tbuckley/cabot-search huggingface dataset:
Strategies to diversify natural products for drug discovery
Authors: Gang Li, Hong‐Xiang Lou
Journal: Medicinal Research Reviews (2017)

Natural product libraries contain specialized metabolites derived from plants, animals, and microorganisms that play a pivotal role in drug discovery due to their immense structural diversity and wide variety of biological activities. The strategies to greatly extend natural product scaffolds through available biological and chemical approaches offer unique opportunities to access a new series of natural product analogues, enabling the construction of diverse natural product-like libraries. The affordability of these structurally diverse molecules has been a crucial step in accelerating drug discovery. This review provides an overview of various approaches to exploit the diversity of compounds for natural product-based drug development, drawing upon a series of examples to illustrate each strategy.
TCT-337 Hemodynamic changes after percutaneous coronary interventions of stenoses with discordant fractional flow reserve and coronary flow reserve
Authors: Gilbert Wijntjens, Yuetsu Kikuta, Tim van de Hoef, Ricardo Petraco, Sukhjinder Nijjer, Guus de Waard, Sayan Sen, Mauro Echavarria Pinto, Valérie Stegehuis, Hernan Mejia-Renteria, Martijn Meuwissen, Ibrahim Danad, Paul Knaapen, Javier Escaned, Justin Davies, Niels Van Royen, Jan Piek
Journal: Journal of the American College of Cardiology (2017)
Response to Comment on Lovshin et al. Dipeptidyl Peptidase 4 Inhibition Stimulates Distal Tubular Natriuresis and Increases in Circulating SDF-1α1-67 in Patients With Type 2 Diabetes. Diabetes Care 2017;40:1073-1081
Authors: Julie A. Lovshin, Leif E. Lovblom, David Z.I. Cherney
Journal: Diabetes Care (2017)

We thank van Baar et al. (1) for their interest in our study (2). We agree that the chronic natriuretic effect(s) of the dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin occurred in the early postprandial state (3 h after a standardized liquid meal during a euglycemic clamp). We cannot, however, rule out that DPP-4 inhibitor–mediated effect(s) on natriuresis persisted for several hours after this sampling period. Recognizing feasibility concerns around having research participants in a highly controlled research setting for prolonged periods, we limited our fractional sodium excretion (FENA) and renal hemodynamic function measurements to 3 h. This was in addition to the 4–5 h that patients had already been in the lab for baseline testing.

We agree that …
Abstract 19045: Impaired Autophagy Induced by Activated mTORC1 Underlies Development of Dystrophic Cardiomyopathy.
Authors: Atsushi Kuno, Ryusuke Hosoda, Rio Sebori, Yoshiyuki Horio
Journal: Circulation (2016)

Purpose: Heart failure is a main cause of death in patients with Duchenne muscular dystrophy. Here, we hypothesized that impaired autophagy contributes to the cardiac phenotype in muscular dystroph...
The Central and Unacknowledged Role of the US Food and Drug Administration in the Design and Execution of Medical Device Pivotal Trials
Authors: Aaron V. Kaplan, Ariel D. Stern
Journal: JAMA Cardiology (2017)

This Viewpoint discusses the role of the US Food and Drug Administration's Center for Devices and Radiologic Health in the design and execution of pivotal trials that are used to support the regulatory approval of high-risk devices.
Abstract 19582: Placement of the Left Side AED Pad is Poor: Training on the Left Compared to the Right Side of a Manikin Does Not Improve Pad Placement
Authors: Mathilde Stærk, Henrik Bødtker, Søren Rahbek, Lauge Vammen, Bo Løfgren
Journal: Circulation (2015)

