Browsing by Subject "PROLIFERATION"

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  • Sola-Carvajal, Agustin; Revechon, Gwladys; Helgadottir, Hafdis T.; Whisenant, Daniel; Hagblom, Robin; Döhla, Julia; Katajisto, Pekka; Brodin, David; Fagerstrom-Billai, Fredrik; Viceconte, Nikenza; Eriksson, Maria (2019)
    Hutchinson-Gilford progeria syndrome (HGPS) is the result of a defective form of the lamin A protein called progerin. While progerin is known to disrupt the properties of the nuclear lamina, the underlying mechanisms responsible for the pathophysiology of HGPS remain less clear. Previous studies in our laboratory have shown that progerin expression in murine epidermal basal cells results in impaired stratification and halted development of the skin. Stratification and differentiation of the epidermis is regulated by asymmetric stem cell division. Here, we show that expression of progerin impairs the ability of stem cells to maintain tissue homeostasis as a result of altered cell division. Quantification of basal skin cells showed an increase in symmetric cell division that correlated with progerin accumulation in HGPS mice. Investigation of the mechanisms underlying this phenomenon revealed a putative role of Wnt/beta-catenin signaling. Further analysis suggested an alteration in the nuclear translocation of beta-catenin involving the inner and outer nuclear membrane proteins, emerin and nesprin-2. Taken together, our results suggest a direct involvement of progerin in the transmission of Wnt signaling and normal stem cell division. These insights into the molecular mechanisms of progerin may help develop new treatment strategies for HGPS.
  • Santos, Joao Manuel; Cervera-Carrascon, Victor; Havunen, Riikka; Zafar, Sadia; Siurala, Mikko; Sorsa, Suvi; Anttila, Marjukka; Kanerva, Anna; Hemminki, Akseli (2018)
    Lymphodepleting preconditioning with high-dose chemotherapy is commonly used to increase the clinical efficacy of adoptive T cell therapy (ACT) strategies, however, with severe toxicity for patients. Conversely, oncolytic adenoviruses are safe and, when engineered to express interleukin-2 (IL-2) and tumor necrosis factor alpha (TNF-alpha), they can achieve antitumor immunomodulatory effects similar to lymphodepletion. Therefore, we compare the safety and efficacy of such adenoviruses with a cyclophosphamide-and fludarabine- containing lymphodepleting regimen in the setting of ACT. Human adenovirus (Ad5/3-E2F-D24-hTNF-alpha-IRES-hIL-2; TILT-123) replication was studied using a Syrian hamster pancreatic tumor model (HapT1) infused with tumor- infiltrating lymphocytes (TILs). Using the oncolytic virus instead of lymphodepletion resulted in superior efficacy and survival. Immune cells responsive to TNF-alpha IL-2 were studied using an immunocompetent mouse melanoma model (B16. OVA) infused with ovalbumin-specific T (OT-I) cells. Here, the adenovirus approach improved tumor control together with increased intratumoral Th1 cytokine levels and infiltration of CD8+ T cells and CD86+ dendritic cells. Similar to humans, lymphodepleting preconditioning caused severe cytopenias, systemic inflammation, and damage to vital organs. Toxicity was minimal in adenovirus- and OT-Itreated mice. These findings demonstrate that ACT can be effectively facilitated by cytokine-coding adenovirus without requiring lymphodepletion, a rationale being clinically investigated.
  • Sinha, Snehadri; Narjus-Sterba, Matilda; Tuomainen, Katja; Kaur, Sippy; Seppänen-Kaijansinkko, Riitta; Salo, Tuula; Mannerström, Bettina; Al-Samadi, Ahmed (2020)
    Mesenchymal stem cells (MSCs) are commonly isolated from bone marrow and adipose tissue. Depending on the tissue of origin, MSCs have different characteristics and physiological effects. In various cancer studies, MSCs have been found to have either tumor-promoting or tumor-inhibiting action. This study investigated the effect of adipose tissue-MSCs (AT-MSCs) and bone marrow-MSCs (BM-MSCs) on global long interspersed nuclear element-1 (LINE-1) methylation, the expression level of microenvironment remodeling genes and cell proliferation, migration and invasion of oral tongue squamous cell carcinoma (OTSCC). Additionally, we studied the effect of human tongue squamous carcinoma (HSC-3)-conditioned media on LINE-1 methylation and the expression of microenvironment remodeling genes in AT-MSCs and BM-MSCs. Conditioned media from HSC-3 or MSCs did not affect LINE-1 methylation level in either cancer cells or MSCs, respectively. In HSC-3 cells, no effect of MSCs-conditioned media was detected on the expression ofICAM1, ITGA3orMMP1. On the other hand, HSC-3-conditioned media upregulatedICAM1andMMP1expression in both types of MSCs. Co-cultures of AT-MSCs with HSC-3 did not induce proliferation, migration or invasion of the cancer cells. In conclusion, AT-MSCs, unlike BM-MSCs, seem not to participate in oral cancer progression.
