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Genomic therapy

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https://www.readbyqxmd.com/read/28225830/ex-vivo-activation-of-cd4-t-cells-from-donors-on-suppressive-art-can-lead-to-sustained-production-of-infectious-hiv-1-from-a-subset-of-infected-cells
#1
John K Bui, Elias K Halvas, Elizabeth Fyne, Michele D Sobolewski, Dianna Koontz, Wei Shao, Brian Luke, Feiyu F Hong, Mary F Kearney, John W Mellors
The fate of HIV-infected cells after reversal of proviral latency is not well characterized. Simonetti, et al. recently showed that CD4+ T-cells containing intact proviruses can clonally expand in vivo and produce low-level infectious viremia. We hypothesized that reversal of HIV latency by activation of CD4+ T-cells can lead to the expansion of a subset of virus-producing cells rather than their elimination. We established an ex vivo cell culture system involving stimulation of CD4+ T-cells from donors on suppressive antiretroviral therapy (ART) with PMA/ionomycin (day 1-7), followed by rest (day 7-21), and then repeat stimulation (day 21-28), always in the presence of high concentrations of raltegravir and efavirenz to effectively block new cycles of viral replication...
February 22, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28225080/dna-g-quadruplexes-in-the-human-genome-detection-functions-and-therapeutic-potential
#2
REVIEW
Robert Hänsel-Hertsch, Marco Di Antonio, Shankar Balasubramanian
Single-stranded guanine-rich DNA sequences can fold into four-stranded DNA structures called G-quadruplexes (G4s) that arise from the self-stacking of two or more guanine quartets. There has been considerable recent progress in the detection and mapping of G4 structures in the human genome and in biologically relevant contexts. These advancements, many of which align with predictions made previously in computational studies, provide important new insights into the functions of G4 structures in, for example, the regulation of transcription and genome stability, and uncover their potential relevance for cancer therapy...
February 22, 2017: Nature Reviews. Molecular Cell Biology
https://www.readbyqxmd.com/read/28224382/retrospective-review-of-genomic-testing-in-breast-cancer-does-it-improve-outcome
#3
Grady M Gastelum, Cyrus Iqbal, Susan G Hilsenbeck, Mothaffar F Rimawi, Polly Niravath
PURPOSE: Tumor genomic testing has become widely available in many clinical settings. However, we do not yet understand how to best harness the information yielded from this testing. We retrospectively investigated the clinical courses of 24 patients who underwent tumor genomic testing to determine whether targeted therapy is associated with improved progression free survival (PFS) compared to standard therapy. METHODS: The patient population comprised metastatic breast cancer patients who underwent tumor genomic testing (testing biopsy specimens of primary or metastatic lesions for 50 commonly mutated genes) at our institution between September 1, 2010 and June 1, 2015...
February 21, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/28223820/flt3-inhibitors-clinical-potential-in-acute-myeloid-leukemia
#4
REVIEW
Marie-Anne Hospital, Alexa S Green, Thiago T Maciel, Ivan C Moura, Anskar Y Leung, Didier Bouscary, Jerome Tamburini
Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy that is cured in as few as 15%-40% of cases. Tremendous improvements in AML prognostication arose from a comprehensive analysis of leukemia cell genomes. Among normal karyotype AML cases, mutations in the FLT3 gene are the ones most commonly detected as having a deleterious prognostic impact. FLT3 is a transmembrane tyrosine kinase receptor, and alterations of the FLT3 gene such as internal tandem duplications (FLT3-ITD) deregulate FLT3 downstream signaling pathways in favor of increased cell proliferation and survival...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28223458/mutation-of-the-n-terminal-region-of-chikungunya-virus-capsid-protein-implications-for-vaccine-design
#5
Adam Taylor, Xiang Liu, Ali Zaid, Lucas Y H Goh, Jody Hobson-Peters, Roy A Hall, Andres Merits, Suresh Mahalingam
Mosquito-transmitted chikungunya virus (CHIKV) is an arthritogenic alphavirus of the Togaviridae family responsible for frequent outbreaks of arthritic disease in humans. Capsid protein, a structural protein encoded by the CHIKV RNA genome, is able to translocate to the host cell nucleolus. In encephalitic alphaviruses, nuclear translocation induces host cell transcriptional shutoff; however, the role of capsid protein nucleolar localization in arthritogenic alphaviruses remains unclear. Using recombinant enhanced green fluorescent protein (EGFP)-tagged expression constructs and CHIKV infectious clones, we describe a nucleolar localization sequence (NoLS) in the N-terminal region of capsid protein, previously uncharacterized in CHIKV...
