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1.
iScience ; 26(3): 106267, 2023 Mar 17.
Article in English | MEDLINE | ID: mdl-36936782

ABSTRACT

Microglia play an important role in neuroinflammation and neurodegeneration. Here, we report an approach for generating microglia-containing cerebral organoids derived from human pluripotent stem cells involving the supplementation of growth factors (FGF, EGF, heparin) and 10% CO2 culture conditions. Using this platform, Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex (ALS-PDC) cerebral organoids were generated from patient-derived induced pluripotent stem cells (iPSCs). These ALS-PDC-affected organoids had more reactive astrocytes and M1 microglia, and had fewer M2 microglia than their unaffected counterparts, leading to impaired microglia-mediated phagocytosis. RNA-seq analysis of ALS-PDC and control organoids indicated that the most significant changes were microglia- and astrocyte-related genes (IFITM1/2, TGF-ß, and GFAP). The most significantly downregulated pathway was type I interferon signaling. Interferon-gamma supplementation increased IFITM expression, enhanced microglia-mediated phagocytosis, and reduced beta-amyloid accumulation in ALS-PDC-affected network. The results demonstrated the feasibility of using microglia-containing organoids for the study of neurodegenerative diseases.

2.
J Hydrol Eng ; 26(9)2021 Sep.
Article in English | MEDLINE | ID: mdl-34497453

ABSTRACT

Hydrologic model intercomparison studies help to evaluate the agility of models to simulate variables such as streamflow, evaporation, and soil moisture. This study is the third in a sequence of the Great Lakes Runoff Intercomparison Projects. The densely populated Lake Erie watershed studied here is an important international lake that has experienced recent flooding and shoreline erosion alongside excessive nutrient loads that have contributed to lake eutrophication. Understanding the sources and pathways of flows is critical to solve the complex issues facing this watershed. Seventeen hydrologic and land-surface models of different complexity are set up over this domain using the same meteorological forcings, and their simulated streamflows at 46 calibration and seven independent validation stations are compared. Results show that: (1) the good performance of Machine Learning models during calibration decreases significantly in validation due to the limited amount of training data; (2) models calibrated at individual stations perform equally well in validation; and (3) most distributed models calibrated over the entire domain have problems in simulating urban areas but outperform the other models in validation.

5.
J Invest Dermatol ; 139(9): 1985-1992.e10, 2019 09.
Article in English | MEDLINE | ID: mdl-30905807

ABSTRACT

ABCB5 is an ABC transporter that was shown to confer low-level multidrug resistance in cancer. In this study, we show that ABCB5 was mutated in 13.75% of the 640 melanoma samples analyzed. Besides nonsense mutations, two mutation hotspots were found in the ABCB5 protein, in the drug-binding pocket and the nucleotide-binding domains. Four mutations, which are representative of the mutation pattern, were selected. ATPase assays showed that these mutations resulted in a decrease in basal ATP hydrolysis by ABCB5. To select informative melanoma cell lines, mutational profiles of the clinical samples were further analyzed. This study showed mutations in the tumor suppressor CDKN2A gene and the NRAS oncogene in 62.5% and 75%, respectively of the samples that had mutations in the ABCB5 gene. No mutation was found in the tumor suppressor PTEN gene, whereas the activating V600E mutation in the BRAF oncogene was found in 25% of the samples with a mutated ABCB5 gene. Studies in four melanoma cell lines with various genetic backgrounds showed an increase in the proliferation and migration capacity of mutant ABCB5-expressing cells, suggesting that ABCB5 plays a role in the development of melanoma as a tumor suppressor gene.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B/genetics , Genes, Tumor Suppressor , Melanoma/genetics , Skin Neoplasms/genetics , ATP Binding Cassette Transporter, Subfamily B/metabolism , Adenosine Triphosphate/metabolism , Adult , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Cyclin-Dependent Kinase Inhibitor p16/genetics , DNA Mutational Analysis , Female , GTP Phosphohydrolases/genetics , Humans , Hydrolysis , Male , Melanoma/pathology , Membrane Proteins/genetics , Middle Aged , Mutation , Skin/pathology , Skin Neoplasms/pathology , Exome Sequencing , Young Adult
6.
AMIA Annu Symp Proc ; 2019: 655-663, 2019.
Article in English | MEDLINE | ID: mdl-32308860

