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Abstract Background Goltz syndrome (GS) is a X-linked disorder defined by defects of mesodermal- and ectodermal-derived structures and caused by PORCN mutations. Features include striated skin-pigmentation, ocular and skeletal malformations and supernumerary or hypoplastic nipples. Generally, GS is associated with in utero lethality in males and most of the reported male patients show mosaicism (only three non-mosaic surviving males have been described so far). Also, precise descriptions of neurological deficits in GS are rare and less severe phenotypes might not only be caused by mosaicism but also by less pathogenic mutations suggesting the need of a molecular genetics and functional work-up of these rare variants. Results We report two cases: one girl suffering from typical skin and skeletal abnormalities, developmental delay, microcephaly, thin corpus callosum, periventricular gliosis and drug-resistant epilepsy caused by a PORCN nonsense-mutation (c.283C > T, p.Arg95Ter). Presence of these combined neurological features indicates that CNS-vulnerability might be a guiding symptom in the diagnosis of GS patients. The other patient is a boy with a supernumerary nipple and skeletal anomalies but also, developmental delay, microcephaly, cerebral atrophy with delayed myelination and drug-resistant epilepsy as predominant features. Skin abnormalities were not observed. Genotyping revealed a novel PORCN missense-mutation (c.847G > C, p.Asp283His) absent in the Genome Aggregation Database (gnomAD) but also identified in his asymptomatic mother. Given that non-random X-chromosome inactivation was excluded in the mother, fibroblasts of the index had been analyzed for PORCN protein-abundance and -distribution, vulnerability against additional ER-stress burden as well as for protein secretion revealing changes. Conclusions Our combined findings may suggest incomplete penetrance for the p.Asp283His variant and provide novel insights into the molecular etiology of GS by adding impaired ER-function and altered protein secretion to the list of pathophysiological processes resulting in the clinical manifestation of GS.

Doxorubicin (DOX) is a widely used chemotherapeutic anticancer drug. Its intrinsic fluorescence properties enable investigation of tumor response, drug distribution and metabolism. First phantom studies in vitro showed optoacoustic property of DOX. We therefore aimed to further investigate the optoacoustic properties of DOX in biological tissue in order to explore its potential as theranostic agent. We analysed doxorubicin hydrochloride (Dox·HCl) and liposomal encapsulated doxorubicin hydrochloride (Dox·Lipo), two common drugs for anti-cancer treatment in clinical medicine. Optoacoustic measurements revealed a strong signal of both doxorubicin substrates at 488 nm excitation wavelength. Post mortem analysis of intra-tumoral injections of DOX revealed a detectable optoacoustic signal even at three days after the injection. We thereby demonstrate the general feasibility of doxorubicin detection in biological tissue by means of optoacoustic tomography, which could be applied for high resolution imaging at mesoscopic depths dictated by effective penetration of visible light into the biological tissues.

Age-related degenerative changes in tendon tissue represent a common cause for acute tendon pathologies. Although the regenerative potential of multipotent mesenchymal stromal cells (MSC) was reported to restore functionality in injured tendon tissue, cellular mechanisms of action remain partly unclear. Potential tenogenic differentiation of applied MSC is affected by various intrinsic and extrinsic factors. The current study presents an in vitro model to evaluate the combined extrinsic effects of decellularized equine tendon matrix, transforming growth factor beta 3 (TGFβ3) and bone morphogenetic protein 12 (BMP12) on the tenogenic fate of equine adipose tissue-derived MSC. Monolayer MSC cultures supplemented with TGFβ3 and BMP12 as well as MSC cultured on tendon matrix scaffolds preloaded with the growth factors were incubated for 3 and 5 days. Histological evaluation and real time reverse transcription polymerase chain reaction (RT-PCR) revealed that growth factor-mediated tenogenic induction of MSC was modified by the conditions of the surrounding microenvironment. While the gene expression pattern in monolayer cultures supplemented with TGFβ3 or TGFβ3 and BMP12 revealed an upregulation for collagen 1A2, collagen 3A1, tenascin c, scleraxis and mohawk ( p < 0.05 ) , the presence of tendon matrix led to an upregulation of decorin and osteopontin as well as to a downregulation of smad8 ( p < 0.05). Preloading of scaffolds with either TGFβ3, or with TGFβ3 and BMP12 promoted a tenocyte-like phenotype and improved cell alignment. Furthermore, gene expression in scaffold culture was modulated by TGFβ3 and/or BMP12, with downregulation of collagen 1A2, collagen 3A1, decorin, scleraxis, smad8 and osteopontin, whereas gene expression of tenascin c was increased. This study shows that growth factor-induced tenogenic differentiation of equine MSC is markedly altered by topographical constraints of decellularized tendon tissue in vitro. While TGFβ3 represents an effective mediator for tenogenic induction, the role of BMP12 in tenogenesis may be of modulatory character and needs further evaluation.

