Against research waste – how the evidence-based research paradigm promotes more ethical and innovative research

With notable negative impacts in clinical research, large numbers of studies simply replicate findings that have previously been confirmed. Caroline Blaine, Klara Brunnhuber and Hans Lund, suggest that much of this waste could be averted with a more structured and careful approach to systematic reviews and propose Evidence-Based Research as a framework for achieving this

A Screen of FDA-Approved Drugs Identifies Inhibitors of Protein Tyrosine Phosphatase 4A3 (PTP4A3 or PRL-3)

Protein tyrosine phosphatase 4A3 (PTP4A3 or PRL-3) is highly expressed in a variety of cancers, where it promotes tumor cell migration and metastasis leading to poor prognosis. Despite its clinical significance, small molecule inhibitors of PRL-3 are lacking. Here, we screened 1443 FDA-approved drugs for their ability to inhibit the activity of the PRL phosphatase family. We identified five specific inhibitors for PRL-3 as well as one selective inhibitor of PRL-2. Additionally, we found nine drugs that broadly and significantly suppressed PRL activity. Two of these broad-spectrum PRL inhibitors, Salirasib and Candesartan, blocked PRL-3-induced migration in human embryonic kidney cells with no impact on cell viability. Both drugs prevented migration of human colorectal cancer cells in a PRL-3 dependent manner and were selective towards PRLs over other phosphatases. In silico modeling revealed that Salirasib binds a putative allosteric site near the WPD loop of PRL-3, while Candesartan binds a potentially novel targetable site adjacent to the CX5R motif. Inhibitor binding at either of these sites is predicted to trap PRL-3 in a closed conformation, preventing substrate binding and inhibiting function

Allergen Exposure in Lymphopenic Fas-Deficient Mice Results in Persistent Eosinophilia Due to Defects in Resolution of Inflammation

Asthma is characterized by chronic airway type-2 inflammation and eosinophilia, yet the mechanisms involved in chronic, non-resolving inflammation remain poorly defined. Previously, our group has found that when Rag-deficient mice were reconstituted with Fas-deficient B6 LPR T cells and sensitized and challenged, the mice developed a prolonged type-2-mediated airway inflammation that continued for more than 6 weeks after the last antigen exposure. Surprisingly, no defect in resolution was found when intact B6 LPR mice or T cell specific Fas-conditional knockout mice were sensitized and challenged. We hypothesize that the homeostatic proliferation induced by adoptive transfer of T cells into Rag-deficient mice may be an important mechanism involved in the lack of resolution. To investigate the role of homeostatic proliferation, we induced lymphopenia in the T cell-specific Fas-conditional knockout mice by non-lethal irradiation and sensitized them when T cells began to repopulate. Interestingly, we found that defective Fas signaling on T cells plus antigen exposure during homeostatic proliferation was sufficient to induce prolonged eosinophilic airway inflammation. In conclusion, our data show that the combination of transient lymphopenia, abnormal Fas-signaling, and antigen exposure leads to the development of a prolonged airway eosinophilic inflammatory phase in our mouse model of experimental asthma

Non-apoptotic Fas (CD95) Signaling on T Cells Regulates the Resolution of Th2-Mediated Inflammation

Fas (CD95/APO-1) and its ligand (FasL/CD95L) promote the resolution of type 2 lung inflammation and eosinophilia. We previously found that Fas-deficiency on T cells, but not eosinophils, delayed resolution of inflammation. However, Fas can signal both cell death and have a positive signaling function that can actually activate cells. In this study, we investigated whether Fas-induced death or Fas-activated signaling pathways promote resolution of allergic lung inflammation. By increasing T cell survival through two Fas-independent pathways, using Bim-deficient T cells or Bcl-xL overexpressing T cells, no differences in resolution of Th2-mediated inflammation was observed. Furthermore, Th2 cells were inherently resistant to Fas-mediated apoptosis and preferentially signaled through non-apoptotic pathways following FasL treatment. Utilizing Fas-mutant mice deficient in apoptotic but sufficient for non-apoptotic Fas signaling pathways, we demonstrate that non-apoptotic Fas signaling in T cells drives resolution of Th2-mediated airway inflammation. Our findings reveal a previously unknown role for non-apoptotic Fas signaling on Th2 cells in the induction of resolution of type 2 inflammation

Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer's disease

Alzheimer's disease (AD) pathology develops many years before the onset of cognitive symptoms. Two pathological processes-aggregation of the amyloid-& beta;(A & beta;) peptide into plaques and the microtubule protein tau into neurofibrillary tangles (NFTs)-are hallmarks of the disease. However, other pathological brain processes are thought to be key disease mediators of A & beta;plaque and NFT pathology. How these additional pathologies evolve over the course of the disease is currently unknown. Here we show that proteomic measurements in autosomal dominant AD cerebrospinal fluid (CSF) linked to brain protein coexpression can be used to characterize the evolution of AD pathology over a timescale spanning six decades. SMOC1 and SPON1 proteins associated with A & beta;plaques were elevated in AD CSF nearly 30 years before the onset of symptoms, followed by changes in synaptic proteins, metabolic proteins, axonal proteins, inflammatory proteins and finally decreases in neurosecretory proteins. The proteome discriminated mutation carriers from noncarriers before symptom onset as well or better than A & beta;and tau measures. Our results highlight the multifaceted landscape of AD pathophysiology and its temporal evolution. Such knowledge will be critical for developing precision therapeutic interventions and biomarkers for AD beyond those associated with A & beta;and tau. Proteomic analysis of cerebrospinal fluid from individuals with autosomal dominant Alzheimer's disease reveals how this complex and chronic disease evolves over many decades

Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer’s disease

Alzheimer’s disease (AD) pathology develops many years before the onset of cognitive symptoms. Two pathological processes—aggregation of the amyloid- (A ) peptide into plaques and the microtubule protein tau into neurofibrillary tangles (NFTs)—are hallmarks of the disease. However, other pathological brain processes are thought to be key disease mediators of A plaque and NFT pathology. How these additional pathologies evolve over the course of the disease is currently unknown. Here we show that proteomic measurements in autosomal dominant AD cerebrospinal fluid (CSF) linked to brain protein coexpression can be used to characterize the evolution of AD pathology over a timescale spanning six decades. SMOC1 and SPON1 proteins associated with A plaques were elevated in AD CSF nearly 30 years before the onset of symptoms, followed by changes in synaptic proteins, metabolic proteins, axonal proteins, inflammatory proteins and finally decreases in neurosecretory proteins. The proteome discriminated mutation carriers from noncarriers before symptom onset as well or better than A and tau measures. Our results highlight the multifaceted landscape of AD pathophysiology and its temporal evolution. Such knowledge will be critical for developing precision therapeutic interventions and biomarkers for AD beyond those associated with A and tau

Determination of Urinary Creatinine in Washington State Residents via Liquid Chromatography/Tandem Mass Spectrometry

A viable, quick, and reliable method for determining urinary creatinine by liquid chromatography/tandem mass spectrometry (LC/MS/MS) was developed and used to evaluate spot urine samples collected for the Washington Environmental Biomonitoring Survey (WEBS): part of the Washington State Department of Health, Public Health Laboratories (PHL). 50 µL of urine was mixed with a 1 : 1 acetonitrile/water solution containing deuterated creatinine as the internal standard and then analyzed by LC/MS/MS. Utilizing electrospray ionization (ESI) in positive mode, the transition ions for creatinine and creatinine-d3 were determined to be 114.0 to 44.1 (quantifier), 114.0 to 86.1 (qualifier), and 117.0 to 47.1 (creatinine-d3). The retention time for creatinine was 0.85 minutes. The linear calibration range was 20–4000 mg/L, with a limit of detection at 1.77 mg/L and a limit of quantitation at 5.91 mg/L. LC/MS/MS and the colorimetric Jaffé reaction were associated significantly (Pearson r=0.9898 and R2=0.9797, ρ≤0.0001). The LC/MS/MS method developed at the PHL to determine creatinine in the spot urine samples had shorter retention times, and was more sensitive, reliable, reproducible, and safer than other LC/MS/MS or commercial methods such as the Jaffé reaction or modified versions thereof

Effects of Breast Milk Feedings versus Formula Feedings on Health and Developmental Outcomes in Preterm Infants: Systematic Literature Review

