Advancing personalized medicine in brain cancer: exploring the role of mRNA vaccines.

Advancing personalized medicine in brain cancer relies on innovative strategies, with mRNA vaccines emerging as a promising avenue. While the initial use of mRNA vaccines was in oncology, their stunning success in COVID-19 resulted in widespread attention, both positive and negative. Regardless of politically biased opinions, which relate more to the antigenic source than form of delivery, we feel it is important to objectively review this modality as relates to brain cancer. This class of vaccines trigger robust immune responses through MHC-I and MHC-II pathways, in both prophylactic and therapeutic settings. The mRNA platform offers advantages of rapid development, high potency, cost-effectiveness, and safety. This review provides an overview of mRNA vaccine delivery technologies, tumor antigen identification, combination therapies, and recent therapeutic outcomes, with a particular focus on brain cancer. Combinatorial approaches are vital to maximizing mRNA cancer vaccine efficacy, with ongoing clinical trials exploring combinations with adjuvants and checkpoint inhibitors and even adoptive cell therapy. Efficient delivery, neoantigen identification, preclinical studies, and clinical trial results are highlighted, underscoring mRNA vaccines' potential in advancing personalized medicine for brain cancer. Synergistic combinatorial therapies play a crucial role, emphasizing the need for continued research and collaboration in this area.

Isolation of clinically relevant concentrations of bone marrow mesenchymal stem cells without centrifugation.

BACKGROUND: This study examined the quality of bone marrow aspirates extracted using a novel, FDA cleared method to optimally target cells from the inner cortical iliac bone surface without the need for centrifugation. This method employs small draws from a single puncture that promote only lateral flow from multiple sites (SSLM method). The study utilized the Marrow Cellutions bone marrow aspiration system (MC system) which is based on the SSLM method and compared the MC system directly to bone marrow concentrates (BMAC) generated by centrifugation of aspirates harvested with a standard aspiration needle. METHODS: Three direct comparisons were conducted evaluating the SSLM draws and BMACs derived from the same patient from contralateral iliac crests. The levels of TNCs/mL, CD34+ cells/mL, CD117+ cells/mL, and CFU-f/mL were compared between the various bone marrow preparations. The cellular content of a series of SSLM draws was also analyzed to determine the total nucleated cell (TNC) count and the concentration of mesenchymal stem/progenitor cells as measured by colony forming unit fibroblasts (CFU-f). RESULTS: In direct comparisons with BMAC systems, SSLM draws yielded significantly higher CFU-f concentrations and comparable concentrations of CD34+ and CD117+ cells. In addition, the average quantity of TNCs/mL in a series of 30 patients utilizing the SSLM draw was 35.2 × 106 ± 17.1 × 106 and the average number of CFU-f/mL was 2885 ± 1716. There were small but significant correlations between the TNCs/mL and the CFU-fs/mL using the SSLM method as well as between the age of the patient and the CFU-fs/mL. CONCLUSIONS: The MC Device, using the SSLM draw technique, produced concentrations of CFU-fs, CD34+ cells and CD117+ cells that were comparable or greater to BMACs derived from the same patient. Given the rapid speed and simplicity of the MC Device, we believe this novel system possesses significant practical advantages to other currently available centrifugation based systems.

Unleashing endogenous TNF-alpha as a cancer immunotherapeutic.

Tumor necrosis factor (TNF)-alpha was originally identified in the 1970s as the serum mediator of innate immunity capable of inducing hemorrhagic necrosis in tumors. Today, a wide spectrum of biological activities have been attributed to this molecule, and clinical translation has mainly occurred not in using it to treat cancer, but rather to inhibit its effects to treat autoimmunity. Clinical trials utilizing systemic TNF-alpha administration have resulted in an unacceptable level of toxicities, which blocked its development. In contrast, localized administration of TNF-alpha in the form of isolated limb perfusion have yielded excellent results in soft tissue sarcomas. Here we describe a novel approach to leveraging the potent antineoplastic activities of TNF-alpha by enhancing activity of locally produced TNF-alpha through extracorporeal removal of soluble TNF-alpha receptors. Specifically, it is known that cancerous tissues are infiltrated with monocytes, T cells, and other cells capable of producing TNF-alpha. It is also known that tumors, as well as cells in the tumor microenvironment produce soluble TNF-alpha receptors. The authors believe that by selectively removing soluble TNF-alpha receptors local enhancement of endogenous TNF-alpha activity may provide for enhanced tumor cell death without associated systemic toxicities.

