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https://www.readbyqxmd.com/read/29349096/safety-and-efficacy-of-aav-retrograde-pancreatic-ductal-gene-delivery-in-normal-and-pancreatic-cancer-mice
#1
Kayla A Quirin, Jason J Kwon, Arafat Alioufi, Tricia Factora, Constance J Temm, Max Jacobsen, George E Sandusky, Kim Shontz, Louis G Chicoine, K Reed Clark, Joshua T Mendell, Murray Korc, Janaiah Kota
Recombinant adeno-associated virus (rAAV)-mediated gene delivery shows promise to transduce the pancreas, but safety/efficacy in a neoplastic context is not well established. To identify an ideal AAV serotype, route, and vector dose and assess safety, we have investigated the use of three AAV serotypes (6, 8, and 9) expressing GFP in a self-complementary (sc) AAV vector under an EF1α promoter (scAAV.GFP) following systemic or retrograde pancreatic intraductal delivery. Systemic delivery of scAAV9.GFP transduced the pancreas with high efficiency, but gene expression did not exceed >45% with the highest dose, 5 × 1012 viral genomes (vg)...
March 16, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29346369/the-rise-of-neglected-tropical-diseases-in-the-new-texas
#2
REVIEW
Peter J Hotez
Within the last five years, the State of Texas has experienced either transmission or outbreaks of Ebola, chikungunya, West Nile, and Zika virus infections. Autochthonous transmission of neglected parasitic and bacterial diseases has also become increasingly reported. The rise of such emerging and neglected tropical diseases (NTDs) has not occurred by accident but instead reflects rapidly evolving changes and shifts in a "new" Texas beset by modern and globalizing forces that include rapid expansions in population together with urbanization and human migrations, altered transportation patterns, climate change, steeply declining vaccination rates, and a new paradigm of poverty known as "blue marble health...
January 2018: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/29346287/development-of-zika-virus-vaccines
#3
REVIEW
Huda Makhluf, Sujan Shresta
Zika virus (ZIKV) is a mosquito-borne flavivirus that emerged as a global threat following the most recent outbreak in Brazil in 2015. ZIKV infection of pregnant women is associated with fetal abnormalities such as microcephaly, and infection of adults can lead to Guillain-Barré syndrome, an autoimmune disease characterized by neurological deficits. Although there are currently licensed vaccines for other flaviviruses, there remains an urgent need for preventative vaccines against ZIKV infection. Herein we describe the current efforts to accelerate the development of ZIKV vaccines using various platforms, including live attenuated virus, inactivated virus, DNA and RNA, viral vectors, and in silico-predicted immunogenic viral epitopes...
January 18, 2018: Vaccines
https://www.readbyqxmd.com/read/29346272/viral-and-antibody-kinetics-and-mosquito-infectivity-of-an-imported-case-of-zika-fever-due-to-asian-genotype-american-strain-in-singapore
#4
Cheong Huat Tan, Li Kiang Tan, Hapuarachchige Chanditha Hapuarachchi, Yee Ling Lai, Pei Sze Jeslyn Wong, Grace Yap, Keng Wai Mak, Wing Yan Wong, Yee Sin Leo, Mei Chun Wong, Lee Ching Ng
We report a case of a Singaporean who acquired Zika virus (ZIKV) during a visit to Cuba. The infection was confirmed using molecular and serological methods. This report highlights potential drawbacks of using IgG serology for diagnosis of flavivirus infections in endemic regions. The low viremia detected during the early phase of this case resulted in low mosquito infectivity rates, suggesting the possibility of ZIKV transmission prior to clinical onset. The report also emphasizes the challenges of public health interventions for Zika fever and the importance of sustaining a low vector population to reduce the risk of arbovirus transmission in vulnerable regions...
January 18, 2018: Viruses
https://www.readbyqxmd.com/read/29344635/eradication-of-cervical-cancer-in-vivo-by-an-aav-vector-that-encodes-shrna-targeting-human-papillomavirus-type-16%C3%A2-e6-e7
#5
Naoto Sato, Yasushi Saga, Ryosuke Uchibori, Tomonori Tsukahara, Masashi Urabe, Akihiro Kume, Hiroyuki Fujiwara, Mitsuaki Suzuki, Keiya Ozawa, Hiroaki Mizukami
The major causative agent of cervical cancer is human papilloma virus (HPV); the viral proteins E6 and E7 induce carcinogenesis through the inactivation of the host tumor-suppressor gene. Therefore, the stable expression of specific inhibitors of E6 and E7 in cancer cells is expected to provide effective treatment for cervical cancer without affecting normal tissue. In this study, we propose a novel therapeutic approach using an adeno-associated virus (AAV) vector encoding short hairpin RNA (shRNA) against the oncoproteins E6 and E7 (shE6E7) of HPV type 16 (HPV‑16), termed AAV‑shE6E7...
