Search results for: urban mutations

Authors: Shima Behzadi

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Background: In many human malignant tumors, microRNA expression is aberrant. This study investigates miR-141 as a prognostic marker in colorectal cancer with K-Ras mutation. Materials and methods: In this case-control study, 100 patients, mostly over the age of 50, who were diagnosed with colorectal cancer were selected. The pathology department of the Mostoufi Pathobiology and Genetics Laboratory in Tehran confirmed the presence of colorectal cancer in samples of paraffin-embedded colon tissue. The case group was composed of patients with codon 12 and 13 mutations in exon 2 of the K-Ras gene, while tumor samples of individuals without these mutations in exon 2 of the K-Ras gene were selected as the control group, with patient consent. The changes in the expression of miR-141 were examined in both groups. Results: The study found that 20% of the patients tested positive for codon 12 mutation, and 10% of patients had codon 13 mutation. As a result, in 30 cases, there was a higher level of miR-141 expression. The miR-141 gene expression level in K-Ras positive tumor samples was 1.5 times higher than its expression level in K-Ras negative samples. This increase in expression was statistically significant, with a p-value of less than 0.001, indicating that the observed results are highly statistically significant. Conclusion: The study revealed that the incidence of typical K-Ras gene mutations among the colorectal cancer patients in the sample matches the national average in Iran. Additionally, the expression of miR-141 can serve as a useful biomarker to aid in the prognosis of colorectal cancer.

Keywords: colorectal cancer, K-Ras gene, miR-141 marker, real time PCR, electrophoresis

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Authors: Sungik Kang, Ja-Hoon Koo

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Globally, urban environments have become unequal, and cities have been segmented by income class. It is predicted that urban inequality has arisen by urban redevelopment and reconstruction projects that improve the urban environment and innovate cities. This study aims to analyze the occurrence and characteristics of urban inequality by using the housing price and sale price and demonstrating the correlation with the urban redevelopment project. This study measures 14 years of urban inequality index for 25 autonomous districts in Seoul and analyzes the correlation between urban inequality with urban redevelopment projects. As a conclusion of this study, first, the urban inequality index of Seoul has been continuously rising since 2015. Trends from 2006 to 2019 have been in U-curved shape in between 2015. In 2019, Seoul's urban inequality index was 0.420, a level similar to that of the 2007 financial crisis. Second, the correlation between urban redevelopment and urban inequality was not statistically significant. Therefore, we judged that urban redevelopment's scale or project structure has nothing with urban inequality. Third, while district designation of urban reconstruction temporarily alleviates urban inequality, the completion of the project increases urban inequality. When designating a district, urban inequality is likely to decrease due to decreased outdated housing transactions. However, the correlation with urban inequality increases as expensive houses has been placed after project completion.

Keywords: urban inequality, urban redevelopment projects, urban reconstruction projects, housing price inequality, panel analysis

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Authors: Ian Campbell, Gillian Mitchell, Paul James, Na Li, Ella Thompson

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The genetic cause of the majority of multiple-case breast cancer families remains unresolved. Next generation sequencing has emerged as an efficient strategy for identifying predisposing mutations in individuals with inherited cancer. We are conducting whole exome sequence analysis of germ line DNA from multiple affected relatives from breast cancer families, with the aim of identifying rare protein truncating and non-synonymous variants that are likely to include novel cancer predisposing mutations. Data from more than 200 exomes show that on average each individual carries 30-50 protein truncating mutations and 300-400 rare non-synonymous variants. Heterogeneity among our exome data strongly suggest that numerous moderate penetrance genes remain to be discovered, with each gene individually accounting for only a small fraction of families (~0.5%). This scenario marks validation of candidate breast cancer predisposing genes in large case-control studies as the rate-limiting step in resolving the missing heritability of breast cancer. The aim of this study is to screen genes that are recurrently mutated among our exome data in a larger cohort of cases and controls to assess the prevalence of inactivating mutations that may be associated with breast cancer risk. We are using the Agilent HaloPlex Target Enrichment System to screen the coding regions of 168 genes in 1,000 BRCA1/2 mutation-negative familial breast cancer cases and 1,000 cancer-naive controls. To date, our interim analysis has identified 21 genes which carry an excess of truncating mutations in multiple breast cancer families versus controls. Established breast cancer susceptibility gene PALB2 is the most frequently mutated gene (13/998 cases versus 0/1009 controls), but other interesting candidates include NPSR1, GSN, POLD2, and TOX3. These and other genes are being validated in a second cohort of 1,000 cases and controls. Our experience demonstrates that beyond PALB2, the prevalence of mutations in the remaining breast cancer predisposition genes is likely to be very low making definitive validation exceptionally challenging.

Keywords: predisposition, familial, exome sequencing, breast cancer

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Authors: Mouhoubi Nedjima, Sassi Boudemagh Souad

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In this paper, we will try to demonstrate the importance of the project approach in the urban to deal with uncertainty, the importance of the involvement of all stakeholders in the urban project process and that the absence of an actor can lead to project failure but also the importance of the urban project management. These points are handled through the following questions: Does the urban adhere to the theory of complexity? Does the project approach bring hope and solution to make urban planning "sustainable"? How converging visions of actors for the same project? Is the management of urban project the solution to support the urban project approach?

