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Purpose: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features. Experimental Design: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55). Results: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04–7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04–1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01–1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%). Conclusions: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.

Background: While protein truncating variants in RAD51C have been shown to predispose to triple negative breast cancer (TNBC) and ovarian cancer, little is known about the pathogenicity of missense (MS) variants. Methods: The frequency of rare RAD51C MS variants were assessed in the BEACCON study of 5,734 familial breast cancer cases and 14,382 population controls, and integrated with tumour sequencing data from 21 cases carrying a candidate variant to assess bi-allelic inactivation. Results: Collectively, a significant enrichment of rare missense variants was detected in cases (MAF < 0.001, OR 1.57, 95%CI 1.00 - 2.44, p = 0.05), particularly for variants with a REVEL score > 0.5 (OR 3.95, 95%CI 1.40 - 12.01, p = 0.006). Despite the large sample size, the majority of variants detected were very rare, precluding definitive conclusions about pathogenicity based solely on the case-control data. Sequencing of 21 tumours from carriers of one of eight candidate MS variants, identified four cases with bi-allelic inactivation through loss of the wild-type allele, while six lost the variant allele and ten remained heterozygous. Loss of the wild-type alleles corresponded strongly with ER- and triple-negative breast tumours and a high homologous recombination deficiency score. Conclusions: Using this approach, the p.Gly264Ser variant, which was previously suspected to be pathogenic based on small case-control analyses and loss of activity in in vitro functional assays, was shown to be benign with similar prevalence in cases and controls, and eight out of nine tumours showing loss of the variant allele or retention of heterozygosity. Conversely, the combined case-control and tumour sequencing data identified p.Ile144Thr, p.Arg212His, p.Gln143Arg and p.Gly114Arg as variants warranting further investigation.

Current methods for dengue virus (DENV) genome amplification, amplify parts of the genome in at least 5 overlapping segments and then combine the output to characterize a full genome. This process is laborious, costly and requires at least 10 primers per serotype, thus increasing the likelihood of PCR bias. We introduce an assay to amplify near full-length dengue virus genomes as intact molecules, sequence these amplicons with third generation “nanopore” technology without fragmenting and use the sequence data to differentiate within-host viral variants with a bioinformatics tool (Nano-Q). The new assay successfully generated near full-length amplicons from DENV serotypes 1, 2 and 3 samples which were sequenced with nanopore technology. Consensus DENV sequences generated by nanopore sequencing had over 99.5% pairwise sequence similarity to Illumina generated counterparts provided the coverage was > 100 with both platforms. Maximum likelihood phylogenetic trees generated from nanopore consensus sequences were able to reproduce the exact trees made from Illumina sequencing with a conservative 99% bootstrapping threshold (after 1000 replicates and 10% burn-in). Pairwise genetic distances of within host variants identified from the Nano-Q tool were less than that of between host variants, thus enabling the phylogenetic segregation of variants from the same host.

Background Breast cancers (BCs) that arise in individuals heterozygous for a germline pathogenic variant in a susceptibility gene, such as BRCA1 and BRCA2, PALB2, and RAD51C, have been shown to exhibit biallelic loss in the respective genes and be associated with triple-negative breast cancer (TNBC) and distinctive somatic mutational signatures. Tumor sequencing thus presents an orthogonal approach to assess the role of candidate genes in BC development. Methods Exome sequencing was performed on paired normal-breast tumor DNA from 124 carriers of germline loss-of-function (LoF) or missense variant carriers in 15 known and candidate BC predisposition genes identified in the BEACCON case-control study. Biallelic inactivation and association with tumor genome features including mutational signatures and homologous recombination deficiency (HRD) score were investigated. Results BARD1-carrying TNBC (4 of 5) displayed biallelic loss and associated high HRD scores and mutational signature 3, as did a RAD51D-carrying TNBC and ovarian cancer. Biallelic loss was less frequent in BRIP1 BCs (4 of 13) and had low HRD scores. In contrast to other established BC genes, BCs from carriers of CHEK2 LoF (6 of 17) or missense (2 of 20) variant had low rates of biallelic loss. Exploratory analysis of BC from carriers of LoF variants in candidate genes such as BLM, FANCM, PARP2, and RAD50 found little evidence of biallelic inactivation. Conclusions BARD1 and RAD51D behave as classic BRCA-like predisposition genes with biallelic inactivation, but this was not observed for any of the candidate genes. However, as demonstrated for CHEK2, the absence of biallelic inactivation does not provide definitive evidence against the gene’s involvement in BC predisposition.

