scholarly journals Genetically engineered pigs manifesting pancreatic agenesis with severe diabetes

2020 ◽  
Vol 8 (2) ◽  
pp. e001792
Author(s):  
Masaki Nagaya ◽  
Koki Hasegawa ◽  
Masahito Watanabe ◽  
Kazuaki Nakano ◽  
Kazutoshi Okamoto ◽  
...  
Keyword(s):  
Perinatal Death ◽  
Treatment Strategies ◽  
Genetically Engineered ◽  
Helix Loop Helix ◽  
Severe Diabetes ◽  
Bhlh Genes ◽  
Undifferentiated Cells ◽  
Pancreatic Agenesis ◽  
Novel Treatment Strategies ◽  
Design And Methods

IntroductionPancreatic duodenum homeobox 1 (Pdx1) expression is crucial for pancreatic organogenesis and is a key regulator of insulin gene expression. Hairy and enhancer of split 1 (Hes1) controls tissue morphogenesis by maintaining undifferentiated cells. Hes1 encodes a basic helix loop helix (bHLH) transcriptional repressor and functionally antagonizes positive bHLH genes, such as the endocrine determination gene neurogenin-3. Here, we generated a new pig model for diabetes by genetic engineering Pdx1 and Hes1 genes.Research design and methodsA transgenic (Tg) chimera pig with germ cells carrying a construct expressing Hes1 under the control of the Pdx1 promoter was used to mate with wild-type gilts to obtain Tg piglets.ResultsThe Tg pigs showed perinatal death; however, this phenotype could be rescued by insulin treatment. The duodenal and splenic lobes of the Tg pigs were slender and did not fully develop, whereas the connective lobe was absent. β cells were not detected, even in the adult pancreas, although other endocrine cells were detected, and exocrine cells functioned normally. The pigs showed no irregularities in any organs, except diabetes-associated pathological alterations, such as retinopathy and renal damage.ConclusionPdx1-Hes1 Tg pigs were an attractive model for the analysis of pancreatic development and testing of novel treatment strategies for diabetes.

scholarly journals Contemporary Mouse Models in Glioma Research

2021 ◽  
Author(s):  
William Hicks ◽  
Cylaina Bird ◽  
Kalil Abdullah
Keyword(s):  
Disease Modeling ◽  
Treatment Strategies ◽  
Genetically Engineered ◽  
Current Status ◽  
Molecular Heterogeneity ◽  
Lower Grade ◽  
Idh Mutations ◽  
Novel Treatment Strategies ◽  
Murine Glioma

Despite advances in understanding of the molecular pathogenesis of glioma, outcomes remain dismal. Developing successful treatments for glioma requires faithful in vivo disease modeling and rigorous preclinical testing. Murine models, including xenograft, syngeneic, and genetically engineered models, are used to study gliomagenesis, identify methods of tumor progression, and test novel treatment strategies. Since the discovery of highly recurrent isocitrate dehydrogenase (IDH) mutations in lower-grade gliomas, there is increasing emphasis on effective modeling of IDH mutant brain tumors. Improvements in preclinical models that capture the phenotypic and molecular heterogeneity of gliomas are critical for the development of effective new therapies. Herein, we explore the current status, advancements, and challenges with contemporary murine glioma models.

scholarly journals Entry of Human Coronavirus NL63 into the Cell

2017 ◽  
Vol 92 (3) ◽  
Author(s):  
Aleksandra Milewska ◽  
Paulina Nowak ◽  
Katarzyna Owczarek ◽  
Artur Szczepanski ◽  
Miroslaw Zarebski ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Three Dimensional ◽  
Treatment Strategies ◽  
Infection Process ◽  
Target Cells ◽  
Human Coronavirus ◽  
Actin Cortex ◽  
Undifferentiated Cells ◽  
Novel Treatment Strategies ◽  
Immortalized Cell

