the Department for Exiting the European Union,1 setting out the government’s approach to collaboration in science and innovation as it negotiates its exit from the EU, acknowledges the strong links between UK researchers and those in the rest of the Europe.

It says that the UK will “continue to be involved in major scientific endeavours in Europe and across the world,” building on its “special relationship” with the EU.

After the UK leaves the EU it will no longer be a member of the drugs regulator the European Medicines Agency, which has left many scientists worrying that …
AB0070 Chondroprotective effects linked to reduction of adipogenesis and regulation of gap junction intercellular communication: regenerative potential therapeutic approach for osteoarthritis
Authors: M Varela Eirin, A Casado-Díaz, J Loureiro, JR Caeiro, JM Quesada-Gόmez, MD Mayán
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Human bone marrow mesenchymal stem cells (hMSCs) exhibit an age-dependent reduction in osteogenesis and an increased propensity toward adipocyte differentiation. This switch has been associated with different bone disorders characterized by reduced bone formation and increased bone marrow fat accumulation. Connexin43 (Cx43) is an integral membrane protein that forms gap junction channels (GJs) and it is implicated in multiple cellular functions including cellular differentiation and control of bone remodelling and cartilage structure and function. <h3>Objectives</h3> In this study we investigated the effect of oleuropein and other molecules isolated from the <i>Olea europaea</i> in cellular differentiation to test if these molecules act as adipogenic suppressors in order to promote bone ad cartilage regeneration through a Cx43-dependent mechanism. <h3>Methods</h3> hMSCs were obtained from bone marrow donors. Human chondrocytes were isolated from cartilage of healthy donors and patients with osteoarthritis (OA). Differentiation assays were carried out in the presence of different concentrations of oleuropein and olive extract (OE). Cellular differentiation was evaluated using histological stains. Scrape loading assays, western-blot, real-time qPCR and immunohistochemistry (IHC) assays were used to study the cellular communication through gap junction (GJs) and the levels and changes in subcellular localization of Cx43 and extracellular matrix (ECM) proteins such as Collagen type II (Col2). <h3>Results</h3> hMSCs treated with olive derived molecules showed a two-fold decrease in adipogenic differentiation, while osteogenesis and chondrogenesis were significantly increased. IHC, RT-qPCR and Western-Bot analysis of hMSCs supplemented with oleuropein/OE showed increased levels of Cx43. On the other hand, OA chondrocytes showed higher levels of Cx43 in comparison with normal chondrocytes; oleuropein and OE treatments significantly decreased Cx43 levels and dye transference through GJ channels. The treatment of OA chondrocytes micromasses with oleuropein and OE increased the levels of proteoglycans and Col2 in the extracellular matrix. These changes in the micromasses were accompanied by a decrease in Cx43 levels improving protein subcellular localization. <h3>Conclusions</h3> Together, our results suggest that the molecules used in this assays, via Cx43 and GJ intercellular communication increase the propensity towards osteogenesis and chondrogenesis, reducing adipocyte differentiation. Our assays indicate that these molecules may represent a potential therapeutic approach for cartilage and bone age-related disorders such as OA in order to promote cartilage regeneration. <h3>Disclosure of Interest</h3> None declared
A Century of Progressing and Advancing Reproductive Health Care
Authors: Cecile Richards
Journal: JAMA (2017)

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