Keywords: strategic planning, project, urban project stakeholders, management

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Authors: Gail Louw, Helena Boshoff, Taeksun Song, Clifton Barry

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Drug resistance in Mycobacterium tuberculosis is primarily attributed to mutations in target genes. These mutations incur a fitness cost and result in bacterial generations that are less fit, which subsequently acquire compensatory mutations to restore fitness. We hypothesize that mutations in specific drug target genes influence bacterial metabolism and cellular function, which affects its ability to develop subsequent resistance to additional agents. We aim to determine whether the sequential acquisition of drug resistance and specific mutations in a well-defined clinical M. tuberculosis strain promotes or limits the development of additional resistance. In vitro mutants resistant to pretomanid, linezolid, moxifloxacin, rifampicin and kanamycin were generated from a pan-susceptible clinical strain from the Beijing lineage. The resistant phenotypes to the anti-TB agents were confirmed by the broth microdilution assay and genetic mutations were identified by targeted gene sequencing. Growth of mono-resistant mutants was done in enriched medium for 14 days to assess in vitro fitness. Double resistant mutants were generated against anti-TB drug combinations at concentrations 5x and 10x the minimum inhibitory concentration. Subsequently, mutation frequencies for these anti-TB drugs in the different mono-resistant backgrounds were determined. The initial level of resistance and the mutation frequencies observed for the mono-resistant mutants were comparable to those previously reported. Targeted gene sequencing revealed the presence of known and clinically relevant mutations in the mutants resistant to linezolid, rifampicin, kanamycin and moxifloxacin. Significant growth defects were observed for mutants grown under in vitro conditions compared to the sensitive progenitor. Mutation frequencies determination in the mono-resistant mutants revealed a significant increase in mutation frequency against rifampicin and kanamycin, but a significant decrease in mutation frequency against linezolid and sutezolid. This suggests that these mono-resistant mutants are more prone to develop resistance to rifampicin and kanamycin, but less prone to develop resistance against linezolid and sutezolid. Even though kanamycin and linezolid both inhibit protein synthesis, these compounds target different subunits of the ribosome, thereby leading to different outcomes in terms of fitness in the mutants with impaired cellular function. These observations showed that oxazolidinone treatment is instrumental in limiting the development of multi-drug resistance in M. tuberculosis in vitro.

Keywords: oxazolidinones, mutations, resistance, tuberculosis

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Authors: Fouad Chebib, Marie Hogan, Ziad El-Zoghby, Maria Irazabal, Sarah Senum, Christina Heyer, Charles Madsen, Emilie Cornec-Le Gall, Atta Behfar, Barbara Ehrlich, Peter Harris, Vicente Torres

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Background: Mutations in PKD1 and PKD2, the genes encoding the proteins polycystin-1 (PC1) and polycystin-2 (PC2) cause autosomal dominant polycystic kidney disease (ADPKD). ADPKD is a systemic disease associated with several extrarenal manifestations. Animal models have suggested an important role for the polycystins in cardiovascular function. The aim of the current study is to evaluate the association of various cardiomyopathies in a large cohort of patients with ADPKD. Methods: Clinical data was retrieved from medical records for all patients with ADPKD and cardiomyopathies (n=159). Genetic analysis was performed on available DNA by direct sequencing. Results: Among the 58 patients included in this case series, 39 patients had idiopathic dilated cardiomyopathy (IDCM), 17 had hypertrophic obstructive cardiomyopathy (HOCM), and 2 had left ventricular noncompaction (LVNC). The mean age at cardiomyopathy diagnosis was 53.3, 59.9 and 53.5 years in IDCM, HOCM and LVNC patients respectively. The median left ventricular ejection fraction at initial diagnosis of IDCM was 25%. Average basal septal thickness was 19.9 mm in patients with HOCM. Genetic data was available in 19, 8 and 2 cases of IDCM, HOCM, and LVNC respectively. PKD1 mutations were detected in 47.4%, 62.5% and 100% of IDCM, HOCM and LVNC cases. PKD2 mutations were detected only in IDCM cases and were overrepresented (36.8%) relative to the expected frequency in ADPKD (~15%). The prevalence of IDCM, HOCM, and LVNC in our ADPKD clinical cohort was 1:17, 1:39 and 1:333 respectively. When compared to the general population, IDCM and HOCM was approximately 10-fold more prevalent in patients with ADPKD. Conclusions: In summary, we suggest that PKD1 or PKD2 mutations may predispose to idiopathic dilated or hypertrophic cardiomyopathy. There is a trend for patients with PKD2 mutations to develop the former and for patients with PKD1 mutations to develop the latter. Predisposition to various cardiomyopathies may be another extrarenal manifestation of ADPKD.

Keywords: autosomal dominant polycystic kidney (ADPKD), polycystic kidney disease, cardiovascular, cardiomyopathy, idiopathic dilated cardiomyopathy, hypertrophic cardiomyopathy, left ventricular noncompaction

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Authors: Feng Ji Mervin Goh, Edmund Chee Jian Pua, Stuart Alexander Cook

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Dilated cardiomyopathy (DCM) is a common cause of heart failure. Genetic mutations account for 50% of DCM cases with TTN mutations being the most common, accounting for up to 25% of DCM cases. However, the genetic architecture underlying Asian DCM patients is unknown. We evaluated 68 patients (female= 17) with DCM who underwent follow-up at the National Heart Centre, Singapore from 2013 through 2014. Clinical data were obtained and analyzed retrospectively. Genomic DNA was subjected to next-generation targeted sequencing. Nextera Rapid Capture Enrichment was used to capture the exons of a panel of 169 cardiac genes. DNA libraries were sequenced as paired-end 150-bp reads on Illumina MiSeq. Raw sequence reads were processed and analysed using standard bioinformatics techniques. The average age of onset of DCM was 46.1±10.21 years old. The average left ventricular ejection fraction (LVEF), left ventricular diastolic internal diameter (LVIDd), left ventricular systolic internal diameter (LVIDs) were 26.1±11.2%, 6.20±0.83cm, and 5.23±0.92cm respectively. The frequencies of mutations in major DCM-associated genes were as follows TTN (5.88% vs published frequency of 20%), LMNA (4.41% vs 6%), MYH7 (5.88% vs 4%), MYH6 (5.88% vs 4%), and SCN5a (4.41% vs 3%). The average callability at 10 times coverage of each major gene were: TTN (99.7%), LMNA (87.1%), MYH7 (94.8%), MYH6 (95.5%), and SCN5a (94.3%). In conclusion, TTN mutations are not common in Singaporean DCM patients. The frequencies of other major DCM-associated genes are comparable to frequencies published in the current literature.