Introduction: Placement of automated external defibrillators (AED) pads is poor, especially placement of the left apical pad is rarely achieved. Sitting on the right side of a victim in cardiac arrest may interfere with correct left side pad placement because the rescuer has to bend over the victim to reach the left mid-axillary line. In addition, the left arm of the victim may hamper access to the left lateral side of the thorax. Hypothesis: Training automated external defibrillation sitting on the left side of a manikin improves AED pad placement compared to sitting to the right. Methods: Laypeople participating in a first aid course were randomized to learn automated external defibrillation sitting on the left or right side of a manikin during AED training. After course completion participants operated a training AED (Lifepak® CR-T AED Trainer, PhysioControl) and placed AED pads according to instructions from the AED. Pads were placed on an anatomically realistic male resuscitation torso with arms (AMBU® Man, AMBU). Participants were instructed to sit on the same side of the manikin as trained. The distance from the center of AED pads to the recommended pad position was measured. Results: In total, 30 volunteers were included and randomized to AED training on the left (n=14, 43% male, age: 47.9 years) and right (n=16, 25% male, age: 46.7 years) side of a manikin. There was no difference in left pad placement when trained on the left or right side (distance to recommended left apical pad position (mean±sd): 5.8±2.1 cm vs 7.0±2.4, p=0.15). The left apical electrode was in all cases placed too medial. Only a minor part of participants (left trained (36%); right trained (31%)) moved the left arm of the manikin to place the left apical pad. No difference was observed with respect to right pad placement when trained on the left or right side respectively (distance to recommended right sternal pad position (mean±sd): 2.7±1.7 cm vs 1.8±0.8 cm, p=0.10). Conclusion: Training automated external defibrillation on the left side of a manikin does not improve pad placement compared to training on the right side. Placement of the left apical pad is poor and future training should emphasize correct left lateral pad placement.
Identity Crisis for Regenerative Cardiac cKit <sup>+</sup> Cells
Authors: Onur Kanisicak, Ronald J. Vagnozzi, Jeffery D. Molkentin
Journal: Circulation Research (2017)

ViewpointsT he concept that cardiac-derived cKit + cells can regen- erate the injured adult heart by transdifferentiating into functioning cardiomyocytes was proposed 14 years ago although it remains controversial because of negative data from multiple independent laboratories.Irreproducibility of cardiac cKit + cell studies was attributed to the differences in cell isolation, selection, and expansion before in vivo application.This Viewpoint will discuss recent results that again change the formula for how cardiac cKit + cells must be isolated and processed to be cardiomyogenic, as well as discuss the uncertain in vivo relevance of cKit + cells as putative cardiomyocyte-producing stem cells.
Low eukaryotic viral richness is associated with faecal microbiota transplantation success in patients with UC
Authors: Nádia Conceição-Neto, Ward Deboutte, Tim Dierckx, Kathleen Machiels, Jun Wang, Kwe Claude Yinda, Piet Maes, Marc Van Ranst, Marie Joossens, Jeroen Raes, Séverine Vermeire, Jelle Matthijnssens
Journal: Gut (2017)

We read with interest the recent Gut study by Zuo and colleagues showing that a good outcome of faecal microbiota transplantation (FMT) in Clostridium difficile infection (CDI) was associated with bacteriophage transfer.1 FMT is an established treatment to restore a balance in disturbed intestinal microbiotas of patients with CDI,2 3 and recent multicentre randomised, double-blind, placebo-controlled trials showed its effectiveness in inducing clinical and endoscopic remission in patients with UC.4 We examined the gut virome dynamics of nine patients with UC who were undergoing FMT (64 patient and 8 healthy donor samples).5 Two patients with UC achieved long-lasting complete remission with mucosal healing (>2 years; figure 1: patient 1 and 3), and one patient reported temporary remission for 6 weeks (figure 1; patient 4).5 The remaining six patients did not respond to treatment. Using the NetoVIR protocol,6 we analysed the faecal virome (both RNA/DNA genomes of phages and eukaryotic viruses) using tailored bioinformatics approaches (see online supplementary data). Irrespective of their outcome, no statistical differences were observed in phageome richness between patients with UC and healthy donors (figure 2A) at any time point, in contrast …
Abstract 18379: Association Between Partial Pressure of Arterial Carbon Dioxide and Neurological Outcome After Cardiac Arrest Treated With Therapeutic Hypothermia
Authors: Chun Song Youn, Soo Hyun Kim, Kyu Nam Park
Journal: Circulation (2016)

