Effect of sodium restriction on blood pressure of unstable or uncontrolled hypertensive patients in primary care

BACKGROUND/OBJECTIVES: The aims of the present study are: 1) to quantify sodium consumption of patients with unstable or uncontrolled hypertension, 2) to investigate if reduced sodium intake can lower BP in these patients, and 3), to assess the acceptability and feasibility of this approach. SUBJECTS/METHODS: This study included 25 adults (age: 50+ years) with frequently elevated BP or patients with uncontrolled, uncomplicated hypertension despite drug treatment in a general practice setting. BP and salt intake (24h urinary excretion and food records) were measured at baseline and after a sodium reduced diet. RESULTS: Mean (+/- SD) systolic (SBP) over diastolic (DBP) blood pressure (mmHg) at baseline was 150.7 (+/- 9.5)/84.149 (+/- 5.6). Mean urinary sodium excretion was 146 mmo1/24h. A reduction of 28 mmol sodium excretion decreased SBP/DBP to 135.5 (+/- 13.0)/82.5 (+/- 12.8) (P < 0.001). After one month of no dietary advice, only in 48%, SBP was still <= 140 mmHg. CONCLUSION: Assessment of sodium intake using food records, 24h urine collections and probing questions to identify use of sodium containing supplements or drugs are essential for tailored advice targeted at sodium intake reduction. The results of the present study indicate that reduced sodium intake can lower BP after 4 weeks in unstable or uncontrolled hypertensive patients

Community standards for open cell migration data

Cell migration research has become a high-content field. However, the quantitative information encapsulated in these complex and high-dimensional datasets is not fully exploited owing to the diversity of experimental protocols and non-standardized output formats. In addition, typically the datasets are not open for reuse. Making the data open and Findable, Accessible, Interoperable, and Reusable (FAIR) will enable meta-analysis, data integration, and data mining. Standardized data formats and controlled vocabularies are essential for building a suitable infrastructure for that purpose but are not available in the cell migration domain. We here present standardization efforts by the Cell Migration Standardisation Organisation (CMSO), an open community-driven organization to facilitate the development of standards for cell migration data. This work will foster the development of improved algorithms and tools and enable secondary analysis of public datasets, ultimately unlocking new knowledge of the complex biological process of cell migration

TP53 outperforms other androgen receptor biomarkers to predict abiraterone or enzalutamide outcome in metastatic castration-resistant prostate cancer

Purpose: To infer the prognostic value of simultaneous androgen receptor (AR) and TP53 profiling in liquid biopsies from patients with metastatic castration-resistant prostate cancer (mCRPC) starting a new line of AR signaling inhibitors (ARSi). Experimental Design: Between March 2014 and April 2017, we recruited patients with mCRPC (n = 168) prior to ARSi in a cohort study encompassing 10 European centers. Blood samples were collected for comprehensive profiling of Cell Search-enriched circulating tumor cells (CTC) and circulating tumor DNA (ctDNA). Targeted CTC RNA sequencing (RNA-seq) allowed the detection of eight AR splice variants (ARV). Low-pass whole-genome and targeted gene-body sequencing of AR and TP53 was applied to identify amplifications, loss of heterozygosity, mutations, and structural rearrangements in ctDNA. Clinical or radiologic progression-free survival (PFS) was estimated by Kaplan-Meier analysis, and independent associations were determined using multivariable Cox regression models. Results: Overall, no single AR perturbation remained associated with adverse prognosis after multivariable analysis. Instead, tumor burden estimates (CTC counts, ctDNA fraction, and visceral metastases) were significantly associated with PFS. TP53 inactivation harbored independent prognostic value [HR 1.88; 95% confidence interval (CI), 1.18-3.00; P = 0.008], and outperformed ARV expression and detection of genomic AR alterations. Using Cox coefficient analysis of clinical parameters and TP53 status, we identified three prognostic groups with differing PFS estimates (median, 14.7 vs. 7.51 vs. 2.62 months; P < 0.0001), which was validated in an independent mCRPC cohort (n = 202) starting first-line ARSi (median, 14.3 vs. 6.39 vs. 2.23 months; P < 0.0001). Conclusions: In an all-comer cohort, tumor burden estimates and TP53 outperform any AR perturbation to infer prognosis. See related commentary by Rebello et al., p. 169

Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis.

