A phase 1b study of placenta-derived mesenchymal stromal cells in patients with idiopathic pulmonary fibrosis

BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a degenerative disease characterized by fibrosis following failed epithelial repair. Mesenchymal stromal cells (MSC), a key component of the stem cell niche in bone marrow and possibly other organs including lung, have been shown to enhance epithelial repair and are effective in preclinical models of inflammation-induced pulmonary fibrosis, but may be profibrotic in some circumstances. METHODS: In this single centre, non-randomized, dose escalation phase 1b trial, patients with moderately severe IPF (diffusing capacity for carbon monoxide (DLCO ) ≥ 25% and forced vital capacity (FVC) ≥ 50%) received either 1 × 10(6) (n = 4) or 2 × 10(6) (n = 4) unrelated-donor, placenta-derived MSC/kg via a peripheral vein and were followed for 6 months with lung function (FVC and DLCO ), 6-min walk distance (6MWD) and computed tomography (CT) chest. RESULTS: Eight patients (4 female, aged 63.5 (57-75) years) with median (interquartile range) FVC 60 (52.5-74.5)% and DLCO 34.5 (29.5-40)% predicted were treated. Both dose schedules were well tolerated with only minor and transient acute adverse effects. MSC infusion was associated with a transient (1% (0-2%)) fall in SaO2 after 15 min, but no changes in haemodynamics. At 6 months FVC, DLCO , 6MWD and CT fibrosis score were unchanged compared with baseline. There was no evidence of worsening fibrosis. CONCLUSIONS: Intravenous MSC administration is feasible and has a good short-term safety profile in patients with moderately severe IPF.

Tissue engineered humanized bone supports human hematopoiesis in vivo

Advances in tissue-engineering have resulted in a versatile tool-box to specifically design a tailored microenvironment for hematopoietic stem cells (HSCs) in order to study diseases that develop within this setting. However, most current in vivo models fail to recapitulate the biological processes seen in humans. Here we describe a highly reproducible method to engineer humanized bone constructs that are able to recapitulate the morphological features and biological functions of the HSC niches. Ectopic implantation of biodegradable composite scaffolds cultured for 4 weeks with human mesenchymal progenitor cells and loaded with rhBMP-7 resulted in the development of a chimeric bone organ including a large number of human mesenchymal cells which were shown to be metabolically active and capable of establishing a humanized microenvironment supportive of the homing and maintenance of human HSCs. A syngeneic mouse-to-mouse transplantation assay was used to prove the functionality of the tissue-engineered ossicles. We predict that the ability to tissue engineer a morphologically intact and functional large-volume bone organ with a humanized bone marrow compartment will help to further elucidate physiological or pathological interactions between human HSCs and their native niches.

Eliciting and encoding expert knowledge on variable selection into classical or Bayesian species distribution models

The quality of species distribution models (SDMs) relies to a large degree on the quality of the input data, from bioclimatic indices to environmental and habitat descriptors (Austin, 2002). Recent reviews of SDM techniques, have sought to optimize predictive performance e.g. Elith et al., 2006. In general SDMs employ one of three approaches to variable selection. The simplest approach relies on the expert to select the variables, as in environmental niche models Nix, 1986 or a generalized linear model without variable selection (Miller and Franklin, 2002). A second approach explicitly incorporates variable selection into model fitting, which allows examination of particular combinations of variables. Examples include generalized linear or additive models with variable selection (Hastie et al. 2002); or classification trees with complexity or model based pruning (Breiman et al., 1984, Zeileis, 2008). A third approach uses model averaging, to summarize the overall contribution of a variable, without considering particular combinations. Examples include neural networks, boosted or bagged regression trees and Maximum Entropy as compared in Elith et al. 2006. Typically, users of SDMs will either consider a small number of variable sets, via the first approach, or else supply all of the candidate variables (often numbering more than a hundred) to the second or third approaches. Bayesian SDMs exist, with several methods for eliciting and encoding priors on model parameters (see review in Low Choy et al. 2010). However few methods have been published for informative variable selection; one example is Bayesian trees (O’Leary 2008). Here we report an elicitation protocol that helps makes explicit a priori expert judgements on the quality of candidate variables. This protocol can be flexibly applied to any of the three approaches to variable selection, described above, Bayesian or otherwise. We demonstrate how this information can be obtained then used to guide variable selection in classical or machine learning SDMs, or to define priors within Bayesian SDMs.

