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https://www.readbyqxmd.com/read/28535287/a-flow-cytometry-based-screen-identifies-mbnl1-modulators-that-rescue-splicing-defects-in-myotonic-dystrophy-type-i
#1
Fan Zhang, Nicole E Bodycombe, Keith M Haskell, Yumei L Sun, Eric T Wang, Carl A Morris, Lyn H Jones, Lauren D Wood, Mathew T Pletcher
Myotonic Dystrophy Type 1 (DM1) is a rare genetic disease caused by expansion of CTG trinucleotide repeats ((CTG)exp) in the 3' untranslated region of the DMPK gene. The repeat transcripts sequester the RNA binding protein Muscleblind-like protein 1 (MBNL1) and hamper its normal function in pre-mRNA splicing. Overexpressing exogenous MBNL1 in the DM1 mouse model has been shown to rescue the splicing defects and reverse myotonia. Although a viable therapeutic strategy, pharmacological modulators of MBNL1 expression have not been identified...
May 23, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28533324/crispr-cas9-genetic-modification-of-cyp3a5-3-in-huh-7-human-hepatocyte-cell-line-leads-to-cell-lines-with-increased-midazolam-and-tacrolimus-metabolism
#2
Casey R Dorr, Rory P Remmel, Amutha Muthusamy, James Fisher, Branden Moriarity, Kazuto Yasuda, Baolin Wu, Weihua Guan, Erin G Schuetz, William S Oetting, Pamala A Jacobson, Ajay K Israni
CRISPR/Cas9 engineering of the CYP3A5 *3 locus (rs776746) in human liver cell line HuH-7 (CYP3A5 *3/*3) led to three CYP3A5 *1 cell lines by deletion of the exon 3B splice junction or point mutation. Cell lines CYP3A5 *1/*3 sd (single deletion), CYP3A5 *1/*1 dd (double deletion) or CYP3A5 *1/*3 pm (point mutation) expressed the CYP3A5 *1 mRNA, had elevated CYP3A5 mRNA (p<0.0005 for all engineered cell lines) and protein expression compared with HuH-7. In metabolism assays, HuH-7 had less tacrolimus (Tac) (all p-values < 0...
May 22, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28529033/high-throughput-characterization-of-hiv-1-reservoir-reactivation-using-a-single-cell-in-droplet-pcr-assay
#3
Robert W Yucha, Kristen S Hobbs, Emily Hanhauser, Louise E Hogan, Wildaliz Nieves, Mehmet O Ozen, Fatih Inci, Vanessa York, Erica A Gibson, Cassandra Thanh, Hadi Shafiee, Rami El Assal, Maja Kiselinova, Yvonne P Robles, Helen Bae, Kaitlyn S Leadabrand, ShuQi Wang, Steven G Deeks, Daniel R Kuritzkes, Utkan Demirci, Timothy J Henrich
Reactivation of latent viral reservoirs is on the forefront of HIV-1 eradication research. However, it is unknown if latency reversing agents (LRAs) increase the level of viral transcription from cells producing HIV RNA or harboring transcriptionally-inactive (latent) infection. We therefore developed a microfluidic single-cell-in-droplet (scd)PCR assay to directly measure the number of CD4(+) T cells that produce unspliced (us)RNA and multiply spliced (ms)RNA following ex vivo latency reversal with either an histone deacetylase inhibitor (romidepsin) or T cell receptor (TCR) stimulation...
May 4, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28524214/-possible-treatments-for-infantile-spinal-atrophy
#4
S I Pascual-Pascual, M Garcia-Romero
The new treatments of spinal muscular atrophy (SMA) due by SMN1 gene deletions are reviewed. There are several ways to increase the protein SMN, its activity and persistence in the tissues. Neuroprotective drugs as olesoxime or riluzole, and drugs acting by epigenetic mechanisms, as histone deacetylase inhibitors, have shown positive effects in preclinical studies but no clear efficacy in clinical trials. They might give in the future added benefits when used associated to other genetic modifying drugs. The best improvements in murine models of SMA and in clinical trials have been reached with antisense oligonucleotides, drugs that modify the splicing of SMN2, and they are expected to get better in the near future...
