Scientific Program

Conference Series Ltd invites all the participants across the globe to attend 6th World Congress on Cell & Stem Cell Research Philadelphia, Pennsylvania, USA.

Day 1 :

OMICS International Stem Cell Research-2016 International Conference Keynote Speaker Haval Shirwan photo
Biography:

Haval Shirwan is a Dr. Michael and Joan Hamilton Endowed Chair in Autoimmune Disease, Professor of Microbiology and Immunology, Director of Molecular Immunomodulation Program at the Institute for Cellular Therapeutics. He has completed his Graduate studies from the University of California in Santa Barbara, CA and Postdoctoral studies from California Institute of Technology in Pasadena, CA. He has joined the University of Louisville in 1998 after holding academic appointments at various academic institutions in the United States. His research focuses on the modulation of immune system for the treatment of immune-based diseases with particular focus on type-1 diabetes, transplantation and development of prophylactic and therapeutic vaccines against cancer and infectious diseases. He is an Inventor on over a dozen of worldwide patents, Founder and CEO/CSO of FasCure Therapeutics, LLC, widely published, organized and lectured at numerous national/international conferences, served on study sections for various federal and non-profit funding agencies and is on the Editorial Board of a dozen of scientific journals. He is Member of several national and international societies and recipient of various awards.

Abstract:

Type-1 diabetes (T1D) is an autoimmune disease initiated and perpetuated by T-cells targeting various auto antigens. Insulin treatment as standard of care is often ineffective in preventing recurrent hyperglycemic episodes with long-term undesired adverse effects. Transplantation of pancreatic islets as a source of beta cells producing insulin has proven effective in improving metabolic control/quality of life and preventing severe hypoglycemia in patients with T1D. Immune rejection of the transplanted islets is presently being controlled by chronic immunosuppression that is not only ineffective in controlling rejection but also has various side effects. Therefore, novel approaches that control rejection in the absence of chronic immunosuppression will have significant impact on the field of islet transplantation. In as much as T-cells are critical to graft rejection, we have developed an effective immunomodulatory approach based on the novel form of immune ligands to target pathogenic T-cells for physical elimination while simultaneously expanding protective Treg cells. The application of this concept to allogeneic and xenogeneic islet transplantation will be discussed.

OMICS International Stem Cell Research-2016 International Conference Keynote Speaker Paul J Davis photo
Biography:

Paul J Davis has obtained his MD degree at Harvard Medical School and his Clinical and Research Training at Albert Einstein College of Medicine; NIH. He is a Professor of Medicine at Albany Medical College (Albany, NY USA) and a Former Chair of the Department of Medicine at Albany. He has Co-Authored 250 refereed papers and he and his colleagues described the cell surface receptor for thyroid hormone. He and co-workers at the Albany College of Pharmacy have generated nanopharmaceuticals of thyroid hormone and hormone analogues that modulate angiogenesis and tumor cell proliferation and viability.

Abstract:

Integrin αvβ3 is concentrated and activated on the surface of tumor cells and dividing endothelial cells where it is critical to cell-cell and cell-extracellular matrix protein interactions and to function of cell surface vascular growth factor receptors. Exploration of the functions of a receptor for thyroid hormone and hormone analogues on the integrin has linked hormone analogues to regulation of expression of genes relevant to angiogenesis to differential regulation of apoptosis (pro- and anti-apoptosis) and to repair of double-strand DNA breaks. Tetraiodothyro-acetic acid (tetrac) is a naturally-occurring deaminated analogue of L-thyroxine (T4) that, when covalently bound to a nanoparticle that precludes its cellular uptake acts exclusively at αvβ3 via a variety of signal transducing kinases and other mechanisms as an anti-cancer/anti-angiogenesis agent. We report here the action of systemic nanoparticulate tetrac (Nano-diamino-tetrac, NDAT or Nanotetrac) on human glioblastoma (U87MG) xenograft size and histology. Ten days’ daily subcutaneous treatment of tumor-bearing nude mice with NDAT (1 mg tetrac-equivalent/kg/day) resulted in a 38% decrease in tumor volume in situ and 47% decrease in tumor weight at sacrifice (p<0.01 vs. control). Blinded histopathologic review of tumors from control and treated animals has revealed essentially complete loss of vascularity without hemorrhage and consequent 5-fold increase in necrotic cells in drug-exposed tumors. There was 4.5-fold increase in apoptotic cells in treated tumors. Changes were significant at p<0.01. NDAT is a novel nanopharmaceutical that acts exclusively on cancer and endothelial cell surfaces to induce apoptosis and systematic devascularization with necrosis.