  • Randall, Ricardo S.; Miyashima, Shunsuke; Blomster, Tiina; Zhang, Jing; Elo, Annakaisa; Karlberg, Anna; Immanen, Juha; Nieminen, Kaisa; Lee, Ji-Young; Kakimoto, Tatsuo; Blajecka, Karolina; Melnyk, Charles W.; Alcasabas, Annette; Forzani, Celine; Matsumoto-Kitano, Miho; Mähönen, Ari Pekka; Bhalerao, Rishikesh; Dewitte, Walter; Helariutta, Yrjö; Murray, James A. H. (2015)
    Higher plant vasculature is characterized by two distinct developmental phases. Initially, a well-defined radial primary pattern is established. In eudicots, this is followed by secondary growth, which involves development of the cambium and is required for efficient water and nutrient transport and wood formation. Regulation of secondary growth involves several phytohormones, and cytokinins have been implicated as key players, particularly in the activation of cell proliferation, but the molecular mechanisms mediating this hormonal control remain unknown. Here we show that the genes encoding the transcription factor AINTEGUMENTA (ANT) and the D-type cyclin CYCD3;1 are expressed in the vascular cambium of Arabidopsis roots, respond to cytokinins and are both required for proper root secondary thickening. Cytokinin regulation of ANT and CYCD3 also occurs during secondary thickening of poplar stems, suggesting this represents a conserved regulatory mechanism.
  • Liu, Xingzhi; Zhang, Hongbo; Cheng, Ruoyu; Gu, Yanzheng; Yin, Yin; Sun, Zhiyong; Pan, Guoqing; Deng, Zhongbin; Yang, Huilin; Deng, Lianfu; Cui, Wenguo; Almeida Santos, Helder; Shi, Qin (2018)
    Antibody-based cancer immune therapy has attracted lots of research interest in recent years; however, it is greatly limited by the easy distribution and burst release of antibodies. In addition, after the clearance of the tissue, healthy tissue regeneration is another challenge for cancer treatment. Herein, we have developed a specific immunological tissue engineering scaffold using the agonistic mouse anti-human CD40 antibody (CD40mAb) incorporated into poly(l-lactide) (PLLA) electrospun fibers through the dopamine (PDA) motif (PLLA-PDA-CD40mAb). CD40mAb is successfully incorporated onto the surface of the electrospun fibrous scaffold, which is proved by immunofluorescence staining, and the PLLA-PDA-CD40mAb scaffold has an anti-tumor effect by locally releasing CD40mAb. Therefore, this immunological electrospun scaffold has very good potential to be developed as a powerful tool for localized tumor treatment, and this is the first to be reported in this area.
