Genetic Phenomena Commons^™

Feature Selection For Support Vector Regression Using A Genetic Algorithm, Shannon B Mckearnan, David M Vock, G Elisabeta Marai, Guadalupe Canahuate, Clifton D Fuller, Julian Wolfson

Faculty, Staff and Student Publications

Support vector regression (SVR) is particularly beneficial when the outcome and predictors are nonlinearly related. However, when many covariates are available, the method's flexibility can lead to overfitting and an overall loss in predictive accuracy. To overcome this drawback, we develop a feature selection method for SVR based on a genetic algorithm that iteratively searches across potential subsets of covariates to find those that yield the best performance according to a user-defined fitness function. We evaluate the performance of our feature selection method for SVR, comparing it to alternate methods including LASSO and random forest, in a simulation study. We …

Mmp9 Clears The Way For Metastatic Cell Penetration Across The Blood-Brain Barrier, Joseph H Mccarty

Faculty, Staff and Student Publications

Although brain metastases are 10-fold more prevalent than primary brain cancers, relatively little is understood about the genes and pathways that promote metastatic cell entry, growth, and survival in the brain. Hence, determining how metastatic tumors colonize the brain and thrive within the neural microenvironment is a topic of both fundamental importance and direct clinical relevance. In this issue, a report by Karreman and colleagues explores pathways that are exploited by metastatic tumor cells to arrest in the circulation, cross the endothelial blood-brain barrier (BBB), and thrive in the brain microenvironment. The authors used elegant imaging tools including intravital fluorescence …

Antibody-Drug Conjugates For Multiple Myeloma: Just The Beginning, Or The Beginning Of The End?, Upasana Ray, Robert Z Orlowski

Faculty, Staff and Student Publications

Multiple myeloma is a malignancy of immunoglobulin-secreting plasma cells that is now often treated in the newly diagnosed and relapsed and/or refractory settings with monoclonal antibodies targeting lineage-specific markers used either alone or in rationally designed combination regimens. Among these are the anti-CD38 antibodies daratumumab and isatuximab, and the anti-Signaling lymphocytic activation molecule family member 7 antibody elotuzumab, all of which are used in their unconjugated formats. Single-chain variable fragments from antibodies also form a key element of the chimeric antigen receptors (CARs) in the B-cell maturation antigen (BCMA)-targeted CAR T-cell products idecabtagene vicleucel and ciltacabtagene autoleucel, which are approved …

Antibody-Drug Conjugates For Multiple Myeloma: Just The Beginning, Or The Beginning Of The End?, Upasana Ray, Robert Z Orlowski

Faculty, Staff and Student Publications

Multiple myeloma is a malignancy of immunoglobulin-secreting plasma cells that is now often treated in the newly diagnosed and relapsed and/or refractory settings with monoclonal antibodies targeting lineage-specific markers used either alone or in rationally designed combination regimens. Among these are the anti-CD38 antibodies daratumumab and isatuximab, and the anti-Signaling lymphocytic activation molecule family member 7 antibody elotuzumab, all of which are used in their unconjugated formats. Single-chain variable fragments from antibodies also form a key element of the chimeric antigen receptors (CARs) in the B-cell maturation antigen (BCMA)-targeted CAR T-cell products idecabtagene vicleucel and ciltacabtagene autoleucel, which are approved …

Antibody-Drug Conjugates For Multiple Myeloma: Just The Beginning, Or The Beginning Of The End?, Upasana Ray, Robert Z Orlowski

Faculty, Staff and Student Publications

Multiple myeloma is a malignancy of immunoglobulin-secreting plasma cells that is now often treated in the newly diagnosed and relapsed and/or refractory settings with monoclonal antibodies targeting lineage-specific markers used either alone or in rationally designed combination regimens. Among these are the anti-CD38 antibodies daratumumab and isatuximab, and the anti-Signaling lymphocytic activation molecule family member 7 antibody elotuzumab, all of which are used in their unconjugated formats. Single-chain variable fragments from antibodies also form a key element of the chimeric antigen receptors (CARs) in the B-cell maturation antigen (BCMA)-targeted CAR T-cell products idecabtagene vicleucel and ciltacabtagene autoleucel, which are approved …

Pancreatic Cancer: Advances And Challenges, Christopher J Halbrook, Costas A Lyssiotis, Marina Pasca Di Magliano, Anirban Maitra

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers. Significant efforts have largely defined major genetic factors driving PDAC pathogenesis and progression. Pancreatic tumors are characterized by a complex microenvironment that orchestrates metabolic alterations and supports a milieu of interactions among various cell types within this niche. In this review, we highlight the foundational studies that have driven our understanding of these processes. We further discuss the recent technological advances that continue to expand our understanding of PDAC complexity. We posit that the clinical translation of these research endeavors will enhance the currently dismal survival rate of this recalcitrant …

