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1.
Bridging the Imaging Gap: PSMA PET/CT Has a High Impact on Treatment Planning in Prostate Cancer Patients with Biochemical Recurrence-A Narrative Review of the Literature.
Ekmekcioglu, Ö, Busstra, M, Klass, ND, Verzijlbergen, F
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2019;(10):1394-1398
Abstract
68Ga- and 18F-labeled prostate-specific membrane antigen (PSMA) molecules have created new opportunities for the unmet diagnostic needs in prostate cancer. The purpose of this article is to give an overview of studies that have examined the role of PSMA PET in treatment planning for prostate cancer patients with biochemical recurrence (BCR). Methods: Medline, Embase, Web of Science, Google Scholar, and Cochrane Central were searched for relevant articles. After excluding the articles that did not fulfill the required criteria, we included in this review 12 publications that reported the impact of PSMA PET on the treatment plan for prostate cancer patients with BCR. Results: All studies in our review emphasized the impact of PSMA PET images on therapy management in prostate cancer patients with BCR. Overall, the impact of PSMA PET/CT on therapy management varied between 30% and 76% among the 1,346 patients included in the review. Upstaging was reported in 32%-67% of the patients. Patients with low prostate-specific antigen values (<0.5 ng/mL) also demonstrated positive lesions, which could not have been detected by means of conventional imaging techniques. Important modifications to the original treatment plan included avoidance of systemic therapy (17%-40%) and PET-directed local therapy (in ≤60% of the patients). Conclusion: PSMA imaging demonstrated a high clinical impact in patients with BCR, with modifications to the original treatment plan occurring among half the patients. Detecting recurrence in BCR can prevent unnecessary toxicity and lead to individualized therapy.
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2.
Effects of dietary intervention and n-3 PUFA supplementation on markers of gut-related inflammation and their association with cardiovascular events in a high-risk population.
Awoyemi, A, Trøseid, M, Arnesen, H, Solheim, S, Seljeflot, I
Atherosclerosis. 2019;:53-59
Abstract
BACKGROUND & AIMS Dysbiosis of the gut microbiota is associated with increased levels of circulating lipopolysaccharide (LPS) and subsequent activation of systemic inflammation. Diet is an important modulator of the gut microbiome. We aimed to investigate whether circulating markers of gut-related inflammation, LPS binding protein (LBP) and soluble CD14 (sCD14) can be modulated by n-3 PUFA supplementation and/or diet counselling, and whether these markers are related to cardiovascular (CV) outcome. METHODS 484 men aged 65-75 years, at high CV-risk, were included and randomized in a 2 × 2 factorial design to 36-month intervention with dietary counselling, n-3 PUFA supplementation, or both. N-3 PUFA supplementation was placebo-controlled. ELISAs were used for determination of the biomarkers measured at baseline and study-end. A composite endpoint was defined as new CV-events and CV-mortality after 36 months. RESULTS There were no significant differences in changes of either LBP or sCD14 in the intervention groups compared to their respective controls (n-3 PUFA vs. placebo: p = 0.58, p = 0.15, diet vs. no-diet: p = 0.53, p = 0.59, respectively). The group with LBP levels above median had about 2-fold unadjusted risk of suffering an endpoint compared to the group below (HR 2.22, 95% CI 1.25-3.96; p = 0.01). A similar tendency was seen for sCD14 (HR 1.72, 95% CI 0.97-3.03; p = 0.06). After adjusting for covariates, LBP remained significantly associated with a two-fold CV-risk, whereas sCD14 gained statistical significance, however, lost when hsCRP was added to the model. CONCLUSIONS In our population, markers of gut-related inflammation associated with 36-month CV outcome. However, neither n-3 PUFA nor diet intervention had an effect on these markers.
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3.
Expression and regulation of the BKRF2, BKRF3 and BKRF4 genes of Epstein-Barr virus.
