tbuckley/cabot-search huggingface dataset:
Abstract 18994: Independent and Combined Effect of Heart Failure and Renal Dysfunction on One-year Mortality in Patients with Acute Myocardial Infarction
Authors: Daisaku Nakatani, Yasuhiko Sakata, Shinichiro Suna, Masaya Usami, Masaya Usami, Sen Matsumoto, Masahiko Hara, Toshimitsu Hamasaki, Yoshio Yasumura, Yasunori Ueda, Hiroshi Sato, Msatsugu Hori, Shinsuke Nanto, Issei Komuro
Journal: Circulation (2012)

Background: A concept of cardio-renal syndrome has been proposed in clinical practice setting. Little is known whether there exist independent and combined effect of heart failure (HF) and renal dysfunction (RD) in patients with acute myocardial infarction (AMI) in the contemporary era. Methods: A total of 4,700 patients with AMI who were registered to the Osaka Acute Coronary Insufficiency Study (OACIS) were studied. Patients were divided based on Killip classification (I, II, III and IV) and estimated glomerular filtration rate (eGFR) with 4 categories (CKD 1,2,3 and 4/5) on admission. One-year mortality rate and risk were compared using log-rank test and Cox regression hazard model. Results: Ninety-one % of patients received reperfusion therapy. There was a linear relationship between both HF (3.7%, 15.2%, 32.7% and 43.0% for Killip I, II, III and IV, P&lt;0.001) and RD (1.2%, 3.4%, 13.6% and 32.5% for CKD 1,2,3 and 4/5, P&lt;0.001) with 1-year mortality rate, respectively. Patients with both Killip IV and CKD4/5 had highest mortality rate of 57.6% and risk with a 27-fold higher compared to those with Killip I and CKD 1 (P&lt;0.001) (shown in figures). Conclusions: In the contemporary reperfusion era, there exists independent and combined effect of HF and RD on 1-year mortality in patients with AMI. Explorations of novel adjunctive strategies to reduce mortality will be needed for AMI complicated with each or both HF and RD.
PTH-077 Vedolizumab in the real world: a tertiary centre experience
Authors: C Manning, S Chan, M Tremelling, R Tighe
Journal: Gut (2017)

Introduction  Vedolizumab is a gut selective α4β7 integrin antibody licenced for treatment of moderate to severe inflammatory bowel disease (IBD) in patients not responding or intolerant to immunomodulators or TNF-alpha antagonists. It has been shown to be effective at induction and maintenance of remission, with a good safety profile[1]. As it is increasingly used in clinical practice we wanted to confirm its effectiveness and safety in our cohort of patients.  Method  IBD patients receiving Vedolizumab at Norfolk & Norwich University Hospital from March 2015 to January 2017 were identified. Details of IBD diagnosis, previous treatments, therapy duration, clinical response and remission were obtained by case notes review.  Results  53 IBD patients (26 male, 27 female) were identified; 27 with Crohn’s, 26 with ulcerative colitis (UC). 18 have since stopped Vedolizumab, while 35 continue. 16 patients received a concomitant immunomodulator. 9 patients were anti-TNF naive, 44 previously failed anti-TNF therapy.  41 patients (77%) showed initial response to treatment (20 Crohn’s, 21 UC). 7 patients (13%) were primary non-responders and stopped therapy. 2 patients stopped therapy within 1 month due to side effects. 3 patients have been treated for less than 2 months and it is too early to assess response. Of the 41 initial responders, 5 subsequently stopped due to loss of response, and 1 had to stop due to side effects. A further 3 received treatment during a clinical trial and stopped therapy when funding was withdrawn despite maintained remission.  32 patients remain in clinical response on Vedolizumab since initiation (60%). 12 of these patients are in clinical remission. 3 additional patients are on treatment but yet to show response, pending further assessment. Longest treatment period is currently 20 months, with mean duration of 7 months.  While response rates are broadly similar between UC and CD, 21 (81%) and 20 (74%) respectively, in this panel Crohn’s patients have a higher remission rate; with 10 patients currently maintaining remission (36%) compared to 2 UC patients (8%). This is probably related to treatment duration (mean duration of 10 months in Crohn’s compared to 5 months for UC).  Vedolizumab has been well tolerated in our cohort, with only 3 patients (6%) developing side effects (listeria infection, perianal sepsis, and chronic cough).  Conclusion  These results confirm that Vedolizumab is a safe and effective treatment for IBD patients intolerant of or unresponsive to immunomodulators/anti-TNF therapy, or where these are contra-indicated. A majority of our patients have shown response to treatment and 12 (23%) achieved sustained remission with a very low incidence of side effects.  Reference  . Sandborn WJet al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med 2013;369:711–721.  Disclosure of Interest  None Declared
Abstract 9928: Reversal of Anticoagulant Activity of Dabigatran and Dabigatran-induced Bleeding in Rats by a Specific Antidote (Antibody Fragment)
Authors: Joanne van Ryn, Tobias Litzenburger, Johanna Schurer
Journal: Circulation (2012)

