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https://www.readbyqxmd.com/read/28527722/crispr-cas9-mediated-ccr5-ablation-in-human-hematopoietic-stem-progenitor-cells-confers-hiv-1-resistance-in%C3%A2-vivo
#1
Lei Xu, Huan Yang, Yang Gao, Zeyu Chen, Liangfu Xie, Yulin Liu, Ying Liu, Xiaobao Wang, Hanwei Li, Weifeng Lai, Yuan He, Anzhi Yao, Liying Ma, Yiming Shao, Bin Zhang, Chengyan Wang, Hu Chen, Hongkui Deng
Transplantation of hematopoietic stem cells (HSCs) with a naturally occurring CCR5 mutation confers a loss of detectable HIV-1 in the patient, making ablation of the CCR5 gene in HSCs an ideal therapy for an HIV-1 cure. Although CCR5 disruption has been attempted in CD4(+) T cells and hematopoietic stem/progenitor cells (HSPCs), efficient gene editing with high specificity and long-term therapeutic potential remains a major challenge for clinical translation. Here, we established a CRISPR/Cas9 gene editing system in human CD34(+) HSPCs and achieved efficient CCR5 ablation evaluated in long-term reconstituted NOD/Prkdc(scid)/IL-2Rγ(null) mice...
May 17, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28525893/rat-embryonic-fibroblasts-immortalized-by-mrps18-2-protein-are-target-for-nk-cells
#2
Muhammad Mushtaq, Pradeepa N Pangigadde, Suhas Darekar, Erik Dissen, Elena Kashuba
Overexpression of the human mitochondrial ribosomal protein MRPS18-2 (S18-2) led to immortalization of primary rat embryonic fibroblasts (REFs). The derived cells (18IM) expressed embryonic stem cell markers. Noteworthy, genes encoding the COX family proteins were up-regulated significantly. It is known that the COX family proteins are involved in the regulation of immune response.In the present work we demonstrate that 18IM cells behave like stem cells when subjected to directed differentiation in vitro. However, unlike stem cells, 18IM cells do not develop tumors in vivo, in SCID mice...
May 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28522586/antitumor-synergism-and-enhanced-survival-with-a-tumor-vasculature-targeted-enzyme-prodrug-system-rapamycin-and-cyclophosphamide
#3
John J Krais, Needa Virani, Partick H McKernan, Quang Nguyen, Kar-Ming Fung, Vassilios I Sikavitsas, Carla D Kurkjian, Roger G Harrison
Mutant cystathionine gamma-lyase was targeted to phosphatidylserine exposed on tumor vasculature through fusion with annexin A1 or annexin A5.  Cystathionine gamma-lyase E58N, R118L, and E338N mutations impart non-native methionine gamma-lyase activity, resulting in tumor-localized generation of highly toxic methylselenol upon systemic administration of non-toxic selenomethionine.  The described therapeutic system circumvents systemic toxicity issues using a novel drug delivery/generation approach and avoids the administration of non-native proteins and/or DNA required with other enzyme prodrug systems...
May 18, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28518151/disulfiram-copper-selectively-eradicates-aml-leukemia-stem-cells-in-vitro-and-in-vivo-by-simultaneous-induction-of-ros-jnk-and-inhibition-of-nf-%C3%AE%C2%BAb-and-nrf2
#4
Bing Xu, Shiyun Wang, Rongwei Li, Kai Chen, Lingli He, Manman Deng, Vinodh Kannappan, Jie Zha, Huijuan Dong, Weiguang Wang
Acute myeloid leukemia (AML) is a heterogeneous malignancy. Despite the advances in past decades, the clinical outcomes of AML patients remain poor. Leukemia stem cells (LSCs) is the major cause of the recurrence of AML even after aggressive treatment making, promoting development of LSC-targeted agents is an urgent clinical need. Although the antitumor activity of disulfiram (DS), an approved anti-alcoholism drug, has been demonstrated in multiple types of tumors including hematological malignancies such as AML, it remains unknown whether this agent would also be able to target cancer stem cells like LSCs...
May 18, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28513891/haematopoietic-stem-cell-transplantation-for-severe-combined-immunodeficiency-long-term-health-outcomes-and-patient-perspectives
#5
Adrian Ys Lee, Katie Frith, Lilian Schneider, John B Ziegler
AIM: To examine the long-term follow-up and health outcomes of patients who have undergone haematopoietic stem cell transplant (HSCT) for severe combined immunodeficiency (SCID). METHODS: Through a structured questionnaire, we examined follow-up arrangements and long-term health outcomes in 22 children who have had a successful HSCT for SCID during the period of 1984-2012 at the Sydney Children's Hospital, Sydney, Australia. RESULTS: Most children considered themselves healthy and 'cured' from SCID...
