Thiol starvation triggers melanoma state switching in an ATF4 and NRF2-dependent manner.

The cystine/glutamate antiporter xCT is an important source of cysteine for cancer cells. Once taken up, cystine is reduced to cysteine and serves as a building block for the synthesis of glutathione, which efficiently protects cells from oxidative damage and prevents ferroptosis. As melanomas are particularly exposed to several sources of oxidative stress, we investigated the biological role of cysteine and glutathione supply by xCT in melanoma.

The integrated stress response effector ATF4 is an obligatory metabolic activator of NRF2.

The redox regulator NRF2 becomes activated upon oxidative and electrophilic stress and orchestrates a response program associated with redox regulation, metabolism, tumor therapy resistance, and immune suppression. Here, we describe an unrecognized link between the integrated stress response (ISR) and NRF2 mediated by the ISR effector ATF4. The ISR is commonly activated after starvation or ER stress and plays a central role in tissue homeostasis and cancer plasticity.

Second hepatitis C virus transmission by blood components since introduction of mandatory NAT screening in Germany.

Background: Viral safety of blood products in Germany has improved significantly over the last two decades. We describe the second documented transfusion-transmitted (TT) episode for the hepatitis C virus (HCV) in Germany since mandatory nucleic acid amplification techniques (NAT) screening was introduced in 1999.

Study Design And Methods: When a repeat donor who had tested negative for anti-HCV tested positive for HCV RNA by NAT in a minipool (MP) of eight, a look-back procedure was initiated.

[Safety of blood and blood products: test methods for the detection of hepatitis B, C, and E virus].

Infections with hepatitis B, C, and E virus (HBV, HCV, and HEV) can be transmitted via blood and cause severe acute or chronic liver infections. To ensure the safety of blood donations and protect recipients from virus transmissions, blood donations in Germany are tested for viral genomes using nucleic acid amplification techniques (NATs) as well as for viral antigens and antibodies by serological testing. This article describes the relevant regulations on the safety of blood and blood products in Germany and the various screening methods.

Genome Sequences of West Nile Virus Reference Materials.

We report the sequences of two West Nile virus (WNV) strains (lineages 1 and 2) developed by the Paul-Ehrlich-Institut as reference materials. The materials are calibrated against the 1 World Health Organization WNV RNA International Standard and are intended for use in nucleic acid technology assays supporting transfusion safety.

NRF2 Enables EGFR Signaling in Melanoma Cells.

Receptor tyrosine kinases (RTK) are rarely mutated in cutaneous melanoma, but the expression and activation of several RTK family members are associated with a proinvasive phenotype and therapy resistance. Epidermal growth factor receptor (EGFR) is a member of the RTK family and is only expressed in a subgroup of melanomas with poor prognosis. The insight into regulators of EGFR expression and activation is important for the understanding of the development of this malignant melanoma phenotype.

The transcription factor NRF2 enhances melanoma malignancy by blocking differentiation and inducing COX2 expression.

The transcription factor NRF2 is the major mediator of oxidative stress responses and is closely connected to therapy resistance in tumors harboring activating mutations in the NRF2 pathway. In melanoma, such mutations are rare, and it is unclear to what extent melanomas rely on NRF2. Here we show that NRF2 suppresses the activity of the melanocyte lineage marker MITF in melanoma, thereby reducing the expression of pigmentation markers.

Detection of hepatitis B virus infection in German blood donors 2008-2015.

Background And Objectives: Assessment of HBV-NAT testing compared to HBsAg and anti-HBc screening in German blood establishments for the period 2008-2015.

Materials And Methods: Blood donations screened for HBsAg and anti-HBc along with HBV-NAT were evaluated. Sensitivity of HBsAg and HBV-NAT tests was compared in 30 HBV seroconversion panels and with the viral load of the NAT-only cases.

[Management of Postoperative Prolonged Air Leak].

Prolonged air leak is one of the most common postoperative complications in thoracic surgery. For elective partial lung resections, postoperative air leak lasting longer than 5 - 7 days is arbitrarily defined as prolonged. There are several predictive factors for the development of prolonged air leak that can be subdivided as either preoperative, such as obstructive pulmonary disease, or intraoperative risk factors, such as pleural adhesions or fused fissures.

Human immunodeficiency virus 1 dual-target nucleic acid technology improves blood safety: 5 years of experience of the German Red Cross blood donor service Baden-Württemberg-Hessen.

Background: RNA viruses are associated with a high frequency of mutations because of the missing proofreading function of polymerases, such as reverse transcriptase. Between 2007 and 2010, six blood donations with false-negative nucleic acid technology (NAT) results were reported in Germany. Therefore, NAT screening in two viral genome regions was introduced by our blood donation service in 2010 on a voluntary basis and became mandatory in Germany since the beginning of 2015.

Blood donor screening for West Nile virus (WNV) revealed acute Usutu virus (USUV) infection, Germany, September 2016.

Between 1 June and 31 December 2016, 13,023 blood donations from the University Hospital Aachen in Germany were routinely screened for West Nile virus (WNV) RNA using the cobas TaqScreen WNV Test. On 28 September 2016, one blood donor was tested positive. Subsequent analysis revealed an acute Usutu virus (USUV) infection.

Three novel presenilin 1 mutations marking the wide spectrum of age at onset and clinical patterns in familial Alzheimer's disease.