Keywords: heart failure, dilated cardiomyopathy, genetics, next-generation sequencing

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Authors: Gan Lu, Xu Lei

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This is an era when urban village is disappearing in China. A series of social phenomenon presented in post-urban village era is forcing rethinking of the future of urban village. Existing monotonous urban renewal mode based on gentrification is questioned, and the social values of urban village has been gaining increasing attention while the daily life and spatial power of underclass is being focused on. Based on the consensus on the positive meaning of urban village phenomenon, social sectors have taken amount of improvement experiments to explore the possibility of modern transition of urban village on the premise of existence. These experiments revealed that urban tremendous changes impact a lot on social daily life, and pointed out that it is necessary to bring up the responsibility of architects and the definition of urban for discussion again.

Keywords: post-urban village era, gentrification, social value, daily life, improvement experiment.

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Authors: Svetlana Zhikrivetskaya, Nataliya Shirokova, Roman Bikanov, Elizaveta Musatova, Yana Kovaleva, Nataliya Vetrova, Ekaterina Pomerantseva

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Nowadays there is a growing number of couples with conceiving problems due to male or female infertility. Genetic abnormalities are responsible for about 31% of all cases of male infertility. These abnormalities include both chromosomal aberrations or aneuploidies and mutations in certain genes. Chromosomal abnormalities can be easily identified, thus the development of screening panels able to reveal genetic reasons of male infertility on gene level is of current interest. There are approximately 2,000 genes involved in male fertility that is the reason why it is very important to determine the most clinically relevant in certain population and ethnic conditions. An infertility screening panel containing 48 mutations in genes AMHR2, CFTR, DNAI1, HFE, KAL1, TSSK2 and AZF locus which are the most clinically relevant for the European population according to databases NCBI and ClinVar was designed. The aim of this research was to confirm clinic relevance of these mutations in the Russian population. Genotyping was performed in 220 patients with different types of male infertility and in 57 healthy males with normozoospermia. Mutations were identified by end-point PCR with TaqMan probes in microfluidic plates. The frequency of 5 mutations in healthy males and 13 mutations in patients with infertility was revealed and estimated. The frequency of mutation c.187C>G in HFE gene was significantly lower for healthy males (8.8%) compared with patients (17.7%) and the values for the European population according to ExAc database (13.7%) and dbSNP (17.2%). Analysis of c.3454G>C, and c.1545_1546delTA mutations in the CFTR gene revealed increased frequency (0.9 and 0.2%, respectively) in patients with infertility compared with data for the European population (0.04%, respectively (ExAc, European (Non-Finnish) and for the Aggregated Populations (0.002% (ExAc), because there is no data for European population for c.1545_1546delTA mutation. The frequency of del508 mutation (CFTR) in patients (1.59%) were lower comparing with male infertility Europeans (3.34-6.25% depending on nationality) and at the same level with healthy Europeans (1.06%, ExAc, European (Non-Finnish). Analysis of c.845G>A (HFE) mutation resulted in decreased frequency in patients (1.8%) in contrast with the European population data (5.1%, respectively, ExAc, European (Non-Finnish). Moreover, obtained data revealed no statistically significant frequency difference for c.845G>A mutation (HFE) between healthy males in the Russian and the European populations. Allele frequencies of mutations c.350G>A (CFTR), c.193A>T (HFE), c.774C>T, and c.80A>G (gene TSSK2) showed no significantly difference among patients with infertility, healthy males and Europeans. Analysis of AZF locus revealed increased frequency for AZFc microdeletion in patients with male infertility. Thereby, the new data of the allele frequencies in infertility patients in the Russian population was obtained. As well as the frequency differences of mutations associated with male infertility among patients, healthy males in the Russian population and the European one were estimated. The revealed differences showed that for high effectiveness of screening panel detecting genetically caused male infertility it is very important to consider ethnic and population characteristics of patients which will be screened.

Keywords: allele frequency, azoospermia, male infertility, mutation, population

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Authors: Xindong An, Kai Gu

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Urban intensification is regarded as the prevalent strategy in many cities of the world to ease the pressures of urban sprawl and deliver sustainable development through increasing the density of built form and activities. However, within the context of intensive development, planning and design control measures that help to maintain and promote the character of existing residential environments have been slow to develop. This causes the possible loss of the character of an area that makes a place unique and distinctive. The purpose of this paper is to explore the way of identifying the character of an urban area for the planning of urban landscape in the implementation of intensification. By employing the theory of urban morphology, the concept of morphological region is used for the analysis and characterisation of the spatial structure of the urban landscape in terms of ground plans, building types, and building and land utilisation. The morphological mapping of the character of urban landscape is suggested, which lays a foundation for more sensitive planning of urban landscape changes.

