scholarly journals TMOD-03. SOMATIC MUTATIONS OF CHROMATIN REGULATOR Kmt2d IN CEREBELLAR PRECURSORS INFLUENCES SHH-MEDULLOBLASTOMA TUMORIGENESIS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi263-vi263
Author(s):  
Reeti Sanghrajka ◽  
I-li Tan ◽  
Alexandre Wojcinski ◽  
Harikrishna Rallapalli ◽  
Daniel Turnbull ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Mouse Models ◽  
Somatic Mutations ◽  
Early Stage ◽  
Pediatric Brain Tumor ◽  
Gene Encoding ◽  
Positive Correlation ◽  
Activating Mutations ◽  
Shh Pathway ◽  
Chromatin Regulator

Abstract Medulloblastoma (MB), the most common malignant pediatric brain tumor, is a classic example of dysregulation of developmental pathways leading to tumorogenesis. Despite advancements in multi-modal therapies, most patients suffer from long-term neurocognitive and neuroendocrine disabilities. The Sonic Hedgehog subgroup of MB (SHH-MB) accounts for ~30% of all cases and originates from ATOH1+ cerebellar granule cell precursors (GCPs). Experimental data in mice has shown that activating mutations in the SHH pathway induce tumors only in rare GCPs, suggesting that additional mutations and epigenetic changes are required to influence tumor progression. The KMT2D gene, encoding the histone-lysine N-methyltransferase 2D, is amongst the ten most frequently mutated genes in MB, with somatic mutations seen in ~15% of all SHH-MB patients. We developed sporadic mouse models of SHH-MB with a low penetrance to enable studies of secondary mutations (Tan, PNAS, 2018). Immunofluorescence staining for KMT2D on early-stage SHH-MB lesions, mid-stage and late-stage tumors revealed that a subset of lesions/tumors (16/98) do not express KMT2D and are negative for H3K4me3. Interestingly, P53 and KMT2D expression showed a positive correlation in ~94% of tumors/lesions and NeuN and KMT2D showed a positive correlation in ~92% of tumors/lesions. In order to determine the roles for KMT2D in GCP proliferation and differentiation, and uncover whether and how KMT2D promotes SHH-MB tumorigenesis, we are using genetic mouse-models whereby Kmt2d is heterozygously or homozygously deleted alone, or in conjunction with activation of the SHH pathway. Mice with SHH-MB tumors expressing SmoM2 and a loss of Kmt2d develop aggressive tumors at high penetrance, with metastatic leptomeningeal spread in the brain stem and spinal cord. Thus, loss of Kmt2d increases SHH-MB tumor progression and leads to malignancy. Ongoing studies are determining how the chromatin landscape and gene expression are changed when Kmt2d is deleted in GCPs.

scholarly journals Early alterations of neurovascular unit in the retina in mouse models of tauopathy

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Fan Xia ◽  
Yonju Ha ◽  
Shuizhen Shi ◽  
Yi Li ◽  
Shengguo Li ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Mouse Models ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Leukocyte Adhesion ◽  
Neurovascular Unit ◽  
Integrated Analysis ◽  
Therapeutic Effects ◽  
Retinal Ganglion ◽  
Potential Biomarker

