Abstract
Survival rates of cancer patients vary widely within and between malignancies. While genetic aberrations are at the root of all cancers, individual genomic features cannot explain these ...distinct disease outcomes. In contrast, intra-tumour heterogeneity (ITH) has the potential to elucidate pan-cancer survival rates and the biology that drives cancer prognosis. Unfortunately, a comprehensive and effective framework to measure ITH across cancers is missing. Here, we introduce a scalable measure of chromosomal copy number heterogeneity (CNH) that predicts patient survival across cancers. We show that the level of ITH can be derived from a single-sample copy number profile. Using gene-expression data and live cell imaging we demonstrate that ongoing chromosomal instability underlies the observed heterogeneity. Analysing 11,534 primary cancer samples from 37 different malignancies, we find that copy number heterogeneity can be accurately deduced and predicts cancer survival across tissues of origin and stages of disease. Our results provide a unifying molecular explanation for the different survival rates observed between cancer types.
Fungi on the skin: dermatophytes and Malassezia White, Theodore C; Findley, Keisha; Dawson, Jr, Thomas L ...
Cold Spring Harbor perspectives in medicine,
08/2014, Letnik:
4, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Several human skin diseases and disorders are associated with two groups of fungi, the dermatophytes and Malassezia. Although these skin-related problems are not generally life threatening, they are ...among the most common diseases and disorders of mankind. These fungi are phylogenetically divergent, with the dermatophytes within the Ascomycota and Malassezia within Basidiomycota. Genome analysis indicates that the adaptations to the skin environment are different in these two groups of fungi. Malassezia are dependent on host lipids and secrete lipases and phospholipases that likely release host fatty acids. The dermatophytes encode multiple enzymes with potential roles in modulating host interactions: polyketide synthases, nonribosomal peptide synthetases, LysM, proteases, kinases, and pseudokinases. These two fungal groups have maximized their interactions with the host using two very different mechanisms.
In general, patients with a cancer suspicion visit the hospital multiple times before diagnosis is completed. Using various "operations management" techniques a few fast track diagnostic services ...were implemented in the Netherlands Cancer Institute (NKI) in 2006. Growing patient numbers and increasing process complexity, led to diminished service levels. To decrease the amount of patient visits and to extend these services beyond the (obvious) breast cancer services, fast track diagnostics is now implemented for all 18 cancer types that present with a frequency of minimally one per week.
The throughput time (first visit to diagnosis conversation) was measured before, and after implementation of fast track diagnostics. The process was redesigned closely involving the multidisciplinary teams. In an eclectic approach elements from lean management, theory of constraints and mathematical analysis were used to organize slots per tumor type for MRI, CT, PET and echography. A post measurement was performed after 3 and 6 months.
In pre measurement access time was calculated to be 10 to 15 workdays, mean throughput time was 6.0 workdays. It proved possible to design the process of 18 tumors as a fast track, of which 7 as "one stop shop" (diagnosis completed in one visit). Involvement of clinical- and board leadership, massive communication efforts and commitment of physicians to reschedule their work proved decisive. After 3 and 6 months of implementation, the mean access time was 8.2 and 8.7 workdays respectively and mean throughput time was 3.4 and 3.3 workdays respectively.
Throughput- and access time were considerably shortened after implementation of fast track diagnostics for 18 cancer types. The involvement of physicians in reorganizing their work and rapid responding to their needs during the implementation phase were a crucial success factor.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Sex chromosomes in males of most eutherian mammals share only a small homologous segment, the pseudoautosomal region (PAR), in which the formation of double-strand breaks (DSBs), pairing and crossing ...over must occur for correct meiotic segregation
. How cells ensure that recombination occurs in the PAR is unknown. Here we present a dynamic ultrastructure of the PAR and identify controlling cis- and trans-acting factors that make the PAR the hottest segment for DSB formation in the male mouse genome. Before break formation, multiple DSB-promoting factors hyperaccumulate in the PAR, its chromosome axes elongate and the sister chromatids separate. These processes are linked to heterochromatic mo-2 minisatellite arrays, and require MEI4 and ANKRD31 proteins but not the axis components REC8 or HORMAD1. We propose that the repetitive DNA sequence of the PAR confers unique chromatin and higher-order structures that are crucial for recombination. Chromosome synapsis triggers collapse of the elongated PAR structure and, notably, oocytes can be reprogrammed to exhibit spermatocyte-like levels of DSBs in the PAR simply by delaying or preventing synapsis. Thus, the sexually dimorphic behaviour of the PAR is in part a result of kinetic differences between the sexes in a race between the maturation of the PAR structure, formation of DSBs and completion of pairing and synapsis. Our findings establish a mechanistic paradigm for the recombination of sex chromosomes during meiosis.