February 21, 2017: MBio
https://www.readbyqxmd.com/read/28223438/dysregulated-gpcr-signaling-and-therapeutic-options-in-uveal-melanoma
#6
Vivian Chua, Dominic Lapadula, Clinita Randolph, Jeffrey L Benovic, Philip Wedegaertner, Andrew E Aplin
: Uveal melanoma (UM) is the most common primary intraocular malignant tumor in adults and arises from the transformation of melanocytes in the uveal tract. Even after treatment of the primary tumor, up to 50% of patients succumb to metastatic disease. The liver is the predominant organ of metastasis. There is an important need to provide effective treatment options for advanced stage UM. In order to provide the preclinical basis for new treatments, it is important to understand the molecular underpinnings of the disease...
February 21, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28223424/hsp70-inhibition-synergistically-enhances-the-effects-of-magnetic-fluid-hyperthermia-in-ovarian-cancer
#7
Karem A Court, Hiroto Hatakeyama, Sherry Y Wu, Mangala S Lingegowda, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Lee Ju-Seog, Carlos Rinaldi, Eduardo J Juan, Anil K Sood, Madeline Torres-Lugo
Hyperthermia has been investigated as a potential treatment for cancer. However, specificity in hyperthermia application remains a significant challenge. Magnetic fluid hyperthermia (MFH) may be an alternative to surpass such a challenge, but implications of MFH at the cellular level are not well understood. Therefore, the present work focused on the examination of gene expression after MFH treatment and using such information to identify target genes that when inhibited could produce an enhanced therapeutic outcome after MFH...
February 21, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28223128/a-screening-assay-for-the-identification-of-host-cell-requirements-and-antiviral-targets-for-hepatitis-d-virus-infection
#8
Bettina Buchmann, Katinka Döhner, Thomas Schirdewahn, Beate Sodeik, Michael P Manns, Heiner Wedemeyer, Sandra Ciesek, Thomas von Hahn
Hepatitis delta virus (HDV) is a minimalistic satellite virus of hepatitis B virus (HBV). HBV/HDV co-infection, i.e. "hepatitis D", is the most severe form of viral hepatitis. No effective therapy for HDV infection is available partly due to the fact that HDV is a highly host-dependent virus devoid of any potentially drugable enzyme encoded in its small genome. In this study we present a semi-automated method to evaluate HDV infection and replication under the influence of different drugs. We utilized a Huh-7/hNTCP cell culture based system in a 96-well plate format, an automated microscope and image acquisition as well as analysis with the CellProfiler software to quantify the impact of these drugs on HDV infection...
February 18, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28221868/somatic-brca1-2-recovery-as-a-resistance-mechanism-after-exceptional-response-to-poly-adp-ribose-polymerase-inhibition
#9
Stephanie Lheureux, Jeff P Bruce, Julia V Burnier, Katherine Karakasis, Patricia A Shaw, Blaise A Clarke, S Y Cindy Yang, Rene Quevedo, Tiantian Li, Mark Dowar, Valerie Bowering, Trevor J Pugh, Amit M Oza
Purpose Durable and long-term responses to the poly (ADP-ribose) polymerase inhibitor olaparib are observed in patients without BRCA1/2 mutations. However, beyond BRCA1/2 mutations, there are no approved biomarkers for olaparib in high-grade serous ovarian cancer (HGSOC). To determine mechanisms of durable response and resistance to olaparib therapy, we performed an analysis of HGSOC tumors from three patients without germline BRCA1/2 mutations who experienced exceptional responses to olaparib. Patients and Methods We performed integrated exome, low-pass genome, and RNA sequence analysis of tumors at diagnosis and upon relapse from patients with platinum-sensitive HGSOC recurrence who were treated > 5 years with olaparib therapy as a single agent...
February 21, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28221115/mycobacterium-tuberculosis-infection-among-asian-elephants-in-captivity
#10
Gary Simpson, Ralph Zimmerman, Elena Shashkina, Liang Chen, Michael Richard, Carol M Bradford, Gwen A Dragoo, Rhonda L Saiers, Charles A Peloquin, Charles L Daley, Paul Planet, Apurva Narachenia, Barun Mathema, Barry N Kreiswirth
Although awareness of tuberculosis among captive elephants is increasing, antituberculosis therapy for these animals is not standardized. We describe Mycobacterium tuberculosis transmission between captive elephants based on whole genome analysis and report a successful combination treatment. Infection control protocols and careful monitoring of treatment of captive elephants with tuberculosis are warranted.