AbstractThe retina, as the only visually accessible tissue in the central nervous system, has attracted significant attention for evaluating it as a biomarker for neurodegenerative diseases. Yet, most of studies focus on characterizing the loss of retinal ganglion cells (RGCs) and degeneration of their axons. There is no integrated analysis addressing temporal alterations of different retinal cells in the neurovascular unit (NVU) in particular retinal vessels. Here we assessed NVU changes in two mouse models of tauopathy, P301S and P301L transgenic mice overexpressing the human tau mutated gene, and evaluated the therapeutic effects of a tau oligomer monoclonal antibody (TOMA). We found that retinal edema and breakdown of blood–retina barrier were observed at the very early stage of tauopathy. Leukocyte adhesion/infiltration, and microglial recruitment/activation were constantly increased in the retinal ganglion cell layer of tau transgenic mice at different ages, while Müller cell gliosis was only detected in relatively older tau mice. Concomitantly, the number and function of RGCs progressively decreased during aging although they were not considerably altered in the very early stage of tauopathy. Moreover, intrinsically photosensitive RGCs appeared more sensitive to tauopathy. Remarkably, TOMA treatment in young tau transgenic mice significantly attenuated vascular leakage, inflammation and RGC loss. Our data provide compelling evidence that abnormal tau accumulation can lead to pathology in the retinal NVU, and vascular alterations occur more manifest and earlier than neurodegeneration in the retina. Oligomeric tau-targeted immunotherapy has the potential to treat tau-induced retinopathies. These data suggest that retinal NVU may serve as a potential biomarker for diagnosis and staging of tauopathy as well as a platform to study the molecular mechanisms of neurodegeneration.

scholarly journals Abstract 2936: Ago2 induces Kras signaling and promotes tumor progression in mouse models of lung adenocarcinoma

2021 ◽  
Author(s):  
Jean C. Tien ◽  
Seema Chugh ◽  
Andrew E. Goodrum ◽  
Yunhui Cheng ◽  
Lisha Wang ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Tumor Progression ◽  
Mouse Models

scholarly journals WNK4 Kinase: from structure to physiology

2021 ◽  
Author(s):  
Adrian Rafael Murillo-de-Ozores ◽  
Alejandro Rodriguez-Gama ◽  
Hector Carbajal-Contreras ◽  
Gerardo Gamba ◽  
Maria Castaneda-Bueno
Keyword(s):  
Oxidative Stress ◽  
Mouse Models ◽  
Serine Threonine Kinase ◽  
Gene Encoding ◽  
Threonine Kinase ◽  
Physiological Conditions ◽  
Different Levels ◽  
Familial Hyperkalemic Hypertension

With No Lysine (K) kinase 4 (WNK4) belongs to a serine-threonine kinase family characterized by the atypical positioning of its catalytic lysine. Despite the fact that WNK4 has been found in many tissues, the majority of its study has revolved around its function in the kidney, specifically as a positive regulator of the thiazide-sensitive NaCl cotransporter (NCC) in the distal convoluted tubule (DCT) of the nephron. This is explained by the description of gain-of-function mutations in the gene encoding WNK4 that cause Familial Hyperkalemic Hypertension (FHHt). This disease is mainly driven by increased downstream activation of the Ste20-related Proline Alanine Rich Kinase (SPAK)/Oxidative Stress Responsive Kinase 1 (OSR1)-NCC pathway, which increases salt reabsorption in the DCT and indirectly impairs renal K+ secretion. Here, we review the large volume of information that has accumulated about different aspects of WNK4 function. We first review the knowledge on WNK4 structure and enumerate the functional domains and motifs that have been characterized. Then, we discuss WNK4 physiological functions based on the information obtained from in vitro studies and from a diverse set of genetically modified mouse models with altered WNK4 function. We then review in vitro and in vivo evidence on the different levels of regulation of WNK4. Finally, we go through the evidence that has suggested how different physiological conditions act through WNK4 to modulate NCC activity.

scholarly journals Combination of Urine Exosomal mRNAs and lncRNAs as Novel Diagnostic Biomarkers for Bladder Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Haiming Huang ◽  
Jialin Du ◽  
Bo Jin ◽  
Lu Pang ◽  
Nan Duan ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Tumor Progression ◽  
Rna Sequencing ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Healthy Controls ◽  
Direct Products ◽  
Diagnostic Biomarkers ◽  
Diagnostic Potential ◽  
Urine Exosomes