January 15, 2018: International Journal of Oncology
https://www.readbyqxmd.com/read/29343574/novel-human-polyomavirus-non-coding-control-regions-differ-in-bi-directional-gene-expression-according-to-host-cell-large-t-antigen-expression-and-clinically-occurring-rearrangements
#6
Elvis T Ajuh, Zongsong Wu, Emma Kraus, Fabian H Weissbach, Tobias Bethge, Rainer Gosert, Nicole Fischer, Hans H Hirsch
Human polyomavirus (HPyV) DNA genomes contain three regions denoted early viral gene region (EVGR) encoding the regulatory T-antigens and one microRNA, late viral gene region (LVGR) encoding the structural Vp capsid proteins, and non-coding control region (NCCR). The NCCR harbours the origin of viral genome replication and bi-directional promoter/enhancer functions governing EVGR- and LVGR-expression on opposite DNA strands. Despite principle similarities, HPyV-NCCRs differ in length, sequence, and architecture...
January 17, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29343568/an-alternate-route-for-adeno-associated-virus-entry-independent-of-aavr
#7
Amanda M Dudek, Sirika Pillay, Andreas S Puschnik, Claude M Nagamine, Fang Cheng, Jianming Qiu, Jan E Carette, Luk H Vandenberghe
Determinants and mechanisms of cell attachment and entry steer the Adeno-Associated Virus (AAV) in its utility as a gene therapy vector. Thus far a systematic assessment of how diverse AAV serotypes engage their proteinaceous receptor AAVR (KIAA0319L) to establish transduction has been lacking, despite potential implications for cell and tissue tropism. Here, a large set of human and simian AAVs as well as in silico reconstructed ancestral AAV capsids were interrogated for AAVR usage. We identified a distinct AAV capsid lineage comprised of AAV4 and AAVrh32...
January 17, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29343567/parainfluenza-virus-infection-sensitizes-cancer-cells-to-dna-damaging-agents-implications-for-oncolytic-virus-therapy
#8
Candace R Fox, Griffith D Parks
We have previously shown that the Parainfluenza virus 5 (PIV5) mutant P/V-CPI- is restricted for spread in normal cells but not in cancer cells in vitro and is effective at reducing tumor burden in mouse model systems. Here we show that P/V-CPI- infection of human laryngeal cancer HEp-2 cells results in the majority of the cells dying, but unexpectedly, over time there is an emergence of a population of cells which survive as P/V-CPI- persistently infected (PI) cells. P/V-CPI- PI cells had elevated levels of basal caspase activation, and viability was highly dependent on activity of cellular inhibitors of apoptosis (IAPs) such as Survivin and XIAP...
January 17, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29342838/biopolymer-based-nanoparticles-for-cystic-fibrosis-lung-gene-therapy-studies
#9
Elena Fernández Fernández, Beatriz Santos-Carballal, Chiara de Santi, Joanne M Ramsey, Ronan MacLoughlin, Sally-Ann Cryan, Catherine M Greene
Lung gene therapy for cystic fibrosis disease has not been successful due to several challenges such as the absence of an appropriate vector. Therefore, optimal delivery of emerging therapeutics to airway epithelial cells demands suitable non-viral systems. In this work, we describe the formulation and the physicochemical investigation of biocompatible and biodegradable polymeric nanoparticles (NPs), including PLGA and chitosan (animal and non-animal), as novel methods for the safe and efficient delivery of CFTR-specific locked nucleic acids (LNAs)...
January 13, 2018: Materials
https://www.readbyqxmd.com/read/29341877/characterizing-the-effects-of-insertion-of-a-5-2%C3%A2-kb-region-of-a-vacv-genome-which-contains-known-immune-evasion-genes-on-mva-immunogenicity
#10
Melissa R Ryerson, Joanna L Shisler
Modified Vaccinia virus Ankara (MVA) is an attenuated Vaccinia virus (VACV) that is a popular vaccine vector candidate against many different pathogens. Its replication-restricted nature makes it a safe vaccine. However, higher doses or multiple boosts of MVA are necessary to elicit an immune response similar to wild-type VACV. Multiple strategies have been used to create modified MVA viruses that remain safe, but have increased immunogenicity. For example, one common strategy is to delete MVA immunomodulatory proteins in hopes of increasing the host immune response...