March 2017: Emerging Infectious Diseases
https://www.readbyqxmd.com/read/28220024/molecular-subtypes-improve-prognostic-value-of-international-metastatic-renal-cell-carcinoma-database-consortium-prognostic-model
#11
Guillermo de Velasco, Aedín C Culhane, André P Fay, A Ari Hakimi, Martin H Voss, Nizar M Tannir, Pheroze Tamboli, Leonard J Appleman, Joaquim Bellmunt, W Kimryn Rathmell, Laurence Albiges, James J Hsieh, Daniel Y C Heng, Sabina Signoretti, Toni K Choueiri
INTRODUCTION: Gene-expression signatures for prognosis have been reported in localized renal cell carcinoma (RCC). The aim of this study was to test the predictive power of two different signatures, ClearCode34, a 34-gene signature model [Eur Urol 2014;66:77-84], and an 8-gene signature model [Eur Urol 2015;67:17-20], in the setting of systemic therapy for metastatic disease. MATERIALS AND METHODS: Metastatic RCC (mRCC) patients from five institutions who were part of TCGA were identified and clinical data were retrieved...
February 20, 2017: Oncologist
https://www.readbyqxmd.com/read/28219395/efficient-precise-knockin-with-a-double-cut-hdr-donor-after-crispr-cas9-mediated-double-stranded-dna-cleavage
#12
Jian-Ping Zhang, Xiao-Lan Li, Guo-Hua Li, Wanqiu Chen, Cameron Arakaki, Gary D Botimer, David Baylink, Lu Zhang, Wei Wen, Ya-Wen Fu, Jing Xu, Noah Chun, Weiping Yuan, Tao Cheng, Xiao-Bing Zhang
BACKGROUND: Precise genome editing via homology-directed repair (HDR) after double-stranded DNA (dsDNA) cleavage facilitates functional genomic research and holds promise for gene therapy. However, HDR efficiency remains low in some cell types, including some of great research and clinical interest, such as human induced pluripotent stem cells (iPSCs). RESULTS: Here, we show that a double cut HDR donor, which is flanked by single guide RNA (sgRNA)-PAM sequences and is released after CRISPR/Cas9 cleavage, increases HDR efficiency by twofold to fivefold relative to circular plasmid donors at one genomic locus in 293 T cells and two distinct genomic loci in iPSCs...
February 20, 2017: Genome Biology
https://www.readbyqxmd.com/read/28217939/pitx2-dependent-gene-regulation-in-atrial-fibrillation-and-rhythm-control
#13
Fahima Syeda, Paulus Kirchhof, Larissa Fabritz
Atrial fibrillation (AF) is a common arrhythmia. Better prevention and treatment of AF are needed to reduce AF-associated morbidity and mortality. There are several major mechanisms that cause AF in patients, including a genetic predisposition to develop AF. Genome-wide association studies (GWAS) have identified genetic variants associated with AF populations, with the strongest hits clustering on chromosome 4q25, close to the gene for the homeobox transcription factor PITX2. The effect of these common gene variants on cardiac PITX2 mRNA is currently under study...
February 19, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28217400/novel-plasma-biomarker-of-atenolol-induced-hyperglycemia-identified-through-a-metabolomics-genomics-integrative-approach
#14
Felipe A de Oliveira, Mohamed H Shahin, Yan Gong, Caitrin W McDonough, Amber L Beitelshees, John G Gums, Arlene B Chapman, Eric Boerwinkle, Stephen T Turner, Reginald F Frye, Oliver Fiehn, Rima Kaddurah-Daouk, Julie A Johnson, Rhonda M Cooper-DeHoff
INTRODUCTION: While atenolol is an effective antihypertensive agent, its use is also associated with adverse events including hyperglycemia and incident diabetes that may offset the benefits of blood pressure lowering. By combining metabolomic and genomic data acquired from hypertensive individuals treated with atenolol, it may be possible to better understand the pathways that most impact the development of an adverse glycemic state. OBJECTIVE: To identify biomarkers that can help predict susceptibility to blood glucose excursions during exposure to atenolol...