A partir da análise comparativa de obras didáticas de DaF (= Deutsch als Fremdsprache: Alemão como Língua Estrangeira) das áreas de “alemão para economistas” e de “alemão para profissionais”, este trabalho investiga até que ponto obras didáticas para o ensino da linguagem comum se distinguem de obras didáticas para o ensino de linguagens técnico-científicas. Além das diferenças e das semelhanças das obras didáticas analisadas, esta pesquisa mostra também os problemas surgidos das necessidades específicas de obras didáticas para o ensino de linguagens técnico-científicas. Os resultados da pesquisa apontam que, embora existam diferenças entre a concepção das obras didáticas para o ensino da linguagem comum e aquelas para o ensino de linguagem técnico-científica, na prática, essas diferenças são insignificantes.

The Egyptian revolution started literally with an open space: at the Tahrir Square in the heart of Cairo. Here it was where many Egyptians for the first time in their lives made the experience of freely talking about politics in public. Since January 2011, many young Egyptians are trying to keep up this “Tahrir experience” by experimenting with new forms of political debate and civic education in Egypt. It was this spirit that resulted in the idea of introducing the Open Space Technology (OST) as a new format of civic education in Egypt. In March 2011 the authors of this article, both working in Egypt for many years, organized the first Open Space in the country. This event encouraged many other national and international institutions and initiatives to adopt and further develop OST in Egypt and other Arab countries. The unexpected popularity of OST in revolutionary Egypt proved that it is in fact the right methodology at the right time in the right context and the right place. OST is a meeting format that fosters dialogue and exchange in a democratic way. It is easy to organize and non-costly. It invites for sharing opinions, discovering common ground, discussing and tackling differences. It helps generating ideas and reflecting about their implementation. This article argues that Open Space (OS), therefore, is a format that perfectly fits the transforming political environment and the socio-cultural setting of Egypt and – most probably – other Arab transformation-states.

The protection of first responders from radioactive contamination with alpha emitters that may result from a radiological accident is of great complexity due to the short range of alpha particles in the air of a few centimeters. To overcome this issue, for the first time, a system mounted on a UAS for the near-real-time remote measurement of alpha particles has been developed, tested, and calibrated. The new system, based on an optical system adapted to be installed on a UAS in order to measure the UV-C fluorescence emitted by alpha particles in the air, has been tested and calibrated, carried out in the laboratory and in field experiments using UV-C LEDs and 241Am sources. In experimental flights, the probability of detecting a point source was determined to be approximately 60%. In the case of a surface extended source, a detection efficiency per unit surface activity of 10 counts per second per MBq cm−2 was calculated. A background count rate of UV-C of around 26 ± 28 s−1 for an integration time of 0.1 s was measured during flights, which led to a decision threshold surface activity of 5 MBq cm−2.

Antiphospholipid syndrome (APS) is defined by recurrent pregnancy morbidity and/or vascular thrombosis associated with the persistent presence of antibodies against anionic phospholipid-binding proteins. Beta 2 glycoprotein I (β2GPI) and prothrombin (PT) are the major antigens for antiphospholipid antibodies (aPL) detectable by functional coagulation [lupus anticoagulant (LA)] or solid-phase assays [anti-β2GPI-dependent cardiolipin (aCL) and anti-β2GPI]. β2GPI-dependent aPL are responsible for the positivity of the three classification laboratory criteria. While medium/high titers of antibodies against β2GPI are risk factors for both the vascular and the obstetric manifestations of APS, persistent low titers are also associated with pregnancy complications. There is evidence from animal models of aPL-dependent fetal loss and from in vitro systems that β2GPI-dependent aPL can be pathogenic. β2GPI is physiologically found in large quantities at the placental level being available for the specific antibodies circulating in the maternal blood. Once bound to the protein, the antibodies trigger a local inflammation via the activation of the complement cascade and affect trophoblast and decidual function. The final result is represented by defective placentation, while thrombotic events are apparently less important. β2GPI is a pleiotropic molecule with scavenging properties towards several molecules including apoptotic material and displays anti-oxidant activity. These functions may explain the β2GPI placental localization in an area of intensive tissue remodeling and low oxygen tension. Since β2GPI interacts also with the complement and the coagulation cascade, its binding with specific antibodies may affect the physiology of placentation in several ways.