Protection from chemotherapy- and antibiotic-mediated dysbiosis of the gut microbiota by a probiotic with digestive enzymes supplement.

There are numerous downstream consequences of marketed drugs like antineoplastic agents on the gut microbiome, an effect that is suggested to contribute to adverse event profiles and may also influence drug responses. In cancer, progress is needed toward modulation of the host microbiome to prevent off-target side effects of drugs such as gastrointestinal mucositis that result from gut dysbiosis. The objective of this study was evaluation of the bioactivity of a supplement consisting of capsules with a blend of 9 probiotic organisms of the genera Lactobacillus and Bifidobacterium plus 10 digestive enzymes, in protecting the human gastrointestinal tract from chemotherapy and an antibiotic. We used the Simulator of Human Intestinal Microbial Ecosystem (SHIME) model, an in vitro model of a stable colon microbiota, and introduced 5-fluorouracil (5-FU) and vancomycin as microbiome-disrupting drugs. The probiotic with digestive enzymes supplement, added in capsules at in vivo doses, improved fermentation activity in the colon reactors and accelerated the recovery of microbial populations following 5-FU/vancomycin treatment. The supplement restored the Bacteroidetes to Firmicutes ratios in the colon reactors, increased the diversity of microbiota, and induced the production of microbial metabolites that elicited anti-inflammatory cytokines in an in vitro model of intestinal inflammation. In the proximal colon, preventative administration of the supplement resulted in full recovery of the gut microbial community after cessation of 5-FU and vancomycin treatment. These results identify a probiotic with digestive enzymes formulation that protects against drug-induced gut dysbiosis, highlighting its potential utility as a component of routine cancer care.

Fibroblasts as a practical alternative to mesenchymal stem cells.

Mesenchymal stem cell (MSC) therapy offers great potential for treatment of disease through the multifunctional and responsive ability of these cells. In numerous contexts, MSC have been shown to reduce inflammation, modulate immune responses, and provide trophic factor support for regeneration. While the most commonly used MSC source, the bone marrow provides relatively little starting material for cellular expansion, and requires invasive extraction means, fibroblasts are easily harvested in large numbers from various biological wastes. Additionally, in vitro expansion of fibroblasts is significantly easier given the robustness of these cells in tissue culture and shorter doubling time compared to typical MSC. In this paper we put forward the concept that in some cases, fibroblasts may be utilized as a more practical, and potentially more effective cell therapy than mesenchymal stem cells. Anti-inflammatory, immune modulatory, and regenerative properties of fibroblasts will be discussed in the context of regenerative medicine.

A new cancer immunotherapy via simultaneous DC-mobilization and DC-targeted IDO gene silencing using an immune-stimulatory nanosystem.

The activity of negative immune regulatory molecules, such as indoleamine 2,3-oxygenase (IDO), significantly attenuates DC (Dendritic cells)-mediated immunotherapy. We have previously reported that knockdown of IDO using siRNA can reinstall anti-tumor immunity. However, a DC-targeted siRNA delivery system for in vivo mobilized DCs remains to be developed, while gene silencing in mobilized DCs for cancer immunotherapy has never been explored. In our study, we developed a novel DC-targeted siRNA delivery system, man-GNR-siIDO, using as a nanocarrier of siRNA specific for IDO (siIDO) and mannose (man) as a guide molecule for targeting DCs. We explored the immunostimulatory man-GNR-siIDO nano-construct in DCs mobilized by Flt3-L, a receptor-type tyrosine kinase ligand, for lung cancer immunotherapy. In vivo DC-targeted gene silencing of IDO resulted in robust anti-tumor immunity as evidenced by promoting DC maturation, up-regulating tumor antigen-specific T-cell proliferation and enhancing tumor-specific cytotoxicity. A combinatorial treatment for Lewis Lung Carcinoma (LLC)-bearing mice, with man-GNR-siIDO and Flt3-L, significantly attenuated tumor growth and delayed tumor formation, suggesting the treatment feasibility of the man-GNR-siIDO system in Flt3-L mobilized DCs in the immunotherapy of lung cancer. Therefore, our study highlights a clinical potential for a first-in-class anti-cancer immunotherapy through simultaneous DC-mobilization and DC-targeted gene silencing of IDO with man-GNR-siIDO and Flt3-L treatments.

Skin Allografting Activates Anti-tumor Immunity and Suppresses Growth of Colon Cancer in Mice.