Immune Checkpoint Therapy-Current Perspectives And Future Directions, Padmanee Sharma, Sangeeta Goswami, Deblina Raychaudhuri, Bilal A Siddiqui, Pratishtha Singh, Ashwat Nagarajan, Jielin Liu, Sumit K Subudhi, Candice Poon, Kristal L Gant, Shelley M Herbrich, Swetha Anandhan, Shajedul Islam, Moran Amit, Gayathri Anandappa, James P Allison

Faculty, Staff and Student Publications

Immune checkpoint therapy (ICT) has dramatically altered clinical outcomes for cancer patients and conferred durable clinical benefits, including cure in a subset of patients. Varying response rates across tumor types and the need for predictive biomarkers to optimize patient selection to maximize efficacy and minimize toxicities prompted efforts to unravel immune and non-immune factors regulating the responses to ICT. This review highlights the biology of anti-tumor immunity underlying response and resistance to ICT, discusses efforts to address the current challenges with ICT, and outlines strategies to guide the development of subsequent clinical trials and combinatorial efforts with ICT.

Hypoxia Increases Atx Expression By Histone Crotonylation In A Hif-2Α-Dependent Manner, Mengxia Qu, Yang Long, Yuqin Wang, Nan Yin, Xiaotian Zhang, Junjie Zhang

Faculty, Staff and Student Publications

Autotaxin (ATX), the key enzyme that generates lysophosphatidic acid (LPA) from lysophosphatidylcholine (LPC), is involved in tumorigenesis through the ATX-LPA axis and is regarded as a valuable target in tumor therapy. Hypoxia is a major feature of solid tumors and contributes to tumor development with striking alterations in the gene expression profile. Here, we show that hypoxia induces ATX expression in a hypoxia-inducible factor (HIF) 2α-dependent fashion in human colon cancer SW480 cells. HIF-2α is directly bound to specific hypoxia response elements (HREs) in the ATX promoter. Under hypoxic conditions, knockout or inhibition of ATX suppressed the migration of SW480 …

Genetic Epidemiology Highlights The Role Of Aortic Strain And Distensibility In Cardiovascular Disease, John W Belmont

Faculty, Staff and Students Publications

No abstract provided.

A Distinct Pattern Of Growth And Rac1 Signaling In Melanoma Brain Metastasis Cells, Ioana Stejerean-Todoran, Phyllis A Gimotty, Andrea Watters, Patricia Brafford, Clemens Krepler, Tetiana Godok, Haiyin Li, Zuriñe Bonilla Del Rio, Anke Zieseniss, Dörthe M Katschinski, Sinem M Sertel, Silvio O Rizzoli, Bradley Garman, Katherine L Nathanson, Xiaowei Xu, Qing Chen, Jack H Oswald, Michal Lotem, Gordon B Mills, Michael A Davies, Michael P Schön, Ivan Bogeski, Meenhard Herlyn, Adina Vultur

Faculty, Staff and Student Publications

Background: Melanoma, the deadliest of skin cancers, has a high propensity to form brain metastases that are associated with a markedly worsened prognosis. In spite of recent therapeutic advances, melanoma brain lesions remain a clinical challenge, biomarkers predicting brain dissemination are not clear and differences with other metastatic sites are poorly understood.

Methods: We examined a genetically diverse panel of human-derived melanoma brain metastasis (MBM) and extracranial cell lines using targeted sequencing, a Reverse Phase Protein Array, protein expression analyses, and functional studies in vitro and in vivo.

Results: Brain-specific genetic alterations were not detected; however, MBM cells in vitro …

Mutation-Agnostic Detection Of Colorectal Cancer Using Liquid Biopsy-Based Methylation-Specific Signatures, Mohamed A Gouda, Dzifa Y Duose, Morten Lapin, Stephanie Zalles, Helen J Huang, Yuanxin Xi, Xiaofeng Zheng, Amira I Aldesoky, Alshimaa M Alhanafy, Mohamed A Shehata, Jing Wang, Scott Kopetz, Funda Meric-Bernstam, Ignacio I Wistuba, Rajyalakshmi Luthra, Filip Janku

Faculty, Staff and Student Publications

Detection of methylation patterns in circulating tumor DNA (ctDNA) can offer a novel approach for cancer diagnostics given the unique signature for each tumor type. We developed a next-generation sequencing (NGS)-based assay targeting 32 CpG sites to detect colorectal cancer-specific ctDNA. NGS was performed on bisulfite-converted libraries and status dichotomization was done using median methylation ratios at all targets. We included plasma samples from patients with metastatic colorectal (n = 20) and non-colorectal cancers (n = 8); and healthy volunteers (n = 4). Median methylation ratio was higher in colorectal cancer compared with non-colorectal cancers (P = .001) and normal …

An Expedited Strategy For Accurate And Timely Integrated Molecular Diagnosis Of Gliomas, Timothy A Gregory, Garret L Williford, Jacob M Maronge, Kristin Alfaro, Gregory N Fuller, John De Groot, Vinay K Puduvalli, Leomar Y Ballester, Nazanin K Majd

Faculty, Staff and Student Publications

No abstract provided.

Longitudinal Global Transcriptomic Profiling Of Preclinical Systemic Sclerosis Reveals Molecular Changes Associated With Disease Progression, Chiara Bellocchi, Lorenzo Beretta, Xuan Wang, Marka A Lyons, Maurizio Marchini, Maurizio Lorini, Vincenzo Carbonelli, Nicola Montano, Shervin Assassi

Faculty, Staff and Student Publications

Objective: To investigate peripheral blood cell (PBCs) global gene expression profile of SSc at its preclinical stage (PreSSc) and to characterize the molecular changes associated with progression to a definite disease over time.

Material and methods: Clinical data and PBCs of 33 participants with PreSSc and 16 healthy controls (HCs) were collected at baseline and follow-up (mean 4.2 years). Global gene expression profiling was conducted by RNA sequencing and a modular analysis was performed.

Results: Comparison of baseline PreSSc to HCs revealed 2889 differentially expressed genes. Interferon signalling was the only activated pathway among top over-represented pathways. Moreover, 10 modules …

Switch-Like Behavior Of Lysosomes And Vcp Supports Spermatocyte Health And Development In Drosophila, Tyler James Butsch

LSU Doctoral Dissertations

Changes to societal norms, such as the educational, marital, and child-bearing expectations have coincided with significant increases in infertility worldwide. Surprisingly, male infertility is responsible for approximately half of all infertility cases worldwide. Thus, a better understanding of sperm development, and how it is affected by age, may permit the design and application of therapeutics to treat various cases male infertility. Here, I have found that lysosomes acidify as germ cells enter the spermatocyte stage. Once active, lysosomes turn over E-cadherin, and likely other proteins, to support plasma membrane stability. Notably, aging negatively impacts lysosome acidification, which can be reversed …

Emt-Activated Secretory And Endocytic Vesicular Trafficking Programs Underlie A Vulnerability To Pi4k2a Antagonism In Lung Cancer, Xiaochao Tan, Guan-Yu Xiao, Shike Wang, Lei Shi, Yanbin Zhao, Xin Liu, Jiang Yu, William K Russell, Chad J Creighton, Jonathan M Kurie

Faculty, Staff and Students Publications

Hypersecretory malignant cells underlie therapeutic resistance, metastasis, and poor clinical outcomes. However, the molecular basis for malignant hypersecretion remains obscure. Here, we showed that epithelial-mesenchymal transition (EMT) initiates exocytic and endocytic vesicular trafficking programs in lung cancer. The EMT-activating transcription factor zinc finger E-box-binding homeobox 1 (ZEB1) executed a PI4KIIIβ-to-PI4KIIα (PI4K2A) dependency switch that drove PI4P synthesis in the Golgi and endosomes. EMT enhanced the vulnerability of lung cancer cells to PI4K2A small-molecule antagonists. PI4K2A formed a MYOIIA-containing protein complex that facilitated secretory vesicle biogenesis in the Golgi, thereby establishing a hypersecretory state involving osteopontin (SPP1) and other prometastatic ligands. …

Genomic-Transcriptomic Evolution In Lung Cancer And Metastasis, Carlos Martínez-Ruiz, James R M Black, Clare Puttick, Mark S Hill, Jonas Demeulemeester, Elizabeth Larose Cadieux, Kerstin Thol, Thomas P Jones, Selvaraju Veeriah, Cristina Naceur-Lombardelli, Antonia Toncheva, Paulina Prymas, Andrew Rowan, Sophia Ward, Laura Cubitt, Foteini Athanasopoulou, Oriol Pich, Takahiro Karasaki, David A Moore, Roberto Salgado, Emma Colliver, Carla Castignani, Michelle Dietzen, Ariana Huebner, Maise Al Bakir, Miljana Tanić, Thomas B K Watkins, Emilia L Lim, Ali M Al-Rashed, Danny Lang, James Clements, Daniel E Cook, Rachel Rosenthal, Gareth A Wilson, Alexander M Frankell, Sophie De Carné Trécesson, Philip East, Nnennaya Kanu, Kevin Litchfield, Nicolai J Birkbak, Allan Hackshaw, Stephan Beck, Peter Van Loo, Mariam Jamal-Hanjani, Charles Swanton, Nicholas Mcgranahan

Faculty, Staff and Student Publications

Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy1. Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study2,3. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression …

Aerosolized Immunotherapeutic Nanoparticle Inhalation Potentiates Pd-L1 Blockade For Locally Advanced Lung Cancer, Yang Liu, William N Crowe, Lulu Wang, W Jeffrey Petty, Amyn A Habib, Dawen Zhao

Faculty, Staff and Student Publications

Despite therapeutic advancements, the prognosis of locally advanced non-small cell lung cancer (LANSCLC), which has invaded multiple lobes or the other lung and intrapulmonary lymph nodes, remains poor. The emergence of immunotherapy with immune checkpoint blockade (ICB) is transforming cancer treatment. However, only a fraction of lung cancer patients benefit from ICB. Significant clinical evidence suggests that the proinflammatory tumor microenvironment (TME) and programmed death-ligand 1 (PD-L1) expression correlate positively with response to the PD-1/PD-L1 blockade. We report here a liposomal nanoparticle loaded with cyclic dinucleotide and aerosolized (AeroNP-CDN) for inhalation delivery to deep-seated lung tumors and target CDN to …

Artificial Intelligence-Based Ct Assessment Of Bronchiectasis: The Copdgene Study, Alejandro A Díaz, Pietro Nardelli, Wei Wang, Rubén San José Estépar, Andrew Yen, Seth Kligerman, Diego J Maselli, Wojciech R Dolliver, Andrew Tsao, José L Orejas, Stefano Aliberti, Timothy R Aksamit, Kendra A Young, Gregory L Kinney, George R Washko, Edwin K Silverman, Raúl San José Estépar

Faculty, Staff and Student Publications

Background

CT is the standard method used to assess bronchiectasis. A higher airway-to-artery diameter ratio (AAR) is typically used to identify enlarged bronchi and bronchiectasis; however, current imaging methods are limited in assessing the extent of this metric in CT scans.

Purpose

To determine the extent of AARs using an artificial intelligence–based chest CT and assess the association of AARs with exacerbations over time.

Materials and Methods

In a secondary analysis of ever-smokers from the prospective, observational, multicenter COPDGene study, AARs were quantified using an artificial intelligence tool. The percentage of airways with AAR greater than 1 (a measure of …

Comparative Analysis Of Dimension Reduction Methods For Cytometry By Time-Of-Flight Data, Kaiwen Wang, Yuqiu Yang, Fangjiang Wu, Bing Song, Xinlei Wang, Tao Wang

Faculty, Staff and Student Publications

While experimental and informatic techniques around single cell sequencing (scRNA-seq) are advanced, research around mass cytometry (CyTOF) data analysis has severely lagged behind. CyTOF data are notably different from scRNA-seq data in many aspects. This calls for the evaluation and development of computational methods specific for CyTOF data. Dimension reduction (DR) is one of the critical steps of single cell data analysis. Here, we benchmark the performances of 21 DR methods on 110 real and 425 synthetic CyTOF samples. We find that less well-known methods like SAUCIE, SQuaD-MDS, and scvis are the overall best performers. In particular, SAUCIE and scvis …

Emotional, Behavioral, And Physical Health Consequences Of Loneliness In Young Adult Survivors Of Childhood Cancer: Results From The Childhood Cancer Survivor Study, Chiara Papini, Ameera A Fayad, Mingjuan Wang, Fiona S M Schulte, I-Chan Huang, Yu-Ping Chang, Rebecca M Howell, Deokumar Srivastava, Wendy M Leisenring, Gregory T Armstrong, Todd M Gibson, Leslie L Robison, Kevin C Oeffinger, Kevin R Krull, Tara M Brinkman

Faculty, Staff and Student Publications

Background: Young adults in the general population are at risk of experiencing loneliness, which has been associated with physical and mental health morbidities. The prevalence and consequences of loneliness in young adult survivors of childhood cancer remain unknown.

Methods: A total of 9664 young adult survivors of childhood cancer (median age at diagnosis 10.5 years [interquartile range (IQR), 5-15], 27.1 years at baseline [IQR, 23-32]) and 2221 siblings enrolled in the Childhood Cancer Survivor Study completed a self-reported survey question assessing loneliness on the Brief Symptom Inventory-18 at baseline and follow-up (median follow-up, 6.6 years). Multivariable models evaluated the prevalence …