Oncogene-evoked replication stress (RS) fuels genomic instability in diverse cancer types. Here we report that BRCA1, traditionally regarded a tumour suppressor, plays an unexpected tumour-promoting ...role in glioblastoma (GBM), safeguarding a protective response to supraphysiological RS levels. Higher BRCA1 positivity is associated with shorter survival of glioma patients and the abrogation of BRCA1 function in GBM enhances RS, DNA damage (DD) accumulation and impairs tumour growth. Mechanistically, we identify a novel role of BRCA1 as a transcriptional co-activator of RRM2 (catalytic subunit of ribonucleotide reductase), whereby BRCA1-mediated RRM2 expression protects GBM cells from endogenous RS, DD and apoptosis. Notably, we show that treatment with a RRM2 inhibitor triapine reproduces the BRCA1-depletion GBM-repressive phenotypes and sensitizes GBM cells to PARP inhibition. We propose that GBM cells are addicted to the RS-protective role of the BRCA1-RRM2 axis, targeting of which may represent a novel paradigm for therapeutic intervention in GBM.
Previous studies have demonstrated widespread exposure of humans to certain benzophenones commonly used as UV filters or UV absorbers; some of which have been demonstrated to have endocrine ...disrupting abilities.
To examine whether benzophenones present in pregnant women pass through the placental barrier to amniotic fluid and further to the fetal blood circulation.
A prospective study of 200 pregnant women with simultaneously collected paired samples of amniotic fluid and maternal serum and urine. In addition, unique samples of human fetal blood (n=4) obtained during cordocentesis: and cord blood (n=23) obtained at delivery, both with paired maternal samples of serum and urine collected simultaneously, were used. All biological samples were analyzed by TurboFlow-liquid chromatography - tandem mass spectrometry for seven different benzophenones.
Benzophenone-1 (BP-1), benzophenone-3 (BP-3), 4-methyl-benzophenone (4-MBP), and 4-hydroxy-benzophenone (4-HBP) were all detectable in amniotic fluid and cord blood samples and except 4-HBP also in fetal blood; albeit at a low frequency. BP-1 and BP-3 were measured at ~10-times lower concentrations in fetal and cord blood compared to maternal serum and 1000-times lower concentration compared to maternal urine levels. Therefore BP-1 and BP-3 were only detectable in the fetal circulation in cases of high maternal exposure indicating some protection by the placental barrier. 4-MBP seems to pass into fetal and cord blood more freely with a median 1:3 ratio between cord blood and maternal serum levels. Only for BP-3, which the women seemed to be most exposed to, did the measured concentrations in maternal urine and serum correlate to concentrations measured in amniotic fluid. Thus, for BP-3, but not for the other tested benzophenones, maternal urinary levels seem to be a valid proxy for fetal exposure.
Detectable levels of several of the investigated benzophenones in human amniotic fluid as well as in fetal and cord blood calls for further investigations of the toxicokinetic and potential endocrine disrupting properties of these compounds in order for better assessment of the risk to the developing fetus.
•Several benzophenones are detectable in amniotic fluid, fetal- and cord blood.•Significant correlation was found between BP-3 in maternal urine and amniotic fluid indication that BP-3 in maternal urine is a valid proxy for fetal exposure.•BP-1 and BP-3 are detectable in cord blood only in cases of high maternal exposure.•4-MBP seem to pass more freely from mother into fetus.
The main objective of this study is to increase the penetration level of photovoltaic (PV) power production in low-voltage (LV) grids by means of solar inverters with reactive power control ...capability. This paper underlines weak points of standard reactive power strategies which are already imposed by certain grid codes, and then, the study introduces a new reactive power control method that is based on sensitivity analysis. The sensitivity analysis shows that the same amount of reactive power becomes more effective for grid voltage support if the solar inverter is located at the end of a feeder. Based on this fundamental knowledge, a location-dependent power factor set value can be assigned to each inverter, and the grid voltage support can be achieved with less total reactive power consumption. In order to prevent unnecessary reactive power absorption from the grid during admissible voltage range or to increase reactive power contribution from the inverters that are closest to the transformer during grid overvoltage condition, the proposed method combines two droop functions that are inherited from the standard cos φ(P) and Q(U) strategies. Its performance comparison in terms of grid losses and voltage variation with different reactive power strategies is provided by modeling and simulating a real suburban LV network.
