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1.
J Pathol ; 253(1): 41-54, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32901952

RESUMO

Low-grade serous ovarian carcinoma (LGSOC) is associated with a poor response to existing chemotherapy, highlighting the need to perform comprehensive genomic analysis and identify new therapeutic vulnerabilities. The data presented here represent the largest genetic study of LGSOCs to date (n = 71), analysing 127 candidate genes derived from whole exome sequencing cohorts to generate mutation and copy-number variation data. Additionally, immunohistochemistry was performed on our LGSOC cohort assessing oestrogen receptor, progesterone receptor, TP53, and CDKN2A status. Targeted sequencing identified 47% of cases with mutations in key RAS/RAF pathway genes (KRAS, BRAF, and NRAS), as well as mutations in putative novel driver genes including USP9X (27%), MACF1 (11%), ARID1A (9%), NF2 (4%), DOT1L (6%), and ASH1L (4%). Immunohistochemistry evaluation revealed frequent oestrogen/progesterone receptor positivity (85%), along with CDKN2A protein loss (10%) and CDKN2A protein overexpression (6%), which were linked to shorter disease outcomes. Indeed, 90% of LGSOC samples harboured at least one potentially actionable alteration, which in 19/71 (27%) cases were predictive of clinical benefit from a standard treatment, either in another cancer's indication or in LGSOC specifically. In addition, we validated ubiquitin-specific protease 9X (USP9X), which is a chromosome X-linked substrate-specific deubiquitinase and tumour suppressor, as a relevant therapeutic target for LGSOC. Our comprehensive genomic study highlighted that there is an addiction to a limited number of unique 'driver' aberrations that could be translated into improved therapeutic paths. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

2.
Am J Med Genet A ; 2020 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-33369125

RESUMO

ALX4 is a homeobox gene expressed in the mesenchyme of developing bone and is known to play an important role in the regulation of osteogenesis. Enlarged parietal foramina (EPF) is a phenotype of delayed intramembranous ossification of calvarial bones due to variants of ALX4. The contrasting phenotype of premature ossification of sutures is observed with heterozygous loss-of-function variants of TWIST1, which is an important regulator of osteoblast differentiation. Here, we describe an individual with a large cranium defect, with dominant transmission from the mother, both carrying disease causing heterozygous variants in ALX4 and TWIST1. The distinct phenotype of absent superior and posterior calvarium in the child and his mother was in sharp contrast to the other affected maternal relatives with a recognizable ALX4-related EPF phenotype. This report demonstrates comorbid disorders of Saethre-Chotzen syndrome and EPF in a mother and her child, resulting in severe skull defects reminiscent of calvarial abnormalities observed with bilallelic ALX4 variants. To our knowledge this is the first instance of ALX4 and TWIST1 variants acting synergistically to cause a unique phenotype influencing skull ossification.

3.
Polymers (Basel) ; 12(12)2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33255192

RESUMO

Additive manufacturing (AM) techniques can help to reduce the time and cost for manufacturing complex shaped parts. The main goal of this research was to determine the best strength structure of six different types of lattice cells, manufactured using the Poly Jet AM technology. In order to perform the tests, six samples with the same structure were created for each lattice type. For testing the samples in compression, an electromechanical test machine was used. finite element analysis (FEA) analysis was used in order to determine the area where the greatest stresses occured and to estimate the maximal compressive strength. The strongest structure was determined by obtaining the maximal compressive strength. This was calculated in two ways: as a ratio between the maximal supported force and the mass of the sample (N/g) and as a ratio between the maximal supported force and the critical section of the sample (MPa).

4.
ACS Synth Biol ; 9(12): 3245-3253, 2020 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-33226772

RESUMO

Recombination can be used in the laboratory to overcome component limitations in synthetic biology by creating enzymes that exhibit distinct activities and stabilities from native proteins. To investigate how recombination affects the properties of an oxidoreductase that transfers electrons in cells, we created ferredoxin (Fd) chimeras by recombining distantly related cyanobacterial and cyanomyophage Fds (53% identity) that present similar midpoint potentials but distinct thermostabilities. Fd chimeras having a wide range of amino acid substitutions retained the ability to coordinate an iron-sulfur cluster, although their thermostabilities varied with the fraction of residues inherited from each parent. The midpoint potentials of chimeric Fds also varied. However, all of the synthetic Fds exhibited midpoint potentials outside of the parental protein range. Each of the chimeric Fds could also support electron transfer between Fd-NADP reductase and sulfite reductase in Escherichia coli, although the chimeric Fds varied in the expression required for similar levels of cellular electron transfer. These results show how Fds can be diversified through recombination and reveal differences in the inheritance of thermostability and electrochemical properties. Furthermore, they illustrate how electron transfer efficiencies of chimeric Fds can be rapidly evaluated using a synthetic metabolic pathway.

