ORCID Profile
0000-0002-9081-3405
Current Organisations
Los Alamos National Laboratory
,
University of Adelaide
,
SA Pathology
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Publisher: Springer Science and Business Media LLC
Date: 2009
Publisher: Research Square Platform LLC
Date: 11-01-2022
DOI: 10.21203/RS.3.RS-1215526/V1
Abstract: Perinatal death, of a fetus or newborn, is a devastating event for families. Following nationwide multicentre recruitment, we assessed ‘genomic autopsy’ as an adjunct to standard autopsy for 200 families who experienced perinatal death, and provided a definite or candidate genetic diagnosis in 105 families. From this understudied cohort, half of the (candidate) diagnoses were phenotype expansions or novel disease genes, revealing previously unknown in-utero presentations of existing developmental disorders, and genomic disorders that are likely incompatible with life. Among the definite diagnoses, 43% were recessively or dominantly inherited, posing a 25% or 50% recurrence risk for future pregnancies. Ten families used their diagnosis for preimplantation or prenatal diagnosis of 12 pregnancies, facilitating the delivery of ten healthy newborns and management of two affected pregnancies. We emphasize the clinical importance of genomic investigations of perinatal death, with short turn-around times, enabling accurate counselling and options for families to prevent recurrence.
Publisher: Springer Science and Business Media LLC
Date: 12-10-2017
DOI: 10.1038/JHH.2017.71
Publisher: Elsevier BV
Date: 03-2015
DOI: 10.1016/J.CELL.2015.02.014
Abstract: Circular RNAs (circRNAs), formed by non-sequential back-splicing of pre-mRNA transcripts, are a widespread form of non-coding RNA in animal cells. However, it is unclear whether the majority of circRNAs represent splicing by-products without function or are produced in a regulated manner to carry out specific cellular functions. We show that hundreds of circRNAs are regulated during human epithelial-mesenchymal transition (EMT) and find that the production of over one-third of abundant circRNAs is dynamically regulated by the alternative splicing factor, Quaking (QKI), which itself is regulated during EMT. Furthermore, by modulating QKI levels, we show the effect on circRNA abundance is dependent on intronic QKI binding motifs. Critically, the addition of QKI motifs is sufficient to induce de novo circRNA formation from transcripts that are normally linearly spliced. These findings demonstrate circRNAs are both purposefully synthesized and regulated by cell-type specific mechanisms, suggesting they play specific biological roles in EMT.
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 29-09-2017
Publisher: The Endocrine Society
Date: 16-06-2020
Abstract: Germline mutations in the succinate dehydrogenase genes (SDHA/B/C/D, SDHAF2—collectively, “SDHx”) have been implicated in paraganglioma (PGL), renal cell carcinoma (RCC), gastrointestinal stromal tumor (GIST), and pituitary adenoma (PA). Negative SDHB tumor staining is indicative of SDH-deficient tumors, usually reflecting an underlying germline SDHx mutation. However, approximately 20% of in iduals with SDH-deficient tumors lack an identifiable germline SDHx mutation. We performed whole-exome sequencing (WES) of germline and tumor DNA followed by Sanger sequencing validation, transcriptome analysis, metabolomic studies, and haplotype analysis in 2 Italian-Australian families with SDH-deficient PGLs and various neoplasms, including RCC, GIST, and PA. Germline WES revealed a novel SDHC intronic variant, which had been missed during previous routine testing, in 4 affected siblings of the index family. Transcriptome analysis demonstrated aberrant SDHC splicing, with the retained intronic segment introducing a premature stop codon. WES of available tumors in this family showed chromosome 1 deletion with loss of wild-type SDHC in a PGL and a somatic gain-of-function KIT mutation in a GIST. The SDHC intronic variant identified was subsequently detected in the second family, with haplotype analysis indicating a founder effect. This is the deepest intronic variant to be reported among the SDHx genes. Intronic variants beyond the limits of standard gene sequencing analysis should be considered in patients with SDH-deficient tumors but negative genetic test results.
Publisher: Springer Science and Business Media LLC
Date: 2012
Publisher: Elsevier BV
Date: 12-1989
Publisher: Springer Science and Business Media LLC
Date: 09-2002
Publisher: American Physical Society (APS)
Date: 31-01-2002
Publisher: Elsevier BV
Date: 1998
Publisher: World Scientific Pub Co Pte Lt
Date: 07-1988
DOI: 10.1142/S0217751X88000709
Abstract: We develop a description of single pion momentum distributions incorporating Bose-Einstein statistics and compare it to data at ISR and collider energies. Events of fixed multiplicity are described by a temperature which varies as a function of multiplicity. For high temperatures the model gives similar results to the recently introduced partition temperature model. while for low temperatures the possibility of pion condensation is explored.
Publisher: Springer Science and Business Media LLC
Date: 25-02-2011
Abstract: MicroRNAs are important components of the regulatory network of biological systems and thousands have been discovered in both animals and plants. Systematic investigations performed in species with sequenced genomes such as Arabidopsis, rice, poplar and Brachypodium have provided insights into the evolutionary relationships of this class of small RNAs among plants. However, miRNAs from barley, one of the most important cereal crops, remain unknown. We performed a large scale study of barley miRNAs through deep sequencing of small RNAs extracted from leaves of two barley cultivars. By using the presence of miRNA precursor sequences in related genomes as one of a number of supporting criteria, we identified up to 100 miRNAs in barley. Of these only 56 have orthologs in wheat, rice or Brachypodium that are known to be expressed, while up to 44 appear to be specifically expressed in barley. Our study, the first large scale investigation of small RNAs in barley, has identified up to 100 miRNAs. We demonstrate that reliable identification of miRNAs via deep sequencing in a species whose genome has not been sequenced requires a more careful analysis of sequencing errors than is commonly performed. We devised a read filtering procedure for dealing with errors. In addition, we found that the use of a large dataset of almost 35 million reads permits the use of read abundance distributions along putative precursor sequences as a practical tool for isolating miRNAs in a large background of reads originating from other non-coding and coding RNAs. This study therefore provides a generic approach for discovering novel miRNAs where no genome sequence is available.
