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https://www.readbyqxmd.com/read/28427156/the-effects-of-dleu1-gene-expression-in-burkitt-lymphoma-bl-potential-mechanism-of-chemoimmunotherapy-resistance-in-bl
#1
Sanghoon Lee, Wen Luo, Tishi Shah, Changhong Yin, Timmy O'Connell, Tae-Hoon Chung, Sherrie L Perkins, Rodney R Miles, Janet Ayello, Erin Morris, Lauren Harrison, Carmella van de Ven, Mitchell S Cairo
Following a multivariant analysis we demonstrated that children and adolescents with Burkitt lymphoma (BL) and a 13q14.3 deletion have a significant decrease in event free survival (EFS) despite identical short intensive multi-agent chemotherapy. However, how this deletion in the 13q14.3 region is associated with a significant decrease in EFS in children and adolescents with BL is largely unknown. The gene Deleted in Lymphocytic Leukemia 1 (DLEU1) is located in the region of 13q14.3. Here, we report that DLEU1 expression is implicated in the regulation of BL programmed cell death, cell proliferation, and expression of apoptotic genes in transcription activator-like effector nuclease (TALEN)s-induced DLEU1 knockdown and DLEU1 overexpressing BL cell lines...
February 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/28409183/combination-of-il-10-and-il-2-induces-oligoclonal-human-cd4-t-cell-expansion-during-xenogeneic-and-allogeneic-gvhd-in-humanized-mice
#2
Sojan Abraham, Hua Guo, Jang-Gi Choi, Chunting Ye, Midhun Ben Thomas, Nora Ortega, Alok Dwivedi, N Manjunath, Guohua Yi, Premlata Shankar
IL-10 is a crucial anti-inflammatory cytokine which can also exert a seemingly divergent immunostimulatory effects under certain conditions. We found high levels of the cytokine in a xenogeneic GVHD model where NOD-scid IL2rγcnull (NSG) mice were transplanted with human PBMCs in presence of IL-2. Presence of exogenous IL-10 altered the kinetics of IL-2 induced human T cell reconstitution in vivo, showing an initial delay, followed by rapid expansion. Further, compared to IL-2 alone, treatment with IL-2 in combination with IL-10 increased survival in most animals and completely protected ∼20% of mice from GVHD...
April 2017: Heliyon
https://www.readbyqxmd.com/read/28406754/spheroid-coculture-of-hematopoietic-stem-progenitor-cells-and-monolayer-expanded-mesenchymal-stem-stromal-cells-in-polydimethylsiloxane-microwells-modestly-improves-in-vitro-hematopoietic-stem-progenitor-cell-expansion
#3
Kathryn Futrega, Kerry Atkinson, William B Lott, Michael R Doran
While two-dimensional (2D) monolayers of mesenchymal stem/stromal cells (MSCs) have been shown to enhance hematopoietic stem/progenitor cell (HSPC) expansion in vitro, expanded cells do not engraft long term in human recipients. This outcome is attributed to the failure of 2D culture to recapitulate the bone marrow (BM) niche signal milieu. Herein, we evaluated the capacity of a novel three-dimensional (3D) coculture system to support HSPC expansion in vitro. A high-throughput polydimethylsiloxane (PDMS) microwell platform was used to manufacture thousands of uniform 3D multicellular coculture spheroids...
April 2017: Tissue Engineering. Part C, Methods
https://www.readbyqxmd.com/read/28405609/preconditioned-mesenchymal-stem-cells-treat-myasthenia-gravis-in-a-humanized-preclinical-model
#4
Muriel Sudres, Marie Maurer, Marieke Robinet, Jacky Bismuth, Frédérique Truffault, Diane Girard, Nadine Dragin, Mohamed Attia, Elie Fadel, Nicola Santelmo, Camille Sicsic, Talma Brenner, Sonia Berrih-Aknin
Myasthenia gravis (MG) with anti-acetylcholine receptor (AChR) Abs is an autoimmune disease characterized by severe defects in immune regulation and thymic inflammation. Because mesenchymal stem cells (MSCs) display immunomodulatory features, we investigated whether and how in vitro-preconditioned human MSCs (cMSCs) could treat MG disease. We developed a new humanized preclinical model by subcutaneously grafting thymic MG fragments into immunodeficient NSG mice (NSG-MG model). Ninety percent of the animals displayed human anti-AChR Abs in the serum, and 50% of the animals displayed MG-like symptoms that correlated with the loss of AChR at the muscle endplates...
