Cosmic rays can drive strong outflows from gas-rich high-redshift disk galaxies

We present simulations of the magnetized interstellar medium (ISM) in models of massive star forming (40 Msun / yr) disk galaxies with high gas surface densities (~100 Msun / pc^2) similar to observed star forming high-redshift disks. We assume that type II supernovae deposit 10 per cent of their energy into the ISM as cosmic rays and neglect the additional deposition of thermal energy or momentum. With a typical Galactic diffusion coefficient for CRs (3e28 cm^2 / s) we demonstrate that this process alone can trigger the local formation of a strong low density galactic wind maintaining vertically open field lines. Driven by the additional pressure gradient of the relativistic fluid the wind speed can exceed 1000 km/s, much higher than the escape velocity of the galaxy. The global mass loading, i.e. the ratio of the gas mass leaving the galactic disk in a wind to the star formation rate becomes of order unity once the system has settled into an equilibrium. We conclude that relativistic particles accelerated in supernova remnants alone provide a natural and efficient mechanism to trigger winds similar to observed mass-loaded galactic winds in high-redshift galaxies. These winds also help explaining the low efficiencies for the conversion of gas into stars in galaxies as well as the early enrichment of the intergalactic medium with metals. This mechanism can be at least of similar importance than the traditionally considered momentum feedback from massive stars and thermal and kinetic feedback from supernova explosions.Comment: 5 pages, 5 figures, accepted in ApJL; corrected titl

Plasma centrifugation does not influence thrombin-antithrombin and plasmin-antiplasmin levels but determines platelet microparticles count

Introduction: Centrifugation is an essential step for plasma preparation to remove residual elements in plasma, especially platelets and platelet-derived microparticles (PMPs). Our working hypothesis was that centrifugation as a preanalytical step may influence some coagulation parameters. Materials and methods: Healthy young men were recruited (N = 17). For centrifugation, two protocols were applied: (A) the first centrifugation at 2500 x g for 15 min and (B) at 2500 x g for 20 min at room temperature with a light brake. In protocol (A), the second centrifugation was carried out at 2500 x g for 15 min, whereas in protocol (B), the second centrifugation involved a 10 min spin at 13,000 x g. Thrombin-antithrombin (TAT) and plasmin-antiplasmin (PAP) complexes concentrations were determined by enzyme-linked immunosorbent assays. PMPs were stained with CD41 antibody and annexin V, and analyzed by flow cytometry method. Procoagulant activity was assayed by the Calibrated Automated Thrombogram method as a slope of thrombin formation (CAT velocity). Results: Median TAT and PAP concentrations did not differ between the centrifugation protocols. The high speed centrifugation reduced the median (IQR) PMP count in plasma from 1291 (841-1975) to 573 (391-1010) PMP/µL (P = 0.001), and CAT velocity from 2.01 (1.31-2.88) to 0.97 (0.82-1.73) nM/min (P = 0.049). Spearman’s rank correlation analysis showed correlation between TAT and PMPs in the protocol A plasma which was (rho = 0.52, P < 0.050) and between PMPs and CAT for protocol A (rho = 0.74, P < 0.050) and protocol B (rho = 0.78, P < 0.050). Conclusion: Centrifugation protocols do not influence the markers of plasminogen (PAP) and thrombin (TAT) generation but they do affect the PMP count and procoagulant activit

Comparison of mutation profile between primary phyllodes tumors of the breast and their paired local recurrences

Phyllodes tumor of the breast (PTB) is a rare neoplasm and accounts for 0.2-2.0% of breast cancer in women. Histopathological diagnosis of the tumor is difficult, and histological features do not always predict the course of the disease and the risk of progression. Pathogenesis and molecular biological characteristics as well as PTB prognostic factors are unknown. In search for genetic factors affecting PTB progression, 10 patients were analyzed for whom material from the primary tumor and local recurrence was available. DNA isolated from paraffin blocks was sequenced using the next-generation sequencing method (NGS). In 4 pairs, consisting of primary tumor and local recurrence, probably pathogenic/pathogenic variants were detected, and in three pairs they were observed in the CDKN2A gene, while other variants were found in PTEN and TP53 genes. NGS results indicate that the above-mentioned variants are hereditary, which suggests that the CDKN2A gene might be involved in cancerogenesis of PTB. Additionally, the selected pathogenic variant of EGFR gene was exclusively detected in one recuurent tumor, which might suggest the involvement of this gene in the mechanism of progression. In order to determine if this variant is associated with progression, the frequency of this mutation should be examined in larger group of malignant and borderline tumors

Relevance of mutations in protein deubiquitinases genes and TP53 in corticotroph pituitary tumors