Calcineurin, a serine/threonine phosphatase regulating transcription factors like NFaT and CREB, is well known for its immune modulatory effects and role in cardiac hypertrophy. Results from experiments with calcineurin knockout animals and calcineurin inhibitors indicate that calcineurin also plays a crucial role in vascular function, especially in vascular smooth muscle cells (VSMCs). In the aorta, calcineurin stimulates the proliferation and migration of VSMCs in response to vascular injury or angiotensin II administration, leading to pathological vessel wall thickening. In the heart, calcineurin mediates coronary artery formation and VSMC differentiation, which are crucial for proper heart development. In pulmonary VSMCs, calcineurin/NFaT signaling regulates the release of Ca2+, resulting in increased vascular tone followed by pulmonary arterial hypertension. In renal VSMCs, calcineurin regulates extracellular matrix secretion promoting fibrosis development. In the mesenteric and cerebral arteries, calcineurin mediates a phenotypic switch of VSMCs leading to altered cell function. Gaining deeper insights into the underlying mechanisms of calcineurin signaling will help researchers to understand developmental and pathogenetical aspects of the vasculature. In this review, we provide an overview of the physiological function and pathophysiology of calcineurin in the vascular system with a focus on vascular smooth muscle cells in different organs. Overall, there are indications that under certain pathological settings reduced calcineurin activity seems to be beneficial for cardiovascular health.

A 68-year-old patient presented with persistent hemoptysis and weight loss. A CT scan showing diffuse bilateral ground-glass opacities and nodules was followed by bronchoscopy. While diffuse alveolar hemorrhage (DAH) could be seen, specimens obtained during bronchoscopy did not provide conclusive histological findings. The decision was made to conduct video-assisted wedge resection, after which histological examinations revealed the diagnosis of bifocal nodular manifestation of an epithelioid angiosarcoma in the lung. Being a rare entity even among sarcomas, these kinds of tumors can be primary lung tissue angiosarcomas or metastatic lesions with primaries in places like the skin, breast, and heart. Treatment usually includes chemotherapy, but prognosis remains grim. This case highlights that in DAH, uncommon causes should be considered, and sufficient probe gathering is the key to early diagnosis and treatment.

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by recurrent vascular thrombosis and miscarriages in the absence of known causes. Antibodies against phospholipid-binding proteins (aPL) are pathogenic players in both clotting and pregnancy APS manifestations. There is sound evidence that antibodies specific for beta2 glycoprotein I (β2GPI) trigger thrombotic and pregnancy complications by interacting with the molecule on the membranes of different cell types of the coagulation cascade, and in placenta tissues. In addition to the humoral response against β2GPI, both peripheral and tissue CD4+ β2GPI-specific T cells have been reported in primary APS as well as in systemic lupus erythematosus (SLE)-associated APS. While adaptive immunity plays a clear role in APS, it is still debated whether innate immunity is involved as well. Acute systemic inflammation does not seem to be present in the syndrome, however, there is sound evidence that complement activation is crucial in animal models and can be found also in patients. Furthermore, neutrophil extracellular traps (NETs) have been documented in arterial and venous thrombi with different etiology, including clots in APS models. Keeping in mind that β2GPI is a pleiotropic glycoprotein, acting as scavenger molecule for infectious agents and apoptotic/damaged body constituents and that self-molecules externalized through NETs formation may become immunogenic autoantigens, we demonstrated β2GPI on NETs, and its ability to stimulate CD4+β2GPI-specific T cells. The aim of this review is to elucidate the role of β2GPI in the cross-talk between the innate and adaptive immunity in APS.

