The only clinically accepted method of fertility preservation in young women facing gonadotoxic chemo- and/or radiotherapy for malignant or autoimmune diseases is cryopreservation of embryos or unfertilized ova, whereas cryopreservation of ovarian tissue for future reimplantation, or in vitro maturation of follicles, and the use of gonadotropin-releasing hormone agonists (GnRHa) are still considered investigational, by several authorities. Whereas previous publications have raised the fear of GnRHaâ€™s possible detrimental effects in patients with hormone receptor-positive breast cancers, recent randomized controlled trials (RCTs) have shown that it either improves or does not affect disease-free survival (DFS) in such patients. This review summarizes the pros and cons of GnRHa co-treatment for fertility preservation, suggesting 5 theoretical mechanisms for GnRHa action: (1) simulating the prepubertal hypogonadotropic milieu, (2) direct effect on GnRH receptors, (3) decreased ovarian perfusion, (4) upregulation of an ovarian-protecting molecule such as sphingosine-1-phosphate, and (5) protecting a possible germinative stem cell. We try to explain the reasons for the discrepancy between most publications that support the use of GnRHa for fertility preservation and the minority of publications that did not support its efficiency.
Zeev Blumenfeld, Israeli Physician, researcher. Recipient Polishuk award, Maurberger award, numerous others Maj, Israel Defense Forces, 1974-1978. Member Society for Gynecologic Investigation, American Fertility Society, Israel Fertility Society (member directory committee 1990-1995).
The periodontium is composed of tissues that surround, support and protect the teeth, which include the gingiva, periodontal ligaments (PDL), alveolar bone, cellular and acellular cementum. Periodontal disease causes major damage to these tissues and is the most common cause of tooth loss in adults. Periodontal stem/progenitor cells (PSC) have been identified as a population of cells that highly express ï¡ï€Smooth Muscle Actin (ï¡SMA) and Sca1 and are associated with the microvascular capillaries.Usinganï¡SMA-CreERt2 mouse model, we deleted the Bmp2 gene in this stem population soon after birth, and discovered a profound phenotype. In the absence of the Bmp2 gene in ï¡SMA+ periodontal stem cells, there was a major loss of alveolar bone and ridge around the teeth, with loss and disorganized acellular cementum and reduced formation of cellular cementum. In addition,picrosirius red staining revealed immature PDLswith PDL attachment loss in selected regions. In the absence of Bmp2 gene, there was a feedforward effect on the vascular stem cell niche, with loss of both CD146+ andaSMA+ stem cells andaccociated CD31+ endothelial cells in the periodontium. We determined a major defect in the quality of the alveolar bone, as determined by acid-etching-SEM evaluation of the osteocytes and canullicular system with reduced numbers of connecting osteocytes. By lineage tracing methods, we show that when the Bmp2 gene is deleted from the PSC, there is a decrease in the capacity of the PSC to lineage trace to alveolar osteoblast and osteocyte, cementoblast and cementocytes, and periodontal ligament fibroblasts. Using highly enrichedï¡ï“MA+ periodontal stem/progenitor cells, expanded in vitro on ECM matrix to maintain stem like properties, globalrna-seq analysis of a time course and response to rBmp2 from 1 hour to 35days, we constructed a gene-cell state pathway model for the role of Bmp2 gene in PSC differentiation. Key features include: 1. Endogenous Bmp2 gene is a critical growth factor for growth and expansion of the PSC, and confirmed in vivo 2. Osterix is a critical early node for regulating a large set of genes that drive formation of periodontal ligaments, cementums, as well as alveolar bone, which is supported by the literature, and enhancer maps with H3K27ac chip-seq, ATAC-seq, and Sp7 chip-seq at four different time windows. We validated that the Bmp2 gene is critical for expansion and growth of the PSC, both in vivo and in vitro. To begin to test components of this model, we deleted the Bmp2 gene in vitro and found that the lackof growth and multilayering were prominent phenotypes, and by rna-seq analysis, massive growth related genes were not activated in the absence of the endogenous Bmp2 gene. By adding rBmp2 one could not rescue the loss of the endogenous gene. By single cell rna-seq at several stages of PSC differentiation, we further defined the cellâ€“state trajectory of PSC differentiation and the role of Bmp2 protein and Bmp2 gene.