ABSTRACT The first steps of human coronavirus NL63 (HCoV-NL63) infection were previously described. The virus binds to target cells by use of heparan sulfate proteoglycans and interacts with the ACE2 protein. Subsequent events, including virus internalization and trafficking, remain to be elucidated. In this study, we mapped the process of HCoV-NL63 entry into the LLC-Mk2 cell line and ex vivo three-dimensional (3D) tracheobronchial tissue. Using a variety of techniques, we have shown that HCoV-NL63 virions require endocytosis for successful entry into the LLC-MK2 cells, and interaction between the virus and the ACE2 molecule triggers recruitment of clathrin. Subsequent vesicle scission by dynamin results in virus internalization, and the newly formed vesicle passes the actin cortex, which requires active cytoskeleton rearrangement. Finally, acidification of the endosomal microenvironment is required for successful fusion and release of the viral genome into the cytoplasm. For 3D tracheobronchial tissue cultures, we also observed that the virus enters the cell by clathrin-mediated endocytosis, but we obtained results suggesting that this pathway may be bypassed. IMPORTANCE Available data on coronavirus entry frequently originate from studies employing immortalized cell lines or undifferentiated cells. Here, using the most advanced 3D tissue culture system mimicking the epithelium of conductive airways, we systematically mapped HCoV-NL63 entry into susceptible cells. The data obtained allow for a better understanding of the infection process and may support development of novel treatment strategies.

scholarly journals Contemporary Mouse Models in Glioma Research

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 712
Author(s):  
William H. Hicks ◽  
Cylaina E. Bird ◽  
Jeffrey I. Traylor ◽  
Diana D. Shi ◽  
Tarek Y. El Ahmadieh ◽  
...  
Keyword(s):  
Disease Modeling ◽  
Treatment Strategies ◽  
Genetically Engineered ◽  
Current Status ◽  
Molecular Heterogeneity ◽  
Lower Grade ◽  
Idh Mutations ◽  
Novel Treatment Strategies ◽  
Murine Glioma

Despite advances in understanding of the molecular pathogenesis of glioma, outcomes remain dismal. Developing successful treatments for glioma requires faithful in vivo disease modeling and rigorous preclinical testing. Murine models, including xenograft, syngeneic, and genetically engineered models, are used to study glioma-genesis, identify methods of tumor progression, and test novel treatment strategies. Since the discovery of highly recurrent isocitrate dehydrogenase (IDH) mutations in lower-grade gliomas, there is increasing emphasis on effective modeling of IDH mutant brain tumors. Improvements in preclinical models that capture the phenotypic and molecular heterogeneity of gliomas are critical for the development of effective new therapies. Herein, we explore the current status, advancements, and challenges with contemporary murine glioma models.

scholarly journals Novel Treatments and Technologies Applied to the Cure of Neuroblastoma

Children ◽  
2021 ◽  
Vol 8 (6) ◽  
pp. 482
Author(s):  
Irene Paraboschi ◽  
Laura Privitera ◽  
Gabriela Kramer-Marek ◽  
John Anderson ◽  
Stefano Giuliani
Keyword(s):  
Research Effort ◽  
Treatment Strategies ◽  
Adverse Outcomes ◽  
Treatment Protocols ◽  
Ongoing Research ◽  
Hematopoietic Stem ◽  
Novel Treatments ◽  
Therapeutic Modalities ◽  
High Risk Disease ◽  
Novel Treatment Strategies

Neuroblastoma (NB) is the most common extracranial solid tumour in childhood, accounting for approximately 15% of all cancer-related deaths in the paediatric population1. It is characterised by heterogeneous clinical behaviour in neonates and often adverse outcomes in toddlers. The overall survival of children with high-risk disease is around 40–50% despite the aggressive treatment protocols consisting of intensive chemotherapy, surgery, radiation therapy and hematopoietic stem cell transplantation2,3. There is an ongoing research effort to increase NB’s cellular and molecular biology knowledge to translate essential findings into novel treatment strategies. This review aims to address new therapeutic modalities emerging from preclinical studies offering a unique translational opportunity for NB treatment.

scholarly journals Immune Cell Modulation of the Extracellular Matrix Contributes to the Pathogenesis of Pancreatic Cancer

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 901
Author(s):  
Ramiz S. Ahmad ◽  
Timothy D. Eubank ◽  
Slawomir Lukomski ◽  
Brian A. Boone
Keyword(s):  
Pancreatic Cancer ◽  
Extracellular Matrix ◽  
Immune Cells ◽  
Immune Cell ◽  
Treatment Strategies ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Cellular Mechanisms ◽  
Novel Treatment Strategies