  • Mozhgani, Sayed-Hamidreza; Piran, Mehran; Zarei-Ghobadi, Mohadeseh; Jafari, Mohieddin; Jazayeri, Seyed-Mohammad; Mokhtari-Azad, Talat; Teymoori-Rad, Majid; Valizadeh, Narges; Farajifard, Hamid; Mirzaie, Mehdi; Khamseh, Azam; Rafatpanah, Houshang; Rezaee, Seyed-Abdolrahim; Norouzi, Mehdi (2019)
    Background Human T-lymphotropic virus 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a progressive disease of the central nervous system that significantly affected spinal cord, nevertheless, the pathogenesis pathway and reliable biomarkers have not been well determined. This study aimed to employ high throughput meta-analysis to find major genes that are possibly involved in the pathogenesis of HAM/TSP. Results High-throughput statistical analyses identified 832, 49, and 22 differentially expressed genes for normal vs. ACs, normal vs. HAM/TSP, and ACs vs. HAM/TSP groups, respectively. The protein-protein interactions between DEGs were identified in STRING and further network analyses highlighted 24 and 6 hub genes for normal vs. HAM/TSP and ACs vs. HAM/TSP groups, respectively. Moreover, four biologically meaningful modules including 251 genes were identified for normal vs. ACs. Biological network analyses indicated the involvement of hub genes in many vital pathways like JAK-STAT signaling pathway, interferon, Interleukins, and immune pathways in the normal vs. HAM/TSP group and Metabolism of RNA, Viral mRNA Translation, Human T cell leukemia virus 1 infection, and Cell cycle in the normal vs. ACs group. Moreover, three major genes including STAT1, TAP1, and PSMB8 were identified by network analysis. Real-time PCR revealed the meaningful down-regulation of STAT1 in HAM/TSP samples than AC and normal samples (P = 0.01 and P = 0.02, respectively), up-regulation of PSMB8 in HAM/TSP samples than AC and normal samples (P = 0.04 and P = 0.01, respectively), and down-regulation of TAP1 in HAM/TSP samples than those in AC and normal samples (P = 0.008 and P = 0.02, respectively). No significant difference was found among three groups in terms of the percentage of T helper and cytotoxic T lymphocytes (P = 0.55 and P = 0.12). Conclusions High-throughput data integration disclosed novel hub genes involved in important pathways in virus infection and immune systems. The comprehensive studies are needed to improve our knowledge about the pathogenesis pathways and also biomarkers of complex diseases.
  • Jokela, Jouni; Oftedal, Linn; Herfindal, Lars; Permi, Perttu; Wahlsten, Matti; Doskeland, Stein Ove; Sivonen, Kaarina (2012)
  • Kohva, E.; Varimo, T.; Huopio, H.; Tenhola, S.; Voutilainen, R.; Toppari, J.; Miettinen, P. J.; Vaaralahti, K.; Viinamäki, J.; Backman, J. T.; Hero, M.; Raivio, T. (2020)
    STUDY QUESTION: Does treatment of constitutional delay of growth and puberty (CDGP) in boys with aromatase inhibitor letrozole (Lz) or conventional low-dose testosterone (T) have differing effects on developing seminiferous epithelium? SUMMARY ANSWER: Anti-Mullerian hormone (AMH) declined similarly in both treatment groups, and the two Sertoli cell-derived markers (AMH and inhibin B (iB)) exhibited differing responses to changes in gonadotrophin milieu. WHAT IS KNOWN ALREADY: Boys with CDGP may benefit from puberty-inducing medication. Peroral Lz activates gonadotrophin secretion, whereas intramuscular low-dose T may transiently suppress gonadotrophins and iB. STUDY DESIGN, SIZE, DURATION: Sera of 28 boys with CDGP who participated in a randomised, controlled, open-label trial at four paediatric centres in Finland between August 2013 and January 2017 were analysed. The patients were randomly assigned to receive either Lz (2.5 mg/day) (n = 15) or T (I mg/kg/month) (n = 13) for 6 months. PARTICIPANTS/MATERIALS, SETTING, METHODS: The 28 patients were at least 14 years of age, showed first signs of puberty, wanted medical attention for CDGP and were evaluated at 0, 3, 6 and 12 months of visits. AMH levels were measured with an electrochemiluminescence immunoassay and L2 levels with liquid chromatography coupled with tandem mass spectrometry. MAIN RESULTS AND THE ROLE OF CHANCE: AMH levels decreased in both treatment groups during the 12-month follow-up (P <0.0001). Between 0 and 3 months, the changes in gonadotrophin levels (increase in the Lz group, decrease in the T group) correlated strongly with the changes in levels of iB (FSH vs iB, r = 0.55, P=0.002; LH vs iB, r =0.72, P LIMITATIONS, REASONS FOR CAUTION: The original trial was not blinded for practical reasons and included a limited number of participants. WIDER IMPLICATIONS OF THE FINDINGS: In early puberty, treatment-induced gonadotrophin stimulus was unable to counteract the androgen-mediated decrease in AMH, while changes in iB levels were associated with changes in gonadotrophin levels. AMH decreased similarly in both groups during the treatment, reassuring safety of developing seminiferous epithelium in both treatment approaches. Since a fixed dose of Li induced variable serum Lz levels with a desired puberty-promoting effect in all boys, more research is needed to aim at a minimal efficient dose per weight.
