Stem cell transplantation as rescue therapy for refractory Crohn's disease: a sytematic review.

PubMed

Labidi, Asma; Serghini, Meriem; Ben Mustapha, Nadia; Fekih, Monia; Boubaker, Jalel; Filali, Azza

2014-11-01

Crohn's disease is a chronic relapsing- remitting affection. It has a strong immunologic component which represent the target of standard therapies including immunosppressants and biological therapies. However, many patients remain refracory or intolerant to these therapies. The aim of this review is to determine the effects of stem cell transplantation in patients with refractory Crohn's disease. Systematic review of observational studies, clinical trials and case reports that focused on the effectiveness and safety of stem cell transplantation in patients with refractory Crohn's disease. Hematopoietic stem cell transplantation seems to be efficient in maintaining clinical and endoscopic remission in patients with Crohn's disease refractory or intolerant to current therapies. However, it has been associated to high morbidity and mortality due to chemotherapy. Mesenchymal stem cell transplantation could induce remission in patients with fistulising refractory Crohns disease with no severe side effects. Its impact on luminal Crohns disease is still controversial. Stem cell transplantation seems to hold promising in patients with refractory Crohn's disease. However, because of the high morbidity and mortality related to chemotherapy, hematopoietic stem cell transplantation should be used as last resort to control this disease. Effectiveness of mesenchymal stem cell transplantation in luminal Crohn's disease has yet to be proven.

Antiangiogenic therapy improves the antitumor effect of adoptive cell immunotherapy by normalizing tumor vasculature.

PubMed

Shi, Shujing; Chen, Longbang; Huang, Guichun

2013-12-01

Abnormal tumor vasculature and subsequent tumor hypoxia contribute to immune tolerance of tumor cells by impeding the homing of cytotoxic T cells into tumor parenchyma and inhibiting their antitumor efficacy. These obstacles might explain why the promising approach of adoptive cell immunotherapy does not exert significant antitumor activity. Hypoxia contributes to immune suppression by activating hypoxia-inducible factor (HIF-1) and the vascular endothelial growth factor pathway, which plays a determining role in promoting tumor cell growth and survival. Tumor hypoxia creates an immunosuppressive microenvironment via the accumulation and subsequent polarization of inflammatory cells toward immune suppression phenotypes, such as myeloid-derived suppressor cells, tumor-associated macrophages, and dendritic cells. Antiangiogenic therapy could normalize tumor vasculature and decrease hypoxic tumor area and thus may be an effective modality to potentiate immunotherapy. Adoptive cell immunotherapy alone is not efficient enough to decrease tumor growth as its antitumor effect is inhibited by the immunosuppressive hypoxic tumor microenvironment. This review describes that combination of antiangiogenic therapy with adoptive cell immunotherapy can exert synergistic antitumor effect, which will contribute to improve strategies for future anticancer therapies.

Hydrogen gas alleviates oxygen toxicity by reducing hydroxyl radical levels in PC12 cells

PubMed Central

Yu, Junchao; Yu, Qiuhong; Liu, Yaling; Zhang, Ruiyun; Xue, Lianbi

2017-01-01

Hyperbaric oxygen (HBO) therapy through breathing oxygen at the pressure of above 1 atmosphere absolute (ATA) is useful for varieties of clinical conditions, especially hypoxic-ischemic diseases. Because of generation of reactive oxygen species (ROS), breathing oxygen gas at high pressures can cause oxygen toxicity in the central nervous system, leading to multiple neurological dysfunction, which limits the use of HBO therapy. Studies have shown that Hydrogen gas (H2) can diminish oxidative stress and effectively reduce active ROS associated with diseases. However, the effect of H2 on ROS generated from HBO therapy remains unclear. In this study, we investigated the effect of H2 on ROS during HBO therapy using PC12 cells. PC12 cells cultured in medium were exposed to oxygen gas or mixed oxygen gas and H2 at 1 ATA or 5 ATA. Cells viability and oxidation products and ROS were determined. The data showed that H2 promoted the cell viability and inhibited the damage in the cell and mitochondria membrane, reduced the levels of lipid peroxidation and DNA oxidation, and selectively decreased the levels of •OH but not disturbing the levels of O2•-, H2O2, or NO• in PC12 cells during HBO therapy. These results indicated that H2 effectively reduced •OH, protected cells against oxygen toxicity resulting from HBO therapy, and had no effect on other ROS. Our data supported that H2 could be potentially used as an antioxidant during HBO therapy. PMID:28362819

Concise Review: Process Development Considerations for Cell Therapy

PubMed Central

Brieva, Thomas; Raviv, Lior; Rowley, Jon; Niss, Knut; Brandwein, Harvey; Oh, Steve; Karnieli, Ohad

2015-01-01

The development of robust and well-characterized methods of production of cell therapies has become increasingly important as therapies advance through clinical trials toward approval. A successful cell therapy will be a consistent, safe, and effective cell product, regardless of the cell type or application. Process development strategies can be developed to gain efficiency while maintaining or improving safety and quality profiles. This review presents an introduction to the process development challenges of cell therapies and describes some of the tools available to address production issues. This article will provide a summary of what should be considered to efficiently advance a cellular therapy from the research stage through clinical trials and finally toward commercialization. The identification of the basic questions that affect process development is summarized in the target product profile, and considerations for process optimization are discussed. The goal is to identify potential manufacturing concerns early in the process so they may be addressed effectively and thus increase the probability that a therapy will be successful. Significance The present study contributes to the field of cell therapy by providing a resource for those transitioning a potential therapy from the research stage to clinical and commercial applications. It provides the necessary steps that, when followed, can result in successful therapies from both a clinical and commercial perspective. PMID:26315572

Autophagy Therapeutic Potential of Garlic in Human Cancer Therapy

PubMed Central

Chu, Yung-Lin; Raghu, Rajasekaran; Lu, Kuan-Hung; Liu, Chun-Ting; Lin, Shu-Hsi; Lai, Yi-Syuan; Cheng, Wei-Cheng; Lin, Shih-Hang; Sheen, Lee-Yan

2013-01-01

Cancer is one of the deadliest diseases against humans. To tackle this menace, humans have developed several high-technology therapies, such as chemotherapy, tomotherapy, targeted therapy, and antibody therapy. However, all these therapies have their own adverse side effects. Therefore, recent years have seen increased attention being given to the natural food for complementary therapy, which have less side effects. Garlic (Dà Suàn; Allium sativum), is one of most powerful food used in many of the civilizations for both culinary and medicinal purpose. In general, these foods induce cancer cell death by apoptosis, autophagy, or necrosis. Studies have discussed how natural food factors regulate cell survival or death by autophagy in cancer cells. From many literature reviews, garlic could not only induce apoptosis but also autophagy in cancer cells. Autophagy, which is called type-II programmed cell death, provides new strategy in cancer therapy. In conclusion, we wish that garlic could be the pioneer food of complementary therapy in clinical cancer treatment and increase the life quality of cancer patients. PMID:24716172

Autophagy therapeutic potential of garlic in human cancer therapy.

PubMed

Chu, Yung-Lin; Raghu, Rajasekaran; Lu, Kuan-Hung; Liu, Chun-Ting; Lin, Shu-Hsi; Lai, Yi-Syuan; Cheng, Wei-Cheng; Lin, Shih-Hang; Sheen, Lee-Yan

2013-07-01

Cancer is one of the deadliest diseases against humans. To tackle this menace, humans have developed several high-technology therapies, such as chemotherapy, tomotherapy, targeted therapy, and antibody therapy. However, all these therapies have their own adverse side effects. Therefore, recent years have seen increased attention being given to the natural food for complementary therapy, which have less side effects. Garlic (Dà Suàn; Allium sativum), is one of most powerful food used in many of the civilizations for both culinary and medicinal purpose. In general, these foods induce cancer cell death by apoptosis, autophagy, or necrosis. Studies have discussed how natural food factors regulate cell survival or death by autophagy in cancer cells. From many literature reviews, garlic could not only induce apoptosis but also autophagy in cancer cells. Autophagy, which is called type-II programmed cell death, provides new strategy in cancer therapy. In conclusion, we wish that garlic could be the pioneer food of complementary therapy in clinical cancer treatment and increase the life quality of cancer patients.

Apoptotic cell infusion treats ongoing collagen-induced arthritis, even in the presence of methotrexate, and is synergic with anti-TNF therapy.

PubMed

Bonnefoy, Francis; Daoui, Anna; Valmary-Degano, Séverine; Toussirot, Eric; Saas, Philippe; Perruche, Sylvain

2016-08-11

Apoptotic cell-based therapies have been proposed to treat chronic inflammatory diseases. The aim of this study was to investigate the effect of intravenous (i.v.) apoptotic cell infusion in ongoing collagen-induced arthritis (CIA) and the interaction of this therapy with other treatments used in rheumatoid arthritis (RA), including methotrexate (MTX) or anti-TNF therapy. The effects of i.v. apoptotic cell infusion were evaluated in a CIA mouse model in DBA/1 mice immunized with bovine type II collagen. The number and functions of antigen-presenting cells (APC), regulatory CD4(+) T cells (Treg), and circulating anti-collagen auto-antibodies were analyzed in CIA mice. Treatment of arthritic mice with i.v. apoptotic cell infusion significantly reduced the arthritis clinical score. This therapeutic approach modified T cell responses against the collagen auto-antigen with selective induction of collagen-specific Treg. In addition, we observed that APC from apoptotic-cell-treated animals were resistant to toll-like receptor ligand activation and favored ex vivo Treg induction, indicating APC reprogramming. Apoptotic cell injection-induced arthritis modulation was dependent on transforming growth factor (TGF)-β, as neutralizing anti-TGF-β antibody prevented the effects of apoptotic cells. Methotrexate did not interfere, while anti-TNF therapy was synergic with apoptotic-cell-based therapy. Overall, our data demonstrate that apoptotic-cell-based therapy is efficient in treating ongoing CIA, compatible with current RA treatments, and needs to be evaluated in humans in the treatment of RA.

Stem Cells for Cardiac Regeneration by Cell Therapy and Myocardial Tissue Engineering

NASA Astrophysics Data System (ADS)

Wu, Jun; Zeng, Faquan; Weisel, Richard D.; Li, Ren-Ke

Congestive heart failure, which often occurs progressively following a myocardial infarction, is characterized by impaired myocardial perfusion, ventricular dilatation, and cardiac dysfunction. Novel treatments are required to reverse these effects - especially in older patients whose endogenous regenerative responses to currently available therapies are limited by age. This review explores the current state of research for two related approaches to cardiac regeneration: cell therapy and tissue engineering. First, to evaluate cell therapy, we review the effectiveness of various cell types for their ability to limit ventricular dilatation and promote functional recovery following implantation into a damaged heart. Next, to assess tissue engineering, we discuss the characteristics of several biomaterials for their potential to physically support the infarcted myocardium and promote implanted cell survival following cardiac injury. Finally, looking ahead, we present recent findings suggesting that hybrid constructs combining a biomaterial with stem and supporting cells may be the most effective approaches to cardiac regeneration.

Cell Therapy Applications for Retinal Vascular Diseases: Diabetic Retinopathy and Retinal Vein Occlusion.

PubMed

Park, Susanna S

2016-04-01

Retinal vascular conditions, such as diabetic retinopathy and retinal vein occlusion, remain leading causes of vision loss. No therapy exists to restore vision loss resulting from retinal ischemia and associated retinal degeneration. Tissue regeneration is possible with cell therapy. The goal would be to restore or replace the damaged retinal vasculature and the retinal neurons that are damaged and/or degenerating from the hypoxic insult. Currently, various adult cell therapies have been explored as potential treatment. They include mesenchymal stem cells, vascular precursor cells (i.e., CD34+ cells, hematopoietic cells or endothelial progenitor cells), and adipose stromal cells. Preclinical studies show that all these cells have a paracrine trophic effect on damaged ischemic tissue, leading to tissue preservation. Endothelial progenitor cells and adipose stromal cells integrate into the damaged retinal vascular wall in preclinical models of diabetic retinopathy and ischemia-reperfusion injury. Mesenchymal stem cells do not integrate as readily but appear to have a primary paracrine trophic effect. Early phase clinical trials have been initiated and ongoing using mesenchymal stem cells or autologous bone marrow CD34+ cells injected intravitreally as potential therapy for diabetic retinopathy or retinal vein occlusion. Adipose stromal cells or pluripotent stem cells differentiated into endothelial colony-forming cells have been explored in preclinical studies and show promise as possible therapies for retinal vascular disorders. The relative safety or efficacy of these various cell therapies for treating retinal vascular disorders have yet to be determined.

Anti-tumor effects on the combination of photodynamic therapy with arsenic compound in TC-1 cells implanted C57BL/6 mice

NASA Astrophysics Data System (ADS)

Lee, Kyu Wan; Wen, Lan Ying; Bae, Su Mi; Park, Choong Hak; Jeon, Woo Kyu; Lee, Doo Yun; Ahn, Woong Shick

2009-06-01

The effects of As4O6 were studied as adjuvant on photodynamic therapy. As4O6 is considered to have anticancer activity via several biological actions such as free radical producing and inhibition of VEGF expression. In vitro experiments, cell proliferation and morphology were determined by MTT assay. Also, quantitative PCR array was performed to study the synergetic mechanism. Additionally, this study was supported by the finding that combination of photodynamic therapy and As4O6 shows an inhibition effect of tumor growth in C57BL/6 mice with TC-1 cells xenographs in vivo. Radachlorin and As4O6 significantly inhibited TC-1 cell proliferation in a dose-dependent manner (P < 0.05). Antiproliferative effect of combination treatment was significantly higher than those of TC-1 cells treated with either photodynamic therapy or As4O6 (62.4 and 52.5% decrease, respectively, compared to photodynamic therapy or As4O6 alone, P < 0.05). In addition, cell proliferation in combination of photodynamic therapy and As4O6 treatment significantly decreased by 77.4% compared to vehicle-only treated TC-1 cells (P < 0.05). Cell survival pathway (Naip1, Tert and Aip1) and p53-dependent pathway (Bax, p21Cip1, Fas, Gadd45, IGFBP-3 and Mdm-2) were markedly increased by combination treatment of photodynamic therapy and As4O6. Besides, the immunology response NEAT pathway (Ly- 12, CD178 and IL-2) also modulated after combination treatment of photodynamic therapy and As4O6. This combination effect apparently shows a same pattern in vivo model. These findings suggest the benefit of the combination treatment of photodynamic therapy and As4O6 for the inhibition of cervical cancer growth.

Application of stem cells in targeted therapy of breast cancer: a systematic review.

PubMed

Madjd, Zahra; Gheytanchi, Elmira; Erfani, Elham; Asadi-Lari, Mohsen

2013-01-01

The aim of this systematic review was to investigate whether stem cells could be effectively applied in targeted therapy of breast cancer. A systematic literature search was performed for original articles published from January 2007 until May 2012. Nine studies met the inclusion criteria for phase I or II clinical trials, of which three used stem cells as vehicles, two trials used autologous hematopoetic stem cells and in four trials cancer stem cells were targeted. Mesenchymal stem cells (MSCs) were applied as cellular vehicles to transfer therapeutic agents. Cell therapy with MSC can successfully target resistant cancers. Cancer stem cells were selectively targeted via a proteasome-dependent suicide gene leading to tumor regression. Wnt/β-catenin signaling pathway has been also evidenced to be an attractive CSC-target. This systematic review focused on two different concepts of stem cells and breast cancer marking a turning point in the trials that applied stem cells as cellular vehicles for targeted delivery therapy as well as CSC-targeted therapies. Applying stem cells as targeted therapy could be an effective therapeutic approach for treatment of breast cancer in the clinic and in therapeutic marketing; however this needs to be confirmed with further clinical investigations.

Ibrutinib Therapy Increases T Cell Repertoire Diversity in Patients with Chronic Lymphocytic Leukemia.

PubMed

Yin, Qingsong; Sivina, Mariela; Robins, Harlan; Yusko, Erik; Vignali, Marissa; O'Brien, Susan; Keating, Michael J; Ferrajoli, Alessandra; Estrov, Zeev; Jain, Nitin; Wierda, William G; Burger, Jan A

2017-02-15

The Bruton's tyrosine kinase inhibitor ibrutinib is a highly effective, new targeted therapy for chronic lymphocytic leukemia (CLL) that thwarts leukemia cell survival, growth, and tissue homing. The effects of ibrutinib treatment on the T cell compartment, which is clonally expanded and thought to support the growth of malignant B cells in CLL, are not fully characterized. Using next-generation sequencing technology, we characterized the diversity of TCRβ-chains in peripheral blood T cells from 15 CLL patients before and after 1 y of ibrutinib therapy. We noted elevated CD4 + and CD8 + T cell numbers and a restricted TCRβ repertoire in all pretreatment samples. After 1 y of ibrutinib therapy, elevated peripheral blood T cell numbers and T cell-related cytokine levels had normalized, and T cell repertoire diversity increased significantly. Dominant TCRβ clones in pretreatment samples declined or became undetectable, and the number of productive unique clones increased significantly during ibrutinib therapy, with the emergence of large numbers of low-frequency TCRβ clones. Importantly, broader TCR repertoire diversity was associated with clinical efficacy and lower rates of infections during ibrutinib therapy. These data demonstrate that ibrutinib therapy increases diversification of the T cell compartment in CLL patients, which contributes to cellular immune reconstitution. Copyright © 2017 by The American Association of Immunologists, Inc.

Ibrutinib therapy increases T cell repertoire diversity in patients with chronic lymphocytic leukemia

PubMed Central

Yin, Qingsong; Sivina, Mariela; Robins, Harlan; Yusko, Erik; Vignali, Marissa; O’Brien, Susan; Keating, Michael J.; Ferrajoli, Alessandra; Estrov, Zeev; Jain, Nitin; Wierda, William G.; Burger, Jan A.

2017-01-01

The BTK inhibitor ibrutinib is a highly effective, new targeted therapy for chronic lymphocytic leukemia (CLL) that thwarts leukemia cell survival, growth, and tissue homing. The effects of ibrutinib treatment on the T cell compartment, which is clonally expanded and thought to support the growth of the malignant B cells in CLL, are not fully characterized. Using next-generation sequencing technology we characterized the diversity of TCRβ chains in peripheral blood T cells from 15 CLL patients before and after one year of ibrutinib therapy. We noted elevated CD4+ and CD8+ T cell numbers and a restricted TCRβ repertoire in all pretreatment samples. After one year of ibrutinib therapy, elevated PB T cell numbers and T-cell related cytokine levels had normalized and T cell repertoire diversity significantly increased. Dominant TCRβ clones in pretreatment samples declined or became undetectable, and the number of productive unique clones significantly increased during ibrutinib therapy, with the emergence of large numbers of low-frequency TCRβ clones. Importantly, broader TCR repertoire diversity was associated with clinical efficacy and lower rates of infections during ibrutinib therapy. These data demonstrate that ibrutinib therapy increases diversification of the T cell compartment in CLL patients, which contributes to cellular immune reconstitution. PMID:28077600

Cancer Nanotheranostics: Improving Imaging and Therapy by Targeted Delivery across Biological Barriers

PubMed Central

Kievit, Forrest M.; Zhang, Miqin

2012-01-01

Cancer nanotheranostics aims to combine imaging and therapy of cancer through use of nanotechnology. The ability to engineer nanomaterials to interact with cancer cells at the molecular level can significantly improve the effectiveness and specificity of therapy to cancers that are currently difficult to treat. In particular, metastatic cancers, drug-resistant cancers, and cancer stem cells impose the greatest therapeutic challenge that requires targeted therapy to treat effectively. Targeted therapy can be achieved with appropriate designed drug delivery vehicles such as nanoparticles, adult stem cells, or T cells in immunotherapy. In this article, we first review the different types of materials commonly used to synthesize nanotheranostic particles and their use in imaging. We then discuss biological barriers that these nanoparticles encounter and must bypass to reach the target cancer cells, including the blood, liver, kidneys, spleen, and particularly the blood-brain barrier. We then review how nanotheranostics can be used to improve targeted delivery and treatment of cancer cells using nanoparticles, adult stem cells, and T cells in immunotherapy. Finally, we discuss development of nanoparticles to overcome current limitations in cancer therapy. PMID:21842473

Mesenchymal Stem Cell Therapy for the Treatment of Vocal Fold Scarring: A Systematic Review of Preclinical Studies

PubMed Central

Wingstrand, Vibe Lindeblad; Jensen, David H.; Bork, Kristian; Sebbesen, Lars; Balle, Jesper; Fischer-Nielsen, Anne; von Buchwald, Christian

2016-01-01

Objectives Therapy with mesenchymal stem cells exhibits potential for the development of novel interventions for many diseases and injuries. The use of mesenchymal stem cells in regenerative therapy for vocal fold scarring exhibited promising results to reduce stiffness and enhance the biomechanical properties of injured vocal folds. This study evaluated the biomechanical effects of mesenchymal stem cell therapy for the treatment of vocal fold scarring. Data Sources PubMed, Embase, the Cochrane Library and Google Scholar were searched. Methods Controlled studies that assessed the biomechanical effects of mesenchymal stem cell therapy for the treatment of vocal fold scarring were included. Primary outcomes were viscoelastic properties and mucosal wave amplitude. Results Seven preclinical animal studies (n = 152 single vocal folds) were eligible for inclusion. Evaluation of viscoelastic parameters revealed a decreased dynamic viscosity (η’) and elastic modulus (G’), i.e., decreased resistance and stiffness, in scarred vocal folds treated with mesenchymal stem cells compared to non-treated scarred vocal folds. Mucosal wave amplitude was increased in scarred vocal folds treated with mesenchymal stem cells vs. non-treated scarred vocal folds. Conclusion The results from these studies suggest an increased regenerative effect of therapy with mesenchymal stem cells for scarred vocal folds and are encouraging for further clinical studies. PMID:27631373

Mesenchymal Stem Cell Therapy for the Treatment of Vocal Fold Scarring: A Systematic Review of Preclinical Studies.

PubMed

Wingstrand, Vibe Lindeblad; Grønhøj Larsen, Christian; Jensen, David H; Bork, Kristian; Sebbesen, Lars; Balle, Jesper; Fischer-Nielsen, Anne; von Buchwald, Christian

2016-01-01

Therapy with mesenchymal stem cells exhibits potential for the development of novel interventions for many diseases and injuries. The use of mesenchymal stem cells in regenerative therapy for vocal fold scarring exhibited promising results to reduce stiffness and enhance the biomechanical properties of injured vocal folds. This study evaluated the biomechanical effects of mesenchymal stem cell therapy for the treatment of vocal fold scarring. PubMed, Embase, the Cochrane Library and Google Scholar were searched. Controlled studies that assessed the biomechanical effects of mesenchymal stem cell therapy for the treatment of vocal fold scarring were included. Primary outcomes were viscoelastic properties and mucosal wave amplitude. Seven preclinical animal studies (n = 152 single vocal folds) were eligible for inclusion. Evaluation of viscoelastic parameters revealed a decreased dynamic viscosity (η') and elastic modulus (G'), i.e., decreased resistance and stiffness, in scarred vocal folds treated with mesenchymal stem cells compared to non-treated scarred vocal folds. Mucosal wave amplitude was increased in scarred vocal folds treated with mesenchymal stem cells vs. non-treated scarred vocal folds. The results from these studies suggest an increased regenerative effect of therapy with mesenchymal stem cells for scarred vocal folds and are encouraging for further clinical studies.

New strategies for improving stem cell therapy in ischemic heart disease.

PubMed

Huang, Peisen; Tian, Xiaqiu; Li, Qing; Yang, Yuejin

2016-11-01

Stem cell therapy is a promising approach to the treatment of ischemic heart disease via replenishing cell loss after myocardial infarction. Both preclinical studies and clinical trials have indicated that cardiac function improved consistently, but very modestly after cell-based therapy. This mainly attributed to low cell survival rate, engraftment and functional integration, which became the major challenges to regenerative medicine. In recent years, several new cell types have been developed to regenerate cardiomyocytes and novel delivery approaches helped to increase local cell retention. New strategies, such as cell pretreatment, gene-based therapy, tissue engineering, extracellular vesicles application and immunologic regulation, have surged and brought about improved cell survival and functional integration leading to better therapeutic effects after cell transplantation. In this review, we summarize these new strategies targeting at challenges of cardiac regenerative medicine and discuss recent evidences that may hint their effectiveness in the future clinical settings.

Advances in Bone Marrow Stem Cell Therapy for Retinal Dysfunction

PubMed Central

Park, Susanna S.; Moisseiev, Elad; Bauer, Gerhard; Anderson, Johnathon D.; Grant, Maria B.; Zam, Azhar; Zawadzki, Robert J.; Werner, John S.; Nolta, Jan A.

2016-01-01

The most common cause of untreatable vision loss is dysfunction of the retina. Conditions, such as age-related macular degeneration, diabetic retinopathy and glaucoma remain leading causes of untreatable blindness worldwide. Various stem cell approaches are being explored for treatment of retinal regeneration. The rationale for using bone marrow stem cells to treat retinal dysfunction is based on preclinical evidence showing that bone marrow stem cells can rescue degenerating and ischemic retina. These stem cells have primarily paracrine trophic effects although some cells can directly incorporate into damaged tissue. Since the paracrine trophic effects can have regenerative effects on multiple cells in the retina, the use of this cell therapy is not limited to a particular retinal condition. Autologous bone marrow-derived stem cells are being explored in early clinical trials as therapy for various retinal conditions. These bone marrow stem cells include mesenchymal stem cells, mononuclear cells and CD34+ cells. Autologous therapy requires no systemic immunosuppression or donor matching. Intravitreal delivery of CD34+ cells and mononuclear cells appears to be tolerated and is being explored since some of these cells can home into the damaged retina after intravitreal administration. The safety of intravitreal delivery of mesenchymal stem cells has not been well established. This review provides an update of the current evidence in support of the use of bone marrow stem cells as treatment for retinal dysfunction. The potential limitations and complications of using certain forms of bone marrow stem cells as therapy are discussed. Future directions of research include methods to optimize the therapeutic potential of these stem cells, non-cellular alternatives using extracellular vesicles, and in vivo high-resolution retinal imaging to detect cellular changes in the retina following cell therapy. PMID:27784628

Near-infrared emitting fluorescent nanocrystals-labeled natural killer cells as a platform technology for the optical imaging of immunotherapeutic cells-based cancer therapy

NASA Astrophysics Data System (ADS)

Taik Lim, Yong; Cho, Mi Young; Noh, Young-Woock; Chung, Jin Woong; Chung, Bong Hyun

2009-11-01

This study describes the development of near-infrared optical imaging technology for the monitoring of immunotherapeutic cell-based cancer therapy using natural killer (NK) cells labeled with fluorescent nanocrystals. Although NK cell-based immunotherapeutic strategies have drawn interest as potent preclinical or clinical methods of cancer therapy, there are few reports documenting the molecular imaging of NK cell-based cancer therapy, primarily due to the difficulty of labeling of NK cells with imaging probes. Human natural killer cells (NK92MI) were labeled with anti-human CD56 antibody-coated quantum dots (QD705) for fluorescence imaging. FACS analysis showed that the NK92MI cells labeled with anti-human CD56 antibody-coated QD705 have no effect on the cell viability. The effect of anti-human CD56 antibody-coated QD705 labeling on the NK92MI cell function was investigated by measuring interferon gamma (IFN- γ) production and cytolytic activity. Finally, the NK92MI cells labeled with anti-human CD56 antibody-coated QD705 showed a therapeutic effect similar to that of unlabeled NK92MI cells. Images of intratumorally injected NK92MI cells labeled with anti-human CD56 antibody-coated could be acquired using near-infrared optical imaging both in vivo and in vitro. This result demonstrates that the immunotherapeutic cells labeled with fluorescent nanocrystals can be a versatile platform for the effective tracking of injected therapeutic cells using optical imaging technology, which is very important in cell-based cancer therapies.

Intravenous apoptotic cell infusion as a cell-based therapy toward improving hematopoietic cell transplantation outcome.

PubMed

Saas, Philippe; Gaugler, Béatrice; Perruche, Sylvain

2010-10-01

Allogeneic hematopoietic cell transplantation (AHCT) is an efficient therapy for different malignant and nonmalignant hematological diseases. However, the use of this therapeutic approach is still limited by some severe toxic side effects, mainly graft-versus-host disease (GvHD). Today, the risk of fatal GvHD restrains the wider application of AHCT to many patients in need of an effective therapy for their high-risk hematologic malignancies. Thus, new strategies, including cell-based therapy approaches, are required. We propose to use intravenous donor apoptotic leukocyte infusion to improve AHCT outcome. In experimental AHCT models, we demonstrated that intravenous apoptotic leukocyte infusion, simultaneously with allogeneic bone marrow grafts, favors hematopoietic engraftment, prevents allo-immunization, and delays acute GvHD onset. Here, we review the different mechanisms and the potential beneficial effects associated with the immunomodulatory properties of apoptotic cells in the AHCT setting. © 2010 New York Academy of Sciences.

Prodrugs for Gene-Directed Enzyme-Prodrug Therapy (Suicide Gene Therapy)

PubMed Central

2003-01-01

This review focuses on the prodrugs used in suicide gene therapy. These prodrugs need to satisfy a number of criteria. They must be efficient and selective substrates for the activating enzyme, and be metabolized to potent cytotoxins preferably able to kill cells at all stages of the cell cycle. Both prodrugs and their activated species should have good distributive properties, so that the resulting bystander effects can maximize the effectiveness of the therapy, since gene transduction efficiencies are generally low. A total of 42 prodrugs explored for use in suicide gene therapy with 12 different enzymes are discussed, particularly in terms of their physiocochemical properties. An important parameter in determining bystander effects generated by passive diffusion is the lipophilicity of the activated form, a property conveniently compared by diffusion coefficients (log P for nonionizable compounds and log D7 for compounds containing an ionizable centre). Many of the early antimetabolite-based prodrugs provide very polar activated forms that have limited abilities to diffuse across cell membranes, and rely on gap junctions between cells for their bystander effects. Several later studies have shown that more lipophilic, neutral compounds have superior diffusion-based bystander effects. Prodrugs of DNA alkylating agents, that are less cell cycle-specific than antimetabolites and more effective against noncycling tumor cells, appear in general to be more active prodrugs, requiring less prolonged dosing schedules to be effective. It is expected that continued studies to optimize the bystander effects and other properties of prodrugs and the activated species they generate will contribute to improvements in the effectiveness of suicide gene therapy. PMID:12686722

Current Status and Future Development of Cell Transplantation Therapy for Periodontal Tissue Regeneration

PubMed Central

Yoshida, Toshiyuki; Washio, Kaoru; Iwata, Takanori; Okano, Teruo; Ishikawa, Isao

2012-01-01

It has been shown that stem cell transplantation can regenerate periodontal tissue, and several clinical trials involving transplantation of stem cells into human patients have already begun or are in preparation. However, stem cell transplantation therapy is a new technology, and the events following transplantation are poorly understood. Several studies have reported side effects and potential risks associated with stem cell transplantation therapy. To protect patients from such risks, governments have placed regulations on stem cell transplantation therapies. It is important for the clinicians to understand the relevant risks and governmental regulations. This paper describes the ongoing clinical studies, basic research, risks, and governmental controls related to stem cell transplantation therapy. Then, one clinical study is introduced as an example of a government-approved periodontal cell transplantation therapy. PMID:22315604

Status of and candidates for cell therapy in liver cirrhosis: overcoming the "point of no return" in advanced liver cirrhosis.

PubMed

Terai, Shuji; Tsuchiya, Atsunori

2017-02-01

The treatment of liver cirrhosis is currently being standardized and developed specifically to reduce activation of hepatic stellate cells (HSCs), inhibit fibrosis, increase degradation of matrix components, and reduce activated myofibroblasts. Cell therapy can be applied in the treatment of liver cirrhosis; however, the characteristic features of this therapy differ from those of other treatments because of the involvement of a living body origin and production of multiple cytokines, chemokines, matrix metalloproteinases (MMPs), and growth factors. Thus, cell therapies can potentially have multiple effects on the damaged liver, including alleviating liver cirrhosis and stimulating liver regeneration with affecting the host cells. Cell therapies initially involved autologous bone marrow cell infusion, and have recently developed to include the use of specific cells such as mesenchymal stem cells and macrophages. The associated molecular mechanisms, routes of administration, possibility of allogeneic cell therapy, and host conditions appropriate for cell therapies are now being extensively analyzed. In this review, we summarize the status and future prospects of cell therapy for liver cirrhosis.

Anti-metastatic and pro-apoptotic effects elicited by combination photodynamic therapy with sonodynamic therapy on breast cancer both in vitro and in vivo.

PubMed

Wang, Pan; Li, Caifeng; Wang, Xiaobing; Xiong, Wenli; Feng, Xiaolan; Liu, Quanhong; Leung, Albert Wingnang; Xu, Chuanshan

2015-03-01

Sono-Photodynamic therapy (SPDT), a new modality for cancer treatment, is aimed at enhancing anticancer effects by the combination of sonodynamic therapy (SDT) and photodynamic therapy (PDT). In this study, we investigated the antitumor effect and possible mechanisms of Chlorin e6 (Ce6) mediated SPDT (Ce6-SPDT) on breast cancer both in vitro and in vivo. MTT assay revealed that the combined therapy markedly enhanced cell viability loss of breast cancer cell lines (MDA-MB-231, MCF-7 and 4T1) compared with SDT and PDT alone. Propidium iodide/hoechst33342 double staining reflected that 4T1 cells with apoptotic morphological characteristics were significantly increased in groups given combined therapy. Besides, the combined therapy caused obvious mitochondrial membrane potential (MMP) loss at early 1 h post SPDT treatment. The generation of intracellular reactive oxygen species (ROS) detected by flow cytometry was greatly increased in 4T1 cells treated with the combination therapy, and the loss of cell viability and MMP could be effectively rescued by pre-treatment with the ROS scavenger N-acetylcysteine (NAC). Further, Ce6-SPDT markedly inhibited the tumor growth (volume and weight) and lung metastasis in 4T1 tumor-bearing mice, but had no effect on the body weight. Hematoxylin and eosin staining revealed obvious tissue destruction with large spaces in the Ce6-SPDT groups, and TUNEL staining indicated tumor cell apoptosis after treatment. Immunohistochemistry analysis showed that the expression level of VEGF and MMP were significantly decreased in the combined groups. These results indicated that Ce6-mediated SPDT enhanced the antitumor efficacy on 4T1 cells compared with SDT and PDT alone, loss of MMP and generation of ROS might be involved. In addition, Ce6-mediated SPDT significantly inhibited tumor growth and metastasis in mouse breast cancer 4T1 xenograft model, in which MMP-9 and VEGF may play a crucial role.

Versican is a potential therapeutic target in docetaxel-resistant prostate cancer

PubMed Central

Arichi, Naoko; Mitsui, Yozo; Hiraki, Miho; Nakamura, Sigenobu; Hiraoka, Takeo; Sumura, Masahiro; Hirata, Hiroshi; Tanaka, Yuichiro; Dahiya, Rajvir; Yasumoto, Hiroaki; Shiina, Hiroaki

2015-01-01

In the current study, we investigated a combination of docetaxel and thalidomide (DT therapy) in castration-resistant prostate cancer (CRPC) patients. We identified marker genes that predict the effect of DT therapy. Using an androgen-insensitive PC3 cell line, we established a docetaxel-resistant PC-3 cell line (DR-PC3). In DR-PC3 cells, DT therapy stronger inhibited proliferation/viability than docetaxel alone. Based on gene ontology analysis, we found versican as a selective gene. This result with the findings of cDNA microarray and validated by quantitative RT-PCR. In addition, the effect of DT therapy on cell viability was the same as the effect of docetaxel plus versican siRNA. In other words, silencing of versican can substitute for thalidomide. In the clinical setting, versican expression in prostate biopsy samples (before DT therapy) correlated with PSA reduction after DT therapy (p<0.05). Thus targeting versican is a potential therapeutic strategy in docetaxel-resistant prostate cancer. PMID:25859560

Immune-Stimulating Combinatorial Therapy for Prostate Cancer

DTIC Science & Technology

2016-10-01

infiltration. 2. Complementary to the studies in 1, we will sort myeloid, lymphoid and cancer cells from freshly dissociated tumors in cases where enough...MION) hyperthermia and external beam radiation therapy; and, 2) developed methodologies that will be used to elucidate the role of key immune cell ...radiation therapy, immunotherapy, prostate cancer, magnetic nanoparticle(s), abscopal effect, immune cells , tumor-infiltrating immune cells , T- cells , CD4

BMI-1 targeting interferes with patient-derived tumor-initiating cell survival and tumor growth in prostate cancer

PubMed Central

Yusuff, Shamila; Davis, Stephani; Flaherty, Kathleen; Huselid, Eric; Patrizii, Michele; Jones, Daniel; Cao, Liangxian; Sydorenko, Nadiya; Moon, Young-Choon; Zhong, Hua; Medina, Daniel J.; Kerrigan, John; Stein, Mark N.; Kim, Isaac Y.; Davis, Thomas W.; DiPaola, Robert S.; Bertino, Joseph R.; Sabaawy, Hatem E.

2016-01-01

Purpose Current prostate cancer (PCa) management calls for identifying novel and more effective therapies. Self-renewing tumor-initiating cells (TICs) hold intrinsic therapy-resistance and account for tumor relapse and progression. As BMI-1 regulates stem cell self-renewal, impairing BMI-1 function for TICs-tailored therapies appears to be a promising approach. Experimental design We have previously developed a combined immunophenotypic and time-of-adherence assay to identify CD49bhiCD29hiCD44hi cells as human prostate TICs. We utilized this assay with patient derived prostate cancer cells and xenograft models to characterize the effects of pharmacological inhibitors of BMI-1. Results We demonstrate that in cell lines and patient-derived TICs, BMI-1 expression is upregulated and associated with stem cell-like traits. From a screened library, we identified a number of post-transcriptional small molecules that target BMI-1 in prostate TICs. Pharmacological inhibition of BMI-1 in patient-derived cells significantly decreased colony formation in vitro and attenuated tumor initiation in vivo, thereby functionally diminishing the frequency of TICs, particularly in cells resistant to proliferation- and androgen receptor (AR)-directed therapies, without toxic effects on normal tissues. Conclusions Our data offer a paradigm for targeting TICs and support the development of BMI-1-targeting therapy for a more effective PCa treatment. PMID:27307599

Stem cells’ guided gene therapy of cancer: New frontier in personalized and targeted therapy

PubMed Central

Mavroudi, Maria; Zarogoulidis, Paul; Porpodis, Konstantinos; Kioumis, Ioannis; Lampaki, Sofia; Yarmus, Lonny; Malecki, Raf; Zarogoulidis, Konstantinos; Malecki, Marek

2014-01-01

Introduction Diagnosis and therapy of cancer remain to be the greatest challenges for all physicians working in clinical oncology and molecular medicine. The statistics speak for themselves with the grim reports of 1,638,910 men and women diagnosed with cancer and nearly 577,190 patients passed away due to cancer in the USA in 2012. For practicing clinicians, who treat patients suffering from advanced cancers with contemporary systemic therapies, the main challenge is to attain therapeutic efficacy, while minimizing side effects. Unfortunately, all contemporary systemic therapies cause side effects. In treated patients, these side effects may range from nausea to damaged tissues. In cancer survivors, the iatrogenic outcomes of systemic therapies may include genomic mutations and their consequences. Therefore, there is an urgent need for personalized and targeted therapies. Recently, we reviewed the current status of suicide gene therapy for cancer. Herein, we discuss the novel strategy: genetically engineered stem cells’ guided gene therapy. Review of therapeutic strategies in preclinical and clinical trials Stem cells have the unique potential for self renewal and differentiation. This potential is the primary reason for introducing them into medicine to regenerate injured or degenerated organs, as well as to rejuvenate aging tissues. Recent advances in genetic engineering and stem cell research have created the foundations for genetic engineering of stem cells as the vectors for delivery of therapeutic transgenes. Specifically in oncology, the stem cells are genetically engineered to deliver the cell suicide inducing genes selectively to the cancer cells only. Expression of the transgenes kills the cancer cells, while leaving healthy cells unaffected. Herein, we present various strategies to bioengineer suicide inducing genes and stem cell vectors. Moreover, we review results of the main preclinical studies and clinical trials. However, the main risk for therapeutic use of stem cells is their cancerous transformation. Therefore, we discuss various strategies to safeguard stem cell guided gene therapy against iatrogenic cancerogenesis. Perspectives Defining cancer biomarkers to facilitate early diagnosis, elucidating cancer genomics and proteomics with modern tools of next generation sequencing, and analyzing patients’ gene expression profiles provide essential data to elucidate molecular dynamics of cancer and to consider them for crafting pharmacogenomics-based personalized therapies. Streamlining of these data into genetic engineering of stem cells facilitates their use as the vectors delivering therapeutic genes into specific cancer cells. In this realm, stem cells guided gene therapy becomes a promising new frontier in personalized and targeted therapy of cancer. PMID:24860662

Adoptive Cell Therapy for Patients with Melanoma

PubMed Central

Dudley, Mark E.

2011-01-01

Adoptive cell therapy can be an effective treatment for some patients with advanced cancer. This report summarizes clinical trial results from the Surgery Branch, NCI, investigating tumor infiltrating lymphocytes (TIL) and gene engineered peripheral blood T cells for the therapy of patients with melanoma and other solid tumors. PMID:21716716

Modulation of the peripheral immune system after low-dose radon spa therapy: Detailed longitudinal immune monitoring of patients within the RAD-ON01 study.

PubMed

Rühle, Paul F; Wunderlich, Roland; Deloch, Lisa; Fournier, Claudia; Maier, Andreas; Klein, Gerhart; Fietkau, Rainer; Gaipl, Udo S; Frey, Benjamin

2017-03-01

The pain-relieving effects of low-dose radon therapies on patients suffering from chronic painful inflammatory diseases have been described for centuries. Even though it has been suggested that low doses of radiation may attenuate chronic inflammation, the underlying mechanisms remain elusive. Thus, the RAD-ON01 study was initiated to examine the effects of radon spa therapy and its low doses of alpha radiation on the human immune system. In addition to an evaluation of pain parameters, blood was drawn from 100 patients suffering from chronic painful degenerative musculoskeletal diseases before as well as 6, 12, 18, and 30 weeks after the start of therapy. We verified significant long-term pain reduction for the majority of patients which was accompanied by modulations of the peripheral immune cells. Detailed immune monitoring was performed using a multicolor flow cytometry-based whole blood assay. After therapy, the major immune cells were only marginally affected. Nevertheless, a small but long-lasting increase in T cells and monocytes was observed. Moreover, neutrophils, eosinophils and, in particular, dendritic cells were temporarily modulated after therapy. Regarding the immune cell subsets, cytotoxic T and NK cells, in particular, were altered. However, the most prominent effects were identified in a strong reduction of the activation marker CD69 on T, B, and NK cells. Simultaneously, the percentage of HLA-DR + T cells was elevated after therapy. The RAD-ON01 study showed for the first time a modulation of the peripheral immune cells following standard radon spa therapy. These modulations are in line with attenuation of inflammation.

Adoptive natural killer cell therapy is effective in reducing pulmonary metastasis of Ewing sarcoma

PubMed Central

Tong, Alexander A.; Hashem, Hasan; Eid, Saada; Allen, Frederick; Kingsley, Daniel

2017-01-01

ABSTRACT The survival of patients with metastatic or relapsed Ewing sarcoma (ES) remains dismal despite intensification of combination chemotherapy and radiotherapy, precipitating the need for novel alternative therapies with minimal side effects. Natural killer (NK) cells are promising additions to the field of cellular immunotherapy. Adoptive NK cell therapy has shown encouraging results in hematological malignancies. Despite these initial promising successes, however, NK cell therapy for solid tumors remains to be investigated using in vivo tumor models. The purpose of this study is to evaluate the efficacy of ex vivo expanded human NK cells in controlling primary and metastatic ES tumor growth in vitro and in vivo. Using membrane-bound IL-21 containing K562 (K562-mbIL-21) expansion platform, we were able to obtain sufficient numbers of expanded NK (eNK) cells that display favorable activation phenotypes and inflammatory cytokine secretion, along with a strong in vitro cytotoxic effect against ES. Furthermore, eNK therapy significantly decreased lung metastasis without any significant therapeutic effect in limiting primary tumor growth in an in vivo xenograft model. Our data demonstrate that eNK may be effective against pulmonary metastatic ES, but challenges remain to direct proper trafficking and augmenting the cytotoxic function of eNK to target primary tumor sites. PMID:28507811

iPS-cell derived dendritic cells and macrophages for cancer therapy.

PubMed

Senju, Satoru

2016-08-01

Antibody-based anti-cancer immunotherapy was recently recognized as one of the truly effective therapies for cancer patients. Antibodies against cell surface cancer antigens, such as CD20, and also those against immune-inhibitory molecules called "immune checkpoint blockers", such as CTLA4 or PD1, have emerged. Large-scale clinical trials have confirmed that, in some cases, antibody-based drugs are superior to conventional chemotherapeutic agents. These antibody-based drugs are now being manufactured employing a mass-production system by pharmaceutical companies. Anti-cancer therapy by immune cells, i.e. cell-based immunotherapy, is expected to be more effective than antibody therapy, because immune cells can recognize, infiltrate, and act in cancer tissues more directly than antibodies. In order to achieve cell-based anti-cancer immunotherapy, it is necessary to develop manufacturing systems for mass-production of immune cells. Our group has been studying immunotherapy with myeloid cells derived from ES cells or iPS cells. These pluripotent stem cells can be readily propagated under constant culture conditions, with expansion into a large quantity. We consider these stem cells to be the most suitable cellular source for mass-production of immune cells. This review introduces our studies on anti-cancer therapy with iPS cell-derived dendritic cells and iPS cell-derived macrophages.

Combination effect of oncolytic adenovirus therapy and herpes simplex virus thymidine kinase/ganciclovir in hepatic carcinoma animal models

PubMed Central

Zheng, Fei-qun; Xu, Yin; Yang, Ren-jie; Wu, Bin; Tan, Xiao-hua; Qin, Yi-de; Zhang, Qun-wei

2009-01-01

Aim: Oncolytic adenovirus, also called conditionally replicating adenovirus (CRAD), can selectively propagate in tumor cells and cause cell lysis. The released viral progeny can infect neighboring cancer cells, initiating a cascade that can lead to the ultimate destruction of the tumor. Suicide gene therapy using herpes simplex virus thymidine kinase (HSV-TK) and ganciclovir (GCV) offers a potential treatment strategy for cancer and is undergoing preclinical trials for a variety of tumors. We hypothesized that HSV-TK gene therapy combined with oncolytic adenoviral therapy would have an enhanced effect compared with the individual effects of the therapies and is a potential novel therapeutic strategy to treat liver cancer. Methods: To address our hypothesis, a novel CRAD was created, which consisted of a telomerase-dependent oncolytic adenovirus engineered to express E1A and HSV-TK genes (Ad-ETK). The combined effect of Ad-ETK and GCV was assessed both in vitro and in vivo in nude mice bearing HepG2 cell-derived tumors. Expression of the therapeutic genes by the transduced tumor cells was analyzed by RT-PCR and Western blotting. Results: We confirmed that Ad-ETK had antitumorigenic effects on human hepatocellular carcinoma (HCC) both in vitro and in vivo, and the TK/GCV system enhanced oncolytic adenoviral therapy. We confirmed that both E1A and HSV-TK genes were expressed in vivo. Conclusion: The Ad-ETK construct should provide a relatively safe and selective approach to killing cancer cells and should be investigated as an adjuvant therapy for hepatocellular carcinoma. PMID:19363518

Could low level laser therapy and highly active antiretroviral therapy lead to complete eradication of HIV-1 in vitro?

NASA Astrophysics Data System (ADS)

Lugongolo, Masixole Yvonne; Manoto, Sello Lebohang; Ombinda-Lemboumba, Saturnin; Maaza, Malik; Mthunzi-Kufa, Patience

2017-02-01

Human immunodeficiency virus (HIV-1) infection remains a major health problem despite the use of highly active antiretroviral therapy (HAART), which has greatly reduced mortality rates. Due to the unavailability of an effective vaccine or a treatment that would completely eradicate the virus, the quest for new and combination therapies continues. In this study we explored the influence of Low Level Laser Therapy (LLLT) in HIV-1 infected and uninfected cells. Literature reports LLLT as widely used to treat different medical conditions such as diabetic wounds, sports injuries and others. The technique involves exposure of cells or tissue to low levels of red and near infrared laser light. Both HIV infected and uninfected cells were laser irradiated at a wavelength of 640 nm with fluencies ranging from 2 to 10 J/cm2 and cellular responses were assessed 24 hours post laser treatment. In our studies, laser therapy had no inhibitory effects in HIV-1 uninfected cells as was indicated by the cell morphology and proliferation results. However, laser irradiation enhanced cell apoptosis in HIV-1 infected cells as the laser fluencies increased. This led to further studies in which laser irradiation would be conducted in the presence of HAART to determine whether HAART would minimise the detrimental effects of laser irradiation in infected cells.

[Insulin pump in type 2 diabetes: B-cell focused treatment].

PubMed

Picková, Klára; Rušavý, Zdeněk

Type 2 diabetes is a disorder characterized by insulin resistance and progressive deterioration of B-cell insulin secretion. B-cell protective strategies for lowering glucolipotoxicity by rapid achievement of normoglycemia using exogenous insulin improve their function and prolong diabetes remission. Insulin pump is an effective treatment method in newly diagnosed diabetes, where even short-term pump therapy is B-cell protective. Combination therapy with insulin pump and antidiabetics targeting the incretin system acts in synergy to protect the B-cell. While the positive effect of insulin pump is apparent even a year after stopping the therapy, the effect of incretins lasts only while on the medication. Short-term insulin treatment, especially delivered by insulin pump, is an effective method of B-cell protection in recent type 2 diabetes.Key words: B-cell function - diabetes mellitus - insulin pump - insulin resistance - type 2 diabetes.

Potential for Enhanced Therapeutic Activity of Biological Cancer Therapies with Doxycycline Combination

PubMed Central

Tang, Hui; Sampath, Padma; Yan, Xinmin; Thorne, Stephen H

2012-01-01

Despite significant strides made in the clinical translation of adoptive immune cell therapies, it is apparent that many tumors incorporate strategies to avoid recognition by receptors expressed on the immune cells, such as NKG2D. Strategies that stabilize the expression of ligands for these receptors may enhance the therapeutic potential of these and related therapies. Doxycycline inhibits matrix metalloproteinases (MMPs) that act to cleave the extracellular domain of MICA/B, ligands for the NKG2D receptor. Doxycycline treatment blocked shedding of MICA/B from a panel of human tumor cells, but also acted to increase their expression and cell surface translocation, possibly through its action on ATM. This meant that many tumor cells displayed increased MICA/B expression and enhanced susceptibility to CIK cells. Interestingly, doxycycline also selectively enhanced the replication of oncolytic vaccinia in many tumor cell lines, leading to increased sensitivity to these therapies. Combination (CIK-oncolytic vaccinia) therapies used in conjunction with doxycyline led to increased anti-tumor effects. The unexpected and pleiotropic beneficial anti-tumor effects of doxycycline on both immune cell and oncolytic viral therapies make it an excellent candidate for rapid clinical testing. PMID:23282955

Genetic modification of hematopoietic stem cells: recent advances in the gene therapy of inherited diseases.

PubMed

Bueren, Juan A; Guenechea, Guillermo; Casado, José A; Lamana, María Luisa; Segovia, José C

2003-01-01

Hematopoietic stem cells constitute a rare population of precursor cells with remarkable properties for being used as targets in gene therapy protocols. The last years have been particularly productive both in the fields of gene therapy and stem cell biology. Results from ongoing clinical trials have shown the first unquestionable clinical benefits of immunodeficient patients transplanted with genetically modified autologous stem cells. On the other hand, severe side effects in a few patients treated with gene therapy have also been reported, indicating the usefulness of further improving the vectors currently used in gene therapy clinical trials. In the field of stem cell biology, evidence showing the plastic potential of adult hematopoietic stem cells and data indicating the multipotency of adult mesenchymal precursor cells have been presented. Also, the generation of embryonic stem cells by means of nuclear transfer techniques has appeared as a new methodology with direct implications in gene therapy.

Mechanisms of cellular therapy in respiratory diseases.

PubMed

Abreu, Soraia C; Antunes, Mariana A; Pelosi, Paolo; Morales, Marcelo M; Rocco, Patricia R M

2011-09-01

Stem cells present a variety of clinical implications in the lungs. According to their origin, these cells can be divided into embryonic and adult stem cells; however, due to the important ethical and safety limitations that are involved in the embryonic stem cell use, most studies have chosen to focus on adult stem cell therapy. This article aims to present and clarify the recent advances in the field of stem cell biology, as well as to highlight the effects of mesenchymal stem cell (MSC) therapy in the context of acute lung injury/acute respiratory distress syndrome and chronic disorders such as lung fibrosis and chronic obstructive pulmonary disease. For this purpose, we performed a critical review of adult stem cell therapies, covering the main clinical and experimental studies published in Pubmed databases in the past 11 years. Different characteristics were extracted from these articles, such as: the experimental model, strain, cellular type and administration route used as well as the positive or negative effects obtained. There is evidence for beneficial effects of MSC on lung development, repair, and remodeling. The engraftment in the injured lung does not occur easily, but several studies report that paracrine factors can be effective in reducing inflammation and promoting tissue repair. MSC releases several growth factors and anti-inflammatory cytokines that regulate endothelial and epithelial permeability and reduce the severity of inflammation. A better understanding of the mechanisms that control cell division and differentiation, as well as of their paracrine effects, is required to enable the optimal use of bone marrow-derived stem cell therapy to treat human respiratory diseases.

Towards Predicting the Response of a Solid Tumour to Chemotherapy and Radiotherapy Treatments: Clinical Insights from a Computational Model

PubMed Central

Powathil, Gibin G.; Adamson, Douglas J. A.; Chaplain, Mark A. J.

2013-01-01

In this paper we use a hybrid multiscale mathematical model that incorporates both individual cell behaviour through the cell-cycle and the effects of the changing microenvironment through oxygen dynamics to study the multiple effects of radiation therapy. The oxygenation status of the cells is considered as one of the important prognostic markers for determining radiation therapy, as hypoxic cells are less radiosensitive. Another factor that critically affects radiation sensitivity is cell-cycle regulation. The effects of radiation therapy are included in the model using a modified linear quadratic model for the radiation damage, incorporating the effects of hypoxia and cell-cycle in determining the cell-cycle phase-specific radiosensitivity. Furthermore, after irradiation, an individual cell's cell-cycle dynamics are intrinsically modified through the activation of pathways responsible for repair mechanisms, often resulting in a delay/arrest in the cell-cycle. The model is then used to study various combinations of multiple doses of cell-cycle dependent chemotherapies and radiation therapy, as radiation may work better by the partial synchronisation of cells in the most radiosensitive phase of the cell-cycle. Moreover, using this multi-scale model, we investigate the optimum sequencing and scheduling of these multi-modality treatments, and the impact of internal and external heterogeneity on the spatio-temporal patterning of the distribution of tumour cells and their response to different treatment schedules. PMID:23874170

Cisplatin and photodynamic therapy exert synergistic inhibitory effects on small-cell lung cancer cell viability and xenograft tumor growth

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, You-Shuang; Peng, Yin-Bo; Yao, Min

Lung cancer is the leading cause of cancer death worldwide. Small-cell lung cancer (SCLC) is an aggressive type of lung cancer that shows an overall 5-year survival rate below 10%. Although chemotherapy using cisplatin has been proven effective in SCLC treatment, conventional dose of cisplatin causes adverse side effects. Photodynamic therapy, a form of non-ionizing radiation therapy, is increasingly used alone or in combination with other therapeutics in cancer treatment. Herein, we aimed to address whether low dose cisplatin combination with PDT can effectively induce SCLC cell death by using in vitro cultured human SCLC NCI-H446 cells and in vivo tumor xenograft model.more » We found that both cisplatin and PDT showed dose-dependent cytotoxic effects in NCI-H446 cells. Importantly, co-treatment with low dose cisplatin (1 μM) and PDT (1.25 J/cm{sup 2}) synergistically inhibited cell viability and cell migration. We further showed that the combined therapy induced a higher level of intracellular ROS in cultured NCI-H446 cells. Moreover, the synergistic effect by cisplatin and PDT was recapitulated in tumor xenograft as revealed by a more robust increase in the staining of TUNEL (a marker of cell death) and decrease in tumor volume. Taken together, our findings suggest that low dose cisplatin combination with PDT can be an effective therapeutic modality in the treatment of SCLC patients.« less

Rapamycin/IL-2 combination therapy in patients with type 1 diabetes augments Tregs yet transiently impairs β-cell function.

PubMed

Long, S Alice; Rieck, Mary; Sanda, Srinath; Bollyky, Jennifer B; Samuels, Peter L; Goland, Robin; Ahmann, Andrew; Rabinovitch, Alex; Aggarwal, Sudeepta; Phippard, Deborah; Turka, Laurence A; Ehlers, Mario R; Bianchine, Peter J; Boyle, Karen D; Adah, Steven A; Bluestone, Jeffrey A; Buckner, Jane H; Greenbaum, Carla J

2012-09-01

Rapamycin/interleukin-2 (IL-2) combination treatment of NOD mice effectively treats autoimmune diabetes. We performed a phase 1 clinical trial to test the safety and immunologic effects of rapamycin/IL-2 combination therapy in type 1 diabetic (T1D) patients. Nine T1D subjects were treated with 2-4 mg/day rapamycin orally for 3 months and 4.5 × 10(6) IU IL-2 s.c. three times per week for 1 month. β-Cell function was monitored by measuring C-peptide. Immunologic changes were monitored using flow cytometry and serum analyses. Regulatory T cells (Tregs) increased within the first month of therapy, yet clinical and metabolic data demonstrated a transient worsening in all subjects. The increase in Tregs was transient, paralleling IL-2 treatment, whereas the response of Tregs to IL-2, as measured by STAT5 phosphorylation, increased and persisted after treatment. No differences were observed in effector T-cell subset frequencies, but an increase in natural killer cells and eosinophils occurred with IL-2 therapy. Rapamycin/IL-2 therapy, as given in this phase 1 study, resulted in transient β-cell dysfunction despite an increase in Tregs. Such results highlight the difficulties in translating therapies to the clinic and emphasize the importance of broadly interrogating the immune system to evaluate the effects of therapy.

The effect of extracorporeal photopheresis alone or in combination therapy on circulating CD4+Foxp3+CD25- T-cells in patients with leukemic cutaneous T-cell lymphoma

PubMed Central

Shiue, Lisa H.; Couturier, Jacob; Lewis, Dorothy E.; Wei, Caimiao; Ni, Xiao; Duvic, Madeleine

2015-01-01

Purpose Extracorporeal photopheresis (ECP) alone or in combination therapy is effective for treatment of leukemic cutaneous T-cell lymphoma (L-CTCL), but its mechanism(s) of action remain unclear. This study was designed to investigate the effect of ECP on regulatory T-cell and CD8+ T-cells in L-CTCL patients. Experimental Design Peripheral blood from 18 L-CTCL patients at baseline, Day 2, 1-month, 3-month, and 6-month post-ECP therapy were analyzed by flow cytometry for CD4+CD25+/high, CD4+Foxp3+CD25+/-, CD3+CD8+, CD3+CD8+CD69+, and CD3+CD8+IFN-γ+ T-cells. Clinical responses were assessed and correlated with changes in these T-cell subsets. Results Twelve of 18 patients achieved clinical responses. The average baseline number of CD4+CD25+/high T-cells of PBMCs in L-CTCL patients was normal (2.2%), but increased at 6-month post-therapy (4.3%, p<0.01). The average baseline number of CD4+Foxp3+ T-cells out of CD4+ T-cells in 9 evaluable patients was high (66.8±13.7%), mostly CD25 negative. The levels of CD4+Foxp3+ T cells in responders were higher (n=6, 93.1±5.7%) than non-responders (n=3, 14.2±16.0%, p<0.01), and they declined in parallel with malignant T-cells. The numbers of CD3+CD8+CD69+ and CD3+CD8+ IFN-γ+ T-cells increased at 3-month post-therapy in 5 of 6 patients studied. Conclusions ECP alone or in combination therapy might be effective in L-CTCL patients whose malignant T-cells have a CD4+Foxp3+CD25- phenotype. PMID:25772268

Enhanced effects by 4-phenylbutyrate in combination with RTK inhibitors on proliferation in brain tumor cell models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marino, Ana-Maria; Center for Molecular Medicine CMM, Karolinska University Hospital, Stockholm; Sofiadis, Anastasios

2011-07-22

Highlights: {yields} The histone deacetylase inhibitor 4-phenylbutyrate substantially enhance efficacy of the receptor tyrosine kinase inhibitors gefitinib or vandetanib in glioma and medulloblastoma cell lines. {yields} Cell death increases and clonogenic survival is reduced in the combination treatments, over mono-therapy. {yields} Combination treatments with these drugs may improve clinical outcome for cancer therapy. -- Abstract: We have investigated in vitro effects of anticancer therapy with the histone deacetylase inhibitor (HDACi) 4-phenylbutyrate (4-PB) combined with receptor tyrosine kinase inhibitors (RTKi) gefitinib or vandetanib on the survival of glioblastoma (U343MGa) and medulloblastoma (D324Med) cells. In comparison with individual effects of these drugs,more » combined treatment with gefitinib/4-PB or vandetanib/4-PB resulted in enhanced cell killing and reduced clonogenic survival in both cell lines. Our results suggest that combined treatment using HDACi and RTKi may beneficially affect the outcome of cancer therapy.« less

Effective cancer laser-therapy design through the integration of nanotechnology and computational treatment planning models

NASA Astrophysics Data System (ADS)

Fisher, Jessica W.; Rylander, Marissa Nichole

2008-02-01

Laser therapies can provide a minimally invasive treatment alternative to surgical resection of tumors. However, the effectiveness of these therapies is limited due to nonspecific heating of target tissue which often leads to healthy tissue injury and extended treatment durations. These therapies can be further compromised due to heat shock protein (HSP) induction in tumor regions where non-lethal temperature elevation occurs, thereby imparting enhanced tumor cell viability and resistance to subsequent chemotherapy and radiation treatments. Introducing multi-walled nanotubes (MWNT) into target tissue prior to laser irradiation increases heating selectivity permitting more precise thermal energy delivery to the tumor region and enhances thermal deposition thereby increasing tumor injury and reducing HSP expression induction. This study investigated the impact of MWNT inclusion in untreated and laser irradiated monolayer cell culture and cell phantom model. Cell viability remained high for all samples with MWNT inclusion and cells integrated into alginate phantoms, demonstrating the non-toxic nature of both MWNTs and alginate phantom models. Following, laser irradiation samples with MWNT inclusion exhibited dramatic temperature elevations and decreased cell viability compared to samples without MWNT. In the cell monolayer studies, laser irradiation of samples with MWNT inclusion experienced up-regulated HSP27, 70 and 90 expression as compared to laser only or untreated samples due to greater temperature increases albeit below the threshold for cell death. Further tuning of laser parameters will permit effective cell killing and down-regulation of HSP. Due to optimal tuning of laser parameters and inclusion of MWNT in phantom models, extensive temperature elevations and cell death occurred, demonstrating MWNT-mediated laser therapy as a viable therapy option when parameters are optimized. In conclusion, MWNT-mediated laser therapies show great promise for effective tumor destruction, but require determination of appropriate MWNT characteristics and laser parameters for maximum tumor destruction.

A Combination of Immune Checkpoint Inhibition with Metronomic Chemotherapy as a Way of Targeting Therapy-Resistant Cancer Cells.

PubMed

Kareva, Irina

2017-10-13

Therapeutic resistance remains a major obstacle in treating many cancers, particularly in advanced stages. It is likely that cytotoxic lymphocytes (CTLs) have the potential to eliminate therapy-resistant cancer cells. However, their effectiveness may be limited either by the immunosuppressive tumor microenvironment, or by immune cell death induced by cytotoxic treatments. High-frequency low-dose (also known as metronomic) chemotherapy can help improve the activity of CTLs by providing sufficient stimulation for cytotoxic immune cells without excessive depletion. Additionally, therapy-induced removal of tumor cells that compete for shared nutrients may also facilitate tumor infiltration by CTLs, further improving prognosis. Metronomic chemotherapy can also decrease the number of immunosuppressive cells in the tumor microenvironment, including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Immune checkpoint inhibition can further augment anti-tumor immune responses by maintaining T cells in an activated state. Combining immune checkpoint inhibition with metronomic administration of chemotherapeutic drugs may create a synergistic effect that augments anti-tumor immune responses and clears metabolic competition. This would allow immune-mediated elimination of therapy-resistant cancer cells, an effect that may be unattainable by using either therapeutic modality alone.

Cost-Effectiveness of Earlier Initiation of Antiretroviral Therapy for Uninsured HIV-Infected Adults

PubMed Central

Schackman, Bruce R.; Goldie, Sue J.; Weinstein, Milton C.; Losina, Elena; Zhang, Hong; Freedberg, Kenneth A.

2001-01-01

Objectives. This study was designed to examine the societal cost-effectiveness and the impact on government payers of earlier initiation of antiretroviral therapy for uninsured HIV-infected adults. Methods. A state-transition simulation model of HIV disease was used. Data were derived from the Multicenter AIDS Cohort Study, published randomized trials, and medical care cost estimates for all government payers and for Massachusetts, New York, and Florida. Results. Quality-adjusted life expectancy increased from 7.64 years with therapy initiated at 200 CD4 cells/μL to 8.21 years with therapy initiated at 500 CD4 cells/μL. Initiating therapy at 500 CD4/μL was a more efficient use of resources than initiating therapy at 200 CD4/μL and had an incremental cost-effectiveness ratio of $17 300 per quality-adjusted life-year gained, compared with no therapy. Costs to state payers in the first 5 years ranged from $5500 to $24 900 because of differences among the states in the availability of federal funds for AIDS drug assistance programs. Conclusions. Antiretroviral therapy initiated at 500 CD4 cells/μL is cost-effective from a societal perspective compared with therapy initiated later. States should consider Medicaid waivers to expand access to early therapy. PMID:11527782

Chimeric Antigen Receptor T-Cell Therapy for the Community Oncologist

PubMed Central

Levine, Bruce L.

2016-01-01

The field of cancer immunotherapy has rapidly progressed in the past decade as several therapeutic modalities have entered into the clinic. One such immunotherapy that has shown promise in the treatment of cancer is the use of chimeric antigen receptor (CAR)-modified T lymphocytes. CARs are engineered receptors constructed from antigen recognition regions of antibodies fused to T-cell signaling and costimulatory domains that can be used to reprogram a patient’s T cells to specifically target tumor cells. CAR T-cell therapy has demonstrated sustained complete responses for some patients with advanced leukemia, and a number of CAR therapies are being evaluated in clinical studies. CAR T-cell therapy-associated toxicities, including cytokine release syndrome, macrophage activation syndrome, and tumor lysis syndrome, have been observed and effectively managed in the clinic. In patients with significant clinical responses, sustained B-cell aplasia has also been observed and is a marker of CAR T-cell persistence that might provide long-term disease control. Education on CAR T-cell therapy efficacy and safety management is critical for clinicians and patients who are considering this novel type of treatment. In the present report, the current landscape of CAR T-cell therapy, the effective management of patients undergoing treatment, and which patients are the most suitable candidates for current trials are discussed. Implications for Practice: The present report describes the current status of chimeric antigen receptor (CAR) T lymphocytes as an immunotherapy for patients with relapsed or refractory B-cell malignancies. CAR T cells targeting CD19, a protein expressed on many B-cell malignancies, typically induce high complete response rates in patients with B-cell leukemia or lymphoma who have very limited therapeutic options. Recent clinical trial results of CD19 CAR T-cell therapies and the management of CAR T-cell-associated adverse events are discussed. The present report will therefore inform physicians regarding the efficacy and safety of CAR T cells as a therapy for B-cell malignancies. PMID:27009942

Hypoxia-activated chemotherapeutic TH-302 enhances the effects of VEGF-A inhibition and radiation on sarcomas.

PubMed

Yoon, C; Lee, H-J; Park, D J; Lee, Y-J; Tap, W D; Eisinger-Mathason, T S K; Hart, C P; Choy, E; Simon, M C; Yoon, S S

2015-06-30

Human sarcomas with a poor response to vascular endothelial growth factor-A (VEGF-A) inhibition and radiation therapy (RT) have upregulation of hypoxia-inducible factor 1α (HIF-1α) and HIF-1α target genes. This study examines the addition of the hypoxia-activated chemotherapy TH-302 to VEGF-A inhibition and RT (a.k.a. trimodality therapy). Trimodality therapy was examined in two xenograft models and in vitro in tumour endothelial cells and sarcoma cell lines. In both mouse models, VEGF-A inhibition and radiation showed greater efficacy than either therapy alone in slowing sarcoma growth. When TH-302 was added, this trimodality therapy completely blocked tumour growth with tumours remaining dormant for over 3 months after cessation of therapy. Trimodality therapy caused 2.6- to 6.2-fold more endothelial cell-specific apoptosis than bimodality therapies, and microvessel density and HIF-1α activity were reduced to 11-13% and 13-20% of control, respectively. When trimodality therapy was examined in vitro, increases in DNA damage and apoptosis were much more pronounced in tumour endothelial cells compared with that in sarcoma cells, especially under hypoxia. The combination of TH-302, VEGF-A inhibition, and RT is highly effective in preclinical models of sarcoma and is associated with increased DNA damage and apoptosis in endothelial cells and decreased HIF-1α activity.

Pharmacoeconomic analysis of consolidation therapy with pemetrexed after first-line chemotherapy for non-small cell lung cancer.

PubMed

Tsuchiya, Takanori; Fukuda, Takashi; Furuiye, Masashi; Kawabuchi, Koichi

2011-12-01

Prolongation of progression-free survival and overall survival have been reported with consolidation therapy after first-line chemotherapy in non-small cell lung cancer, but only a few pharmacoeconomic analyses have been performed. We performed a pharmacoeconomic analysis to assess the cost-effectiveness of consolidation therapy with pemetrexed compared with non-consolidation therapy. We developed a Markov model to evaluate the incremental cost-effectiveness ratio (ICER) of consolidation therapy with pemetrexed compared with non-consolidation therapy based on previous reports. We analyzed all histology groups together, and individually analyzed non-squamous cell carcinoma, in which pemetrexed has been shown to be more effective, and squamous cell carcinoma, in which pemetrexed has been shown to be less effective. We conducted a Monte-Carlo simulation to assess the uncertainty for our analysis model and the willingness to pay using thresholds. The ICER for consolidation therapy with pemetrexed was about US$ 109,024/life years gained (LYG) (JPY 12.5 million/LYG) and US$ 203,022/quality-adjusted life years (QALY) (JPY 23.3 million/QALY) for all histology. For non-squamous cell carcinoma, respective values were US$ 80,563/LYG (JPY 9.3 million/LYG) and US$ 150,115/QALY (JPY 17.3 million/QALY). Both % of probability at a threshold of JPY 5.0 million (US$ 43,478) for all histology and non-squamous cell carcinoma were less than 0.1%. This result indicates that it is difficult to use consolidation therapy as the standard of care in Japan while being covered by general medical insurance. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Combining Adoptive Cell Therapy with Cytomegalovirus-Based Vaccine Is Protective against Solid Skin Tumors.

PubMed

Grenier, Jeremy M; Yeung, Stephen T; Qiu, Zhijuan; Jellison, Evan R; Khanna, Kamal M

2017-01-01

Despite many years of research, cancer vaccines have largely been ineffective in the treatment of established cancers. Many barriers to immune-mediated destruction of malignant cells exist, and these likely limit the efficacy of cancer vaccines. In this study, we sought to enhance the efficacy of a cytomegalovirus (CMV)-based vaccine targeting melanoma by combining vaccination with other forms of immunotherapy. Adoptive cell therapy in humans and in animal models has been shown to be effective for tumor regression. Thus, in this study, we assessed whether CMV-based vaccines in combination with adoptively transferred antitumor T cells could provide greater antitumor protection than either therapy alone. Our results show that adoptive cell therapy greatly enhanced the antitumor effects of CMV-based vaccines targeting the foreign model antigen, OVA, or the melanoma differentiation antigen, gp100. Combination adoptive cell therapy and vaccination induced the upregulation of the inhibitory ligands, PD-L1, and Qa-1 b , on B16 tumor cells. This expression paralleled the infiltration of tumors by vaccine-stimulated T cells which also expressed high levels of the receptors PD-1 and NKG2A/C/E, suggesting a potential mechanism of tumor immune evasion. Surprisingly, therapeutic blockade of the PD-1/PD-L1 and NKG2A/Qa-1 b axes did not delay tumor growth following vaccination, suggesting that the presence of inhibitory ligands within malignant tissue may not be an effective biomarker for successful combination therapy with CMV-based vaccines. Overall, our studies show that therapeutic CMV-based vaccines in combination with adoptive T cell transfer alone are effective for tumor rejection.

Combining Adoptive Cell Therapy with Cytomegalovirus-Based Vaccine Is Protective against Solid Skin Tumors

PubMed Central

Grenier, Jeremy M.; Yeung, Stephen T.; Qiu, Zhijuan; Jellison, Evan R.; Khanna, Kamal M.

2018-01-01

Despite many years of research, cancer vaccines have largely been ineffective in the treatment of established cancers. Many barriers to immune-mediated destruction of malignant cells exist, and these likely limit the efficacy of cancer vaccines. In this study, we sought to enhance the efficacy of a cytomegalovirus (CMV)-based vaccine targeting melanoma by combining vaccination with other forms of immunotherapy. Adoptive cell therapy in humans and in animal models has been shown to be effective for tumor regression. Thus, in this study, we assessed whether CMV-based vaccines in combination with adoptively transferred antitumor T cells could provide greater antitumor protection than either therapy alone. Our results show that adoptive cell therapy greatly enhanced the antitumor effects of CMV-based vaccines targeting the foreign model antigen, OVA, or the melanoma differentiation antigen, gp100. Combination adoptive cell therapy and vaccination induced the upregulation of the inhibitory ligands, PD-L1, and Qa-1b, on B16 tumor cells. This expression paralleled the infiltration of tumors by vaccine-stimulated T cells which also expressed high levels of the receptors PD-1 and NKG2A/C/E, suggesting a potential mechanism of tumor immune evasion. Surprisingly, therapeutic blockade of the PD-1/PD-L1 and NKG2A/Qa-1b axes did not delay tumor growth following vaccination, suggesting that the presence of inhibitory ligands within malignant tissue may not be an effective biomarker for successful combination therapy with CMV-based vaccines. Overall, our studies show that therapeutic CMV-based vaccines in combination with adoptive T cell transfer alone are effective for tumor rejection. PMID:29387061

Transplantation of embryonic stem cell-derived dopaminergic neurons in MPTP-treated monkeys.

PubMed

Takahashi, Jun; Takagi, Yasushi; Saiki, Hidemoto

2009-01-01

One of the target diseases of cell-replacement therapy is Parkinson's disease. Clinical experiences with fetal dopaminergic cell graft have shown that the therapy is effective, but limited and accompanied by side effects, such as dyskinesia. So, the therapy needs to be further improved and sophisticated. Embryonic stem (ES) cells are expected to be another donor cell for the treatment, because of its proliferative and differentiation capacities. For clinical application, experiments using non-human primates are important, because size, anatomy, and biological characteristics of the brain are different between rodents and primates. Here, we would like to discuss induction of dopaminergic neurons from monkey ES cells and cell transplantation into the brain of monkey Parkinson's disease model.

The Basics of Artificial Antigen Presenting Cells in T Cell-Based Cancer Immunotherapies.

PubMed

Neal, Lillian R; Bailey, Stefanie R; Wyatt, Megan M; Bowers, Jacob S; Majchrzak, Kinga; Nelson, Michelle H; Haupt, Carl; Paulos, Chrystal M; Varela, Juan C

2017-01-01

Adoptive T cell transfer (ACT) can mediate objective responses in patients with advanced malignancies. There have been major advances in this field, including the optimization of the ex vivo generation of tumor-reactive lymphocytes to ample numbers for effective ACT therapy via the use of natural and artificial antigen presenting cells (APCs). Herein we review the basic properties of APCs and how they have been manufactured through the years to augment vaccine and T cell-based cancer therapies. We then discuss how these novel APCs impact the function and memory properties of T cells. Finally, we propose new ways to synthesize aAPCs to augment the therapeutic effectiveness of antitumor T cells for ACT therapy.

The Basics of Artificial Antigen Presenting Cells in T Cell-Based Cancer Immunotherapies

PubMed Central

Neal, Lillian R.; Bailey, Stefanie R.; Wyatt, Megan M.; Bowers, Jacob S.; Majchrzak, Kinga; Nelson, Michelle H.; Haupt, Carl; Paulos, Chrystal M.; Varela, Juan C.

2017-01-01

Adoptive T cell transfer (ACT) can mediate objective responses in patients with advanced malignancies. There have been major advances in this field, including the optimization of the ex vivo generation of tumor-reactive lymphocytes to ample numbers for effective ACT therapy via the use of natural and artificial antigen presenting cells (APCs). Herein we review the basic properties of APCs and how they have been manufactured through the years to augment vaccine and T cell-based cancer therapies. We then discuss how these novel APCs impact the function and memory properties of T cells. Finally, we propose new ways to synthesize aAPCs to augment the therapeutic effectiveness of antitumor T cells for ACT therapy. PMID:28825053

Challenges and opportunities for stem cell therapy in patients with chronic kidney disease

PubMed Central

Hickson, LaTonya J.; Eirin, Alfonso; Lerman, Lilach O.

2016-01-01

Chronic kidney disease (CKD) is a global healthcare burden affecting billions of individuals worldwide. The kidney has limited regenerative capacity from chronic insults, and for the most common causes of CKD, no effective treatment exists to prevent progression to end-stage kidney failure. Therefore, novel interventions, such as regenerative cell-based therapies, need to be developed for CKD. Given the risk of allosensitization, autologous transplantation of cells to boost regenerative potential is preferred. Therefore, verification of cell function and vitality in CKD patients is imperative. Two cell types have been most commonly applied in regenerative medicine. Endothelial progenitor cells contribute to neovasculogenesis primarily through paracrine angiogenic activity and partly by differentiation into mature endothelial cells in situ. Mesenchymal stem cells also exert paracrine effects, including pro-angiogenic, anti-inflammatory, and anti-fibrotic activity. However, in CKD, multiple factors may contribute to reduced cell function, including older age, coexisting cardiovascular disease, diabetes, chronic inflammatory states, and uremia, which may limit the effectiveness of an autologous cell-based therapy approach. This review highlights current knowledge on stem and progenitor cell function and vitality, aspects of the uremic milieu that may serve as a barrier to therapy, and novel methods to improve stem cell function for potential transplantation. PMID:26924058

Challenges and opportunities for stem cell therapy in patients with chronic kidney disease.

PubMed

Hickson, LaTonya J; Eirin, Alfonso; Lerman, Lilach O

2016-04-01

Chronic kidney disease (CKD) is a global health care burden affecting billions of individuals worldwide. The kidney has limited regenerative capacity from chronic insults, and for the most common causes of CKD, no effective treatment exists to prevent progression to end-stage kidney failure. Therefore, novel interventions, such as regenerative cell-based therapies, need to be developed for CKD. Given the risk of allosensitization, autologous transplantation of cells to boost regenerative potential is preferred. Therefore, verification of cell function and vitality in CKD patients is imperative. Two cell types have been most commonly applied in regenerative medicine. Endothelial progenitor cells contribute to neovasculogenesis primarily through paracrine angiogenic activity and partly by differentiation into mature endothelial cells in situ. Mesenchymal stem cells also exert paracrine effects, including proangiogenic, anti-inflammatory, and antifibrotic activity. However, in CKD, multiple factors may contribute to reduced cell function, including older age, coexisting cardiovascular disease, diabetes, chronic inflammatory states, and uremia, which may limit the effectiveness of an autologous cell-based therapy approach. This Review highlights current knowledge on stem and progenitor cell function and vitality, aspects of the uremic milieu that may serve as a barrier to therapy, and novel methods to improve stem cell function for potential transplantation. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Mesenchymal Stem Cell Based Therapy for Prostate Cancer

DTIC Science & Technology

2015-11-01

Award Number: W81XWH-13-1-0304 TITLE: Mesenchymal Stem Cell-Based Therapy for Prostate Cancer PRINCIPAL INVESTIGATOR: John Isaacs CONTRACTING...TITLE AND SUBTITLE Mesenchymal Stem Cell-Based Therapy for Prostate Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-13-1-0304 5c. PROGRAM ELEMENT...effective therapy for castrate resistant metastatic prostate cancer (CRPC). Based upon a substantial published literature from multiple groups, as well as

Photodynamic Therapy with Hypericin Improved by Targeting HSP90 Associated Proteins

PubMed Central

Solár, Peter; Chytilová, Mária; Solárová, Zuzana; Mojžiš, Ján; Ferenc, Peter; Fedoročko, Peter

2011-01-01

In this study we have focused on the response of SKBR-3 cells to both single 17-DMAG treatment as well as its combination with photodynamic therapy with hypericin. Low concentrations of 17-DMAG without any effect on survival of SKBR-3 cells significantly reduced metabolic activity, viability and cell number when combined with photodynamic therapy with hypericin. Moreover, IC10 concentation of 17-DMAG resulted in significant increase of SKBR-3 cells in G1 phase of the cell cycle, followed by an increase of cells in G2 phase when combined with photodynamic therapy. Furthermore, 17-DMAG already decreased HER2, Akt, P-Erk1/2 and survivin protein levels in SKBR-3 cells a short time after its application. In this regard, 17-DMAG protected also SKBR-3 cells against both P-Erk1/2 as well as survivin upregulations induced by photodynamic therapy with hypericin. Interestingly, IC10 concentration of 17-DMAG led to total depletion of Akt, P-Erk1/2 proteins and to decrease of survivin level at 48 h. On the other hand, 17-DMAG did not change HER2 relative expression in SKBR-3 cells, but caused a significant decrease of HER2 mRNA in MCF-7 cells characterized by low HER2 expression. These results show that targeting HSP90 client proteins increases the efficiency of antineoplastic effect of photodynamic therapy in vitro. PMID:27721334

Treatment With mANT2 shRNA Enhances Antitumor Therapeutic Effects Induced by MUC1 DNA Vaccination

PubMed Central

Choi, Yun; Jeon, Yong H; Jang, Ji-Young; Chung, June-Key; Kim, Chul-Woo

2011-01-01

In this study, we developed a combination therapy (pcDNA3/hMUC1+mANT2 shRNA) to enhance the efficiency of MUC1 DNA vaccination by combining it with mANT2 short hairpin RNA (shRNA) treatment in immunocompetent mice. mANT2 shRNA treatment alone increased the apoptosis of BMF cells (B16F1 murine melanoma cell line coexpressing an MUC1 and Fluc gene) and rendered BMF tumor cells more susceptible to lysis by MUC1-associated CD8+ T cells. Furthermore, combined therapy enhanced MUC1 associated T-cell immune response and antitumor effects, and resulted in a higher cure rate than either treatment alone (pcDNA3/hMUC1 or mANT2 shRNA therapy alone). Human MUC1 (hMUC1)-loaded CD11c+ cells in the draining lymph nodes of BMF-bearing mice treated with the combined treatment were found to be most effective at generating hMUC1-associated CD8+IFNγ+ T cells. Furthermore, the in vitro killing activities of hMUC1-associated cytotoxic T cells (CTLs) in the combined therapy were greater than in the respective monotherapies. Cured animals treated with the combined treatment rejected a rechallenge by BMF cells, but not a rechallenge by B16F1-Fluc cells at 14 days after treatment, and showed MUC1 antigen-associated immune responses. These results suggest that combined therapy enhances antitumor activity, and that it offers an effective antitumor strategy for treating melanoma. PMID:21063392

A new insight in chimeric antigen receptor-engineered T cells for cancer immunotherapy.