Dr. Stephen Harris' lab is interested in various aspects of gene regulation since 1965. Working in Dr. Bert Oï¿½Malley lab, he proved that estrogen induced the ovalbumin gene at the mRNA level in 1974. He has worked on various aspects of gene regulation by growth factors and androgens since that time. In 1990, he began his studies of bone and teeth with Dr. Greg Mundy in San Antonio TX, and a focus on the Bmp2 and Bmp4 genes. During that time, he also worked with Stuart Kauffman on computational and theoretical models of gene regulation at the transcription level. In 1999, he began various systems biology approaches in the lab to study large sets of gene expression pattern with microarrays and regulation by Bmp2 in osteoblast models. With his interest in system biology and gene network approaches, he has spent the past two years relearning Unix commands and simple programming with the help of several computer experts here at the UTHSCSA. Our university has made a major investment in expanding our next generation sequencing hardware and bioinformatics tools and he is directly helping in that effort. With Dr. Bo Demeler, we now have a supercomputer with over 500 nodes that he routinely uses to analyze any of the NGS sequence files, with the software packages and our own scripts we have installed on this supercomputer. The bioinformatics tools and databases at GEO and elsewhere now make this one of the most exciting areas in medicine and biology.
Recombinase-activating gene (RAG)deficient SCID patients lack B and T lymphocytes due to the inability to rearrange immunoglobulin and T-cell receptor genes. The two RAG genes are acting as a required dimer to initiate gene recombination. Gene therapy is a valid treatment alternative for RAG-SCID patients, wholack a suitable bone marrow donor, but developing such therapy for RAG1/2has proven challenging. Hence, we tested clinically relevant lentiviral SIN vectors with different internal promoters (UCOE, PGK, MND, and UCOE-MND) driving codon optimized versions of the RAG1 or RAG2 genes to ensure optimal expression. We used Rag1-/-or Rag2-/-mice as a preclinical model for RAG-SCID to assess the efficacy of the various vectors at low vector copy number. In parallel, the-conditioning regimen in these mice was optimized using busulfan instead of commonly used total body irradiation. We observed that B and T cell reconstitutiondirectly correlated with RAG1 and RAG2 expression. Mice receiving low Rag1/2 expression showed poor immune reconstitution; however high Rag1/2 expression resulted in a lymphocyte reconstitution comparable to mice receiving wild type stem cells.Efficiency and safetyof our clinical RAG1 lentivirus batch was assessed in Rag1-/- mice model showing that functional restoration of RAG1-deficiency can be achieved with clinically acceptable vectors. Additionally, RAG1-SCID patient CD34+ cells transduced with our clinical RAG1 vector andtransplanted into NSG mice led to fully restored human B and T cell development. Together with favourable safety data, these results substantiate a clinical trial for RAG1 SCID which is planned for Q1 2020.
Prof Dr Frank J.T. Staal obtained his bachelor and master degrees (both cum laude) in Medical Biology at Utrecht University. He obtained his PhD degree (1993) at the Department of Genetics, Stanford University School of Medicine under the supportive guidance of professors Leonard and Leonore Herzenberg where was taught the intricacies of flow cytometry. His thesis dealt with transcriptional regulation of HIV expression in T-lymphocytes and involved many functional flow cytometric assays and cell sorting experiments. In 1993 he became postdoctoral fellow at the Netherlands Cancer Institute for 2 years, after which he moved back to Utrecht University as fellow of the Royal Academy of Sciences (KNAW) in the laboratory of professor Hans Clevers. In 2000 he was recruited to Erasmus Medical Center (EMC) Rotterdam to start his own laboratory on human T cell development and became assistant professor. In 2004 he was appointed associate professor at EMC and expanded his research to Wnt signalling in blood stem cells and T cells, as well as to gene therapy for immune disorders. In 2008 he was recruited to the Leiden University Medical Center (LUMC) and became full professor of Molecular Stem Cell biology. His inaugural speech (Jan 15th, 2010) was entitled ï¿½to T or not to Tï¿½)Together with Jacques van Dongen he heads the LUMC Flow cytometry Core Facility.
