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Human adipose-derived mesenchymal stromal cells (ASC) are showing clinical promise for the treatment of a range of inflammatory and degenerative conditions. These lipoaspirate-derived cells are part of the abundant and accessible source of heterogeneous stromal vascular fraction (SVF). They are typically isolated and expanded from the SVF adherent cell culture for at least 2 weeks and as such represent a relatively undefined population of cells. We isolated ASC directly from lipoaspirate using a cocktail of antibodies combined with immunomagnetic bead sorting. This method allowed for the rapid enrichment of a defined and untouched ASC population (referred to as MACS-derived ASC) that were then compared to culture-derived ASC. This comparison found that MACS-derived ASC contain a greater proportion of cells with activity in differentiation assays. There were also significant differences in the secretion levels of some key paracrine molecules. Moreover, when the MACS-derived ASC were subjected to adherent tissue culture, rapid changes in gene expression were observed. This indicates that culturing cells may alter the clinical utility of these cells. Although MACS-derived ASC are more defined compared to culture-derived ASC, further investigations using a comprehensive multicolor flow cytometry panel revealed that this cell population is more heterogeneous than previously appreciated. Additional studies are therefore required to more precisely delineate phenotypically distinct ASC subsets with the most therapeutic potential. This research highlights the disparity between MACS-derived and culture-derived ASC and the need for further characterization.

In China, the ageing population and the prevalence of dementia are projected to escalate significantly by 2050 resulting in a substantial increase in health and economic burden on caregivers, healthcare facilities, healthcare providers and communities. There is no published national dementia policy or strategy in China. This case report describes significant barriers contributing to diagnostic problems and inadequate care of dementia through the case of an older female in rural China, whose condition deteriorated due to neuropsychiatric and functional symptoms of undiagnosed dementia. Intersectoral collaboration between care organisations facilitated delivery of a non-pharmacological intervention programme which was associated with improvements in the patient’s functional and neuropsychiatric symptoms. The case demonstrates that recruitment and training of a wider range of health and care professionals and caregivers in a systematic approach to non-pharmacological interventions could help overcome barriers to the specialised care needs of people with dementia where resources are lacking.

BackgroundFetal growth restriction often results from poor placental function and is a major cause of stillbirth. Clinically, fetal growth restriction is difficult to diagnose and currently has no effective treatment. Trophoblasts are unique placental cells that form the feto-maternal interface and facilitate nutrient and gas exchange. Fetal growth restriction is linked to inadequate trophoblast function. However, our understanding of the mechanisms underlying this dysfunction are poor, in part because of our inability to isolate and study the trophoblast stem cells from which mature trophoblasts arise in pathologic pregnancies.MethodsCells isolated from first-trimester placentae using the Hoechst side-population technique were propagated or differentiated into mature trophoblasts. Side-population trophoblasts were isolated from normal third-trimester and growth restricted placentae using the same technique. First and third-trimester side-population trophoblasts were compared by microarray analysis.ResultsFirst-trimester side-population trophoblasts could be propagated in an undifferentiated state or differentiated, via intermediate cytotrophoblasts, into syncytiotrophoblast or extravillous trophoblasts. Using the same technique, side-population trophoblasts could be isolated from term placentae for the first time, demonstrating that while they were present at consistent levels throughout gestation (~3·5%), side-population trophoblasts were significantly depleted in growth restricted pregnancies (0·32%).ConclusionsOur novel method of isolating a population of human trophoblast stem cell-like cells directly from human placental tissue throughout gestation provides the first insights into trophoblast dysfunction in pregnancy pathologies. The depletion of side-population trophoblasts in growth restricted placentae may contribute to poor placental function.

Although formalin fixed paraffin embedded (FFPE) tissue is a major biological source in cancer research, it is challenging to work with due to macromolecular fragmentation and nucleic acid crosslinking. Therefore, it is important to characterise the quality of data that can be obtained from FFPE samples. We have compared three independent platforms (next generation sequencing, microarray and NanoString) for profiling microRNAs (miRNAs) using clinical FFPE samples from hepatoblastoma (HB) patients. The number of detected miRNAs ranged from 228 to 345 (median=294) using the next generation sequencing platform, whereas 79 to 125 (median=112) miRNAs were identified using microarrays in three HB samples, including technical replicates. NanoString identified 299 to 372 miRNAs in two samples. Between the platforms, we observed high reproducibility and significant levels of shared detection. However, for commonly detected miRNAs, a strong correlation between platforms was not observed. Analysis of 10 additional HB samples with NanoString identified significantly overlapping miRNA expression profiles, and an alternative pattern was identified in a poorly differentiated HB with an aggressive phenotype. This investigation serves as a roadmap for future studies investigating miRNA expression in clinical FFPE samples, and as a guideline for the selection of an appropriate platform.