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.BACKGROUND: There are multiple existing and emerging therapeutic avenues for metastatic prostate cancer, with a common denominator, which is the need for predictive biomarkers. Circulating tumor DNA (ctDNA) has the potential to cost-efficiently accelerate precision medicine trials to improve clinical efficacy and diminish costs and toxicity. However, comprehensive ctDNA profiling in metastatic prostate cancer to date has been limited. METHODS: A combination of targeted and low-pass whole genome sequencing was performed on plasma cell-free DNA and matched white blood cell germline DNA in 364 blood samples from 217 metastatic prostate cancer patients. RESULTS: ctDNA was detected in 85.9% of baseline samples, correlated to line of therapy and was mirrored by circulating tumor cell enumeration of synchronous blood samples. Comprehensive profiling of the androgen receptor (AR) revealed a continuous increase in the fraction of patients with intra-AR structural variation, from 15.4% during first-line metastatic castration-resistant prostate cancer therapy to 45.2% in fourth line, indicating a continuous evolution of AR during the course of the disease. Patients displayed frequent alterations in DNA repair deficiency genes (18.0%). Additionally, the microsatellite instability phenotype was identified in 3.81% of eligible samples (≥ 0.1 ctDNA fraction). Sequencing of non-repetitive intronic and exonic regions of PTEN, RB1, and TP53 detected biallelic inactivation in 47.5%, 20.3%, and 44.1% of samples with ≥ 0.2 ctDNA fraction, respectively. Only one patient carried a clonal high-impact variant without a detectable second hit. Intronic high-impact structural variation was twice as common as exonic mutations in PTEN and RB1. Finally, 14.6% of patients presented false positive variants due to clonal hematopoiesis, commonly ignored in commercially available assays. CONCLUSIONS: ctDNA profiles appear to mirror the genomic landscape of metastatic prostate cancer tissue and may cost-efficiently provide somatic information in clinical trials designed to identify predictive biomarkers. However, intronic sequencing of the interrogated tumor suppressors challenges the ubiquitous focus on coding regions and is vital, together with profiling of synchronous white blood cells, to minimize erroneous assignments which in turn may confound results and impede true associations in clinical trials.The Belgian Foundation Against Cancer (grant number C/2014/227); Kom op tegen Kanker (Stand up to Cancer), the Flemish Cancer Society (grant number 00000000116000000206); Royal College of Surgeons/Cancer Research UK (C19198/A1533); The Cancer Research Funds of Radiumhemmet, through the PCM program at KI (grant number 163012); The Erling-Persson family foundation (grant number 4-2689-2016); the Swedish Research Council (grant number K2010-70X-20430-04-3), and the Swedish Cancer Foundation (grant number 09-0677)

Activation of PAC1 by maxadilan: a new human target engagement biomarker

Activation of PAC1 by maxadilan: a new human target engagement biomarker Linde Buntinx1*, Marleen Depre1, Els Ampe1, Anne Vanhecken1 and Jan De Hoon1 1 Center for Clinical Pharmacology, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium Background: Maxadilan, isolated from the sand fly Lutzomyia longipalpis, is a potent vasodilator peptide activating the mammalian PAC1 receptor, a promising target for migraine therapy (1). Therefore, maxadilan is suggested as a target-engagement tool to study PAC1 antagonists. Objectives: (1) To determine, as a first in human study, the dose response, safety and time course of the dermal blood flow (DBF) after intradermal (ID) injections of maxadilan in the human forearm and (2) to assess the inter-arm and inter-period reproducibility of this response, as measured with Laser Doppler Imaging (LDI). Results: Maxadilan was found to be safe based on AE reporting, ECG, vital signs, physical examination and safety laboratory assessments. ID maxadilan (0.9, 3 and 10ng) produced a robust increase in DBF compared to baseline and placebo. Forearm DBF response to 0.9ng ID injections of maxadilan in healthy male volunteers was reproducible between periods (Concordance correlation coefficient (CCC)>0.7) and between arms (CCC>0.7) when data were calculated as AUC0-180min (perfusion units*min). An increase in DBF was observed already 5 minutes after maxadilan injection and reached a plateau-phase after 60 minutes lasting until 72 hours, with an unexpected peak at 24 hours, compared to baseline and placebo. Sample size calculations show that samples of approximately 10 subjects are sufficient to detect a 50% difference between 2 independent groups with 80% power. Conclusion: As intradermal injections of maxadilan induce reproducible changes in dermal blood flow, it is an appealing new target-engagement biomarker for the study of PAC1 receptor antagonists in early clinical development studies. References: 1. Lerner EA, Iuga AO, Reddy VB. Maxadilan, a PAC1 receptor agonist from sand flies. Peptides 2007 28: 1651-4.status: publishe