May 17, 2017: Journal of Paediatrics and Child Health
https://www.readbyqxmd.com/read/28513593/jak3-deficiency-blocks-innate-lymphoid-cell-development
#6
M L Robinette, M Cella, J B Telliez, T K Ulland, A D Barrow, K Capuder, S Gilfillan, L-L Lin, L D Notarangelo, M Colonna
Loss-of-function mutations in the tyrosine kinase JAK3 cause autosomal recessive severe combined immunodeficiency (SCID). Defects in this form of SCID are restricted to the immune system, which led to the development of immunosuppressive JAK inhibitors. We find that the B6.Cg-Nr1d1(tm1Ven)/LazJ mouse line purchased from Jackson Laboratories harbors a spontaneous mutation in Jak3, generating a SCID phenotype and an inability to generate antigen-independent professional cytokine-producing innate lymphoid cells (ILCs)...
May 17, 2017: Mucosal Immunology
https://www.readbyqxmd.com/read/28513351/mind-the-fathers-associations-of-parental-childhood-adversities-with-borderline-personality-disorder-pathology-in-female-adolescents
#7
Corinna Reichl, Romuald Brunner, Anna Fuchs, Birger Holz, Peter Parzer, Gloria Fischer-Waldschmidt, Franz Resch, Michael Kaess
Previous research revealed significant relations between the experience of childhood adversity (CA) and the development of borderline personality disorder (BPD) in adulthood. However, it is still uncertain whether parental CA could have a transgenerational association with adolescent BPD. We investigated associations between parents' CA (antipathy, neglect, physical abuse) and BPD traits within a clinical adolescent sample and tested for mediating variables. The sample consists of 91 female inpatients, along with 84 mothers and 59 fathers...
May 17, 2017: Journal of Personality Disorders
https://www.readbyqxmd.com/read/28513348/measurement-invariance-between-genders-on-two-measures-of-borderline-personality-disorder
#8
Amy Paggeot, Steven Huprich
Gender bias in the diagnosis and assessment of borderline personality disorder (BPD) has been the subject of much controversy in the psychological research literature. Evidence regarding differential prevalence rates and diagnostic rates in clinical settings between genders has been mixed, and measurement bias is one potential explanation for these mixed findings. A total of 340 participants were recruited from a Midwestern university and four outpatient community mental health clinics. They were administered two structured clinical interviews for BPD that were then evaluated for measurement invariance...
May 17, 2017: Journal of Personality Disorders
https://www.readbyqxmd.com/read/28512763/impact-of-mlh1-expression-on-tumour-evolution-after-curative-surgical-tumour-resection-in-a-murine-orthotopic-xenograft-model-for-human-msi-colon-cancer
#9
Katy Meunier, Marianne Ferron, Claire Calmel, Jean-François Fléjou, Marc Pocard, Françoise Praz
Colorectal cancers (CRCs) displaying microsatellite instability (MSI) most often result from MLH1 deficiency. The aim of this study was to assess the impact of MLH1 expression per se on tumour evolution after curative surgical resection using a xenograft tumour model. Transplantable tumours established with the human MLH1-deficient HCT116 cell line and its MLH1-complemented isogenic clone, mlh1-3, were implanted onto the caecum of NOD/SCID mice. Curative surgical resection was performed at day 10 in half of the animals...
May 16, 2017: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/28511686/intrathymic-injection-of-hematopoietic-progenitor-cells-establishes-functional-t-cell-development-in-a-mouse-model-of-severe-combined-immunodeficiency
#10
Andrea Z Tuckett, Raymond H Thornton, Richard J O'Reilly, Marcel R M van den Brink, Johannes L Zakrzewski
BACKGROUND: Even though hematopoietic stem cell transplantation can be curative in patients with severe combined immunodeficiency, there is a need for additional strategies boosting T cell immunity in individuals suffering from genetic disorders of lymphoid development. Here we show that image-guided intrathymic injection of hematopoietic stem and progenitor cells in NOD-scid IL2rγ(null) mice is feasible and facilitates the generation of functional T cells conferring protective immunity...
May 16, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28507865/reconstitution-of-human-keloids-in-mouse-skin
#11
Ataru Sunaga, Hideaki Kamochi, Shunji Sarukawa, Hirokazu Uda, Yasushi Sugawara, Rintaro Asahi, Daekwan Chi, Shiho Nakagawa, Koji Kanayama, Kotaro Yoshimura
BACKGROUND: Keloids are a dermal fibroproliferative scar of unknown etiology. There is no good animal model for the study of keloids, which hinders the development and assessment of treatments for keloids. METHODS: Human keratinocytes and dermal fibroblasts were isolated from 3 human skin tissues: normal skin, white scars, and keloids. A mixed-cell slurry containing keratinocytes and dermal fibroblasts was poured into a double chamber implanted on the back of NOD/Shi-scid/IL-2Rγnull mice...