IntroductionCorticotroph pituitary neuroendocrine tumors (PitNETs) develop from ACTH-producing cells. They commonly cause Cushing’s disease (CD), however, some remain clinically silent. Recurrent USP8, USP48, BRAF and TP53 mutations occur in corticotroph PitNETs. The aim of our study was to determine frequency and relevance of these mutations in a possibly large series of corticotroph PitNETs.MethodsStudy included 147 patients (100 CD and 47 silent tumors) that were screened for hot-spot mutations in USP8, USP48 and BRAF with Sanger sequencing, while 128 of these patients were screened for TP53 mutations with next generation sequencing and immunohistochemistry.ResultsUSP8 mutations were found in 41% CD and 8,5% silent tumors, while USP48 mutations were found in 6% CD patients only. Both were more prevalent in women. They were related to higher rate of biochemical remission, non-invasive tumor growth, its smaller size and densely granulated histology, suggesting that these mutation may be favorable clinical features. Multivariate survival analyses did not confirm possible prognostic value of mutation in protein deubiquitinases. No BRAF mutations were found. Four TP53 mutations were identified (2 in CD, 2 in silent tumors) in tumors with size &gt;10mm including 3 invasive ones. They were found in Crooke’s cell and sparsely granulated tumors. Tumors with missense TP53 mutations had higher TP53 immunoreactivity score than wild-type tumors. Tumor with frameshift TP53 variant had low protein expression. TP53 mutation was a poor prognostic factor in CD according to uni- and multivariate survival analyses in spite of low mutations frequency.ConclusionsWe confirmed high prevalence of USP8 mutations and low incidence of USP48 and TP53 mutations. Changes in protein deubiquitinases genes appear to be favorable prognostic factors in CD. TP53 mutations are rare, occur in both functioning and silent tumors and are related to poor clinical outcome in CD

Inflammatory Proteins HMGA2 and PRTN3 as Drivers of Vulvar Squamous Cell Carcinoma Progression.

Current knowledge on the biology of squamous cell vulvar carcinoma (VSCC) is limited. We aimed to identify protein markers of VSCC tumors that would permit to stratify patients by progression risk. Early-stage tumors from patients who progressed (progVSCC) and from those who were disease-free (d-fVSCC) during follow-up, along with normal vulvar tissues were examined by mass spectrometry-based proteomics. Differentially expressed proteins (DEPs) were then verified in solid tissues and blood samples of patients with VSCC tumors and vulvar premalignant lesions. In progVSCC vs. d-fVSCC tumors, the immune response was the most over-represented Gene Ontology category for the identified DEPs. Pathway profiling suggested bacterial infections to be linked to aggressive VSCC phenotypes. High Mobility Group AT-Hook 2 (HMGA2) and Proteinase 3 (PRTN3) were revealed as proteins predicting VSCC progression. HMGA2 and PRTN3 abundances are associated with an aggressive phenotype, and hold promise as markers for VSCC patient stratification. It appears that vulvovaginal microflora disturbances trigger an inflammatory response contributing to cancer progression, suggesting that bacterial rather than viral infection status should be considered in the development of targeted therapies in VSCC

Monoclonal gammopathy of undetermined significance – the role of genetic and infectious agents in the pathogenesis of the disease

Monoclonal gammopathy of undetermined significance (MGUS) is a disorder characterized by an increased concentration of one type of immunoglobulin following a clonal proliferation of plasma cells. The etiology and pathogenesis of MGUS are not fully understood. The risk factors of proven importance include family history and hormonal factors. Recently carried out cohort studies have shown that the molecular abnormalities in this disease are connected with specific loci in the genome, i.e. 2p, 3p and 7p, within which the following genes have been identified: DNMT3A and DTNB (2p), and TRAK1 ULK4 (3p) and CDCA7L (7p). Both the invalid responses to auto- and exoantigens are the factors contributing to the formation of cytogenetic and molecular abnormalities. So far, little attention had been paid to the role of infections in the development and progression of MGUS to multiple myeloma (MM). Only an increased susceptibility to infections and a significant reduction of specific antibodies against various pathogens (i. e. Streptococcus pneumoniae) were documented in patients with MGUS. This paper aims to explain the role of known and newly discovered genetic factors in the development and progression of MGUS, and an indication of the important role of infections in the course of the disease and to draw attention to the necessity of the immunoprophylaxis

Przydatność określania obecności mutacji BRAF V600E w biopsji aspiracyjnej celowanej cienkoigłowej w zmianach niezdeterminowanych

