A5056864152- Occupational and environmental lung diseases
- CRISPR and Genetic Engineering
- Epigenetics and DNA Methylation
- Lung Cancer Treatments and Mutations
- RNA regulation and disease
- Virus-based gene therapy research
- RNA modifications and cancer
- RNA Interference and Gene Delivery
- Fibroblast Growth Factor Research
- Cancer Genomics and Diagnostics
- Tissue Engineering and Regenerative Medicine
- RNA and protein synthesis mechanisms
- Autophagy in Disease and Therapy
- Endoplasmic Reticulum Stress and Disease
- Cytomegalovirus and herpesvirus research
- Cancer, Hypoxia, and Metabolism
- PI3K/AKT/mTOR signaling in cancer
- Peptidase Inhibition and Analysis
- Tracheal and airway disorders
- Lung Cancer Research Studies
- Vibrio bacteria research studies
- Phagocytosis and Immune Regulation
- Aquaculture disease management and microbiota
- RNA Research and Splicing
- Viral gastroenteritis research and epidemiology
Twin Cities Orthopedics
2024-2025
University of Minnesota
2024-2025
University Hospital of Bern
2015-2024
University of Bern
2018-2024
University of Massachusetts Chan Medical School
2019-2024
East China University of Science and Technology
2011-2012
Abstract Prime editors (PEs) mediate genome modification without utilizing double-stranded DNA breaks or exogenous donor as a template. PEs facilitate nucleotide substitutions local insertions deletions within the based on template sequence encoded prime editing guide RNA (pegRNA). However, efficacy of in adult mice has not been established. Here we report an NLS-optimized SpCas9-based editor that improves efficiency both fluorescent reporter cells and at endogenous loci cultured cell lines....
Prime editor (PE) has tremendous promise for gene therapy. However, it remains a challenge to deliver PE (>6.3 kb) in vivo. Although can be split into two fragments and delivered using dual adeno-associated viruses (AAVs), choice of sites within Cas9-which affects editing efficiency-is limited due the large size PE. Furthermore, overexpressing reverse transcriptase mammalian cells might disrupt translation termination via its RNase H domain. Here, we developed compact without domain that...
CRISPR-Cas systems are bacterial adaptive immune pathways that have revolutionized biotechnology and biomedical applications. Despite the potential for human therapeutic development, there many hurdles must be overcome before its use in clinical settings. Some safety concerns arise from editing activity unintended cell types or tissues upon vivo delivery (e.g., by adeno-associated virus (AAV) vectors). Although tissue-specific promoters serotypes with tissue tropisms can used, suitably...
Abstract Anticancer therapies currently used in the clinic often can neither eradicate tumor nor prevent disease recurrence due to resistance. In this study, we showed that chemoresistance pemetrexed, a multi-target anti-folate (MTA) chemotherapeutic agent for non-small cell lung cancer (NSCLC), is associated with stem cell-like phenotype characterized by an enriched gene signature, augmented aldehyde dehydrogenase activity and greater clonogenic potential. Mechanistically, MTA requires...
Abstract Analysis of off-target editing is an important aspect the development safe nuclease-based genome therapeutics. in vivo assessment nuclease activity has primarily been indirect (based on discovery vitro, cells or via computational prediction) through ChIP-based detection double-strand break (DSB) DNA repair factors, which can be cumbersome. Herein we describe GUIDE-tag, enables one-step, analysis mouse liver and lung. The GUIDE-tag system utilizes tethering between Cas9 donor to...
Drug resistance and tumor heterogeneity are formidable challenges in cancer medicine, which is particularly relevant for KRAS-mutant cancers, the epitome of malignant tumors recalcitrant to targeted therapy efforts first-line chemotherapy. In this study, we delineate that lung cells resistant pemetrexed (MTA) anti-MEK drug trametinib acquire an exquisite dependency on endoplasmic reticulum (ER) stress signaling, rendering selectively susceptible blockage HSP90, receptor tyrosine kinase AXL,...
Genome editing in the lung has potential to provide long-term expression of therapeutic protein treat genetic diseases. Yet efficient delivery CRISPR remains a challenge. The NIH Somatic Cell Editing (SCGE) Consortium is developing safe and effective methods for genome disease tissues. Methods developed by consortium members are independently validated SCGE small animal testing center establish rigor reproducibility. We have dual adeno-associated virus (AAV) platform that supports...