C/EBPÎ± is a transcription factor that regulates proliferation and differentiation of hematopoietic progenitors. C/EBPÎ± is down-regulated in MDSC from tumour bearing mice and C/EBPÎ±knock out mice display greater MDSC tumour infiltration, vascularization and growth. MTL-CEBPA is a liposomal formulation of a small activating RNA that up-regulates expression of C/EBPÎ±. In patients withhepatocellular carcinoma MTL-CEBPA was found to be well tolerated and demonstrated pharmacodynamic activity, including immune modulation of peripheral blood, and anti-tumour activity. The combination of MTL-CEBPA with sorafenib showed significantly improved tumour growth inhibition compared to single agents in a diethylnitrosamine induced model of hepatocellular carcinoma in Wistar rats. The combination of MTL-CEBPA with PD-1 mAb showed significantly improved tumour growth inhibition compared to single agents in CT26 syngeneic model of colon cancer in BALB/c mice. Investigators reported that Sorafenib induced complete responses in three of four patients with advanced hepatocellular carcinoma previously treated with MTL-CEBPA. MTL-CEBPA in combination with sorafenib is currently being evaluated in an ongoing Phase 1b study in patients with advanced hepatocellular carcinoma. Our current hypothesis is that MTL-CEBPA sensitises solid tumours to sorafenib and PD-1 mAb by modulating the tumour immune microenvironment.
Professor Nagy Habib is an academic surgeon and in July 2003 was awarded the position of professor of hepatobiliary surgery in the department of surgery and cancer, Faculty of Medicine, Imperial College London. Professor Habib is director of the hepatopancreatobiliary (HPB) unit at Hammersmith Hospital. North west London has the best one-year, three-year, five-year and ten-year survival figures in England for patients with liver cancer. The average ten-year survival figure is about three times higher in north west London compared to the average for the whole of England (17.98 versus 6.66 years). Patients with pancreatic cancer in north west London have the best three-year, five-year and ten-year survival rates compared to the rest of England. The ten-year survival figure in north west London was almost double the rest of London and four times the average for the whole of England. The 30-day operative mortality is the lowest in Europe (1.3% in 1,000 consecutive liver resections). Professor Habib was selected as one of the top 10 surgeons in the UK by the Saturday Times Magazine and he was honoured to be elected to join the French Academy of Surgeons and the European Surgical Association. He has published more than 340 articles in scientific journals.
Obesity, Type 2 diabetes and CVDs constitute the deadly metabolic triad of noncommunicable diseases (NCDs), and have been a major public health concern across the globe including India. The etiology is multifactorial with inflammation viewed as the predominant pathology underlining NCDs. Despite several approaches to manage NCDs, its long term occurrence complemented with secondary complications needs to be addressed as priority. Interestingly, we have established an indigenous Obese Mutant rat model (Muts) , which portray the frank prediabetic conditions akin to human subjects including increase in : BMI HOMA IR, pro- inflammatory cytokines, Insulin Resistance, and oxidative stress. In the present study we have explored the beneficial effects of adult stem cells i.e Mesenchymal stem cells (MSCs) to assess their efficacy to overcome the Obesogenic and the preclinical milieu. Interestingly, MSCs are endowed with inherent immunomodulatory, anti inflammatory and multipotent functions and their ability to home at the site of injury and inflammation reinstate for their autocrine and paracrine functions. Intramuscular injection of human placental MSCs (hPMSCs/1x106) to Muts (5 doses ) and followed up post transplantation for 45 days, demonstrated significant reduction in (a) HOMA-IR, (b) Impaired Glucose Tolerance, (c) oxidative stress, (d) pro inflammatory cytokines and TNF-Î±,(e) upregulation of insulin dependent phosphorylation, and (f) predominant homing of DiD - labelled hPMSCs in visceral adipose tissue when compared to its Control (untreated).Our findings does advocate for the possible clinical applications of MSCs either to prevent or delay the metabolic alterations leading to frank diabetes or allied NCDs.
Dr.Vijayalakshmi V completed her PhD from National Institute of Nutrition (NIN)/Osmania University, Hyderabad, India in the faculty of Biochemistry. Currently she is a Director-Grade Scientist heading the Stem Cell Biology unit at NIN/Indian Council of Medical Research, Government of India. She has published several papers (>80) in reputed journals, 2 patents, 4 book chapters and serving as an editorial board member of repute, Research Advisor of Nan Yang Academy of Sciences (Singapore), Fellow of Telangana Academy of Sciences, Bell & Melinda Gates Foundation Awardee, and Member of Stem Cell committee in several institutes.