  Introduction: Fine-needle aspiration biopsy (FNAB) is regarded as the gold standard method for the diagnosis of thyroid nodules, but it has its limitations. Additional methods that would improve sensitivity and specificity in the diagnosis of thyroid cancer (TC), especially in indeterminate lesions. Molecular tests seem to be such a tool. BRAF V600E mutation (the most common in TC) can be detected in FNAB and can be potentially a very useful ancillary marker for FNAB practice. The aim of our study was to evaluate the usefulness of the detection of the BRAF V600E mutation in FNAC in the early diagnosis of TC in patients with indeterminate cytology. Material and method: 2290 FNAB were performed and 147 indeterminate results (group 3, 4, and 5 of the Bethesda system) were obtained. Material from these groups was submitted for molecular tests for the occurrence of BRAF V600E mutation. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the tests were calculated. Results: Determining the presence of BRAF V600E mutation in FNAC material in groups 3 and 4 together and in group 5 is associated with sensitivity of TC diagnosis of 37.5% and 81.8%, respectively. In all cases the detection of BRAF V600E mutation was associated with histopathologically proving the presence of TC (specificity of the test — 100%). Conclusions: The presence of BRAF V600E mutation in FNAC material is always associated with the presence of TC. The usefulness of determining the presence of BRAF V600E in FNAC in cytological groups 3 and 4 is associated with low sensitivity in the diagnosis of thyroid cancer. Due to its high specificity BRAF V600E study may be useful in determining the scope of surgery in patients in cytological group 5. (Endokrynol Pol 2016; 67 (1): 41–47)    Wstęp: Biopsja aspiracyjna celowana cienkoigłowa (BACC) jest uznawana za złoty standard w diagnostyce guzków tarczycy. Ma ona jednak swoje ograniczenia. Poszukiwane są więc dodatkowe metody, które poprawiłyby czułość i specyficzność diagnozowania raka tarczycy, zwłaszcza w przypadku zmian niezdeterminowanych w BACC. Badania molekularne wydają się być takim narzędziem. Mutacja BRAF V600E (najczęstsza w raku tarczycy) może być wykrywana w materiale z biopsji i może wspomagać BACC w rozpoznawaniu raka tarczycy. Celem pracy była ocena przydatności wykrywania mutacji BRAF V600E w BACC w zmianach niezdeterminowanych we wczesnej diagnostyce pacjentów ze zmianami ogniskowymi w tarczycy. Materiał i metody: Przeprowadzono 2290 BACC, uzyskując w 147 próbkach wyniki niezdeterminowane (grupy 3, 4 i 5 wg klasyfikacji Bethesda). W grupie tej przeprowadzono badania molekularne w kierunku występowania mutacji BRAF V600E. Obliczono czułość, swoistość, wartość predykcyjną dodatnią, wartość predykcyjną ujemną i dokładność testu. Wyniki: Obecność mutacji BRAF V600E w grupach cytologicznych 3 i 4 łącznie oraz w grupie 5 wiązała się z czułością w rozpoznawaniu raka tarczycy odpowiednio 37,5% i 81,8%. W każdym przypadku wykrycia mutacji BRAF V600E w badaniu pooperacyjnym rozpoznano raka tarczycy (specyficzność testu —100%). Wnioski: Obecność mutacji BRAF V600E w materiale BACC jest zawsze związana z obecnością RT. Przydatność określenia obecności BRAF V600E w BACC w grupach cytologicznych 3 i 4 jest związana z niską czułością rozpoznania RT. Ze względu na wysoką specyficzność BRAF V600E badania mogą być przydatne w określaniu zakresu operacji u pacjentów z grupy cytologicznej 5. (Endokrynol Pol 2016; 67 (1): 41–47)

Filaggrin Gene Defects Are Independent Risk Factors for Atopic Asthma in a Polish Population: A Study in ECAP Cohort

BACKGROUND: FLG null variants of which 2282del4 and R501X are the most frequent in Caucasians are established risk factors for atopic dermatitis (AD) with an effect probably mediated through impairment of epidermal barrier. Among subjects with AD FLG defects are also consistently associated with asthma and allergic rhinitis (AR) but it is less clear to what extent these associations are also present independently from skin disease. The aim of the present study was to evaluate the role of 2282del4 and R501X in predisposing to these allergic phenotypes in a Polish population. METHODOLOGY: 2282del4 and R501X were typed among 3,802 participants of the Epidemiology of Allergic Diseases in Poland (ECAP) survey, a cross-sectional population-based study using ECRHS II and ISAAC questionnaires, and ambulatory examination. PRINCIPAL FINDINGS: The FLG null variants were associated with AD (OR = 2.01, CI: 1.20-3.36, P = 0.007), allergic rhinitis (in particular persistent form, OR = 1.69, CI:1.12-2.54, P = 0.011), and asthma (in particular atopic asthma, OR = 2.22, CI:1.24-3.96, P = 0.006). Association with atopic asthma (but not persistent allergic rhinitis) was also present in the absence of AD, (OR = 2.02, CI: 1.07-3.81, P = 0.027) as well as in the absence of AD and history of broadly defined inflammatory skin disease (OR = 2.30, CI: 1.07-4.93, P = 0.03). Association to atopic asthma would have not been found if diagnosis was made by questionnaire only (OR = 1.15, CI: 0.58-2.32, P = 0.8). We did not observe an association between FLG variants and allergic sensitizations (P = 0.8) or total IgE. (P = 0.6). CONCLUSIONS/SIGNIFICANCE: In a Polish population FLG 2282del4 and R501X carriage increases risk for development of AD and atopic asthma (also in the absence of AD or history thereof). This suggests that interventions aimed at restoring epidermal barrier may have a general role in asthma prophylaxis/treatment