Break: Networking & Refreshments 11:05-11:25 @ Foyer
  • Stem Cells, Cell Metabolism, Apoptosis and Cancer Disease, Cell and Gene Therapy
Speaker
Biography:

Brian Mehling, M.D., M.S. is a practicing American orthopedic trauma surgeon, researcher, and philanthropist. Dr. Mehling started his path in medicine through undergraduate study at Harvard University, obtaining his Bachelor of Arts and Master of Science degrees in Biochemistry from Ohio State University. Completing his degree of medicine at Wright State University School of Medicine, Dr. Mehling received post graduate education through residencies and fellowships at St. Joseph’s Hospital in Paterson, NJ and the Graduate Hospital in Philadelphia, PA. Dr. Mehling operates his own practice, Mehling Orthopedics, in both West Islip, NY and Hackensack. NJ.

Abstract:

BHI Therapeutic Sciences, LLC is a healthcare research and consulting company, dedicated to the development of stem cell therapies. Our scientific and medical teams are focused on IRB-approved protocols, designed to measure the safety and efficacy of intravenous, intra-articular, and intrathecal stem cell treatments. The purpose of our study is primarily to monitor the immune response in order to validate the safety of intravenous infusion of human umbilical cord blood derived MSCs (UC-MSCs), and secondly, to evaluate effects on biomarkers associated with chronic inflammation. Twenty patients were treated for conditions associated with chronic inflammation and for the purpose of anti-aging. They have been given one intravenous infusion of UC-MSCs. Our study of blood test markers of 20 patients with chronic inflammation before and within three months after MSCs treatment demonstrates that there is no significant changes and MSCs treatment was safe for the patients. Analysis of different indicators of chronic inflammation and aging included in initial, 24-hours, two weeks and three months protocols showed that stem cell treatment was safe for the patients; there were no adverse reactions. Moreover data from follow up protocols demonstrates significant improvement in energy level, hair, nails growth and skin conditions. Intravenously administered UC-MSCs were safe and effective in the improvement of symptoms related to chronic inflammation. Further close monitoring and inclusion of more patients are necessary to fully characterize the advantages of UC-MSCs application in treatment of symptoms related to chronic inflammation

Speaker
Biography:

Lewis Clarke obtained his Master of Science from University of Texas at Dallas in 1977 in Human Development with Biostatistics. In 1986, he completed his Doctor of Medicine degree from Texas Tech School of Medicine. In 1987, he received his Ph.D. from the Department of Cell Biology and Neurobiology at University of Texas Health Sciences Center at Dallas. He completed his medical internship at Emory University and Baylor College of Medicine in 1986 and finished his residency training at Baylor College of Medicine in Physical Medicine and Rehabilitation. He has a clinical and research practice in the Houston Texas area and has started two rehabilitation hospitals.

Abstract:

Intrinsic mechanisms of neuronal repair in the central nervous system through neuroregenerative processes have previously been presented. Similar biochemical and neurochemical mechanisms exist which are known to be neuroprotective. Exploiting and augmenting these intrinsic processes could minimize or mitigate neuronal damage in acute brain and spinal cord injuries resulting from stroke or trauma. The inflammatory response together with the oxidative stress of the acute injury represent the most likely therapeutic targets for intervention. Similarly, in chronic, progressive neurodegenerative disorders resulting from repetitive cumulative minimally-traumatic injuries such as concussion and subsequent chronic trauma encephalopathies (CTE), persistent or chronic neuroinflammation and the products of oxidative stress responses could account for the observed brain pathologies. The multiple pathologies present in various combinations in all neurodegenerative disorders include β-amyloid and amyloid plaques, hyperphosphorylated tau protein, neurofibrillary tangles, and microglial activation. It is now understood that within the CNS there exists a protective and anti-inflammatory neurochemistry many components of which can also promote neurogenesis and functional as well as structural restoration. It is intuitive that given the numerous interdependent and symbiotic systems involved in the preservation of the integrity and function of the brain, no single intervention or therapy is likely. A logical beginning would be to increase antioxidant gene expression and the scavenging of free radicals, suppressing or blocking the NMDA receptor to decrease glutamate and aspartate-induced cytotoxicity, inhibiting pro-inflammatory cytokines and metalloproteinases, enhancing anti-inflammatory cytokines, and suppressing activation of microglia. The augmentation of mitochondrial number and energy production is DNA protective and would address all cellular function including stem cell production, migration, and differentiation. Much is now known about the contribution of CoQ10, carnitine, lipoic acid, and pyrroloquinoline quinone in this regard. An integrative approach should include bioactive lipids in the mitochondrial membrane, eicosanoid modulating PUFA’s, sigma 1 receptors, and neurosteroids produced de novo in the glia. These are also catalysts and promote neurogenesis and neurite outgrowth through their activation of sigma 1 receptors in the mitochondrial membrane lipid rafts of the endoplasmic reticulum. Activated sigma 1 receptors increase calcium in the mitochondria resulting in activation of the TCA cycle, increasing mitochondrial hypermetabolism ultimately resulting in neurite outgrowth as well as neuroprotection. Neurodegenerative processes are multifactorial in etiology. Controlling inflammatory reactions and preventing their chronicity and curtailing oxidative and cytotoxic effects of acute neurologic injuries would be neuroprotective in the acute phase and avert the chronic encephalopathies. These same neuroprotective mechanisms are also neuroregenerative.

Speaker
Biography:

Shanmugasundaram Ganapathy-Kanniappan obtained his Ph.D degree from the University of Madras and underwent postdoctoral training at premier institutes such as National Institute of Immunology (NII), New Delhi, University of California at Los Angeles (UCLA) and Johns Hopkins University. Currently, he is an assistant professor at the Johns Hopkins University School of Medicine. He has several publications in reputed journals and has written many reviews and a book chapter on cancer metabolism and therapeutic opportunities.

Abstract:

Cancer-related high mortality rate and poor prognosis are often attributed to metastasis, the process of dissemination of cancer cells to distal organs from the primary site of origin. Further metastatic cancers are often known to be refractory to therapies. Development of an effective therapeutic strategy for metastatic cancer relies on the identification of sensitive molecular targets that are specific and critical for the growth and propagation of metastatic cells. However, tumor heterogeneity impedes the complete understanding of the metastatic proclivity any solid malignancy and the elucidation of potential therapeutic target. Further, the complexity of metastatic process [which involves sequential steps like dissociation of cancer cells from the site of origin, transport in the circulation, and final sequestration into distal organs] also confound the identification of any sensitive target or pathway. Recently, we reported an algorithm of matrigel-free, anchorage independent growth condition to select and isolate “metastatic potential” cells from heterogeneous population of cancer cells. Our preliminary data show that these early-stage metastatic cancer cells undergo a metabolic reprogram to facilitate growth and development. More importantly, such metabolic reprogramming involves upregulation of cancer-stem cell markers. Emerging reports indicate cancer-stem cell markers affect energy metabolism in cancer cells. Together, we show that metabolic reprogramming and metastatic potential of cancer cells are correlated with the expression of one or more cancer-stem cell markers. Thus, cancer stem cell markers remain as attractive target for therapeutic interference with cancer metabolism as well as metastasis.

Nirmala Mavila

Cedars-Sinai Medical Center, USA

Title: Prominin1 in liver development and disease
Speaker
Biography:

Nirmala Mavila, completed her PhD in Biotechnology from Mysore University, India. She completed her postdoctoral trainings at Purdue University and Children’s Hospital Los Angeles before joining as a faculty at Cedars-Sinai Medical Center, Los Angeles, CA. Her main research interest is progenitor/stem cells in liver development, regeneration and diseases.

Abstract:

Prominin1 (PROM1, CD133) is a penta-transmembrane glycoprotein known to express in various kinds of progenitor cells. It was originally discovered as a hematopoietic stem cell marker. Its expression is restricted to the plasma membrane protrusions and has been identified as a cholesterol binding protein. However its function yet to be identified. Studies have demonstrated that PROM1 positive tumor initiating cells form more aggressive tumors in xenograft models compared to PROM1 negative cancer cells. Its expression found to be correlated with poor prognosis of various cancers. It is believed that PROM1 maintains the stem cell-ness of progenitor cells and losses its expression during cellular differentiation. Our recent studies have demonstrated that murine embryonic liver progenitor cells or hepatoblasts expresses PROM1 as early as embryonic stage E11 and reduces its expression as the liver develops into a mature organ. Our studies also have demonstrated that Fibroblast growth factor receptor 2 mediated activation of AKT-beta-catenin signaling, plays an important role in the proliferation of PROM1 positive hepatoblasts and liver cancer stem cells in vitro. Importantly, our recent studies have demonstrated an increased expression of PROM1 in cholestatic liver diseases. However its pathological significance is yet to be discovered.

Break: Lunch Break 13:05-13:50 @ Benzamin’s Restaurant
Speaker
Biography:

Lucie Bacakova, MD, PhD, Assoc. Prof. has graduated from the Faculty of General Medicine, Charles University, Prague, Czechoslovakia in 1984. She has completed her Ph.D at the age of 32 years from the Czechoslovak Academy of Sciences, and became Associated Professor at the 2nd Medical Faculty, Charles University. She is the Head of the Department of Biomaterials and Tissue Engineering, Institute of Physiology, Academy of Sciences of the Czech Republic. She is a specialist for studies on cell-material interaction and vascular, bone and skin tissue engineering. She has published more than 150 papers in reputed journals (h-index 26).

Abstract:

Adipose-derived stem cells (ASCs) are promising for engineering of various tissues, such as bone, cartilage, blood vessels, heart, skeletal muscle, neural tissue, skin, liver or pancreatic islet cells. ASCs have been already clinically applied for cell-assisted lipotransfer for tissue augmentation, for healing the wound after radiation therapy and for skin rejuvenation. Due to their immunosuppressive and immunomodulatory function, ASCs have been clinically tested and applied for treatment of inflammatory and autoimmune diseases. The adipose tissue can be obtained by a relative non-invasive method, i.e. liposuction. The quality and quantity of isolated ASCs can be influenced by parameters of liposuction, such as the type of anesthesia, composition of the tumescent solution, and particularly the amount of negative pressure. In this study, we focused on ASCs isolated from lipoaspirates taken from the same patient (a 43-year-old woman) under low negative pressure (-200 mmHg, LP) or high negative pressure (-700 mm Hg, HP). The number of isolated ASCs and their subsequent proliferation activity in vitro was higher in cells obtained under HP. These differences persisted in passaged cells (tested up to 3 passages), and also after cryopreservation of cells. However, when confluent ASCs were exposed to an osteogenic medium for 5 days, the osteogenic cell differentiation, measured by intensity of fluorescence of collagen I, alkaline phosphatase and osteocalcin, was more pronounced in cells obtained under LP. Thus, ASCs obtained under both pressures have specific advantages, and their choice depends on their application, i.e. if their rapid growth or early osteogenic differentiation is required.

Biography:

Jian Zhou is a scientist and researcher,currently working in Beijing Stomatological Hospital, China.His research intersted areas are stem cell,regenarative medicine,odontoblastspecification and dentin regeneration.

Abstract:

New endodontic therapies that attempt to regenerate dental pulp and dentin may provide alternative solutions to traditional procedures. Previously, we have reported that odontogenesis factors, BMP7 and Wnt10a are highly expressed by odontoblasts. Consistently, BMP and canonical Wnt signaling pathways synergistically promote odontogenesis in vitro. To examine Wnt and BMP mediated dental pulp regeneration, we delivered the two factors into endodontically treated porcine incisors. The regenerated dental pulp and dentin were assessed by histological analysis, micro-CT, scanning electronic microscope (SEM), and hardness tests by nanoindentation. The present study aimed to: 1) quantify the regenerated dentin using histological analysis and micro-CT; 2) measure mechanical parameters of regenerated dentin; 3) assess the microstruture of the regenerated dentin by scanning electronic microscope (SEM).We regenerated dentin and dental pulp in endodontically treated teeth by homing and inducing endogenous perioapical cell migration and differentiation into dental pulp cells. Our results demonstrate that the two factors induce dentin regeneration and that the mechanical character and mineral density of regenerated dentin is comparable to the native dentin. This research supports a new approach to endodontic therapy as regenerative pulp and dentin have been shown to function like the native tooth.

Speaker
Biography:

Wen-Chi, Yang has completed her MD at the age of 25 years from Kaohsiung medical university and completed her Ph.D at the age of 38 years from the same university. She had 2 years postdoctoral studies from Harvard Medical School during 2007 to 2009 and half year postdoctoral studies from Massachusetts Institute of Technology after then. She is hematology, medical oncology and hospice care specialist in Taiwan. She is the attending physician of Yuan’s general hospital. She is also chief stuff of molecular medicine lab in Yuan’s general hospital.

Abstract:

Anemia is a common condition in the older population. Unexplained anemia (UA) contributes one third of anemia in older ages. And most of those patients can meet at least one of the diagnosis criteria of myelodysplastic syndrome (MDS). In MDS, leukemia transformation is a lethal problem. Many genes alternations and clinical characteristics have been reported to associate with leukemia transformation in MDS patients. Iron overload is one majority causes. Siderophores help transport iron. Type 2-hydroxybutyrate dehydrogenase (BDH2) is a rate-limiting factor in the biogenesis of siderophores. We analyzed 187 MDS patients, compared with de novo acute myeloid leukemia patients and normal bone marrow patients. Elevated BDH2mRNA expression was observed in MDS patient bone marrow (P=0.009) and was related to ferritin levels (P=0.049). The higher BDH2 expression (15%) group showed a greater risk for leukemia transformation than the lower expression group (3.18%) (P=0.017). We investigated the mechanism by using RNA-interference–mediated-knockdown of BDH2 (BDH2-KD) in the leukemia cell line, THP1. Cell cycle arrest and increasing apoptosis rate by surviving were noticed in BDH2-KD cells. Here we present a novel predictor of leukemia transformation in MDS, that relates to iron metabolism, apoptosis and cell cycle control.

Speaker
Biography:

John A. Barrett has completed his Ph.D. from Saint Johns University, NY. He is presently Vice President of R & D and head of translational research at Ziopharm Oncology with a research focus in immunotherapy, oncology, targeted radiopharmaceuticals and biomarkers. During his career he was responsible for numerous INDs and NDAs and has authored 45 papers in peer review journals.

Abstract:

Immunotherapy has been shown to be effective in breast cancer patients. In breast cancer, CD8+ T-cells, are activated by IL-12, have been shown to correlate with anti-tumor activity and prolonged survival. Ad-RTS-IL-12 (Ad) is a replication-incompetent adenovirus engineered to express IL-12, via our RheoSwitch Therapeutic System® gene switch. When injected directly into a tumor. IL-12 expression is off devoid of the activator ligand, veledimex (V), while IL-12 production is turned on in a dose-dependent manner by V p.o. Mechanistic studies in the 4T1 syngeneic mouse breast tumor model with Ad+V have shown a dose-related increase in tumor IL-12 mRNA and IL-12 protein expression. Cessation of V resulted in a return to baseline IL-12 mRNA and IL-12 protein expression. These changes correlated with a local and systemic immune and anti-tumor response. Low dose chemotherapy primes the immune system and in combination with immunotherapy may augment tumor specific T-cells resulting in enhanced efficacy. In the 4T1 mouse mammary tumor model Ad (1e10vp)+V (30 mg/m2) with low dose chemotherapy significantly inhibited tumor growth in a supra-additive fashion concomitant with increased median survival vs. single agent alone. Based on these results an open label, phase 2 trial evaluating the safety of inducible IL-12 expression in heavily pretreated subjects with recurrent/metastatic breast cancer was performed. In this study, treatment with Ad+V resulted in increase in IL-12, downstream IFNg followed by rapid increase in IL-10 and IP-10. In the 12 subjects administrated Ad+ V there was a total of 16 non-injected evaluable lesions in 7 subjects. Of the 16 lesions, 1 lesion had decrease in lesion diameter ranging from 10- 19%, 2 lesions 30-49%, and 3 lesions 50-100%. Most common ≥ Grade 3 treatment emergent adverse events in BC and melanoma included neutropenia and hyponatremia (16% each), hypotension, cytokine release syndrome, AST increase (11% each), dehydration, fatigue, pyrexia (8% each). All TEAEs and SAEs ≥ Grade 3 reversed rapidly upon discontinuation of veledimex The results of this study showed biologic activity with an acceptable therapeutic index. In summary, Ad+V is a novel gene therapy which controls local expression of IL-12, which may result in the collapse of tumor stroma and stimulating an anti-cancer T cell immune response. The ability to regulate the production of IL-12 by modulating V dosing may result in an improved therapeutic index in combination with standard of care.

Speaker
Biography:

Anderson completed her PhD at the University of Manchester, UK in the Faculty of Medicine. She is the Established Chair in Biomedical Sciences at the University of Bradford. She has published more than 450 papers, 8 books, successfully supervised 30 PhD students, has an Hirsch factor of 51. She is Editor –in- Chief of a Book Series for the Royal Society of Chemistry and is Consultant to many International Organisations, such as the World Health Organisation/ International Programme of Chemical Safety. She is/ has been member of the editorial Board of ten international journals.

Abstract:

Nanotechnology has preceded nanotoxicology and little is known of the effects of nanoparticles in human systems, let alone in diseased individuals. Therefore, the effects of titanium dioxide (TiO2) nanoparticles in peripheral blood lymphocytes from patients with respiratory diseases [lung cancer, chronic obstructive pulmonary disease (COPD) and asthma] were compared with those in healthy Individuals, to determine differences in sensitivity to nanochemical insult. The Comet assay was performed according to recommended guidelines. The micronucleus assay and ras oncoprotein detection were conducted according to published standard methods. The results showed statistically significant concentration-dependent genotoxic effects of TiO2 NPs in both respiratory patient and control groups in the Comet assay. The TiO2 NPs caused DNA damage in a concentration dependent manner in both groups (respiratory and healthy controls) with the exception of the lowest TiO2 concentration (10 µg/ml) which did not induce significant damage in healthy controls (ns). When OTM data were used to compare the whole patient group and the control group, the patient group had more DNA damage (p > 0.001) with the exception of 10 µg/ml of TiO2 that caused less significant damage to patient lymphocytes (p < 0.05). Similarly, there was an increase in the pattern of cytogenetic damage measured in the MN assay without statistical significance except when compared to the negative control of healthy individuals. Furthermore, when modulation of ras p21 expression was investigated, regardless of TiO2 treatment, only lung cancer and COPD patients expressed measurable ras p21 levels. All results were achieved in the absence of cytotoxicity.

Break: Networking & Refreshments 15:55-16:10

Qing Ma

University of Texas M.D. Anderson Cancer Center, USA

Title: The role of complement system in GVHD
Speaker
Biography:

Qing Ma has completed her Ph.D. in 1990 from Thomas Jefferson University and subsequently postdoctoral studies at Harvard Medical School. She is currently associate professor of Cancer Medicine at UT M.D. Anderson Cancer Center.

Abstract:

Graft-verses-host disease (GVHD) is a major complication in allogeneic bone marrow transplantation, and characterized by epithelial cell injury in skin, intestine and liver. The development of GVHD involves donor T cell activation including proliferation, differentiation and inflammatory cytokine production, which lead to specific tissue damage. The interactions between the complement system and lymphocytes have been shown to regulate alloreactive T cell and APC function in the setting of allograft rejection. In recently published studies, we demonstrated that reduced GVHD mortality/morbidity in C3-deficient mice is associated with a decrease in donor Th1/Th17 polarization and Th1-driven DC activation. The number of donor-derived T cells including IFNγ+, IL17+ and IL17+IFNγ+ subsets was decreased in secondary lymphoid organs of C3-/- recipients. We conclude that C3 regulates Th1/17 differentiation in BMT, and define a novel function of the complement system in GVHD. To investigate whether anti-complement therapy has any impact on human T cell activation, a drug candidate Compstatin was used to inhibit C3 activation in this study. We found the frequency of IFN-γ (Th1), IL-4 (Th2), IL-17 (Th17), IL-2 and TNF-α producing cells were significantly reduced among activated CD4+ cells in the presence of Compstatin. Compstatin treatment decreased the proliferation of both CD4+ and CD8+ T cells upon TCR stimulation. We examined complement deposition in the skin and lip biopsy samples of patients diagnosed with cutaneous GVHD. C3 deposition was detected in the squamous epithelium and dermis, blood vessels and damaged sweat glands, and associated with gland damage and regeneration. We conclude that C3 mediates Th1/Th17 polarization in human T cell activation and skin GVHD in patients.

Speaker
Biography:

Dinulescu is an Assistant Professor at Harvard Medical School. She received her Ph.D. from Oregon Health and Science University and completed her postdoctoral studies in the field of Cancer Genetics at MIT. Dr. Dinulescu’s research interests focus on cancer biology, malignancies of the gonads and reproductive tract, with a special emphasis on ovarian cancer research and endometriosis. Our laboratory is actively investigating the key contribution of cancer stem cells (CSCs) to tumor chemoresistance. Our current studies focus on better understanding the mechanism of stem cell signaling in the maintenance of the CSC niche and ovarian tumorigenesis. The aim is to harness the power of nanotechnology to develop improved “homing” technologies for the delivery of therapeutic agents specifically targeting and sensitizing ovarian cancer cells, including CSCs, in a spatio-temporal fashion.

Abstract:

Cancer stem cells (CSCs) are considered to be important for tumor development, metastasis, and chemoresistance based on their key ability to survive standard cancer chemotherapies. Multiple studies have now defined CSCs as having an increased tumorigenic ability in serial transplantation experiments conducted in tumor xenografts. This assay, however, may not be entirely accurate in clearly identifying CSCs. Nevertheless, there is enough evidence to support the idea that CSCs are necessary to initiate and propagate tumor diversity. In addition, CSCs are studied in multiple solid tumors, including ovarian cancer, due to their intrinsic chemoresistance properties. Thus, while non-CSCs have been shown to be sensitive to available therapies, CSCs are enriched in response to treatment and regenerate an increasingly platinum resistant tumor. Furthermore, similar to normal stem cells, CSCs are likely shielded from damage and injury by the tumor niche microenvironment, which makes it difficult to target them therapeutically. The cellular origin of ovarian cancer stem cells has been difficult to identify. Multiple stem cell models have been proposed. One model proposes that CSCs can originate either from somatic adult stem cells or from progenitor non-stem cells. The ovarian surface epithelium and distal fallopian tube, which are tumor initiation sites, consist of both adult stem cells and also progenitor cells that are relatively undifferentiated and capable of differentiating into distinct morphological subtypes. We have recently found that ovarian cancer and somatic stem cells share common molecular pathways and markers, which is consistent with the model that some cancer stem cells may either arise from adult stem cells or most likely evolve to mimic somatic stem cell properties.

Speaker
Biography:

Thomas Bartosh completed his PhD degree in Cell Biology and Genetics from The University of North Texas HSC. He joined the Institute for Regenerative Medicine (IRM) at Texas A&M University in 2008 to develop therapies with mesenchymal stem cells (MSCs). Currently, he an Assistant Professor of Internal Medicine and Director of flow cytometry and microscopy at the IRM. He studies the advantages of using three-dimensional (3-D) culture methods to activate MSCs and exploit their inherent therapeutic potential. This approach was pioneered by Dr. Bartosh at the IRM and has been highlighted in numerous publications.

Abstract:

Mesenchymal stem cells (MSCs) have many potential applications in cancer therapy. In particular, there is interest in exploiting the notable tumor-tropic properties of MSCs to deliver anti-cancer factors directly into tumors. Previously we reported that when MSCs are prepared as spheroids in 3-D hanging drop cultures, expression of tumor-suppressive factors (TRAIL, IL-24, CD82) was augmented and MSC size was effectively reduced resulting in improved vascular mobility and tumor-homing potential of the cells. Therefore, here we tested the effects of MSCs in spheroids on growth and phenotype of various cancer cells. Within hanging drop co-cultures of MSCs and breast cancer cells (BCCs), the MSCs rapidly surrounded the BCCs and promoted formation of cancer spheroids then disappeared 24-48 hours later. Further experiments revealed that BCCs internalized and degraded MSCs in spheroids, a process resembling cell cannibalism/entosis. The resulting BCCs showed markedly delayed tumorigenicity after injection into mice and displayed features of cellular dormancy. Moreover, sphere-derived MSCs (SDMs) delivered intravenously effectively reduced growth of breast cancer metastasis in lungs of mice. Importantly high cell viability, small cell size, and elevated expression of tumor-suppressive factors were not diminished with cryopreservation of SDMs suggesting that cell banks can be prepared for ‘off-the-shelf’ patient therapies. The results here provide new insight into the interactions between MSCs and cancer cells and indicate that MSCs prepared as spheroids have enhanced tumor-suppressive properties. Collectively, 3-D cultures of MSCs and cancer cells are useful to model the tumor niche in further research and to effectively precondition MSCs for cancer therapies.

Speaker
Biography:

Humayoon S. Satti is a PhD student at Quaid-i-Azam University, Islamabad, Pakistan. He is also working as a Scientific Officer at Armed Forces Bone Marrow Transplant Centre, Pakistan. He is a recipient of ASH visitor Training program 2011 and HEC indigenous Scholarship award (2009-14). He has published 9 papers in national and international journals and currently working as co-investigator in two phase-I/II human clinical trials exploring therapeutic potential of human mesenchymal stem cells in diseases like GVHD and spinal cord injury.

Abstract:

Introduction: Mesenchymal stem cells (MSC) transplantation has recently immerged as promising therapeutic approach to treat spinal cord injury. We report safety and preliminary findings on efficacy of intrathecal injection of cultured autologous bone marrow derived MSCs (BM-MSCs) in 10 patients suffering from spinal cord injury. All patients had traumatic spinal injury at thoracic level resulting in complete paraplegia. Patients received 3 doses of autologous BM-MSCs via intrathecal injection. Primary endpoint was safety which was documented by two independent neurologists four weeks after receiving last injection. ASIA scoring, MRI and neurophysiological tests were carried out before treatment and 12 months after receiving treatment. Results: The patients received at median 3 doses of 1.2 x106 MSCs/Kg body weight. The procedure was well tolerated in all subjects with no adverse event or serious complication observed during median follow up of 263 days (range: 100-602 days). Six patients suffered from chronic injury, with median duration of 33 months since time of injury (range: 10 to 55 months). Four of them have completed one year of follow up and two have displayed benefits in neurogenic bowel and bladder incontinence, besides limited improvement in hip flexor muscle power. However none has yet shown improvement in ASIA scale. Interestingly, all four patients with sub-acute injury showed some degree of improvement in sensory and motor functions in preliminary reports. These patients also exhibited improved bowel and/ or bladder control. Detailed report on efficacy will follow on completion of one year follow up of the remainder patients. Conclusion: This pilot study demonstrated that intrathecal administration of cultured autologous BM-MSCs is safe and feasible for treatment of spinal cord injury.