In our group we explore a new generation of smart living implants combining not only active therapeutics but also stem cells, as a novel strategy to regenerate stabilized cartilage and avoid prosthesis, by achieving regeneration of its subchondral bone foundation, requirement which is failing today in the clinic. In our group, a unique nanotechnology strategy is used to entrap, protect, and stabilize therapeutic agents into polymer coatings:nanoreservoirs,covering nanofibres of implantable nanofibrous membranes for bone and cartilage regeneration. Upon contact with cells, therapeutic agents become available through enzymatic degradation of the nanoreservoirs. As cells grow, divide, and infiltrate deeper into the porous membrane, they trigger slow and progressive release of therapeutic agents that, in turn, stimulate further cell proliferation. The nanoreservoirs technology enables to reduce the quantities of required therapeutic agent (compared to soaked membranes for instance) thereby reducing costs (1-8). Clinical trial: phase 1, (FR, UK, SP, SW)will be submitted Feasibility and safety assessment of a therapeutic implant based on an activepolymeric wound dressing and autologous mesenchymal stem cells derived from bone marrow for the treatment of femoral cartilage isolated lesions 1. Mendoza-Palomares, S. Facca, C. Cortez, C, N. Messadeq, A. Dierich, A.P.R. Johnston, D. Mainard, J.C. Voegel, F. Caruso, N. Benkirane-Jessel, Active multilayered capsules for in vivo bone formation. Proc. Natl. Acad. Sci. USA.2010, 107, 3406. 2. Facca S, Lahiri D, Fioretti F, Agarwal A, Benkirane-Jessel N, In vivo osseointegration of nano-designed composite coatings on titanium implants. ACS Nano2011, 5: 4790-4799. 3. C. Mendoza, A. Ferrand, S. Facca, F. Fioretti, D. Mainard, N. Benkirane-Jessel, Smart hybrid materials equipped by nanoreservoirs of therapeutics. ACS Nano.2012, 6, 483.3. 4. Eap S, Ferrand F, Schiavi J, Keller L, Fioretti F, Ladam G, Benkirane-Jessel N. Collagen implants equipped by â€œfishscaleâ€- like nanoreservoirs of growth factors for bone regeneration. Nanomedicine. 2014, 9, 1253â€“1261 5. Keller L, Wagner Q, Pugliano M, Breda P, Ehlinger M, SchwintÃ© P and Benkirane-Jessel N. Bi-layered Nano Active Implant with Hybrid Stem Cell Microtissues for Tuned Cartilage Hypertrophy. Journal of Stem Cell Research and Therapeutics. 2015. 1(1): 00004. DOI: 10.15406/jsrt.2015.01.00004. 6. Keller L, Wagner Q, SchwintÃ© P, Benkirane-Jessel N. Double Compartmented and Hybrid Implant Outfitted with Well-Organized 3D Stem Cells for Osteochondral Regenerative Nanomedicine. Nanomedicine (Lond) 2015 10, 2833-2845 7. Keller L, SchwintÃ© P, Gomez-Barrena E, Arruebo M, Benkirane-Jessel N. Smart Implants as Novel Strategy to Regenerate Well-Founded Cartilage. Trends in Biotechnology, 2017, 35, 8â€“11 8. Keller L, Pijnenburg L P, Idoux-Gillet Y, Bornert F â€¦â€¦and Benkirane-Jessel N, A therapeutic bone wound dressing combined with stem cells for osteoarticular regeneration: the ARTiCAR preclinical safety studyNature Communication. 10, Article number: 2156 (2019)
Dr. Nadia Benkirane is Research director (DR1) at INSERM (French National Institute for Health and Medical Research) and head of the â€œRegenerative Nanomedicineâ€ laboratory, UMR1260 Inserm-Unistra, Strasbourg, France. She was leader of â€œActive Biomaterials and Tissue Engineeringâ€ team INSERM 977. She received her Ph.D. from University Louis Pasteur, ULP, Strasbourg, France for the work on Development of pseudopeptides as synthetic vaccines. Dr. Jessel (Benkirane) then held a postdoctoral position in collaboration with the Institut Pasteur, Paris, France, working on Immunotherapy HIV, and another postdoctoral position on the application of modified peptides as vaccines against FMDV (Plum Island Animal Disease Center, ARS, USDA, Greenport, NY 11944-0848, USA). She joined the INSERM U595 in 2002 as a post-doc, and received the diploma to direct the research (HDR) in 2004. Dr. Jessel got the permanent position (CR1) in the INSERM 595 laboratory in 2004 and Research Director (DR2) position in the INSERM 977 and head of â€œactive Biomaterials and Tissue Engineering team from 2009 until 2012). Currently Research Director (DR1)and head of the INSERM UMR 1260 (Regenerative Nanomedicine". Dr. Jessel possesses expertise in diverse fields of molecular and cellular biology, immunochemistry, tissue engineering and biomedical engineering. In the last 10 years, she focused her research on the bio-functionalization of multilayered polyelectrolyte architectures with emphasis on the use of these architectures to induce specific cellular responses and gain control over cell proliferation and differentiation. Dr.Benkirane-Jessel hasmore than 138 publications (h index: 36) with peer-reviewed publications in high impact factor journals (Proc. Nat. Acad. Sci. USA; Adv. Mater.; Adv. Funct. Mater.; Small; Nanoletters, Biomaterials, ACS Nano), 5 chapters reviews and 5 international patents, she is a regular referee for a number of scientific journals (Nature nanotechnology, Nature Materials, ACS nano, Biomaterials, Nanolettersâ€¦). She was under the contract (Interface INSERM/Clinic 2008-2013) and she got also â€œPrime dâ€™ExcellenceScientifiqueâ€ from the INSERM, 2010-2014 and the PEDR from the INSERM on 2016 for 4 years.