April 2017: Plastic and Reconstructive Surgery. Global Open
https://www.readbyqxmd.com/read/28507809/t-cell-therapy-targeting-a-public-neoantigen-in-microsatellite-instable-colon-cancer-reduces-in-vivo-tumor-growth
#12
Else M Inderberg, Sébastien Wälchli, Marit R Myhre, Sissel Trachsel, Hilde Almåsbak, Gunnar Kvalheim, Gustav Gaudernack
T-cell receptor (TCR) transfer is an attractive strategy to increase the number of cancer-specific T cells in adoptive cell therapy. However, recent clinical and pre-clinical findings indicate that careful consideration of the target antigen is required to limit the risk of off-target toxicity. Directing T cells against mutated proteins such as frequently occurring frameshift mutations may thus be a safer alternative to tumor-associated self-antigens. Furthermore, such frameshift mutations result in novel polypeptides allowing selection of TCRs from the non-tolerant T-cell repertoire circumventing the problem of low affinity TCRs due to central tolerance...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28507796/lyg1-exerts-antitumor-function-through-promoting-the-activation-proliferation-and-function-of-cd4-t-cells
#13
Huihui Liu, Yanfei Zhang, Zhengyang Liu, Pingzhang Wang, Xiaoning Mo, Weiwei Fu, Wanchang Liu, Yingying Cheng, Wenling Han
Identification of novel stimulatory cytokines with antitumor function would have great value in tumor immunotherapy investigations. Here, we report LYG1 (Lysozyme G-like 1) identified through the strategy of Immunogenomics as a novel classical secretory protein with tumor-inhibiting function. LYG1 recombinant protein (rhLYG1) could significantly suppress the growth of B16 tumors in WT B6 mice, but not in SCID-beige mice, Rag1(-/-) mice, CD4(+)- or CD8(+) T cell-deleted mice. It could increase the number of CD4(+) and CD8(+) T cells in tumor-infiltrating lymphocytes, tumor-draining lymph nodes, and spleens, and promote IFNγ production by T cells in tumor-bearing mice...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28506771/15d-pgj2-as-an-endoplasmic-reticulum-stress-manipulator-in-multiple-myeloma-in-vitro-and-in-vivo
#14
Marcelo Sperandio, Ana Paula D Demasi, Elizabeth F Martinez, Sara O Saad, Fernando V Pericole, Karla P Vieira, Nadir S Freitas, Vera C Araújo, Amy Louise Brown, Juliana Trindade Clemente-Napimoga, Marcelo Henrique Napimoga
Multiple myeloma (MM) is characterised by intense protein folding and, consequently endoplasmic reticulum (ER) stress. The prostaglandin 15d-PGJ2 is able to raise oxidative stress levels within the cell and potentially trigger cell death. The aim of this study was to evaluate the antineoplastic effect of 15d-PGJ2 on MM in vitro and in vivo via ER and oxidative stress pathways. MM.1R and MM.1S cell lines were treated with 15d-PGJ2 at 1-10μM and evaluated with regard to proliferation, mRNA expression of PRDX1, PRDX4, GRP78, GRP94, CHOP, BCL-2 and BAX...
May 12, 2017: Experimental and Molecular Pathology
https://www.readbyqxmd.com/read/28500074/disease-specific-effects-of-matrix-and-growth-factors-on-adhesion-and-migration-of-rheumatoid-synovial-fibroblasts
#15
Stephanie Lefèvre, Maria Schwarz, Florian M P Meier, Birgit Zimmermann-Geller, Ingo H Tarner, Markus Rickert, Jürgen Steinmeyer, Michael Sauerbier, Stefan Rehart, Ulf Müller-Ladner, Elena Neumann
In rheumatoid arthritis (RA), cartilage and bone matrix are degraded, and extracellular matrix (ECM) proteins, acting as cellular activators, are liberated. Similar to ECM proteins, matrix-bound chemokines, cytokines, and growth factors (GFs) influence functional properties of key cells in RA, especially synovial fibroblasts. The role of these molecules on attachment, migration, and proinflammatory and prodestructive activation of RASFs was analyzed. Adhesion/migration of RASFs were examined under GF-enriched (GF(+)) or -reduced (GF(-)) conditions with or without addition of matrix-associated GFs, TGF-β, and platelet-derived GF to GF(-) or culture supernatants...