Keywords: character areas, urban intensification, urban morphology, urban landscape

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Authors: Markus Bredel, Sindhu Nair, Hoa Q. Trummell, Rajani Rajbhandari, Christopher D. Willey, Lewis Z. Shi, Zhuo Zhang, William J. Placzek, James A. Bonner

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Purpose: EGFR-targeted monoclonal antibodies (mAbs) provide clinical benefit in some patients with H&N squamous cell carcinoma (HNSCC), but others progress with minimal response. Missense mutations in the EGFR ectodomain (ECD) can be acquired under mAb therapy by mimicking the effect of large deletions on receptor untethering and activation. Little is known about the contribution of EGFR ECD mutations to EGFR activation and anti-EGFR response in HNSCC. Methods: We selected patient-derived HNSCC cells (UM-SCC-1) for resistance to mAb Cetuximab (CTX) by repeated, stepwise exposure to mimic what may occur clinically and identified two concurrent EGFR ECD mutations (UM-SCC-1R). We examined the competence of the mutants to bind EGF ligand or CTX. We assessed the potential impact of the mutations through visual analysis of space-filling models of the native sidechains in the original structures vs. their respective side-chain mutations. We performed CRISPR in combination with site-directed mutagenesis to test for the effect of the mutants on ligand-independent EGFR activation and sorting. We determined the effects on receptor internalization, endocytosis, downstream signaling, and radiation sensitivity. Results: UM-SCC-1R cells carried two non-synonymous missense mutations (G33S and N56K) mapping to domain I in or near the EGF binding pocket of the EGFR ECD. Structural modeling predicted that these mutants restrict the adoption of a tethered, inactive EGFR conformation while not permitting association of EGFR with the EGF ligand or CTX. Binding studies confirmed that the mutant, untethered receptor displayed a reduced affinity for both EGF and CTX but demonstrated sustained activation and presence at the cell surface with diminished internalization and sorting for endosomal degradation. Single and double-mutant models demonstrated that the G33S mutant is dominant over the N56K mutant in its effect on EGFR activation and EGF binding. CTX-resistant UM-SCC-1R cells demonstrated cross-resistance to mAb Panitumuab but, paradoxically, remained sensitive to the reversible receptor tyrosine kinase inhibitor Erlotinib. Conclusions: HNSCC cells can select for EGFR ECD mutations under EGFR mAb exposure that converge to trap the receptor in an open, constitutively activated state. These mutants impede the receptor’s competence to bind mAbs and EGF ligand and alter its endosomal trafficking, possibly explaining certain cases of clinical mAb and radiation resistance.

Keywords: head and neck cancer, EGFR mutation, resistance, cetuximab

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Authors: Zoe Goldberger, Priscilla S. Briquez, Jeffrey A. Hubbell

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Tumor cells have mutations resulting from genetic instability that the immune system can actively recognize. Immune checkpoint immunotherapy (ICI) is commonly used in the clinic to re-activate immune reactions against mutated proteins, called neoantigens, resulting in tumor remission in cancer patients. However, only around 20% of patients show durable response to ICI. While tumor mutational burden (TMB) has been approved by the Food and Drug Administration (FDA) as a criterion for ICI therapy, the relevance of the subcellular localizations of the mutated proteins within the tumor cell has not been investigated. Here, we hypothesized that localization of mutations impacts the effect of immune responsiveness to ICI. We analyzed publicly available tumor mutation sequencing data of ICI treated patients from 3 independent datasets. We extracted the subcellular localization from the UniProtKB/Swiss-Prot database and quantified the proportion of membrane, cytoplasmic, nuclear, or secreted mutations per patient. We analyzed this information in relation to response to ICI treatment and overall survival of patients showing with 1722 ICI-treated patients that high mutational burden localized at the membrane (mTMB), correlate with ICI responsiveness, and improved overall survival in multiple cancer types. We anticipate that our results will ameliorate predictability of cancer patient response to ICI with potential implications in clinical guidelines to tailor ICI treatment. This would not only increase patient survival for those receiving ICI, but also patients’ quality of life by reducing the number of patients enduring non-effective ICI treatments.

Keywords: cancer, immunotherapy, membrane neoantigens, efficacy prediction, biomarkers

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Authors: N. C. van der Merwe, J. Oosthuizen, M. F. Makhetha, J. Adams, B. K. Dajee, S-R. Schneider

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Women representing high-risk breast cancer families, who tested negative for pathogenic mutations in BRCA1 and BRCA2, are four times more likely to develop breast cancer compared to women in the general population. Sequencing of genes involved in genomic stability and DNA repair led to the identification of novel contributors to familial breast cancer risk. These include BLM and PALB2. Bloom's syndrome is a rare homozygous autosomal recessive chromosomal instability disorder with a high incidence of various types of neoplasia and is associated with breast cancer when in a heterozygous state. PALB2, on the other hand, binds to BRCA2 and together, they partake actively in DNA damage repair. Archived DNA samples of 66 BRCA1/2 negative high-risk breast cancer patients were retrospectively selected based on the presence of an extensive family history of the disease ( > 3 affecteds per family). All coding regions and splice-site boundaries of both genes were screened using High-Resolution Melting Analysis. Samples exhibiting variation were bi-directionally automated Sanger sequenced. The clinical significance of each variant was assessed using various in silico and splice site prediction algorithms. Comprehensive screening identified a total of 11 BLM and 26 PALB2 variants. The variants detected ranged from global to rare and included three novel mutations. Three BLM and two PALB2 likely pathogenic mutations were identified that could account for the disease in these extensive breast cancer families in the absence of BRCA mutations (BLM c.11T > A, p.V4D; BLM c.2603C > T, p.P868L; BLM c.3961G > A, p.V1321I; PALB2 c.421C > T, p.Gln141Ter; PALB2 c.508A > T, p.Arg170Ter). Conclusion: The study confirmed the contribution of pathogenic mutations in BLM and PALB2 to the familial breast cancer burden in South Africa. It explained the presence of the disease in 7.5% of the BRCA1/2 negative families with an extensive family history of breast cancer. Segregation analysis will be performed to confirm the clinical impact of these mutations for each of these families. These results justify the inclusion of both these genes in a comprehensive breast and ovarian next generation sequencing cancer panel and should be screened simultaneously with BRCA1 and BRCA2 as it might explain a significant percentage of familial breast and ovarian cancer in South Africa.