INTRODUCTION: The tumor cells could escape from the immune elimination through the immunoediting mechanisms including the generation of immunosuppressive or immunoregulative cells. By contrast, allograft transplantation could activate the immune system and induce a strong allogenic response. The aim of this study was to investigate the efficacy of allogenic skin transplantation in the inhibition of tumor growth through the activation of allogenic immune response. METHODS: Full-thickness skin transplantation was performed from C57BL/6 (H-2b) donors to BALB/c (H-2d) recipients that were receiving subcutaneous injection of isogenic CT26 colon cancer cells (2 × 106 cells) at the same time. The tumor size and pathological changes, cell populations and cytokine profiles were evaluated at day 14 post-transplantation. RESULTS: The results showed that as compared to non-transplant group, the allogenic immune response in the skin-grafting group inhibited the growth of tumors, which was significantly associated with increased numbers of intra-tumor infiltrating lymphocytes, increased populations of CD11c+MHC-classII+CD86+ DCs, CD3+CD4+ T cells, CD3+CD8+ T cells, and CD19+ B cells, as well as decreased percentage of CD4+CD25+Foxp3+ T cells in the spleens. In addition, the levels of serum IgM and IgG, tumor necrosis factor (TNF)-α and interferon (IFN)-γ were significantly higher within the tumor in skin transplant groups than that in non-transplant group. CONCLUSIONS: Allogenic skin transplantation suppresses the tumor growth through activating the allogenic immune response, and it may provide a new immunotherapy option for the clinical refractory tumor treatment.

Effect of Infla-Kine supplementation on the gene expression of inflammatory markers in peripheral mononuclear cells and on C-reactive protein in blood.

BACKGROUND: Chronic inflammation is a predisposing factor to numerous degenerative diseases including cancer, heart failure and Alzheimer's disease. Infla-Kine is a natural supplement comprised of a proprietary blend of Lactobacillus fermentum extract, burdock seed (arctigenin), zinc, alpha lipoic acid, papaya enzyme and an enhanced absorption bio-curcumin complex (BCM-95®). METHODS: Infla-Kine was administered twice daily to 24 health volunteers for 4 weeks. Quantitative RT-PCR was used to assess mRNA transcripts of IL-1b, IL8, IL-6, NF-κB, and TNF-α from peripheral blood mononuclear cells (PBMC). C reactive protein (CRP) was measured from serum. Additionally, quality of life questionnaires were employed to assess general feeling of well-being. Assessments were made before treatment and at conclusion of treatment (4 weeks). RESULTS: As compared to pre-treatment, after 4 weeks, a statistically significant reduction of IL8, IL-6, NF-κB, and TNF-α transcripts was observed in PBMC. Furthermore, reduction of IL-1b transcript and serum CRP was observed but did not reach statistical significance. Quality of life improvements were most prevalent in muscle and joint pains. CONCLUSIONS: Overall, our data demonstrate that twice daily administration of Infla-Kine for 4 weeks reduces inflammatory markers and quality of life in healthy volunteers.

Cellular immunotherapy of cancer: an overview and future directions.

The clinical success of checkpoint inhibitors has led to a renaissance of interest in cancer immunotherapies. In particular, the possibility of ex vivo expanding autologous lymphocytes that specifically recognize tumor cells has attracted much research and clinical trial interest. In this review, we discuss the historical background of tumor immunotherapy using cell-based approaches, and provide some rationale for overcoming current barriers to success of autologous immunotherapy. An overview of adoptive transfer of lymphocytes, tumor infiltrating lymphocytes and dendritic cell therapies is provided. We conclude with discussing the possibility of gene-manipulating immune cells in order to augment therapeutic activity, including silencing of the immune-suppressive zinc finger orphan nuclear receptor, NR2F6, as an attractive means of overcoming tumor-associated immune suppression.

Induction and characterization of anti-tumor endothelium immunity elicited by ValloVax therapeutic cancer vaccine.