May 17, 2017: Revista de Neurologia
https://www.readbyqxmd.com/read/28522460/soluble-pd-l1-as-a-biomarker-in-malignant-melanoma-and-checkpoint-blockade
#5
Jun Zhou, Kathleen M Mahoney, Anita Giobbie-Hurder, Fengmin Zhao, Sandra Lee, Xiaoyun Liao, Scott Rodig, Jingjing Li, Xinqi Wu, Lisa H Butterfield, Matthias Piesche, Michael P Manos, Lauren M Eastman, Glenn Dranoff, Gordon J Freeman, F Stephen Hodi
Blockade of the pathway including Programmed death-ligand 1 (PD-L1) and its receptor Programmed cell death protein 1 (PD-1) has produced clinical benefits in patients with a variety of cancers.  Elevated levels of soluble PD-L1 (sPD-L1) have been associated with worse prognosis in renal cell carcinoma and multiple myeloma.  However, the regulatory roles and function of sPD-L1 particularly in connection with immune checkpoint blockade treatment are not fully understood.  We identified four splice variants of PD-L1 in melanoma cells, and all of them are secreted...
May 18, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28521287/5azadc-treatment-upregulates-mir-375-level-and-represses-hpv16-e6-expression
#6
Adrien Morel, Aurélie Baguet, Jérôme Perrard, Caroline Demeret, Elise Jacquin, David Guenat, Christiane Mougin, Jean-Luc Prétet
High risk human papillomaviruses are the etiological agents of cervical cancer and HPV16 is the most oncogenic genotype. Immortalization and transformation of infected cells requires the overexpression of the two viral oncoproteins E6 and E7 following HPV DNA integration into the host cell genome. Integration often leads to the loss of the E2 open reading frame and the corresponding protein can no longer act as a transcriptional repressor on p97 promoter. Recently, it has been proposed that long control region methylation also contributes to the regulation of E6/E7 expression...
May 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28507310/molecular-and-functional-characterization-of-the-bmpr2-gene-in-pulmonary-arterial-hypertension
#7
Guillermo Pousada, Vincenzo Lupo, Sheila Cástro-Sánchez, María Álvarez-Satta, Ana Sánchez-Monteagudo, Adolfo Baloira, Carmen Espinós, Diana Valverde
Pulmonary arterial hypertension is a progressive disease that causes the obstruction of precapillary pulmonary arteries and a sustained increase in pulmonary vascular resistance. The aim was to analyze functionally the variants found in the BMPR2 gene and to establish a genotype-phenotype correlation. mRNA expression studies were performed using pSPL3 vector, studies of subcellular localization were performed using pEGFP-N1 vector and luciferase assays were performed using pGL3-Basic vector. We have identified 30 variants in the BMPR2 gene in 27 of 55 patients...
May 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28504190/expression-and-alternative-splicing-of-the-cyclin-dependent-kinase-inhibitor-3-gene-in-human-cancer
#8
W Douglas Cress, Peng Yu, Jie Wu
The cyclin-dependent kinase inhibitor-3 (CDKN3) gene encodes a dual-specificity protein tyrosine phosphatase that dephosphorylates CDK1/CDK2 and other proteins. CDKN3 is often overexpressed in human cancer, and this overexpression correlates with reduced survival in several types of cancer. CDKN3 transcript variants and mutations have also been reported. The mechanism of CDKN3 overexpression and the role of CDKN3 transcript variants in human cancer are not entirely clear. Here, we review the literature and provide additional data to assess the correlation of CDKN3 expression with patient survival...
May 11, 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/28503307/clinical-significance-of-intronic-variants-in-braf-inhibitor-resistant-melanomas-with-altered-braf-transcript-splicing
#9
Gulietta M Pupo, Suzanah C Boyd, Carina Fung, Matteo S Carlino, Alexander M Menzies, Bernadette Pedersen, Peter Johansson, Nicholas K Hayward, Richard F Kefford, Richard A Scolyer, Georgina V Long, Helen Rizos
Alternate BRAF splicing is the most common mechanism of acquired resistance to BRAF inhibitor treatment in melanoma. Recently, alternate BRAF exon 4-8 splicing was shown to involve an intronic mutation, located 51 nucleotides upstream of BRAF exon 9 within a predicted splicing branch point. This intronic mutation was identified in a single cell line but has not been examined in vivo. Herein we demonstrate that in three melanomas biopsied from patients with acquired resistance to BRAF inhibitors, alternate BRAF exon 4-8 splicing is not associated with this intronic branch point mutation...
2017: Biomarker Research
https://www.readbyqxmd.com/read/28500234/niclosamide-and-bicalutamide-combination-treatment-overcomes-enzalutamide-and-bicalutamide-resistant-prostate-cancer
#10
Chengfei Liu, Cameron M Armstrong, Wei Lou, Alan P Lombard, Vito Cucchiara, Xinwei Gu, Joy C Yang, Nagalakshmi Nadiminty, Chong-Xian Pan, Christopher P Evans, Allen C Gao
Activation of the androgen receptor (AR) and its splice variants is linked to advanced prostate cancer and drives resistance to antiandrogens. The roles of AR and AR variants in the development of resistance to androgen deprivation therapy (ADT) and bicalutamide treatment, however, are still incompletely understood. To determine whether AR variants play a role in bicalutamide resistance, we developed bicalutamide resistant LNCaP cells (LNCaP-BicR) and found that these resistant cells express significantly increased levels of AR variants, particularly AR-V7, both at the mRNA and protein levels...