Publisher: American Physical Society (APS)
Date: 10-1990
Publisher: The Endocrine Society
Date: 09-2014
DOI: 10.1210/JC.2014-1265
Abstract: Bilateral macronodular adrenal hyperplasia (BMAH) is a rare form of adrenal Cushing's syndrome. Familial cases have been reported, but at the time we conducted this study, the genetic basis of BMAH was unknown. Recently, germline variants of armadillo repeat containing 5 (ARMC5) in patients with isolated BMAH and somatic, second-hit mutations in tumor nodules, were identified. Our objective was to identify the genetic basis of familial BMAH. We performed whole exome capture and sequencing of 2 affected in iduals from each of 4 BMAH families (BMAH-01, BMAH-02, BMAH-03, and BMAH-05). Based on clinical evaluation, there were 7, 3, 3, and 4 affected in iduals in these families, respectively. Sanger sequencing of ARMC5 was performed in 1 other BMAH kindred, BMAH-06. Exome sequencing identified novel variants Chr16:g.31477540, c.2139delT, p.(Thr715Leufs*1) (BMAH-02) and Chr16:g.31473811, c.943C→T, p.(Arg315Trp) (BMAH-03) in ARMC5 (GRch37/hg19), validated by Sanger sequencing. BMAH-01 had a recently reported mutation Chr16:g.31476121, c.1777C→T, p.(Arg593Trp). Sanger sequencing of ARMC5 in BMAH-06 identified a previously reported mutation, Chr16:g. 31473688 c.799C→T, p.(Arg267*). The genetic basis of BMAH in BMAH-05 was not identified. Our studies have detected ARMC5 mutations in 4 of 5 BMAH families tested, confirming that these mutations are a frequent cause of BMAH. Two of the 4 families had novel mutations, indicating allelic heterogeneity. Preclinical evaluation did not predict mutation status. The ARMC5-negative family had unusual prominent hyperaldosteronism. Further studies are needed to determine the penetrance of BMAH in ARMC5 mutation-positive relatives of affected patients, the practical utility of genetic screening and genotype-phenotype correlations.
Publisher: Springer Science and Business Media LLC
Date: 29-01-2020
DOI: 10.1186/S12902-020-0495-8
Abstract: Apart from PRKAR1A mutations in a subset of cyclical Cushing’s syndrome due to primary pigmented nodular adrenocortical disease, the molecular basis of cyclical Cushing’s syndrome has not been investigated. We speculated that cyclical Cushing’s syndrome may be due to mutations in the clock genes that govern circadian rhythms, including the hypothalamic-pituitary-adrenal axis. A 47-year-old man presented with mass effects from a sellar lesion. He was ultimately diagnosed with cyclical Cushing’s disease due to a giant corticotrophinoma. We performed whole exome sequencing of germline and tumour DNA, SNP array of tumour DNA and tumour immunohistochemistry in order to detect variants in candidate circadian ituitary-associated genes. We identified a rare germline missense variant in the aryl hydrocarbon receptor ( AHR ) gene, which has previously been indirectly linked to pituitary tumorigenesis and clock system disruption. The AHR variant was found in a highly conserved site involved in phosphorylation. It was predicted to be damaging by multiple in silico tools and AHR tumour immunohistochemistry demonstrated loss of the normal nuclear staining pattern, suggestive of an inactivating mutation. We also found a novel, damaging germline missense variant in the retinoid X receptor gamma ( RXRG ) gene, multiple somatic chromosomal gains (including AHR ), and a somatic mutational signature consistent with oncogenesis that may have acted synergistically with the AHR variant. This is the first report of an AHR variant with predicted pathogenicity in the pituitary adenoma setting. Our preliminary data suggest that the highly conserved AHR gene may represent a link between pituitary tumorigenesis, the hypothalamic-pituitary-adrenal axis and the clock system. Further research may indicate a role for the gene in the development of cyclical Cushing’s disease.
Publisher: American Physical Society (APS)
Date: 15-03-1996
Publisher: Wiley
Date: 06-03-2020
DOI: 10.1002/AJMG.A.61541
Publisher: American Physical Society (APS)
Date: 03-1999
Publisher: Springer Science and Business Media LLC
Date: 17-02-2020
DOI: 10.1186/S12881-020-0971-Z
Abstract: We report a large family with four successive generations, presenting with a complex phenotype of severe congenital neutropenia (SCN), partially penetrant monocytosis, and hearing loss of varying severity. We performed whole exome sequencing to identify the causative variants. Sanger sequencing was used to perform segregation analyses on remaining family members. We identified and classified a pathogenic GFI1 variant and a likely pathogenic variant in MYO6 which together explain the complex phenotypes seen in this family. We present a case illustrating the benefits of a broad screening approach that allows identification of oligogenic determinants of complex human phenotypes which may have been missed if the screening was limited to a targeted gene panel with the assumption of a syndromic disorder. This is important for correct genetic diagnosis of families and disentangling the range and severity of phenotypes associated with high impact variants.
Publisher: Elsevier BV
Date: 07-2017
DOI: 10.1016/J.JAUT.2017.03.002
Abstract: Next generation sequencing of T and B cell receptors is emerging as a valuable and effective method to diagnose and monitor hematopoietic malignancies. So far, this approach has not been fully explored in regard to autoimmune diseases. T cells develop in the thymus where they undergo positive and negative selection, and the autoimmune regulator (Aire) is central in the establishment of immunological tolerance. Loss of Aire leads to severe multiorgan autoimmune disease with infiltration of autoreactive T cells in affected organs. Here, we have utilized next generation sequencing technology to investigate the T cell receptor repertoire in autoimmunity induced by immunization of mice with a self-antigen, myeloperoxidase. By investigating the T cell receptor repertoire in peripheral blood, spleen and lumbar lymph nodes from naïve and immunized Aire -/- mice and wild type littermates, changes in the usage of V and J genes were evident. Our results identify TCR clonotypes which could be potential targets for immune therapy. Also, Aire -/- autoimmunity is driven by a variety of autoantigens where the autoimmune response is highly polyclonal, and access to the most adjacent immunologically active tissue is required to identify T cell receptor sequences that are potentially unique to the antigen in Aire-/- immunized mice.
