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Genomic therapy

Wen-Lei Shi, Ting Zhang, Jiang-Rui Zhou, Yong-Hua Huang, Chun-Lei Jiang
Glucocorticoids (GCs) play a vital role in the regulation of blood pressure by their permissive effects in potentiating vasoactive responses to catecholamines through glucocorticoid receptors. GCs achieve this function by controlling vascular smooth muscle tone. Clinically, low to moderate doses of GCs are generally used in the treatment of septic shock in recent years. GCs are now known to have both genomic and non-genomic effects. While genomic effects of GCs were well studied, few non-genomic effects were reported, much less the non-genomic mechanisms...
October 22, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Jay N Lozier, Mark T Kloos, Elizabeth P Merricks, Nathaly Lemoine, Margaret H Whitford, Robin A Raymer, Dwight A Bellinger, Timothy C Nichols
Animals with hemophilia are models for gene therapy, factor replacement, and inhibitor development in humans. We have actively sought dogs with severe hemophilia A that have novel factor VIII mutations unlike the previously described factor VIII intron 22 inversion. A male Old English Sheepdog with recurrent soft-tissue hemorrhage and hemarthrosis was diagnosed with severe hemophilia A (factor VIII activity less than 1% of normal). We purified genomic DNA from this dog and ruled out the common intron 22 inversion; we then sequenced all 26 exons...
2016: Comparative Medicine
Rebekah M Martin, Jie Cao, Sylvain Brisse, Virginie Passet, Weisheng Wu, Lili Zhao, Preeti N Malani, Krishna Rao, Michael A Bachman
Klebsiella pneumoniae is among the most common causes of hospital-acquired infections and has emerged as an urgent threat to public health due to carbapenem antimicrobial resistance. K. pneumoniae commonly colonizes hospitalized patients and causes extraintestinal infections such as urinary tract infection, bloodstream infection (septicemia), and pneumonia. If colonization is an intermediate step before infection, then detection and characterization of colonizing isolates could enable strategies to prevent or empirically treat K...
September 2016: MSphere
Rajarsi Mandal, Yasin Şenbabaoğlu, Alexis Desrichard, Jonathan J Havel, Martin G Dalin, Nadeem Riaz, Ken-Wing Lee, Ian Ganly, A Ari Hakimi, Timothy A Chan, Luc G T Morris
Recent clinical trials have demonstrated a clear survival advantage in advanced head and neck squamous cell carcinoma (HNSCC) patients treated with immune checkpoint blockade. These emerging results reveal that HNSCC is one of the most promising frontiers for immunotherapy research. However, further progress in head and neck immuno-oncology will require a detailed understanding of the immune infiltrative landscape found in these tumors. We leveraged transcriptome data from 280 tumors profiled by The Cancer Genome Atlas (TCGA) to comprehensively characterize the immune landscape of HNSCC in order to develop a rationale for immunotherapeutic strategies in HNSCC and guide clinical investigation...
October 20, 2016: JCI Insight
Vellingiri Balachandar, Venkatesan Dhivya, Mohan Gomathi, Subramaniam Mohanadevi, Balasubramanian Venkatesh, Bharathi Geetha
Human induced pluripotent stem cells (hiPSCs) are pluripotent stem cells generated from somatic cells by the introduction of a combination of pluripotency-associated genes such as OCT4, SOX2, along with either KLF4 and c-MYC or NANOG and LIN28 via retroviral or lentiviral vectors. Most importantly, hiPSCs are similar to human embryonic stem cells (hESCs) functionally as they are pluripotent and can potentially differentiate into any desired cell type when provided with the appropriate cues, but do not have the ethical issues surrounding hESCs...