January 13, 2018: Virus Research
https://www.readbyqxmd.com/read/29341430/tuberculosis-vaccines-opportunities-and-challenges
#11
REVIEW
Bingdong Zhu, Hazel M Dockrell, Tom H M Ottenhoff, Thomas G Evans, Ying Zhang
Tuberculosis (TB) is a serious disease around the world. Bacillus Calmette-Guérin (BCG) is the only TB vaccine licensed for use in human beings, and is effective in protecting infants and children against severe miliary and meningeal TB. However, BCG's protective efficacy is variable in adults. Novel TB vaccine candidates being developed include whole-cell vaccines (recombinant BCG (rBCG), attenuated Mycobacterium tuberculosis, killed M. tuberculosis or Mycobacterium vaccae), adjuvanted protein subunit vaccines, viral vector-delivered subunit vaccines, plasmid DNA vaccines, RNA-based vaccines etc...
January 17, 2018: Respirology: Official Journal of the Asian Pacific Society of Respirology
https://www.readbyqxmd.com/read/29341226/molecular-details-of-spontaneous-insertion-and-interaction-of-hcv-non-structure-3-protease-protein-domain-with-pip2-containing-membrane
#12
Huynh Minh Hung, Tran Dieu Hang, Minh Tho Nguyen
Hepatitis C virus (HCV), known as the leading cause of liver cirrhosis, viral hepatitis and hepatocellular carcinoma, has been affecting more than 150 million people globally. The HCV non-structure 3 (NS3) protease protein domain plays a key role in HCV replication and pathogenesis; and is currently a primary target for HCV antiviral therapy. Through unbiased molecular dynamics simulations which take advantage of the novel highly mobile membrane mimetic model, we constructed the membrane-bound state of the protein domain at the atomic level...
January 17, 2018: Proteins
https://www.readbyqxmd.com/read/29339763/glucocorticoid-receptor-gr%C3%AE-regulates-glucocorticoid-induced-ocular-hypertension-in-mice
#13
Gaurang C Patel, Yang Liu, J Cameron Millar, Abbot F Clark
Prolonged glucocorticoid (GC) therapy can cause GC-induced ocular hypertension (OHT), which if left untreated progresses to iatrogenic glaucoma and permanent vision loss. The alternatively spliced isoform of glucocorticoid receptor GRβ acts as dominant negative regulator of GR activity, and it has been shown that overexpressing GRβ in trabecular meshwork (TM) cells inhibits GC-induced glaucomatous damage in TM cells. The purpose of this study was to use viral vectors to selectively overexpress the GRβ isoform in the TM of mouse eyes treated with GCs, to precisely dissect the role of GRβ in regulating steroid responsiveness...
January 16, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29338737/transcriptome-profiling-of-whitefly-guts-in-response-to-tomato-yellow-leaf-curl-virus-infection
#14
Liang Geng, Li-Xin Qian, Ruo-Xuan Shao, Yin-Quan Liu, Shu-Sheng Liu, Xiao-Wei Wang
BACKGROUND: Plant viruses in agricultural crops are of great concern worldwide, and over 75% of them are transmitted from infected to healthy plants by insect vectors. Tomato yellow leaf curl virus (TYLCV) is a begomovirus, which is the largest and most economically important group of plant viruses, transmitted by the whitefly Bemisia tabaci. The circulation of TYLCV in the insect involves complex insect-virus interactions, whereas the molecular mechanisms of these interactions remain ambiguous...
January 16, 2018: Virology Journal
https://www.readbyqxmd.com/read/29338001/modelling-the-large-scale-yellow-fever-outbreak-in-luanda-angola-and-the-impact-of-vaccination
#15
Shi Zhao, Lewi Stone, Daozhou Gao, Daihai He
BACKGROUND: Yellow fever (YF), transmitted via bites of infected mosquitoes, is a life-threatening viral disease endemic to tropical and subtropical regions of Africa and South America. YF has largely been controlled by widespread national vaccination campaigns. Nevertheless, between December 2015 and August 2016, YF resurged in Angola, quickly spread and becoming the largest YF outbreak for the last 30 years. Recently, YF resurged again in Brazil (December 2016). Thus, there is an urgent need to gain better understanding of the transmission pattern of YF...
