Early and late endothelial response in breast cancer metastasis in mice : simultaneous quantification of endothelial biomarkers using a mass spectrometry-based method

The endothelium plays an important role in cancer metastasis, but the mechanisms involved are still not clear. In the present work, we characterised the changes in endothelial function at early and late stages of breast cancer progression in an orthotopic model of murine mammary carcinoma (4T1 cells). Endothelial function was analysed based on simultaneous microflow liquid chromatography' tandem mass spectrometry using multiple reaction monitoring (microLC/MS-MRM) quantification of 12 endothelium-related biomarkers, including those reflecting glycocalyx disruption' syndecan-1 (SDC-1), endocan (ESM-1); endothelial inflammation' vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), E-selectin (E-sel); endothelial permeability' fms-like tyrosine kinase 1 (FLT-1), angiopoietin 2 (Angpt-2); and haemostasis' von Willebrand factor (vWF), tissue plasminogen activator (t-PA), plasminogen activator inhibitor 1 (PAI-1), as well as those that are pathophysiologically linked to endothelial function' adrenomedullin (ADM) and adiponectin (ADN). The early phase of metastasis in mouse plasma was associated with glycocalyx disruption (increased SDC-1 and ESM-1), endothelial inflammation [increased soluble VCAM-1 (sVCAM-1)] and increased vascular permeability (Angpt-2). During the late phase of metastasis, additional alterations in haemostasis (increased PAI-1 and vWF), as well as a rise in ADM and substantial fall in ADN concentration, were observed. In conclusion, in a murine model of breast cancer metastasis, we identified glycocalyx disruption, endothelial inflammation and increased endothelial permeability as important events in early metastasis, while the late phase of metastasis was additionally characterised by alterations in haemostasis

The prevalence of orodental trauma during epileptic seizures in terms of dental treatment – Survey study

Introduction Epilepsy is one of the most common neurological disorders. Seizures that occur during attacks may lead to head injuries. It is crucial to establish proper prophylactic management against trauma occurrence, as nowadays prevention is not sufficient. Aim Assessment of the frequency of head and intraoral trauma during epileptic seizures and to evaluate factors that may predispose to injuries. Material and Methods The questionnaire was carried out among 106 patients with epilepsy. Survey conducted questions regarding development of the disease and occurrence of orodental and head trauma. Results were statistically analyzed with the chi-square test (p<0.05). Results 52.4% of subjects admitted the occurrence of oral trauma during epileptic seizures. The most common were lips, tongue or cheeks injuries. 18% patients suffered from tooth crack and 17% from tooth fracture. 50% of respondents suffered from head trauma during seizures: 41% patients reported bruises, 39% burns, 37% wounds, 10% nose fractures, 7% eye socket trauma and 3% skull crack. 14.1% of respondents experienced dentist refusal to undertake treatment, while 4% of patients had epileptic attack during dental procedures. Conclusions Dental trauma is common result of epileptic seizures. It is necessary to implement prophylactic management to prevent hard and soft tissues injuries, for example by using custom-made mouthguards. Moreover, specially designed dental programs for this group of patients should be provided

Seasonal adaptation:Geographic photoperiod-temperature patterns explain genetic variation in the common vole <i>Tsh</i> receptor

The vertebrate photoperiodic neuroendocrine system uses the photoperiod as a proxy to time the annual rhythms in reproduction. The thyrotropin receptor (TSHR) is a key protein in the mammalian seasonal reproduction pathway. Its abundance and function can tune sensitivity to the photoperiod. To investigate seasonal adaptation in mammals, the hinge region and the first part of the transmembrane domain of the Tshr gene were sequenced for 278 common vole (Microtus arvalis) specimens from 15 localities in Western Europe and 28 localities in Eastern Europe. Forty-nine single nucleotide polymorphisms (SNPs; twenty-two intronic and twenty-seven exonic) were found, with a weak or lack of correlation with pairwise geographical distance, latitude, longitude, and altitude. By applying a temperature threshold to the local photoperiod-temperature ellipsoid, we obtained a predicted critical photoperiod (pCPP) as a proxy for the spring onset of local primary food production (grass). The obtained pCPP explains the distribution of the genetic variation in Tshr in Western Europe through highly significant correlations with five intronic and seven exonic SNPs. The relationship between pCPP and SNPs was lacking in Eastern Europe. Thus, Tshr, which plays a pivotal role in the sensitivity of the mammalian photoperiodic neuroendocrine system, was targeted by natural selection in Western European vole populations, resulting in the optimized timing of seasonal reproduction.</p

