Caffeine is widely used to manage apnea of prematurity, and reduces the incidence of bronchopulmonary dysplasia (BPD). Deregulated transforming growth factor (TGF)- signaling underlies arrested ...postnatal lung maturation in BPD. It is unclear whether caffeine impacts TGF- signaling or postnatal lung development in affected lungs.
Dyes in Carbon Nanotube Arrays Lackner, G; Mayer-Uhma, T; Endler, I ...
Journal of materials science and engineering. B,
06/2012, Letnik:
2, Številka:
6
Journal Article
The infiltration of dissolved dies into vertically aligned carbon nanotube arrays （VA-CNT） is reported. The ultra hydrophobic surface of a CNT array can be completely infiltrated on a surface area of ...48 mmz by an appropriate choice of solvent. This is so far not possible by evaporation techniques. Depending on the solvent type, the CNT alignment remains unaltered, which is strongly modified, or even lost. The infiltrated CNT array provides a well ordered electrode structure for organic solar cells. The CNT can simultaneously serve as electron acceptor in combination with an appropriate donor dye. Sensors and organic LED are among further applications.
Sexual activity (SA) and sexual function (SF) after completion of treatment are central for quality of life (QoL) in women affected by gynecological cancer (GC). The aim of this study was to analyze ...the sexual outcome and overall QoL of women after treatment for primary GC compared with a healthy control group (CG).
In a multicenter cross-sectional study, 77 women aged 28 to 67 years were surveyed at least 12 months after completion of primary therapy for cervical, endometrial, or vulvar cancer gynecological cancer group (GCG). Data were collected through validated questionnaires (Female Sexual Function Index-d, EORTC Quality of Life Questionnaire-C30, and Sexual Activity Questionnaire) and compared to a control of 60 healthy women (CG).
In the GCG, 41.3% were sexually active compared to 78.0% in the CG. Twelve women of the CG and 42 women of the GCG indicated the reasons for their sexual inactivity. The most common reason for sexual inactivity in the GCG was "the-presence-of-a-physical-problem" 18/42 (42.9%) vs 2/12 (16.7%) in the CG, whereas in the CG, "because-I-do-not-have-a-partner" was most common 6/12 (50.0%) vs 11/42 (26.2%) in the GCG. Sexually active patients in the GCG had an SF comparable to the CG. In multivariate analysis of the total cohort (n = 137), relationship status solid partnership vs living alone; odds ratio (OR), 33.82; 95% confidence interval (CI), 4.83-236.70, smoking (OR, 0.25; 95% CI, 0.06-1.03), and age (OR, 0.87; 95% CI, 0.79-0.94) influenced SA significantly. The probability of SA thereby decreased with increasing age. Quality of life and subjective general health status were not significantly different between the GCG and the CG (EORTC Quality of Life Questionnaire-C30 score 68.25 vs 69.67).
A high number of patients with GC remain sexually inactive after treatment, indicating that women experience persistent functional problems. However, women who regain SA after completed treatment have a good overall SF and vice versa.
High-grade neuroepithelial tumor of the central nervous system with BCOR alteration (HGNET-BCOR) is a rare, highly malignant tumor. At the time of this publication, no standard protocol exists to ...treat this tumor entity. In this work, we tested the responsiveness of the primary culture PhKh1 derived from tumor tissue from a pediatric HGNET-BCOR patient (P1) to inhibitors of the Sonic hedgehog pathway combined with radiation. The SMO inhibitors vismodegib and itraconazole had low effect on the proliferation of the PhKh1 cells. However, the GLI inhibitor arsenic trioxide reduced the expression of GLI target genes in the PhKh1 cells and in combination with radiotherapy significantly decreased their clonogenic potential. PhKh1 cells resistant to arsenic trioxide were characterized by the overexpression of molecular chaperones. We combined arsenic trioxide and radiation in the relapse therapy protocol of P1, achieving complete remission after seven weeks. Clinical remission lasted for six months, when P1 developed systemic metastases. Meanwhile, an increase in the concentration of circulating tumor DNA carrying a BCOR internal tandem duplication was observed. Molecular characterization of a second patient (P2) was also performed. In P2, we detected a larger tandem duplication and greater activation of the Sonic hedgehog pathway than in P1. These findings suggest that combining arsenic trioxide with radiotherapy may represent a new therapeutic approach. Moreover, peripheral blood analysis for circulating tumor DNA could help in the early detection of systemic metastases.
Patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) have dismal outcomes, and <20% undergo allogeneic hematopoietic stem cell transplantation (alloHSCT). Those with venetoclax ...failure have worse outcomes (median survival, 2–3 months) without alloHSCT. SIERRA investigated the use of iodine-131 apamistamab (Iomab-B), a 131I-labeled anti–cluster of differentiation (CD)-45 monoclonal antibody, to enable alloHSCT in patients with active R/R AML; Iomab-B was compared with conventional care (CC).
To report outcomes from SIERRA patients with failed targeted therapies.
Patients >55 years of age with R/R AML were randomized (1:1) to receive Iomab-B followed by fludarabine, total body irradiation (2 Gy), and alloHSCT or CC (physician's choice of therapy, including targeted agents and alloHSCT if leukemia-free). Crossover to Iomab-B–based alloHSCT was permitted for CC patients with progression or without complete remission.