  • El Missiry, Mohamed; Awad, Shady Adnan; Koskela, Hanna Laura Maria; Al-Samadi, Ahmed; Ekblom, Marja; Markevan, Berit; Astrand-Grundstrom, Ingbritt; Wold, Maren; Svedahl, Ellen Rabben; Juhl, Birgitte Ravn; Bjerrum, Ole Weis; Haulin, Inger; Porkka, Kimmo; Olsson-Stromberg, Ulla; Hjorth-Hansen, Henrik; Mustjoki, Satu (2016)
    Tyrosine kinase inhibitors (TKIs) used in the treatment of chronic myeloid leukaemia have been reported to induce immunomodulatory effects. We aimed to assess peripheral blood (PB) and bone marrow (BM) lymphocyte status at the diagnosis and during different TKI therapies and correlate it with treatment responses. BM and PB samples were acquired from 105 first-line TKI-treated patients. Relative number of BM lymphocytes was evaluated from MGG-stained BM aspirates, and immunophenotypic analyses were performed with multicolour flow cytometry. Early 3-month expansion of BM lymphocytes was found during all different TKIs (imatinib n = 71, 20 %; dasatinib n = 25, 21 %; nilotinib n = 9, 22 %; healthy controls n = 14, 12 %, p <0.0001). Increased PB lymphocyte count was only observed during dasatinib therapy. The BM lymphocyte expansion was associated with early molecular response; patients with 3-month BCR-ABL1 <10 % showed higher lymphocyte counts than patients with BCR-ABL1 > 10 % (23 vs. 17 %, p <0.05). Detailed phenotypic analysis showed that BM lymphocyte expansion consisted of various lymphocyte subclasses, but especially the proportion of CD19+ B cells and CD3negCD16/56+ NK cells increased from diagnostic values. During dasatinib treatment, the lymphocyte balance in both BM and PB was shifted more to cytotoxic direction (increased CD8+CD57+ and CD8+HLA-DR+ cells, and low T regulatory cells), whereas no major immunophenotypic differences were observed between imatinib and nilotinib patients. Early BM lymphocytosis occurs with all current first-line TKIs and is associated with better treatment responses. PB and BM immunoprofile during dasatinib treatment markedly differs from both imatinib- and nilotinib-treated patients.
  • Hasegawa, Yuki; Tang, Dave; Takahashi, Naoko; Hayashizaki, Yoshihide; Forrest, Alistair R. R.; Suzuki, Harukazu; FANTOM Consortium; Sajantila, Antti (2014)
  • Trela, Ewelina; Lan, Qiang; Myllymäki, Satu-Marja; Villeneuve, Clémentine; Lindström, Riitta; Kumar, Vinod; Wickström, Sara A.; Mikkola, Marja L. (2021)
    The mammary gland develops from the surface ectoderm during embryogenesis and proceeds through morphological phases defined as placode, hillock, bud, and bulb stages followed by branching morphogenesis. During this early morphogenesis, the mammary bud undergoes an invagination process where the thickened bud initially protrudes above the surface epithelium and then transforms to a bulb and sinks into the underlying mesenchyme. The signaling pathways regulating the early morphogenetic steps have been identified to some extent, but the underlying cellular mechanisms remain ill defined. Here, we use 3D and 4D confocal microscopy to show that the early growth of the mammary rudiment is accomplished by migration-driven cell influx, with minor contributions of cell hypertrophy and proliferation. We delineate a hitherto undescribed invagination mechanism driven by thin, elongated keratinocytes-ring cells-that form a contractile rim around the mammary bud and likely exert force via the actomyosin network. Furthermore, we show that conditional deletion of nonmuscle myosin IIA (NMIIA) impairs invagination, resulting in abnormal mammary bud shape.