Introduction: Current guidelines for the management after cardiac arrest (CA) recommend to maintain partial pressure of arterial CO2 (PaCO2) at 35 to 45mmHg. However, it is still unclear if exposur...
Séroprévalence des anticorps contre le poliovirus chez les individus résidant au Portugal, 2002
Authors: Marta Pires de Miranda, M Carmo Gomes, H Rebelo de Andrade
Journal: Eurosurveillance (2007)

Au Portugal, le dernier cas de poliomyelite cause par le poliovirus indigene sauvage a ete recense en 1986 et le pays a ete declare indemne de poliomyelite en 2002.
The Promise and Practice of Genetics on Diabetes Care: The Fog Rises to Reveal a Field of Genetic Complexity in <i>HNF1B</i>
Authors: Stephen S. Rich
Journal: Diabetes Care (2017)

Diabetes is a common disease characterized by the disruption of glucose homeostasis that results when insulin, the hormone that converts glucose from the blood into energy used by the body’s cellular machinery, is absent (through autoimmune destruction of the pancreatic β-cells in type 1 diabetes) or inefficient (increased insulin resistance or reduced insulin sensitivity in type 2 diabetes). There are multiple pathways to developing diabetes, yet practically all involve an underlying genetic etiology with an environmental trigger.

The extent of knowledge of genetic factors and environmental factors differs across the forms of diabetes. In the case of type 1 diabetes, the concordance in monozygotic twins (genetically identical) is ∼50%, with familial aggregation and modeling suggesting a major impact of genetics on risk (1). The genetic contribution to type 1 diabetes is well described, with HLA genes accounting for one-half of the genetic risk (2) and ∼50 other sites in the genome contributing the majority of the remaining genetic risk (3). The familial (heritable) contribution to type 2 diabetes has also been estimated through twin studies, with monozygotic twin concordance rising from ∼50% in middle age to nearly 80% later in life (4). Complexity in assessment of the contribution of genetic factors to type 2 diabetes arises from the impact of other familial and behavioral factors that are associated with risk, including obesity, reduced physical activity, and dietary habits. Although the overall risk of type 2 diabetes appears “more heritable” than type 1 diabetes, the estimated effects of ∼100 sites across the genome account for ∼10% of the risk (5). Similar investigations have shown other types of diabetes to be heritable, including neonatal diabetes (6), maturity-onset diabetes of the young (MODY) (7), gestational diabetes mellitus (8), and latent autoimmune diabetes in adults (LADA) (9), and numerous studies have shown diabetes complications …
Characterization of the anti-angiogenic effects of TIMP-4.
Authors: Cecilia A. Fernández, Gwendolyn Louis, Marsha A. Moses
Journal: Cancer Research (2004)