2016: Stem Cell Investigation
Genevieve M Weir, Olga Hrytsenko, Tara Quinton, Neil L Berinstein, Marianne M Stanford, Marc Mansour
BACKGROUND: Future cancer immunotherapies will combine multiple treatments to generate functional immune responses to cancer antigens through synergistic, multi-modal mechanisms. In this study we explored the combination of three distinct immunotherapies: a class I restricted peptide-based cancer vaccine, metronomic cyclophosphamide (mCPA) and anti-PD-1 treatment in a murine tumor model expressing HPV16 E7 (C3). METHODS: Mice were implanted with C3 tumors subcutaneously...
2016: Journal for Immunotherapy of Cancer
Sarah K Tasian, David T Teachey, Yong Li, Feng Shen, Richard C Harvey, I-Ming Chen, Theresa Ryan, Tiffaney L Vincent, Cheryl L Willman, Alexander E Perl, Stephen P Hunger, Mignon L Loh, Martin Carroll, Stephan A Grupp
Philadelphia chromosome-like B-cell lymphoblastic leukemia (BCR-ABL1-like or Ph-like ALL) is associated with activated JAK/STAT, SRC/ABL, and/or PI3K/Akt/mTOR signaling and poor clinical outcomes. Inhibitors of PI3K pathway signaling (PI3Ki) have been minimally investigated in Ph-like ALL to date. We hypothesized that targeted inhibition of PI3Kα, PI3Kδ, PI3K/mTOR, or TORC1/TORC2 would decrease leukemia proliferation and abrogate aberrant kinase signaling. We further hypothesized that combined PI3K pathway and JAK inhibition or PI3K pathway and SRC/ABL inhibition would have superior efficacy compared to inhibitor monotherapy...
October 24, 2016: Blood
Fara Brasó-Maristany, Simone Filosto, Steven Catchpole, Rebecca Marlow, Jelmar Quist, Erika Francesch-Domenech, Darren A Plumb, Leila Zakka, Patrycja Gazinska, Gianmaria Liccardi, Pascal Meier, Albert Gris-Oliver, Maggie Chon U Cheang, Anna Perdrix-Rosell, Manar Shafat, Elodie Noël, Nirmesh Patel, Kristen McEachern, Maurizio Scaltriti, Pau Castel, Farzana Noor, Richard Buus, Sumi Mathew, Johnathan Watkins, Violeta Serra, Pierfrancesco Marra, Anita Grigoriadis, Andrew N Tutt
Triple-negative breast cancers (TNBCs) have poor prognosis and lack targeted therapies. Here we identified increased copy number and expression of the PIM1 proto-oncogene in genomic data sets of patients with TNBC. TNBC cells, but not nonmalignant mammary epithelial cells, were dependent on PIM1 for proliferation and protection from apoptosis. PIM1 knockdown reduced expression of the anti-apoptotic factor BCL2, and dynamic BH3 profiling of apoptotic priming revealed that PIM1 prevents mitochondrial-mediated apoptosis in TNBC cell lines...
October 24, 2016: Nature Medicine
Philip Egan, Stephen Drain, Caroline Conway, Anthony J Bjourson, H Denis Alexander
Plasma cell myeloma is a clinically heterogeneous malignancy accounting for approximately one to 2% of newly diagnosed cases of cancer worldwide. Treatment options, in addition to long-established cytotoxic drugs, include autologous stem cell transplant, immune modulators, proteasome inhibitors and monoclonal antibodies, plus further targeted therapies currently in clinical trials. Whilst treatment decisions are mostly based on a patient's age, fitness, including the presence of co-morbidities, and tumour burden, significant scope exists for better risk stratification, sub-classification of disease, and predictors of response to specific therapies...
October 21, 2016: International Journal of Molecular Sciences
Kenji Amemiya, Yosuke Hirotsu, Taichiro Goto, Hiroshi Nakagomi, Hitoshi Mochizuki, Toshio Oyama, Masao Omata
Identifying genetic alterations in tumors is critical for molecular targeting of therapy. In the clinical setting, formalin-fixed paraffin-embedded (FFPE) tissue is usually employed for genetic analysis. However, DNA extracted from FFPE tissue is often not suitable for analysis because of its low levels and poor quality. Additionally, FFPE sample preparation is time-consuming. To provide early treatment for cancer patients, a more rapid and robust method is required for precision medicine. We present a simple method for genetic analysis, called touch imprint cytology combined with massively paralleled sequencing (touch imprint cytology [TIC]-seq), to detect somatic mutations in tumors...