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a five-year survival rate of only 9%. PDAC is characterized by a dense, fibrotic stroma composed of extracellular matrix (ECM) proteins. This desmoplastic stroma is a hallmark of PDAC, representing a significant physical barrier that is immunosuppressive and obstructs penetration of cytotoxic chemotherapy agents into the tumor microenvironment (TME). Additionally, dense ECM promotes hypoxia, making tumor cells refractive to radiation therapy and alters their metabolism, thereby supporting proliferation and survival. In this review, we outline the significant contribution of fibrosis to the pathogenesis of pancreatic cancer, with a focus on the cross talk between immune cells and pancreatic stellate cells that contribute to ECM deposition. We emphasize the cellular mechanisms by which neutrophils and macrophages, specifically, modulate the ECM in favor of PDAC-progression. Furthermore, we investigate how activated stellate cells and ECM influence immune cells and promote immunosuppression in PDAC. Finally, we summarize therapeutic strategies that target the stroma and hinder immune cell promotion of fibrogenesis, which have unfortunately led to mixed results. An enhanced understanding of the complex interactions between the pancreatic tumor ECM and immune cells may uncover novel treatment strategies that are desperately needed for this devastating disease.

scholarly journals Current Insights into Immunology and Novel Therapeutics of Atopic Dermatitis

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1392
Author(s):  
Hidaya A. Kader ◽  
Muhammad Azeem ◽  
Suhib A. Jwayed ◽  
Aaesha Al-Shehhi ◽  
Attia Tabassum ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Skin Diseases ◽  
Current Knowledge ◽  
Treatment Strategies ◽  
Developed Countries ◽  
Food Allergies ◽  
Th2 Response ◽  
Therapeutic Outcomes ◽  
Environmental Agents ◽  
Novel Treatment Strategies

Atopic dermatitis (AD) is one of the most prevalent inflammatory disease among non-fatal skin diseases, affecting up to one fifth of the population in developed countries. AD is characterized by recurrent pruritic and localized eczema with seasonal fluctuations. AD initializes the phenomenon of atopic march, during which infant AD patients are predisposed to progressive secondary allergies such as allergic rhinitis, asthma, and food allergies. The pathophysiology of AD is complex; onset of the disease is caused by several factors, including strong genetic predisposition, disrupted epidermal barrier, and immune dysregulation. AD was initially characterized by defects in the innate immune system and a vigorous skewed adaptive Th2 response to environmental agents; there are compelling evidences that the disorder involves multiple immune pathways. Symptomatic palliative treatment is the only strategy to manage the disease and restore skin integrity. Researchers are trying to more precisely define the contribution of different AD genotypes and elucidate the role of various immune axes. In this review, we have summarized the current knowledge about the roles of innate and adaptive immune responsive cells in AD. In addition, current and novel treatment strategies for the management of AD are comprehensively described, including some ongoing clinical trials and promising therapeutic agents. This information will provide an asset towards identifying personalized targets for better therapeutic outcomes.

scholarly journals Molecular mechanisms underpinning sarcomas and implications for current and future therapy

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Victoria Damerell ◽  
Michael S. Pepper ◽  
Sharon Prince
Keyword(s):  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Treatment Strategies ◽  
Mesenchymal Transition ◽  
Mesenchymal To Epithelial Transition ◽  
Cells Of Origin ◽  
Novel Treatment Strategies ◽  
Future Therapy

AbstractSarcomas are complex mesenchymal neoplasms with a poor prognosis. Their clinical management is highly challenging due to their heterogeneity and insensitivity to current treatments. Although there have been advances in understanding specific genomic alterations and genetic mutations driving sarcomagenesis, the underlying molecular mechanisms, which are likely to be unique for each sarcoma subtype, are not fully understood. This is in part due to a lack of consensus on the cells of origin, but there is now mounting evidence that they originate from mesenchymal stromal/stem cells (MSCs). To identify novel treatment strategies for sarcomas, research in recent years has adopted a mechanism-based search for molecular markers for targeted therapy which has included recapitulating sarcomagenesis using in vitro and in vivo MSC models. This review provides a comprehensive up to date overview of the molecular mechanisms that underpin sarcomagenesis, the contribution of MSCs to modelling sarcomagenesis in vivo, as well as novel topics such as the role of epithelial-to-mesenchymal-transition (EMT)/mesenchymal-to-epithelial-transition (MET) plasticity, exosomes, and microRNAs in sarcomagenesis. It also reviews current therapeutic options including ongoing pre-clinical and clinical studies for targeted sarcoma therapy and discusses new therapeutic avenues such as targeting recently identified molecular pathways and key transcription factors.