Publisher: Proceedings of the National Academy of Sciences
Date: 25-04-2023
Abstract: Policymakers must make management decisions despite incomplete knowledge and conflicting model projections. Little guidance exists for the rapid, representative, and unbiased collection of policy-relevant scientific input from independent modeling teams. Integrating approaches from decision analysis, expert judgment, and model aggregation, we convened multiple modeling teams to evaluate COVID-19 reopening strategies for a mid-sized United States county early in the pandemic. Projections from seventeen distinct models were inconsistent in magnitude but highly consistent in ranking interventions. The 6-mo-ahead aggregate projections were well in line with observed outbreaks in mid-sized US counties. The aggregate results showed that up to half the population could be infected with full workplace reopening, while workplace restrictions reduced median cumulative infections by 82%. Rankings of interventions were consistent across public health objectives, but there was a strong trade-off between public health outcomes and duration of workplace closures, and no win-win intermediate reopening strategies were identified. Between-model variation was high the aggregate results thus provide valuable risk quantification for decision making. This approach can be applied to the evaluation of management interventions in any setting where models are used to inform decision making. This case study demonstrated the utility of our approach and was one of several multimodel efforts that laid the groundwork for the COVID-19 Scenario Modeling Hub, which has provided multiple rounds of real-time scenario projections for situational awareness and decision making to the Centers for Disease Control and Prevention since December 2020.
Publisher: Research Square Platform LLC
Date: 21-02-2022
DOI: 10.21203/RS.3.RS-1366032/V1
Abstract: Congenital abnormalities and infections are the predominant cause of perinatal death in developed countries. While standard-of-care autopsy investigations can ascertain the event that caused the death, the aetiology cannot always be established. Genetic approaches have demonstrated utility in identifying the underlying causes of congenital anomalies and infectious diseases, but the feasibility of simultaneous metagenomic and genomic analyses has not been examined. To determine the potential of this consolidated approach, genome sequencing was performed on DNA from lung in 20 cases of fetal death. Causative microbes were correctly identified in 4/7 known infection cases and plausible causative microbes identified for 2/5 cases unresolved from standard investigations. No significant microbial load was identified in 8/8 cases due to congenital abnormality. While methods for concurrent human and microbial genome analyses still require optimisation, this dual approach should improve the diagnostic yield compared to current standard-of-care investigations, enabling more accurate counselling and appropriate care in subsequent pregnancies.
Publisher: Hindawi Limited
Date: 11-07-2016
DOI: 10.1002/HUMU.23032
Abstract: Ectrodactyly/split hand-foot malformation is genetically heterogeneous with more than 100 syndromic associations. Acinar dysplasia is a rare congenital lung lesion of unknown etiology, which is frequently lethal postnatally. To date, there have been no reports of combinations of these two phenotypes. Here, we present an infant from a consanguineous union with both ectrodactyly and autopsy confirmed acinar dysplasia. SNP array and whole-exome sequencing analyses of the affected infant identified a novel homozygous Fibroblast Growth Factor Receptor 2 (FGFR2) missense mutation (p.R255Q) in the IgIII domain (D3). Expression studies of Fgfr2 in development show localization to the affected limbs and organs. Molecular modeling and genetic and functional assays support that this mutation is at least a partial loss-of-function mutation, and contributes to ectrodactyly and acinar dysplasia only in homozygosity, unlike previously reported heterozygous activating FGFR2 mutations that cause Crouzon, Apert, and Pfeiffer syndromes. This is the first report of mutations in a human disease with ectrodactyly with pulmonary acinar dysplasia and, as such, homozygous loss-of-function FGFR2 mutations represent a unique syndrome.
Publisher: Elsevier BV
Date: 05-2002
Publisher: World Scientific Pub Co Pte Lt
Date: 12-1996
DOI: 10.1142/S0218301396000384
Abstract: We extend the polaron variational treatment previously developed for the propagator to the case where one nucleon and n external mesons are present. Using the particle representation of the scalar Wick-Cutkosky model this is done in lowest order of an expansion of the exact action around a retarded quadratic trial action. In particular, we evaluate the form factor for scattering of mesons from the scalar nucleon and determine the radius of the dressed particle. After analytic continuation to Minkowski space we study elastic meson-nucleon scattering both analytically and numerically near threshold and show that it is essential to incorporate the correct behavior of the retardation function at large proper times. Only if this is done the optical theorem is approximately fulfilled over a range of energies and coupling constants.
Publisher: Springer Science and Business Media LLC
Date: 31-08-2019
DOI: 10.1007/S12022-019-09587-0
Abstract: Somatic GNAS and USP8 mutations have been implicated in sporadic somatotrophinomas and corticotrophinomas, respectively. However, no genes are known to be recurrently mutated in sporadic prolactinomas. The prevalence of copy number variants (CNV), which is emerging as a mechanism of tumorigenesis in sporadic pituitary adenomas in general, is also unclear in prolactinomas. To characterize the genetic events underpinning sporadic prolactinomas, we performed whole exome sequencing of paired tumor and germline DNA from 12 prolactinoma patients. We observed recurrent large-scale CNV, most commonly in the form of copy number gains. We also identified sequence variants of interest in 15 genes. This included the DRD2, PRL, TMEM67, and MLH3 genes with plausible links to prolactinoma formation. Of the 15 genes of interest, CNV was seen at the gene locus in the corresponding tumor in 10 cases, and pituitary expression of eight genes was in the top 10% of tissues. However, none of our shortlisted somatic variants appeared to be classical driver mutations as no variant was found in more than one tumor. Future directions of research include mechanistic studies to investigate how CNV may contribute to prolactinoma formation, larger studies of relevant prolactinoma subsets according to clinical characteristics, and additional genetic investigations for aberrations not captured by whole exome sequencing.