SYK inhibition targets acute myeloid leukemia stem cells by blocking their oxidative metabolism

Spleen tyrosine kinase (SYK) is an important oncogene and signaling mediator activated by cell surface receptors crucial for acute myeloid leukemia (AML) maintenance and progression. Genetic or pharmacologic inhibition of SYK in AML cells leads to increased differentiation, reduced proliferation, and cellular apoptosis. Herein, we addressed the consequences of SYK inhibition to leukemia stem-cell (LSC) function and assessed SYK-associated pathways in AML cell biology. Using gain-of-function MEK kinase mutant and constitutively active STAT5A, we demonstrate that R406, the active metabolite of a small-molecule SYK inhibitor fostamatinib, induces differentiation and blocks clonogenic potential of AML cells through the MEK/ERK1/2 pathway and STAT5A transcription factor, respectively. Pharmacological inhibition of SYK with R406 reduced LSC compartment defined as CD34+CD38-CD123+ and CD34+CD38-CD25+ in vitro, and decreased viability of LSCs identified by a low abundance of reactive oxygen species. Primary leukemic blasts treated ex vivo with R406 exhibited lower engraftment potential when xenotransplanted to immunodeficient NSG/J mice. Mechanistically, these effects are mediated by disturbed mitochondrial biogenesis and suppression of oxidative metabolism (OXPHOS) in LSCs. These mechanisms appear to be partially dependent on inhibition of STAT5 and its target gene MYC, a well-defined inducer of mitochondrial biogenesis. In addition, inhibition of SYK increases the sensitivity of LSCs to cytarabine (AraC), a standard of AML induction therapy. Taken together, our findings indicate that SYK fosters OXPHOS and participates in metabolic reprogramming of AML LSCs in a mechanism that at least partially involves STAT5, and that SYK inhibition targets LSCs in AML. Since active SYK is expressed in a majority of AML patients and confers inferior prognosis, the combination of SYK inhibitors with standard chemotherapeutics such as AraC constitutes a new therapeutic modality that should be evaluated in future clinical trials

Ancient DNA reveals interstadials as a driver of common vole population dynamics during the last glacial period

Aim Many species experienced population turnover and local extinction during the Late Pleistocene. In the case of megafauna, it remains challenging to disentangle climate change and the activities of Palaeolithic hunter-gatherers as the main cause. In contrast, the impact of humans on rodent populations is likely to be negligible. This study investigated which climatic and/or environmental factors affect the population dynamics of the common vole. This temperate rodent is widespread across Europe and was one of the most abundant small mammal species throughout the Late Pleistocene. Location Europe. Taxon Common vole (Microtus arvalis). Methods We generated a dataset comprised of 4.2 kb long fragment of mitochondrial DNA (mtDNA) from 148 ancient and 51 modern specimens sampled from multiple localities across Europe and covering the last 60 thousand years (ka). We used Bayesian inference to reconstruct their phylogenetic relationships and to estimate the age of the specimens that were not directly dated. Results We estimated the time to the most recent common ancestor of all last glacial and extant common vole lineages to be 90 ka ago and the divergence of the main mtDNA lineages present in extant populations to between 55 and 40 ka ago, which is earlier than most previous estimates. We detected several lineage turnovers in Europe during the period of high climate variability at the end of Marine Isotope Stage 3 (MIS 3; 57-29 ka ago) in addition to those found previously around the Pleistocene/Holocene transition. In contrast, data from the Western Carpathians suggest continuity throughout the Last Glacial Maximum (LGM) even at high latitudes. Main Conclusions The main factor affecting the common vole populations during the last glacial period was the decrease in open habitat during the interstadials, whereas climate deterioration during the LGM had little impact on population dynamics. This suggests that the rapid environmental change rather than other factors was the major force shaping the histories of the Late Pleistocene faunas.info:eu-repo/semantics/publishedVersio