7.
Artigo em Inglês | MEDLINE | ID: mdl-33138255

RESUMO

BACKGROUND: Assessing the use of multiple medications in cancer patients is crucial as such use may affect cancer outcomes. This study reports the prevalence of non-cancer medication use at breast cancer diagnosis, its associated factors, and its effect on survival. METHODS: We identified all women diagnosed with primary invasive breast cancer between 1 January 2007 and 31 December 2016, from four population-based breast cancer registries, in Auckland, Waikato, Wellington, and Christchurch, New Zealand. Through linkage to the pharmaceutical records, we obtained information on non-cancer medications that were dispensed for a minimum of 90 days' supply between one year before cancer diagnosis and first cancer treatment. We performed ordered logistic regressions to identify associated factors and Cox regressions to investigate its effect on patient survival. RESULTS: Of 14,485 patients, 52% were dispensed at least one drug (mean-1.3 drugs; maximum-13 drugs), with a higher prevalence observed in patients who were older, treated at a public facility, more economically deprived, and screen-detected. The use of 2-3 drugs showed a reduced non-breast cancer mortality (HR = 0.75, 95%CI = 0.60-0.92) in previously hospitalised patients, with other groups showing non-significant associations when adjusted for confounding factors. Drug use was not associated with changes in breast cancer-specific mortality. CONCLUSIONS: Non-cancer medication use at breast cancer diagnosis was common in New Zealand, more prevalent in older and disadvantaged women, and showed no effect on breast cancer-specific mortality, but a reduction in other cause mortality with the use of 2-3 drugs.

8.
Breast Cancer ; 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33044617

RESUMO

BACKGROUND: We aim to examine the characteristics and survival of patients with de novo metastatic breast cancer (dnMBC) and recurrent metastatic breast cancer (rMBC) in New Zealand. METHODS: This study included women diagnosed with dnMBC and women who developed rMBC between 2010 and 2017. The Kaplan-Meier method was used to examine cancer-specific survival. Cox proportional hazards regression was used to estimate the adjusted hazard ratio (HR) of cancer-specific mortality by ethnicity, age, year of diagnosis, socioeconomic deprivation, site of metastases, number of metastatic sites, biomarker subtype and MBC subgroup. RESULTS: We included 2177 MBC patients (667 dnMBC and 1510 rMBC). The median survival of dn MBC patients was 26 months compared to 18 months for rMBC. There were no differences in breast-cancer specific mortality by ethnicity or socioeconomic deprivation. The adjusted HR for patients with visceral metastases compared to patients with non-visceral metastases was 1.41, and the adjusted HR for triple negative disease compared to Luminal A disease was 2.24. Compared to dnMBC, the adjusted HRs for rMBC patients with a metastatic-free interval of < 2 years, 2-4 years, 5-7 year and 8 + years were 1.81, 1.47, 1.08 and 0.82, respectively. CONCLUSIONS: The survival for patients with MBC in New Zealand is very similar to other developed countries. Patients with dnMBC had a much better prognosis than those with recurrent disease. Patients with triple negative disease or non-luminal HER2 positive disease had the worst prognosis. The prognosis for patient with rMBC improved the longer the time from diagnosis to the development of metastases.

10.
NPJ Breast Cancer ; 6: 34, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32802943

RESUMO

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.