Double-strand breaks (DSBs) initiate the homologous recombination that is crucial for meiotic chromosome pairing and segregation. Here, we unveil mouse ANKRD31 as a lynchpin governing multiple ...aspects of DSB formation. Spermatocytes lacking ANKRD31 have altered DSB locations and fail to target DSBs to the pseudoautosomal regions (PARs) of sex chromosomes. They also have delayed and/or fewer recombination sites but, paradoxically, more DSBs, suggesting DSB dysregulation. Unrepaired DSBs and pairing failures—stochastic on autosomes, nearly absolute on X and Y—cause meiotic arrest and sterility in males. Ankrd31-deficient females have reduced oocyte reserves. A crystal structure defines a pleckstrin homology (PH) domain in REC114 and its direct intermolecular contacts with ANKRD31. In vivo, ANKRD31 stabilizes REC114 association with the PAR and elsewhere. Our findings inform a model in which ANKRD31 is a scaffold anchoring REC114 and other factors to specific genomic locations, thereby regulating DSB formation.
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•REC114 directly interacts with ANKRD31, a novel factor required for normal fertility•ANKRD31 influences the distribution of double-strand breaks genome-wide•ANKRD31 is essential for the recombination between X and Y chromosomes•A crystal structure reveals a PH domain in REC114 and its contacts with ANKRD31
Boekhout et al. discover ANKRD31 as a REC114 interactor and key player in meiotic recombination. ANKRD31 acts as a molecular scaffold to regulate double-strand break formation and promote X-Y recombination. An atomic resolution structure illuminates the conserved features of REC114-ANKRD31 interaction, including an unexpected pleckstrin homology domain in REC114.
Mycoparasites in Basidiomycota comprise a diverse group of fungi, both morphologically and phylogenetically. They interact with their hosts through either fusion-interaction or ...colacosome-interaction. Colacosomes are subcellular structures formed by the mycoparasite at the host–parasite interface, which penetrate the parasite and host cell walls. Previously, these structures were detected in 19 fungal species, usually by means of transmission electron microscopy. Most colacosome-forming species have been assigned to Microbotryomycetes ( Pucciniomycotina , Basidiomycota ), a highly diverse class, comprising saprobic yeasts, mycoparasites, and phytoparasites. In general, these myco- and phytoparasites are dimorphic organisms, with a parasitic filamentous morph and saprobic yeast morph. We investigated colacosome-forming mycoparasites based on fungarium material, freshly collected specimens, and cultures of yeast morphs. We characterised the micromorphology of filamentous morphs, the physiological characteristics of yeast morphs, and inferred phylogenetic relationships based on DNA sequence data from seven loci. We outline and employ an epifluorescence-based microscopic method to assess the presence and organisation of colacosomes. We describe five new species in the genus Colacogloea , the novel dimorphic mycoparasite Mycogloiocolax gerardii , and provide the first report of a sexual, mycoparasitic morph in Colacogloea philyla and in the genus Slooffia . We detected colacosomes in eight fungal species, which brings the total number of known colacosome-forming fungi to 27. Finally, we revealed three distinct types of colacosome organisation in Microbotryomycetes .
Chinese Daqu is used as a starter for liquor and vinegar fermentations. It is produced by solid state fermentation of cereal–pulse mixtures. A succession of fungi, lactic acid bacteria and Bacillus ...spp. was observed during the production of Daqu. Mesophilic bacteria followed by fungi, dominated the first phase of fermentation. Next, lactic acid bacteria increased in relative abundance, resulting in an increase of the acidity of Daqu. At the final stages of fermentation, Bacillus spp. and thermophilic fungi became the dominant groups, possibly due to their tolerance to low water activity and high temperature. Both culture-dependent and culture-independent analyses confirmed that Bacillus spp. were ubiquitous throughout the process. Yeast species such as Wickerhamomyces anomalus, Saccharomycopsis fibuligera and Pichia kudriavzevii were present throughout almost the entire fermentation process, but the zygomycetous fungus Lichtheimia corymbifera proliferated only during the final stages of fermentation. Canonical correspondence analysis (CCA) revealed the significance of acidity, moisture content and temperature in correlation with the composition of the microbial communities at different stages.
•A succession of fungi, lactic acid bacteria and Bacillus spp. was observed.•Bacillus licheniformis was present throughout the entire process.•Lichtheimia corymbifera proliferated only during the final stages of fermentation.•Both culture-dependent and culture-independent approaches were used in this study.•CCA revealed the importance of acidity and temperature on the fermentation.
Abstract
Purpose
Among middle aged and older adults (>50 years) (MAOA) insufficient PA is highly prevalent. Although many PA interventions for MAOA are effective in research settings, the actual ...impact on public health is often limited, due to low participation when implemented in real-life settings. The issue of low participation in PA interventions is well-documented, but most research so far seems to focus on demographic characteristics as potential explanations, rather than explanations that may lie within the actual communication about the intervention. Therefore, more insight in how persuasive communication can be applied when implementing PA interventions is relevant. This study examines the opinions of MAOA on how communication about PA interventions should be shaped.