Publisher: BMJ
Date: 27-01-2020
DOI: 10.1136/JMEDGENET-2019-106700
Abstract: Pseudodiastrophic dysplasia (PDD) is a severe skeletal dysplasia associated with prenatal manifestation and early lethality. Clinically, PDD is classified as a ‘dysplasia with multiple joint dislocations’ however, the molecular aetiology of the disorder is currently unknown. Whole exome sequencing (WES) was performed on three patients from two unrelated families, clinically diagnosed with PDD, in order to identify the underlying genetic cause. The functional effects of the identified variants were characterised using primary cells and human cell-based overexpression assays. WES resulted in the identification of biallelic variants in the established skeletal dysplasia genes, B3GAT3 (family 1) and CANT1 (family 2). Mutations in these genes have previously been reported to cause ‘multiple joint dislocations, short stature, and craniofacial dysmorphism with or without congenital heart defects’ (‘JDSCD’ B3GAT3) and Desbuquois dysplasia 1 (CANT1), disorders in the same nosological group as PDD. Follow-up of the B3GAT3 variants demonstrated significantly reduced B3GAT3/GlcAT-I expression. Downstream in vitro functional analysis revealed abolished biosynthesis of glycosaminoglycan side chains on proteoglycans. Functional evaluation of the CANT1 variant showed impaired nucleotidase activity, which results in inhibition of glycosaminoglycan synthesis through accumulation of uridine diphosphate. For the families described in this study, the PDD phenotype was caused by mutations in the known skeletal dysplasia genes B3GAT3 and CANT1 , demonstrating the advantage of genomic analyses in delineating the molecular diagnosis of skeletal dysplasias. This finding expands the phenotypic spectrum of B3GAT3-related and CANT1-related skeletal dysplasias to include PDD and highlights the significant phenotypic overlap of conditions within the proteoglycan biosynthesis pathway.
Publisher: CSIRO Publishing
Date: 1991
DOI: 10.1071/PH910363
Abstract: There has recently been significant progress in the calculation of the twist-two piece of the quark arton distributions corresponding to models like the MIT bag. However, in evaluating the required matrix elements of the quark field operators Signal and Thomas (1988, 1989) resorted to the Peierls-Yoccoz (1957) approximation-albeit with some cautionary remarks. We point out a problem with that approach which is solved by using the Peierls-Thouless (1962) approximation for the hadronic states. The very simple case of a nonrelativistic constant density quark wavefunction is solved in detail.
Publisher: Springer Science and Business Media LLC
Date: 13-04-2021
DOI: 10.1038/S41375-021-01246-W
Abstract: The majority of studies assessing the contribution of pathogenic germline variants (PGVs) to cancer predisposition have focused on patients with single cancers. We analyzed 45 known cancer predisposition genes (CPGs) in germline s les of 202 patients with hematological malignancies (HMs) plus one or more other independent cancer managed at major tertiary medical centers on two different continents. This included 120 patients with therapy-related myeloid neoplasms (t-MNs), where the HM occurred after cytotoxic treatment for a first malignancy, and 82 patients with multiple cancers in which the HM was not preceded by cytotoxic therapy (MC-HM). Using American College of Medical Genetics/Association for Molecular Pathology variant classification guidelines, 13% of patients had PGVs, most frequently identified in CHEK2 (17% of PGVs), BRCA1 (13%), DDX41 (13%), and TP53 (7%). The frequency of PGVs in MC-HM was higher than in t-MN, although not statistically significant (18 vs. 9% p = 0.085). The frequency of PGVs in lymphoid and myeloid HM patients was similar (19 vs. 17.5% p > 0.9). Critically, patients with PGVs in BRCA1, BRCA2 or TP53 did not satisfy current clinical phenotypic criteria for germline testing. Our data suggest that a personal history of multiple cancers, one being a HM, should trigger screening for PGVs.
Publisher: Wiley
Date: 06-04-2015
DOI: 10.1002/AJMG.A.37075
Abstract: The Allan-Herndon-Dudley syndrome is caused by mutations in the thyroid hormone transporter, Monocarboxylate transporter 8 (MCT8). It is characterized by profound intellectual disability and abnormal thyroid function. We report on a patient with Allan-Herndon-Dudley syndrome (AHDS) with profound sensorineural hearing loss which is not usually a feature of AHDS and which may have been due to a coexisting nonsense mutation in Microphthalmia-associated transcription factor (MITF).
Publisher: Elsevier BV
Date: 12-1988
Publisher: American Society of Hematology
Date: 24-03-2020
DOI: 10.1182/BLOODADVANCES.2019000901
Abstract: First reported in 1999, germline runt-related transcription factor 1 (RUNX1) mutations are a well-established cause of familial platelet disorder with predisposition to myeloid malignancy (FPD-MM). We present the clinical phenotypes and genetic mutations detected in 10 novel RUNX1-mutated FPD-MM families. Genomic analyses on these families detected 2 partial gene deletions, 3 novel mutations, and 5 recurrent mutations as the germline RUNX1 alterations leading to FPD-MM. Combining genomic data from the families reported herein with aggregated published data sets resulted in 130 germline RUNX1 families, which allowed us to investigate whether specific germline mutation characteristics (type, location) could explain the large phenotypic heterogeneity between patients with familial platelet disorder and different HMs. Comparing the somatic mutational signatures between the available familial (n = 35) and published sporadic (n = 137) RUNX1-mutated AML patients showed enrichment for somatic mutations affecting the second RUNX1 allele and GATA2. Conversely, we observed a decreased number of somatic mutations affecting NRAS, SRSF2, and DNMT3A and the collective genes associated with CHIP and epigenetic regulation. This is the largest aggregation and analysis of germline RUNX1 mutations performed to date, providing a unique opportunity to examine the factors underlying phenotypic differences and disease progression from FPD to MM.