scholarly journals Unique Genomic Landscape of High-Grade Neuroendocrine Cervical Carcinoma: Implications for Rethinking Current Treatment Paradigms

2020 ◽  
pp. 972-987
Author(s):  
Ramez N. Eskander ◽  
Julia Elvin ◽  
Laurie Gay ◽  
Jeffrey S. Ross ◽  
Vincent A. Miller ◽  
...  
Keyword(s):  
Treatment Strategies ◽  
Current Treatment ◽  
High Grade ◽  
Novel Treatment ◽  
Sample Average ◽  
Genomic Landscape ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Sample Range ◽  
Novel Treatment Strategies

PURPOSE High-grade neuroendocrine cervical cancer (HGNECC) is an uncommon malignancy with limited therapeutic options; treatment is patterned after the histologically similar small-cell lung cancer (SCLC). To better understand HGNECC biology, we report its genomic landscape. PATIENTS AND METHODS Ninety-seven patients with HGNECC underwent comprehensive genomic profiling (182-315 genes). These results were subsequently compared with a cohort of 1,800 SCLCs. RESULTS The median age of patients with HGNECC was 40.5 years; 83 patients (85.6%) harbored high-risk human papillomavirus (HPV). Overall, 294 genomic alterations (GAs) were identified (median, 2 GAs/sample; average, 3.0 GAs/sample, range, 0-25 GAs/sample) in 109 distinct genes. The most frequently altered genes were PIK3CA (19.6% of cohort), MYC (15.5%), TP53 (15.5%), and PTEN (14.4%). RB1 GAs occurred in 4% versus 32% of HPV-positive versus HPV-negative tumors ( P < .0001). GAs in HGNECC involved the following pathways: PI3K/AKT/mTOR (41.2%); RAS/MEK (11.3%); homologous recombination (9.3%); and ERBB (7.2%). Two tumors (2.1%) had high tumor mutational burden (TMB; both with MSH2 alterations); 16 (16.5%) had intermediate TMB. Seventy-one patients (73%) had ≥ 1 alteration that was theoretically druggable. Comparing HGNECC with SCLC, significant differences in TMB, microsatellite instability, HPV-positive status, and in PIK3CA, MYC, PTEN, TP53, ARID1A, and RB1 alteration rates were found. CONCLUSION This large cohort of patients with HGNECC demonstrated a genomic landscape distinct from SCLC, calling into question the biologic and therapeutic relevance of the histologic similarities between the entities. Furthermore, 73% of HGNECC tumors had potentially actionable alterations, suggesting novel treatment strategies for this aggressive malignancy.

scholarly journals A Classification of Basic Helix-Loop-Helix Transcription Factors of Soybean

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Karen A. Hudson ◽  
Matthew E. Hudson
Keyword(s):  
Transcription Factors ◽  
Genome Sequence ◽  
Search Algorithm ◽  
Soybean Genome ◽  
Binding Potential ◽  
Future Research ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
Bhlh Genes ◽  
Wide Range

The complete genome sequence of soybean allows an unprecedented opportunity for the discovery of the genes controlling important traits. In particular, the potential functions of regulatory genes are a priority for analysis. The basic helix-loop-helix (bHLH) family of transcription factors is known to be involved in controlling a wide range of systems critical for crop adaptation and quality, including photosynthesis, light signalling, pigment biosynthesis, and seed pod development. Using a hidden Markov model search algorithm, 319 genes with basic helix-loop-helix transcription factor domains were identified within the soybean genome sequence. These were classified with respect to their predicted DNA binding potential, intron/exon structure, and the phylogeny of the bHLH domain. Evidence is presented that the vast majority (281) of these 319 soybean bHLH genes are expressed at the mRNA level. Of these soybean bHLH genes, 67% were found to exist in two or more homeologous copies. This dataset provides a framework for future studies on bHLH gene function in soybean. The challenge for future research remains to define functions for the bHLH factors encoded in the soybean genome, which may allow greater flexibility for genetic selection of growth and environmental adaptation in this widely grown crop.

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