Molecular, pathological, radiological, and immune profiling of non-brainstem pediatric high-grade glioma from the HERBY phase II randomized trial

The HERBY trial was a phase II open-label, randomized, multicenter trial evaluating bevacizumab (BEV) in addition to temozolomide/radiotherapy in patients with newly diagnosed non-brainstem high-grade glioma (HGG) between the ages of 3 and 18 years. We carried out comprehensive molecular analysis integrated with pathology, radiology, and immune profiling. In post-hoc subgroup analysis, hypermutator tumors (mismatch repair deficiency and somatic POLE/POLD1 mutations) and those biologically resembling pleomorphic xanthoastrocytoma ([PXA]-like, driven by BRAF_V600E or NF1 mutation) had significantly more CD8+ tumor-infiltrating lymphocytes, and longer survival with the addition of BEV. Histone H3 subgroups (hemispheric G34R/V and midline K27M) had a worse outcome and were immune cold. Future clinical trials will need to take into account the diversity represented by the term ‘‘HGG’’ in the pediatric population

Molecular Tools for Monitoring the Ecological Sustainability of a Stone Bio-Consolidation Treatment at the Royal Chapel, Granada

Background: Biomineralization processes have recently been applied in situ to protect and consolidate decayed ornamental stone of the Royal Chapel in Granada (Spain). While this promising method has demonstrated its efficacy regarding strengthening of the stone, little is known about its ecological sustainability.Methodology/Principal Findings: Here, we report molecular monitoring of the stone-autochthonous microbiota before and at 5, 12 and 30 months after the bio-consolidation treatment (medium/long-term monitoring), employing the well-known molecular strategy of DGGE analyses. Before the bio-consolidation treatment, the bacterial diversity showed the exclusive dominance of Actinobacteria (100%), which decreased in the community (44.2%) after 5 months, and Gamma-proteobacteria (30.24%) and Chloroflexi (25.56%) appeared. After 12 months, Gamma-proteobacteria vanished from the community and Cyanobacteria (22.1%) appeared and remained dominant after thirty months, when the microbiota consisted of Actinobacteria (42.2%) and Cyanobacteria (57.8%) only. Fungal diversity showed that the Ascomycota phylum was dominant before treatment (100%), while, after five months, Basidiomycota (6.38%) appeared on the stone, and vanished again after twelve months. Thirty months after the treatment, the fungal population started to stabilize and Ascomycota dominated on the stone (83.33%) once again. Members of green algae (Chlorophyta, Viridiplantae) appeared on the stone at 5, 12 and 30 months after the treatment and accounted for 4.25%, 84.77% and 16.77%, respectively.Conclusions: The results clearly show that, although a temporary shift in the bacterial and fungal diversity was observed during the first five months, most probably promoted by the application of the bio-consolidation treatment, the microbiota tends to regain its initial stability in a few months. Thus, the treatment does not seem to have any negative side effects on the stone-autochthonous microbiota over that time. The molecular strategy employed here is suggested as an efficient monitoring tool to assess the impact on the stone-autochthonous microbiota of the application of biomineralization processes as a restoration/conservation procedure.This work was supported by the European Regional Development Fund (ERDF), Junta de Andalucía (Spain) and the “Fortalecimiento de la I+D+i” program from the University of Granada, co-financed by grant RNM-3493 and Research Group BIO-103 from Junta de Andalucía, as well as by the Spanish Government through “José Castillejo” program from the “Ministerio de Educación, Cultura y Deporte” (I+D+i 2008-2011), and by the Austrian Science Fund (FWF) under Grant “Elise-Richter V194-B20”

Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial

The HERBY trial was a phase II open-label, randomized, multicenter trial evaluating bevacizumab (BEV) in addition to temozolomide/radiotherapy in patients with newly diagnosed non-brainstem high-grade glioma (HGG) between the ages of 3 and 18 years. We carried out comprehensive molecular analysis integrated with pathology, radiology, and immune profiling. In post-hoc subgroup analysis, hypermutator tumors (mismatch repair deficiency and somatic POLE/POLD1 mutations) and those biologically resembling pleomorphic xanthoastrocytoma ([PXA]-like, driven by BRAF_V600E or NF1 mutation) had significantly more CD8+ tumor-infiltrating lymphocytes, and longer survival with the addition of BEV. Histone H3 subgroups (hemispheric G34R/V and midline K27M) had a worse outcome and were immune cold. Future clinical trials will need to take into account the diversity represented by the term “HGG” in the pediatric population

Variable Stars in Galactic Globular Clusters

Based on a search of the literature up to May 2001, the number of known variable stars in Galactic globular clusters is approximately 3000. Of these, more than 2200 have known periods and the majority (approximately 1800) are of the RR Lyrae type. In addition to the RR Lyrae population, there are approximately 100 eclipsing binaries, 120 SX Phe variables, 60 Cepheids (including population II Cepheids, anomalous Cepheids and RV Tauri) and 120 SR/red variables. The mean period of the fundamental mode RR Lyrae variables is 0.585, for the overtone variables it is 0.342 (0.349 for the first-overtone pulsators and 0.296 for the second-overtone pulsators) and approximately 30% are overtone pulsators. These numbers indicate that about 65% of RR Lyrae variables in Galactic globular clusters belong to Oosterhoff type I systems. The mean period of the RR Lyrae variables in the Oosterhoff type I clusters seems to be correlated with metal abundance in the sense that the periods are longer in the more metal poor clusters. Such a correlation does not exist for the Oosterhoff type II clusters. Most of the Cepheids are in clusters with blue horizontal branches.Comment: 45 pages, 10 figures, to be published in AJ November 200