April 6, 2017: JCI Insight
https://www.readbyqxmd.com/read/28399128/creation-of-an-immunodeficient-hla-transgenic-mouse-humamice-and-functional-validation-of-human-immunity-after-transfer-of-hla-matched-human-cells
#5
Yang Zeng, Bingrun Liu, Marie-Thérèse Rubio, Xinyue Wang, David M Ojcius, Ruoping Tang, Antoine Durrbach, Zhitao Ru, Yusen Zhou, Yu-Chun Lone
Research on human immunology has been hindered by the lack of optimal small animal models, given that the protective immune responses of human and non-human species show significant differences. However, due to ethical constraints[1] and the high cost of clinical trials, it is urgent to improve the current animal models that can mimic faithfully human physiology, particularly the human immune system (HIS). HIS mice had been generated recently by engrafting human hematopoietic stem cells (hHSCs) or human peripheral mononuclear cells (hPBMCs) into highly immuno-deficient mice such as NSG, NOG or NRG mice...
2017: PloS One
https://www.readbyqxmd.com/read/28390927/a-novel-hemolytic-complement-sufficient-nsg-mouse-model-supports-studies-of-complement-mediated-antitumor-activity-in-vivo
#6
Mohit K Verma, Julia Clemens, Lisa Burzenski, Stephen B Sampson, Michael A Brehm, Dale L Greiner, Leonard D Shultz
Monoclonal antibodies (mAbs) have emerged as a mainstream therapeutic option against cancer. mAbs mediate tumor cell-killing through several mechanisms including complement-dependent cytotoxicity (CDC). However, studies of mAb-mediated CDC against tumor cells remain largely dependent on in vitro systems. Previously developed and widely used NOD-scid IL2rγ(null) (NSG) mice support enhanced engraftment of many primary human tumors. However, NSG mice have a 2-bp deletion in the coding region of the hemolytic complement (Hc) gene, and it is not possible to evaluate CDC activity in NSG mice...
April 6, 2017: Journal of Immunological Methods
https://www.readbyqxmd.com/read/28390865/spdef-induces-quiescence-of-colorectal-cancer-cells-by-changing-the-transcriptional-targets-of-%C3%AE-catenin
#7
Yuan-Hung Lo, Taeko K Noah, Min-Shan Chen, Winnie Zou, Ester Borras, Eduardo Vilar, Noah F Shroyer
BACKGROUND & AIMS: The canonical Wnt signaling pathway activates the transcriptional activity of β-catenin. This pathway is often activated in colorectal cancer cells, but strategies to block it in tumors have not been effective. The SAM pointed domain containing ETS transcription factor (SPDEF) suppresses formation of colon tumors by unclear mechanisms. We investigated these mechanisms and the effects of SPDEF on β-catenin activity in mouse models of colorectal cancer (CRC), CRC cell lines, and mouse and human normal and cancer colonoids...
April 5, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28381574/defining-a-novel-role-for-the-coxsackie-and-adenovirus-receptor-in-human-adenovirus-serotype-5-transduction-in-vitro-in-the-presence-of-mouse-serum
#8
Estrella Lopez-Gordo, Andor Doszpoly, Margaret R Duffy, Lynda Coughlan, Angela C Bradshaw, Katie M White, Laura Denby, Stuart A Nicklin, Andrew H Baker
Human adenoviral serotype 5 (HAdV-5) vectors have predominantly hepatic tropism when delivered intravascularly, resulting in immune activation and toxicity. Coagulation FX binding to HAdV-5 mediates liver transduction and provides protection from virion neutralisation in mice. FX is dispensable for liver transduction in mice lacking IgM antibodies or complement, suggesting alternative transduction pathways exist. To identify novel factor(s) mediating HAdV-5 FX-independent entry, we investigated HAdV-5 transduction in vitro in the presence of serum from immunocompetent C57BL/6 or immunocompromised mice lacking IgM antibodies (Rag 2(-/-) and NSG)...