May 12, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28498452/calpain-and-ar-v7-two-potential-therapeutic-targets-to-overcome-acquired-docetaxel-resistance-in-castration-resistant-prostate-cancer-cells
#11
Lei Liu, Ning Lou, Xiang Li, Guanghua Xu, Hailong Ruan, Wen Xiao, Bin Qiu, Lin Bao, Changfei Yuan, Xinmian Huang, Keshan Wang, Qi Cao, Ke Chen, Hongmei Yang, Xiaoping Zhang
Docetaxel-based chemotherapy has been widely used as the first-line treatment for castration-resistant prostate cancer (CRPC) patients. However, the mechanisms of docetaxel-resistance remain unclear. In the present study with the establishment of 2 in vitro models of docetaxel-resistant CRPC cell sublines, we firstly reported that activation of calpain may play a promotional role in the resistance of docetaxel in prostate cancer, meanwhile using the calpain inhibitor combined with docetaxel improved the efficiency of docetaxel in docetaxel-resistant cell sublines...
May 4, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28496181/the-neuronal-k-cl-co-transporter-2-slc12a5-modulates-insulin-secretion
#12
Shams Kursan, Timothy S McMillen, Pavani Beesetty, Eduardo Dias-Junior, Mohammed M Almutairi, Abu A Sajib, J Ashot Kozak, Lydia Aguilar-Bryan, Mauricio Di Fulvio
Intracellular chloride concentration ([Cl(-)]i) in pancreatic β-cells is kept above electrochemical equilibrium due to the predominant functional presence of Cl(-) loaders such as the Na(+)K(+)2Cl(-) co-transporter 1 (Slc12a2) over Cl(-)extruders of unidentified nature. Using molecular cloning, RT-PCR, Western blotting, immunolocalization and in vitro functional assays, we establish that the "neuron-specific" K(+)Cl(-) co-transporter 2 (KCC2, Slc12a5) is expressed in several endocrine cells of the pancreatic islet, including glucagon secreting α-cells, but particularly in insulin-secreting β-cells, where we provide evidence for its role in the insulin secretory response...
May 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28494016/the-host-ubiquitin-dependent-segregase-vcp-p97-is-required-for-the-onset-of-human-cytomegalovirus-replication
#13
Yao-Tang Lin, James Prendergast, Finn Grey
The human cytomegalovirus major immediate early proteins IE1 and IE2 are critical drivers of virus replication and are considered pivotal in determining the balance between productive and latent infection. IE1 and IE2 are derived from the same primary transcript by alternative splicing and regulation of their expression likely involves a complex interplay between cellular and viral factors. Here we show that knockdown of the host ubiquitin-dependent segregase VCP/p97, results in loss of IE2 expression, subsequent suppression of early and late gene expression and, ultimately, failure in virus replication...
May 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28481415/large-conductance-ca-2-activated-k-channel-activation-by-apical-p2y-receptor-agonists-requires-hydrocortisone-in-differentiated-airway-epithelium
#14
Nathan A Zaidman, Angela Panoskaltsis-Mortari, Scott M O'Grady
In the present study we investigated the role of hydrocortisone (HC) on UTP-stimulated ion transport in differentiated, pseudostratified epithelia derived from normal human bronchial basal cells. The presence of a UTP stimulated, paxilline-sensitive large conductance Ca(2+) -activated K(+) (BK) current was demonstrated in control epithelia but was not stimulated in epithelia differentiated in the absence of HC (HC0). Addition of the BK opener NS11021 directly activated channels in control epithelia however under HC0 conditions, activation only occurred when UTP was added after NS11021...
May 8, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28476891/drosophila-tg-a-transglutaminase-is-secreted-via-an-unconventional-golgi-independent-mechanism-involving-exosomes-and-two-types-of-fatty-acylations
#15
Toshio Shibata, Jinki Hadano, Daichi Kawasaki, Xiaoqing Dong, Shun-Ichiro Kawabata
Transglutaminases (TGs) play essential intracellular and extracellular roles by covalently cross-linking many proteins. Drosophila TG is encoded by one gene and has two alternative splicing-derived isoforms, TG-A and TG-B, which contain distinct N-terminal 46- and 38-amino acid sequences, respectively. The TGs identified to date do not have a typical endoplasmic reticulum (ER)-signal peptide, and the molecular mechanisms of their secretion under physiologic conditions are unclear. Immunocytochemistry revealed that TG-A localizes to multivesicular-like structures, whereas TG-B localizes to the cytosol...