  • Brboric, Anja; Vasylovska, Svitlana; Saarimäki-Vire, Jonna; Espes, Daniel; Caballero-Corbalan, Jose; Larfors, Gunnar; Otonkoski, Timo; Lau, Joey (2019)
    Background: Murine boundary cap-derived neural crest stem cells (NCSCs) are capable of enhancing islet function by stimulating beta cell proliferation as well as increasing the neural and vascular density in the islets both in vitro and in vivo. This study aimed to isolate NCSC-like cells from human bone marrow. Methods: CD271 magnetic cell separation and culture techniques were used to purify a NCSC-enriched population of human bone marrow. Analyses of the CD271+ and CD271- fractions in terms of protein expression were performed, and the capacity of the CD271+ bone marrow cells to form 3-dimensional spheres when grown under non-adherent conditions was also investigated. Moreover, the NCSC characteristics of the CD271+ cells were evaluated by their ability to migrate toward human islets as well as human islet-like cell clusters (ICC) derived from pluripotent stem cells. Results: The CD271+ bone marrow population fulfilled the criterion of being multipotent stem cells, having the potential to differentiate into glial cells, neurons as well as myofibroblasts in vitro. They had the capacity to form 3-dimensional spheres as well as an ability to migrate toward human islets, further supporting their NCSC identity. Additionally, we demonstrated similar migration features toward stem cell-derived ICC. Conclusion: The results support the NCSC identity of the CD271-enriched human bone marrow population. It remains to investigate whether the human bone marrow-derived NCSCs have the ability to improve transplantation efficacy of not only human islets but stem cell-derived ICC as well.
  • Boku, Shuken; Takeshi, Izumi; Abe, Seiji; Takahashi, Tomohisa; Nishi, Akira; Nomaru, Hiroko; Naka, Yasuhiko; Kang, Gina; Nagashima, Masako; Hishimoto, Akitoyo; Hishimoto, Akitoyo; Enomoto, Shingo; Duran Torres, Gilberto; Tanigaki, Kenji; Zhang, Jinghang; Ye, Kenny; Kato, Shigeki; Männistö, Pekka Topias; Kobayashi, Kazuto; Hiroi, Noboru (2018)
    Working memory capacity, a critical component of executive function, expands developmentally from childhood through adulthood. Anomalies in this developmental process are seen in individuals with autism spectrum disorder (ASD), schizophrenia and intellectual disabilities (ID), implicating this atypical process in the trajectory of developmental neuropsychiatric disorders. However, the cellular and neuronal substrates underlying this process are not understood. Duplication and triplication of copy number variants of 22q11.2 are consistently and robustly associated with cognitive deficits of ASD and ID in humans, and overexpression of small 22q11.2 segments recapitulates dimensional aspects of developmental neuropsychiatric disorders in mice. We capitalized on these two lines of evidence to delve into the cellular substrates for this atypical development of working memory. Using a region- and cell-type-selective gene expression approach, we demonstrated that copy number elevations of catechol-O-methyl-transferase (COMT) or Tbx1, two genes encoded in the two small 22q11.2 segments, in adult neural stem/progenitor cells in the hippocampus prevents the developmental maturation of working memory capacity in mice. Moreover, copy number elevations of COMT or Tbx1 reduced the proliferation of adult neural stem/progenitor cells in a cell-autonomous manner in vitro and migration of their progenies in the hippocampus granular layer in vivo. Our data provide evidence for the novel hypothesis that copy number elevations of these 22q11.2 genes alter the developmental trajectory of working memory capacity via suboptimal adult neurogenesis in the hippocampus.
  • Gui, Jinghua; Huang, Yunxian; Kracklauer, Martin; Toddie-Moore, Daniel John; Kikushima, Kenji; Nix, Stephanie; Ishimoto, Yukitaka; Shimmi, Osamu (2019)
    At the level of organ formation, tissue morphogenesis drives developmental processes in animals, often involving the rearrangement of two-dimensional (2D) structures into more complex three-dimensional (3D) tissues. These processes can be directed by growth factor signaling pathways. However, little is known about how such morphological changes affect the spatiotemporal distribution of growth factor signaling. Here, using the Drosophila pupal wing, we address how decapentaplegic (Dpp)/bone morphogenetic protein (BMP) signaling and 3D wing morphogenesis are coordinated. Dpp, expressed in the longitudinal veins (LVs) of the pupal wing, initially diffuses laterally within both dorsal and ventral wing epithelia during the inflation stage to regulate cell proliferation. Dpp localization is then refined to the LVs within each epithelial plane, but with active interplanar signaling for vein patterning/differentiation, as the two epithelia appose. Our data further suggest that the 3D architecture of the wing epithelia and the spatial distribution of BMP signaling are tightly coupled, revealing that 3D morphogenesis is an emergent property of the interactions between extracellular signaling and tissue shape changes.
