First-in-man mesenchymal stem cells for radiation-induced xerostomia (MESRIX):study protocol for a randomized controlled trial.

BACKGROUND: Salivary gland hypofunction and xerostomia are major complications following radiotherapy for head and neck cancer and may lead to debilitating oral disorders and impaired quality of life. Currently, only symptomatic treatment is available. However, mesenchymal stem cell (MSC) therapy has shown promising results in preclinical studies. Objectives are to assess safety and efficacy in a first-in-man trial on adipose-derived MSC therapy (ASC) for radiation-induced xerostomia. METHODS: This is a single-center, phase I/II, randomized, placebo-controlled, double-blinded clinical trial. A total of 30 patients are randomized in a 1:1 ratio to receive ultrasound-guided, administered ASC or placebo to the submandibular glands. The primary outcome is change in unstimulated whole salivary flow rate. The secondary outcomes are safety, efficacy, change in quality of life, qualitative and quantitative measurements of saliva, as well as submandibular gland size, vascularization, fibrosis, and secretory tissue evaluation based on contrast-induced magnetic resonance imaging (MRI) and core-needle samples. The assessments are performed at baseline (1 month prior to treatment) and 1 and 4 months following investigational intervention. DISCUSSION: The trial is the first attempt to evaluate the safety and efficacy of adipose-derived MSCs (ASCs) in patients with radiation-induced xerostomia. The results may provide evidence for the effectiveness of ASC in patients with salivary gland hypofunction and xerostomia and deliver valuable information for the design of subsequent trials. TRIAL REGISTRATION: EudraCT, Identifier: 2014-004349-29. Registered on 1 April 2015. ClinicalTrials.gov, Identifier: NCT02513238. First received on 2 July 2015. The trial is prospectively registered. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13063-017-1856-0) contains supplementary material, which is available to authorized users

Genomic Steppe ancestry in skeletons from the Neolithic Single Grave Culture in Denmark

The Gjerrild burial provides the largest and best-preserved assemblage of human skeletal material presently known from the Single Grave Culture (SGC) in Denmark. For generations it has been debated among archaeologists if the appearance of this archaeological complex represents a continuation of the previous Neolithic communities, or was facilitated by incoming migrants. We sampled and analysed five skeletons from the Gjerrild cist, buried over a period of c. 300 years, 2600/2500-2200 cal BCE. Despite poor DNA preservation, we managed to sequence the genome (>1X) of one individual and the partial genomes (0.007X and 0.02X) of another two individuals. Our genetic data document a female (Gjerrild 1) and two males (Gjerrild 5 + 8), harbouring typical Neolithic K2a and HV0 mtDNA haplogroups, but also a rare basal variant of the R1b1 Y-chromosomal haplogroup. Genome-wide analyses demonstrate that these people had a significant Yamnaya-derived (i.e. steppe) ancestry component and a close genetic resemblance to the Corded Ware (and related) groups that were present in large parts of Northern and Central Europe at the time. Assuming that the Gjerrild skeletons are genetically representative of the population of the SGC in broader terms, the transition from the local Neolithic Funnel Beaker Culture (TRB) to SGC is not characterized by demographic continuity. Rather, the emergence of SGC in Denmark was part of the Late Neolithic and Early Bronze Age population expansion that swept across the European continent in the 3rd millennium BCE, resulting in various degrees of genetic replacement and admixture processes with previous Neolithic populations

Genomic Steppe ancestry in skeletons from the Neolithic Single Grave Culture in Denmark.