Abstract Background Cardiovascular disease is the leading cause of death worldwide. Cardiac electrical remodeling including altered ion channel expression and imbalance of calcium homeostasis can have detrimental effects on cardiac function. While it has been extensively reported that miR-221/222 are involved in structural remodeling, their role in electrical remodeling still has to be evaluated. We previously reported that subunits of the L-type Ca2+ channel (LTCC) are direct targets of miR-221/222. Furthermore, HL-1 cells transfected with miR-221 or -222 mimics showed a reduction in LTCC current density while the voltage-dependence of activation was not altered. The aim of the present study was to determine the influence of miR-221/222 on cardiomyocyte calcium handling and function. Results Transient transfection of HL-1 cells with miR-221/222 mimics led to slower depolarization-dependent Ca2+ entry and increased proportion of non-responding cells. Angiotensin II-induced Ca2+ release from the SR was not affected by miR-221/222. In miR-222-transfected neonatal cardiomyocytes the isoprenaline-induced positive inotropic effect on the intracellular Ca2+ transient was lost and the positive chronotropic effect on spontaneous beating activity was strongly reduced. This could have severe consequences for cardiomyocytes and could lead to a reduced contractility and systolic dysfunction of the whole heart. Conclusions This study adds a new role of miR-221/222 in cardiomyocytes by showing the impact on β-adrenergic regulation of LTCC function, calcium handling and beating frequency. Together with the previous report that miR-221/222 reduce GIRK1/4 function and LTCC current density, it expands our knowledge about the role of these miRs on cardiac ion channel regulation.

Abstract The EGF receptor (EGFR) has been extensively studied in tumor biology and recently a role in cardiovascular pathophysiology was suggested. The mineralocorticoid receptor (MR) is an important effector of the renin–angiotensin–aldosterone-system and elicits pathophysiological effects in the cardiovascular system; however, the underlying molecular mechanisms are unclear. Our aim was to investigate the importance of EGFR for MR-mediated cardiovascular pathophysiology because MR is known to induce EGFR expression. We identified a SNP within the EGFR promoter that modulates MR-induced EGFR expression. In RNA-sequencing and qPCR experiments in heart tissue of EGFR KO and WT mice, changes in EGFR abundance led to differential expression of cardiac ion channels, especially of the T-type calcium channel CACNA1H. Accordingly, CACNA1H expression was increased in WT mice after in vivo MR activation by aldosterone but not in respective EGFR KO mice. Aldosterone- and EGF-responsiveness of CACNA1H expression was confirmed in HL-1 cells by Western blot and by measuring peak current density of T-type calcium channels. Aldosterone-induced CACNA1H protein expression could be abrogated by the EGFR inhibitor AG1478. Furthermore, inhibition of T-type calcium channels with mibefradil or ML218 reduced diameter, volume and BNP levels in HL-1 cells. In conclusion the MR regulates EGFR and CACNA1H expression, which has an effect on HL-1 cell diameter, and the extent of this regulation seems to depend on the SNP-216 (G/T) genotype. This suggests that the EGFR may be an intermediate for MR-mediated cardiovascular changes and that SNP analysis can help identify subgroups of patients that will benefit most from MR antagonists.

Species in the subgenus Artibeus Leach, 1821 are widely distributed in Brazil. Conserved karyotypes characterize the group with identical diploid number and chromosome morphology. Recent studies suggested that the heterochromatin distribution and accumulation patterns can vary among species. In order to assess whether variation can also occur within species, we have analyzed the chromosomal distribution of constitutive heterochromatin in A. planirostris (Spix, 1823) and A. lituratus (Olfers, 1818) from Central Amazon (North Brazil) and contrasted our findings with those reported for other localities in Brazil. In addition, Ag-NOR staining and FISH with 18S rDNA, telomeric, and LINE-1 probes were performed to assess the potential role that these different repetitive markers had in shaping the current architecture of heterochromatic regions. Both species presented interindividual variation of constitutive heterochromatin. In addition, in A. planirostris the centromeres of most chromosomes are enriched with LINE-1, colocated with pericentromeric heterochromatin blocks. Overall, our data indicate that amplification and differential distribution of the investigated repetitive DNAs might have played a significant role in shaping the chromosome architecture of the subgenus Artibeus. [ABSTRACT FROM AUTHOR]