: It is estimated that children below 18 years constitute 50% of the refugee population worldwide, which is the highest figure in a decade. Due to conflicts like the Syrian crises, children are ...continuously exposed to traumatic events. Trauma exposure can cause mental health problems that may in turn increase the risk of morbidity and mortality. Tools such as questionnaires and interview guides are being used extensively, despite the fact that only a few have been tested and their validity confirmed in refugee children and youth. : Our aim was to provide a systematic review of the validated screening and measurement tools available for assessment of trauma and mental health among refugee children and youth. : We systematically searched the databases PubMed, PsycINFO and PILOTS. The search yielded 913 articles and 97 were retained for further investigation. In accordance with the PRISMA guidelines two authors performed the eligibility assessment. The full text of 23 articles was assessed and 9 met the eligibility criteria. Results : Only nine studies had validated trauma and mental health tools in refugee children and youth populations. A serious lack of validated tools for refugee children below the age of 6 was identified. : There is a lack of validated trauma and mental health tools, especially for refugees below the age of 6. Detection and treatment of mental health issues among refugee children and youth should be a priority both within the scientific community and in practice in order to reduce morbidity and mortality.
Essentials Platelet function may influence bleeding risk in thrombocytopenia, but useful tests are needed. A flow cytometric platelet aggregation test independent of the patient platelet count was ...made. Platelet aggregation was reduced in thrombocytopenic patients with hematological cancer. High platelet aggregation ruled out bleeding tendency in thrombocytopenic patients.
Background Methods for testing platelet aggregation in thrombocytopenia are lacking. Objective To establish a flow-cytometric test of in vitro platelet aggregation independently of the patient's platelet count, and examine the association of aggregation with a bleeding history in thrombocytopenic patients. Patients/methods We established a flow-cytometric assay of platelet aggregation, and measured samples from healthy individuals preincubated with antiplatelet drugs, and samples from two patients with inherited platelet disorders. Then, we included 19 healthy individuals and 20 patients with platelet counts of ≤ 50 × 10
L
, diagnosed with acute myeloid leukemia or myelodysplastic syndrome. We measured platelet aggregation and platelet activation by platelet surface expression of activated glycoprotein IIb-IIIa, P-selectin and CD63 after addition of agonists: collagen-related peptide, thrombin receptor-activating peptide (TRAP), and ADP. Results The platelet aggregation assay showed a low intraserial coefficient of variation of ≤ 3%. Similar results were obtained for platelet-rich plasma and isolated platelets at platelet counts of > 10 × 10
L
; otherwise, platelet isolation was required. The platelet aggregation percentage decreased with increasing antiplatelet drug concentration. Platelet aggregation in patients was reduced as compared with healthy individuals: 42% (interquartile range IQR 27-58) versus 66% (IQR 60-67) for TRAP; 41% (IQR 25-48) versus 70% (IQR 69-72) for collagen-related peptide; and 44% (IQR 30-53) versus 65% (IQR 46-72) for ADP. Platelet activation after stimulation was reduced in patients and correlated with platelet aggregation (e.g. r = 0.78-0.81 when stimulated with collagen-related peptide). Platelet aggregation had a negative predictive value of 100% for a bleeding tendency among patients. Conclusion The established platelet aggregation assay was applicable for thrombocytopenic patients, and improved the identification of bleeding risk.
Aims:
The number of asylum seekers in Europe is increasing and is likely to do so continuously due to conflicts, poverty and climate. Asylum seekers are exposed to many health risk factors related to ...their migration process and this study aimed to explore their general health status on arrival at an immigration country.
Methods:
A retrospective study including 1907 general health assessments (GHAs) of adult asylum seekers arriving in Denmark between 1 September 2017 and 31 December 2019 was undertaken. The GHA is offered to all adult asylum seekers as part of the health-care reception programme. Only asylum seekers who attended the GHA within 1 month of their arrival in Denmark were included. Data comprised sociodemographic factors, health outcomes, and indication of exposure to trauma and torture. Data were described by absolute and relative frequencies, means and through regression analyses.
Results:
The majority of asylum seekers were male (58.6%) of Middle Eastern origin with a mean age of 33.6 years (SD = 12.1). More than half (60.1%) of the participants had one or more physical health complaints, whereas mental health complaints were less frequent (25.0%). Asylum seekers, who had been exposed to trauma were more likely to have physical health complaints (OR 1.52, 95% CI 1.22;1.89) and to have symptoms of mental health problems (OR 12.71, 95% CI 8.76;18.45). These complaints were substantially elevated for survivors of torture.
Conclusions:
This relatively high prevalence of health complaints, both physical and mental, emphasises the necessity of providing appropriate and timely health care from the very beginning of the asylum process.