ABSTRACT

To overcome limitations of previously developed scientific productivity ranking services, we created the Biomedical Informatics Researchers ranking website (rank.informatics-review.com). The website is composed of four key components that work together to create the automatically updating ranking website: 1) list of biomedical informatics researchers, 2) Google Scholar scraper, 3) display page, and 4) updater. The interactive website has facilitated identification of leaders in each of the key citation statistics categories (i.e., number of citations, h-index, and i10-index), and it has allowed other groups, such as tenure and promotions committees, to more effectively and efficiently evaluate researchers and interpret the various citation statistics reported by candidates. Creation of the biomedical informatics researcher ranking website highlights the vast differences in scholarly productivity among members of the biomedical informatics research community. Future efforts are underway to add new functionality to the website and to expand the work to identify top papers in biomedical informatics.


Subject(s)
Bibliometrics , Biomedical Research , Informatics , Internet , Research Personnel/statistics & numerical data , Humans , Information Storage and Retrieval , Leadership , Periodicals as Topic/statistics & numerical data , Research Personnel/classification
8.
Interact J Med Res ; 7(1): e3, 2018 02 05.
Article in English | MEDLINE | ID: mdl-29402763

ABSTRACT

BACKGROUND: Genetic sequencing is critically important to diagnostic health care efforts in the United States today, yet it is still inaccessible to many. Meanwhile, the internet and social networking have made crowdfunding a realistic avenue for individuals and groups hoping to fund medical and research causes, including patients in need of whole exome genetic sequencing (WES). OBJECTIVE: Amplify Hope is an educational program designed to investigate what factors affect the success of medical crowdfunding campaigns. We conducted a needs assessment, a series of 25 interviews concerning crowdfunding, and provided training on best practices identified through our assessment for 11 individuals hoping to run their medical crowdfunding campaigns to raise money for patients to access trio WES to identify the mutated proteins that caused their apparent inherited disease. METHODS: The crowdfunding education was given in a 30-day training period with resources such as webinars, fact sheets and a crowdfunding training guide emailed to each participant. All campaigns were launched on the same date and were given 30 days to raise the same goal amount of US $5000. Reviewing the 4 crowdfunding campaigns that raised the goal amount within the 30-day period, we sought to identify features that made the 4 crowdfunding campaigns successful. In addition, we sought to assess which factors the resulting 75 donors report as influencing their decision to donate to a campaign. Finally, we investigated whether crowdfunding campaigns for exome sequencing had an impact on increasing applicant's and donors' knowledge of genomics. RESULTS: Of the 86 study inquiries, 11 participants submitted the required forms and launched their crowdfunding campaigns. A total of 4 of the 11 campaigns raised their goal amounts within 30 days. CONCLUSIONS: We found that social media played an important role in all campaigns. Specifically, a strong social media network, an active outreach process to networks, as well as engagement within the study all correlated with a higher success rate. Amplify Hope donors were more likely to support projects that were near their fundraising goals, and they found video far more effective for learning about genomics than any other medium.