The effect of sodium lauryl sulphate and triclosan on hamster cheek pouch mucosa

It has recently been shown that triclosan protects the human skin from the inflammation that may be caused by exposure to sodium lauryl sulphate (SLS). The aim of the present study was to examine whether triclosan can protect the hamster cheek pouch mucosa from the irritation caused by exposure to SLS. After four daily applications of a paste containing SLS, the epithelium of the hamster cheek pouch showed consistently prominent structural changes, especially basal hyperplasia, acanthosis, hypergranulosis, and hyperkeratosis. Identical morphological changes were also observed after applications of a paste containing SLS together with triclosan. In contrast, after applications of a paste containing triclosan alone, the cheek pouch mucosa revealed a histological structure essentially similar to the non-treated control mucosa. From these results, we may conclude that SLS, but not triclosan, irritates the hamster cheek pouch epithelium. Moreover, triclosan does not protect the cheek pouch mucosa against structural changes induced by SLS. It must be taken into account that triclosan does not always offer protection against the side-effects of SLS

Analysis of three human interleukin 5 structures suggests a possible receptor binding mechanism.

AbstractWe compared three crystal structures of human interleukin 5 (hIL5) expressed in either E. coli (hIL5E.coli), Sf9 cells (hIL5Sf9) or Drosophila cells (hIL5Drosophila). The dimeric hIL5 structures show subtle but significant conformational differences which are probably a consequence of the different crystallization conditions trapping this protein into one of two states. We refer to these two distinct conformations as the `open' and `tight' state, according to the packing around the cleft between the two subunits. We hypothesize that these two stable conformational states reflect the structure of the free or receptor bound hIL5

β-agonists selectively modulate proinflammatory gene expression in skeletal muscle cells via non-canonical nuclear crosstalk mechanisms.

The proinflammatory cytokine Tumour Necrosis Factor (TNF)-α is implicated in a variety of skeletal muscle pathologies. Here, we have investigated how in vitro cotreatment of skeletal muscle C2C12 cells with β-agonists modulates the TNF-α-induced inflammatory program. We observed that C2C12 myotubes express functional TNF receptor 1 (TNF-R1) and β2-adrenoreceptors (β2-ARs). TNF-α activated the canonical Nuclear Factor-κB (NF-κB) pathway and Mitogen-Activated Protein Kinases (MAPKs), culminating in potent induction of NF-κB-dependent proinflammatory genes. Cotreatment with the β-agonist isoproterenol potentiated the expression of inflammatory mediators, including Interleukin-6 (IL-6) and several chemokines. The enhanced production of chemotactic factors upon TNF-α/isoproterenol cotreatment was also suggested by the results from migrational analysis. Whereas we could not explain our observations by cytoplasmic crosstalk, we found that TNF-R1-and β2-AR-induced signalling cascades cooperate in the nucleus. Using the IL-6 promoter as a model, we demonstrated that TNF-α/isoproterenol cotreatment provoked phosphorylation of histone H3 at serine 10, concomitant with enhanced promoter accessibility and recruitment of the NF-κB p65 subunit, cAMP-response element-binding protein (CREB), CREB-binding protein (CBP) and RNA polymerase II. In summary, we show that β-agonists potentiate TNF-α action, via nuclear crosstalk, that promotes chromatin relaxation at selected gene promoters. Our data warrant further study into the mode of action of β-agonists and urge for caution in their use as therapeutic agents for muscular disorders