Combinatorial Effect of Non-Steroidal Anti-inflammatory Drugs and NF-κB Inhibitors in Ovarian Cancer Therapy

Several epidemiological studies have correlated the use of non-steroidal anti-inflammatory drugs (NSAID) with reduced risk of ovarian cancer, the most lethal gynecological cancer, diagnosed usually in late stages of the disease. We have previously established that the pro-apoptotic cytokine melanoma differentiation associated gene-7/Interleukin-24 (mda-7/IL-24) is a crucial mediator of NSAID-induced apoptosis in prostate, breast, renal and stomach cancer cells. In this report we evaluated various structurally different NSAIDs for their efficacies to induce apoptosis and mda-7/IL-24 expression in ovarian cancer cells. While several NSAIDs induced apoptosis, Sulindac Sulfide and Diclofenac most potently induced apoptosis and reduced tumor growth. A combination of these agents results in a synergistic effect. Furthermore, mda-7/IL-24 induction by NSAIDs is essential for programmed cell death, since inhibition of mda-7/IL-24 by small interfering RNA abrogates apoptosis. mda-7/IL-24 activation leads to upregulation of growth arrest and DNA damage inducible (GADD) 45 α and γ and JNK activation. The NF-κB family of transcription factors has been implicated in ovarian cancer development. We previously established NF-κB/IκB signaling as an essential step for cell survival in cancer cells and hypothesized that targeting NF-κB could potentiate NSAID-mediated apoptosis induction in ovarian cancer cells. Indeed, combining NSAID treatment with NF-κB inhibitors led to enhanced apoptosis induction. Our results indicate that inhibition of NF-κB in combination with activation of mda-7/IL-24 expression may lead to a new combinatorial therapy for ovarian cancer

Chicken Pleiotrophin: Regulation of Tissue Specific Expression by Estrogen in the Oviduct and Distinct Expression Pattern in the Ovarian Carcinomas

Pleiotrophin (PTN) is a developmentally-regulated growth factor which is widely distributed in various tissues and also detected in many kinds of carcinomas. However, little is known about the PTN gene in chickens. In the present study, we found chicken PTN to be highly conserved with respect to mammalian PTN genes (91–92.6%) and its mRNA was most abundant in brain, heart and oviduct. This study focused on the PTN gene in the oviduct where it was detected in the glandular (GE) and luminal (LE) epithelial cells. Treatment of young chicks with diethylstilbesterol induced PTN mRNA and protein in GE and LE, but not in other cell types of the oviduct. Further, several microRNAs, specifically miR-499 and miR-1709 were discovered to influence PTN expression via its 3′-UTR which suggests that post-transcriptional regulation influences PTN expression in chickens. We also compared expression patterns and CpG methylation status of the PTN gene in normal and cancerous ovaries from chickens. Our results indicated that PTN is most abundant in the GE of adenocarcinoma of cancerous, but not normal ovaries of hens. Bisulfite sequencing revealed that 30- and 40% of −1311 and −1339 CpG sites are demethylated in ovarian cancer cells, respectively. Collectively, these results indicate that chicken PTN is a novel estrogen-induced gene expressed mainly in the oviductal epithelia implicating PTN regulation of oviduct development and egg formation, and also suggest that PTN is a biomarker for epithelial ovarian carcinoma that could be used for diagnosis and monitoring effects of therapies for the disease

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

The impact of patient feedback on the medical performance of qualified doctors: a systematic review

Background: Patient feedback is considered integral to quality improvement and professional development. However, while popular across the educational continuum, evidence to support its efficacy in facilitating positive behaviour change in a postgraduate setting remains unclear. This review therefore aims to explore the evidence that supports, or refutes, the impact of patient feedback on the medical performance of qualified doctors. // Methods: Electronic databases PubMed, EMBASE, Medline and PsycINFO were systematically searched for studies assessing the impact of patient feedback on medical performance published in the English language between 2006-2016. Impact was defined as a measured change in behaviour using Barr’s (2000) adaptation of Kirkpatrick’s four level evaluation model. Papers were quality appraised, thematically analysed and synthesised using a narrative approach. // Results: From 1,269 initial studies, 20 articles were included (qualitative (n=8); observational (n=6); systematic review (n=3); mixed methodology (n=1); randomised control trial (n=1); and longitudinal (n=1) design). One article identified change at an organisational level (Kirkpatrick level 4); six reported a measured change in behaviour (Kirkpatrick level 3b); 12 identified self-reported change or intention to change (Kirkpatrick level 3a), and one identified knowledge or skill acquisition (Kirkpatrick level 2). No study identified a change at the highest level, an improvement in the health and wellbeing of patients. The main factors found to influence the impact of patient feedback were: specificity; perceived credibility; congruence with physician self-perceptions and performance expectations; presence of facilitation and reflection; and inclusion of narrative comments. The quality of feedback facilitation and local professional cultures also appeared integral to positive behaviour change. // Conclusion: Patient feedback can have an impact on medical performance. However, actionable change is influenced by several contextual factors and cannot simply be guaranteed. Patient feedback is likely to be more influential if it is specific, collected through credible methods and contains narrative information. Data obtained should be fed back in a way that facilitates reflective discussion and encourages the formulation of actionable behaviour change. A supportive cultural understanding of patient feedback and its intended purpose is also essential for its effective use