Abstract Background Molecular testing of lung adenocarcinoma for oncogenic driver mutations has become standard in pathology practice. The aim of the study was to analyze the EGFR, KRAS, ALK, RET, ROS1, BRAF, ERBB2, MET and PIK3CA mutational status in a representative cohort of Swiss patients with lung adenocarcinoma and to correlate the mutational status with clinicopathological patient characteristics. Methods All patients who underwent molecular testing of newly diagnosed lung adenocarcinoma during a 4-year period (2014–2018) were included. Molecular analyses were performed with Sanger sequencing (n = 158) and next generation sequencing (n = 311). ALK, ROS1 and RET fusion gene analyses were also performed with fluorescence in situ hybridization and immunohistochemistry/immunocytochemistry. Demographic and clinical data were obtained from the medical records. Results Of 469 patients with informative EGFR mutation analyses, 90 (19.2%) had EGFR mutations. KRAS mutations were present in 33.9% of the patients, while 6.0% of patients showed ALK rearrangement. BRAF, ERBB2, MET and PIK3CA mutations and ROS1 and RET rearrangements were found in 2.6%, 1.9%, 1.9%, 1.5%, 1.7% and 0.8% of the patients, respectively. EGFR mutation was significantly associated with female gender and never smoking status. ALK translocations were more frequent in never smokers, while KRAS mutations were more commonly found in ever smokers. The association between KRAS mutational status and female gender was statistically significant only on multivariate analysis after adjusting for smoking. Conclusion The EGFR mutation rate in the current study is among the higher previously reported mutation rates, while the frequencies of KRAS, BRAF, ERBB2 and PIK3CA mutations and ALK, ROS1 and RET rearrangements are similar to the results of previous reports. EGFR and KRAS mutations were significantly associated with gender and smoking. ALK rearrangements showed a significant association with smoking status alone.

During aging, the cardiovascular system is especially prone to a decline in function and to life-expectancy limiting diseases. Cardiovascular aging is associated with increased arterial stiffness and vasoconstriction as well as left ventricular hypertrophy and reduced diastolic function. Pathological changes include endothelial dysfunction, atherosclerosis, fibrosis, hypertrophy, inflammation, and changes in micromilieu with increased production of reactive oxygen and nitrogen species. The renin-angiotensin-aldosterone-system is an important mediator of electrolyte and blood pressure homeostasis and a key contributor to pathological remodeling processes of the cardiovascular system. Its effects are partially conveyed by the mineralocorticoid receptor (MR), a ligand-dependent transcription factor, whose activity increases during aging and cardiovascular diseases without correlating changes of its ligand aldosterone. There is growing evidence that the MR can be enzymatically and non-enzymatically modified and that these modifications contribute to ligand-independent modulation of MR activity. Modifications reported so far include phosphorylation, acetylation, ubiquitination, sumoylation and changes induced by nitrosative and oxidative stress. This review focuses on the different posttranslational modifications of the MR, their impact on MR function and degradation and the possible implications for cardiovascular aging and diseases.

BackgroundCritically ill patients with coronavirus disease 2019 (COVID-19) have a profound hypercoagulable state and often develop coagulopathy which leads to organ failure and death. Because of a prolonged activated partial-thromboplastin time (aPTT), a relationship with anti-phospholipid antibodies (aPLs) has been proposed, but results are controversial. Functional assays for aPL (i.e., lupus anticoagulant) can be influenced by concomitant anticoagulation and/or high levels of C reactive protein. The presence of anti-cardiolipin (aCL), anti-beta2-glycoprotein I (anti-β2GPI), and anti-phosphatidylserine/prothrombin (aPS/PT) antibodies was not investigated systematically. Epitope specificity of anti-β2GPI antibodies was not reported.ObjectiveTo evaluate the prevalence and the clinical association of aPL in a large cohort of COVID-19 patients, and to characterize the epitope specificity of anti-β2GPI antibodies.MethodsELISA and chemiluminescence assays were used to test 122 sera of patients suffering from severe COVID-19. Of them, 16 displayed major thrombotic events.ResultsAnti-β2GPI IgG/IgA/IgM was the most frequent in 15.6/6.6/9.0% of patients, while aCL IgG/IgM was detected in 5.7/6.6% by ELISA. Comparable values were found by chemiluminescence. aPS/PT IgG/IgM were detectable in 2.5 and 9.8% by ELISA. No association between thrombosis and aPL was found. Reactivity against domain 1 and 4-5 of β2GPI was limited to 3/58 (5.2%) tested sera for each domain and did not correlate with aCL/anti-β2GPI nor with thrombosis.ConclusionsaPL show a low prevalence in COVID-19 patients and are not associated with major thrombotic events. aPL in COVID-19 patients are mainly directed against β2GPI but display an epitope specificity different from antibodies in antiphospholipid syndrome.

The article presents a case study by the Center for Evidence-Based Crime Policy, the Seattle Police Department (SPD), the City of Seattle, and the Seattle Neighborhood Group on the 2014 implementation of a community policing program in areas of Seattle, Washington with high rates of juvenile crime.