Dabigatran etexilate (DE) is the prodrug of dabigatran, a direct potent thrombin inhibitor, approved as an alternative to warfarin for prevention of strokes in patients with atrial fibrillation. However, as with any anticoagulant, bleeding risks are associated with its use. Though there is no specific antidote available, an antibody fragment (Fab) against dabigatran is currently in development to neutralize its activity. Inhibition of dabigatran and its metabolites was tested in vitro using a diluted thrombin time assay. The ability of the Fab alone to induce coagulation was tested in various assays in human plasma including endogenous thrombin potential (ETP, 5 pM tissue factor) and ecarin chromogenic assay (ECA). Dabigatran etexilate (DE), 30 mg/kg was given orally to rats every 8 hrs to achieve supratherapeutic levels of dabigatran and induce bleeding in a rat tail bleeding model. 45 min after the last dose increasing i.v. Fab doses were given to test for bleeding reversal. Ex vivo clotting and plasma levels of dabigatran and Fab were measured. The Fab potently binds dabigatran (Kd 2 pM). Anticoagulant activity of dabigatran and its metabolites was inhibited with an IC 50 of 3.5 and 2.0 nM in human plasma. Fab had no effect on thrombin generation (ETP, 0.89-fold of control), in contrast FEIBA resulted in ∼2-fold increase in ETP. ECA was not elevated with Fab vs control. DE (30 mg/kg p.o.) was given in 8 hr intervals to achieve steady state levels in the rat, with supratherapeutic plasma levels (1500 nM or ~750 ng/mL). This resulted in ~2-fold increase in tail cut bleeding time. There was a rapid, dose-dependent decrease in blood loss after i.v. injection of Fab, which was maintained for 6 hrs after the highest dose of Fab. aPTT, TT and ECT were all reversed. Treating rats with warfarin (0.5 mg/kg p.o.) over 3 days resulted in a 2-fold elevation of blood loss. Similar doses of Fab had no effect on reversing this elevated blood loss. These data show the specificity and selectivity of the antibody fragment for dabigatran. Administration of the Fab after DE resulted in a safe and rapid reversal of blood loss, which correlated with reversal of ex vivo clotting tests. Thus this agent holds promise for reversing dabigatran-induced anticoagulation and bleeding effects.
Mechanistic/mammalian target of rapamycin: Recent pathological aspects and inhibitors
Authors: Mohammed S. Abdel‐Maksoud, Mohammed I. El‐Gamal, Dalia Reyane Benhalilou, Sandy Ashraf, Shatha Abdulghaffar Mohammed, Chang‐Hyun Oh
Journal: Medicinal Research Reviews (2018)

Abstract The mechanistic/mammalian target of rapamycin (mTOR), also known as the mechanistic target of rapamycin, regulates many normal cell processes such as transcription, cell growth, and autophagy. Overstimulation of mTOR by its ligands, amino acids, sugars, and/or growth factors leads to physiological disorders, including cancer and neurodegenerative diseases. In this study, we reviewed the recent advances regarding the mechanism that involves mTOR in cancer, aging, and neurodegenerative diseases. The chemical and biological properties of recently reported small molecules that function as mTOR kinase inhibitors, including adenosine triphosphate‐competitive inhibitors and dual mTOR/PI3K inhibitors, have also been reviewed. We focused on the reports published in the literature from 2012 to 2017.
Medical records were destroyed in infected blood cover-up, inquiry hears
Authors: Clare Dyer
Journal: BMJ (2018)

The UK government engaged in a cover-up and in some cases the NHS altered or destroyed the medical records of patients who received blood products infected with HIV and hepatitis C in the 1970s and 1980s, the public inquiry into the saga was told in a preliminary hearing.

Lawyers representing core participants affected by the use of contaminated blood or blood products outlined the allegations as the first UK-wide public inquiry into the matter with power to compel witnesses opened for a three day initial hearing.