PubMed

Zhang, Erhao; Xu, Hanmei

2017-01-03

Adoptive cell therapy using chimeric antigen receptor (CAR)-engineered T cells has emerged as a very promising approach to combating cancer. Despite its ability to eliminate tumors shown in some clinical trials, CAR-T cell therapy involves some significant safety challenges, such as cytokine release syndrome (CRS) and "on-target, off-tumor" toxicity, which is related to poor control of the dose, location, and timing of T cell activity. In the past few years, some strategies to avoid the side effects of CAR-T cell therapy have been reported, including suicide gene, inhibitory CAR, dual-antigen receptor, and the use of exogenous molecules as switches to control the CAR-T cell functions. Because of the advances of the CAR paradigm and other forms of cancer immunotherapy, the most effective means of defeating the cancer has become the integration therapy with the combinatorial control system of switchable dual-receptor CAR-T cell and immune checkpoint blockade.

The Flipside of the Power of Engineered T Cells: Observed and Potential Toxicities of Genetically Modified T Cells as Therapy.

PubMed

Bedoya, Felipe; Frigault, Matthew J; Maus, Marcela V

2017-02-01

Autologous T cells modified to recognize novel antigen targets are a novel form of therapy for cancer. We review the various potential forms of observed and hypothetical toxicities associated with genetically modified T cells. Despite the focus on toxicities in this review, re-directed T cells represent a powerful and highly effective form of anti-cancer therapy; we remain optimistic that the common toxicities will become routinely manageable and that some theoretical toxicity will be exceedingly rare, if ever observed. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Stem cell therapies and regenerative medicine in China.

PubMed

Huang, Sha; Fu, XiaoBing

2014-02-01

Stem cells are the core of tissue repair and regeneration, and a promising cell source for novel therapies. In recent years, research into stem cell therapies has been particularly exciting in China. The remarkable advancements in basic stem cell research and clinically effective trials have led to fresh insights into regenerative medicine, such as treatments for sweat gland injury after burns, diabetes, and liver injury. High hopes have inspired numerous experimental and clinical trials. At the same time, government investment and policy support of research continues to increase markedly. However, numerous challenges must be overcome before novel stem cell therapies can achieve meaningful clinical outcomes.

Using the cost-effectiveness of allogeneic islet transplantation to inform induced pluripotent stem cell-derived β-cell therapy reimbursement.

PubMed

Archibald, Peter R T; Williams, David J

2015-11-01

In the present study a cost-effectiveness analysis of allogeneic islet transplantation was performed and the financial feasibility of a human induced pluripotent stem cell-derived β-cell therapy was explored. Previously published cost and health benefit data for islet transplantation were utilized to perform the cost-effectiveness and sensitivity analyses. It was determined that, over a 9-year time horizon, islet transplantation would become cost saving and 'dominate' the comparator. Over a 20-year time horizon, islet transplantation would incur significant cost savings over the comparator (GB£59,000). Finally, assuming a similar cost of goods to islet transplantation and a lack of requirement for immunosuppression, a human induced pluripotent stem cell-derived β-cell therapy would dominate the comparator over an 8-year time horizon.

Gene therapy for ocular diseases meditated by ultrasound and microbubbles (Review)

PubMed Central

WAN, CAIFENG; LI, FENGHUA; LI, HONGLI

2015-01-01

The eye is an ideal target organ for gene therapy as it is easily accessible and immune-privileged. With the increasing insight into the underlying molecular mechanisms of ocular diseases, gene therapy has been proposed as an effective approach. Successful gene therapy depends on efficient gene transfer to targeted cells to prove stable and prolonged gene expression with minimal toxicity. At present, the main hindrance regarding the clinical application of gene therapy is not the lack of an ideal gene, but rather the lack of a safe and efficient method to selectively deliver genes to target cells and tissues. Ultrasound-targeted microbubble destruction (UTMD), with the advantages of high safety, repetitive applicability and tissue targeting, has become a potential strategy for gene- and drug delivery. When gene-loaded microbubbles are injected, UTMD is able to enhance the transport of the gene to the targeted cells. High-amplitude oscillations of microbubbles act as cavitation nuclei which can effectively focus ultrasound energy, produce oscillations and disruptions that increase the permeability of the cell membrane and create transient pores in the cell membrane. Thereby, the efficiency of gene therapy can be significantly improved. The UTMD-mediated gene delivery system has been widely used in pre-clinical studies to enhance gene expression in a site-specific manner in a variety of organs. With reasonable application, the effects of sonoporation can be spatially and temporally controlled to improve localized tissue deposition of gene complexes for ocular gene therapy applications. In addition, appropriately powered, focused ultrasound combined with microbubbles can induce a reversible disruption of the blood-retinal barrier with no significant side effects. The present review discusses the current status of gene therapy of ocular diseases as well as studies on gene therapy of ocular diseases meditated by UTMD. PMID:26151686

Human mesenchymal stem cells suppress donor CD4(+) T cell proliferation and reduce pathology in a humanized mouse model of acute graft-versus-host disease.

PubMed

Tobin, L M; Healy, M E; English, K; Mahon, B P

2013-05-01

Acute graft-versus-host disease (aGVHD) is a life-threatening complication following allogeneic haematopoietic stem cell transplantation (HSCT), occurring in up to 30-50% of patients who receive human leucocyte antigen (HLA)-matched sibling transplants. Current therapies for steroid refractory aGVHD are limited, with the prognosis of patients suboptimal. Mesenchymal stem or stromal cells (MSC), a heterogeneous cell population present in many tissues, display potent immunomodulatory abilities. Autologous and allogeneic ex-vivo expanded human MSC have been utilized to treat aGVHD with promising results, but the mechanisms of therapeutic action remain unclear. Here a robust humanized mouse model of aGVHD based on delivery of human peripheral blood mononuclear cells (PBMC) to non-obese diabetic (NOD)-severe combined immunodeficient (SCID) interleukin (IL)-2rγ(null) (NSG) mice was developed that allowed the exploration of the role of MSC in cell therapy. MSC therapy resulted in the reduction of liver and gut pathology and significantly increased survival. Protection was dependent upon the timing of MSC therapy, with conventional MSC proving effective only after delayed administration. In contrast, interferon (IFN)-γ-stimulated MSC were effective when delivered with PBMC. The beneficial effect of MSC therapy in this model was not due to the inhibition of donor PBMC chimerism, as CD45(+) and T cells engrafted successfully in this model. MSC therapy did not induce donor T cell anergy, FoxP3(+) T regulatory cells or cause PBMC apoptosis in this model; however, it was associated with the direct inhibition of donor CD4(+) T cell proliferation and reduction of human tumour necrosis factor-α in serum. © 2012 British Society for Immunology.

Exosomes from Cardiomyocyte Progenitor Cells and Mesenchymal Stem Cells Stimulate Angiogenesis Via EMMPRIN.

PubMed

Vrijsen, Krijn R; Maring, Janita A; Chamuleau, Steven A J; Verhage, Vera; Mol, Emma A; Deddens, Janine C; Metz, Corina H G; Lodder, Kirsten; van Eeuwijk, Esther C M; van Dommelen, Susan M; Doevendans, Pieter A; Smits, Anke M; Goumans, Marie-José; Sluijter, Joost P G

2016-10-01

To date, cellular transplantation therapy has not yet fulfilled its high expectations for cardiac repair. A major limiting factor is lack of long-term engraftment of the transplanted cells. Interestingly, transplanted cells can positively affect their environment via secreted paracrine factors, among which are extracellular vesicles, including exosomes: small bi-lipid-layered vesicles containing proteins, mRNAs, and miRNAs. An exosome-based therapy will therefore relay a plethora of effects, without some of the limiting factors of cell therapy. Since cardiomyocyte progenitor cells (CMPC) and mesenchymal stem cells (MSC) induce vessel formation and are frequently investigated for cardiac-related therapies, the pro-angiogenic properties of CMPC and MSC-derived exosome-like vesicles are investigated. Both cell types secrete exosome-like vesicles, which are efficiently taken up by endothelial cells. Endothelial cell migration and vessel formation are stimulated by these exosomes in in vitro models, mediated via ERK/Akt-signaling. Additionally, these exosomes stimulated blood vessel formation into matrigel plugs. Analysis of pro-angiogenic factors revealed high levels of extracellular matrix metalloproteinase inducer (EMMPRIN). Knockdown of EMMPRIN on CMPCs leads to a diminished pro-angiogenic effect, both in vitro and in vivo. Therefore, CMPC and MSC exosomes have powerful pro-angiogenic effects, and this effect is largely mediated via the presence of EMMPRIN on exosomes. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Novel therapies in advanced renal cell carcinoma: management of adverse events from sorafenib and sunitinib.

PubMed

Ivanyi, Philipp; Winkler, Thomas; Ganser, Arnold; Reuter, Christoph; Grünwald, Viktor

2008-03-01

Sorafenib and Sunitinib are the first tyrosine kinase inhibitors licensed for the treatment of advanced renal cell carcinoma. In contrast to conventional chemotherapy, targeted therapies have distinct and specific side effects. Selective review in Medline and the data base of the American Society of Clinical Oncology on the treatment and side effects of tyrosine kinase inhibitors in renal cell carcinoma, drawing on the authors' own experience. Tyrosine kinase inhibitors are characterized by a variety of uncommon side effects, such as lassitude, mucosal inflammation and skin changes. The detection and treatment of adverse events are critical for interdisciplinary cancer treatment in order to ensure patients' safety. This article offers an overview of the unwanted effects of drug therapy in the management of renal cell carcinoma.

Chimeric Antigen Receptor-Modified T Cells for Solid Tumors: Challenges and Prospects

PubMed Central

Guo, Yelei; Wang, Yao; Han, Weidong

2016-01-01

Recent studies have highlighted the successes of chimeric antigen receptor-modified T- (CART-) cell-based therapy for B-cell malignancies, and early phase clinical trials have been launched in recent years. The few published clinical studies of CART cells in solid tumors have addressed safety and feasibility, but the clinical outcome data are limited. Although antitumor effects were confirmed in vitro and in animal models, CART-cell-based therapy still faces several challenges when directed towards solid tumors, and it has been difficult to achieve the desired outcomes in clinical practice. Many studies have struggled to improve the clinical responses to and benefits of CART-cell treatment of solid tumors. In this review, the status quo of CART cells and their clinical applications for solid tumors will be summarized first. Importantly, we will suggest improvements that could increase the therapeutic effectiveness of CART cells for solid tumors and their future clinical applications. These interventions will make treatment with CART cells an effective and routine therapy for solid tumors. PMID:26998495

The path to successful commercialization of cell and gene therapies: empowering patient advocates.

PubMed

Bauer, Gerhard; Abou-El-Enein, Mohamed; Kent, Alastair; Poole, Brian; Forte, Miguel

2017-02-01

Often, novel gene and cell therapies provide hope for many people living with incurable diseases. To facilitate and accelerate a successful regulatory approval and commercialization path for effective, safe and affordable cell and gene therapies, the involvement of patient advocacy groups (PAGs) should be considered early in the development process. This report provides a thorough overview of the various roles PAGs play in the clinical translation of cell and gene therapies and how they can bring about positive changes in the regulatory process, infrastructure improvements and market stability. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Sonodynamic therapy--a review of the synergistic effects of drugs and ultrasound.

PubMed

Rosenthal, Ionel; Sostaric, Joe Z; Riesz, Peter

2004-09-01

Sonodynamic therapy, the ultrasound dependent enhancement of cytotoxic activities of certain compounds (sonosensitizers) in studies with cells in vitro and in tumor bearing animals, is reviewed. The attractive features of this modality for cancer treatment emerges from the ability to focus the ultrasound energy on malignancy sites buried deep in tissues and to locally activate a preloaded sonosensitizer. Possible mechanisms of sonodynamic therapy include generation of sonosensitizer derived radicals which initiate chain peroxidation of membrane lipids via peroxyl and/or alkoxyl radicals, the physical destabilization of the cell membrane by the sonosensitizer thereby rendering the cell more susceptible to shear forces or ultrasound enhanced drug transport across the cell membrane (sonoporation). Evidence against the role of singlet oxygen in sonodynamic therapy is discussed. The mechanism of sonodynamic therapy is probably not governed by a universal mechanism, but may be influenced by multiple factors including the nature of the biological model, the sonosensitizer and the ultrasound parameters. The current review emphasizes the effect of ultrasound induced free radicals in sonodynamic therapy.

TIL therapy broadens the tumor-reactive CD8+ T cell compartment in melanoma patients

PubMed Central

Kvistborg, Pia; Shu, Chengyi Jenny; Heemskerk, Bianca; Fankhauser, Manuel; Thrue, Charlotte Albæk; Toebes, Mireille; van Rooij, Nienke; Linnemann, Carsten; van Buuren, Marit M.; Urbanus, Jos H.M.; Beltman, Joost B.; thor Straten, Per; Li, Yong F.; Robbins, Paul F.; Besser, Michal J.; Schachter, Jacob; Kenter, Gemma G.; Dudley, Mark E.; Rosenberg, Steven A.; Haanen, John B.A.G.; Hadrup, Sine Reker; Schumacher, Ton N.M.

2012-01-01

There is strong evidence that both adoptive T cell transfer and T cell checkpoint blockade can lead to regression of human melanoma. However, little data are available on the effect of these cancer therapies on the tumor-reactive T cell compartment. To address this issue we have profiled therapy-induced T cell reactivity against a panel of 145 melanoma-associated CD8+ T cell epitopes. Using this approach, we demonstrate that individual tumor-infiltrating lymphocyte cell products from melanoma patients contain unique patterns of reactivity against shared melanoma-associated antigens, and that the combined magnitude of these responses is surprisingly low. Importantly, TIL therapy increases the breadth of the tumor-reactive T cell compartment in vivo, and T cell reactivity observed post-therapy can almost in full be explained by the reactivity observed within the matched cell product. These results establish the value of high-throughput monitoring for the analysis of immuno-active therapeutics and suggest that the clinical efficacy of TIL therapy can be enhanced by the preparation of more defined tumor-reactive T cell products. PMID:22754759

TIL therapy broadens the tumor-reactive CD8(+) T cell compartment in melanoma patients.

PubMed

Kvistborg, Pia; Shu, Chengyi Jenny; Heemskerk, Bianca; Fankhauser, Manuel; Thrue, Charlotte Albæk; Toebes, Mireille; van Rooij, Nienke; Linnemann, Carsten; van Buuren, Marit M; Urbanus, Jos H M; Beltman, Joost B; Thor Straten, Per; Li, Yong F; Robbins, Paul F; Besser, Michal J; Schachter, Jacob; Kenter, Gemma G; Dudley, Mark E; Rosenberg, Steven A; Haanen, John B A G; Hadrup, Sine Reker; Schumacher, Ton N M

2012-07-01

There is strong evidence that both adoptive T cell transfer and T cell checkpoint blockade can lead to regression of human melanoma. However, little data are available on the effect of these cancer therapies on the tumor-reactive T cell compartment. To address this issue we have profiled therapy-induced T cell reactivity against a panel of 145 melanoma-associated CD8(+) T cell epitopes. Using this approach, we demonstrate that individual tumor-infiltrating lymphocyte cell products from melanoma patients contain unique patterns of reactivity against shared melanoma-associated antigens, and that the combined magnitude of these responses is surprisingly low. Importantly, TIL therapy increases the breadth of the tumor-reactive T cell compartment in vivo, and T cell reactivity observed post-therapy can almost in full be explained by the reactivity observed within the matched cell product. These results establish the value of high-throughput monitoring for the analysis of immuno-active therapeutics and suggest that the clinical efficacy of TIL therapy can be enhanced by the preparation of more defined tumor-reactive T cell products.

Effect of low-level laser-treated mesenchymal stem cells on myocardial infarction.

PubMed

El Gammal, Zaynab H; Zaher, Amr M; El-Badri, Nagwa

2017-09-01

Cardiovascular disease is the leading cause of death worldwide. Although cardiac transplantation is considered the most effective therapy for end-stage cardiac diseases, it is limited by the availability of matching donors and the complications of the immune suppressive regimen used to prevent graft rejection. Application of stem cell therapy in experimental animal models was shown to reverse cardiac remodeling, attenuate cardiac fibrosis, improve heart functions, and stimulate angiogenesis. The efficacy of stem cell therapy can be amplified by low-level laser radiation. It is well established that the bio-stimulatory effect of low-level laser is influenced by the following parameters: wavelength, power density, duration, energy density, delivery time, and the type of irradiated target. In this review, we evaluate the available experimental data on treatment of myocardial infarction using low-level laser. Eligible papers were characterized as in vivo experimental studies that evaluated the use of low-level laser therapy on stem cells in order to attenuate myocardial infarction. The following descriptors were used separately and in combination: laser therapy, low-level laser, low-power laser, stem cell, and myocardial infarction. The assessed low-level laser parameters were wavelength (635-804 nm), power density (6-50 mW/cm 2 ), duration (20-150 s), energy density (0.96-1 J/cm 2 ), delivery time (20 min-3 weeks after myocardial infarction), and the type of irradiated target (bone marrow or in vitro-cultured bone marrow mesenchymal stem cells). The analysis focused on the cardioprotective effect of this form of therapy, the attenuation of scar tissue, and the enhancement of angiogenesis as primary targets. Other effects such as cell survival, cell differentiation, and homing are also included. Among the evaluated protocols using different parameters, the best outcome for treating myocardial infarction was achieved by treating the bone marrow by one dose of low-level laser with 804 nm wavelength and 1 J/cm 2 energy density within 4 h of the infarction. This approach increased stem cell survival, proliferation, and homing. It has also decreased the infarct size and cell apoptosis, leading to enhanced heart functions. These effects were stable for 6 weeks. However, more studies are still required to assess the effects of low-level laser on the genetic makeup of the cell, the nuclei, and the mitochondria of mesenchymal stromal cells (MSCs).

Effect of Photobiomodulation on Mesenchymal Stem Cells.

PubMed

Fekrazad, Reza; Asefi, Sohrab; Allahdadi, Mahdi; Kalhori, Katayoun A M

2016-11-01

The purpose of this study was to review available literature about the effect of photobiomodulation (PBM) on mesenchymal stem cells (MSCs). The effects of coherent and noncoherent light sources such as low-level lasers and light-emitting diodes (LEDs) on cells and tissues, known as PBM, form the basis of photomedicine. This treatment technique effects cell function, proliferation, and migration, and plays an important role in tissue regeneration. Stem cells have been found to be helpful elements in tissue regeneration, and the combination of stem cell therapy and laser therapy appears to positively affect treatment results. An electronic search in PubMed was conducted of publications from the previous 12 years. English language articles related to the subject were found using selected key words. The full texts of potentially suitable articles were assessed according to inclusion and exclusion criteria. After evaluation, 30 articles were deemed relevant according to the inclusion criteria. The energy density of the laser was 0.7-9 J/cm 2 . The power used for visible light was 30-110 mW and that used for infrared light was 50-800 mW. Nearly all studies showed that low-level laser therapy had a positive effect on cell proliferation. Similar outcomes were found for LED; however, some studies suggest that the laser alone is not effective, and should be used as an adjunct tool. PBM has positive effects on MSCs. This review concluded that doses of 0.7-4 J/cm 2 and wavelengths of 600-700 nm are appropriate for light therapy. The results were dependent upon different parameters; therefore, optimization of parameters used in light therapy to obtain favorable results is required to provide more accurate comparison.

The interplay between the immune system and chemotherapy: emerging methods for optimizing therapy.

PubMed

Ghiringhelli, François; Apetoh, Lionel

2014-01-01

Preclinical studies have revealed an unexpected ability of the immune system to contribute to the success of chemotherapy and radiotherapy. Anticancer therapies can trigger immune system activation by promoting the release of danger signals from dying tumor cells and/or the elimination of immunosuppressive cells. We have, however, recently discovered that some chemotherapies, such as 5-fluorouracil and gemcitabine, exert conflicting effects on anticancer immune responses. Although 5-fluorouracil and Gem selectively eliminated myeloid-derived suppressive cells in tumor-bearing rodents, these chemotherapies promoted the release of IL-1β and the development of pro-angiogenic IL-17-producing CD4 T cells. The ambivalent effects of chemotherapy on immune responses should thus be carefully considered to design effective combination therapies based on chemotherapy and immune modulators. Herein, we discuss how the initial findings underscoring the key role of the immune system in mediating the antitumor efficacy of anticancer agents could begin to translate into effective therapies in humans.

[Adoptive Cell Therapy with Immune Checkpoint Blockade].

PubMed

Aruga, Atsushi

2017-09-01

Cancer immunotherapy are taking a leading role of cancer therapy due to the development of the immune checkpoint blockade. To date, however, only about 20% of patients have clinical responses and the cancer-specific T cells in cancer site are required to obtain beneficial effects. There has been an innovative development in the field of adoptive cell therapy, especially receptor gene-modified T cells in recent years. The effector cells mostly express PD-1, therefore the cytotoxic reactivity of the effector cells are inhibited by PD-L1. The combination of the adoptive cell therapy and the immune checkpoint blockade is expected to enhance efficacy. On the other hand, the immune-related adverse events may also be enhanced, therefore, it is needed to develop the combination therapy carefully, improving the cancer antigen-specificity or dealing with the cytokine release syndrome.

A high dose of intravenous immunoglobulin increases CD94 expression on natural killer cells in women with recurrent spontaneous abortion.

PubMed

Shimada, Shigeki; Takeda, Masamitsu; Nishihira, Jun; Kaneuchi, Masanori; Sakuragi, Noriaki; Minakami, Hisanori; Yamada, Hideto

2009-11-01

A high dose of intravenous immunoglobulin (HIVIg) therapy is effective in various diseases such as autoimmune diseases, and also is expected to have efficacy in recurrent spontaneous abortion (RSA). The aim of this study was to understand immunological mechanisms of this therapy. By flowcytometric analyses, we examined phenotypic changes of a variety of immunological cells including natural killer (NK) cells, cytotoxic T cells, regulatory T cells and macrophages in peripheral blood of RSA women with HIVIg therapy (n = 8). Expression percentages of inhibitory CD94 on NK cells significantly (P = 0.01) increased after the therapy (58.8 +/- 21.4% versus 71.0 +/- 17.6%). Mechanisms of possible efficacy of HIVIg therapy for RSA may include enhancement of CD94 expression and subsequent suppression of NK cell cytotoxicity.

[Effect of M007 mediated photodynamic therapy on proliferation of human osteosarcoma MG63 cells in vitro].

PubMed

Zhou, Yu-Kai; Wu, Wen-Zhi; Zhang, Lan; Yang, Chun-Hui; Wang, Yan-Ping

2012-01-01

To investigate the effect of a new photosensitizer, M007 mediated photodynamic therapy on proliferation of human osteosarcoma MG63 cells in vitro. Human osteosarcoma MG63 cells were prepared as 1 x 10(6) /mL single-cell suspension, and 1 mL cells were transferred into 60 mL culture dish, then treated with 5 different gradient dosages (0, 2, 4, 8, 16 micromol/L) of M007 followed by photodynamic therapy or dark reaction for 10 min. The survival rate of the cells and the mode of cell death were detected by flow cytometry with the stain of Annexin V-FITC/PI. The effect on proliferation of survival cells was observed by MTT assay and colony-forming assay. M007 mediated photodynamic therapy induced the inactivation of MG63 human osteosarcoma cells in the way of late apoptosis/necrosis or becoming naked nucleus predominately. More than 90% MG63 cells in M007-PDT group were dead under the treatment of 2-16 micromol/L M007. The survival rates of 4-16 micromol/L M007-PDT group were steadily less than 1%. The optical densities did not increase with extension of culture time in 2-8 micromol/L M007-PDT group (P > 0.05). There were 16 survival alive cells found occasionally in 2 micromol/L M007-PDT group, but no colonies found in other groups. M007 mediated photodynamic therapy totally inactivated human osteosarcoma MG63 cells in vitro with the dosage more than 4 micromol/L.

Modeling the effects of space structure and combination therapies on phenotypic heterogeneity and drug resistance in solid tumors.

PubMed

Lorz, Alexander; Lorenzi, Tommaso; Clairambault, Jean; Escargueil, Alexandre; Perthame, Benoît

2015-01-01

Histopathological evidence supports the idea that the emergence of phenotypic heterogeneity and resistance to cytotoxic drugs can be considered as a process of selection in tumor cell populations. In this framework, can we explain intra-tumor heterogeneity in terms of selection driven by the local cell environment? Can we overcome the emergence of resistance and favor the eradication of cancer cells by using combination therapies? Bearing these questions in mind, we develop a model describing cell dynamics inside a tumor spheroid under the effects of cytotoxic and cytostatic drugs. Cancer cells are assumed to be structured as a population by two real variables standing for space position and the expression level of a phenotype of resistance to cytotoxic drugs. The model takes explicitly into account the dynamics of resources and anticancer drugs as well as their interactions with the cell population under treatment. We analyze the effects of space structure and combination therapies on phenotypic heterogeneity and chemotherapeutic resistance. Furthermore, we study the efficacy of combined therapy protocols based on constant infusion and bang-bang delivery of cytotoxic and cytostatic drugs.

Light-Emitting Diode (LED) therapy improves occipital cortex damage by decreasing apoptosis and increasing BDNF-expressing cells in methanol-induced toxicity in rats.

PubMed

Ghanbari, Amir; Ghareghani, Majid; Zibara, Kazem; Delaviz, Hamdallah; Ebadi, Elham; Jahantab, Mohammad Hossein

2017-05-01

Methanol-induced retinal toxicity, frequently associated with elevated free radicals and cell edema, is characterized by progressive retinal ganglion cell (RGC) death and vision loss. Previous studies investigated the effect of photomodulation on RGCs, but not the visual cortex. In this study, the effect of 670nm Light-Emitting Diode (LED) therapy on RGCs and visual cortex recovery was investigated in a seven-day methanol-induced retinal toxicity protocol in rats. Methanol administration showed a reduction in the number of RGCs, loss of neurons (neuronal nuclear antigen, NeuN+), activation of glial fibrillary acidic protein (GFAP+) expressing cells, suppression of brain-derived neurotrophic factor (BDNF+) positive cells, increase in apoptosis (caspase 3+) and enhancement of nitric oxide (NO) release in serum and brain. On the other hand, LED therapy significantly reduced RGC death, in comparison to the methanol group. In addition, the number of BDNF positive cells was significantly higher in the visual cortex of LED-treated group, in comparison to methanol-intoxicated and control groups. Moreover, LED therapy caused a significant decrease in cell death (caspase 3+ cells) and a significant reduction in the NO levels, both in serum and brain tissue, in comparison to methanol-intoxicated rats. Overall, LED therapy demonstrated a number of beneficial effects in decreasing oxidative stress and in functional recovery of RGCs and visual cortex. Our data suggest that LED therapy could be a potential condidate as a non-invasive approach for treatment of retinal damage, which needs further clinicl studies. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Versatile graphene biosensors for enhancing human cell therapy.

PubMed

Vlăsceanu, George M; Amărandi, Roxana-Maria; Ioniță, Mariana; Tite, Teddy; Iovu, Horia; Pilan, Luisa; Burns, Jorge S

2018-05-01

Technological advances in engineering and cell biology stimulate novel approaches for medical treatment, in particular cell-based therapy. The first cell-based gene therapy against cancer was recently approved by the US Food and Drug Administration. Progress in cancer diagnosis includes a blood test detecting five cancer types. Numerous stem cell phase I/II clinical trials showing safety and efficacy will soon pursue qualifying criteria for advanced therapy medicinal products (ATMP), aspiring to join the first stem-cell therapy approved by the European Medicines Agency. Cell based therapy requires extensive preclinical characterisation of biomarkers indicating mechanisms of action crucial to the desired therapeutic effect. Quantitative analyses monitoring critical functions for the manufacture of optimal cell and tissue-based clinical products include successful potency assays for implementation. The challenge to achieve high quality measurement is increasingly met by progress in biosensor design. We adopt a cell therapy perspective to highlight recent examples of graphene-enhanced biointerfaces for measurement of biomarkers relevant to cancer treatment, diagnosis and tissue regeneration. Graphene based biosensor design problems can thwart their use for health care transformative point of care testing and real-time applications. We discuss concerns to be addressed and emerging solutions for establishing clinical grade biosensors to accelerate human cell therapy. Copyright © 2018 Elsevier B.V. All rights reserved.

Granulocyte-colony stimulating factor therapy to induce neovascularization in ischemic heart disease.

PubMed

Ripa, Rasmus Sejersten

2012-03-01

Cell based therapy for ischemic heart disease has the potential to reduce post infarct heart failure and chronic ischemia. Treatment with granulocyte-colony stimulating factor (G-CSF) mobilizes cells from the bone marrow to the peripheral blood. Some of these cells are putative stem or progenitor cells. G-CSF is injected subcutaneously. This therapy is intuitively attractive compared to other cell based techniques since repeated catheterizations and ex vivo cell purification and expansion are avoided. Previous preclinical and early clinical trials have indicated that treatment with G-CSF leads to improved myocardial perfusion and function in acute or chronic ischemic heart disease. The hypothesis of this thesis is that patient with ischemic heart disease will benefit from G-CSF therapy. We examined this hypothesis in two clinical trials with G-CSF treatment to patients with either acute myocardial infarction or severe chronic ischemic heart disease. In addition, we assed a number of factors that could potentially affect the effect of cell based therapy. Finally, we intended to develop a method for in vivo cell tracking in the heart. Our research showed that subcutaneous G-CSF along with gene therapy do not improve myocardial function in patients with chronic ischemia despite a large increase in circulation bone marrow-derived cells. Also, neither angina pectoris nor exercise capacity was improved compared to placebo treatment. We could not identify differences in angiogenic factors or bone marrow-derived cells in the blood that could explain the neutral effect of G-CSF. Next, we examined G-CSF as adjunctive therapy following ST segment elevation myocardial infarction. We did not find any effect of G-CSF neither on the primary endpoint--regional myocardial function--nor on left ventricular ejection fraction (secondary endpoint) compared to placebo treatment. In subsequent analyses, we found significant differences in the types of cells mobilized from the bone marrow by G-CSF. This could explain why intracoronary injections of unfractionated bone marrow-derived cells have more effect that mobilization with G-CSF. A number of other factors could explain the neutral effect of G-CSF in our trial compared to previous studies. These factors include timing of the treatment, G-CSF dose, and study population. It is however, remarkable that the changes in our G-CSF group are comparable to the results of previous non-blinded studies, whereas the major differences are in the control/placebo groups. We found that ejection fraction, wall motion, edema, perfusion, and infarct size all improve significantly in the first month following ST-segment myocardial infarction with standard guideline treatment (including acute mechanical revascularization), but without cell therapy. This is an important factor to take into account when assessing the results of non-controlled trials. Finally, we found that ex vivo labeling of cells with indium-111 for in vivo cell tracking after intramyocardial injection is problematic. In our hand, a significant amount of indium-111 remained in the myocardium despite cell death. It is difficult to determine viability of the cells after injection in human trials, and it is thus complicated to determine if the activity in the myocardium tracks viable cells. Cell based therapy is still in the explorative phase, but based on the intense research within this field it is our hope that the clinical relevance of the therapy can be determined in the foreseeable future. Ultimately, this will require large randomized, double-blind and placebo-controlled trials with "hard" clinical endpoints like mortality and morbidity.

A cellular automata model for avascular solid tumor growth under the effect of therapy

NASA Astrophysics Data System (ADS)

Reis, E. A.; Santos, L. B. L.; Pinho, S. T. R.

2009-04-01

Tumor growth has long been a target of investigation within the context of mathematical and computer modeling. The objective of this study is to propose and analyze a two-dimensional stochastic cellular automata model to describe avascular solid tumor growth, taking into account both the competition between cancer cells and normal cells for nutrients and/or space and a time-dependent proliferation of cancer cells. Gompertzian growth, characteristic of some tumors, is described and some of the features of the time-spatial pattern of solid tumors, such as compact morphology with irregular borders, are captured. The parameter space is studied in order to analyze the occurrence of necrosis and the response to therapy. Our findings suggest that transitions exist between necrotic and non-necrotic phases (no-therapy cases), and between the states of cure and non-cure (therapy cases). To analyze cure, the control and order parameters are, respectively, the highest probability of cancer cell proliferation and the probability of the therapeutic effect on cancer cells. With respect to patterns, it is possible to observe the inner necrotic core and the effect of the therapy destroying the tumor from its outer borders inwards.

Immunosuppressive myeloid cells induced by chemotherapy attenuate antitumor CD4+ T-cell responses through the PD-1-PD-L1 axis.

PubMed

Ding, Zhi-Chun; Lu, Xiaoyun; Yu, Miao; Lemos, Henrique; Huang, Lei; Chandler, Phillip; Liu, Kebin; Walters, Matthew; Krasinski, Antoni; Mack, Matthias; Blazar, Bruce R; Mellor, Andrew L; Munn, David H; Zhou, Gang

2014-07-01

In recent years, immune-based therapies have become an increasingly attractive treatment option for patients with cancer. Cancer immunotherapy is often used in combination with conventional chemotherapy for synergistic effects. The alkylating agent cyclophosphamide (CTX) has been included in various chemoimmunotherapy regimens because of its well-known immunostimulatory effects. Paradoxically, cyclophosphamide can also induce suppressor cells that inhibit immune responses. However, the identity and biologic relevance of these suppressor cells are poorly defined. Here we report that cyclophosphamide treatment drives the expansion of inflammatory monocytic myeloid cells (CD11b(+)Ly6C(hi)CCR2(hi)) that possess immunosuppressive activities. In mice with advanced lymphoma, adoptive transfer (AT) of tumor-specific CD4(+) T cells following cyclophosphamide treatment (CTX+CD4 AT) provoked a robust initial antitumor immune response, but also resulted in enhanced expansion of monocytic myeloid cells. These therapy-induced monocytes inhibited long-term tumor control and allowed subsequent relapse by mediating functional tolerization of antitumor CD4(+) effector cells through the PD-1-PD-L1 axis. PD-1/PD-L1 blockade after CTX+CD4 AT therapy led to persistence of CD4(+) effector cells and durable antitumor effects. Depleting proliferative monocytes by administering low-dose gemcitabine effectively prevented tumor recurrence after CTX+CD4 AT therapy. Similarly, targeting inflammatory monocytes by disrupting the CCR2 signaling pathway markedly potentiated the efficacy of cyclophosphamide-based therapy. Besides cyclophosphamide, we found that melphalan and doxorubicin can also induce monocytic myeloid suppressor cells. These findings reveal a counter-regulation mechanism elicited by certain chemotherapeutic agents and highlight the importance of overcoming this barrier to prevent late tumor relapse after chemoimmunotherapy. ©2014 American Association for Cancer Research.

LASERS IN MEDICINE: Light-oxygen effect in cells and its potential applications in tumour therapy (review)

NASA Astrophysics Data System (ADS)

Zakharov, S. D.; Ivanov, Andrei V.

1999-12-01

The light-oxygen effect (POE) represents damage (and at low optical doses, activation) of cells by photogeneration of molecular singlet oxygen from O2 dissolved in cells, in accordance with the reaction: 3O2+hν→1O2→ biological effect. The phases of evolution of the LOE are similar to the phases, observed in cell experiments, of the photodynamic effect (PDE) the mechanism of which is the basis of the familiar method of photodynamic cancer therapy. The reported proofs of the occurrence of the LOE are in the form of detailed spectra of the biological action of optical radiation on cells recorded in four spectral intervals with the aid of tunable lasers. Allowances are made for the relationships governing a new type of cell excitation, associated with reversible structural transitions in the biomembrane. A demonstration is reported of the same efficiency of cw and pulsed irradiation. An analysis is made of the reasons why the optical doses initiating the PDE and the LOE are comparable. The results are given of the first experimental applications of the LOE in tumour therapy. Identification of the primary photoacceptor (O2) in cell biostimulation and photodestruction provides a scientific basis for the development of low-intensity laser light-oxygen cancer therapy methods.

Effect of low level laser therapy and high intensity laser therapy on endothelial cell proliferation in vitro: preliminary communication

NASA Astrophysics Data System (ADS)

Lukowicz, Malgorzata; Szymanska, Justyna; Goralczyk, Krzysztof; Zajac, Andrzej; Rość, Danuta

2013-01-01

Background: The main purpose of this study was to analyze the influence of power intensity and wavelength of Low Level Laser Therapy (LLLT) and HILT (High Intensity Laser Therapy) on endothelial cell proliferation. Material and methods: The tests were done on human umbilical vein endothelial cells (HUVEC). Cultures were exposed to laser irradiation of 660 nm and 670 nm at different dosages, power output was 10 - 40 mW as well as 820 nm with power 100 mW and 808 nm with power 1500 mW. Energy density was from 0.28 to 11,43 J/cm2. Cell proliferation of a control and tested culture was evaluated with a colorimetric device to detect live cells. The tests were repeated 8 times. Results: We observed good effects of LLLT on live isolated ECs and no effects in experiments on previous deep-frozen cultures. Also HILT stimulated the proliferation of HUVEC. Conclusion: Endothelial cells play a key role in vascular homeostasis in humans. We observed the stimulatory effect of LLLT and HILT on proliferation of HUVEC. Many factors influence the proliferation of EC, so is it necessary to continue the experiment with different doses, intensity and cell concentration.

Controversies in targeted therapy of adult T cell leukemia/lymphoma: ON target or OFF target effects?

PubMed

Nasr, Rihab; El Hajj, Hiba; Kfoury, Youmna; de Thé, Hugues; Hermine, Olivier; Bazarbachi, Ali

2011-06-01

Adult T cell leukemia/lymphoma (ATL) represents an ideal model for targeted therapy because of intrinsic chemo-resistance of ATL cells and the presence of two well identified targets: the HTLV-I retrovirus and the viral oncoprotein Tax. The combination of zidovudine (AZT) and interferon-alpha (IFN) has a dramatic impact on survival of ATL patients. Although the mechanism of action remains unclear, arguments in favor or against a direct antiviral effect will be discussed. Yet, most patients relapse and alternative therapies are mandatory. IFN and arsenic trioxide induce Tax proteolysis, synergize to induce apoptosis in ATL cells and cure Tax-driven ATL in mice through specific targeting of leukemia initiating cell activity. These results provide a biological basis for the clinical success of arsenic/IFN/AZT therapy in ATL patients and suggest that both extinction of viral replication (AZT) and Tax degradation (arsenic/IFN) are needed to cure ATL.

Safety and effectiveness of stem cell therapies in early-phase clinical trials in stroke: a systematic review and meta-analysis.

PubMed

Nagpal, Anjali; Choy, Fong Chan; Howell, Stuart; Hillier, Susan; Chan, Fiona; Hamilton-Bruce, Monica A; Koblar, Simon A

2017-08-30

Stem cells have demonstrated encouraging potential as reparative therapy for patients suffering from post-stroke disability. Reperfusion interventions in the acute phase of stroke have shown significant benefit but are limited by a narrow window of opportunity in which they are beneficial. Thereafter, rehabilitation is the only intervention available. The current review summarises the current evidence for use of stem cell therapies in stroke from early-phase clinical trials. The safety and feasibility of administering different types of stem cell therapies in stroke seem to be reasonably proven. However, the effectiveness needs still to be established through bigger clinical trials with more pragmatic clinical trial designs that address the challenges raised by the heterogeneous nature of stroke per se, as well those due to unique characteristics of stem cells as therapeutic agents.

E phage gene transfection associated to chemotherapeutic agents increases apoptosis in lung and colon cancer cells.

PubMed

Rama, Ana R; Prados, Jose; Melguizo, Consolacion; Alvarez, Pablo J; Ortiz, Raúl; Madeddu, Roberto; Aranega, Antonia

2011-01-01

The limited ability of conventional therapies to achieve the long-term survival of metastatic lung and colon cancer patients suggests the need for new treatment options. In this respect, genes encoding cytotoxic proteins have been proposed as a new strategy to enhance the activity of drugs, and combined therapies involving such genes and classical antitumoral drugs have been studied intensively. The E gene from phiX174 encodes a membrane protein with a toxic domain that leads to a decrease in tumour cell growth rates. Therefore, in order to improve the anti-tumour effects of currently used chemotherapeutic drugs on cancer cells, we investigated the association of the E suicide gene with these antineoplastic drugs. The E gene has antitumoral effects in both lung and colon cancer cells. In addition, expression of this gene induces ultrastructural changes in lung cancer transfected cells (A-549), although the significance of these changes remains unknown. The effect of combined therapy (gene and cytotoxic therapy) enhances the inhibition of tumour cell proliferation in comparison to single treatments. Indeed, our in vitro results indicate that an experimental therapeutic strategy based on this combination of E gene therapy and cytotoxic drugs may result in a new treatment strategy for patients with advanced lung and colon cancer.

Promoting effects of adipose-derived stem cells on breast cancer cells are reversed by radiation therapy.

PubMed

Baaße, Annemarie; Juerß, Dajana; Reape, Elaine; Manda, Katrin; Hildebrandt, Guido

2018-04-01

Partial breast irradiation of early breast cancer patients after lumpectomy and the use of endogenous adipose tissue (AT) for breast reconstruction are promising applications to reduce the side effects of breast cancer therapy. This study tries to investigate the possible risks associated with these therapeutic approaches. It also examines the influence of adipose derived stem cells (ADSCs) as part of the breast cancer microenvironment, and endogenous AT on breast cancer cells following radiation therapy. ADSCs, isolated from human reduction mammoplasties of healthy female donors, exhibited multilineage capacity and specific surface markers. The promoting effects of ADSCs on the growth and survival fraction of breast cancer cells were reversed by treatment with high (8 Gy) or medium (2 Gy) radiation doses. In addition, a suppressing influence on breast cancer growth could be detected by co-culturing with irradiated ADSCs (8 Gy). Furthermore the clonogenic survival of unirradiated tumor cells was reduced by medium of irradiated ADSCs. In conclusion, radiation therapy changed the interactions of ADSCs and breast cancer cells. On the basis of our work, the importance of further studies to exclude potential risks of ADSCs in regenerative applications and radiotherapy has been emphasized.

Heterogeneity and proliferation of invasive cancer subclones in game theory models of the Warburg effect.

PubMed

Archetti, M

2015-04-01

The Warburg effect, a switch from aerobic energy production to anaerobic glycolysis, promotes tumour proliferation and motility by inducing acidification of the tumour microenvironment. Therapies that reduce acidity could impair tumour growth and invasiveness. I analysed the dynamics of cell proliferation and of resistance to therapies that target acidity, in a population of cells, under the Warburg effect. The dynamics of mutant cells with increased glycolysis and motility has been assessed in a multi-player game with collective interactions in the framework of evolutionary game theory. Perturbations of the level of acidity in the microenvironment have been used to simulate the effect of therapies that target glycolysis. The non-linear effects of glycolysis induce frequency-dependent clonal selection leading to coexistence of glycolytic and non-glycolytic cells within a tumour. Mutants with increased motility can invade such a polymorphic population and spread within the tumour. While reducing acidity may produce a sudden reduction in tumour cell proliferation, frequency-dependent selection enables it to adapt to the new conditions and can enable the tumour to restore its original levels of growth and invasiveness. The acidity produced by glycolysis acts as a non-linear public good that leads to coexistence of cells with high and low glycolysis within the tumour. Such a heterogeneous population can easily adapt to changes in acidity. Therapies that target acidity can only be effective in the long term if the cost of glycolysis is high, that is, under non-limiting oxygen concentrations. Their efficacy, therefore, is reduced when combined with therapies that impair angiogenesis. © 2015 The Authors Cell Proliferation Published by John Wiley & Sons Ltd.

Molecular basis of differentiation therapy for soft tissue sarcomas

PubMed Central

Luther, Gaurav; Rames, Richard; Wagner, Eric R.; Zhu, Gaohui; Luo, Qing; Bi, Yang; Kim, Stephanie H.; Gao, Jian-Li; Huang, Enyi; Yang, Ke; Wang, Linyuan; Liu, Xing; Li, Mi; Hu, Ning; Su, Yuxi; Luo, Xiaoji; Chen, Liang; Luo, Jinyong; Haydon, Rex C.; Luu, Hue H.; Zhou, Lan; He, Tong-Chuan

2015-01-01

Stem cells are undifferentiated precursor cells with the capacity for proliferation or terminal differentiation. Progression down the differentiation cascade results in a loss of proliferative potential in exchange for the differentiated phenotype. This balance is tightly regulated in the physiologic state. Recent studies, however, have demonstrated that during tumorigenesis, disruptions preventing terminal differentiation allow cancer cells to maintain a proliferative, precursor cell phenotype. Current therapies (i.e., chemotherapy and radiation therapy) target the actively proliferating cells in tumor masses, which in many cases inevitably induce therapy-resistant cancer cells. It is conceivable that promising therapy regimens can be developed by treating human cancers by inducing terminal differentiation, thereby restoring the interrupted pathway and shifting the balance from proliferation to differentiation. For example, osteosarcoma (OS) is a primary bone cancer caused by differentiation defects in mesenchymal stem cells (MSCs) for which several differentiation therapies have shown great promise. In this review, we discuss the various differentiation therapies in the treatment of human sarcomas with a focus on OS. Such therapies hold great promise as they not only inhibit tumorigenesis, but also avoid the adverse effects associated with conventional chemotherapy regimens. Furthermore, it is conceivable that a combination of conventional therapies with differentiation therapy should significantly improve anticancer efficacy and reduce drug-resistance in the clinical management of human cancers, including sarcomas. PMID:26912947

Effects of Cetuximab and Erlotinib on the behaviour of cancer stem cells in head and neck squamous cell carcinoma.

PubMed

Setúbal Destro Rodrigues, Maria Fernanda; Gammon, Luke; Rahman, Muhammad M; Biddle, Adrian; Nunes, Fabio Daumas; Mackenzie, Ian C

2018-03-02

The therapeutic responses of many solid tumours to chemo- and radio-therapies are far from fully effective but therapies targeting malignancy-related cellular changes show promise for further control. In head and neck squamous cell carcinoma, the epidermal growth factor receptor (EGFR) is commonly overexpressed and investigation of agents that block this receptor indicate a limited response when used alone but an ability to enhance the actions of other drugs. The hierarchical stem cell patterns present in tumours generate cellular heterogeneity and this is further complicated by cancer stem cells (CSC) shifting between epithelial (Epi-CSC) and mesenchymal (EMT-CSC) states. To clarify how such heterogeneity influences responses to EGFR blocking, we examined the effects of Cetuximab and Erlotinib on the cell sub-populations in HNSCC cell lines. These agents reduced cell proliferation for all subpopulations but induced little cell death. They did however induce large shifts of cells between the EMT-CSC, Epi-CSC and differentiating cell compartments. Loss of EMT-CSCs reduced cell motility and is expected to reduce invasion and metastasis. EGFR blocking also induced shifts of Epi-CSCs into the differentiating cell compartment which typically has greater sensitivity to chemo/radiation, an effect expected to enhance the overall response of tumour cell populations to adjunctive therapies.

Effects of Cetuximab and Erlotinib on the behaviour of cancer stem cells in head and neck squamous cell carcinoma

PubMed Central

Setúbal Destro Rodrigues, Maria Fernanda; Gammon, Luke; Rahman, Muhammad M.; Biddle, Adrian; Nunes, Fabio Daumas; Mackenzie, Ian C.

2018-01-01

The therapeutic responses of many solid tumours to chemo- and radio-therapies are far from fully effective but therapies targeting malignancy-related cellular changes show promise for further control. In head and neck squamous cell carcinoma, the epidermal growth factor receptor (EGFR) is commonly overexpressed and investigation of agents that block this receptor indicate a limited response when used alone but an ability to enhance the actions of other drugs. The hierarchical stem cell patterns present in tumours generate cellular heterogeneity and this is further complicated by cancer stem cells (CSC) shifting between epithelial (Epi-CSC) and mesenchymal (EMT-CSC) states. To clarify how such heterogeneity influences responses to EGFR blocking, we examined the effects of Cetuximab and Erlotinib on the cell sub-populations in HNSCC cell lines. These agents reduced cell proliferation for all subpopulations but induced little cell death. They did however induce large shifts of cells between the EMT-CSC, Epi-CSC and differentiating cell compartments. Loss of EMT-CSCs reduced cell motility and is expected to reduce invasion and metastasis. EGFR blocking also induced shifts of Epi-CSCs into the differentiating cell compartment which typically has greater sensitivity to chemo/radiation, an effect expected to enhance the overall response of tumour cell populations to adjunctive therapies. PMID:29568372

Neuroprotective therapies in glaucoma: II. Genetic nanotechnology tools.

PubMed

Nafissi, Nafiseh; Foldvari, Marianna

2015-01-01

Neurotrophic factor genome engineering could have many potential applications not only in the deeper understanding of neurodegenerative disorders but also in improved therapeutics. The fields of nanomedicine, regenerative medicine, and gene/cell-based therapy have been revolutionized by the development of safer and efficient non-viral technologies for gene delivery and genome editing with modern techniques for insertion of the neurotrophic factors into clinically relevant cells for a more sustained pharmaceutical effect. It has been suggested that the long-term expression of neurotrophic factors is the ultimate approach to prevent and/or treat neurodegenerative disorders such as glaucoma in patients who do not respond to available treatments or are at the progressive stage of the disease. Recent preclinical research suggests that novel neuroprotective gene and cell therapeutics could be promising approaches for both non-invasive neuroprotection and regenerative functions in the eye. Several progenitor and retinal cell types have been investigated as potential candidates for glaucoma neurotrophin therapy either as targets for gene therapy, options for cell replacement therapy, or as vehicles for gene delivery. Therefore, in parallel with deeper understanding of the specific protective effects of different neurotrophic factors and the potential therapeutic cell candidates for glaucoma neuroprotection, the development of non-invasive and highly specific gene delivery methods with safe and effective technologies to modify cell candidates for life-long neuroprotection in the eye is essential before investing in this field.

Novel targets for sensitizing breast cancer cells to TRAIL-induced apoptosis with siRNA delivery.

PubMed

Thapa, Bindu; Bahadur Kc, Remant; Uludağ, Hasan

2018-02-01

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in variety of cancer cells without affecting most normal cells, which makes it a promising agent for cancer therapy. However, TRAIL therapy is clinically not effective due to resistance induction. To identify novel regulators of TRAIL that can aid in therapy, protein targets whose silencing sensitized breast cancer cells against TRAIL were screened with an siRNA library against 446 human apoptosis-related proteins in MDA-231 cells. Using a cationic lipopolymer (PEI-αLA) for delivery of library members, 16 siRNAs were identified that sensitized the TRAIL-induced death in MDA-231 cells. The siRNAs targeting BCL2L12 and SOD1 were further evaluated based on the novelty and their ability to sensitize TRAIL induced cell death. Silencing both targets sensitized TRAIL-mediated cell death in MDA-231 cells as well as TRAIL resistant breast cancer cells, MCF-7. Combination of TRAIL and siRNA silencing BCL2L12 had no effect in normal human umbilical vein cells and human bone marrow stromal cell. The silencing of BCL2L12 and SOD1 enhanced TRAIL-mediated apoptosis in MDA-231 cells via synergistically activating capsase-3 activity. Hence, here we report siRNAs targeting BCL2L12 and SOD1 as a novel regulator of TRAIL-induced cell death in breast cancer cells, providing a new approach for enhancing TRAIL therapy for breast cancer. The combination of siRNA targeting BCL2L12 and TRAIL can be a highly effective synergistic pair in breast cancer cells with minimal effect on the non-transformed cells. © 2017 UICC.

Stem cell gene therapy for fanconi anemia: report from the 1st international Fanconi anemia gene therapy working group meeting.

PubMed

Tolar, Jakub; Adair, Jennifer E; Antoniou, Michael; Bartholomae, Cynthia C; Becker, Pamela S; Blazar, Bruce R; Bueren, Juan; Carroll, Thomas; Cavazzana-Calvo, Marina; Clapp, D Wade; Dalgleish, Robert; Galy, Anne; Gaspar, H Bobby; Hanenberg, Helmut; Von Kalle, Christof; Kiem, Hans-Peter; Lindeman, Dirk; Naldini, Luigi; Navarro, Susana; Renella, Raffaele; Rio, Paula; Sevilla, Julián; Schmidt, Manfred; Verhoeyen, Els; Wagner, John E; Williams, David A; Thrasher, Adrian J

2011-07-01

Survival rates after allogeneic hematopoietic cell transplantation (HCT) for Fanconi anemia (FA) have increased dramatically since 2000. However, the use of autologous stem cell gene therapy, whereby the patient's own blood stem cells are modified to express the wild-type gene product, could potentially avoid the early and late complications of allogeneic HCT. Over the last decades, gene therapy has experienced a high degree of optimism interrupted by periods of diminished expectation. Optimism stems from recent examples of successful gene correction in several congenital immunodeficiencies, whereas diminished expectations come from the realization that gene therapy will not be free of side effects. The goal of the 1st International Fanconi Anemia Gene Therapy Working Group Meeting was to determine the optimal strategy for moving stem cell gene therapy into clinical trials for individuals with FA. To this end, key investigators examined vector design, transduction method, criteria for large-scale clinical-grade vector manufacture, hematopoietic cell preparation, and eligibility criteria for FA patients most likely to benefit. The report summarizes the roadmap for the development of gene therapy for FA.

[New possibilities will open up in human gene therapy].

PubMed

Portin, Petter

2016-01-01

Gene therapy is divided into somatic and germ line therapy. The latter involves reproductive cells or their stem cells, and its results are heritable. The effects of somatic gene therapy are generally restricted to a single tissue of the patient in question. Until now, all gene therapies in the world have belonged to the regime of somatic therapy, germ line therapy having been a theoretical possibility only. Very recently, however, a method has been developed which is applicable to germ line therapy as well. In addition to technical challenges, severe ethical problems are associated with germ line therapy, demanding opinion statement.

ReNeuron Group plc.

PubMed

Sinden, John D

2006-01-01

ReNeuron is a UK-based pioneer in stem cell research and development. The Company has leading edge, proprietary somatic stem cell technologies from which it is developing groundbreaking cell therapy products. ReNeuron's focus is on cell therapy treatments designed to reverse the effects of major diseases such as stroke, diabetes and diseases of the eye.

Aluminum–phthalocyanine chloride associated to poly(methyl vinyl ether-co-maleic anhydride) nanoparticles as a new third-generation photosensitizer for anticancer photodynamic therapy

PubMed Central

Muehlmann, Luis Alexandre; Ma, Beatriz Chiyin; Longo, João Paulo Figueiró; Almeida Santos, Maria de Fátima Menezes; Azevedo, Ricardo Bentes

2014-01-01

Photodynamic therapy is generally considered to be safer than conventional anticancer therapies, and it is effective against different kinds of cancer. However, its clinical application has been significantly limited by the hydrophobicity of photosensitizers. In this work, a system composed of the hydrophobic photosensitizer aluminum–phthalocyanine chloride (AlPc) associated with water dispersible poly(methyl vinyl ether-co-maleic anhydride) nanoparticles is described. AlPc was associated with nanoparticles produced by a method of solvent displacement. This system was analyzed for its physicochemical characteristics, and for its photodynamic activity in vitro in cancerous (murine mammary carcinoma cell lineage 4T1, and human mammary adenocarcinoma cells MCF-7) and noncancerous (murine fibroblast cell lineage NIH/3T3, and human mammary epithelial cell lineage MCF-10A) cell lines. Cell viability and the elicited mechanisms of cell death were evaluated after the application of photodynamic therapy. This system showed improved photophysical and photochemical properties in aqueous media in comparison to the free photosensitizer, and it was effective against cancerous cells in vitro. PMID:24634582

Synergistic Effects of NDRG2 Overexpression and Radiotherapy on Cell Death of Human Prostate LNCaP Cells.

PubMed

Alizadeh Zarei, M; Takhshid, M A; Behzad Behbahani, A; Hosseini, S Y; Okhovat, M A; Rafiee Dehbidi, Gh R; Mosleh Shirazi, M A

2017-09-01

Radiation therapy is among the most conventional cancer therapeutic modalities with effective local tumor control. However, due to the development of radio-resistance, tumor recurrence and metastasis often occur following radiation therapy. In recent years, combination of radiotherapy and gene therapy has been suggested to overcome this problem. The aim of the current study was to explore the potential synergistic effects of N-Myc Downstream-Regulated Gene 2 (NDRG2) overexpression, a newly identified candidate tumor suppressor gene, with radiotherapy against proliferation of prostate LNCaP cell line. In this study, LNCaP cells were exposed to X-ray radiation in the presence or absence of NDRG2 overexpression using plasmid PSES- pAdenoVator-PSA-NDRG2-IRES-GFP. The effects of NDRG2 overexpression, X-ray radiation or combination of both on the cell proliferation and apoptosis of LNCaP cells were then analyzed using MTT assay and flow cytometery, respectively. Results of MTT assay showed that NDRG2 overexpression and X-ray radiation had a synergistic effect against proliferation of LNCaP cells. Moreover, NDRG2 overexpression increased apoptotic effect of X-ray radiation in LNCaP cells synergistically. Our findings suggested that NDRG2 overexpression in combination with radiotherapy may be an effective therapeutic option against prostate cancer.

T-cell and natural killer cell therapies for hematologic malignancies after hematopoietic stem cell transplantation: enhancing the graft-versus-leukemia effect

PubMed Central

Cruz, C. Russell; Bollard, Catherine M.

2015-01-01

Hematopoietic stem cell transplantation has revolutionized the treatment of hematologic malignancies, but infection, graft-versus-host disease and relapse are still important problems. Calcineurin inhibitors, T-cell depletion strategies, and immunomodulators have helped to prevent graft-versus-host disease, but have a negative impact on the graft-versus-leukemia effect. T cells and natural killer cells are both thought to be important in the graft-versus-leukemia effect, and both cell types are amenable to ex vivo manipulation and clinical manufacture, making them versatile immunotherapeutics. We provide an overview of these immunotherapeutic strategies following hematopoietic stem cell transplantation, with discussions centered on natural killer and T-cell biology. We discuss the contributions of each cell type to graft-versus-leukemia effects, as well as the current research directions in the field as related to adoptive cell therapy after hematopoietic stem cell transplantation. PMID:26034113

Cell cycle-tailored targeting of metastatic melanoma: Challenges and opportunities.

PubMed

Haass, Nikolas K; Gabrielli, Brian

2017-07-01

The advent of targeted therapies of metastatic melanoma, such as MAPK pathway inhibitors and immune checkpoint antagonists, has turned dermato-oncology from the "bad guy" to the "poster child" in oncology. Current targeted therapies are effective, although here is a clear need to develop combination therapies to delay the onset of resistance. Many antimelanoma drugs impact on the cell cycle but are also dependent on certain cell cycle phases resulting in cell cycle phase-specific drug insensitivity. Here, we raise the question: Have combination trials been abandoned prematurely as ineffective possibly only because drug scheduling was not optimized? Firstly, if both drugs of a combination hit targets in the same melanoma cell, cell cycle-mediated drug insensitivity should be taken into account when planning combination therapies, timing of dosing schedules and choice of drug therapies in solid tumors. Secondly, if the combination is designed to target different tumor cell subpopulations of a heterogeneous tumor, one drug effective in a particular subpopulation should not negatively impact on the other drug targeting another subpopulation. In addition to the role of cell cycle stage and progression on standard chemotherapeutics and targeted drugs, we discuss the utilization of cell cycle checkpoint control defects to enhance chemotherapeutic responses or as targets themselves. We propose that cell cycle-tailored targeting of metastatic melanoma could further improve therapy outcomes and that our real-time cell cycle imaging 3D melanoma spheroid model could be utilized as a tool to measure and design drug scheduling approaches. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Immuno-Oncology-The Translational Runway for Gene Therapy: Gene Therapeutics to Address Multiple Immune Targets.

PubMed

Weß, Ludger; Schnieders, Frank

2017-12-01

Cancer therapy is once again experiencing a paradigm shift. This shift is based on extensive clinical experience demonstrating that cancer cannot be successfully fought by addressing only single targets or pathways. Even the combination of several neo-antigens in cancer vaccines is not sufficient for successful, lasting tumor eradication. The focus has therefore shifted to the immune system's role in cancer and the striking abilities of cancer cells to manipulate and/or deactivate the immune system. Researchers and pharma companies have started to target the processes and cells known to support immune surveillance and the elimination of tumor cells. Immune processes, however, require novel concepts beyond the traditional "single-target-single drug" paradigm and need parallel targeting of diverse cells and mechanisms. This review gives a perspective on the role of gene therapy technologies in the evolving immuno-oncology space and identifies gene therapy as a major driver in the development and regulation of effective cancer immunotherapy. Present challenges and breakthroughs ranging from chimeric antigen receptor T-cell therapy, gene-modified oncolytic viruses, combination cancer vaccines, to RNA therapeutics are spotlighted. Gene therapy is recognized as the most prominent technology enabling effective immuno-oncology strategies.

Chemical modification of chitosan for efficient gene therapy.

PubMed

Jiang, Hu-Lin; Cui, Peng-Fei; Xie, Rong-Lin; Cho, Chong-Su

2014-01-01

Gene therapy involves the introduction of foreign genetic material into cells in order to exert a therapeutic effect. Successful gene therapy relies on effective vector system. Viral vectors are highly efficient in transfecting cells, but the undesirable complications limit their therapeutic applications. As a natural biopolymer, chitosan has been considered to be a good gene carrier candidate due to its ideal character which combines biocompatibility, low toxicity with high cationic density together. However, the low cell specificity and low transfection efficiency of chitosan as a gene carrier need to be overcome before undertaking clinical trials. This chapter is principally on those endeavors such as chemical modifications using cell-specific ligands and stimuli-response groups as well as penetrating modifications that have been done to increase the performances of chitosan in gene therapy. © 2014 Elsevier Inc. All rights reserved.

Evaluation of Immune Responses Mediated by Listeria-Stimulated Human Dendritic Cells: Implications for Cancer Vaccine Therapy

DTIC Science & Technology

2012-07-01

Mediated by Listeria -Stimulated Human Dendritic Cells: Implications for Cancer Vaccine Therapy PRINCIPAL INVESTIGATOR: David J. Chung, M D , Ph D...CONTRACT NUMBER Evaluation of Immune Responses Mediated by Listeria -Stimulated Human Dendritic Cells: Implications for Cancer Vaccine Therapy 5b...Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT The purpose of this project is to study the immunomodulatory effect of Listeria on

Hyaluronan Enhances Bone Marrow Cell Therapy for Myocardial Repair After Infarction

PubMed Central

Chen, Chien-Hsi; Wang, Shoei-Shen; Wei, Erika IH; Chu, Ting-Yu; Hsieh, Patrick CH

2013-01-01

Hyaluronan (HA) has been shown to play an important role during early heart development and promote angiogenesis under various physiological and pathological conditions. In recent years, stem cell therapy, which may reduce cardiomyocyte apoptosis, increase neovascularization, and prevent cardiac fibrosis, has emerged as a promising approach to treat myocardial infarction (MI). However, effective delivery of stem cells for cardiac therapy remains a major challenge. In this study, we tested whether transplanting a combination of HA and allogeneic bone marrow mononuclear cells (MNCs) promotes cell therapy efficacy and thus improves cardiac performance after MI in rats. We showed that HA provided a favorable microenvironment for cell adhesion, proliferation, and vascular differentiation in MNC culture. Following MI in rats, compared with the injection of HA alone or MNC alone, injection of both HA and MNCs significantly reduced inflammatory cell infiltration, cardiomyocyte apoptosis, and infarct size and also improved cell retention, angiogenesis, and arteriogenesis, and thus the overall cardiac performance. Ultimately, HA/MNC treatment improved vasculature engraftment of transplanted cells in the infarcted region. Together, our results indicate that combining the biocompatible material HA with bone marrow stem cells exerts a therapeutic effect on heart repair and may further provide potential treatment for ischemic diseases. PMID:23295948

Safe and targeted anticancer therapy for ovarian cancer using a novel class of curcumin analogs

PubMed Central

2013-01-01

A diagnosis of advanced ovarian cancer is the beginning of a long and arduous journey for a patient. Worldwide, approximately half of the individuals undergoing therapy for advanced cancer will succumb to the disease, or consequences of treatment. Well-known and widely-used chemotherapeutic agents such as cisplatin, paclitaxel, 5-fluorouracil, and doxorubicin are toxic to both cancer and non-cancerous cells, and have debilitating side effects Therefore, development of new targeted anticancer therapies that can selectively kill cancer cells while sparing the surrounding healthy tissues is essential to develop more effective therapies. We have developed a new class of synthetic curcumin analogs, diarylidenyl-piperidones (DAPs), which have higher anticancer activity and enhanced bio-absorption than curcumin. The DAP backbone structure exhibits cytotoxic (anticancer) activity, whereas the N-hydroxypyrroline (-NOH) moiety found on some variants functions as a cellular- or tissue-specific modulator (antioxidant) of cytotoxicity. The anticancer activity of the DAPs has been evaluated using a number of ovarian cancer cell lines, and the safety has been evaluated in a number of non-cancerous cell lines. Both variations of the DAP compounds showed similar levels of cell death in ovarian cancer cells, however the compounds with the -NOH modification were less toxic to non-cancerous cells. The selective cytotoxicity of the DAP–NOH compounds suggests that they will be useful as safe and effective anticancer agents. This article reviews some of the key findings of our work with the DAP compounds, and compares this to some of the targeted therapies currently used in ovarian cancer therapy. PMID:23663277

Platelet-Rich Plasma Peptides: Key for Regeneration

PubMed Central

Sánchez-González, Dolores Javier; Méndez-Bolaina, Enrique; Trejo-Bahena, Nayeli Isabel

2012-01-01

Platelet-derived Growth Factors (GFs) are biologically active peptides that enhance tissue repair mechanisms such as angiogenesis, extracellular matrix remodeling, and cellular effects as stem cells recruitment, chemotaxis, cell proliferation, and differentiation. Platelet-rich plasma (PRP) is used in a variety of clinical applications, based on the premise that higher GF content should promote better healing. Platelet derivatives represent a promising therapeutic modality, offering opportunities for treatment of wounds, ulcers, soft-tissue injuries, and various other applications in cell therapy. PRP can be combined with cell-based therapies such as adipose-derived stem cells, regenerative cell therapy, and transfer factors therapy. This paper describes the biological background of the platelet-derived substances and their potential use in regenerative medicine. PMID:22518192

The synergistic effect of photodynamic therapy and photothermal therapy in the presence of gold-gold sulfide nanoshells conjugated Indocyanine green on HeLa cells.

PubMed

Ghorbani, Farzaneh; Attaran-Kakhki, Neda; Sazgarnia, Ameneh

2017-03-01

Photodynamic therapy (PDT) and photothermal therapy (PTT) are two known optical remedies of cancer. PTT can be combined with other therapies. One of the limitations of optical therapies is the penetration of light into biological tissues, which reduces its effectiveness due to usage of photosensitizers and PTT agents, which are absorbed in the NIR region that provides the maximum penetration. For instance, Indocyanine green (ICG) serves as a photosensitizer and Gold nanostructures as agents for PTT. GGS is a gold nanoshell with two absorption peaks in the NIR and visible regions. The aim of this study is to evaluate the synergistic effect of PDT and PTT in the presence of GGS conjugated with ICG. After synthesizing GGS, ICG was conjugated with GGS. The specifications and cytotoxicity of agents were identified. Cells were irradiated by an 808nm laser with or without the agents and three laser outputs were achieved, with each having four different exposure times. The viability of treated cells was determined via MTT assay. The irradiation of the laser did not produce any significant effect by itself or in the presence of GGS. The maximum cell death recorded for GGS, ICG and GGS-ICG were 15±7%, 50±3% and 31±3% respectively. ICG and GGS-ICG differs significantly for exposures higher than 2250J/cm 2 . The conjugate was provided through a simple process and a greater chemical stability compared to GGS was achieved. Moreover, it induced a stronger photodynamic and photothermal effect on the cells. This is a promising result which can help enhance the effectiveness of a minimally invasive treatment. Copyright © 2016 Elsevier B.V. All rights reserved.

Potential for Stem Cell-Based Periodontal Therapy

PubMed Central

Bassir, Seyed Hossein; Wisitrasameewong, Wichaya; Raanan, Justin; Ghaffarigarakani, Sasan; Chung, Jamie; Freire, Marcelo; Andrada, Luciano C.; Intini, Giuseppe

2015-01-01

Periodontal diseases are highly prevalent and are linked to several systemic diseases. The goal of periodontal treatment is to halt the progression of the disease and regenerate the damaged tissue. However, achieving complete and functional periodontal regeneration is challenging because the periodontium is a complex apparatus composed of different tissues, including bone, cementum, and periodontal ligament. Stem cell-based regenerative therapy may represent an effective therapeutic tool for periodontal regeneration due to their plasticity and ability to differentiate into different cell lineages. This review presents and critically analyzes the available information on stem cell-based therapy for the regeneration of periodontal tissues and suggests new avenues for the development of more effective therapeutic protocols. PMID:26058394

Response to apatinib in chemotherapy-failed advanced spindle cell breast carcinoma.

PubMed

Zhou, Na; Liu, Congmin; Hou, Helei; Zhang, Chuantao; Liu, Dong; Wang, Guanqun; Liu, Kewei; Zhu, Jingjuan; Lv, Hongying; Li, Tianjun; Zhang, Xiaochun

2016-11-01

Spindle cell carcinoma of the breast is a rare subtype of metaplastic carcinoma, and no effective chemotherapy special for metaplastic carcinoma exists until now. As spindle cell carcinomas of the breast are typically "Triple Negative", endocrine therapy and molecular therapy targeted to Her2 might not be favorable, resulting in poor prognosis. Apatinib is currently being tested in patients with breast or lung cancers. Here we report a successful case using Apatinib to treat spindle cell carcinoma of breast.A 52- year- old woman presented with a gradually enlarged lump in left breast, which was revealed to be a triple-negative spindle cell carcinoma, underwent a modified radical mastectomy. After the first line chemotherapy with Cyclophosphamide and Epirubicin, multiple metastases in bilateral lung and left anterior thoracic wall appeared. After disease progressed with therapy of Bevacizumab combined with Albumin-bound Paclitaxel and Cisplatin, we treated the patient with Apatinib according to her VEGFR expression, which showed nearly complete response and controllable and tolerated side effects. Next-generation sequencing analysis of the tumor specimen and real time ctDNA was performed to observe the mutated gene numbers matched with therapeutic effect. The present case can help to provide a new and effective therapy strategy to treat advanced spindle cell carcinoma.

Response to apatinib in chemotherapy-failed advanced spindle cell breast carcinoma

PubMed Central

Zhou, Na; Liu, Congmin; Hou, Helei; Zhang, Chuantao; Liu, Dong; Wang, Guanqun; Liu, Kewei; Zhu, Jingjuan; Lv, Hongying; Li, Tianjun; Zhang, Xiaochun

2016-01-01

Spindle cell carcinoma of the breast is a rare subtype of metaplastic carcinoma, and no effective chemotherapy special for metaplastic carcinoma exists until now. As spindle cell carcinomas of the breast are typically “Triple Negative”, endocrine therapy and molecular therapy targeted to Her2 might not be favorable, resulting in poor prognosis. Apatinib is currently being tested in patients with breast or lung cancers. Here we report a successful case using Apatinib to treat spindle cell carcinoma of breast. A 52- year- old woman presented with a gradually enlarged lump in left breast, which was revealed to be a triple-negative spindle cell carcinoma, underwent a modified radical mastectomy. After the first line chemotherapy with Cyclophosphamide and Epirubicin, multiple metastases in bilateral lung and left anterior thoracic wall appeared. After disease progressed with therapy of Bevacizumab combined with Albumin-bound Paclitaxel and Cisplatin, we treated the patient with Apatinib according to her VEGFR expression, which showed nearly complete response and controllable and tolerated side effects. Next-generation sequencing analysis of the tumor specimen and real time ctDNA was performed to observe the mutated gene numbers matched with therapeutic effect. The present case can help to provide a new and effective therapy strategy to treat advanced spindle cell carcinoma. PMID:27738308

Stem cell therapies in preclinical models of stroke. Is the aged brain microenvironment refractory to cell therapy?

PubMed

Sandu, Raluca Elena; Balseanu, Adrian Tudor; Bogdan, Catalin; Slevin, Mark; Petcu, Eugen; Popa-Wagner, Aurel

2017-08-01

Stroke is a devastating disease demanding vigorous search for new therapies. Initial enthusiasm to stimulate restorative processes in the ischemic brain by means of cell-based therapies has meanwhile converted into a more balanced view recognizing impediments that may be related to unfavorable age-associated environments. Recent results using a variety of drug, cell therapy or combination thereof suggest that, (i) treatment with Granulocyte-Colony Stimulating Factor (G-CSF) in aged rats has primarily a beneficial effect on functional outcome most likely via supportive cellular processes such as neurogenesis; (ii) the combination therapy, G-CSF with mesenchymal cells (G-CSF+BM-MSC or G-CSF+BM-MNC) did not further improve behavioral indices, neurogenesis or infarct volume as compared to G-CSF alone in aged animals; (iii) better results with regard to integration of transplanted cells in the aged rat environment have been obtained using iPS of human origin; (iv) mesenchymal cells may be used as drug carriers for the aged post-stroke brains. While the middle aged brain does not seem to impair drug and cell therapies, in a real clinical practice involving older post-stroke patients, successful regenerative therapies would have to be carried out for a much longer time. Copyright © 2017. Published by Elsevier Inc.

Quality cell therapy manufacturing by design.

PubMed

Lipsitz, Yonatan Y; Timmins, Nicholas E; Zandstra, Peter W

2016-04-01

Transplantation of live cells as therapeutic agents is poised to offer new treatment options for a wide range of acute and chronic diseases. However, the biological complexity of cells has hampered the translation of laboratory-scale experiments into industrial processes for reliable, cost-effective manufacturing of cell-based therapies. We argue here that a solution to this challenge is to design cell manufacturing processes according to quality-by-design (QbD) principles. QbD integrates scientific knowledge and risk analysis into manufacturing process development and is already being adopted by the biopharmaceutical industry. Many opportunities to incorporate QbD into cell therapy manufacturing exist, although further technology development is required for full implementation. Linking measurable molecular and cellular characteristics of a cell population to final product quality through QbD is a crucial step in realizing the potential for cell therapies to transform healthcare.

PD-L1 expression on malignant cells is no prerequisite for checkpoint therapy.

PubMed

Kleinovink, Jan Willem; Marijt, Koen A; Schoonderwoerd, Mark J A; van Hall, Thorbald; Ossendorp, Ferry; Fransen, Marieke F

2017-01-01

Immunotherapy with PD-1/PD-L1-blocking antibodies is clinically effective for several tumor types, but the mechanism is not fully understood. PD-L1 expression on tumor biopsies is generally regarded as an inclusion criterion for this cancer therapy. Here, we describe the PD-L1-blocking therapeutic responses of preclinical tumors in which PD-L1 expression was removed from cancer cells, but not from immune infiltrate. Lack of PD-L1 expression on malignant cells delayed tumor outgrowth in a CD8 + T cell-mediated fashion, showing the importance of this molecule in immune suppression. PD-L1 expression was evident on myeloid-infiltrating cells in the microenvironment of these tumors and targeting stromal PD-L1 with blocking antibody therapy had additional antitumor effect, demonstrating that PD-L1 on both malignant cells and immune cells is involved in the mechanism of immunotherapeutic antibodies. Importantly, comparable results were obtained with PD-1-blocking therapy. These findings have implications for inclusion of cancer patients in PD-1/PD-L1 blockade immunotherapies.

PD-L1 expression on malignant cells is no prerequisite for checkpoint therapy

PubMed Central

Marijt, Koen A.; Schoonderwoerd, Mark J. A.; Ossendorp, Ferry; Fransen, Marieke F.

2017-01-01

ABSTRACT Immunotherapy with PD-1/PD-L1-blocking antibodies is clinically effective for several tumor types, but the mechanism is not fully understood. PD-L1 expression on tumor biopsies is generally regarded as an inclusion criterion for this cancer therapy. Here, we describe the PD-L1-blocking therapeutic responses of preclinical tumors in which PD-L1 expression was removed from cancer cells, but not from immune infiltrate. Lack of PD-L1 expression on malignant cells delayed tumor outgrowth in a CD8+ T cell-mediated fashion, showing the importance of this molecule in immune suppression. PD-L1 expression was evident on myeloid-infiltrating cells in the microenvironment of these tumors and targeting stromal PD-L1 with blocking antibody therapy had additional antitumor effect, demonstrating that PD-L1 on both malignant cells and immune cells is involved in the mechanism of immunotherapeutic antibodies. Importantly, comparable results were obtained with PD-1-blocking therapy. These findings have implications for inclusion of cancer patients in PD-1/PD-L1 blockade immunotherapies. PMID:28507803

The Alpha Stem Cell Clinic: a model for evaluating and delivering stem cell-based therapies.

PubMed

Trounson, Alan; DeWitt, Natalie D; Feigal, Ellen G

2012-01-01

Cellular therapies require the careful preparation, expansion, characterization, and delivery of cells in a clinical environment. There are major challenges associated with the delivery of cell therapies and high costs that will limit the companies available to fully evaluate their merit in clinical trials, and will handicap their application at the present financial environment. Cells will be manufactured in good manufacturing practice or near-equivalent facilities with prerequisite safety practices in place, and cell delivery systems will be specialized and require well-trained medical and nursing staff, technicians or nurses trained to handle cells once delivered, patient counselors, as well as statisticians and database managers who will oversee the monitoring of patients in relatively long-term follow-up studies. The model proposed for Alpha Stem Cell Clinics will initially use the capacities and infrastructure that exist in the most advanced tertiary medical clinics for delivery of established bone marrow stem cell therapies. As the research evolves, they will incorporate improved procedures and cell preparations. This model enables commercialization of medical devices, reagents, and other products required for cell therapies. A carefully constructed cell therapy clinical infrastructure with the requisite scientific, technical, and medical expertise and operational efficiencies will have the capabilities to address three fundamental and critical functions: 1) fostering clinical trials; 2) evaluating and establishing safe and effective therapies, and 3) developing and maintaining the delivery of therapies approved by the Food and Drug Administration, or other regulatory agencies.

The influence of macrophages on mesenchymal stromal cell therapy: passive or aggressive agents?

PubMed Central

Carty, F.; English, K.

2017-01-01

Summary Mesenchymal stromal cells (MSC) have emerged as promising cell therapies for multiple conditions based on demonstrations of their potent immunomodulatory and regenerative capacities in models of inflammatory disease. Understanding the effects of MSC on T cells has dominated the majority of work carried out in this field to date; recently, however, a number of studies have shown that the therapeutic effect of MSC requires the presence of macrophages. It is timely to review the mechanisms and manner by which MSC modulate macrophage populations in order to design more effective MSC therapies and clinical studies. A complex cross‐talk exists through which MSC and macrophages communicate, a communication that is not controlled exclusively by MSC. Here, we examine the evidence that suggests that MSC not only respond to inflammatory macrophages and adjust their secretome accordingly, but also that macrophages respond to encounters with MSC, creating a feedback loop which contributes to the immune regulation observed following MSC therapy. Future studies examining the effects of MSC on macrophages should consider the antagonistic role that macrophages play in this exchange. PMID:28108980

Heat shock protein 90 (HSP90) is overexpressed in p16-negative oropharyngeal squamous cell carcinoma, and its inhibition in vitro potentiates the effects of chemoradiation.