Of 153 patients, 94 (61%) received targeted therapies, including inhibitors of B-cell lymphoma 2 (BCL-2; venetoclax; 65%), fms-like tyrosine kinase 3 (FLT-3; 24%), and isocitrate dehydrogenase (IDH; 10%) prior to randomization, with a balanced distribution between groups. In the CC group, 27 (35%) received targeted therapies as salvage prior to alloHSCT; of those, 7 (26%) responded and received alloHSCT. Eleven of 20 nonresponders (55%) crossed over to receive Iomab-B followed by alloHSCT. All patients who received Iomab-B (n=66) underwent alloHSCT vs 14 (18.2%) in the CC group. Of evaluable patients (Iomab, 59; CC, 64), durable complete remission (dCR) was achieved in 13 (22%) vs 0. Of the 13 dCR patients, 10 (77%) had prior targeted-therapy failure and 7 (54%) had venetoclax failure; 1-year survival was 90% (9/10) in all prior targeted therapy–failure patients and 85% (6/7) in those with prior venetoclax failure. The overall safety of the groups with and without prior targeted therapy was comparable.
Patients with failure of targeted therapies, including venetoclax, were able to undergo alloHSCT with the Iomab-B–led regimen. Of those who achieved dCR with Iomab-B, >70% had previous targeted-therapy failure, including >50% with previous venetoclax failure. The majority of dCR patients were long-term survivors. Iomab-B significantly improves outcomes in patients with prior targeted-therapy failure. (www.sierratrial. com or clinicaltrials.gov NCT02665065).
Conjugated Microporous Polymers
In article 2200385, Martin Mayer, Dana Schwarz, and co‐workers show that adsorption of anthropogenic contaminants such as pharmaceuticals requires tailored adsorbents ...such as conjugated microporous polymers. Coating these polymer networks around mesoporous silica increased the adsorption performance and enabled easy separation by sedimentation. Easy purification allowed the reuse of the hybrid materials.
ABSTRACT The analysis of the early star formation history (SFH) of nearby galaxies, obtained from their resolved stellar populations, is relevant as a test for cosmological models. However, the early ...time resolution of observationally derived SFHs is limited by several factors. Thus, direct comparison of observationally derived SFHs with those derived from theoretical models of galaxy formation is potentially biased. Here we investigate and quantify this effect. For this purpose, we analyze the duration of the early star formation activity in a sample of four Local Group dwarf galaxies and test whether they are consistent with being true fossils of the pre-reionization era; i.e., if the quenching of their star formation occurred before cosmic reionization by UV photons was completed. Two classical dSph (Cetus and Tucana) and two dTrans (LGS-3 and Phoenix) isolated galaxies with total stellar masses between and have been studied. Accounting for time resolution effects, the SFHs peak as much as 1.25 Gyr earlier than the optimal solutions. Thus, this effect is important for a proper comparison of model and observed SFHs. It is also shown that none of the analyzed galaxies can be considered a true fossil of the pre-reionization era, although it is possible that the outer regions of Cetus and Tucana are consistent with quenching by reionization.
Abstract
Background: Cyclin-dependent kinase 8 (CDK8) is part of the mediator complex that can either positively or negatively influence transcription. CDK8 is known to phosphorylate signal ...transducer and activator of transcription 1 (STAT1) at the position Ser727. STAT1 activity is regulated by JAK-mediated phosphorylation of tyrosine701 which leads to dimerization, nuclear translocation and IFN-γ induced phosphorylation mediated by CDK8. Introduction of an alanine mutation at the phosphorylation site STAT1-S727 results in enhanced NK cell cytotoxicity accompanied by increased levels of perforin and granzyme B (Putz et al. 2013).
Method: Here we present the discovery and development of potent and selective CDK8 inhibitors guided by crystallography. The inhibitory effect of optimized compounds BI 9811 and BI 1347 on STAT1 phosphorylation and perforin release was investigated in the human NK cell line NK-92MI. Direct effects on cancer cells were furthermore analyzed in a broad panel of cell lines. The compound BI 1347 was profiled in vivo in the orthotopic B16-F10 melanoma mouse model.
Results: Highly potent and selective CDK8 inhibitors were identified with an IC50 of below 10 nM in a biochemical kinase assay, which translated in a potent down regulation of the STAT1- Ser727 signal and in increased perforin and granzyme B secretion. BI 9811 and BI 1347 were highly selective for CDK8, as tested in a broad kinase panel and showed no cytotoxic activity on NK cells and most cancer cell lines, which distinguishes this compound class from published CDK8 inhibitors. A representative molecule out of this compound class demonstrated in vivo biomarker modulation and survival increase in the murine B16-F10 melanoma mouse model.
Conclusion: We developed potent CDK8 inhibitors that show activation of NK cells that translates into biomarker modulation (pSTAT1Ser727) and in vivo efficacy.
Citation Format: Marco H. Hofmann, Harald Engelhardt, Sebastian Carotta, Heribert Arnhof, Dirk Scharn, Marc Kerenyi, Moritz Mayer, Gerhard Gmaschitz, Georg Egger, Christian Engelhardt, Michael Sanderson, Maria A. Impagnatiello, Renate Schnitzer, Mark Pearson, Darryl McConnell, Norbert Kraut, Jürgen Moll. Development of selective and potent CDK8 inhibitors that increase NK cell activity, which translates in tumor surveillance abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4630. doi:10.1158/1538-7445.AM2017-4630
PDF