Methods
We conducted 31 semi-structured interviews with MAOA. Recruitment was done by way of convenience sample, within the personal and professional network of the researchers. Thematic analysis was applied by using a-priori defined themes based on the persuasive communication theory of McGuire, i.e. the message, channel, source, receiver and target-behavior.
Results
Preliminary findings demonstrated that the message content, channel, and source should be aligned with certain demographics of the receiver. For example, the message should focus on social and mental benefits on PA, rather than referring to age-associated limitations or health benefits. In contrast to middle aged adults, the older adults seemed to dislike social media as channel. General practitioners were the preferred source to inform about interventions. Regarding the target behavior, words like “sports” should be avoided in favor of words like ‘being active’. Final results will be available within 3 months.
Conclusions
By identifying the features that MAOA prefer regarding the message, channel, source, receiver and target behavior of communication about PA intervention, relevant insights about how MAOA can be reached for interventions will be gained. This can contribute to moving beyond merely developing PA interventions that are proven effective in research settings, to implementing such interventions in a way that contributes to reaching sufficient numbers of MOAO to participate in PA interventions, thus substantially contributing to public health.
Support/Funding Source
This research was funded by ZonMw Implementation network Sports and PA.
Abstract
Aim
Although there are many proven effective physical activity (PA) interventions for middle-aged and older adults (MAOA), implementation in a real world setting is often lacking. ...Intermediary organizations (further referred to as ‘stakeholders’) often determine the final exposure of the intervention to the target population and therefore have a crucial role in the implementation process. This study provides insight in stakeholders’ perceptions of barriers and facilitators (i.e. implementation determinants) regarding implementation of PA interventions among MAOA.
Method
A semi-structured interview guide was developed based on the Consolidated Framework for Implementation Research (CFIR), including five domains of implementation determinants, i.e.: interventions characteristics, outer setting (e.g., the target population’s needs and policies), inner setting (e.g., organizational goals ), individuals’ characteristics (e.g., stakeholders’ self-efficacy) and the implementation process. Using snowball sampling (starting with the regional health counselor) stakeholders were recruited to participate in the interviews. Thematic analyses, guided by a CFIR-based codebook, was applied.
Results
We completed 25 interviews, involving representatives of regional health counselors (n = 5), municipalities (n = 3), sportservice organizations (n = 5), welfare organizations (n = 3), and several individual organizations. Analyses showed that in all CFIR domains relevant implementation determinants were identified. Stakeholders mentioned being able to play a relevant role in the implementation of PA intervention. Collaboration between organizations is essential to successfully perform all steps needed to implement interventions. Focusing on a broader perspective than increasing PA behavior, such as stimulating positive health seemed an important facilitator when implementing PA intervention. An often mentioned barrier was that most policy plans currently focus on youth, consequently resulting in a lack of means to implement interventions for MAOA.
Conclusion
Gaining insight in the perception of stakeholders’ most relevant implementation determinants is a crucial step in the development of an effective implementation plan. In a next phase of our study, a collaboration meeting between stakeholders will be organized in which determinants will be ranked. The ranking of these determinants will be discussed with the symposium audience as well. Matching the implementation determinants, potential implementation strategies will be discussed.
Background and aims
Amazonia comprises a mosaic of ecosystems that harbor high biodiversity. Knowledge about fungal diversity and ecology in this region remains very limited. Here, we examine soil ...fungal communities in forests of the Colombian Amazonia and their relationship to important edaphic variables.
Methods
Fungal communities were studied in
terra-firme
forests dominated by arbuscular mycorrhizal (AM) trees,
terra-firme
forests with the ectomycorrhizal (EcM) tree
Pseudomonotes tropenbosii
(Dipterocarpaceae), and white sand forests (WSF) with the EcM host plant genera
Dicymbe
and
Aldina
(Fabaceae). Fungal community composition was determined through 454-pyrosequencing of the ITS2 region of ribosomal DNA. We established the impact of the type of forest and edaphic parameters in structuring the fungal communities.
Results
We found a high diversity of fungi with 2,507 OTUs occurring in the soil samples studied. Carbon content and pH were the main edaphic factors contributing to structure the fungal community across all forests. Fungal community composition differs among
terra-firme
plots and WSF, while it was similar among AM and EcM-dominated areas in
terra-firme
. Our results revealed an important EcM fungal diversity in
terra-firme
AM-forests, where some EcM plants such as the ones in the genera
Coccoloba
and
Neea
occur scattered within an AM-matrix.
Conclusions
This is a first approximation to understand the ecology of soil fungal communities in forests of the Colombian Amazonia. We found that fungal soil communities have a spatial variation related to forest type (
terra-firme
and WSF), soil pH, and soil carbon content. Due to the strong correlation between vegetation and soil fertility in Amazonia, it is difficult to understand the effects of those factors to the fungal communities.
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