PubMed

Patel, Kirtesh; Wen, Jing; Magliocca, Kelly; Muller, Susan; Liu, Yuan; Chen, Zhuo Georgia; Saba, Nabil; Diaz, Roberto

2014-11-01

Cisplatin and radiation therapy remain the current standard for treating locally advanced SCCHN. Novel treatment approaches are needed, especially in patients with human papilloma virus (HPV)-negative disease who have worse outcomes despite multimodality therapy. Using our institutional review board approved database, we obtained twenty oropharyngeal squamous cell carcinoma (SCC) tissue samples: ten p16 positive, ten p16-negative. Because p16 expression is strongly associated with HPV positivity in oropharyngeal SCC, p16 status was used as a marker of HPV. We subsequently analyzed, via immunohistochemistry, heat shock protein 90 (HSP90) protein levels. Using HPV-positive and HPV-negative SCC cell lines, we compared baseline HSP90 expression levels and the effect of the HSP90 inhibitor ganetespib on viability and apoptosis. Clonogenic survival of HPV-negative cells treated with ganetespib, radiation therapy, and/or cisplatin was then investigated. We characterize the effects of ganetespib on proteins that are thought to drive DNA damage resistance in HPV-negative cells. HSP90 expression was significantly higher in p16-negative compared with p16-positive samples (p = 0.016) and in HPV-negative cell lines compared with positive cells. Ganetespib increased cytotoxicity and induced apoptosis in HPV-negative more than positive cells. Adding ganetespib to cisplatin and/or radiation therapy in HPV-negative cells further decreased clonogenic survival. Finally, ganetespib downregulated expressions of EGFR, ERK, AKT, p53, and HIF-1α. Ganetespib inhibited HPV-negative SCCHN viability and potentiated cell kill when combined with cisplatin or radiation therapy in vitro. With HSP90 expression higher in HPV-negative cells and in p16-negative patients, further exploration of the clinical activity of HSP90 inhibitors in SCCHN is warranted.

Combined antitumor activity of the nitroreductase/CB1954 suicide gene system and γ-rays in HeLa cells in vitro

PubMed Central

Teng, Geling; Ju, Yuanrong; Yang, Yepeng; Hua, Hu; Chi, Jingyu; Mu, Xiuan

2016-01-01

Escherichia coli nitroreductase (NTR) may convert the prodrug CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) into a bifunctional alkylating agent, which may lead to DNA crosslinks and the apoptosis of cancer cells. NTR/CB1954 has been demonstrated to be an effective gene therapy in cancer cells. The present study examined whether the NTR/CB1954 suicide gene system had cytotoxic effects on HeLa cells and may improve the radiosensitivity of HeLa cells to γ-rays. It was observed that the NTR/CB1954 suicide gene system exerted marked cytotoxic effects on HeLa cells. The combined therapeutic effects of NTR/CB1954 and γ-rays on HeLa cells demonstrated a synergistic effect. CB1954 at concentrations of 12.5 and 25 µmol/l increased the sensitization enhancement ratio of HeLa cells to 1.54 and 1.66, respectively. Therefore, when compared with monotherapy, the combined therapy of NTR/CB1954 and γ-rays may increase the apoptotic rate and enhance the radiosensitivity of HeLa cells. The combined therapy of γ-ray radiation and the NTR/CB1954 suicide gene system may be a novel and potent therapeutic method for the treatment of cervical carcinoma. PMID:27840931

Combined antitumor activity of the nitroreductase/CB1954 suicide gene system and γ-rays in HeLa cells in vitro.

PubMed

Teng, Geling; Ju, Yuanrong; Yang, Yepeng; Hua, Hu; Chi, Jingyu; Mu, Xiuan

2016-12-01

Escherichia coli nitroreductase (NTR) may convert the prodrug CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) into a bifunctional alkylating agent, which may lead to DNA crosslinks and the apoptosis of cancer cells. NTR/CB1954 has been demonstrated to be an effective gene therapy in cancer cells. The present study examined whether the NTR/CB1954 suicide gene system had cytotoxic effects on HeLa cells and may improve the radiosensitivity of HeLa cells to γ‑rays. It was observed that the NTR/CB1954 suicide gene system exerted marked cytotoxic effects on HeLa cells. The combined therapeutic effects of NTR/CB1954 and γ‑rays on HeLa cells demonstrated a synergistic effect. CB1954 at concentrations of 12.5 and 25 µmol/l increased the sensitization enhancement ratio of HeLa cells to 1.54 and 1.66, respectively. Therefore, when compared with monotherapy, the combined therapy of NTR/CB1954 and γ‑rays may increase the apoptotic rate and enhance the radiosensitivity of HeLa cells. The combined therapy of γ‑ray radiation and the NTR/CB1954 suicide gene system may be a novel and potent therapeutic method for the treatment of cervical carcinoma.

Aging and stem cell therapy: AMPK as an applicable pharmacological target for rejuvenation of aged stem cells and achieving higher efficacy in stem cell therapy.

PubMed

Khorraminejad-Shirazi, Mohammadhossein; Farahmandnia, Mohammad; Kardeh, Bahareh; Estedlal, Alireza; Kardeh, Sina; Monabati, Ahmad

2017-10-19

In recent years, tissue regeneration has become a promising field for developing stem cell-based transplantation therapies for human patients. Adult stem cells are affected by the same aging mechanisms that involve somatic cells. One of the mechanisms involved in cellular aging is hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) and disruption of 5' adenosine monophosphate-activated protein kinase (AMPK). Aging of stem cells results in their impaired regenerative capacity and depletion of stem cell pools in adult tissue, which results in lower efficacy of stem cell therapy. By utilizing an effective therapeutic intervention for aged stem cells, stem cell therapy can become more promising for future application. mTORC1 inhibition is a practical approach to preserve the stem cell pool. In this article, we review the dynamic interaction between sirtuin (silent mating type information regulation 2 homolog) 1, AMPK, and mTORC1. We propose that using AMPK activators such as 5-aminoimidazole-4-carboxamide ribonucleotide, A769662, metformin, and oxidized nicotinamide adenine dinucleotide (NAD + ) are practical ways to be employed for achieving better optimized results in stem cell-based transplantation therapies. Copyright © 2017 King Faisal Specialist Hospital & Research Centre. Published by Elsevier B.V. All rights reserved.

[Active forms of oxygen and nitrogen in blood cells of patients with rheumatoid arthritis: effect of laser therapy].

PubMed

Ostrakhovich, E A; Ilich-Stoianovich, O; Afanas'ev, I B

2001-01-01

Infrared pulse laser therapy was studied for its impact on the production of active forms of oxygen and nitrogen by neutrophils from patients with rheumatoid arthritis (RA). The authors determined the non-activated and PMA-activated production of superoxide anion-radical, peroxynitrite, peripheral neurophilic NAD.PH-oxidase and superoxide dismutase activities, and the red blood cell concentrations of reduced glutathione. Before therapy, non-activation RA neurophilic production of superoxide was much higher than in donors. Laser therapy made this parameter normal. Similarly, neutrophilic peroxynitrite production (defined by dihydrorhodamine oxidation) in RA patients was 1.7 times higher than the normal values. IF-laser therapy decreased peroxynitrite production to the values observed in donors. It is important that the therapy caused increased SOD activity (that was lower in RA patients prior to therapy) up to apparently control values. Thus, IF-laser therapy has a certain antioxidative effect by increasing SOD activity in RA patients' blood cells and reducing the production of highly reactive oxygen and nitrogen forms.

Enhanced CAR T cell therapy: A novel approach for head and neck cancers.

PubMed

Wang, Songlin; Zhu, Zhao

2018-05-05

Head and neck cancer that presents in locally advanced stages often results in a bad prognosis with an increased recurrence rate even after curative resections. Radiation therapy is then applied, with multiple side effects, as adjuvant regional therapy. Because of the high rate of recurrence and mortality, new therapies are needed for patients suffering from head and neck malignant tumors.CAR (chimeric antigen receptor) T cell therapy, which was first devised about 25 years ago, causes the killing or apoptosis of target tumor cells through inducing the secretion of cytokines and granzymes by T cells (Cheadle et al., 2014). CARs are comprised of three canonical domains for antigen recognition, T cell activation, and co-stimulation, and are synthetic receptors that reprogram immune cells for therapeutic treatment of multiple tumors (Sadelain, 2017). This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Chimeric Antigen Receptors T Cell Therapy in Solid Tumor: Challenges and Clinical Applications.

PubMed

Mirzaei, Hamid R; Rodriguez, Analiz; Shepphird, Jennifer; Brown, Christine E; Badie, Behnam

2017-01-01

Adoptive cellular immunotherapy (ACT) employing engineered T lymphocytes expressing chimeric antigen receptors (CARs) has demonstrated promising antitumor effects in advanced hematologic cancers, such as relapsed or refractory acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma, supporting the translation of ACT to non-hematological malignancies. Although CAR T cell therapy has made remarkable strides in the treatment of patients with certain hematological cancers, in solid tumors success has been limited likely due to heterogeneous antigen expression, immunosuppressive networks in the tumor microenvironment limiting CAR T cell function and persistence, and suboptimal trafficking to solid tumors. Here, we outline specific approaches to overcome barriers to CAR T cell effectiveness in the context of the tumor microenvironment and offer our perspective on how expanding the use of CAR T cells in solid tumors may require modifications in CAR T cell design. We anticipate these modifications will further expand CAR T cell therapy in clinical practice.

Priming of the Cells: Hypoxic Preconditioning for Stem Cell Therapy.

PubMed

Wei, Zheng Z; Zhu, Yan-Bing; Zhang, James Y; McCrary, Myles R; Wang, Song; Zhang, Yong-Bo; Yu, Shan-Ping; Wei, Ling

2017-10-05

Stem cell-based therapies are promising in regenerative medicine for protecting and repairing damaged brain tissues after injury or in the context of chronic diseases. Hypoxia can induce physiological and pathological responses. A hypoxic insult might act as a double-edged sword, it induces cell death and brain damage, but on the other hand, sublethal hypoxia can trigger an adaptation response called hypoxic preconditioning or hypoxic tolerance that is of immense importance for the survival of cells and tissues. This review was based on articles published in PubMed databases up to August 16, 2017, with the following keywords: "stem cells," "hypoxic preconditioning," "ischemic preconditioning," and "cell transplantation." Original articles and critical reviews on the topics were selected. Hypoxic preconditioning has been investigated as a primary endogenous protective mechanism and possible treatment against ischemic injuries. Many cellular and molecular mechanisms underlying the protective effects of hypoxic preconditioning have been identified. In cell transplantation therapy, hypoxic pretreatment of stem cells and neural progenitors markedly increases the survival and regenerative capabilities of these cells in the host environment, leading to enhanced therapeutic effects in various disease models. Regenerative treatments can mobilize endogenous stem cells for neurogenesis and angiogenesis in the adult brain. Furthermore, transplantation of stem cells/neural progenitors achieves therapeutic benefits via cell replacement and/or increased trophic support. Combinatorial approaches of cell-based therapy with additional strategies such as neuroprotective protocols, anti-inflammatory treatment, and rehabilitation therapy can significantly improve therapeutic benefits. In this review, we will discuss the recent progress regarding cell types and applications in regenerative medicine as well as future applications.

Role of zoledronic acid in oncolytic virotherapy: Promotion of antitumor effect and prevention of bone destruction.

PubMed

Yamakawa, Yasuaki; Tazawa, Hiroshi; Hasei, Joe; Osaki, Shuhei; Omori, Toshinori; Sugiu, Kazuhisa; Komatsubara, Tadashi; Uotani, Kouji; Fujiwara, Tomohiro; Yoshida, Aki; Kunisada, Toshiyuki; Urata, Yasuo; Kagawa, Shunsuke; Ozaki, Toshifumi; Fujiwara, Toshiyoshi

2017-09-01

Osteosarcoma is an aggressive malignant bone tumor that causes bone destruction. Although tumor-specific replicating oncolytic adenovirus OBP-301 induces an antitumor effect in an osteosarcoma tumor, it cannot prevent bone destruction. Zoledronic acid (ZOL) is a clinically available agent that inhibits bone destruction. In this study, we investigated the potential of combination therapy with OBP-301 and ZOL against osteosarcomas with bone destruction. The antitumor activity of OBP-301 and ZOL in monotherapy or combination therapy was assessed using three human osteosarcoma cell lines (143B, MNNG/HOS, SaOS-2). The cytotoxic effect of OBP-301 and/or ZOL was measured by assay of cell apoptosis. The effect of OBP-301 and ZOL on osteoclast activation was investigated. The potential of combination therapy against tumor growth and bone destruction was analyzed using an orthotopic 143B osteosarcoma xenograft tumor model. OBP-301 and ZOL decreased the viability of human osteosarcoma cells. Combination therapy with OBP-301 and ZOL displayed a synergistic antitumor effect, in which OBP-301 promoted apoptosis through suppression of anti-apoptotic myeloid cell leukemia 1 (MCL1). Combination therapy significantly inhibited tumor-mediated osteoclast activation, tumor growth and bone destruction compared to monotherapy. These results suggest that combination therapy of OBP-301 and ZOL suppresses osteosarcoma progression via suppression of MCL1 and osteoclast activation. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Light-oxygen effect in cells and its potential applications in tumour therapy (review)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zakharov, S D; Ivanov, Andrei V

1999-12-31

The light-oxygen effect (POE) represents damage (and at low optical doses, activation) of cells by photogeneration of molecular singlet oxygen from O{sub 2} dissolved in cells, in accordance with the reaction: {sup 3}O{sub 2}+h{nu}{yields}{sup 1}O{sub 2}{yields} biological effect. The phases of evolution of the LOE are similar to the phases, observed in cell experiments, of the photodynamic effect (PDE) the mechanism of which is the basis of the familiar method of photodynamic cancer therapy. The reported proofs of the occurrence of the LOE are in the form of detailed spectra of the biological action of optical radiation on cells recordedmore » in four spectral intervals with the aid of tunable lasers. Allowances are made for the relationships governing a new type of cell excitation, associated with reversible structural transitions in the biomembrane. A demonstration is reported of the same efficiency of cw and pulsed irradiation. An analysis is made of the reasons why the optical doses initiating the PDE and the LOE are comparable. The results are given of the first experimental applications of the LOE in tumour therapy. Identification of the primary photoacceptor (O{sub 2}) in cell biostimulation and photodestruction provides a scientific basis for the development of low-intensity laser light-oxygen cancer therapy methods. (lasers in medicine)« less

Combination of anginex gene therapy and radiation decelerates the growth and pulmonary metastasis of human osteosarcoma xenografts.

PubMed

Zhao, Kai; Yang, Shang-You; Geng, Jun; Gong, Xuan; Gong, Weiming; Shen, Lin; Ning, Bin

2018-06-01

Investigate whether rAAV-anginex gene therapy combined with radiotherapy could decrease growth and pulmonary metastasis of osteosarcoma in mice and examine the mechanisms involved in this therapeutic strategy. During in vitro experiment, multiple treatment regimes (rAAV-eGFP, radiotherapy, rAAV-anginex, combination therapy) were applied to determine effects on proliferation of endothelial cells (ECs) and G-292 osteosarcoma cells. During in vivo analysis, the same multiple treatment regimes were applied to osteosarcoma tumor-bearing mice. Use microcomputed tomography to evaluate tumor size. Eight weeks after tumor cell inoculation, immunohistochemistry was used to assess the therapeutic efficacy according to microvessel density (MVD), proliferating cell nuclear antigen (PCNA), and terminal-deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) assays. Metastasis of lungs was also evaluated by measuring number of metastatic nodules and wet weight of metastases. The proliferation of ECs and the tumor volumes in combination therapy group were inhibited more effectively than the other three groups at end point (P < 0.05). Cell clone assay showed anginex had radiosensitization effect on ECs. Immunohistochemistry showed tumors from mice treated with combination therapy exhibited the lowest MVD and proliferation rate, with highest apoptosis rate, as confirmed by IHC staining for CD34 and PCNA and TUNEL assays (P < 0.05). Combination therapy also induced the fewest metastatic nodules and lowest wet weights of the lungs (P < 0.05). rAAV-anginex combined with radiotherapy induced apoptosis of osteosarcoma cells and inhibited tumor growth and pulmonary metastasis on the experimental osteosarcoma models. We conclude that the primary mechanism of this process may be due to sensitizing effect of anginex to radiotherapy. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Chimeric Antigen Receptor T Cell Therapy in Hematology.

PubMed

Ataca, Pınar; Arslan, Önder

2015-12-01

It is well demonstrated that the immune system can control and eliminate cancer cells. Immune-mediated elimination of tumor cells has been discovered and is the basis of both cancer vaccines and cellular therapies including hematopoietic stem cell transplantation. Adoptive T cell transfer has been improved to be more specific and potent and to cause less off-target toxicity. Currently, there are two forms of engineered T cells being tested in clinical trials: T cell receptor (TCR) and chimeric antigen receptor (CAR) modified T cells. On 1 July 2014, the United States Food and Drug Administration granted 'breakthrough therapy' designation to anti-CD19 CAR T cell therapy. Many studies were conducted to evaluate the benefits of this exciting and potent new treatment modality. This review summarizes the history of adoptive immunotherapy, adoptive immunotherapy using CARs, the CAR manufacturing process, preclinical and clinical studies, and the effectiveness and drawbacks of this strategy.

Inhibition of cell-mediated immunity by the histone deacetylase inhibitor vorinostat: implications for therapy of cutaneous T-cell lymphoma.

PubMed

Stephen, Sasha; Morrissey, Kelly A; Benoit, Bernice M; Kim, Ellen J; Vittorio, Carmela C; Nasta, Sunita D; Showe, Louise C; Wysocka, Maria; Rook, Alain H

2012-02-01

Several histone deacetylase inhibitors (HDACi), including vorinostat, have been approved for the therapy of cutaneous T-cell lymphoma (CTCL). Emerging data suggest that HDACi may exert immune suppressive effects which would be disadvantageous for therapy of CTCL. We describe a patient with Sezary syndrome who was monitored for drug-induced immunosuppression while undergoing treatment with vorinostat. Analysis of the patient's natural killer cell function before and after initiation of treatment confirmed inhibition of this important cell-mediated immune function. In addition, the in vitro effects of vorinostat on the immunity of healthy volunteers confirmed that this class of drug can profoundly suppress multiple arms of the cellular immune response. These findings raise concerns of increased susceptibility to infection in this high-risk population.

Proteomic profiling reveals that resveratrol inhibits HSP27 expression and sensitizes breast cancer cells to doxorubicin therapy.

PubMed

Díaz-Chávez, José; Fonseca-Sánchez, Miguel A; Arechaga-Ocampo, Elena; Flores-Pérez, Ali; Palacios-Rodríguez, Yadira; Domínguez-Gómez, Guadalupe; Marchat, Laurence A; Fuentes-Mera, Lizeth; Mendoza-Hernández, Guillermo; Gariglio, Patricio; López-Camarillo, César

2013-01-01

The use of chemopreventive natural compounds represents a promising strategy in the search for novel therapeutic agents in cancer. Resveratrol (3,4',5-trans-trihydroxystilbilene) is a dietary polyphenol found in fruits, vegetables and medicinal plants that exhibits chemopreventive and antitumor effects. In this study, we searched for modulated proteins with preventive or therapeutic potential in MCF-7 breast cancer cells exposed to resveratrol. Using two-dimensional electrophoresis we found significant changes (FC >2.0; p≤0.05) in the expression of 16 proteins in resveratrol-treated MCF-7 cells. Six down-regulated proteins were identified by tandem mass spectrometry (ESI-MS/MS) as heat shock protein 27 (HSP27), translationally-controlled tumor protein, peroxiredoxin-6, stress-induced-phosphoprotein-1, pyridoxine-5'-phosphate oxidase-1 and hypoxanthine-guanine phosphoribosyl transferase; whereas one up-regulated protein was identified as triosephosphate isomerase. Particularly, HSP27 overexpression has been associated to apoptosis inhibition and resistance of human cancer cells to therapy. Consistently, we demonstrated that resveratrol induces apoptosis in MCF-7 cells. Apoptosis was associated with a significant increase in mitochondrial permeability transition, cytochrome c release in cytoplasm, and caspases -3 and -9 independent cell death. Then, we evaluated the chemosensitization effect of increasing concentrations of resveratrol in combination with doxorubicin anti-neoplastic agent in vitro. We found that resveratrol effectively sensitize MCF-7 cells to cytotoxic therapy. Next, we evaluated the relevance of HSP27 targeted inhibition in therapy effectiveness. Results evidenced that HSP27 inhibition using RNA interference enhances the cytotoxicity of doxorubicin. In conclusion, our data indicate that resveratrol may improve the therapeutic effects of doxorubicin in part by cell death induction. We propose that potential modulation of HSP27 levels using natural alternative agents, as resveratrol, may be an effective adjuvant in breast cancer therapy.

Dynamics of the HIV infection under antiretroviral therapy: A cellular automata approach

NASA Astrophysics Data System (ADS)

González, Ramón E. R.; Coutinho, Sérgio; Zorzenon dos Santos, Rita Maria; de Figueirêdo, Pedro Hugo

2013-10-01

The dynamics of human immunodeficiency virus infection under antiretroviral therapy is investigated using a cellular automata model where the effectiveness of each drug is self-adjusted by the concentration of CD4+ T infected cells present at each time step. The effectiveness of the drugs and the infected cell concentration at the beginning of treatment are the control parameters of the cell population’s dynamics during therapy. The model allows describing processes of mono and combined therapies. The dynamics that emerges from this model when considering combined antiretroviral therapies reproduces with fair qualitative agreement the phases and different time scales of the process. As observed in clinical data, the results reproduce the significant decrease in the population of infected cells and a concomitant increase of the population of healthy cells in a short timescale (weeks) after the initiation of treatment. Over long time scales, early treatment with potent drugs may lead to undetectable levels of infection. For late treatment or treatments starting with a low density of CD4+ T healthy cells it was observed that the treatment may lead to a steady state in which the T cell counts are above the threshold associated with the onset of AIDS. The results obtained are validated through comparison to available clinical trial data.

Human Embryonic Stem Cell Therapy in Crohn’s Disease: A Case Report

PubMed Central

Shroff, Geeta

2016-01-01

Patient: Male, 21 Final Diagnosis: Crohn’s disease Symptoms: Intolerance to specific foods • abdominal pain and diarrhea Medication: Human embryonic stem cell therapy Clinical Procedure: Human embryonic stem cell transplantation Specialty: Gastroenterology Objective: Unusual or unexpected effect of treatment Background: Crohn’s disease is a chronic inflammatory disease of the intestines, mainly the colon and ileum, related with ulcers and fistulae. It is estimated to affect 565 000 people in the United States. Currently available therapies, such as antibiotics, thiopurines, and anti-tumor necrosis factor-alpha agents, are only observed to reduce the complications associated with Crohn’s disease and to improve quality of life, but cannot cure the disease. Stem cell therapy appears to have certain advantages over conventional therapies. Our study aimed to evaluate the efficacy of human embryonic stem cell therapy in a patient with Crohn’s disease. Case Report: A 21-year-old male with chief complaints of intolerance to specific foods, abdominal pain, and diarrhea underwent human embryonic stem cell therapy for two months. After undergoing human embryonic stem cell therapy, the patient showed symptomatic relief. He had no complaints of back pain, abdominal pain, or diarrhea and had improved digestion. The patient had no signs and symptoms of skin infection, and had improved limb stamina, strength, and endurance. The condition of patient was stable after the therapy. Conclusions: Human embryonic stem cell therapy might serve as a new optimistic treatment approach for Crohn’s disease. PMID:26923312

Stem Cell Gene Therapy for Fanconi Anemia: Report from the 1st International Fanconi Anemia Gene Therapy Working Group Meeting

PubMed Central

Tolar, Jakub; Adair, Jennifer E; Antoniou, Michael; Bartholomae, Cynthia C; Becker, Pamela S; Blazar, Bruce R; Bueren, Juan; Carroll, Thomas; Cavazzana-Calvo, Marina; Clapp, D Wade; Dalgleish, Robert; Galy, Anne; Gaspar, H Bobby; Hanenberg, Helmut; Von Kalle, Christof; Kiem, Hans-Peter; Lindeman, Dirk; Naldini, Luigi; Navarro, Susana; Renella, Raffaele; Rio, Paula; Sevilla, Julián; Schmidt, Manfred; Verhoeyen, Els; Wagner, John E; Williams, David A; Thrasher, Adrian J

2011-01-01

Survival rates after allogeneic hematopoietic cell transplantation (HCT) for Fanconi anemia (FA) have increased dramatically since 2000. However, the use of autologous stem cell gene therapy, whereby the patient's own blood stem cells are modified to express the wild-type gene product, could potentially avoid the early and late complications of allogeneic HCT. Over the last decades, gene therapy has experienced a high degree of optimism interrupted by periods of diminished expectation. Optimism stems from recent examples of successful gene correction in several congenital immunodeficiencies, whereas diminished expectations come from the realization that gene therapy will not be free of side effects. The goal of the 1st International Fanconi Anemia Gene Therapy Working Group Meeting was to determine the optimal strategy for moving stem cell gene therapy into clinical trials for individuals with FA. To this end, key investigators examined vector design, transduction method, criteria for large-scale clinical-grade vector manufacture, hematopoietic cell preparation, and eligibility criteria for FA patients most likely to benefit. The report summarizes the roadmap for the development of gene therapy for FA. PMID:21540837

Cell therapy for basement membrane-linked diseases.

PubMed

Nyström, Alexander; Bornert, Olivier; Kühl, Tobias

2017-01-01

For most disorders caused by mutations in genes encoding basement membrane (BM) proteins, there are at present only limited treatment options available. Genetic BM-linked disorders can be viewed as especially suited for treatment with cell-based therapy approaches because the proteins that need to be restored are located in the extracellular space. In consequence, complete and permanent engraftment of cells does not necessarily have to occur to achieve substantial causal therapeutic effects. For these disorders cells can be used as transient vehicles for protein replacement. In addition, it is becoming evident that BM-linked genetic disorders are modified by secondary diseases mechanisms. Cell-based therapies have also the ability to target such disease modifying mechanisms. Thus, cell therapies can simultaneously provide causal treatment and symptomatic relief, and accordingly hold great potential for treatment of BM-linked disorders. However, this potential has for most applications and diseases so far not been realized. Here, we will present the state of cell therapies for BM-linked diseases. We will discuss use of both pluripotent and differentiated cells, the limitation of the approaches, their challenges, and the way forward to potential wider implementation of cell therapies in the clinics. Copyright © 2016 Elsevier B.V. All rights reserved.

Natural compounds and combination therapy in colorectal cancer treatment.

PubMed

Rejhová, A; Opattová, A; Čumová, A; Slíva, D; Vodička, P

2018-01-20

Colorectal cancer (CRC) therapy using conventional chemotherapeutics represents a considerable burden for the patient's organism because of high toxicity while the response is relatively low. Our review summarizes the findings about natural compounds as chemoprotective agents for decreasing risk of CRC. It also identifies natural compounds which possess anti-tumor effects of various characteristics, mainly in vitro on colorectal cell lines or in vivo studies on experimental models, but also in a few clinical trials. Many of natural compounds suppress proliferation by inducing cell cycle arrest or induce apoptosis of CRC cells resulting in the inhibition of tumor growth. A novel employment of natural substances is a so-called combination therapy - administration of two or more substances - conventional chemotherapeutics and a natural compound or more natural compounds at a time. Some natural compounds may sensitize to conventional cytotoxic therapy, reinforce the drug effective concentration, intensify the combined effect of both administered therapeutics or exert cytotoxic effects specifically on tumor cells. Moreover, combined therapy by targeting multiple signaling pathways, uses various mechanisms to reduce the development of resistance to antitumor drugs. The desired effect could be to diminish burden on the patient's organism by replacing part of the dose of a conventional chemotherapeutic with a natural substance with a defined effect. Many natural compounds are well tolerated by the patients and do not cause toxic effects even at high doses. Interaction of conventional chemotherapeutics with natural compounds introduces a new aspect in the research and therapy of cancer. It could be a promising approach to potentially achieve improvements, while minimizing of adverse effects associated with conventional chemotherapy. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Immunoglobulin therapy in hematologic neoplasms and after hematopoietic cell transplantation.

PubMed

Ueda, Masumi; Berger, Melvin; Gale, Robert Peter; Lazarus, Hillard M

2018-03-01

Immunoglobulins are used to prevent or reduce infection risk in primary immune deficiencies and in settings which exploit its anti-inflammatory and immune-modulatory effects. Rigorous proof of immunoglobulin efficacy in persons with lympho-proliferative neoplasms, plasma cell myeloma, and persons receiving hematopoietic cell transplants is lacking despite many clinical trials. Further, there are few consensus guidelines or algorithms for use in these conditions. Rapid development of new therapies targeting B-cell signaling and survival pathways and increased use of chimeric antigen receptor T-cell (CAR-T) therapy will likely result in more acquired deficiencies of humoral immunity and infections in persons with cancer. We review immunoglobulin formulations and discuss efficacy and potential adverse effects in the context of preventing infections and in graft-versus-host disease. We suggest an algorithm for evaluating acquired deficiencies of humoral immunity in persons with hematologic neoplasms and recommend appropriate use of immunoglobulin therapy. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Controversies in Targeted Therapy of Adult T Cell Leukemia/Lymphoma: ON Target or OFF Target Effects?

PubMed Central

Nasr, Rihab; Hajj, Hiba El; Kfoury, Youmna; de Thé, Hugues; Hermine, Olivier; Bazarbachi, Ali

2011-01-01

Adult T cell leukemia/lymphoma (ATL) represents an ideal model for targeted therapy because of intrinsic chemo-resistance of ATL cells and the presence of two well identified targets: the HTLV-I retrovirus and the viral oncoprotein Tax. The combination of zidovudine (AZT) and interferon-alpha (IFN) has a dramatic impact on survival of ATL patients. Although the mechanism of action remains unclear, arguments in favor or against a direct antiviral effect will be discussed. Yet, most patients relapse and alternative therapies are mandatory. IFN and arsenic trioxide induce Tax proteolysis, synergize to induce apoptosis in ATL cells and cure Tax-driven ATL in mice through specific targeting of leukemia initiating cell activity. These results provide a biological basis for the clinical success of arsenic/IFN/AZT therapy in ATL patients and suggest that both extinction of viral replication (AZT) and Tax degradation (arsenic/IFN) are needed to cure ATL. PMID:21994752

Effects of highly active antiretroviral therapy on thymical reconstitution of CD4 T lymphocytes in vertically HIV-infected children.

PubMed

Correa, Rafael; Muñoz-Fernández, Angeles

2002-05-24

CD4 T-cell percentages, viral load and thymic function measured as T-cell receptor rearrangement excision circle (TREC) levels were determined every 2-3 months in six treated HIV-infected children for 4 years. All children experienced a marked increase in CD4 cell count after therapy, accompanied by a concomitantly marked increase in TREC levels. In children, the decrease in viral load caused by antiviral therapy leads to an increase in CD4 T cells, mainly because of a recovery in the thymic production of new T cells.

Toll-Like Receptor 7 Agonist GS-9620 Induces HIV Expression and HIV-Specific Immunity in Cells from HIV-Infected Individuals on Suppressive Antiretroviral Therapy.

PubMed

Tsai, Angela; Irrinki, Alivelu; Kaur, Jasmine; Cihlar, Tomas; Kukolj, George; Sloan, Derek D; Murry, Jeffrey P

2017-04-15

Antiretroviral therapy can suppress HIV replication to undetectable levels but does not eliminate latent HIV, thus necessitating lifelong therapy. Recent efforts to target this persistent reservoir have focused on inducing the expression of latent HIV so that infected cells may be recognized and eliminated by the immune system. Toll-like receptor (TLR) activation stimulates antiviral immunity and has been shown to induce HIV from latently infected cells. Activation of TLR7 leads to the production of several stimulatory cytokines, including type I interferons (IFNs). In this study, we show that the selective TLR7 agonist GS-9620 induced HIV in peripheral blood mononuclear cells (PBMCs) from HIV-infected individuals on suppressive antiretroviral therapy. GS-9620 increased extracellular HIV RNA 1.5- to 2-fold through a mechanism that required type I IFN signaling. GS-9620 also activated HIV-specific T cells and enhanced antibody-mediated clearance of HIV-infected cells. Activation by GS-9620 in combination with HIV peptide stimulation increased CD8 T cell degranulation, production of intracellular cytokines, and cytolytic activity. T cell activation was again dependent on type I IFNs produced by plasmacytoid dendritic cells. GS-9620 induced phagocytic cell maturation and improved effector-mediated killing of HIV-infected CD4 T cells by the HIV envelope-specific broadly neutralizing antibody PGT121. Collectively, these data show that GS-9620 can activate HIV production and improve the effector functions that target latently infected cells. GS-9620 may effectively complement orthogonal therapies designed to stimulate antiviral immunity, such as therapeutic vaccines or broadly neutralizing antibodies. Clinical studies are under way to determine if GS-9620 can target HIV reservoirs. IMPORTANCE Though antiretroviral therapies effectively suppress viral replication, they do not eliminate integrated proviral DNA. This stable intermediate of viral infection is persistently maintained in reservoirs of latently infected cells. Consequently, lifelong therapy is required to maintain viral suppression. Ultimately, new therapies that specifically target and eliminate the latent HIV reservoir are needed. Toll-like receptor agonists are potent enhancers of innate antiviral immunity that can also improve the adaptive immune response. Here, we show that a highly selective TLR7 agonist, GS-9620, activated HIV from peripheral blood mononuclear cells isolated from HIV-infected individuals with suppressed infection. GS-9620 also improved immune effector functions that specifically targeted HIV-infected cells. Previously published studies on the compound in other chronic viral infections show that it can effectively induce immune activation at safe and tolerable clinical doses. Together, the results of these studies suggest that GS-9620 may be useful for treating HIV-infected individuals on suppressive antiretroviral therapy. Copyright © 2017 Tsai et al.

Toll-Like Receptor 7 Agonist GS-9620 Induces HIV Expression and HIV-Specific Immunity in Cells from HIV-Infected Individuals on Suppressive Antiretroviral Therapy

PubMed Central

Tsai, Angela; Irrinki, Alivelu; Kaur, Jasmine; Cihlar, Tomas; Kukolj, George

2017-01-01

ABSTRACT Antiretroviral therapy can suppress HIV replication to undetectable levels but does not eliminate latent HIV, thus necessitating lifelong therapy. Recent efforts to target this persistent reservoir have focused on inducing the expression of latent HIV so that infected cells may be recognized and eliminated by the immune system. Toll-like receptor (TLR) activation stimulates antiviral immunity and has been shown to induce HIV from latently infected cells. Activation of TLR7 leads to the production of several stimulatory cytokines, including type I interferons (IFNs). In this study, we show that the selective TLR7 agonist GS-9620 induced HIV in peripheral blood mononuclear cells (PBMCs) from HIV-infected individuals on suppressive antiretroviral therapy. GS-9620 increased extracellular HIV RNA 1.5- to 2-fold through a mechanism that required type I IFN signaling. GS-9620 also activated HIV-specific T cells and enhanced antibody-mediated clearance of HIV-infected cells. Activation by GS-9620 in combination with HIV peptide stimulation increased CD8 T cell degranulation, production of intracellular cytokines, and cytolytic activity. T cell activation was again dependent on type I IFNs produced by plasmacytoid dendritic cells. GS-9620 induced phagocytic cell maturation and improved effector-mediated killing of HIV-infected CD4 T cells by the HIV envelope-specific broadly neutralizing antibody PGT121. Collectively, these data show that GS-9620 can activate HIV production and improve the effector functions that target latently infected cells. GS-9620 may effectively complement orthogonal therapies designed to stimulate antiviral immunity, such as therapeutic vaccines or broadly neutralizing antibodies. Clinical studies are under way to determine if GS-9620 can target HIV reservoirs. IMPORTANCE Though antiretroviral therapies effectively suppress viral replication, they do not eliminate integrated proviral DNA. This stable intermediate of viral infection is persistently maintained in reservoirs of latently infected cells. Consequently, lifelong therapy is required to maintain viral suppression. Ultimately, new therapies that specifically target and eliminate the latent HIV reservoir are needed. Toll-like receptor agonists are potent enhancers of innate antiviral immunity that can also improve the adaptive immune response. Here, we show that a highly selective TLR7 agonist, GS-9620, activated HIV from peripheral blood mononuclear cells isolated from HIV-infected individuals with suppressed infection. GS-9620 also improved immune effector functions that specifically targeted HIV-infected cells. Previously published studies on the compound in other chronic viral infections show that it can effectively induce immune activation at safe and tolerable clinical doses. Together, the results of these studies suggest that GS-9620 may be useful for treating HIV-infected individuals on suppressive antiretroviral therapy. PMID:28179531

Therapeutic potential of CAR-T cell-derived exosomes: a cell-free modality for targeted cancer therapy.

PubMed

Tang, Xiang-Jun; Sun, Xu-Yong; Huang, Kuan-Ming; Zhang, Li; Yang, Zhuo-Shun; Zou, Dan-Dan; Wang, Bin; Warnock, Garth L; Dai, Long-Jun; Luo, Jie

2015-12-29

Chimeric antigen receptor (CAR)-based T-cell adoptive immunotherapy is a distinctively promising therapy for cancer. The engineering of CARs into T cells provides T cells with tumor-targeting capabilities and intensifies their cytotoxic activity through stimulated cell expansion and enhanced cytokine production. As a novel and potent therapeutic modality, there exists some uncontrollable processes which are the potential sources of adverse events. As an extension of this impactful modality, CAR-T cell-derived exosomes may substitute CAR-T cells to act as ultimate attackers, thereby overcoming some limitations. Exosomes retain most characteristics of parent cells and play an essential role in intercellular communications via transmitting their cargo to recipient cells. The application of CAR-T cell-derived exosomes will make this cell-based therapy more clinically controllable as it also provides a cell-free platform to diversify anticancer mediators, which responds effectively to the complexity and volatility of cancer. It is believed that the appropriate application of both cellular and exosomal platforms will make this effective treatment more practicable.

Hyperbaric Oxygen Therapy in Treating Long-Term Gastrointestinal Adverse Effects Caused by Radiation Therapy in Patients With Pelvic Cancer

ClinicalTrials.gov

2011-07-14

Bladder Cancer; Cervical Cancer; Colorectal Cancer; Endometrial Cancer; Gastrointestinal Complications; Long-term Effects Secondary to Cancer Therapy in Adults; Ovarian Cancer; Prostate Cancer; Radiation Toxicity; Sarcoma; Testicular Germ Cell Tumor; Vaginal Cancer

ADOPTIVE-CELL-TRANSFER THERAPY FOR THE TREATMENT OF PATIENTS WITH CANCER

PubMed Central

Dudley, Mark E.; Rosenberg, Steven A.

2008-01-01

Adoptive immunotherapy — the isolation of antigen-specific cells, their ex vivo expansion and activation, and subsequent autologous administration — is a promising approach to inducing antitumour immune responses. The molecular identification of tumour antigens and the ability to monitor the persistence and transport of transferred cells has provided new insights into the mechanisms of tumour immunotherapy. Recent studies have shown the effectiveness of cell-transfer therapies for the treatment of patients with selected metastatic cancers. These studies provide a blueprint for the wider application of adoptive-cell-transfer therapy, and emphasize the requirement for in vivo persistence of the cells for therapeutic efficacy. PMID:12951585

Caspase-3-independent pathways proceeding in bystander effect of HSV-tk/GCV system

NASA Astrophysics Data System (ADS)

Lin, Juqiang; Ma, Yan; Zeng, Shaoqun; Zhang, Zhihong

2008-02-01

HSV-tk/GCV system, which is the virus-directed enzyme/prodrug therapy of herpes simplex virus (HSV) thymidine kinase (tk) gene / the anti-viral reagent ganciclovir (GCV), is one of the promising approaches in the rapidly growing area of gene therapy. As gene therapy of cancer such as suicide gene therapy has entered the clinic, another therapy effect which is called 'bystander effect' was reported. Bystander effect can lead to killing of non-transduced tumor cells in the immediate vicinity of GCV-treated HSV-TK-positive cells. Now the magnitude of 'bystander effect' is an essential factor for this anti-tumor approach in vivo. However, the mechanism which HSV-tk/ACV brings "bystander effect" is poorly understood. In this study, we monitor the activation of caspase-3 in HSV-tk/GCV system by a FRET probe CD3, a FRET-based indicator for activity of caspase3, which is composed of an enhanced cyan fluorescent protein, a caspase-sensitive linker, and a red fluorescent protein from Discosoma with efficient maturation property. Through application of CD3 we have visualized the activation of caspase-3 in tk gene positive human adenoid cystic carcinoma (ACC-M) cells but not in bystander effect of HSV-tk/GCV system induced by GCV. This finding provides needed information for understanding the mechanisms by which suicide gene approaches actually kill cancer cells, and may prove to be helpful for the clinical treatment of cancers.

Micro-RNA-181a suppresses progestin-promoted breast cancer cell growth.

PubMed

Gu, Muqing; Wang, Lijuan; Yang, Chun; Li, Xue; Jia, Chanwei; Croteau, Stephane; Ruan, Xiangyan; Hardy, Pierre

2018-08-01

Recent investigations have indicated that hormone therapy may increase the risk of breast cancer (BC), and the addition of synthetic progestins may play a critical role in this. Several studies have pointed out the important role of progesterone receptor membrane component 1 (PGRMC1) in the development of BC, especially with hormone therapy using progestins. Although the deregulation of microRNA-181a (miR-181a) is often associated with human BC, the effect of miR-181a on PGRMC1 expression during hormone therapy has not been investigated. Cell viability assay and apoptosis assay were performed to investigate the pro-BC effect of progestin (norethisterone, NET) and anti-BC effect of miR-181a on MCF-7 cells. Quantitative RT-PCR and Western blot analysis were used to evaluate gene expressions in the NET-treated MCF-7 cells. NET dose-dependently increased BC cell viability and this effect was accompanied by increased expression of PGRMC1. Overexpression of miR-181a strongly reduced the cell viability of MCF-7 cells, mainly through increased apoptosis, which was evidenced by substantially increased gene expression of pro-apoptosis factors such as BAX and CASPASE 9 in miR-181a overexpressed cells. Importantly, miR-181a abrogated NET-stimulated cell viability and PGRMC1 expression. We provide evidence that miR-181a promotes MCF-7 cell apoptosis. Moreover, miR-181a suppressed NET-provoked cell viability and PGRMC1 expression in MCF-7 cells. These data may suggest a therapeutic strategy of using miR-181a to reduce BC risk in progestin hormone replacement therapy. Copyright © 2018 Elsevier B.V. All rights reserved.

Inhibition of Regulatory Volume Decrease Enhances the Cytocidal Effect of Hypotonic Shock in Hepatocellular Carcinoma.

PubMed

Kudou, Michihiro; Shiozaki, Atsushi; Kosuga, Toshiyuki; Ichikawa, Daisuke; Konishi, Hirotaka; Morimura, Ryo; Komatsu, Shuhei; Ikoma, Hisashi; Fujiwara, Hitoshi; Okamoto, Kazuma; Hosogi, Shigekuni; Nakahari, Takashi; Marunaka, Yoshinori; Otsuji, Eigo

2016-01-01

Background : Hypotonic shock induces cytocidal effects through cell rupture, and cancer therapy based on this mechanism has been clinically administered to hepatocellular carcinoma patients. We herein investigated the effectiveness of hypotonic shock combined with the inhibition of regulatory volume decrease as cancer therapy for hepatocellular carcinoma. Methods : Morphological changes in human hepatocellular carcinoma cell lines were observed under a differential interference contrast microscope connected to a high-speed digital video camera. Cell volume changes under hypotonic shock with or without chloride, potassium, or water channel blockers were observed using a high-resolution flow cytometer. In order to investigate cytocidal effects, the number of surviving cells was compared after exposure to hypotonic solution with and without each channel blocker (re-incubation experiment). Results : Video recordings showed that cells exposed to distilled water rapidly swelled and then ruptured. Cell volume measurements revealed regulatory volume decrease under mild hypotonic shock, whereas severe hypotonic shock increased the number of broken fragments as a result of cell rupture. Moreover, regulatory volume decrease was inhibited in cells treated with each channel blocker. Re-incubation experiments showed the cytocidal effects of hypotonic shock in cells exposed to hypotonic solution, and additional treatments with each channel blocker enhanced these effects. Conclusion : The inhibition of regulatory volume decrease with chloride, potassium, or water channel blockers may enhance the cytocidal effects of hypotonic shock in hepatocellular carcinoma. Hypotonic shock combined with the inhibition of regulatory volume decrease was a more effective therapy than hypotonic shock alone.

Inhibition of Regulatory Volume Decrease Enhances the Cytocidal Effect of Hypotonic Shock in Hepatocellular Carcinoma

PubMed Central

Kudou, Michihiro; Shiozaki, Atsushi; Kosuga, Toshiyuki; Ichikawa, Daisuke; Konishi, Hirotaka; Morimura, Ryo; Komatsu, Shuhei; Ikoma, Hisashi; Fujiwara, Hitoshi; Okamoto, Kazuma; Hosogi, Shigekuni; Nakahari, Takashi; Marunaka, Yoshinori; Otsuji, Eigo

2016-01-01

Background: Hypotonic shock induces cytocidal effects through cell rupture, and cancer therapy based on this mechanism has been clinically administered to hepatocellular carcinoma patients. We herein investigated the effectiveness of hypotonic shock combined with the inhibition of regulatory volume decrease as cancer therapy for hepatocellular carcinoma. Methods: Morphological changes in human hepatocellular carcinoma cell lines were observed under a differential interference contrast microscope connected to a high-speed digital video camera. Cell volume changes under hypotonic shock with or without chloride, potassium, or water channel blockers were observed using a high-resolution flow cytometer. In order to investigate cytocidal effects, the number of surviving cells was compared after exposure to hypotonic solution with and without each channel blocker (re-incubation experiment). Results: Video recordings showed that cells exposed to distilled water rapidly swelled and then ruptured. Cell volume measurements revealed regulatory volume decrease under mild hypotonic shock, whereas severe hypotonic shock increased the number of broken fragments as a result of cell rupture. Moreover, regulatory volume decrease was inhibited in cells treated with each channel blocker. Re-incubation experiments showed the cytocidal effects of hypotonic shock in cells exposed to hypotonic solution, and additional treatments with each channel blocker enhanced these effects. Conclusion: The inhibition of regulatory volume decrease with chloride, potassium, or water channel blockers may enhance the cytocidal effects of hypotonic shock in hepatocellular carcinoma. Hypotonic shock combined with the inhibition of regulatory volume decrease was a more effective therapy than hypotonic shock alone. PMID:27471568

Small RNA Enhances Antitumor T-cell Therapy | Center for Cancer Research

Cancer.gov

Adoptive T-cell transfer is an effective form of anticancer immunotherapy in which patients receive infusions of cytotoxic T cells that seek out and destroy targeted cancer cells. This type of therapy is usually preceded by a lymphodepleting chemotherapy regimen and combined with high doses of the cytokine interleukin-2 (IL-2) to eliminate immunosuppressive and other immune

Current perspectives on the use of ancillary materials for the manufacture of cellular therapies.

PubMed

Solomon, Jennifer; Csontos, Lynn; Clarke, Dominic; Bonyhadi, Mark; Zylberberg, Claudia; McNiece, Ian; Kurtzberg, Joanne; Bell, Rosemarie; Deans, Robert

2016-01-01

Continued growth in the cell therapy industry and commercialization of cell therapies that successfully advance through clinical trials has led to increased awareness around the need for specialized and complex materials utilized in their manufacture. Ancillary materials (AMs) are components or reagents used during the manufacture of cell therapy products but are not intended to be part of the final products. Commonly, there are limitations in the availability of clinical-grade reagents used as AMs. Furthermore, AMs may affect the efficacy of the cell product and subsequent safety of the cell therapy for the patient. As such, AMs must be carefully selected and appropriately qualified during the cell therapy development process. However, the ongoing evolution of cell therapy research, limited number of clinical trials and registered cell therapy products results in the current absence of specific regulations governing the composition, compliance, and qualification of AMs often leads to confusion by suppliers and users in this field. Here we provide an overview and interpretation of the existing global framework surrounding AM use and investigate some common misunderstandings within the industry, with the aim of facilitating the appropriate selection and qualification of AMs. The key message we wish to emphasize is that in order to most effectively mitigate risk around cell therapy development and patient safety, users must work with their suppliers and regulators to qualify each AM to assess source, purity, identity, safety, and suitability in a given application. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Stem Cell Therapy for the Central Nervous System in Lysosomal Storage Diseases.

PubMed

Siddiqi, Faez; Wolfe, John H

2016-10-01

Neurological diseases with genetic etiologies result in the loss or dysfunction of neural cells throughout the CNS. At present, few treatment options exist for the majority of neurogenetic diseases. Stem cell transplantation (SCT) into the CNS has the potential to be an effective treatment modality because progenitor cells may replace lost cells in the diseased brain, provide multiple trophic factors, or deliver missing proteins. This review focuses on the use of SCT in lysosomal storage diseases (LSDs), a large group of monogenic disorders with prominent CNS disease. In most patients the CNS disease results in intellectual disability that is refractory to current standard-of-care treatment. A large amount of preclinical work on brain-directed SCT has been performed in rodent LSD models. Cell types that have been used for direct delivery into the CNS include neural stem cells, embryonic and induced pluripotent stem cells, and mesenchymal stem cells. Hematopoietic stem cells have been an effective therapy for the CNS in a few LSDs and may be augmented by overexpression of the missing gene. Current barriers and potential strategies to improve SCT for translation into effective patient therapies are discussed.

Cell-based therapeutic strategies for multiple sclerosis

PubMed Central

Scolding, Neil J; Pasquini, Marcelo; Reingold, Stephen C; Cohen, Jeffrey A; Atkins, Harold; Banwell, Brenda; Bar-Or, Amit; Bebo, Bruce; Bowen, James; Burt, Richard; Calabresi, Peter; Cohen, Jeffrey; Comi, Giancarlo; Connick, Peter; Cross, Anne; Cutter, Gary; Derfuss, Tobias; Ffrench-Constant, Charles; Freedman, Mark; Galipeau, Jacques; Goldman, Myla; Goldman, Steven; Goodman, Andrew; Green, Ari; Griffith, Linda; Hartung, Hans-Peter; Hemmer, Bernhard; Hyun, Insoo; Iacobaeus, Ellen; Inglese, Matilde; Jubelt, Burk; Karussis, Dimitrios; Küry, Patrick; Landsman, Douglas; Laule, Cornelia; Liblau, Roland; Mancardi, Giovanni; Ann Marrie, Ruth; Miller, Aaron; Miller, Robert; Miller, David; Mowry, Ellen; Muraro, Paolo; Nash, Richard; Ontaneda, Daniel; Pasquini, Marcelo; Pelletier, Daniel; Peruzzotti-Jametti, Luca; Pluchino, Stefano; Racke, Michael; Reingold, Stephen; Rice, Claire; Ringdén, Olle; Rovira, Alex; Saccardi, Riccardo; Sadiq, Saud; Sarantopoulos, Stefanie; Savitz, Sean; Scolding, Neil; Soelberg Sorensen, Per; Pia Sormani, Maria; Stuve, Olaf; Tesar, Paul; Thompson, Alan; Trojano, Maria; Uccelli, Antonio; Uitdehaag, Bernard; Utz, Ursula; Vukusic, Sandra; Waubant, Emmanuelle; Wilkins, Alastair

2017-01-01

Abstract The availability of multiple disease-modifying medications with regulatory approval to treat multiple sclerosis illustrates the substantial progress made in therapy of the disease. However, all are only partially effective in preventing inflammatory tissue damage in the central nervous system and none directly promotes repair. Cell-based therapies, including immunoablation followed by autologous haematopoietic stem cell transplantation, mesenchymal and related stem cell transplantation, pharmacologic manipulation of endogenous stem cells to enhance their reparative capabilities, and transplantation of oligodendrocyte progenitor cells, have generated substantial interest as novel therapeutic strategies for immune modulation, neuroprotection, or repair of the damaged central nervous system in multiple sclerosis. Each approach has potential advantages but also safety concerns and unresolved questions. Moreover, clinical trials of cell-based therapies present several unique methodological and ethical issues. We summarize here the status of cell-based therapies to treat multiple sclerosis and make consensus recommendations for future research and clinical trials. PMID:29053779

Metabolic and structural integrity of magnetic nanoparticle-loaded primary endothelial cells for targeted cell therapy.

PubMed

Orynbayeva, Zulfiya; Sensenig, Richard; Polyak, Boris

2015-05-01

To successfully translate magnetically mediated cell targeting from bench to bedside, there is a need to systematically assess the potential adverse effects of magnetic nanoparticles (MNPs) interacting with 'therapeutic' cells. Here, we examined in detail the effects of internalized polymeric MNPs on primary rat endothelial cells' structural intactness, metabolic integrity and proliferation potential. The intactness of cytoskeleton and organelles was studied by fluorescent confocal microscopy, flow cytometry and high-resolution respirometry. MNP-loaded primary endothelial cells preserve intact cytoskeleton and organelles, maintain normal rate of proliferation, calcium signaling and mitochondria energy metabolism. This study provides supportive evidence that MNPs at doses necessary for targeting did not induce significant adverse effects on structural integrity and functionality of primary endothelial cells - potential cell therapy vectors.

Antigen-specific CTLs: to produce autologous cells product for adoptive cellular therapy.

PubMed

Liu, Sai; Shao, Yi; Xu, Jie; Jiang, Na; Dai, Yanchao; Wang, Yu; Sun, Huanqing; Sun, Jianping; Zhang, Yonghong

2017-06-01

As antiretroviral therapy provides long term viral suppression but no cure, alternative therapies such as adoptive cellular therapy have thus been investigated in the anti-AIDS field. This study sought to establish a HLA-A02 specific CTL cell culture method with comparison of the effects of different cytokines used in CTL cultivation to decide the best cultivation environment. In order to produce CTLs with targeted HLA-A02 restricted antigen specificity for adoptive cellular therapy, we evaluated autologous PBMC cultivation in different cytokine environment to select a better expansion condition to produce qualified CTL production. We co-cultivated PBMC and peptides of these patients with HLA-A02 allele with different cytokines. After cultivation, multiple parameters were tested. 1) Cytokines IL-2 alone can effectively amplify HLA-A02 specific CTL cells, and the count of CTLs was >85% all through the process. 2) The HLA-A02 specific cells at the end of the cultivation were mainly CD3+CD8+ cells. 3) The interferon stimulation test had shown that the expanded CTLs secreted more IFN-γ than before cultivation (0.9% -11.70%). This model of CTL cultivation is successful in redirecting the specificity of antigen recognition and safely for HLA-A02+ patients cell adoptive therapy. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

The use of cell-sheet technique eliminates arrhythmogenicity of skeletal myoblast-based therapy to the heart with enhanced therapeutic effects.

PubMed

Narita, Takuya; Shintani, Yasunori; Ikebe, Chiho; Kaneko, Masahiro; Harada, Narumi; Tshuma, Nomathamsanqa; Takahashi, Kunihiko; Campbell, Niall G; Coppen, Steven R; Yashiro, Kenta; Sawa, Yoshiki; Suzuki, Ken

2013-09-20

Clinical application of skeletal myoblast transplantation has been curtailed due to arrhythmogenicity and inconsistent therapeutic benefits observed in previous studies. However, these issues may be solved by the use of a new cell-delivery mode. It is now possible to generate "cell-sheets" using temperature-responsive dishes without artificial scaffolds. This study aimed to validate the safety and efficacy of epicardial placement of myoblast-sheets (myoblast-sheet therapy) in treating heart failure. After coronary artery ligation in rats, the same numbers of syngeneic myoblasts were transplanted by intramyocardial injection or cell-sheet placement. Continuous radio-telemetry monitoring detected increased ventricular arrhythmias, including ventricular tachycardia, after intramyocardial injection compared to the sham-control, while these were abolished in myoblast-sheet therapy. This effect was conjunct with avoidance of islet-like cell-cluster formation that disrupts electrical conduction, and with prevention of increased arrhythmogenic substrates due to exaggerated inflammation. Persistent ectopic donor cells were found in the lung only after intramyocardial injection, strengthening the improved safety of myoblast-sheet therapy. In addition, myoblast-sheet therapy enhanced cardiac function, corresponding to a 9.2-fold increase in donor cell survival, compared to intramyocardial injection. Both methods achieved reduced infarct size, decreased fibrosis, attenuated cardiomyocyte hypertrophy, and increased neovascular formation, in association with myocardial upregulation of a group of relevant molecules. The pattern of these beneficial changes was similar between two methods, but the degree was more substantial after myoblast-sheet therapy. The cell-sheet technique enhanced safety and therapeutic efficacy of myoblast-based therapy, compared to the current method, thereby paving the way for clinical application. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Regulated and Unregulated Clinical Trials of Stem Cell Therapies for Stroke

PubMed Central

Liska, Michael G.; Crowley, Marci G.; Borlongan, Cesar V.

2017-01-01

Several lines of laboratory investigations reporting solid safety profiles and robust efficacy readouts of stem cells in clinically relevant animal models have advanced stem cell transplantation as an experimental therapy for stroke. Unfortunately, translating laboratory findings into effective clinical trials entails rigorous regulatory examinations, which posed a major challenge in the application of stem cells to patients. As a consequence of this slow pace of clinical entry, and a media-propagated hype narrating stem cells as a “magic bullet”, a dangerous market has been created for unregulated stem cell clinics. These clinics are often guilty of misleading patients and delivering low-quality, even harmful, treatments. Additionally, these medical tourism-purported clinical procedures, which have been performed even in the US, are likely to negatively impact on the true science and clinical value of stem cells. For the full potential of stem cell therapies to be realized, these pressing public misconceptions and regulatory clinical concerns must be addressed. Here, we provide the scientific evidence supporting the safe and effective conduct of stem cells. Arguably, relying on such evidence-based science to dictate the translation of stem cells from the laboratory to the clinic should allow an objective assessment of the risks and the rewards, and the delineation of the hype from hope of this experimental stroke therapy. PMID:28127687

Evaluation of Silicon Phthalocyanine 4 Photodynamic Therapy Against Human Cervical Cancer Cells In Vitro and in Mice

PubMed Central

Gadzinski, Jill A.; Guo, Jianxia; Philips, Brian J.; Basse, Per; Craig, Ethan K.; Bailey, Lisa; Comerci, John T.; Eiseman, Julie L.

2017-01-01

Background Cervical cancer is the second most common cancer in women worldwide [1]. Photodynamic therapy has been used for cervical intraepithelial neoplasia with good responses, but few studies have used newer phototherapeutics. We evaluated the effectiveness of photodynamic therapy using Pc 4 in vitro and in vivo against human cervical cancer cells. Methods CaSki and ME-180 cancer cells were grown as monolayers and spheroids. Cell growth and cytotoxicity were measured using a methylthiazol tetrazolium assay. Pc 4 cellular uptake and intracellular distrubtion were determined. For in vitro Pc 4 photodynamic therapy cells were irradiated at 667nm at a fluence of 2.5 J/cm2 at 48 h. SCID mice were implanted with CaSki and ME-180 cells both subcutaneously and intracervically. Forty-eight h after Pc 4 photodynamic therapy was administered at 75 and 150 J/cm2. Results The IC50s for Pc 4 and Pc 4 photodynamic therapy for CaSki and ME-180 cells as monolayers were, 7.6μM and 0.016μM and >10μM and 0.026μM; as spheroids, IC50s of Pc 4 photodynamic therapy were, 0.26μM and 0.01μM. Pc 4 was taken up within cells and widely distributed in tumors and tissues. Intracervical photodynamic therapy resulted in tumor death, however mice died due to gastrointestinal toxicity. Photodynamic therapy resulted in subcutaneous tumor death and growth delay. Conclusions Pc 4 photodynamic therapy caused death within cervical cancer cells and xenografts, supporting development of Pc 4 photodynamic therapy for treatment of cervical cancer. Support: P30-CA47904, CTSI BaCCoR Pilot Program. PMID:28890844

T cell Bim levels reflect responses to anti–PD-1 cancer therapy

PubMed Central

Dronca, Roxana S.; Liu, Xin; Harrington, Susan M.; Chen, Lingling; Cao, Siyu; Kottschade, Lisa A.; McWilliams, Robert R.; Block, Matthew S.; Nevala, Wendy K.; Thompson, Michael A.; Mansfield, Aaron S.; Park, Sean S.; Markovic, Svetomir N.

2016-01-01

Immune checkpoint therapy with PD-1 blockade has emerged as an effective therapy for many advanced cancers; however, only a small fraction of patients achieve durable responses. To date, there is no validated blood-based means of predicting the response to PD-1 blockade. We report that Bim is a downstream signaling molecule of the PD-1 pathway, and its detection in T cells is significantly associated with expression of PD-1 and effector T cell markers. High levels of Bim in circulating tumor-reactive (PD-1+CD11ahiCD8+) T cells were prognostic of poor survival in patients with metastatic melanoma who did not receive anti–PD-1 therapy and were also predictive of clinical benefit in patients with metastatic melanoma who were treated with anti–PD-1 therapy. Moreover, this circulating tumor-reactive T cell population significantly decreased after successful anti–PD-1 therapy. Our study supports a crucial role of Bim in both T cell activation and apoptosis as regulated by PD-1 and PD-L1 interactions in effector CD8+ T cells. Measurement of Bim levels in circulating T cells of patients with cancer may provide a less invasive strategy to predict and monitor responses to anti–PD-1 therapy, although future prospective analyses are needed to validate its utility. PMID:27182556

Efficacy of Vismodegib (Erivedge) for Basal Cell Carcinoma Involving the Orbit and Periocular Area.

PubMed

Demirci, Hakan; Worden, Francis; Nelson, Christine C; Elner, Victor M; Kahana, Alon

2015-01-01

Evaluate the effectiveness of vismodegib in the management of basal cell carcinoma with orbital extension and/or extensive periocular involvement. Retrospective chart review of 6 consecutive patients with biopsy-proven orbital basal cell carcinoma and 2 additional patients with extensive periocular basal cell carcinoma who were treated with oral vismodegib (150 mg/day) was performed. Basal cell carcinoma extended in the orbit in 6 of 8 patients (involving orbital bones in 1 patient), and 2 of 8 patients had extensive periocular involvement (1 with basal cell nevus syndrome). Vismodegib therapy was the only treatment in 6 patients, off-label neoadjuvant in 1 patient, and adjuvant treatment in 1 patient. Orbital tumors in all 4 patients who received vismodegib as sole treatment showed partial response with a mean 83% shrinkage in tumor size after a median of 7 months of therapy. In the 2 patients receiving vismodegib as neoadjuvant or adjuvant therapies, there was complete response after a median of 7 months of therapy and no evidence of clinical recurrence after discontinuing therapy for a median of 15 months. The 2 patients with extensive periocular involvement experienced complete clinical response after a median 14 months of treatment. During treatment, the most common side effects were muscle spasm (75%) followed by alopecia (50%), dysgeusia (25%), dysosmia, and episodes of diarrhea and constipation (13%). Basal cell carcinoma with orbital extension and extensive periocular involvement responds to vismodegib therapy. The long-term prognosis remains unknown, and additional prospective studies are indicated.

Gene and cell therapy for children — New medicines, new challenges?☆

PubMed Central

Buckland, Karen F.; Bobby Gaspar, H.

2014-01-01

The range of possible gene and cell therapy applications is expanding at an extremely rapid rate and advanced therapy medicinal products (ATMPs) are currently the hottest topic in novel medicines, particularly for inherited diseases. Paediatric patients stand to gain enormously from these novel therapies as it now seems plausible to develop a gene or cell therapy for a vast number of inherited diseases. There are a wide variety of potential gene and cell therapies in various stages of development. Patients who received first gene therapy treatments for primary immune deficiencies (PIDs) are reaching 10 and 15 years post-treatment, with robust and sustained immune recovery. Cell therapy clinical trials are underway for a variety of tissues including corneal, retinal and muscle repair and islet cell transplantation. Various cell therapy approaches are also being trialled to enhance the safety of bone marrow transplants, which should improve survival rates in childhood cancers and PIDs. Progress in genetic engineering of lymphocyte populations to target and kill cancerous cells is also described. If successful these ATMPs may enhance or replace the existing chemo-ablative therapy for several paediatric cancers. Emerging applications of gene therapy now include skin and neurological disorders such as epidermolysis bullosa, epilepsy and leukodystrophy. Gene therapy trials for haemophilia, muscular dystrophy and a range of metabolic disorders are underway. There is a vast array of potential advanced therapy medicinal products (ATMPs), and these are likely to be more cost effective than existing medicines. However, the first clinical trials have not been without setbacks and some of the key adverse events are discussed. Furthermore, the arrival of this novel class of therapies brings many new challenges for the healthcare industry. We present a summary of the key non-clinical factors required for successful delivery of these potential treatments. Technological advances are needed in vector design, raw material manufacture, cell culture and transduction methodology, and particularly in making all these technologies readily scalable. PMID:24583376

Attempted photodynamic therapy against patagial squamous cell carcinoma in an African rose-ringed parakeet (Psittacula krameri).

PubMed

Suedmeyer, Wm Kirk; Henry, Carolyn; McCaw, Dudley; Boucher, Magalie

2007-12-01

A 5-yr-old female African rose-ringed parakeet (Psittacula krameri) presented with an ulcerated mass in the medial postpatagial area of the right wing. Biopsy specimens of the mass demonstrated a well-differentiated squamous cell carcinoma. Photodynamic therapy resulted in tumor cell necrosis and initial reduction in tumor burden, but complete remission was not achieved. Based on this and other avian cases, it appears that photodynamic therapy designed to eradicate squamous cell carcinoma in avian species using protocols modeled after canine, feline, and human photodynamic therapy protocols may not be useful. It is hypothesized that differences in light penetration, photosensitizing agent pharmacokinetics, and wound healing properties in avian species necessitate alteration of photodynamic therapy protocols if this treatment modality is to be effective in avian oncology.

The Development of Stem Cell-Based Treatment for Liver Failure.

PubMed

Zhu, Tiantian; Li, Yuwen; Guo, Yusheng; Zhu, Chuanlong

2017-01-01

Liver failure is a devastating clinical syndrome with a persistently mortality rate despite advanced care. Orthotopic liver transplantation protected patients from hepatic failure. Yet, limitations including postoperative complications, high costs, and shortages of donor organs defect its application. The development of stem cell therapy complements the deficiencies of liver transplantation, due to the inherent ability of stem cells to proliferate and differentiate. Understand the source of stem cells, as well as the advantages and disadvantages of stem cell therapy. Based on published papers, we discussed the cell sources and therapeutic effect of stem cells. We also summarized the pros and cons, as well as optimization of stem cell-based treatment. Finally outlook future prospects of stem cell therapy. Stem cells may be harvested from a variety of human tissues, and then used to promote the convalescence of hepatocellular function. The emergence of the co-cultured system, tissueengineered technology and genetic modfication has further enhanced the functionality of stem cells. However, the tumorigenicity, the low survival rate and the scarcity of long-term treatment effect are obstacles for the further development of stem cell therapy. In this review, we highlight current research findings and present the future prospects in the area of stem cell-based treatment for liver failure. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Combining antiangiogenic therapy with adoptive cell immunotherapy exerts better antitumor effects in non-small cell lung cancer models.

PubMed

Shi, Shujing; Wang, Rui; Chen, Yitian; Song, Haizhu; Chen, Longbang; Huang, Guichun

2013-01-01

Cytokine-induced killer cells (CIK cells) are a heterogeneous subset of ex-vivo expanded T lymphocytes which are characterized with a MHC-unrestricted tumor-killing activity and a mixed T-NK phenotype. Adoptive CIK cells transfer, one of the adoptive immunotherapy represents a promising nontoxic anticancer therapy. However, in clinical studies, the therapeutic activity of adoptive CIK cells transfer is not as efficient as anticipated. Possible explanations are that abnormal tumor vasculature and hypoxic tumor microenvironment could impede the infiltration and efficacy of lymphocytes. We hypothesized that antiangiogenesis therapy could improve the antitumor activity of CIK cells by normalizing tumor vasculature and modulating hypoxic tumor microenvironment. We combined recombinant human endostatin (rh-endostatin) and CIK cells in the treatment of lung carcinoma murine models. Intravital microscopy, dynamic contrast enhanced magnetic resonance imaging, immunohistochemistry, and flow cytometry were used to investigate the tumor vasculature and hypoxic microenvironment as well as the infiltration of immune cells. Our results indicated that rh-endostatin synergized with adoptive CIK cells transfer to inhibit the growth of lung carcinoma. We found that rh-endostatin normalized tumor vasculature and reduced hypoxic area in the tumor microenvironment. Hypoxia significantly inhibited the proliferation, cytotoxicity and migration of CIK cells in vitro and impeded the homing of CIK cells into tumor parenchyma ex vivo. Furthermore, we found that treatment with rh-endostatin significantly increased the homing of CIK cells and decreased the accumulation of suppressive immune cells in the tumor tissue. In addition, combination therapy produced higher level of tumor-infiltration lymphocytes compared with other treatments. Our results demonstrate that rh-endostatin improves the therapeutic effect of adoptive CIK cells therapy against lung carcinomas and unmask the mechanisms of the synergistic antitumor efficacy, providing a new rationale for combining antiangiogenesis therapy with immunotherapy in the treatment of lung cancer.

Combining Antiangiogenic Therapy with Adoptive Cell Immunotherapy Exerts Better Antitumor Effects in Non-Small Cell Lung Cancer Models

PubMed Central

Shi, Shujing; Wang, Rui; Chen, Yitian; Song, Haizhu; Chen, Longbang; Huang, Guichun

2013-01-01

Introduction Cytokine-induced killer cells (CIK cells) are a heterogeneous subset of ex-vivo expanded T lymphocytes which are characterized with a MHC-unrestricted tumor-killing activity and a mixed T-NK phenotype. Adoptive CIK cells transfer, one of the adoptive immunotherapy represents a promising nontoxic anticancer therapy. However, in clinical studies, the therapeutic activity of adoptive CIK cells transfer is not as efficient as anticipated. Possible explanations are that abnormal tumor vasculature and hypoxic tumor microenvironment could impede the infiltration and efficacy of lymphocytes. We hypothesized that antiangiogenesis therapy could improve the antitumor activity of CIK cells by normalizing tumor vasculature and modulating hypoxic tumor microenvironment. Methods We combined recombinant human endostatin (rh-endostatin) and CIK cells in the treatment of lung carcinoma murine models. Intravital microscopy, dynamic contrast enhanced magnetic resonance imaging, immunohistochemistry, and flow cytometry were used to investigate the tumor vasculature and hypoxic microenvironment as well as the infiltration of immune cells. Results Our results indicated that rh-endostatin synergized with adoptive CIK cells transfer to inhibit the growth of lung carcinoma. We found that rh-endostatin normalized tumor vasculature and reduced hypoxic area in the tumor microenvironment. Hypoxia significantly inhibited the proliferation, cytotoxicity and migration of CIK cells in vitro and impeded the homing of CIK cells into tumor parenchyma ex vivo. Furthermore, we found that treatment with rh-endostatin significantly increased the homing of CIK cells and decreased the accumulation of suppressive immune cells in the tumor tissue. In addition, combination therapy produced higher level of tumor-infiltration lymphocytes compared with other treatments. Conclusions Our results demonstrate that rh-endostatin improves the therapeutic effect of adoptive CIK cells therapy against lung carcinomas and unmask the mechanisms of the synergistic antitumor efficacy, providing a new rationale for combining antiangiogenesis therapy with immunotherapy in the treatment of lung cancer. PMID:23799045

Additive effect by combination of Akt inhibitor, MK-2206, and PDGFR inhibitor, tyrphostin AG 1296, in suppressing anaplastic thyroid carcinoma cell viability and motility.

PubMed

Che, Huan-Yong; Guo, Hang-Yuan; Si, Xu-Wei; You, Qiao-Ying; Lou, Wei-Ying

2014-01-01

The phosphatidylinositol-3-kinase/Akt pathway and receptor tyrosine kinases regulate many tumorigenesis related cellular processes including cell metabolism, cell survival, cell motility, and angiogenesis. Anaplastic thyroid carcinoma (ATC) is a rare type of thyroid cancer with no effective systemic therapy. It has been shown that Akt activation is associated with tumor progression in ATC. Here we observed the additive effect between an Akt inhibitor (MK-2206) and a novel platelet-derived growth factor receptor inhibitor (tyrphostin AG 1296) in ATC therapy. We found an additive effect between MK-2206 and tyrphostin AG 1296 in suppressing ATC cell viability. The combination of MK-2206 and tyrphostin AG 1296 induces additive apoptosis, additive suppression of the Akt signaling pathway, as well as additive inhibition of cell migration and invasion of ATC cells. Furthermore, the combination of MK-2206 and tyrphostin AG 1296 induced additive suppression of ATC tumor growth in vivo. In summary, our studies suggest that the combination of Akt and receptor tyrosine kinase inhibitors may be an efficient therapeutic strategy for ATC treatment, which might shed new light on ATC therapy.

Translating G-CSF as an Adjunct Therapy to Stem Cell Transplantation for Stroke.

PubMed

Peña, Ike dela; Borlongan, Cesar V

2015-12-01

Among recently investigated stroke therapies, stem cell treatment holds great promise by virtue of their putative ability to replace lost cells, promote endogenous neurogenesis,and produce behavioral and functional improvement through their "bystander effects." Translating stem cell in the clinic, however, presents a number of technical difficulties. A strategy suggested to enhance therapeutic utility of stem cells is combination therapy, i.e., co-transplantation of stem cells or adjunct treatment with pharmacological agents and substrates,which is assumed to produce more profound therapeutic benefits by circumventing limitations of individual treatments and facilitating complementary brain repair processes. We previously demonstrated enhanced functional effects of cotreatment with granulocyte-colony stimulating factor (GCSF)and human umbilical cord blood cell (hUCB) transplantation in animal models of traumatic brain injury (TBI). Here,we suggest that the aforementioned combination therapy may also produce synergistic effects in stroke. Accordingly, G-CSF treatment may reduce expression of pro-inflammatory cytokines and enhance neurogenesis rendering a receptive microenvironment for hUCB engraftment. Adjunct treatment of GCSF with hUCB may facilitate stemness maintenance and guide neural lineage commitment of hUCB cells. Moreover, regenerative mechanisms afforded by G-CSF-mobilized endogenous stem cells, secretion of growth factors by hUCB grafts and G-CSF-recruited endothelial progenitor cells(EPCs), as well as the potential graft–host integration that may promote synaptic circuitry re-establishment could altogether produce more pronounced functional improvement in stroked rats subjected to a combination G-CSF treatment and hUCB transplantation. Nevertheless, differences in pathology and repair processes underlying TBI and stroke deserve consideration when testing the effects of combinatorial G-CSF and hUCB cell transplantation for stroke treatment. Further studies are also required to determine the safety and efficacy of this intervention in both preclinical and clinical stroke studies.

Selenorhodamine Photosensitizers for Photodynamic Therapy of P-Glycoprotein-Expressing Cancer Cells

PubMed Central

2015-01-01

We examined a series of selenorhodamines with amide and thioamide functionality at the 5-position of a 9-(2-thienyl) substituent on the selenorhodamine core for their potential as photosensitizers for photodynamic therapy (PDT) in P-glycoprotein (P-gp) expressing cells. These compounds were examined for their photophysical properties (absorption, fluorescence, and ability to generate singlet oxygen), for their uptake into Colo-26 cells in the absence or presence of verapamil, for their dark and phototoxicity toward Colo-26 cells, for their rates of transport in monolayers of multidrug-resistant, P-gp-overexpressing MDCKII-MDR1 cells, and for their colocalization with mitochondrial specific agents in Colo-26 cells. Thioamide derivatives 16b and 18b were more effective photosensitizers than amide derivatives 15b and 17b. Selenorhodamine thioamides 16b and 18b were useful in a combination therapy to treat Colo-26 cells in vitro: a synergistic therapeutic effect was observed when Colo-26 cells were exposed to PDT and treatment with the cancer drug doxorubicin. PMID:25250825

5-fluorouracil enhances the antitumor effect of sorafenib and sunitinib in a xenograft model of human renal cell carcinoma.

PubMed

Miyake, Makito; Anai, Satoshi; Fujimoto, Kiyohide; Ohnishi, Sayuri; Kuwada, Masaomi; Nakai, Yasushi; Inoue, Takeshi; Tomioka, Atsushi; Tanaka, Nobumichi; Hirao, Yoshihiko

2012-06-01

Sorafenib and sunitinib are multi-kinase inhibitors with antitumor activity in patients with advanced renal cell carcinoma (RCC). Several studies have evaluated the effect of sorafenib/sunitinib in combination with chemotherapeutic agents in different types of tumor. However, few studies have addressed the activity of fluorinated pyrimidine in combination with sorafenib/sunitinib. In this study, we examined the potential of combination therapy with 5FU and sorafenib/sunitinib in human RCC cell lines. Three human RCC cell lines, ACHN, Caki-1 and Caki-2, were used to assess sensitivity to 5-fluorouracil (5FU), sorafenib and sunitinib alone or in combination using an in vitro cell survival assay. Caki-2 cells demonstrated significantly higher resistance to 5FU and sorafenib as compared to ACHN and Caki-1. Additive antitumor effects of the combination therapy were observed in the in vitro study. There was a tendency for a positive correlation between the sensitivity to sunitinib and platelet-derived growth factor β (PDGFR-β) expression levels, which were examined by reverse transcription polymerase chain reaction. Caki-1 xenograft models were prepared by inoculating cells subcutaneously into nude mice, which were divided randomly into six groups: control, 5FU (8 mg/kg/day, intraperitoneally), sorafenib (15 mg/kg/day, orally), sunitinib (20 mg/kg/day, orally), and 5FU with sorafenib or sunitinib. The treatments were administered on 5 days each week, and tumor growth was monitored for 42 days following inoculation of cells. Synergistic antitumor effects of the combination therapy were observed in an in vivo study. The resected tumors were evaluated using the Ki-67 labeling index and microvessel density. Both the Ki-67 labeling index and microvessel density were decreased in tumors treated with the combination therapy compared to those treated with sorafenib/sunitinib alone. These findings suggest that the combination therapy of 5FU with sorafenib/sunitinib may be an effective therapeutic modality for advanced RCC patients.

Potential role of herbal remedies in stem cell therapy: proliferation and differentiation of human mesenchymal stromal cells.

PubMed

Udalamaththa, Vindya Lankika; Jayasinghe, Chanika Dilumi; Udagama, Preethi Vidya

2016-08-11

Stem cell therapy has revolutionized modern clinical therapy with the potential of stem cells to differentiate into many different cell types which may help to replace different cell lines of an organism. Innumerous trials are carried out to merge new scientific knowledge and techniques with traditional herbal extracts that may result in less toxic, affordable, and highly available natural alternative therapeutics. Currently, mesenchyamal stromal cell (MSC) lines are treated with individual and mixtures of crude herbal extracts, as well as with purified compounds from herbal extracts, to investigate the mechanisms and effects of these on stem cell growth and differentiation. Human MSCs (hMSCs) possess multilineage, i.e., osteogenic, neurogenic, adipogenic, chondrogenic, and myogenic, differentiation abilities. The proliferative and differentiation properties of hMSCs treated with herbal extracts have shown promise in diseases such as osteoporosis, neurodegenerative disorders, and other tissue degenerative disorders. Well characterized herbal extracts that result in increased rates of tissue regeneration may be used in both stem cell therapy and tissue engineering for replacement therapy, where the use of scaffolds and vesicles with enhanced attaching and proliferative properties could be highly advantageous in the latter. Although the clinical application of herbal extracts is still in progress due to the variability and complexity of bioactive constituents, standardized herbal preparations will strengthen their application in the clinical context. We have critically reviewed the proliferative and differentiation effects of individual herbal extracts on hMSCs mainly derived from bone marrow and elaborated on the plausible underlying mechanisms of action. To be fruitfully used in reparative and regenerative therapy, future directions in this area of study should (i) make use of hMSCs derived from different non-traditional sources, including medical waste material (umbilical cord, Wharton's jelly, and placenta), (ii) take account of the vast numbers of herbal extracts used in traditional medicine globally, and (iii) investigate the mechanisms and pathways of their effects on hMSCs.

Priming of the Cells: Hypoxic Preconditioning for Stem Cell Therapy

PubMed Central

Wei, Zheng Z; Zhu, Yan-Bing; Zhang, James Y; McCrary, Myles R; Wang, Song; Zhang, Yong-Bo; Yu, Shan-Ping; Wei, Ling

2017-01-01

Objective: Stem cell-based therapies are promising in regenerative medicine for protecting and repairing damaged brain tissues after injury or in the context of chronic diseases. Hypoxia can induce physiological and pathological responses. A hypoxic insult might act as a double-edged sword, it induces cell death and brain damage, but on the other hand, sublethal hypoxia can trigger an adaptation response called hypoxic preconditioning or hypoxic tolerance that is of immense importance for the survival of cells and tissues. Data Sources: This review was based on articles published in PubMed databases up to August 16, 2017, with the following keywords: “stem cells,” “hypoxic preconditioning,” “ischemic preconditioning,” and “cell transplantation.” Study Selection: Original articles and critical reviews on the topics were selected. Results: Hypoxic preconditioning has been investigated as a primary endogenous protective mechanism and possible treatment against ischemic injuries. Many cellular and molecular mechanisms underlying the protective effects of hypoxic preconditioning have been identified. Conclusions: In cell transplantation therapy, hypoxic pretreatment of stem cells and neural progenitors markedly increases the survival and regenerative capabilities of these cells in the host environment, leading to enhanced therapeutic effects in various disease models. Regenerative treatments can mobilize endogenous stem cells for neurogenesis and angiogenesis in the adult brain. Furthermore, transplantation of stem cells/neural progenitors achieves therapeutic benefits via cell replacement and/or increased trophic support. Combinatorial approaches of cell-based therapy with additional strategies such as neuroprotective protocols, anti-inflammatory treatment, and rehabilitation therapy can significantly improve therapeutic benefits. In this review, we will discuss the recent progress regarding cell types and applications in regenerative medicine as well as future applications. PMID:28937044

Dual-Mode Imaging-Guided Synergistic Chemo- and Magnetohyperthermia Therapy in a Versatile Nanoplatform To Eliminate Cancer Stem Cells.