2298  Very little is known about the ability of TIMP-4 to directly inhibit angiogenesis. In the past, TIMP-4 had been shown to inhibit tumor cell invasion in vitro and to retard the growth of tumor cells that overexpress TIMP-4 when implanted into mice. This study also suggested that TIMP-4 might be an angiogenesis inhibitor based on the observation that TIMP-4 overexpressing tumors showed reduced microvascular density. However, more recent studies have shown that TIMP-4 stimulates the growth of the same tumor type when TIMP-4 was delivered by adenoviral transfection. It has largely been assumed that TIMP-4, by virtue of being a tissue inhibitor of matrix metalloproteinases, also inhibits angiogenesis despite the fact that TIMP-4 has not specifically tested for its ability to inhibit angiogenic processes in vitro and angiogenesis in vivo. Previous work from our laboratory and others demonstrates that another TIMP, TIMP-2, inhibits angiogenesis by two distinct pathways, one which is dependent on the inhibition of matrix metalloproteinases (MMPs) and the other which is MMP inhibition-independent. We have shown that a fragment of TIMP-2 lacking MMP-inhibitory activity inhibits the proliferation of endothelial cells in vitro and angiogenesis in vivo. Given the high degree of homology between TIMP-2 and TIMP-4, and the fact that both have been shown to share the ability to bind MMP-2 through their carboxy-terminal domains, we hypothesized that TIMP-4 might share anti-proliferative and MMP inhibition-independent anti-angiogenic activities with TIMP-2. In order to test this hypothesis, we cloned TIMP-4 from a human heart cDNA library and subcloned it into the pPICZaA vector for expression in the Pichia pastoris yeast expression system. Expressed TIMP-4 was then purified by His-affinity followed by C4 reverse phase HPLC. In order to confirm the bioactivity of the protein, we first tested the purified TIMP-4 for its ability to inhibit MMP activity, and found that, consistent with previously published results, TIMP-4 inhibited MMP activity with an IC50 of approximately 15 nM. We next examined the effect of TIMP-4 on angiogenic processes, specifically capillary endothelial cell migration and proliferation. Our results demonstrate that TIMP-4 inhibits capillary EC migration at doses comparable to those reported for other cell types. Unlike TIMP-2, TIMP-4 did not significantly inhibit capillary EC proliferation, even at very high doses. We further compared the effects of the anti-proliferative domain of TIMP-2 (Loop 6) and Loop 6 of TIMP-4 (T4L6) and found that Loop 6 of TIMP-4 did not significantly inhibit capillary endothelial cell proliferation activity. Results of in vivo angiogenesis assays will also be presented.
Progression-free duration of NSCLC patients after cessation of Nivolumab
Authors: Atsuto Mouri, Ou Yamaguti, Takahiro Uchida, Ayako Shiono, Harue Utugi, Fuyumi Nishihara, Yoshitake Murayama, Kunihiko Kobayashi, Hiroshi Kagamu
Journal: Annals of Oncology (2017)
Sorveglianza sulle malattie infettive tra i rifugiati kosovari in Albania, Aprile-Giugno 1999
Authors: M Valenciano, A Pinto, D Coulombier, E Hashorva, M Murthi
Journal: Eurosurveillance (1999)

L'Albania, un paese con 3,5 milioni di abitanti, sta fronteggiando una crisi sociale ed economica. Il reddito medio pro capite e inferiore a 1.000 $US l'anno e, dal 1995, la disoccupazione e aumentata del 2,7% (1). I fattori maggiormente limitanti da un punto di vista sociale sono la poverta e l'emigrazione. Il paese e suddiviso in 37 provincie amministrative e l'assistenza sanitaria primaria si avvale di una rete di 1.500 presidi (in cui operano infermieri e ostetriche) e 602 centri medici (coordinati da medici di famiglia). L'assistenza medica secondaria e fornita da 53 policlinici distribuiti nelle citta delle provincie, 34 ospedali provinciali e 10 ospedali regionali. L'assistenza terziaria e presente solo a Tirana, nel Centro Ospedaliero Universitario (2). Il sistema di sorveglianza nazionale ha sotto osservazione 73 patologie: i centri medici e i presidi sanitari notificano agli epidemiologi provinciali che, ogni mese, inviano le informazioni all'Institute of Public Health (IPH) a Tirana. La riuscita della sorveglianza e limitata dall'affidabilita, dalla qualita dei dati e dalla loro mancata trasmissione, dalla sottonotifica e da problemi nel ritorno delle informazioni (3).
“Step-clipping” method: a technique for detecting previously bleeding diverticula
Authors: Hirosato Tamari, Taiki Aoyama, Shinji Nagata, Kenjiro Shigita, Naoki Asayama, Akira Fukumoto, Shinichi Mukai
Journal: Endoscopy (2017)

