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https://www.readbyqxmd.com/read/29334371/cooperative-targeting-of-melanoma-heterogeneity-with-an-axl-antibody-drug-conjugate-and-braf-mek-inhibitors
#1
Julia Boshuizen, Louise A Koopman, Oscar Krijgsman, Aida Shahrabi, Elke Gresnigt- van den Heuvel, Maarten A Ligtenberg, David W Vredevoogd, Kristel Kemper, Thomas Kuilman, Ji-Ying Song, Nora Pencheva, Jens Thing Mortensen, Marnix Geukes Foppen, Elisa A Rozeman, Christian U Blank, Maarten L Janmaat, David Satijn, Esther C W Breij, Daniel S Peeper, Paul W H I Parren
Intratumor heterogeneity is a key factor contributing to therapeutic failure and, hence, cancer lethality. Heterogeneous tumors show partial therapy responses, allowing for the emergence of drug-resistant clones that often express high levels of the receptor tyrosine kinase AXL. In melanoma, AXL-high cells are resistant to MAPK pathway inhibitors, whereas AXL-low cells are sensitive to these inhibitors, rationalizing a differential therapeutic approach. We developed an antibody-drug conjugate, AXL-107-MMAE, comprising a human AXL antibody linked to the microtubule-disrupting agent monomethyl auristatin E...
January 15, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29334207/screening-for-causative-mutations-of-major-prolificacy-genes-in-iranian-fat-tailed-sheep
#2
Ramin Abdoli, Seyed Ziaeddin Mirhoseini, Navid Ghavi Hossein-Zadeh, Pouya Zamani
Background: The presence of different missense mutations in sheep breeds have shown that the bone morphogenetic protein receptor 1B (BMPR1B), bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF9) genes play a vital role in ovulation rate and prolificacy in ewes. Therefore, the present study aims to investigate BMPR1B, BMP15 and GDF9 gene mutations in prolific ewes of Iranian fat-tailed Lori-Bakhtiari sheep. MATERIALS AND METHODS: In the present experimental study, genomic DNA was extracted from whole blood of 10 prolific Lori-Bakhtiari ewes with at least two twinning records in the first four parities to identify point mutations of the BMPR1B, BMP15 and GDF9 genes, using DNA sequencing...
April 2018: International Journal of Fertility & Sterility
https://www.readbyqxmd.com/read/29333086/ethical-and-safety-issues-of-stem-cell-based-therapy
#3
REVIEW
Vladislav Volarevic, Bojana Simovic Markovic, Marina Gazdic, Ana Volarevic, Nemanja Jovicic, Nebojsa Arsenijevic, Lyle Armstrong, Valentin Djonov, Majlinda Lako, Miodrag Stojkovic
Results obtained from completed and on-going clinical studies indicate huge therapeutic potential of stem cell-based therapy in the treatment of degenerative, autoimmune and genetic disorders. However, clinical application of stem cells raises numerous ethical and safety concerns. In this review, we provide an overview of the most important ethical issues in stem cell therapy, as a contribution to the controversial debate about their clinical usage in regenerative and transplantation medicine. We describe ethical challenges regarding human embryonic stem cell (hESC) research, emphasizing that ethical dilemma involving the destruction of a human embryo is a major factor that may have limited the development of hESC-based clinical therapies...
2018: International Journal of Medical Sciences
https://www.readbyqxmd.com/read/29332568/fgf-21-as-a-potential-biomarker-for-mitochondrial-diseases
#4
Leila Motlagh Scholle, Diana Lehmann, Marcus Deschauer, Torsten Kraya, Stephan Zierz
The diagnosis of mitochondrial diseases is still challenging due to clinical and genetical heterogeneity. The development of advanced technologies including Whole-Exome-Sequencing (WES) and Whole-Genome-Sequencing (WGS) have led to improvements in genetic diagnosis. However, a reliable biomarker in serum could enhance and ease the diagnosis and indeed reduce the need for muscle biopsy. Several studies suggest Fibroblast growth factor 21 (FGF-21) as a biomarker for diagnosis in mitochondrial disorders. It is known, that in patients with mitochondrial disorders, the expression of FGF-21 gets elevated in an effort to counteract the underlying metabolic deficiency...
January 10, 2018: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29330548/shox-haploinsufficiency-presenting-with-isolated-short-long-bones-in-the-second-and-third-trimester
#5
Shwetha Ramachandrappa, Abhijit Kulkarni, Hina Gandhi, Cheryl Ellis, Renata Hutt, Lesley Roberts, Rosol Hamid, Aris Papageorghiou, Sahar Mansour
Haploinsufficiency of the transcription factor short stature homeobox (SHOX) manifests as a spectrum of clinical phenotypes, ranging from disproportionate short stature and Madelung deformity to isolated short stature. Here, we describe five infants with molecularly confirmed diagnoses of SHOX haploinsufficiency who presented in utero with short long bones during routine antenatal scanning from as early as 19 weeks gestation. Other foetal growth parameters were normal. The molecular basis of SHOX haploinsufficiency was distinct in each case...