May 12, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28499126/control-of-tumor-initiation-by-nkg2d-naturally-expressed-on-ovarian-cancer-cells
#16
Xin Cai, Andrea Caballero-Benitez, Mesfin M Gewe, Isaac C Jenkins, Charles W Drescher, Roland K Strong, Thomas Spies, Veronika Groh
Cancer cells may co-opt the NKG2D lymphocyte receptor to complement the presence of its ligands for autonomous stimulation of oncogenic signaling. Previous studies raise the possibility that cancer cell NKG2D may induce high malignancy traits, but its full oncogenic impact is unknown. Using epithelial ovarian cancer as model setting, we show here that ex vivo NKG2D(+) cancer cells have stem-like capacities, and provide formal in vivo evidence linking NKG2D stimulation with the development and maintenance of these functional states...
May 9, 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/28498812/structure-based-discovery-of-clomifene-as-a-potent-inhibitor-of-cancer-associated-mutant-idh1
#17
Mengzhu Zheng, Weiguang Sun, Suyu Gao, Shanshan Luan, Dan Li, Renqi Chen, Qian Zhang, Lixia Chen, Jiangeng Huang, Hua Li
Isocitrate dehydrogenase (IDH) plays an indispensable role in the tricarboxylic acid cycle, and IDH mutations are present in nearly 75% of glioma and 20% of acute myeloid leukemia. One IDH1R132H inhibitor (clomifene citrate) was found by virtual screening method, which can selectively suppress mutant enzyme activities in vitro and in vivo with a dose-dependent manner. The molecular docking indicated that clomifene occupied the allosteric site of the mutant IDH1. Enzymatic kinetics also demonstrated that clomifene inhibited mutant enzyme in a non-competitive manner...
April 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28497484/cd44-variant-isoform-9-emerges-in-response-to-injury-and-contributes-to-the-regeneration-of-the-gastric-epithelium
#18
Nina Bertaux-Skeirik, Mark Wunderlich, Emma Teal, Jayati Chakrabarti, Jacek Biesiada, Maxime Mahe, Nambirajan Sundaram, Joel Gabre, Jennifer Hawkins, Jian Gao, Amy C Engevik, Li Yang, Jiang Wang, James R Goldenring, Joseph E Qualls, Mario Medvedovic, Michael A Helmrath, Tayyab Diwan, James C Mulloy, Yana Zavros
Cluster-of-differentiation gene 44, in particular CD44 variant isoform 9 (CD44v9), emerges during regeneration of the gastric epithelium in response to injury. In particular, CD44v9 is expressed within Spasmolytic Polypeptide/TFF2-Expressing Metaplasia (SPEM) glands during gastric repair, but the function is unknown. Here we tested the hypothesis that age dependent expression of CD44v9 marks a regenerative cell lineage responsive to infiltrating macrophages during regeneration of the gastric epithelium. Acetic acid injury was induced in CD44-deficient (CD44KO) and C57BL/6 (BL6) mice...
May 12, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28496009/dynamic-changes-in-clonal-cytogenetic-architecture-during-progression-of-chronic-lymphocytic-leukemia-in-patients-and-patient-derived-murine-xenografts
#19
Nicholas J Davies, Marwan Kwok, Clive Gould, Ceri E Oldreive, Jingwen Mao, Helen Parry, Edward Smith, Angelo Agathanggelou, Guy Pratt, Alexander Malcolm R Taylor, Paul Moss, Mike Griffiths, Tatjana Stankovic
Subclonal heterogeneity and clonal selection influences disease progression in chronic lymphocytic leukemia (CLL). It is therefore important that therapeutic decisions are made based on an understanding of the CLL clonal architecture and its dynamics in individual patients. Identification of cytogenetic abnormalities by FISH remains the cornerstone of contemporary clinical practice and provides a simple means for prognostic stratification. Here, we demonstrate that multiplexed-FISH can enhance recognition of CLL subclonal repertoire and its dynamics during disease progression, both in patients and CLL patient-derived xenografts (PDX)...
April 26, 2017: Oncotarget
https://www.readbyqxmd.com/read/28495135/inflammatory-cytokines-and-functional-impairment-in-drug-free-subjects-with-mood-disorder
#20
Carolina David Wiener, Fernanda Pedrotti Moreira, Taiane Azevedo Cardoso, Thaise Campos Mondin, Pedro Vieira da Silva Magalhães, Flavio Kapczinski, Luciano Dias de Mattos Souza, Ricardo Azevedo da Silva, Jean Pierre Oses, Karen Jansen
OBJECTIVE: To assess the association between peripheral levels of inflammatory cytokines and functional impairment in subjects with Bipolar Disorder (BD), Major Depressive Disorder (MDD) and population controls. METHODS: This was a cross-sectional study with a matched sample of drug-free young adults with BD (n=48), MDD (n=48) and population controls (n=48). Mood disorder was confirmed by a certified psychologist using the Structured Clinical Interview for DSM-IV (SCID-I)...
June 15, 2017: Journal of Neuroimmunology
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