9.
Sci Rep ; 8(1): 653, 2018 01 12.
Article in English | MEDLINE | ID: mdl-29330521

ABSTRACT

Analysis of 501 melanoma exomes revealed RGS7, which encodes a GTPase-accelerating protein (GAP), to be a tumor-suppressor gene. RGS7 was mutated in 11% of melanomas and was found to harbor three recurrent mutations (p.R44C, p.E383K and p.R416Q). Structural modeling of the most common recurrent mutation of the three (p.R44C) predicted that it destabilizes the protein due to the loss of an H-bond and salt bridge network between the mutated position and the serine and aspartic acid residues at positions 58 as 61, respectively. We experimentally confirmed this prediction showing that the p.R44C mutant protein is indeed destabilized. We further show RGS7 p.R44C has weaker catalytic activity for its substrate Gαo, thus providing a dual mechanism for its loss of function. Both of these effects are expected to contribute to loss of function of RGS7 resulting in increased anchorage-independent growth, migration and invasion of melanoma cells. By mutating position 56 in the R44C mutant from valine to cysteine, thereby enabling the formation of a disulfide bridge between the two mutated positions, we slightly increased the catalytic activity and reinstated protein stability, leading to the rescue of RGS7's function as a tumor suppressor. Our findings identify RGS7 as a novel melanoma driver and point to the clinical relevance of using strategies to stabilize the protein and, thereby, restore its function.


Subject(s)
Melanoma/genetics , Mutation , RGS Proteins/chemistry , RGS Proteins/metabolism , Cell Line, Tumor , Cell Movement , Cell Proliferation , Disulfides/chemistry , GTP-Binding Protein alpha Subunits, Gi-Go/metabolism , Humans , Hydrogen Bonding , Melanoma/metabolism , Models, Molecular , Neoplasm Invasiveness , Protein Conformation , Protein Stability , RGS Proteins/genetics
10.
Proc IEEE Int Symp Biomed Imaging ; 2017: 929-932, 2017 Apr.
Article in English | MEDLINE | ID: mdl-31636811

ABSTRACT

Diagnosis of breast carcinomas has so far been limited to the morphological interpretation of epithelial cells and the assessment of epithelial tissue architecture. Consequently, most of the automated systems have focused on characterizing the epithelial regions of the breast to detect cancer. In this paper, we propose a system for classification of hematoxylin and eosin (H&E) stained breast specimens based on convolutional neural networks that primarily targets the assessment of tumor-associated stroma to diagnose breast cancer patients. We evaluate the performance of our proposed system using a large cohort containing 646 breast tissue biopsies. Our evaluations show that the proposed system achieves an area under ROC of 0.92, demonstrating the discriminative power of previously neglected tumor associated stroma as a diagnostic biomarker.

11.
Clin Cancer Res ; 22(15): 3810-20, 2016 08 01.
Article in English | MEDLINE | ID: mdl-26994145

ABSTRACT

PURPOSE: We undertook a multidimensional clinical genomics study of children and adolescent young adults with relapsed and refractory cancers to determine the feasibility of genome-guided precision therapy. EXPERIMENTAL DESIGN: Patients with non-central nervous system solid tumors underwent a combination of whole exome sequencing (WES), whole transcriptome sequencing (WTS), and high-density single-nucleotide polymorphism array analysis of the tumor, with WES of matched germline DNA. Clinically actionable alterations were identified as a reportable germline mutation, a diagnosis change, or a somatic event (including a single nucleotide variant, an indel, an amplification, a deletion, or a fusion gene), which could be targeted with drugs in existing clinical trials or with FDA-approved drugs. RESULTS: Fifty-nine patients in 20 diagnostic categories were enrolled from 2010 to 2014. Ages ranged from 7 months to 25 years old. Seventy-three percent of the patients had prior chemotherapy, and the tumors from these patients with relapsed or refractory cancers had a higher mutational burden than that reported in the literature. Thirty patients (51% of total) had clinically actionable mutations, of which 24 (41%) had a mutation that was currently targetable in a clinical trial setting, 4 patients (7%) had a change in diagnosis, and 7 patients (12%) had a reportable germline mutation. CONCLUSIONS: We found a remarkably high number of clinically actionable mutations in 51% of the patients, and 12% with significant germline mutations. We demonstrated the clinical feasibility of next-generation sequencing in a diverse population of relapsed and refractory pediatric solid tumors. Clin Cancer Res; 22(15); 3810-20. ©2016 AACR.