Bleeding of colonic diverticula is a common complaint, but it remains challenging to treat endoscopically because of the difficulty in determining the responsible diverticulum, particularly if the bleeding stops spontaneously. Additionally, endoscopic examinations lasting > 60 minutes are, in some cases, also problematic [1]. Thus, an innovative diagnostic technique is eagerly anticipated.
TCT-220 Impact of Clinical SYNTAX Score on 5 Years Clinical Outcomes in Patients Treated With Cobalt-Chromium Everolimus-Eluting Stent
Authors: Takashi Hiromasa, Shoichi Kuramitsu, Hiroyuki Jinnouchi, Makoto Hyodo, Yoshimitsu Soga, Shinichi Shirai, Kenji Ando
Journal: Journal of the American College of Cardiology (2017)
Abstract 15342: Does Ivabradine Affect Sympathetic Overdrive and Arterial Stiffening in Hypertensive Patients With Metabolic Syndrome?
Authors: K. Dimitriadis, C. Tsioufis, E. Koutra, T. Kalos, I. Liatakis, E. Andrikou, P. Vasileiou, I. Andrikou, D. Tousoulis
Journal: Circulation (2015)

Introduction: Hypertension and metabolic syndrome are related to sympathetic overdrive and arterial stiffening, while there are no data whether ivabradine modulates sympathetic activity and vascular abnormalities in this setting. Hypothesis: To assess the effect of ivabradine on muscle sympathetic nerve activity (MSNA) and arterial stiffness in hypertensive patients with metabolic syndrome. Methods: We studied 36 patients with essential hypertension [age: 56±10 years, 30 males, office blood pressure (BP): 148/92±14/11 mmHg] on antihypertensive therapy with a fixed combination of perindopril/amlodipine. Patients were randomized with a ratio 2:1 to ivabradine (5 mg twice daily) or no ivabradine (control group). Metabolic syndrome was defined according to the Adult Treatment Panel III criteria. In all participants at baseline and at 6 months follow-up arterial stiffness was evaluated on the basis of carotid to femoral pulse wave velocity (PWV) while sympathetic drive was assessed by MSNA estimations based on established methodology (microneurography). Results: Patients on ivabradine (n=24) compared to controls (n=12) did not differ regarding baseline BP, creatinine, glucose and lipid profile (p=NS or all). There was no significant difference in the reduction of office BP between the two study groups (p=NS). However, hypertensive patients in the ivabradine group were characterized by a reduction in carotid to femoral PWV from 11.5±0.9 m/sec to 9.8±1.2 m/sec (p&lt;0.001) and sympathetic nerve traffic as reflected by MSNA levels from 86.2±2.5 bursts per 100 heart beats to 74.8±2.4 bursts per 100 heart beats (p&lt;0.001) at 6 months. No significant changes in PWV and MSNA were observed in the control group (p=NS). Conclusions: In hypertensive patients with metabolic syndrome, treatment with ivabradine reduces sympathetic activation and arterial stiffening as reflected by lower MSNA and PWV levels at 6 months follow-up. These findings suggest that ivabradine could exhibit additional therapeutic properties in the setting of dysmetabolic hypertension.
Assessment of healing of esophageal fistulae following stent placement without complete stent removal
Authors: Claudia Zitron, Adriane Pelosof, Eloy Taglieri, Gabriel Corbetta, Otavio Micelli Neto, Alvaro Seraphim
Journal: Endoscopy (2017)

Anastomotic leaks and fistulae are among the major life-threatening post-esophagectomy complications, with incidence rates ranging from 3 % to 10 %, increasing post-surgical mortality to about 20 % [1].
Topically applied virus-like particles containing HIV-1 Pr55gag protein reach skin antigen-presenting cells after mild skin barrier disruption
Authors: Fiorenza Rancan, Zahra Afraz, Sabrina Hadam, Lina Weiß, Hélène Perrin, Alexander Kliche, Petra Schrade, Sebastian Bachmann, Monika Schäfer-Korting, Ulrike Blume-Peytavi, Ralf Wagner, Béhazine Combadière, Annika Vogt
Journal: Journal of Controlled Release (2017)
A risk score to predict the development of hepatic encephalopathy in a population‐based cohort of patients with cirrhosis
Authors: Elliot B. Tapper, Neehar D. Parikh, Neil Sengupta, Jessica Mellinger, David Ratz, Anna S.‐F. Lok, Grace L. Su
Journal: Hepatology (2017)

