Study of Fluid Experiment System (FES)/CAST/Holographic Ground System (HGS)

The use of holographic and schlieren optical techniques for studying the concentration gradients in solidification processes has been used by several investigators over the years. The HGS facility at MSFC has been primary resource in researching this capability. Consequently, scientific personnel have been able to utilize these techniques in both ground based research and in space experiments. An important event in the scientific utilization of the HGS facilities was the TGS Crystal Growth and the casting and solidification technology (CAST) experiments that were flown on the International Microgravity Laboratory (IML) mission in March of this year. The preparation and processing of these space observations are the primary experiments reported in this work. This project provides some ground-based studies to optimize on the holographic techniques used to acquire information about the crystal growth processes flown on IML. Since the ground-based studies will be compared with the space-based experimental results, it is necessary to conduct sufficient ground based studies to best determine how the experiment worked in space. The current capabilities in computer based systems for image processing and numerical computation have certainly assisted in those efforts. As anticipated, this study has certainly shown that these advanced computing capabilities are helpful in the data analysis of such experiments

Study of FES/CAST/HGS

The microgravity materials processing program has been instrumental in providing the crystal growth community with an experimental environment to better understand the phenomena associated with the growing of crystals. In many applications one may pursue the growth of large single crystals which cannot be grown on earth due to convective driven flows. A microgravity environment is characterized by neither convection of buoyancy. Consequently superior crystals are able to be grown in space. On the other hand, since neither convection nor buoyancy dominates the fluid flow in a microgravity environment, then lesser dominating phenomena can affect crystal growth, such as surface driven flows or diffusion limited solidification. In the case of experiments that are to be flown in space using the Fluid Experiments System (FES), diffusion limited growth should be the dominating phenomenon. The use of holographic and Schlieren optical techniques for studying the concentration gradients in solidification processes has been used by several investigators over the years. The Holographic Ground System (HGS) facility at MSFC has been a primary resource in researching this capability. Consequently scientific personnel have been able to utilize these techniques in both ground based research and in space experiments. An important event in the scientific utilization of the HGS facilities was the TGS (triglycine sulfate) Crystal Growth and the Casting and Solidification Technology (CAST) experiments that were flown on the International Microgravity Lab (IML) mission in March of this year. The preparation and processing of these space observations are the primary experiments reported in this work. This project provides some ground-based studies to optimize on the holographic techniques used to acquire information about the crystal growth processes flown on IML. Since the ground-based studies will be compared with the space-based experimental results, it is necessary to conduct sufficient ground based studies to best determine how the experiment in space worked. The current capabilities in computer based systems for image processing and numerical computation have certainly assisted in those efforts. As anticipated, this study has certainly shown that these advanced computing capabilities are helpful in the data analysis of such experiments

Leading sustainable improvement in university teaching and learning : Lessons from the sector