In what has been described as the worst treatment disaster in the NHS, thousands of people with haemophilia and others received blood products infected with the viruses. For several years after …
The role of flavonoids in autoimmune diseases: Therapeutic updates
Authors: Kannan R.R. Rengasamy, Haroon Khan, Shanmugaraj Gowrishankar, Ricardo J.L. Lagoa, Fawzi M. Mahomoodally, Ziyad Khan, Shanoo Suroowan, Devesh Tewari, Gokhan Zengin, Sherif T.S. Hassan, Shunmugiah Karutha Pandian
Journal: Pharmacology & Therapeutics (2018)
Abstract 12888: Tissue Inhibitor of Metalloproteinase-3 Knockout Mice Exhibit Enhanced Energy Expenditure through Thermogenesis
Authors: Yohsuke Hanaoka, Osamu Yasuda, Hirofumi Soejima, Keishi Miyata, Eiichiro Yamamoto, Keisuke Fukuo, Hiromi Rakugi, Yuichi Oike, Shokei K Mitsuyama, Hisao Ogawa
Journal: Circulation (2013)

Objective: Tissue inhibitors of metalloproteinases (TIMPs) regulate matrix metalloproteinase activity and maintain extracellular matrix homeostasis. TIMP-3 is unique among TIMPs in that it is bound...
SEIZURE PROPHYLAXIS IN GLIOMA - UK NEUROSURGICAL SURVEY AND CLINICAL TRIAL
Authors: Michael Jenkinson, Colin Watts, Luke Vale, Anthony Marson, Helen Bulbeck, Robin Grant
Journal: Neuro-Oncology (2018)

There is no consensus regarding the utility of prophylactic anti-Epileptic Drugs (AED) given to patients with supratentorial glioma before surgery, who have not had seizures. Newer AEDs have fewer adverse effects but their efficacy in preventing new onset seizures remains to be proven. In 2016, we surveyed all members of the Society of British Neurosurgeons (SBNS) to determine current practice and establish whether a randomised controlled trial (RCT) of AED vs no AED would be feasible. Survey of neurosurgeons/centres dealing with glioma patients in the UK regarding:(i) routine use of AED in patients with glioma(ii) preferred AED (iii) willingness to participate in a RCT of prophylactic AED(iv) were patients seen in a dedicated specialist neurosurgical clinic before surgery. A four point scale was used regarding usage of AEDs “almost always”, “usually”, “rarely”, “almost never” to avoid centering bias. 71% of 35 respondents almost never prescribed AEDs while 14% almost always prescribed AEDs. 51.4% would use Levetiracetam, 11.4% phenytoin and 37.1% not applicable. 74.3% would be interested in participating in a RCT. 60% of patients were seen in a dedicated specialist neurosurgical clinic before surgery. Conclusions: Based on responses of the survey a UK RCT trial of Levetiracetam vs no AED was considered feasible and a proposal (Seizure Prophylaxis IN Glioma - SPRING) was submitted to NIHR HTA. The application was successful. SPRING will start recruiting patients over three years from Jan 2019 in 15 neurosurgical centres across the UK. National Institute of Health Research for funding, (NIHR), and UCB for supplying AED.
Feasibility and utility of arterial spin labelling perfusion in neuro-oncology MRI protocols in the UK
Authors: Ms Julia Markus, Dr Magdalena Sokolska, Prof Rolf Jager, Dr Harpreet Hyare
Journal: Neuro-Oncology (2018)

Arterial spin labelling, (ASL) is an MRI perfusion technique that uses endogenous contrast and is currently underused in neuro-oncology MRI protocols in the UK. The purpose of this study was to examine the feasibility, ease of implementation and added value of arterial spin labelling (ASL) perfusion imaging in neuro-oncology protocols. Radiographers at a large tertiary MRI centre received in-house training in protocol selection and performing pseudo-continuous ASL (pcASL). During a 10 month period, 104 consecutive patients with gliomas, undergoing diagnostic MRI at 3.0 T, underwent an extended MRI protocol that included pcASL. ASL perfusion weighted images (ASL-PWI) were automatically generated by the scanner and archived together with conventional imaging. A qualitive retrospective survey was performed for feedback on the process. A sub-group of patients with available follow up imaging (n=39) were selected for further analysis (n=39: 20 glioblastoma multiforme, 15 astrocytoma, 4 oligodendroglioma). Two observers examined images and concluded RANO scores in two parts: conventional images alone and conventional imaging with ASL-PWI. Confidence was measured using Likert scales 1–5 (1,very unconfident to 5, very confident) and differences compared. Lastly, all diagnoses were checked against follow up imaging. 90% of radiographers felt either confident or very confident in performing ASL technique. 100% of reviewed PWIs were considered diagnostic quality. A statistically significant increase in average confidence levels was observed for inclusion of ASL (4.44 (SD 0.8)) compared to conventional imaging alone (4.02 (SD 0.65)). ASL is a reliable, non-contrast, low cost and well tolerated technique that can be easily implemented. ASL-PWI can be produced at time of scanning which can be utilised to build confidence in assessing response to treatment in low and high grade gliomas.
Association of Soluble TNFR-1 Concentrations with Long-Term Decline in Kidney Function: The Multi-Ethnic Study of Atherosclerosis
Authors: Pavan K. Bhatraju, Leila R. Zelnick, Michael Shlipak, Ronit Katz, Bryan Kestenbaum
Journal: Journal of the American Society of Nephrology (2018)