May 5, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28472998/in-silico-prioritization-and-further-functional-characterization-of-spink1-intronic-variants
#16
Wen-Bin Zou, Hao Wu, Arnaud Boulling, David N Cooper, Zhao-Shen Li, Zhuan Liao, Jian-Min Chen, Claude Férec
BACKGROUND: SPINK1 (serine protease inhibitor, kazal-type, 1), which encodes human pancreatic secretory trypsin inhibitor, is one of the most extensively studied genes underlying chronic pancreatitis. Recently, based upon data from qualitative reverse transcription-PCR (RT-PCR) analyses of transfected HEK293T cells, we concluded that 24 studied SPINK1 intronic variants were not of pathological significance, the sole exceptions being two canonical splice site variants (i.e., c.87 + 1G > A and c...
May 4, 2017: Human Genomics
https://www.readbyqxmd.com/read/28460447/sodium-butyrate-improves-porcine-host-defense-peptide-expression-and-relieves-the-inflammatory-response-upon-toll-like-receptor-2-activation-and-histone-deacetylase-inhibition-in-porcine-kidney-cells
#17
Xiujing Dou, Junlan Han, Wentao Song, Na Dong, Xinyao Xu, Wei Zhang, Anshan Shan
Host defense peptides (HDPs) are an important component of the innate immune system and possess direct antimicrobial and immunomodulatory activities. Dietary regulation of HDPs synthesis has emerged as a novel non-antibiotic approach to combat pathogen infection. There are species- and tissue-dependent characteristics of the regulation and mechanism of HDPs. In this study, we investigated whether the histone deacetylase inhibitor (HDACi) sodium butyrate (NaB) could induce HDP expression and the mechanism underlying NaB-regulated HDP expression in PK-15 cells...
April 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28455885/an-extremely-rare-splice-site-mutation-in-the-gene-encoding-complement-factor-i-in-a-patient-with-atypical-hemolytic-uremic-syndrome
#18
Tina S Ipe, Jooeun Lim, Meredith Anne Reyes, Mike Ero, Christopher Leveque, Bradley Lewis, Jamey Kain
BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney failure. The disease is difficult to diagnose due to its similarity with other hematologic disorders, such as thrombotic thrombocytopenic purpura (TTP). However, genetic mutations are found in 50-70% of patients with aHUS and can be useful in its diagnosis. STUDY DESIGN AND METHODS: A 40-year-old male presented to our hospital with acute kidney injury, evidenced by high creatinine levels (8...
April 28, 2017: Journal of Clinical Apheresis
https://www.readbyqxmd.com/read/28445500/sf3b1-is-a-stress-sensitive-splicing-factor-that-regulates-both-hsf1-concentration-and-activity
#19
Karen S Kim Guisbert, Eric Guisbert
The heat shock response (HSR) is a well-conserved, cytoprotective stress response that activates the HSF1 transcription factor. During severe stress, cells inhibit mRNA splicing which also serves a cytoprotective function via inhibition of gene expression. Despite their functional interconnectedness, there have not been any previous reports of crosstalk between these two pathways. In a genetic screen, we identified SF3B1, a core component of the U2 snRNP subunit of the spliceosome, as a regulator of the heat shock response in Caenorhabditis elegans...
2017: PloS One
https://www.readbyqxmd.com/read/28433559/the-kcnh2-ivs9-28a-g-mutation-causes-aberrant-isoform-expression-and-herg-trafficking-defect-in-cardiomyocytes-derived-from-patients-affected-by-long-qt-syndrome-type-2
#20
Manuela Mura, Ashish Mehta, Chrishan J Ramachandra, Rita Zappatore, Federica Pisano, Maria Chiara Ciuffreda, Vincenzo Barbaccia, Lia Crotti, Peter J Schwartz, Winston Shim, Massimiliano Gnecchi
BACKGROUND: Long QT Syndrome type 2 (LQT2) is caused by mutations in the KCNH2 gene that encodes for the α-subunit (hERG) of the ion channel conducting the rapid delayed rectifier potassium current (IKr). We have previously identified a disease causing mutation (IVS9-28A/G) in the branch point of the splicing of KCNH2 intron 9. However, the mechanism through which this mutation causes the disease is unknown. METHODS AND RESULTS: We generated human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from fibroblasts of two IVS9-28A/G mutation carriers...
April 12, 2017: International Journal of Cardiology
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