Publisher: Springer Science and Business Media LLC
Date: 14-05-2019
DOI: 10.1038/S41375-019-0479-8
Abstract: Therapy-related myeloid neoplasms (T-MN) are poorly characterized secondary hematological malignancies following chemotherapy/radiotherapy exposure. We compared the clinical and mutational characteristics of T-MN (n = 129) and primary myelodysplastic syndrome (P-MDS, n = 108) patients. Although the somatic mutation frequency was similar between T-MN and P-MDS patients (93% in both groups), the pattern was distinct. TP53 mutations were more frequent in T-MN (29.5 vs. 7%), while spliceosomal complex mutations were more common in P-MDS (56.5 vs. 25.6%). In contrast to P-MDS, the ring sideroblasts (RS) phenotype was not associated with better survival in T-MN, most probably due to genetic association with TP53 mutations. SF3B1 was mutated in 96% of P-MDS with ≥15% RS, but in only 32% T-MN. TP53 mutations were detected in 92% T-MN with ≥15% RS and SF3B1 wild-type cases. Interestingly, T-MN and P-MDS patients with "Very low" or "Low" Revised International Prognostic Scoring System (IPSS-R) showed similar biological and clinical characteristics. In a Cox regression analysis, TP53 mutation was a poor prognostic factor in T-MN, independent of IPSS-R cytogenetics, disease-modifying therapy, and NRAS mutation. Our data have direct implications for T-MN management and provide evidence that, in addition to conventional disease parameters, mutational analysis should be incorporated in T-MN risk stratification.
Publisher: Elsevier BV
Date: 02-2001
Publisher: Springer Science and Business Media LLC
Date: 11-08-2020
DOI: 10.1038/S41375-020-01011-5
Abstract: Blast-phase chronic myeloid leukemia (BP-CML) is associated with additional chromosomal aberrations, RUNX1 mutations being one of the most common. Tyrosine kinase inhibitor therapy has only limited efficacy in BP-CML, and characterization of more defined molecular subtypes is warranted in order to design better treatment modalities for this poor prognosis patient group. Using whole-exome and RNA sequencing we demonstrate that PHF6 and BCORL1 mutations, IKZF1 deletions, and AID/RAG-mediated rearrangements are enriched in RUNX1 mut BP-CML leading to typical mutational signature. On transcriptional level interferon and TNF signaling were deregulated in primary RUNX1 mut CML cells and stem cell and B-lymphoid factors upregulated giving a rise to distinct phenotype. This was accompanied with the sensitivity of RUNX1 mut blasts to CD19-CAR T cells in ex vivo assays. High-throughput drug sensitivity and resistance testing revealed leukemia cells from RUNX1 mut patients to be highly responsive for mTOR-, BCL2-, and VEGFR inhibitors and glucocorticoids. These findings were further investigated and confirmed in CRISPR/Cas9-edited homozygous RUNX1 −/− and heterozygous RUNX1 −/mut BCR-ABL positive cell lines. Overall, our study provides insights into the pathogenic role of RUNX1 mutations and highlights personalized targeted therapy and CAR T-cell immunotherapy as potentially promising strategies for treating RUNX1 mut BP-CML patients.
Publisher: EMBO
Date: 06-06-2018
Publisher: Elsevier BV
Date: 06-2001
Publisher: American Society of Hematology
Date: 02-12-2021
Publisher: Springer Science and Business Media LLC
Date: 19-02-2020
Publisher: Oxford University Press (OUP)
Date: 09-07-2013
DOI: 10.1093/BIOINFORMATICS/BTT375
Abstract: Motivation: With the advent of relatively affordable high-throughput technologies, DNA sequencing of cancers is now common practice in cancer research projects and will be increasingly used in clinical practice to inform diagnosis and treatment. Somatic (cancer-only) single nucleotide variants (SNVs) are the simplest class of mutation, yet their identification in DNA sequencing data is confounded by germline polymorphisms, tumour heterogeneity and sequencing and analysis errors. Four recently published algorithms for the detection of somatic SNV sites in matched cancer–normal sequencing datasets are VarScan, SomaticSniper, JointSNVMix and Strelka. In this analysis, we apply these four SNV calling algorithms to cancer–normal Illumina exome sequencing of a chronic myeloid leukaemia (CML) patient. The candidate SNV sites returned by each algorithm are filtered to remove likely false positives, then characterized and compared to investigate the strengths and weaknesses of each SNV calling algorithm. Results: Comparing the candidate SNV sets returned by VarScan, SomaticSniper, JointSNVMix2 and Strelka revealed substantial differences with respect to the number and character of sites returned the somatic probability scores assigned to the same sites their susceptibility to various sources of noise and their sensitivities to low-allelic-fraction candidates. Availability: Data accession number SRA081939, code at /snv-caller-review/ Contact: david.adelson@adelaide.edu.au Supplementary information: Supplementary data are available at Bioinformatics online.
Publisher: AIP
Date: 2000
DOI: 10.1063/1.1330904
Publisher: Elsevier BV
Date: 08-1994
Publisher: World Scientific Pub Co Pte Lt
Date: 30-01-1991
DOI: 10.1142/S0217732391000233
Abstract: Recently deep inelastic scattering experiments have implied that the ‘sea’ of the nucleon breaks flavor SU(2) symmetry. We examine the possible origins of this symmetry breaking in the Fermi statistics of the quarks and antiquarks in the sea and the requirements of chiral symmetry. We show that the present data have a natural explanation in terms of the long-range pion structure of the nucleon. Further work may lead to useful bounds on the parameters of bag models of the nucleon.
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 28-03-2019
Publisher: American Physical Society (APS)
Date: 16-11-1998
Publisher: Elsevier BV
Date: 03-1998
Publisher: Springer Science and Business Media LLC
Date: 09-2004
Publisher: Elsevier BV
Date: 02-2006
DOI: 10.1016/J.JTBI.2005.06.025
Abstract: The rearrangement of receptors by oligomeric adhesion molecules constitutes a configurational mechanism able to sculpture membranes and dislocate receptors from cytoplasmic anchorage. This provides a conceptual framework for complex cellular processes in mechanical terms, as a dynamic balance between extracellular and intracellular driving forces.