ValloVax is a placental endothelium derived vaccine which induces tissue-nonspecific antitumor immunity by blocking tumor angiogesis. To elucidate mechanisms of action, we showed that production of ValloVax, which involves treating placental endothelial cells with IFN-gamma, results in upregulation of HLA and costimulatory molecules. It was shown that in mixed lymphocyte reaction, ValloVax induces Type I cytokines and allo-proliferative responses. Plasma from ValloVax immunized mice was capable of killing in vitro tumor-like endothelium but not control endothelium. Using defined antigens associated with tumor endothelial cells, specific molecular entities were identified as being targeted by ValloVax induced antibodies. Binding of predominantly IgG antibodies to ValloVax cells was confirmed by flow cytometry. Further suggesting direct killing of tumor endothelial cells was expression of TUNEL positive cells, as well as, reduction in tumor oxygenation. Supporting a role for antibody mediated responses, cell depletion experiments suggested a predominant role of B cells in maintaining an intact anti-tumor endothelial response. Adoptive transfer experiments suggested that infusion of CD3+ T cells from immunized mice was sufficient to transfer tumor protection. Generation of memory T cells selective to tumor endothelial specific markers was observed. Functional confirmation of memory responses was observed in tumor rechallenge experiments. Furthermore, we observed that both PD-1 or CTLA-4 blockade augmented antitumor effects of ValloVax. These data suggest a T cell induced B cell mediated anti-tumor endothelial response and set the framework clinical trials through elucidation of mechanism of action.

Human endometrial regenerative cells alleviate carbon tetrachloride-induced acute liver injury in mice.

BACKGROUND: The endometrial regenerative cell (ERC) is a novel type of adult mesenchymal stem cell isolated from menstrual blood. Previous studies demonstrated that ERCs possess unique immunoregulatory properties in vitro and in vivo, as well as the ability to differentiate into functional hepatocyte-like cells. For these reasons, the present study was undertaken to explore the effects of ERCs on carbon tetrachloride (CCl4)-induced acute liver injury (ALI). METHODS: An ALI model in C57BL/6 mice was induced by administration of intraperitoneal injection of CCl4. Transplanted ERCs were intravenously injected (1 million/mouse) into mice 30 min after ALI induction. Liver function, pathological and immunohistological changes, cell tracking, immune cell populations and cytokine profiles were assessed 24 h after the CCl4 induction. RESULTS: ERC treatment effectively decreased the CCl4-induced elevation of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and improved hepatic histopathological abnormalities compared to the untreated ALI group. Immunohistochemical staining showed that over-expression of lymphocyte antigen 6 complex, locus G (Ly6G) was markedly inhibited, whereas expression of proliferating cell nuclear antigen (PCNA) was increased after ERC treatment. Furthermore, the frequency of CD4+ and CD8+ T cell populations in the spleen was significantly down-regulated, while the percentage of splenic CD4+CD25+FOXP3+ regulatory T cells (Tregs) was obviously up-regulated after ERC treatment. Moreover, splenic dendritic cells in ERC-treated mice exhibited dramatically decreased MHC-II expression. Cell tracking studies showed that transplanted PKH26-labeled ERCs engrafted to lung, spleen and injured liver. Compared to untreated controls, mice treated with ERCs had lower levels of IL-1ß, IL-6, and TNF-α but higher level of IL-10 in both serum and liver. CONCLUSIONS: Human ERCs protect the liver from acute injury in mice through hepatocyte proliferation promotion, as well as through anti-inflammatory and immunoregulatory effects.

Safety of targeting tumor endothelial cell antigens.

The mechanisms underlying discrimination between "self" and "non-self", a central immunological principle, require careful consideration in immune oncology therapeutics where eliciting anti-cancer immunity must be weighed against the risk of autoimmunity due to the self origin of tumors. Whole cell vaccines are one promising immunotherapeutic avenue whereby a myriad of tumor antigens are introduced in an immunogenic context with the aim of eliciting tumor rejection. Despite the possibility collateral damage to healthy tissues, cancer immunotherapy can be designed such that off target autoimmunity remains limited in scope and severity or completely non-existent. Here we provide an immunological basis for reconciling the safety of cancer vaccines, focusing on tumor endothelial cell vaccines, by discussing the following topics: (a) Antigenic differences between neoplastic and healthy tissues that can be leveraged in cancer vaccine design; (b) The layers of tolerance that control T cell responses directed against antigens expressed in healthy tissues and tumors; and, (c) The hierarchy of antigenic epitope selection and display in response to whole cell vaccines, and how antigen processing and presentation can afford a degree of selectivity against tumors. We conclude with an example of early clinical data utilizing ValloVax™, an immunogenic placental endothelial cell vaccine that is being advanced to target the tumor endothelium of diverse cancers, and we report on the safety and efficacy of ValloVax™ for inducing immunity against tumor endothelial antigens.

Cancer anti-angiogenesis vaccines: Is the tumor vasculature antigenically unique?

Angiogenesis is essential for the growth and metastasis of solid tumors. The tumor endothelium exists in a state of chronic activation and proliferation, fueled by the tumor milieu where angiogenic mediators are aberrantly over-expressed. Uncontrolled tumor growth, immune evasion, and therapeutic resistance are all driven by the dysregulated and constitutive angiogenesis occurring in the vasculature. Accordingly, great efforts have been dedicated toward identifying molecular signatures of this pathological angiogenesis in order to devise selective tumor endothelium targeting therapies while minimizing potential autoimmunity against physiologically normal endothelium. Vaccination with angiogenic antigens to generate cellular and/or humoral immunity against the tumor endothelium has proven to be a promising strategy for inhibiting or normalizing tumor angiogenesis and reducing cancer growth. Here we review tumor endothelium vaccines developed to date including active immunization strategies using specific tumor endothelium-associated antigens and whole endothelial cell-based vaccines designed to elicit immune responses against diverse target antigens. Among the novel therapeutic options, we describe a placenta-derived endothelial cell vaccine, ValloVax™, a polyvalent vaccine that is antigenically similar to proliferating tumor endothelium and is supported by pre-clinical studies to be safe and efficacious against several tumor types.

Scalable efficient expansion of mesenchymal stem cells in xeno free media using commercially available reagents.

BACKGROUND: The rapid clinical translation of mesenchymal stem cells (MSC) has resulted in the development of cell-based strategies for multiple indications. Unfortunately one major barrier to widespread implementation of MSC-based therapies is the limited supply of fetal calf serum (FCS) used to expand cells to therapeutic numbers. Additionally, the xenogeneic element of fetal calf serum has been previously demonstrated to stimulate antibody mediated reactions and in some cases sensitization leading to anaphylaxis. METHOD: XcytePLUS™ media, a human platelet lysate based product, was used to supplement the culture medium at 5, 7.5 and 10% and compared to fetal calf serum at 10%, for human umbilical cord MSC expansion. Properties of the expanded cells were investigated. RESULTS: This study demonstrated equivalent or superior effects of human platelet lysate compared to standard FCS supplemented media, based on doubling rate, without loss of identity or function, as demonstrated with flow cytometry characterization. Differentiation into osteocytes, adipocytes and chondrocytes was comparable from cells expanded in either media supplement. CONCLUSIONS: These data support the implementation of human platelet lysate supplemented media as an alternative to xenogeneic containing preparations which may lead to safer MSC products with therapeutic uses.

Induction of tumor inhibitory anti-angiogenic response through immunization with interferon Gamma primed placental endothelial cells: ValloVax™.

BACKGROUND: While the concept of angiogenesis blockade as a therapeutic intervention for cancer has been repeatedly demonstrated, the full promise of this approach has yet to be realized. Specifically, drugs such as VEGF-blocking antibodies or kinase inhibitors suffer from the drawbacks of resistance development, as well as off-target toxicities. Previous studies have demonstrated feasibility of specifically inducing immunity towards tumor endothelium without consequences of systemic autoimmunity in both animal models and clinical settings. METHOD: Placenta-derived endothelial cells were isolated and pretreated with interferon gamma to enhance immunogenicity. Syngeneic mice received subcutaneous administration of B16 melanoma, 4 T1 mammary carcinoma, and Lewis Lung Carcinoma (LLC), followed by administration of control saline, control placental endothelial cells, and interferon gamma primed endothelial cells (ValloVax™). Tumor volume was quantified. An LLC metastasis model was also established and treated under similar conditions. Furthermore, a safety analysis in non-tumor bearing mice bracketing the proposed clinical dose was conducted. RESULTS: ValloVax™ immunization led to significant reduction of tumor growth and metastasis as compared to administration of non-treated placental endothelial cells. Mitotic inactivation by formalin fixation or irradiation preserved tumor inhibitory activity. Twenty-eight day evaluation of healthy male and female mice immunized with ValloVax™ resulted in no abnormalities or organ toxicities. CONCLUSION: Given the established rationale behind the potential therapeutic benefit of inhibiting tumor angiogenesis as a treatment for cancer, immunization against a variety of endothelial cell antigens may produce the best clinical response, enhancing efficacy and reducing the likelihood of the development of treatment resistance. These data support the clinical evaluation of irradiated ValloVax™ as an anti-angiogenic cancer vaccine.

Newer developments in the immunotherapy of malignant melanoma.

Individuals with malignant melanoma present a variety of immune abnormalities including but not limited to cellular immune dysfunction, antigen presentation deficits, and cytokine production defects. Therefore, enhancing the immune system potential represents an appealing avenue for melanoma therapy. The authors review the immune therapies currently in clinical use as well as the most promising immunotherapy candidates. Ipilimumab, a monoclonal antibody against the CTLA-4, was approved for the therapy of advanced melanoma in 2011. In addition, sizeable anti-melanoma activity has recently been shown with the use of other agents including anti-PD-1/anti-PD-1 ligand antibodies. Consequently, these experimental immunotherapy agents may soon become important items in the anti-melanoma armamentarium.

Intracavernous administration of bone marrow mononuclear cells: a new method of treating erectile dysfunction?

While PDE5 inhibitors have revolutionized treatment of ED, approximately 30% of patients are non-responsive. A significant cause of this is vascular and smooth muscle dysfunction, as well as nerve atrophy. Autologous administration of bone marrow mononuclear cells (BMMC) has been performed in over 2000 cardiac patients without adverse effects, for stimulation of angiogenesis/regeneration. Despite its ease of access, and dependence on effective vasculature for function, comparatively little has been perform in terms of BMMC therapy for ED. Here we outline the rationale for use of autologous BMMC in patients with ED, as well as provide early safety data on the first use of this procedure clinically.

Malignant melanoma in pigmented skin: does the current interventional model fit a different clinical, histologic, and molecular entity?

BACKGROUND: Although the incidence of malignant melanoma in African Americans is considerably lower than in Caucasians, African Americans have a less-favorable prognosis related to later presentation and more deeply invasive lesions at diagnosis. OBJECTIVE: To review the current literature addressing the specific clinical, histopathologic, and molecular features of melanoma in darkly pigmented individuals. METHODS: We reviewed the most up-to-date literature pertaining to melanoma in this patient population, including data from clinical studies, epidemiologic analyses, and molecular and genetic studies. RESULTS: Several studies have suggested differences between lightly and darkly pigmented populations with regard to clinicopathologic character and the underlying genetic processes affecting its pathogenesis. CONCLUSION: Further investigation is warranted to better elucidate the clinical and underlying biological differences in melanoma between Caucasians and African Americans. Such research may help to ameliorate the disparities in melanoma outcomes through improved screening, public health measures aimed at prevention, and potentially novel targeted therapeutic approaches.

Endometrial regenerative cells for treatment of heart failure: a new stem cell enters the clinic.

Heart failure is one of the key causes of morbidity and mortality world-wide. The recent findings that regeneration is possible in the heart have made stem cell therapeutics the Holy Grail of modern cardiovascular medicine. The success of cardiac regenerative therapies hinges on the combination of an effective allogeneic "off the shelf" cell product with a practical delivery system. In 2007 Medistem discovered the Endometrial Regenerative Cell (ERC), a new mesenchymal-like stem cell. Medistem and subsequently independent groups have demonstrated that ERC are superior to bone marrow mesenchymal stem cells (MSC), the most widely used stem cell source in development. ERC possess robust expansion capability (one donor can generate 20,000 patients doses), key growth factor production and high levels of angiogenic activity. ERC have been published in the peer reviewed literature to be significantly more effect at treating animal models of heart failure (Hida et al. Stem Cells 2008).Current methods of delivering stem cells into the heart suffer several limitations in addition to poor delivery efficiency. Surgical methods are highly invasive, and the classical catheter based techniques are limited by need for sophisticated cardiac mapping systems and risk of myocardial perforation. Medistem together with Dr. Amit Patel Director of Clinical Regenerative Medicine at University of Utah have developed a novel minimally invasive delivery method that has been demonstrated safe and effective for delivery of stem cells (Tuma et al. J Transl Med 2012). Medistem is evaluating the combination of ERC, together with our retrograde delivery procedure in a 60 heart failure patient, double blind, placebo controlled phase II trial. To date 17 patients have been dosed and preliminary analysis by the Data Safety Monitoring Board has allowed for trial continuation.The combined use of a novel "off the shelf" cell together with a minimally invasive 30 minute delivery method provides a potentially paradigm-shifting approach to cardiac regenerative therapy.

Muehrcke's lines (Leukonychia striata) due to transretinoic acid therapy for acute promyelocytic leukemia.

Transverse leukonychia (Leukonychia striata or Muehrcke's lines) has been described with the use of several drugs in oncology, mainly chemotherapeutic agents. This condition is thought to represent an abnormality of the vascular nail bed. As the diagnosis is clinical and the condition is self-limited, referral to other specialists is usually not required. We report the first case of transverse leukonychia related to the use of transretinoic acid for acute promyelocytic leukemia. Physician awareness of transverse leukonychia is important in order to reassure the patients and avoid unnecessary (and often not inexpensive) diagnostic work-up.