Subject(s)
Genomics , Neoplasms/genetics , Neoplasms/therapy , Precision Medicine , Adolescent , Adult , Biomarkers, Tumor , Child , Child, Preschool , Drug Resistance, Neoplasm , Female , Genomics/methods , Germ-Line Mutation , Humans , Infant , Male , Molecular Targeted Therapy , Mutation , Neoplasms/diagnosis , Polymorphism, Single Nucleotide , Precision Medicine/methods , Recurrence , Exome Sequencing , Young Adult
12.
Expert Rev Mol Diagn ; 15(12): 1589-603, 2015.
Article in English | MEDLINE | ID: mdl-26565429

ABSTRACT

Transcriptomic technologies are evolving to diagnose cancer earlier and more accurately to provide greater predictive and prognostic utility to oncologists and patients. Digital techniques such as RNA sequencing are replacing still-imaging techniques to provide more detailed analysis of the transcriptome and aberrant expression that causes oncogenesis, while companion diagnostics are developing to determine the likely effectiveness of targeted treatments. This article examines recent advancements in molecular profiling research and technology as applied to cancer diagnosis, clinical applications and predictions for the future of personalized medicine in oncology.


Subject(s)
Biomarkers, Tumor , Gene Expression Profiling , Neoplasms/diagnosis , Neoplasms/genetics , Transcriptome , Animals , Biomedical Research , Gene Expression Profiling/methods , Genomics/methods , Humans , Molecular Diagnostic Techniques , Precision Medicine/methods , Technology Transfer
13.
Nat Genet ; 47(12): 1408-10, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26502337

ABSTRACT

Analysis of 501 melanoma exomes identified RASA2, encoding a RasGAP, as a tumor-suppressor gene mutated in 5% of melanomas. Recurrent loss-of-function mutations in RASA2 were found to increase RAS activation, melanoma cell growth and migration. RASA2 expression was lost in ≥30% of human melanomas and was associated with reduced patient survival. These findings identify RASA2 inactivation as a melanoma driver and highlight the importance of RasGAPs in cancer.


Subject(s)
Biomarkers, Tumor/genetics , Exome/genetics , Melanoma/genetics , Mutation/genetics , Skin Neoplasms/genetics , ras GTPase-Activating Proteins/genetics , High-Throughput Nucleotide Sequencing/methods , Humans , Melanoma/mortality , Melanoma/pathology , Prognosis , Skin Neoplasms/mortality , Skin Neoplasms/pathology , Survival Rate
14.
Stud Health Technol Inform ; 216: 1004, 2015.
Article in English | MEDLINE | ID: mdl-26262305

ABSTRACT

We developed the Biomedical Informatics Researchers ranking website (rank.informatics-review.com) to overcome many of the limitations of previous scientific productivity ranking strategies. The website is composed of four key components that work together to create an automatically updating ranking website: (1) list of biomedical informatics researchers, (2) Google Scholar scraper, (3) display page, and (4) updater. The site has been useful to other groups in evaluating researchers, such as tenure and promotions committees in interpreting the various citation statistics reported by candidates. Creation of the Biomedical Informatics Researchers ranking website highlights the vast differences in scholarly productivity among members of the biomedical informatics research community.


Subject(s)
Bibliometrics , Internet/organization & administration , Journal Impact Factor , Medical Informatics/organization & administration , Search Engine/methods , Software , Biomedical Research , User-Computer Interface
15.
Expert Rev Proteomics ; 12(4): 391-405, 2015 Aug.
Article in English | MEDLINE | ID: mdl-26145529

ABSTRACT

In the last two decades, advances in genomic, transcriptomic and proteomic methods have enabled us to identify and classify cancers by their molecular profiles. Many anticipate that a molecular taxonomy of cancer will not only lead to more effective subtyping of cancers but also earlier diagnoses, more informative prognoses and more targeted treatments. This article reviews recent technological developments in the field of proteomics, recent discoveries in proteomic cancer biomarker research and trends in clinical use. Readers are also informed of examples of successful commercialization, and the future of proteomics in cancer diagnostics.