Publisher: Elsevier BV
Date: 07-2022
DOI: 10.1016/J.JMOLDX.2022.04.004
Abstract: Mutation detection is increasingly used for the management of hematological malignancies. Prior whole transcriptome and whole exome sequencing studies using total RNA and DNA identified erse mutation types in cancer-related genes associated with treatment failure in patients with chronic myeloid leukemia. Variants included single-nucleotide variants and small insertions/deletions, plus fusion transcripts and partial or whole gene deletions. The hypothesis that all of these mutation types could be detected by a single cost-effective hybridization capture next-generation sequencing method using total RNA was assessed. A method was developed that targeted 130 genes relevant for myeloid and lymphoid leukemia. Retrospective s les with 121 precharacterized variants were tested using total RNA and/or DNA. Concordance of detection of precharacterized variants using RNA or DNA was 96%, whereas the enhanced sensitivity identified additional variants. Comparison between 24 matched DNA and RNA s les demonstrated 95.3% of 170 variants detectable using DNA were detected using RNA, including all but one variant predicted to activate nonsense-mediated decay. RNA identified an additional 10 variants, including fusion transcripts. Furthermore, the true effect of splice variants on RNA splicing was only evident using RNA. In conclusion, capture sequencing using total RNA alone is suitable for detecting a range of variants relevant in chronic myeloid leukemia and may be more broadly applied to other hematological malignancies where erse variant types define risk groups.
Publisher: World Scientific Pub Co Pte Lt
Date: 09-1988
DOI: 10.1142/S0217732388001239
Abstract: It is not possible to obtain both the quark and antiquark momentum distributions from inclusive muon scattering as the electromagnetic structure function is dependent on a linear combination of these. We shall present a method here which extracts these distributions from semi-inclusive muon scattering. Knowledge of the quark fragmentation functions is not required.
Publisher: American Physical Society (APS)
Date: 25-09-2000
Publisher: American Society of Hematology
Date: 31-07-2017
DOI: 10.1182/BLOODADVANCES.2017006825
Abstract: Germ line variants in ASXL1 and BIM are strong biomarkers of response to imatinib in chronic phase CML. A combined Sokal risk and ASXL1 and BIM variant model identified a subgroup of patients with the greatest risk of treatment failure.
Publisher: American Society of Hematology
Date: 30-08-2018
DOI: 10.1182/BLOOD-2018-02-832253
Abstract: Next-generation sequencing revealed variants in cancer-associated genes at diagnosis of CML more frequently in patients with poor outcomes. All patients at BC had mutated cancer genes, including fusions, that predated BCR-ABL1 kinase domain mutations in a majority.
Publisher: Wiley
Date: 02-06-2016
DOI: 10.1111/PBI.12388
Abstract: Elucidation of the gene networks underlying the response to N supply and demand will facilitate the improvement of the N uptake efficiency of plants. We undertook a transcriptomic analysis of maize to identify genes responding to both a non-growth-limiting decrease in NO3- provision and to development-based N demand changes at seven representative points across the life cycle. Gene co-expression networks were derived by cluster analysis of the transcript profiles. The majority of NO3--responsive transcription occurred at 11 (D11), 18 (D18) and 29 (D29) days after emergence, with differential expression predominating in the root at D11 and D29 and in the leaf at D18. A cluster of 98 probe sets was identified, the expression pattern of which is similar to that of the high-affinity NO3- transporter (NRT2) genes across the life cycle. The cluster is enriched with genes encoding enzymes and proteins of lipid metabolism and transport, respectively. These are candidate genes for the response of maize to N supply and demand. Only a few patterns of differential gene expression were observed over the entire life cycle however, the composition of the classes of the genes differentially regulated at in idual time points was unique, suggesting tightly controlled regulation of NO3--responsive gene expression.
Publisher: American Physical Society (APS)
Date: 15-03-1996
Publisher: Oxford University Press (OUP)
Date: 2011
Abstract: The physiological role and mechanism of nutrient storage within vacuoles of specific cell types is poorly understood. Transcript profiles from Arabidopsis thaliana leaf cells differing in calcium concentration ([Ca], epidermis & mM versus mesophyll & mM) were compared using a microarray screen and single-cell quantitative PCR. Three tonoplast-localized Ca2+ transporters, CAX1 (Ca2+/H+-antiporter), ACA4, and ACA11 (Ca2+-ATPases), were identified as preferentially expressed in Ca-rich mesophyll. Analysis of respective loss-of-function mutants demonstrated that only a mutant that lacked expression of both CAX1 and CAX3, a gene ectopically expressed in leaves upon knockout of CAX1, had reduced mesophyll [Ca]. Reduced capacity for mesophyll Ca accumulation resulted in reduced cell wall extensibility, stomatal aperture, transpiration, CO2 assimilation, and leaf growth rate increased transcript abundance of other Ca2+ transporter genes altered expression of cell wall–modifying proteins, including members of the pectinmethylesterase, expansin, cellulose synthase, and polygalacturonase families and higher pectin concentrations and thicker cell walls. We demonstrate that these phenotypes result from altered apoplastic free [Ca2+], which is threefold greater in cax1/cax3 than in wild-type plants. We establish CAX1 as a key regulator of apoplastic [Ca2+] through compartmentation into mesophyll vacuoles, a mechanism essential for optimal plant function and productivity.
Publisher: American Physical Society (APS)
Date: 18-08-1999
Publisher: Public Library of Science (PLoS)
Date: 24-08-2020
Publisher: American Society of Hematology
Date: 12-10-2023
DOI: 10.1182/BLOODADVANCES.2023010045
Abstract: In iduals with germline variants associated with hereditary hematopoietic malignancies (HHMs) have a highly variable risk for leukemogenesis. Gaps in our understanding of pre-malignant states in HHMs have h ered efforts to design effective clinical surveillance programs, provide personalized pre-emptive treatments and inform appropriate counselling for patients. We used the largest known comparative international cohort of germline RUNX1, GATA2, or DDX41 variant carriers without and with hematopoietic malignancies (HMs) to identify patterns of genetic drivers that are unique to each HHM syndrome before and after leukemogenesis. These patterns included striking heterogeneity in rates of early-onset clonal hematopoiesis (CH), with a high prevalence of CH in RUNX1 and GATA2 variant carriers who did not have malignancies ("carriers-without HM"). We observed a paucity of CH in DDX41 carriers-without HM. In RUNX1 carriers-without HM with CH, we detected variants in TET2, PHF6, and, most frequently, BCOR. These genes were recurrently mutated in RUNX1-driven malignancies, suggesting CH is a direct precursor to malignancy in RUNX1-driven HHMs. Leukemogenesis in RUNX1 and DDX41 carriers was often driven by second-hits in RUNX1 and DDX41, respectively. This study may inform the development of HHM-specific clinical trials and gene-specific approaches to clinical monitoring. For ex le, trials investigating the potential benefits of monitoring DDX41 carriers-without HM for low-frequency second hits in DDX41 may now be beneficial. Similarly, trials monitoring carriers-without HM with RUNX1 germline variants for the acquisition of somatic variants in BCOR, PHF6, TET2, and second hits in RUNX1 are warranted.
