Ageing does not result in a decline in cell synthetic activity in an injury prone tendon

Advancing age is a well-known risk factor for tendon disease. Energy-storing tendons [e.g., human Achilles, equine superficial digital flexor tendon (SDFT)] are particularly vulnerable and it is thought that injury occurs following an accumulation of micro-damage in the extracellular matrix (ECM). Several authors suggest that age-related micro-damage accumulates due to a failure of the aging cell population to maintain the ECM or an imbalance between anabolic and catabolic pathways. We hypothesized that ageing results in a decreased ability of tendon cells to synthesize matrix components and matrix-degrading enzymes, resulting in a reduced turnover of the ECM and a decreased ability to repair micro-damage. The SDFT was collected from horses aged 3-30 years with no signs of tendon injury. Cell synthetic and degradative ability was assessed at the mRNA and protein levels. Telomere length was measured as an additional marker of cell ageing. There was no decrease in cellularity or relative telomere length with increasing age, and no decline in mRNA or protein levels for matrix proteins or degradative enzymes. The results suggest that the mechanism for age-related tendon deterioration is not due to reduced cellularity or a loss of synthetic functionality and that alternative mechanisms should be considered

The impact of the demographic transition on dengue in Thailand: Insights from a statistical analysis and mathematical modeling

Background: An increase in the average age of dengue hemorrhagic fever (DHF) cases has been reported in Thailand. The cause of this increase is not known. Possible explanations include a reduction in transmission due to declining mosquito populations, declining contact between human and mosquito, and changes in reporting. We propose that a demographic shift toward lower birth and death rates has reduced dengue transmission and lengthened the interval between large epidemics. Methods and Findings: Using data from each of the 72 provinces of Thailand, we looked for associations between force of infection (a measure of hazard, defined as the rate per capita at which susceptible individuals become infected) and demographic and climactic variables. We estimated the force of infection from the age distribution of cases from 1985 to 2005. We find that the force of infection has declined by 2% each year since a peak in the late 1970s and early 1980s. Contrary to recent findings suggesting that the incidence of DHF has increased in Thailand, we find a small but statistically significant decline in DHF incidence since 1985 in a majority of provinces. The strongest predictor of the change in force of infection and the mean force of infection is the median age of the population. Using mathematical simulations of dengue transmission we show that a reduced birth rate and a shift in the population's age structure can explain the shift in the age distribution of cases, reduction of the force of infection, and increase in the periodicity of multiannual oscillations of DHF incidence in the absence of other changes. Conclusions: Lower birth and death rates decrease the flow of susceptible individuals into the population and increase the longevity of immune individuals. The increase in the proportion of the population that is immune increases the likelihood that an infectious mosquito will feed on an immune individual, reducing the force of infection. Though the force of infection has decreased by half, we find that the critical vaccination fraction has not changed significantly, declining from an average of 85% to 80%. Clinical guidelines should consider the impact of continued increases in the age of dengue cases in Thailand. Countries in the region lagging behind Thailand in the demographic transition may experience the same increase as their population ages. The impact of demographic changes on the force of infection has been hypothesized for other diseases, but, to our knowledge, this is the first observation of this phenomenon

Chemotherapy-Response Monitoring of Breast Cancer Patients Using Quantitative Ultrasound-Based Intra-Tumour Heterogeneities

© 2017 The Author(s). Anti-cancer therapies including chemotherapy aim to induce tumour cell death. Cell death introduces alterations in cell morphology and tissue micro-structures that cause measurable changes in tissue echogenicity. This study investigated the effectiveness of quantitative ultrasound (QUS) parametric imaging to characterize intra-tumour heterogeneity and monitor the pathological response of breast cancer to chemotherapy in a large cohort of patients (n = 100). Results demonstrated that QUS imaging can non-invasively monitor pathological response and outcome of breast cancer patients to chemotherapy early following treatment initiation. Specifically, QUS biomarkers quantifying spatial heterogeneities in size, concentration and spacing of acoustic scatterers could predict treatment responses of patients with cross-validated accuracies of 82 ± 0.7%, 86 ± 0.7% and 85 ± 0.9% and areas under the receiver operating characteristic (ROC) curve of 0.75 ± 0.1, 0.80 ± 0.1 and 0.89 ± 0.1 at 1, 4 and 8 weeks after the start of treatment, respectively. The patients classified as responders and non-responders using QUS biomarkers demonstrated significantly different survivals, in good agreement with clinical and pathological endpoints. The results form a basis for using early predictive information on survival-linked patient response to facilitate adapting standard anti-cancer treatments on an individual patient basis