BackgroundThe recent discovery of miRNAs and lncRNAs in urine exosomes has emerged as promising diagnostic biomarkers for bladder cancer (BCa). However, mRNAs as the direct products of transcription has not been well evaluated in exosomes as biomarkers for BCa diagnosis. The purpose of this study was to identify tumor progression-related mRNAs and lncRNAs in urine exosomes that could be used for detection of BCa.MethodsRNA-sequencing was performed to identify tumor progression-related biomarkers in three matched superficial tumor and deep infiltrating tumor regions of muscle-invasive bladder cancer (MIBC) specimens, differently expressed mRNAs and lncRNAs were validated in TCGA dataset (n = 391) in the discovery stage. Then candidate RNAs were chosen for evaluation in urine exosomes of a training cohort (10 BCa and 10 healthy controls) and a validation cohort (80 BCa and 80 healthy controls) using RT-qPCR. The diagnostic potential of the candidates were evaluated by receiver operating characteristic (ROC) curves.ResultsRNA sequencing revealed 8 mRNAs and 32 lncRNAs that were significantly upregulated in deep infiltrating tumor region. After validation in TCGA database, 10 markedly dysregulated RNAs were selected for further investigation in urine exosomes, of which five (mRNAs: KLHDC7B, CASP14, and PRSS1; lncRNAs: MIR205HG and GAS5) were verified to be significantly dysregulated. The combination of the five RNAs had the highest AUC to disguising the BCa (0.924, 95% CI, 0.875–0.974) or early stage BCa patients (0.910, 95% CI, 0.850 to 0.971) from HCs. The expression levels of these five RNAs were correlated with tumor stage, grade, and hematuria degrees.ConclusionsThese findings highlight the potential of urine exosomal mRNAs and lncRNAs profiling in the early diagnosis and provide new insights into the molecular mechanisms involved in BCa.

scholarly journals Influence of Pars Plana Vitrectomy on Ocular Surface using Non-Invasive Keratograph 5M

2018 ◽  
Author(s):  
Lingling Fan ◽  
Lun Liu ◽  
Jian Gao ◽  
Jie Zheng ◽  
Yajing Xu ◽  
...  
Keyword(s):  
Ocular Surface ◽  
Pars Plana Vitrectomy ◽  
Significant Positive Correlation ◽  
Early Stage ◽  
Ocular Surface Disease Index ◽  
Preoperative Level ◽  
Positive Correlation ◽  
Surface Damages ◽  
Pars Plana ◽  
Tear Meniscus Height

Abstract Background: The noninvasive Keratography has been used in evaluating surgery-induced ocular surface changes, while few were known about the influence of pars plana vitrectomy (PPV) on ocular surface. This study aimed to evaluate the influence of PPV on ocular surface using Keratograph 5M. Methods: 30 patients (30 eyes) undergoing primary PPV were recruited in the study. Ocular Surface Disease Index (OSDI) questionnaire was performed. Ocular surface parameters, including tear meniscus height (TMH), noninvasive tear break up time (NITBUT) and bulbar redness score were obtained preoperatively, at 1 week, 2 weeks, 4 weeks, 8 weeks and 12 weeks postoperatively by Keratograph 5M. Correlations between all the clinical parameters were analyzed further. Results: The percentages of both photophobia and gritty within 4 weeks after PPV were significantly higher than preoperation, while they decreased to the preoperative levels at both 8 weeks and 12 weeks postoperatively. The percentage of sore eyes within 2 weeks postoperatively was significantly higher than preoperation, but there were no significant differences between the percentages of preoperation and 4 weeks, 8 weeks and 12 weeks postoperatively. OSDI score increased significantly within 8 weeks postoperatively, but it returned to the preoperative level at 12 weeks. TMH was increased significantly at the first week after PPV, and recoverd to preoperative level at 2 weeks postoperatively. Both NITBUT-first and NITBUT-average shortened significantly within 8 weeks postoperatively, but they gradually improved to the preoperative levels at 12 weeks. Bulbar redness score was significantly higher than preoperative level within 4 weeks postoperatively, but it returned to the preoperative level at 8 weeks. NITBUT-first and NITBUT-average had a significant positive correlation at each visit. OSDI score had a significant positive correlation with bulbar redness, and TMH had a significant positive correlation with NITBUT-average at both 1 week and 2 weeks postoperatively. Conclusions: Keratograph 5M can provide a reliable noninvasive method to assess the influence of PPV on ocular surface. PPV may cause various changes in both symptoms and signs of ocular surface damages at an early stage, while all these changes will return to preoperative levels gradually at 12 weeks postoperatively.