Breast cancer stem cells (BCSCs) play a critical role in breast cancer metastasis and relapse. It is well-known that BCSCs exhibit characteristic CD44high/CD24low markers. In this study, we identified a new E3 ubiquitin ligase, FBXL2, that plays a critical role in defining breast cancer cell stemness. FBXL2 expression was significantly lower in CD44high/CD24low sub-populations of breast cancer cells. Knockout of FBXL2 using CRISPR/Cas9 induced cell stemness, concomitant with upregulation of E2A/Twist, whereas ectopic-expression of FBXL2 significantly reduced BCSC stemness in vitro and inhibited tumor initiation in vivo. Notably, TGF-Î² markedly down-regulated FBXL2 expression, resulting in an significant increase in mammosphere formation, which can be reversed by restored expression of FBXL2. In spontaneous breast cancer mice model (MMTV-PyMT), FBXL2 mRNA and protein levels were significantly reduced in lung metastasis nodules. Furthermore, FBXL2 expression was significantly down regulated in CD44high/CD24low cells derived from PDX mouse models. We also demonstrate that reduction of FBXL2 expression was responsible for breast cancer resistance to paclitaxel. Together, these results indicate that FBXL2 plays a key role in the regulation of BCSC stemness and drug resistance and that FBXL2 may be a new therapeutic target for breast cancer treatment.
Dr. Zhi-Xiong Jim Xiao has completed his PhD from University of Massachusetts at Amherst, USA and postdoctoral studies from Harvard University and Dana Farber Cancer Institute, USA. He has served as a full professor at Boston University School of Medicine. He is currently Director of Center of Growth, Metabolism and Aging at Sichuan University, China. He has published more than 75 papers in high caliber journals including Nature, Cancer Cell, Molecular Cell and PNAS. He has been serving as a receiving editor of Cell Death and Diseases.
Myocardial infarction (MI) is the leading cause of heart failure (HF) worldwide. Current therapies are unable to replace lost cardiac tissue after MI and fail to prevent progression towards HF. Our research group identified a new cardiac stem cell type, the cardiac atrial appendage stem cells (CASCs), with superior cardiomyogenic differentiation potential. Whether CASCs transplantation can prevent loss of cardiac function and adverse cellular remodeling following MI, remains unknown. Methods: Permanent LAD ligation was performed in female Sprague Dawley rats. MI animals were randomly assigned to either CASCs injection (2.5x106 Â± 1x106 cells) in the MI border zone (MI+CASCs, n=12) or no injection (MI, n=12) at surgery. SHAM-operated animals served as control (n=10). Four weeks post-surgery, global cardiac function was assessed by conventional echocardiography and hemodynamic measurements. LV single cardiomyocytes were enzymatically isolated from the border zone. Contractile properties of single cardiomyocytes were assessed by unloaded cell shortening at 4Hz. Interstitial collagen deposition was evaluated from cryosections. Results: CASCs transplantation improved LV ejection fraction (86%Â±3 MI+CASCs vs 58%Â±5 MI) and reduced the increased end-systolic volume seen in MI (26ÂµlÂ±7 MI+CASCs vs 101ÂµlÂ±20 MI). Anterior wall thickness was normalized in the MI+CASCs group (1.47Â±0.06 cm vs 1.06Â±0.08 cm in MI group). Mean LV systolic pressure significantly decreased (32mmHgÂ±2 MI+CASCs vs 45mmHgÂ±2 MI) and dP/dtmax significantly increased after CASCs transplantation (9001 mmHg/sÂ±704 vs 6224 mmHg/sÂ±234 in MI). There was no difference in dP/dtmin. Unloaded cell shortening of single cardiomyocytes from the transplanted group (7.1%Â±0.5) was improved compared to MI cardiomyocytes (5.4%Â±0.3). Finally, global cardiac fibrosis tended to be smaller in the MI+CASCs group. Conclusion: CASCs transplantation improves global cardiac function in vivo and prevents adverse cardiomyocyte remodeling after MI. Altogether, this study suggests that CASCs therapy is a promising cellular tool to restore cardiac function after ischemic injury.