TNF receptor-1 (TNFR-1), which plays a causative role in endothelial cell dysfunction and inflammation, is expressed on the cell surface in glomerular and peritubular capillary endothelium of the kidneys. Higher soluble TNF receptor-1 (sTNFR-1) concentrations are associated with kidney disease progression among persons with established diabetic kidney disease. However, no studies have assessed sTNFR-1's role in long-term kidney function changes in a multiethnic population without cardiovascular disease at baseline.We tested associations between baseline sTNFR-1 concentrations and 10-year decline in eGFR (incident ≥40% decline and annual proportional decline) among 2548 participants in the Multi-Ethnic Study of Atherosclerosis (MESA), a prospective cohort study. Serum creatinine concentrations were determined at enrollment and study years 3, 5, and 10.Mean age of participants was 61 years old, 53% were women, and mean baseline eGFR was 79 ml/min per 1.73 m2. Serum sTNFR-1 was inversely associated with baseline eGFR. Over median follow-up of 9.3 years, 110 participants developed ≥40% decline in eGFR; each SD higher concentration of sTNFR1 was associated with higher risk of 40% eGFR decline (adjusted hazard ratio, 1.43; 95% confidence interval [95% CI], 1.16 to 1.77; P<0.001). The highest sTNFR-1 tertile was associated with adjusted annualized decline in eGFR of 1.94% (95% CI, 1.79 to 2.09). Associations persisted across subgroups defined by demographics, hypertension, diabetes, and baseline CKD status.Elevated serum sTNFR-1 concentrations are associated with faster declines in eGFR over the course of a decade in a multiethnic population, independent of previously known risk factors for kidney disease progression.
Abstract A12: Non-small cell lung tumor-derived autoantibodies can distinguish benign from malignant pulmonary nodules
Authors: Kristin J. Lastwika, Julia Kargl, Yuzheng Zhang, Xiaodong Zhu, David Shelley, Edward Lo, Wei Wu, Sudhakar N. Pipavath, Paul E. Kinahan, A. McGarry Houghton, Paul D. Lampe
Journal: Clinical Cancer Research (2018)

Abstract High-risk smokers are currently being screened with low-dose CT imaging after the National Lung Screening Trial demonstrated a 20% reduction in lung cancer mortality. Unfortunately, small pulmonary nodules are a common finding in smokers (present in 25-50%), with very few (&amp;lt;2.5%) nodules ultimately determined to be cancer. We observed a 4-fold increase in lung tumor-associated B cells compared to normal lung and hypothesized that lung-tumor derived autoantibodies could be useful biomarkers for malignant nodule diagnosis. We first discovered 13 IgG or IgM autoantibodies found in both non-small cell lung tumor and peripheral plasma (n=10) on a large (~17,000) protein array. These autoantibodies were predominantly absent in plasma from patients with benign nodules (n=10). In the plasma from an expanded nodule positive cohort (n=250) we validated 3/13 autoantibodies on a targeted protein array and 5/13 autoantibodies on a high-density antibody array. By using both antibody arrays (to measure antigen-autoantibody complexes) and protein arrays (to measure free autoantibody), we obtained a comprehensive picture of malignant nodule-associated autoantibodies. When we combine our top two autoantibodies (one free and one complexed with antigen) with two features from CT images, they yield an AUC = 0.92 (72% sensitivity at 90% specificity). These observations indicate that our noninvasive autoantibody biomarkers can increase the diagnostic accuracy of pulmonary nodules identified by CT imaging. Citation Format: Kristin J. Lastwika, Julia Kargl, Yuzheng Zhang, Xiaodong Zhu, David Shelley, Edward Lo, Wei Wu, Sudhakar N. Pipavath, Paul E. Kinahan, A. McGarry Houghton, Paul D. Lampe. Non-small cell lung tumor-derived autoantibodies can distinguish benign from malignant pulmonary nodules [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr A12.
Tenascin-C accelerates adverse ventricular remodelling after myocardial infarction by modulating macrophage polarization
Authors: Taizo Kimura, Kazuko Tajiri, Akira Sato, Satoshi Sakai, Zheng Wang, Toshimichi Yoshida, Toshimitsu Uede, Michiaki Hiroe, Kazutaka Aonuma, Masaki Ieda, Kyoko Imanaka-Yoshida
Journal: Cardiovascular Research (2018)