For genes with reliable estimates of disease risk associated with loss-of-function variants, case-control data can be used to estimate the proportion of variants of typical risk effect for defined groups of variants, of relevance for variant classification. A calculation was derived for a maximum likelihood estimate of the proportion of pathogenic variants of typical effect from case-control data and applied to rare variant counts for ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, and RAD51D from published breast cancer studies: BEACCON (5770 familial cases and 5741 controls) and breast cancer risk after diagnostic sequencing (60,466 familial and population-based cases and 53,461 controls). There was significant evidence of pathogenic variants among rare noncoding variants, in particular deeper intronic variants, for BRCA1 (13%, p = 8.3 × 10

This paper presents the design and dynamic response of a proposed non- Micro-Electro Mechanical Systems (MEMS) 1D torsional spring resonant scanner. The torsional spring was selected as the compliant structure of the device, and it was fabricated using aluminum with dimensions of 49 x 3.50 x 0.18 mm (L x W x T). An Analysis of Variance (ANOVA) test was performed to determine the difference in mean between the operating resonant frequency and the three types of materials, which are aluminum, stainless steel, and carbon steel. The device operates at a resonant frequency of 80.65 Hz, yielding a maximum scanning angle of 58.06 ˚. Hysteresis was observed from the frequency response chart of the system. By comparing the resonant frequency of the experimental results with the dynamic analysis of this device, the percentage error of the resonant frequency and optical scanning angle was found to be 6.67% and 16.84%, respectively.

Background Loss-of-function variants in RAD51C are associated with familial ovarian cancer, but its role in hereditary breast cancer remains unclear. The aim of this study was to couple breast tumor sequencing with case-control data to clarify the contribution of RAD51C to hereditary breast cancer. Methods RAD51C was sequenced in 3080 breast cancer index cases that were negative in BRCA1/2 clinical tests and 4840 population-matched cancer-free controls. Pedigree and pathology data were analyzed. Nine breast cancers and one ovarian cancer from RAD51C variant carriers were sequenced to identify biallelic inactivation of RAD51C, copy number variation, mutational signatures, and the spectrum of somatic mutations in breast cancer driver genes. The promoter of RAD51C was analyzed for DNA methylation. Results A statistically significant excess of loss-of-function variants was identified in 3080 cases (0.4%) compared with 2 among 4840 controls (0.04%; odds ratio = 8.67, 95% confidence interval = 1.89 to 80.52, P< .001), with more than half of the carriers having no personal or family history of ovarian cancer. In addition, the association was highly statistically significant among cases with estrogen-negative (P Conclusions This study provides evidence that germline loss-of-function variants of RAD51C are associated with hereditary breast cancer, particularly triple-negative type. RAD51C-null breast cancers possess similar genomic and clinical features to BRCA1-null cancers and may also be vulnerable to DNA double-strand break inducing chemotherapies and poly ADP-ribose polymerase inhibitors.

International education has been severely disrupted by the COVID-19 pandemic given that it is highly reliant on student mobility. This chapter examines the nature and extent of the pandemic’s impact on student experience and the higher education sector in Australia, reflects on the key factors that underpin Australia’s success over the past decade, and describes the challenges international students, both onshore and offshore face, and the governments’ responses towards these challenges. The chapter also explores how Australia and other competing countries managed COVID-19, their varying success in controlling it, and the effects on students’ experience and perception. Lastly, we suggest future policy directions in a post-COVID world where the pandemic has exposed and exacerbated key issues such as financial insecurity of students and the changing landscape of online teaching. The arguments made in this chapter are based on opinions gathered and informed by the Council of International Students Australia’s (CISA) consultation with sector stakeholders and feedback received from students and student associations through CISA’s Student Complaint Portal and direct consultation.