Dr. M. Hendrikx graduated from Catholic University Leuven Medical School, specialized in cardiothoracic surgery and received his PhD degree in 1994. He is Chief Cardiothoracic Surgery and Associated Professor at UHasselt since 1996, where he heads a lab for experimental cardiology and cardiac surgery. He published over 80 peer reviewed papers and participated as PI in several multicentric trials.
Anti-angiogenesis therapies have become the standard care for patients with metastatic colorectal cancer (mCRC). Unfortunately, only modest efficacies are observed which have been attributed to the presence of cancer stem cells (CSCs) in the tumor.Here, we examined whether the stemness-high GATA6-overexpressing clones derived respectively from HCT-116 and HT-29 humanCRC cells were more potent than their vector-control counterparts in promoting the angiogenesis of HUVECs. Indeed, we found that the conditioned media (CM) collected from the aforementioned clones enhanced the tube formation, migration, invasion, and DNA synthesis of HUVECs more effectively than their respective vector clones which might be attributed in part to a significantly increased production/secretion of MMP-9 by HUVECs. In addition, the mRNA levels of several angiogenic factors and cytokines were significantly elevated in the GATA6-overexpressing human CRC clones. Accordingly, increased levels of IL-6, IL-8, and VEGF were also detected in the CM collected from these cells and the co-treatment with either a small-molecule VEGFR2 inhibitor or an IL-8 neutralizing antibody suppressed the tube formation-enhancing activities of the CM. Intriguingly, a drastically increased activation of NF-ï«B was found in these cells and the tube formation-enhancing effects of the CM collected from them were abolished by the treatment of PDTC, a NF-ï«B inhibitor, before their collection. Finally, the IHC staining results showed that the blood vessel densities were much higher in the xenograft tumors grown from the GATA6-overexpressing clones.Together, our findings support thatCSCs, by producing large amounts of various angiogenic factors, could inducestronger tumor angiogenesis.
Yeu Su has completed his Ph.D. from the University of Wisconsin-Madison, USA, and thepost-doctoralstudies from the Johns Hopkins Oncology Center, USA. Dr. Su went back to Taiwan and became an Associate Professor in the Institute of Pharmacology of National Yang-Ming University (NYMU) in 1993. In 2000, he moved to the Institute of Biopharmaceutical Sciences of the same University and became a full professor in 2005. So far he has published ~ 60 papers and got 5 awards for outstanding research.
The study focuses on the development of principally novel priority-oriented healthcare strategy â€” targeted therapy in regenerative medicine known as Â«Strategy of Pharmacological Control over Intracellular Signal Transduction in Regeneration-Competent CellsÂ» (Patented by RU â„– 2599289 Â«Tissue regeneration stimulating agentÂ», 2016). It implies selective action of promising drugs on specific key elements in the signaling cascade responsible for functional activity of various progenitor cells (including stem cells) and elements of tissue microenvironment. The role of NF-ÐºB, IKK, PKC, PKB, PI3K, ERK Â½, p38, adenylate cyclase, PKA, JAKs, STAT3, JNK, p53 in the realization of functioning progenitor elements of different classes and cells of tissue microenvironment was studied. On the models of posthypoxic encephalopathy, skin wound and cytostatic myelosuppression in experimental animals the therapeutic effects and mechanisms of action of modifiers of signal molecules activity were studied. The specificity of the involvement of a number of signaling molecules in the regulation of cell cycle and development of progenitor cells of various classes, as well as in the production of humoral factors by microenvironment cells was revealed. The neuroregenerative effects of JNK inhibitors, the early healing effects of the PKA inhibitor, hemostimulating and hemoprotective properties PKA activators, JNK inhibitors and other was shown. An algorithm and approaches for estimating the potential efficiency and many-sided selectivity of the modifiers of signaling molecules activity as targeted hemostimulators were developed. The effectiveness of various targeted pharmacological agents determined by the selective effect on different types of regenerative-competent cells was demonstrated on the models of cytostatic myelosuppression of various genesis. The perspective of using intracellular signaling molecules in regenerative-competent cells as targets of drugs for regenerative medicine was shown. The developed theoretical and applied platform can be used to launch synthesis of principally novel preparations with regenerative activity. The study was supported by Grants of the President of the Russia (MD-893.2013.7 and MD-3096.2015.7), and by the RFBR (No. 18-015-00013).