Presenilin 1 (PSEN1) mutations are the major cause of autosomal dominant Alzheimer's disease (ADAD). Here we report three novel PSEN1 mutations: Ile238_Lys239insIle, Ala246Pro and Ala164Val from patients who manifested in their twenties, forties and seventies, respectively, with variant clinical presentations of dementia. These cases exemplify the tremendous heterogeneity of clinical phenotypes and age of onset associated with PSEN1 mutations.

World Health Organization International Standard To Harmonize Assays for Detection of Mycoplasma DNA.

Nucleic acid amplification technique (NAT)-based assays (referred to here as NAT assays) are increasingly used as an alternative to culture-based approaches for the detection of mycoplasma contamination of cell cultures. Assay features, like the limit of detection or quantification, vary widely between different mycoplasma NAT assays. Biological reference materials may be useful for harmonization of mycoplasma NAT assays.

Risk Minimization Measures for Blood Screening HIV-1 Nucleic Acid Amplification Technique Assays in Germany.

Background: Several publications describe HIV-1 RNA false-negative results or viral load underquantitation associated with Communauté Européenne(CE)-marked qualitative or quantitative nucleic acid amplification technique (NAT) assays. 6 cases occurred during blood screening in Germany, with 2 of them causing HIV-1 transmissions to recipients of blood components. The implicated NAT assays were mono-target assays amplifying in different viral genome regions (gag or long terminal repeat).

How safe is safe: new human immunodeficiency virus Type 1 variants missed by nucleic acid testing.

Background: Nucleic acid amplification techniques (NAT) in routine blood donor screening considerably reduce the diagnostic window phase period. Nevertheless, several reports of false-negative NAT results were published. Here, four cases of human immunodeficiency virus Type 1 (HIV-1) RNA-positive blood donations that escaped detection by NAT screening are described.

First transmission of human immunodeficiency virus Type 1 by a cellular blood product after mandatory nucleic acid screening in Germany.

Background: In February 2007, a 63-year-old man underwent surgery. Retrospective testing with nucleic acid testing (NAT) showed that the patient was human immunodeficiency virus Type 1 (HIV-1) positive 10 days after transfusion. The transfusion-transmitted infection had been identified by a donor-related lookback started in April 2007 after anti-HIV seroconversion.

Experience of mandatory nucleic acid test (NAT) screening across all blood organizations in Germany: NAT yield versus breakthrough transmissions.

Background: Mandatory nucleic acid test (NAT) blood screening was introduced in Germany in 1999 for hepatitis C virus (HCV) RNA and in 2004 for human immunodeficiency virus Type 1 (HIV-1) RNA. Minimal sensitivity limits of 5000 IU HCV RNA/mL and 10,000 IU HIV-1 RNA/mL were defined for the individual donation facilitating testing of minipools (MPs). The NAT yield obtained from all blood organizations is summarized.

Consistency of quantitation of HCV genotype 4 from egypt across three HCV-RNA amplification assays.

Different quantitative assays for HCV-RNA are available that report test results in International Units (IU)/ml based on the WHO International Standard. Thus, assays have been calibrated with standard material containing HCV genotype 1, so the consistency of quantitation might differ between assays for other HCV genotypes. Three commercial HCV nucleic acid amplification techniques (HCV-NAT) were compared for quantitation consistency of genotype 4 and 1 specimens from an Egyptian blood donor panel (n = 92).

The hyaluronic acid-binding protease: a novel vascular and inflammatory mediator?

A serine protease in human plasma termed hyaluronan-binding protease HABP is structurally related to plasminogen-activators, coagulation FXII and hepathocyte growth factor activator. This protease has coagulation and fibrinolysis-related activities, although a physiologic role in haemostasis still requires confirmation. In more recent years accumulating information became available supporting the hypothesis that HABP plays also a significant role in the regulation of cells in the vasculature and in the perivascular environment.

Induction of intracellular signalling in human endothelial cells by the hyaluronan-binding protease involves two distinct pathways.

Recently a novel plasma serine protease with high affinity to hyaluronic acid and glycosaminoglycans, such as heparin and heparan sulfate, has been described and termed hyaluronan-binding protease (HABP). HABP cleaves kininogen in vitro, releasing the vasoactive peptide bradykinin, and activates plasminogen activators, suggesting a vascular cell-directed physiological function of this novel plasma protease. Here we show that HABP stimulates human umbilical vein endothelial cells (HUVECs) by activating two distinct cell-surface receptors.

Novel mutation in the ALS2 gene in juvenile amyotrophic lateral sclerosis.

We present a 32-year-old Turkish male with juvenile amyotrophic lateral sclerosis 2 and a previously unrecognized homozygous deletion in exon 4 of the ALS2 gene (553delA). Disease progression is more rapid than in the ALS2 phenotype cases described to date. The patient's consanguineous parents carry the mutation in the heterozygous state as do his two unaffected brothers.

Inhibition of bFGF/EGF-dependent endothelial cell proliferation by the hyaluronan-binding protease from human plasma.

Recently we identified a plasma serine protease with a high affinity to glycosaminoglycans like heparin or hyaluronic acid, termed hyaluronan-binding protease (HABP). Since glycosaminoglycans are found on cell surfaces and in the extracellular matrix a physiological role of this plasma protease in a pericellular environment was postulated. Here we studied the influence of HABP on the regulation of endothelial cell growth.