Standard treatment for advanced malignant pleural mesothelioma (MPM) is a cisplatin/pemetrexed (MTA) regimen; however, this confronted by drug resistance. Proteotoxic stress in the endoplasmic reticulum (ER) hallmark of cancer and some rely on signalling response to cytotoxic chemotherapeutics. We hypothesise that ER adaptive unfolded protein (UPR) play role chemotherapy resistance MPM. In vitro three-dimensional (3D) ex vivo organotypic culture were used enrich chemotherapy-resistant...
Malignant pleural mesothelioma (MPM) is a lethal cancer with limited treatment options. No targeted therapy has emerged yet. Here, we performed an integrated molecular characterization of patient tumors in the TCGA dataset, and discovered that endoplasmic reticulum (ER) stress adaptive unfolded protein response (UPR) signaling are characteristically deregulated MPM. Consequently, pharmacological perturbation ER stress/UPR axis by HA15, agent induces persistent proteotoxic ER, selectively...
While prime editing offers improved precision compared to traditional CRISPR-Cas9 systems, concerns remain regarding potential off-target effects, including epigenetic changes such as DNA methylation. In this study, we investigated whether induces aberrant CpG methylation patterns. Whole-genome bisulfite sequencing revealed overall similarity between Cas9-edited, and PE2-edited cells. However, localized were observed, particularly in islands exon regions. The group showed a higher proportion...
Malignant pleural mesothelioma (MPM) is an aggressive cancer with dismal prognosis, largely due to poor response rates and rapid relapse after first-line pemetrexed (MTA)/cisplatin chemotherapy. A better understanding of the molecular mechanisms underlying chemotherapy sensitivity duration represents a significant but still unmet clinical need. In this study, we reported on kinome CRISPR/Cas9 knockout screen that identified several G2-M checkpoint kinases, including WEE1, whose loss function...
Oncogenic KRAS mutations are prevalent in human cancers, but effective treatment of KRAS-mutant malignancies remains a major challenge the clinic. Increasing evidence suggests that aberrant metabolism plays central role KRAS-driven oncogenic transformation. The aim this study is to identify selective metabolic dependency induced by mutant and exploit it for disease. We performed an integrated analysis RNAi- CRISPR-based functional genomic datasets (n = 5) novel genes selectively required...
Subcellullar localizations and cross-immunities of GAPDHs from six common pathogenic bacteria in aquaculture were investigated.Subcellullar Edwardsiella tarda EIB202, ictaluri ATCC33202, Aeromonas hydrophila LSA34, Vibrio anguillarum MVM425, alginolyticus EPGS020401 harveyi VIB647 analysed with Western blotting, indirect immunofluorescence flow cytometry examinations. Immunoprotections different recombinant against these pathogens investigated zebrafish model. blotting subcellular...
Malignant pleural mesothelioma (MPM) is a lethal malignancy etiologically caused by asbestos exposure, for which there are few effective treatment options. Although carcinogenesis associated with reactive oxygen species (ROS), the bona fide oncogenic signaling pathways that regulate ROS homeostasis and bypass ROS-evoked apoptosis in MPM poorly understood. In this study, we demonstrate mitogen-activated protein kinase (MAPK) pathway RAS-RAF-MEK-ERK hyperactive molecular driver of MPM,...
Oncogenic activation of the FGFR pathway is frequent in lung and other cancers. However, due to drug resistance, pharmacological blockage aberrant signaling has provided little clinical benefit patients with FGFR-amplified tumors. The determining factors for limited efficacy FGFR-targeted therapy remain incompletely understood. In this study, we performed kinome-wide CRISPR/Cas9 loss-of-function screens FGFR1-amplified cancer cells treated an inhibitor. These identified PLK1 as a potent...
Escape from programmed cell death is a hallmark of cancer. In this study, we investigated the anti-apoptotic mechanisms and explored therapeutic potential BCL-2 homology domain-3 (BH3) mimetics in malignant pleural mesothelioma (MPM), lethal thoracic malignancy with an extreme dearth treatment options. By implementing integrated analysis functional genomic data MPM cells quantitative proteomics patients' tumors, identified BCL-XL as driver that overexpressed confers oncogenic dependency MPM....