11.
ANZ J Surg ; 90(9): 1716-1720, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32783268

RESUMO

BACKGROUND: Primary mycotic aneurysms and prosthetic graft infections are traditionally managed by resection of infected vascular tissue and revascularisation with an extra-anatomical bypass. Long-term patency for this method has been reported to be poor with associated high reinfection and limb amputation rates. The aim of this study was to analyse the outcomes of those patients in our department between 2010 and 2018 whom had revascularisation with in-situ arterial reconstruction using cryopreserved allograft as a conduit. METHODS: The data were retrospectively reviewed and 13 patients were identified. There were five patients with primary mycotic aneurysms and eight patients with prosthetic graft infections, three of which were complicated by aortoenteric fistulae (AEF). RESULTS: There were three peri-operative mortalities (23%) with all three mortalities related to graft re-infection and post-implantation haemorrhage; two of these from uncontrolled bile leaks related to the original AEF with persistent graft contamination. The 10 surviving patients were followed up for a mean duration of 15.8 months with an overall primary graft patency of 89% and no incidence of graft re-infection or aneurysmal degeneration. CONCLUSION: Patients that survived the peri-operative period demonstrated acceptable medium-term allograft durability, with the most favourable outcomes observed in those patients who had arterial infections uncomplicated by AEF. The main barrier to more wide-spread use in our state remains inadequate supply of banked cryopreserved tissue.

12.
Front Psychol ; 11: 1934, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32849136

RESUMO

This study examined the effects of two pedagogical training approaches on parent-child dyads' discussion of scientific content in an informal museum setting. Forty-seven children (mean age = 5.43) and their parents were randomly assigned to training conditions where an experimenter modeled one of two different pedagogical approaches when interacting with the child and a science-based activity: (1) a scientific inquiry-based process or (2) a scientific statement-sharing method. Both approaches provided the same information about scientific mechanisms but differed in the process through which that content was delivered. Immediately following the training, parents were invited to model the same approach with their child with a novel science-based activity. Results indicated significant differences in the process through which parents prompted discussion of the targeted information content: when talking about causal scientific concepts, parents in the scientific inquiry condition were significantly more likely to pose questions to their child than parents in the scientific statements condition. Moreover, children in the scientific inquiry condition were marginally more responsive to parental causal talk and provided significantly more scientific content in response. These findings provide initial evidence that training parents to guide their children using scientific inquiry-based approaches in informal learning settings can encourage children to participate in more joint scientific conversations.

13.
JAMA Oncol ; 6(8): 1218-1230, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32614418

RESUMO

Importance: The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population. Objective: To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers. Design, Setting, and Participants: Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected. Main Outcomes and Measures: BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview. Results: Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P < .001), as well as developing 2 (OR, 7.97; 95% CI, 5.47-11.60; P < .001) and 3 (OR, 19.60; 95% CI, 4.64-82.89; P < .001) primary tumors. A higher frequency of breast (OR, 5.47; 95% CI, 4.06-7.37; P < .001) and prostate (OR, 1.39; 95% CI, 1.09-1.78; P = .008) cancers was associated with a higher probability of being a BRCA2 PV carrier. Among cancers other than breast and prostate, pancreatic cancer was associated with a higher probability (OR, 3.00; 95% CI, 1.55-5.81; P = .001) and colorectal cancer with a lower probability (OR, 0.47; 95% CI, 0.29-0.78; P = .003) of being a BRCA2 PV carrier. Conclusions and Relevance: Significant differences in the cancer spectrum were observed in male BRCA2, compared with BRCA1, PV carriers. These data may inform future recommendations for surveillance of BRCA1/2-associated cancers and guide future prospective studies for estimating cancer risks in men with BRCA1/2 PVs.

14.
Genet Med ; 22(10): 1653-1666, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32665703

RESUMO

PURPOSE: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. METHODS: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. RESULTS: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10-72). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10-50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10-22) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10-12) carriers. The associations in the prospective cohort were similar. CONCLUSION: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.