Subject(s)
Neoplasm Proteins/metabolism , Neoplasms/metabolism , Proteomics , Biomarkers, Tumor/metabolism , Humans , Mass Spectrometry , Protein Array Analysis
16.
Front Genet ; 6: 215, 2015.
Article in English | MEDLINE | ID: mdl-26136771

ABSTRACT

This article will review recent impact of massively parallel next-generation sequencing (NGS) in our understanding and treatment of cancer. While whole exome sequencing (WES) remains popular and effective as a method of genetically profiling different cancers, advances in sequencing technology has enabled an increasing number of whole-genome based studies. Clinically, NGS has been used or is being developed for genetic screening, diagnostics, and clinical assessment. Though challenges remain, clinicians are in the early stages of using genetic data to make treatment decisions for cancer patients. As the integration of NGS in the study and treatment of cancer continues to mature, we believe that the field of cancer genomics will need to move toward more complete 100% genome sequencing. Current technologies and methods are largely limited to coding regions of the genome. A number of recent studies have demonstrated that mutations in non-coding regions may have direct tumorigenic effects or lead to genetic instability. Non-coding regions represent an important frontier in cancer genomics.

17.
Hum Mutat ; 35(11): 1301-10, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25113440

ABSTRACT

Protein tyrosine phosphatases (PTPs) tightly regulate tyrosine phosphorylation essential for cell growth, adhesion, migration, and survival. We performed a mutational analysis of the PTP gene family in cutaneous metastatic melanoma and identified 23 phosphatase genes harboring somatic mutations. Among these, receptor-type tyrosine-protein phosphatase delta (PTPRD) was one of the most highly mutated genes, harboring 17 somatic mutations in 79 samples, a prevalence of 21.5%. Functional evaluation of six PTPRD mutations revealed enhanced anchorage-dependent and anchorage-independent growth. Interestingly, melanoma cells expressing mutant PTPRD were significantly more migratory than cells expressing wild-type PTPRD or vector alone, indicating a novel gain-of-function associated with mutant PTPRD. To understand the molecular mechanisms of PTPRD mutations, we searched for its binding partners by converting the active PTPRD enzyme into a "substrate trap" form. Using mass spectrometry and coimmunoprecipitation, we report desmoplakin, a desmosomal protein that is implicated in cell-cell adhesion, as a novel PTPRD substrate. Further analysis showed reduced phosphatase activity of mutant PTPRD against desmoplakin. Our findings identify an essential signaling cascade that is disrupted in melanoma. Moreover, because PTPRD is also mutated in glioblastomas and adenocarcinoma of the colon and lung, our data might be applicable to a large number of human cancers.


Subject(s)
Melanoma/genetics , Melanoma/metabolism , Mutation , Receptor-Like Protein Tyrosine Phosphatases, Class 2/genetics , Receptor-Like Protein Tyrosine Phosphatases, Class 2/metabolism , Carrier Proteins , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation , DNA Mutational Analysis , Desmoplakins/metabolism , Gene Expression , Humans , Intercellular Junctions/metabolism , Models, Biological , Phosphorylation , Protein Binding , Protein Transport , Substrate Specificity
18.
J Invest Dermatol ; 134(2): 452-460, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24008424

ABSTRACT

Patients with advanced metastatic melanoma have poor prognosis and the genetics underlying its pathogenesis are poorly understood. High-throughput sequencing has allowed comprehensive discovery of somatic mutations in cancer samples. Here, on analysis of our whole-genome and whole-exome sequencing data of 29 melanoma samples, we identified several genes that harbor recurrent nonsynonymous mutations. These included MAP3K5 (mitogen-activated protein kinase kinase kinase-5), which in a prevalence screen of 288 melanomas was found to harbor a R256C substitution in 5 cases. All MAP3K5-mutated samples were wild type for BRAF, suggesting a mutual exclusivity for these mutations. Functional analysis of the MAP3K5 R256C mutation revealed attenuation of MKK4 (mitogen-activated protein kinase kinase 4) activation through increased binding of the inhibitory protein thioredoxin (TXN/TRX-1/Trx), resulting in increased proliferation and anchorage-independent growth of melanoma cells. This mutation represents a potential target for the design of new therapies to treat melanoma.