scholarly journals Unregulated actin polymerization by WASp causes defects of mitosis and cytokinesis in X-linked neutropenia

2007 ◽  
Vol 204 (9) ◽  
pp. 2213-2224 ◽  
Author(s):  
Dale A. Moulding ◽  
Michael P. Blundell ◽  
David G. Spiller ◽  
Michael R.H. White ◽  
Giles O. Cory ◽  
...  
Keyword(s):  
Live Cell Imaging ◽  
Actin Polymerization ◽  
Cell Imaging ◽  
Human Gene ◽  
Filamentous Actin ◽  
Gene Encoding ◽  
Activating Mutations ◽  
Spindle Midzone ◽  
Underlying Mechanisms ◽  
Syndrome Protein

Specific mutations in the human gene encoding the Wiskott-Aldrich syndrome protein (WASp) that compromise normal auto-inhibition of WASp result in unregulated activation of the actin-related protein 2/3 complex and increased actin polymerizing activity. These activating mutations are associated with an X-linked form of neutropenia with an intrinsic failure of myelopoiesis and an increase in the incidence of cytogenetic abnormalities. To study the underlying mechanisms, active mutant WASpI294T was expressed by gene transfer. This caused enhanced and delocalized actin polymerization throughout the cell, decreased proliferation, and increased apoptosis. Cells became binucleated, suggesting a failure of cytokinesis, and micronuclei were formed, indicative of genomic instability. Live cell imaging demonstrated a delay in mitosis from prometaphase to anaphase and confirmed that multinucleation was a result of aborted cytokinesis. During mitosis, filamentous actin was abnormally localized around the spindle and chromosomes throughout their alignment and separation, and it accumulated within the cleavage furrow around the spindle midzone. These findings reveal a novel mechanism for inhibition of myelopoiesis through defective mitosis and cytokinesis due to hyperactivation and mislocalization of actin polymerization.

Autophagy Markers p62, LC3II and Beclin1 Correlate with Clark Levels in Melanoma Tumors

2021 ◽  
Author(s):  
Reyhaneh Hizomi Arani ◽  
Hadiseh Mohammadpour ◽  
Mohammad Amin Moosavi ◽  
Alireza Abdollahi ◽  
Marveh Rahmati
Keyword(s):  
Gene Expression ◽  
Tumor Progression ◽  
Early Stage ◽  
Mitotic Rate ◽  
Beclin 1 ◽  
Roc Curve Analysis ◽  
Mechanism Of Degradation ◽  
Associated Proteins ◽  
Potential Prognostic Factor ◽  
Autophagy Activity

Abstract BackgroundThe prognosis of melanoma depends on early diagnosis and timely treatment. Autophagy as a mechanism of degradation/recycling of cellular debris, has potential to be evaluated as prognostic biomarker in current research. MethodsIn this study, ATG5 and Beclin 1 gene expression in different Clark levels of melanoma were evaluated in a retrospective study of 10 years in the cancer institute of Tehran, Iran. The autophagy activity and the correlation with clinicopathological data were also investigated in a tissue microarray series of 52 melanomas after immunohistochemical staining for the autophagy-associated proteins p62, LC3II and Beclin1. The possibility of autophagy biomarkers were assessed by ROC curve analysis.ResultsThe patterns of ATG5 and Beclin1 gene expression are different. While ATG5 was increased in the early stage and then decreased as the stage was progressed in comparison to tumor margin, the Beclin1 expression was decreased and not altered during tumor progression. However, Beclin1 expression at the protein level was increased with tumor progression. The expression of LC3II was also raised while the p62 levels were declined as the tumor progressed, suggesting an increased autophagy activity in melanoma patients. Melanoma ulceration was positively correlated with Beclin 1 and LC3II expression and inversely correlated with p62 (p<0.05). Autophagy markers expression did not significantly correlate with melanoma mitotic rate and thickness. ConclusionsAutophagy is a potential prognostic factor in the early stage of melanoma and could be considered as a therapeutic target.