Over 40% of patients with cirrhosis will develop hepatic encephalopathy (HE). HE is associated with decreased survival, falls, motor vehicle accidents, and frequent hospitalization. Accordingly, we aimed to develop a tool to risk‐stratify patients for HE development. We studied a population‐based cohort of all patients with cirrhosis without baseline HE (n = 1,979) from the Veterans Administration from Michigan, Indiana, and Ohio (January 1, 2005‐December 31, 2010) using demographic, clinical, laboratory, and pharmacy data. The primary outcome was the development of HE. Risk scores were constructed with both baseline and longitudinal data (annually updated parameters) and validated using bootstrapping. The cohort had a mean age of 58.0 ± 8.3 years, 36% had hepatitis C, and 17% had ascites. Opiates, benzodiazepines, statins, and nonselective beta‐blockers were taken at baseline by 24%, 13%, 17%, and 12%, respectively. Overall, 863 (43.7%) developed HE within 5 years. In multivariable models, risk factors (hazard ratio, 95% confidence interval) for HE included higher bilirubin (1.07, 1.05‐1.09) and nonselective beta‐blocker use (1.34, 1.09‐1.64), while higher albumin (0.54, 0.48‐0.59) and statin use (0.80, 0.65‐0.98) were protective. Other clinical factors, including opiate and benzodiazepine use, were not predictive. The areas under the receiver operating characteristics curve for HE using the four significant variables in baseline and longitudinal models were 0.68 (0.66‐0.70) and 0.73 (0.71‐0.75), respectively. Model effects were validated and converted into a risk score. A score ≤0 in our longitudinal model assigns a 6% 1‐year probability of HE, while a score &gt;20 assigns a 38% 1‐year risk. Conclusion : Patients with cirrhosis can be stratified by a simple risk score for HE that accounts for changing clinical data; our data also highlight a role for statins in reducing cirrhosis complications including HE. (H epatology 2017).
TCT-335 Clinical Implications of 3-Vessel Fractional Flow Reserve Measurement in Patients with Coronary Artery Disease
Authors: Joo Myung Lee, Bon-Kwon Koo, Eun-Seok Shin, Chang-Wook Nam, Joon-Hyung Doh, Doyeon Hwang, Jonghanne Park, Xinyang Hu, Jianan Wang, Ahn Chul, Fei Ye, Shaoliang Chen, Junqing Yang, Jiyan Chen, Nobuhiro Tanaka, Hiroyoshi Yokoi, Hitoshi Matsuo, Hiroaki Takashima, Yasutsugu Shiono, Takashi Akasaka
Journal: Journal of the American College of Cardiology (2017)
P2.01-031 CCL Chemokines May Play an Important Role in Cisplatin Resistance
Authors: Sarah-Louise Ryan, Peter Godwin, Susan Heavey, Kazuo Umezawa, Martin Barr, Steven Gray, Bryan Stanfill, Anthony Davies, Sinead Cuffe, Stephen Finn, Derek Richard, Kathy Gately, Kenneth O’Byrne, Anne-Marie Baird
Journal: Journal of Thoracic Oncology (2017)
David McGechie Duncan
Authors: Roderick Duncan
Journal: BMJ (2017)

My father, David McGechie Duncan, was born in Glasgow, but grew up in Forfar, Angus, the son of a minister. After qualifying and house jobs in Dumfries, he moved to England, where he spent the rest of his working life. He spent most of it as a GP in what was the small market town of Wellingborough in Northamptonshire. The town expanded a great deal from the 1960s, and, in time, the small surgery in the senior partner’s house became inadequate for the number of patients …