Subject(s)
MAP Kinase Kinase Kinase 5/genetics , Melanoma/genetics , Melanoma/pathology , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Thioredoxins/metabolism , Apoptosis/physiology , Cell Proliferation , HEK293 Cells , Humans , MAP Kinase Kinase 4/metabolism , MAP Kinase Kinase Kinase 5/metabolism , Melanoma/metabolism , Models, Genetic , Point Mutation , Protein Binding , RNA, Small Interfering/genetics , Signal Transduction/physiology , Skin Neoplasms/metabolism , Tumor Cells, Cultured
19.
Genet Res (Camb) ; 96: e009, 2014 Aug 13.
Article in English | MEDLINE | ID: mdl-25579084

ABSTRACT

In order to address the unmet needs and create opportunities that benefit patients with rare disease in India, a group of volunteers created a not-for-profit organization named Organization for Rare Diseases India (ORDI; www.ordindia.org). ORDI plans to represent the collective voice and advocate the needs of patients with rare diseases and other stakeholders in India. The ORDI team members come from diverse backgrounds such as genetics, molecular diagnostics, drug development, bioinformatics, communications, information technology, patient advocacy and public service. ORDI builds on the lessons learned from numerous similar organizations in the USA, European Union and disease-specific rare disease foundations in India. In this review, we provide a background on the landscape of rare diseases and the organizations that are active in this area globally and in India. We discuss the unique challenges in tackling rare diseases in India, and highlight the unmet needs of the key stakeholders of rare diseases. Finally, we define the vision, mission, goals and objectives of ORDI, identify the key developments in the health care context in India and welcome community feedback and comments on our approach.


Subject(s)
Health Services Accessibility/economics , Organizations, Nonprofit/organization & administration , Patient Advocacy , Rare Diseases/epidemiology , Rare Diseases/therapy , Humans , India/epidemiology , Organizational Objectives
20.
Proc Natl Acad Sci U S A ; 110(33): 13481-6, 2013 Aug 13.
Article in English | MEDLINE | ID: mdl-23901115

ABSTRACT

Synonymous mutations, which do not alter the protein sequence, have been shown to affect protein function [Sauna ZE, Kimchi-Sarfaty C (2011) Nat Rev Genet 12(10):683-691]. However, synonymous mutations are rarely investigated in the cancer genomics field. We used whole-genome and -exome sequencing to identify somatic mutations in 29 melanoma samples. Validation of one synonymous somatic mutation in BCL2L12 in 285 samples identified 12 cases that harbored the recurrent F17F mutation. This mutation led to increased BCL2L12 mRNA and protein levels because of differential targeting of WT and mutant BCL2L12 by hsa-miR-671-5p. Protein made from mutant BCL2L12 transcript bound p53, inhibited UV-induced apoptosis more efficiently than WT BCL2L12, and reduced endogenous p53 target gene transcription. This report shows selection of a recurrent somatic synonymous mutation in cancer. Our data indicate that silent alterations have a role to play in human cancer, emphasizing the importance of their investigation in future cancer genome studies.


Subject(s)
Apoptosis/genetics , Gene Expression Regulation/genetics , Genome, Human/genetics , Melanoma/genetics , Muscle Proteins/genetics , Proto-Oncogene Proteins c-bcl-2/genetics , Base Sequence , Blotting, Western , DNA Primers/genetics , Exome/genetics , Genetic Vectors/genetics , HEK293 Cells , Humans , Immunoprecipitation , Lentivirus , MicroRNAs/genetics , Molecular Sequence Data , Muscle Proteins/metabolism , Mutation/genetics , Polymorphism, Single Nucleotide/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , RNA, Small Interfering/genetics , Real-Time Polymerase Chain Reaction , Sequence Analysis, DNA , Tumor Suppressor Protein p53/metabolism
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