Abstract  Cichlidae is the most species-rich freshwater family of Perciformes and has attracted the attention of aquarium hobbyists, aquaculturists, and sport fisherman. Oreochromis niloticus is very important in aquaculture today and is currently used in varied areas of study as an ‘experimental model’. Oreochromis niloticus has been characterized using classical and molecular cytogenetic techniques, with special attention paid to heterochromatin structure and the identification of sex chromosomes. In this study, we compare the genome of O. niloticus with that of other cichlids from Africa and South America using genomic in-situ hybridization (GISH). Our results show that at least some elements comprising the pericentromeric heterochromatin of Nile tilapia are species-specific and that the sequence of the majority of the long arm of the largest chromosome pair is conserved within the tilapiine group, which is composed of the genera Tilapia, Oreochromis, and Sarotherodon. It is suggested that the extensive regions of repeated DNA in the largest chromosome pair of O. niloticus resulted from chromosome rearrangement or accumulation caused by recombination suppression during the evolutionary history of the tilapiines. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRs) contribute to different aspects of cardiovascular pathology, among them cardiac hypertrophy and atrial fibrillation. Cardiac miR expression was analyzed in a mouse model with structural and electrical remodeling. Next-generation sequencing revealed that miR-208b-3p was ~25-fold upregulated. Therefore, the aim of our study was to evaluate the impact of miR-208b on cardiac protein expression. First, an undirected approach comparing whole RNA sequencing data to miR-walk 2.0 miR-208b 3′-UTR targets revealed 58 potential targets of miR-208b being regulated. We were able to show that miR-208b mimics bind to the 3′ untranslated region (UTR) of voltage-gated calcium channel subunit alpha1 C and Kcnj5, two predicted targets of miR-208b. Additionally, we demonstrated that miR-208b mimics reduce GIRK1/4 channel-dependent thallium ion flux in HL-1 cells. In a second undirected approach we performed mass spectrometry to identify the potential targets of miR-208b. We identified 40 potential targets by comparison to miR-walk 2.0 3′-UTR, 5′-UTR and CDS targets. Among those targets, Rock2 and Ran were upregulated in Western blots of HL-1 cells by miR-208b mimics. In summary, miR-208b targets the mRNAs of proteins involved in the generation of cardiac excitation and propagation, as well as of proteins involved in RNA translocation (Ran) and cardiac hypertrophic response (Rock2).

Clinical studies have reported different diagnostic/predictive values of antibodies to domain 1 or 4/5 of β2glycoproteinI in terms of risk of thrombosis and pregnancy complications in patients with antiphospholipid syndrome. To obtain direct evidence for the pathogenic role of anti-domain 1 or anti-domain 4/5 antibodies, we analyzed the in vivo pro-coagulant effect of two groups of 5 sera IgG each reacting selectively with domain 1 or domain 5 in lipopolysaccharide (LPS)-treated rats. Antibody-induced thrombus formation in mesenteric vessels was followed by intravital microscopy, and vascular deposition of β2glycoproteinI, human IgG and C3 was analyzed by immunofluorescence. Five serum IgG with undetectable anti-β2glycoproteinI antibodies served as controls. All the anti-domain 1-positive IgG exhibited potent pro-coagulant activity while the anti-domain 5-positive and the negative control IgG failed to promote blood clot and vessel occlusion. A stronger granular deposit of IgG/C3 was found on the mesenteric endothelium of rats treated with anti-domain 1 antibodies, as opposed to a mild linear IgG staining and absence of C3 observed in rats receiving anti-domain 5 antibodies. Purified anti-domain 5 IgG, unlike anti-domain 1 IgG, did not recognize cardiolipin-bound β2glycoproteinI while being able to interact with fluid-phase β2glycoproteinI. These findings may explain the failure of anti-domain 5 antibodies to exhibit a thrombogenic effect in vivo, and the interaction of these antibodies with circulating β2glycoproteinI suggests their potential competitive role with the pro-coagulant activity of anti-domain 1 antibodies. These data aim at better defining “really at risk” patients for more appropriate treatments to avoid recurrences and disability.