January 16, 2018: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/29337870/glioblastoma-under-siege-an-overview-of-current-therapeutic-strategies
#16
REVIEW
Mayra Paolillo, Cinzia Boselli, Sergio Schinelli
Glioblastoma is known to be one of the most lethal and untreatable human tumors. Surgery and radiotherapy in combination with classical alkylating agents such as temozolomide offer little hope to escape a poor prognosis. For these reasons, enormous efforts are currently devoted to refine in vivo and in vitro models with the specific goal of finding new molecular aberrant pathways, suitable to be targeted by a variety of therapeutic approaches, including novel pharmaceutical formulations and immunotherapy strategies...
January 16, 2018: Brain Sciences
https://www.readbyqxmd.com/read/29336892/gene-therapy-and-gene-editing-strategies-for-hemoglobinopathies
#17
REVIEW
Maria Rosa Lidonnici, Giuliana Ferrari
Gene therapy for hemoglobinopathies is currently based on transplantation of autologous hematopoietic stem cells genetically modified with an integrating lentiviral vector expressing a globin gene under the control of globin transcriptional regulatory elements. Studies and safety works demonstrated the potential therapeutic efficacy and safety of this approach, providing the rationale for clinical translation. The outcomes of early clinical trials, although showing promising results, have highlighted the current limitations to a more general application...
January 3, 2018: Blood Cells, Molecules & Diseases
https://www.readbyqxmd.com/read/29336259/p53-as-the-focus-of-gene-therapy-past-present-and-future
#18
Joana Fa Valente, Joao A Queiroz, Fani Sousa
BACKGROUND: Several gene deviations can be responsible for triggering oncogenic processes. However, mutations in tumour suppressor genes are usually more associated to malignant diseases, being p53 one of the most affected and studied element. p53 is implicated in a number of known cellular functions, including DNA damage repair, cell cycle arrest in G1/S and G2/M and apoptosis, being an interesting target for cancer treatment. OBJECTIVE: Considering these facts, the development of gene therapy approaches focused on p53 expression and regulation seems to be a promising strategy for cancer therapy...
January 15, 2018: Current Drug Targets
https://www.readbyqxmd.com/read/29335220/adeno-associated-virus-vector-mediated-expression-of-dj-1-attenuates-learning-and-memory-deficits-in-2-2%C3%A2-4-4%C3%A2-tetrabromodiphenyl-ether-bde-47-treated-mice
#19
Juan Zhuang, Shan Wang, Qun Shan, Zi-Feng Zhang, Meng-Qiu Li, Gui-Hong Zheng, Shao-Hua Fan, Dong-Mei Wu, Bin Hu, Jun Lu, Yuan-Lin Zheng
Evidence indicates that oxidative stress is the central pathological feature of 2, 2´, 4, 4´-tetrabromodiphenyl ether (BDE-47)-induced neurotoxicity. Protein kinase C delta (PKCδ), an oxidative stress-sensitive kinase, can be proteolytically cleaved to yield a catalytically active fragment (PKCδ-CF) that is involved in various neurodegenerative disorders. Here, we showed that BDE-47 treatment increased ROS, malondialdehyde, and protein carbonyl levels in the mouse hippocampus. In turn, excessive ROS induced caspase-3-dependent PKCδ activation and stimulated NF-κB p65 nuclear translocation, resulting in inflammation in the mouse hippocampus...
January 8, 2018: Journal of Hazardous Materials
https://www.readbyqxmd.com/read/29335006/genetic-dissection-of-the-neuro-glio-vascular-machinery-in-the-adult-brain
#20
Gregory W Kirschen, Rachel Kéry, Hanxiao Liu, Afrinash Ahamad, Liang Chen, Wendy Akmentin, Ramya Kumar, Joel Levine, Qiaojie Xiong, Shaoyu Ge
The adult brain actively controls its metabolic homeostasis via the circulatory system at the blood brain barrier interface. The mechanisms underlying the functional coupling from neuron to vessel remain poorly understood. Here, we established a novel method to genetically isolate the individual components of this coupling machinery using a combination of viral vectors. We first discovered a surprising non-uniformity of the glio-vascular structure in different brain regions. We carried out a viral injection screen and found that intravenous Canine Adenovirus 2 (CAV2) preferentially targeted perivascular astrocytes throughout the adult brain, with sparing of the hippocampal hilus from infection...
January 15, 2018: Molecular Brain
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