Gleb N. Zyuz`kov is a Scientist Secretary of Institute, Head of the laboratory of pathophysiology and experimental therapy. Ph.D, MD, Professor of RAS. Author of 62 patents on inventions. International Award of Elsevier`s "SciVal/Scopus Award RussiaÂ» (2012). ÐÐµ is: Scientist Secretary of the Tomsk branch of Â«National society for regenerative medicineÂ» (Russia) and Tomsk branch of Â«Russian scientific society of PharmacologyÂ»; member of Â«Tomsk Professors SocietyÂ»; expert of: Russian Academy of Sciences, Ministry of Science of Russia, Russian Science Foundation; member of Editorial Board of Journals: Â«Stem cells Research and Therapeutics InternationalÂ», Â«American Journal of Biomedical Science & ResearchÂ».
We have prepared 125I-labeled cholera toxin B subunit (125I-labeled CT-B, a specific activity of 98 Ci/mmol) and found that it binds to rat intestinal epithelial cell membranes, rat IEC-6 and human Caco-2 intestinal epithelial cells with high affinity. The binding of labeled protein was completely inhibited by unlabeled thymosin-Î±1 (TM-Î±1), interferon-Î±2 (IFN-Î±2), and the synthetic peptide LKEKK that corresponds to residues 16-20 in TM-Î±1 and 131-135 in IFN-Î±2, but was not inhibited by the synthetic peptide KKEKL with inverted amino acid sequence. Thus, TM-Î±1, IFN-Î±2, and the peptide LKEKK bind with high affinity and specificity to the cholera toxin receptor on rat intestinal epithelial cell membranes, IEC-6 and Caco-2 cells. It was found that CT-B and the peptide: LKEKK at concentrations of 10 1000 nM increased in a dose-dependent manner the nitric oxide (NO) production and the soluble guanylate cyclase (sGC) activity in IEC-6 and Caco-2 cells. Taking into account that NO acts as a primary activator of sGC, it can be assumed that the effect of CT-B and the peptide: LKEKK on on the target cell is realized in the following way: increase in the iNOS expression â†’ increase in the NO production â†’ increase in the sGC activity â†’ increase in intracellular levels of cGMP.
Professor Elena Vitalâ€™evna Navolotskaya is a Scientist in the Field of Biochemistry and Bioorganic Chemistry in Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry (Moscow, RF). Her Research Interests Focus on the Study of the Properties and the Molecular Mechanism of Action of Peptide Bioregulators. She Graduated with Distinction from Lomonosov Moscow State University (Biochemistry, Bioorganic Chemistry). She has Diplomas of PhD (RF, Biochemistry), Doctor of Science (RF, Immunology), Professor (RF, Biochemistry). She is Head of the Laboratory of Peptide Bioregulators in Branch of Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry (Pushchino, Moscow Region, RF), and Professor of Pushchino State Natural Science Institute (Pushchino, Moscow Region, RF). Prof. Navolotskaya has published over 100 peer-reviewed papers covering peptides, proteins, their receptors and signal transduction.