Keywords: Bloom Syndrome, familial breast cancer, PALB2, South Africa

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Authors: Wen-Yang Hu, Ranli Lu, Mark Maienschein-Cline, Danping Hu, Larisa Nonn, Toshi Shioda, Gail S. Prins

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Background: Genetic mutations are highly associated with increased prostate cancer risk. In addition to whole genome sequencing, somatic mutations can be identified by aligning transcriptome sequences to the human genome. Here we analyzed bulk RNAseq and single cell RNAseq data of human prostate cancer cells and their matched non-cancer cells in benign regions from 4 individual patients. Methods: Sequencing raw reads were aligned to the reference genome hg38 using STAR. Variants were annotated using Annovar with respect to overlap gene annotation information, effect on gene and protein sequence, and SIFT annotation of nonsynonymous variant effect. We determined cancer-specific novel alleles by comparing variant calls in cancer cells to matched benign cells from the same individual by selecting unique alleles that were only detected in the cancer samples. Results: In bulk RNAseq data from 3 patients, the most common variants were the noncoding mutations at UTR3/UTR5, and the major variant types were single-nucleotide polymorphisms (SNP) including frameshift mutations. C>T transversion is the most frequently presented substitution of SNP. A total of 222 genes carrying unique exonic or UTR variants were revealed in cancer cells across 3 patients but not in benign cells. Among them, transcriptome levels of 7 genes (CITED2, YOD1, MCM4, HNRNPA2B1, KIF20B, DPYSL2, NR4A1) were significantly up or down regulated in cancer stem cells. Out of the 222 commonly mutated genes in cancer, 19 have nonsynonymous variants and 11 are damaged genes with variants including SIFT, frameshifts, stop gain/loss, and insertions/deletions (indels). Two damaged genes, activating transcription factor 6 (ATF6) and histone demethylase KDM3A are of particular interest; the former is a survival factor for certain cancer cells while the later positively activates androgen receptor target genes in prostate cancer. Further, single cell RNAseq data of cancer cells and their matched non-cancer benign cells from both primary 2D and 3D tumoroid cultures were analyzed. Similar to the bulk RNAseq data, single cell RNAseq in cancer demonstrated that the exonic mutations are less common than noncoding variants, with SNPs including frameshift mutations the most frequently presented types in cancer. Compared to cancer stem cell enriched-3D tumoroids, 2D cancer cells carried 3-times higher variants, 8-times more coding mutations and 10-times more nonsynonymous SNP. Finally, in both 2D primary and 3D tumoroid cultures, cancer stem cells exhibited fewer coding mutations and noncoding SNP or insertions/deletions than non-stem cancer cells. Summary: Our study demonstrates the usefulness of bulk and single cell RNAseaq data in identifying somatic mutations in prostate cancer, providing an alternative method in screening candidate genes for prostate cancer diagnosis and potential therapeutic targets. Cancer stem cells carry fewer somatic mutations than non-stem cancer cells due to their inherited immortal stand DNA from parental stem cells that explains their long-lived characteristics.

Keywords: prostate cancer, stem cell, genomic mutation, RNAseq

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Authors: Michael Stewart

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Mutation testing is a type of software testing proposed in the 1970s where program statements are deliberately changed to introduce simple errors so that test cases can be validated to determine if they can detect the errors. Test cases are executed against the mutant code to determine if one fails, detects the error and ensures the program is correct. One major issue with this type of testing was it became intensive computationally to generate and test all possible mutations for complex programs. This paper used reinforcement learning and parallel processing within the context of mutation testing for the selection of mutation operators and test cases that reduced the computational cost of testing and improved test suite effectiveness. Experiments were conducted using sample programs to determine how well the reinforcement learning-based algorithm performed with one live mutation, multiple live mutations and no live mutations. The experiments, measured by mutation score, were used to update the algorithm and improved accuracy for predictions. The performance was then evaluated on multiple processor computers. With reinforcement learning, the mutation operators utilized were reduced by 50 – 100%.

Keywords: automated-testing, machine learning, mutation testing, parallel processing, reinforcement learning, software engineering, software testing

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Authors: Samira Ghasempourkazemi

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In terms of the COVID-19 pandemic, lots of mutations in the urban system, which have systemic impacts, have clearly appeared. COVID-19 not only had a direct impact on health but also caused significant losses to other departments, including the economy, education, tourism, environment and the construction industry. Therefore, the pandemic caused a disruption in the whole urban system. Particularly, today’s large urban areas are not designed in order to be compatible during a pandemic. Hence, cities are more vulnerable to infectious disease threats according to the population density, built environment and socioeconomic aspects. Considering the direct relationship between population and rate of infection, higher rates are given to those individuals located in areas with high-density populations. Population density can be a factor that seems to have a strong impact on the spread of infectious diseases. Thus, the preliminary hypothesis can be related to a densely populated areas which become hotspots for the rapid spread of the pandemic due to high levels of interaction. In addition, some other indicators can be effective in this condition, such as age range, education and socio-economy. To figure out the measure of infectious disease risk in densely populated areas in Istanbul is an objective of this study. Besides, this study intends to figure out Vulnerability Index in the case of COVID-19. In order to achieve the proper result, the considered method can be Analytic Hierarchy Process (AHP) by involving the mentioned variables. In the end, the study represents the COVID Vulnerability of densely populated areas in a metro city and the gaps that need to be identified and plugged for the pandemic-resilience city of tomorrow.