Publisher: Elsevier BV
Date: 07-1991
Publisher: American Physical Society (APS)
Date: 11-1991
Publisher: Elsevier BV
Date: 03-1990
Publisher: Oxford University Press (OUP)
Date: 03-05-2016
DOI: 10.1093/BIOINFORMATICS/BTW239
Abstract: The standard method used by high-throughput genome sequencing facilities for detecting mislabelled s les is to use independently generated high-density SNP data to determine s le identity. However, as it has now become commonplace to have multiple s les sequenced from the same source, such as for analysis of somatic variants using matched tumour and normal s les, we can directly use the genotype information inherent in the sequence data to match s les and thus bypass the need for additional laboratory testing. Here we present BAM-matcher, a tool that can rapidly determine whether two BAM files represent s les from the same biological source by comparing their genotypes. BAM-matcher is designed to be simple to use, provides easily interpretable results, and is suitable for deployment at early stages of data processing pipelines. Availability and implementation: BAM-matcher is licensed under the Creative Commons by Attribution license, and is available from: acgf/bam-matcher . Supplementary information: Supplementary data are available at Bioinformatics online. Contact: paul.wang@sa.gov.au
Publisher: American Society of Hematology
Date: 29-07-2022
Publisher: Springer Science and Business Media LLC
Date: 25-01-2023
Publisher: Elsevier BV
Date: 05-1986
Publisher: American Association for Cancer Research (AACR)
Date: 02-2013
DOI: 10.1158/0008-5472.CAN-13-2424
Abstract: Nutlin-3a is a small-molecule antagonist of p53/MDM2 that is being explored as a treatment for sarcoma. In this study, we examined the molecular mechanisms underlying the sensitivity of sarcomas to Nutlin-3a. In an ex vivo tissue explant system, we found that TP53 pathway alterations (TP53 status, MDM2/MDM4 genomic lification/mRNA overexpression, MDM2 SNP309, and TP53 SNP72) did not confer apoptotic or cytostatic responses in sarcoma tissue biopsies (n = 24). Unexpectedly, MDM2 status did not predict Nutlin-3a sensitivity. RNA sequencing revealed that the global transcriptomic profiles of these sarcomas provided a more robust prediction of apoptotic responses to Nutlin-3a. Expression profiling revealed a subset of TP53 target genes that were transactivated specifically in sarcomas that were highly sensitive to Nutlin-3a. Of these target genes, the GADD45A promoter region was shown to be hypermethylated in 82% of wild-type TP53 sarcomas that did not respond to Nutlin-3a, thereby providing mechanistic insight into the innate ability of sarcomas to resist apoptotic death following Nutlin-3a treatment. Collectively, our findings argue that the existing benchmark biomarker for MDM2 antagonist efficacy (MDM2 lification) should not be used to predict outcome but rather global gene expression profiles and epigenetic status of sarcomas dictate their sensitivity to p53/MDM2 antagonists. Cancer Res 74(3) 921–31. ©2013 AACR.
Publisher: Springer Science and Business Media LLC
Date: 12-2013
Publisher: American Society of Hematology
Date: 25-02-2016
DOI: 10.1182/BLOOD-2015-10-676098
Abstract: Novel missense germ line DDX41 mutations define an earlier age of onset of hematologic malignancies than loss-of-function alleles. Carriers of DDX41 germ line mutations usually have normal blood counts until a myeloid or lymphoid malignancy develops.
Publisher: Springer Science and Business Media LLC
Date: 27-10-2015
DOI: 10.1038/LEU.2015.301
Publisher: American Physical Society (APS)
Date: 05-1992
Publisher: Springer Science and Business Media LLC
Date: 14-11-2019
DOI: 10.1038/S41525-019-0103-X
Abstract: We describe a sibling pair displaying an early infantile-onset, progressive neurodegenerative phenotype, with symptoms of developmental delay and epileptic encephalopathy developing from 12 to 14 months of age. Using whole exome sequencing, compound heterozygous variants were identified in SLC5A6 , which encodes the sodium-dependent multivitamin transporter (SMVT) protein. SMVT is an important transporter of the B-group vitamins biotin, pantothenate, and lipoate. The protein is ubiquitously expressed and has major roles in vitamin uptake in the digestive system, as well as transport of these vitamins across the blood–brain barrier. Pathogenicity of the identified variants was demonstrated by impaired biotin uptake of mutant SMVT. Identification of this vitamin transporter as the genetic basis of this disorder guided targeted therapeutic intervention, resulting clinically in improvement of the patient’s neurocognitive and neuromotor function. This is the second report of biallelic mutations in SLC5A6 leading to a neurodegenerative disorder due to impaired biotin, pantothenate and lipoate uptake. The genetic and phenotypic overlap of these cases confirms mutations in SLC5A6 as the genetic cause of this disease phenotype. Recognition of the genetic disorder caused by SLC5A6 mutations is essential for early diagnosis and to facilitate timely intervention by triple vitamin (biotin, pantothenate, and lipoate) replacement therapy.
Publisher: Hindawi Limited
Date: 11-08-2016
DOI: 10.1002/HUMU.23058
Publisher: Oxford University Press (OUP)
Date: 21-11-2007
DOI: 10.1093/BIOINFORMATICS/BTL591
Abstract: Motivation: Global gene expression measurements as obtained, for ex le, in microarray experiments can provide important clues to the underlying transcriptional control mechanisms and network structure of a biological cell. In the absence of a detailed understanding of this gene regulation, current attempts at classification of expression data rely on clustering and pattern recognition techniques employing ad-hoc similarity criteria. To improve this situation, a better understanding of the expected relationships between expression profiles of genes associated by biological function is required. Results: It is shown that perturbation expansions familiar from biological systems theory make precise predictions for the types of relationships to be expected for expression profiles of biologically associated genes, even if the underlying biological factors responsible for this association are not known. Classification criteria are derived, most of which are not usually employed in clustering algorithms. The approach is illustrated by using the AtGenExpress Arabidopsis thaliana developmental expression map. Contact: andreas.schreiber@adelaide.edu.au Supplementary information: Supplementary material is available at Bioinformatics online.