Abstract 17268: ApoA-I Mimetic Peptide 4F Suppresses the Elevation of Pro-Inflammatory Lipid Mediators in Mouse Models of Inflammatory Bowel Disease

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
David Meriwether ◽  
Carmen Volpe ◽  
Victor Grijalva ◽  
Ellen O’Connor ◽  
Nasrin Dorreh ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Mouse Models ◽  
Inflammatory Mediators ◽  
Bowel Disease ◽  
Ex Vivo ◽  
Early Stage ◽  
Lipid Mediators ◽  
Serosal Side ◽  
Ussing Chambers ◽  
Inflammatory Bowel

Introduction: Inflammatory bowel disease (IBD) has been linked to an increased prevalence of early stage vascular disease. ApoA-I mimetic peptides including 4F are potential therapeutic agents for the treatment of inflammatory diseases including atherosclerosis, and their mechanism of action appears localized to the intestine. We have reported that 4F protects against the development of disease in both the piroxicam-accelerated IL10-/- and myeloid COX2-/- mouse models of IBD. Hypothesis: We previously reported that plasma and lesion levels of oxidized products of linoleic and arachidonic acid correlate with disease in mouse models of atherosclerosis, and that 4F protects against disease in these models while inhibiting accumulation of these pro-inflammatory mediators. We thus sought to determine the complete lipid pro-inflammatory mediator profiles of both the COX2- and IL10-dependent models of IBD, while also determining the effect of 4F on the pro-inflammatory lipid profiles. Methods: We developed and validated a LC-ESI-MS/MS method for determining the levels of 40 lipid inflammatory mediators in both intestinal tissue and plasma, and we analyzed the effects of both disease and 4F upon these mediators in both IBD models. We also employed Ussing chambers to investigate ex vivo the direct effect of 4F on the clearance of pro-inflammatory lipid mediators from intestinal explants and serosal-side lipoproteins. Results: Disease in both models correlated with significantly elevated tissue and plasma levels of multiple lipid pro-inflammatory mediators, while the protective effects of 4F correlated with the significant suppression of most of these mediators. Of interest, 4F inhibited the disease dependent increase of 15HETE, 12HETE, 5HETE, 13HODE, LTB4, 6ketoPGF1α, PGF2α, and TXB2 in the COX2-/- model; and 15HETE, 12HETE, 13HODE, LTB4, and LTE4 in the IL10-/- model. Ex vivo, we showed that 4F could directly clear the pro-inflammatory mediators from inflamed intestinal explants, while also mediating their trans-intestinal efflux from serosal-side lipoproteins. Conclusions: 4F appears to protect against IBD in part by inhibiting the accumulation of pro-inflammatory lipid mediators, through a mechanism that involves the intestinal clearance of these mediators from tissue and plasma.

scholarly journals Antitumor Sulfur Compounds from Allium Species (Onion, Welsh Onion, and Garlic)

2017 ◽  
Vol 12 (8) ◽  
pp. 1934578X1701200 ◽  
Author(s):  
Toshihiro Nohara ◽  
Yukio Fujiwara
Keyword(s):  
Ovarian Cancer ◽  
Tumor Progression ◽  
Mouse Models ◽  
Sulfur Compounds ◽  
Welsh Onion ◽  
Allium Species

Sulfur compounds obtained from onion, Welsh onion, and garlic are reviewed. A major component (onionin A1) depressed tumor progression and metastasis in both osteosarcoma and ovarian cancer-bearing mouse models.

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