Lynch syndrome (LS) is one of the most common hereditary cancer predisposition syndromes worldwide. Individuals with LS have a high risk of developing colorectal or endometrial cancer, as well as ...several other cancers. LS is caused by autosomal dominant pathogenic variants in one of the DNA mismatch repair (MMR) genes MLH1, MSH2, PMS2 or MSH6, and typically include truncating variants, such as frameshift, nonsense or splicing variants. However, a significant number of missense, intronic, or silent variants, or small in-frame insertions/deletions, are detected during genetic screening of the MMR genes. The clinical effects of these variants are often more difficult to predict, and a large fraction of these variants are classified as variants of uncertain significance (VUS). It is pivotal for the clinical management of LS patients to have a clear genetic diagnosis, since patients benefit widely from screening, preventive and personal therapeutic measures. Moreover, in families where a pathogenic variant is identified, testing can be offered to family members, where non-carriers can be spared frequent surveillance, while carriers can be included in cancer surveillance programs. It is therefore important to reclassify VUSs, and, in this regard, functional assays can provide insight into the effect of a variant on the protein or mRNA level. Here, we briefly describe the disorders that are related to MMR deficiency, as well as the structure and function of MSH6. Moreover, we review the functional assays that are used to examine VUS identified in MSH6 and discuss the results obtained in relation to the ACMG/AMP PS3/BS3 criterion. We also provide a compiled list of the MSH6 variants examined by these assays. Finally, we provide a future perspective on high-throughput functional analyses with specific emphasis on the MMR genes.
Phthalates are suspected of endocrine disrupting effects. We aimed to develop an analytical method for simultaneous determination of several phthalate metabolites in human urine, serum, and seminal ...plasma and to study correlations between levels of metabolites in these matrices. Thirteen metabolites were determined in samples from 60 young Danish men. Metabolites of common di-ester phthalates were detected in most urine samples. Summed di-(2-ethylhexyl) phthalate (DEHP) metabolites were excreted in urine in the highest amount (median = 91.1 ng/mL), followed by monoethyl phthalate (MEP), mono-iso-butyl phthalate (MiBP), mono-n-butyl phthalate (MnBP), mono-benzyl phthalate (MBzP), and finally summed di-isononyl phthalate (DiNP) metabolites. All these metabolite levels correlated significantly, indicating that when a participant was highly exposed to one phthalate he was also highly exposed to other phthalates. Several metabolites were also detectable in serum and in seminal plasma, although in much lower levels. Significant correlations between MEP and MiBP levels in serum and urine were observed, showing that serum levels could be used as biomarkers of human exposure. For DEHP and DiNP metabolites, correlations between urine and serum levels were only observed for mono(2-ethyl-5-carboxypentyl) phthalate (MECPP) and mono-(4-methyl-7-carboxyheptyl) phthalate (MCiOP), indicating that these secondary carboxylated metabolites were better serum markers than primary metabolites mono(2-ethylhexyl) phthalate (MEHP) and mono-iso-nonyl phthalate (MiNP). In seminal plasma, only MEP levels correlated significantly to levels in urine and in serum.
The aim was to evaluate the associations of environmental phenol and paraben concentrations with the oxidative microenvironment in adipose tissue. This study was conducted in a subsample (n = 144) of ...the GraMo cohort (Southern Spain). Concentrations of 9 phenols and 7 parabens, and levels of oxidative stress biomarkers were quantified in adipose tissue. Associations were estimated using multivariable linear regression analyses adjusted for potential confounders.
Benzophenone-3 (BP-3) concentration was borderline associated with enhanced glutathione peroxidase (GPx) activity exp(β) = 1.20, p = 0.060 and decreased levels of reduced glutathione (GSH) exp(β) = 0.55, p = 0.070. Concentrations of bisphenol A (BPA) and methylparaben (MeP) were associated to lower glutathione reductase (GRd) activity exp(β) = 0.83, exp(β) = 0.72, respectively, and BPA was borderline associated to increased levels of oxidized glutathione (GSSG) exp(β) = 1.73, p-value = 0.062. MeP was inversely associated to both hemeoxygenase-1 (HO-1) and superoxide dismustase (SOD) activity, as well as to the levels of thiobarbituric acid reactive substances (TBARS) 0.75 < exp(β) < 0.79.
Our results suggest that some specific non-persistent pollutants may be associated with a disruption of the activity of relevant antioxidant enzymes, in addition to the depletion of the glutathione stock. They might act as a tissue-specific source of free radicals, contributing to the oxidative microenvironment in the adipose tissue.
•We analyzed phenols, parabens and oxidative stress in adipose tissue.•BP-3 was associated with enhanced GPx activity and decreased GSH levels.•BPA was associated with lower GRd activity and increased GSSG.•MeP was associated with lower GRd, HO-1, SOD, and TBARS.•These pollutants might act as a tissue-specific source of free radicals.
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