Sudden cardiac death (SCD) in people before the age of 35 years is a devastating event for any family. The causes of SCD in the young can be broadly divided into two groups: heritable cardiac disorders that affect the heart structure (cardiomyopathies) and primary electrical disorders (cardiac ion channelopathies). Genetic testing is vital as those suffering from cardiac ion channelopathies have structurally normal hearts, and those with cardiomyopathies may only show subtle abnormalities in the heart and these signs may not be detected during an autopsy. Post-mortem genetic testing of SCD victims is important to identify the underlying genetic cause. This is important as family cascade screening may be undertaken to identify those who may be at risk and provide vital information about risk stratification and clinical management. The development of massively parallel sequencing (MPS) has made it possible for the simultaneous screening of multiple patients for hundreds of genes. In light of this, we opted to develop an MPS approach for SCD analysis that would allow us to screen for mutations in genes implicated in cardiomyopathies and cardiac ion channelopathies. The rationale behind this panel was to limit it to genes carrying the greatest mutation load. If no likely pathogenic gene variant were found then testing could cascade to whole exome/genome sequencing as a gene-discovery exercise. The overarching aim was to design and validate a custom-cardiac panel that satisfies the diagnostic requirements of LabPLUS (Auckland City Hospital, Auckland, NZ) and the guidelines provided by the Royal College of Pathologists of Australasia and the Association for Clinical Genetic Science.

Although formalin fixed paraffin embedded (FFPE) tissue is a major biological source in cancer research, it is challenging to work with due to macromolecular fragmentation and nucleic acid crosslinking. Therefore, it is important to characterise the quality of data that can be obtained from FFPE samples. We have compared three independent platforms (next generation sequencing, microarray and NanoString) for profiling microRNAs (miRNAs) using clinical FFPE samples from hepatoblastoma (HB) patients. The number of detected miRNAs ranged from 228 to 345 (median=294) using the next generation sequencing platform, whereas 79 to 125 (median=112) miRNAs were identified using microarrays in three HB samples, including technical replicates. NanoString identified 299 to 372 miRNAs in two samples. Between the platforms, we observed high reproducibility and significant levels of shared detection. However, for commonly detected miRNAs, a strong correlation between platforms was not observed. Analysis of 10 additional HB samples with NanoString identified significantly overlapping miRNA expression profiles and an alternative pattern was identified in a poorly differentiated HB with an aggressive phenotype. This investigation serves as a roadmap for future studies investigating miRNA expression in clinical FFPE samples and as a guideline for the selection of an appropriate platform.

Pancreatic neuroendocrine tumors (pNETs) are uncommon cancers arising from pancreatic islet cells. Here we report the analysis of gene mutation, copy number, and RNA expression of 57 sporadic well-differentiated pNETs. pNET genomes are dominated by aneuploidy, leading to concordant changes in RNA expression at the level of whole chromosomes and chromosome segments. We observed two distinct patterns of somatic pNET aneuploidy that are associated with tumor pathology and patient prognosis. Approximately 26% of the patients in this series had pNETs with genomes characterized by recurrent loss of heterozygosity (LoH) of 10 specific chromosomes, accompanied by bi-allelic MEN1 inactivation and generally poor clinical outcome. Another ~40% of patients had pNETs that lacked this recurrent LoH pattern but had chromosome 11 LoH, bi-allelic MEN1 inactivation, and universally good clinical outcome. The somatic aneuploidy allowed pathogenic germline variants (e.g., ATM) to be expressed unopposed, with RNA expression patterns showing inactivation of downstream tumor suppressor pathways. No prognostic associations were found with tumor morphology, single gene mutation, or expression of RNAs reflecting the activity of immune, differentiation, proliferative or tumor suppressor pathways. In pNETs, single gene mutations appear to be less important than aneuploidy, with MEN1 the only statistically significant recurrently mutated driver gene. In addition, only one pNET in the series had clearly actionable single nucleotide variants (SNVs) (in PTEN and FLCN) confirmed by corroborating RNA expression changes. The two clinically relevant patterns of LoH described here define a novel oncogenic mechanism and a plausible route to genomic precision oncology for this tumor type.

