17 research outputs found
Prefeasibility study for the Port of Itajai
No full textIn southern Brazil, in the province of Santa Catarina, the port of Itajai is situated. The port is located at the mouth of the river Itajai-Acu, about 3 km inland. The Port of Itajai is very important for both the local and national economy because of its role in foreign trade, and due to this prominent role in the community many stakeholders are involved. To allow larger vessels into the harbour of Itajai there has been a constant process of deepening the approach channel and the harbour basin. In order to compete sedimentation process in the harbour basin will change. From a commercial point of view it is very interesting to search for other solutions to keep the river at the required depth besides dredging. There are four main principal solutions to reduce the sedimentation of the harbour basin: reduce the sediment production, reduce the transport capacity of the river, increase the flow velocity and redirect the sediment. All these possibilities have a positive effect on the sedimentation in the harbour. Reducing the transport capacity of the river with the use of a sand trap is expected to have the most effect. with surrounding harbours it is important to allow safe navigation of larger vessels as this results in greater cargo handling at lower cost. Due to recent developments the Port of Itajai is investigating the possibility to receive vessels with a length of 300 m overall, 45 m beam and 14 m draught. The Port of Itajai is facing two different kinds of problems, one concerning the alignment and the other concerning sedimentation. In order to deal with the problems the current situation was mapped. The river, sea and harbour characteristics are given; river discharges, flood events, harbour development, harbour lay out, tide, wind and wave direction. At this moment the approach channel of the harbour deals with some imperfections, which makes it difficult, sometimes even impossible, for the design vessel to sail through the channel. Also the current turning circle is a problem as turning of the new design vessel will be extremely difficult and the safety is questionable. With a cost benefit analysis the best possible location for a larger turning basin is determined and a number of changes for the alignment are given. Without human interventions the estuarine system would be in a dynamic equilibrium. The bathymetry would adjust to varying conditions and oscillate around this dynamic equilibrium depth. This is the depth for which the average annual sedimentation is zero. When the natural dynamic equilibrium is disturbed as a result of deepening the estuary, the system will try to restore itself. This causes sedimentation and maintenance dredging is required to maintain the newly dredged areas. The volume of the required maintenance dredging depends on the extent of the disturbance in relation to the equilibrium situation. A larger deepening will lead to smaller flow velocities and therefore to higher sedimentation rates. The sedimentation that occurs in the Itajai Acu estuary is a complex ensemble of processes, which is influenced by processes at the boundary conditions. The two most important processes are the tidal fluctuations and river discharge. To gain insight in the wet system, hand calculations and a 1D-computer model were made. The effect of a number of human interventions on the Itajai-Acu river are determined with hand calculations. With the 1D-modelling software, SOBEK, the effects of the planned dredging are determined.Hydraulic EngineeringCivil Engineering and Geoscience
Detecting clonality in contralateral breast cancers
No full textWhen a second tumor arises in the contralateral breast in a patient with a previous or synchronous breast cancer, it is of clinical importance to determine if this tumor is a new unrelated tumor or a metastasis, i.e. clone, of the primary tumor. A new, unrelated tumor may be treated similarly as the first one since treatment was successful, while a distant metastasis demands a change of therapy and has a more adverse prognosis. In clinic, a second tumor is generally regarded as a new primary. If there is clinical suspicion that the second tumor may be a metastasis, clinico-pathological characteristics of the two tumors are used assess the clonality status. Clinico-pathological characteristics, however, are not reliable predictors to determine if a second tumor is a metastasis. Recent studies have investigated tumor clonality using techniques from molecular genetics. These models appear to perform well, but have several drawbacks.In this thesis a more advanced classification model is being developed that can detect tumor clonality based on SNP array data. For this, two segmentation algorithms, ASCAT and OncoSNP, and two comparison methods, Log LR and adapted SI, have been incorporated. For each tumor, the segmentation algorithms construct a copy number profile based on the SNP array data. Given the copy number profiles, the comparison methods compute a p-value which reflects the probability that a pair is of clonal origin. Both comparison methods are permutation methods which test the null hypothesis of independence against the alternative hypothesis assuming clonality. The proposed model consists of a decision tree which assigns each pair to one of six categories depending on the significance of the four resulting p-values.The model has been tested on 23 fresh frozen pairs by means of expert judgment. The results were promising: the four pairs which were unanimously labeled as clonal by the experts were also regarded as such by the model. No independent pairs were assigned as clonal by the model. Moreover, the decision tree showed to have a higher sensitivity than the clinical assessments as the latter only managed to detect two out of four clonal pairs. A discordance between the clinico-pathological judgments and decision tree results was found for three out of 18 pairs for which both assessments were available.The model appears to be suitable in practice, but is not yet applicable as a stand-alone model. There were two ambiguous pairs which were labeled as independent by the model but for which the experts had varying opinions about the clonality status. Until the ambiguous pairs can be reliably categorized, it is advised to take into account both the model results and clinical assessments when determining tumor clonality. Finally, the performance of the model remains to be tested on FFPE pairs.Applied Mathematic
Pressures in Sand from Waves and Caisson Motion