Chen, LW, Hung, CH, Wang, SS, Yen, JB, Liu, AC, Hung, YH, Chang, PJ
Virus research. 2018;:76-89
Abstract
The BKRF2, BKRF3 and BKRF4 genes of Epstein-Barr virus (EBV) are located close together in the viral genome, which encode glycoprotein L, uracil-DNA glycosylase and a tegument protein, respectively. Here, we demonstrate that the BKRF2 gene behaves as a true-late lytic gene, whereas the BKRF3 and BKRF4 genes belong to the early lytic gene family. Our results further reveal that both BKRF3 and BKRF4 promoters are new synergistic targets of Zta and Rta, two EBV latent-to-lytic switch transactivators. Multiple Rta- and Zta-responsive elements within the BKRF3 and BKRF4 promoters were identified and characterized experimentally. Importantly, we show that DNA methylation is absolutely required for activation of the BKRF4 promoter by Zta alone or in combination with Rta. Moreover, we find that sodium butyrate, an inducing agent of EBV reactivation, is capable of activating the BKRF4 promoter through a mechanism independent of Zta and Rta. Overall, our studies highlight the complexity of transcriptional regulation of lytic genes within the BKRF2-BKRF3-BKRF4 gene locus.
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4.
Consumption of pomegranate decreases plasma lipopolysaccharide-binding protein levels, a marker of metabolic endotoxemia, in patients with newly diagnosed colorectal cancer: a randomized controlled clinical trial.
González-Sarrías, A, Núñez-Sánchez, MA, Ávila-Gálvez, MA, Monedero-Saiz, T, Rodríguez-Gil, FJ, Martínez-Díaz, F, Selma, MV, Espín, JC
Food & function. 2018;(5):2617-2622
Abstract
Gut microbiota dysbiosis alters the intestinal barrier function, increases plasma lipopolysaccharide (LPS) levels, which promotes endotoxemia, and contributes to the onset and development of colorectal cancer (CRC). We report here for the first time the reduction of plasma LPS-binding protein (LBP) levels, a marker of endotoxemia, after pomegranate consumption in newly diagnosed CRC patients.
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5.
Elobixibat, the first-in-class Ileal Bile Acid Transporter inhibitor, for the treatment of Chronic Idiopathic Constipation.
Miner, PB
Expert opinion on pharmacotherapy. 2018;(12):1381-1388
Abstract
Elobixibat is the first in class ileal bile acid transporter (IBAT) inhibitor. IBAT inhibitors block ileal absorption of bile acids by: (1) interrupting the enterohepatic circulation of bile resulting in a fall in serum cholesterol and (2) increasing the delivery of bile acids into the colon. Increasing colonic bile acids causes mucosal fluid secretion and enhances colonic motor activity. Changes in colonic physiology may be useful in treating constipation. Areas covered: In this review, the author reviews the prevalence and medical cost of Chronic Idiopathic Constipation (CIC) and the heterogeneity of the CIC patient population as a complicating factor in drug development and clinical care. He also reviews the history of Bile Acid cathartics and the complex pharmacophysiology of bile therapy with fluid and electrolyte shifts, colonic motor function changes and mucosal immunologic activation. Finally, the author reviews elobixabat development and the clinical trials that demonstrate improvement in constipation. Expert opinion: The early phases of elobixibat development provide confirmation of high IBAT binding affinity which translates into the expected inhibition of enterohepatic bile acid circulation and enhanced delivery of ileal bile acids to the colon associated with expected physiological changes. Elobixibat as a treatment of CIC appears promising.
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6.
The Endotoxemia Marker Lipopolysaccharide-Binding Protein is Reduced in Overweight-Obese Subjects Consuming Pomegranate Extract by Modulating the Gut Microbiota: A Randomized Clinical Trial.