Keywords: infectious disease, COVID-19, urban system, densely populated area

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Authors: Dimitrios Triantakonstantis, Demetris Stathakis

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Urban areas have been expanded throughout the globe. Monitoring and modeling urban growth have become a necessity for a sustainable urban planning and decision making. Urban prediction models are important tools for analyzing the causes and consequences of urban land use dynamics. The objective of this research paper is to analyze and model the urban change, which has been occurred from 1990 to 2000 using CORINE land cover maps. The model was developed using drivers of urban changes (such as road distance, slope, etc.) under an Artificial Neural Network modeling approach. Validation was achieved using a prediction map for 2006 which was compared with a real map of Urban Atlas of 2006. The accuracy produced a Kappa index of agreement of 0,639 and a value of Cramer's V of 0,648. These encouraging results indicate the importance of the developed urban growth prediction model which using a set of available common biophysical drivers could serve as a management tool for the assessment of urban change.

Keywords: artificial neural networks, CORINE, urban atlas, urban growth prediction

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Authors: Tanushree Jaitly, Shailendra Gupta, Leila Taher, Gerold Schuler, Julio Vera

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Genomics-based personalized medicine is a promising approach to fight aggressive tumors based on patient's specific tumor mutation and expression profiles. A remarkable case is, dendritic cell-based immunotherapy, in which tumor epitopes targeting patient's specific mutations are used to design a vaccine that helps in stimulating cytotoxic T cell mediated anticancer immunity. Here we present a computational pipeline for epitope-based personalized cancer vaccines using patient-specific haplotype and cancer mutation profiles. In the workflow proposed, we analyze Whole Exome Sequencing and RNA Sequencing patient data to detect patient-specific mutations and their expression level. Epitopes including the tumor mutations are computationally predicted using patient's haplotype and filtered based on their expression level, binding affinity, and immunogenicity. We calculate binding energy for each filtered major histocompatibility complex (MHC)-peptide complex using docking studies, and use this feature to select good epitope candidates further.

Keywords: cancer immunotherapy, epitope prediction, NGS data, personalized medicine

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Authors: Sun Ailu, Zhao Wanmin

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In the process of rapid urbanization, old urban renewal is an important task in China's urban construction. This study, using status survey and Analytic Hierarchy Process (AHP) method, taking Chongqing of China as an example, puts forward the problems faced by the old urban area from the aspects of function, facilities and environment. Further, this study summarizes the types of the old urban area and proposes space renewal strategies for three typical old urban areas, such as old residential area, old factory and old market. These old urban areas are confronted with the problems of functional layout confounding, lack of infrastructure and poor living environment. At last, this paper proposes spatial strategies for urban renewal, which are hoped to be useful for urban renewal management in China.

Keywords: old urban renewal, renewal mode, renewal strategy, Chongqing, China

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Authors: Hong Chen, Li Heping

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China's urbanization rate has exceeded 60%, and in the long term, China's urbanization development will enter a new stage of transformation and development focusing on quality improvement, and urban renewal has become an important part of China's urban development. In the past, many cities in the process of renewal in order to maximize the pursuit of economic interests, large-scale demolition of the old to build new, accelerating the disappearance of regional history and culture, aggravating the homogenization of the city. With the changes in the economic and social development environment, urban renewal requires a more comprehensive perspective of action. Starting from the perspective of the core of urban management theory, this paper is oriented to culture-enabled urban renewal and takes the urban renewal of Changbin Road Area in Yuzhong District of Chongqing as an example to expound the problems and renewal strategies in its urban renewal, so as to provide references for the urban renewal of other Chinese cities in the new period.

Keywords: Urban management, Urban culture, Urban renewal in mountainous areas, urban renewal

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Authors: N. R. Ramkumar

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The foremost aim of physical education has been to inculcate a healthy mind in a healthy body. The aim of this study was to find out the differences in nutritional awareness among urban, semi urban and rural girls of South India. The investigator administered a nutritional awareness questionnaire consisting of 25 statements among 100 rural; 100 semi urban and 100 urban girls studying in different schools in South India. The filled up questionnaire were scored and the total scores for all the twenty five statements were considered as the nutritional awareness level of the subjects. The differences on nutritional awareness among urban, semi urban and rural girls were tested for statistical significance using ANOVA. In all cases 0.05 level was fixed to test the significance. The results proved that there were significant differences on nutritional awareness among urban, semi urban and rural girls (P<0.05). The paired mean comparisons proved that urban girls were having highest nutritional awareness (M: 86.86), followed by semi urban girls (M: 81.86) and then by rural girls (M: 79.48). The differences between urban and semi urban girls and urban and rural girls were significant and there was no significant differences between semi urban and rural girls. The findings of this study proved that rural girls were significantly having lesser nutritional awareness and hence the study recommends the strong need of nutritional education for rural girls in South India.