PubMed

Tang, Jinglong; Zhou, Huige; Liu, Jiaming; Liu, Jing; Li, Wanqi; Wang, Yuqing; Hu, Fan; Huo, Qing; Li, Jiayang; Liu, Ying; Chen, Chunying

2017-07-19

Cancer stem cells (CSCs) have been identified as a new target for therapy in diverse cancers. Traditional therapies usually kill the bulk of cancer cells, but are often unable to effectively eliminate CSCs, which may lead to drug resistance and cancer relapse. Herein, we propose a novel strategy: fabricating multifunctional magnetic Fe 3 O 4 @PPr@HA hybrid nanoparticles and loading it with the Notch signaling pathway inhibitor N-[N-(3,5-difluorophenacetyl-l-alanyl)]-S-phenylglycinet-butylester (DAPT) to eliminate CSCs. Hyaluronic acid ligands greatly enhance the accumulation of the hybrid nanoparticles in the tumor site and in the CSCs. Both hyaluronase in the tumor microenvironment and the magnetic hyperthermia effect of the inner magnetic core can accelerate the release of DAPT. This controlled release of DAPT in the tumor site further enhances the ability of the combination of chemo- and magnetohyperthermia therapy to eliminate cancer stem cells. With the help of polypyrrole-mediated photoacoustic and Fe 3 O 4 -mediated magnetic resonance imaging, the drug release can be precisely monitored in vivo. This versatile nanoplatform enables effective elimination of the cancer stem cells and monitoring of the drugs.

Particle Therapy for Non-Small Cell Lung Tumors: Where Do We Stand? A Systematic Review of the Literature

PubMed Central

Wink, Krista C. J.; Roelofs, Erik; Solberg, Timothy; Lin, Liyong; Simone, Charles B.; Jakobi, Annika; Richter, Christian; Lambin, Philippe; Troost, Esther G. C.

2014-01-01

This review article provides a systematic overview of the currently available evidence on the clinical effectiveness of particle therapy for the treatment of non-small cell lung cancer and summarizes findings of in silico comparative planning studies. Furthermore, technical issues and dosimetric uncertainties with respect to thoracic particle therapy are discussed. PMID:25401087

Stem Cell Therapy in Bladder Dysfunction: Where Are We? And Where Do We Have to Go?

PubMed Central

Lee, Sang-Rae; Song, Yun Seob; Lee, Hong Jun

2013-01-01

To date, stem cell therapy for the bladder has been conducted mainly on an experimental basis in the areas of bladder dysfunction. The therapeutic efficacy of stem cells was originally thought to be derived from their ability to differentiate into various cell types. Studies about stem cell therapy for bladder dysfunction have been limited to an experimental basis and have been less focused than bladder regeneration. Bladder dysfunction was listed in MESH as “urinary bladder neck obstruction”, “urinary bladder, overactive”, and “urinary bladder, neurogenic”. Using those keywords, several articles were searched and studied. The bladder dysfunction model includes bladder outlet obstruction, cryoinjured, diabetes, ischemia, and spinal cord injury. Adipose derived stem cells (ADSCs), bone marrow stem cells (BMSCs), and skeletal muscle derived stem cells (SkMSCs) are used for transplantation to treat bladder dysfunction. The main mechanisms of stem cells to reconstitute or restore bladder dysfunction are migration, differentiation, and paracrine effects. The aim of this study is to review the stem cell therapy for bladder dysfunction and to provide the status of stem cell therapy for bladder dysfunction. PMID:24151627

Chimeric antigen receptor T-cell therapy in AML: How close are we?

PubMed Central

Gill, Saar

2016-01-01

The majority of patients presenting with acute myeloid leukemia (AML) initially respond to chemotherapy but post-remission therapy is required to consolidate this response and achieve long-term disease-free survival. The most effective form of post-remission therapy relies on T-cell immunotherapy in the form of allogeneic hematopoietic cell transplantation (HCT). However, patients with active disease cannot usually expect to be cured with HCT. This inherent dichotomy implies that traditional T cell-based immunotherapy in the form of allogeneic HCT stops being efficacious somewhere between the measurable residual disease (MRD) and the morphologically obvious range. This is in part because the full power of T cells must be restrained in order to avoid lethal graft-versus-host disease (GVHD) and partly because only a sub-population of donor T cells are expected to be able to recognize AML cells via their T cell receptor. Chimeric antigen receptor (CAR) T cell therapy, most advanced in the treatment of patients with B-cell malignancies, may circumvent some of these limitations. However, major challenges remain to be overcome before CAR T cell therapy can be safely applied to AML. PMID:27890255

Accelerating cancer therapy development: the importance of combination strategies and collaboration. Summary of an Institute of Medicine workshop.

PubMed

LoRusso, Patricia M; Canetta, Renzo; Wagner, John A; Balogh, Erin P; Nass, Sharyl J; Boerner, Scott A; Hohneker, John

2012-11-15

Cancer cells contain multiple genetic changes in cell signaling pathways that drive abnormal cell survival, proliferation, invasion, and metastasis. Unfortunately, patients treated with single agents inhibiting only one of these pathways--even if showing an initial response--often develop resistance with subsequent relapse or progression of their cancer, typically via the activation of an alternative uninhibited pathway. Combination therapies offer the potential for inhibiting multiple targets and pathways simultaneously to more effectively kill cancer cells and prevent or delay the emergence of drug resistance. However, there are many unique challenges to developing combination therapies, including devising and applying appropriate preclinical tests and clinical trial designs, prioritizing which combination therapies to test, avoiding overlapping toxicity of multiple agents, and overcoming legal, cultural, and regulatory barriers that impede collaboration among multiple companies, organizations, and/or institutions. More effective strategies to efficiently develop combination cancer therapies are urgently needed. Thus, the Institute of Medicine's National Cancer Policy Forum recently convened a workshop with the goal of identifying barriers that may be impeding the development of combination investigational cancer therapies, as well as potential solutions to overcome those barriers, improve collaboration, and ultimately accelerate the development of promising combinations of investigational cancer therapies. ©2012 AACR.

Antinociceptive effect of intrathecal microencapsulated human pheochromocytoma cell in a rat model of bone cancer pain.

PubMed

Li, Xiao; Li, Guoqi; Wu, Shaoling; Zhang, Baiyu; Wan, Qing; Yu, Ding; Zhou, Ruijun; Ma, Chao

2014-07-08

Human pheochromocytoma cells, which are demonstrated to contain and release met-enkephalin and norepinephrine, may be a promising resource for cell therapy in cancer-induced intractable pain. Intrathecal injection of alginate-poly (l) lysine-alginate (APA) microencapsulated human pheochromocytoma cells leads to antinociceptive effect in a rat model of bone cancer pain, and this effect was blocked by opioid antagonist naloxone and alpha 2-adrenergic antagonist rauwolscine. Neurochemical changes of cerebrospinal fluid are in accordance with the analgesic responses. Taken together, these data support that human pheochromocytoma cell implant-induced antinociception was mediated by met-enkephalin and norepinephrine secreted from the cell implants and acting at spinal receptors. Spinal implantation of microencapsulated human pheochromocytoma cells may provide an alternative approach for the therapy of chronic intractable pain.

Polyamine-Blocking Therapy Reverses Immunosuppression in the Tumor Microenvironment

PubMed Central

Hayes, Candace S.; Shicora, Allyson C.; Keough, Martin P.; Snook, Adam E.; Burns, Mark R.; Gilmour, Susan K.

2014-01-01

Correcting T cell immunosuppression may unleash powerful antitumor responses, however, knowledge about the mechanisms and modifiers that may be targeted to improve therapy remains incomplete. Here we report that polyamine elevation in cancer, a common metabolic aberration in aggressive lesions, contributes significantly to tumor immunosuppression and that a polyamine depletion strategy can exert antitumor effects that may also promote immunity. A polyamine-blocking therapy (PBT) that combines the well-characterized ornithine decarboxylase (ODC) inhibitor difluoromethylornithine (DFMO) with AMXT1501, a novel inhibitor of the polyamine transport system, blocked tumor growth in immunocompetent mice but not in athymic nude mice lacking T cells. PBT had little effect on the proliferation of epithelial tumor cells but it increased the number of apoptotic cells. Analysis of CD45+ tumor immune infiltrates revealed that PBT decreased levels of Gr-1+CD11b+ myeloid suppressor cells and increased CD3+ T cells. Strikingly, in a model of neoadjuvant therapy, mice administered PBT one week before surgical resection of engrafted mammary tumors exhibited resistance to subsequent tumor re-challenge. Collectively, our results indicate that therapies targeting polyamine metabolism do not act exclusively as anti-proliferative agents, but also act strongly to prevent immune escape by the tumor. PBT may offer a general approach to heighten immune responses in cancer. PMID:24778323

Chemoradiotherapy for esophageal squamous cell cancer.

PubMed

Sasaki, Yusuke; Kato, Ken

2016-09-01

Chemoradiotherapy has been clinically indicated for patients with resectable esophageal squamous cell carcinoma who refuse surgical resection and in locally advanced unresectable esophageal squamous cell carcinoma patients. Concurrent chemoradiotherapy prolongs survival than radiation therapy alone when given as definitive treatment. Therefore, chemoradiotherapy is recognized as the standard non-invasive treatment for patients with localized esophageal cancer who opt for non-surgical treatment. JCOG9906 showed promising outcomes for stage II/III ESCC patients. But there are some problems about chemoradiotherapy for esophageal squamous cell carcinoma. Late toxicities are sometimes lethal for patients who achieved complete response even after years. Salvage treatment for residual or recurrent disease is unestablished. Modified Radiation Therapy Oncology Group regimen at the dose of 50.4 Gy reduced late toxicities without reducing efficacy. Optimal timings and procedure of salvage surgery and endoscopic therapy is evaluated in JCOG0909. Strategy including salvage therapy after chemoradiotherapy should be considered at the time of starting the treatment. Targeted therapy has not shown adding effect for chemoradiotherapy for esophageal squamous cell carcinoma yet. New agents, such as immune checkpoint inhibitors, are expected to show synergistic effect with chemoradiotherapy for esophageal squamous cell carcinoma. Further investigation is needed. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Muscle Stem Cell Therapy for the Treatment of DMD Associated Cardiomyopathy

DTIC Science & Technology

2012-10-01

2009;27(8):1954-1962. 44. Abarbanell AM, Coffey AC, Fehrenbacher JW, et al. Proinflammatory cytokine effects on mesenchymal stem cell therapy for...signaling pathway functions as a commitment switch for osteogenic and adipogenic differentiation of mesenchymal stem cells (MSCs) (22). Activation...mediate reduced osteoblastogenesis and enhanced adipogenesis of human mesenchymal stem cells in modeled microgravity. J Bone Miner Res. 2005;20(10

Tumor Therapeutics Work as Stress Inducers to Enhance Tumor Sensitivity to Natural Killer (NK) Cell Cytolysis by Up-regulating NKp30 Ligand B7-H6.

PubMed

Cao, Guoshuai; Wang, Jian; Zheng, Xiaodong; Wei, Haiming; Tian, Zhigang; Sun, Rui

2015-12-11

Immune cells are believed to participate in initiating anti-tumor effects during regular tumor therapy such as chemotherapy, radiation, hyperthermia, and cytokine injection. One of the mechanisms underlying this process is the expression of so-called stress-inducible immunostimulating ligands. Although the activating receptor NKG2D has been proven to play roles in tumor therapy through targeting its ligands, the role of NKp30, another key activating receptor, is seldom addressed. In this study, we found that the NKp30 ligand B7-H6 was widely expressed in tumor cells and closely correlated to their susceptibility to NK cell lysis. Further studies showed that treatment of tumor cells with almost all standard tumor therapeutics, including chemotherapy (cisplatin, 5-fluorouracil), radiation therapy, non-lethal heat shock, and cytokine therapy (TNF-α), could up-regulate the expression of B7-H6 in tumor cells and enhance tumor sensitivity to NK cell cytolysis. B7-H6 shRNA treatment effectively dampened sensitization of tumor cells to NK-mediated lysis. Our study not only reveals the possibility that tumor therapeutics work as stress inducers to enhance tumor sensitivity to NK cell cytolysis but also suggests that B7-H6 could be a potential target for tumor therapy in the future. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Siloxane nanoprobes for labeling and dual modality imaging of neural stem cells

PubMed Central

Addington, Caroline P.; Cusick, Alex; Shankar, Rohini Vidya; Agarwal, Shubhangi; Stabenfeldt, Sarah E.; Kodibagkar, Vikram D.

2015-01-01

Cell therapy represents a promising therapeutic for a myriad of medical conditions, including cancer, traumatic brain injury, and cardiovascular disease among others. A thorough understanding of the efficacy and cellular dynamics of these therapies necessitates the ability to non-invasively track cells in vivo. Magnetic resonance imaging (MRI) provides a platform to track cells as a non-invasive modality with superior resolution and soft tissue contrast. We recently reported a new nanoprobe platform for cell labeling and imaging using fluorophore doped siloxane core nanoemulsions as dual modality (1H MRI/Fluorescence), dual-functional (oximetry/detection) nanoprobes. Here, we successfully demonstrate the labeling, dual-modality imaging, and oximetry of neural progenitor/stem cells (NPSCs) in vitro using this platform. Labeling at a concentration of 10 μl/104 cells with a 40%v/v polydimethylsiloxane core nanoemulsion, doped with rhodamine, had minimal effect on viability, no effect on migration, proliferation and differentiation of NPSCs and allowed for unambiguous visualization of labeled NPSCs by 1H MR and fluorescence and local pO2 reporting by labeled NPSCs. This new approach for cell labeling with a positive contrast 1H MR probe has the potential to improve mechanistic knowledge of current therapies, and guide the design of future cell therapies due to its clinical translatability. PMID:26597417

The small molecule survivin inhibitor YM155 may be an effective treatment modality for colon cancer through increasing apoptosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Wan Lu, E-mail: lvvlchina@msn.cn; Lee, Mi-Ra, E-mail: mira1125@yonsei.ac.kr; Cho, Mee-Yon, E-mail: meeyon@yonsei.ac.kr

Survivin has a known beneficial role in the survival of both cancer cells and normal cells. Therapies targeting survivin have been proposed as an alternative treatment modality for various tumors; however, finding the proper indication for this toxic therapy is critical for reducing unavoidable side effects. We recently observed that high survivin expression in CD133{sup +} cells is related to chemoresistance in Caco-2 colon cancer cells. However, the effect of survivin-targeted therapy on CD133{sup +} colon cancer is unknown. In this study, we investigated the roles of CD133 and survivin expression in colon cancer biology in vitro and comparatively analyzed themore » anticancer effects of survivin inhibitor on CD133{sup +} cells (ctrl-siRNA group) and small interfering RNA (siRNA)-induced CD133{sup −} cells (CD133-siRNA group) obtained from a single colon cancer cell line. CD133 knockdown via siRNA transfection did not change the tumorigenicity of cells, although in vitro survivin expression levels in CD133{sup +} cells were higher than those in siRNA-induced CD133{sup −} cells. The transfection procedure seemed to induce survivin expression. Notably, a significant number of CD133{sup −} cells (33.8%) was found in the cell colonies of the CD133-siRNA group. In the cell proliferation assay after treatment, YM155 and a combination of YM155 and 5-fluorouracil (5-FU) proved to be far more effective than 5-FU alone. A significantly increased level of apoptosis was observed with increasing doses of YM155 in all groups. However, significant differences in therapeutic effect and apoptosis among the mock, ctrl-siRNA, and CD133-siRNA groups were not detected. Survivin inhibitor is an effective treatment modality for colon cancer; however, the role of CD133 and the use of survivin expression as a biomarker for this targeted therapy must be verified.« less

Preparation of pancreatic β-cells from human iPS cells with small molecules

PubMed Central

2012-01-01

Human induced pluripotent stem (iPS) cells obtained from patients are expected to be a useful source for cell transplantation therapy, because many patients (including those with type 1 diabetes and severe type 2 diabetes) are on waiting lists for transplantation for a long time due to the shortage of donors. At present, many concerns related to clinical application of human iPS cells have been raised, but rapid development of methods for the establishment, culture, and standardization of iPS cells will lead autologous cell therapy to be realistic sooner or later. However, establishment of a method for preparing some of desired cell types is still challenging. Regarding pancreatic β-cells, there have been many reports about differentiation of these cells from human embryonic stem (ES)/iPS cells, but a protocol for clinical application has still not been established. Since there is clear proof that cell transplantation therapy is effective for diabetes based on the results of clinical islet transplantation, pancreatic β-cells prepared from human iPS cells are considered likely to be effective for reducing the burden on patients. In this article, the current status of procedures for preparing pancreatic β-cells from human ES/iPS cells, including effective use of small molecules, is summarized, and some of the problems that still need to be overcome are discussed. PMID:22722666

Imaging Stem Cell Therapy for the Treatment of Peripheral Arterial Disease

PubMed Central

Ransohoff, Julia D.; Wu, Joseph C.

2013-01-01

Arteriosclerotic cardiovascular diseases are among the leading causes of morbidity and mortality worldwide. Therapeutic angiogenesis aims to treat ischemic myocardial and peripheral tissues by delivery of recombinant proteins, genes, or cells to promote neoangiogenesis. Concerns regarding the safety, side effects, and efficacy of protein and gene transfer studies have led to the development of cell-based therapies as alternative approaches to induce vascular regeneration and to improve function of damaged tissue. Cell-based therapies may be improved by the application of imaging technologies that allow investigators to track the location, engraftment, and survival of the administered cell population. The past decade of investigations has produced promising clinical data regarding cell therapy, but design of trials and evaluation of treatments stand to be improved by emerging insight from imaging studies. Here, we provide an overview of pre-clinical and clinical experience using cell-based therapies to promote vascular regeneration in the treatment of peripheral arterial disease. We also review four major imaging modalities and underscore the importance of in vivo analysis of cell fate for a full understanding of functional outcomes. PMID:22239638

Genome Therapy of Myotonic Dystrophy Type 1 iPS Cells for Development of Autologous Stem Cell Therapy.

PubMed

Gao, Yuanzheng; Guo, Xiuming; Santostefano, Katherine; Wang, Yanlin; Reid, Tammy; Zeng, Desmond; Terada, Naohiro; Ashizawa, Tetsuo; Xia, Guangbin

2016-08-01

Myotonic dystrophy type 1 (DM1) is caused by expanded Cytosine-Thymine-Guanine (CTG) repeats in the 3'-untranslated region (3' UTR) of the Dystrophia myotonica protein kinase (DMPK) gene, for which there is no effective therapy. The objective of this study is to develop genome therapy in human DM1 induced pluripotent stem (iPS) cells to eliminate mutant transcripts and reverse the phenotypes for developing autologous stem cell therapy. The general approach involves targeted insertion of polyA signals (PASs) upstream of DMPK CTG repeats, which will lead to premature termination of transcription and elimination of toxic mutant transcripts. Insertion of PASs was mediated by homologous recombination triggered by site-specific transcription activator-like effector nuclease (TALEN)-induced double-strand break. We found genome-treated DM1 iPS cells continue to maintain pluripotency. The insertion of PASs led to elimination of mutant transcripts and complete disappearance of nuclear RNA foci and reversal of aberrant splicing in linear-differentiated neural stem cells, cardiomyocytes, and teratoma tissues. In conclusion, genome therapy by insertion of PASs upstream of the expanded DMPK CTG repeats prevented the production of toxic mutant transcripts and reversal of phenotypes in DM1 iPS cells and their progeny. These genetically-treated iPS cells will have broad clinical application in developing autologous stem cell therapy for DM1.

Polymeric mixed micelles loaded mitoxantrone for overcoming multidrug resistance in breast cancer via photodynamic therapy

PubMed Central

Zhao, Yiqiao; Yu, Hua; Zhou, Haiyu; Chen, Meiwan

2017-01-01

Mitoxantrone (MIT) is an anticancer agent with photosensitive properties that is commonly used in various cancers. Multidrug resistance (MDR) effect has been an obstacle to using MIT for cancer therapy. Photochemical internalization, on account of photodynamic therapy, has been applied to improve the therapeutic effect of cancers with MDR effect. In this study, an MIT-poly(ε-caprolactone)-pluronic F68-poly(ε-caprolactone)/poly(d,l-lactide-co-glycolide)–poly(ethylene glycol)–poly(d,l-lactide-co-glycolide) (MIT-PFP/PPP) mixed micelles system was applied to reverse the effect of MDR in MCF-7/ADR cells via photochemical reaction when exposed to near-infrared light. MIT-PFP/PPP mixed micelles showed effective interaction with near-infrared light at the wavelength of 660 nm and exerted great cytotoxicity in MCF-7/ADR cells with irradiation. Furthermore, MIT-PFP/PPP mixed micelles could improve reactive oxygen species (ROS) levels, decrease P-glycoprotein activity, and increase the cellular uptake of drugs with improved intracellular drug concentrations, which induced cell apoptosis in MCF-7/ADR cells under irradiation, despite MDR effect, as indicated by the increased level of cleaved poly ADP-ribose polymerase. These findings suggested that MIT-PFP/PPP mixed micelles may become a promising strategy to effectively reverse the MDR effect via photodynamic therapy in breast cancer. PMID:28919756

A possible usage of a CDK4 inhibitor for breast cancer stem cell-targeted therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Han, Yu Kyeong; Lee, Jae Ho; Park, Ga-Young

2013-01-25

Highlights: ► A CDK4 inhibitor may be used for breast cancer stem cell-targeted therapy. ► The CDK4 inhibitor differentiated the cancer stem cell population (CD24{sup −}/CD44{sup +}) of MDA-MB-231. ► The differentiation of the cancer stem cells by the CDK4 inhibitor radiosensitized MDA-MB-231. -- Abstract: Cancer stem cells (CSCs) are one of the main reasons behind cancer recurrence due to their resistance to conventional anti-cancer therapies. Thus, many efforts are being devoted to developing CSC-targeted therapies to overcome the resistance of CSCs to conventional anti-cancer therapies and decrease cancer recurrence. Differentiation therapy is one potential approach to achieve CSC-targeted therapies.more » This method involves inducing immature cancer cells with stem cell characteristics into more mature or differentiated cancer cells. In this study, we found that a CDK4 inhibitor sensitized MDA-MB-231 cells but not MCF7 cells to irradiation. This difference appeared to be associated with the relative percentage of CSC-population between the two breast cancer cells. The CDK4 inhibitor induced differentiation and reduced the cancer stem cell activity of MDA-MB-231 cells, which are shown by multiple marker or phenotypes of CSCs. Thus, these results suggest that radiosensitization effects may be caused by reducing the CSC-population of MDA-MB-231 through the use of the CDK4 inhibitor. Thus, further investigations into the possible application of the CDK4 inhibitor for CSC-targeted therapy should be performed to enhance the efficacy of radiotherapy for breast cancer.« less

Potential mechanism in sonodynamic therapy and focused ultrasound induced apoptosis in sarcoma 180 cells in vitro.

PubMed

Tang, Wei; Liu, Quanhong; Wang, Xiaobing; Wang, Pan; Zhang, Jing; Cao, Bing

2009-12-01

Sonodynamic therapy employs a combination of ultrasound and a sonosensitizer to enhance the cytotoxic effect of ultrasound and promote apoptosis. However, the mechanism underlying the synergistic effect of ultrasound and hematoporphyrin is still unclear. In this study, we investigated mechanism of the induction of apoptosis by sonodynamic therapy in Sarcoma 180 cells. The cell suspension was treated by 1.75-MHz focused continuous ultrasound at an acoustic power (I(SATA)) of 1.4+/-0.07 W/cm(2) for 3 min in the absence or presence of 20 microg/ml hematoporphyrin. The proportion of apoptotic cells was determined by flow cytometry. We then analyzed the reactive oxygen species generation and localization by confocal microscopy. Western blotting and reverse transcriptase-polymerase chain reaction were used to analyze the expression of caspase-8, caspase-9, poly(ADP)-ribose polymerase, and nuclear factor-kappaB. The findings of our study indicate that ultrasound treatment induced the activation of nuclear factor-kappaB as an early stress response. When cells were pretreated with hematoporphyrin, the initial response to the therapy was the formation of (1)O(2) in the mitochondria. Our results primarily demonstrate that the mechanisms of induction of apoptosis by ultrasound and hematoporphyrin-sonodynamic therapies are very different. Our findings can provide a basis for explaining the synergistic effect of ultrasound and hematoporphyrin.

Gold nanorods as a theranostic platform for in vitro and in vivo imaging and photothermal therapy of inflammatory macrophages

NASA Astrophysics Data System (ADS)

Qin, Jinbao; Peng, Zhiyou; Li, Bo; Ye, Kaichuang; Zhang, Yuxin; Yuan, Fukang; Yang, Xinrui; Huang, Lijia; Hu, Junqing; Lu, Xinwu

2015-08-01

Inflammatory macrophages play pivotal roles in the development of atherosclerosis. Theranostics, a promising approach for local imaging and photothermal therapy of inflammatory macrophages, has drawn increasing attention in biomedical research. In this study, gold nanorods (Au NRs) were synthesized, and their in vitro photothermal effects on the macrophage cell line (Ana-1 cells) under 808 nm near infrared reflection (NIR) were investigated by the CCK8 assay, calcein AM/PI staining, flow cytometry, transmission electron microscopy (TEM), silver staining and in vitro micro-computed tomography (CT) imaging. These Au NRs were then applied to an apolipoprotein E knockout (Apo E) mouse model to evaluate their effects on in vivo CT imaging and their effectiveness as for the subsequent photothermal therapy of macrophages in femoral artery restenosis under 808 nm laser irradiation. In vitro photothermal ablation treatment using Au NRs exhibited a significant cell-killing efficacy of macrophages, even at relatively low concentrations of Au NRs and low NIR powers. In addition, the in vivo results demonstrated that the Au NRs are effective for in vivo imaging and photothermal therapy of inflammatory macrophages in femoral artery restenosis. This study shows that Au nanorods are a promising theranostic platform for the diagnosis and photothermal therapy of inflammation-associated diseases.Inflammatory macrophages play pivotal roles in the development of atherosclerosis. Theranostics, a promising approach for local imaging and photothermal therapy of inflammatory macrophages, has drawn increasing attention in biomedical research. In this study, gold nanorods (Au NRs) were synthesized, and their in vitro photothermal effects on the macrophage cell line (Ana-1 cells) under 808 nm near infrared reflection (NIR) were investigated by the CCK8 assay, calcein AM/PI staining, flow cytometry, transmission electron microscopy (TEM), silver staining and in vitro micro-computed tomography (CT) imaging. These Au NRs were then applied to an apolipoprotein E knockout (Apo E) mouse model to evaluate their effects on in vivo CT imaging and their effectiveness as for the subsequent photothermal therapy of macrophages in femoral artery restenosis under 808 nm laser irradiation. In vitro photothermal ablation treatment using Au NRs exhibited a significant cell-killing efficacy of macrophages, even at relatively low concentrations of Au NRs and low NIR powers. In addition, the in vivo results demonstrated that the Au NRs are effective for in vivo imaging and photothermal therapy of inflammatory macrophages in femoral artery restenosis. This study shows that Au nanorods are a promising theranostic platform for the diagnosis and photothermal therapy of inflammation-associated diseases. Electronic supplementary information (ESI) available: Figures. See DOI: 10.1039/c5nr02521d

Cellular innate immunity and restriction of viral infection: implications for lentiviral gene therapy in human hematopoietic cells.

PubMed

Kajaste-Rudnitski, Anna; Naldini, Luigi

2015-04-01

Hematopoietic gene therapy has tremendous potential to treat human disease. Nevertheless, for gene therapy to be efficacious, effective gene transfer into target cells must be reached without inducing detrimental effects on their biological properties. This remains a great challenge for the field as high vector doses and prolonged ex vivo culture conditions are still required to reach significant transduction levels of clinically relevant human hematopoietic stem and progenitor cells (HSPCs), while other potential target cells such as primary macrophages can hardly be transduced. The reasons behind poor permissiveness of primary human hematopoietic cells to gene transfer partly reside in the retroviral origin of lentiviral vectors (LVs). In particular, host antiviral factors referred to as restriction factors targeting the retroviral life cycle can hamper LV transduction efficiency. Furthermore, LVs may activate innate immune sensors not only in differentiated hematopoietic cells but also in HSPCs, with potential consequences on transduction efficiency as well as their biological properties. Therefore, better understanding of the vector-host interactions in the context of hematopoietic gene transfer is important for the development of safer and more efficient gene therapy strategies. In this review, we briefly summarize the current knowledge regarding innate immune recognition of lentiviruses in primary human hematopoietic cells as well as discuss its relevance for LV-based ex vivo gene therapy approaches.

In Search of Mechanisms Associated with Mesenchymal Stem Cell-Based Therapies for Acute Kidney Injury

PubMed Central

de Almeida, Danilo C; Donizetti-Oliveira, Cassiano; Barbosa-Costa, Priscilla; Origassa, Clarice ST; Câmara, Niels OS

2013-01-01

Acute kidney injury (AKI) is classically described as a rapid loss of kidney function. AKI affects more than 15% of all hospital admissions and is associated with elevated mortality rates. Although many advances have occurred, intermittent or continuous renal replacement therapies are still considered the best options for reversing mild and severe AKI syndrome. For this reason, it is essential that innovative and effective therapies, without side effects and complications, be developed to treat AKI and the end-stages of renal disease. Mesenchymal stem cell (MSC) based therapies have numerous advantages in helping to repair inflamed and damaged tissues and are being considered as a new alternative for treating kidney injuries. Numerous experimental models have shown that MSCs can act via differentiation-independent mechanisms to help renal recovery. Essentially, MSCs can secrete a pool of cytokines, growth factors and chemokines, express enzymes, interact via cell-to-cell contacts and release bioagents such as microvesicles to orchestrate renal protection. In this review, we propose seven distinct properties of MSCs which explain how renoprotection may be conferred: 1) anti-inflammatory; 2) pro-angiogenic; 3) stimulation of endogenous progenitor cells; 4) anti-apoptotic; 5) anti-fibrotic; 6) anti-oxidant; and 7) promotion of cellular reprogramming. In this context, these mechanisms, either individually or synergically, could induce renal protection and functional recovery. This review summarises the most important effects and benefits associated with MSC-based therapies in experimental renal disease models and attempts to clarify the mechanisms behind the MSC-related renoprotection. MSCs may prove to be an effective, innovative and affordable treatment for moderate and severe AKI. However, more studies need to be performed to provide a more comprehensive global understanding of MSC-related therapies and to ensure their safety for future clinical applications. PMID:24353358

Stem cells and other innovative intra-articular therapies for osteoarthritis: what does the future hold?

PubMed Central

2012-01-01

Osteoarthritis (OA), the most common type of arthritis in the world, is associated with suffering due to pain, productivity loss, decreased mobility and quality of life. Systemic therapies available for OA are mostly symptom modifying and have potential gastrointestinal, renal, hepatic, and cardiac side effects. BMC Musculoskeletal Disorders recently published a study showing evidence of reparative effects demonstrated by homing of intra-articularly injected autologous bone marrow stem cells in damaged cartilage in an animal model of OA, along with clinical and radiographic benefit. This finding adds to the growing literature showing the potential benefit of intra-articular (IA) bone marrow stem cells. Other emerging potential IA therapies include IL-1 receptor antagonists, conditioned autologous serum, botulinum toxin, and bone morphogenetic protein-7. For each of these therapies, trial data in humans have been published, but more studies are needed to establish that they are safe and effective. Several additional promising new OA treatments are on the horizon, but challenges remain to finding safe and effective local and systemic therapies for OA. Please see related article: http://www.biomedcentral.com/1471-2474/12/259 PMID:22551396

A quality risk management model approach for cell therapy manufacturing.

PubMed

Lopez, Fabio; Di Bartolo, Chiara; Piazza, Tommaso; Passannanti, Antonino; Gerlach, Jörg C; Gridelli, Bruno; Triolo, Fabio

2010-12-01

International regulatory authorities view risk management as an essential production need for the development of innovative, somatic cell-based therapies in regenerative medicine. The available risk management guidelines, however, provide little guidance on specific risk analysis approaches and procedures applicable in clinical cell therapy manufacturing. This raises a number of problems. Cell manufacturing is a poorly automated process, prone to operator-introduced variations, and affected by heterogeneity of the processed organs/tissues and lot-dependent variability of reagent (e.g., collagenase) efficiency. In this study, the principal challenges faced in a cell-based product manufacturing context (i.e., high dependence on human intervention and absence of reference standards for acceptable risk levels) are identified and addressed, and a risk management model approach applicable to manufacturing of cells for clinical use is described for the first time. The use of the heuristic and pseudo-quantitative failure mode and effect analysis/failure mode and critical effect analysis risk analysis technique associated with direct estimation of severity, occurrence, and detection is, in this specific context, as effective as, but more efficient than, the analytic hierarchy process. Moreover, a severity/occurrence matrix and Pareto analysis can be successfully adopted to identify priority failure modes on which to act to mitigate risks. The application of this approach to clinical cell therapy manufacturing in regenerative medicine is also discussed. © 2010 Society for Risk Analysis.

The Application of Nanomaterials in Stem Cell Therapy for Some Neurological Diseases.

PubMed

Zhang, Guilong; Khan, Ahsan Ali; Wu, Hao; Chen, Lukui; Gu, Yuchun; Gu, Ning

2018-02-08

Stem cell therapy provides great promising therapeutic benefits for various neurological disorders. Cell transplantation has emerged as cell replacement application for nerve damage. Recently, nanomaterials obtain wide development in various industrial and medical fields, and nanoparticles have been applied in the neurological field for tracking and treating nervous system diseases. Combining stem cells with nanotechnology has raised more and more attentions; and it has demonstrated that the combination has huge effects on clinical diagnosis and therapeutics in multiple central nervous system diseases, meanwhile, improves prognosis. The aim of this review was to give a brief overview of the application of nanomaterials in stem cell therapy for neurological diseases. Nanoparticles not only promote stem cell proliferation and differentiation in vitro or in vivo, but also play dominant roles on stem cell imaging and tracking. Furthermore, via delivering genes or drugs, nanoparticles can participate in stem cell therapeutic applications for various neurological diseases, such as ischemic stroke, spinal cord injury (SCI), multiple sclerosis (MS), Parkinson's disease (PD), Alzheimer's disease (AD) and gliomas. However, nanoparticles have potential cytotoxic effects on nerve cells, which are related to their physicochemical properties. Nano-stem cell-based therapy as a promising strategy has the ability to affect neuronal repair and regeneration in the central nervous system. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Fibrocytes: A Novel Stromal Cells to Regulate Resistance to Anti-Angiogenic Therapy and Cancer Progression.

PubMed

Goto, Hisatsugu; Nishioka, Yasuhiko

2017-12-29

An adequate blood supply is essential for cancer cells to survive and grow; thus, the concept of inhibiting tumor angiogenesis has been applied to cancer therapy, and several drugs are already in clinical use. It has been shown that treatment with those anti-angiogenic drugs improved the response rate and prolonged the survival of patients with various types of cancer; however, it is also true that the effect was mostly limited. Currently, the disappointing clinical results are explained by the existence of intrinsic or acquired resistance to the therapy mediated by both tumor cells and stromal cells. This article reviews the mechanisms of resistance mediated by stromal cells such as endothelial cells, pericytes, fibroblasts and myeloid cells, with an emphasis on fibrocytes, which were recently identified as the cell type responsible for regulating acquired resistance to anti-angiogenic therapy. In addition, the other emerging role of fibrocytes as mediator-producing cells in tumor progression is discussed.

Improved survival of mice bearing liver metastases of colon cancer cells treated with a combination of radioimmunotherapy and antiangiogenic therapy.

PubMed

Kinuya, Seigo; Yokoyama, Kunihiko; Koshida, Kiyoshi; Mori, Hirofumi; Shiba, Kazuhiro; Watanabe, Naoto; Shuke, Noriyuki; Bai, Jingming; Michigishi, Takatoshi; Tonami, Norihisa

2004-07-01

We attempted to determine whether the combined regimen of radioimmunotherapy (RIT) and antiangiogenic therapy would favorably affect the survival of animals bearing liver metastases of colon cancer cells. Daily antiangiogenic therapy with 2-methoxyestradiol (2-ME), 75 mg/kg, was initiated at 3 days following intrasplenic cell inoculation of LS180 colon cancer cells. RIT with 7 MBq of (131)I-A7, an IgG1 anti-colorectal monoclonal antibody, or (131)I-HPMS-1, an irrelevant IgG1, was conducted at 7 days. Production of vascular endothelial growth factor (VEGF) by LS180 cells was assessed in vitro. All nontreated mice died by 31 days following cell inoculation ( n=5). Monotherapy comprising 2-ME treatment resulted in slightly better survival of mice ( n=8) ( P<0.05). (131)I-A7 RIT displayed a marked therapeutic effect ( n=8) ( P<0.001); however, all animals eventually died due to metastases by 99 days. The combined regimen of (131)I-A7 RIT and antiangiogenic therapy demonstrated a superior therapeutic effect in comparison to monotherapy consisting of either RIT or antiangiogenic therapy ( n=10) ( P<0.05); three mice survived the entire 160-day observation period. The combination of antiangiogenic therapy and (131)I-HPMS-1 RIT failed to provide an appreciable benefit ( n=5). Treatment with 2-ME decreased VEGF production by LS180 cells in a dose-dependent fashion. In conclusion, a combination regimen comprising RIT and antiangiogenic therapy initiated at the early stage of metastasis would be of great benefit in terms of improvement of the therapeutic efficacy with respect to liver metastases.

A meta-analysis of cytokine-induced killer cells therapy in combination with minimally invasive treatment for hepatocellular carcinoma.

PubMed

Li, Xiaofeng; Dai, Dong; Song, Xiuyu; Liu, Jianjing; Zhu, Lei; Xu, Wengui

2014-10-01

There was a continuing controversy on whether the adoptive transfusion of cytokine-induced killer cells (CIK) therapy should have been recommended to reduce the recurrence and metastasis of hepatocellular carcinoma (HCC) after minimally invasive therapy such as TACE (transarterial chemoembolization) or TACE plus RFA (radiofrequency ablation) treatment. The meta-analysis was conducted to compare the effectiveness of CIK cells transfusion therapy combined with TACE or TACE plus RFA treatment with that of minimally invasive therapy alone. Relevant studies were identified by electronic search using a combination of "hepatocellular carcinoma" and "cytokine-induced killer cells". Overall survival (OS) rates and recurrence-free survival (RFS) rates were compared as the major outcome measures. The meta-analysis was divided into two sub-studies (sub-study 1: CIK+TACE+RFA versus TACE+RFA; sub-study 2: CIK+TACE versus TACE) to avoid the risk of bias as we could. Meta-analysis data suggested that CIK cells transfusion therapy combined with TACE plus RFA treatment was associated with higher 1-year RFS rate (odds ratio [OR]=2.46) and 1-year, 2-year OS rates (OR: 1-year=2.09; 3-year=2.16) than TACE plus RFA treatment alone in sub-study 1. For sub-study 2, there were significant differences between CIK+TACE group and TACE group for OS rates (OR: half-year=3.29; 1-year=3.71; 2-year=7.37). CIK cells transfusion therapy truly showed a synergistic effect for HCC patients after minimally invasive treatment especially for a long-term survival. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Taking advantage of the potential of mesenchymal stromal cells in liver regeneration: Cells and extracellular vesicles as therapeutic strategies

PubMed Central

Fiore, Esteban Juan; Domínguez, Luciana María; Bayo, Juan; García, Mariana Gabriela; Mazzolini, Guillermo Daniel

2018-01-01

Cell-based therapies for acute and chronic liver diseases are under continuous progress. Mesenchymal stem/stromal cells (MSCs) are multipotent cells able to migrate selectively to damaged tissue and contribute to its healing and regeneration. The MSC pro-regenerative effect occurs due to their immunomodulatory capacity and their ability to produce factors that promote cell protection and survival. Likewise, it has been observed that part of their paracrine effect is mediated by MSC-derived extracellular vesicles (EVs). EVs contain proteins, lipids and nucleic acids (DNA, mRNA, miRNA, lncRNA) from the cell of origin, allowing for intercellular communication. Recently, different studies have demonstrated that MSC-derived EVs could reproduce, at least in part, the biological effects obtained by MSC-based therapies. Moreover, due to EVs’ stability for long periods of time and easy isolation methods they have become a therapeutic option to MSCs treatments. This review summarizes the latest results achieved in clinical trials using MSCs as cell therapy for liver regeneration, the role of EVs in liver physiopathology and the potential of MSCderived EVs as intercellular mediators and therapeutic tools in liver diseases. PMID:29930465

Combinational Therapy Enhances the Effects of Anti-IGF-1R mAb Figitumumab to Target Small Cell Lung Cancer

PubMed Central

Shen, Hongchang; Xu, Jun; Zhu, Linhai; Liu, Qi; Du, Jiajun

2015-01-01

Background Small cell lung cancer (SCLC) is a recalcitrant malignancy with distinct biologic properties. Antibody targeting therapy has been actively investigated as a new drug modality. Methods We tested the expression of IGF-1R and calculated the survival in 61 SCLC patients. We also evaluated the anti-tumor effects of anti-IGF-1R monoclonal antibody Figitumumab (CP) on SCLC, and tried two drug combinations to improve CP therapy. Results Our clinical data suggested that high IGF-1R expression was correlated with low SCLC patient survival. We then demonstrated the effect of CP was likely through IGF-1R blockage and down-regulation without IGF-1R auto-phosphorylation and PI3K/AKT activation. However, we observed elevated MEK/ERK activation upon CP treatment in SCLC cells, and this MEK/ERK activation was enhanced by ß-arrestin1 knockdown while attenuated by ß-arrestin2 knockdown. We found both MEK/ERK inhibitor and metformin could enhance CP treatment in SCLC cells. We further illustrated the additive effect of metformin was likely through promoting further IGF-1R down-regulation. Conclusion Our results highlighted the potential of anti-IGF-1R therapy and the adjuvant therapy strategy with either MEK/ERK inhibitor or metformin to target SCLC, warranting further studies. PMID:26287334

Bioengineering of injectable encapsulated aggregates of pluripotent stem cells for therapy of myocardial infarction

NASA Astrophysics Data System (ADS)

Zhao, Shuting; Xu, Zhaobin; Wang, Hai; Reese, Benjamin E.; Gushchina, Liubov V.; Jiang, Meng; Agarwal, Pranay; Xu, Jiangsheng; Zhang, Mingjun; Shen, Rulong; Liu, Zhenguo; Weisleder, Noah; He, Xiaoming

2016-10-01

It is difficult to achieve minimally invasive injectable cell delivery while maintaining high cell retention and animal survival for in vivo stem cell therapy of myocardial infarction. Here we show that pluripotent stem cell aggregates pre-differentiated into the early cardiac lineage and encapsulated in a biocompatible and biodegradable micromatrix, are suitable for injectable delivery. This method significantly improves the survival of the injected cells by more than six-fold compared with the conventional practice of injecting single cells, and effectively prevents teratoma formation. Moreover, this method significantly enhances cardiac function and survival of animals after myocardial infarction, as a result of a localized immunosuppression effect of the micromatrix and the in situ cardiac regeneration by the injected cells.

Brain Cancer Stem Cells Display Preferential Sensitivity to Akt Inhibition

PubMed Central

Eyler, Christine E.; Foo, Wen-Chi; LaFiura, Katherine M.; McLendon, Roger E.; Hjelmeland, Anita B.; Rich, Jeremy N.

2009-01-01

Malignant brain tumors are among the most lethal cancers, and conventional therapies are largely limited to palliation. Novel therapies targeted against specific molecular pathways may offer improved efficacy and reduced toxicity compared to conventional therapies, but initial clinical trials of molecular targeted agents in brain cancer therapy have been frequently disappointing. In brain tumors and other cancers, subpopulations of tumor cells have recently been characterized by their ability to self-renew and initiate tumors. Although these cancer stem cells, or tumor initiating cells, are often only present in small numbers in human tumors, mounting evidence suggests that cancer stem cells contribute to tumor maintenance and therapeutic resistance. Thus, the development of therapies that target cancer stem cell signal transduction and biologies may improve brain tumor patient survival. We now demonstrate that populations enriched for cancer stem cells are preferentially sensitive to an inhibitor of Akt, a prominent cell survival and invasion signaling node. Treatment with an Akt inhibitor more potently reduced the numbers of viable brain cancer stem cells relative to matched non-stem cancer cells associated with a preferential induction of apoptosis and a suppression of neurosphere formation. Akt inhibition also reduced the motility and invasiveness of all tumor cells but had a greater impact on cancer stem cell behaviors. Furthermore, inhibition of Akt activity in cancer stem cells increased survival of immunocompromised mice bearing human glioma xenografts in vivo. Together, these results suggest that Akt inhibitors may function as effective anti-cancer stem cell therapies. PMID:18802038

Synergistically killing activity of aspirin and histone deacetylase inhibitor valproic acid (VPA) on hepatocellular cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Xiaofei; Zhu, Yanshuang; He, Huabin

Highlights: •Novel combination therapy using aspirin and valproic acid (VPA). •Combination of aspirin and VPA elicits synergistic cytotoxic effects. •Combination of aspirin and VPA significantly reduces the drug dosage required alone. •Combination of aspirin and VPA significantly inhibit tumor growth. •Lower dose of aspirin in combination therapy will minimize side effects of aspirin. -- Abstract: Aspirin and valproic acid (VPA) have been extensively studied for inducing various malignancies growth inhibition respectively, despite their severe side effects. Here, we developed a novel combination by aspirin and VPA on hepatocellular cancer cells (HCCs). The viability of HCC lines were analyzed by MTTmore » assay, apoptotic analysis of HepG2 and SMMC-7721 cell was performed. Real time-PCR and Western blotting were performed to determine the expression of apoptosis related genes and proteins such as Survivin, Bcl-2/Bax, Cyclin D1 and p15. Moreover, orthotopic xenograft tumors were challenged in nude mice to establish murine model, and then therapeutic effect was analyzed after drug combination therapy. The viability of HCC lines’ significantly decreased after drug combination treatment, and cancer cell apoptosis in combination group increasingly induced compared with single drug use. Therapeutic effect was significantly enhanced by combination therapy in tumor volume and tumor weight decrease. From the data shown here, aspirin and VPA combination have a synergistic killing effect on hepatocellular cancers cells proliferation and apoptosis.« less

Glucose metabolism-targeted therapy and withaferin A are effective for epidermal growth factor receptor tyrosine kinase inhibitor-induced drug-tolerant persisters.

PubMed

Kunimasa, Kei; Nagano, Tatsuya; Shimono, Yohei; Dokuni, Ryota; Kiriu, Tatsunori; Tokunaga, Shuntaro; Tamura, Daisuke; Yamamoto, Masatsugu; Tachihara, Motoko; Kobayashi, Kazuyuki; Satouchi, Miyako; Nishimura, Yoshihiro

2017-07-01

In pathway-targeted cancer drug therapies, the relatively rapid emergence of drug-tolerant persisters (DTPs) substantially limits the overall therapeutic benefit. However, little is known about the roles of DTPs in drug resistance. In this study, we investigated the features of epidermal growth factor receptor-tyrosine kinase inhibitor-induced DTPs and explored a new treatment strategy to overcome the emergence of these DTPs. We used two EGFR-mutated lung adenocarcinoma cell lines, PC9 and II-18. They were treated with 2 μM gefitinib for 6, 12, or 24 days or 6 months. We analyzed the mRNA expression of the stem cell-related markers by quantitative RT-PCR and the expression of the cellular senescence-associated proteins. Then we sorted DTPs according to the expression pattern of CD133 and analyzed the features of sorted cells. Finally, we tried to ablate DTPs by glucose metabolism targeting therapies and a stem-like cell targeting drug, withaferin A. Drug-tolerant persisters were composed of at least two types of cells, one with the properties of cancer stem-like cells (CSCs) and the other with the properties of therapy-induced senescent (TIS) cells. The CD133 high cell population had CSC properties and the CD133 low cell population had TIS properties. The CD133 low cell population containing TIS cells showed a senescence-associated secretory phenotype that supported the emergence of the CD133 high cell population containing CSCs. Glucose metabolism inhibitors effectively eliminated the CD133 low cell population. Withaferin A effectively eliminated the CD133 high cell population. The combination of phloretin and withaferin A effectively suppressed gefitinib-resistant tumor growth. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Current research on pharmacologic and regenerative therapies for osteoarthritis

PubMed Central

Zhang, Wei; Ouyang, Hongwei; Dass, Crispin R; Xu, Jiake

2016-01-01

Osteoarthritis (OA) is a degenerative joint disorder commonly encountered in clinical practice, and is the leading cause of disability in elderly people. Due to the poor self-healing capacity of articular cartilage and lack of specific diagnostic biomarkers, OA is a challenging disease with limited treatment options. Traditional pharmacologic therapies such as acetaminophen, non-steroidal anti-inflammatory drugs, and opioids are effective in relieving pain but are incapable of reversing cartilage damage and are frequently associated with adverse events. Current research focuses on the development of new OA drugs (such as sprifermin/recombinant human fibroblast growth factor-18, tanezumab/monoclonal antibody against β-nerve growth factor), which aims for more effectiveness and less incidence of adverse effects than the traditional ones. Furthermore, regenerative therapies (such as autologous chondrocyte implantation (ACI), new generation of matrix-induced ACI, cell-free scaffolds, induced pluripotent stem cells (iPS cells or iPSCs), and endogenous cell homing) are also emerging as promising alternatives as they have potential to enhance cartilage repair, and ultimately restore healthy tissue. However, despite currently available therapies and research advances, there remain unmet medical needs in the treatment of OA. This review highlights current research progress on pharmacologic and regenerative therapies for OA including key advances and potential limitations. PMID:26962464

Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway* | Office of Cancer Genomics

Cancer.gov

Plasticity of the cell state has been proposed to drive resistance to multiple classes of cancer therapies, thereby limiting their effectiveness. A high-mesenchymal cell state observed in human tumors and cancer cell lines has been associated with resistance to multiple treatment modalities across diverse cancer lineages, but the mechanistic underpinning for this state has remained incompletely understood.

Lymphoma immunotherapy: vaccines, adoptive cell transfer and immunotransplant

PubMed Central

Brody, Joshua; Levy, Ronald

2017-01-01

Therapy for non-Hodgkin lymphoma has benefited greatly from basic science and clinical research such that chemotherapy and monoclonal antibody therapy have changed some lymphoma subtypes from uniformly lethal to curable, but the majority of lymphoma patients remain incurable. Novel therapies with less toxicity and more specific targeting of tumor cells are needed and immunotherapy is among the most promising of these. Recently completed randomized trials of idiotype vaccines and earlier-phase trials of other vaccine types have shown the ability to induce antitumor T cells and some clinical responses. More recently, trials of adoptive transfer of antitumor T cells have demonstrated techniques to increase the persistence and antitumor effect of these cells. Herein, we discuss lymphoma immunotherapy clinical trial results and what lessons can be taken to improve their effect, including the combination of vaccination and adoptive transfer in an approach we have dubbed ‘immunotransplant’. PMID:20636025

Targeted Therapy for Cancer

Cancer.gov

Targeted therapy is a type of cancer treatment that targets the changes in cancer cells that help them grow, divide, and spread. Learn how targeted therapy works against cancer and about side effects that may occur.

Trial Watch: Immunotherapy plus radiation therapy for oncological indications.

PubMed

Vacchelli, Erika; Bloy, Norma; Aranda, Fernando; Buqué, Aitziber; Cremer, Isabelle; Demaria, Sandra; Eggermont, Alexander; Formenti, Silvia Chiara; Fridman, Wolf Hervé; Fucikova, Jitka; Galon, Jérôme; Spisek, Radek; Tartour, Eric; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

2016-01-01

Malignant cells succumbing to some forms of radiation therapy are particularly immunogenic and hence can initiate a therapeutically relevant adaptive immune response. This reflects the intrinsic antigenicity of malignant cells (which often synthesize a high number of potentially reactive neo-antigens) coupled with the ability of radiation therapy to boost the adjuvanticity of cell death as it stimulates the release of endogenous adjuvants from dying cells. Thus, radiation therapy has been intensively investigated for its capacity to improve the therapeutic profile of several anticancer immunotherapies, including (but not limited to) checkpoint blockers, anticancer vaccines, oncolytic viruses, Toll-like receptor (TLR) agonists, cytokines, and several small molecules with immunostimulatory effects. Here, we summarize recent preclinical and clinical advances in this field of investigation.

Treating Diet-Induced Diabetes and Obesity with Human Embryonic Stem Cell-Derived Pancreatic Progenitor Cells and Antidiabetic Drugs

PubMed Central

Bruin, Jennifer E.; Saber, Nelly; Braun, Natalie; Fox, Jessica K.; Mojibian, Majid; Asadi, Ali; Drohan, Campbell; O’Dwyer, Shannon; Rosman-Balzer, Diana S.; Swiss, Victoria A.; Rezania, Alireza; Kieffer, Timothy J.

2015-01-01

Summary Human embryonic stem cell (hESC)-derived pancreatic progenitor cells effectively reverse hyperglycemia in rodent models of type 1 diabetes, but their capacity to treat type 2 diabetes has not been reported. An immunodeficient model of type 2 diabetes was generated by high-fat diet (HFD) feeding in SCID-beige mice. Exposure to HFDs did not impact the maturation of macroencapsulated pancreatic progenitor cells into glucose-responsive insulin-secreting cells following transplantation, and the cell therapy improved glucose tolerance in HFD-fed transplant recipients after 24 weeks. However, since diet-induced hyperglycemia and obesity were not fully ameliorated by transplantation alone, a second cohort of HFD-fed mice was treated with pancreatic progenitor cells combined with one of three antidiabetic drugs. All combination therapies rapidly improved body weight and co-treatment with either sitagliptin or metformin improved hyperglycemia after only 12 weeks. Therefore, a stem cell-based therapy may be effective for treating type 2 diabetes, particularly in combination with antidiabetic drugs. PMID:25801507

Targeted therapy with MXD3 siRNA, anti-CD22 antibody and nanoparticles for precursor B-cell acute lymphoblastic leukaemia.

PubMed

Satake, Noriko; Duong, Connie; Chen, Cathy; Barisone, Gustavo A; Diaz, Elva; Tuscano, Joseph; Rocke, David M; Nolta, Jan; Nitin, Nitin

2014-11-01

Conventional chemotherapy for precursor B-cell (preB) acute lymphoblastic leukaemia (ALL) has limitations that could be overcome by targeted therapy. Previously, we discovered a potential therapeutic molecular target, MDX3 (MAX dimerization protein 3), in preB ALL. In this study, we hypothesize that an effective siRNA therapy for preB ALL can be developed using antiCD22 antibody (αCD22 Ab) and nanoparticles. We composed nanocomplexes with super paramagnetic iron oxide nanoparticles (SPIO NPs), αCD22 Abs and MXD3 siRNA molecules based on physical interactions between the molecules. We demonstrated that the MXD3 siRNA-αCD22 Ab-SPIO NP complexes entered leukaemia cells and knocked down MXD3, leading the cells to undergo apoptosis and resulting in decreased live cell counts in the cell line Reh and in primary preB ALL samples in vitro. Furthermore, the cytotoxic effects of the MXD3 siRNA-αCD22 Ab-SPIO NP complexes were significantly enhanced by addition of the chemotherapy drugs vincristine or doxorubicin. We also ruled out potential cytotoxic effects of the MXD3 siRNA-αCD22 Ab-SPIO NP complexes on normal primary haematopoietic cells. Normal B cells were affected while CD34-positive haematopoietic stem cells and non-B cells were not. These data suggest that MXD3 siRNA-αCD22 Ab-SPIO NP complexes have the potential to be a new targeted therapy for preB ALL. © 2014 John Wiley & Sons Ltd.

Roles of p38 and JNK protein kinase pathways activated by compound cantharidin capsules containing serum on proliferation inhibition and apoptosis of human gastric cancer cell line

PubMed Central

Sun, Yonghao; Zhang, Dejuan; Mao, Mao; Lu, Yangping; Jiao, Ning

2017-01-01

The aim of the present study was to investigate the inhibitory effect of compound cantharides capsules (CCCs) on the viability and apoptosis of human gastric cancer cell lines, BGC-823 and SGC-7901, and to detect its regulation of gene expression levels, as well as its inhibition mechanisms. Each cell line was grouped into a control group, CCC serum group, 5-fluorouracil (5-FU) group, combination therapy group (CCC serum + 5-FU) and serum control group. Growth curves were measured and flow cytometry was used to detect cell apoptosis and cell viability. The mRNA expression level of proliferation-related C-MYC and p53 genes were assayed by reverse transcription-quantitative polymerase chain reaction. Protein phosphorylation levels of proliferating cell nuclear antigen, p38 mitogen-activated protein kinase, extracellular signal-related kinase 1/2, c-Jun N-terminal kinase (JNK) and IκB were assayed by western blotting. The combined CCC serum and 5-FU group exhibited a higher inhibition rate in both cell lines and CCC serum therapy demonstrated a similar effect to 5-FU treatment, as demonstrated in the MTT and cell growth assay. Combined therapy significantly decreased the C-MYC mRNA expression levels and increased p53 mRNA expression levels (P<0.05). Combined therapy of 5-FU and CCC was more significant compared with CCC serum or 5-FU only (P<0.05). P38 and JNK-related protein phosphorylation are involved in apoptosis initiated by CCC combined 5-FU therapy. Combined therapy was able to significantly inhibit human gastric cancer cell growth (P<0.05), and advance cell apoptosis compared with CCC serum only. CCC serum resulted in downregulation of the c-Myc gene and upregulation of the p53 gene. p38 and JNK-related protein phosphorylation is involved in the inhibition of cell viability and apoptosis of human gastric cancer cell lines. PMID:28810654

Roles of p38 and JNK protein kinase pathways activated by compound cantharidin capsules containing serum on proliferation inhibition and apoptosis of human gastric cancer cell line.

PubMed

Sun, Yonghao; Zhang, Dejuan; Mao, Mao; Lu, Yangping; Jiao, Ning

2017-08-01

The aim of the present study was to investigate the inhibitory effect of compound cantharides capsules (CCCs) on the viability and apoptosis of human gastric cancer cell lines, BGC-823 and SGC-7901, and to detect its regulation of gene expression levels, as well as its inhibition mechanisms. Each cell line was grouped into a control group, CCC serum group, 5-fluorouracil (5-FU) group, combination therapy group (CCC serum + 5-FU) and serum control group. Growth curves were measured and flow cytometry was used to detect cell apoptosis and cell viability. The mRNA expression level of proliferation-related C-MYC and p53 genes were assayed by reverse transcription-quantitative polymerase chain reaction. Protein phosphorylation levels of proliferating cell nuclear antigen, p38 mitogen-activated protein kinase, extracellular signal-related kinase 1/2, c-Jun N-terminal kinase (JNK) and IκB were assayed by western blotting. The combined CCC serum and 5-FU group exhibited a higher inhibition rate in both cell lines and CCC serum therapy demonstrated a similar effect to 5-FU treatment, as demonstrated in the MTT and cell growth assay. Combined therapy significantly decreased the C-MYC mRNA expression levels and increased p53 mRNA expression levels (P<0.05). Combined therapy of 5-FU and CCC was more significant compared with CCC serum or 5-FU only (P<0.05). P38 and JNK-related protein phosphorylation are involved in apoptosis initiated by CCC combined 5-FU therapy. Combined therapy was able to significantly inhibit human gastric cancer cell growth (P<0.05), and advance cell apoptosis compared with CCC serum only. CCC serum resulted in downregulation of the c-Myc gene and upregulation of the p53 gene. p38 and JNK-related protein phosphorylation is involved in the inhibition of cell viability and apoptosis of human gastric cancer cell lines.

Interleukin-2 therapy reverses some immunosuppressive effects of skeletal unloading

NASA Technical Reports Server (NTRS)

Armstrong, Jason W.; Balch, Signe; Chapes, Stephen K.

1994-01-01

Using antiorthostatic suspension, we characterized hematopoietic changes that may be responsible for the detrimental effect of skeletal unloading on macrophage development. Skeletally unloaded mice had suppressed macrophage development in unloaded and loaded bones, which indicated a systemic effect. Bone marrow cells from unloaded mice secreted less macrophage colony-stimulating factor and interleukin-6 than control mice. Additionally, T-lymphocyte proliferation was reduced after skeletal unloading. We show that polyethylene glycol-interleukin-2 therapy reversed the effects of skeletal unloading on macrophage development and cell proliferation.

Combined Therapy Conquers Resistant Tumors: Bortezomib and TRAIL | Center for Cancer Research

Cancer.gov

The principal strategy in the battle against cancer is simple: kill as many tumor cells as possible while sparing healthy cells. Unfortunately, traditional treatments, such as chemotherapy and radiation, have substantial side effects, and many cancers develop resistance to therapy.

Pulsed magnetic field enhances therapeutic efficiency of mesenchymal stem cells in chronic neuropathic pain model.

PubMed

Mert, Tufan; Kurt, Akif Hakan; Altun, İdiris; Celik, Ahmet; Baran, Furkan; Gunay, Ismail

2017-05-01

Cell-based or magnetic field therapies as alternative approaches to pain management have been tested in several experimental pain models. The aim of this study therefore was to investigate the actions of the cell-based therapy (adipose tissue derived mesenchymal stem cells; ADMSC) or pulsed magnetic field (PMF) therapy and magneto-cell therapy (combination of ADMSC and PMF) in chronic constriction nerve injury model (CCI). The actions of individual ADMSC (route dependent [systemic or local], time-dependent [a day or a week after surgery]), or PMF and their combination (magneto-cell) therapies on hyperalgesia and allodynia were investigated by using thermal plantar test and a dynamic plantar aesthesiometer, respectively. In addition, various cytokine levels (IL-1β, IL-6, and IL-10) of rat sciatic nerve after CCI were analyzed. Following the CCI, both latency and threshold significantly decreased. ADMSC or PMF significantly increased latencies and thresholds. The combination of ADMSC with PMF even more significantly increased latency and threshold when compared with ADMSC alone. However, ADMSC-induced decrease in pro-inflammatory or increase in anti-inflammatory cytokines levels were partially prevented by PMF treatments. Present findings may suggest that both cell-based and magnetic therapies can effectively attenuate chronic neuropathic pain symptoms. Combined magneto-cell therapy may also efficiently reverse neuropathic signs. Bioelectromagnetics. 38:255-264, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Natural Killer Cell-Based Therapies Targeting Cancer: Possible Strategies to Gain and Sustain Anti-Tumor Activity

PubMed Central

Dahlberg, Carin I. M.; Sarhan, Dhifaf; Chrobok, Michael; Duru, Adil D.; Alici, Evren

2015-01-01

Natural killer (NK) cells were discovered 40 years ago, by their ability to recognize and kill tumor cells without the requirement of prior antigen exposure. Since then, NK cells have been seen as promising agents for cell-based cancer therapies. However, NK cells represent only a minor fraction of the human lymphocyte population. Their skewed phenotype and impaired functionality during cancer progression necessitates the development of clinical protocols to activate and expand to high numbers ex vivo to be able to infuse sufficient numbers of functional NK cells to the cancer patients. Initial NK cell-based clinical trials suggested that NK cell-infusion is safe and feasible with almost no NK cell-related toxicity, including graft-versus-host disease. Complete remission and increased disease-free survival is shown in a small number of patients with hematological malignances. Furthermore, successful adoptive NK cell-based therapies from haploidentical donors have been demonstrated. Disappointingly, only limited anti-tumor effects have been demonstrated following NK cell infusion in patients with solid tumors. While NK cells have great potential in targeting tumor cells, the efficiency of NK cell functions in the tumor microenvironment is yet unclear. The failure of immune surveillance may in part be due to sustained immunological pressure on tumor cells resulting in the development of tumor escape variants that are invisible to the immune system. Alternatively, this could be due to the complex network of immune-suppressive compartments in the tumor microenvironment, including myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells. Although the negative effect of the tumor microenvironment on NK cells can be transiently reverted by ex vivo expansion and long-term activation, the aforementioned NK cell/tumor microenvironment interactions upon reinfusion are not fully elucidated. Within this context, genetic modification of NK cells may provide new possibilities for developing effective cancer immunotherapies by improving NK cell responses and making them less susceptible to the tumor microenvironment. Within this review, we will discuss clinical trials using NK cells with a specific reflection on novel potential strategies, such as genetic modification of NK cells and complementary therapies aimed at improving the clinical outcome of NK cell-based immune therapies. PMID:26648934

Evolutionary dynamics of imatinib-treated leukemic cells by stochastic approach

NASA Astrophysics Data System (ADS)

Pizzolato, Nicola; Valenti, Davide; Adorno, Dominique Persano; Spagnolo, Bernardo

2009-09-01

The evolutionary dynamics of a system of cancerous cells in a model of chronic myeloid leukemia (CML) is investigated by a statistical approach. Cancer progression is explored by applying a Monte Carlo method to simulate the stochastic behavior of cell reproduction and death in a population of blood cells which can experience genetic mutations. In CML front line therapy is represented by the tyrosine kinase inhibitor imatinib which strongly affects the reproduction of leukemic cells only. In this work, we analyze the effects of a targeted therapy on the evolutionary dynamics of normal, first-mutant and cancerous cell populations. Several scenarios of the evolutionary dynamics of imatinib-treated leukemic cells are described as a consequence of the efficacy of the different modelled therapies. We show how the patient response to the therapy changes when a high value of the mutation rate from healthy to cancerous cells is present. Our results are in agreement with clinical observations. Unfortunately, development of resistance to imatinib is observed in a fraction of patients, whose blood cells are characterized by an increasing number of genetic alterations. We find that the occurrence of resistance to the therapy can be related to a progressive increase of deleterious mutations.

Toward precision manufacturing of immunogene T-cell therapies.

PubMed

Xu, Jun; Melenhorst, J Joseph; Fraietta, Joseph A

2018-05-01

Cancer can be effectively targeted using a patient's own T cells equipped with synthetic receptors, including chimeric antigen receptors (CARs) that redirect and reprogram these lymphocytes to mediate tumor rejection. Over the past two decades, several strategies to manufacture genetically engineered T cells have been proposed, with the goal of generating optimally functional cellular products for adoptive transfer. Based on this work, protocols for manufacturing clinical-grade CAR T cells have been established, but these complex methods have been used to treat only a few hundred individuals. As CAR T-cell therapy progresses into later-phase clinical trials and becomes an option for more patients, a major consideration for academic institutions and industry is developing robust manufacturing processes that will permit scaling-out production of immunogene T-cell therapies in a reproducible and efficient manner. In this review, we will discuss the steps involved in cell processing, the major obstacles surrounding T-cell manufacturing platforms and the approaches for improving cellular product potency. Finally, we will address the challenges of expanding CAR T-cell therapy to a global patient population. Copyright © 2018 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Viability of long-term gene therapy in the cochlea.

PubMed

Atkinson, Patrick J; Wise, Andrew K; Flynn, Brianna O; Nayagam, Bryony A; Richardson, Rachael T

2014-04-22

Gene therapy has been investigated as a way to introduce a variety of genes to treat neurological disorders. An important clinical consideration is its long-term effectiveness. This research aims to study the long-term expression and effectiveness of gene therapy in promoting spiral ganglion neuron survival after deafness. Adenoviral vectors modified to express brain derived neurotrophic factor or neurotrophin-3 were unilaterally injected into the guinea pig cochlea one week post ototoxic deafening. After six months, persistence of gene expression and significantly greater neuronal survival in neurotrophin-treated cochleae compared to the contralateral cochleae were observed. The long-term gene expression observed indicates that gene therapy is potentially viable; however the degeneration of the transduced cells as a result of the original ototoxic insult may limit clinical effectiveness. With further research aimed at transducing stable cochlear cells, gene therapy may be an efficacious way to introduce neurotrophins to promote neuronal survival after hearing loss.

Cell-based therapeutic strategies for multiple sclerosis.

PubMed

Scolding, Neil J; Pasquini, Marcelo; Reingold, Stephen C; Cohen, Jeffrey A

2017-11-01

The availability of multiple disease-modifying medications with regulatory approval to treat multiple sclerosis illustrates the substantial progress made in therapy of the disease. However, all are only partially effective in preventing inflammatory tissue damage in the central nervous system and none directly promotes repair. Cell-based therapies, including immunoablation followed by autologous haematopoietic stem cell transplantation, mesenchymal and related stem cell transplantation, pharmacologic manipulation of endogenous stem cells to enhance their reparative capabilities, and transplantation of oligodendrocyte progenitor cells, have generated substantial interest as novel therapeutic strategies for immune modulation, neuroprotection, or repair of the damaged central nervous system in multiple sclerosis. Each approach has potential advantages but also safety concerns and unresolved questions. Moreover, clinical trials of cell-based therapies present several unique methodological and ethical issues. We summarize here the status of cell-based therapies to treat multiple sclerosis and make consensus recommendations for future research and clinical trials. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.

Boron neutron capture therapy induces cell cycle arrest and cell apoptosis of glioma stem/progenitor cells in vitro.

PubMed

Sun, Ting; Zhang, Zizhu; Li, Bin; Chen, Guilin; Xie, Xueshun; Wei, Yongxin; Wu, Jie; Zhou, Youxin; Du, Ziwei

2013-08-06

Glioma stem cells in the quiescent state are resistant to clinical radiation therapy. An almost inevitable glioma recurrence is due to the persistence of these cells. The high linear energy transfer associated with boron neutron capture therapy (BNCT) could kill quiescent and proliferative cells. The present study aimed to evaluate the effects of BNCT on glioma stem/progenitor cells in vitro. The damage induced by BNCT was assessed using cell cycle progression, apoptotic cell ratio and apoptosis-associated proteins expression. The surviving fraction and cell viability of glioma stem/progenitor cells were decreased compared with differentiated glioma cells using the same boronophenylalanine pretreatment and the same dose of neutron flux. BNCT induced cell cycle arrest in the G2/M phase and cell apoptosis via the mitochondrial pathway, with changes in the expression of associated proteins. Glioma stem/progenitor cells, which are resistant to current clinical radiotherapy, could be effectively killed by BNCT in vitro via cell cycle arrest and apoptosis using a prolonged neutron irradiation, although radiosensitivity of glioma stem/progenitor cells was decreased compared with differentiated glioma cells when using the same dose of thermal neutron exposure and boronophenylalanine pretreatment. Thus, BNCT could offer an appreciable therapeutic advantage to prevent tumor recurrence, and may become a promising treatment in recurrent glioma.

Therapeutic effects of combination using glucosamine plus tacrolimus (FK-506) on the development of atopic dermatitis-like skin lesions in NC/Nga mice.

PubMed

Kim, C-H; Cheong, K A; Park, C D; Lee, A-Y

2012-05-01

Tacrolimus (FK-506) has been found to exhibit potent inhibitory effects on spontaneously developed dermatitis. We previously showed that glucosamine prevents the development of Atopic dermatitis (AD)-like skin lesions in NC/Nga mice. The aims of our study were to investigate the synergistic therapeutic efficacy of combination of glucosamine plus FK-506 in dermatophagoides farina (Df)-induced AD-like skin lesions in NC/Nga mice and to determine the underlying therapeutic mechanisms. The Df-induced NC/Nga mice with a clinical score of 8 were used for treatment with glucosamine (500 mg/kg) alone, FK-506 (1.0 mg/kg) or in combination. The synergistic effects of combination therapy were evaluated by dermatitis scores, skin histology and immunological parameters such as IgE, Th2-mediated cytokines and chemokines, CD3(+) T cells and CLA(+) T cells. Combined therapy using glucosamine plus FK-506 improved the development of AD-like skin lesions as exemplified by a significant decrease in total skin symptom severity scores. The suppression of dermatitis by combined therapy was accompanied by a decrease in the plasma level of IgE and in the splenic level of IL-5, IL-13, TARC and eotaxin. Histological finding indicated that the dermal infiltration of inflammatory cells including mast cells and eosinophils was greatly reduced. Particularly, immunohistological evaluation reveals a reduction in CD3(+) T cells and CLA(+) cells in the combined therapy. Our findings suggest that combination therapy of glucosamine plus FK-506 was more synergistic efficacy than single-modality treatment with either alone to improve the development of established dermatitis in NC/Nga mice model. This combined immunosuppressive therapy may provide an effective therapeutic strategy for the treatment of AD. © 2011 The Authors. Scandinavian Journal of Immunology © 2011 Blackwell Publishing Ltd.

B Lymphocytes in Rheumatoid Arthritis and the Effects of Anti-TNF-α Agents on B Lymphocytes: A Review of the Literature.

PubMed

Pala, Ozlem; Diaz, Alain; Blomberg, Bonnie B; Frasca, Daniela

2018-06-01

The aim of this article was to review published research related to B lymphocytes in rheumatoid arthritis, their role in the pathogenesis of the disease, the effects of tumor necrosis factor (TNF)-α inhibitors on B lymphocytes, the risk for infection, and responses to vaccines. A PubMed search was conducted to review recent advances related to B lymphocytes and the effects of anti-TNF-α on B lymphocytes in rheumatoid arthritis. B lymphocytes play an important role in the pathogenesis of rheumatoid arthritis. In this review, we summarize the major mechanisms by which B lymphocytes play a pathologic role in the development and propagation of the disease, as B lymphocytes are recruited to the synovial fluid, where they contribute to local inflammation through the secretion of pro-inflammatory mediators (cytokines, chemokines, micro-RNAs) and present antigens to T cells. We discuss the effects of TNF-α, either direct or indirect, on B lymphocytes expressing receptors for this cytokine. We also show that total B-cell numbers have been reported to be reduced in the blood of patients with rheumatoid arthritis versus healthy controls, but are significantly increased up to normal levels in patients undergoing anti-TNF-α therapy. As for B-cell subsets, controversial results have been reported, with studies showing decreased frequencies of total memory B cells (and memory subsets) and others showing no differences in patients versus healthy controls. Studies investigating the effects of anti-TNF-α therapy have also given controversial results, with therapy found to increase (or not) the frequency of memory B lymphocytes, in patients with rheumatoid arthritis versus healthy controls. Those highly variable results could have been due to differences in patient characteristics and limited numbers of subjects. Finally, we summarize the effects of blocking TNF-α with anti-TNF-α agents on possible infections that patients with rheumatoid arthritis may contract, as well as on responses to vaccination. B lymphocytes play a significant role in the pathogenesis of rheumatoid arthritis, and B cell-depletion therapy has a major effect on the course of the disease. The advances in treatment of rheumatoid arthritis include the development of targeted therapies. Anti-TNF-α therapies are widely used despite potentially serious adverse events. The data on the effects of anti-TNF-α therapies on B lymphocytes are limited and conflicting. There is a need for larger studies to better understand the effects of newly discovered therapies on the different cells of the immune system. Copyright © 2018 Elsevier HS Journals, Inc. All rights reserved.

In vitro evaluation of wound healing and antimicrobial potential of ozone therapy.

PubMed

Borges, Gabriel Álvares; Elias, Silvia Taveira; da Silva, Sandra Márcia Mazutti; Magalhães, Pérola Oliveira; Macedo, Sergio Bruzadelli; Ribeiro, Ana Paula Dias; Guerra, Eliete Neves Silva

2017-03-01

Although ozone therapy is extensively applied when wound repair and antimicrobial effect are necessary, little is known about cellular mechanisms regarding this process. Thus, this study aimed to evaluate ozone cytotoxicity in fibroblasts (L929) and keratinocytes (HaCaT) cell lines, its effects on cell migration and its antimicrobial activity. Cells were treated with ozonated phosphate-buffered saline (8, 4, 2, 1, 0.5 and 0.25 μg/mL ozone), chlorhexidine 0.2% or buffered-solution, and cell viability was determined through MTT assay. The effect of ozone on cell migration was evaluated through scratch wound healing and transwell migration assays. The minimum inhibitory concentrations for Candida albicans and Staphylococcus aureus were determined. Ozone showed no cytotoxicity for the cell lines, while chlorhexidine markedly reduced cell viability. Although no significant difference between control and ozone-treated cells was observed in the scratch assay, a considerable increase in fibroblasts migration was noticed on cells treated with 8 μg/mL ozonated solution. Ozone alone did not inhibit growth of microorganisms; however, its association with chlorhexidine resulted in antimicrobial activity. This study confirms the wound healing and antimicrobial potential of ozone therapy and presents the need for studies to elucidate the molecular mechanisms through which it exerts such biological effects. Copyright © 2017 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

The ratio of cancer cells to stroma after induction therapy in the treatment of non-small cell lung cancer.

PubMed

Goto, Masaki; Naito, Masahito; Saruwatari, Koichi; Hisakane, Kakeru; Kojima, Motohiro; Fujii, Satoshi; Kuwata, Takeshi; Ochiai, Atsushi; Nomura, Shogo; Aokage, Keiju; Hishida, Tomoyuki; Yoshida, Junji; Yokoi, Kohei; Tsuboi, Masahiro; Ishii, Genichiro

2017-02-01

Induction therapy induces degenerative changes of various degrees in both cancerous and non-cancerous cells of non-small cell lung cancer (NSCLC). The effect of induction therapy on histological characteristics, in particular the ratio of residual cancer cells to non-cancerous components, is unknown. Seventy-four NSCLC patients treated with induction therapy followed by surgery were enrolled. Residual cancer cells were identified using anti-pan-cytokeratin antibody (AE1/AE3). We analyzed and quantified the following three factors via digital image analysis; (1) the tumor area containing cancer cells and non-cancerous components (TA), (2) the total area of AE1/AE3 positive cancer cells (TACC), (3) the percentage of TACC to TA (%TACC). These factors were also analyzed in a matched control group (surgery alone, n = 80). The median TACC of the induction therapy group was significantly lower than that of the control group (p < 0.01). In addition, the median %TACC of the induction therapy group (5.9 %) was significantly lower than that of the control group (58.6 %) (p < 0.01). TACC had a strong positive correlation with TA in the control group (r = 0.93), but not in the induction therapy group. Conversely, TACC had a strong positive correlation with %TACC in the induction therapy group (r = 0.95), but not in the control group. Unlike the control group, the smaller the total area of residual cancer cells, the higher residual tumor contained non-cancerous components in the induction group, which may be the characteristic histological feature of NSCLC after induction therapy.

Antitumor effect of the integrin α4 signaling inhibitor JK273 in non-small cell lung cancer NCI-H460 cells.

PubMed

Lu, Thien Nhan; Ganganna, Bogonda; Pham, Thuy Trang; Vo, Anh Van; Lu, Thien Phuc; Nguyen, Huong-Giang Thi; Nguyen, My-Nuong Thi; Huynh, Phuong Nguyen; Truong, Ngoc Tuyen; Lee, Jongkook

2017-09-16

Lung cancer accounts for the highest death rate among cancers worldwide, with most patients being diagnosed with non-small cell lung cancer (NSCLC), urging more effective therapies. We report that JK273, a pyrrolo[2,3-d]pyrimidine analog, which inhibits α4 integrin signaling, showed a selective cytotoxic effect against HCI-H460 NSCLC cells, with an IC 50 of 0.98 ± 0.15 μM, but showed less sensitivity to fibroblasts with a selectivity index (SI) greater than 30. This effect was attributed to cell cycle arrest at S phase by JK273 treatment, resulting in the apoptosis of NCI-H460 cells, further confirmed by exposing phosphatidylserine and morphological changes. Taken together with the previous study of JK273 inhibiting cell migration, we propose that JK273 could serve as an antitumor compound to specifically target cancer cells but not non-cancerous cells by triggering programmed cell death, in addition to anti-metastatic effects in cancer therapy. Copyright © 2017 Elsevier Inc. All rights reserved.

Induction of Early Autophagic Process on Leishmania amazonensis by Synergistic Effect of Miltefosine and Innovative Semi-synthetic Thiosemicarbazone

PubMed Central

Scariot, Débora B.; Britta, Elizandra A.; Moreira, Amanda L.; Falzirolli, Hugo; Silva, Cleuza C.; Ueda-Nakamura, Tânia; Dias-Filho, Benedito P.; Nakamura, Celso V.

2017-01-01

Drug combination therapy is a current trend to treat complex diseases. Many benefits are expected from this strategy, such as cytotoxicity decrease, retardation of resistant strains development, and activity increment. This study evaluated in vitro combination between an innovative thiosemicarbazone molecule – BZTS with miltefosine, a drug already consolidated in the leishmaniasis treatment, against Leishmania amazonensis. Cytotoxicity effects were also evaluated on macrophages and erythrocytes. Synergistic antileishmania effect and antagonist cytotoxicity were revealed from this combination therapy. Mechanisms of action assays were performed in order to investigate the main cell pathways induced by this treatment. Mitochondrial dysfunction generated a significant increase of reactive oxygen and nitrogen species production, causing severe cell injuries and promoting intense autophagy process and consequent apoptosis cell death. However, this phenomenon was not strong enough to promote dead in mammalian cell, providing the potential selective effect of the tested combination for the protozoa. Thus, the results confirmed that drugs involved in distinct metabolic routes are promising agents for drug combination therapy, promoting a synergistic effect. PMID:28270805

Tyrosine kinase inhibitors and mesenchymal stromal cells: effects on self-renewal, commitment and functions

PubMed Central

Borriello, Adriana; Caldarelli, Ilaria; Bencivenga, Debora; Stampone, Emanuela; Perrotta, Silverio; Oliva, Adriana; Ragione, Fulvio Della

2017-01-01

The hope of selectively targeting cancer cells by therapy and eradicating definitively malignancies is based on the identification of pathways or metabolisms that clearly distinguish “normal” from “transformed” phenotypes. Some tyrosine kinase activities, specifically unregulated and potently activated in malignant cells, might represent important targets of therapy. Consequently, tyrosine kinase inhibitors (TKIs) might be thought as the “vanguard” of molecularly targeted therapy for human neoplasias. Imatinib and the successive generations of inhibitors of Bcr-Abl1 kinase, represent the major successful examples of TKI use in cancer treatment. Other tyrosine kinases have been selected as targets of therapy, but the efficacy of their inhibition, although evident, is less definite. Two major negative effects exist in this therapeutic strategy and are linked to the specificity of the drugs and to the role of the targeted kinase in non-malignant cells. In this review, we will discuss the data available on the TKIs effects on the metabolism and functions of mesenchymal stromal cells (MSCs). MSCs are widely distributed in human tissues and play key physiological roles; nevertheless, they might be responsible for important pathologies. At present, bone marrow (BM) MSCs have been studied in greater detail, for both embryological origins and functions. The available data are evocative of an unexpected degree of complexity and heterogeneity of BM-MSCs. It is conceivable that this grade of intricacy occurs also in MSCs of other organs. Therefore, in perspective, the negative effects of TKIs on MSCs might represent a critical problem in long-term cancer therapies based on such inhibitors. PMID:27750212

Effectiveness of local therapy for stage I non-small-cell lung cancer in nonagenarians.