No full textIn The Netherlands recurring floods have occurred in the southwestern part of the country from infrequent large storm surge from the ocean. The Delta plan was originated to increase the safety against flooding. This resulted in shortening of the coastline by closure of various estuaries, including the Eastern Scheldt estuary. A closure of the large estuary is needed during impending storm surge conditions, which will require a major structure. Gates on the structure will be open to allow for normal tidal action in mild weather. They will be closed when storm surge conditions threaten. A major question for the design of such a large structure is the competency of the sand for providing an adequate foundation. Various methods have been developed for estimating the competency of the sand, including numerical models, which attempt to predict the support conditions. These numerical models have been developed by engineers in The Netherlands. It is customary to question the validity of any numerical model until it has been verified by physical measurements. Therefore, it is desired to provide a validation for the numerical models that predict the dynamic conditions in the sand from waves and structure motion in the Eastern Scheldt region. PURPOSE OF THIS STUDY The purpose of this study is to create a carefully controlled laboratory experiment at large scale which will provide physical measurements to which the numerical models can be compared. A large structure is desired which is subject to large standing waves. The dimensions of the Wave Research Facility at Oregon State University are such that both conditions can be realized. The results of the model study will be compared with predictions from various numerical models by others. The large scale is desired in order to reduce or eliminate scale effects which are known to exist between small model studies and large prototype conditions. SCOPE OF THE WORK A set of thirteen tests were designed for measuring the important parameters which define the support capabilities of the sand. A suitable sand was located near Astoria, Oregon, and a sufficient quantity was trucked to Corvallis. A suitable test sand bed was established on which a caisson was placed. Standing waves were subjected to the caisson and the sand upstream from it and measurements were made of water surface fluctuations, water pressures, caisson motion, pressure fluctuations within the sand, and the porosity of the sand. Details of the experiments are explained later in this report. GENERAL CONCLUSIONS The testing was successful. Three configurations for the caisson and upstream filter were investigated as detailed later in this report. Three separate wave frequencies were studied. The majority of the 36 channels of information were recorded and visual records are included in this report. In addition, analogue and digital records were made on magnetic tape, which are being delivered to the Delft Hydraulics Laboratory with this report
Scanning a DNA molecule for bound proteins using hybrid magnetic and optical tweezers
No full textThe functional state of the genome is determined by its interactions with proteins that bind, modify, and move along the DNA. To determine the positions and binding strength of proteins localized on DNA we have developed a combined magnetic and optical tweezers apparatus that allows for both sensitive and label-free detection. A DNA loop, that acts as a scanning probe, is created by looping an optically trapped DNA tether around a DNA molecule that is held with magnetic tweezers. Upon scanning the loop along the ?-DNA molecule, EcoRI proteins were detected with ?17 nm spatial resolution. An offset of 33±5 nm for the detected protein positions was found between back and forwards scans, corresponding to the size of the DNA loop and in agreement with theoretical estimates. At higher applied stretching forces, the scanning loop was able to remove bound proteins from the DNA, showing that the method is in principle also capable of measuring the binding strength of proteins to DNA with a force resolution of 0.1 pN/[Formula: see text]. The use of magnetic tweezers in this assay allows the facile preparation of many single-molecule tethers, which can be scanned one after the other, while it also allows for direct control of the supercoiling state of the DNA molecule, making it uniquely suitable to address the effects of torque on protein-DNA interactions.BN/BionanoscienceApplied Science
A case-only study to identify genetic modifiers of breast cancer risk for <em>BRCA1/BRCA2</em> mutation carriers
No full text\ua9 2021, The Author(s).Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers
The role of genetic breast cancer susceptibility variants as prognostic factors
No full textRecent genome-wide association studies identified 11 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. We investigated these and 62 other SNPs for their prognostic relevance. Confirmed BC risk SNPs rs17468277 (CASP8), rs1982073 (TGFB1), rs2981582 (FGFR2), rs13281615 (8q24), rs3817198 (LSP1), rs889312 (MAP3K1), rs3803662 (TOX3), rs13387042 (2q35), rs4973768 (SLC4A7), rs6504950 (COX11) and rs10941679 (5p12) were genotyped for 25 853 BC patients with the available follow-up; 62 other SNPs, which have been suggested as BC risk SNPs by a GWAS or as candidate SNPs from individual studies, were genotyped for replication purposes in subsets of these patients. Cox proportional hazard models were used to test the association of these SNPs with overall survival (OS) and BC-specific survival (BCS). For the confirmed loci, we performed an accessory analysis of publicly available gene expression data and the prognosis in a different patient group. One of the 11 SNPs, rs3803662 (TOX3) and none of the 62 candidate/GWAS SNPs were associated with OS and/or BCS at P<0.01. The genotypic-specific survival for rs3803662 suggested a recessive mode of action [hazard ratio (HR) of rare homozygous carriers=1.21; 95% CI: 1.09-1.35, P=0.0002 and HR=1.29; 95% CI: 1.12-1.47, P=0.0003 for OS and BCS, respectively]. This association was seen similarly in all analyzed tumor subgroups defined by nodal status, tumor size, grade and estrogen receptor. Breast tumor expression of these genes was not associated with prognosis. With the exception of rs3803662 (TOX3), there was no evidence that any of the SNPs associated with BC susceptibility were associated with the BC survival. Survival may be influenced by a distinct set of germline variants from those influencing susceptibility. © The Author 2012. Published by Oxford University Press. All rights reserved
Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.