Use of entomotoxicology in estimating post-mortem interval and determining cause of death

Entomotoksykologia pozwala na oszacowanie czasu i przyczyny zgonu w przypadkach, gdy zwłoki uległy rozkładowi i tkanki niezbędne do analiz toksykologicznych nie są już dostępne. Uzyskanie informacji o potencjalnie obecnych w ciele denata substancjach toksycznych jest możliwe poprzez ich izolację z obecnych na zwłokach lub w ich pobliżu larw i poczwarek przedstawicieli muchówek (Diptera) i/lub osobników dorosłych, np. chrząszczy (Coleoptera). Celem artykułu jest podsumowanie dotychczasowego stanu wiedzy z zakresu entomotoksykologii z wykorzystaniem przykładów z literatury oraz zaprezentowanie wpływu wybranych substancji toksycznych i leków na rozwój żerujących na zwłokach larw owadów.Entomotoxicology allows the estimation of the post-mortem interval and the determination of the cause of death in cases in which the corpse has decomposed and the tissues necessary for toxicological analysis are no longer available. Obtaining information about toxic substances potentially present in the body is possible by isolation of larvae and pupae of true flies (Diptera) and/or adult forms of, e.g., beetles (Coleoptera) present on or near the corpse. This article was intended to summarize the current knowledge in the field of entomotoxicology, including examples from the literature, and to present the impact of selected toxic substances and medicines on the development of necrophagous larvae of insects

Use of molecular methods in the identification of the species, age and sex of insects useful in forensic entomology

Entomologia sądowa wykorzystuje owady do ustalania czasu i przyczyny śmierci, a nawet miejsca, w którym nastąpiła. W tym celu stosowane są dwie metody. Metoda rozwojowa opiera się na wzorcach rozwoju larw w określonych warunkach temperaturowo-środowiskowych. Metoda sukcesyjna analizuje występujące w różnych środowiskach wzorce pojawiania się poszczególnych taksonów na zwłokach. W obu tych metodach najistotniejszą kwestią jest poprawna identyfikacja gatunków. W poniższym artykule zaprezentowane zostały molekularne metody identyfikacji, takie jak barkoding DNA czy analiza krzywych denaturacji DNA o wysokiej rozdzielczości (DNA-HRM-PCR).Forensic entomology uses insects to determine the time, cause and place of death. To this end, two entomological methods are used. The development-based method uses the patterns of insect larvae development under the specific thermal and environmental conditions. The succession-based method analyzes the sequence of insect succession on the body in various environmental conditions. The proper insect species identification is essential in both methods. In this article, the molecular methods of species, age and sex identification are presented such as DNA barcoding or DNA-HRM-PCR

Phylogeography of mammals in Europe - research conception and selected qestions

Filogeografia zajmuje się poznawaniem zasad i procesów rządzących geograficznym rozmieszeniem linii rodowych (genetycznych), a w szczególności tych w obrębie jednego gatunku lub pomiędzy blisko spokrewnionymi gatunkami. W celu ustalenia i zobrazowania ewolucyjnych zależności pomiędzy liniami genetycznymi wykorzystywane są techniki biologii molekularnej (jądrowe i mitochondrialne markery DNA), paleontologia (datowanie skamieniałości) oraz narzędzia bioinformatyczne. Informacje te pozwalają na scharakteryzowanie struktury filogeograficznej ssaków w Europie (m.in. identyfikację stref wtórnego kontaktu i terenów stanowiących refugia glacjalne), odtworzenie najbardziej prawdopodobnego scenariusza wtórnego zasiedlania terenów polodowcowych oraz oszacowanie wpływu ostatniego zlodowacenia na postglacjalną historię ssaków w Europie.Phylogeography is a field of study concerned with the principles and processes governing the geographic distributions of genealogical lineages, especially those within and among closely related species. To establish and illustrate the evolutionary relationships between genetic lineages nuclear and mitochondrial DNA markers, fossil records and bioinformatics are used. The obtained information has allowed characterization of phylogeographic patterns in European mammal populations (e.g. identification of post-glacial suture zones and glacial refugia), reconstruction of the most probable post-glacial recolonization scenarios and estimation of how the Last Glacial Maximum influenced the post-glacial history of mammals in Europe