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Nitya V Sharma, Kathryn L Pellegrini, Veronique Ouellet, Felipe O Giuste, Selvi Ramalingam, Kenneth Watanabe, Eloise Adam-Granger, Lucresse Fossouo, Sungyong You, Michael R Freeman, Paula Vertino, Karen Conneely, Adeboye O Osunkoya, Dominique Trudel, Anne-Marie Mes-Masson, John A Petros, Fred Saad, Carlos S Moreno
BACKGROUND: Patients with locally advanced or recurrent prostate cancer typically undergo androgen deprivation therapy (ADT), but the benefits are often short-lived and the responses variable. ADT failure results in castration-resistant prostate cancer (CRPC), which inevitably leads to metastasis. We hypothesized that differences in tumor transcriptional programs may reflect differential responses to ADT and subsequent metastasis. RESULTS: We performed whole transcriptome analysis of 20 patient-matched Pre-ADT biopsies and 20 Post-ADT prostatectomy specimens, and identified two subgroups of patients (high impact and low impact groups) that exhibited distinct transcriptional changes in response to ADT...
October 11, 2018: Cancers
Lei Ye, Lei X Sun, Min H Wu, Jin Wang, Xin Ding, Hui Shi, Sheng L Lu, Lin Wu, Juan Wei, Liang Li, Yu F Wang
Disruption of normal barrier function is a fundamental factor in the pathogenesis of inflammatory bowel disease, and intestinal stem cell (ISC) transplantation may be an optional treatment for patients. However, it is complicated and inefficient to isolate ISCs from the intestine, which hampers its wide application in clinic. We developed a two-step protocol in which mesenchymal stem cells (MSCs) were first induced into Sox17- or Foxa2-positive definitive endoderm cells by activin A treatment and then into Lgr5-positive ISC-like cells by miR-17 and FGF2 treatment...
August 24, 2018: Molecular Therapy. Nucleic Acids
Simmi Saini, Gagandeep Kaur Walia, Mohinder Pal Sachdeva, Vipin Gupta
Obesity is one of the largest global health problems associated with increased morbidity and mortality mediated by its association with several other metabolic disorders. The interaction between the genes and environment plays an important role in the manifestation of obesity. Despite a high heritability (40-70%) of obesity, the search for genetic variants associated with obesity susceptibility has been a challenging task. To date, limited studies have been conducted in India, restricted to the validation of few genetic variants identified by genomewide association studies...
September 2018: Journal of Genetics
Nishanth Uli, Eduardo Michelen-Gomez, Enrique I Ramos, Todd E Druley
The role of DNA methylation patterns in complex phenotypes remains unclear. To explore this question, we adapted our methods for rare variant analysis to characterize genome-wide murine DNA hybridization array to investigate methylation at CpG islands, shores, and regulatory elements. We have applied this platform to compare age and tissue- specific methylation differences in the brain and spleen of young and aged mice. As expected from prior studies, there are clear global differences in organ-specific, but not age-specific, methylation due mostly to changes at repetitive elements...
2018: PloS One
Rasoul Godini, Hossein Fallahi
Development of an embryo from a single cell, zygote, to multicellular morulae requires activation of hundreds of genes that were mostly inactivated before fertilization. Inevitably, transcription factors (TFs) would be involved in modulating the drastic changes in gene expression pattern observed at all preimplantation stages. Despite many ongoing efforts to uncover the role of TFs at the early stages of embryogenesis, still many unanswered questions remained that need to be explored. This could be done by studying the expression pattern of multiple genes obtained by high-throughput techniques...
September 24, 2018: Journal of Cellular Physiology
Jia-Heng Li, Zhan Zhang, Ming-Ze Du, Yi-Chun Guan, Jian-Ning Yao, Hai-Yang Yu, Bi-Jun Wang, Xing-Ling Wang, She-Ling Wu, Zhen Li
microRNA (miR)-141-3p has context-dependent effects on tumor progression. In this study, we attempted to explore the expression and function of miR-141-3p in cervical cancer. We found that miR-141-3p expression was significantly increased in cervical cancer specimens relative to normal cervical tissues. Moreover, miR-141-3p levels were associated with tumor size and lymph node metastasis status. Ectopic expression of miR-141-3p significantly increased cervical cancer cell proliferation, colony formation, invasion, and epithelial to mesenchymal transition, whereas depletion of miR-141-3p suppressed cervical cancer cell proliferation and invasion...
September 14, 2018: Archives of Biochemistry and Biophysics
Woosuk Choi, Alina X Yang, Michelle A Waltenburg, Shawn Choe, Madeline Steiner, Ahmed Radwan, Jingjun Lin, Carrol W Maddox, Adam W Stern, Richard L Fredrickson, Gee W Lau
Because of exposure to environmental pollutants, infectious agents and genetic predisposition, companion animals develop respiratory illnesses similar to those in humans. Older dogs of smaller breeds develop canine infectious respiratory disease (CIRD), chronic bronchitis (CB), and chronic obstructive pulmonary disease (COPD), with chronic lung infection, airway goblet cell hyperplasia and metaplasia (GCHM) and mucus hypersecretion. Excessive mucus clogs airways, reduces gas exchanges, disables the mucociliary clearance and reduces drug penetration...