No full textAge at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition
Incorporating progesterone receptor expression into the PREDICT breast prognostic model
No full textBackground: Predict Breast (www.predict.nhs.uk) is an online prognostication and treatment benefit tool for early invasive breast cancer. The aim of this study was to incorporate the prognostic effect of progesterone receptor (PR) status into a new version of PREDICT and to compare its performance to the current version (2.2). Method: The prognostic effect of PR status was based on the analysis of data from 45,088 European patients with breast cancer from 49 studies in the Breast Cancer Association Consortium. Cox proportional hazard models were used to estimate the hazard ratio for PR status. Data from a New Zealand study of 11,365 patients with early invasive breast cancer were used for external validation. Model calibration and discrimination were used to test the model performance. Results: Having a PR-positive tumour was associated with a 23% and 28% lower risk of dying from breast cancer for women with oestrogen receptor (ER)-negative and ER-positive breast cancer, respectively. The area under the ROC curve increased with the addition of PR status from 0.807 to 0.809 for patients with ER-negative tumours (p = 0.023) and from 0.898 to 0. 902 for patients with ER-positive tumours (p = 2.3 x 10(-6)) in the New Zealand cohort. Model calibration was modest with 940 observed deaths compared to 1151 predicted. Conclusion: The inclusion of the prognostic effect of PR status to PREDICT Breast has led to an improvement of model performance and more accurate absolute treatment benefit predic-tions for individual patients. Further studies should determine whether the baseline hazard function requires recalibration. (C) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Genome Instability and Cance
Genetic predisposition to in situ and invasive lobular carcinoma of the breast.
No full textInvasive lobular breast cancer (ILC) accounts for 10-15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI) for ILC = 1.13 (1.09-1.18), P = 6.0 × 10(-10); P-het for ILC vs IDC ER+ tumors = 1.8 × 10(-4)). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P<0.05. Two SNPs showed significantly stronger associations for ILC than LCIS (rs2981579/10q26/FGFR2, P-het = 0.04 and rs889312/5q11/MAP3K1, P-het = 0.03); and two showed stronger associations for LCIS than ILC (rs6678914/1q32/LGR6, P-het = 0.001 and rs1752911/6q14, P-het = 0.04). In addition, seven of the 75 known loci showed significant differences between ER+ tumors with IDC and ILC histology, three of these showing stronger associations for ILC (rs11249433/1p11, rs2981579/10q26/FGFR2 and rs10995190/10q21/ZNF365) and four associated only with IDC (5p12/rs10941679; rs2588809/14q24/RAD51L1, rs6472903/8q21 and rs1550623/2q31/CDCA7). In conclusion, we have identified one novel lobular breast cancer specific predisposition polymorphism at 7q34, and shown for the first time that common breast cancer polymorphisms predispose to LCIS. We have shown that many of the ER+ breast cancer predisposition loci also predispose to ILC, although there is some heterogeneity between ER+ lobular and ER+ IDC tumors. These data provide evidence for overlapping, but distinct etiological pathways within ER+ breast cancer between morphological subtypes
Incorporating progesterone receptor expression into the PREDICT breast prognostic model
No full textPredict Breast (www.predict.nhs.uk) is an online prognostication and treatment benefit tool for early invasive breast cancer. The aim of this study was to incorporate the prognostic effect of progesterone receptor (PR) status into a new version of PREDICT and to compare its performance to the current version (2.2). The prognostic effect of PR status was based on the analysis of data from 45,088 European patients with breast cancer from 49 studies in the Breast Cancer Association Consortium. Cox proportional hazard models were used to estimate the hazard ratio for PR status. Data from a New Zealand study of 11,365 patients with early invasive breast cancer were used for external validation. Model calibration and discrimination were used to test the model performance. Having a PR-positive tumour was associated with a 23% and 28% lower risk of dying from breast cancer for women with oestrogen receptor (ER)-negative and ER-positive breast cancer, respectively. The area under the ROC curve increased with the addition of PR status from 0.807 to 0.809 for patients with ER-negative tumours (p = 0.023) and from 0.898 to 0.902 for patients with ER-positive tumours (p = 2.3 × 10 ) in the New Zealand cohort. Model calibration was modest with 940 observed deaths compared to 1151 predicted. The inclusion of the prognostic effect of PR status to PREDICT Breast has led to an improvement of model performance and more accurate absolute treatment benefit predictions for individual patients. Further studies should determine whether the baseline hazard function requires recalibration. [Abstract copyright: Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.