Publisher: Stichting Nase
Date: 06-2020
DOI: 10.4193/RHIN19.403
Abstract: Background: RNA sequencing (RNA-Seq) allows the characterization of a global transcriptomic signature in a least-biased fashion, but few studies have applied this method to investigate the pathophysiology of CRS. Methods: We collected mucosal tissue s les from 6 CRS without nasal polyps (CRSsNP), 6 CRS with nasal polyps (CRSwNP), and 6 control patients. Additional matched polyp s les were collected from the 6 CRSwNP patients. RNA was extracted and sequenced on the Illumina HiSeq-2500. Differential gene expression and pathway analyses were performed. Results: CRSsNP showed evidence of upregulated interferon-mediated immunity, MHC-class-I mediated antigen presentation, CXCR3 binding, neutrophil chemotaxis and degranulation, and potential downregulation of genes related to cilia movement and production. CRSwNP polyp tissue showed upregulation of B-cell mediated immune responses, but reduced expression of genes related to epithelial morphogenesis and haemostasis. Polyps also showed a generalized reduction of positive gene regulation. The sinonasal transcriptomic signature was largely determined by tissue type (polyp versus mucosa) and disease phenotype, with minimal signal originating from the in idual patient. Conclusion: RNA-Seq is a useful tool to explore the complex pathophysiology of CRS. Our findings stress the importance of tissue selection in molecular research utilizing sinonasal tissue, and demonstrate the limitation of the sNP/wNP paradigm (and the importance of endotyping). On the other hand, classical CRSsNP/wNP disease phenotypes played some role in determining the global transcriptomic signature, and should not be hastily discarded. The value of RNA-Seq-described transcriptomic signatures in exploring endotypes is yet to be explored in future studies.
Publisher: American Physical Society (APS)
Date: 02-1994
Publisher: Springer Science and Business Media LLC
Date: 09-03-2015
DOI: 10.1038/LEU.2015.67
Publisher: Springer Science and Business Media LLC
Date: 18-03-2006
DOI: 10.1007/S10142-006-0025-4
Abstract: Assaying relative and absolute levels of gene expression in a erse series of tissues is a central step in the process of characterizing gene function and a necessary component of almost all publications describing in idual genes or gene family members. However, throughout the literature, such studies lack consistency in genotype, tissues analyzed, and growth conditions applied, and, as a result, the body of information that is currently assembled is fragmented and difficult to compare between different studies. The development of a comprehensive platform for assaying gene expression that is available to the entire research community provides a major opportunity to assess whole biological systems in a single experiment. It also integrates detailed knowledge and information on in idual genes into a unified framework that provides both context and resource to explore their contributions in a broader biological system. We have established a data set that describes the expression of 21,439 barley genes in 15 tissues s led throughout the development of the barley cv. Morex grown under highly controlled conditions. Rather than attempting to address a specific biological question, our experiment was designed to provide a reference gene expression data set for barley researchers a gene expression atlas and a comparative data set for those investigating genes or regulatory networks in other plant species. In this paper we describe the tissues s led and their transcriptomes, and provide summary information on genes that are either specifically expressed in certain tissues or show correlated expression patterns across all 15 tissue s les. Using specific ex les and an online tutorial, we describe how the data set can be interrogated for patterns and levels of barley gene expression and how the resulting information can be used to generate and/or test specific biological hypotheses.
Publisher: AIP
Date: 2010
DOI: 10.1063/1.3479353
Publisher: Elsevier BV
Date: 02-2023
DOI: 10.1016/J.PATHOL.2022.05.015
Abstract: The identification of a somatic mutation associated with myeloid malignancy is of diagnostic importance in myeloproliferative neoplasms (MPNs). In iduals with no mutation detected in common screening tests for variants in JAK2, CALR, and MPL are described as 'triple-negative' and pose a diagnostic challenge if there is no other evidence of a clonal disorder. To identify potential drivers that might explain the clinical phenotype, we used an extended sequencing panel to characterise a cohort of 44 previously diagnosed triple-negative MPN patients for canonical mutations in JAK2, MPL and CALR at low variant allele frequency (found in 4/44 patients), less common variants in the JAK-STAT signalling pathway (12 patients), or other variants in recurrently mutated genes from myeloid malignancies (18 patients), including hotspot variants of potential clinical relevance in eight patients. In one patient with thrombocytosis we identified biallelic germline MPL variants. Neither MPL variant was activating in cell proliferation assays, and one of the variants was not expressed on the cell surface, yet co-expression of both variants led to thrombopoietin hypersensitivity. Our results highlight the clinical value of extended sequencing including germline variant analysis and illustrate the need for detailed functional assays to determine whether rare variants in JAK2 or MPL are pathogenic.
Publisher: Elsevier BV
Date: 06-1989
Publisher: Springer Science and Business Media LLC
Date: 27-02-2021
DOI: 10.1186/S12920-021-00911-4
Abstract: Periventricular nodular heterotopia (PNH) is a malformation of cortical development characterized by nodules of abnormally migrated neurons. The cause of posteriorly placed PNH is not well characterised and we present a case that provides insights into the cause of posterior PNH. We report a fetus with extensive posterior PNH in association with biallelic variants in LAMC3 . LAMC3 mutations have previously been shown to cause polymicrogyria and pachygyria in the occipital cortex, but not PNH. The occipital location of PNH in our case and the proposed function of LAMC3 in cortical development suggest that the identified LAMC3 variants may be causal of PNH in this fetus. We hypothesise that this finding extends the cortical phenotype associated with LAMC3 and provides valuable insight into genetic cause of posterior PNH.
Publisher: Elsevier BV
Date: 05-1996
No related grants have been discovered for Andreas Schreiber.