Keywords: nutrition, awareness, urban, semi urban, rural girls

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Authors: Zeynep Yazgan, Gökhan Aygün, Reyhan Çalışkan

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Objective: Invasive fungal infections are a serious threat in terms of morbidity and mortality, especially in immunocompromised patients. The most frequently isolated agents are Aspergillus genus fungi, and sensitivity to azoles, which are the first choice in treatment, decreases. In our study, we aimed to investigate the use of the agar plate screening method as a fast, easy, and practical method in determining azole resistance in Aspergillus spp. species. Methods: Our study was conducted with 125 Aspergillus spp. isolates produced from various clinical samples. Aspergillus spp. isolates were identified by conventional methods and azole resistance was determined by gradient test and agar plate screening method. Broth microdilution method was applied to resistant isolates, and CypA-L98H and CypA-M220 mutations in the cyp51A gene were investigated. Results: In our study, 55 A. fumigatus complex (44%), 42 A. flavus (33.6%), 6 A. terreus (5%), 4 A. niger (3%) and 18 Aspergillus spp. (14%) were identified. With the gradient test method, resistance to VOR and POS was detected in 1 (1.8%) of A.fumigatus isolates, and resistance to ITR was detected in 3 (5.45%). With the agar plate method, 1 of the A.fumigatus isolates (1.8%) had VOR, ITR, POS, 1 of the A.terreus isolates (16.7%) had VOR, 1 of the A.niger isolates (25%) had ITR. Resistance to VOR and POS was detected in 2 Aspergillus spp. isolates (11%), and resistance to ITR was detected in 1 (5.6%). Sensitivity and specificity were determined as 100% for VOR and POS in A. fumigatus species, 33.3% and 100% for ITR, respectively, 100% for ITR in A. flavus species, and 100% for ITR and POS in A. terreus species. By broth microdilution method in 7 isolates in which resistance was detected by gradient test and/or agar plate screening method; 1 A.fumigatus resistant to ITR, VOR, POS, 2 A.fumigatus resistant to ITR, 2 Aspergillus spp. ITR, VOR, POS MICs were determined as 2µg/ml and 8µg/ml, 8µg/ml and >32µg/ml, 0.5µg/ml and 4µg/ml, respectively. CypA-L98H mutations were detected in 5 of these isolates, CypA-M220 mutations were detected in 6, and no mutation was detected in 1. CypA-L98H and CypA-M220 mutations were detected in 1 isolate for which resistance was not detected. Conclusion: The need for rapid antifungal susceptibility screening tests is increasing in the treatment of aspergillosis. Although the sensitivity of the agar plate method was determined to be 33.3% for A.fumigatus ITR in our study, its sensitivity and specificity were determined to be 100% for ITR, VOR, and POS in other species. The low sensitivity value detected for A.fumigatus showed that agar plate drug concentrations should be updated in accordance with the latest regulations of EUCAST guidelines. The CypA-L98H and CypA-M220 mutations detected in our study suggested that the distribution of azole resistance-related mutations in different regions in our country should be investigated. In conclusion, it is thought that the agar plate method, which can be easily applied to detect azole resistance, is a fast and practical method in routine use and can contribute to both the determination of effective treatment strategies and the generation of epidemiological data.

Keywords: Aspergillus, agar plate, azole resistance, cyp51A, cypA-L98H, cypA-M220

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Authors: Saima Saleem, Zubair Abbasi, Abdul Hameed, Mansoor Ahmed Khan, Navid Rashid Qureshi, Abid Azhar

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Oral Squamous Cell Carcinoma (OSCC) is the leading cause of death in the developing countries like Pakistan. This problem aggravates because of the excessive use of available chewing products. In spite of widespread information on their use and purported legislations against their use the Pakistani markets are classical examples of selling chewable carcinogenic mutagens. Reported studies indicated that these products are rich in reactive oxygen species (ROS) and polyphenols. TP53 gene is involved in the suppression of tumor. It has been reported that somatic mutations caused by TP53 gene are the foundation of the cancer. This study aims to find the loss of TP53 functions due to mutation/polymorphism caused by genomic alteration and interaction with tobacco and its related ingredients. Total 260 tissues and blood specimens were collected from OSCC patients and compared with age and sex matched controls. Mutations in exons 2-11 of TP53 were examined by PCR-SSCP. Samples showing mobility shift were directly sequenced. Two mutations were found in exon 4 at nucleotide position 108 and 215 and one in exon 7 at nucleotide position 719 of the coding sequences in patient’s tumor samples. These results show that substitution of proline with arginine at codon 72 and serine with threonine at codon 240 of p53 protein. These polymorphic changes, found in tumor samples of OSCC, could be involved in loss of heterozygocity and apoptotic activity in the binding domain of TP53. The model of the mutated TP53 gene elaborated a nonfunctional unfolded p53 protein, suggesting an important role of these mutations in p53 protein inactivation and malfunction. This nonfunctional 3D model also indicates that exogenous tobacco related carcinogens may act as DNA-damaging agents affecting the structure of DNA. The interpretations could be helpful in establishing the pathways responsible for tumor formation in OSCC patients.

Keywords: TP53 mutation/polymorphism, OSCC, PCR-SSCP, direct DNA sequencing, 3D structure

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Authors: Najmehossadat Enjoo

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Beautification means all mindfully measurements to improve quality of urban environment which makes the city more suitable for its inhabitants' life. Purpose of beautification is to provide an environment in which all citizens take pleasure. Beautification aims at urban environment's quality improvement. In space among buildings and constructions some supplementary elements are required to furnish urban life; equipment like house furniture makes life possible in a space surrounded with stones, concrete, and glass. Such elements regulate the flow of movement, rest, recreation and stress in a city and exhilarate it. Urban furniture is the common term used for such facilities and capabilities. Nowadays, experience and application of urban elements have proved that to what extent using proper equipment and furniture can positively affect the citizens and users of urban environments.

Keywords: urban servitudes, urban design, urban furniture, visage of city

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Authors: K. C. Tanuja, Mamatha P. Raj

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Urbanisation is happening rapidly all over the world. As population increasing in the urban settlements, its required to provide quality of life to all the inhabitants who live in. Urban design is a place making strategic planning. Urban design principles promote visualising any place environmentally, socially and economically viable. Urban design strategies include building mass, transit development, economic viability and sustenance and social aspects.

Keywords: livable streets, social interaction, pedestrian use, urban design

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Authors: Yuheng Tao

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Rapid urbanization has brought the consequences of incompatible and excessive homogeneity of urban system, and urban color planning has become one of the most effective ways to restore the characteristics of cities. Among the many urban color design research, the establishment of urban theme colors has rarely been discussed. This study took the "New Taipei City Environmental Aesthetic Color” project as a research case and conducted mixed-method research that included expert interviews and quantitative survey data. This study introduces how theme colors were selected by the experts and investigates public’s perception and preference of the selected theme colors. Several findings include 1) urban memory plays a significant role in determining urban theme colors; 2) When establishing urban theme colors, areas/cities with relatively weak urban memory are given priority to be defined; 3) Urban theme colors that imply cultural attributes are more widely accepted by the public; 4) A representative city theme color helps conserve culture rather than guiding innovation. In addition, this research rearranges the urban color symbolism and specific content of urban theme colors and provides a more scientific urban theme color selection scheme for urban planners.

Keywords: urban theme color, urban color attribute, public perception, public preferences

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Authors: R. R. Govind

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In the digital age, artificial intelligence (AI) is having a significant impact on the rapid changes that cities are experiencing. This study explores the profound impact of AI on urban morphology, especially with regard to promoting friendly design choices. It addresses a significant research gap by examining the real-world effects of integrating AI into urban design and management. The main objective is to outline a framework for integrating AI to transform urban settings. The study employs an urban design framework to effectively navigate complicated urban environments, emphasize the need for urban management, and provide efficient planning and design strategies. Taking Gangtok's informal settlements as a focal point, the study employs AI methodologies such as machine learning, predictive analytics, and generative AI to tackle issues of 'urban informality'. The insights garnered not only offer valuable perspectives but also unveil AI's transformative potential in addressing contemporary urban challenges.

Keywords: urban design, artificial intelligence, urban challenges, machine learning, urban informality

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Authors: Fiona Lord

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This paper presents research on strengthening urban governance and planning practices for sustainable and regenerative city transformations looking at urban governance in Cambodia as a case study. Transformations to urban sustainability and regeneration require systemic and long-term transformation processes, across multiple levels of society and inclusive of multiple urban actors. This paper presents the emerging findings of a qualitative case study comparing the urban governance and planning practices in two of Cambodia's secondary cities - Battambang and Sihanoukville. The lessons learned have broader implications for how governance and planning can be strengthened to initiate and sustain urban sustainability transformations in other developing country cities of Cambodia and the Southeast Asia region.

Keywords: Cambodia, planning practices, urban governance, urban sustainability transformations

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Authors: Yu-Mi Song, Sung-Ah Kim, Dongyoun Shin

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Cities are complex systems of diverse and inter-tangled activities. These activities and their complex interrelationships create diverse urban phenomena. And such urban phenomena have considerable influences on the lives of citizens. This research aimed to develop a method to reveal the causes and effects among diverse urban elements in order to enable better understanding of urban activities and, therefrom, to make better urban planning strategies. Specifically, this study was conducted to solve a data-recommendation problem found on a Korean public data homepage. First, a correlation analysis was conducted to find the correlations among random urban data. Then, based on the results of that correlation analysis, the weighted data network of each urban data was provided to people. It is expected that the weights of urban data thereby obtained will provide us with insights into cities and show us how diverse urban activities influence each other and induce feedback.

Keywords: big data, machine learning, ontology model, urban data model

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Authors: Mina Rabipour, Elena Pallaske, Floyd Hassenrück, Rocio Rebollido-Rios

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Protein tyrosine kinases, including Lyn kinase of the Src family kinases (SFK), regulate cell proliferation, survival, and differentiation. Lyn kinase has been implicated in various cancers, positioning it as a promising therapeutic target. However, the conserved ATP-binding pocket across SFKs makes developing selective inhibitors challenging. This study aims to address this limitation by exploring the potential for allosteric modulation of Lyn kinase, focusing on how its structural dynamics and specific oncogenic mutations impact its conformation and function. To achieve this, we combined homology modeling, molecular dynamics simulations, and data science techniques to conduct microsecond-length simulations. Our approach allowed a detailed investigation into the interplay between Lyn’s catalytic and regulatory domains, identifying key conformational states involved in allosteric regulation. Additionally, we evaluated the structural effects of Dasatinib, a competitive inhibitor, and ATP binding on Lyn active conformation. Notably, our simulations show that cancer-related mutations, specifically I364L/N and E290D/K, shift Lyn toward an inactive conformation, contrasting with the active state of the wild-type protein. This may suggest how these mutations contribute to aberrant signaling in cancer cells. We conducted a dynamical network analysis to assess residue-residue interactions and the impact of mutations on the Lyn intramolecular network. This revealed significant disruptions due to mutations, especially in regions distant from the ATP-binding site. These disruptions suggest potential allosteric sites as therapeutic targets, offering an alternative strategy for Lyn inhibition with higher specificity and fewer off-target effects compared to ATP-competitive inhibitors. Our findings provide insights into Lyn kinase regulation and highlight allosteric sites as avenues for selective drug development. Targeting these sites may modulate Lyn activity in cancer cells, reducing toxicity and improving outcomes. Furthermore, our computational strategy offers a scalable approach for analyzing other SFK members or kinases with similar properties, facilitating the discovery of selective allosteric modulators and contributing to precise cancer therapies.

Keywords: lyn tyrosine kinase, mutation analysis, conformational changes, dynamic network analysis, allosteric modulation, targeted inhibition

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