October 24, 2016: Cancer Medicine
Eileen N Oni, Ronald P Hart
Several recent publications sought to investigate the effects of ethanol treatment on models of central nervous system development, specifically through changes in DNA methylation. Regulation of DNA methylation causes a long-lasting, epigenetic change in the capacity of the genome to respond to developmental or metabolic stimuli. Changes in technologies for quantifying DNA methylation have increased the ability to identify and interpret potential effects of ethanol. Here, we review these recent studies in order to evaluate the detection technologies and bioinformatic analyses...
October 2016: Current Pharmacology Reports
Ibiayi Dagogo-Jack, Corey M Gill, Daniel P Cahill, Sandro Santagata, Priscilla K Brastianos
Development of brain metastasis (BM) portends a dismal prognosis for patients with cancer. Melanomas and carcinomas of the lung, breast, and kidney are the most common malignancies to metastasize to the brain. Recent advances in molecular genetics have enabled the identification of actionable, clinically relevant genetic alterations within primary tumors and their corresponding metastases. Adoption of genotype-guided treatment strategies in the management of systemic malignancy has resulted in dramatic and durable responses...
October 20, 2016: Pharmacology & Therapeutics
Morgan S Schrock, Jenna R Karras, Matthew J Guggenbiller, Teresa Druck, Bahadir Batar, Kay Huebner
Expression of Fhit and Wwox protein is frequently lost or reduced in many human cancers. In this report, we provide data that further characterizes the molecular consequences of Fhit loss in the initiation of DNA double-strand breaks (DSBs), and of Wwox loss in altered repair of DSBs. We show that loss of Fhit initiates mild genome instability in early passage mouse kidney cells, confirming that DNA damage associated with Fhit-deficiency is not limited to cancer cells. We also demonstrate that the cause of Fhit-deficient DSBs: thymidine deficiency-induced replication stress, can be resolved with thymidine supplementation in early passage mouse kidney cells before extensive genome instability occurs...
September 26, 2016: Advances in Biological Regulation
Feixiong Cheng, Junfei Zhao, Ariella B Hanker, Monica Red Brewer, Carlos L Arteaga, Zhongming Zhao
PURPOSE: Phosphatidylinositol 3-kinase (PI3K)/AKT pathway aberrations are common in human breast cancer. Furthermore, PIK3CA mutations are commonly associated with resistance to anti-epidermal growth factor receptor 2 (HER2) or anti-estrogen receptor (ER) agents in HER2 or ER positive (HER2(+)/ER(+)) breast cancer. Hence, deciphering the underlying mechanisms of PIK3CA mutations in HER2(+)/ER(+) breast cancer would provide novel insights into elucidating resistance to anti-HER2/ER therapies...
October 22, 2016: Breast Cancer Research and Treatment
Samah Nassereddine, Taiga Nishihori, Eric Padron, Rami Mahfouz, Ali Bazarbachi, Rami S Komrokji, Mohamed A Kharfan-Dabaja
Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic neoplastic disorders most commonly occurring in the elderly population; MDS has a tendency to progress to acute leukemia. Although epigenetic therapies have improved the outcomes of MDS patients, allogeneic hematopoietic cell transplantation remains the only curative option. Molecular characterization of MDS using next-generation sequencing has expanded not only the knowledge on MDS but also the depth of understanding of evolution and contribution of recurrent somatic mutations in precursor conditions...