Better understanding of the signaling pathways that regulate human bone marrow stromal stem cell (hBMSC) differentiation into boneforming osteoblasts is crucial for their clinical use in regenerative medicine. Chemical biology approaches using small molecules targeting specific signaling pathways are increasingly employed to manipulate stem cell differentiation fate. Methods: We employed alkaline phosphatase activity and staining assays to assess osteoblast differentiation and Alizarin R staining to assess mineralized matrix formation of cultured hBMSCs. Changes in gene expression were assessed using an Agilent microarray platform, and data normalization and bioinformatics were performed using GeneSpring software. For in vivo ectopic bone formation experiments, hMSCs were mixed with hydroxyapatiteâ€“ tricalcium phosphate granules and implanted subcutaneously into the dorsal surface of 8-week-old female nude mice. Hematoxylin and eosin staining and Sirius Red staining were used to detect bone formation in vivo. Results: We identified several compounds which inhibited osteoblastic differentiation of hMSCs. In particular, we identified ruxolitinib (INCB018424) (3 Î¼M), an inhibitor of JAK-STAT signaling that inhibited osteoblastic differentiation and matrix mineralization of hMSCs in vitro and reduced ectopic bone formation in vivo. Global gene expression profiling of ruxolitinibtreated cells identified 847 upregulated and 822 downregulated mRNA transcripts, compared to vehicle-treated control cells. Bioinformatic analysis revealed differential regulation of multiple genetic pathways, including TGFÎ² and insulin signaling, endochondral ossification, and focal adhesion. Conclusions: We identified ruxolitinib as an important regulator of osteoblast differentiation of hMSCs. It is plausible that inhibition of osteoblast differentiation by ruxolitinib may represent a novel therapeutic strategy for the treatment of pathological conditions caused by accelerated osteoblast differentiation and mineralization.
Nihal AlMuraikhi is a Ph.D candidate expected to be awarded by the end of this year from Imperial College London. She is a lecturer at the Stem Cell Unit of the Medical School of King Saud University, Riyadh, Saudi Arabia.
Breast cancer is the most common malignancy in women worldwide and the leading cause of cancer death in developing countries. Anthracyclines(e.g. Doxorubicin) appear to be the most potent therapy for hormone refractory breast cancer, however, the cardiotoxic side-effects limit survival by 20-30%, particularly after co-treatment with Doxorubicin and Trastuzumab. Discovery of better therapeutic strategies to circumvent treatment-induced cardiac mobidities remain a challenge, largely due to the heterogeneity and genetic diversity of human breast cancers as well as lack of model systems that truly mimic the human disease phenotype. To address this, we have successfully developed the first ever induced pluripotent stem cells (iPSCs) from peripheral blood mononuclear cells (PBMCs) of Estrogen Receptor positive breast cancer patients of Indian descent. These cells are truly pluripotent (express SSEA4, Tra1-60, Tra1-81, Oct4, Nanog etc.)and show an ability to differentiate into cells of all three germ layers. Furthermore, we have successfully differentiated these human breast cancer (and -age, -gender matched healthy control) iPSCs into mature and functional beating cardiomyocytes that express markers of mature cardiac cells, such as, Troponin T, Nkx2-5at an average efficiency of â‰¥85% by flowcytometry. Notably, these iPSC-derived cardiomyocytes retain the genetic profile of the source patient(s) and show increased doxorubicin induced cytotoxicity compared to their healthy counterparts, underscoring their potential for disease modeling. We propose the use of these cancer patient-derived cardiac cells for preclinical drug screening for chemotherapeutic drugs alongside cardioprotective agents to identify novel combinatorial treatment regimen(s) for circumventing doxorubicin-induced cardiotoxicity in breast cancer patients.
Dr.Bhatt did PhD in Breast Cancer from University of Illinois-Urbana Champaign, USA and postdoctoral studies from Harvard University, USA. She was bestowed with Mary K. Iacocca research accolade through her nomination by Harvard University for distinguished scientific achievements. She has been awarded scientific fundings both in USA and India. She serves as Chief Scientific Officer with a leading Biotechnology Company involved in cancer drug discovery research and diagnostics. She has published more than 25 papers in peer-reviewed international scientific journals, editorials and meeting abstracts and has served on the editorial board of some of these journals of high international repute.
YD Teng is Co-Director, Neurotrauma Recovery Research and Director, Laboratory of SCI, Stem Cell Biology and Neurofacilitation Research, Departments of PM&R and Neurosurgery, Harvard Medical School/Spaulding Rehabilitation Hospital Network and Brigham and Womenï¿½s Hospital. He investigates functional multipotency of stem cells and recovery neurobiology through multimodal approaches that integrate stem cell biology, neural and glial biology, chemical and genetic engineering, molecular pharmacology and neural oncology. Work of his team has received the prestigious Apple award of the American Spinal Injury Association (2011), the ERF New investigator award from the foundation of PM&R (2004) and the Mayfield award and Larson Research award of the CNS/AANS Joint Section on Disorders of the Spine and Peripheral Nerves (2012, 2015 & 2016). Prof. Teng reviews for >50 academic and clinical journals and holds study section membership of the NIH, VA, DoD, European Union academic organizations, research and education institutions and scientific and academic foundations. He was elected President (2013-2014) of the American Society for Neural Therapy and Repair.