Lungesyge (Tuberkulose) hos Kvæget.

Lungesyge (Tuberkulose) hos Kvæget

BRAF(V600) inhibition alters the microRNA cargo in the vesicular secretome of malignant melanoma cells

The BRAF inhibitors vemurafenib and dabrafenib can be used to treat patients with metastatic melanomas harboring BRAF(V600) mutations. Initial antitumoral responses are often seen, but drug-resistant clones with reactivation of the MEK-ERK pathway soon appear. Recently, the secretome of tumor-derived extracellular vesicles (EVs) has been ascribed important functions in cancers. To elucidate the possible functions of EVs in BRAF-mutant melanoma, we determined the RNA content of the EVs, including apoptotic bodies, microvesicles, and exosomes, released from such cancer cells after vemurafenib treatment. We found that vemurafenib significantly increased the total RNA and protein content of the released EVs and caused significant changes in the RNA profiles. RNA sequencing and quantitative PCR show that cells and EVs from vemurafenib-treated cell cultures and tumor tissues harvested from cell-derived and patient-derived xenografts harbor unique miRNAs, especially increased expression of miR-211-5p. Mechanistically, the expression of miR-211-5p as a result of BRAF inhibition was induced by increased expression of MITF that regulates the TRPM1 gene resulting in activation of the survival pathway. In addition, transfection of miR-211 in melanoma cells reduced the sensitivity to vemurafenib treatment, whereas miR-211-5p inhibition in a vemurafenib resistant cell line affected the proliferation negatively. Taken together, our results show that vemurafenib treatment induces miR-211-5p up-regulation in melanoma cells both in vitro and in vivo, as well as in subsets of EVs, suggesting that EVs may provide a tool to understand malignant melanoma progression.1114sciescopu

Investigating dietary life histories and mobility of children buried in St Gertrude Church Cemetery, Riga, Latvia (15th– 17th centuries AD)

Carbon and nitrogen isotope profiles were obtained from incremental dentine analysis of 19 non‐adults from a cemetery in Riga, Latvia. The research compared the life histories and diet between people buried in two mass graves and the general cemetery. The δ13C profiles of several children from the mass graves were similar but did not resemble the patterns seen in children from the general cemetery, suggesting that they probably represented a different population group. The rise in δ15N values towards the end of the life of four individuals from one mass grave suggests they were victims of an historically documented famine

A patient-derived xenograft pre-clinical trial reveals treatment responses and a resistance mechanism to karonudib in metastatic melanoma

Karonudib (TH1579) is a novel compound that exerts anti-tumor activities and has recently entered phase I clinical testing. The aim of this study was to conduct a pre-clinical trial in patient-derived xenografts to identify the possible biomarkers of response or resistance that could guide inclusion of patients suffering from metastatic melanoma in phase II clinical trials. Patient-derived xenografts from 31 melanoma patients with metastatic disease were treated with karonudib or a vehicle for 18 days. Treatment responses were followed by measuring tumor sizes, and the models were categorized in the response groups. Tumors were harvested and processed for RNA sequencing and protein analysis. To investigate the effect of karonudib on T-cell-mediated anti-tumor activities, tumor-infiltrating T cells were injected in mice carrying autologous tumors and the mice treated with karonudib. We show that karonudib has heterogeneous anti-tumor effect on metastatic melanoma. Thus, based on the treatment responses, we could divide the 31 patient-derived xenografts in three treatment groups: progression group (32%), suppression group (42%), and regression group (26%). Furthermore, we show that karonudib has anti-tumor effect, irrespective of major melanoma driver mutations. Also, we identify high expression of ABCB1, which codes for p-gp pumps as a resistance biomarker. Finally, we show that karonudib treatment does not hamper T-cell-mediated anti-tumor responses. These findings can be used to guide future use of karonudib in clinical use with a potential approach as precision medicine

A novel length back-calculation approach accounting for ontogenetic changes in the fish length – otolith size relationship during the early life of sprat (Sprattus sprattus)

(Sprattus sprattus), accounting for ontogenetic changes in the relationship between fish length and otolith length. In sprat, metamorphosis from larvae to juveniles is characterized by the coincidence of low length growth, strong growth in body height, and maximal otolith growth. Consequently, the method identifies a point of metamorphosis for an individual as the otolith radius at maximum increment widths. By incorporating this information in our back-calculation method, estimated length growth for the early larval stage was more than 60% higher compared with the result of the biological intercept model. After minimal length growth during metamorphosis, we found the highest increase in length during the early juvenile stage. We thus located the strongest growth potential in the early juvenile stage, which is supposed to be critical in determining recruitment strength in Baltic sprat

The persistence of epiphyseal scars in the distal radius in adult individuals

The use of radiographic imaging in the estimation of chronological age facilitates the analysis of structures not visible on gross morphological inspection. Following the completion of epiphyseal fusion, a thin radio-opaque band, the epiphyseal scar, may be observed at the locus of the former growth plate. The obliteration of this feature has previously been interpreted as the final stage of skeletal maturation and consequently has been included as a criterion in several methods of age estimation, particularly from the distal radius. Due to the recommendations relating to age estimation in living individuals, accurate assessment of age from the distal radius is of great importance in human identification; however, the validity of the interpretation of the obliteration of the epiphyseal scar as an age-related process has not been tested. A study was undertaken to assess the persistence of epiphyseal scars in adults between 20 and 50 years of age through the assessment of 616 radiographs of left and right distal radii from a cross-sectional population. This study found that 86 % of females and 78 % of males retained some remnant of the epiphyseal scar in the distal radius. The relationships between chronological age, biological sex and the persistence of the epiphyseal scar were not statistically significant. The findings of this study indicate that the epiphyseal scars may persist in adult individuals until at least 50 years of age. No maximum age should therefore be applied to the persistence of an epiphyseal scar in the distal radius

The cystic fibrosis microbiome in an ecological perspective and its impact in antibiotic therapy

The recent focus on the cystic fibrosis (CF) complex microbiome has led to the recognition that the microbes can interact between them and with the host immune system, affecting the disease progression and treatment routes. Although the main focus remains on the interactions between traditional pathogens, growing evidence supports the contribution and the role of emergent species. Understanding the mechanisms and the biological effects involved in polymicrobial interactions may be the key to improve effective therapies and also to define new strategies for disease control. This review focuses on the interactions between microbe-microbe and host-microbe, from an ecological point of view, discussing their impact on CF disease progression. There are increasing indications that these interactions impact the success of antimicrobial therapy. Consequently, a new approach where therapy is personalized to patients by taking into account their individual CF microbiome is suggested.Portuguese Foundation for Science and Technology (FCT), the strategic funding of UID/BIO/04469/2013-CEB and UID/EQU/00511/2013-LEPABE units. This study was also supported by FCT and the European Community fund FEDER, through Program COMPETE, under the scope of the Projects “DNA mimics” PIC/IC/82815/2007, RECI/BBB-EBI/0179/2012 (FCOMP-01-0124-FEDER-027462), “BioHealth—Biotechnology and Bioengineering approaches to improve health quality”, Ref. NORTE-07-0124-FEDER-000027 and NORTE-07-0124-FEDER-000025—RL2_ Environment and Health, co-funded by the Programa Operacional Regional do Norte (ON.2 – O Novo Norte), QREN, FEDER. The authors also acknowledge the grant of Susana P. Lopes (SFRH/BPD/95616/2013) and of the COST-Action TD1004: Theragnostics for imaging and therapy