August 2016: Metabolomics: Open Access
https://www.readbyqxmd.com/read/28217082/genomic-editing-of-non-coding-rna-genes-with-crispr-cas9-ushers-in-a-potential-novel-approach-to-study-and-treat-schizophrenia
#15
REVIEW
Chuanjun Zhuo, Weihong Hou, Lirong Hu, Chongguang Lin, Ce Chen, Xiaodong Lin
Schizophrenia is a genetically related mental illness, in which the majority of genetic alterations occur in the non-coding regions of the human genome. In the past decade, a growing number of regulatory non-coding RNAs (ncRNAs) including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) have been identified to be strongly associated with schizophrenia. However, the studies of these ncRNAs in the pathophysiology of schizophrenia and the reverting of their genetic defects in restoration of the normal phenotype have been hampered by insufficient technology to manipulate these ncRNA genes effectively as well as a lack of appropriate animal models...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28216025/pi3k-akt-mtor-inhibitors-in-breast-cancers-from-tumor-cell-signaling-to-clinical-trials
#16
REVIEW
Dey Nandini, De Pradip, Leyland-Jones Brian
Breast cancer (BC) is the most common women cancer and second most common cause of cancer death in women. A woman living in the Unites States has 12.3% lifetime risk of being diagnosed with BC. From the genomics point of view, the most common three subtypes of BC encountered in clinics are HR+, HER2+, and TNBC or basal-like BC. Estrogen receptor (ER) status or HER2 amplification or chemotherapy is not sufficient to understand the underlying mechanisms of disease progression and resistance (de novo or acquire)...
February 16, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28215225/transcription-factors-in-breast-cancer-lessons-from-recent-genomic-analyses-and-therapeutic-implications
#17
E Zacksenhaus, J C Liu, Z Jiang, Y Yao, L Xia, M Shrestha, Y Ben-David
Multiplatform genomic analyses have identified 93 frequently altered genes in breast cancer. Of these, as many as 49 genes are directly or indirectly involved in transcription. These include constitutive and inducible DNA-binding transcription factors (DB-TFs, 13 genes), corepressors/coactivators (14 genes), epigenetic (10), and mediator/splicing/rRNA (3) factors. At least nine additional genes are immediate upstream regulators of transcriptional cofactors. G:profiler analysis reveals that these alterations affect cell cycle, development/differentiation, steroid hormone, and chromatin modification pathways...
2017: Advances in Protein Chemistry and Structural Biology
https://www.readbyqxmd.com/read/28214658/an-association-study-of-established-breast-cancer-reproductive-and-lifestyle-risk-factors-with-tumour-subtype-defined-by-the-prognostic-70-gene-expression-signature-mammaprint-%C3%A2
#18
M Makama, C A Drukker, E J Th Rutgers, L Slaets, F Cardoso, M A Rookus, K Tryfonidis, L J Van't Veer, M K Schmidt
BACKGROUND: Reproductive and lifestyle factors influence both breast cancer risk and prognosis; this might be through breast cancer subtype. Subtypes defined by immunohistochemical hormone receptor markers and gene expression signatures are used to predict prognosis of breast cancer patients based on their tumour biology. We investigated the association between established breast cancer risk factors and the 70-gene prognostication signature in breast cancer patients. PATIENTS AND METHODS: Standardised questionnaires were used to obtain information on established risk factors of breast cancer from the Dutch patients of the MINDACT trial...
February 16, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28214593/jak-stat-pathway-directed-therapy-of-t-cell-leukemia-lymphoma-inspired-by-functional-and-structural-genomics
#19
REVIEW
Thomas A Waldmann
Abnormal activation of the γc cytokine JAK/STAT signaling pathway assessed by STAT3 or STAT5b phosphorylation was present in a proportion of many T-cell malignancies. Activating mutations of STAT3/STAT5b and JAK1/3 were present in some but not in all cases with constitutive signaling pathway activation. Using shRNA analysis pSTAT malignant T-cell lines were addicted to JAKs/STATs whether they were mutated or not. Activating JAK/STAT mutations were not sufficient to support leukemic cell proliferation but only augmented upstream pathway signals...
February 15, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28213959/combining-induced-pluripotent-stem-cells-and-genome-editing-technologies-for-clinical-applications
#20
Chia-Yu Chang, Hsiao-Chien Ting, Hong-Lin Su, Jing-Ren Jeng
In this review, we introduce current developments in induced pluripotent stem cells (iPSCs), site-specific nuclease (SSN)-mediated genome editing tools, and the combined application of these two novel technologies in biomedical research and therapeutic trials. The sustainable pluripotent property of iPSCs in vitro not only provides unlimited cell sources for basic research but also benefits precision medicines for human diseases. In addition, rapidly evolving SSN tools efficiently tailor genetic manipulations for exploring gene functions and can be utilized to correct genetic defects of congenital diseases in the near future...
February 17, 2017: Cell Transplantation
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