April 5, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28371964/tips-and-tricks-to-improve-clinical-and-aesthetic-outcomes-in-latissimus-dorsi-flap-breast-reconstruction
#9
Rosaria Laporta, Michail Sorotos, Benedetto Longo, Fabio Santanelli di Pompeo
Background The aim of this study is to present technical strategies to decrease donor-site complications, to optimize breast shaping, and to achieve symmetry in one-stage procedure in latissimus dorsi (LD) flap reconstruction. Methods Between 2004 and 2014, a retrospective review was performed on LD flap reconstructions. Demographics, reconstructive details, clinical, and aesthetic outcomes were collected and analyzed. Patients were divided in historical control group (HCG) and new strategy group (NSG)...
April 3, 2017: Journal of Reconstructive Microsurgery
https://www.readbyqxmd.com/read/28359245/the-%C3%AE-2-adrenergic-agonist-salbutamol-inhibits-migration-invasion-and-metastasis-of-the-human-breast-cancer-mda-mb-231-cell-line
#10
Ezequiel Mariano Rivero, Cecilia Pérez Piñero, Lucía Gargiulo, Frank Entschladen, Kurt Zänker, Ariana Bruzzone, Isabel Alicia Lüthy
BACKGROUND: Breast cancer is the most diagnosed and the major cause of cancer death in women worldwide. Metastasis is the main cause of these deaths. The metastatic cascade involves multiple steps and it has been described that adrenergic receptors can modulate this process at multiple levels. However, β-adrenergic action in breast cancer is controversial. We have previously shown that β-adrenergic agonists inhibit cell proliferation and tumor growth of numerous breast cancer models...
March 30, 2017: Current Cancer Drug Targets
https://www.readbyqxmd.com/read/28355107/pathology-of-aging-in-nod-scid-gamma-female-mice
#11
Sara F Santagostino, Rodolfo J Ricart Arbona, Melissa A Nashat, Julie R White, Sebastien Monette
In the past decade, NOD.Cg- Prkdc(scid) Il2rg(tm1Wjl)/SzJ (NSG, NOD scid gamma) mice have become a model of choice in several areas of biomedical research; however, comprehensive data on their spontaneous age-related pathology are not currently available in the literature. The prevalence of spontaneous morbidity affecting aged NSG female breeders enrolled in a parasitology study was documented with classification of neoplastic and non-neoplastic (inflammatory, metabolic, degenerative) lesions. Malignant mammary neoplasms were most commonly diagnosed, often accompanied by pulmonary metastases, while a low frequency of lymphoma and histiocytic sarcoma was documented...
January 1, 2017: Veterinary Pathology
https://www.readbyqxmd.com/read/28337806/the-pharmacological-profile-of-a-novel-highly-potent-bisphosphonate-ox14-1-fluoro-2-imidazo-1-2-%C3%AE-pyridin-3-yl-ethyl-bisphosphonate
#12
M A Lawson, F H Ebetino, A Mazur, A D Chantry, J Paton-Hough, H R Evans, D Lath, M K Tsoumpra, M W Lundy, R L M Dobson, M Quijano, A A Kwaasi, J E Dunford, X Duan, J T Triffitt, G Jeans, R G G Russell
Bisphosphonates are widely used in the treatment of clinical disorders characterized by increased bone resorption, including osteoporosis, Paget's disease and the skeletal complications of malignancy. The anti-resorptive potency of the nitrogen-containing bisphosphonates on bone in vivo is now recognised to depend upon two key properties, namely mineral binding affinity and inhibitory activity on farnesyl pyrophosphate synthase (FPPS), and these properties vary independently of each other in individual bisphosphonates...