15.
Mod Pathol ; 2020 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-32724153

RESUMO

TP53 mutations are implicated in the progression of mucinous borderline tumors (MBOT) to mucinous ovarian carcinomas (MOC). Optimized immunohistochemistry (IHC) for TP53 has been established as a proxy for the TP53 mutation status in other ovarian tumor types. We aimed to confirm the ability of TP53 IHC to predict TP53 mutation status in ovarian mucinous tumors and to evaluate the association of TP53 mutation status with survival among patients with MBOT and MOC. Tumor tissue from an initial cohort of 113 women with MBOT/MOC was stained with optimized IHC for TP53 using tissue microarrays (75.2%) or full sections (24.8%) and interpreted using established criteria as normal or abnormal (overexpression, complete absence, or cytoplasmic). Cases were considered concordant if abnormal IHC staining predicted deleterious TP53 mutations. Discordant tissue microarray cases were re-evaluated on full sections and interpretational criteria were refined. The initial cohort was expanded to a total of 165 MBOT and 424 MOC for the examination of the association of survival with TP53 mutation status, assessed either by TP53 IHC and/or sequencing. Initially, 82/113 (72.6%) cases were concordant using the established criteria. Refined criteria for overexpression to account for intratumoral heterogeneity and terminal differentiation improved concordance to 93.8% (106/113). In the expanded cohort, 19.4% (32/165) of MBOT showed evidence for TP53 mutation and this was associated with a higher risk of recurrence, disease-specific death, and all-cause mortality (overall survival: HR = 4.6, 95% CI 1.5-14.3, p = 0.0087). Within MOC, 61.1% (259/424) harbored a TP53 mutation, but this was not associated with survival (overall survival, p = 0.77). TP53 IHC is an accurate proxy for TP53 mutation status with refined interpretation criteria accounting for intratumoral heterogeneity and terminal differentiation in ovarian mucinous tumors. TP53 mutation status is an important biomarker to identify MBOT with a higher risk of mortality.

16.
BMC Res Notes ; 13(1): 349, 2020 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-32698852

RESUMO

OBJECTIVE: Ovarian fibromas and adenofibromas are rare ovarian tumours. They are benign tumours composed of spindle-like stromal cells (pure fibroma) or a mixture of fibroblast and epithelial components (adenofibroma). We have previously shown that 40% of benign serous ovarian tumours are likely primary fibromas due to the neoplastic alterations being restricted to the stromal compartment of these tumours. We further explore this finding by comparing benign serous tumours to pure fibromas. RESULTS: Performing copy number aberration (CNA) analysis on the stromal component of 45 benign serous tumours and 8 pure fibromas, we have again shown that trisomy of chromosome 12 is the most common aberration in ovarian fibromas. CNAs were more frequent in the pure fibromas than the benign serous tumours (88% vs 33%), however pure fibromas more frequently harboured more than one CNA event compared with benign serous tumours. As these extra CNA events observed in the pure fibromas were unique to this subset our data indicates a unique tumour evolution. Gene expression analysis on the two cohorts was unable to show gene expression changes that differed based on tumour subtype. Exome analysis did not reveal any recurrently mutated genes.

18.
J Med Genet ; 2020 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-32546565

RESUMO

PURPOSE: The known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes. METHODS: We sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14 135 EOC cases and 28 655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics. RESULTS: The ORs associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 to 5.68; p=0.00068), 1.99 for POLK (95% CI 1.15 to 3.43; p=0.014) and 4.07 for SLX4 (95% CI 1.34 to 12.4; p=0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 to 1.00, p=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive. CONCLUSIONS: We have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.

20.
Environ Pollut ; 264: 114663, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32388297

RESUMO

Pollution of coastal and marine environments by mismanaged anthropogenic debris is a global threat requiring complex, multilateral solutions and mitigation strategies. International efforts to catalogue and quantify the density, extent and nature of mismanaged waste have not yet assessed the heterogeneity of debris between nearby areas. Better understanding of how debris types and density can be used as a proxy between regions and between land and seafloor habitats at a global scale can aid in developing cost effective and representative debris monitoring systems. Using volunteer collected clean-up and survey data, we compared the proportion and density of both total debris and specific items across 19,428 coastal land and seafloor sites from International Coastal Cleanups and Dive Against Debris surveys, from 86 countries between 2011 and 2018. We show that although some items common on land are also common on the seafloor, there is an overall global mismatch between debris types and densities on land and the seafloor from nearby areas. Correlations in land/seafloor debris type/density occurred primarily for items which entangle and/or sink, including fishing line, plastic bags, glass and polyethylene terephthalate (PET) bottles. Minimal similarity between land and seafloor surveys occurs for items which float or degrade. We suggest that to accurately evaluate local debris density, land and seafloor surveys are required to gain a holistic understanding. When detailed information on debris type, relative concentration, and likely source and transport are assessed, more cost effective and efficient policy interventions can be designed and implemented from local through to global scales.


Assuntos
Plásticos , Resíduos/análise , Ecossistema , Monitoramento Ambiental , Vidro , Humanos
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