  • Al-Samadi, Ahmed; Awad, Shady Adnan; Tuomainen, Katja; Zhao, Yue; Salem, Abdelhakim; Parikka, Mataleena; Salo, Tuula (2017)
    The crosstalk between immune cells, cancer cells, and extracellular vesicles (EVs) secreted by cancer cells remains poorly understood. We created three-dimensional (3D) cell culture models using human leiomyoma discs and Myogel to study the effects of immune cells on highly (HSC-3) and less (SCC-25) invasive oral tongue squamous cell carcinoma (OTSCC) cell lines. Additionally, we studied the effects of EVs isolated from these cell lines on the cytotoxicity of CD8(+) T and NK cells isolated from three healthy donors. Our analysis included the effects of these EVs on innate immunity in zebrafish larvae. Activated immune cells significantly decreased the proliferation of both OTSCC cell lines and associated with a diminished invasion area of HSC-3 cells. In general, EVs from SCC-25 increased the cytotoxic activity of CD8(+) T and NK cells more than those from HSC-3 cells. However, this effect varied depending on the source and the immune and cancer cell subgroups. In zebrafish, the amount of IL-13 mRNA was decreased by SCC-25 EVs. This study describes promising in vitro and in vivo models to investigate interactions between immune cells, cancer cells, and EVs.
  • Dekoninck, Sophie; Hannezo, Edouard; Sifrim, Alejandro; Miroshnikova, Yekaterina A.; Aragona, Mariaceleste; Malfait, Milan; Gargouri, Souhir; de Neunheuser, Charlotte; Dubois, Christine; Voet, Thierry; Wickström, Sara A.; Simons, Benjamin D.; Blanpain, Cédric (2020)
    Summary During embryonic and postnatal development, organs and tissues grow steadily to achieve their final size at the end of puberty. However, little is known about the cellular dynamics that mediate postnatal growth. By combining in vivo clonal lineage tracing, proliferation kinetics, single-cell transcriptomics, and in vitro micro-pattern experiments, we resolved the cellular dynamics taking place during postnatal skin epidermis expansion. Our data revealed that harmonious growth is engineered by a single population of developmental progenitors presenting a fixed fate imbalance of self-renewing divisions with an ever-decreasing proliferation rate. Single-cell RNA sequencing revealed that epidermal developmental progenitors form a more uniform population compared with adult stem and progenitor cells. Finally, we found that the spatial pattern of cell division orientation is dictated locally by the underlying collagen fiber orientation. Our results uncover a simple design principle of organ growth where progenitors and differentiated cells expand in harmony with their surrounding tissues.
  • Giri, Anil K.; Aittokallio, Tero (2019)
    DNA methyltransferase inhibitors (DNMTi) decitabine and azacytidine are approved therapies for myelodysplastic syndrome and acute myeloid leukemia, and their combinations with other anticancer agents are being tested as therapeutic options for multiple solid cancers such as colon, ovarian, and lung cancer. However, the current therapeutic challenges of DNMTis include development of resistance, severe side effects and no or partial treatment responses, as observed in more than half of the patients. Therefore, there is a critical need to better understand the mechanisms of action of these drugs. In order to discover molecular targets of DNMTi therapy, we identified 638 novel CpGs with an increased methylation in response to decitabine treatment in HCT116 cell lines and validated the findings in multiple cancer types (e.g., bladder, ovarian, breast, and lymphoma) cell lines, bone marrow mononuclear cells from primary leukemia patients, as well as peripheral blood mononuclear cells and ascites from platinum resistance epithelial ovarian cancer patients. Azacytidine treatment also increased methylation of these CpGs in colon, ovarian, breast, and lymphoma cancer cell lines. Methylation at 166 identified CpGs strongly correlated (vertical bar r vertical bar >= 0.80) with corresponding gene expression in HCT116 cell line. Differences in methylation at some of the identified CpGs and expression changes of the corresponding genes was observed in TCGA colon cancer tissue as compared to adjacent healthy tissue. Our analysis revealed that hypermethylated CpGs are involved in cancer cell proliferation and apoptosis by P53 and olfactory receptor pathways, hence influencing DNMTi responses. In conclusion, we showed hypermethylation of CpGs as a novel mechanism of action for DNMTi agents and identified 638 hypermethylated molecular targets (CpGs) common to decitabine and azacytidine therapy. These novel results suggest that hypermethylation of CpGs should be considered when predicting the DNMTi responses and side effects in cancer patients.