March 24, 2017: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/28337279/agr2-promotes-the-proliferation-migration-and-regulates-epithelial-mesenchymal-transition-in-salivary-adenoid-cystic-carcinoma
#13
Si-Rui Ma, Liang Mao, Wei-Wei Deng, Yi-Cun Li, Lin-Lin Bu, Guang-Tao Yu, Wen-Feng Zhang, Zhi-Jun Sun
Salivary adenoid cystic carcinoma (AdCC) is a common head and neck cancer with the propensity for local spread and distant metastasis. In our previous study, elevated expression of Anterior gradient 2 (AGR2) was detected in head and neck squamous cell carcinoma (HNSCC), associated with epithelial-mesenchymal transition (EMT) and cancer stemness. However, to date, the expression and function of AGR2 in AdCC has yet to be elucidated. In the present study, human AdCC tissue microarrays including 18 cases of normal salivary gland (NSG), 12 cases of pleomorphic adenoma (PMA) and 72 cases of AdCC were employed for immunohistochemical staining analysis...
2017: American Journal of Translational Research
https://www.readbyqxmd.com/read/28319446/good-laboratory-practice-preclinical-safety-studies-for-gsk2696273-mlv-vector-based-ex-vivo-gene-therapy-for-adenosine-deaminase-deficiency-severe-combined-immunodeficiency-in-nsg-mice
#14
Nicola Carriglio, Jan Klapwijk, Raisa Jofra Hernandez, Michela Vezzoli, Franck Chanut, Rhiannon Lowe, Draghici Elena, Melanie Nord, Paola Albertini, Patrizia Cristofori, Jane Richards, Hazel Staton, Jonathan Appleby, Alessandro Aiuti, Aisha V Sauer
GSK2696273 (autologous CD34+ cells transduced with retroviral vector that encodes for the human adenosine deaminase [ADA] enzyme) is a gamma-retroviral ex vivo gene therapy of bone marrow-derived CD34+ cells for the treatment of adenosine deaminase deficiency severe combined immunodeficiency (ADA-SCID). ADA-SCID is a severe monogenic disease characterized by immunologic and nonimmunologic symptoms. Bone-marrow transplant from a matched related donor is the treatment of choice, but it is available for only a small proportion of patients...
March 2017: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/28306193/diphtheria-toxin-based-anti-human-cd19-immunotoxin-for-targeting-human-cd19-tumors
#15
Qian Zheng, Zhaohui Wang, Huiping Zhang, Qi Huang, Joren C Madsen, David H Sachs, Christene A Huang, Zhirui Wang
CD19 is expressed on normal and neoplastic B cells and is a promising target for immunotherapy. However, there is still an unmet need to further develop novel therapeutic drugs for the treatment of the refractory/relapsing human CD19(+) tumors. We have developed a diphtheria toxin-based anti-human CD19 immunotoxin for targeting human CD19(+) tumors. We have constructed three isoforms of the CD19 immunotoxin: monovalent, bivalent and foldback diabody. In vitro binding affinity and efficacy analysis demonstrated that the bivalent isoform had the highest binding affinity and in vitro efficacy...
March 17, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28299779/the-related-neuronal-endosomal-proteins-neep21-nsg1-and-p19-nsg2-have-divergent-expression-profiles-in-vivo
#16
Kelly Barford, Chan Choo Yap, Noelle D Dwyer, Bettina Winckler
Endosomal maturation and transport constitutes a complex trafficking system present in all cell types. Neurons have adapted their endosomal system to meet their unique and complex needs. These adaptations include repurposing existing proteins to diversify endocytosis and trafficking, as well as preferential expression of certain regulators more highly in neurons than other cell types. These neuronal regulators include the family of Neuron-Specific Gene family members (Nsg), NEEP21 (Nsg1), and P19 (Nsg2). NEEP21/Nsg1 plays a role in the trafficking of multiple receptors, including the cell adhesion molecule L1/NgCAM, the neurotransmitter receptor GluA2, and β-APP...