González-Sarrías, A, Romo-Vaquero, M, García-Villalba, R, Cortés-Martín, A, Selma, MV, Espín, JC
Molecular nutrition & food research. 2018;(11):e1800160
Abstract
SCOPE Gut microbiota dysbiosis, intestinal barrier failure, obesity, metabolic endotoxemia, and pro-inflammatory status promote cardiovascular risk. However, the modulation of the gut microbiome to prevent endotoxemia in obesity has been scarcely studied. We investigated the association between gut microbiota modulation and plasma lipopolysaccharide-binding protein (LBP), a surrogate marker of endotoxemia, in overweight-obese individuals. METHODS AND RESULTS In a randomized trial, 49 overweight-obese subjects (body mass index> 27 kg m-2 ) with mild hypelipidemia daily consumed, in a cross-over fashion, two doses (D1 and D2, lasting 3 weeks each) of pomegranate extract (PE) or placebo alternating with 3 weeks of wash-out periods. A significant decrease (p < 0.05) of plasma LBP and a marginal decrease (p = 0.054) of high-sensitivity C-reactive protein were observed, but only after PE-D2 administration (656 mg phenolics). 16S rDNA sequencing analyses revealed the increase of microorganisms important for maintaining normal balance of gut microbiota and gut barrier function, particularly Bacteroides, Faecalibacterium, Butyricicoccus, Odoribacter, and Butyricimonas. PE-D2 also decreased pro-inflammatory microorganisms including Parvimonas, Methanobrevibacter, and Methanosphaera. Remarkably, plasma LBP reduction was significantly associated (p < 0.05) with both Faecalibacterium and Odoribacter increase and Parvimonas decrease. CONCLUSIONS Consumption of PE decreased endotoxemia in overweight-obese individuals by reshaping the gut microbiota, mainly through the modulation of Faecalibacterium, Odoribacter, and Parvimonas.
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7.
Safety, tolerability and pharmacodynamics of apical sodium-dependent bile acid transporter inhibition with volixibat in healthy adults and patients with type 2 diabetes mellitus: a randomised placebo-controlled trial.
Tiessen, RG, Kennedy, CA, Keller, BT, Levin, N, Acevedo, L, Gedulin, B, van Vliet, AA, Dorenbaum, A, Palmer, M
BMC gastroenterology. 2018;(1):3
Abstract
BACKGROUND Pathogenesis in non-alcoholic steatohepatitis (NASH) involves abnormal cholesterol metabolism and hepatic accumulation of toxic free cholesterol. Apical sodium-dependent bile acid transporter (ASBT) inhibition in the terminal ileum may facilitate removal of free cholesterol from the liver by reducing recirculation of bile acids (BAs) to the liver, thereby stimulating new BA synthesis from cholesterol. The aim of this phase 1 study in adult healthy volunteers (HVs) and patients with type 2 diabetes mellitus (T2DM) was to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of ASBT inhibition with volixibat (SHP626; formerly LUM002). METHODS Participants were randomised 3:1 to receive once-daily oral volixibat (0.5 mg, 1 mg, 5 mg or 10 mg) or placebo for 28 days in two cohorts (HV and T2DM). Assessments included safety, faecal BA and serum 7α-hydroxy-4-cholesten-3-one (C4; BA synthesis biomarker). RESULTS Sixty-one individuals were randomised (HVs: placebo, n = 12; volixibat, n = 38; T2DM: placebo, n = 3; volixibat, n = 8). No deaths or treatment-related serious adverse events were reported. Mild or moderate gastrointestinal adverse events were those most frequently reported with volixibat. With volixibat, mean total faecal BA excretion on day 28 was ~1.6-3.2 times higher in HVs (643.73-1239.3 μmol/24 h) and ~8 times higher in T2DM (1786.0 μmol/24 h) than with placebo (HVs: 386.93 μmol/24 h; T2DM: 220.00 μmol/24 h). With volixibat, mean C4 concentrations increased by ~1.3-5.3-fold from baseline to day 28 in HVs and by twofold in T2DM. CONCLUSIONS Volixibat was generally well tolerated. Increased faecal BA excretion and serum C4 levels support the mechanistic rationale for exploring ASBT inhibition in NASH. The study was registered with the Dutch clinical trial authority (Centrale Commissie Mensgebonden Onderzoek; trial registration number NL44732.056.13; registered 24 May 2013).