PubMed

Arnold, Brian N; Thomas, Daniel C; Rosen, Joshua E; Salazar, Michelle C; Detterbeck, Frank C; Blasberg, Justin D; Boffa, Daniel J; Kim, Anthony W

2017-09-01

Stage I non-small-cell lung cancer is potentially curable, yet older patients undergo treatment at lower rates than younger patients. This analysis sought to describe the treatment outcomes of nonagenarians with stage I non-small-cell lung cancer to better guide treatment decisions in this population. The National Cancer DataBase was queried for patients age ≥90 years old with stage I non-small-cell lung cancer (tumors ≤4 cm). Patients were divided into 3 groups: local therapy, other therapy, or no treatment. The primary outcomes were 5-year overall and relative survival. Of the 616 patients identified, 33% (202) were treated with local therapy, 34% (207) were treated with other therapy, and 34% (207) underwent no treatment. Compared with local therapy, overall mortality was significantly higher with no treatment (hazard ratio 2.50, 95% confidence interval, 1.95-3.21) and other therapy (hazard ratio 1.43, 95% confidence interval, 1.11-1.83). The 5-year relative survival was 81% for local therapy, 49% for other therapy, and 32% for no treatment (P < .0001). Nonagenarians managed with local therapy for stage I non-small-cell lung cancer (tumors ≤4 cm) have better overall survival than those receiving other therapy or no treatment and should be considered for treatment with either operation or stereotactic body radiation therapy if able to tolerate treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

The host immunological response to cancer therapy: An emerging concept in tumor biology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Voloshin, Tali; Voest, Emile E.; Shaked, Yuval, E-mail: yshaked@tx.technion.ac.il

Almost any type of anti-cancer treatment including chemotherapy, radiation, surgery and targeted drugs can induce host molecular and cellular immunological effects which, in turn, can lead to tumor outgrowth and relapse despite an initial successful therapy outcome. Tumor relapse due to host immunological effects is attributed to angiogenesis, tumor cell dissemination from the primary tumors and seeding at metastatic sites. This short review will describe the types of host cells that participate in this process, the types of factors secreted from the host following therapy that can promote tumor re-growth, and the possible implications of this unique and yet onlymore » partially-known process. It is postulated that blocking these specific immunological effects in the reactive host in response to cancer therapy may aid in identifying new host-dependent targets for cancer, which in combination with conventional treatments can prolong therapy efficacy and extend survival. Additional studies investigating this specific research direction—both in preclinical models and in the clinical setting are essential in order to advance our understanding of how tumors relapse and evade therapy. -- Highlights: • Cancer therapy induces host molecular and cellular pro-tumorigenic effects. • Host effects in response to therapy may promote tumor relapse and metastasis. • The reactive host consists of immunological mediators promoting tumor re-growth. • Blocking therapy-induced host mediators may improve outcome.« less

Small RNA Enhances Antitumor T-cell Therapy | Center for Cancer Research

Cancer.gov

Adoptive T-cell transfer is an effective form of anticancer immunotherapy in which patients receive infusions of cytotoxic T cells that seek out and destroy targeted cancer cells. This type of therapy is usually preceded by a lymphodepleting chemotherapy regimen and combined with high doses of the cytokine interleukin-2 (IL-2) to eliminate immunosuppressive and other immune cells and to enhance the survival and activity of the transplanted cells. Unfortunately, these high-intensity treatments often lead to severe side effects, such as a prolonged reduction of white blood cells, an increased risk of clotting events, or an accumulation of fluid in the tissues, which limit the pool of patients healthy enough to receive the treatment and can result in prolonged hospitalization and higher health care costs. New approaches that are less toxic but equally effective could allow for more widespread use of adoptive T-cell transfer.

12P-conjugated PEG-modified gold nanorods combined with near-infrared laser for tumor targeting and photothermal therapy.

PubMed

Zhan, Tao; Li, Pengfei; Bi, Shan; Dong, Biao; Song, Hongwei; Ren, Hui; Wang, Liping

2012-09-01

Gold nanorods have been reported as potential tumor photothermal therapy in vivo and in vitro. However, development of the safe and efficient tumor-targeting gold nanorods for in vivo localized tumor therapy is still a challenge. In our present study, we synthesized the PEG modified gold nanorods and demonstrated its negligible cytotoxicity in vitro. These nanorods also have been demonstrated to efficiently ablate the different kinds of tumor cells in vitro after exposure to the near-infrared laser. When the PEG modified gold nanorods conjugated with the 12P (sequence: TACHQHVRMVRP), this conjugate showed great tumor-targeting and hyperthermia effects on the human liver cancer cell line HepG2 in vitro when coupled with the near-infrared laser treatment. To determine the potential hyperthermia effect of PEG modified gold nanorods or 12P conjugate on tumor cells in vivo, the mice hepatic cancer cells were used to induce the subcutaneous tumor-bearing model in ICR mice. The significant inhibition effects of near-infrared laser mediated PEG modified gold nanorods or 12P conjugate on the tumor growth were observed. These composite results suggest that the 12P-conjugated PEG modified gold nanorods exhibit great biocompatible, particular tumor-targeting and effective photothermal ablation of tumor cells, which warrant the potential therapeutic value of this conjugate for further application in in vivo localized tumor therapy.

Effect of aging on stem cells

PubMed Central

Ahmed, Abu Shufian Ishtiaq; Sheng, Matilda HC; Wasnik, Samiksha; Baylink, David J; Lau, Kin-Hing William

2017-01-01

Pluripotent stem cells have the remarkable self-renewal ability and are capable of differentiating into multiple diverse cells. There is increasing evidence that the aging process can have adverse effects on stem cells. As stem cells age, their renewal ability deteriorates and their ability to differentiate into the various cell types is altered. Accordingly, it is suggested aging-induced deterioration of stem cell functions may play a key role in the pathophysiology of the various aging-associated disorders. Understanding the role of the aging process in deterioration of stem cell function is crucial, not only in understanding the pathophysiology of aging-associated disorders, but also in future development of novel effective stem cell-based therapies to treat aging-associated diseases. This review article first focuses on the basis of the various aging disease-related stem cell dysfunction. It then addresses the several concepts on the potential mechanism that causes aging-related stem cell dysfunction. It also briefly discusses the current potential therapies under development for aging-associated stem cell defects. PMID:28261550

Stem cells in animal asthma models: a systematic review.

PubMed

Srour, Nadim; Thébaud, Bernard

2014-12-01

Asthma control frequently falls short of the goals set in international guidelines. Treatment options for patients with poorly controlled asthma despite inhaled corticosteroids and long-acting β-agonists are limited, and new therapeutic options are needed. Stem cell therapy is promising for a variety of disorders but there has been no human clinical trial of stem cell therapy for asthma. We aimed to systematically review the literature regarding the potential benefits of stem cell therapy in animal models of asthma to determine whether a human trial is warranted. The MEDLINE and Embase databases were searched for original studies of stem cell therapy in animal asthma models. Nineteen studies were selected. They were found to be heterogeneous in their design. Mesenchymal stromal cells were used before sensitization with an allergen, before challenge with the allergen and after challenge, most frequently with ovalbumin, and mainly in BALB/c mice. Stem cell therapy resulted in a reduction of bronchoalveolar lavage fluid inflammation and eosinophilia as well as Th2 cytokines such as interleukin-4 and interleukin-5. Improvement in histopathology such as peribronchial and perivascular inflammation, epithelial thickness, goblet cell hyperplasia and smooth muscle layer thickening was universal. Several studies showed a reduction in airway hyper-responsiveness. Stem cell therapy decreases eosinophilic and Th2 inflammation and is effective in several phases of the allergic response in animal asthma models. Further study is warranted, up to human clinical trials. Copyright © 2014 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Synergistic effect of the combination of triethylene-glycol modified Fe3O4 nanoparticles and ultrasound wave on MCF-7 cells

NASA Astrophysics Data System (ADS)

Ebrahimi Fard, Ali; Zarepour, Atefeh; Zarrabi, Ali; Shanei, Ahmad; Salehi, Hossein

2015-11-01

Cancer is a group of disease characterized by uncontrolled growth and spread of abnormal cells in the body. The clinical treatments for cancer include surgery, chemotherapy and radiotherapy. Currently, employing new approaches for treatment has attracted more attentions. One of these approaches is sonodynamic therapy, which is an analogous approach based on the synergistic effect of ultrasound and a chemical component referred to as sonosensitizer. Recent years applications of nanotechnology have witnessed a tremendous expansion of research in medicine especially in treatment of cancers. The combination of sonodynamic therapy and nanotechnology can introduce a new way for cancer therapy. In this study, we used therapeutic ultrasonic waves with intensity of 1 MHz and different concentrations of Fe3O4 nanoparticles, as sonosensitizer, to investigate their combination effect on MCF-7 cell line. Briefly, we divided cells into four different groups; control, cells which got in touch with nanoparticles, cells that with exposure to ultrasound waves and cells which were influenced with combination of nanoparticles and ultrasonic waves. Finally, cell viability assay was used for detection of cytotoxicity effects. Experimental results revealed a significant decrease in viability of cells, which were affected by the combined action of ultrasound field and Fe3O4 nanoparticles, compared to the separate exposure of Fe3O4 nanoparticles or ultrasonic field. The synergic effect of ultrasound waves and Fe ions might be due to the production of toxic free radicals.

Targeting Glutamine Induces Apoptosis: A Cancer Therapy Approach

PubMed Central

Chen, Lian; Cui, Hengmin

2015-01-01

Glutamine metabolism has been proved to be dysregulated in many cancer cells, and is essential for proliferation of most cancer cells, which makes glutamine an appealing target for cancer therapy. In order to be well used by cells, glutamine must be transported to cells by specific transporters and converted to glutamate by glutaminase. There are currently several drugs that target glutaminase under development or clinical trials. Also, glutamine metabolism restriction has been proved to be effective in inhibiting tumor growth both in vivo and vitro through inducing apoptosis, growth arrest and/or autophagy. Here, we review recent researches about glutamine metabolism in cancer, and cell death induced by targeting glutamine, and their potential roles in cancer therapy. PMID:26402672

Pituitary cell differentiation from stem cells and other cells: toward restorative therapy for hypopituitarism?

PubMed

Willems, Christophe; Vankelecom, Hugo

2014-01-01

The pituitary gland, key regulator of our endocrine system, produces multiple hormones that steer essential physiological processes. Hence, deficient pituitary function (hypopituitarism) leads to severe disorders. Hypopituitarism can be caused by defective embryonic development, or by damage through tumor growth/resection and traumatic brain injury. Lifelong hormone replacement is needed but associated with significant side effects. It would be more desirable to restore pituitary tissue and function. Recently, we showed that the adult (mouse) pituitary holds regenerative capacity in which local stem cells are involved. Repair of deficient pituitary may therefore be achieved by activating these resident stem cells. Alternatively, pituitary dysfunction may be mended by cell (replacement) therapy. The hormonal cells to be transplanted could be obtained by (trans-)differentiating various kinds of stem cells or other cells. Here, we summarize the studies on pituitary cell regeneration and on (trans-)differentiation toward hormonal cells, and speculate on restorative therapies for pituitary deficiency.

Antiangiogenic cancer drug sunitinib exhibits unexpected proangiogenic effects on endothelial cells

PubMed Central

Norton, Kerri-Ann; Han, Zheyi; Popel, Aleksander S; Pandey, Niranjan B

2014-01-01

Angiogenesis, the formation of new blood vessels, is an essential step for cancer progression, but antiangiogenic therapies have shown limited success. Therefore, a better understanding of the effects of antiangiogenic treatments on endothelial cells is necessary. In this study, we evaluate the changes in cell surface vascular endothelial growth factor receptor (VEGFR) expression on endothelial cells in culture treated with the antiangiogenic tyrosine kinase inhibitor drug sunitinib, using quantitative flow cytometry. We find that proangiogenic VEGFR2 cell surface receptor numbers are increased with sunitinib treatment. This proangiogenic effect might account for the limited effects of sunitinib as a cancer therapy. We also find that this increase is inhibited by brefeldin A, an inhibitor of protein transport from the endoplasmic reticulum to the Golgi apparatus. The complex dynamics of cell surface VEGFRs may be important for successful treatment of cancer with antiangiogenic therapeutics. PMID:25228815

BDNF/TrkB signaling protects HT-29 human colon cancer cells from EGFR inhibition

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brunetto de Farias, Caroline; Children's Cancer Institute, 90420-140 Porto Alegre, RS; Laboratory of Neuropharmacology and Neural Tumor Biology, Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, 90050-170 Porto Alegre, RS

2012-08-24

Highlights: Black-Right-Pointing-Pointer BDNF protected HT-29 colorectal cancer cells from the antitumor effect of cetuximab. Black-Right-Pointing-Pointer TrkB inhibition potentiated the antitumor effect of cetuximab. Black-Right-Pointing-Pointer BDNF/TrkB signaling might be involved in resistance to anti-EGFR therapy. -- Abstract: The clinical success of targeted treatment of colorectal cancer (CRC) is often limited by resistance to anti-epidermal growth factor receptor (EGFR) therapy. The neurotrophin brain-derived neurotrophic factor (BDNF) and its receptor TrkB have recently emerged as anticancer targets, and we have previously shown increased BDNF levels in CRC tumor samples. Here we report the findings from in vitro experiments suggesting that BDNF/TrkB signaling canmore » protect CRC cells from the antitumor effects of EGFR blockade. The anti-EGFR monoclonal antibody cetuximab reduced both cell proliferation and the mRNA expression of BDNF and TrkB in human HT-29 CRC cells. The inhibitory effect of cetuximab on cell proliferation and survival was counteracted by the addition of human recombinant BDNF. Finally, the Trk inhibitor K252a synergistically enhanced the effect of cetuximab on cell proliferation, and this effect was blocked by BDNF. These results provide the first evidence that increased BDNF/TrkB signaling might play a role in resistance to EGFR blockade. Moreover, it is possible that targeting TrkB could potentiate the anticancer effects of anti-EGFR therapy.« less

Cellular models and therapies for age-related macular degeneration

PubMed Central

Forest, David L.; Johnson, Lincoln V.; Clegg, Dennis O.

2015-01-01

ABSTRACT Age-related macular degeneration (AMD) is a complex neurodegenerative visual disorder that causes profound physical and psychosocial effects. Visual impairment in AMD is caused by the loss of retinal pigmented epithelium (RPE) cells and the light-sensitive photoreceptor cells that they support. There is currently no effective treatment for the most common form of this disease (dry AMD). A new approach to treating AMD involves the transplantation of RPE cells derived from either human embryonic or induced pluripotent stem cells. Multiple clinical trials are being initiated using a variety of cell therapies. Although many animal models are available for AMD research, most do not recapitulate all aspects of the disease, hampering progress. However, the use of cultured RPE cells in AMD research is well established and, indeed, some of the more recently described RPE-based models show promise for investigating the molecular mechanisms of AMD and for screening drug candidates. Here, we discuss innovative cell-culture models of AMD and emerging stem-cell-based therapies for the treatment of this vision-robbing disease. PMID:26035859

Application of HSVtk suicide gene to X-SCID gene therapy: Ganciclovir treatment offsets gene corrected X-SCID B cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Uchiyama, Toru; Kumaki, Satoru; Ishikawa, Yoshinori

Recently, a serious adverse effect of uncontrolled clonal T cell proliferation due to insertional mutagenesis of retroviral vector was reported in X-SCID gene therapy clinical trial. To offset the side effect, we have incorporated a suicide gene into therapeutic retroviral vector for selective elimination of transduced cells. In this study, B-cell lines from two X-SCID patients were transduced with bicistronic retroviral vector carrying human {gamma}c chain cDNA and Herpes simplex virus thymidine kinase gene. After confirmation of functional reconstitution of the {gamma}c chain, the cells were treated with ganciclovir (GCV). The {gamma}c chain positive cells were eliminated under low concentrationmore » without cytotoxicity on untransduced cells and have not reappeared at least for 5 months. Furthermore, the {gamma}c chain transduced cells were still sensitive to GCV after five months. These results demonstrated the efficacy of the suicide gene therapy although further in vivo studies are required to assess feasibility of this approach in clinical trial.« less

Lineage plasticity-mediated therapy resistance in prostate cancer.

PubMed

Blee, Alexandra M; Huang, Haojie

2018-06-12

Therapy resistance is a significant challenge for prostate cancer treatment in clinic. Although targeted therapies such as androgen deprivation and androgen receptor (AR) inhibition are effective initially, tumor cells eventually evade these strategies through multiple mechanisms. Lineage reprogramming in response to hormone therapy represents a key mechanism that is increasingly observed. The studies in this area have revealed specific combinations of alterations present in adenocarcinomas that provide cells with the ability to transdifferentiate and perpetuate AR-independent tumor growth after androgen-based therapies. Interestingly, several master regulators have been identified that drive plasticity, some of which also play key roles during development and differentiation of the cell lineages in the normal prostate. Thus, further study of each AR-independent tumor type and understanding underlying mechanisms are warranted to develop combinational therapies that combat lineage plasticity in prostate cancer.

Fight fire with fire: Gene therapy strategies to cure HIV.

PubMed

Huyghe, Jon; Magdalena, Sips; Vandekerckhove, Linos

2017-08-01

Human Immunodeficiency Virus (HIV) to date remains one of the most notorious viruses mankind has ever faced. Despite enormous investments in HIV research for more than 30 years an effective cure for HIV has been elusive. Areas covered: Combination antiretroviral therapy (cART) suppresses active viral replication, but is not able to eliminate the virus completely due to stable integration of HIV inside the host genome of infected cells and the establishment of a latent reservoir, that is insensitive to cART. Nevertheless, this latent HIV reservoir is fully capable to refuel viral replication when treatment is stopped, creating a major obstacle towards a cure for HIV. Several gene therapy approaches ranging from the generation of HIV resistant CD4 + T cells to the eradication of HIV infected cells by immune cell engineering are currently under pre-clinical and clinical investigation and may present a promising road to a cure. In this review, we focus on the status and the prospects of gene therapy strategies to cure/eradicate HIV. Expert commentary: Recent advances in gene therapy for oncology and infectious diseases indicate that gene therapy may be a feasible and very potent cure strategy, and therefore a potential game changer in the search for an effective HIV cure.

Transferrin receptors and the targeted delivery of therapeutic agents against cancer

PubMed Central

Daniels, Tracy R.; Bernabeu, Ezequiel; Rodríguez, José A.; Patel, Shabnum; Kozman, Maggie; Chiappetta, Diego A.; Holler, Eggehard; Ljubimova, Julia Y.; Helguera, Gustavo; Penichet, Manuel L.

2012-01-01

Background Traditional cancer therapy can be successful in destroying tumors, but can also cause dangerous side effects. Therefore, many targeted therapies are in development. The transferrin receptor (TfR) functions in cellular iron uptake through its interaction with transferrin. This receptor is an attractive molecule for the targeted therapy of cancer since it is upregulated on the surface of many cancer types and is efficiently internalized. This receptor can be targeted in two ways: 1) for the delivery of therapeutic molecules into malignant cells or 2) to block the natural function of the receptor leading directly to cancer cell death. Scope of review In the present article we discuss the strategies used to target the TfR for the delivery of therapeutic agents into cancer cells. We provide a summary of the vast types of anti-cancer drugs that have been delivered into cancer cells employing a variety of receptor binding molecules including Tf, anti-TfR antibodies, or TfR-binding peptides alone or in combination with carrier molecules including nanoparticles and viruses. Major conclusions Targeting the TfR has been shown to be effective in delivering many different therapeutic agents and causing cytotoxic effects in cancer cells in vitro and in vivo. General significance The extensive use of TfR for targeted therapy attests to the versatility of targeting this receptor for therapeutic purposes against malignant cells. More advances in this area are expected to further improve the therapeutic potential of targeting the TfR for cancer therapy leading to an increase in the number of clinical trials of molecules targeting this receptor. PMID:21851850

Hypoxia/hepatoma dual specific suicide gene expression plasmid delivery using bio-reducible polymer for hepatocellular carcinoma therapy.

PubMed

Kim, Hyun Ah; Nam, Kihoon; Lee, Minhyung; Kim, Sung Wan

2013-10-10

Gene therapy is suggested as a promising alternative strategy of hepatocellular carcinoma (HCC, also called hepatoma) therapy. To achieve a successful and safe gene therapy, tight regulation of gene expression is required to minimize side-effects in normal tissues. In this study, we developed a novel hypoxia and hepatoma dual specific gene expression vector. The constructed vectors were transfected into various cell lines using bio-reducible polymer, PAM-ABP. First, pAFPS-Luc or pAFPL-Luc vector was constructed with the alpha-fectoprotein (AFP) promoter and enhancer for hepatoma tissue specific gene expression. Then, pEpo-AFPL-Luc was constructed by insertion of the erythropoietin (Epo) enhancer for hypoxic cancer specific gene expression. In vitro transfection assay showed that pEpo-AFPL-Luc transfected hepatoma cell increased gene expression under hypoxic condition. To confirm the therapeutic effect of dual specific vector, herpes simplex virus thymidine kinase (HSV-TK) gene was introduced for cancer cell killing. The pEpo-AFPL-TK was transfected into hepatoma cell lines in the presence of ganciclovir (GCV) pro-drug. Caspase-3/7, MTT and TUNEL assays elucidated that pEpo-AFPL-TK transfected cells showed significant increasing of death rate in hypoxic hepatoma cells compared to controls. Therefore, the hypoxia/hepatoma dual specific gene expression vector with the Epo enhancer and AFP promoter may be useful for hepatoma specific gene therapy. © 2013.

Synthesis of upconversion nanoparticles conjugated with graphene oxide quantum dots and their use against cancer cell imaging and photodynamic therapy.

PubMed

Choi, Seung Yoo; Baek, Seung Hoon; Chang, Sung-Jin; Song, Yohan; Rafique, Rafia; Lee, Kang Taek; Park, Tae Jung

2017-07-15

Multifunctional nanocomposite has a huge potential for cell imaging, drug delivery, and improving therapeutic effect with less side effects. To date, diverse approaches have been demonstrated to endow a single nanostructure with multifunctionality. Herein, we report the synthesis and application of core-shell nanoparticles composed with upconversion nanoparticle (UCNP) as a core and a graphene oxide quantum dot (GOQD) as a shell. The UCNP was prepared and applied for imaging-guided analyses of upconversion luminescence. GOQD was prepared and employed as promising drug delivery vehicles to improve anti-tumor therapy effect in this study. Unique properties of UCNPs and GOQDs were incorporated into a single nanostructure to provide desirable functions for cell imaging and drug delivery. In addition, hypocrellin A (HA) was loaded on GOQDs for photo-dynamic therapy (PDT). HA, a commonly used chemotherapy drug and a photo-sensitizer, was conjugated with GOQD by π-π interaction and loaded on PEGylated UCNP without complicated synthetic process, which can break structure of HA. Applying these core-shell nanoparticles to MTT assay, we demonstrated that the UCNPs with GOQD shell loaded with HA could be excellent candidates as multifunctional agents for cell imaging, drug delivery and cell therapy. Copyright © 2016 Elsevier B.V. All rights reserved.

Regulation of miRNA Expression by Low-Level Laser Therapy (LLLT) and Photodynamic Therapy (PDT)

PubMed Central

Kushibiki, Toshihiro; Hirasawa, Takeshi; Okawa, Shinpei; Ishihara, Miya

2013-01-01

Applications of laser therapy, including low-level laser therapy (LLLT), phototherapy and photodynamic therapy (PDT), have been proven to be beneficial and relatively less invasive therapeutic modalities for numerous diseases and disease conditions. Using specific types of laser irradiation, specific cellular activities can be induced. Because multiple cellular signaling cascades are simultaneously activated in cells exposed to lasers, understanding the molecular responses within cells will aid in the development of laser therapies. In order to understand in detail the molecular mechanisms of LLLT and PDT-related responses, it will be useful to characterize the specific expression of miRNAs and proteins. Such analyses will provide an important source for new applications of laser therapy, as well as for the development of individualized treatments. Although several miRNAs should be up- or down-regulated upon stimulation by LLLT, phototherapy and PDT, very few published studies address the effect of laser therapy on miRNA expression. In this review, we focus on LLLT, phototherapy and PDT as representative laser therapies and discuss the effects of these therapies on miRNA expression. PMID:23807510

Regulation of miRNA expression by low-level laser therapy (LLLT) and photodynamic therapy (PDT).

PubMed

Kushibiki, Toshihiro; Hirasawa, Takeshi; Okawa, Shinpei; Ishihara, Miya

2013-06-27

Applications of laser therapy, including low-level laser therapy (LLLT), phototherapy and photodynamic therapy (PDT), have been proven to be beneficial and relatively less invasive therapeutic modalities for numerous diseases and disease conditions. Using specific types of laser irradiation, specific cellular activities can be induced. Because multiple cellular signaling cascades are simultaneously activated in cells exposed to lasers, understanding the molecular responses within cells will aid in the development of laser therapies. In order to understand in detail the molecular mechanisms of LLLT and PDT-related responses, it will be useful to characterize the specific expression of miRNAs and proteins. Such analyses will provide an important source for new applications of laser therapy, as well as for the development of individualized treatments. Although several miRNAs should be up- or down-regulated upon stimulation by LLLT, phototherapy and PDT, very few published studies address the effect of laser therapy on miRNA expression. In this review, we focus on LLLT, phototherapy and PDT as representative laser therapies and discuss the effects of these therapies on miRNA expression.

Muscle Stem Cell Therapy for the Treatment of DMD Associated Cardiomyopathy

DTIC Science & Technology

2013-10-01

Fehrenbacher JW et al. Proinflammatory cytokine effects on mesenchymal stem cell therapy for the ischemic heart. Ann Thorac Surg Sep 2009;88:1036–1043. 45 Payne... mesenchymal stem cells (MSCs) (5). Activation of RhoA-ROCK signaling in cultured MSCs in vitro induces their osteogenesis but Figure 5 Angiogenesis...osteoblastogenesis and enhanced adipogenesis of human mesenchymal stem cells in modeled microgravity. J Bone Miner Res. 2005;20(10):1858-66. PMCID

A heterotypic bystander effect for tumor cell killing after adeno-associated virus/phage-mediated, vascular-targeted suicide gene transfer.

PubMed

Trepel, Martin; Stoneham, Charlotte A; Eleftherohorinou, Hariklia; Mazarakis, Nicholas D; Pasqualini, Renata; Arap, Wadih; Hajitou, Amin

2009-08-01

Suicide gene transfer is the most commonly used cytotoxic approach in cancer gene therapy; however, a successful suicide gene therapy depends on the generation of efficient targeted systemic gene delivery vectors. We recently reported that selective systemic delivery of suicide genes such as herpes simplex virus thymidine kinase (HSVtk) to tumor endothelial cells through a novel targeted adeno-associated virus/phage vector leads to suppression of tumor growth. This marked effect has been postulated to result primarily from the death of cancer cells by hypoxia following the targeted disruption of tumor blood vessels. Here, we investigated whether an additional mechanism of action is involved. We show that there is a heterotypic "bystander" effect between endothelial cells expressing the HSVtk suicide gene and tumor cells. Treatment of cocultures of HSVtk-transduced endothelial cells and non-HSVtk-transduced tumor cells with ganciclovir results in the death of both endothelial and tumor cells. Blocking of this effect by 18alpha-glycyrrhetinic acid indicates that gap junctions between endothelial and tumor cells are largely responsible for this phenomenon. Moreover, the observed bystander killing is mediated by connexins 43 and 26, which are expressed in endothelial and tumor cell types. Finally, this heterotypic bystander effect is accompanied by a suppression of tumor growth in vivo that is independent of primary gene transfer into host-derived tumor vascular endothelium. These findings add an alternative nonmutually exclusive and potentially synergistic cytotoxic mechanism to cancer gene therapy based on targeted adeno-associated virus/phage and further support the promising role of nonmalignant tumor stromal cells as therapeutic targets.

Advances in Monitoring Cell-Based Therapies with Magnetic Resonance Imaging: Future Perspectives

PubMed Central

Ngen, Ethel J.; Artemov, Dmitri

2017-01-01

Cell-based therapies are currently being developed for applications in both regenerative medicine and in oncology. Preclinical, translational, and clinical research on cell-based therapies will benefit tremendously from novel imaging approaches that enable the effective monitoring of the delivery, survival, migration, biodistribution, and integration of transplanted cells. Magnetic resonance imaging (MRI) offers several advantages over other imaging modalities for elucidating the fate of transplanted cells both preclinically and clinically. These advantages include the ability to image transplanted cells longitudinally at high spatial resolution without exposure to ionizing radiation, and the possibility to co-register anatomical structures with molecular processes and functional changes. However, since cellular MRI is still in its infancy, it currently faces a number of challenges, which provide avenues for future research and development. In this review, we describe the basic principle of cell-tracking with MRI; explain the different approaches currently used to monitor cell-based therapies; describe currently available MRI contrast generation mechanisms and strategies for monitoring transplanted cells; discuss some of the challenges in tracking transplanted cells; and suggest future research directions. PMID:28106829

The Warburg effect: molecular aspects and therapeutic possibilities.

PubMed

Ngo, Hanh; Tortorella, Stephanie M; Ververis, Katherine; Karagiannis, Tom C

2015-04-01

It has been about nine decades since the proposal of Otto Warburg on the metabolism of cancer cells. Unlike normal cells which undergo glycolysis and oxidative phosphorylation in the presence of oxygen, proliferating and cancer cells exhibit an increased uptake of glucose and increased rate of glycolysis and predominantly undergo lactic acid fermentation. Whether this phenomenon is the consequence of genetic dysregulation in cancer or is the cause of cancer still remains unknown. However, there is certainly a strong link between the genetic factors, epigenetic modulation, cancer immunosurveillance and the Warburg effect, which will be discussed in this review. Dichloroacetate and 3-bromopyruvate are among the substances that have been studied as potential cancer therapies. With our expanding knowledge of cellular metabolism, therapies targeting the Warburg effect appear very promising. This review discusses different aspects of these emerging therapies.

[Electronic data processing-assisted high dosage therapy with stem cell transplantation at the Donauspital].

PubMed

Habertheuer, K H; Kier, P; Ruckser, R; Scherz, M; Höniger, S; Sebesta, C; Tiefengraber, E; Schmid, A; Mandl, A; Sterz, M

1995-01-01

Organization of high dose chemotherapy with stem cell transplantation essentially requires EDV-support. "ONCOBASE" has been adapted into the Donauspital network on May 1, 1992. We report about the 2-year clinical experience with ONCOBASE: 1. ONCOBASE effectively supports communication between the ward, ambulance and hospital pharmacy (where all cytostatics are prepared). 2. ONCOBASE provides better surveillance concerning all therapeutic procedures including cytostatic drugs and supportive therapies. 3. ONCOBASE allows the generation of medical letters which include all drugs and supportive therapies delivered. 4. Since ONCOBASE is a database program, all informations concerning the patients are registered. These include cumulative drug doses, information on side effects, blood cell kinetics after previous therapies, kinetics of tumor markers and results of further examinations. 5. ONCOBASE permits rapid data exchange with other hospital networks using the communication data record governed by the "Arbeitskreis für EDV der deutschen Gesellschaft für Hämatoonkologie".

The Immunogenicity and Immune Tolerance of Pluripotent Stem Cell Derivatives

PubMed Central

Liu, Xin; Li, Wenjuan; Fu, Xuemei; Xu, Yang

2017-01-01

Human embryonic stem cells (hESCs) can undergo unlimited self-renewal and differentiate into all cell types in human body, and therefore hold great potential for cell therapy of currently incurable diseases including neural degenerative diseases, heart failure, and macular degeneration. This potential is further underscored by the promising safety and efficacy data from the ongoing clinical trials of hESC-based therapy of macular degeneration. However, one main challenge for the clinical application of hESC-based therapy is the allogeneic immune rejection of hESC-derived cells by the recipient. The breakthrough of the technology to generate autologous-induced pluripotent stem cells (iPSCs) by nuclear reprogramming of patient’s somatic cells raised the possibility that autologous iPSC-derived cells can be transplanted into the patients without the concern of immune rejection. However, accumulating data indicate that certain iPSC-derived cells can be immunogenic. In addition, the genomic instability associated with iPSCs raises additional safety concern to use iPSC-derived cells in human cell therapy. In this review, we will discuss the mechanism underlying the immunogenicity of the pluripotent stem cells and recent progress in developing immune tolerance strategies of human pluripotent stem cell (hPSC)-derived allografts. The successful development of safe and effective immune tolerance strategy will greatly facilitate the clinical development of hPSC-based cell therapy. PMID:28626459

Combined enzyme/prodrug treatment by genetically engineered AT-MSC exerts synergy and inhibits growth of MDA-MB-231 induced lung metastases.

PubMed

Matuskova, Miroslava; Kozovska, Zuzana; Toro, Lenka; Durinikova, Erika; Tyciakova, Silvia; Cierna, Zuzana; Bohovic, Roman; Kucerova, Lucia

2015-04-09

Metastatic spread of tumor cells remains a serious problem in cancer treatment. Gene-directed enzyme/prodrug therapy mediated by tumor-homing genetically engineered mesenchymal stromal cells (MSC) represents a promising therapeutic modality for elimination of disseminated cells. Efficacy of gene-directed enzyme/prodrug therapy can be improved by combination of individual systems. We aimed to define the combination effect of two systems of gene therapy mediated by MSC, and evaluate the ability of systemically administered genetically engineered mesenchymal stromal cells to inhibit the growth of experimental metastases derived from human breast adenocarcinoma cells MDA-MB-231/EGFP. Human adipose tissue-derived mesenchymal stromal cells (AT-MSC) were retrovirally transduced with fusion yeast cytosine deaminase::uracil phosphoribosyltransferase (CD::UPRT) or with Herpes simplex virus thymidine kinase (HSVtk). Engineered MSC were cocultured with tumor cells in the presence of prodrugs 5-fluorocytosin (5-FC) and ganciclovir (GCV). Combination effect of these enzyme/prodrug approaches was calculated. SCID/bg mice bearing experimental lung metastases were treated with CD::UPRT-MSC, HSVtk-MSC or both in combination in the presence of respective prodrug(s). Treatment efficiency was evaluated by EGFP-positive cell detection by flow cytometry combined with real-time PCR quantification of human cells in mouse organs. Results were confirmed by histological and immunohistochemical examination. We demonstrated various extent of synergy depending on tested cell line and experimental setup. The strongest synergism was observed on breast cancer-derived cell line MDA-MB-231/EGFP. Systemic administration of CD::UPRT-MSC and HSVtk-MSC in combination with 5-FC and GCV inhibited growth of MDA-MB-231 induced lung metastases. Combined gene-directed enzyme/prodrug therapy mediated by MSC exerted synergic cytotoxic effect and resulted in high therapeutic efficacy in vivo.

Stem cells in bone diseases: current clinical practice.

PubMed

Beyth, Shaul; Schroeder, Josh; Liebergall, Meir

2011-01-01

Bone is an obvious candidate tissue for stem cell therapy. This review provides an update of existing stem cell-based clinical treatments for bone pathologies. A systematic computerized literature search was conducted. The following databases were accessed on 10 February 2011: NIH clinical trials database, PubMed, Ovid and Cochrane Reviews. Stem cell therapy offers new options for bone conditions, both acquired and inherited. There is still no agreement on the exact definition of 'mesenchymal stem cells'. Consequently, it is difficult to appreciate the effect of culture expansion and the feasibility of allogeneic transplantation. Based on the sound foundations of pre-clinical research, stem cell-based treatments and protocols have recently emerged. Well-designed prospective clinical trials are needed in order to establish and develop stem cell therapy for bone diseases.

Stem Cell Therapy for Incontinence: Where Are We Now? What is the Realistic Potential?

PubMed Central

Dissaranan, Charuspong; Cruz, Michelle A.; Couri, Bruna M.; Goldman, Howard B.

2011-01-01

A significant number of women experience stress urinary incontinence (SUI), which greatly affects their quality of life. Recent research investigating utilization of stem cells and their derivatives for the prevention and treatment of SUI has been performed to test the effect of cell source and method of administration in several animal models of SUI. The type of stem cell, timing of optimal dose or doses after injury, mechanism of action of stem cells, and route of administration must be investigated both preclinically and clinically before stem cell therapy becomes a possible treatment for SUI, although the future of this therapy looks promising. This article reviews the progress in stem cell research for incontinence and describes areas of future work as suggested by research in other fields. PMID:21842258

The development of hematopoietic and mesenchymal stem cell transplantation as an effective treatment for multiple sclerosis

PubMed Central

Holloman, Jameson P; Ho, Calvin C; Hukki, Arushi; Huntley, Jennifer L; Gallicano, G Ian

2013-01-01

This article examines the current use and future implications of stem cell therapy in treating Multiple Sclerosis (MS). MS is the most common neurological disease in young adults, affecting approximately two million people worldwide. Currently there is no cure for MS. The standard treatment of MS involves disease-modifying drugs, which work to alleviate the symptoms of MS. However, these drugs carry adverse side effects and are ineffective in preventing disease progression in many MS patients. Hematopoietic stem cell transplantation (HSCT) was first used in 1995 to treat patients with severe rapidly progressing MS. The HSCT treatment protocol has evolved into a less intense conditioning regimen that is currently demonstrating efficacy in treating patients with variable disease severity—with best results in early-stage rapidly progressing MS patients with active CNS inflammation. Mesenchymal stem cell therapy (MSCT) is an experimental stem cell therapy currently undergoing clinical trials. Animal models and early clinical trials have shown promise that MSCT might be a low risk treatment to precipitate neuroregeneration and immunomodulation in MS patients. Specifically, neuroprogenitor and placental-derived mesenchymal stem cells offer the best hope for a practical treatment for MS. Stem cell therapy, and perhaps a combinatorial therapeutic approach, holds promise for a better treatment for MS. PMID:23862098

The Effects of Forest Therapy on Coping with Chronic Widespread Pain: Physiological and Psychological Differences between Participants in a Forest Therapy Program and a Control Group.

PubMed

Han, Jin-Woo; Choi, Han; Jeon, Yo-Han; Yoon, Chong-Hyeon; Woo, Jong-Min; Kim, Won

2016-02-24

This study aimed to investigate the effects of a two-day forest therapy program on individuals with chronic widespread pain. Sixty one employees of a public organization providing building and facilities management services within the Seoul Metropolitan area participated in the study. Participants were assigned to an experimental group (n = 33) who participated in a forest therapy program or a control group (n = 28) on a non-random basis. Pre- and post-measures of heart rate variability (HRV), Natural Killer cell (NK cell) activity, self-reported pain using the visual analog scale (VAS), depression level using the Beck Depression Inventory (BDI), and health-related quality of life measures using the EuroQol Visual Analog Scale (EQ-VAS) were collected in both groups. The results showed that participants in the forest therapy group, as compared to the control group, showed physiological improvement as indicated by a significant increase in some measures of HRV and an increase in immune competence as indicated by NK cell activity. Participants in the forest therapy group also reported significant decreases in pain and depression, and a significant improvement in health-related quality of life. These results support the hypothesis that forest therapy is an effective intervention to relieve pain and associated psychological and physiological symptoms in individuals with chronic widespread pain.

A functional bioassay to determine the activity of anti-VEGF antibody therapy in blood of patients with cancer.

PubMed

Wentink, Madelon Q; Broxterman, Henk J; Lam, Siu W; Boven, Epie; Walraven, Maudy; Griffioen, Arjan W; Pili, Roberto; van der Vliet, Hans J; de Gruijl, Tanja D; Verheul, Henk M W

2016-10-11

Only a small proportion of patients respond to anti-VEGF therapy, pressing the need for a reliable biomarker that can identify patients who will benefit. We studied the biological activity of anti-VEGF antibodies in patients' blood during anti-VEGF therapy by using the Ba/F3-VEGFR2 cell line, which is dependent on VEGF for its growth. Serum samples from 22 patients with cancer before and during treatment with bevacizumab were tested for their effect on proliferation of Ba/F3-VEGFR2 cells. Vascular endothelial growth factor as well as bevacizumab concentrations in serum samples from these patients were determined by enzyme linked immunosorbent assay (ELISA). The hVEGF-driven cell proliferation was effectively blocked by bevacizumab (IC 50 3.7 μg ml -1 ; 95% CI 1.7-8.3 μg ml -1 ). Cell proliferation was significantly reduced when patients' serum during treatment with bevacizumab was added (22-103% inhibition compared with pre-treatment). Although bevacizumab levels were not related, on-treatment serum VEGF levels were correlated with Ba/F3-VEGFR2 cell proliferation. We found that the neutralising effect of anti-VEGF antibody therapy on the biological activity of circulating VEGF can be accurately determined with a Ba/F3-VEGFR2 bioassay. The value of this bioassay to predict clinical benefit of anti-VEGF antibody therapy needs further clinical evaluation in a larger randomised cohort.

Kill and spread the word: stimulation of antitumor immune responses in the context of radiotherapy.

PubMed

Gaipl, Udo S; Multhoff, Gabriele; Scheithauer, Heike; Lauber, Kirsten; Hehlgans, Stefanie; Frey, Benjamin; Rödel, Franz

2014-01-01

Besides the direct, targeted effects of ionizing irradiation (x-ray) on cancer cells, namely DNA damage and cell death induction, indirect, nontargeted ones exist, which are mediated in large part by the immune system. Immunogenic forms of tumor cell death induced by x-ray, including immune modulating danger signals like the heat shock protein 70, adenosine triphosphate, and high-mobility group box 1 protein are presented. Further, antitumor effects exerted by cells of the innate (natural killer cells) as well as adaptive immune system (T cells activated by dendritic cells) are outlined. Tumor cell death inhibiting molecules such as survivin are introduced as suitable target for molecularly tailored therapies in combination with x-ray. Finally, reasonable combinations of immune therapies with radiotherapy are discussed.

Radiation Therapy Induces Macrophages to Suppress T-Cell Responses Against Pancreatic Tumors in Mice.

PubMed

Seifert, Lena; Werba, Gregor; Tiwari, Shaun; Giao Ly, Nancy Ngoc; Nguy, Susanna; Alothman, Sara; Alqunaibit, Dalia; Avanzi, Antonina; Daley, Donnele; Barilla, Rocky; Tippens, Daniel; Torres-Hernandez, Alejandro; Hundeyin, Mautin; Mani, Vishnu R; Hajdu, Cristina; Pellicciotta, Ilenia; Oh, Philmo; Du, Kevin; Miller, George

2016-06-01

The role of radiation therapy in the treatment of patients with pancreatic ductal adenocarcinoma (PDA) is controversial. Randomized controlled trials investigating the efficacy of radiation therapy in patients with locally advanced unresectable PDA have reported mixed results, with effects ranging from modest benefit to worse outcomes compared with control therapies. We investigated whether radiation causes inflammatory cells to acquire an immune-suppressive phenotype that limits the therapeutic effects of radiation on invasive PDAs and accelerates progression of preinvasive foci. We investigated the effects of radiation therapy in p48(Cre);LSL-Kras(G12D) (KC) and p48(Cre);LSLKras(G12D);LSL-Trp53(R172H) (KPC) mice, as well as in C57BL/6 mice with orthotopic tumors grown from FC1242 cells derived from KPC mice. Some mice were given neutralizing antibodies against macrophage colony-stimulating factor 1 (CSF1 or MCSF) or F4/80. Pancreata were exposed to doses of radiation ranging from 2 to 12 Gy and analyzed by flow cytometry. Pancreata of KC mice exposed to radiation had a higher frequency of advanced pancreatic intraepithelial lesions and more foci of invasive cancer than pancreata of unexposed mice (controls); radiation reduced survival time by more than 6 months. A greater proportion of macrophages from radiation treated invasive and preinvasive pancreatic tumors had an immune-suppressive, M2-like phenotype compared with control mice. Pancreata from mice exposed to radiation had fewer CD8(+) T cells than controls, and greater numbers of CD4(+) T cells of T-helper 2 and T-regulatory cell phenotypes. Adoptive transfer of T cells from irradiated PDA to tumors of control mice accelerated tumor growth. Radiation induced production of MCSF by PDA cells. A neutralizing antibody against MCSF prevented radiation from altering the phenotype of macrophages in tumors, increasing the anti-tumor T-cell response and slowing tumor growth. Radiation treatment causes macrophages murine PDA to acquire an immune-suppressive phenotype and disabled T-cell-mediated anti-tumor responses. MCSF blockade negates this effect, allowing radiation to have increased efficacy in slowing tumor growth. Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.

Importance of the stem cell microenvironment for ophthalmological cell-based therapy

PubMed Central

Wan, Peng-Xia; Wang, Bo-Wen; Wang, Zhi-Chong

2015-01-01

Cell therapy is a promising treatment for diseases that are caused by cell degeneration or death. The cells for clinical transplantation are usually obtained by culturing healthy allogeneic or exogenous tissue in vitro. However, for diseases of the eye, obtaining the adequate number of cells for clinical transplantation is difficult due to the small size of tissue donors and the frequent needs of long-term amplification of cells in vitro, which results in low cell viability after transplantation. In addition, the transplanted cells often develop fibrosis or degrade and have very low survival. Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPS) are also promising candidates for cell therapy. Unfortunately, the differentiation of ESCs can bring immune rejection, tumorigenicity and undesired differentiated cells, limiting its clinical application. Although iPS cells can avoid the risk of immune rejection caused by ES cell differentiation post-transplantation, the low conversion rate, the risk of tumor formation and the potentially unpredictable biological changes that could occur through genetic manipulation hinder its clinical application. Thus, the desired clinical effect of cell therapy is impaired by these factors. Recent research findings recognize that the reason for low survival of the implanted cells not only depends on the seeded cells, but also on the cell microenvironment, which determines the cell survival, proliferation and even reverse differentiation. When used for cell therapy, the transplanted cells need a specific three-dimensional structure to anchor and specific extra cellular matrix components in addition to relevant cytokine signaling to transfer the required information to support their growth. These structures present in the matrix in which the stem cells reside are known as the stem cell microenvironment. The microenvironment interaction with the stem cells provides the necessary homeostasis for cell maintenance and growth. A large number of studies suggest that to explore how to reconstruct the stem cell microenvironment and strengthen its combination with the transplanted cells are key steps to successful cell therapy. In this review, we will describe the interactions of the stem cell microenvironment with the stem cells, discuss the importance of the stem cell microenvironment for cell-based therapy in ocular diseases, and introduce the progress of stem cell-based therapy for ocular diseases. PMID:25815128

Nitric oxide donor augments antineoplastic effects of arginine deprivation in human melanoma cells.

PubMed

Mayevska, Oksana; Chen, Oleh; Karatsai, Olena; Bobak, Yaroslav; Barska, Maryna; Lyniv, Liliana; Pavlyk, Iuliia; Rzhepetskyy, Yuriy; Igumentseva, Natalia; Redowicz, Maria Jolanta; Stasyk, Oleh

2017-06-15

Anticancer therapy based on recombinant arginine-degrading enzymes has been proposed for the treatment of several types of malignant cells deficient in arginine biosynthesis. One of the predicted side effects of such therapy is restricted bioavailability of nitric oxide as arginine catabolic product. Prolonged NO limitation may lead to unwanted disturbances in NO-dependent vasodilation, cardiovascular and immune systems. This problem can be overcome by co-supplementation with exogenous NO donor. However, NO may potentially counteract anticancer effects of therapy based on arginine deprivation. In this study, we evaluate for the first time the effects of an exogenous NO donor, sodium nitroprusside, on viability and metastatic properties of two human melanoma cell lines SK-MEL-28 and WM793 under arginine-deprived conditions. It was revealed that NO did not rescue melanoma cells from specific effects evoked by arginine deprivation, namely decreased viability and induction of apoptosis, dramatically reduced motility, invasiveness and clonogenic potential. Moreover, sodium nitroprusside co-treatment augmented several of these antineoplastic effects. We report that a combination of NO-donor and arginine deprivation strongly and specifically impaired metastatic behavior of melanoma cells. Thus, sodium nitroprusside can be considered as an adjuvant for the more efficient treatment of malignant melanoma and possibly other tumors with arginine-degrading enzymes. Copyright © 2017 Elsevier Inc. All rights reserved.

Current and emerging global themes in the bioethics of regenerative medicine: the tangled web of stem cell translation.

PubMed

Chan, Sarah

2017-10-01

Probably the most serious problem facing the field of regenerative medicine today is the challenge of effective translation and development of viable stem cell-based therapies. Particular concerns have been raised over the growing market in unproven cell therapies. In this article, I explore recent developments in the stem cell therapy landscape and argue that while the sale of unproven therapies undoubtedly poses ethical concerns, it must be understood as part of a larger problem at the interface between biomedicine, healthcare, publics, policy and the market. Addressing this will require a broader perspective incorporating the shifting relationships between different stakeholder groups, the global politics of research and innovation, and the evolving role of publics and patients with respect to science.

Current and emerging global themes in the bioethics of regenerative medicine: the tangled web of stem cell translation

PubMed Central

Chan, Sarah

2017-01-01

Probably the most serious problem facing the field of regenerative medicine today is the challenge of effective translation and development of viable stem cell-based therapies. Particular concerns have been raised over the growing market in unproven cell therapies. In this article, I explore recent developments in the stem cell therapy landscape and argue that while the sale of unproven therapies undoubtedly poses ethical concerns, it must be understood as part of a larger problem at the interface between biomedicine, healthcare, publics, policy and the market. Addressing this will require a broader perspective incorporating the shifting relationships between different stakeholder groups, the global politics of research and innovation, and the evolving role of publics and patients with respect to science. PMID:29119870

Gene therapy of uterine leiomyoma: adenovirus-mediated herpes simplex virus thymidine kinase/ganciclovir treatment inhibits growth of human and rat leiomyoma cells in vitro and in a nude mouse model.

PubMed

Salama, S A; Kamel, M; Christman, G; Wang, H Q; Fouad, H M; Al-Hendy, A

2007-01-01

Uterine leiomyomas (LM) affect a high percentage of reproductive-age women. They develop as discrete, well-defined tumors that are easily accessible with imaging techniques--making this disease ideal for localized gene therapy approaches. In this study, we determined the efficacy of adenovirus-mediated herpes simplex virus thymidine kinase gene transfer in combination with ganciclovir (Ad-TK/GCV) as a potential therapy for LM. Rat ELT-3 LM cells and human LM cells were transfected with different multiplicity of infections (10-100 plaque forming units [PFU]/cell) of Ad-TK and treated with GCV (5, 10, or 20 microg/ml) for 5 days. To test the bystander effect, Ad-TK-transfected ELT-3 cells (100 PFU/cell) or LM cells (10 PFU/cell) were cocultured with corresponding nontransfected cells at increasing percentages and treated with GCV followed by cell counting. In ELT-3 cells transfected with Ad-TK/GCV (10, 20, 50, or 100 PFU/cell), the cell count was reduced by 24, 42, 77, and 87%, respectively, compared with the control cells (transfected with Ad-Lac Z/GCV). Similarly, in LM cells transfected with Ad-TK/GCV (10, 50, or 100 PFU/cell), the cell count was reduced by 31, 62, and 82%, respectively, compared with the control. A strong bystander effect was noted in both ELT-3 and LM cells with significant killing (p = 0.001) at a ratio of infected:uninfected cells of only 1:99 and maximal killing at 1:4. This study demonstrates the potential efficacy of the Ad-TK/GCV gene therapy approach as a viable nonsurgical alternative treatment for uterine LM.

Tanshinone IIA Increases the Bystander Effect of Herpes Simplex Virus Thymidine Kinase/Ganciclovir Gene Therapy via Enhanced Gap Junctional Intercellular Communication

PubMed Central

Liu, Xijuan; Wu, Yingya; Du, Biaoyan; Li, Jiefen; Zhou, Jing; Li, Jingjing; Tan, Yuhui

2013-01-01

The bystander effect is an intriguing phenomenon by which adjacent cells become sensitized to drug treatment during gene therapy with herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV). This effect is reported to be mediated by gap junctional intercellular communication (GJIC), and therefore, we postulated that upregulation of genes that facilitate GJIC may enhance the HSV-tk/GCV bystander effect. Previous findings have shown Tanshinone IIA (Tan IIA), a chemical substance derived from a Chinese medicine herb, promotes the upregulation of the connexins Cx26 and Cx43 in B16 cells. Because gap junctions are formed by connexins, we hypothesized that Tan IIA might increase GJIC. Our results show that Tan IIA increased GJIC in B16 melanoma cells, leading to more efficient GCV-induced bystander killing in cells stably expressing HSV-tk. Additionally, in vivo experiments demonstrated that tumors in mice with 10% HSV-tk positive B16 cells and 90% wild-type B16 cells became smaller following treatment with the combination of GCV and Tan IIA as compared to GCV or Tan IIA alone. These data demonstrate that Tan IIA can augment the bystander effect of HSV-tk/GCV system through increased gap junction coupling, which adds strength to the promising strategy that develops connexins inducer to potentiate the effects of suicide gene therapy. PMID:23861780

Health benefits, costs, and cost-effectiveness of earlier eligibility for adult antiretroviral therapy and expanded treatment coverage: a combined analysis of 12 mathematical models.

PubMed

Eaton, Jeffrey W; Menzies, Nicolas A; Stover, John; Cambiano, Valentina; Chindelevitch, Leonid; Cori, Anne; Hontelez, Jan A C; Humair, Salal; Kerr, Cliff C; Klein, Daniel J; Mishra, Sharmistha; Mitchell, Kate M; Nichols, Brooke E; Vickerman, Peter; Bakker, Roel; Bärnighausen, Till; Bershteyn, Anna; Bloom, David E; Boily, Marie-Claude; Chang, Stewart T; Cohen, Ted; Dodd, Peter J; Fraser, Christophe; Gopalappa, Chaitra; Lundgren, Jens; Martin, Natasha K; Mikkelsen, Evelinn; Mountain, Elisa; Pham, Quang D; Pickles, Michael; Phillips, Andrew; Platt, Lucy; Pretorius, Carel; Prudden, Holly J; Salomon, Joshua A; van de Vijver, David A M C; de Vlas, Sake J; Wagner, Bradley G; White, Richard G; Wilson, David P; Zhang, Lei; Blandford, John; Meyer-Rath, Gesine; Remme, Michelle; Revill, Paul; Sangrujee, Nalinee; Terris-Prestholt, Fern; Doherty, Meg; Shaffer, Nathan; Easterbrook, Philippa J; Hirnschall, Gottfried; Hallett, Timothy B

2014-01-01

New WHO guidelines recommend initiation of antiretroviral therapy for HIV-positive adults with CD4 counts of 500 cells per μL or less, a higher threshold than was previously recommended. Country decision makers have to decide whether to further expand eligibility for antiretroviral therapy accordingly. We aimed to assess the potential health benefits, costs, and cost-effectiveness of various eligibility criteria for adult antiretroviral therapy and expanded treatment coverage. We used several independent mathematical models in four settings-South Africa (generalised epidemic, moderate antiretroviral therapy coverage), Zambia (generalised epidemic, high antiretroviral therapy coverage), India (concentrated epidemic, moderate antiretroviral therapy coverage), and Vietnam (concentrated epidemic, low antiretroviral therapy coverage)-to assess the potential health benefits, costs, and cost-effectiveness of various eligibility criteria for adult antiretroviral therapy under scenarios of existing and expanded treatment coverage, with results projected over 20 years. Analyses assessed the extension of eligibility to include individuals with CD4 counts of 500 cells per μL or less, or all HIV-positive adults, compared with the previous (2010) recommendation of initiation with CD4 counts of 350 cells per μL or less. We assessed costs from a health-system perspective, and calculated the incremental cost (in US$) per disability-adjusted life-year (DALY) averted to compare competing strategies. Strategies were regarded very cost effective if the cost per DALY averted was less than the country's 2012 per-head gross domestic product (GDP; South Africa: $8040; Zambia: $1425; India: $1489; Vietnam: $1407) and cost effective if the cost per DALY averted was less than three times the per-head GDP. In South Africa, the cost per DALY averted of extending eligibility for antiretroviral therapy to adult patients with CD4 counts of 500 cells per μL or less ranged from $237 to $1691 per DALY averted compared with 2010 guidelines. In Zambia, expansion of eligibility to adults with a CD4 count threshold of 500 cells per μL ranged from improving health outcomes while reducing costs (ie, dominating the previous guidelines) to $749 per DALY averted. In both countries results were similar for expansion of eligibility to all HIV-positive adults, and when substantially expanded treatment coverage was assumed. Expansion of treatment coverage in the general population was also cost effective. In India, the cost for extending eligibility to all HIV-positive adults ranged from $131 to $241 per DALY averted, and in Vietnam extending eligibility to patients with CD4 counts of 500 cells per μL or less cost $290 per DALY averted. In concentrated epidemics, expanded access for key populations was also cost effective. Our estimates suggest that earlier eligibility for antiretroviral therapy is very cost effective in low-income and middle-income settings, although these estimates should be revisited when more data become available. Scaling up antiretroviral therapy through earlier eligibility and expanded coverage should be considered alongside other high-priority health interventions competing for health budgets. Bill & Melinda Gates Foundation, WHO. Copyright © 2014 Eaton et al. Open Access article distributed under the terms of CC BY-NC-ND. Published by .. All rights reserved.

Efficient and safe gene delivery to human corneal endothelium using magnetic nanoparticles.

PubMed

Czugala, Marta; Mykhaylyk, Olga; Böhler, Philip; Onderka, Jasmine; Stork, Björn; Wesselborg, Sebastian; Kruse, Friedrich E; Plank, Christian; Singer, Bernhard B; Fuchsluger, Thomas A

2016-07-01

To develop a safe and efficient method for targeted, anti-apoptotic gene therapy of corneal endothelial cells (CECs). Magnetofection (MF), a combination of lipofection with magnetic nanoparticles (MNPs; PEI-Mag2, SO-Mag5, PalD1-Mag1), was tested in human CECs and in explanted human corneas. Effects on cell viability and function were investigated. Immunocompatibility was assessed in human peripheral blood mononuclear cells. Silica iron-oxide MNPs (SO-Mag5) combined with X-tremeGENE-HP achieved high transfection efficiency in human CECs and explanted human corneas, without altering cell viability or function. Magnetofection caused no immunomodulatory effects in human peripheral blood mononuclear cells. Magnetofection with anti-apoptotic P35 gene effectively blocked apoptosis in CECs. Magnetofection is a promising tool for gene therapy of corneal endothelial cells with potential for targeted on-site delivery.

Inhibition of Hepatitis B Virus and Induction of Hepatoma Cell Apoptosis by ASGPR-Directed Delivery of shRNAs

PubMed Central

Yao, Xinxin; Shi, Chuan; Sun, Lifang; Yuan, Lu; Lei, Ping; Zhu, Huifen; Liu, Hongbo; Wu, Xiongwen; Ning, Qin; Zhou, Chun; Shen, Guanxin

2012-01-01

Hepatitis B virus (HBV) infection is a worldwide liver disease and nearly 25% of chronic HBV infections terminate in hepatocellular carcinoma (HCC). Currently, there is no effective therapy to inhibit HBV replication and to eliminate hepatoma cells, making it highly desired to develop novel therapies for these two stages of the HBV-caused detrimental disease. Recently, short hairpin RNA (shRNA) has emerged as a potential therapy for virus-infected disease and cancer. Here, we have generated a shRNA, pGenesil-siHBV4, which effectively inhibits HBV replication in the human hepatoma cell line HepG2.2.15. The inhibitory effects of pGenesil-siHBV4 are manifested by the decrease of both the HBV mRNA level and the protein levels of the secreted HBV surface antigen (HBsAg) and HBV e antigen (HBeAg), and by the reduction of secreted HBV DNA. Using mouse hydrodynamic tail vein injection, we demonstrate that pGenesil-siHBV4 is effective in inhibiting HBV replication in vivo. Because survivin plays a key role in cancer cell escape from apoptosis, we further generated pGenesil-siSurvivin, a survivin-silencing shRNA, and showed its effect of triggering apoptosis of HBV-containing hepatoma cells. To develop targeted shRNA therapy, we have identified that as a specific binder of the asialoglycoprotein receptor (ASGPR), jetPEI-Hepatocyte delivers pGenesil-siHBV4 and pGenesil-siSurvivin specifically to hepatocytes, not other types of cells. Finally, co-transfection of pGenesil-siHBV4 and pGenesil-siSurvivin exerts synergistic effects in inducing hepatoma cell apoptosis, a novel approach to eliminate hepatoma by downregulating survivin via multiple mechanisms. The application of these novel shRNAs with the jetPEI-Hepatocyte targeting strategy demonstrates the proof-of-principle for a promising approach to inhibit HBV replication and eliminate hepatoma cells with high specificity. PMID:23094023

Interventions for treating painful sickle cell crisis during pregnancy.

PubMed

Martí-Carvajal, Arturo J; Peña-Martí, Guiomar E; Comunián-Carrasco, Gabriella; Martí-Peña, Arturo J

2009-01-21

Sickle cell disease is a group of genetic haemoglobin disorders. All over the world, about 300,000 children with these disorders are born each year. Acute sickle cell pain episodes are the most common cause of hospitalisation. Pregnancy in women with sickle cell disease is associated with an increased incidence of maternal and fetal morbidity and mortality. The painful crisis is a severe complication of this illness, and it requires several interventions: packed red cell transfusion, fluid replacement therapy, analgesic drugs, oxygen therapy and steroids; but the approach is not standardised. To assess the effectiveness and safety of different regimens of packed red cell transfusion, oxygen therapy, fluid replacement therapy, analgesic drugs, and steroids for the treatment of painful sickle cell crisis during pregnancy. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (December 2007), the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register (October 2007), LILACS database (1982 to December 2007) and the following web sites: ClinicalTrials.gov (http://www.clinicaltrials.gov) (December 5, 2007); Current Controlled Trials (http://controlled-trials.com/) (December 5, 2007), and Sistema de Información Esencial en Terapéutica y Salud (http://www.icf.uab.es/informacion/Papyrus/sietes.asp) (December 1, 2007). We also handsearched the European Haematology Association conference (June 2007), the American Society of Hematology conference (December 2007) and reference lists of all retrieved articles. We intended to include randomised clinical trials. We intended to summarise data by standard Cochrane Collaboration methodologies. We could not find any randomised clinical trials on interventions (packed red cell transfusion, oxygen therapy, fluid replacement therapy, analgesic drugs, and steroids) for the treatment of painful sickle cell crisis during pregnancy. This review found no randomised clinical trials on the safety and efficacy of interventions for treating painful sickle cell crisis during pregnancy. The effects of interventions need to be tested in randomised clinical trials.

CD25 Preselective Anti-HIV Vectors for Improved HIV Gene Therapy

PubMed Central

Kalomoiris, Stefanos; Lawson, Je'Tai; Chen, Rachel X.; Bauer, Gerhard; Nolta, Jan A.

2012-01-01

Abstract As HIV continues to be a global public health problem with no effective vaccine available, new and innovative therapies, including HIV gene therapies, need to be developed. Due to low transduction efficiencies that lead to low in vivo gene marking, therapeutically relevant efficacy of HIV gene therapy has been difficult to achieve in a clinical setting. Methods to improve the transplantation of enriched populations of anti-HIV vector-transduced cells may greatly increase the in vivo efficacy of HIV gene therapies. Here we describe the development of preselective anti-HIV lentiviral vectors that allow for the purification of vector-transduced cells to achieve an enriched population of HIV-resistant cells. A selectable protein, human CD25, not normally found on CD34+ hematopoietic progenitor cells (HPCs), was incorporated into a triple combination anti-HIV lentiviral vector. Upon purification of cells transduced with the preselective anti-HIV vector, safety was demonstrated in CD34+ HPCs and in HPC-derived macrophages in vitro. Upon challenge with HIV-1, improved efficacy was observed in purified preselective anti-HIV vector-transduced macrophages compared to unpurified cells. These proof-of-concept results highlight the potential use of this method to improve HIV stem cell gene therapy for future clinical applications. PMID:23216020

Cost-effectiveness of community-based strategies to strengthen the continuum of HIV care in rural South Africa: a health economic modelling analysis.

PubMed

Smith, Jennifer A; Sharma, Monisha; Levin, Carol; Baeten, Jared M; van Rooyen, Heidi; Celum, Connie; Hallett, Timothy B; Barnabas, Ruanne V

2015-04-01

Home HIV counselling and testing (HTC) achieves high coverage of testing and linkage to care compared with existing facility-based approaches, particularly among asymptomatic individuals. In a modelling analysis we aimed to assess the effect on population-level health and cost-effectiveness of a community-based package of home HTC in KwaZulu-Natal, South Africa. We parameterised an individual-based model with data from home HTC and linkage field studies that achieved high coverage (91%) and linkage to antiretroviral therapy (80%) in rural KwaZulu-Natal, South Africa. Costs were derived from a linked microcosting study. The model simulated 10,000 individuals over 10 years and incremental cost-effectiveness ratios were calculated for the intervention relative to the existing status quo of facility-based testing, with costs discounted at 3% annually. The model predicted implementation of home HTC in addition to current practice to decrease HIV-associated morbidity by 10–22% and HIV infections by 9–48% with increasing CD4 cell count thresholds for antiretroviral therapy initiation. Incremental programme costs were US$2·7 million to $4·4 million higher in the intervention scenarios than at baseline, and costs increased with higher CD4 cell count thresholds for antiretroviral therapy initiation; antiretroviral therapy accounted for 48–87% of total costs. Incremental cost-effectiveness ratios per disability-adjusted life-year averted were $1340 at an antiretroviral therapy threshold of CD4 count lower than 200 cells per μL, $1090 at lower than 350 cells per μL, $1150 at lower than 500 cells per μL, and $1360 at universal access to antiretroviral therapy. Community-based HTC with enhanced linkage to care can result in increased HIV testing coverage and treatment uptake, decreasing the population burden of HIV-associated morbidity and mortality. The incremental cost-effectiveness ratios are less than 20% of South Africa's gross domestic product per person, and are therefore classed as very cost effective. Home HTC can be a viable means to achieve UNAIDS' ambitious new targets for HIV treatment coverage. National Institutes of Health, Bill & Melinda Gates Foundation, Wellcome Trust.

ent-Jungermannenone C Triggers Reactive Oxygen Species-Dependent Cell Differentiation in Leukemia Cells.

PubMed

Yue, Zongwei; Xiao, Xinhua; Wu, Jinbao; Zhou, Xiaozhou; Liu, Weilong; Liu, Yaxi; Li, Houhua; Chen, Guoqiang; Wu, Yingli; Lei, Xiaoguang

2018-02-23

Acute myeloid leukemia (AML) is a hematologic malignancy that is characterized by clonal proliferation of myeloid blasts. Despite the progress that has been made in the treatment of various malignant hematopoietic diseases, the effective treatment of AML remains very challenging. Differentiation therapy has emerged as a promising approach for leukemia treatment, and new and effective chemical agents to trigger the differentiation of AML cells, especially drug-resistant cells, are urgently required. Herein, the natural product jungermannenone C, a tetracyclic diterpenoid isolated from liverworts, is reported to induce cell differentiation in AML cells. Interestingly, the unnatural enantiomer of jungermannenone C (1) was found to be more potent than jungermannenone C in inducing cell differentiation. Furthermore, compound 1 targets peroxiredoxins I and II by selectively binding to the conserved cysteine residues and leads to cellular reactive oxygen species accumulation. Accordingly, ent-jungermannenone C (1) shows potential for further investigation as an effective differentiation therapy against AML.

Cancer Systems Biology: a peak into the future of patient care?

PubMed Central

Werner, Henrica M. J.; Mills, Gordon B.; Ram, Prahlad T.

2015-01-01

Traditionally, scientific research has focused on studying individual events, such as single mutations, gene function or the effect of the manipulation of one protein on a biological phenotype. A range of technologies, combined with the ability to develop robust and predictive mathematical models, is beginning to provide information that will enable a holistic view of how the genomic and epigenetic aberrations in cancer cells can alter the homeostasis of signalling networks within these cells, between cancer cells and the local microenvironment, at the organ and organism level. This systems biology process needs to be integrated with an iterative approach wherein hypotheses and predictions that arise from modelling are refined and constrained by experimental evaluation. Systems biology approaches will be vital for developing and implementing effective strategies to deliver personalized cancer therapy. Specifically, these approaches will be important to select those patients most likely to benefit from targeted therapies as well as for the development and implementation of rational combinatorial therapies. Systems biology can help to increase therapy efficacy or bypass the emergence of resistance, thus converting the current (often short term) effects of targeted therapies into durable responses, ultimately to improve quality of life and provide a cure. PMID:24492837

Hepatic artery infusion therapy is effective for chemotherapy-resistant liver metastatic colorectal cancer.

PubMed

Goi, Takanori; Naruse, Takayuki; Kimura, Youhei; Fujimoto, Daisuke; Morikawa, Mitsuhiro; Koneri, Kenji; Yamaguchi, Akio

2015-10-09

Systemic FOLFOX (folinic acid (leucovorin (LV)), 5-fluorouracil (5-FU), and oxaliplatin), FOLFIRI (LV, 5-FU, and irinotecan), or FOLFOXIRI (5-FU, leucovorin, oxaliplatin, and irinotecan) chemotherapy regimens and additional molecular-target treatments, including anti-vascular endothelial growth factor, anti-epidermal growth factor receptor, and anti-multi-kinase antibodies, have been recommended for unresectable recurrent colorectal cancers. However, no effective treatments are currently available for cases refractory to these therapies. Therefore, the development of alternative therapies is desired. In the present study, we administered and observed the effectiveness of hepatic artery infusion therapy (HAIC) in patients with unresectable liver metastatic colorectal cancers refractory to systemic chemotherapy. In addition, we observed that in an experimental system with anticancer drug-resistant colorectal cancer lines, apoptosis and cell death could be induced by increasing anticancer drug concentrations. The subjects had liver metastatic colorectal cancers that were unresponsive to systemic chemotherapy (FOLFOX/FOLFIRI) or to additional molecular-target therapies for progressive disease. Hepatic infusion tube placement was conducted according to the Seldinger method to insert a catheter with a side hole via the right femoral artery. A coiling procedure was performed to prevent drug influx into the gastroduodenal artery. Ten subjects were selected, and the results were evaluated after HAIC (5-FU and LV administered once weekly). Moreover, anticancer drug-resistant colorectal cancer lines were subsequently prepared to investigate whether increased anticancer drug concentrations could induce apoptosis or cell death. Of the 10 subjects, 3 (30 %) showed partial response and 4 (40 %) showed no change according to computed tomography imaging findings obtained after hepatic artery infusion. The disease control rate was 70 %. Eight subjects had improved quality of life. Survival time ranged from 2 to 16 months (median, 9 months). Meanwhile, we found that higher anticancer drug concentrations induced apoptosis and cell death in an anticancer drug-resistant colorectal cancer cell line. HAIC was effective in some systemic chemotherapy-resistant colorectal cancers with liver metastases and should be considered as an effective palliative therapy. This supports the finding that apoptosis and cell death could be induced in anticancer drug-resistant colorectal cancer cells in a drug concentration-dependent manner.

Modelling cell population growth with applications to cancer therapy in human tumour cell lines.

PubMed

Basse, Britta; Baguley, Bruce C; Marshall, Elaine S; Wake, Graeme C; Wall, David J N

2004-01-01

In this paper we present an overview of the work undertaken to model a population of cells and the effects of cancer therapy. We began with a theoretical one compartment size structured cell population model and investigated its asymptotic steady size distributions (SSDs) (On a cell growth model for plankton, MMB JIMA 21 (2004) 49). However these size distributions are not similar to the DNA (size) distributions obtained experimentally via the flow cytometric analysis of human tumour cell lines (data obtained from the Auckland Cancer Society Research Centre, New Zealand). In our one compartment model, size was a generic term, but in order to obtain realistic steady size distributions we chose size to be DNA content and devised a multi-compartment mathematical model for the cell division cycle where each compartment corresponds to a distinct phase of the cell cycle (J. Math. Biol. 47 (2003) 295). We then incorporated another compartment describing the possible induction of apoptosis (cell death) from mitosis phase (Modelling cell death in human tumour cell lines exposed to anticancer drug paclitaxel, J. Math. Biol. 2004, in press). This enabled us to compare our model to flow cytometric data of a melanoma cell line where the anticancer drug, paclitaxel, had been added. The model gives a dynamic picture of the effects of paclitaxel on the cell cycle. We hope to use the model to describe the effects of other cancer therapies on a number of different cell lines. Copyright 2004 Elsevier Ltd.

Dioscin augments HSV-tk-mediated suicide gene therapy for melanoma by promoting connexin-based intercellular communication

PubMed Central

Li, Bin; Wu, Yingya; Liu, Xijuan; Tan, Yuhui; Du, Biaoyan

2017-01-01

Suicide gene therapy is a promising strategy against melanoma. However, the low efficiency of the gene transfer technique can limit its application. Our preliminary data showed that dioscin, a glucoside saponin, could upregulate the expression of connexins Cx26 and Cx43, major components of gap junctions, in melanoma cells. We hypothesized that dioscin may increase the bystander effect of herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) through increasing the formation of gap junctions. Further analysis showed that dioscin indeed could increase the gap junctional intercellular communication in B16 melanoma cells, resulting in more efficient GCV-induced bystander killing in B16tk cells. By contrast, overexpression of dominant negative Cx43 impaired the cell-cell communication of B16 cells and subsequently weakened the bystander effect of HSV-tk/GCV gene therapy. In vivo, combination treatment with dioscin and GCV of tumor-bearing mice with 30% positive B16tk cells and 70% wild-type B16 cells caused a significant reduction in tumor volume and weight compared to treatment with GCV or dioscin alone. Taken together, these results demonstrated that dioscin could augment the bystander effect of the HSV-tk/GCV system through increasing connexin-mediated gap junction coupling. PMID:27903977

Translating G-CSF as an adjunct therapy to stem cell transplantation for stroke

PubMed Central

dela Peña, Ike; Borlongan, Cesar V.

2015-01-01

Among recently investigated stroke therapies, stem cell treatment holds great promise by virtue of their putative ability to replace lost cells, promote endogenous neurogenesis and produce behavioral and functional improvement through their “bystander effects.” Translating stem cell in the clinic, however, presents a number of technical difficulties. A strategy suggested to enhance therapeutic utility of stem cells is combination therapy, i.e., cotransplantation of stem cells or adjunct treatment with pharmacological agents and substrates, which is assumed to produce more profound therapeutic benefits by circumventing limitations of individual treatments, and facilitating complementary brain repair processes. We previously demonstrated enhanced functional effects of co-treatment with granulocyte-colony stimulating factor (G-CSF) and human umbilical cord blood cell (hUCB) transplantation in animal models of traumatic brain injury (TBI). Here, we suggest that the aforementioned combination therapy may also produce synergistic effects in stroke. Accordingly, G-CSF treatment may reduce expression of pro-inflammatory cytokines and enhance neurogenesis rendering a receptive microenvironment for hUCB engraftment. Adjunct treatment of G-CSF with hUCB may facilitate stemness maintenance and guide neural lineage commitment of hUCB cells. Moreover, regenerative mechanisms afforded by G-CSF-mobilized endogenous stem cells, secretion of growth factors by hUCB grafts and G-CSF-recruited endothelial progenitor cells (EPCs) , as well as the potential graft–host integration that may promote synaptic circuitry re-establishment could altogether produce more pronounced functional improvement in stroked rats subjected to a combination G-CSF treatment and hUCB transplantation. Nevertheless, differences in pathology and repair processes underlying TBI and stroke deserve consideration when testing effects of combinatorial G-CSF and hUCB cell transplantation for stroke treatment. Further studies are also required to determine safety and efficacy of this intervention in both preclinical and clinical stroke studies. PMID:26482176

Increased soluble vascular cell adhesion molecule-1 plasma levels and soluble intercellular adhesion molecule-1 during antiretroviral therapy interruption and retention of elevated soluble vascular cellular adhesion molecule-1 levels following resumption of antiretroviral therapy.

PubMed

Papasavvas, Emmanouil; Azzoni, Livio; Pistilli, Maxwell; Hancock, Aidan; Reynolds, Griffin; Gallo, Cecile; Ondercin, Joe; Kostman, Jay R; Mounzer, Karam; Shull, Jane; Montaner, Luis J

2008-06-19

We investigated the effect of short viremic episodes on soluble markers associated with endothelial stress and cardiovascular disease risk in chronically HIV-1-infected patients followed during continuous antiretroviral therapy, antiretroviral therapy interruption and antiretroviral therapy resumption. We assessed changes in plasma levels of von Willebrand factor, soluble vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 by enzyme-linked immunosorbent assay, as well as T-cell activation (CD8+/CD38+, CD8+/HLA-DR+ and CD3+/CD95+) by flow cytometry, in 36 chronically HIV-1-infected patients participating in a randomized study. Patients were divided into the following three groups: a, on continuous antiretroviral therapy; b, on a 6-week antiretroviral therapy interruption; or c, on antiretroviral therapy interruption extended to the achievement of viral set point. Although all measurements remained stable over a 40-week follow-up on antiretroviral therapy, plasma levels of soluble vascular cell adhesion molecule-1 (P < 0.0001) and soluble intercellular adhesion molecule-1 (P = 0.003) increased during treatment interruption in correlation with viral rebound and T-cell activation. No significant changes in von Willebrand factor were observed in any of the groups. After resuming antiretroviral therapy, soluble vascular cell adhesion molecule-1 levels remained elevated even after achievement of viral suppression to less than 50 copies/ml. The prompt rise in plasma soluble vascular cell adhesion molecule-1 and soluble intercellular adhesion molecule-1 upon viral rebound suggests an acute increase in endothelial stress upon treatment interruption, which may persists after viral resuppression of virus. Thus, viral replication during short-term treatment interruption may increase the overall cardiovascular risk during and beyond treatment interruption.

Effects of hypoxia on osteogenic differentiation of mesenchymal stromal cells used as a cell therapy for avascular necrosis of the femoral head.

PubMed

Ciapetti, Gabriela; Granchi, Donatella; Fotia, Caterina; Savarino, Lucia; Dallari, Dante; Del Piccolo, Nicola; Donati, Davide Maria; Baldini, Nicola

2016-09-01

Avascular necrosis of the femoral head (AVN) occurs as common result of various conditions or develops as a primary entity, with a high freqency in young adults. Because of its tendency toward osteoarthritis requiring total hip arthroplasty, alternative treatments are being advocated, including cell therapy with mesenchymal stromal cells (MSCs). Because osteonecrotic bone is a severely hypoxic tissue, with a 1-3% oxygen tension, the survival and function of multipotent cells is questionable. In this study, the proliferative, immunophenotypic and osteogenic properties of bone marrow (BM)-derived MSCs from a clinical series of patients with AVN were evaluated under in vitro conditions mimicking the hypoxic milieu of AVN to verify the rationale for cell therapy. MSCs retrieved from the iliac crest (BM-MSC) were isolated, expanded and induced to osteogenic differentiation under a 2% pO2 atmosphere (hypoxia) in comparison with the standard 21% pO2 (normoxia) that is routinely used in cell culture assays. Both proliferation and colony-forming ability were significantly enhanced in hypoxia-exposed BM-MSCs compared with BM-MSCs under normoxia. The expression of bone-related genes, including alkaline phosphatase, Type I collagen, and osteocalcin was significantly increased under hypoxia. Moreover, mineral deposition after osteogenic induction was not hampered, but in some cases even enhanced under low oxygen tension. These findings support autologous cell therapy as an effective treatment to stimulate bone healing in the hypoxic microenvironment of AVN. Copyright © 2016 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Escalated regeneration in sciatic nerve crush injury by the combined therapy of human amniotic fluid mesenchymal stem cells and fermented soybean extracts, Natto.

PubMed

Pan, Hung-Chuan; Yang, Dar-Yu; Ho, Shu-Peng; Sheu, Meei-Ling; Chen, Chung-Jung; Hwang, Shiaw-Min; Chang, Ming-Hong; Cheng, Fu-Chou

2009-08-23

Attenuation of inflammatory cell deposits and associated cytokines prevented the apoptosis of transplanted stem cells in a sciatic nerve crush injury model. Suppression of inflammatory cytokines by fermented soybean extracts (Natto) was also beneficial to nerve regeneration. In this study, the effect of Natto on transplanted human amniotic fluid mesenchymal stem cells (AFS) was evaluated. Peripheral nerve injury was induced in SD rats by crushing a sciatic nerve using a vessel clamp. Animals were categorized into four groups: Group I: no treatment; Group II: fed with Natto (16 mg/day for 7 consecutive days); Group III: AFS embedded in fibrin glue; Group IV: Combination of group II and III therapy. Transplanted AFS and Schwann cell apoptosis, inflammatory cell deposits and associated cytokines, motor function, and nerve regeneration were evaluated 7 or 28 days after injury. The deterioration of neurological function was attenuated by AFS, Natto, or the combined therapy. The combined therapy caused the most significantly beneficial effects. Administration of Natto suppressed the inflammatory responses and correlated with decreased AFS and Schwann cell apoptosis. The decreased AFS apoptosis was in line with neurological improvement such as expression of early regeneration marker of neurofilament and late markers of S-100 and decreased vacuole formation. Administration of either AFS, or Natto, or combined therapy augmented the nerve regeneration. In conclusion, administration of Natto may rescue the AFS and Schwann cells from apoptosis by suppressing the macrophage deposits, associated inflammatory cytokines, and fibrin deposits.