  • Yanku, Yifat; Bitman-Lotan, Eliya; Zohar, Yaniv; Kurant, Estee; Zielke, Norman; Eilers, Martin; Orian, Amir (2018)
    The HECT-type ubiquitin ligase HECT, UBA and WWE Domain Containing 1, (HUWE1) regulates key cancer-related pathways, including the Myc oncogene. It affects cell proliferation, stress and immune signaling, mitochondria homeostasis, and cell death. HUWE1 is evolutionarily conserved from Caenorhabditis elegance to Drosophila melanogaster and Humans. Here, we report that the Drosophila ortholog, dHUWE1 (CG8184), is an essential gene whose loss results in embryonic lethality and whose tissue-specific disruption establishes its regulatory role in larval salivary gland development. dHUWE1 is essential for endoreplication of salivary gland cells and its knockdown results in the inability of these cells to replicate DNA. Remarkably, dHUWE1 is a survival factor that prevents premature activation of JNK signaling, thus preventing the disintegration of the salivary gland, which occurs physiologically during pupal stages. This function of dHUWE1 is general, as its inhibitory effect is observed also during eye development and at the organismal level. Epistatic studies revealed that the loss of dHUWE1 is compensated by dMyc proeitn expression or the loss of dmP53. dHUWE1 is therefore a conserved survival factor that regulates organ formation during Drosophila development.
  • Torrieri, Giulia; Fontana, Flavia; Figueiredo, Patricia; Liu, Zehua; Almeida Ferreira, Monica; Talman, Virpi; Martins, João Pedro; Fusciello, Manlio; Moslova, Karina; Teesalu, Tambet; Cerullo, Vincenzo; Hirvonen, Jouni; Ruskoaho, Heikki; Balasubramanian, Vimalkumar; Santos, Hélder A. (2020)
    The advent of nanomedicine has recently started to innovate the treatment of cardiovascular diseases, in particular myocardial infarction. Although current approaches are very promising, there is still an urgent need for advanced targeting strategies. In this work, the exploitation of macrophage recruitment is proposed as a novel and synergistic approach to improve the addressability of the infarcted myocardium achieved by current peptide-based heart targeting strategies. For this purpose, an acetalated dextran-based nanosystem is designed and successfully functionalized with two different peptides, atrial natriuretic peptide (ANP) and linTT1, which target, respectively, cardiac cells and macrophages associated with atherosclerotic plaques. The biocompatibility of the nanocarrier is screened on both macrophage cell lines and primary macrophages, showing high safety, in particular after functionalization of the nanoparticles' surface. Furthermore, the system shows higher association versus uptake ratio towards M2-like macrophages (approximately 2-fold and 6-fold increase in murine and human primary M2-like macrophages, respectively, compared to M1-like). Overall, the results demonstrate that the nanosystem has potential to exploit the "hitchhike" effect on M2-like macrophages and potentially improve, in a dual targeting strategy, the ability of the ANP peptide to target infarcted heart.
  • Patel, Ketan; Simbi, Biggy; Ritvos, Olli; Vaiyapuri, Sakthivel; Dhoot, Gurtej K. (2019)
    Aberrant activation of signalling pathways has been postulated to promote age related changes in skeletal muscle. Cell signalling activation requires not only the expression of ligands and receptors but also an appropriate environment that facilitates their interaction. Here we first examined the expression of SULF1/SULF2 and members of RTK (receptor tyrosine kinase) and the Wnt family in skeletal muscle of normal and a mouse model of accelerated ageing. We show that SULF1/SULF2 and these signalling components, a feature of early muscle development are barely detectable in early postnatal muscle. Real time qPCR and immunocytochemical analysis showed gradual but progressive up-regulation of SULF1/SULF2 and RTK/Wnt proteins not only in the activated satellite cells but also on muscle fibres that gradually increased with age. Satellite cells on isolated muscle fibres showed spontaneous in vivo satellite cell activation and progressive reduction in proliferative potential and responsiveness to HGF (hepatocyte growth factor) and dysregulated myogenic differentiation with age. Finally, we show that SULF1/SULF2 and RTK/Wnt signalling components are expressed in progeric mouse muscles at earlier stage but their expression is attenuated by an intervention that promotes muscle repair and growth.