The pathophysiological mechanisms of sepsis-induced cardiac dysfunction are largely unknown. The Toll-like receptor 4 (TLR4) is expressed in cardiac myocytes and is involved in bacterial endotoxin-mediated inflammatory disorders. TLR4 signaling leads to activation of the nuclear factor kappa B followed by increased expression of cytokines. Several protein phosphatases including PP2Cβ, PP2A or PP1 are known to act as regulators of this signaling pathway. Here, we examined the role of PP5 for the inflammatory response to the bacterial endotoxin lipopolysaccharide in the heart using a transgenic mouse model with cardiac myocyte directed overexpression of PP5. In these transgenic mice, basal cardiac contractility was reduced, in vivo as well as in vitro, but LPS-induced cardiac dysfunction was less pronounced compared to wild type mice. Quantitative RT-PCR suggested an attenuated NF-κB signaling in the heart and cardiac expression of heat shock protein 25 (HSP25) was increased in PP5 transgenic mice. From our data we assume that PP5 increases stress tolerance of cardiac myocytes by downregulation of NF-κB signaling and upregulation of HSP25 expression.

PurposeLung cancer in never smokers is recognized as a distinct molecular, clinicopathologic and epidemiologic entity. The aim of the study was to investigate the molecular profile in Swiss never smokers with lung adenocarcinoma and to correlate the mutation status with clinicopathologic and demographic patient characteristics and outcome.MethodsOne hundred thirty-eight never smokers diagnosed with lung adenocarcinoma at the University Hospital Zurich between 2011-2018 were included in the study. Data from the electronic medical records were reviewed to characterize clinicopathologic and demographic features, molecular profile, treatment and outcome.ResultsThe majority of patients were female (58.7%) with a median age at diagnosis of 64.5 years (range, 27.1-94.2 years). The most common mutations were EGFR (58.7%) followed by ALK (12.3%), TP53 (5.8%), MET (5.8%), KRAS (4.3%), ERBB2 (4.3%), PIK3CA (2.9%), BRAF (2.2%), ROS1 (1.4%), RET (1.4%), CTNNB1 (0.7%), PARP1 (0.7%), TET1 (0.7%) and PIK3CG (0.7%). Median overall survival (mOS) was 51.0 months (mo). Early clinical stage (p = 0.002) and treatment with targeted therapy (HR 2.53, 95% CI 1.35-4.74, p = 0.004) were independently associated with longer mOS. Patients with oncogenic driver mutations had significantly longer mOS (52.2 mo) compared to patients without mutations (16.9 mo) (HR 3.38, 95% CI 1.52-7.55, p = 0.003). Besides, patients with EGFR mutated (57.8 mo) or ALK rearranged (59.9 mo) tumors had significantly longer mOS compared to the EGFR wildtype (35.0 mo), ALK wildtype (46.5 mo) and pan-negative (16.9 mo) cohorts (HR 2.35, 95% CI 1.37-4.04, p = 0.002; HR 7.80, 95% CI 3.28-18.55, p < 0.001; HR 3.96, 95% CI 1.21-12.95, p = 0.023 and HR 34.78, 95% CI 3.48-34.65, p = 0.003).ConclusionNever smokers with lung adenocarcinoma display distinct clinicopathologic and molecular features and are characterized by a high incidence of targetable mutations. Never smokers with targetable mutations have significantly longer survival compared to patients without mutations.

PURPOSE:The aim of this study was to evaluate the vascular and parenchymal CT imaging findings, including vessel and cardiac chamber diameter measurements, in patients newly diagnosed with chronic thromboembolic pulmonary hypertension (CTEPH). The CT imaging findings were correlated with hemodynamic measurements and patient outcome. METHODS:Vascular and parenchymal CT findings were assessed on retrospectively ECG-gated MDCT angiography scans in 76 patients newly diagnosed with CTEPH. The diameters of the right and left ventricle (dRV, dLV), the right and left atrium (dRA, dLA), the ascending aorta (dAA), the right and left pulmonary arteries (drPA, dlPA), and the main pulmonary artery (dPA) were measured on axial CT scans. The CT imaging findings were correlated with demographic and hemodynamic data and adverse patient outcome due to right heart failure (RHF). RESULTS:The majority of patients showed chronic PE, mosaic perfusion, disparity in segmental vessel size, parenchymal densities, bronchial dilatation, and bronchial collaterals in CT. Mean pulmonary artery pressure (mPAP) was not significantly different in patients with and those without chronic PE, mosaic perfusion, disparity in segmental vessel size, parenchymal densities, bronchial dilatation, and bronchial collaterals. Mean PAP showed significant correlations with the CT metrics of dRV/dLV ratio, dRA, dRV, dPA and dPA/dAA ratio, but no correlation with the central thrombi score. By backward linear regression, the dPA/dAA ratio independently correlated with mPAP. Patients who died of RHF tended to have a higher frequency of exclusively chronic peripheral PE and greater dRV/dLV ratios on presenting CT scans compared with survivors. CONCLUSION:The majority of patients newly diagnosed with CTEPH show vascular signs of chronic PE, mosaic perfusion, parenchymal densities, disparity in segmental vessel size, bronchial dilatation, and bronchial collaterals on presenting CT scans. Particularly CTEPH patients with exclusively chronic peripheral PE and increased dRV/dLV ratios seem to be at risk of adverse outcome due to RHF.