Abstract Aims Tenascin-C (TN-C) is an extracellular matrix protein undetected in the normal adult heart, but expressed in several heart diseases associated with inflammation. We previously reported that serum TN-C levels of myocardial infarction (MI) patients were elevated during the acute stage, and that patients with high peak TN-C levels were at high risk of left ventricular (LV) remodelling and poor outcome, suggesting that TN-C could play a significant role in the progression of ventricular remodelling. However, the detailed molecular mechanisms associated with this process remain unknown. We aimed to elucidate the role and underlying mechanisms associated with TN-C in adverse remodelling after MI. Methods and results MI was induced by permanent ligation of the coronary artery of TN-C knockout (TN-C-KO) and wild type (WT) mice. In WT mice, TN-C was expressed at the borders between intact and necrotic areas, with a peak at 3 days post-MI and observed in the immediate vicinity of infiltrating macrophages. TN-C-KO mice were protected from ventricular adverse remodelling as evidenced by a higher LV ejection fraction as compared with WT mice (19.0 ± 6.3% vs. 10.6 ± 4.4%; P &lt; 0.001) at 3 months post-MI. During the acute phase, flow-cytometric analyses showed a decrease in F4/80+CD206lowCD45+ M1 macrophages and an increase in F4/80+CD206highCD45+ M2 macrophages in the TN-C-KO heart. To clarify the role of TN-C on macrophage polarization, we examined the direct effect of TN-C on bone marrow-derived macrophages in culture, observing that TN-C promoted macrophage shifting into an M1 phenotype via Toll-like receptor 4 (TLR4). Under M2-skewing conditions, TN-C suppressed the expression of interferon regulatory factor 4, a key transcription factor that controls M2-macrophage polarization, via TLR4, thereby inhibiting M2 polarization. Conclusion These results suggested that TN-C accelerates LV remodelling after MI, at least in part, by modulating M1/M2-macrophage polarization.
Abstract 17986: Multiple Single Day Blood Pressure Measurements and Their Impact on Coronary Heart Disease, Stroke, and Heart Failure Risk Prediction: The Atherosclerosis Risk In Communities (ARIC) Study
Authors: Abayomi Ogunwale, Alanna C Morrison, Rhiannon Dodge, Salim Virani, Addison Taylor, Rebecca Gottesman, Eric Yang, Peng Wei, Eric Boerwinkle, Gerardo Heiss, Christie Ballantyne, Vijay Nambi
Journal: Circulation (2013)

BACKGROUND: Although systolic blood pressure (SBP) varies through the day, single SBP measures are used in all coronary heart disease (CHD), heart failure (HF) and stroke risk prediction equations. Changes in SBP clearly affect estimated risk. However, the magnitude of change in risk when different SBP measures performed within one day are used in risk equations is not known. METHODS: Same day multiple SBP measurements (sitting, standing and supine) were performed by certified technicians using a Dinamap device in 11,075 ARIC study participants (mean age 53.9 ± 5.7 years, 57% with history of smoking, 10% diabetic and 31% hypertensive). We estimated 10 year CHD, HF and stroke risks for each SBP measure and classified individuals as 0-5%, 5-10%, 10-20% and &gt;20% risk.Then, we evaluated changes in individual risks within a day. Results: (Table): Substituting mean sitting SBP for standing and supine SBP in the Framingham CHD Risk Score (FRS) reclassified 8.3% and 10.2% of the subjects, and in the ARIC Coronary Risk Score (ACRS), 7.1% and 9.6%, respectively. Similarly, when stroke and HF risks were evaluated using ARIC risk scores 11.7% and 12.3% were reclassified when standing SBP was used, and 10.7% and 11.7% were reclassified with supine SBP measures. The maximum changes in an individual’s estimated 10 year risk were 21%, 26% and 24% for CHD, stroke and HF risk, suggesting greater than one risk category (e.g.,low to high risk) change in a day. When different sitting SBP measures (taken within minutes of each other) were used, 6.7%, 6.5%, 6.5% and 8.0% of subjects were reclassified when FRS, ACRS, ARIC stroke and HF risks were estimated. CONCLUSION: SBP changes within a day can result in statistically significant changes in estimated CHD, stroke, and HF risk. Our study has implications for the use of a single SBP measure to determine an individual’s cardiovascular risk, and raises questions on the utility of current risk prediction algorithms in patient management.