Background: Gestation is the period of time between conception and birth. Infants being born between 20 and 37 weeks before completion of pregnancy are considered preterm. Infants who are born preterm are at risk for an abundance of acute and long-term complications related to health and development. Some of these include necrotizing enterocolitis, lack of lung surfactant, feeding intolerance, and infection. Since preterm infants are more prone to contract infections due to their underdeveloped immune systems, there has long been a debate whether mother’s breast milk versus formula milk is more beneficial in the growth and development of the preterm infant. The purpose of this project was to explore the health and development outcomes in breastfed babies versus formula fed babies. Purpose: The purpose of this systematic literature review is to determine the benefits of breastfeeding on a preterm infant’s development and health compared to formula feeding. Methodology: Studies have been systematically reviewed using the John Hopkins Evidence-Based Practice Model. Databases used include MEDLINE Complete, PubMed, CINAHL, and Complementary Index. Keywords used to facilitate our search include preterm infants, breastfeeding, breast milk, formula feeding, development, and growth. A PRISMA Flow Diagram summarizes our systematic research screening process based on specific inclusion and exclusion criteria. Twenty articles were appraised for evidence and quality levels before analysis of results. Results: Preliminary results suggest that breastfeeding supplies infants with the most benefits for their development and their health. Final analysis will be shared at the Symposium

How to improve the study design of clinical trials in internal medicine: Recent advances in the evidence-based methodology

Meta-research has highlighted that up to half of all clinical studies may be redundant and do not add any value. We suggest that such unnecessary studies will continue to be prepared and published unless researchers systematically and transparently identify and consider the existing evidence. This approach of identifying and utilizing the existing knowledge base before and after conducting a new trial is called Evidence-Based Research (EBR), defined as the use of prior research in a systematic and transparent way to inform a new study so that it is answering questions that matter in a valid, efficient, and accessible manner. This paper describes the issues that have led to the development of the EBR approach, suggests what researchers should do to avoid wasteful and unnecessary research, and outlines the benefits of conducting evidence-based research. Finally, we present the international EBR Network established to support the efforts to minimize waste in research and increase the value of clinical studies

Effects of fucoidan supplementation on inflammatory and immune response after high-intensity exercise

Introduction High-intensity exercise (HIE) can damage the musculotendon complex and impact the immune response, resulting in post-exercise inflammation. Sufficient rest and recovery will improve muscular resilience against future damaging bouts; however, HIE with minimal durations of rest is common in athletic competitions that facilitate persistent inflammation and immune dysregulation. Fucoidans are fucose-rich sulfated polysaccharides with demonstrated anti-inflammatory and pro-immune responses. Fucoidans may improve inflammation and immune responses, which may prove beneficial for individuals who regularly engage in repeated HIE. The research purpose was to investigate the safety and efficacy of fucoidans on inflammatory and immune markers following HIE. Methods Eight male and eight female participants were randomized into a double-blind, placebo-controlled, counterbalanced, crossover design study and supplemented with 1 g/day fucoidan from Undaria pinnatifida (UPF) or placebo (PL) for 2 weeks. Supplementation periods concluded with HIE testing, followed by 1 week of washout. HIE involved one > 30 s Wingate anaerobic test (WAnT) and eight 10 s WAnT intervals. Blood was drawn pre-exercise, immediately post-exercise, 30 min, and 60 min post-exercise to assess immune and inflammatory markers. Blood markers, peak power (PP), and mean power (MP) were analyzed using a 2 (condition) × 4 (time) design. Significance was set at α = .05. Results A time-by-condition interaction was observed for interleukin-6 (p = .01) and interleukin-10 (p = .008). Post hoc analysis revealed greater interleukin-6 and interleukin-10 concentrations at 30 min post HIE with UPF supplementation (p = .002 and p = .005, respectively). No effects of condition were observed for all blood markers or performance outcomes with UPF supplementation (p > .05). Main effects of time were observed for white blood cells, red blood cells, red cell distribution width, mean platelet volume, neutrophils, lymphocytes, monocytes, eosinophils, basophils, natural killer cells, B and T-lymphocytes, CD4 and CD8 cells (p < .05). Discussion No adverse events were reported throughout the study period, indicating a positive safety profile of UPF. While notable changes in biomarkers occurred up to 1 hr post HIE, few differences were observed between supplementation conditions. There did appear to be a modest effect of UPF on inflammatory cytokines potentially warranting further investigation. However, fucoidan supplementation did not influence exercise performance