Mammographic density (MD) influences breast cancer risk, but how this is mediated is unknown. Molecular differences between breast cancers arising in the context of the lowest and highest quintiles of mammographic density may identify the mechanism through which MD drives breast cancer development. Women diagnosed with invasive or in situ breast cancer where MD measurement was also available (n = 842) were identified from the Lifepool cohort of >54,000 women participating in population-based mammographic screening. This group included 142 carcinomas in the lowest quintile of MD and 119 carcinomas in the highest quintile. Clinico-pathological and family history information were recorded. Tumor DNA was collected where available (n = 56) and sequenced for breast cancer predisposition and driver gene mutations, including copy number alterations. Compared to carcinomas from low-MD breasts, those from high-MD breasts were significantly associated with a younger age at diagnosis and features associated with poor prognosis. Low- and high-MD carcinomas matched for grade, histological subtype, and hormone receptor status were compared for somatic genetic features. Low-MD carcinomas had a significantly increased frequency of TP53 mutations, higher homologous recombination deficiency, higher fraction of the genome altered, and more copy number gains on chromosome 1q and losses on 17p. While high-MD carcinomas showed enrichment of tumor-infiltrating lymphocytes in the stroma. The data demonstrate that when tumors were matched for confounding clinico-pathological features, a proportion in the lowest quintile of MD appear biologically distinct, reflective of microenvironment differences between the lowest and highest quintiles of MD.

The aim of the study was to evaluate the efficacy of liver fibrosis (LF) with acoustic radiation force impulse (ARFI) elastography for post-transplant (post-LT) HCV recurrence.We enrolled 89 adult recipients of living donor liver transplantation (LDLT) who had HCV, with or without post-LT HCV recurrence and treated or not treated. The post-LT HCV recurrence was diagnosed on the basis of RNA viral load present. ARFI examination was performed every 3 months for all patients, with shear wave velocity (SWV) obtained quantitatively in m/s and correlated with histopathologic fibrosis scoring of liver biopsy (LB).There were 50 (50 of 89) patients without HCV recurrence and 39 (39 of 89) with post-LT recurrence in the 89 patients studied. The recurrent group had significantly higher median SWVs (1.87 ± 0.52 vs 1.37 ± 0.52 m/s, P .0001), in which 18 (18 of 39) patients had antiviral drug treatment and obtained significant improvement with SWVs from 1.83 ± 0.49 to 1.68 ± 0.56 m/s, P = .043. The correlations of LF staging between ARFI elastography and Ishak histopathologic LF scores showed great significance, P = .045. The HCV RNA titer after antiviral treatment decreased from 3,831,750 to 0, P .0001, but the RNA titer of nontreated patients remained high and the median SWV increased. The Ishak LF staging in the nontreated group progressed from stage 1 to 2, P = .012 and SWV increased from 1.69 ± 0.54 to 1.91 ± 0.66 m/s, P = .085 at 1-year follow-up.ARFI elastography has efficient quantitative LF monitoring correlated with histopathologic staging for post-LT HCV recurrence. It could be an alternative, noninvasive method for frequent LB in the disease follow-up.

Background Our aim in this study was to evaluate long-term efficiency of hepatic venous balloon angioplasty (BA) and stent placement (SP) for hepatic venous outflow obstruction (HVOO) in pediatric liver transplantation (LT). Methods From January 1999 to September 2016, 262 pediatric patients underwent LT at our hospital. Ten were diagnosed with HVOO, which included 8 living donor grafts and 2 split liver grafts. BA and SP were used in management of these 10 patients with HVOO. After intervention, Doppler ultrasound (DUS) was the major follow-up modality for comparing efficiency of BA and SP. Results The incidence of HVOO was 3.8% (10 of 262) in our pediatric LTs. Of the 10 HVOO cases, 5 had SP, 3 had BA once, 1 had BA twice, and 1 had BA twice along with SP. The patent hepatic vein was maintained after a mean follow-up of 7.4 (range, 0.04–17) years. Recurrent rate of HVOO after BA was 42%. Neither recurrent HVOO nor stent migration occurred after SP and throughout long-term follow-up. Conclusion Hepatic venous SP was found to be more effective and safe than BA for treatment of HVOO in pediatric LT for long-term follow-up.

Difference in gene expressions is characteristic of the function of different cell types and those genes with low expression variance can be used as standards for quantitative gene expression studies. Microarray technology is used to study global gene expression within a cell; hence, represents a suitable source of data to mine for genes with low expression variance. The coefficient of variation (COV) of each gene was determined and a threshold of less than 0.1 COV was used to select stably expressed genes in each data set. Our results showed that microtubule affinity-regulating kinase 3 (MARK3) has the lowest COV in eight microarray datasets. In addition, the gene expression of housekeeping genes, which is very likely to be stably expressed, tends to fluctuate highly under different conditions, marking them as being less reliable for use as reference genes.