How cell death shapes cancer

Apoptosis has been established as a mechanism of anti-cancer defense. Members of the BCL-2 family are critical mediators of apoptotic cell death in health and disease, often found to be deregulated in cancer and believed to lead to the survival of malignant clones. However, over the years, a number of studies pointed out that a model in which cell death resistance unambiguously acts as a barrier against malignant disease might be too simple. This is based on paradoxical observations made in tumor patients as well as mouse models indicating that apoptosis can indeed drive tumor formation, at least under certain circumstances. One possible explanation for this phenomenon is that apoptosis can promote proliferation critically needed to compensate for cell loss, for example, upon therapy, and to restore tissue homeostasis. However, this, at the same time, can promote tumor development by allowing expansion of selected clones. Usually, tissue resident stem/progenitor cells are a major source for repopulation, some of them potentially carrying (age-, injury- or therapy-induced) genetic aberrations deleterious for the host. Thereby, apoptosis might drive genomic instability by facilitating the emergence of pathologic clones during phases of proliferation and subsequent replication stress-associated DNA damage. Tumorigenesis initiated by repeated cell attrition and repopulation, as confirmed in different genetic models, has parallels in human cancers, exemplified in therapy-induced secondary malignancies and myelodysplastic syndromes in patients with congenital bone marrow failure syndromes. Here, we aim to review evidence in support of the oncogenic role of stress-induced apoptosis

A new cuticle scale hydrolysing protease from beauveria brongniartii

From a screening for the production of new proteases specific for cuticle scales, Beauveria brongniartii was selected producing an alkaline Ca++ dependent protease. The purified had a molecular weight of 27 kDa and a pI value of 8.0. Substrate specificities of model substrates (wool with partially removed cuticles treated with SDS) were analyzed by protein release, dissolved organic carbon (DOC) and nitrogen analysis. The C/N ratio of released material turned out to be a good parameter to determine the site of action of proteases on fibres. Compared to other enzymes, the fungal protease preferentially hydrolyzed cuticle scales and has thus a potential for antishrinking pre-treatment of wool fabrics

Enzymatic synthesis of Tinuvin

Coupling of 3-(3-tert-butyl-4-hydroxyphenyl) propionic acid methylester to 1H-benzotriazole using a laccase from Trametes hirsuta was studied. The potentially resulting coupling product Tinuvin 1130 is an important UV-absorber used in polymer based materials. Oxidation of the phenol by the laccase led to homomolecular coupling reactions while the laccase did not attack 1H-benzotriazole. Due to the homomolecular reaction of the phenol in the presence of laccase coupling of phenol and 1H-benzotriazole was only observed when 1H-benzotriazole was applied in four-fold molar excess. The reaction was monitored by UV/vis spectroscopy, TLC and MS (ion trap) analysis. Coupling of 1H-benzotriazole took place in ortho position according to the postulated mechanism

Vaccines as alternatives to antibiotics for food producing animals. Part 2:new approaches and potential solutions

Vaccines and other alternative products are central to the future success of animal agriculture because they can help minimize the need for antibiotics by preventing and controlling infectious diseases in animal populations. To assess scientific advancements related to alternatives to antibiotics and provide actionable strategies to support their development, the United States Department of Agriculture, with support from the World Organisation for Animal Health, organized the second International Symposium on Alternatives to Antibiotics. It focused on six key areas: vaccines; microbial-derived products; non-nutritive phytochemicals; immune-related products; chemicals, enzymes, and innovative drugs; and regulatory pathways to enable the development and licensure of alternatives to antibiotics. This article, the second part in a two-part series, highlights new approaches and potential solutions for the development of vaccines as alternatives to antibiotics in food producing animals; opportunities, challenges and needs for the development of such vaccines are discussed in the first part of this series. As discussed in part 1 of this manuscript, many current vaccines fall short of ideal vaccines in one or more respects. Promising breakthroughs to overcome these limitations include new biotechnology techniques, new oral vaccine approaches, novel adjuvants, new delivery strategies based on bacterial spores, and live recombinant vectors; they also include new vaccination strategies in-ovo, and strategies that simultaneously protect against multiple pathogens. However, translating this research into commercial vaccines that effectively reduce the need for antibiotics will require close collaboration among stakeholders, for instance through public–private partnerships. Targeted research and development investments and concerted efforts by all affected are needed to realize the potential of vaccines to improve animal health, safeguard agricultural productivity, and reduce antibiotic consumption and resulting resistance risks

Recovery and performance in sport: Consensus statement

© 2018 Human Kinetics, Inc. The relationship between recovery and fatigue and its impact on performance has attracted the interest of sport science for many years. An adequate balance between stress (training and competition load, other life demands) and recovery is essential for athletes to achieve continuous high-level performance. Research has focused on the examination of physiological and psychological recovery strategies to compensate external and internal training and competition loads. A systematic monitoring of recovery and the subsequent implementation of recovery routines aims at maximizing performance and preventing negative developments such as underrecovery, nonfunctional overreaching, the overtraining syndrome, injuries, or illnesses. Due to the inter- and intraindividual variability of responses to training, competition, and recovery strategies, a diverse set of expertise is required to address the multifaceted phenomena of recovery, performance, and their interactions to transfer knowledge from sport science to sport practice. For this purpose, a symposium on Recovery and Performance was organized at the Technical University Munich Science and Study Center Raitenhaslach (Germany) in September 2016. Various international experts from many disciplines and research areas gathered to discuss and share their knowledge of recovery for performance enhancement in a variety of settings. The results of this meeting are outlined in this consensus statement that provides central definitions, theoretical frameworks, and practical implications as a synopsis of the current knowledge of recovery and performance. While our understanding of the complex relationship between recovery and performance has significantly increased through research, some important issues for future investigations are also elaborated