Cell-Based Therapies for Joint Disease in Veterinary Medicine: What We Have Learned and What We Need to Know

PubMed Central

Bogers, Sophie Helen

2018-01-01

Biological cell-based therapies for the treatment of joint disease in veterinary patients include autologous-conditioned serum, platelet-rich plasma, and expanded or non-expanded mesenchymal stem cell products. This narrative review outlines the processing and known mechanism of action of these therapies and reviews current preclinical and clinical efficacy in joint disease in the context of the processing type and study design. The significance of variation for biological activity and consequently regulatory approval is also discussed. There is significant variation in study outcomes for canine and equine cell-based products derived from whole blood or stem cell sources such as adipose and bone marrow. Variation can be attributed to altering bio-composition due to factors including preparation technique and source. In addition, study design factors like selection of cases with early vs. late stage osteoarthritis (OA), or with intra-articular soft tissue injury, influence outcome variation. In this under-regulated field, variation raises concerns for product safety, consistency, and efficacy. Cell-based therapies used for OA meet the Food and Drug Administration’s (FDA’s) definition of a drug; however, researchers must consider their approach to veterinary cell-based research to meet future regulatory demands. This review explains the USA’s FDA guidelines as an example pathway for cell-based therapies to demonstrate safety, effectiveness, and manufacturing consistency. An understanding of the variation in production consistency, effectiveness, and regulatory concerns is essential for practitioners and researchers to determine what products are indicated for the treatment of joint disease and tactics to improve the quality of future research. PMID:29713634

Oxygen and indocyanine green loaded phase-transition nanoparticle-mediated photo-sonodynamic cytotoxic effects on rheumatoid arthritis fibroblast-like synoviocytes.

PubMed

Tang, Qin; Cui, Jianyu; Tian, Zhonghua; Sun, Jiangchuan; Wang, Zhigang; Chang, Shufang; Zhu, Shenyin

2017-01-01

Photodynamic therapy and sonodynamic therapy are developing, minimally invasive, and site-specific modalities for cancer therapy. A combined strategy PSDT (photodynamic therapy followed by sonodynamic therapy) has been proposed in this study. Here, we aimed to develop novel biodegradable poly(DL-lactide- co -glycolic acid) phase-transition nanoparticles simultaneously loaded with oxygen and indocyanine green (OI-NPs) and to investigate the cytotoxic effects and the potential mechanisms of OI-NP-mediated PSDT on MH7A synoviocytes. The OI-NPs were prepared using a modified double emulsion method and the physicochemical properties were determined. The cellular uptake of OI-NPs was detected by confocal microscopy and flow cytometry. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide assay, flow cytometry, and Hoechst 33342/propidium iodide double staining were used to determine the cytotoxic effect of OI-NP-mediated PSDT on MH7A cells. Fluorescence microscope and fluorescence microplate reader were used to detect reactive oxygen species (ROS) generation. The OI-NPs were a stable and efficient carrier to deliver oxygen and indocyanine green, and enhanced cellular uptake was observed in MH7A cells with the nanoparticles. OI-NP-mediated PSDT caused more serious cell damage and more evident cell apoptosis, compared with other groups. Furthermore, increased generation of intracellular ROS was detected in MH7A cells treated with PSDT. Interestingly, the OI-NP-mediated PSDT-induced cell viability loss was effectively rescued by pretreatment with the ROS scavenger N -acetylcysteine. Multifunctional OI-NPs were successfully developed and characterized for the combined delivery of oxygen and indocyanine green, and OI-NP-mediated PSDT would be a potential cytotoxic treatment for MH7A cells. This study may provide a novel strategy for the treatment of RA and develop a model of theranostic application through phase-transition nanoparticle-mediated PSDT in the future.

Oxygen and indocyanine green loaded phase-transition nanoparticle-mediated photo-sonodynamic cytotoxic effects on rheumatoid arthritis fibroblast-like synoviocytes

PubMed Central

Tang, Qin; Cui, Jianyu; Tian, Zhonghua; Sun, Jiangchuan; Wang, Zhigang; Chang, Shufang; Zhu, Shenyin

2017-01-01

Background Photodynamic therapy and sonodynamic therapy are developing, minimally invasive, and site-specific modalities for cancer therapy. A combined strategy PSDT (photodynamic therapy followed by sonodynamic therapy) has been proposed in this study. Here, we aimed to develop novel biodegradable poly(DL-lactide-co-glycolic acid) phase-transition nanoparticles simultaneously loaded with oxygen and indocyanine green (OI-NPs) and to investigate the cytotoxic effects and the potential mechanisms of OI-NP–mediated PSDT on MH7A synoviocytes. Methods The OI-NPs were prepared using a modified double emulsion method and the physicochemical properties were determined. The cellular uptake of OI-NPs was detected by confocal microscopy and flow cytometry. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide assay, flow cytometry, and Hoechst 33342/propidium iodide double staining were used to determine the cytotoxic effect of OI-NP–mediated PSDT on MH7A cells. Fluorescence microscope and fluorescence microplate reader were used to detect reactive oxygen species (ROS) generation. Results The OI-NPs were a stable and efficient carrier to deliver oxygen and indocyanine green, and enhanced cellular uptake was observed in MH7A cells with the nanoparticles. OI-NP–mediated PSDT caused more serious cell damage and more evident cell apoptosis, compared with other groups. Furthermore, increased generation of intracellular ROS was detected in MH7A cells treated with PSDT. Interestingly, the OI-NP–mediated PSDT-induced cell viability loss was effectively rescued by pretreatment with the ROS scavenger N-acetylcysteine. Conclusion Multifunctional OI-NPs were successfully developed and characterized for the combined delivery of oxygen and indocyanine green, and OI-NP–mediated PSDT would be a potential cytotoxic treatment for MH7A cells. This study may provide a novel strategy for the treatment of RA and develop a model of theranostic application through phase-transition nanoparticle-mediated PSDT in the future. PMID:28123298

Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway.

PubMed

Viswanathan, Vasanthi S; Ryan, Matthew J; Dhruv, Harshil D; Gill, Shubhroz; Eichhoff, Ossia M; Seashore-Ludlow, Brinton; Kaffenberger, Samuel D; Eaton, John K; Shimada, Kenichi; Aguirre, Andrew J; Viswanathan, Srinivas R; Chattopadhyay, Shrikanta; Tamayo, Pablo; Yang, Wan Seok; Rees, Matthew G; Chen, Sixun; Boskovic, Zarko V; Javaid, Sarah; Huang, Cherrie; Wu, Xiaoyun; Tseng, Yuen-Yi; Roider, Elisabeth M; Gao, Dong; Cleary, James M; Wolpin, Brian M; Mesirov, Jill P; Haber, Daniel A; Engelman, Jeffrey A; Boehm, Jesse S; Kotz, Joanne D; Hon, Cindy S; Chen, Yu; Hahn, William C; Levesque, Mitchell P; Doench, John G; Berens, Michael E; Shamji, Alykhan F; Clemons, Paul A; Stockwell, Brent R; Schreiber, Stuart L

2017-07-27

Plasticity of the cell state has been proposed to drive resistance to multiple classes of cancer therapies, thereby limiting their effectiveness. A high-mesenchymal cell state observed in human tumours and cancer cell lines has been associated with resistance to multiple treatment modalities across diverse cancer lineages, but the mechanistic underpinning for this state has remained incompletely understood. Here we molecularly characterize this therapy-resistant high-mesenchymal cell state in human cancer cell lines and organoids and show that it depends on a druggable lipid-peroxidase pathway that protects against ferroptosis, a non-apoptotic form of cell death induced by the build-up of toxic lipid peroxides. We show that this cell state is characterized by activity of enzymes that promote the synthesis of polyunsaturated lipids. These lipids are the substrates for lipid peroxidation by lipoxygenase enzymes. This lipid metabolism creates a dependency on pathways converging on the phospholipid glutathione peroxidase (GPX4), a selenocysteine-containing enzyme that dissipates lipid peroxides and thereby prevents the iron-mediated reactions of peroxides that induce ferroptotic cell death. Dependency on GPX4 was found to exist across diverse therapy-resistant states characterized by high expression of ZEB1, including epithelial-mesenchymal transition in epithelial-derived carcinomas, TGFβ-mediated therapy-resistance in melanoma, treatment-induced neuroendocrine transdifferentiation in prostate cancer, and sarcomas, which are fixed in a mesenchymal state owing to their cells of origin. We identify vulnerability to ferroptic cell death induced by inhibition of a lipid peroxidase pathway as a feature of therapy-resistant cancer cells across diverse mesenchymal cell-state contexts.

Adaptive non-linear control for cancer therapy through a Fokker-Planck observer.

PubMed

Shakeri, Ehsan; Latif-Shabgahi, Gholamreza; Esmaeili Abharian, Amir

2018-04-01

In recent years, many efforts have been made to present optimal strategies for cancer therapy through the mathematical modelling of tumour-cell population dynamics and optimal control theory. In many cases, therapy effect is included in the drift term of the stochastic Gompertz model. By fitting the model with empirical data, the parameters of therapy function are estimated. The reported research works have not presented any algorithm to determine the optimal parameters of therapy function. In this study, a logarithmic therapy function is entered in the drift term of the Gompertz model. Using the proposed control algorithm, the therapy function parameters are predicted and adaptively adjusted. To control the growth of tumour-cell population, its moments must be manipulated. This study employs the probability density function (PDF) control approach because of its ability to control all the process moments. A Fokker-Planck-based non-linear stochastic observer will be used to determine the PDF of the process. A cost function based on the difference between a predefined desired PDF and PDF of tumour-cell population is defined. Using the proposed algorithm, the therapy function parameters are adjusted in such a manner that the cost function is minimised. The existence of an optimal therapy function is also proved. The numerical results are finally given to demonstrate the effectiveness of the proposed method.

Breast Cancer Stem Cell Therapeutics, Multiple Strategies Versus Using Engineered Mesenchymal Stem Cells With Notch Inhibitory Properties: Possibilities and Perspectives.

PubMed

Bose, Bipasha; Sen, Utsav; Shenoy P, Sudheer

2018-01-01

Relapse cases of cancers are more vigorous and difficult to control due to the preponderance of cancer stem cells (CSCs). Such CSCs that had been otherwise dormant during the first incidence of cancer gradually appear as radiochemoresistant cancer cells. Hence, cancer therapeutics aimed at CSCs would be an effective strategy for mitigating the cancers during relapse. Alternatively, CSC therapy can also be proposed as an adjuvant therapy, along-with the conventional therapies. As regenerative stem cells (RSCs) are known for their trophic effects, anti-tumorogenicity, and better migration toward an injury site, this review aims to address the use of adult stem cells such as dental pulp derived; cord blood derived pure populations of regenerative stem cells for targeting CSCs. Indeed, pro-tumorogenicity of RSCs is of concern and hence has also been dealt with in relation to breast CSC therapeutics. Furthermore, as notch signaling pathways are upregulated in breast cancers, and anti-notch antibody based and sh-RNA based therapies are already in the market, this review focuses the possibilities of engineering RSCs to express notch inhibitory proteins for breast CSC therapeutics. Also, we have drawn a comparison among various possibilities of breast CSC therapeutics, about, notch1 inhibition. J. Cell. Biochem. 119: 141-149, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Cell therapies: realizing the potential of this new dimension to medical therapeutics.

PubMed

Singh, Pawanbir; Williams, David J

2008-08-01

Stem cells promise to treat conditions poorly served by conventional therapeutics. Cells from both embryonic and somatic tissues are being used to create cell therapies for genetic, traumatic and degenerative conditions. The current human, healthcare and fiscal costs of these conditions are significant. This review summarizes the use of stem cells for neurological and cardiac disorders and diabetes to determine the requirements for generic translational research to assist such therapies to be a reality. While there are multiple strategies in each disease area, with no clear favourite, there are clear opportunities in treatments that use a single cell type. A key requirement is to work with pluripotent progenitor cells to cultivate and differentiate a sufficiently large population of functioning cells. Challenges also arise in determining and achieving timely delivery of the correct dose of cells to where they can most effectively treat the disease and best benefit individual patients. (c) 2008 John Wiley & Sons, Ltd.

Effective control of acute myeloid leukaemia and acute lymphoblastic leukaemia progression by telomerase specific adoptive T-cell therapy.

PubMed

Sandri, Sara; De Sanctis, Francesco; Lamolinara, Alessia; Boschi, Federico; Poffe, Ornella; Trovato, Rosalinda; Fiore, Alessandra; Sartori, Sara; Sbarbati, Andrea; Bondanza, Attilio; Cesaro, Simone; Krampera, Mauro; Scupoli, Maria T; Nishimura, Michael I; Iezzi, Manuela; Sartoris, Silvia; Bronte, Vincenzo; Ugel, Stefano

2017-10-20

Telomerase (TERT) is a ribonucleoprotein enzyme that preserves the molecular organization at the ends of eukaryotic chromosomes. Since TERT deregulation is a common step in leukaemia, treatments targeting telomerase might be useful for the therapy of hematologic malignancies. Despite a large spectrum of potential drugs, their bench-to-bedside translation is quite limited, with only a therapeutic vaccine in the clinic and a telomerase inhibitor at late stage of preclinical validation. We recently demonstrated that the adoptive transfer of T cell transduced with an HLA-A2-restricted T-cell receptor (TCR), which recognize human TERT with high avidity, controls human B-cell chronic lymphocytic leukaemia (B-CLL) progression without severe side-effects in humanized mice. In the present report, we show the ability of our approach to limit the progression of more aggressive leukemic pathologies, such as acute myeloid leukaemia (AML) and B-cell acute lymphoblastic leukaemia (B-ALL). Together, our findings demonstrate that TERT-based adoptive cell therapy is a concrete platform of T cell-mediated immunotherapy for leukaemia treatment.

Effective control of acute myeloid leukaemia and acute lymphoblastic leukaemia progression by telomerase specific adoptive T-cell therapy

PubMed Central

Lamolinara, Alessia; Boschi, Federico; Poffe, Ornella; Trovato, Rosalinda; Fiore, Alessandra; Sartori, Sara; Sbarbati, Andrea; Bondanza, Attilio; Cesaro, Simone; Krampera, Mauro; Scupoli, Maria T.; Nishimura, Michael I.; Iezzi, Manuela; Sartoris, Silvia; Bronte, Vincenzo; Ugel, Stefano

2017-01-01

Telomerase (TERT) is a ribonucleoprotein enzyme that preserves the molecular organization at the ends of eukaryotic chromosomes. Since TERT deregulation is a common step in leukaemia, treatments targeting telomerase might be useful for the therapy of hematologic malignancies. Despite a large spectrum of potential drugs, their bench-to-bedside translation is quite limited, with only a therapeutic vaccine in the clinic and a telomerase inhibitor at late stage of preclinical validation. We recently demonstrated that the adoptive transfer of T cell transduced with an HLA-A2-restricted T-cell receptor (TCR), which recognize human TERT with high avidity, controls human B-cell chronic lymphocytic leukaemia (B-CLL) progression without severe side-effects in humanized mice. In the present report, we show the ability of our approach to limit the progression of more aggressive leukemic pathologies, such as acute myeloid leukaemia (AML) and B-cell acute lymphoblastic leukaemia (B-ALL). Together, our findings demonstrate that TERT-based adoptive cell therapy is a concrete platform of T cell-mediated immunotherapy for leukaemia treatment. PMID:29152058

[Stem cell therapy in cardiovascular diseases].

PubMed

Vértesaljai, Márton; Piróth, Zsolt; Fontos, Géza; Andréka, Gyórgy; Font, Gusztáv; Szánthó, Gergely; Réti, Marienn; Masszi, Tamás; Andréka, Peter

2005-11-20

Myocardial infarction is the leading cause of congestive heart failure in the industrialized world. Current treatments fail to address the underlying scarring and cell loss, which are the causes of ischaemic heart failure. Recent interest has focused on stem cells, which are undifferentiated and pluripotent cells that can proliferate, potentially self-renew, and differentiate into cardiomyocytes and endothelial cells. Myocardial regeneration is the most widely studied and debated example of stem cell plasticity. Early reports from animal and clinical investigations disagree on the extent of myocardial renewal in adults, but evidence indicates that cardiomyocytes were generated in what was previously considered a postmitotic organ. So far, candidates for cardiac stem cell therapy have been limited to patients with acute myocardial infarction and chronic ischaemic heart failure. Currently, bone marrow stem cells seem to be the most attractive cell type for these patients. The cells may be delivered by means of direct surgical injection, intracoronary infusion, retrograde venous infusion, and transendocardial infusion. Stem cells may directly increase cardiac contractility or passively limit infarct expansion and remodeling. Early phase I clinical studies indicate that stem cell transplantation is feasible and may have beneficial effects on ventricular remodeling after myocardial infarction. Future randomized clinical trials will establish the magnitude of benefit and the effect on mortality after stem cell therapy.

Differential effect of EGFR inhibitors on tamoxifen-resistant breast cancer cells.

PubMed

Kim, Sangmin; Lee, Jeongmin; Oh, Soo Jin; Nam, Seok Jin; Lee, Jeong Eon

2015-09-01

Although tamoxifen is the most common and effective therapy for treatment of estrogen receptor-α (ER-α) breast cancer patients, resistance of endocrine therapy occurs, either de novo or acquired during therapy. Here, we investigated the clinical value of epidermal growth factor receptor (EGFR) in tamoxifen-resistant (TamR) patients and the differential effect of EGFR inhibitors, neratinib and gefitinib, on TamR breast cancer cell model. The morphology of TamR MCF7 cells showed mesenchymal phenotypes and did not induce cell death by tamoxifen treatment compared with tamoxifen‑sensitive (TamS) MCF7 cells. In addition, mesenchymal marker proteins, including N-cadherin (N-cad), fibronectin (FN), and Slug, significantly increased in TamR cells. In contrast, ER-α and E-cadherin (E-cad) were greatly decreased. We also found that the levels of EGFR and HER2 expression were increased in TamR cells. Furthermore, we observed that EGFR expression was directly involved with poor prognosis of tamoxifen-treated breast cancer patients using the GSE1378 date set. Thus, we treated TamR and TamS cells with EGFR inhibitors, neratinib and gefitinib, respectively. Interestingly, neratinib induced apoptotic cell death of TamR but not gefitinib. Cleaved PARP-1 expression was also increased by neratinib treatment in TamR cells. Therefore, we suggest that neratinib may be a potential therapeutic drug for treating TamR breast cancer.

Ex vivo γ-retroviral gene therapy of dogs with X-linked severe combined immunodeficiency and the development of a thymic T cell lymphoma.

PubMed

Kennedy, Douglas R; Hartnett, Brian J; Kennedy, Jeffrey S; Vernau, William; Moore, Peter F; O'Malley, Thomas; Burkly, Linda C; Henthorn, Paula S; Felsburg, Peter J

2011-07-15

We have previously shown that in vivo γ-retroviral gene therapy of dogs with X-linked severe combined immunodeficiency (XSCID) results in sustained T cell reconstitution and sustained marking in myeloid and B cells for up to 4 years with no evidence of any serious adverse effects. The purpose of this study was to determine whether ex vivo γ-retroviral gene therapy of XSCID dogs results in a similar outcome. Eight of 12 XSCID dogs treated with an average of dose of 5.8 × 10(6) transduced CD34(+) cells/kg successfully engrafted producing normal numbers of gene-corrected CD45RA(+) (naïve) T cells. However, this was followed by a steady decrease in CD45RA(+) T cells, T cell diversity, and thymic output as measured by T cell receptor excision circles (TRECs) resulting in a T cell lymphopenia. None of the dogs survived past 11 months post treatment. At necropsy, few gene-corrected thymocytes were observed correlating with the TREC levels and one of the dogs was diagnosed with a thymic T cell lymphoma that was attributed to the gene therapy. This study highlights the outcome differences between the ex vivo and in vivo approach to γ-retroviral gene therapy and is the first to document a serious adverse event following gene therapy in a canine model of a human genetic disease. Copyright © 2011 Elsevier B.V. All rights reserved.

Ex Vivo γ-Retroviral Gene Therapy of Dogs with X-linked Severe Combined Immunodeficiency and the Development of a Thymic T Cell Lymphoma

PubMed Central

Kennedy, Douglas R.; Hartnett, Brian J.; Kennedy, Jeffrey S.; Vernau, William; Moore, Peter F.; O’Malley, Thomas; Burkly, Linda C.; Henthorn, Paula S.; Felsburg, Peter J.

2011-01-01

We have previously shown that in vivo γ-retroviral gene therapy of dogs with X-linked severe combined immunodeficiency (XSCID) results in sustained T cell reconstitution and sustained marking in myeloid and B cells for up to 4 years with no evidence of any serious adverse effects. The purpose of this study was to determine whether ex vivo γ-retroviral gene therapy of XSCID dogs results in a similar outcome. Eight of 12 XSCID dogs treated with an average of dose of 5.8 × 106 transduced CD34+ cells/kg successfully engrafted producing normal numbers of gene-corrected CD45RA+ (naïve) T cells. However, this was followed by a steady decrease in CD45RA+ T cells, T cell diversity, and thymic output as measured by T cell receptor excision circles (TRECs) resulting in a T cell lymphopenia. None of the dogs survived past 11 months post treatment. At necropsy, few gene-corrected thymocytes were observed correlating with the TREC levels and one of the dogs was diagnosed with a thymic T cell lymphoma that was attributed to the gene therapy. This study highlights the outcome differences between the ex vivo and in vivo approach to γ-retroviral gene therapy and is the first to document a serious adverse event following gene therapy in a canine model of a human genetic disease. PMID:21536334

Stem cell mobilization with cyclophosphamide overcomes the suppressive effect of lenalidomide therapy on stem cell collection in multiple myeloma.

PubMed

Mark, Tomer; Stern, Jessica; Furst, Jessica R; Jayabalan, David; Zafar, Faiza; LaRow, April; Pearse, Roger N; Harpel, John; Shore, Tsiporah; Schuster, Michael W; Leonard, John P; Christos, Paul J; Coleman, Morton; Niesvizky, Ruben

2008-07-01

A total of 28 treatment-naïve patients with stage II or III multiple myeloma (MM) were treated with the combination of clarithromycin, lenalidomide, and dexamethasone (BiRD). Stem cells were collected following granulocyte-colony stimulating factor (G-CSF) or cyclophosphamide (Cy) plus G-CSF mobilization at maximum response. Sufficient stem cells for 2 autologous stem cell transplants were collected from all patients mobilized with Cy plus G-CSF, versus 33% mobilized with G-CSF alone (P < .0001). The duration of prior lenalidomide therapy did not correlate with success of stem cell harvests (P = .91). In conclusion, Cy can be added to G-CSF for stem cell mobilization to successfully overcome the suppressive effect of prior treatment with lenalidomide.

Stem Cell Mobilization with Cyclophosphamide Overcomes the Suppressive Effect of Lenalidomide Therapy on Stem Cell Collection in Multiple Myeloma

PubMed Central

Mark, Tomer; Stern, Jessica; Furst, Jessica R.; Jayabalan, David; Zafar, Faiza; LaRow, April; Pearse, Roger N.; Harpel, John; Shore, Tsiporah; Schuster, Michael W.; Leonard, John P.; Christos, Paul J.; Coleman, Morton; Niesvizky, Ruben

2013-01-01

A total of 28 treatment-naïve patients with stage II or III multiple myeloma (MM) were treated with the combination of clarithromycin, lenalidomide, and dexamethasone (BiRD). Stem cells were collected following granulocyte- colony stimulating factor (G-CSF) or cyclophosphamide (Cy) plus G-CSF mobilization at maximum response. Sufficient stem cells for 2 autologous stem cell transplants were collected from all patients mobilized with Cy plus G-CSF, versus 33% mobilized with G-CSF alone (P<.0001). The duration of prior lenalidomide therapy did not correlate with success of stem cell harvests (P = .91). In conclusion, Cy can be added to G-CSF for stem cell mobilization to successfully overcome the suppressive effect of prior treatment with lenalidomide. PMID:18541199

Boron neutron capture therapy induces cell cycle arrest and cell apoptosis of glioma stem/progenitor cells in vitro

PubMed Central

2013-01-01

Background Glioma stem cells in the quiescent state are resistant to clinical radiation therapy. An almost inevitable glioma recurrence is due to the persistence of these cells. The high linear energy transfer associated with boron neutron capture therapy (BNCT) could kill quiescent and proliferative cells. Methods The present study aimed to evaluate the effects of BNCT on glioma stem/progenitor cells in vitro. The damage induced by BNCT was assessed using cell cycle progression, apoptotic cell ratio and apoptosis-associated proteins expression. Results The surviving fraction and cell viability of glioma stem/progenitor cells were decreased compared with differentiated glioma cells using the same boronophenylalanine pretreatment and the same dose of neutron flux. BNCT induced cell cycle arrest in the G2/M phase and cell apoptosis via the mitochondrial pathway, with changes in the expression of associated proteins. Conclusions Glioma stem/progenitor cells, which are resistant to current clinical radiotherapy, could be effectively killed by BNCT in vitro via cell cycle arrest and apoptosis using a prolonged neutron irradiation, although radiosensitivity of glioma stem/progenitor cells was decreased compared with differentiated glioma cells when using the same dose of thermal neutron exposure and boronophenylalanine pretreatment. Thus, BNCT could offer an appreciable therapeutic advantage to prevent tumor recurrence, and may become a promising treatment in recurrent glioma. PMID:23915425

Combinatorial therapy with adenoviral-mediated PTEN and a PI3K inhibitor suppresses malignant glioma cell growth in vitro and in vivo by regulating the PI3K/AKT signaling pathway.

PubMed

Nan, Yang; Guo, Liyun; Song, Yunpeng; Wang, Le; Yu, Kai; Huang, Qiang; Zhong, Yue

2017-08-01

Glioblastoma is a highly invasive and challenging tumor of the central nervous system. The mutation/deletion of the tumor suppressor phosphatase and tensin homolog (PTEN) gene is the main genetic change identified in glioblastomas. PTEN plays a critical role in tumorigenesis and has been shown to be an important therapeutic target. The phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 is commonly used to inhibit glioma cell growth via regulation of the PI3K/AKT signaling pathway. In this study, we examined the growth inhibitory effects of a combinatorial therapy of adenoviral-mediated PTEN (Ad-PTEN) and LY294002 on LN229 and U251 glioma cells in vitro and on tumor xenografts in vivo. In vitro, LN229 and U251 glioma cells were treated by combinatorial therapy with Ad-PTEN and LY294002. The growth ability was determined by MTT assay. The cell cycle distribution was analyzed by flow cytometry. Cell invasive ability was analyzed by transwell invasion assay and cell apoptosis analysis via FITC-Annexin V analysis. In vivo, U251 subcutaneous glioblastoma xenograft was used to assay anti-tumor effect of combinatorial therapy with Ad-PTEN and LY294002 by mean volume of tumors, immunohistochemistry and TUNEL method. The combinatorial treatment clearly suppressed cell proliferation, arrested the cell cycle, reduced cell invasion and promoted cell apoptosis compared with the Ad-PTEN or LY294002 treatment alone. The treatment worked by inhibiting the PI3K/AKT pathway. In addition, the growth of U251 glioma xenografts treated with the combination of Ad-PTEN and LY294002 was significantly inhibited compared with those treated with Ad-PTEN or LY294002 alone. Our data indicated that the combination of Ad-PTEN and LY294002 effectively suppressed the malignant growth of human glioma cells in vitro and in tumor xenografts, suggesting a promising new approach for glioma gene therapy that warrants further investigation.

A theranostic nrGO@MSN-ION nanocarrier developed to enhance the combination effect of sonodynamic therapy and ultrasound hyperthermia for treating tumor

NASA Astrophysics Data System (ADS)

Chen, Yu-Wei; Liu, Tse-Ying; Chang, Po-Hsueh; Hsu, Po-Hung; Liu, Hao-Li; Lin, Hong-Cheu; Chen, San-Yuan

2016-06-01

Sonodynamic therapy (SDT), which induces activation of sonosensitizers in cancer cells through ultrasound irradiation, has emerged as an alternative and promising noninvasive therapeutic approach to kill both superficial and deep parts of tumors. In this study, mesoporous silica (MSN) grown on reduced graphene oxide nanosheet (nrGO) capped with Rose Bengal (RB)-PEG-conjugated iron-oxide nanoparticles (IONs), nrGO@MSN-ION-PEG-RB, was strategically designed to have targeted functionality and therapeutic efficacy under magnetic guiding and focused ultrasound (FUS) irradiation, respectively. The singlet oxygen produced by ultrasound-activated RB and the ultrasound-induced heating effect was enhanced by rGO and IONs, which improved the cytotoxic effect in cancer cells. In an animal experiment, we demonstrated that the combination of sonodynamic/hyperthermia therapy with magnetic guidance using this nanocomposite therapeutic agent can produce remarkable efficacious therapy in tumor growth inhibition. Furthermore, the combination effect induced by FUS irradiation produces significant damage to both superficial and deep parts of the targeted tumor.Sonodynamic therapy (SDT), which induces activation of sonosensitizers in cancer cells through ultrasound irradiation, has emerged as an alternative and promising noninvasive therapeutic approach to kill both superficial and deep parts of tumors. In this study, mesoporous silica (MSN) grown on reduced graphene oxide nanosheet (nrGO) capped with Rose Bengal (RB)-PEG-conjugated iron-oxide nanoparticles (IONs), nrGO@MSN-ION-PEG-RB, was strategically designed to have targeted functionality and therapeutic efficacy under magnetic guiding and focused ultrasound (FUS) irradiation, respectively. The singlet oxygen produced by ultrasound-activated RB and the ultrasound-induced heating effect was enhanced by rGO and IONs, which improved the cytotoxic effect in cancer cells. In an animal experiment, we demonstrated that the combination of sonodynamic/hyperthermia therapy with magnetic guidance using this nanocomposite therapeutic agent can produce remarkable efficacious therapy in tumor growth inhibition. Furthermore, the combination effect induced by FUS irradiation produces significant damage to both superficial and deep parts of the targeted tumor. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr07782f

Evaluating In Vitro DNA Damage Using Comet Assay.

PubMed

Lu, Yanxin; Liu, Yang; Yang, Chunzhang

2017-10-11

DNA damage is a common phenomenon for each cell during its lifespan, and is defined as an alteration of the chemical structure of genomic DNA. Cancer therapies, such as radio- and chemotherapy, introduce enormous amount of additional DNA damage, leading to cell cycle arrest and apoptosis to limit cancer progression. Quantitative assessment of DNA damage during experimental cancer therapy is a key step to justify the effectiveness of a genotoxic agent. In this study, we focus on a single cell electrophoresis assay, also known as the comet assay, which can quantify single and double-strand DNA breaks in vitro. The comet assay is a DNA damage quantification method that is efficient and easy to perform, and has low time/budget demands and high reproducibility. Here, we highlight the utility of the comet assay for a preclinical study by evaluating the genotoxic effect of olaparib/temozolomide combination therapy to U251 glioma cells.

An update clinical application of amniotic fluid-derived stem cells (AFSCs) in cancer cell therapy and tissue engineering.

PubMed

Gholizadeh-Ghaleh Aziz, Shiva; Fathi, Ezzatollah; Rahmati-Yamchi, Mohammad; Akbarzadeh, Abolfazl; Fardyazar, Zahra; Pashaiasl, Maryam

2017-06-01

Recent studies have elucidated that cell-based therapies are promising for cancer treatments. The human amniotic fluid stem (AFS) cells are advantageous cells for such therapeutic schemes that can be innately changed to express therapeutic proteins. HAFSCs display a natural tropism to cancer cells in vivo. They can be useful in cancer cells targeting. Moreover, they are easily available from surplus diagnostic samples during pregnancy and less ethical and legal concern are associated with the collection and application than other putative cells are subjected. This review will designate representatives of amniotic fluid and stem cell derived from amniotic fluid. For this propose, we collect state of human AFS cells data applicable in cancer therapy by dividing this approach into two main classes (nonengineered and engineered based approaches). Our study shows the advantage of AFS cells over other putative cells types in terms differentiation ability to a wide range of cells by potential and effective use in preclinical studies for a variety of diseases. This study has shown the elasticity of human AFS cells and their favorable potential as a multipotent cell source for regenerative stem cell therapy and capable of giving rise to multiple lineages including such as osteoblasts and adipocyte.

Application of orange essential oil as an antistaphylococcal agent in a dressing model.

PubMed

Muthaiyan, Arunachalam; Biswas, Debabrata; Crandall, Philip G; Wilkinson, Brian J; Ricke, Steven C

2012-08-16

Staphylococcus aureus is the pathogen most often and prevalently involved in skin and soft tissue infections. In recent decades outbreaks of methicillin-resistant S. aureus (MRSA) have created major problems for skin therapy, and burn and wound care units. Topical antimicrobials are most important component of wound infection therapy. Alternative therapies are being sought for treatment of MRSA and one area of interest is the use of essential oils. With the increasing interest in the use and application of natural products, we screened the potential application of terpeneless cold pressed Valencia orange oil (CPV) for topical therapy against MRSA using an in vitro dressing model and skin keratinocyte cell culture model. The inhibitory effect of CPV was determined by disc diffusion vapor assay for MRSA and vancomycin intermediate-resistant S. aureus (VISA) strains. Antistaphylococcal effect of CPV in an in vitro dressing model was tested on S. aureus inoculated tryptic soya agar plate. Bactericidal effect of CPV on MRSA and VISA infected keratinocyte cells was examined by enumeration of extra- and intra-cellular bacterial cells at different treatment time points. Cytotoxic effects on human skin cells was tested by adding CPV to the keratinocyte (HEK001) cells grown in serum free KSFM media, and observed by phase-contrast microscope. CPV vapour effectively inhibited the MRSA and VISA strains in both disc diffusion vapour assay and in vitro dressing model. Compared to untreated control addition of 0.1% CPV to MRSA infected keratinocyte decreased the viable MRSA cells by 2 log CFU/mL in 1 h and in VISA strain 3 log CFU/mL reduction was observed in 1 h. After 3 h viable S. aureus cells were not detected in the 0.2% CPV treatment. Bactericidal concentration of CPV did not show any cytotoxic effect on the human skin keratinocyte cells in vitro. At lower concentration addition of CPV to keratinocytes infected with MRSA and VISA rapidly killed the bacterial cells without causing any toxic effect to the keratinocytes. Therefore, the results of this study warrant further in vivo study to evaluate the potential of CPV as a topical antistaphylococcal agent.

Whole-brain low-intensity pulsed ultrasound therapy markedly improves cognitive dysfunctions in mouse models of dementia - Crucial roles of endothelial nitric oxide synthase.

PubMed

Eguchi, Kumiko; Shindo, Tomohiko; Ito, Kenta; Ogata, Tsuyoshi; Kurosawa, Ryo; Kagaya, Yuta; Monma, Yuto; Ichijo, Sadamitsu; Kasukabe, Sachie; Miyata, Satoshi; Yoshikawa, Takeo; Yanai, Kazuhiko; Taki, Hirofumi; Kanai, Hiroshi; Osumi, Noriko; Shimokawa, Hiroaki

2018-05-22

Therapeutic focused-ultrasound to the hippocampus has been reported to exert neuroprotective effects on dementia. In the present study, we examined whether the whole-brain LIPUS (low-intensity pulsed ultrasound) therapy is effective and safe in 2 mouse models of dementia (vascular dementia, VaD and Alzheimer's disease, AD), and if so, to elucidate the common underlying mechanism(s) involved. We used bilateral carotid artery stenosis (BCAS) model with micro-coils in male C57BL/6 mice as a VaD model and 5XFAD transgenic mice as an AD model. We applied the LIPUS therapy (1.875 MHz, 6.0 kHz, 32cycles) to the whole brain. In both models, the LIPUS therapy markedly ameliorated cognitive impairments (Y-maze test and/or passive avoidance test) associated with improved cerebral blood flow (CBF). Mechanistically, the LIPUS therapy significantly increased CD31-positive endothelial cells and Olig2-positive oligodendrocyte precursor cells (OPCs) in the VaD model, while it reduced Iba-1-positive microglias and amyloid-β (Aβ) plaque in the AD model. In both models, endothelium-related genes were significantly upregulated in RNA-sequencing, and expressions of endothelial nitric oxide synthase (eNOS) and neurotrophins were upregulated in Western blotting. Interestingly, the increases in glia cells and neurotrophin expressions showed significant correlations with eNOS expression. Importantly, these beneficial effects of LIPUS were absent in eNOS-knockout mice. These results indicate that the whole-brain LIPUS is an effective and non-invasive therapy for dementia by activating specific cells corresponding to each pathology, for which eNOS activation plays an important role as a common mechanism. Copyright © 2018. Published by Elsevier Inc.

Personalizing Stem Cell Research and Therapy: The Arduous Road Ahead or Missed Opportunity?

PubMed Central

Patel, S.A.; King, C.C.; Lim, P.K.; Habiba, U.; Dave, M.; Porecha, R.; Rameshwar, P.

2010-01-01

The euphoria of stem cell therapy has diminished, allowing scientists, clinicians and the general public to seriously re-examine how and what types of stem cells would effectively repair damaged tissue, prevent further tissue damage and/or replace lost cells. Importantly, there is a growing recognition that there are substantial person-to-person differences in the outcome of stem cell therapy. Even though the small molecule pharmaceuticals have long remained a primary focus of the personalized medicine research, individualized or targeted use of stem cells to suit a particular individual could help forecast potential failures of the therapy or identify, early on, the individuals who might benefit from stem cell interventions. This would however demand collaboration among several specialties such as pharmacology, immunology, genomics and transplantation medicine. Such transdisciplinary work could also inform how best to achieve efficient and predictable stem cell migration to sites of tissue damage, thereby facilitating tissue repair. This paper discusses the possibility of polarizing immune responses to rationalize and individualize therapy with stem cell interventions, since generalized “one-size-fits-all” therapy is difficult to achieve in the face of the diverse complexities posed by stem cell biology. We also present the challenges to stem cell delivery in the context of the host related factors. Although we focus on the mesenchymal stem cells in this paper, the overarching rationale can be extrapolated to other types of stem cells as well. Hence, the broader purpose of this paper is to initiate a dialogue within the personalized medicine community by expanding the scope of inquiry in the field from pharmaceuticals to stem cells and related cell-based health interventions. PMID:20563265

Role of Epidermal Growth Factor Receptors and Their Ligands in Normal Mammary Epithelial and Breast Cancer Cells

DTIC Science & Technology

1997-07-01

have an estrogen receptor and progesterone receptor negative phenotype, high proliferation rates, poor response to endocrine therapy, and reduced...mitogenic effects of estrogen, progesterone and prolactin in breast cancer cell lines (3), and part of the growth promoting effects of an activated ras...of the cases (51,52), and an inverse relationship with estrogen and progesterone receptors; in such tumors, a poor response to endocrine therapy

Stochastic modelling of the eradication of the HIV-1 infection by stimulation of latently infected cells in patients under highly active anti-retroviral therapy.

PubMed

Sánchez-Taltavull, Daniel; Vieiro, Arturo; Alarcón, Tomás

2016-10-01

HIV-1 infected patients are effectively treated with highly active anti-retroviral therapy (HAART). Whilst HAART is successful in keeping the disease at bay with average levels of viral load well below the detection threshold of standard clinical assays, it fails to completely eradicate the infection, which persists due to the emergence of a latent reservoir with a half-life time of years and is immune to HAART. This implies that life-long administration of HAART is, at the moment, necessary for HIV-1-infected patients, which is prone to drug resistance and cumulative side effects as well as imposing a considerable financial burden on developing countries, those more afflicted by HIV, and public health systems. The development of therapies which specifically aim at the removal of this latent reservoir has become a focus of much research. A proposal for such therapy consists of elevating the rate of activation of the latently infected cells: by transferring cells from the latently infected reservoir to the active infected compartment, more cells are exposed to the anti-retroviral drugs thus increasing their effectiveness. In this paper, we present a stochastic model of the dynamics of the HIV-1 infection and study the effect of the rate of latently infected cell activation on the average extinction time of the infection. By analysing the model by means of an asymptotic approximation using the semi-classical quasi steady state approximation (QSS), we ascertain that this therapy reduces the average life-time of the infection by many orders of magnitudes. We test the accuracy of our asymptotic results by means of direct simulation of the stochastic process using a hybrid multi-scale Monte Carlo scheme.

Arctigenin preferentially induces tumor cell death under glucose deprivation by inhibiting cellular energy metabolism.

PubMed

Gu, Yuan; Qi, Chunting; Sun, Xiaoxiao; Ma, Xiuquan; Zhang, Haohao; Hu, Lihong; Yuan, Junying; Yu, Qiang

2012-08-15

Selectively eradicating cancer cells with minimum adverse effects on normal cells is a major challenge in the development of anticancer therapy. We hypothesize that nutrient-limiting conditions frequently encountered by cancer cells in poorly vascularized solid tumors might provide an opportunity for developing selective therapy. In this study, we investigated the function and molecular mechanisms of a natural compound, arctigenin, in regulating tumor cell growth. We demonstrated that arctigenin selectively promoted glucose-starved A549 tumor cells to undergo necrosis by inhibiting mitochondrial respiration. In doing so, arctigenin elevated cellular level of reactive oxygen species (ROS) and blocked cellular energy metabolism in the glucose-starved tumor cells. We also demonstrated that cellular ROS generation was caused by intracellular ATP depletion and played an essential role in the arctigenin-induced tumor cell death under the glucose-limiting condition. Furthermore, we combined arctigenin with the glucose analogue 2-deoxyglucose (2DG) and examined their effects on tumor cell growth. Interestingly, this combination displayed preferential cell-death inducing activity against tumor cells compared to normal cells. Hence, we propose that the combination of arctigenin and 2DG may represent a promising new cancer therapy with minimal normal tissue toxicity. Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.

Radiofrequency currents exert cytotoxic effects in NB69 human neuroblastoma cells but not in peripheral blood mononuclear cells

PubMed Central

HERNÁNDEZ-BULE, MARÍA LUISA; ROLDÁN, ERNESTO; MATILLA, JOAQUÍN; TRILLO, MARÍA ÁNGELES; ÚBEDA, ALEJANDRO

2012-01-01

Recently, a number of electric and electrothermal therapies have been applied to the treatment of specific cancer types. However, the cellular and molecular mechanisms involved in the response to such therapies have not been well characterized yet. Capacitive-resistive electric transfer (CRET) therapy uses electric currents at frequencies within the 0.45–0.6 MHz range to induce hyperthermia in target tissues. Preliminary trials in cancer patients have shown consistent signs that CRET could slow down growth of tumor tissues in brain gliomas, without inducing detectable damage in the surrounding healthy tissue. Previous studies by our group have shown that subthermal treatment with 0.57-MHz electric currents can induce a cytostatic, not cytotoxic response in HepG2 human hepatocarcinoma cells; such effect being mediated by cell cycle alterations. In contrast, the study of the response of NB69 human neuroblastoma cells to the same electric treatment revealed consistent indications of cytotoxic effects. The present study extends the knowledge on the response of NB69 cells to the subthermal stimulus, comparing it to that of primary cultures of human peripheral blood mononuclear cells (PBMC) exposed to the same treatment. The results showed no sensitivity of PBMC to the 0.57 MHz subthermal currents and confirmed that the treatment exerts a cytotoxic action in NB69 cells. The data also revealed a previously undetected cytostatic response of the neuroblastoma cell line. CRET currents affected NB69 cell proliferation by significantly reducing the fraction of cells in the phase G2/M of the cell cycle at 12 h of exposure. These data provide new information on the mechanisms of response to CRET therapy, and are consistent with a cytotoxic and/or cytostatic action of the electric treatment, which would affect human cells of tumor origin but not normal cells with a low proliferation rate. PMID:22843038

Radiofrequency currents exert cytotoxic effects in NB69 human neuroblastoma cells but not in peripheral blood mononuclear cells.

PubMed

Hernández-Bule, María Luisa; Roldán, Ernesto; Matilla, Joaquín; Trillo, María Angeles; Ubeda, Alejandro

2012-10-01

Recently, a number of electric and electrothermal therapies have been applied to the treatment of specific cancer types. However, the cellular and molecular mechanisms involved in the response to such therapies have not been well characterized yet. Capacitive-resistive electric transfer (CRET) therapy uses electric currents at frequencies within the 0.45-0.6 MHz range to induce hyperthermia in target tissues. Preliminary trials in cancer patients have shown consistent signs that CRET could slow down growth of tumor tissues in brain gliomas, without inducing detectable damage in the surrounding healthy tissue. Previous studies by our group have shown that subthermal treatment with 0.57-MHz electric currents can induce a cytostatic, not cytotoxic response in HepG2 human hepatocarcinoma cells; such effect being mediated by cell cycle alterations. In contrast, the study of the response of NB69 human neuroblastoma cells to the same electric treatment revealed consistent indications of cytotoxic effects. The present study extends the knowledge on the response of NB69 cells to the subthermal stimulus, comparing it to that of primary cultures of human peripheral blood mononuclear cells (PBMC) exposed to the same treatment. The results showed no sensitivity of PBMC to the 0.57 MHz subthermal currents and confirmed that the treatment exerts a cytotoxic action in NB69 cells. The data also revealed a previously undetected cytostatic response of the neuroblastoma cell line. CRET currents affected NB69 cell proliferation by significantly reducing the fraction of cells in the phase G2/M of the cell cycle at 12 h of exposure. These data provide new information on the mechanisms of response to CRET therapy, and are consistent with a cytotoxic and/or cytostatic action of the electric treatment, which would affect human cells of tumor origin but not normal cells with a low proliferation rate.

Targeting chemotherapy-resistant leukemia by combining DNT cellular therapy with conventional chemotherapy.

PubMed

Chen, Branson; Lee, Jong Bok; Kang, Hyeonjeong; Minden, Mark D; Zhang, Li

2018-04-24

While conventional chemotherapy is effective at eliminating the bulk of leukemic cells, chemotherapy resistance in acute myeloid leukemia (AML) is a prevalent problem that hinders conventional therapies and contributes to disease relapse, and ultimately patient death. We have recently shown that allogeneic double negative T cells (DNTs) are able to target the majority of primary AML blasts in vitro and in patient-derived xenograft models. However, some primary AML blast samples are resistant to DNT cell therapy. Given the differences in the modes of action of DNTs and chemotherapy, we hypothesize that DNT therapy can be used in combination with conventional chemotherapy to further improve their anti-leukemic effects and to target chemotherapy-resistant disease. Drug titration assays and flow-based cytotoxicity assays using ex vivo expanded allogeneic DNTs were performed on multiple AML cell lines to identify therapy-resistance. Primary AML samples were also tested to validate our in vitro findings. Further, a xenograft model was employed to demonstrate the feasibility of combining conventional chemotherapy and adoptive DNT therapy to target therapy-resistant AML. Lastly, blocking assays with neutralizing antibodies were employed to determine the mechanism by which chemotherapy increases the susceptibility of AML to DNT-mediated cytotoxicity. Here, we demonstrate that KG1a, a stem-like AML cell line that is resistant to DNTs and chemotherapy, and chemotherapy-resistant primary AML samples both became more susceptible to DNT-mediated cytotoxicity in vitro following pre-treatment with daunorubicin. Moreover, chemotherapy treatment followed by adoptive DNT cell therapy significantly decreased bone marrow engraftment of KG1a in a xenograft model. Mechanistically, daunorubicin increased the expression of NKG2D and DNAM-1 ligands on KG1a; blocking of these pathways attenuated DNT-mediated cytotoxicity. Our results demonstrate the feasibility and benefit of using DNTs as an immunotherapy after the administration of conventional chemotherapy.

Concise Review: Apoptotic Cell-Based Therapies-Rationale, Preclinical Results and Future Clinical Developments.

PubMed

Saas, Philippe; Daguindau, Etienne; Perruche, Sylvain

2016-06-01

The objectives of this review are to summarize the experimental data obtained using apoptotic cell-based therapies, and then to discuss future clinical developments. Indeed, apoptotic cells exhibit immunomodulatory properties that are reviewed here by focusing on more recent mechanisms. These immunomodulatory mechanisms are in particular linked to the clearance of apoptotic cells (called also efferocytosis) by phagocytes, such as macrophages, and the induction of regulatory T cells. Thus, apoptotic cell-based therapies have been used to prevent or treat experimental inflammatory diseases. Based on these studies, we have identified critical steps to design future clinical trials. This includes: the administration route, the number and schedule of administration, the appropriate apoptotic cell type to be used, as well as the apoptotic signal. We also have analyzed the clinical relevancy of apoptotic-cell-based therapies in experimental models. Additional experimental data are required concerning the treatment of inflammatory diseases (excepted for sepsis) before considering future clinical trials. In contrast, apoptotic cells have been shown to favor engraftment and to reduce acute graft-versus-host disease (GvHD) in different relevant models of transplantation. This has led to the conduct of a phase 1/2a clinical trial to alleviate GvHD. The absence of toxic effects obtained in this trial may support the development of other clinical studies based on this new cell therapy. Stem Cells 2016;34:1464-1473. © 2016 AlphaMed Press.

The cryo-thermal therapy eradicated melanoma in mice by eliciting CD4+ T-cell-mediated antitumor memory immune response.

PubMed

He, Kun; Liu, Ping; Xu, Lisa X

2017-03-23

Tumor metastasis is a major concern in tumor therapy. In our previous studies, a novel tumor therapeutic modality of the cryo-thermal therapy has been presented, highlighting its effect on the suppression of distal metastasis and leading to long-term survival in 4T1 murine mammary carcinoma model. To demonstrate the therapeutic efficacy in other aggressive tumor models and further investigate the mechanism of long-term survival induced, in this study, spontaneous metastatic murine B16F10 melanoma model was used. The cryo-thermal therapy induced regression of implanted melanoma and prolonged long-term survival while inhibiting lung metastasis. It also promoted the activation of CD4 + CD25 - conventional T cells, while reduced the percentage of CD4 + CD25 + regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in the spleen, lung and blood. Furthermore, the cryo-thermal therapy enhanced the cytolytic function of CD8 + T cells and induced differentiation of CD8 + T cells into memory stem T cell (T SCM ), and differentiation of CD4 + T cells into dominant CD4-CTL, Th1 and Tfh subsets in the spleen for 90 days after the treatment. It was found that good therapeutic effect was mainly dependent on CD4 + T cells providing a durable memory antitumor immune response. At the same time, significant increase of serum IFN-γ was also observed to provide an ideal microenvironment of antitumor immunity. Further study showed that the rejection of re-challenge of B16F10 but not GL261 tumor in the treated mice in 45 or 60 days after the treatment, implied a strong systemic and melanoma-specific memory antitumor immunity induced by the treatment. Thus the cryo-thermal therapy would be considered as a new therapeutic strategy to prevent tumor recurrence and metastasis with potential clinical applications in the near future.

CFHR1-Modified Neural Stem Cells Ameliorated Brain Injury in a Mouse Model of Neuromyelitis Optica Spectrum Disorders.

PubMed

Shi, Kaibin; Wang, Zhen; Liu, Yuanchu; Gong, Ye; Fu, Ying; Li, Shaowu; Wood, Kristofer; Hao, Junwei; Zhang, Guang-Xian; Shi, Fu-Dong; Yan, Yaping

2016-11-01

A major hurdle for effective stem cell therapy is ongoing inflammation in the target organ. Reconditioning the lesion microenvironment may be an effective way to promote stem cell therapy. In this study, we showed that engineered neural stem cells (NSCs) with complement factor H-related protein 1, a complement inhibitor protein, can attenuate inflammatory infiltration and immune-mediated damage of astrocytes, an important pathogenic progress in patients with neuromyelitis optica spectrum disorders. Furthermore, we demonstrated that transplantation of the complement factor H-related protein 1-modified NSCs effectively blocked the complement activation cascade and inhibited formation of the membrane attack complex, thus contributing to the protection of endogenous and transplanted NSC-differentiated astrocytes. Therefore, manipulation of the lesion microenvironment contributes to a more effective cell replacement therapeutic strategy for autoimmune diseases of the CNS. Copyright © 2016 by The American Association of Immunologists, Inc.

Eradication of melanomas by targeted elimination of a minor subset of tumor cells

PubMed Central

Schmidt, Patrick; Kopecky, Caroline; Hombach, Andreas; Zigrino, Paola; Mauch, Cornelia; Abken, Hinrich

2011-01-01

Proceeding on the assumption that all cancer cells have equal malignant capacities, current regimens in cancer therapy attempt to eradicate all malignant cells of a tumor lesion. Using in vivo targeting of tumor cell subsets, we demonstrate that selective elimination of a definite, minor tumor cell subpopulation is particularly effective in eradicating established melanoma lesions irrespective of the bulk of cancer cells. Tumor cell subsets were specifically eliminated in a tumor lesion by adoptive transfer of engineered cytotoxic T cells redirected in an antigen-restricted manner via a chimeric antigen receptor. Targeted elimination of less than 2% of the tumor cells that coexpress high molecular weight melanoma-associated antigen (HMW-MAA) (melanoma-associated chondroitin sulfate proteoglycan, MCSP) and CD20 lastingly eradicated melanoma lesions, whereas targeting of any random 10% tumor cell subset was not effective. Our data challenge the biological therapy and current drug development paradigms in the treatment of cancer. PMID:21282657

Tumor angiogenesis assessment using multi-fluorescent scans on murine slices by Markov random field framework

NASA Astrophysics Data System (ADS)

Laifa, Oumeima; Le Guillou-Buffello, Delphine; Racoceanu, Daniel

2017-11-01

The fundamental role of vascular supply in tumor growth makes the evaluation of the angiogenesis crucial in assessing effect of anti-angiogenic therapies. Since many years, such therapies are designed to inhibit the vascular endothelial growth factor (VEGF). To contribute to the assessment of anti-angiogenic agent (Pazopanib) effect on vascular and cellular structures, we acquired data from tumors extracted from a murine tumor model using Multi- Fluorescence Scanning. In this paper, we implemented an unsupervised algorithm combining the Watershed segmentation and Markov Random Field model (MRF). This algorithm allowed us to quantify the proportion of apoptotic endothelial cells and to generate maps according to cell density. Stronger association between apoptosis and endothelial cells was revealed in the tumors receiving anti-angiogenic therapy (n = 4) as compared to those receiving placebo (n = 4). A high percentage of apoptotic cells in the tumor area are endothelial. Lower density cells were detected in tumor slices presenting higher apoptotic endothelial areas.

Depletion kinetics of circulating prostate cancer cells studied by in vivo flow cytometer

NASA Astrophysics Data System (ADS)

Liu, Guangda; Guo, Jin; Li, Yan; Chen, Yun; Gu, Zhengqin; Chen, Tong; Wang, Cheng; Wei, Xunbin

2010-11-01

Prostate cancer is the most common malignancy in American men and the second leading cause of deaths from cancer, after lung cancer. The tumor usually grows slowly and remains confined to the gland for many years. During this time, the tumor produces little or no symptoms or outward signs. As the cancer advances, however, it can metastasize throughout other areas of the body, such as the bones, lungs, and liver. Surgical resection, hormonal therapy, chemotherapy and radiation therapy are the foundation of current prostate cancer therapies. Treatments for prostate cause both short- and long-term side effects that may be difficult to accept. Molecular mechanisms of prostate cancer metastasis need to be understood better and new therapies must be developed to selectively target to unique characteristics of cancer cell growth and metastasis. We have developed the "in vivo microscopy" to study the mechanisms that govern prostate cancer cell spread through the microenvironment in vivo in real-time confocal nearinfrared fluorescence imaging. A recently developed "in vivo flow cytometer" and optical imaging are used to assess prostate cancer cell spreading and the circulation kinetics of prostate cancer cells. A real- time quantitative monitoring of circulating prostate cancer cells by the in vivo flow cytometer will be useful to assess the effectiveness of the potential therapeutic interventions.

Studying depletion kinetics of circulating prostate cancer cells by in vivo flow cytometer

NASA Astrophysics Data System (ADS)

Liu, Guangda; Gu, Zhengqin; Guo, Jin; Li, Yan; Chen, Yun; Chen, Tong; Wang, Cheng; Wei, Xunbin

2011-03-01

Prostate cancer is the most common malignancy in American men and the second leading cause of deaths from cancer, after lung cancer. The tumor usually grows slowly and remains confined to the gland for many years. During this time, the tumor produces little or no symptoms or outward signs. As the cancer advances, however, it can metastasize throughout other areas of the body, such as the bones, lungs, and liver. Surgical resection, hormonal therapy, chemotherapy and radiation therapy are the foundation of current prostate cancer therapies. Treatments for prostate cause both short- and long-term side effects that may be difficult to accept. Molecular mechanisms of prostate cancer metastasis need to be understood better and new therapies must be developed to selectively target to unique characteristics of cancer cell growth and metastasis. We have developed the "in vivo microscopy" to study the mechanisms that govern prostate cancer cell spread through the microenvironment in vivo in real-time confocal near-infrared fluorescence imaging. A recently developed "in vivo flow cytometer" and optical imaging are used to assess prostate cancer cell spreading and the circulation kinetics of prostate cancer cells. A real- time quantitative monitoring of circulating prostate cancer cells by the in vivo flow cytometer will be useful to assess the effectiveness of the potential therapeutic interventions.

Combined regimen of photodynamic therapy mediated by Gallium phthalocyanine chloride and Metformin enhances anti-melanoma efficacy

PubMed Central

Filip, Gabriela Adriana; Olteanu, Diana; Cenariu, Mihai; Tabaran, Flaviu; Ion, Rodica Mariana; Gligor, Lucian; Baldea, Ioana

2017-01-01

Background Melanoma therapy is challenging, especially in advanced cases, due to multiple developed tumor defense mechanisms. Photodynamic therapy (PDT) might represent an adjuvant treatment, because of its bimodal action: tumor destruction and immune system awakening. In this study, a combination of PDT mediated by a metal substituted phthalocyanine—Gallium phthalocyanine chloride (GaPc) and Metformin was used against melanoma. The study aimed to: (1) find the anti-melanoma efficacy of GaPc-PDT, (2) assess possible beneficial effects of Metformin addition to PDT, (3) uncover some of the mechanisms underlining cell killing and anti-angiogenic effects. Methods Two human lightly pigmented melanoma cell lines: WM35 and M1/15 subjected to previous Metformin exposure were treated by GaPc-PDT. Cell viability, death mechanism, cytoskeleton alterations, oxidative damage, were assessed by means of colorimetry, flowcytometry, confocal microscopy, spectrophotometry, ELISA, Western Blotting. Results GaPc proved an efficient photosensitizer. Metformin addition enhanced cell killing by mechanisms dependent on the cell line, namely apoptosis in the metastatic M1/15 and necrosis in the radial growth phase, WM35. Cell death mechanism relied on the inhibition of nuclear transcription factor (NF)-κB activation and tumor necrosis factor (TNF)—related apoptosis-inducing ligand (TRAIL) sensitization, leading to TRAIL and TNF-α induced apoptosis. Metformin diminished the anti-angiogenic effect of PDT. Conclusions Metformin addition to GaPc-PDT increased tumor cell killing through enhanced oxidative damage and induction of proapoptotic mechanisms, but altered PDT anti-angiogenic effects. General significance Combination of Metformin and PDT might represent a solution to enhance the efficacy, leading to a potential adjuvant role of PDT in melanoma therapy. PMID:28278159

Combined regimen of photodynamic therapy mediated by Gallium phthalocyanine chloride and Metformin enhances anti-melanoma efficacy.

PubMed

Tudor, Diana; Nenu, Iuliana; Filip, Gabriela Adriana; Olteanu, Diana; Cenariu, Mihai; Tabaran, Flaviu; Ion, Rodica Mariana; Gligor, Lucian; Baldea, Ioana

2017-01-01

Melanoma therapy is challenging, especially in advanced cases, due to multiple developed tumor defense mechanisms. Photodynamic therapy (PDT) might represent an adjuvant treatment, because of its bimodal action: tumor destruction and immune system awakening. In this study, a combination of PDT mediated by a metal substituted phthalocyanine-Gallium phthalocyanine chloride (GaPc) and Metformin was used against melanoma. The study aimed to: (1) find the anti-melanoma efficacy of GaPc-PDT, (2) assess possible beneficial effects of Metformin addition to PDT, (3) uncover some of the mechanisms underlining cell killing and anti-angiogenic effects. Two human lightly pigmented melanoma cell lines: WM35 and M1/15 subjected to previous Metformin exposure were treated by GaPc-PDT. Cell viability, death mechanism, cytoskeleton alterations, oxidative damage, were assessed by means of colorimetry, flowcytometry, confocal microscopy, spectrophotometry, ELISA, Western Blotting. GaPc proved an efficient photosensitizer. Metformin addition enhanced cell killing by mechanisms dependent on the cell line, namely apoptosis in the metastatic M1/15 and necrosis in the radial growth phase, WM35. Cell death mechanism relied on the inhibition of nuclear transcription factor (NF)-κB activation and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) sensitization, leading to TRAIL and TNF-α induced apoptosis. Metformin diminished the anti-angiogenic effect of PDT. Metformin addition to GaPc-PDT increased tumor cell killing through enhanced oxidative damage and induction of proapoptotic mechanisms, but altered PDT anti-angiogenic effects. Combination of Metformin and PDT might represent a solution to enhance the efficacy, leading to a potential adjuvant role of PDT in melanoma therapy.

Promising Diabetes Therapy Based on the Molecular Mechanism for Glucose Toxicity: Usefulness of SGLT2 Inhibitors as well as Incretin-Related Drugs.

PubMed

Kaneto, Hideaki; Obata, Atsushi; Shimoda, Masashi; Kimura, Tomohiko; Hirukawa, Hidenori; Okauchi, Seizo; Matsuoka, Taka-Aki; Kaku, Kohei

2016-01-01

Pancreatic β-cell dysfunction and insulin resistance are the main characteristics of type 2 diabetes. Chronic exposure of β-cells to hyperglycemia leads to the deterioration of β-cell function. Such phenomena are well known as pancreatic β-cell glucose toxicity. MafA, a strong transactivator of insulin gene, is particularly important for the maintenance of mature β-cell function, but its expression level is significantly reduced under diabetic conditions which is likely associated with β-cell failure. Reduction of incretin receptor expression level in β-cells in diabetes is also likely associated with β-cell failure. On the other hand, incretin-related drugs and sodium-glucose co-transporter 2 (SGLT2) inhibitors are promising diabetes therapy based on the mechanism for pancreatic β-cell glucose toxicity. Indeed, it was shown that incretin-related drugs exerted protective effects on β-cells through the augmentation of IRS-2 expression especially in the presence of pioglitazone. It was also shown that incretin-related drug and/or pioglitazone exerted more protective effects on β-cells at the early stage of diabetes compared to the advanced stage. SGLT2 inhibitors, new hypoglycemic agents, also exert beneficial effects for the protection of pancreatic β-cells as well as for the reduction of insulin resistance in various insulin target tissues. Taken together, it is important to select appropriate therapy based on the molecular mechanism for glucose toxicity.

Extracellular vesicles and cardiovascular disease therapy

PubMed Central

Amosse, Jérémy; Martinez, Maria Carmen

2017-01-01

Cardiovascular disease (CVD) constitutes one of the leading causes of mortality worldwide, therefore representing a major public health concern. Despite recent advances in the treatment of patients with acute myocardial infarction (AMI), such as bypass surgery or percutaneous coronary intervention, pathological cardiac remodeling often predisposes survivors to fatal heart failure. In this context, the proven efficacy of stem cell-regenerative therapies constitutes a promising therapeutic perspective with is nevertheless slow down by safety and ethical concerns. Recent studies have underscored the capacity of stem cell-derived extracellular vesicles (EV) to recapitulate the regenerative properties of their parental cells therefore offering a therapeutic alternative to cell therapy in cardiovascular regenerative medicine. In this article, we review the functional relevance of using stem cell-derived EV as therapeutically agents and detail the identified molecular pathways that they used to exert their effects. We also discuss the advantages of using such an acellular regenerative therapy, in regard with parental stem cells, and address the limitations, which would need to be resolved, before their clinical translation. PMID:29359141

Activation of Phosphatidylcholine-Specific Phospholipase C in Breast and Ovarian Cancer: Impact on MRS-Detected Choline Metabolic Profile and Perspectives for Targeted Therapy

PubMed Central

Podo, Franca; Paris, Luisa; Cecchetti, Serena; Spadaro, Francesca; Abalsamo, Laura; Ramoni, Carlo; Ricci, Alessandro; Pisanu, Maria Elena; Sardanelli, Francesco; Canese, Rossella; Iorio, Egidio

2016-01-01

Elucidation of molecular mechanisms underlying the aberrant phosphatidylcholine cycle in cancer cells plays in favor of the use of metabolic imaging in oncology and opens the way for designing new targeted therapies. The anomalous choline metabolic profile detected in cancer by magnetic resonance spectroscopy and spectroscopic imaging provides molecular signatures of tumor progression and response to therapy. The increased level of intracellular phosphocholine (PCho) typically detected in cancer cells is mainly attributed to upregulation of choline kinase, responsible for choline phosphorylation in the biosynthetic Kennedy pathway, but can also be partly produced by activation of phosphatidylcholine-specific phospholipase C (PC-PLC). This hydrolytic enzyme, known for implications in bacterial infection and in plant survival to hostile environmental conditions, is reported to be activated in mitogen- and oncogene-induced phosphatidylcholine cycles in mammalian cells, with effects on cell signaling, cell cycle regulation, and cell proliferation. Recent investigations showed that PC-PLC activation could account for 20–50% of the intracellular PCho production in ovarian and breast cancer cells of different subtypes. Enzyme activation was associated with PC-PLC protein overexpression and subcellular redistribution in these cancer cells compared with non-tumoral counterparts. Moreover, PC-PLC coimmunoprecipitated with the human epidermal growth factor receptor-2 (HER2) and EGFR in HER2-overexpressing breast and ovarian cancer cells, while pharmacological PC-PLC inhibition resulted into long-lasting HER2 downregulation, retarded receptor re-expression on plasma membrane and antiproliferative effects. This body of evidence points to PC-PLC as a potential target for newly designed therapies, whose effects can be preclinically and clinically monitored by metabolic imaging methods. PMID:27532027

Reduction of MDSCs with all-trans retinoic acid improves CAR therapy efficacy for sarcomas

PubMed Central

Long, Adrienne H.; Highfill, Steven L.; Cui, Yongzhi; Smith, Jillian P.; Walker, Alec J.; Ramakrishna, Sneha; El-Etriby, Rana; Galli, Susana; Tsokos, Maria G.; Orentas, Rimas J.; Mackall, Crystal L.

2016-01-01

Genetically engineered T cells expressing CD19-specific chimeric antigen receptors (CARs) have shown impressive activity against B cell malignancies, and preliminary results suggest that T cells expressing a first generation disialoganglioside (GD2)-specific CAR can also provide clinical benefit in patients with neuroblastoma. We sought to assess the potential of GD2-CAR therapies to treat pediatric sarcomas. We observed that 18/18 (100%) of osteosarcomas, 2/15 (13%) of rhabdomyosarcomas, and 7/35 (20%) of Ewing sarcomas expressed GD2. T cells engineered to express a third generation GD2-CAR incorporating the 14g2a-scFv with the CD28, OX40, and CD3ζ signaling domains (14g2a.CD28.OX40.ζ) mediated efficient and comparable lysis of both GD2+ sarcoma and neuroblastoma cell lines in vitro. However in xenograft models, GD2-CAR T cells had no antitumor effect against GD2+ sarcoma, despite effectively controlling GD2+ neuroblastoma. We observed that pediatric sarcoma xenografts, but not neuroblastoma xenografts, induced large populations of monocytic and granulocytic murine myeloid-derived suppressor cells (MDSCs) that inhibited human CAR T-cell responses in vitro. Treatment of sarcoma-bearing mice with all-trans retinoic acid (ATRA) largely eradicated monocytic MDSCs and diminished the suppressive capacity of granulocytic MDSCs. Combined therapy using GD2-CAR T cells plus ATRA significantly improved antitumor efficacy against sarcoma xenografts. We conclude that retinoids provide a clinically accessible class of agents capable of diminishing the suppressive effects of MDSCs, and that co-administration of retinoids may enhance the efficacy of CAR therapies targeting solid tumors. PMID:27549124

Adipose-derived Stem Cells Stimulated with n-Butylidenephthalide Exhibit Therapeutic Effects in a Mouse Model of Parkinson's Disease.

PubMed

Chi, Kang; Fu, Ru-Huei; Huang, Yu-Chuen; Chen, Shih-Yin; Hsu, Ching-Ju; Lin, Shinn-Zong; Tu, Chi-Tang; Chang, Li-Hsun; Wu, Ping-An; Liu, Shih-Ping

2018-03-01

Parkinson's disease (PD) causes motor dysfunction and dopaminergic cell death. Drug treatments can effectively reduce symptoms but often cause unwanted side effects. Stem cell therapies using cell replacement or indirect beneficial secretomes have recently emerged as potential therapeutic strategies. Although various types of stem cells have been proposed as possible candidates, adipose-derived stem cells (ADSCs) are easily obtainable, more abundant, less ethically disputed, and able to differentiate into multiple cell lineages. However, treatment of PD using adult stem cells is known to be less efficacious than neuron or embryonic stem cell transplantation. Therefore, improved therapies are urgently needed. n-Butylidenephthalide (BP), which is extracted from Angelica sinensis, has been shown to have anti-inflammatory and neuroprotective effects. Indeed, we previously demonstrated that BP treatment of ADSCs enhances the expression of neurogenesis and homing factors such as nuclear receptor related 1 protein, stromal-derived factor 1, and brain-derived neurotrophic factor. In the present study, we examined the ability of BP-pretreated ADSC transplantation to improve PD motor symptoms and protect dopamine neurons in a mouse model of PD. We evaluated the results using neuronal behavior tests such as beam walking, rotarod, and locomotor activity tests. ADSCs with or without BP pretreatment were transplanted into the striatum. Our findings demonstrated that ADSC transplantation improved motor abilities with varied efficacies and that BP stimulation improved the therapeutic effects of transplantation. Dopaminergic cell numbers returned to normal in ADSC-transplanted mice after 22 d. In summary, stimulating ADSCs with BP improved PD recovery efficiency. Thus, our results provide important new strategies to improve stem cell therapies for neurodegenerative diseases in future studies.

Adoptive Cell Therapy for Metastatic Melanoma.

PubMed

Merhavi-Shoham, Efrat; Itzhaki, Orit; Markel, Gal; Schachter, Jacob; Besser, Michal J

Adoptive cell therapy (ACT) of tumor-infiltrating lymphocytes (TILs) is a powerful form of immunotherapy by inducing durable complete responses that significantly extend the survival of melanoma patients. Mutation-derived neoantigens were recently identified as key factors for tumor recognition and rejection by TILs. The isolation of T-cell receptor (TCR) genes directed against neoantigens and their retransduction into peripheral T cells may provide a new form of ACT.Genetic modifications of T cells with chimeric antigen receptors (CARs) have demonstrated remarkable clinical results in hematologic malignancies, but are so far less effective in solid tumors. Only very limited reports exist in melanoma. Progress in CAR T-cell engineering, including neutralization of inhibitory signals or additional safety switches, may open opportunities also in melanoma.We review clinical results and latest developments of adoptive therapies with TILs, T-cell receptor, and CAR-modified T cells and discuss future directions for the treatment of melanoma.

A Multimodal System with Synergistic Effects of Magneto-Mechanical, Photothermal, Photodynamic and Chemo Therapies of Cancer in Graphene-Quantum Dot-Coated Hollow Magnetic Nanospheres

PubMed Central

Wo, Fangjie; Xu, Rujiao; Shao, Yuxiang; Zhang, Zheyu; Chu, Maoquan; Shi, Donglu; Liu, Shupeng

2016-01-01

In this study, a multimodal therapeutic system was shown to be much more lethal in cancer cell killing compared to a single means of nano therapy, be it photothermal or photodynamic. Hollow magnetic nanospheres (HMNSs) were designed and synthesized for the synergistic effects of both magneto-mechanical and photothermal cancer therapy. By these combined stimuli, the cancer cells were structurally and physically destroyed with the morphological characteristics distinctively different from those by other therapeutics. HMNSs were also coated with the silica shells and conjugated with carboxylated graphene quantum dots (GQDs) as a core-shell composite: HMNS/SiO2/GQDs. The composite was further loaded with an anticancer drug doxorubicin (DOX) and stabilized with liposomes. The multimodal system was able to kill cancer cells with four different therapeutic mechanisms in a synergetic and multilateral fashion, namely, the magnetic field-mediated mechanical stimulation, photothermal damage, photodynamic toxicity, and chemotherapy. The unique nanocomposites with combined mechanical, chemo, and physical effects will provide an alternative strategy for highly improved cancer therapy efficiency. PMID:26941842

A Multimodal System with Synergistic Effects of Magneto-Mechanical, Photothermal, Photodynamic and Chemo Therapies of Cancer in Graphene-Quantum Dot-Coated Hollow Magnetic Nanospheres.

PubMed

Wo, Fangjie; Xu, Rujiao; Shao, Yuxiang; Zhang, Zheyu; Chu, Maoquan; Shi, Donglu; Liu, Shupeng

2016-01-01

In this study, a multimodal therapeutic system was shown to be much more lethal in cancer cell killing compared to a single means of nano therapy, be it photothermal or photodynamic. Hollow magnetic nanospheres (HMNSs) were designed and synthesized for the synergistic effects of both magneto-mechanical and photothermal cancer therapy. By these combined stimuli, the cancer cells were structurally and physically destroyed with the morphological characteristics distinctively different from those by other therapeutics. HMNSs were also coated with the silica shells and conjugated with carboxylated graphene quantum dots (GQDs) as a core-shell composite: HMNS/SiO2/GQDs. The composite was further loaded with an anticancer drug doxorubicin (DOX) and stabilized with liposomes. The multimodal system was able to kill cancer cells with four different therapeutic mechanisms in a synergetic and multilateral fashion, namely, the magnetic field-mediated mechanical stimulation, photothermal damage, photodynamic toxicity, and chemotherapy. The unique nanocomposites with combined mechanical, chemo, and physical effects will provide an alternative strategy for highly improved cancer therapy efficiency.

Aging tumour cells to cure cancer: "pro-senescence" therapy for cancer.

PubMed

Calcinotto, Arianna; Alimonti, Andrea

2017-01-19

Robust scientific evidence demonstrates that senes-cence induction in cancer works as a potent weapon to eradicate tumorigenesis. Therapies that enhance senescence not only promote a stable cell growth arrest but also work as a strong stimulus for the acti-vation of the antitumour immune response. However, recent advances suggest that if senescent tumour cells are not cleared from the tumours, they may promote tumour progression and metastasis. In this article, we focus on concepts that are relevant to a pro-senescence therapeutic approach, including caveats, and we propose therapeutic strategies that involve the combined use of pro-senescence therapies with im-munotherapies to promote the clearance of senescent tumour cells. In our opinion, these approaches may avoid potential negative effects of pro-senescence therapies and may also enhance the efficacy of cur-rently available immunotherapies.

In vivo selective cancer-tracking gadolinium eradicator as new-generation photodynamic therapy agent

PubMed Central

Zhang, Tao; Lan, Rongfeng; Chan, Chi-Fai; Law, Ga-Lai; Wong, Wai-Kwok; Wong, Ka-Leung

2014-01-01

In this work, we demonstrate a modality of photodynamic therapy (PDT) through the design of our truly dual-functional—PDT and imaging—gadolinium complex (Gd-N), which can target cancer cells specifically. In the light of our design, the PDT drug can specifically localize on the anionic cell membrane of cancer cells in which its laser-excited photoemission signal can be monitored without triggering the phototoxic generation of reactive oxygen species—singlet oxygen—before due excitation. Comprehensive in vitro and in vivo studies had been conducted for the substantiation of the effectiveness of Gd-N as such a tumor-selective PDT photosensitizer. This treatment modality does initiate a new direction in the development of “precision medicine” in line with stem cell and gene therapies as tools in cancer therapy. PMID:25453097

Synergizing Radiation Therapy and Immunotherapy for Curing Incurable Cancers: Opportunities and Challenges

PubMed Central

Hodge, James W.; Guha, Chandan; Neefjes, Jacques; Gulley, James L.

2012-01-01

The combination of radiation therapy and immunotherapy holds particular promise as a strategy for cancer therapeutics. There is evidence that immunotherapy is most beneficial alone when employed early in the disease process or in combination with standard therapies (e.g., radiation) later in the disease process. Indeed, radiation may act synergistically with immunotherapy to enhance immune responses, inhibit immunosuppression, and/or alter the phenotype of tumor cells, thus rendering them more susceptible to immune-mediated killing. Furthermore, as monotherapies, both immunotherapy and radiation may be insufficient to eliminate tumor masses. However, following immunization with a cancer vaccine, the destruction of even a small percentage of tumor cells by radiation could result in cross-priming and presentation of tumor antigens to the immune system, thereby potentiating antitumor responses. Learning how to exploit radiation-induced changes to tumor-cell antigens, and how to induce effective immune responses to these cumulatively immunogenic stimuli, is an exciting frontier in cancer therapy research. This review examines a) mechanisms by which many forms of radiation therapy can induce or augment antitumor immune responses and b) preclinical systems that demonstrate that immunotherapy can be effectively combined with radiation therapy. Finally, we review current clinical trials where standard-of-care radiation therapy is being combined with immunotherapy. PMID:18777956

Targeted cancer therapy--are the days of systemic chemotherapy numbered?

PubMed

Joo, Won Duk; Visintin, Irene; Mor, Gil

2013-12-01

Targeted therapy or molecular targeted therapy has been defined as a type of treatment that blocks the growth of cancer cells by interfering with specific cell molecules required for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells as with traditional chemotherapy. There is a growing number of FDA approved monoclonal antibodies and small molecules targeting specific types of cancer suggestive of the growing relevance of this therapeutic approach. Targeted cancer therapies, also referred to as "Personalized Medicine", are being studied for use alone, in combination with other targeted therapies, and in combination with chemotherapy. The objective of personalized medicine is the identification of patients that would benefit from a specific treatment based on the expression of molecular markers. Examples of this approach include bevacizumab and olaparib, which have been designated as promising targeted therapies for ovarian cancer. Combinations of trastuzumab with pertuzumab, or T-DM1 and mTOR inhibitors added to an aromatase inhibitor are new therapeutic strategies for breast cancer. Although this approach has been seen as a major step in the expansion of personalized medicine, it has substantial limitations including its high cost and the presence of serious adverse effects. The Cancer Genome Atlas is a useful resource to identify novel and more effective targets, which may help to overcome the present limitations. In this review we will discuss the clinical outcome of some of these new therapies with a focus on ovarian and breast cancer. We will also discuss novel concepts in targeted therapy, the target of cancer stem cells. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Lichenoid dermatitis in three patients with metastatic melanoma treated with anti-PD-1 therapy.

PubMed

Joseph, Richard W; Cappel, Mark; Goedjen, Brent; Gordon, Matthew; Kirsch, Brandon; Gilstrap, Cheryl; Bagaria, Sanjay; Jambusaria-Pahlajani, Anokhi

2015-01-01

Therapies that activate the immune system through blocking the binding of programmed death ligand 1 (PD-L1) present on tumors and PD-1 (programmed death 1) present on activated immune cells are revolutionizing the care for patients with cancer. These therapies work by inhibiting negative regulators of the immune system, thereby decreasing a tumor's ability to evade the immune system. The side effects of anti-PD-1/PD-L1 therapies are generally mild and as expected are related to autoimmune reactions. Two of the most common side effects of anti-PD-1/PD-L1 therapies are rash and pruritus occurring in approximately 20% of patients. Although the rash is generally recognized to be immune mediated, the exact mechanisms of the rash remain unclear. Herein, we report three cases of lichenoid dermatitis in three patients treated with MK-3475 (anti-PD-1) that were characterized with marked T-cell infiltrates with few PD-1-positive cells. The rashes in all three patients were relatively mild, allowing treatment to continue despite the rashes. ©2014 American Association for Cancer Research.

Clinical Advances of Hypoxia-Activated Prodrugs in Combination With Radiation Therapy.

PubMed

Mistry, Ishna N; Thomas, Matthew; Calder, Ewen D D; Conway, Stuart J; Hammond, Ester M

2017-08-01

With the increasing incidence of cancer worldwide, the need for specific, effective therapies is ever more urgent. One example of targeted cancer therapeutics is hypoxia-activated prodrugs (HAPs), also known as bioreductive prodrugs. These prodrugs are inactive in cells with normal oxygen levels but in hypoxic cells (with low oxygen levels) undergo chemical reduction to the active compound. Hypoxia is a common feature of solid tumors and is associated with a more aggressive phenotype and resistance to all modes of therapy. Therefore, the combination of radiation therapy and bioreductive drugs presents an attractive opportunity for synergistic effects, because the HAP targets the radiation-resistant hypoxic cells. Hypoxia-activated prodrugs have typically been precursors of DNA-damaging agents, but a new generation of molecularly targeted HAPs is emerging. By targeting proteins associated with tumorigenesis and survival, these compounds may result in greater selectivity over healthy tissue. We review the clinical progress of HAPs as adjuncts to radiation therapy and conclude that the use of HAPs alongside radiation is vastly underexplored at the clinical level. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Targeted Therapies in Non-Small Cell Lung Cancer—Beyond EGFR and ALK

PubMed Central

Rothschild, Sacha I.