The evolution of entrepreneurial learning

- Purpose The purpose of this paper is to present an evolutionary perspective on entrepreneurial learning, whilst also accounting for fundamental ecological processes, by focusing on the development of key recurring, knowledge components within nascent and growing small businesses. - Design/methodology/approach The paper relates key developments within the organizational evolution literature to research on entrepreneurial learning, with arguments presented in favor of adopting a multi‐level co‐evolutionary perspective that captures and explains hidden ecological process, such as niche‐construction. - Findings It is argued in the paper that such a multi‐level focus on key recurring knowledge components can shed new light on the process of entrepreneurial learning and lead to the cross‐fertilization of ideas across different domains of study, by offering researchers the opportunity to use the framework of variation‐selection‐retention to develop a multi‐level representation of organizational and entrepreneurial learning. - Originality/value Entrepreneurial learning viewed in this way, as a multi‐level struggle for survival amongst competing knowledge components, can provide entrepreneurs with a set of evolutionary heuristics as they re‐interpret their understanding of the evolution of their business.

Creating the reasonable adventurer: The co-evolution of student and learning environment

Purpose: This paper seeks to address the issue of how are graduate skills developed. The focus is not on which skills, but rather what type of learning environments is required within Higher Education to support the development of skills valued and demanded by SMEs within Australia. Approach: This paper takes a step back to consider the underlying issue of how an individual student's habits of thought are altered. In doing so, the past works of Morgan, Dewey, Whitehead, and Tyler are synthesized with the modern work of Baxter Magolda, Heath, and Biggs. Findings: It is argued that that without the development of a student-centred learning environment, most graduates will not develop the types of skills demanded by SMEs in a meaningfully way. That the failure to treat knowledge and skills as equal drivers of curriculum design will result in an imbalance that relegates skill development to a secondary learning outcome. Practical Implications: By removing the distraction of what skills should be developed, a clearer focus is possible regarding how educators should assist students to develop a broad array of generic graduate skills. From this perspective, skills can be viewed as an essential element of the educational process, rather than a new element that must be squeezed in between content. Value of Paper: This paper extends recent discussion of skills development through the use of an evolutionary perspective. Viewed as a process of creating social change, education becomes increasingly connected to a world that lays beyond institutional boundaries, thus promoting the notion of developing graduates for the world that awaits them.

Cell surface heparan sulfate proteoglycans as novel markers of human neural stem cell fate determination

Multipotent neural stem cells (NSCs) provide a model to investigate neurogenesis and develop mechanisms of cell transplantation. In order to define improved markers of stemness and lineage specificity, we examined self-renewal and multi-lineage markers during long-term expansion and under neuronal and astrocyte differentiating conditions in human ESC-derived NSCs (hNSC H9 cells). In addition, with proteoglycans ubiquitous to the neural niche, we also examined heparan sulfate proteoglycans (HSPGs) and their regulatory enzymes. Our results demonstrate that hNSC H9 cells maintain self-renewal and multipotent capacity during extended culture and express HS biosynthesis enzymes and several HSPG core protein syndecans (SDCs) and glypicans (GPCs) at a high level. In addition, hNSC H9 cells exhibit high neuronal and a restricted glial differentiative potential with lineage differentiation significantly increasing expression of many HS biosynthesis enzymes. Furthermore, neuronal differentiation of the cells upregulated SDC4, GPC1, GPC2, GPC3 and GPC6 expression with increased GPC4 expression observed under astrocyte culture conditions. Finally, downregulation of selected HSPG core proteins altered hNSC H9 cell lineage potential. These findings demonstrate an involvement for HSPGs in mediating hNSC maintenance and lineage commitment and their potential use as novel markers of hNSC and neural cell lineage specification.