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8.
Mass Spectrometry-Based Identification of Extracellular Domains of Cell Surface N-Glycoproteins: Defining the Accessible Surfaceome for Immunophenotyping Stem Cells and Their Derivatives.
Fujinaka, CM, Waas, M, Gundry, RL
Methods in molecular biology (Clifton, N.J.). 2018;:57-78
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Abstract
Human stem cells and their progeny are valuable for a variety of research applications and have the potential to revolutionize approaches to regenerative medicine. However, we currently have limited tools to permit live isolation of homogeneous populations of cells apt for mechanistic studies or cellular therapies. While these challenges can be overcome through the use of immunophenotyping based on accessible cell surface markers, the success of this process depends on the availability of reliable antibodies and well-characterized markers, which are lacking for most stem cell lineages. This chapter outlines an iterative process for the development of new cell surface marker barcodes for identifying and selecting stem cell derived progeny of specific cell types, subtypes, and maturation stages, where antibody-independent identification of cell surface proteins is achieved using a modern chemoproteomic approach to specifically identify N-glycoproteins localized to the cell surface. By taking advantage of a large repository of available cell surfaceome data, proteins that are unlikely to confer cell type specificity can be rapidly eliminated from consideration. Subsequently, targeted quantitation by mass spectrometry can be used to refine candidates of interest, and a bioinformatic visualization tool is key to mapping experimental data to candidate protein sequences for the purpose of epitope selection during the antibody development phase. Overall, the process of developing cell surface barcodes for immunophenotyping is iterative and can include multiple rounds of discovery, refinement, and validation depending on the phenotypic resolution required.
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9.
Daratumumab (anti-CD38) induces loss of CD38 on red blood cells.
Sullivan, HC, Gerner-Smidt, C, Nooka, AK, Arthur, CM, Thompson, L, Mener, A, Patel, SR, Yee, M, Fasano, RM, Josephson, CD, et al
Blood. 2017;(22):3033-3037
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10.
Neutrophil elastase cleavage of the gC1q domain impairs the EMILIN1-α4β1 integrin interaction, cell adhesion and anti-proliferative activity.
Maiorani, O, Pivetta, E, Capuano, A, Modica, TM, Wassermann, B, Bucciotti, F, Colombatti, A, Doliana, R, Spessotto, P
Scientific reports. 2017;:39974
Abstract
The extracellular matrix glycoprotein EMILIN1 exerts a wide range of functions mainly associated with its gC1q domain. Besides providing functional significance for adhesion and migration, the direct interaction between α4β1 integrin and EMILIN1-gC1q regulates cell proliferation, transducing net anti-proliferative effects. We have previously demonstrated that EMILIN1 degradation by neutrophil elastase (NE) is a specific mechanism leading to the loss of functions disabling its regulatory properties. In this study we further analysed the proteolytic activity of NE, MMP-3, MMP-9, and MT1-MMP on EMILIN1 and found that MMP-3 and MT1-MMP partially cleaved EMILIN1 but without affecting the functional properties associated with the gC1q domain, whereas NE was able to fully impair the interaction of gC1q with the α4β1 integrin by cleaving this domain outside of the E933 integrin binding site. By a site direct mutagenesis approach we mapped the bond between S913 and R914 residues and selected the NE-resistant R914W mutant still able to interact with the α4β1 integrin after NE treatment. Functional studies showed that NE impaired the EMILIN1-α4β1 integrin interaction by cleaving the gC1q domain in a region crucial for its proper structural conformation, paving the way to better understand NE effects on EMILIN1-cell interaction in pathological context.