Changes in articular cartilage after meniscectomy and meniscus replacement using a biodegradable porous polymer implant

Purpose: To evaluate the long-term effects of implantation of a biodegradable polymer meniscus implant on articular cartilage degeneration and compare this to articular cartilage degeneration after meniscectomy. Methods: Porous polymer polycaprolacton-based polyurethane meniscus implants were implanted for 6 or 24 months in the lateral compartment of Beagle dog knees. Contralateral knees were meniscectomized, or left intact and served as controls. Articular cartilage degeneration was evaluated in detail using India ink staining, routine histology, immunochemistry for denatured (Col2-¾M) and cleaved (Col2-¾Cshort) type II collagen, Mankin’s grading system, and cartilage thickness measurements. Results: Histologically, fibrillation and substantial immunohistochemical staining for both denatured and cleaved type II collagen were found in all three treatment groups. The cartilage of the three groups showed identical degradation patterns. In the 24 months implant group, degradation appeared to be more severe when compared to the 6 months implant group and meniscectomy group. Significantly more cartilage damage (India ink staining, Mankin’s grading system, and cartilage thickness measurements) was found in the 24 months implant group compared to the 6 months implant group and meniscectomy group. Conclusion: Degradation of the cartilage matrix was the result of both mechanical overloading as well as localized cell-mediated degradation. The degeneration patterns were highly variable between animals. Clinical application of a porous polymer implant for total meniscus replacement is not supported by this study.

Mortes evitáveis em vítimas com traumatismos

OBJETIVO: Descrever métodos e estimativas de mortalidade proporcional por mortes evitáveis e tipos de não conformidades do atendimento relacionadas a esses eventos. MÉTODOS: Revisão sistemática de publicações sobre mortes evitáveis em vítimas com traumatismos entre 2000 e 2009. Foi realizada pesquisa nas bases de dados Lilacs, SciELO e Medline utilizando-se a estratégia de busca com as palavras-chave "trauma", "avoidable", "preventable", "interventions" e "complications", e os descritores em ciências da saúde "death", "cause of death" e "hospitals". RESULTADOS: Identificaram-se 29 artigos publicados no período, com predomínio de estudos retrospectivos (96,5%). Os métodos mais comumente utilizados para definir a evitabilidade do óbito foram painel de especialistas ou pontuação de índices de gravidade, tendo sido empregadas as seguintes categorias: evitável, potencialmente evitável e não evitável. A média da mortalidade proporcional por mortes evitáveis dos estudos foi de 10,7% (dp 11,5%). As não conformidades mais comumente relatadas nas publicações foram sistema inadequado de atendimento ao traumatizado e erro na avaliação e tratamento. CONCLUSÕES: Observaram-se falhas na uniformização dos termos empregados para categorizar as mortes e as não conformidadades encontradas. Portanto, sugere-se a padronização da taxonomia da classificação das mortes e dos tipos de não conformidades observadas

Representation of the verb's argument-structure in the human brain

<p>Abstract</p> <p>Background</p> <p>A verb's argument structure defines the number and relationships of participants needed for a complete event. One-argument (intransitive) verbs require only a subject to make a complete sentence, while two- and three-argument verbs (transitives and ditransitives) normally take direct and indirect objects. Cortical responses to verbs embedded into sentences (correct or with syntactic violations) indicate the processing of the verb's argument structure in the human brain. The two experiments of the present study examined whether and how this processing is reflected in distinct spatio-temporal cortical response patterns to isolated verbs and/or verbs presented in minimal context.</p> <p>Results</p> <p>The magnetoencephalogram was recorded while 22 native German-speaking adults saw 130 German verbs, presented one at a time for 150 ms each in experiment 1. Verb-evoked electromagnetic responses at 250 – 300 ms after stimulus onset, analyzed in source space, were higher in the left middle temporal gyrus for verbs that take only one argument, relative to two- and three-argument verbs. In experiment 2, the same verbs (presented in different order) were preceded by a proper name specifying the subject of the verb. This produced additional activation between 350 and 450 ms in or near the left inferior frontal gyrus, activity being larger and peaking earlier for one-argument verbs that required no further arguments to form a complete sentence.</p> <p>Conclusion</p> <p>Localization of sources of activity suggests that the activation in temporal and frontal regions varies with the degree by which representations of an event as a part of the verbs' semantics are completed during parsing.</p