2015-01-01

Systemic therapy for non-small cell lung cancer (NSCLC) has undergone a dramatic paradigm shift over the past decade. Advances in our understanding of the underlying biology of NSCLC have revealed distinct molecular subtypes. A substantial proportion of NSCLC depends on oncogenic molecular aberrations (so-called “driver mutations”) for their malignant phenotype. Personalized therapy encompasses the strategy of matching these subtypes with effective targeted therapies. EGFR mutations and ALK translocation are the most effectively targeted oncogenes in NSCLC. EGFR mutations and ALK gene rearrangements are successfully being targeted with specific tyrosine kinase inhibitors. The number of molecular subgroups of NSCLC continues to grow. The scope of this review is to discuss recent data on novel molecular targets as ROS1, BRAF, KRAS, HER2, c-MET, RET, PIK3CA, FGFR1 and DDR2. Thereby the review will focus on therapeutic strategies targeting these aberrations. Moreover, the emerging challenge of acquired resistance to initially effective therapies will be discussed. PMID:26018876

Targeted Therapies in Non-Small Cell Lung Cancer-Beyond EGFR and ALK.

PubMed

Rothschild, Sacha I

2015-05-26

Systemic therapy for non-small cell lung cancer (NSCLC) has undergone a dramatic paradigm shift over the past decade. Advances in our understanding of the underlying biology of NSCLC have revealed distinct molecular subtypes. A substantial proportion of NSCLC depends on oncogenic molecular aberrations (so-called "driver mutations") for their malignant phenotype. Personalized therapy encompasses the strategy of matching these subtypes with effective targeted therapies. EGFR mutations and ALK translocation are the most effectively targeted oncogenes in NSCLC. EGFR mutations and ALK gene rearrangements are successfully being targeted with specific tyrosine kinase inhibitors. The number of molecular subgroups of NSCLC continues to grow. The scope of this review is to discuss recent data on novel molecular targets as ROS1, BRAF, KRAS, HER2, c-MET, RET, PIK3CA, FGFR1 and DDR2. Thereby the review will focus on therapeutic strategies targeting these aberrations. Moreover, the emerging challenge of acquired resistance to initially effective therapies will be discussed.

The host immunological response to cancer therapy: An emerging concept in tumor biology.

PubMed

Voloshin, Tali; Voest, Emile E; Shaked, Yuval

2013-07-01

Almost any type of anti-cancer treatment including chemotherapy, radiation, surgery and targeted drugs can induce host molecular and cellular immunological effects which, in turn, can lead to tumor outgrowth and relapse despite an initial successful therapy outcome. Tumor relapse due to host immunological effects is attributed to angiogenesis, tumor cell dissemination from the primary tumors and seeding at metastatic sites. This short review will describe the types of host cells that participate in this process, the types of factors secreted from the host following therapy that can promote tumor re-growth, and the possible implications of this unique and yet only partially-known process. It is postulated that blocking these specific immunological effects in the reactive host in response to cancer therapy may aid in identifying new host-dependent targets for cancer, which in combination with conventional treatments can prolong therapy efficacy and extend survival. Additional studies investigating this specific research direction-both in preclinical models and in the clinical setting are essential in order to advance our understanding of how tumors relapse and evade therapy. Copyright © 2013 Elsevier Inc. All rights reserved.

Doxorubicin-loaded photosensitive magnetic liposomes for multi-modal cancer therapy.

PubMed

Shah, Saqlain A; Aslam Khan, M U; Arshad, M; Awan, S U; Hashmi, M U; Ahmad, N

2016-12-01

Multifunctional magnetic nanosystems have attracted an enormous attention of researchers for their potential applications in cancer diagnostics and therapy. The localized nanotherapies triggered by the external stimuli, like magnetic fields and visible light, are significant in clinical applications. We report a liposomal system that aims to treat cancer by magnetic hyperthermia, photodynamic therapy and chemotherapy simultaneously. The liposomes enclose clinically used photosensitizer m-THPC (Foscan) and anti-cancer drug doxorubicin, in its hydrophobic lipid bilayers, and contains magnetite nanoparticles in hydrophilic core. Three different sizes of magnetic nanoparticles (10, 22 and 30nm) and liposomes (40, 70 and 110nm) were used in this study. Magnetite single domain nanoparticles forming the magnetic core were superparamagnetic but liposomes expressed slight coercivity and hysteresis due to the clustering of nanoparticles in the core. This enhanced the heating efficiency (specific power loss) of the liposomes under an AC field (375kHz, 170Oe). Cell viability and toxicity were studied on HeLa cells using MTT assay and proteomic analysis. Confocal and fluorescence microscopy were used to study the photosensitizer's profile and cells response to combined therapy. It revealed that combined therapy almost completely eliminated the cancer cells as opposed to the separate treatments. Magnetic hyperthermia and photodynamic therapies were almost equally effective whereas chemotherapy showed the least effect. Copyright © 2016. Published by Elsevier B.V.

Effects of hydroxyurea on blood rheology in sickle cell anemia: A two-years follow-up study.

PubMed

Lemonne, Nathalie; Möckesch, Berenike; Charlot, Keyne; Garnier, Yohann; Waltz, Xavier; Lamarre, Yann; Antoine-Jonville, Sophie; Etienne-Julan, Maryse; Hardy-Dessources, Marie-Dominique; Romana, Marc; Connes, Philippe

2017-01-01

The aim of the present study was to test the effects of hydroxyurea (HU) therapy on clinical, hematological and hemorheological parameters in adult patients with sickle cell anemia (SCA). Hematological and hemorheological parameters were measured in 28 SCA patients before HU therapy (i.e., baseline) and at 6, 12 and 24 months of treatment. RBC deformability was determined by ektacytometry at 30 Pa. RBC aggregation properties were investigated by light-backscatter method. Blood viscosity was measured at 225 s-1 by a cone-plate viscometer. The rates of vaso-occlusive crises and acute chest syndrome were lower at 1 and 2 years of HU therapy compared to baseline. The proportion of patients with leg ulcers tended to decrease after 2 years of treatment. Hemoglobin oxygen saturation improved with HU therapy. HU therapy induced a decrease of platelet and white blood cell counts and a rise in fetal hemoglobin level and mean cell volume. While hemoglobin concentrations increased under HU, blood viscosity remained unchanged all along the study. RBC deformability increased over baseline values at 6 months of HU therapy and continued to rise until the end of the follow-up period. In conclusion, the improvement in RBC deformability probably compensates the increase of hemoglobin on blood viscosity and participates to the improvement of the clinical status of patients.

Effects of low-dose light-emitting-diode therapy in combination with water bath for atopic dermatitis in NC/Nga mice.

PubMed

Kim, Chang-Hyun; Cheong, Kyung Ah; Lim, Won Suk; Park, Hyung-Moo; Lee, Ai-Young

2016-01-01

Light-emitting diode (LED) phototherapy and water bath therapy have beneficial effect on atopic dermatitis (AD)-like skin disease. However, not all current treatments work well and alternative therapies are need. The contribution of combination therapy with low-dose 850 nm LED and water bath was investigated on dermatophagoides farina (Df)-induced dermatitis in NC/Nga mice. Low-dose LED (10, 15, and 20 J/cm(2) ) irradiation, water bath (36 ± 1°C) were administered separately and together to the Df-induced NC/Nga mice in acrylic jar once a day for 2 weeks. Combined therapy with low-dose LED therapy and water bath therapy significantly ameliorated the development of AD-like skin lesions. These effects were correlated with the suppression of total IgE, NO, histamine, and Th2-mediated immune responses. Furthermore, combination therapy significantly reduced the infiltration of inflammatory cells and the induction of thymic stromal lymphopoietin (TSLP) in the skin lesions. The beneficial therapeutic effects of this combination therapy might regulate by the inhibition of various immunological responses including Th2-mediated immune responses, inflammatory mediators such as IgE, histamine, and NO, as well as inflammatory cells. The combination therapy of LED and water bath might be used as an efficacious, safe, and steroid-free alternative therapeutic strategy for the treatment of AD. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Activation of photodynamic therapy in vitro with Cerenkov luminescence generated from Yttrium-90 (Conference Presentation)

NASA Astrophysics Data System (ADS)

Hartl, Brad A.; Hirschberg, Henry; Marcu, Laura; Cherry, Simon R.

2016-03-01

Translation of photodynamic therapy to the clinical setting has primarily been limited to easily accessible and/or superficial diseases where traditional light delivery can be performed noninvasively. Cerenkov luminescence, as generated from medically relevant radionuclides, has been suggested as a means to deliver light to deeper tissues noninvasively in order to overcome this depth limitation. We report on the use of Cerenkov luminescence generated from Yttrium-90 as a means to active the photodynamic therapy process in monolayer tumor cell cultures. The current study investigates the utility of Cerenkov luminescence for activating both the clinically relevant aminolevulinic acid at 1.0 mM and also the more efficient photosensitizer TPPS2a at 1.2 µM. Cells were incubated with aminolevulinic acid for 6 hours prior to radionuclide addition, as well as additional daily treatments for three days. TPPS2a was delivered as a single treatment with an 18 hour incubation time before radionuclide addition. Experiments were completed for both C6 glioma cells and MDA-MB-231 breast tumor cells. Although aminolevulinic acid proved ineffective for generating a therapeutic effect at any activity for either cell line, TPPS2a produced at least a 20% therapeutic effect at activities ranging from 6 to 60 µCi/well for the C6 cell line. Current results demonstrate that it may be possible to generate a therapeutic effect in vivo using Cerenkov luminescence to activate the photodynamic therapy process with clinically relevant photosensitizers.

p53 activated by AND gate genetic circuit under radiation and hypoxia for targeted cancer gene therapy

PubMed Central

Ding, Miao; Li, Rong; He, Rong; Wang, Xingyong; Yi, Qijian; Wang, Weidong

2015-01-01

Radio-activated gene therapy has been developed as a novel therapeutic strategy against cancer; however, expression of therapeutic gene in peritumoral tissues will result in unacceptable toxicity to normal cells. To restrict gene expression in targeted tumor mass, we used hypoxia and radiation tolerance features of tumor cells to develop a synthetic AND gate genetic circuit through connecting radiation sensitivity promoter cArG6, heat shock response elements SNF1, HSF1 and HSE4 with retroviral vector plxsn. Their construction and dynamic activity process were identified through downstream enhanced green fluorescent protein and wtp53 expression in non-small cell lung cancer A549 cells and in a nude mice model. The result showed that AND gate genetic circuit could be activated by lower required radiation dose (6 Gy) and after activated, AND gate could induce significant apoptosis effects and growth inhibition of cancer cells in vitro and in vivo. The radiation- and hypoxia-activated AND gate genetic circuit, which could lead to more powerful target tumoricidal activity represented a promising strategy for both targeted and effective gene therapy of human lung adenocarcinoma and low dose activation character of the AND gate genetic circuit implied that this model could be further exploited to decrease side-effects of clinical radiation therapy. PMID:26177264

Uncovering the Origin of Skin Side Effects from EGFR-Targeted Therapies | Center for Cancer Research

Cancer.gov

The epidermal growth factor receptor (EGFR), a key regulator of cell proliferation, is often mutated or overexpressed in a variety of cancer types. EGFR-targeted therapies, including monoclonal antibodies and small molecule inhibitors, can effectively treat patients whose tumors depend on aberrant EGFR signaling. Within a few weeks of initiating therapy, however, patients

Targeted alpha therapy using Radium-223: From physics to biological effects.

PubMed

Marques, I A; Neves, A R; Abrantes, A M; Pires, A S; Tavares-da-Silva, E; Figueiredo, A; Botelho, M F

2018-05-25

With the advance of the use of ionizing radiation in therapy, targeted alpha therapy (TAT) has assumed an important role around the world. This kind of therapy can potentially reduce side effects caused by radiation in normal tissues and increased destructive radiobiological effects in tumor cells. However, in many countries, the use of this therapy is still in a pioneering phase. Radium-223 ( 223 Ra), an alpha-emitting radionuclide, has been the first of its kind to be approved for the treatment of bone metastasis in metastatic castration-resistant prostate cancer. Nevertheless, the interaction mechanism and the direct effects of this radiopharmaceutical in tumor cells are not fully understood neither characterized at a molecular level. In fact, the ways how TAT is linked to radiobiological effects in cancer is not yet revised. Therefore, this review introduces some physical properties of TAT that leads to biological effects and links this information to the hallmarks of cancer. The authors also collected the studies developed with 223 Ra to correlate with the three categories reviewed - properties of TAT, 5 R's of radiobiology and hallmarks of cancer- and with the promising future to this radiopharmaceutical. Copyright © 2018 Elsevier Ltd. All rights reserved.

Quasispecies dynamics and the emergence of drug resistance during zidovudine therapy of HIV infection.

PubMed

Frost, S D; McLean, A R

1994-03-01

To investigate the roles of mutation, competition and population dynamics in the emergence of drug resistant mutants during zidovudine therapy. A mathematical model of the population dynamics of the viral quasispecies during zidovudine therapy was investigated. The model was used to simulate changes in the numbers of uninfected and infected cells and the composition of the viral quasispecies in the years following initiation of therapy. Resulting scenarios in asymptomatic and AIDS patients were compared. The model was also used to investigate the efficacy of a treatment regimen involving alternating zidovudine and dideoxyinosine therapy. The behaviour of the model can be divided into three stages. Before therapy, mutation maintains a small pool of resistant mutants, outcompeted to very low levels by sensitive strains. When therapy begins there is a dramatic fall in the total viral load and resistant strains suddenly have the competitive advantage. Thus, it is resistant strains that infect the rising number of uninfected CD4+ cells. During this second stage the rapid effects of population dynamics swamp any effects of mutation between strains. When the populations of infected and uninfected cells approach their treatment equilibrium levels, mutation again becomes important in the slow generation of highly resistant strains. The short-term reduction in viral replication at the initiation of therapy generates a pool of uninfected cells which cause the eventual increase in viral burden. This increase is associated with (but not caused by) a rise in frequency of resistant strains which are at a competitive advantage in the presence of the drug. When therapy is ceased, reversion of resistance is slow as resistant strains are nearly as fit as sensitive strains in the absence of drug.

Inhibitory effect of Survivin promoter-regulated oncolytic adenovirus carrying P53 gene against gallbladder cancer.

PubMed

Liu, Chen; Sun, Bin; An, Ni; Tan, Weifeng; Cao, Lu; Luo, Xiangji; Yu, Yong; Feng, Feiling; Li, Bin; Wu, Mengchao; Su, Changqing; Jiang, Xiaoqing

2011-12-01

Gene therapy has become an important strategy for treatment of malignancies, but problems remains concerning the low gene transferring efficiency, poor transgene expression and limited targeting specific tumors, which have greatly hampered the clinical application of tumor gene therapy. Gallbladder cancer is characterized by rapid progress, poor prognosis, and aberrantly high expression of Survivin. In the present study, we used a human tumor-specific Survivin promoter-regulated oncolytic adenovirus vector carrying P53 gene, whose anti-cancer effect has been widely confirmed, to construct a wide spectrum, specific, safe, effective gene-viral therapy system, AdSurp-P53. Examining expression of enhanced green fluorecent protein (EGFP), E1A and the target gene P53 in the oncolytic adenovirus system validated that Survivin promoter-regulated oncolytic adenovirus had high proliferation activity and high P53 expression in Survivin-positive gallbladder cancer cells. Our in vitro cytotoxicity experiment demonstrated that AdSurp-P53 possessed a stronger cytotoxic effect against gallbladder cancer cells and hepatic cancer cells. The survival rate of EH-GB1 cells was lower than 40% after infection of AdSurp-P53 at multiplicity of infection (MOI) = 1 pfu/cell, while the rate was higher than 90% after infection of Ad-P53 at the same MOI, demonstrating that AdSurp-P53 has a potent cytotoxicity against EH-GB1 cells. The tumor growth was greatly inhibited in nude mice bearing EH-GB1 xenografts when the total dose of AdSurp-P53 was 1 × 10(9) pfu, and terminal dUTP nick end-labeling (TUNEL) revealed that the apoptotic rate of cancer cells was (33.4 ± 8.4)%. This oncolytic adenovirus system overcomes the long-standing shortcomings of gene therapy: poor transgene expression and targeting of only specific tumors, with its therapeutic effect better than the traditional Ad-P53 therapy regimen already on market; our system might be used for patients with advanced gallbladder cancer and other cancers, who are not sensitive to chemotherapy, radiotherapy, or who lost their chance for surgical treatment. Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Cell banking for regulatory T cell-based therapy: strategies to overcome the impact of cryopreservation on the Treg viability and phenotype

PubMed Central

Gołąb, Karolina; Grose, Randall; Placencia, Veronica; Wickrema, Amittha; Solomina, Julia; Tibudan, Martin; Konsur, Evelyn; Ciepły, Kamil; Marek-Trzonkowska, Natalia; Trzonkowski, Piotr; Millis, J. Michael; Fung, John; Witkowski, Piotr

2018-01-01

The first clinical trials with adoptive Treg therapy have shown safety and potential efficacy. Feasibility of such therapy could be improved if cells are cryopreserved and stored until optimal timing for infusion. Herein, we report the evaluation of two cell-banking strategies for Treg therapy: 1) cryopreservation of CD4+ cells for subsequent Treg isolation/expansion and 2) cryopreservation of ex-vivo expanded Tregs (CD4+CD25hiCD127lo/- cells). First, we checked how cryopreservation affects cell viability and Treg markers expression. Then, we performed Treg isolation/expansion with the final products release testing. We observed substantial decrease in cell number recovery after thawing and overnight culture. This observation might be explained by the high percentage of necrotic and apoptotic cells found just after thawing. Furthermore, we noticed fluctuations in percentage of CD4+CD25hiCD127- and CD4+FoxP3+ cells obtained from cryopreserved CD4+ as well as Treg cells. However, after re-stimulation Tregs expanded well, presented a stable phenotype and fulfilled the release criteria at the end of expansions. Cryopreservation of CD4+ cells for subsequent Treg isolation/expansion and cryopreservation of expanded Tregs with re-stimulation and expansion after thawing, are promising solutions to overcome detrimental effects of cryopreservation. Both of these cell-banking strategies for Treg therapy can be applied when designing new clinical trials. PMID:29515766

Cell banking for regulatory T cell-based therapy: strategies to overcome the impact of cryopreservation on the Treg viability and phenotype.

PubMed

Gołąb, Karolina; Grose, Randall; Placencia, Veronica; Wickrema, Amittha; Solomina, Julia; Tibudan, Martin; Konsur, Evelyn; Ciepły, Kamil; Marek-Trzonkowska, Natalia; Trzonkowski, Piotr; Millis, J Michael; Fung, John; Witkowski, Piotr

2018-02-09

The first clinical trials with adoptive Treg therapy have shown safety and potential efficacy. Feasibility of such therapy could be improved if cells are cryopreserved and stored until optimal timing for infusion. Herein, we report the evaluation of two cell-banking strategies for Treg therapy: 1) cryopreservation of CD4 + cells for subsequent Treg isolation/expansion and 2) cryopreservation of ex-vivo expanded Tregs (CD4 + CD25 hi CD127 lo/- cells). First, we checked how cryopreservation affects cell viability and Treg markers expression. Then, we performed Treg isolation/expansion with the final products release testing. We observed substantial decrease in cell number recovery after thawing and overnight culture. This observation might be explained by the high percentage of necrotic and apoptotic cells found just after thawing. Furthermore, we noticed fluctuations in percentage of CD4 + CD25 hi CD127 - and CD4 + FoxP3 + cells obtained from cryopreserved CD4 + as well as Treg cells. However, after re-stimulation Tregs expanded well, presented a stable phenotype and fulfilled the release criteria at the end of expansions. Cryopreservation of CD4 + cells for subsequent Treg isolation/expansion and cryopreservation of expanded Tregs with re-stimulation and expansion after thawing, are promising solutions to overcome detrimental effects of cryopreservation. Both of these cell-banking strategies for Treg therapy can be applied when designing new clinical trials.

Leukemia cell proliferation and death in chronic lymphocytic leukemia patients on therapy with the BTK inhibitor ibrutinib.

PubMed

Burger, Jan A; Li, Kelvin W; Keating, Michael J; Sivina, Mariela; Amer, Ahmed M; Garg, Naveen; Ferrajoli, Alessandra; Huang, Xuelin; Kantarjian, Hagop; Wierda, William G; O'Brien, Susan; Hellerstein, Marc K; Turner, Scott M; Emson, Claire L; Chen, Shih-Shih; Yan, Xiao-Jie; Wodarz, Dominik; Chiorazzi, Nicholas

2017-01-26

BACKGROUND. Ibrutinib is an effective targeted therapy for patients with chronic lymphocytic leukemia (CLL) that inhibits Bruton's tyrosine kinase (BTK), a kinase involved in B cell receptor signaling. METHODS. We used stable isotopic labeling with deuterated water ( 2 H 2 O) to measure directly the effects of ibrutinib on leukemia cell proliferation and death in 30 patients with CLL. RESULTS. The measured average CLL cell proliferation ("birth") rate before ibrutinib therapy was 0.39% of the clone per day (range 0.17%-1.04%); this decreased to 0.05% per day (range 0%-0.36%) with treatment. Death rates of blood CLL cells increased from 0.18% per day (average, range 0%-0.7%) prior to treatment to 1.5% per day (range 0%-3.0%) during ibrutinib therapy, and they were even higher in tissue compartments. CONCLUSIONS. This study provides the first direct in vivo measurements to our knowledge of ibrutinib's antileukemia actions, demonstrating profound and immediate inhibition of CLL cell proliferation and promotion of high rates of CLL cell death. TRIAL REGISTRATION. This trial was registered at clinicaltrials.gov (NCT01752426). FUNDING. This study was supported by a Cancer Center Support Grant (National Cancer Institute grant P30 CA016672), an NIH grant (CA081554) from the National Cancer Institute, MD Anderson's Moon Shots Program in CLL, and Pharmacyclics, an AbbVie company.

Influence of p53 status on the effects of boron neutron capture therapy in glioblastoma.

PubMed

Seki, Keiko; Kinashi, Yuko; Takahashi, Sentaro

2015-01-01

The tumor suppressor gene p53 is mutated in glioblastoma. We studied the relationship between the p53 gene and the biological effects of boron neutron capture therapy (BNCT). The human glioblastoma cells; A172, expressing wild-type p53, and T98G, with mutant p53, were irradiated by the Kyoto University Research Reactor (KUR). The biological effects after neutron irradiation were evaluated by the cell killing effect, 53BP1 foci assay and apoptosis induction. The survival-fraction data revealed that A172 was more radiosensitive than T98G, but the difference was reduced when boronophenylalanine (BPA) was present. Both cell lines exhibited similar numbers of foci, suggesting that the initial levels of DNA damage did not depend on p53 function. Detection of apoptosis revealed a lower rate of apoptosis in the T98G. BNCT causes cell death in glioblastoma cells, regardless of p53 mutation status. In T98G cells, cell killing and apoptosis occurred effectively following BNCT. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

SFRP1 is a possible candidate for epigenetic therapy in non-small cell lung cancer.

PubMed

Taguchi, Y-H; Iwadate, Mitsuo; Umeyama, Hideaki

2016-08-12

Non-small cell lung cancer (NSCLC) remains a lethal disease despite many proposed treatments. Recent studies have indicated that epigenetic therapy, which targets epigenetic effects, might be a new therapeutic methodology for NSCLC. However, it is not clear which objects (e.g., genes) this treatment specifically targets. Secreted frizzled-related proteins (SFRPs) are promising candidates for epigenetic therapy in many cancers, but there have been no reports of SFRPs targeted by epigenetic therapy for NSCLC. This study performed a meta-analysis of reprogrammed NSCLC cell lines instead of the direct examination of epigenetic therapy treatment to identify epigenetic therapy targets. In addition, mRNA expression/promoter methylation profiles were processed by recently proposed principal component analysis based unsupervised feature extraction and categorical regression analysis based feature extraction. The Wnt/β-catenin signalling pathway was extensively enriched among 32 genes identified by feature extraction. Among the genes identified, SFRP1 was specifically indicated to target β-catenin, and thus might be targeted by epigenetic therapy in NSCLC cell lines. A histone deacetylase inhibitor might reactivate SFRP1 based upon the re-analysis of a public domain data set. Numerical computation validated the binding of SFRP1 to WNT1 to suppress Wnt signalling pathway activation in NSCLC. The meta-analysis of reprogrammed NSCLC cell lines identified SFRP1 as a promising target of epigenetic therapy for NSCLC.

Effects of intratracheal mesenchymal stromal cell therapy during recovery and resolution after ventilator-induced lung injury.

PubMed

Curley, Gerard F; Ansari, Bilal; Hayes, Mairead; Devaney, James; Masterson, Claire; Ryan, Aideen; Barry, Frank; O'Brien, Timothy; Toole, Daniel O'; Laffey, John G

2013-04-01

Mesenchymal stromal cells (MSCs) have been demonstrated to attenuate acute lung injury when delivered by intravenous or intratracheal routes. The authors aimed to determine the efficacy of and mechanism of action of intratracheal MSC therapy and to compare their efficacy in enhancing lung repair after ventilation-induced lung injury with intravenous MSC therapy. : After induction of anesthesia, rats were orotracheally intubated and subjected to ventilation-induced lung injury (respiratory rate 18(-1) min, P insp 35 cm H2O,) to produce severe lung injury. After recovery, animals were randomized to receive: (1) no therapy, n = 4; (2) intratracheal vehicle (phosphate-buffered saline, 300 µl, n = 8); (3) intratracheal fibroblasts (4 × 10 cells, n = 8); (4) intratracheal MSCs (4 × 10(6) cells, n = 8); (5) intratracheal conditioned medium (300 µl, n = 8); or (6) intravenous MSCs (4 × 10(6) cells, n = 4). The extent of recovery after acute lung injury and the inflammatory response was assessed after 48 h. Intratracheal MSC therapy enhanced repair after ventilation-induced lung injury, improving arterial oxygenation (mean ± SD, 146 ± 3.9 vs. 110.8 ± 21.5 mmHg), restoring lung compliance (1.04 ± 0.11 vs. 0.83 ± 0.06 ml · cm H2O(-1)), reducing total lung water, and decreasing lung inflammation and histologic injury compared with control. Intratracheal MSC therapy attenuated alveolar tumor necrosis factor-α (130 ± 43 vs. 488 ± 211 pg · ml(-1)) and interleukin-6 concentrations (138 ± 18 vs. 260 ± 82 pg · ml(-1)). The efficacy of intratracheal MSCs was comparable with intravenous MSC therapy. Intratracheal MSCs seemed to act via a paracine mechanism, with conditioned MSC medium also enhancing lung repair after injury. Intratracheal MSC therapy enhanced recovery after ventilation-induced lung injury via a paracrine mechanism, and was as effective as intravenous MSC therapy.

[The role of cellular senescence in carcinogenesis and antitumor therapy].

PubMed

Mosieniak, Grazyna; Strzeszewska, Anna

2014-01-01

Cellular senescence is the process that lead to terminal growth arrest induced by unrepairable double strand DNA damage (DSB). Moreover, activation of the oncogenes as well as inhibition of the tumor suppressor genes were shown to contribute to senescence induction and the senescent cells were identified in the premalignant lesions. Thus senescence is considered as an natural antitumor barrier that act at the early stages of cancerogenesis to stop the proliferation of transformed cells. Interestingly, the premalignant cells that escaped senescence and progress into full blown tumor cells still remain sensitive to induction of senescence, for example during chemio- or radiotherapy. Thus, induction of cancer cell senescence, similarly to apoptosis, is considered to restrain tumor growth and thus contribute to effectiveness of anticancer therapy. The senescent cells, although do not proliferate, remain viable and metabolically active. They secret a lot of cytokines, mitogens as well as enzymes degrading extracellular matrix. These factors can have opposing effect on neighboring cells, leading to senescence induction or stimulation of proliferation. Thus, senescence can act as an double edge sword that inhibit the propagation of potentially dangerous, transformed cells on one hand or induce cell division of the same cell on the other. Presently a lot of work is focused on finding new therapeutic strategies that would involve the tumor targeted senescence induction in both early late stages of cancer development. Nevertheless, the unwanted influence of the senescent cells on the microenvironment, requires careful monitoring the effects of pro-senescent therapies in each case.

Effects of verteporfin-mediated photodynamic therapy on endothelial cells

NASA Astrophysics Data System (ADS)

Kraus, Daniel; Chen, Bin

2015-03-01

Photodynamic therapy (PDT) is a treatment modality in which cytotoxic reactive oxygen species are generated from oxygen and other biological molecules when a photosensitizer is activated by light. PDT has been approved for the treatment of cancers and age-related macular degeneration (AMD) due to its effectiveness in cell killing and manageable normal tissue complications. In this study, we characterized the effects of verteporfin-PDT on SVEC mouse endothelial cells and determined its underlying cell death mechanisms. We found that verteporfin was primarily localized in mitochondria and endoplasmic reticulum (ER) in SVEC cells. Light treatment of photosensitized SVEC cells induced a rapid onset of cell apoptosis. In addition to significant structural damages to mitochondria and ER, verteporfin-PDT caused substantial degradation of ER signaling molecules, suggesting ER stress. These results demonstrate that verteporfin-PDT triggered SVEC cell apoptosis by both mitochondrial and ER stress pathways. Results from this study may lead to novel therapeutic approaches to enhance PDT outcome.

The potential of mesenchymal stromal cells as a novel cellular therapy for multiple sclerosis

PubMed Central

Auletta, Jeffery J; Bartholomew, Amelia M; Maziarz, Richard T; Deans, Robert J; Miller, Robert H; Lazarus, Hillard M; Cohen, Jeffrey A

2012-01-01

Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the CNS for which only partially effective therapies exist. Intense research defining the underlying immune pathophysiology is advancing both the understanding of MS as well as revealing potential targets for disease intervention. Mesenchymal stromal cell (MSC) therapy has the potential to modulate aberrant immune responses causing demyelination and axonal injury associated with MS, as well as to repair and restore damaged CNS tissue and cells. This article reviews the pathophysiology underlying MS, as well as providing a cutting-edge perspective into the field of MSC therapy based upon the experience of authors intrinsically involved in MS and MSC basic and translational science research. PMID:22642335

The role of metabolic therapy in treating glioblastoma multiforme

PubMed Central

Maroon, Joseph C.; Seyfried, Thomas N.; Donohue, Joseph P.; Bost, Jeffrey

2015-01-01

Glioblastoma multiforme (GBM) is an aggressive and nearly uniformly fatal malignancy of the central nervous system. Despite extensive research and clinical trials over the past 50 years, very little progress has been made to significantly alter its lethal prognosis. The current standard of care (SOC) includes maximal surgical resection, radiation therapy and chemotherapy and temozolomide (TMZ), including the selective use of glucocorticoids for symptom control. These same treatments, however, have the potential to create an environment that may actually facilitate tumor growth and survival. Research investigating the unique metabolic needs of tumor cells has led to the proposal of a new metabolic treatment for various cancers including GBMs that may enhance the effectiveness of the SOC. The goal of metabolic cancer therapy is to restrict GBM cells of glucose, their main energy substrate. By recognizing the underlying energy production requirements of cancer cells, newly proposed metabolic therapy is being used as an adjunct to standard GBM therapies. This review will discuss the calorie restricted ketogenic diet (CR-KD) as a promising potential adjunctive metabolic therapy for patients with GBMs. The effectiveness of the CR-KD is based on the “Warburg Effect” of cancer metabolism and the microenvironment of GBM tumors. We will review recent case reports, clinical studies, review articles, and animal model research using the CR-KD and explain the principles of the Warburg Effect as it relates to CR-KD and GBMs. PMID:25949849

Role of NK cells in immunotherapy and virotherapy of solid tumors.

PubMed

Cantoni, Claudia; Grauwet, Korneel; Pietra, Gabriella; Parodi, Monica; Mingari, Maria Cristina; Maria, Andrea De; Favoreel, Herman; Vitale, Massimo

2015-01-01

Although natural killer (NK) cells are endowed with powerful cytolytic activity against cancer cells, their role in different therapies against solid tumors has not yet been fully elucidated. Their interactions with various elements of the tumor microenvironment as well as their possible effects in contributing to and/or limiting oncolytic virotherapy render this potential immunotherapeutic tool still difficult to exploit at the bedside. Here, we will review the current literature with the aim of providing new hints to manage this powerful cell type in future innovative therapies, such as the use of NK cells in combination with new cytokines, specific mAbs (inducing ADCC), Tyr-Kinase inhibitors, immunomodulatory drugs and/or the design of oncolytic viruses aimed at optimizing the effect of NK cells in virotherapy.

Advancing Cancer Therapy with Present and Emerging Immuno-Oncology Approaches

PubMed Central

Kamta, Jeff; Chaar, Maher; Ande, Anusha; Altomare, Deborah A.; Ait-Oudhia, Sihem

2017-01-01

Immuno-oncology (I-O) is a young and growing field on the frontier of cancer therapy. Contrary to cancer therapies that directly target malignant cells, I-O therapies stimulate the body’s immune system to target and attack the tumor, which is otherwise invisible to, or inhibiting the immune response. To this end, several methods have been developed: First, passive therapies that enable T-cells to fight the tumor without direct manipulation, typically through binding and modifying the intracellular signaling of surface receptors. Checkpoint inhibitors, perhaps the most well known of I-O therapies; are an example of such. These are monoclonal antibodies that block binding of the tumor cell at receptors that inactivate the T-cell. A variety of small molecules can achieve the same effect by affecting metabolic or signaling pathways to boost the immune response or prevent its attenuation. Drugs originally formulated for unrelated disease states are now being used to treat cancer under the I-O approach. Second, active therapies which often involve direct manipulations that occur in vitro and once introduced to the patient will directly attack the tumor. Adoptive cell transfer is the oldest of these methods. It involves the removal of T-cells from the body, which are then expanded and genetically modified for specificity toward tumor-associated antigens (TAAs), and then reintroduced to the patient. A similar approach is taken with cancer vaccines, where TAAs are identified and reintroduced with adjuvants to stimulate an immune response, sometimes in the context of antigen-presenting cells or viral vectors. Oncolytic viruses are genetically modified natural viruses for selectivity toward tumor cells. The resulting cytotoxicity has the potential to elicit an immune response that furthers tumor cell killing. A final active approach is bi-specific T-cell engagers. These modified antibodies act to link a T-cell and tumor cell through surface receptors and thereby forcibly generate immune recognition. The therapies in each of these subfields are all still very new and ongoing clinical trials could provide even further additions. The full therapeutic potential of the aforementioned therapies, alone or in combination, has yet to be realized, but holds great promise for the future of cancer treatment. PMID:28459041

Medulloblastoma stem cells: Promising targets in medulloblastoma therapy.

PubMed

Huang, Guo-Hao; Xu, Qing-Fu; Cui, You-Hong; Li, Ningning; Bian, Xiu-Wu; Lv, Sheng-Qing

2016-05-01

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Despite great improvements in the therapeutic regimen, relapse and leptomeningeal dissemination still pose great challenges to the long-term survival of MB patients. Developing more effective strategies has become extremely urgent. In recent years, a number of malignancies, including MB, have been found to contain a subpopulation of cancer cells known as cancer stem cells (CSCs), or tumor initiating/propagating cells. The CSCs are thought to be largely responsible for tumor initiation, maintenance, dissemination, and relapse; therefore, their pivotal roles have revealed them to be promising targets in MB therapy. Our growing understanding of the major medulloblastoma molecular subgroups and the derivation of some of these groups from specific stem or progenitor cells adds additional layers to the CSC knowledge base. Herein we review the current knowledge of MB stem cells, highlight the molecular mechanisms relating to MB relapse and leptomeningeal dissemination, and incorporate these with the need to develop more effective and accurate therapies for MB patients. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Advances in evidence-based cancer adoptive cell therapy.

PubMed

Ge, Chunlei; Li, Ruilei; Song, Xin; Qin, Shukui

2017-04-01

Adoptive cell therapy (ACT) has been developed in cancer treatment by transferring/infusing immune cells into cancer patients, which are able to recognize, target, and destroy tumor cells. Recently, sipuleucel-T and genetically-modified T cells expressing chimeric antigen receptors (CAR) show a great potential to control metastatic castration-resistant prostate cancer and hematologic malignancies in clinic. This review summarized some of the major evidence-based ACT and the challenges to improve cell quality and reduce the side effects in the field. This review also provided future research directions to make sure ACT widely available in clinic.

Fucoidan-coated CuS nanoparticles for chemo-and photothermal therapy against cancer

PubMed Central

Jang, Bian; Moorthy, Madhappan Santha; Manivasagan, Panchanathan; Xu, Li; Song, Kyeongeun; Lee, Kang Dae; Kwak, Minseok; Oh, Junghwan; Jin, Jun-O

2018-01-01

In advanced cancer therapy, the combinational therapeutic effect of photothermal therapy (PTT) using near-infrared (NIR) light-responsive nanoparticles (NPs) and anti-cancer drug delivery-mediated chemotherapy has been widely applied. In the present study, using a facile, low-cost, and solution-based method, we developed and synthesized fucoidan, a natural polymer isolated from seaweed that has demonstrated anti-cancer effect, and coated NPs with it as an ideal candidate in chemo-photothermal therapy against cancer cells. Fucoidan-coated copper sulfide nanoparticles (F-CuS) act not only as a nanocarrier to enhance the intracellular delivery of fucoidan but also as a photothermal agent to effectively ablate different cancer cells (e.g., HeLa, A549, and K562), both in vitro and in vivo, with the induction of apoptosis under 808 nm diode laser irradiation. These results point to the potential usage of F-CuS in treating human cancer. PMID:29560098

Uterine-derived progenitor cells are immunoprivileged and effectively improve cardiac regeneration when used for cell therapy.

PubMed

Ludke, Ana; Wu, Jun; Nazari, Mansoreh; Hatta, Kota; Shao, Zhengbo; Li, Shu-Hong; Song, Huifang; Ni, Nathan C; Weisel, Richard D; Li, Ren-Ke

2015-07-01

Cell therapy to prevent cardiac dysfunction after myocardial infarction (MI) is less effective in aged patients because aged cells have decreased regenerative capacity. Allogeneic transplanted stem cells (SCs) from young donors are usually rejected. Maintaining transplanted SC immunoprivilege may dramatically improve regenerative outcomes. The uterus has distinct immune characteristics, and we showed that reparative uterine SCs home to the myocardium post-MI. Here, we identify immunoprivileged uterine SCs and assess their effects on cardiac regeneration after allogeneic transplantation. We found more than 20% of cells in the mouse uterus have undetectable MHC I expression by flow cytometry. Uterine MHC I((neg)) and MHC I((pos)) cells were separated by magnetic cell sorting. The MHC I((neg)) population expressed the SC markers CD34, Sca-1 and CD90, but did not express MHC II or c-kit. In vitro, MHC I((neg)) and ((pos)) SCs show colony formation and endothelial differentiation capacity. In mixed leukocyte co-culture, MHC I((neg)) cells showed reduced cell death and leukocyte proliferation compared to MHC I((pos)) cells. MHC I((neg)) and ((pos)) cells had significantly greater angiogenic capacity than mesenchymal stem cells. The benefits of intramyocardial injection of allogeneic MHC I((neg)) cells after MI were comparable to syngeneic bone marrow cell transplantation, with engraftment in cardiac tissue and limited recruitment of CD4 and CD8 cells up to 21 days post-MI. MHC I((neg)) cells preserved cardiac function, decreased infarct size and improved regeneration post-MI. This new source of immunoprivileged cells can induce neovascularization and could be used as allogeneic cell therapy for regenerative medicine. Copyright © 2015 Elsevier Ltd. All rights reserved.

D-amino acid oxidase gene therapy sensitizes glioma cells to the antiglycolytic effect of 3-bromopyruvate.

PubMed

El Sayed, S M; Abou El-Magd, R M; Shishido, Y; Chung, S P; Sakai, T; Watanabe, H; Kagami, S; Fukui, K

2012-01-01

Glioma tumors are refractory to conventional treatment. Glioblastoma multiforme is the most aggressive type of primary brain tumors in humans. In this study, we introduce oxidative stress-energy depletion (OSED) therapy as a new suggested treatment for glioblastoma. OSED utilizes D-amino acid oxidase (DAO), which is a promising therapeutic protein that induces oxidative stress and apoptosis through generating hydrogen peroxide (H2O2). OSED combines DAO with 3-bromopyruvate (3BP), a hexokinase II (HK II) inhibitor that interferes with Warburg effect, a metabolic alteration of most tumor cells that is characterized by enhanced aerobic glycolysis. Our data revealed that 3BP induced depletion of energetic capabilities of glioma cells. 3BP induced H2O2 production as a novel mechanism of its action. C6 glioma transfected with DAO and treated with D-serine together with 3BP-sensitized glioma cells to 3BP and decreased markedly proliferation, clonogenic power and viability in a three-dimensional tumor model with lesser effect on normal astrocytes. DAO gene therapy using atelocollagen as an in vivo transfection agent proved effective in a glioma tumor model in Sprague-Dawley (SD) rats, especially after combination with 3BP. OSED treatment was safe and tolerable in SD rats. OSED therapy may be a promising therapeutic modality for glioma.

Preclinical imaging methods for assessing the safety and efficacy of regenerative medicine therapies

NASA Astrophysics Data System (ADS)

Scarfe, Lauren; Brillant, Nathalie; Kumar, J. Dinesh; Ali, Noura; Alrumayh, Ahmed; Amali, Mohammed; Barbellion, Stephane; Jones, Vendula; Niemeijer, Marije; Potdevin, Sophie; Roussignol, Gautier; Vaganov, Anatoly; Barbaric, Ivana; Barrow, Michael; Burton, Neal C.; Connell, John; Dazzi, Francesco; Edsbagge, Josefina; French, Neil S.; Holder, Julie; Hutchinson, Claire; Jones, David R.; Kalber, Tammy; Lovatt, Cerys; Lythgoe, Mark F.; Patel, Sara; Patrick, P. Stephen; Piner, Jacqueline; Reinhardt, Jens; Ricci, Emanuelle; Sidaway, James; Stacey, Glyn N.; Starkey Lewis, Philip J.; Sullivan, Gareth; Taylor, Arthur; Wilm, Bettina; Poptani, Harish; Murray, Patricia; Goldring, Chris E. P.; Park, B. Kevin

2017-10-01

Regenerative medicine therapies hold enormous potential for a variety of currently incurable conditions with high unmet clinical need. Most progress in this field to date has been achieved with cell-based regenerative medicine therapies, with over a thousand clinical trials performed up to 2015. However, lack of adequate safety and efficacy data is currently limiting wider uptake of these therapies. To facilitate clinical translation, non-invasive in vivo imaging technologies that enable careful evaluation and characterisation of the administered cells and their effects on host tissues are critically required to evaluate their safety and efficacy in relevant preclinical models. This article reviews the most common imaging technologies available and how they can be applied to regenerative medicine research. We cover details of how each technology works, which cell labels are most appropriate for different applications, and the value of multi-modal imaging approaches to gain a comprehensive understanding of the responses to cell therapy in vivo.

Intracellular delivery and passive tumor targeting of a self-assembled nanogel containing carborane clusters for boron neutron capture therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kawasaki, Riku; JST-ERATO, Japan Science and Technology Agency; Sasaki, Yoshihiro

Boron neutron capture therapy, based on the release of thermal neutron irradiation from boron, is a targeted radiation therapy for cancer. Targeted and sufficient accumulation of boron in tumor cells to achieve cytotoxic efficacy and reduce off-target effects remains a challenge. Carborane has been investigated for use as a delivery agent in boron neutron capture therapy because of its high boron content and chemical stability; however, it is cytotoxic, making safe delivery difficult. The aim of this study was to investigate the potential of carborane-bearing pullulan nanogels to safely and effectively deliver boron to tumor cells in vitro and in vivo and,more » consequently, assess their potential as a boron neutron capture therapeutic. Murine fibrosarcoma cells (CMS5a) were used for in vitro investigations of nanogel cytotoxicity, cell uptake. A mouse fibrosarcoma xenograft model was used to investigate the bio-distribution of nanogels after intravenous administration. The nanogels produced no apparent cytotoxicity and underwent cell uptake in CMS5a cells after a 24 h incubation at up to 2000 μg/mL and 400 μg/mL, respectively. The internalized nanogels were localized around the nuclear membrane. The nanogels were administered intravenously to mice bearing fibrosarcoma xenografts. Nanogel tumor localization likely occurred through the enhanced permeation and retention effect. The nanogels successfully reduced the cytotoxicity of carborane, were internalized into tumor cells, acted as a dual-delivery therapeutic and accumulated in tumors in vivo. Consequently, they demonstrate significant potential as a boron neutron capture therapeutic. - Highlights: • A carborane-bearing pullulan nanogel is developed as a boron delivery agent. • The nanogels are cell-friendly and show effective cell uptake for drug delivery. • The nanogels show passive tumor targeting by enhanced permeation and retention.« less

Tumour Vascular Shutdown and Cell Death Following Ultrasound-Microbubble Enhanced Radiation Therapy

PubMed Central

El Kaffas, Ahmed; Gangeh, Mehrdad J.; Farhat, Golnaz; Tran, William Tyler; Hashim, Amr; Giles, Anoja; Czarnota, Gregory J.

2018-01-01

High-dose radiotherapy effects are regulated by acute tumour endothelial cell death followed by rapid tumour cell death instead of canonical DNA break damage. Pre-treatment with ultrasound-stimulated microbubbles (USMB) has enabled higher-dose radiation effects with conventional radiation doses. This study aimed to confirm acute and longitudinal relationships between vascular shutdown and tumour cell death following radiation and USMB in a wild type murine fibrosarcoma model using in vivo imaging. Methods: Tumour xenografts were treated with single radiation doses of 2 or 8 Gy alone, or in combination with low-/high-concentration USMB. Vascular changes and tumour cell death were evaluated at 3, 24 and 72 h following therapy, using high-frequency 3D power Doppler and quantitative ultrasound spectroscopy (QUS) methods, respectively. Staining using in situ end labelling (ISEL) and cluster of differentiation 31 (CD31) of tumour sections were used to assess cell death and vascular distributions, respectively, as gold standard histological methods. Results: Results indicated a decrease in the power Doppler signal of up to 50%, and an increase of more than 5 dBr in cell-death linked QUS parameters at 24 h for tumours treated with combined USMB and radiotherapy. Power Doppler and quantitative ultrasound results were significantly correlated with CD31 and ISEL staining results (p < 0.05), respectively. Moreover, a relationship was found between ultrasound power Doppler and QUS results, as well as between micro-vascular densities (CD31) and the percentage of cell death (ISEL) (R2 0.5-0.9). Conclusions: This study demonstrated, for the first time, the link between acute vascular shutdown and acute tumour cell death using in vivo longitudinal imaging, contributing to the development of theoretical models that incorporate vascular effects in radiation therapy. Overall, this study paves the way for theranostic use of ultrasound in radiation oncology as a diagnostic modality to characterize vascular and tumour response effects simultaneously, as well as a therapeutic modality to complement radiation therapy. PMID:29290810

Combined inhibitors of angiogenesis and histone deacetylase: efficacy in rat hepatoma.

PubMed

Ganslmayer, Marion; Zimmermann, Annette; Zopf, Steffen; Herold, Christoph

2011-08-21

To evaluate the antitumoral effect of combined inhibitors of angiogenesis and histone deacetylases in an experimental rat hepatoma model. MH7777A hepatoma cells were injected into the liver of male Buffalo rats. After 7 d treatment with the vascular endothelial growth factor receptor antagonist PTK787/ZK222584 (PTK/ZK), the histone deacetylase inhibitor MS-275, tamoxifen (TAM) and/or retinoic acid was initiated (n ≥ 8 animals/group). Natural tumor development was shown in untreated control groups (control 1 with n = 12, control 2 with n = 8). The control groups were initiated at different time points to demonstrate the stability of the hepatoma model. For documentation of possible side effects, we documented any change in body weight, loss of fur and diarrhea. After 21 d treatment, the rats were euthanized. Main target parameters were tumor size and metastasis rate. Additionally, immunohistochemistry for the proliferating cell nuclear antigen (PCNA) and TdT-mediated dUTP-biotin nick end labeling (TUNEL) assay were performed. The control groups developed large tumor nodules with extrahepatic tumor burden in the lung and abdominal organs (control 1: 6.18 cm(3) ± 4.14 cm(3) and control 2: 8.0 cm(3) ± 4.44 cm(3) 28 d after tumor cell injection). The tumor volume did not differ significantly in the control groups (P = 0.13). As single agents MS-275 and PTK/ZK reduced tumor volume by 58.6% ± 2.6% and 48.7% ± 3.2% vs control group 1, which was significant only for MS-275 (P = 0.025). The combination of MS-275 and PTK/ZK induced a nearly complete and highly significant tumor shrinkage by 90.3% ± 1% (P = 0.005). Addition of TAM showed no further efficacy, while quadruple therapy with retinoic acid increased antitumoral efficacy (tumor reduction by 93 ± 1%) and side effects. PCNA positive cells were not significantly reduced by the single agents, while dual therapy (MS-275 and PTK/ZK) and quadruple therapy reduced the PCNA-positive cell fraction significantly by 9.1 and 20.6% vs control 1 (P < 0.05). The number of TUNEL-positive cells, markers for ongoing apoptosis, was increased significantly by the single agents (control 1: 6.9%, PTK/ZK: 11.4%, MS-275: 12.2% with P < 0.05 vs control 1). The fraction of TUNEL-positive cells was upregulated highly significantly by dual therapy (18.4%) and quadruple therapy (24.8%, P < 0.01 vs control 1). For the proliferating (PCNA positive) and apoptotic cell fraction, quadruple therapy was significantly superior to dual therapy (P = 0.01). Combined PTK/ZK and MS-275 were highly effective in this hepatoma model. Quadruple therapy enhanced the effects microscopically, but not macroscopically. These results should be investigated further.

Computational Models of HIV-1 Resistance to Gene Therapy Elucidate Therapy Design Principles

PubMed Central

Aviran, Sharon; Shah, Priya S.; Schaffer, David V.; Arkin, Adam P.

2010-01-01

Gene therapy is an emerging alternative to conventional anti-HIV-1 drugs, and can potentially control the virus while alleviating major limitations of current approaches. Yet, HIV-1's ability to rapidly acquire mutations and escape therapy presents a critical challenge to any novel treatment paradigm. Viral escape is thus a key consideration in the design of any gene-based technique. We develop a computational model of HIV's evolutionary dynamics in vivo in the presence of a genetic therapy to explore the impact of therapy parameters and strategies on the development of resistance. Our model is generic and captures the properties of a broad class of gene-based agents that inhibit early stages of the viral life cycle. We highlight the differences in viral resistance dynamics between gene and standard antiretroviral therapies, and identify key factors that impact long-term viral suppression. In particular, we underscore the importance of mutationally-induced viral fitness losses in cells that are not genetically modified, as these can severely constrain the replication of resistant virus. We also propose and investigate a novel treatment strategy that leverages upon gene therapy's unique capacity to deliver different genes to distinct cell populations, and we find that such a strategy can dramatically improve efficacy when used judiciously within a certain parametric regime. Finally, we revisit a previously-suggested idea of improving clinical outcomes by boosting the proliferation of the genetically-modified cells, but we find that such an approach has mixed effects on resistance dynamics. Our results provide insights into the short- and long-term effects of gene therapy and the role of its key properties in the evolution of resistance, which can serve as guidelines for the choice and optimization of effective therapeutic agents. PMID:20711350

A smart drug: a pH-responsive photothermal ablation agent for Golgi apparatus activated cancer therapy.

PubMed

Xue, Fengfeng; Wen, Ying; Wei, Peng; Gao, Yilin; Zhou, Zhiguo; Xiao, Shuzhang; Yi, Tao

2017-06-13

We report a pH-responsive photothermal ablation agent (pH-PTT) based on cyanine dyes for photothermal therapy (PTT). The nanoparticles formed by BSA and pH-PTT preferentially accumulated in the Golgi apparatus of cancer cells compared to normal cells, and thus can be specifically activated by the acidic Golgi apparatus in cancer cells for effective PTT both ex vivo and in vivo.

BCL2 Inhibition by Venetoclax: Targeting the Achilles' Heel of the Acute Myeloid Leukemia Stem Cell?

PubMed

Pullarkat, Vinod A; Newman, Edward M

2016-10-01

Venetoclax is an oral drug with an excellent side-effect profile that has the potential to revolutionize acute myeloid leukemia (AML) therapy in two areas. Venetoclax-based combination therapies could be a bridge to hematopoietic cell transplant with curative intent for patients with refractory/relapsed AML, and venetoclax-based therapy could provide meaningful survival prolongation for older patients with AML who are not candidates for more aggressive therapies. Cancer Discov; 6(10); 1082-3. ©2016 AACR.See related article by Konopleva and colleagues, p. 1106. ©2016 American Association for Cancer Research.

Two is better than one: advances in pathogen-boosted immunotherapy and adoptive T-cell therapy.

PubMed

Xin, Gang; Schauder, David M; Zander, Ryan; Cui, Weiguo

2017-09-01

The recent tremendous successes in clinical trials take cancer immunotherapy into a new era and have attracted major attention from both academia and industry. Among the variety of immunotherapy strategies developed to boost patients' own immune systems to fight against malignant cells, the pathogen-based and adoptive cell transfer therapies have shown the most promise for treating multiple types of cancer. Pathogen-based therapies could either break the immune tolerance to enhance the effectiveness of cancer vaccines or directly infect and kill cancer cells. Adoptive cell transfer can induce a strong durable antitumor response, with recent advances including engineering dual specificity into T cells to recognize multiple antigens and improving the metabolic fitness of transferred cells. In this review, we focus on the recent prospects in these two areas and summarize some ongoing studies that represent potential advancements for anticancer immunotherapy, including testing combinations of these two strategies.

Proton Therapy

MedlinePlus

... effects of the treatment. top of page What equipment is used? Proton beam therapy uses special machines, ... tumor cells. top of page Who operates the equipment? With backgrounds in mechanical, electrical, software, hardware and ...

Improving Therapy of Chronic Lymphocytic Leukemia (CLL) with Chimeric Antigen Receptor (CAR) T Cells

PubMed Central

Fraietta, Joseph A.; Schwab, Robert D.; Maus, Marcela V.

2016-01-01

Adoptive cell immunotherapy for the treatment of chronic lymphocytic leukemia (CLL) has heralded a new era of synthetic biology. The infusion of genetically-engineered, autologous chimeric antigen receptor (CAR) T cells directed against CD19 expressed by normal and malignant B cells represents a novel approach to cancer therapy. The results of recent clinical trials of CAR T cells in relapsed and refractory CLL have demonstrated long-term disease-free remissions, underscoring the power of harnessing and re-directing the immune system against cancer. This review will briefly summarize T cell therapies in development for CLL disease. We discuss the role of T cell function and phenotype, T cell culture optimization, CAR design, and approaches to potentiate the survival and anti-tumor effects of infused lymphocytes. Future efforts will focus on improving the efficacy of CAR T cells for the treatment of CLL and incorporating adoptive cell immunotherapy into standard medical management of CLL. PMID:27040708

Improving therapy of chronic lymphocytic leukemia with chimeric antigen receptor T cells.

PubMed

Fraietta, Joseph A; Schwab, Robert D; Maus, Marcela V

2016-04-01

Adoptive cell immunotherapy for the treatment of chronic lymphocytic leukemia (CLL) has heralded a new era of synthetic biology. The infusion of genetically engineered, autologous chimeric antigen receptor (CAR) T cells directed against CD19 expressed by normal and malignant B cells represents a novel approach to cancer therapy. The results of recent clinical trials of CAR T cells in relapsed and refractory CLL have demonstrated long-term disease-free remissions, underscoring the power of harnessing and redirecting the immune system against cancer. This review will briefly summarize T-cell therapies in development for CLL disease. We discuss the role of T-cell function and phenotype, T-cell culture optimization, CAR design, and approaches to potentiate the survival and anti-tumor effects of infused lymphocytes. Future efforts will focus on improving the efficacy of CAR T cells for the treatment of CLL and incorporating adoptive cell immunotherapy into standard medical management of CLL. Copyright © 2016 Elsevier Inc. All rights reserved.

Cancer and Radiation Therapy: Current Advances and Future Directions

PubMed Central

Baskar, Rajamanickam; Lee, Kuo Ann; Yeo, Richard; Yeoh, Kheng-Wei

2012-01-01

In recent years remarkable progress has been made towards the understanding of proposed hallmarks of cancer development and treatment. However with its increasing incidence, the clinical management of cancer continues to be a challenge for the 21st century. Treatment modalities comprise of radiation therapy, surgery, chemotherapy, immunotherapy and hormonal therapy. Radiation therapy remains an important component of cancer treatment with approximately 50% of all cancer patients receiving radiation therapy during their course of illness; it contributes towards 40% of curative treatment for cancer. The main goal of radiation therapy is to deprive cancer cells of their multiplication (cell division) potential. Celebrating a century of advances since Marie Curie won her second Nobel Prize for her research into radium, 2011 has been designated the Year of Radiation therapy in the UK. Over the last 100 years, ongoing advances in the techniques of radiation treatment and progress made in understanding the biology of cancer cell responses to radiation will endeavor to increase the survival and reduce treatment side effects for cancer patients. In this review, principles, application and advances in radiation therapy with their biological end points are discussed. PMID:22408567

Cancer and radiation therapy: current advances and future directions.

PubMed

Baskar, Rajamanickam; Lee, Kuo Ann; Yeo, Richard; Yeoh, Kheng-Wei

2012-01-01

In recent years remarkable progress has been made towards the understanding of proposed hallmarks of cancer development and treatment. However with its increasing incidence, the clinical management of cancer continues to be a challenge for the 21st century. Treatment modalities comprise of radiation therapy, surgery, chemotherapy, immunotherapy and hormonal therapy. Radiation therapy remains an important component of cancer treatment with approximately 50% of all cancer patients receiving radiation therapy during their course of illness; it contributes towards 40% of curative treatment for cancer. The main goal of radiation therapy is to deprive cancer cells of their multiplication (cell division) potential. Celebrating a century of advances since Marie Curie won her second Nobel Prize for her research into radium, 2011 has been designated the Year of Radiation therapy in the UK. Over the last 100 years, ongoing advances in the techniques of radiation treatment and progress made in understanding the biology of cancer cell responses to radiation will endeavor to increase the survival and reduce treatment side effects for cancer patients. In this review, principles, application and advances in radiation therapy with their biological end points are discussed.

Allogeneic cell therapy bioprocess economics and optimization: downstream processing decisions.

PubMed

Hassan, Sally; Simaria, Ana S; Varadaraju, Hemanthram; Gupta, Siddharth; Warren, Kim; Farid, Suzanne S

2015-01-01

To develop a decisional tool to identify the most cost effective process flowsheets for allogeneic cell therapies across a range of production scales. A bioprocess economics and optimization tool was built to assess competing cell expansion and downstream processing (DSP) technologies. Tangential flow filtration was generally more cost-effective for the lower cells/lot achieved in planar technologies and fluidized bed centrifugation became the only feasible option for handling large bioreactor outputs. DSP bottlenecks were observed at large commercial lot sizes requiring multiple large bioreactors. The DSP contribution to the cost of goods/dose ranged between 20-55%, and 50-80% for planar and bioreactor flowsheets, respectively. This analysis can facilitate early decision-making during process development.

The novel oral imatinib microemulsions: physical properties, cytotoxicity activities and improved Caco-2 cell permeability.

PubMed

Gundogdu, Evren; Karasulu, Hatice Yesim; Koksal, Cinel; Karasulu, Ercüment

2013-01-01

The objective of this study was to formulate imatinib (IM) loaded to water-in-oil (w/o) microemulsions as an alternative formulation for cancer therapy and to evaluate the cytotoxic effect of microemulsions Caco-2 and MCF-7. Moreover, permeability studies were also performed with Caco-2 cells. W/o microemulsion systems were developed by using pseudo-ternary phase diagram. According to cytotoxicity studies, all formulations did not exert a cytotoxic effect on Caco-2 cells. Furthermore, all formulations had a significant cytotoxic effect on MCF-7 cells and the cytotoxic effect of M3IM was significantly more than that of other microemulsions and IM solution (p < 0.05). The permeability studies of IM across Caco-2 cells showed that permeability value from apical to basolateral was higher than permeability value of other formulations. In conclusion, the microemulsion formulations as a drug carrier, especially M3IM formulation, may be used as an effective alternative breast cancer therapy for oral delivery of IM.

Mesenchymal stem cell therapy ameliorates diabetic nephropathy via the paracrine effect of renal trophic factors including exosomes

PubMed Central

Nagaishi, Kanna; Mizue, Yuka; Chikenji, Takako; Otani, Miho; Nakano, Masako; Konari, Naoto; Fujimiya, Mineko

2016-01-01

Bone marrow-derived mesenchymal stem cells (MSCs) have contributed to the improvement of diabetic nephropathy (DN); however, the actual mediator of this effect and its role has not been characterized thoroughly. We investigated the effects of MSC therapy on DN, focusing on the paracrine effect of renal trophic factors, including exosomes secreted by MSCs. MSCs and MSC-conditioned medium (MSC-CM) as renal trophic factors were administered in parallel to high-fat diet (HFD)-induced type 2 diabetic mice and streptozotocin (STZ)-induced insulin-deficient diabetic mice. Both therapies showed approximately equivalent curative effects, as each inhibited the exacerbation of albuminuria. They also suppressed the excessive infiltration of BMDCs into the kidney by regulating the expression of the adhesion molecule ICAM-1. Proinflammatory cytokine expression (e.g., TNF-α) and fibrosis in tubular interstitium were inhibited. TGF-β1 expression was down-regulated and tight junction protein expression (e.g., ZO-1) was maintained, which sequentially suppressed the epithelial-to-mesenchymal transition of tubular epithelial cells (TECs). Exosomes purified from MSC-CM exerted an anti-apoptotic effect and protected tight junction structure in TECs. The increase of glomerular mesangium substrate was inhibited in HFD-diabetic mice. MSC therapy is a promising tool to prevent DN via the paracrine effect of renal trophic factors including exosomes due to its multifactorial action. PMID:27721418

Antitumor activity of combined endostatin and thymidine kinase gene therapy in C6 glioma models.

PubMed

Chen, Yan; Huang, Honglan; Yao, Chunshan; Su, Fengbo; Guan, Wenming; Yan, Shijun; Ni, Zhaohui

2016-09-01

The combination of Endostatin (ES) and Herpes Simplex Virus thymidine kinase (HSV-TK) gene therapy is known to have antitumor activity in bladder cancer. The potential effect of ES and TK therapy in glioma has not yet been investigated. In this study, pTK-internal ribosome entry site (IRES), pIRES-ES, and pTK-IRES-ES plasmids were constructed; pIRES empty vector served as the negative control. The recombinant constructs were transfected into human umbilical vein endothelial cells (HUVECs) ECV304 and C6 rat glioma cell line. Ganciclovir (GCV) was used to induce cell death in transfected C6 cells. We found that ECV304 cells expressing either ES or TK-ES showed reduced proliferation, decreased migration capacity, and increased apoptosis, as compared to untransfected cells or controls. pTK-IRES-ES/GCV or pTK-IRES/GCV significantly suppressed cell proliferation and induced cell apoptosis in C6 cells, as compared to the control. In addition, the administration of pIRES-ES, pTK-IRES/GCV, or pTK-IRES-ES/GCV therapy improved animal activity and behavior; was associated with prolonged animal survival, and a lower microvessel density (MVD) value in tumor tissues of C6 glioma rats. In comparison to others, dual gene therapy in form of pTK-IRES-ES/GCV had a significant antitumor activity against C6 glioma. These findings indicate combined TK and ES gene therapy was associated with a superior antitumor efficacy as compared to single gene therapy in C6 glioma. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Lipopolysaccharide-coated CuS nanoparticles promoted anti-cancer and anti-metastatic effect by immuno-photothermal therapy

PubMed Central

Moorthy, Madhappan S.; Zhang, Wei; Zeng, Ling; Kang, Mingyeong; Kwak, Minseok; Oh, Junghwan; Jin, Jun-O

2017-01-01

To meet the ultimate goal of cancer therapy, which is treating not only the primary tumor but also preventing metastatic cancer, the concept of combining immunotherapy with photothermal therapy (PTT) is gaining great interest. Here, we studied the new material, lipopolysaccharide (LPS) coated copper sulfide nanoparticles (LPS-CuS), for the immuno-photothermal therapy. We evaluated the effect of LPS-CuS for induction of apoptosis of CT26 cells and activation of dendritic cells. Moreover, the LPS-CuS and laser irradiation was examined anti-metastasis effect by liver metastasis model mouse in vivo. Through PTT, LPS-CuS induced elimination of CT26 tumor in BALB/c mice, which produced cancer antigens. In addition, released LPS and cancer antigen by PTT promoted dendritic cell activation in tumor draining lymph node (drLN), and consequently, enhanced the tumor antigen-specific immune responses. Finally, the primary tumor cured mice by LPS-CuS-mediated PTT completely resisted secondary tumor injection in the spleen and also prevented liver metastasis. Our results demonstrated the potential usage of LPS-CuS for the immuno-photothermal therapy against various types of cancer by showing the clear elimination of primary colon carcinoma with complete prevention of spleen and liver metastasis. PMID:29285274

Celecoxib-Induced Self-Assembly of Smart Albumin-Doxorubicin Conjugate for Enhanced Cancer Therapy.

PubMed

Shi, Leilei; Xu, Li; Wu, Chenwei; Xue, Bai; Jin, Xin; Yang, Jiapei; Zhu, Xinyuan

2018-03-14

Recent years have witnessed the great contributions that drug combination therapy has made for enhanced cancer therapy. However, because of the complicated pharmacokinetics of combined drug formulations, the majority of combination strategies show severe adverse effects at high dosage and poor biodistribution in vivo. To overcome these deficiencies and achieve enhanced cancer therapy, we put forward a method to construct a smart albumin-based nanoplatform, denoted as K237-HSA-DC, for codelivery of cyclooxygenase-2 (COX-2) inhibitor (celecoxib) and chemotherapeutic agent (doxorubicin, DOX). Both in vitro and in vivo studies indicate that K237-HSA-DC exhibits the best therapeutic efficacy on tumor cells compared with all the other formulations. Moreover, K237-HSA-DC shows fewer side effects on normal organs in contrast to other formulations. To understand the reasons behind the improved drug efficacy in depth, we performed a cell metabonomics-based mechanism study and found that celecoxib could enhance the inhibitory effect of DOX on the transport of glucose into cells and then lead to subsequent significant energy metabolism inhibition. Considering the above-mentioned advantages of K237-HSA-DC, we believe the smart albumin-based nanoplatform can serve as a promising drug delivery system for enhanced cancer therapy.

Bone marrow mesenchymal stem cells combined with minocycline improve spinal cord injury in a rat model

PubMed Central

Chen, Dayong; Zeng, Wei; Fu, Yunfeng; Gao, Meng; Lv, Guohua

2015-01-01

The aims of this study were to assess that the effects of bone marrow mesenchymal stem cells (BMSCs) combination with minocycline improve spinal cord injury (SCI) in rat model. In the present study, the Wistar rats were randomly divided into five groups: control group, SCI group, BMSCs group, Minocycline group and BMSCs + minocycline group. Basso, Beattie and Bresnahan (BBB) test and MPO activity were used to assess the effect of combination therapy on locomotion and neutrophil infiltration. Inflammation factors, VEGF and BDNF expression, caspase-3 activation, phosphorylation-p38MAPK, proNGF, p75NTR and RhoA expressions were estimated using commercial kits or western blot, respectively. BBB scores were significantly increased and MPO activity was significantly undermined by combination therapy. In addition, combination therapy significantly decreased inflammation factors in SCI rats. Results from western blot showed that combination therapy significantly up-regulated the protein of VEGF and BDNF expression and down-regulated the protein of phosphorylation-p38MAPK, proNGF, p75NTR and RhoA expressions in SCI rats. Combination therapy stimulation also suppressed the caspase-3 activation in SCI rats. These results demonstrated that the effects of bone marrow mesenchymal stem cells combination with minocycline improve SCI in rat model. PMID:26722382

Gold Nano Popcorn Attached SWCNT Hybrid Nanomaterial for Targeted Diagnosis and Photothermal Therapy of Human Breast Cancer Cells

PubMed Central

Beqa, Lule; Fan, Zhen; Singh, Anant Kumar; Senapati, Dulal; Ray, Paresh Chandra

2011-01-01

Breast cancer presents greatest challenge in health care in today’s world. The key to ultimately successful treatment of breast cancer disease is an early and accurate diagnosis. Current breast cancer treatments are often associated with severe side effects. Driven by the need, we report the design of novel hybrid nanomaterial using gold nano popcorn-attached single wall carbon nanotube for targeted diagnosis and selective photothermal treatment. Targeted SK-BR-3 human breast cancer cell sensing have been performed in 10 cancer cells/mL level, using surface enhanced Raman scattering of single walls carbon nanotube’s D and G bands. Our data show that S6 aptamer attached hybrid nanomaterial based SERS assay is highly sensitive to targeted human breast cancer SK-BR-3 cell line and it will be able to distinguish it from other non targeted MDA-MB breast cancer cell line and HaCaT normal skin cell line. Our results also show that 10 minutes of photothermal therapy treatment by 1.5 W/cm2 power, 785 nm laser is enough to kill cancer cells very effectively using S6 aptamer attached hybrid nanomaterials. Possible mechanisms for targeted sensing and operating principle for highly efficient photothermal therapy have been discussed. Our experimental results reported here open up a new possibility for using aptamers modified hybrid nanomaterial for reliable diagnosis and targeted therapy of cancer cell lines quickly. PMID:21842867

Gold nano-popcorn attached SWCNT hybrid nanomaterial for targeted diagnosis and photothermal therapy of human breast cancer cells.

PubMed

Beqa, Lule; Fan, Zhen; Singh, Anant Kumar; Senapati, Dulal; Ray, Paresh Chandra

2011-09-01

Breast cancer presents greatest challenge in health care in today's world. The key to ultimately successful treatment of breast cancer disease is an early and accurate diagnosis. Current breast cancer treatments are often associated with severe side effects. Driven by the need, we report the design of novel hybrid nanomaterial using gold nano popcorn-attached single wall carbon nanotube for targeted diagnosis and selective photothermal treatment. Targeted SK-BR-3 human breast cancer cell sensing have been performed in 10 cancer cells/mL level, using surface enhanced Raman scattering of single walls carbon nanotube's D and G bands. Our data show that S6 aptamer attached hybrid nanomaterial based SERS assay is highly sensitive to targeted human breast cancer SK-BR-3 cell line and it will be able to distinguish it from other non targeted MDA-MB breast cancer cell line and HaCaT normal skin cell line. Our results also show that 10 min of photothermal therapy treatment by 1.5 W/cm(2) power, 785 nm laser is enough to kill cancer cells very effectively using S6 aptamer attached hybrid nanomaterials. Possible mechanisms for targeted sensing and operating principle for highly efficient photothermal therapy have been discussed. Our experimental results reported here open up a new possibility for using aptamers modified hybrid nanomaterial for reliable diagnosis and targeted therapy of cancer cell lines quickly.

Non-small cell lung carcinoma therapy using mTOR-siRNA.

PubMed

Matsubara, Hirochika; Sakakibara, Kenji; Kunimitsu, Tamo; Matsuoka, Hiroyasu; Kato, Kaori; Oyachi, Noboru; Dobashi, Yoh; Matsumoto, Masahiko

2012-01-01

Molecular targeting agents play important roles in non-small-cell lung cancer (NSCLC) therapy. Published studies have investigated new drugs categorized as molecular targeting agents that inhibit the mammalian target of rapamycin (mTOR). We focused on a small interfering RNA (siRNA) that specifically inhibits mTOR and has fewer side effects. To evaluate the antitumor effects of the siRNA, cell proliferation, apoptosis, and migration were assessed. In the study group, the siRNA was transfected into NSCLC cells. The number of cells present after 6 days of culture was counted to determine changes in cell proliferation. The level of apoptosis was evaluated by the detection of DNA-histone complexes in the cytoplasmic fraction using an absorption spectrometer. Changes in migration were evaluated by calculating the number of cells that passed through a specific filter using a commercial chemotaxis assay kit. mTOR-siRNA transfection inhibited cell proliferation as indicated by 37.3% (p = 0.034) decrease in the number of cells compared with the control cells. Analysis of the level of apoptosis in NSCLC cells revealed 16.7% (p = 0.016) increase following mTOR-siRNA transfection, and mTOR-siRNA transfection significantly inhibited cell migration by 39.2% (p = 0.0001). We confirmed that mTOR-siRNA induces apoptosis and inhibits the proliferation and migration of NSCLC cells in vitro. Further studies using mTOR-siRNA may aid in the development of an alternative therapy that maximizes the antineoplastic effect of mTOR inhibition.

Non-small cell lung carcinoma therapy using mTOR-siRNA

PubMed Central

Matsubara, Hirochika; Sakakibara, Kenji; Kunimitsu, Tamo; Matsuoka, Hiroyasu; Kato, Kaori; Oyachi, Noboru; Dobashi, Yoh; Matsumoto, Masahiko

2012-01-01

Molecular targeting agents play important roles in non-small-cell lung cancer (NSCLC) therapy. Published studies have investigated new drugs categorized as molecular targeting agents that inhibit the mammalian target of rapamycin (mTOR). We focused on a small interfering RNA (siRNA) that specifically inhibits mTOR and has fewer side effects. To evaluate the antitumor effects of the siRNA, cell proliferation, apoptosis, and migration were assessed. In the study group, the siRNA was transfected into NSCLC cells. The number of cells present after 6 days of culture was counted to determine changes in cell proliferation. The level of apoptosis was evaluated by the detection of DNA-histone complexes in the cytoplasmic fraction using an absorption spectrometer. Changes in migration were evaluated by calculating the number of cells that passed through a specific filter using a commercial chemotaxis assay kit. mTOR-siRNA transfection inhibited cell proliferation as indicated by 37.3% (p = 0.034) decrease in the number of cells compared with the control cells. Analysis of the level of apoptosis in NSCLC cells revealed 16.7% (p = 0.016) increase following mTOR-siRNA transfection, and mTOR-siRNA transfection significantly inhibited cell migration by 39.2% (p = 0.0001). We confirmed that mTOR-siRNA induces apoptosis and inhibits the proliferation and migration of NSCLC cells in vitro. Further studies using mTOR-siRNA may aid in the development of an alternative therapy that maximizes the antineoplastic effect of mTOR inhibition. PMID:22400071

Time-Dependent Recovery of Human Synovial Membrane Mesenchymal Stem Cell Function After High-Dose Steroid Therapy: Case Report and Laboratory Study.

PubMed

Yasui, Yukihiko; Hart, David A; Sugita, Norihiko; Chijimatsu, Ryota; Koizumi, Kota; Ando, Wataru; Moriguchi, Yu; Shimomura, Kazunori; Myoui, Akira; Yoshikawa, Hideki; Nakamura, Norimasa

2018-03-01

The use of mesenchymal stem cells from various tissue sources to repair injured tissues has been explored over the past decade in large preclinical models and is now moving into the clinic. To report the case of a patient who exhibited compromised mesenchymal stem cell (MSC) function shortly after use of high-dose steroid to treat Bell's palsy, who recovered 7 weeks after therapy. Case report and controlled laboratory study. A patient enrolled in a first-in-human clinical trial for autologous implantation of a scaffold-free tissue engineered construct (TEC) derived from synovial MSCs for chondral lesion repair had a week of high-dose steroid therapy for Bell's palsy. Synovial tissue was harvested for MSC preparation after a 3-week recovery period and again at 7 weeks after therapy. The MSC proliferation rates and cell surface marker expression profiles from the 3-week sample met conditions for further processing. However, the cells failed to generate a functional TEC. In contrast, MSCs harvested at 7 weeks after steroid therapy were functional in this regard. Further in vitro studies with MSCs and steroids indicated that the effect of in vivo steroids was likely a direct effect of the drug on the MSCs. This case suggests that MSCs are transiently compromised after high-dose steroid therapy and that careful consideration regarding timing of MSC harvest is critical. The drug profiles of MSC donors and recipients must be carefully monitored to optimize opportunities to successfully repair damaged tissues.

Biochemistry and biology: heart-to-heart to investigate cardiac progenitor cells.

PubMed

Chimenti, Isotta; Forte, Elvira; Angelini, Francesco; Messina, Elisa; Giacomello, Alessandro

2013-02-01

Cardiac regenerative medicine is a rapidly evolving field, with promising future developments for effective personalized treatments. Several stem/progenitor cells are candidates for cardiac cell therapy, and emerging evidence suggests how multiple metabolic and biochemical pathways strictly regulate their fate and renewal. In this review, we will explore a selection of areas of common interest for biology and biochemistry concerning stem/progenitor cells, and in particular cardiac progenitor cells. Numerous regulatory mechanisms have been identified that link stem cell signaling and functions to the modulation of metabolic pathways, and vice versa. Pharmacological treatments and culture requirements may be exploited to modulate stem cell pluripotency and self-renewal, possibly boosting their regenerative potential for cell therapy. Mitochondria and their many related metabolites and messengers, such as oxygen, ROS, calcium and glucose, have a crucial role in regulating stem cell fate and the balance of their functions, together with many metabolic enzymes. Furthermore, protein biochemistry and proteomics can provide precious clues on the definition of different progenitor cell populations, their physiology and their autocrine/paracrine regulatory/signaling networks. Interdisciplinary approaches between biology and biochemistry can provide productive insights on stem/progenitor cells, allowing the development of novel strategies and protocols for effective cardiac cell therapy clinical translation. This article is part of a Special Issue entitled Biochemistry of Stem Cells. Copyright © 2012 Elsevier B.V. All rights reserved.

Cell therapy in joint disorders.

PubMed

Counsel, Peter D; Bates, Daniel; Boyd, Richard; Connell, David A

2015-01-01

Articular cartilage possesses poor natural healing mechanisms, and a variety of non-cell-based and cell-based treatments aim to promote regeneration of hyaline cartilage. A review of the literature to December 2013 using PubMed with search criteria including the keywords stem cell, cell therapy, cell transplantation, cartilage, chondral, and chondrogenic. Forty-five articles were identified that employed local mesenchymal stem cell (MSC) therapy for joint disorders in humans. Nine comparative studies were identified, consisting of 3 randomized trials, 5 cohort studies, and 1 case-control study. Clinical review. Level 4. Studies were assessed for stem cell source, method of implantation, comparison groups, and concurrent surgical techniques. Two studies comparing MSC treatment to autologous chondrocyte implantation found similar efficacy. Three studies reported clinical benefits with intra-articular MSC injection over non-MSC controls for cases undergoing debridement with or without marrow stimulation, although a randomized study found no significant clinical difference at 2-year follow-up but reported better 18-month magnetic resonance imaging and histologic scores in the MSC group. No human studies have compared intra-articular MSC therapy to non-MSC techniques for osteoarthritis in the absence of surgery. Mesenchymal stem cell-based therapies appear safe and effective for joint disorders in large animal preclinical models. Evidence for use in humans, particularly, comparison with more established treatments such as autologous chondrocyte implantation and microfracture, is limited.

A targeted complement-dependent strategy to improve the outcome of mAb therapy, and characterization in a murine model of metastatic cancer

PubMed Central

Elvington, Michelle; Huang, Yuxiang; Morgan, B. Paul; Qiao, Fei; van Rooijen, Nico; Atkinson, Carl

2012-01-01

Complement inhibitors expressed on tumor cells provide an evasion mechanism against mAb therapy and may modulate the development of an acquired antitumor immune response. Here we investigate a strategy to amplify mAb-targeted complement activation on a tumor cell, independent of a requirement to target and block complement inhibitor expression or function, which is difficult to achieve in vivo. We constructed a murine fusion protein, CR2Fc, and demonstrated that the protein targets to C3 activation products deposited on a tumor cell by a specific mAb, and amplifies mAb-dependent complement activation and tumor cell lysis in vitro. In syngeneic models of metastatic lymphoma (EL4) and melanoma (B16), CR2Fc significantly enhanced the outcome of mAb therapy. Subsequent studies using the EL4 model with various genetically modified mice and macrophage-depleted mice revealed that CR2Fc enhanced the therapeutic effect of mAb therapy via both macrophage-dependent FcγR-mediated antibody-dependent cellular cytotoxicity, and by direct complement-mediated lysis. Complement activation products can also modulate adaptive immunity, but we found no evidence that either mAb or CR2Fc treatment had any effect on an antitumor humoral or cellular immune response. CR2Fc represents a potential adjuvant treatment to increase the effectiveness of mAb therapy of cancer. PMID:22442351

Concise Review: Pluripotent Stem Cell-Derived Cardiac Cells, A Promising Cell Source for Therapy of Heart Failure: Where Do We Stand?

PubMed

Gouadon, Elodie; Moore-Morris, Thomas; Smit, Nicoline W; Chatenoud, Lucienne; Coronel, Ruben; Harding, Sian E; Jourdon, Philippe; Lambert, Virginie; Rucker-Martin, Catherine; Pucéat, Michel

2016-01-01

Heart failure is still a major cause of hospitalization and mortality in developed countries. Many clinical trials have tested the use of multipotent stem cells as a cardiac regenerative medicine. The benefit for the patients of this therapeutic intervention has remained limited. Herein, we review the pluripotent stem cells as a cell source for cardiac regeneration. We more specifically address the various challenges of this cell therapy approach. We question the cell delivery systems, the immune tolerance of allogenic cells, the potential proarrhythmic effects, various drug mediated interventions to facilitate cell grafting and, finally, we describe the pathological conditions that may benefit from such an innovative approach. As members of a transatlantic consortium of excellence of basic science researchers and clinicians, we propose some guidelines to be applied to cell types and modes of delivery in order to translate pluripotent stem cell cardiac derivatives into safe and effective clinical trials. © 2015 AlphaMed Press.

Human papillomavirus status and the relative biological effectiveness of proton radiotherapy in head and neck cancer cells.