January 12, 2018: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/29330344/parathyroid-hormone-related-protein-exhibits-antioxidant-features-in-osteoblastic-cells-through-its-n-terminal-and-osteostatin-domains
#6
S Portal-Núñez, J A Ardura, D Lozano, I Martínez de Toda, M De la Fuente, G Herrero-Beaumont, R Largo, P Esbrit
OBJECTIVES: Oxidative stress plays a major role in the onset and progression of involutional osteoporosis. However, classical antioxidants fail to restore osteoblast function. Interestingly, the bone anabolism of parathyroid hormone (PTH) has been shown to be associated with its ability to counteract oxidative stress in osteoblasts. The PTH counterpart in bone, which is the PTH-related protein (PTHrP), displays osteogenic actions through both its N-terminal PTH-like region and the C-terminal domain...
January 2018: Bone & Joint Research
https://www.readbyqxmd.com/read/29330306/an-rb-family-independent-e2f3-transcription-factor-variant-impairs-stat5-signaling-and-mammary-gland-remodeling-during-pregnancy-in-mice
#7
Yang Liao, Wei Du
E2F transcription factors are regulated by binding to the retinoblastoma (Rb) tumor suppressor family of proteins. Previously, we reported an E2FLQ mutation that disrupts the binding with Rb proteins without affecting E2F's transcriptional activity. We also showed that mouse embryonic fibroblasts (MEFs) with an E2F3LQ mutation exhibit increased E2F activity and more rapid cell proliferation. In this report, we analyzed E2F3LQ mice to further characterize the in vivo consequences of Rb family-independent E2F3 activity...
January 12, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29330302/controlled-dimerization-of-insulin-like-growth-factor-1-and-insulin-receptors-reveal-shared-and-distinct-activities-of-holo-and-hybrid-receptors
#8
Jingci Chen, Alison M Nagle, Yu-Fen Wang, David N Boone, Adrian V Lee
Breast cancer development and progression is influenced by insulin-like growth factor 1 (IGF1R) and insulin receptor (InsR) signaling that drive cancer phenotypes such as cell growth, proliferation, and migration. IGF1R and InsR form IGF1R/InsR hybrid receptors (HybR) consisting of one molecule of IGF1R and one molecule of InsR. The specific signaling and functions of HybR are largely unknown as HybR is activated by both IGF1 and insulin, and no cellular system expresses HybR in the absence of holo-IGF1R or holo-InsR...
January 12, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29330256/osteoprotegerin-is-associated-with-major-bleeding-but-not-with-cardiovascular-outcomes-in-patients-with-acute-coronary-syndromes-insights-from-the-plato-platelet-inhibition-and-patient-outcomes-trial
#9
Thor Ueland, Axel Åkerblom, Tatevik Ghukasyan, Annika E Michelsen, Pål Aukrust, Richard C Becker, Maria Bertilsson, Anders Himmelmann, Stefan K James, Agneta Siegbahn, Robert F Storey, Frederic Kontny, Lars Wallentin
BACKGROUND: Elevated levels of osteoprotegerin, a secreted tumor necrosis factor-related molecule, might be associated with adverse outcomes in patients with coronary artery disease. We measured plasma osteoprotegerin concentrations on hospital admission, at discharge, and at 1 and 6 months after discharge in a predefined subset (n=5135) of patients with acute coronary syndromes in the PLATO (Platelet Inhibition and Patient Outcomes) trial. METHODS AND RESULTS: The associations between osteoprotegerin and the composite end point of cardiovascular death, nonprocedural spontaneous myocardial infarction or stroke, and non-coronary artery bypass grafting major bleeding during 1 year of follow-up were assessed by Cox proportional hazards models...
January 12, 2018: Journal of the American Heart Association
https://www.readbyqxmd.com/read/29330027/selective-estrogen-receptor-modulator-ormeloxifene-suppresses-embryo-implantation-via-inducing-mir-140-and-targeting-insulin-like-growth-factor-1-receptor-in-rat-uterus
#10
Vijay K Sirohi, Kanchan Gupta, Rohit Kumar, Vinay Shukla, Anila Dwivedi
Ormeloxifene, the non-steroidal SERM contraceptive, inhibits endometrial receptivity and embryo implantation via countering nidatory estrogen. However, the molecular mechanism of ormeloxifene action responsible for its contraceptive efficacy still remains unclear. Herein, we aimed to identify the miRNAs modulated under the influence of ormeloxifene and to explore their role in endometrial receptivity and embryo implantation. By doing microRNA sequencing analysis, a total of 168 miRNAs were found to be differentially expressed in uterine tissue of ormeloxifene-treated rats, on day 5 (10:00 h) of pregnancy i...