The Gjerrild burial provides the largest and best-preserved assemblage of human skeletal material presently known from the Single Grave Culture (SGC) in Denmark. For generations it has been debated among archaeologists if the appearance of this archaeological complex represents a continuation of the previous Neolithic communities, or was facilitated by incoming migrants. We sampled and analysed five skeletons from the Gjerrild cist, buried over a period of c. 300 years, 2600/2500-2200 cal BCE. Despite poor DNA preservation, we managed to sequence the genome (>1X) of one individual and the partial genomes (0.007X and 0.02X) of another two individuals. Our genetic data document a female (Gjerrild 1) and two males (Gjerrild 5 + 8), harbouring typical Neolithic K2a and HV0 mtDNA haplogroups, but also a rare basal variant of the R1b1 Y-chromosomal haplogroup. Genome-wide analyses demonstrate that these people had a significant Yamnaya-derived (i.e. steppe) ancestry component and a close genetic resemblance to the Corded Ware (and related) groups that were present in large parts of Northern and Central Europe at the time. Assuming that the Gjerrild skeletons are genetically representative of the population of the SGC in broader terms, the transition from the local Neolithic Funnel Beaker Culture (TRB) to SGC is not characterized by demographic continuity. Rather, the emergence of SGC in Denmark was part of the Late Neolithic and Early Bronze Age population expansion that swept across the European continent in the 3rd millennium BCE, resulting in various degrees of genetic replacement and admixture processes with previous Neolithic populations

Genomic Steppe ancestry in skeletons from the Neolithic Single Grave Culture in Denmark.

The Gjerrild burial provides the largest and best-preserved assemblage of human skeletal material presently known from the Single Grave Culture (SGC) in Denmark. For generations it has been debated among archaeologists if the appearance of this archaeological complex represents a continuation of the previous Neolithic communities, or was facilitated by incoming migrants. We sampled and analysed five skeletons from the Gjerrild cist, buried over a period of c. 300 years, 2600/2500-2200 cal BCE. Despite poor DNA preservation, we managed to sequence the genome (>1X) of one individual and the partial genomes (0.007X and 0.02X) of another two individuals. Our genetic data document a female (Gjerrild 1) and two males (Gjerrild 5 + 8), harbouring typical Neolithic K2a and HV0 mtDNA haplogroups, but also a rare basal variant of the R1b1 Y-chromosomal haplogroup. Genome-wide analyses demonstrate that these people had a significant Yamnaya-derived (i.e. steppe) ancestry component and a close genetic resemblance to the Corded Ware (and related) groups that were present in large parts of Northern and Central Europe at the time. Assuming that the Gjerrild skeletons are genetically representative of the population of the SGC in broader terms, the transition from the local Neolithic Funnel Beaker Culture (TRB) to SGC is not characterized by demographic continuity. Rather, the emergence of SGC in Denmark was part of the Late Neolithic and Early Bronze Age population expansion that swept across the European continent in the 3rd millennium BCE, resulting in various degrees of genetic replacement and admixture processes with previous Neolithic populations

Calprotectin — A Novel Marker of Obesity

BACKGROUND: The two inflammatory molecules, S100A8 and S100A9, form a heterodimer, calprotectin. Plasma calprotectin levels are elevated in various inflammatory disorders. We hypothesized that plasma calprotectin levels would be increased in subjects with low-grade systemic inflammation i.e. either obese subjects or subjects with type 2 diabetes. METHODOLOGY/PRINCIPAL FINDINGS: Plasma calprotectin and skeletal muscle S100A8 mRNA levels were measured in a cohort consisting of 199 subjects divided into four groups depending on presence or absence of type 2 diabetes (T2D), and presence or absence of obesity. There was a significant interaction between obesity and T2D (p = 0.012). Plasma calprotectin was increased in obese relative to non-obese controls (p<0.0001), whereas it did not differ between obese and non-obese patients with T2D (p = 0.62). S100A8 mRNA levels in skeletal muscle were not influenced by obesity or T2D. Multivariate regression analysis (adjusting for age, sex, smoking and HOMA2-IR) showed plasma calprotectin to be strongly associated with BMI, even when further adjusted for fitness, CRP, TNF-alpha or neutrophil number. CONCLUSIONS/SIGNIFICANCE: Plasma calprotectin is a marker of obesity in individuals without type 2 diabetes