A 3D in vitro model reflecting the androgen deprivation state in prostate cancer bone metastasis

In castrate-resistant prostate cancer (CRPC), the prevailing organ for metastasis is bone, where the survival of cancer cells is regulated by the permissive metastatic niche offered by the bone marrow. The tumour microenvironment and cellular interactions with the matrix and bone cells enable metastasis and lead to cancer cells becoming androgen resistant. Hence, 3D models that mimic CRPC in terms of an androgen deprivation state (ADS) are needed to identify the mechanisms for CPRC growth in bone and further develop therapeutic strategies.

Expression profiling of lymph nodes in tuberculosis patients reveal inflammatory milieu at site of infection

Extrapulmonary manifestations constitute 15 to 20% of tuberculosis cases, with lymph node tuberculosis (LNTB) as the most common form of infection. However, diagnosis and treatment advances are hindered by lack of understanding of LNTB biology. To identify host response, Mycobacterium tuberculosis infected lymph nodes from LNTB patients were studied by means of transcriptomics and quantitative proteomics analyses. The selected targets obtained by comparative analyses were validated by quantitative PCR and immunohistochemistry. This approach provided expression data for 8,728 transcripts and 102 proteins, differentially regulated in the infected human lymph node. Enhanced inflammation with upregulation of T-helper1-related genes, combined with marked dysregulation of matrix metalloproteinases, indicates tissue damage due to high immunoactivity at infected niche. This expression signature was accompanied by significant upregulation of an immunoregulatory gene, leukotriene A4 hydrolase, at both transcript and protein levels. Comparative transcriptional analyses revealed LNTB-specific perturbations. In contrast to pulmonary TB-associated increase in lipid metabolism, genes involved in fatty-acid metabolism were found to be downregulated in LNTB suggesting differential lipid metabolic signature. This study investigates the tissue molecular signature of LNTB patients for the first time and presents findings that indicate the possible mechanism of disease pathology through dysregulation of inflammatory and tissue-repair processes.

If dung beetles (Scarabaeidae: Scarabaeinae) arose in association with dinosaurs, did they also suffer a mass co-extinction at the K-Pg boundary?

The evolutionary success of beetles and numerous other terrestrial insects is generally attributed to co-radiation with flowering plants but most studies have focused on herbivorous or pollinating insects. Non-herbivores represent a significant proportion of beetle diversity yet potential factors that influence their diversification have been largely unexamined. In the present study, we examine the factors driving diversification within the Scarabaeidae, a speciose beetle family with a range of both herbivorous and non-herbivorous ecologies. In particular, it has been long debated whether the key event in the evolution of dung beetles (Scarabaeidae: Scarabaeinae) was an adaptation to feeding on dinosaur or mammalian dung. Here we present molecular evidence to show that the origin of dung beetles occurred in the middle of the Cretaceous, likely in association with dinosaur dung, but more surprisingly the timing is consistent with the rise of the angiosperms. We hypothesize that the switch in dinosaur diet to incorporate more nutritious and less fibrous angiosperm foliage provided a palatable dung source that ultimately created a new niche for diversification. Given the well-accepted mass extinction of non-avian dinosaurs at the Cretaceous-Paleogene boundary, we examine a potential co-extinction of dung beetles due to the loss of an important evolutionary resource, i.e., dinosaur dung. The biogeography of dung beetles is also examined to explore the previously proposed "out of Africa" hypothesis. Given the inferred age of Scarabaeinae as originating in the Lower Cretaceous, the major radiation of dung feeders prior to the Cenomanian, and the early divergence of both African and Gondwanan lineages, we hypothesise that that faunal exchange between Africa and Gondwanaland occurred during the earliest evolution of the Scarabaeinae. Therefore we propose that both Gondwanan vicariance and dispersal of African lineages is responsible for present day distribution of scarabaeine dung beetles and provide examples.