June 1, 2017: Journal of Comparative Neurology
https://www.readbyqxmd.com/read/28286209/esophageal-adenocarcinoma-cells-and-xenograft-tumors-exposed-to-erb-b2-receptor-tyrosine-kinase-2-and-3-inhibitors-activate-transforming-growth-factor-beta-signaling-which-induces-epithelial-to-mesenchymal-transition
#17
Eva A Ebbing, Anne Steins, Evelyn Fessler, Phylicia Stathi, Willem Joost Lesterhuis, Kausilia K Krishnadath, Louis Vermeulen, Jan Paul Medema, Maarten F Bijlsma, Hanneke W M van Laarhoven
BACKGROUND & AIMS: Drugs that inhibit the erb-b2 receptor tyrosine kinase 2 (ERBB2 or HER2) are the standard treatment of patients with different types of cancer, including HER2-overexpressing gastroesophageal tumors. Unfortunately, cancer cells become resistant to these drugs, so overall these drugs provide little benefit to patients with these tumors. We investigated mechanisms that mediate resistance of esophageal adenocarcinoma (EAC) cells and patient-derived xenograft (PDX) tumors to ERBB inhibitors...
March 9, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28282033/pi3k%C3%AE-and-pi3k%C3%AE-isoforms-have-distinct-functions-in-regulating-pro-tumoural-signalling-in-the-multiple-myeloma-microenvironment
#18
R E Piddock, N Loughran, C R Marlein, S D Robinson, D R Edwards, S Yu, G E Pillinger, Z Zhou, L Zaitseva, M J Auger, S A Rushworth, K M Bowles
Phosphoinositide-3-kinase and protein kinase B (PI3K-AKT) is upregulated in multiple myeloma (MM). Using a combination of short hairpin RNA (shRNA) lentivirus-mediated knockdown and pharmacologic isoform-specific inhibition we investigated the role of the PI3K p110γ (PI3Kγ) subunit in regulating MM proliferation and bone marrow microenvironment-induced MM interactions. We compared this with inhibition of the PI3K p110δ (PI3kδ) subunit and with combined PI3kδ/γ dual inhibition. We found that MM cell adhesion and migration were PI3Kγ-specific functions, with PI3kδ inhibition having no effect in MM adhesion or migration assays...
March 10, 2017: Blood Cancer Journal
https://www.readbyqxmd.com/read/28275460/reactivation-of-hiv-1-proviruses-in-immune-compromised-mice-engrafted-with-human-voa-negative-cd4-t-cells
#19
EDITORIAL
Zhe Yuan, Guobin Kang, Wuxun Lu, Qingsheng Li
BACKGROUND: HIV-1 infection remains incurable on antiretroviral therapy (ART) due to virus latency. To date, enhanced co-culture assays, including viral outgrowth assays (VOA), are commonly used to measure HIV-1 latent reservoirs and evaluate latency-reversing agents (LRAs). However, VOA can only reactivate a small fraction of intact proviruses. METHODS: To explore the utility of NOD scid gamma (NSG) mice as an in vivo model to reactivate HIV-1 proviruses from VOA-negative CD4+ T cells, resting CD4+ T cells from an HIV-1 latently infected individual were isolated and the human CD4+ T cells corresponding to VOA-positive and VOA-negative CD4+ T cells were engrafted into NSG mice...
January 1, 2017: Journal of Virus Eradication
https://www.readbyqxmd.com/read/28264583/crispr-mediated-knockout-of-cybb-in-nsg-mice-establishes-a-model-of-chronic-granulomatous-disease-for-human-stem-cell-gene-therapy-transplants
#20
Colin L Sweeney, Uimook Choi, Chengyu Liu, Sherry Koontz, Seung-Kwon Ha, Harry L Malech
Chronic granulomatous disease (CGD) is characterized by defects in the production of microbicidal reactive oxygen species (ROS) by phagocytes. Testing of gene and cell therapies for the treatment of CGD in human hematopoietic cells requires preclinical transplant models. The use of the lymphocyte-deficient NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl/)SzJ (NSG) mouse strain for human hematopoietic cell xenografts to test CGD therapies is complicated by the presence of functional mouse granulocytes capable of producing ROS for subsequent bacterial and fungal killing...
March 6, 2017: Human Gene Therapy
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