Overall, the investigation found that universities that wish to improve the quality of teaching and learning should take an approach that aims to be: collaborative and developmental; embedded; sustainable; and focused on enabling innovation and enhancement. The seven interlinked insights characteristic of sustainable, positive change in teaching and learning in Australian universities are as follows. 1. Efforts to improve the quality of teaching and learning are aligned with the strategic direction of the university The evidence indicates that efforts to improve the quality of teaching and learning within an institution should be aligned with the strategic direction of the university. While this might seem self evident, the findings indicate that there are sometimes tensions between overall institutional priorities and efforts to enhance the quality of teaching and learning. Careful strategic thinking can ensure efforts to enhance teaching and learning provide a means through which universities can enact aspects of their strategic plans. 2. Senior executives support teaching and learning enhancement, and resources for those improvements are allocated as part of the universityʼs planning and budget cycle The study found that embedding and sustaining good teaching and learning practice requires high-level support within an institution. In addition to providing stable representation and championing of teaching and learning, effective support was found to also incorporate institutional investment in the form of funding and resourcing positions and initiatives. It was found that sustainability relies on institutional funding that ensured ongoing impetus for, and successful work in, enhancing teaching and learning. 3. Staff workload allocations allow time for innovation, enhancement and improvement in teaching and learning The project findings indicate that the major factor inhibiting efforts to improve teaching and learning is high staff workloads and the consequent lack of time to engage with, and contribute to, teaching and learning enhancement efforts. This finding mirrors those of several other recent Australian studies of the changing academic profession, although this current project notes the applicability of workload matters to both academic and professional staff. If leaders in Australian universities wish to enhance teaching and learning, fresh thinking, policy and planning is needed around academic and professional staff roles and workload allocation. 4. Effective leadership proactively manages tensions between discipline research endeavours and efforts to improve teaching and learning This research found that a major cultural impediment to enhancing teaching and learning is the privileging of research over teaching and learning within an institution. The findings suggest that effective leadership and management of the tensions that arise between research endeavours and efforts to improve teaching and learning are critical if the latter are to be successful. The findings suggest that the reconciliation of research and teaching and learning can be achieved to some extent through a range of means, including the facilitation of research and scholarship around teaching and learning. Leading sustainable change in university teaching and learning: Lessons from the sector 6 5. Teaching and learning are supported by relevant research and scholarship conducted within the institution and in collaboration with other institutions and relevant bodies The study findings indicate the importance of research and scholarship in the area of teaching and learning. External interface, networking and exchange with stakeholders and bodies outside the institution are critical to ensuring enhancement efforts fit with the broader context in which they are occurring. Some of the benefits of engaging in such research and scholarship were: increased reflection on practice; a heightened awareness of the link between an individualʼs own teaching and their studentsʼ outcomes; increased innovation in teaching; improved morale; enhancing the quality of teaching and learning both within an institution and more broadly; and opportunities to both benchmark and improve teaching performance. The potential for research into teaching and learning to contribute to resolving the tensions between discipline research and teaching and learning was also noted. 6. A distributed teaching and learning support structure exists within the institution and is coordinated from the centre The findings of this research showed that a distributed institutional support structure for teaching and learning enhancement, coordinated from the centre, was perceived to be the most effective approach. Most commonly this involved cooperation between a central teaching and learning centre and one or more of: teaching and learning committees; the associate deans (teaching and learning) or equivalent; educational development and other staff located in the faculties; and a critical mass of people with a commitment to teaching and learning improvement and enhancement who have the capacity to lead. 7. Mechanisms to recognise excellence in teaching and learning and to enable teaching and learning career pathways are in place This study found that professional development, reward and recognition mechanisms and enabling career pathways for those committed to teaching and learning are important components in the successful leadership of teaching and learning enhancement. The project findings indicate the centrality of linking efforts to enhance teaching and learning with promotion opportunities. The research findings indicate that university promotion criteria that incorporate excellence in teaching and learning scholarship and practice allow appropriate recognition, enable the sustainability of excellent practice and help embed enhancement

Homologous recombination DNA repair defects in PALB2- associated breast cancers

Abstract: Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n = 11) or second somatic mutations (n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD

Development and validation of a targeted gene sequencing panel for application to disparate cancers

Next generation sequencing has revolutionised genomic studies of cancer, having facilitated the development of precision oncology treatments based on a tumour’s molecular profile. We aimed to develop a targeted gene sequencing panel for application to disparate cancer types with particular focus on tumours of the head and neck, plus test for utility in liquid biopsy. The final panel designed through Roche/Nimblegen combined 451 cancer-associated genes (2.01 Mb target region). 136 patient DNA samples were collected for performance and application testing. Panel sensitivity and precision were measured using well-characterised DNA controls (n = 47), and specificity by Sanger sequencing of the Aryl Hydrocarbon Receptor Interacting Protein (AIP) gene in 89 patients. Assessment of liquid biopsy application employed a pool of synthetic circulating tumour DNA (ctDNA). Library preparation and sequencing were conducted on Illumina-based platforms prior to analysis with our accredited (ISO15189) bioinformatics pipeline. We achieved a mean coverage of 395x, with sensitivity and specificity of >99% and precision of >97%. Liquid biopsy revealed detection to 1.25% variant allele frequency. Application to head and neck tumours/cancers resulted in detection of mutations aligned to published databases. In conclusion, we have developed an analytically-validated panel for application to cancers of disparate types with utility in liquid biopsy

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms