Medicine and Health Sciences Commons^™

Inhibition Of The Cd47-Sirpα Axis For Cancer Therapy: A Systematic Review And Meta-Analysis Of Emerging Clinical Data, Ji Son, Rodney Cheng-En Hsieh, Heather Y Lin, Kate J Krause, Ying Yuan, Amadeo B Biter, James Welsh, Michael A Curran, David S Hong

Faculty, Staff and Student Publications

CD47-SIRPα interaction acts as a "don't eat me" signal and is exploited by cancer to downregulate innate and adaptive immune surveillance. There has been intense interest to develop a mechanism of blockade, and we aimed to analyze the emerging data from early clinical trials. We performed a systematic review and meta-analysis of relevant databases and conference abstracts including clinical trials using CD47 and/or SIRPα inhibitors in cancer treatment. Nonlinear mixed models were applied for comparison of response and toxicity. We retrieved 317 articles, 24 of which were eligible. These included 771 response-evaluable patients with hematologic (47.1%) and solid tumors (52.9%). …

Cell-Directed Aptamer Therapeutic Targeting For Cancers Including Those Within The Central Nervous System, Jun Wei, Renduo Song, Aria Sabbagh, Anantha Marisetty, Neal Shukla, Dexing Fang, Hinda Najem, Martina Ott, James Long, Lijie Zhai, Maciej S Lesniak, Charles David James, Leonidas Platanias, Michael Curran, Amy B Heimberger

Faculty, Staff and Student Publications

Osteopontin (OPN) is produced by tumor cells as well as by myeloid cells and is enriched in the tumor microenvironment (TME) of many cancers. Given the roles of OPN in tumor progression and immune suppression, we hypothesized that targeting OPN with aptamers that have high affinity and specificity could be a promising therapeutic strategy. Bi-specific aptamers targeting ligands for cellular internalization were conjugated to siRNAs to suppress OPN were created, and therapeutic leads were selected based on target engagement and

Comparison Of Psma-Based 18f-Dcfpyl Pet/Ct And Pelvic Multiparametric Mri For Lesion Detection In The Pelvis In Patients With Prostate Cancer, Trinh T Nguyen, Priya R Bhosale, Guofan Xu, Tinsu Pan, Peng Wei, Yang Lu

Faculty, Staff and Student Publications

Purpose: To directly compare the performance of pelvic mpMRI versus recently approved and increasingly used PSMA-based 18F-DCFPyL PET/CT in intermediate-high risk and biochemical recurrent prostate cancer patient cohort while exploring their potential differing applications in specific clinical scenarios.

Methods: A retrospective analysis was performed on patients who had 18F-DCFPyL PET/CT and pelvic mpMRI done from September 2021 to January 2022 at a single institution. The inclusion criteria were paired exams within a 3-month interval. Exclusion criteria were intervening treatment between exams, a change in PSA by more than 50% and absolute difference more than 1 ng/mL, or concurrent history of …

Checkpoint Inhibitors As Immunotherapy For Fungal Infections: Promises, Challenges, And Unanswered Questions, Sebastian Wurster, Stephanie S Watowich, Dimitrios P Kontoyiannis

Faculty, Staff and Student Publications

Opportunistic fungal infections have high mortality in patients with severe immune dysfunction. Growing evidence suggests that the immune environment of invasive fungal infections and cancers share common features of immune cell exhaustion through activation of immune checkpoint pathways. This observation gave rise to several preclinical studies and clinical case reports describing blockade of the Programmed Cell Death Protein 1 and Cytotoxic T-Lymphocyte Antigen 4 immune checkpoint pathways as an adjunct immune enhancement strategy to treat opportunistic fungal infections. The first part of this review summarizes the emerging evidence for contributions of checkpoint pathways to the immunopathology of fungal sepsis, opportunistic …

A Yeast Model For Trichohepatoenteric Syndrome Suggests Strong Loss Of Ski2 Function In Most Causative Mutations, Luisa J Orlando, Matthew K Yim, Thomson Hallmark, Michael Cotner, Sean J Johnson, Ambro Van Hoof

Faculty, Staff and Student Publications

The intestinal and immune disorder trichohepatoenteric syndrome (THES) is characterized by mutations in human Ski2 and Ski3, also known as SKIV2L and TTC37, respectively. The mechanism by which these mutations leads to the immunodeficiency, chronic diarrhea, failure to thrive and liver disease associated with THES is unknown. To what degree THES patient mutations in Ski2 affect Ski2 function and how the differences in Ski2 function could lead to varying patient outcomes has not been studied. Here, we assayed function of THES ski2 mutants in the yeast homolog. Our results show that most THES patient mutations cause severe dysfunction in Ski2. …

An Autoencoder-Based Deep Learning Method For Genotype Imputation, Meng Song, Jonathan Greenbaum, Joseph Luttrell, Weihua Zhou, Chong Wu, Zhe Luo, Chuan Qiu, Lan Juan Zhao, Kuan-Jui Su, Qing Tian, Hui Shen, Huixiao Hong, Ping Gong, Xinghua Shi, Hong-Wen Deng, Chaoyang Zhang

Faculty, Staff and Student Publications

Genotype imputation has a wide range of applications in genome-wide association study (GWAS), including increasing the statistical power of association tests, discovering trait-associated loci in meta-analyses, and prioritizing causal variants with fine-mapping. In recent years, deep learning (DL) based methods, such as sparse convolutional denoising autoencoder (SCDA), have been developed for genotype imputation. However, it remains a challenging task to optimize the learning process in DL-based methods to achieve high imputation accuracy. To address this challenge, we have developed a convolutional autoencoder (AE) model for genotype imputation and implemented a customized training loop by modifying the training process with a …

Recurrent Hgnet-Mn1 Altered (Astroblastoma Mn1-Altered) Of The Foramen Magnum: Case Report And Molecular Classification, Sricharan Gopakumar, Malcolm F Mcdonald, Himanshu Sharma, Claudio E Tatsui, Gregory N Fuller, Ganesh Rao

Faculty, Staff and Student Publications

Background: Astroblastoma is a rare primary brain tumor of unclear origin, often occurring in young patients less than 30-years-old. It typically arises supratentorially and is diagnosed based on histological features including vascular hyalinization and perivascular pseudorosettes. Recent molecular characterization of primary CNS high-grade neuroepithelial tumors with meningioma I alteration (HGNET-MN1) found that HGNET-MN1 and tumors with morphological signatures of astroblastoma clustered together. Further analysis revealed such astroblastomas have MN1 alteration and the 2021 WHO classification of tumors of the CNS now recognizes astroblastoma MN1-altered as a new entity.

Case description: Here, we present the case of …

Hypermethylation Of Pi3k-Akt Signalling Pathway Genes Is Associated With Human Neural Tube Defects, Tian Tian, Xinyuan Lai, Kuanhui Xiang, Xiao Han, Shengju Yin, Robert M Cabrera, John W Steele, Yunping Lei, Xuanye Cao, Richard H Finnell, Linlin Wang, Aiguo Ren

Faculty, Staff and Students Publications

Neural tube defects (NTDs) are a group of common and severe congenital malformations. The PI3K-AKT signalling pathway plays a crucial role in the neural tube development. There is limited evidence concerning any possible association between aberrant methylation in PI3K-AKT signalling pathway genes and NTDs. Therefore, we aimed to investigate potential associations between aberrant methylation of PI3K-AKT pathway genes and NTDs. Methylation studies of PI3K-AKT pathway genes utilizing microarray genome-methylation data derived from neural tissues of ten NTD cases and eight non-malformed controls were performed. Targeted DNA methylation analysis was subsequently performed in an independent cohort of 73 NTD cases and …

Decidualization Of Human Endometrial Stromal Cells Requires Steroid Receptor Coactivator-3, Vineet K Maurya, Maria M Szwarc, David M Lonard, William E Gibbons, San-Pin Wu, Bert W O'Malley, Francesco J Demayo, John P Lydon

Faculty, Staff and Students Publications

Steroid receptor coactivator-3 (SRC-3; also known as NCOA3 or AIB1) is a member of the multifunctional p160/SRC family of coactivators, which also includes SRC-1 and SRC-2. Clinical and cell-based studies as well as investigations on mice have demonstrated pivotal roles for each SRC in numerous physiological and pathophysiological contexts, underscoring their functional pleiotropy. We previously demonstrated the critical involvement of SRC-2 in murine embryo implantation as well as in human endometrial stromal cell (HESC) decidualization, a cellular transformation process required for trophoblast invasion and ultimately placentation. We show here that, like SRC-2, SRC-3 is expressed in the epithelial and stromal …

Current State Of The Art In Hypoplastic Left Heart Syndrome, Aditya K Birla, Sunita Brimmer, Walker D Short, Oluyinka O Olutoye, Jason A Shar, Suriya Lalwani, Philippe Sucosky, Anitha Parthiban, Sundeep G Keswani, Christopher A Caldarone, Ravi K Birla

Faculty, Staff and Students Publications

Hypoplastic left heart syndrome (HLHS) is a complex congenital heart condition in which a neonate is born with an underdeveloped left ventricle and associated structures. Without palliative interventions, HLHS is fatal. Treatment typically includes medical management at the time of birth to maintain patency of the ductus arteriosus, followed by three palliative procedures: most commonly the Norwood procedure, bidirectional cavopulmonary shunt, and Fontan procedures. With recent advances in surgical management of HLHS patients, high survival rates are now obtained at tertiary treatment centers, though adverse neurodevelopmental outcomes remain a clinical challenge. While surgical management remains the standard of care for …

Evolution Of Genetic Networks For Human Creativity, I Zwir, C Del-Val, M Hintsanen, K M Cloninger, R Romero-Zaliz, A Mesa, J Arnedo, R Salas, G F Poblete, E Raitoharju, O Raitakari, L Keltikangas-Järvinen, G A De Erausquin, I Tattersall, T Lehtimäki, C R Cloninger

Staff and Researcher Publications

The genetic basis for the emergence of creativity in modern humans remains a mystery despite sequencing the genomes of chimpanzees and Neanderthals, our closest hominid relatives. Data-driven methods allowed us to uncover networks of genes distinguishing the three major systems of modern human personality and adaptability: emotional reactivity, self-control, and self-awareness. Now we have identified which of these genes are present in chimpanzees and Neanderthals. We replicated our findings in separate analyses of three high-coverage genomes of Neanderthals. We found that Neanderthals had nearly the same genes for emotional reactivity as chimpanzees, and they were intermediate between modern humans and …

Germline Polymorphisms In Mgmt Associated With Temozolomide-Related Myelotoxicity Risk In Patients With Glioblastoma Treated On Nrg Oncology/Rtog 0825, Michael E Scheurer, Renke Zhou, Mark R Gilbert, Melissa L Bondy, Erik P Sulman, Ying Yuan, Yanhong Liu, Elizabeth Vera, Merideth M Wendland, Emad F Youssef, Volker W Stieber, Ritsuko R Komaki, John C Flickinger, Lawrence C Kenyon, H Ian Robins, Grant K Hunter, Ian R Crocker, Samuel T Chao, Stephanie L Pugh, Terri S Armstrong

Faculty, Staff and Students Publications

BACKGROUND: We sought to identify clinical and genetic predictors of temozolomide-related myelotoxicity among patients receiving therapy for glioblastoma.

METHODS:Patients (n = 591) receiving therapy on NRG Oncology/RTOG 0825 were included in the analysis. Cases were patients with severe myelotoxicity (grade 3 and higher leukopenia, neutropenia, and/or thrombocytopenia); controls were patients without such toxicity. A risk-prediction model was built and cross-validated by logistic regression using only clinical variables and extended using polymorphisms associated with myelotoxicity.

RESULTS: 23% of patients developed myelotoxicity (n = 134). This toxicity was first reported during the concurrent phase of therapy for 56 patients; 30 …

Modeling Nonsegmented Negative-Strand Rna Virus (Nnsv) Transcription With Ejective Polymerase Collisions And Biased Diffusion, Felipe-Andrés Piedra, David Henke, Anubama Rajan, Donna M Muzny, Harsha Doddapaneni, Vipin K Menon, Kristi L Hoffman, Matthew C Ross, Sara J Javornik Cregeen, Ginger Metcalf, Richard A Gibbs, Joseph F Petrosino, Vasanthi Avadhanula, Pedro A Piedra

Faculty, Staff and Students Publications

Infections by non-segmented negative-strand RNA viruses (NNSV) are widely thought to entail gradient gene expression from the well-established existence of a single promoter at the 3' end of the viral genome and the assumption of constant transcriptional attenuation between genes. But multiple recent studies show viral mRNA levels in infections by respiratory syncytial virus (RSV), a major human pathogen and member of NNSV, that are inconsistent with a simple gradient. Here we integrate known and newly predicted phenomena into a biophysically reasonable model of NNSV transcription. Our model succeeds in capturing published observations of respiratory syncytial virus and vesicular stomatitis …

Evaluation Of Cervical Spine Pathology In Children With Loeys-Dietz Syndrome, Marc Andrew Prablek, Melissa Lopresti, Brandon Bertot, Shaine Alaine Morris, David Bauer, Sandi Lam, Vijay Ravindra

Faculty, Staff and Students Publications

BACKGROUND: Loeys-Dietz syndrome (LDS) is a genetic connective tissue disorder associated with multiple musculoskeletal anomalies, including cervical spine instability. We sought to examine the nature of imaging for cervical spine instability in children with LDS due to likely pathogenic or pathogenic variants in

METHODS: A retrospective chart review was conducted, examining relevant data for all children with LDS screened at our institution from 2004 through 2021. Cervical spine X-rays were used to assess cervical instability, cervical lordosis, and basilar impression.

RESULTS: A total of 39 patients were identified; 16 underwent cervical spine screening (56.25% male). Median age at initial screening …

The Third International Hackathon For Applying Insights Into Large-Scale Genomic Composition To Use Cases In A Wide Range Of Organisms, Kimberly Walker, Divya Kalra, Rebecca Lowdon, Guangyi Chen, David Molik, Daniela C Soto, Fawaz Dabbaghie, Ahmad Al Khleifat, Medhat Mahmoud, Luis F Paulin, Muhammad Sohail Raza, Susanne P Pfeifer, Daniel Paiva Agustinho, Elbay Aliyev, Pavel Avdeyev, Enrico R Barrozo, Sairam Behera, Kimberley Billingsley, Li Chuin Chong, Deepak Choubey, Wouter De Coster, Yilei Fu, Alejandro R Gener, Timothy Hefferon, David Morgan Henke, Wolfram Höps, Anastasia Illarionova, Michael D Jochum, Maria Jose, Rupesh K Kesharwani, Sree Rohit Raj Kolora, Jędrzej Kubica, Priya Lakra, Damaris Lattimer, Chia-Sin Liew, Bai-Wei Lo, Chunhsuan Lo, Anneri Lötter, Sina Majidian, Suresh Kumar Mendem, Rajarshi Mondal, Hiroko Ohmiya, Nasrin Parvin, Carolina Peralta, Chi-Lam Poon, Ramanandan Prabhakaran, Marie Saitou, Aditi Sammi, Philippe Sanio, Nicolae Sapoval, Najeeb Syed, Todd Treangen, Gaojianyong Wang, Tiancheng Xu, Jianzhi Yang, Shangzhe Zhang, Weiyu Zhou, Fritz J Sedlazeck, Ben Busby

Faculty, Staff and Students Publications

In October 2021, 59 scientists from 14 countries and 13 U.S. states collaborated virtually in the Third Annual Baylor College of Medicine & DNANexus Structural Variation hackathon. The goal of the hackathon was to advance research on structural variants (SVs) by prototyping and iterating on open-source software. This led to nine hackathon projects focused on diverse genomics research interests, including various SV discovery and genotyping methods, SV sequence reconstruction, and clinically relevant structural variation, including SARS-CoV-2 variants. Repositories for the projects that participated in the hackathon are available at https://github.com/collaborativebioinformatics.

In Alzheimer-Prone Brain Regions, Metabolism And Risk-Gene Expression Are Strongly Correlated, Fengdan Ye, Quentin Funk, Elijah Rockers, Joshua M Shulman, Joseph C Masdeu, Belen Pascual

Duncan NRI Faculty and Staff Publications

Neuroimaging in the preclinical phase of Alzheimer’s disease provides information crucial to early intervention, particularly in people with a high genetic risk. Metabolic network modularity, recently applied to the study of dementia, is increased in Alzheimer’s disease patients compared with controls, but network modularity in cognitively unimpaired elderly with various risks of developing Alzheimer’s disease needs to be determined. Based on their 5-year cognitive progression, we stratified 117 cognitively normal participants (78.3 ± 4.0 years of age, 52 women) into three age-matched groups, each with a different level of risk for Alzheimer’s disease. From their fluorodeoxyglucose PET we constructed metabolic …

Environmental And Genetic Factors Affecting Bone Diseases And Phenotypes In Mouse Models, Wei Dong

Theses and Dissertations (ETD)

Bone diseases and phenotypes are affected in multiple ways. We focused on studying the effects of genetic and environmental factors, especially their impact on bone properties. Firstly, we investigated the effects of β-caryophyllene (BCP), a naturally occurring dietary cannabinoid, on protecting bone from vitamin D deficiency in mice fed on a diet lacking or supplemented with vitamin D (VD). We found that the VD-deficient diet enhanced the length of femur and tibia bones (P<0.05), and increased bone volume (BV; P<0.01) and the trabecular bone volume fraction (BV/TV; P <0.01) compared to the D+ diet. When given BCP-containing diet, mice exhibited higher BV and bone mineral density (BMD; P<0.05) than the control group. The trabecular and cortical bone were also affected by VD and BCP. In addition, the inclusion of dietary BCP improved the serum concentrations of klotho (P < 0.05). In summary, these data indicate that BCP enhances the level of klotho in the serum, leading to improved bone properties and mineralization in an experimental mouse model. Under conditions lacking UV light, the D-deficient diet could affect multiple properties of bone, including trabecular and cortical bone, in mice. The D-deficient diet can also result in weight loss in mice.

My second project is to evaluate the bone properties in a mouse model with Il-1rn mutation. When knockout for IL-1rn, mice of Balb/c genomic background exhibited …

Identifying The Molecular Cause Of Extreme Endoplasmic Reticulum Dilation In Pediatric Osteosarcoma And Its Relationship To The Disease, Rachael Wood

Theses and Dissertations (ETD)

Pediatric osteosarcoma tumors are characterized by an unusual abundance of grossly dilated endoplasmic reticulum and an immense genomic instability that has complicated identifying new effective molecular therapeutic targets. Here we report a novel molecular signature that encompasses the majority of 108 patient tumor samples, PDXs and osteosarcoma cell lines. These tumors exhibit reduced expression of four critical COPII vesicle proteins that has resulted in the accumulation of procollagen-I protein within ‘hallmark’ dilated ER. Using CRISPR activation technology, increased expression of only SAR1A and SEC24D to physiologically normal levels was sufficient to restore both collagen-I secretion and resolve dilated ER morphology …

Genetic Testing In Ambulatory Cardiology Clinics Reveals High Rate Of Findings With Clinical Management Implications, David R Murdock, Eric Venner, Donna M Muzny, Ginger A Metcalf, Mullai Murugan, Trevor D Hadley, Varuna Chander, Paul S De Vries, Xiaoming Jia, Aliza Hussain, Ali M Agha, Aniko Sabo, Shoudong Li, Qingchang Meng, Jianhong Hu, Xia Tian, Michelle Cohen, Victoria Yi, Christie L Kovar, Marie-Claude Gingras, Viktoriya Korchina, Chad Howard, Daniel L Riconda, Stacey Pereira, Hadley S Smith, Zohra A Huda, Alexandria Buentello, Patricia R Marino, Lee Leiber, Ashok Balasubramanyam, Christopher I Amos, Andrew B Civitello, Mihail G Chelu, Ronald Maag, Amy L Mcguire, Eric Boerwinkle, Xander H T Wehrens, Christie M Ballantyne, Richard A Gibbs

Faculty, Staff and Students Publications

PURPOSE: Cardiovascular disease (CVD) is the leading cause of death in adults in the United States, yet the benefits of genetic testing are not universally accepted.

METHODS: We developed the "HeartCare" panel of genes associated with CVD, evaluating high-penetrance Mendelian conditions, coronary artery disease (CAD) polygenic risk, LPA gene polymorphisms, and specific pharmacogenetic (PGx) variants. We enrolled 709 individuals from cardiology clinics at Baylor College of Medicine, and samples were analyzed in a CAP/CLIA-certified laboratory. Results were returned to the ordering physician and uploaded to the electronic medical record.

RESULTS: Notably, 32% of patients had a genetic finding with clinical …

Nitrous Oxide Adaptation On Gene Expression In Breast Cancer Cells, Harsh Chheda, Estevan Ruiz Limón López, Zainab Mahmood, Ankit Sharma, Tina Tran, Uzma Abdulbaseer, Farouk Alshatti, James A. Radosevich

Chemistry and Physics Faculty Proceedings, Presentations, Speeches, Lectures

Hypothesis and Objective: Genes participating in the notch signaling pathway are influenced by exposure to high nitrous oxide (HNO) levels. Notch signaling pathway genes are responsible for regulating cell fate, differentiation, and apoptosis. Dysregulation of these genes can contribute to tumorigenesis. Alterations in the expression of these genes in MCF7 breast cancer cells could help determine the effects of the notch signaling pathway on tumorigenesis as a result of exposure to nitrous oxide.

Methods: Samples of cDNA from MCF7 and MCF7-HNO cells were used in DNA microarray analysis. Qualifying genes of interest provided a p value < .05. Differentially expressed genes (DEGs) were defined and categorized using the Gene Oncology Uniprot (GO) Molecular Function database. These cells were further analyzed using a proprietary bioinformatics analysis created by our laboratory.

Results: Exposure to HNO …

Lysergic Acid Diethylamide Induces Increased Signalling Entropy In Rats’ Prefrontal Cortex, Aurora Savino, Charles D. Nichols

School of Graduate Studies Faculty Publications

Psychedelic drugs are gaining attention from the scientific community as potential new compounds for the treatment of psychiatric diseases such as mood and substance use disorders. The 5-HT2A receptor has been identified as the main molecular target, and early studies pointed to an effect on the expression of neuroplasticity genes. Analysing RNA-seq data from the prefrontal cortex of rats chronically treated with lysergic acid diethylamide (LSD), we describe the psychedelic-induced rewiring of gene co-expression networks, which become less centralised but more complex, with an overall increase in signalling entropy typical of highly plastic systems. Intriguingly, signalling entropy mirrors, at the …

Comparing Empirical Kinship Derived Heritability For Imaging Genetics Traits In The Uk Biobank And Human Connectome Project, Si Gao, Brian Donohue, Kathryn S. Hatch, Shuo Chen, Tianzhou Ma, Yizhou Ma, Mark D. Kvarta, Bhim M. Adhikari, Neda Jahanshad, John Blangero

School of Medicine Publications

Imaging genetics analyses use neuroimaging traits as intermediate phenotypes to infer the degree of genetic contribution to brain structure and function in health and/or illness. Coefficients of relatedness (CR) summarize the degree of genetic similarity among subjects and are used to estimate the heritability – the proportion of phenotypic variance explained by genetic factors. The CR can be inferred directly from genome-wide genotype data to explain the degree of shared variation in common genetic polymorphisms (SNP-heritability) among related or unrelated subjects. We developed a central processing and graphics processing unit (CPU and GPU) accelerated Fast and Powerful Heritability Inference …

Role Of Smad2 And Smad3 On Adipose Tissue Development And Function, Roshan Kumari

Theses and Dissertations (ETD)

Introduction: Obesity and its associated metabolic syndrome are major medical problems worldwide including United States. Adipose tissue is the primary site of energy storage, playing important roles in health. Adipose tissue also has other critical functions, producing adipocytokines and contributing to normal nutrient metabolism, which in turn play important roles in satiety, inflammation, and total energy homeostasis. Activin A and activin B play important roles in maintaining body composition and energy homeostasis. This dissertation highlights the role of activin/SMADs signaling in adipose tissue development, function, and maintenance.

SMAD2/3 proteins are downstream mediators of transforming growth factor-β (TGFβ) family signaling, including …

The Ratio Method: Addressing Complex Tort Liability In The Fourth Industrial Revolution, Harrison C. Margolin, Grant H. Frazier

St. Mary's Law Journal

Emerging technologies of the Fourth Industrial Revolution show fundamental promise for improving productivity and quality of life, though their misuse may also cause significant social disruption. For example, while artificial intelligence will be used to accelerate society’s processes, it may also displace millions of workers and arm cybercriminals with increasingly powerful hacking capabilities. Similarly, human gene editing shows promise for curing numerous diseases, but also raises significant concerns about adverse health consequences related to the corruption of human and pathogenic genomes.

In most instances, only specialists understand the growing intricacies of these novel technologies. As the complexity and speed of …

Super-Resolution Microscopy Reveals Photoreceptor-Specific Subciliary Location And Function Of Ciliopathy-Associated Protein Cep290, Valencia L Potter, Abigail R Moye, Michael A Robichaux, Theodore G Wensel

Faculty, Staff and Students Publications

Mutations in the cilium-associated protein CEP290 cause retinal degeneration as part of multiorgan ciliopathies or as retina-specific diseases. The precise location and the functional roles of CEP290 within cilia and, specifically, the connecting cilia (CC) of photoreceptors, remain unclear. We used super-resolution fluorescence microscopy and electron microscopy to localize CEP290 in the CC and in the primary cilia of cultured cells with subdiffraction resolution and to determine effects of CEP290 deficiency in 3 mutant models. Radially, CEP290 localizes in close proximity to the microtubule doublets in the region between the doublets and the ciliary membrane. Longitudinally, it is distributed throughout …

Integrating Patient-Reported Outcomes Into Clinical Genetic Testing For Familial Hypercholesterolemia, Rachele M. Hendricks-Sturrup, Robert Block, Christine Y. Lu

Journal of Patient-Centered Research and Reviews

Patient-reported outcomes (PROs) and PRO measures (PROMs) are often used to help clinicians and researchers understand patients’ personal concerns, feelings, experiences, and perspectives following the implementation of an intervention. Notably, PROs and PROMs can inform health systems, health policy, and payers on the utility of clinical genetic testing based on each patient’s personal values, perspectives, and potential health behaviors subsequent to testing. In this topic synopsis, we discuss the underexplored role of and implications for PROs and PROMs following genetic testing for familial hypercholesterolemia (FH), an autosomal dominant genetic disorder of cholesterol metabolism that can lead to highly premature fatal …

Collagen-Based Biomaterials With Possible Therapeutic Effects, Ramona Mihaela Nedelcuţă, Gigi Călin, Mihai Cristian Nedelcuţă, Vlad Dumitru Baleanu, Dragos Virgil Davitoiu, Bogdan Socea, Bogdan-Petre Stănoiu

Journal of Mind and Medical Sciences

Epidermolysis bullosa (EB) is a rare, serious genetic disease, incurable through the current means. Apart from this initial definition, there was later some ease in the definition of the disease, including the manifestations of toxic epidermal necrolysis and Stevens Johnson syndrome in this entity. In medical practice, there are cases that do not overlap with the description in the literature, thus the treatment must be adapted and personalized to the particularities. We present the case of a female new-born, with "de novo" mutation for the early-onset antenatal epidermolysis and our personalized therapeutic management, based on collagen from bovine corneas by …

How Opportune Is Multigene Testing In Metastatic Colorectal Cancer? A Review, Cristina Orlov-Slavu, Andreea Parosanu, Mihaela Olaru, Dragos Serban, Ioana Paunica, Cornelia Nitipir

Journal of Mind and Medical Sciences

Personalized treatment in oncology is the most innovative method of care. The best method to establish personalized treatment is by genetic characterization of the malignant cell.

Theoretically, the more detailed the characterization, the more effective the choice of treatment becomes. Currently, there are fast and relatively low-cost options that allow such genetic characterization. However, test results sometimes do not detect targetable alterations and, even if they do detect, the use of the treatment-alteration combination does not always generate a satisfactory oncological response.

The present paper aims to answer two questions. First, how targetable can the most common gene alterations in …

Rare Variants In Kdr, Encoding Vegf Receptor 2, Are Associated With Tetralogy Of Fallot., Doris Škorić-Milosavljević, Najim Lahrouchi, Fernanda M. Bosada, Gregor Dombrowsky, Simon G. Williams, Robert Lesurf, Fleur V Y Tjong, Roddy Walsh, Ihssane El Bouchikhi, Jeroen Breckpot, Enrique Audain, Aho Ilgun, Leander Beekman, Ilham Ratbi, Alanna Strong, Maximilian Muenke, Solveig Heide, Alison M. Muir, Mariam Hababa, Laura A. Cross, Dihong Zhou, T Pastinen, German Competence Network For Congenital Heart Defects, Elaine Zackai, Samir Atmani, Karim Ouldim, Najlae Adadi, Katharina Steindl, Anita Rauch, David Brook, Anna Wilsdon, Irene Kuipers, Nico A. Blom, Barbara J. Mulder, Heather C. Mefford, Boris Keren, Pascal Joset, Paul Kruszka, Isabelle Thiffault, Sarah E. Sheppard, Amy Roberts, Elisabeth M. Lodder, Bernard D. Keavney, Sally-Ann B. Clur, Seema Mital, Marc-Philip Hitz, Vincent M. Christoffels, Alex V. Postma, Connie R. Bezzina

Manuscripts, Articles, Book Chapters and Other Papers

Purpose: Rare genetic variants in KDR, encoding the vascular endothelial growth factor receptor 2 (VEGFR2), have been reported in patients with tetralogy of Fallot (TOF). However, their role in disease causality and pathogenesis remains unclear.

Methods: We conducted exome sequencing in a familial case of TOF and large-scale genetic studies, including burden testing, in >1,500 patients with TOF. We studied gene-targeted mice and conducted cell-based assays to explore the role of KDR genetic variation in the etiology of TOF.

Results: Exome sequencing in a family with two siblings affected by TOF revealed biallelic missense variants in KDR. Studies in knock-in …

Multi-Phenotype Genome-Wide Association Studies Of The Norfolk Island Isolate Implicate Pleiotropic Loci Involved In Chronic Kidney Disease, Ngan K. Tran, Rodney A. Lea, Samuel Holland, Quan Nguyen, Arti M. Raghubar, Heidi G. Sutherland, Miles C. Benton, Nicholas B. Blackburn, Joanne E. Curran, John Blangero

School of Medicine Publications

Chronic kidney disease (CKD) is a persistent impairment of kidney function. Genome-wide association studies (GWAS) have revealed multiple genetic loci associated with CKD susceptibility but the complete genetic basis is not yet clear. Since CKD shares risk factors with cardiovascular diseases and diabetes, there may be pleiotropic loci at play but may go undetected when using single phenotype GWAS. Here, we used multi-phenotype GWAS in the Norfolk Island isolate (n = 380) to identify new loci associated with CKD. We performed a principal components analysis on different combinations of 29 quantitative traits to extract principal components (PCs) representative of multiple …