Insights into the innate immunity of the Mediterranean mussel Mytilus galloprovincialis

<p>Abstract</p> <p>Background</p> <p>Sessile bivalves of the genus <it>Mytilus </it>are suspension feeders relatively tolerant to a wide range of environmental changes, used as sentinels in ecotoxicological investigations and marketed worldwide as seafood. Mortality events caused by infective agents and parasites apparently occur less in mussels than in other bivalves but the molecular basis of such evidence is unknown. The arrangement of Mytibase, interactive catalogue of 7,112 transcripts of <it>M. galloprovincialis</it>, offered us the opportunity to look for gene sequences relevant to the host defences, in particular the innate immunity related genes.</p> <p>Results</p> <p>We have explored and described the Mytibase sequence clusters and singletons having a putative role in recognition, intracellular signalling, and neutralization of potential pathogens in <it>M. galloprovincialis</it>. Automatically assisted searches of protein signatures and manually cured sequence analysis confirmed the molecular diversity of recognition/effector molecules such as the antimicrobial peptides and many carbohydrate binding proteins. Molecular motifs identifying complement C1q, C-type lectins and fibrinogen-like transcripts emerged as the most abundant in the Mytibase collection whereas, conversely, sequence motifs denoting the regulatory cytokine MIF and cytokine-related transcripts represent singular and unexpected findings. Using a cross-search strategy, 1,820 putatively immune-related sequences were selected to design oligonucleotide probes and define a species-specific Immunochip (DNA microarray). The Immunochip performance was tested with hemolymph RNAs from mussels injected with <it>Vibrio splendidus </it>at 3 and 48 hours post-treatment. A total of 143 and 262 differentially expressed genes exemplify the early and late hemocyte response of the <it>Vibrio</it>-challenged mussels, respectively, with AMP trends confirmed by qPCR and clear modulation of interrelated signalling pathways.</p> <p>Conclusions</p> <p>The Mytibase collection is rich in gene transcripts modulated in response to antigenic stimuli and represents an interesting window for looking at the mussel immunome (transcriptomes mediating the mussel response to non-self or abnormal antigens). On this basis, we have defined a new microarray platform, a mussel Immunochip, as a flexible tool for the experimental validation of immune-candidate sequences, and tested its performance on <it>Vibrio</it>-activated mussel hemocytes. The microarray platform and related expression data can be regarded as a step forward in the study of the adaptive response of the <it>Mytilus </it>species to an evolving microbial world.</p

Epithelial-mesenchymal transition and cancer stem cells: a dangerously dynamic duo in breast cancer progression

Aberrant activation of a latent embryonic program - known as the epithelial-mesenchymal transition (EMT) - can endow cancer cells with the migratory and invasive capabilities associated with metastatic competence. The induction of EMT entails the loss of epithelial characteristics and the de novo acquisition of a mesenchymal phenotype. In breast cancer, the EMT state has been associated with cancer stem cell properties including expression of the stem cell-associated CD44+/CD24-/low antigenic profile, self-renewal capabilities and resistance to conventional therapies. Intriguingly, EMT features are also associated with stem cells isolated from the normal mouse mammary gland and human breast reduction tissues as well as the highly aggressive metaplastic and claudin-low breast tumor subtypes. This has implications for the origin of these breast tumors as it remains unclear whether they derive from cells that have undergone EMT or whether they represent an expansion of a pre-existing stem cell population that expresses EMT-associated markers to begin with. In the present review, we consider the current evidence connecting EMT and stem cell attributes and discuss the ramifications of these newly recognized links for our understanding of the emergence of distinct breast cancer subtypes and breast cancer progression

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe