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Biomedical Engineering and Bioengineering Commons™
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Articles 1 - 8 of 8
Full-Text Articles in Biomedical Engineering and Bioengineering
Metastatic Tumor Evolution In Di#3;Use Gastric Cancer And Cancer Organoid Modeling Implicate Tgfbr2 As A Potential Driver, Patrick Flaherty
Metastatic Tumor Evolution In Di#3;Use Gastric Cancer And Cancer Organoid Modeling Implicate Tgfbr2 As A Potential Driver, Patrick Flaherty
Patrick Flaherty
Background: Gastric cancer is the second-leading cause of global cancer deaths, with metastatic disease representing the primary cause of mortality. To identify candidate drivers involved in oncogenesis and tumor evolution, we conduct an extensive genome sequencing analysis of metastatic progression in a diffuse gastric
cancer. This involves a comparison between a primary tumor from a hereditary diffuse gastric cancer syndrome proband and its recurrence as an ovarian metastasis.
Results: Both the primary tumor and ovarian metastasis have common biallelic loss-of-function of both the CDH1 and TP53 tumor suppressors, indicating a common genetic origin. While the primary tumor exhibits amplification of …
Systematic Genomic Identification Of Colorectal Cancer Genes Delineating Advanced From Early Clinical Stage, Patrick Flaherty
Systematic Genomic Identification Of Colorectal Cancer Genes Delineating Advanced From Early Clinical Stage, Patrick Flaherty
Patrick Flaherty
Background: Colorectal cancer is the third leading cause of cancer deaths in the United States. The initial assessment of colorectal cancer involves clinical staging that takes into account the extent of primary tumor invasion, determining the number of lymph nodes with metastatic cancer and the identification of metastatic sites
in other organs. Advanced clinical stage indicates metastatic cancer, either in regional lymph nodes or in distant organs. While the genomic and genetic basis of colorectal cancer has been elucidated to some degree, less is known about the identity of specific cancer genes that are associated with advanced clinical stage and …
Rvd: A Command-Line Program For Ultrasensitive Rare Single Nucleotide Variant Detection Using Targeted Next-Generation Dna Resequencing, Patrick Flaherty
Rvd: A Command-Line Program For Ultrasensitive Rare Single Nucleotide Variant Detection Using Targeted Next-Generation Dna Resequencing, Patrick Flaherty
Patrick Flaherty
Background: Rare single nucleotide variants play an important role in genetic diversity and heterogeneity of specific human disease. For example, an individual clinical sample can harbor rare mutations at minor frequencies. Genetic diversity within an individual clinical sample is oftentimes reflected in rare mutations. Therefore, detecting
rare variants prior to treatment may prove to be a useful predictor for therapeutic response. Current rare variant detection algorithms using next generation DNA sequencing are limited by inherent sequencing error rate and platform availability.
Findings: Here we describe an optimized implementation of a rare variant detection algorithm called RVD for use in targeted …
Ultrasensitive Detection Of Rare Mutations Using Next-Generation Targeted Resequencing, Patrick Flaherty
Ultrasensitive Detection Of Rare Mutations Using Next-Generation Targeted Resequencing, Patrick Flaherty
Patrick Flaherty
With next-generation DNA sequencing technologies, one can interrogate a specific genomic region of interest at very high depth of coverage and identify less prevalent, rare mutations in heterogeneous
clinical samples. However, the mutation detection levels are limited by the error rate of the sequencing technology as well as by the
availability of variant-calling algorithms with high statistical power and low false positive rates. We demonstrate that we can robustly detect
mutations at 0.1% fractional representation. This represents accurate detection of one mutant per every 1000 wild-type alleles. To achieve
this sensitive level of mutation detection, we integrate a high accuracy …
Genome-Wide Requirements For Resistance To Functionally Distinct Dna-Damaging Agents, Patrick Flaherty
Genome-Wide Requirements For Resistance To Functionally Distinct Dna-Damaging Agents, Patrick Flaherty
Patrick Flaherty
The mechanistic and therapeutic differences in the cellular response to DNA-damaging compounds are not completely understood, despite intense study. To expand our knowledge of DNA damage, we assayed the effects of 12 closely related DNA-damaging agents on the complete pool of ;4,700 barcoded homozygous deletion strains of
Saccharomyces cerevisiae. In our protocol, deletion strains are pooled together and grown competitively in the presence of compound. Relative strain sensitivity is determined by hybridization of PCR-amplified barcodes to an oligonucleotide array carrying the barcode complements. These screens identified genes in well-characterized DNAdamage-response pathways as well as genes whose role in the …
A Latent Variable Model For Chemogenomic Profiling, Patrick Flaherty
A Latent Variable Model For Chemogenomic Profiling, Patrick Flaherty
Patrick Flaherty
Motivation: In haploinsufficiency profiling data, pleiotropic genes
are often misclassified by clustering algorithms that impose the constraint that a gene or experiment belong to only one cluster. We
have developed a general probabilistic model that clusters genes and
experiments without requiring that a given gene or drug only appear
in one cluster. The model also incorporates the functional annotation
of known genes to guide the clustering procedure.
Results: We applied our model to the clustering of 79 chemogenomic
experiments in yeast. Known pleiotropic genes PDR5 and MAL11 are
more accurately represented by the model than by a clustering procedure that …
Chemogenomic Profiling: Identifying The Functional Interactions Of Small Molecules In Yeast, Patrick Flaherty
Chemogenomic Profiling: Identifying The Functional Interactions Of Small Molecules In Yeast, Patrick Flaherty
Patrick Flaherty
We demonstrate the efficacy of a genome-wide protocol in yeast
that allows the identification of those gene products that functionally
interact with small molecules and result in the inhibition of
cellular proliferation. Here we present results from screening 10
diverse compounds in 80 genome-wide experiments against the
complete collection of heterozygous yeast deletion strains. These
compounds include anticancer and antifungal agents, statins, alverine
citrate, and dyclonine. In several cases, we identified previously
known interactions; furthermore, in each case, our analysis
revealed novel cellular interactions, even when the relationship
between a compound and its cellular target had been well established.
In …
Functional Profiling Of The Saccharomyces Cerevisiae Genome, Patrick Flaherty
Functional Profiling Of The Saccharomyces Cerevisiae Genome, Patrick Flaherty
Patrick Flaherty
Determining the effect of gene deletion is a fundamental approach to understanding gene function. Conventional genetic screens exhibit biases, and genes contributing to a phenotype are often missed. We systematically constructed a nearly complete collection of gene-deletion mutants (96% of annotated open reading frames, or ORFs) of the yeast Saccharomyces cerevisiae. DNA sequences dubbed 'molecular bar codes' uniquely identify each strain, enabling their growth to be analysed in parallel and the fitness contribution of each gene to be quantitatively assessed by hybridization to high-density oligonucleotide arrays. We show that previously known and new genes are necessary for optimal growth …