Venetoclax-based therapies in pediatric advanced MDS and relapsed/refractory AML: a multicenter retrospective analysis

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Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial

Objective: Assess ustekinumab efficacy (week 24/week 52) and safety (week 16/week 24/week 60) in patients with active psoriatic arthritis (PsA) despite treatment with conventional and/or biological anti-tumour necrosis factor (TNF) agents. Methods: In this phase 3, multicentre, placebo-controlled trial, 312 adults with active PsA were randomised (stratified by site, weight (≤100 kg/>100 kg), methotrexate use) to ustekinumab 45 mg or 90 mg at week 0, week 4, q12 weeks or placebo at week 0, week 4, week 16 and crossover to ustekinumab 45 mg at week 24, week 28 and week 40. At week 16, patients with <5% improvement in tender/swollen joint counts entered blinded early escape (placebo→45 mg, 45 mg→90 mg, 90 mg→90 mg). The primary endpoint was ≥20% improvement in American College of Rheumatology (ACR20) criteria at week 24. Secondary endpoints included week 24 Health Assessment Questionnaire-Disability Index (HAQ-DI) improvement, ACR50, ACR70 and ≥75% improvement in Psoriasis Area and Severity Index (PASI75). Efficacy was assessed in all patients, anti-TNF-naïve (n=132) patients and anti-TNF-experienced (n=180) patients. Results: More ustekinumab-treated (43.8% combined) than placebo-treated (20.2%) patients achieved ACR20 at week 24 (p<0.001). Significant treatment differences were observed for week 24 HAQ-DI improvement (p<0.001), ACR50 (p≤0.05) and PASI75 (p<0.001); all benefits were sustained through week 52. Among patients previously treated with ≥1 TNF inhibitor, sustained ustekinumab efficacy was also observed (week 24 combined vs placebo: ACR20 35.6% vs 14.5%, PASI75 47.1% vs 2.0%, median HAQ-DI change −0.13 vs 0.0; week 52 ustekinumab-treated: ACR20 38.9%, PASI75 43.4%, median HAQ-DI change −0.13). No unexpected adverse events were observed through week 60. Conclusions: The interleukin-12/23 inhibitor ustekinumab (45/90 mg q12 weeks) yielded significant and sustained improvements in PsA signs/symptoms in a diverse population of patients with active PsA, including anti-TNF-experienced PsA patients

Long non-coding RNAs as novel therapeutic targets in juvenile myelomonocytic leukemia

Juvenile myelomonocytic leukemia (JMML) treatment primarily relies on hematopoietic stem cell transplantation and results in long-term overall survival of 50-60%, demonstrating a need to develop novel treatments. Dysregulation of the non-coding RNA transcriptome has been demonstrated before in this rare and unique disorder of early childhood. In this study, we investigated the therapeutic potential of targeting overexpressed long non-coding RNAs (lncRNAs) in JMML. Total RNA sequencing of bone marrow and peripheral blood mononuclear cell preparations from 19 untreated JMML patients and three healthy children revealed 185 differentially expressed lncRNA genes (131 up- and 54 downregulated). LNA GapmeRs were designed for 10 overexpressed and validated lncRNAs. Molecular knockdown (>= 70% compared to mock control) after 24 h of incubation was observed with two or more independent GapmeRs in 6 of them. For three lncRNAs (lnc-THADA-4, lnc-ACOT9-1 and NRIR) knockdown resulted in a significant decrease of cell viability after 72 h of incubation in primary cultures of JMML mononuclear cells, respectively. Importantly, the extent of cellular damage correlated with the expression level of the lncRNA of interest. In conclusion, we demonstrated in primary JMML cell cultures that knockdown of overexpressed lncRNAs such as lnc-THADA-4, lnc-ACOT9-1 and NRIR may be a feasible therapeutic strategy

cDNA Library Generation for the Analysis of Small RNAs by High-Throughput Sequencing

The RNome of a cell is highly diverse and consists besides messenger RNAs (mRNAs), transfer RNAs (tRNAs), and ribosomal RNAs (rRNAs) also of other small and long transcript entities without apparent coding potential. This class of molecules, commonly referred to as non-protein-coding RNAs (ncRNAs), is involved in regulating numerous biological processes and thought to contribute to cellular complexity. Therefore, much effort is put into their identification and further functional characterization. Here we provide a cost-effective and reliable method for cDNA library construction of small RNAs in the size range of 20-500 residues. The effectiveness of the described method is demonstrated by the analysis of ribosome-associated small RNAs in the eukaryotic model organism Trypanosoma brucei