September 16, 2016: Clinical Lymphoma, Myeloma & Leukemia
James Heng Chiak Sim, Cynthia Truong, Samuel S Minot, Nick Greenfield, Indre Budvytiene, Akshar Lohith, Victoria Anikst, Nader Pourmand, Niaz Banaei
Understanding the contribution of relapse and reinfection to recurrent Clostridium difficile infection (CDI) has implications for therapy and infection prevention, respectively. We used whole genome sequencing to determine the relation of C. difficile strains isolated from patients with recurrent CDI at an academic medical center in the United States. Thirty-five toxigenic C. difficile isolates from 16 patients with 19 recurrent CDI episodes with median time of 53.5days (range, 13-362) between episodes were whole genome sequenced on the Illumina MiSeq platform...
October 5, 2016: Diagnostic Microbiology and Infectious Disease
Fausto Petrelli, Sandro Barni, Giacomo Bregni, Filippo de Braud, Serena Di Cosimo
BACKGROUND: The interest in platinum salts in breast cancer (BC) therapy has been recently renewed as inhibition of DNA damage response may enhance the effects of DNA-damaging agents in BC tumors with high genomic instability. The present systematic review and meta-analysis of randomized trials were performed to assess the efficacy and safety of therapy with platinum salts in patients with locally advanced or metastatic (hereinafter advanced) BC. METHODS: We searched PubMed, EMBASE, SCOPUS, Web of Science, the Cochrane Library, and CINAHL for phase II/III clinical trials that assessed efficacy of platinum-based therapy in patients with advanced BC...
October 21, 2016: Breast Cancer Research and Treatment
Franziska Hopfner, Dietrich Haubenberger, Wendy R Galpern, Katrina Gwinn, Ashlee Van't Veer, Samantha White, Kailash Bhatia, Charles H Adler, David Eidelberg, William Ondo, Glenn T Stebbins, Caroline M Tanner, Rick C Helmich, Fred A Lenz, Roy V Sillitoe, David Vaillancourt, Jerrold L Vitek, Elan D Louis, Holly A Shill, Matthew P Frosch, Tatiana Foroud, Gregor Kuhlenbäumer, Andrew Singleton, Claudia M Testa, Mark Hallett, Rodger Elble, Günther Deuschl
Essential tremor (ET) is a common cause of significant disability, but its etiologies and pathogenesis are poorly understood. Research has been hampered by the variable definition of ET and by non-standardized research approaches. The National Institute of Neurological Disorders and Stroke (USA) invited experts in ET and related fields to discuss current knowledge, controversies, and gaps in our understanding of ET and to develop recommendations for future research. Discussion focused on phenomenology and phenotypes, therapies and clinical trials, pathophysiology, pathology, and genetics...
October 4, 2016: Parkinsonism & related Disorders
Lei Shi, Wenfa Zhang, Fagui Zou, Lihua Mei, Gang Wu, Yong Teng
BACKGROUND: Hepatocellular carcinoma (HCC) has very high prevalence and associated-mortality. However, targeted therapies that are currently used in clinical practice for HCC have certain limitations, in part because of the lack of reliable and clinically applicable biomarkers that can be used for diagnosis and prognosis assessments and for the surveillance of treatment effectiveness. METHODS: Meta-analysis was used to analyze the integrated microarray data for global identification of a set of robust biomarkers for HCC...
October 21, 2016: BMC Cancer
Katharina Grundler, Raffaela Rotter, Sloane Tilley, Joachim Pircher, Thomas Czermak, Mustaf Yakac, Erik Gaitzsch, Steffen Massberg, Florian Krötz, Hae-Young Sohn, Ulrich Pohl, Hanna Mannell, Bjoern F Kraemer
INTRODUCTION: Platelets possess critical hemostatic functions in the system of thrombosis and hemostasis, which can be affected by a multitude of external factors. Previous research has shown that platelets have the capacity to synthesize proteins de novo and more recently a multicatalytic protein complex, the proteasome, has been discovered in platelets. Due to its vital function for cellular integrity, the proteasome has become a therapeutic target for anti-proliferative drug therapies in cancer...
October 13, 2016: Thrombosis Research
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