January 9, 2018: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/29329462/silibinin-from-silybum-marianum-stimulates-embryonic-stem-cell-vascular-differentiation-via-the-stat3-pi3-k-akt-axis-and-nitric-oxide
#11
Enas Hussein Ali, Fatemeh Sharifpanah, Maria Wartenberg, Heinrich Sauer
Silibinin, the bioactive compound of milk thistle (Silybum marianum), exerts tissue protective and regenerative effects that may include stem cell differentiation toward vascular cells. The purpose of the present study was to investigate whether silibinin stimulates blood vessel formation from mouse embryonic stem (ES) cells and to unravel the underlying signaling cascade. Vascular branching points were assessed by confocal laser scanning microscopy and computer-assisted image analysis of CD31-positive cell structures...
January 12, 2018: Planta Medica
https://www.readbyqxmd.com/read/29329193/mustn1-a-developmentally-regulated-pan-musculoskeletal-cell-marker-and-regulatory-gene
#12
REVIEW
Michael Hadjiargyrou
The Mustn1 gene encodes a small nuclear protein (~9.6 kDa) that does not belong to any known family. Its genomic organization consists of three exons interspersed by two introns and it is highly homologous across vertebrate species. Promoter analyses revealed that its expression is regulated by the AP family of transcription factors, especially c-Fos, Fra-2 and JunD. Mustn1 is predominantly expressed in the major tissues of the musculoskeletal system: bone, cartilage, skeletal muscle and tendon. Its expression has been associated with normal embryonic development, postnatal growth, exercise, and regeneration of bone and skeletal muscle...
January 12, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29329052/efficient-and-cost-effective-generation-of-hepatocyte-like-cells-through-microparticle-mediated-delivery-of-growth-factors-in-a-3d-culture-of-human-pluripotent-stem-cells
#13
Zeinab Heidariyan, Mohammad Hossein Ghanian, Mohsen Ashjari, Zahra Farzaneh, Mostafa Najarasl, Mehran Rezaei Larijani, Abbas Piryaei, Massoud Vosough, Hossein Baharvand
Biomedical application of human pluripotent stem cell-derived hepatocyte-like cells (hPSC-HLCs) relies on efficient large-scale differentiation, which is commonly performed by a suspension culture of three-dimensional (3D) multicellular spheroids in bioreactors. However, this approach requires large amounts of growth factors (GFs) and the need to overcome limited diffusional transport posed by the inherent 3D structure of hPSC spheroids. Here, we have hypothesized that localized delivery of GFs by incorporation of GF-laden degradable polymeric microparticles (MPs) within the hPSC spheroids would circumvent such limitations...
January 2, 2018: Biomaterials
https://www.readbyqxmd.com/read/29328778/engineering-approaches-to-study-cellular-decision-making
#14
Pamela K Kreeger, Laura E Strong, Kristyn S Masters
In their native environment, cells are immersed in a complex milieu of biochemical and biophysical cues. These cues may include growth factors, the extracellular matrix, cell-cell contacts, stiffness, and topography, and they are responsible for regulating cellular behaviors such as adhesion, proliferation, migration, apoptosis, and differentiation. The decision-making process used to convert these extracellular inputs into actions is highly complex and sensitive to changes both in the type of individual cue (e...
January 12, 2018: Annual Review of Biomedical Engineering
https://www.readbyqxmd.com/read/29328449/bioinformatics-analysis-to-screen-key-genes-implicated-in-the-differentiation-of-induced-pluripotent-stem-cells-to-hepatocytes
#15
Rui Lin, Yufeng Wang, Kun Ji, Zhongyan Liu, Shuai Xiao, Dehua Zhou, Quanning Chen, Baomin Shi
Due to the lack of potential organs, hepatocellular transplantation has been considered for treating end-stage liver disease. Induced pluripotent stem cells (iPSCs) are reverted from somatic cells and are able to differentiate into hepatocytes. The present study aimed to investigate the mechanisms underlying iPSC differentiation to hepatocytes. GSE66076 was downloaded from the Gene Expression Omnibus; this database includes data from 3 undifferentiated (T0), 3 definitive endoderm (T5), and 3 early hepatocyte (T24) samples across hepatic‑directed differentiation of iPSCs...