September 16, 2018: Cellular Microbiology
Daniel Schill, Joshua Nord, Lisa Ann Cirillo
We have previously shown that cooperative, interdependent binding by the pioneer factors FoxO1 and FoxA1/2 is required for recruitment of RNA polymerase II and H3K27 acetylation to the promoters of insulin regulated genes. However, the underlying mechanisms are unknown. In this study, we demonstrate that, in HepG2 cells, FoxO1 and FoxA2 form a complex on DNA that is disrupted by insulin treatment. Insulin mediated phosphorylation of FoxO1 and FoxA2 does not impair their cooperative binding to mononucleosome particles assembled from the IGFBP1 promoter, indicating that direct disruption of complex formation by phosphorylation is not responsible for the loss of interdependent FoxO1:FoxA1/2 binding following insulin treatment...
August 24, 2018: Biochemistry and Cell Biology, Biochimie et Biologie Cellulaire
Robert Neff, Craig M Rush, Blair Smith, Floor J Backes, David E Cohn, Paul J Goodfellow
FOXA2, a member of the forkhead family of DNA-binding proteins, is frequently mutated in uterine cancers. Most of the mutations observed in uterine cancers are frameshifts and stops. FOXA2 is considered to be a driver gene in uterine cancers, functioning as a haploinsufficient tumor suppressor. The functional consequences of FOXA2 mutations, however, have not yet been determined. We evaluated the effects that frameshift mutations as well as a recurrent missense mutation have on FOXA2 transcriptional activity...
August 9, 2018: International Journal of Cancer. Journal International du Cancer
Sonya Galcheva, Sara Al-Khawaga, Khalid Hussain
Hyperinsulinaemic hypoglycaemia (HH) is a heterogeneous condition with dysregulated insulin secretion which persists in the presence of low blood glucose levels. It is the most common cause of severe and persistent hypoglycaemia in neonates and children. Recent advances in genetics have linked congenital HH to mutations in 14 different genes that play a key role in regulating insulin secretion (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A, HNF1A, HK1, PGM1, PPM2, CACNA1D, FOXA2). Histologically, congenital HH can be divided into 3 types: diffuse, focal and atypical...
August 2018: Best Practice & Research. Clinical Endocrinology & Metabolism
Vasumathi Kameswaran, Maria L Golson, Mireia Ramos-Rodríguez, Kristy Ou, Yue J Wang, Jia Zhang, Lorenzo Pasquali, Klaus H Kaestner
Type 2 diabetes mellitus (T2DM) is characterized by the inability of the insulin-producing β-cells to overcome insulin resistance. We previously identified an imprinted region on chromosome 14, the DLK1 - MEG3 locus, as being downregulated in islets from humans with T2DM. In this study, using targeted epigenetic modifiers, we prove that increased methylation at the promoter of Meg3 in mouse βTC6 β-cells results in decreased transcription of the maternal transcripts associated with this locus. As a result, the sensitivity of β-cells to cytokine-mediated oxidative stress was increased...
September 2018: Diabetes
Chenyi Ye, Mo Chen, Erman Chen, Weixu Li, Shengdong Wang, Qianhai Ding, Cong Wang, Chenhe Zhou, Lan Tang, Weiduo Hou, Kai Hang, Rongxin He, Zhijun Pan, Wei Zhang
Forkhead box protein A2 (FOXA2) is a core transcription factor that controls cell differentiation and may have an important role in bone metabolism. However, the role of FOXA2 during osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) remains largely unknown. In this study, decreased expression of FOXA2 was observed during osteogenic differentiation of rat BMSCs (rBMSCs). FOXA2 knockdown significantly increased osteoblast-specific gene expression, the number of mineral deposits and alkaline phosphatase activity, whereas FOXA2 overexpression inhibited osteogenesis-specific activities...
August 6, 2018: Cell Death & Disease
Ching-In Lau, Diana C Yánez, Anisha Solanki, Eleftheria Papaioannou, José Ignacio Saldaña, Tessa Crompton
The Foxa1 and Foxa2 transcription factors are essential for mouse development. Here we show that they are expressed in thymic epithelial cells (TEC) where they regulate TEC development and function, with important consequences for T-cell development. TEC are essential for T-cell differentiation, lineage decisions and repertoire selection. Conditional deletion of Foxa1 and Foxa2 from murine TEC led to a smaller thymus with a greater proportion of TEC and a greater ratio of medullary to cortical TEC. Cell-surface MHCI expression was increased on cortical TEC in the conditional Foxa1Foxa2 knockout thymus, and MHCII expression was reduced on both cortical and medullary TEC populations...