Mitochondria- as well as p53-based signaling pathways are central for the execution of the intrinsic apoptotic cascade. Their contribution to rubella virus (RV)-induced apoptosis was addressed through time-specific evaluation of characteristic parameters such as permeabilization of the mitochondrial membrane and subsequent release of the pro-apoptotic proteins apoptosis-inducing factor (AIF) and cytochrome c from mitochondria. Additionally, expression and localization pattern of p53 and selected members of the multifunctional and stress-inducible cyclophilin family were examined. The application of pifithrin μ as an inhibitor of p53 shuttling to mitochondria reduced RV-induced cell death to an extent similar to that of the broad spectrum caspase inhibitor z-VAD-fmk (benzyloxycarbonyl-V-A-D-(OMe)-fmk). However, RV progeny generation was not altered. This indicates that, despite an increased survival rate of its cellular host, induction of apoptosis neither supports nor restricts RV replication. Moreover, some of the examined apoptotic markers were affected in a strain-specific manner and differed between the cell culture-adapted strains: Therien and the HPV77 vaccine on the one hand, and a clinical isolate on the other. In summary, the results presented indicate that the transcription-independent mitochondrial p53 program contributes to RV-induced apoptosis.

We present a 74-year-old male with nonspecific interstitial pneumonia (NSIP) during treatment with ibrutinib for mantle cell lymphoma. Previously, the patient had received six cycles of bendamustine and rituximab and six cycles of R-CHOP, followed by rituximab maintenance therapy. Respiratory tract complications of ibrutinib other than infectious pneumonia have not been mentioned in larger trials, but individual case reports hinted to a possible association with the development of pneumonitis. In our patient, the onset of alveolitis that progressed towards NSIP together with the onset of ibrutinib treatment suggests causality. One week after ibrutinib was discontinued, nasal symptoms resolved first. A follow-up CT showed a reduction in the reticular hyperdensities and ground-glass opacities, suggestive of restitution of the lung disease. To our knowledge, this is the first case showing a strong link between ibrutinib and interstitial lung disease, strengthening a previous report on subacute pneumonitis. Our findings have clinical implications because pulmonary side effects were reversible at this early stage. We, therefore, suggest close monitoring for respiratory side effects in patients receiving ibrutinib.

BackgroundForthright reporting of financial ties and conflicts of interest of researchers is associated with public trust in and esteem for the scientific enterprise.Methods/principal findingsWe searched Lexis/Nexis Academic News for the top news stories in science published in 2004 and 2005. We conducted a content analysis of 1152 newspaper stories. Funders of the research were identified in 38% of stories, financial ties of the researchers were reported in 11% of stories, and 5% reported financial ties of sources quoted. Of 73 stories not reporting on financial ties, 27% had financial ties publicly disclosed in scholarly journals.Conclusions/significanceBecause science journalists often did not report conflict of interest information, adherence to gold-standard recommendations for science journalism was low. Journalists work under many different constraints, but nonetheless news reports of scientific research were incomplete, potentially eroding public trust in science.

The Amazon aquatic ecosystems have been modified by the human population growth, going through changes in their water bodies and aquatic biota. The spectacled alligator (Caiman crocodilus crocodilus) has a wide distribution and adaptability to several environments, even those polluted ones. This study aimed to investigate if a Caiman species living in urban streams of Manaus city (Amazonas State, Brazil) is affected by environmental pollution. For that, it was used classical and molecular cytogenetic procedures, in addition to micronucleus and comet assays. Although the karyotype macrostructure remains unaltered (2 n = 42 chromosomes; 24 t + 18 m/sm; NF = 60), the genotoxic analysis and the cytogenetic mapping of repetitive DNA sequences demonstrated that polluted environments alter the genome of the specimens, affecting both the chromosomal organization and the genetic material.