January 5, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29328402/mir%C3%A2-203%C3%A2-3p-participates-in-the-suppression-of-diabetes%C3%A2-associated-osteogenesis-in-the-jaw-bone-through-targeting-smad1
#16
Yuying Tang, Leilei Zheng, Jie Zhou, Yang Chen, Lan Yang, Feng Deng, Yun Hu
Certain microRNAs (miRs) have important roles in the maintenance of bone development and metabolism, and a variety of miRs are known to be deregulated in diabetes. The present study investigated the role of miR‑203‑3p in the regulation of bone loss by assessing jaw bones of a rat model of type 2 diabetes. The results indicated that miR‑203‑3p inhibited osteogenesis in the jaws of diabetic rats and in rat bone marrow mesenchymal stem cells cultured in high‑glucose medium. A luciferase re-porter assay was used to verify the bioinformatics prediction that miR‑203‑3p targets the 3'‑untranslated region of Smad1, which is an important mediator of the bone morphogenetic protein (BMP)/Smad pathway...
January 9, 2018: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29328361/logistic-regression-analysis-for-the-identification-of-the-metastasis-associated-signaling-pathways-of-osteosarcoma
#17
Yang Liu, Wei Sun, Xiaojun Ma, Yuedong Hao, Gang Liu, Xiaohui Hu, Houlai Shang, Pengfei Wu, Zexue Zhao, Weidong Liu
Osteosarcoma (OS) is the most common histological type of primary bone cancer. The present study was designed to identify the key genes and signaling pathways involved in the metastasis of OS. Microarray data of GSE39055 were downloaded from the Gene Expression Omnibus database, which included 19 OS biopsy specimens before metastasis (control group) and 18 OS biopsy specimens after metastasis (case group). After the differentially expressed genes (DEGs) were identified using the Linear Models for Microarray Analysis package, hierarchical clustering analysis and unsupervised clustering analysis were performed separately, using orange software and the self-organization map method...
January 2, 2018: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29327467/erbb3-binding-protein-ebp1-is-a-novel-dppa4-cofactor-in-human-pluripotent-cells
#18
Priyanka Somanath, Kelly M Bush, Paul S Knoepfler
Developmental Pluripotency-Associated-4 (DPPA4) is one of the few core pluripotency genes lacking clearly defined molecular and cellular functions. Here we used a proteomics screening approach of human embryonic stem cell (hESC) nuclear extract to determine DPPA4 molecular functions through identification of novel cofactors. Unexpectedly, the signaling molecule ERBB3-binding protein 1 (EBP1) was the strongest candidate binding partner for DPPA4 in hESC. EBP1 is a growth factor signaling mediator present in two isoforms, p48 and p42...
January 12, 2018: Stem Cells
https://www.readbyqxmd.com/read/29327207/phenotypic-and-functional-characteristics-of-human-schwann-cells-as-revealed-by-cell-based-assays-and-rna-seq
#19
Paula V Monje, David Sant, Gaofeng Wang
This study comprehensively addresses the phenotype, function, and whole transcriptome of primary human and rodent Schwann cells (SCs) and highlights key species-specific features beyond the expected donor variability that account for the differential ability of human SCs to proliferate, differentiate, and interact with axons in vitro. Contrary to rat SCs, human SCs were insensitive to mitogenic factors other than neuregulin and presented phenotypic variants at various stages of differentiation, along with a mixture of proliferating and senescent cells, under optimal growth-promoting conditions...
January 11, 2018: Molecular Neurobiology
https://www.readbyqxmd.com/read/29326336/arid5b-as-a-critical-downstream-target-of-the-tal1-complex-that-activates-the-oncogenic-transcriptional-program-and-promotes-t-cell-leukemogenesis
#20
Wei Zhong Leong, Shi Hao Tan, Phuong Cao Thi Ngoc, Stella Amanda, Alice Wei Yee Yam, Wei-Siang Liau, Zhiyuan Gong, Lee N Lawton, Daniel G Tenen, Takaomi Sanda
The oncogenic transcription factor TAL1/SCL induces an aberrant transcriptional program in T-cell acute lymphoblastic leukemia (T-ALL) cells. However, the critical factors that are directly activated by TAL1 and contribute to T-ALL pathogenesis are largely unknown. Here, we identified AT-rich interactive domain 5B (ARID5B) as a collaborating oncogenic factor involved in the transcriptional program in T-ALL. ARID5B expression is down-regulated at the double-negative 2-4 stages in normal thymocytes, while it is induced by the TAL1 complex in human T-ALL cells...
January 11, 2018: Genes & Development
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