Background microRNAs (miRNAs) are emerging as key regulators of the immune system, but their role in CD8+ T cell differentiation is not well explored. Some evidence suggests that signals from cell surface receptors influence the expression of miRNAs in CD8+ T cells, and may have consequent effects on cell phenotype and function. We set out to investigate whether common gamma chain cytokines modulated human CD8+ T cell expression of miR-146a, which previous studies have associated with different stages of CD8+ differentiation. We also investigated how changes in miR-146a related to other miRNAs that alter with CD8+ differentiation status. Methods We treated human CD8+ T cells with the cytokines IL-2, IL-7 or IL-15 either at rest or after stimulation with anti-CD3 and anti-CD28. For some experiments we also purified human CD8+ T cell subsets ex vivo . Flow cytometry was used in parallel to assess cell surface memory marker expression. Total RNA from these cells was subjected to microarray analysis and real-time PCR for miRNA expression. Nucleofection studies were performed to assess potential mRNA targets of miR-146a. Results We find that miR-146a is up-regulated in naïve CD8+ T cells exposed to IL-2 or IL-15, even in the absence of an activating T cell receptor stimulus, but not when IL-7 is also present. miR-146a expression correlates with a memory phenotype in both ex vivo and in vitro cultured cells although in our hands overexpression of miR-146a was not sufficient alone to drive a full memory phenotype. In ex vivo analysis, miR-146a was one of a small number of miRNAs that was differentially expressed between naïve and memory CD8+ T cells. Conclusions miR-146a is emerging as a critical regulator of immune system. Our data shows that miR-146a expression is strongly influenced by the cytokine milieu even in the absence of a T cell receptor stimulus. Our results have implications for studies designed to assess the function of miR-146a, help to define a fingerprint of miRNA expression in CD8+ T cell subsets and may be useful when designing optimal protocols for T cell expansion as efficacy of T cell immunotherapy is correlated with an `early’ memory phenotype.

本研究探討影響國內企業自願揭露預計未來研發費用之因素，以及該自願性揭露是否可提高股價的資訊內涵。實證結果顯示，當公司存在較低之私有資訊成本、盈餘表現較佳、盈餘波動性較小、股份盈餘偏離倍數較低時，公司將傾向揭露其預計未來研發費用之資訊、揭露的明確度亦較高。另外，預計未來研發費用資訊之揭露可提高次期的未來盈餘反應係數，亦即能增進股票報酬與未來盈餘之間的關係。進一步發現，公司實際之研發費用與原先所揭露預期投入研發費用之差異，與次年度之股票報酬呈現顯著負相關，而此結果主要來自實際研發費用低於揭露之預計研發費用時，顯示投資人對於較不可靠的前瞻性資訊有負向反應。

Because of the limitations to the functionality that Si can provide, integration of light emitting materials such as GaAs and other III-V materials provides the promise for the combination of electrical and optical devices onto a Si platform. Monolithic integration, compare to hybrid integration, is the more cost effective and reliable way to combine these dissimilar materials. However, materials compatibility issues such as lattice mismatch, polar-on-non-polar epitaxy, and thermal mismatch make the direct growth of high quality GaAs-based material on Si difficult. However, with the use of SiGe virtual substrates, Si substrates that have the Ge lattice constant, this goal can be achieved since Ge and GaAs have a small lattice mismatch of only 0.07%. High quality GaAs on Si having a threading dislocation density lower than 3x10 cm³ on offcut SiGe virtual substrates has been demonstrated.While utilizing SiGe virtual substrate technology to enable high quality GaAs on Si, we have studied the crack formation in GaAs layers on SiGe resulting from the thermal mismatch between the film and the substrate. GaAs has a thermal expansion coefficient of 5.8×10/°C while the value for Si and the SiGe substrate is 2.6x10 °C. The thermal expansion coefficient of the SiGe virtual substrate is mainly dictated by the underlying Si substrate. As a result of the thermal mismatch, crack arrays can form in GaAs layers grown over a critical thickness after a temperature change. These cracks can act as electrical shorting paths and can also limit the usable area for device fabrication, and therefore need to be eliminated. We have reported the experimental and calculated critical cracking thickness of GaAs on Si and SiGe in this work and have discussed possible strategies in the control of crack formation.We have also studied the luminescent characteristics of Ino.2GaAs quantum wells grown on the SiGe virtual substrates and other substrates such as GaAs, Si, and Ge. The luminescent intensities of InGaAs quantum wells on SiGe approach that of ones grown on GaAs substrates and out performs structures on Si and Ge substrates, an unexpected advantage for InGaAs quantum well integration on SiGe.In this work, we have also reported the first working optical interconnect on Si using SiGe virtual substrate technology. This relatively simple device structure proves the feasibility of monolithically integrated optical circuit architectures on the Si microelectronic platform. The performance of various optical interconnect structures is analyzed, and an alternative waveguide structure is proposed.