September 2018: Journal of Autoimmunity
Masaki Shoji, Hiroki Minato, Soichiro Ogaki, Masahide Seki, Yutaka Suzuki, Shoen Kume, Takashi Kuzuhara
The crosstalk between cells is important for differentiation of cells. Murine-derived feeder cells, SNL76/7 feeder cells (SNLs) or mouse primary embryonic fibroblast feeder cells (MEFs) are widely used for culturing undifferentiated human induced pluripotent stem cells (hiPSCs). It is still unclear whether different culture conditions affect the induction efficiency of definitive endoderm (DE) differentiation from hiPSCs. Here we show that the efficiency of DE differentiation from hiPSCs cultured on MEFs was higher than that of hiPSCs cultured on SNLs...
2018: PloS One
Rebecca Playne, Kathryn Jones, Bronwen Connor
Reprogramming technology holds great promise for the study and treatment of Parkinson's disease (PD) as patient-specific ventral midbrain dopamine (vmDA) neurons can be generated. This should facilitate the investigation of early changes occurring during PD pathogenesis, permitting the identification of new drug targets and providing a platform for drug screening. To date, most studies using reprogramming technology to study PD have employed induced pluripotent stem cells. Research into PD using direct reprogramming has been limited due to an inability to generate high yields of authentic human vmDA neurons...
2018: Journal of Stem Cells & Regenerative Medicine
Diti Chatterjee Bhowmick, Aleksandar Jeremic
Human islet amyloid polypeptide (hIAPP) is the principal constituent of amyloid deposits and toxic oligomers in the pancreatic islets. Together with hyperglycemia, hIAPP-derived oligomers and aggregates are important culprits in type 2 diabetes mellitus (T2DM). Here, we explored the role of the cell's main proteolytic complex, the proteasome, in hIAPP turnover in normal and stressed β-cells evoked by chronic hyperglycemia. Moderate inhibition (10-35%) of proteasome activity/function in cultured human islets by the proteasome inhibitor lactacystin enhanced intracellular accumulation of hIAPP...
September 14, 2018: Journal of Biological Chemistry
T Guo, G Cao, Y Li, Z Zhang, J E Nör, B H Clarkson, J Liu
Previously, we reported that the fluorapatite (FA)-modified polycaprolactone (PCL) nanofiber could be an odontogenic/osteogenic inductive tissue-engineering scaffold by inducing stem cell differentiation and mineralization. The present study aimed to explore which of the signal pathways affected this differentiation and mineralization process. The Human Signal Transduction PathwayFinder RT2 Profiler PCR Array was used to analyze the involvement of potential signal transduction pathways during human dental pulp stem cell (DPSCs) osteogenic differentiation induced by FA-modified PCL nanofiber scaffolds...
July 1, 2018: Journal of Dental Research
Maheul Ploton, Claire Mazuy, Céline Gheeraert, Vanessa Dubois, Alexandre Berthier, Julie Dubois-Chevalier, Xavier Maréchal, Kadiombo Bantubungi, Hélène Diemer, Sarah Cianférani, Jean-Marc Strub, Audrey Helleboid-Chapman, Jérôme Eeckhoute, Bart Staels, Philippe Lefebvre
BACKGROUND & AIMS: Embedded into a complex signaling network that coordinates glucose uptake, usage and production, the nuclear bile acid receptor FXR is expressed in several glucose-processing organs including the liver. Hepatic gluconeogenesis is controlled through allosteric regulation of gluconeogenic enzymes and by glucagon/cAMP-dependent transcriptional regulatory pathways. We aimed to elucidate the role of FXR in the regulation of fasting hepatic gluconeogenesis. METHODS: The role of FXR in hepatic gluconeogenesis was assessed in vivo and in mouse primary hepatocytes...
July 5, 2018: Journal of Hepatology
Natalia Petersen, Thomas M Frimurer, Marianne Terndrup Pedersen, Kristoffer L Egerod, Nicolai J Wewer Albrechtsen, Jens J Holst, Anne Grapin-Botton, Kim B Jensen, Thue W Schwartz
BACKGROUND & AIMS: Glucagon-like peptide 1 (GLP1) is produced by L cells in the intestine, and agonists of the GLP1 receptor are effective in the treatment of diabetes. Levels of GLP1 increase with numbers of L cells. Therefore, agents that increase numbers of L cell might be developed for treatment of diabetes. Ras homologue family member A (RhoA) signaling through Rho-associated coiled-coil-containing protein kinases 1 and 2 (ROCK1 and ROCK2) controls cell differentiation, but it is not clear whether this pathway regulates enteroendocrine differentiation in the intestinal epithelium...
October 2018: Gastroenterology
Andrew M Kelleher, Jessica Milano-Foster, Susanta K Behura, Thomas E Spencer
Uterine glands are essential for pregnancy establishment. By employing forkhead box A2 (FOXA2)-deficient mouse models coupled with leukemia inhibitory factor (LIF) repletion, we reveal definitive roles of uterine glands in embryo implantation and stromal cell decidualization. Here we report that LIF from the uterine glands initiates embryo-uterine communication, leading to embryo attachment and stromal cell decidualization. Detailed histological and molecular analyses discovered that implantation crypt formation does not involve uterine glands, but removal of the luminal epithelium is delayed and subsequent decidualization fails in LIF-replaced glandless but not gland-containing FOXA2-deficient mice...
June 22, 2018: Nature Communications
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