PubMed

Wang, Li; Wang, Xiaochun; Li, Yuting; Han, Shichao; Zhu, Jinming; Wang, Xiaofang; Molkentine, David P; Blanchard, Pierre; Yang, Yining; Zhang, Ruiping; Sahoo, Narayan; Gillin, Michael; Zhu, Xiaorong Ronald; Zhang, Xiaodong; Myers, Jeffrey N; Frank, Steven J

2017-04-01

Human papillomavirus (HPV)-positive oropharyngeal carcinomas response better to X-ray therapy (XRT) than HPV-negative disease. Whether HPV status influences the sensitivity of head and neck cancer cells to proton therapy or the relative biological effectiveness (RBE) of protons versus XRT is unknown. Clonogenic survival was used to calculate the RBE; immunocytochemical analysis and neutral comet assay were used to evaluate unrepaired DNA double-strand breaks. HPV-positive cells were more sensitive to protons and the unrepaired double-strand breaks were more numerous in HPV-positive cells than in HPV-negative cells (p < .001). Protons killed more cells than did XRT at all fraction sizes (all RBEs > 1.06). Cell line type and radiation fraction size influenced the RBE. HPV-positive cells were more sensitive to protons than HPV-negative cells maybe through the effects of HPV on DNA damage and repair. The RBE for protons depends more on cell type and fraction size than on HPV status. © 2016 Wiley Periodicals, Inc. Head Neck 39: 708-715, 2017. © 2016 Wiley Periodicals, Inc.

Effective Gene Therapy of Mice with Congenital Erythropoietic Porphyria Is Facilitated by a Survival Advantage of Corrected Erythroid Cells

PubMed Central

Robert-Richard, Elodie; Moreau-Gaudry, François; Lalanne, Magalie; Lamrissi-Garcia, Isabelle; Cario-André, Muriel; Guyonnet-Dupérat, Véronique; Taine, Laurence; Ged, Cécile; de Verneuil, Hubert

2008-01-01

Achieving long-term expression of a therapeutic gene in a given hematopoietic lineage remains an important goal of gene therapy. Congenital erythropoietic porphyria (CEP) is a severe autosomal-recessive disorder characterized by a deficiency in uroporphyrinogen III synthase (UROS), the fourth enzyme of the heme biosynthetic pathway. We used a recently obtained murine model to check the feasibility of gene therapy in this disease. Lentivirus-mediated transfer of the human UROS cDNA into hematopoietic stem cells (HSCs) from Urosmut248 mice resulted in a complete and long-term enzymatic, metabolic, and phenotypic correction of the disease, favored by a survival advantage of corrected red blood cells. These results demonstrate that the cure of this mouse model of CEP at a moderate transduction level supports the proof of concept of a gene therapy in this disease by transplantation of genetically modified hematopoietic stem cells. PMID:18179890

Gene therapy for cardiovascular disease mediated by ultrasound and microbubbles

PubMed Central

2013-01-01

Gene therapy provides an efficient approach for treatment of cardiovascular disease. To realize the therapeutic effect, both efficient delivery to the target cells and sustained expression of transgenes are required. Ultrasound targeted microbubble destruction (UTMD) technique has become a potential strategy for target-specific gene and drug delivery. When gene-loaded microbubble is injected, the ultrasound-mediated microbubble destruction may spew the transported gene to the targeted cells or organ. Meanwhile, high amplitude oscillations of microbubbles increase the permeability of capillary and cell membrane, facilitating uptake of the released gene into tissue and cell. Therefore, efficiency of gene therapy can be significantly improved. To date, UTMD has been successfully investigated in many diseases, and it has achieved outstanding progress in the last two decades. Herein, we discuss the current status of gene therapy of cardiovascular diseases, and reviewed the progress of the delivery of genes to cardiovascular system by UTMD. PMID:23594865

Elimination of established murine colon carcinoma metastases by antibody-interleukin 2 fusion protein therapy.

PubMed

Xiang, R; Lode, H N; Dolman, C S; Dreier, T; Varki, N M; Qian, X; Lo, K M; Lan, Y; Super, M; Gillies, S D; Reisfeld, R A

1997-11-01

A recombinant humanized antibody-interleukin 2 fusion protein (huKS1/4-IL-2) was used to direct IL-2 to the tumor microenvironment and elicit a T cell-mediated eradication of established pulmonary and hepatic CT26-KSA colon carcinoma metastases in syngeneic BALB/c mice. This antitumor effect was specific because a fusion protein, which was nonreactive with these tumor cells, failed to exert any such effect. The efficacy of the huKS1/4-IL-2 fusion protein in eliminating metastases was documented because mixtures of monoclonal antibody huKS1/4 with recombinant human IL-2 were ineffective and, at best, only partially reduced tumor load. Two lines of evidence indicated the eradication of metastases and the absence of minimal residual disease in animals treated with the fusion protein: first, the lack of detection of CT26-KSA cells by reverse transcription-PCR, which can detect one tumor cell in 10(6) liver cells; and second, the tripling of life span. The effector mechanism involved in this tumor eradication is dependent on T cells because the IL-2-directed therapy is ineffective in T cell-deficient SCID mice. The essential effector cells were further characterized as CD8+ T cells by in vivo depletion studies. Such T cells, isolated from tumor-bearing mice after fusion protein therapy, elicited MHC class I-restricted cytotoxicity in vitro against colon carcinoma target cells. Taken together, these data indicate that fusion protein-directed IL-2 therapy induces a T cell-dependent host immune response capable of eradicating established colon cancer metastases in an animal tumor model.

Effects of Intravenous Administration of Human Umbilical Cord Blood Stem Cells in 3-Acetylpyridine-Lesioned Rats

PubMed Central

Calatrava-Ferreras, Lucía; Gonzalo-Gobernado, Rafael; Herranz, Antonio S.; Reimers, Diana; Montero Vega, Teresa; Jiménez-Escrig, Adriano; Richart López, Luis Alberto; Bazán, Eulalia

2012-01-01

Cerebellar ataxias include a heterogeneous group of infrequent diseases characterized by lack of motor coordination caused by disturbances in the cerebellum and its associated circuits. Current therapies are based on the use of drugs that correct some of the molecular processes involved in their pathogenesis. Although these treatments yielded promising results, there is not yet an effective therapy for these diseases. Cell replacement strategies using human umbilical cord blood mononuclear cells (HuUCBMCs) have emerged as a promising approach for restoration of function in neurodegenerative diseases. The aim of this work was to investigate the potential therapeutic activity of HuUCBMCs in the 3-acetylpyridine (3-AP) rat model of cerebellar ataxia. Intravenous administered HuUCBMCs reached the cerebellum and brain stem of 3-AP ataxic rats. Grafted cells reduced 3-AP-induced neuronal loss promoted the activation of microglia in the brain stem, and prevented the overexpression of GFAP elicited by 3-AP in the cerebellum. In addition, HuUCBMCs upregulated the expression of proteins that are critical for cell survival, such as phospho-Akt and Bcl-2, in the cerebellum and brain stem of 3-AP ataxic rats. As all these effects were accompanied by a temporal but significant improvement in motor coordination, HuUCBMCs grafts can be considered as an effective cell replacement therapy for cerebellar disorders. PMID:23150735

Effective elimination of cancer stem cells by magnetic hyperthermia.

PubMed

Sadhukha, Tanmoy; Niu, Lin; Wiedmann, Timothy Scott; Panyam, Jayanth

2013-04-01

Cancer stem cells (CSCs) are a subpopulation of cancer cells that have stem cell-like properties and are thought to be responsible for tumor drug resistance and relapse. Therapies that can effectively eliminate CSCs will, therefore, likely inhibit tumor recurrence. The objective of our study was to determine the susceptibility of CSCs to magnetic hyperthermia, a treatment that utilizes superparamagnetic iron oxide nanoparticles placed in an alternating magnetic field to generate localized heat and achieve selective tumor cell kill. SPIO NPs having a magnetite core of 12 nm were used to induce magnetic hyperthermia in A549 and MDA-MB-231 tumor cells. Multiple assays for CSCs, including side population phenotype, aldehyde dehydrogenase expression, mammosphere formation, and in vivo xenotransplantation, indicated that magnetic hyperthermia reduced or, in some cases, eliminated the CSC subpopulation in treated cells. Interestingly, conventional hyperthermia, induced by subjecting cells to elevated temperature (46 °C) in a water bath, was not effective in eliminating CSCs. Our studies show that magnetic hyperthermia has pleiotropic effects, inducing acute necrosis in some cells while stimulating reactive oxygen species generation and slower cell kill in others. These results suggest the potential for lower rates of tumor recurrence after magnetic hyperthermia compared to conventional cancer therapies.

Regulation of stem cell-based therapies in Canada: current issues and concerns.

PubMed

von Tigerstrom, Barbara; Nguyen, Thu Minh; Knoppers, Bartha Maria

2012-09-01

Stem cell therapies offer enormous potential for the treatment of a wide range of diseases and conditions. Despite the excitement over such advances, regulators are faced with the challenge of determining criteria to ensure stem cells and their products are safe and effective for human use. However, stem cell-based products and therapies present unique regulatory challenges because standard drug development models do not wholly apply given the complexity and diversity of these products and therapies. As a result, regulatory requirements are often unclear and ambiguous creating unnecessary barriers for research. In order to better understand the barriers that might affect Canadian stem cell researchers, we sought feedback from stakeholders regarding areas of uncertainty or concern about existing regulatory oversight of cell therapies. A selection of Canadian researchers and clinicians working in the area of stem cell research were interviewed to assess certain key questions: 1) whether current regulatory requirements are easily accessible and well understood; 2) whether regulatory requirements create important challenges or barriers; and 3) whether there is a need for further guidance on the issue. The results of this survey are summarized and compared to issues and concerns experienced in other countries, as reported in the literature, to identify challenges which may be on the horizon and to provide possible solutions for regulatory reform.

Overcoming chemotherapy drug resistance by targeting inhibitors of apoptosis proteins (IAPs).

PubMed

Rathore, Rama; McCallum, Jennifer E; Varghese, Elizabeth; Florea, Ana-Maria; Büsselberg, Dietrich

2017-07-01

Inhibitors of apoptosis (IAPs) are a family of proteins that play a significant role in the control of programmed cell death (PCD). PCD is essential to maintain healthy cell turnover within tissue but also to fight disease or infection. Uninhibited, IAPs can suppress apoptosis and promote cell cycle progression. Therefore, it is unsurprising that cancer cells demonstrate significantly elevated expression levels of IAPs, resulting in improved cell survival, enhanced tumor growth and subsequent metastasis. Therapies to target IAPs in cancer has garnered substantial scientific interest and as resistance to anti-cancer agents becomes more prevalent, targeting IAPs has become an increasingly attractive strategy to re-sensitize cancer cells to chemotherapies, antibody based-therapies and TRAIL therapy. Antagonism strategies to modulate the actions of XIAP, cIAP1/2 and survivin are the central focus of current research and this review highlights advances within this field with particular emphasis upon the development and specificity of second mitochondria-derived activator of caspase (SMAC) mimetics (synthetic analogs of endogenously expressed inhibitors of IAPs SMAC/DIABLO). While we highlight the potential of SMAC mimetics as effective single agent or combinatory therapies to treat cancer we also discuss the likely clinical implications of resistance to SMAC mimetic therapy, occasionally observed in cancer cell lines.

Anodal Transcranial Direct Current Stimulation Enhances Survival and Integration of Dopaminergic Cell Transplants in a Rat Parkinson Model.

PubMed

Winkler, Christian; Reis, Janine; Hoffmann, Nadin; Gellner, Anne-Kathrin; Münkel, Christian; Curado, Marco Rocha; Furlanetti, Luciano; Garcia, Joanna; Döbrössy, Máté D; Fritsch, Brita

2017-01-01

Restorative therapy concepts, such as cell based therapies aim to restitute impaired neurotransmission in neurodegenerative diseases. New strategies to enhance grafted cell survival and integration are still needed to improve functional recovery. Anodal direct current stimulation (DCS) promotes neuronal activity and secretion of the trophic factor BDNF in the motor cortex. Transcranial DCS applied to the motor cortex transiently improves motor symptoms in Parkinson's disease (PD) patients. In this proof-of-concept study, we combine cell based therapy and noninvasive neuromodulation to assess whether neurotrophic support via transcranial DCS would enhance the restitution of striatal neurotransmission by fetal dopaminergic transplants in a rat Parkinson model. Transcranial DCS was applied daily for 20 min on 14 consecutive days following striatal transplantation of fetal ventral mesencephalic (fVM) cells derived from transgenic rat embryos ubiquitously expressing GFP. Anodal but not cathodal transcranial DCS significantly enhanced graft survival and dopaminergic reinnervation of the surrounding striatal tissue relative to sham stimulation. Behavioral recovery was more pronounced following anodal transcranial DCS, and behavioral effects correlated with the degree of striatal innervation. Our results suggest anodal transcranial DCS may help advance cell-based restorative therapies in neurodegenerative diseases. In particular, such an assistive approach may be beneficial for the already established cell transplantation therapy in PD.

The regulation of immune cells by Lactobacilli: a potential therapeutic target for anti-atherosclerosis therapy

PubMed Central

Ding, Ya-Hui; Qian, Lin-Yan; Pang, Jie; Lin, Jing-Yang; Xu, Qiang; Wang, Li-Hong; Huang, Dong-Sheng; Zou, Hai

2017-01-01

Atherosclerosis is an inflammatory disease regulated by several immune cells including lymphocytes, macrophages and dendritic cells. Gut probiotic bacteria like Lactobacilli have been shown immunomodificatory effects in the progression of atherogenesis. Some Lactobacillus stains can upregulate the activity of regulatory T-lymphocytes, suppress T-lymphocyte helper (Th) cells Th1, Th17, alter the Th1/Th2 ratio, influence the subsets ratio of M1/M2 macrophages, inhibit foam cell formation by suppressing macrophage phagocytosis of oxidized low-density lipoprotein, block the activation of the immune system with dendritic cells, which are expected to suppress the atherosclerosis-related inflammation. However, various strains can have various effects on inflammation. Some other Lactobacillus strains were found have potential pro-atherogenic effect through promote Th1 cell activity, increase pro-inflammatory cytokines levels as well as decrease anti-inflammatory cytokines levels. Thus, identifying the appropriate strains is essential to the therapeutic potential of Lactobacilli as an anti-atherosclerotic therapy. PMID:28938693

Combination of SLC administration and Tregs depletion is an attractive strategy for targeting hepatocellular carcinoma

PubMed Central

2013-01-01

Background Secondary lymphoid tissue chemokine (SLC) is a key CC chemokine for chemotaxis of immune cells and has been an attractive candidate for anti-tumor treatments. However, among the immune cells recruited by SLC to tumors, the CD25+ Foxp3+ regulatory T cells (Tregs) compromise the anti-tumor effects. In this study, we proposed the combination therapy of intratumoral co-administration of SLC and anti-CD25 monoclonal antibodies (mAbs). We hypothesized that the intratumoral injections of SLC and depletion of Tregs would have stronger inhibition effects on the progression of hepatocellular carcinoma (HCC) in mice. Methods C57BL/6 mice were inoculated subcutaneously with the murine HCC cell line, and mice with visible tumors were treated intratumorally with SLC, SLC plus anti-CD25 mAbs or the control antibodies. The percentages of Tregs, effector CD8+ T cells and CD4+ T cells were checked in the tumors, lymph nodes, spleen and liver at regular intervals. The levels of intratumoral IL-12, IFN-γ, IL-10 and TGF-β1 were evaluated. The final anti-tumor effects were measured by the tumor volume and weight as well as the intratumoral activity of MMP2 and MMP9. Bone-marrow-derived dendritic cells were used to explore the mechanisms of maturation induced by SLC in vitro. Results Our experiments showed the combination therapy significantly decreased the frequency of Tregs, and increased CD8+ T cells and CD4+ T cells at tumor sites. These alterations were accompanied by an increased level of IL-12 and IFN-γ, and decreased level of IL-10 and TGF-β1. Unexpectedly, we observed a significantly decreased percentage of Tregs, and increased CD8+ T cells and CD4+ T cells in the lymph nodes, spleen and liver after the combination therapy. The growth and invasiveness of HCC was also maximally inhibited in the combination therapy compared with the SLC alone. Furthermore, we confirmed SLC induced the maturation of DCs via NF-κB p65 and this maturation would benefit the combination therapy. Conclusions Our data demonstrated that intratumoral co-administration of SLC and anti-CD25 mAbs was an effective treatment for HCC, which was correlated with the altered tumor microenvironment and systemically optimized percentages of Tregs, CD8+ T cells and CD4+ T cells in peripheral immune organs. PMID:24304581

Differential Efficacy of Combined Therapy With Radiation and AEE788 in High and Low EGFR-Expressing Androgen-Independent Prostate Tumor Models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huamani, Jessica; Willey, Christopher; Thotala, Dinesh

2008-05-01

Purpose: To determine the efficacy of combining radiation (XRT) with a dual epidermal growth factor receptor (EGFR)/vascular endothelial growth factor receptor inhibitor, AEE788, in prostate cancer models with different levels of EGFR expression. Methods and Materials: Immunoblotting was performed for EGFR, phosphorylated-EGFR, and phosphorylated-AKT in prostate cancer cells. Clonogenic assays were performed on DU145, PC-3, and human umbilical vein endothelial cells treated with XRT {+-} AEE788. Tumor xenografts were established for DU145 and PC-3 on hind limbs of athymic nude mice assigned to four treatment groups: (1) control, (2) AEE788, (3) XRT, and (4) AEE788 + XRT. Tumor blood flowmore » and growth measurements were performed using immunohistochemistry and imaging. Results: AEE788 effectively decreased phosphorylated-EGFR and phosphorylated-AKT levels in DU145 and PC-3 cells. Clonogenic assays showed no radiosensitization for DU145 and PC-3 colonies treated with AEE788 + XRT. However, AEE788 caused decreased proliferation in DU145 cells. AEE788 showed a radiosensitization effect in human umbilical vein endothelial cells and increased apoptosis susceptibility. Concurrent AEE788 + XRT compared with either alone led to significant tumor growth delay in DU145 tumors. Conversely, PC-3 tumors derived no added benefit from combined-modality therapy. In DU145 tumors, a significant decrease in tumor blood flow with combination therapy was shown by using power Doppler sonography and tumor blood vessel destruction on immunohistochemistry. Maldi-spectrometry (MS) imaging showed that AEE788 is bioavailable and heterogeneously distributed in DU145 tumors undergoing therapy. Conclusions: AEE788 + XRT showed efficacy in vitro/in vivo with DU145-based cell models, whereas PC-3-based models were adequately treated with XRT alone without added benefit from combination therapy. These findings correlated with differences in EGFR expression and showed effects on both tumor cell proliferation and vascular destruction.« less

Meta-Analysis of Cell-based CaRdiac stUdiEs (ACCRUE) in patients with acute myocardial infarction based on individual patient data.

PubMed

Gyöngyösi, Mariann; Wojakowski, Wojciech; Lemarchand, Patricia; Lunde, Ketil; Tendera, Michal; Bartunek, Jozef; Marban, Eduardo; Assmus, Birgit; Henry, Timothy D; Traverse, Jay H; Moyé, Lemuel A; Sürder, Daniel; Corti, Roberto; Huikuri, Heikki; Miettinen, Johanna; Wöhrle, Jochen; Obradovic, Slobodan; Roncalli, Jérome; Malliaras, Konstantinos; Pokushalov, Evgeny; Romanov, Alexander; Kastrup, Jens; Bergmann, Martin W; Atsma, Douwe E; Diederichsen, Axel; Edes, Istvan; Benedek, Imre; Benedek, Theodora; Pejkov, Hristo; Nyolczas, Noemi; Pavo, Noemi; Bergler-Klein, Jutta; Pavo, Imre J; Sylven, Christer; Berti, Sergio; Navarese, Eliano P; Maurer, Gerald

2015-04-10

The meta-Analysis of Cell-based CaRdiac study is the first prospectively declared collaborative multinational database, including individual data of patients with ischemic heart disease treated with cell therapy. We analyzed the safety and efficacy of intracoronary cell therapy after acute myocardial infarction (AMI), including individual patient data from 12 randomized trials (ASTAMI, Aalst, BOOST, BONAMI, CADUCEUS, FINCELL, REGENT, REPAIR-AMI, SCAMI, SWISS-AMI, TIME, LATE-TIME; n=1252). The primary end point was freedom from combined major adverse cardiac and cerebrovascular events (including all-cause death, AMI recurrance, stroke, and target vessel revascularization). The secondary end point was freedom from hard clinical end points (death, AMI recurrence, or stroke), assessed with random-effects meta-analyses and Cox regressions for interactions. Secondary efficacy end points included changes in end-diastolic volume, end-systolic volume, and ejection fraction, analyzed with random-effects meta-analyses and ANCOVA. We reported weighted mean differences between cell therapy and control groups. No effect of cell therapy on major adverse cardiac and cerebrovascular events (14.0% versus 16.3%; hazard ratio, 0.86; 95% confidence interval, 0.63-1.18) or death (1.4% versus 2.1%) or death/AMI recurrence/stroke (2.9% versus 4.7%) was identified in comparison with controls. No changes in ejection fraction (mean difference: 0.96%; 95% confidence interval, -0.2 to 2.1), end-diastolic volume, or systolic volume were observed compared with controls. These results were not influenced by anterior AMI location, reduced baseline ejection fraction, or the use of MRI for assessing left ventricular parameters. This meta-analysis of individual patient data from randomized trials in patients with recent AMI revealed that intracoronary cell therapy provided no benefit, in terms of clinical events or changes in left ventricular function. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01098591. © 2015 American Heart Association, Inc.

Transplantation of human cord blood mononuclear cells and umbilical cord-derived mesenchymal stem cells in autism

PubMed Central

2013-01-01

Background Autism is a pervasive neurodevelopmental disorder. At present there are no defined mechanisms of pathogenesis and therapy is mostly limited to behavioral interventions. Stem cell transplantation may offer a unique treatment strategy for autism due to immune and neural dysregulation observed in this disease. This non-randomized, open-label, single center phase I/II trial investigated the safety and efficacy of combined transplantation of human cord blood mononuclear cells (CBMNCs) and umbilical cord-derived mesenchymal stem cells (UCMSCs) in treating children with autism. Methods 37 subjects diagnosed with autism were enrolled into this study and divided into three groups: CBMNC group (14 subjects, received CBMNC transplantation and rehabilitation therapy), Combination group (9 subjects, received both CBMNC and UCMSC transplantation and rehabilitation therapy), and Control group (14 subjects, received only rehabilitation therapy). Transplantations included four stem cell infusions through intravenous and intrathecal injections once a week. Treatment safety was evaluated with laboratory examinations and clinical assessment of adverse effects. The Childhood Autism Rating Scale (CARS), Clinical Global Impression (CGI) scale and Aberrant Behavior Checklist (ABC) were adopted to assess the therapeutic efficacy at baseline (pre-treatment) and following treatment. Results There were no significant safety issues related to the treatment and no observed severe adverse effects. Statistically significant differences were shown on CARS, ABC scores and CGI evaluation in the two treatment groups compared to the control at 24 weeks post-treatment (p < 0.05). Conclusions Transplantation of CBMNCs demonstrated efficacy compared to the control group; however, the combination of CBMNCs and UCMSCs showed larger therapeutic effects than the CBMNC transplantation alone. There were no safety issues noted during infusion and the whole monitoring period. Trial registration ClinicalTrials.gov: NCT01343511, Title “Safety and Efficacy of Stem Cell Therapy in Patients with Autism”. PMID:23978163

Assessment of Erythroid and Granulocytic Hematopoietic Lineages in Patients with Non-Small-Cell Lung Carcinoma.

PubMed

Goldberg, V E; Polyakova, T Yu; Popova, N O; Vysotskaya, V V; Simolina, E I; Belevich, Yu V; Tuzikova, T P; Goldberg, A V; Zhdanov, V V; Miroshnichenko, L A; Udut, E V; Simanina, E V; Dygai, A M; Zyuz'kov, G N

2017-08-01

The toxic effects of combined cisplatin/docetaxel therapy cycles on erythroid and granulocytic hematopoietic lineages as well as their intercycle recovery were examined in patients with stage III-IV non-small-cell lung carcinoma. Responsiveness of the blood system to this therapy remained at a high level. Combined therapy pronouncedly activated the key elements of the erythroid and granulocytic hematopoietic lineages leading to accumulation of immature and mature myelokaryocytes in the bone marrow, enlargement of the medullary pool of mature neutrophils, and increase in the count of medullary erythroid and granulocytic precursor cells under conditions of their accelerated maturation.

Adoptive cell therapy: past, present and future.

PubMed

Cohen, Jonathan E; Merims, Sharon; Frank, Stephen; Engelstein, Roni; Peretz, Tamar; Lotem, Michal

2017-01-01

The immune system is a potent inhibitor of tumor growth with curative potential, constituting in many eyes the future of antineoplastic therapy. Adoptive cell therapy (ACT) is a form of immunotherapy in which autologous cancer-cognate lymphocytes are expanded and modified ex vivo and re-infused to combat the tumor. This review follows the evolvement of ACT and treatment protocols, focusing on unresolved dilemmas regarding this treatment while providing evidence for its effectiveness in refractory patients. Future directions of ACT are discussed, in particular with regard to genetic engineering of autologous cells, and the role of ACT in the era of checkpoint inhibitors is addressed.

Fifty Years of Research in ARDS. Cell-based Therapy for Acute Respiratory Distress Syndrome. Biology and Potential Therapeutic Value.

PubMed

Laffey, John G; Matthay, Michael A

2017-08-01

On the basis of several preclinical studies, cell-based therapy has emerged as a potential new therapeutic for acute respiratory distress syndrome (ARDS). Of the various cell-based therapy options, mesenchymal stem/stromal cells (MSCs) from bone marrow, adipose tissue, and umbilical cord have the most experimental data to support their potential efficacy for lung injury from both infectious and noninfectious causes. Mechanistically, MSCs exert their beneficial effects by release of paracrine factors, microvesicles, and transfer of mitochondria, all of which have antiinflammatory and pro-resolving effects on injured lung endothelium and alveolar epithelium, including enhancing the resolution of pulmonary edema by up-regulating sodium-dependent alveolar fluid clearance. MSCs also have antimicrobial effects mediated by release of antimicrobial factors and by up-regulating monocyte/macrophage phagocytosis. Phase 2a clinical trials to establish safety in ARDS are in progress, and two phase 1 trials did not report any serious adverse events. Several issues need further study, including: determining the optimal methods for large-scale production, reconstitution of cryopreserved cells for clinical use, defining cell potency assays, and determining the therapeutic potential of conditioned media derived from MSCs. Because ARDS is a heterogeneous syndrome, targeting MSCs to patients with ARDS with a more hyperinflammatory endotype may further enhance their potential for efficacy.

Update on B-cell targeted therapies for systemic lupus erythematosus.

PubMed

Mok, Chi Chiu

2014-06-01

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by flares and remission, leading to accrual of organ damage over time as a result of persistent tissue inflammation and treatment-related complications. Novel therapies aiming at better treatment response and fewer adverse effects are being tested in the pipeline. This review summarizes the B-cell abnormalities observed in patients with SLE, and updates recent data on the efficacy and safety of B-cell targeted therapies in the treatment of SLE. The pitfalls of clinical trial design and future directions of the development of SLE therapeutics are discussed. The variability of clinical response to treatment in SLE reflects the clinical and immunological heterogeneity of the disease. The treatment plan for patients with SLE should be individualized with the aim of eradicating disease activity, preventing flares and minimizing treatment-related complications. Despite the disappointment of recent clinical trials, B-cell remains the promising target of future SLE therapies. Results from ongoing clinical trials on B-cell targeted biological agents are eagerly awaited.

Stop and go: hematopoietic cell transplantation in the era of chimeric antigen receptor T cells and checkpoint inhibitors.

PubMed

Ghosh, Arnab; Politikos, Ioannis; Perales, Miguel-Angel

2017-11-01

For several decades, hematopoietic cell transplantation (HCT) has been considered the standard curative therapy for many patients with hematological malignancies. In addition to the cytotoxic effects of the chemotherapy and radiation used in the conditioning regimen, the benefits of HCT are derived from a reset of the immune system and harnessing the ability of donor T cells to eliminate malignant cells. With the dawn of the era of immunotherapies in the form of checkpoint inhibitors and chimeric antigen receptor (CAR) T cells, the role of HCT has evolved. Immunotherapy with checkpoint inhibitors is increasingly being used for relapsed Hodgkin and non-Hodgkin lymphoma after autologous HCT. Checkpoint inhibitors are also being tested after allogeneic HCT with observable benefits in treating hematological malignancies, but with a potential risk of increased graft versus host disease and transplant-related mortality. Immunotherapy with Cluster of differentiation 19 CAR T cells are powerful options with aggressive B-cell malignancies both for therapy and as induction leading to allogeneic HCT. Although immunotherapies with checkpoint inhibition and CAR T cells are increasingly being used to treat hematological malignancies, HCT remains a standard of care for most of the diseases with the best chance of cure. Combination of these therapies with HCT has the potential to more effectively treat hematological malignancies.

Gold nanocages for imaging and therapy of prostate cancer cells

NASA Astrophysics Data System (ADS)

Sironi, Laura; Avvakumova, Svetlana; Galbiati, Elisabetta; Locarno, Silvia A.; Macchi, Chiara; D'Alfonso, Laura; Ruscica, Massimiliano; Magni, Paolo; Collini, Maddalena; Romeo, Sergio; Chirico, Giuseppe; Prosperi, Davide

2016-04-01

Gold nanocages (AuNCs) have been shown to be a useful tool both for imaging and hyperthermia therapy of cancer, thanks to their outstanding optical properties, low toxicity and facile functionalization with targeting molecules, including peptides and antibodies. In particular, hyperthermia is a minimally invasive therapy which takes advantage of the peculiar properties of gold nanoparticles to efficiently convert the absorbed light into heat. Here, we use AuNCs for the selective targeting and imaging of prostate cancer cells. Moreover, we report the hyperthermic effect characterization of the AuNCs both in solution and internalized in cells. Prostate cancer cells were irradiated at different exposure times, with a pulsed near infrared laser, and the cellular viability was evaluated by confocal microscopy.

Quantitative assessment of barriers to the clinical development and adoption of cellular therapies: A pilot study

PubMed Central

Rikabi, Sarah; French, Anna; Pinedo-Villanueva, Rafael; Morrey, Mark E; Wartolowska, Karolina; Judge, Andrew; MacLaren, Robert E; Mathur, Anthony; Williams, David J; Wall, Ivan; Birchall, Martin; Reeve, Brock; Atala, Anthony; Barker, Richard W; Cui, Zhanfeng; Furniss, Dominic; Bure, Kim; Snyder, Evan Y; Karp, Jeffrey M; Price, Andrew; Carr, Andrew; Brindley, David A

2014-01-01

There has been a large increase in basic science activity in cell therapy and a growing portfolio of cell therapy trials. However, the number of industry products available for widespread clinical use does not match this magnitude of activity. We hypothesize that the paucity of engagement with the clinical community is a key contributor to the lack of commercially successful cell therapy products. To investigate this, we launched a pilot study to survey clinicians from five specialities and to determine what they believe to be the most significant barriers to cellular therapy clinical development and adoption. Our study shows that the main concerns among this group are cost-effectiveness, efficacy, reimbursement, and regulation. Addressing these concerns can best be achieved by ensuring that future clinical trials are conducted to adequately answer the questions of both regulators and the broader clinical community. PMID:25383173

Quantitative assessment of barriers to the clinical development and adoption of cellular therapies: A pilot study.

PubMed

Davies, Benjamin M; Rikabi, Sarah; French, Anna; Pinedo-Villanueva, Rafael; Morrey, Mark E; Wartolowska, Karolina; Judge, Andrew; MacLaren, Robert E; Mathur, Anthony; Williams, David J; Wall, Ivan; Birchall, Martin; Reeve, Brock; Atala, Anthony; Barker, Richard W; Cui, Zhanfeng; Furniss, Dominic; Bure, Kim; Snyder, Evan Y; Karp, Jeffrey M; Price, Andrew; Carr, Andrew; Brindley, David A

2014-01-01

There has been a large increase in basic science activity in cell therapy and a growing portfolio of cell therapy trials. However, the number of industry products available for widespread clinical use does not match this magnitude of activity. We hypothesize that the paucity of engagement with the clinical community is a key contributor to the lack of commercially successful cell therapy products. To investigate this, we launched a pilot study to survey clinicians from five specialities and to determine what they believe to be the most significant barriers to cellular therapy clinical development and adoption. Our study shows that the main concerns among this group are cost-effectiveness, efficacy, reimbursement, and regulation. Addressing these concerns can best be achieved by ensuring that future clinical trials are conducted to adequately answer the questions of both regulators and the broader clinical community.

Cell and molecular mechanisms of pathogenesis and treatment of cancer.

PubMed Central

Rew, D. A.

1998-01-01

Surgery remains the mainstay of treatment for most classes of human solid tumours, with the principal exception of lymphomas, but it is insufficient in many cases to guarantee cure. With few exceptions, recurrent and metastatic solid tumours continue to defy attempts to develop effective adjuvant therapies. Recent insights into tumour biology reveal an increasingly complex picture of cell and molecular processes which confer heterogeneity and resistance to treatment upon tumours. These insights may also yield new targets for more effective adjuvant therapies. PMID:9616488

Cellular therapies: Day by day, all the way.

PubMed

Atilla, Erden; Kilic, Pelin; Gurman, Gunhan

2018-04-18

Tremendous effort and knowledge have elucidated a new era of 'cellular therapy,' also called "live" or "living" drugs. There are currently thousands of active clinical trials that are ongoing, seeking hope for incurable conditions thanks to the increased accessibility and reliability of gene editing and cellular reprogramming. Accomplishments in various adoptive T cell immunotherapies and chimeric antigen receptor (CART) T cell therapies oriented researchers to the field. Cellular therapies are believed to be the next generation of curative therapeutics in many ways, the classification and nomenclature for these applications have not yet reached a consensus. Trends in recent years are moving towards making tissues and cell processes only in centers with production permits. It is quite promising that competent authorities have increased licensing activities of tissue and cell establishments in their countries, under good practice (GxP) rules, and preclinical and clinical trials involving cell-based therapies have led to significant investments. Despite the initiatives undertaken and the large budgets that have been allocated, only limited success has been achieved in cellular therapy compared to conventional drug development. Cost, and cost effectiveness, are important issues for these novel therapies to meet unmet clinical needs, and there are still many scientific, translational, commercializational, and ethical questions that do not have answers. The main objectives of this review is to underline the current position of cellular therapies in research, highlight the timely topic of immunotherapy and chimeric antigen receptor (CAR) T-cell treatment, and compile information related to regulations and marketing of cellular therapeutic approaches worldwide. Copyright © 2018 Elsevier Ltd. All rights reserved.

Concise Review: Mind the Gap: Challenges in Characterizing and Quantifying Cell- and Tissue-Based Therapies for Clinical Translation

PubMed Central

Rayment, Erin A; Williams, David J

2010-01-01

There are many challenges associated with characterizing and quantifying cells for use in cell- and tissue-based therapies. From a regulatory perspective, these advanced treatments must not only be safe and effective but also be made by high-quality manufacturing processes that allow for on-time delivery of viable products. Although sterility assays can be adapted from conventional bioprocessing, cell- and tissue-based therapies require more stringent safety assessments, especially in relation to use of animal products, immune reaction, and potential instability due to extended culture times. Furthermore, cell manufacturers who plan to use human embryonic stem cells in their therapies need to be particularly stringent in their final purification steps, due to the unrestricted growth potential of these cells. This review summarizes the current issues in characterization and quantification for cell- and tissue-based therapies, dividing these challenges into the regulatory themes of safety, potency, and manufacturing quality. It outlines current assays in use, as well as highlights the limits of many of these product release tests. Mode of action is discussed, with particular reference to in vitro surrogate assays that can be used to provide information to correlate with proposed in vivo patient efficacy. Importantly, this review highlights the requirement for basic research to improve current knowledge on the in vivo fate of these treatments; as well as an improved stakeholder negotiation process to identify the measurement requirements that will ensure the manufacture of the best possible cell- and tissue-based therapies within the shortest timeframe for the most patient benefit. PMID:20333747

Effective photodynamic therapy in drug-resistant prostate cancer cells utilizing a non-viral antitumor vector (a secondary publication).

PubMed

Yamauchi, Masaya; Honda, Norihiro; Hazama, Hisanao; Tachikawa, Shoji; Nakamura, Hiroyuki; Kaneda, Yasufumi; Awazu, Kunio

2016-03-31

There is an urgent need to develop an efficient strategy for the treatment of drug-resistant prostate cancer. Photodynamic therapy (PDT), in which low incident levels of laser energy are used to activate a photosensitizer taken up by tumor cells, is expected as a novel therapy for the treatment of prostate cancer because of the minimal invasive nature of PDT. The present study was designed to assess the efficacy of a novel vector approach combined with a conventional porphyrin-based photosensitizer. Our group focused on a non-viral vector (hemagglutinating virus of Japan envelope; HVJ-E) combined with protoporphyrin IX (PpIX) lipid, termed the porphyrus envelope (PE). It has been previously confirmed that HVJ-E has drug-delivering properties and can induce cancer-specific cell death. The PE (HVJ-E contained in PpIX lipid) was developed as a novel photosensitizer. In this study, the antitumor and PDT efficacy of the PE against hormone-antagonistic human prostate cancer cells (PC-3) were evaluated. Our results demonstrated that, under specific circumstances, PDT using the PE was very effective against PC-3 cells. A novel therapy for drug-resistant prostate cancer based on this vector approach is eagerly anticipated.

Monitoring tumor metastasis by in vivo imaging and flow cytometer

NASA Astrophysics Data System (ADS)

Gu, Zhenqin; Guo, Jin; Liu, Guangda; Li, Yan; Chen, Yun; Chen, Tong; Wang, Chen; Wei, Xunbin

2009-08-01

Prostate cancer is the most common malignancy in American men and the second leading cause of deaths from cancer, after lung cancer. The tumor usually grows slowly and remains confined to the gland for many years. During this time, the tumor produces little or no symptoms or outward signs. As the cancer advances, however, it can metastasize throughout other areas of the body, such as the bones, lungs, and liver. Surgical resection, hormonal therapy, chemotherapy and radiation therapy are the foundation of current prostate cancer therapies. Treatments for prostate cause both short- and long-term side effects that may be difficult to accept. Molecular mechanisms of prostate cancer metastasis need to be understood better and new therapies must be developed to selectively target to unique characteristics of cancer cell growth and metastasis. We have developed the "in vivo microscopy" to study the mechanisms that govern prostate cancer cell spread through the microenvironment in vivo in real-time confocal nearinfrared fluorescence imaging. A recently developed "in vivo flow cytometer" and optical imaging are used to assess prostate cancer cell spreading and the circulation kinetics of prostate cancer cells. A real- time quantitative monitoring of circulating prostate cancer cells by the in vivo flow cytometer will be useful to assess the effectiveness of the potential therapeutic interventions.

Emerging treatment options for refractory angina pectoris: ranolazine, shock wave treatment, and cell-based therapies.

PubMed

Gennari, Marco; Gambini, Elisa; Bassetti, Beatrice; Capogrossi, Maurizio; Pompilio, Giulio

2014-01-01

A challenge of modern cardiovascular medicine is to find new, effective treatments for patients with refractory angina pectoris, a clinical condition characterized by severe angina despite optimal medical therapy. These patients are not candidates for surgical or percutaneous revascularization. Herein we review the most up-to-date information regarding the modern approach to the patient with refractory angina pectoris, from conventional medical management to new medications and shock wave therapy, focusing on the use of endothelial precursor cells (EPCs) in the treatment of this condition. Clinical limitations of the efficiency of conventional approaches justify the search for new therapeutic options. Regenerative medicine is considered the next step in the evolution of organ replacement therapy. It is driven largely by the same health needs as transplantation and replacement therapies, but it aims further than traditional approaches, such as cell-based therapy. Increasing knowledge of the role of circulating cells derived from bone marrow (EPCs) on cardiovascular homeostasis in physiologic and pathologic conditions has prompted the clinical use of these cells to relieve ischemia. The current state of therapeutic angiogenesis still leaves many questions unanswered. It is of paramount importance that the treatment is delivered safely. Direct intramyocardial and intracoronary administration has demonstrated acceptable safety profiles in early trials, and may represent a major advance over surgical thoracotomy. The combined efforts of bench and clinical researchers will ultimately answer the question of whether cell therapy is a suitable strategy for treatment of patients with refractory angina.

Mesenchymal stem cells expressing interleukin-18 inhibit breast cancer in a mouse model.

PubMed

Liu, Xiaoyi; Hu, Jianxia; Li, Yueyun; Cao, Weihong; Wang, Yu; Ma, Zhongliang; Li, Funian

2018-05-01

Development of an improved breast cancer therapy has been an elusive goal of cancer gene therapy for a long period of time. Human mesenchymal stem cells derived from umbilical cord (hUMSCs) genetically modified with the interleukin (IL)-18 gene (hUMSCs/IL-18) were previously demonstrated to be able to suppress the proliferation, migration and invasion of breast cancer cells in vitro . In the present study, the effect of hUMSCs/IL-18 on breast cancer in a mouse model was investigated. A total of 128 mice were divided into 2 studies (the early-effect study and the late-effect study), with 4 groups in each, including the PBS-, hUMSC-, hUMSC/vector- and hUMSC/IL-18-treated groups. All treatments were injected along with 200 µl PBS. Following therapy, the tumor size, histological examination, and expression of lymphocytes, Ki-67, cluster of differentiation 31 and cytokines [interleukin (IL)-18, IL-12, interferon (IFN)-γ and TNF-α] in each group were analyzed. Proliferation of cells (assessed by measuring tumor size and Ki-67 expression) and metastasis, (by determining pulmonary and hepatic metastasis) of breast cancer cells in the hUMSC/IL-18 group were significantly decreased compared with all other groups. hUMSCs/IL-18 suppressed tumor cell proliferation by activating immunocytes and immune cytokines, decreasing the proliferation index of proliferation marker protein Ki-67 of tumor cells and inhibiting tumor angiogenesis. Furthermore, hUMSCs/IL-18 were able to induce a more marked and improved therapeutic effect in the tumor sites, particularly in early tumors. The results of the present study indicate that hUMSCs/IL-18 were able to inhibit the proliferation and metastasis of breast cancer cells in vivo , possibly leading to an approach for a novel antitumor therapy in breast cancer.

Glucose Addiction in Cancer Therapy: Advances and Drawbacks.

PubMed

Granja, Sara; Pinheiro, Céline; Reis, Rui Manuel; Martinho, Olga; Baltazar, Fátima

2015-01-01

While normal differentiated cells primarily use mitochondrial respiration to generate the required energy for cellular processes, most cancer cells rely on glycolysis, even in sufficient oxygen conditions. This phenomenon is known as the "Warburg effect" or aerobic glycolysis and the metabolic reprogramming of cancer cells towards this altered energy metabolism is currently recognized as one of the "hallmarks of cancer". Aerobic glycolysis underlies the rapid growth of tumor cells, with high rates of glucose consumption and lactic acid production, leading to cellular acidosis. Metabolic reprogramming renders cancer cells dependent on specific metabolic enzymes or pathways that could be exploited in cancer therapy. The development of treatments that target tumor glucose metabolism is receiving renewed attention, with several drugs targeting metabolic pathways currently in clinical trials. The search for suitable targets, however, is limited by the high plasticity of the metabolic network that can induce compensatory routes. Deregulated glucose metabolism is a prominent feature associated with resistance to classical chemotherapy or oncogene-targeted therapies, strengthening the clinical potential of combining these therapies with glycolysis inhibitors. The aim of this review is to compare the advances of different therapeutic strategies targeting the glucose "addiction" of tumor cells, highlighting their potential as effective weapons against cancer. We further discuss recent evidence for the involvement of glucose metabolism as a compensatory response to the use of drugs that target different signaling pathways, where the combination with glycolysis inhibitors could prove extraordinarily useful.

Developing Induced Pluripotent Stem Cell-Based Therapy for the Masses.

PubMed

Rao, Mahendra S; Atala, Anthony

2016-02-01

The discovery of induced pluripotent stem cells and the ability to manufacture them using clinically compliant protocols has the potential to revolutionize the field of regenerative medicine. However, realizing this potential requires the development of processes that are reliable, reproducible, and cost-effective and that at the same time do not compromise the safety of the individuals receiving this therapy. In the present report, we discuss how cost reductions can be obtained using our experience with obtaining approval of biologic agents, autologous therapy, and the recent approval of cord blood banks. Significance: For therapy to be widely available, the cost of manufacturing stem cells must be reduced. The steps proposed in the present report, when implemented, have the potential to reduce these costs significantly. ©AlphaMed Press.

Combination of an agonistic anti-CD40 monoclonal antibody and the COX-2 inhibitor celecoxib induces anti-glioma effects by promotion of type-1 immunity in myeloid cells and T-cells

PubMed Central

Kosaka, Akemi; Ohkuri, Takayuki

2014-01-01

Malignant gliomas are heavily infiltrated by immature myeloid cells that mediate immuno-suppression. Agonistic CD40 monoclonal antibody (mAb) has been shown to activate myeloid cells and promote antitumor immunity. Our previous study has also demonstrated blockade of cyclooxygenase-2 (COX-2) reduces immunosuppressive myeloid cells, thereby suppressing glioma development in mice. We therefore hypothesized that a combinatory strategy to modulate myeloid cells via two distinct pathways, i.e., CD40/CD40L stimulation and COX-2 blockade, would enhance anti-glioma immunity. We used three different mouse glioma models to evaluate therapeutic effects and underlying mechanisms of a combination regimen with an agonist CD40 mAb and the COX-2 inhibitor celecoxib. Treatment of glioma-bearing mice with the combination therapy significantly prolonged survival compared with either anti-CD40 mAb or celecoxib alone. The combination regimen promoted maturation of CD11b+ cells in both spleen and brain, and enhanced Cxcl10 while suppressing Arg1 in CD11b+Gr-1+ cells in the brain. Anti-glioma activity of the combination regimen was T-cell dependent because depletion of CD4+ and CD8+ cells in vivo abrogated the anti-glioma effects. Furthermore, the combination therapy significantly increased the frequency of CD8+ T-cells, enhanced IFN-γ-production and reduced CD4+CD25+Foxp3+ T regulatory cells in the brain, and induced tumor-antigen-specific T-cell responses in lymph nodes. Our findings suggest that the combination therapy of anti-CD40 mAb with celecoxib enhances anti-glioma activities via promotion of type-1 immunity both in myeloid cells and T-cells. PMID:24878890

The Use of Biologic Therapies in Uveitis.

PubMed

Schwartzman, Sergio; Schwartzman, Monica

2015-12-01

Therapy for autoimmune ophthalmic disease is currently evolving. The improved understanding of the abnormal immune response in the various forms of uveitis has resulted in targeted therapy. The aberrations of the immune system have been characterized by atypical cell populations, cytokine expression, and cell-cell interactions. Different patterns of cytokine expression have now been delineated in the abnormal uveal tract with exaggerated and/or abnormal expression of TNF, IL-1, IL-2, IL-6, and IL-17. The development of therapies for other conditions in which these cytokines play an important role has resulted in the availability of biological agents that have been adopted for use in the therapy for uveitis. Adalimumab and infliximab have been the best studied anti-TNF agents and indeed have now been recommended by an expert panel as first-line treatment of ocular manifestations of Behçet's disease and second-line treatment for other forms of uveitis (Levy-Clarke et al. (Ophthalmology, 2013). Other anti-TNF agents have been studied as well. Daclizumab, a monoclonal antibody directed against the IL-2 receptor, has also demonstrated utility in treating uveitis as have some of the anti-IL1 agents. Gevokizumab has been granted orphan drug designation for the treatment of resistant forms of uveitis. Therapies affecting IL-6, including tocilizumab are being studied, and available medications that block antigen presenting cell and T cell interaction such as abatacept have been reported to be effective in uveitis. Interferons as well as rituximab have also been evaluated in small studies. Although these biologic therapies have provided a larger armamentarium to treat uveitis, challenges remain. Uveitis is not a single illness; rather, it is a manifestation of many potential systemic diseases that may have very specific individual therapeutic targets. Identifying and characterizing these underlying diseases is not always achieved, and more importantly, the most effective therapies for each entity have not been defined.

A comparison of the effect of short-acting and long-acting cloxacillin-based dry-cow therapy on somatic cell counts after calving in cows also given internal teat sealants.

PubMed

Whitfield, L K; Laven, R A

2018-01-01

To compare, in cows treated with an internal teat sealant, the effect of short-acting and long-acting cloxacillin-based dry-cow therapy on somatic cell counts (SCC) after calving. Cows from a spring-calving, pasture-based dairy farm in the Manawatu-Whanganui region of New Zealand were randomly allocated to receive either a short-acting cloxacillin and ampicillin dry-cow therapy and internal teat sealant (n=291) or a long-acting cloxacillin and ampicillin dry-cow therapy and internal teat sealant (n=288) at the end of lactation. Cows were managed on-farm with routine husbandry procedures through the dry period and following calving. A multivariable logistic regression model was used to determine the association between length of action of dry-cow therapy and the proportion of cows with a SCC >150,000 cells/mL at the first herd test after calving. Age of cow, mean SCC for the preceding season and interval from calving to the first post-calving herd test were all associated with the proportion of cows with an individual SCC >150,000 cells/mL at the first herd test (p<0.001) Treatment with the short-acting dry-cow therapy was not associated with decreased odds of cows having a SCC >150,000 cells/mL at the first herd test compared with treatment with long-acting dry-cow therapy (OR=0.724; 95% CI=0.40-1.30). In this herd, which routinely used internal teat sealants, the use of short-acting cloxacillin-based dry-cow therapy did not result in an increased proportion of cows with elevated SSC post-calving. This was a single farm, single year study but indicates that in this herd, changing from a long-acting to a short-acting antimicrobial may have no impact on the prevalence of subclinical mastitis.

[Principles of adoptive cell therapy based on "Tumor Infiltrating Lymphocytes"].

PubMed

Martins, Filipe; Orcurto, Angela; Michielin, Olivier; Coukos, George

2016-05-18

Adoptive cell therapy consists in the use of T lymphocytes for therapeutic purposes. Up to now, of limited use in clinical practice for logistical reasons, technical progress and substantial level of evidence obtained in the last decade allow its arrival in universitary hospitals. We will principally discuss the administration of expanded tumor infiltrating T cells in the treatment of metastatic melanoma. This treatment modality exploits the natural specificity of these cells and aims to potentiate their effectiveness. This personalized immunotherapy detains a potential for expansion to many other advanced tumor types.

Synergistic effects of plasma-activated medium and chemotherapeutic drugs in cancer treatment

NASA Astrophysics Data System (ADS)

Chen, Chao-Yu; Cheng, Yun-Chien; Cheng, Yi-Jing

2018-04-01

Chemotherapy is an important treatment method for metastatic cancer, but the drug-uptake efficiency of cancer cells needs to be enhanced in order to diminish the side effects of chemotherapeutic drugs and improve survival. The use of a nonequilibrium low-temperature atmospheric-pressure plasma jet (APPJ) has been demonstrated to exert selective effects in cancer therapy and to be able to enhance the uptake of molecules by cells, which makes an APPJ a good candidate adjuvant in combination chemotherapy. This study estimated the effects of direct helium-based APPJ (He-APPJ) exposure (DE) and He-APPJ-activated RPMI medium (PAM) on cell viability and migration. Both of these treatments decreased cell viability and inhibited cell migration, but to different degrees in different cell types. The use of PAM as a culture medium resulted in the dialkylcarbocyanine (DiI) fluorescent dye entering the cells more efficiently. PAM was combined with the anticancer drug doxorubicin (Doxo) to treat human heptocellular carcinoma HepG2 cells and human adenocarcinomic alveolar basal epithelial A549 cells. The results showed that the synergistic effects of combined PAM and Doxo treatment resulted in stronger lethality in cancer cells than did PAM or Doxo treatment alone. To sum up, PAM has potential as an adjuvant in combination with other drugs to improve curative cancer therapies.

Mesenchymal stromal cells and rheumatic diseases: new tools from pathogenesis to regenerative therapies.

PubMed

Cipriani, Paola; Ruscitti, Piero; Di Benedetto, Paola; Carubbi, Francesco; Liakouli, Vasiliki; Berardicurti, Onorina; Ciccia, Francesco; Triolo, Giovanni; Giacomelli, Roberto

2015-07-01

In recent years, mesenchymal stromal cells (MSCs) have been largely investigated and tested as a new therapeutic tool for several clinical applications, including the treatment of different rheumatic diseases. MSCs are responsible for the normal turnover and maintenance of adult mesenchymal tissues as the result of their multipotent differentiation abilities and their secretion of a variety of cytokines and growth factors. Although initially derived from bone marrow, MSCs are present in many different tissues such as many peri-articular tissues. MSCs may exert immune-modulatory properties, modulating different immune cells in both in vitro and in vivo models, and they are considered immune-privileged cells. At present, these capacities are considered the most intriguing aspect of their biology, introducing the possibility that these cells may be used as effective therapy in autoimmune diseases. Therefore, stem cell therapies may represent an innovative approach for the treatment of rheumatic diseases, especially for the forms that are not responsive to standard treatments or alternatively still lacking a definite therapy. At present, although the data from scientific literature appear to suggest that such treatments might be more effective whether administered as soon as possible, the use of MSCs in clinical practice is likely to be restricted to patients with a long history of a severe refractory disease. Further results from larger clinical trials are needed to corroborate preclinical findings and human non-controlled studies, and advancement in the knowledge of MSCs might provide information about the therapeutic role of these cells in the treatment of many rheumatic diseases. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

3D mathematical modeling of glioblastoma suggests that transdifferentiated vascular endothelial cells mediate resistance to current standard-of-care therapy

PubMed Central

Yan, Huaming; Romero-López, Mónica; Benitez, Lesly I.; Di, Kaijun; Frieboes, Hermann B.; Hughes, Christopher C. W.; Bota, Daniela A.; Lowengrub, John S.

2017-01-01

Glioblastoma (GBM), the most aggressive brain tumor in human patients, is decidedly heterogeneous and highly vascularized. Glioma stem/initiating cells (GSC) are found to play a crucial role by increasing cancer aggressiveness and promoting resistance to therapy. Recently, crosstalk between GSC and vascular endothelial cells has been shown to significantly promote GSC self-renewal and tumor progression. Further, GSC also transdifferentiate into bona-fide vascular endothelial cells (GEC), which inherit mutations present in GSC and are resistant to traditional anti-angiogenic therapies. Here we use 3D mathematical modeling to investigate GBM progression and response to therapy. The model predicted that GSC drive invasive fingering and that GEC spontaneously form a network within the hypoxic core, consistent with published experimental findings. Standard-of-care treatments using DNA-targeted therapy (radiation/chemo) together with anti-angiogenic therapies, reduced GBM tumor size but increased invasiveness. Anti-GEC treatments blocked the GEC support of GSC and reduced tumor size but led to increased invasiveness. Anti-GSC therapies that promote differentiation or disturb the stem cell niche effectively reduced tumor invasiveness and size, but were ultimately limited in reducing tumor size because GEC maintain GSC. Our study suggests that a combinatorial regimen targeting the vasculature, GSC, and GEC, using drugs already approved by the FDA, can reduce both tumor size and invasiveness and could lead to tumor eradication. PMID:28536277

A versatile nanoplatform for synergistic combination therapy to treat human esophageal cancer.

PubMed

Wang, Xin-Shuai; Kong, De-Jiu; Lin, Tzu-Yin; Li, Xiao-Cen; Izumiya, Yoshihiro; Ding, Xue-Zhen; Zhang, Li; Hu, Xiao-Chen; Yang, Jun-Qiang; Gao, She-Gan; Lam, Kit S; Li, Yuan-Pei

2017-06-01

One of the major goals of precision oncology is to promote combination therapy to improve efficacy and reduce side effects of anti-cancer drugs based on their molecular mechanisms. In this study, we aimed to develop and validate new nanoformulations of docetaxel (DTX) and bortezomib (BTZ) for targeted combination therapy to treat human esophageal cancer. By leveraging our versatile disulfide cross-linked micelles (DCMs) platform, we developed nanoformulations of DTX and BTZ (named DTX-DCMs and BTZ-DCMs). Their physical properties were characterized; their anti-cancer efficacies and mechanisms of action were investigated in a human esophageal cancer cell line in vitro. Furthermore, the in vitro anti-tumor activities of combination therapies (concurrent drug treatment, sequential drug treatment, and treatment using different ratios of the drugs) were examined in comparison with the single drug treatment and free drug strategies. These drug-loaded nanoparticles were spherical in shape and relatively small in size of approximately 20-22 nm. The entrapment efficiencies of DTX and BTZ into nanoparticles were 82.4% and 84.1%, respectively. The drug release rates of DTX-DCMs and BTZ-DCMs were sustained, and greatly increased in the presence of GSH. These nanodrugs were effectively internalized by KYSE30 esophageal cancer cells, and dose-dependently induced cell apoptosis. We further revealed a strong synergistic effect between DTX-DCMs and BTZ-DCMs against KYSE30 esophageal cancer cells. Sequential combination therapy with DTX-DCMs followed by BTZ-DCMs exhibited the best anti-tumor efficacy in vitro. This study demonstrates that DTX and BTZ could be successfully nanoformulated into disulfide cross-linked micelles. The nanoformulations of DTX and BTZ demonstrate an immense potential for synergistic combination therapy to treat human esophageal cancer.

Clinical Evidence for the Earlier Initiation of Insulin Therapy in Type 2 Diabetes

PubMed Central

2013-01-01

Abstract The natural history of type 2 diabetes mellitus (T2DM) is a relentless progression of β-cell failure and dysregulation of β-cell function with increasing metabolic derangement. Insulin remains the only glucose-lowering therapy that is efficacious throughout this continuum. However, the timing of introduction and the choice of insulin therapy remain contentious because of the heterogeneity of T2DM and the well-recognized behavioral and therapeutic challenges associated with this mode of therapy. Nevertheless, the early initiation of basal insulin has been shown to improve glycemic control and affect long-term outcomes in people with T2DM and is a treatment strategy supported by international guidelines as part of an individualized approach to chronic disease management. The rationale for early initiation of insulin is based on evidence demonstrating multifaceted benefits, including overcoming the glucotoxic effects of hyperglycemia, thereby facilitating “β-cell rest,” and preserving β-cell mass and function, while also improving insulin sensitivity. Independent of its effects on glycemic control, insulin possesses anti-inflammatory and antioxidant properties that may help protect against endothelial dysfunction and damage resulting in vascular disease. Insulin therapy and the achievement of good glycemic control earlier in T2DM provide long-term protection to end organs via “metabolic memory” regardless of subsequent treatments and degree of glycemic control. This is evidenced from long-term observations continuing from trials such as the United Kingdom Prospective Diabetes Study. As such, early initiation of insulin therapy may not only help to avoid the effects of prolonged glycemic burden, but may also positively alter the course of disease progression. PMID:23786228

Cooperative effect between immunotherapy and antiangiogenic therapy leads to effective tumor rejection in tolerant Her-2/neu mice.

PubMed

Cuadros, Camilo; Dominguez, Ana Lucia; Frost, Gregory I; Borgstrom, Per; Lustgarten, Joseph

2003-09-15

Immunotherapy is an attractive strategy for cancer treatment. However, self-tolerance is one of the major mechanisms that dampen immune responses against self-tumor antigens. We have demonstrated that Her-2/neu transgenic mice (neu mice) are tolerant to neu antigens and contain only a low avidity repertoire for neu. However, this repertoire has antitumor activity. Immunizations of neu mice are capable of activating the low-avidity T cells that, at best, retard the tumor growth. To increase the efficacy of the antitumor responses in neu mice, we hypothesized that immunotherapy in combination with antiangiogenic therapy would be a more efficient strategy for tumor eradication. The rationale for using this combination was that by decreasing the growth rate of the tumor with an antiangiogenic therapy, the low-avidity repertoire of neu mice stimulated by immunotherapeutic intervention would be more effective in destroying the slow growing tumor. To test this hypothesis, we stably expressed a soluble form of the Flt-1 vascular endothelial growth factor receptor (sFlt-1) on N202.1A cells, using a retrovirus vector. Expression of sFlt-1 on N202.1A (N202-Flt) cells significantly inhibited the tumor growth compared with N202.1A parental cells. In contrast to the application of immunotherapy alone or antiangiogenic therapy alone, which delayed the tumor growth, the combination of the two therapies provided complete inhibition of tumor growth in Her-2/neu mice. These results indicate that the use of tumor targeting with immunotherapy in simultaneous combination with antiangiogenic therapy provides a more efficient strategy for the treatment of solid tumors.

Minocycline attenuates colistin-induced neurotoxicity via suppression of apoptosis, mitochondrial dysfunction and oxidative stress

PubMed Central

Dai, Chongshan; Ciccotosto, Giuseppe D.; Cappai, Roberto; Wang, Yang; Tang, Shusheng; Xiao, Xilong; Velkov, Tony

2017-01-01

Background: Neurotoxicity is an adverse effect patients experience during colistin therapy. The development of effective neuroprotective agents that can be co-administered during polymyxin therapy remains a priority area in antimicrobial chemotherapy. The present study investigates the neuroprotective effect of the synergistic tetracycline antibiotic minocycline against colistin-induced neurotoxicity. Methods: The impact of minocycline pretreatment on colistin-induced apoptosis, caspase activation, oxidative stress and mitochondrial dysfunction were investigated using cultured mouse neuroblastoma-2a (N2a) and primary cortical neuronal cells. Results: Colistin-induced neurotoxicity in mouse N2a and primary cortical cells gives rise to the generation of reactive oxygen species (ROS) and subsequent cell death via apoptosis. Pretreatment of the neuronal cells with minocycline at 5, 10 and 20 μM for 2 h prior to colistin (200 μM) exposure (24 h), had an neuroprotective effect by significantly decreasing intracellular ROS production and by upregulating the activities of the anti-ROS enzymes superoxide dismutase and catalase. Minocycline pretreatment also protected the cells from colistin-induced mitochondrial dysfunction, caspase activation and subsequent apoptosis. Immunohistochemical imaging studies revealed colistin accumulates within the dendrite projections and cell body of primary cortical neuronal cells. Conclusions: To our knowledge, this is first study demonstrating the protective effect of minocycline on colistin-induced neurotoxicity by scavenging of ROS and suppression of apoptosis. Our study highlights that co-administration of minocycline kills two birds with one stone: in addition to its synergistic antimicrobial activity, minocycline could potentially ameliorate unwanted neurotoxicity in patients undergoing polymyxin therapy. PMID:28204513

[Proangiogenic cell-based therapy for treatment of ischemic diseases].

PubMed

Silvestre, Jean-Sébastien

2009-11-01

The application of endothelial progenitor cells (EPC) cell-based therapy for regenerative medicine constitutes a promising therapeutic avenue for the treatment of cardiovascular diseases. Based on experimental studies demonstrating that bone marrow-, blood- or tissue-derived stem/progenitor cells improve the functional recovery after ischemia, clinical trials were initiated to address this new therapeutic concept. Although autolougous cell therapy was shown to improve perfusion and function of ischemic tissues, a number of issues remain to be adressed. The nature of the mobilizing, migratory and homing signals, and the mechanisms of action need to be identified and further defined. In addition, strategies to enhance homing, survival and therapeutic potential of EPC need to be developped to improve therapeutic effect and counteract EPC dysfunction in aged patients with cardiovascular risk factors. The present review article will discuss the mechanisms of action of different types of adult stem cells and several approaches to improve their therapeutic efficiency.

Photo-excitable hybrid nanocomposites for image-guided photo/TRAIL synergistic cancer therapy.

PubMed

Lin, Gan; Zhang, Yang; Zhu, Congqing; Chu, Chengchao; Shi, Yesi; Pang, Xin; Ren, En; Wu, Yayun; Mi, Peng; Xia, Haiping; Chen, Xiaoyuan; Liu, Gang

2018-05-22

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in cancer cells without toxicity to normal cells. However, the efficiency is greatly limited by its short half-life and wild resistance in various cancer cells. In this study, we reported a micellar hybrid nanoparticle to carry TRAIL ligand (denoted as IPN@TRAIL) for a novel photo-excited TRAIL therapy. These IPN@TRAIL offered increased TRAIL stability, prolonged half-life and enhanced tumor accumulation, monitored by dual mode imaging. Furthermore, IPN@TRAIL nanocomposites enhanced wrapped TRAIL therapeutic efficiency greatly towards resistant cancer cells by TRAIL nanovectorization. More importantly, when upon external laser, these nanocomposites not only triggered tumor photothermal therapy (PTT), but also upregulated the expression of death receptors (DR4 and DR5), resulting in a greater apoptosis mediated by co-delivered TRAIL ligand. Such photo/TRAIL synergistic effect showed its great killing effects in a controllable manner on TRAIL-resistant A549 tumor model bearing mice. Finally, these nanocomposites exhibited rapid clearance without obvious systemic toxicity. All these features rendered our nanocomposites a promising theranostic platform in cancer therapy. Copyright © 2018 Elsevier Ltd. All rights reserved.

The use of mesenchymal stem cells (MSCs) for amyotrophic lateral sclerosis (ALS) therapy - a perspective on cell biological mechanisms.

PubMed

Tang, Bor Luen

2017-10-26

Recent clinical trials of mesenchymal stem cells (MSCs) transplantation have demonstrated procedural safety and clinical proof of principle with a modest indication of benefit in patients with amyotrophic lateral sclerosis (ALS). While replacement therapy remained unrealistic, the clinical efficacy of this therapeutic option could be potentially enhanced if we could better decipher the mechanisms underlying some of the beneficial effects of transplanted cells, and work toward augmenting or combining these in a strategic manner. Novel ways whereby MSCs could act in modifying disease progression should also be explored. In this review, I discuss the known, emerging and postulated mechanisms of action underlying effects that transplanted MSCs may exert to promote motor neuron survival and/or to encourage regeneration in ALS. I shall also speculate on how transplanted cells may alter the diseased environment so as to minimize non-neuron cell autonomous damages by immune cells and astrocytes.

Inactivation of myeloma cancer cells by helium and argon plasma jets: The effect comparison and the key reactive species

NASA Astrophysics Data System (ADS)

Chen, Zeyu; Cui, Qingjie; Chen, Chen; Xu, Dehui; Liu, Dingxin; Chen, H. L.; Kong, Michael G.

2018-02-01

In plasma cancer therapy, the inactivation of cancer cells under plasma treatment is closely related to the reactive oxygen and nitrogen species (RONS) induced by plasmas. Quantitative study on the plasma-induced RONS that related to cancer cells apoptosis is critical for advancing the research of plasma cancer therapy. In this paper, the effects of several reactive species on the inactivation of LP-1 myeloma cancer cells are comparatively studied with variable working gas composition, surrounding gas composition, and discharge power. The results show that helium plasma jet has a higher cell inactivation efficiency than argon plasma jet under the same discharge power. By comparing the concentration of aqueous phase reactive species and the cell inactivation efficiency under different working gases and discharge powers, it is demonstrated that the inactivation efficiency of LP-1 myeloma cancer cells is strongly correlated with the concentration of peroxynitrite (ONOOH/ONOO-).

The hitchhikers guide to cancer stem cell theory: markers, pathways and therapy.

PubMed

Fábián, Ákos; Vereb, György; Szöllősi, János

2013-01-01

Cancer stem cell (CSC) biology is a rapidly developing field within cancer research. CSCs are postulated to be a unique cell population exclusively capable of infinite self renewal, multilineage differentiation and with ability to evade conventional cytotoxic cancer therapy. These traits distinguish CSCs from their more differentiated counterparts, which possess only limited or no potential for self renewal and tumor initiation. Therefore, CSCs would be the driving motor of malignant growth and therapy resistance. Accordingly, successful cancer treatment would need to eliminate this highly potent group of cells, since even small residual numbers would suffice to recapitulate the disease after therapy. Putative CSCs has been identified in a broad range of human malignancies and several cell surface markers have been associated with their stem cell phenotype. Despite all efforts, a pure CSC population has not been isolated and often in vitro clonogenic and in vivo tumorigenic potential is found in several cell populations with occasionally contradictory surface marker signatures. Here, we give a brief overview of recent advances in CSC theory, including the signaling pathways in CSCs that also appear crucial for stem cells homeostasis in normal tissues. We discuss evidence for the interaction of CSCs with the stromal tumor environment. Finally, we review the emerging potentially effective CSC-targeted treatment strategies and their future role in therapy. Copyright © 2012 International Society for Advancement of Cytometry.

Multidimensional nanomaterials for the control of stem cell fate

NASA Astrophysics Data System (ADS)

Chueng, Sy-Tsong Dean; Yang, Letao; Zhang, Yixiao; Lee, Ki-Bum

2016-09-01

Current stem cell therapy suffers low efficiency in giving rise to differentiated cell lineages, which can replace the original damaged cells. Nanomaterials, on the other hand, provide unique physical size, surface chemistry, conductivity, and topographical microenvironment to regulate stem cell differentiation through multidimensional approaches to facilitate gene delivery, cell-cell, and cell-ECM interactions. In this review, nanomaterials are demonstrated to work both alone and synergistically to guide selective stem cell differentiation. From three different nanotechnology families, three approaches are shown: (1) soluble microenvironmental factors; (2) insoluble physical microenvironment; and (3) nano-topographical features. As regenerative medicine is heavily invested in effective stem cell therapy, this review is inspired to generate discussions in the potential clinical applications of multi-dimensional nanomaterials.

[Immunotherapy for refractory viral infections].

PubMed

Morio, Tomohiro; Fujita, Yuriko; Takahashi, Satoshi

Various antiviral agents have been developed, which are sometimes associated with toxicity, development of virus-resistant strain, and high cost. Virus-specific T-cell (VST) therapy provides an alternative curative therapy that can be effective for a prolonged time without eliciting drug resistance. VSTs can be directly separated using several types of capture devices and can be obtained by stimulating peripheral blood mononuclear cells with viral antigens (virus, protein, or peptide) loaded on antigen-presenting cells (APC). APC can be transduced with virus-antigen coding plasmid or pulsed with overlapping peptides. VST therapy has been studied in drug non-responsive viral infections after hematopoietic cell transplantation (HCT). Several previous studies have demonstrated the efficacy of VST therapy without significant severe GVHD. In addition, VSTs from a third-party donor have been prepared and administered for post-HCT viral infection. Although target viruses of VSTs include herpes virus species and polyomavirus species, a wide variety of pathogens, such as papillomavirus, intracellular bacteria, and fungi, can be treated by pathogen-specific T-cells. Perhaps, these specific T-cells could be used for opportunistic infections in other immunocompromised hosts in the near future.

Induction of pluripotent stem cells transplantation therapy for ischemic stroke.

PubMed

Jiang, Mei; Lv, Lei; Ji, Haifeng; Yang, Xuelian; Zhu, Wei; Cai, Liying; Gu, Xiaju; Chai, Changfeng; Huang, Shu; Sun, Jian; Dong, Qiang

2011-08-01

Stroke can cause permanent neurological damage, complications, and even death. However, there is no treatment exists to restore its lost function. Human embryonic stems transplantation therapy was a novel and potential therapeutic approach for stroke. However, as we have seen, the ethical controversy pertains to embryonic stem cell research. Human induced pluripotent stem cells (iPSCs) are the latest generation of stem cells that may be a solution to the controversy of using embryonic cells. In our study, we generated iPSCs from adult human fibroblasts by introduction of four defined transcription factors (Oct4, Sox2, Nanog, and Lin-28). And then, we investigated the efficacy of iPSCs transplantation therapy for stroke on the animal models of middle cerebral artery occlusion. Surprisingly, we found that transplanted iPSCs migrated to injured brain areas, and differentiated into neuron-like cells successfully. After 4-16 days iPSCs grafting, sensorimotor function of rats has been improved significantly. In one word, we may prove that iPSCs therapy in stroke to be an effective form of treatment.

Effectiveness of Combined Therapy with Pirfenidone and Erythromycin for Unclassifiable Interstitial Pneumonia Induced by HTLV-1-associated Bronchioloalveolar Disorder (HABA)

PubMed Central

Yokohori, Naoko; Sato, Akitoshi; Hasegawa, Mizue; Katsura, Hideki; Hiroshima, Kenzo; Takemura, Tamiko

2017-01-01

Human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus involved in the pathogenesis of adult T-cell leukemia (ATL) and HTVL-1-associated bronchioloalveolar disorder (HABA). The clinical and pathological findings of HABA have been characterized as either a diffuse panbronchiolitis (DPB) pattern or idiopathic interstitial pneumonia (IIP) pattern. Treatments for HABA include corticosteroids for the IIP pattern and erythromycin for the DPB pattern. We herein report a case of HABA-associated unclassifiable interstitial pneumonia that improved with combined therapy with pirfenidone and erythromycin. This is the first report on the effectiveness of combined therapy with pirfenidone and erythromycin for HABA. PMID:28050003

Modalities and future prospects of gene therapy in heart transplantation.

PubMed

Vassalli, Giuseppe; Roehrich, Marc-Estienne; Vogt, Pierre; Pedrazzini, Giovanni B; Siclari, Francesco; Moccetti, Tiziano; von Segesser, Ludwig K

2009-06-01

Heart transplantation is the treatment of choice for many patients with end-stage heart failure. Its success, however, is limited by organ shortage, side effects of immunosuppressive drugs, and chronic rejection. Gene therapy is conceptually appealing for applications in transplantation, as the donor organ is genetically manipulated ex vivo before transplantation. Localised expression of immunomodulatory genes aims to create a state of immune privilege within the graft, which could eliminate the need for systemic immunosuppression. In this review, recent advances in the development of gene therapy in heart transplantation are discussed. Studies in animal models have demonstrated that genetic modification of the donor heart with immunomodulatory genes attenuates ischaemia-reperfusion injury and rejection. Alternatively, bone marrow-derived cells genetically engineered with donor-type major histocompatibility complex (MHC) class I or II promote donor-specific hyporesponsiveness. Genetic engineering of naïve T cells or dendritic cells may induce regulatory T cells and regulatory dendritic cells. Despite encouraging results in animal models, however, clinical gene therapy trials in heart transplantation have not yet been started. The best vector and gene to be delivered remain to be identified. Pre-clinical studies in non-human primates are needed. Nonetheless, the potential of gene therapy as an adjunct therapy in transplantation is essentially intact.

Predominant Improvement of Alpha Cell Function after Steroid Therapy in a Patient with Autoimmune Pancreatitis: Case Report.

PubMed

Takeshima, Ken; Ariyasu, Hiroyuki; Iwakura, Hiroshi; Kawai, Shintaro; Uraki, Shinsuke; Inaba, Hidefumi; Furuta, Machi; Warigaya, Kenji; Murata, Shin-Ichi; Akamizu, Takashi

2018-06-01

Autoimmune pancreatitis (AIP) is a subset of inflammatory pancreatic disease, responsive to corticosteroid therapy. It is prone to being affected by diabetes mellitus, but the effectiveness of steroid therapy on pancreatic endocrine function is still controversial. We present a case of AIP, focusing on pancreatic endocrine function after steroid therapy. The patient was referred to our hospital with exacerbation of diabetic control and pancreatic swelling. By admission, the insulin secretory capacity was severely impaired. The patient was diagnosed with AIP and treated with prednisolone, resulting in marked improvement of the pancreatic swelling. Glycemic control worsened transiently after initiation of steroid therapy, but insulin requirements decreased along with tapering prednisolone dosage. Pancreatic cytology showed that the acinar structure had been destroyed, and the islets had disappeared. Insulin and glucagon immunostaining revealed slightly scattered alpha and beta cells within the fibrotic stroma. The patient notably showed improved pancreatic alpha cell function predominantly after steroid therapy, despite partial improvement of beta cell function. An imbalance between alpha and beta cell function may contribute to insufficient diabetic control in some patients with AIP. The pancreatic endocrine function test in combination with pancreatic cytology could be helpful when considering the treatment strategy for diabetic control in patients with AIP.

Response of head and neck squamous cell carcinoma cells carrying PIK3CA mutations to selected targeted therapies.

PubMed

Wirtz, Eric D; Hoshino, Daisuke; Maldonado, Anthony T; Tyson, Darren R; Weaver, Alissa M

2015-06-01

The PIK3CA mutation is one of the most common mutations in head and neck squamous cell carcinoma (HNSCC). Through this research we attempt to elicit the role of oncogene dependence and effects of targeted therapy on this PIK3CA mutation. (1) To determine the role of oncogene dependence on PIK3CA-one of the more common and targetable oncogenes in HNSCC, and (2) to evaluate the consequence of this oncogene on the effectiveness of newly developed targeted therapies. This was a cell culture-based, in vitro study performed at an academic research laboratory assessing the viability of PIK3CA-mutated head and neck cell lines when treated with targeted therapy. PIK3CA-mutated head and neck cell lines were treated with 17-AAG, GDC-0941, trametinib, and BEZ-235. Assessment of cell viability of HNSCC cell lines characterized for PIK3CA mutations or SCC25 cells engineered to express the PIK3CA hotspot mutations E545K or H1047R. Surprisingly, in engineered cell lines, the hotspot E545K and H1047R mutations conferred increased, rather than reduced, IC50 assay measurements when treated with the respective HSP90, PI3K, and MEK inhibitors, 17-AAG, GDC-0941, and trametinib, compared with the SCC25 control cell lines. When treated with BEZ-235, H1047R-expressing cell lines showed increased sensitivity to inhibition compared with control, whereas those expressing E545K showed slightly increased sensitivity of unclear significance. (1) The PIK3CA mutations within our engineered cell model did not lead to enhanced oncogene-dependent cell death when treated with direct inhibition of the PI3K enzyme yet did show increased sensitivity compared with control with dual PI3K/mTOR inhibition. (2) Oncogene addiction to PIK3CA hotspot mutations, if it occurs, is likely to evolve in vivo in the context of additional molecular changes that remain to be identified. Additional study is required to develop new model systems and approaches to determine the role of targeted therapy in the treatment of PI3K-overactive HNSCC tumors.

Modeling combination therapy for breast cancer with BET and immune checkpoint inhibitors.

PubMed

Lai, Xiulan; Stiff, Andrew; Duggan, Megan; Wesolowski, Robert; Carson, William E; Friedman, Avner

2018-05-07

CTLA-4 is an immune checkpoint expressed on active anticancer T cells. When it combines with its ligand B7 on dendritic cells, it inhibits the activity of the T cells. The Bromo- and Extra-Terminal (BET) protein family includes proteins that regulate the expression of key oncogenes and antiapoptotic proteins. BET inhibitor (BETi) has been shown to reduce the expression of MYC by suppressing its transcription factors and to down-regulate the hypoxic transcriptome response to VEGF-A. This paper develops a mathematical model of the treatment of cancer by combination therapy of BETi and CTLA-4 inhibitor. The model shows that the two drugs are positively correlated in the sense that the tumor volume decreases as the dose of each of the drugs is increased. The model also considers the effect of the combined therapy on levels of myeloid-derived suppressor cells (MDSCs) and the overexpression of TNF-[Formula: see text], which may predict gastrointestinal side effects of the combination.

Use of Nanoparticle Contrast Agents for Cell Tracking with Computed Tomography

PubMed Central

2017-01-01

Efforts to develop novel cell-based therapies originated with the first bone marrow transplant on a leukemia patient in 1956. Preclinical and clinical examples of cell-based treatment strategies have shown promising results across many disciplines in medicine, with recent advances in immune cell therapies for cancer producing remarkable response rates, even in patients with multiple treatment failures. However, cell-based therapies suffer from inconsistent outcomes, motivating the search for tools that allow monitoring of cell delivery and behavior in vivo. Noninvasive cell imaging techniques, also known as cell tracking, have been developed to address this issue. These tools can allow real-time, quantitative, and long-term monitoring of transplanted cells in the recipient, providing insight on cell migration, distribution, viability, differentiation, and fate, all of which play crucial roles in treatment efficacy. Understanding these parameters allows the optimization of cell choice, delivery route, and dosage for therapy and advances cell-based therapy for specific clinical uses. To date, most cell tracking work has centered on imaging modalities such as MRI, radionuclide imaging, and optical imaging. However, X-ray computed tomography (CT) is an emerging method for cell tracking that has several strengths such as high spatial and temporal resolution, and excellent quantitative capabilities. The advantages of CT for cell tracking are enhanced by its wide availability and cost effectiveness, allowing CT to become one of the most popular clinical imaging modalities and a key asset in disease diagnosis. In this review, we will discuss recent advances in cell tracking methods using X-ray CT in various applications, in addition to predictions on how the field will progress. PMID:28485976

Immunomodulation of glioma cells after gene therapy: induction of major histocompatibility complex class I but not class II antigen in vitro.

PubMed

Parsa, A T; Chi, J H; Hurley, P T; Jeyapalan, S A; Bruce, J N

2001-09-01

Acquired immunity has been demonstrated in Fischer rats bearing syngeneic 9L tumors after herpes simplex virus (HSV) thymidine kinase (TK) gene transfection and ganciclovir treatment. The nature of this immunity in rats and its relevance to the HSV TK/ganciclovir protocol for human subjects remain to be determined. In this study, levels of major histocompatibility complex (MHC) Class I and II antigen expression were measured before and after HSV TK transfection, in an effort to document immunomodulatory changes caused by gene therapy. Tumor cells from the 9L gliosarcoma cell line, three primary human glioma cultures, and the human glioma cell line U87 MG were transduced with HSV TK vector-containing supernatant from fibroblast-producing cells (titer of 5 x 10(6) colony-forming units/ml) and selected in G418 medium for neomycin resistance. Clones were pooled or individually selected for cell-killing assays with ganciclovir, to confirm TK expression (10(3) cells/well in a 96-well dish). Northern analyses using MHC Class I and Class II complementary deoxyribonucleic acid probes were performed on blots containing total ribonucleic acid from wild-type tumor cells and HSV TK transfectants. A beta-actin complementary deoxyribonucleic acid probe served as an internal control. Cell surface expression was confirmed with flow cytometry. The induction of MHC Class I was tested for cycloheximide and genistein sensitivity. All cell cultures exhibited increases in MHC Class I but not MHC Class II expression, as determined by Northern analysis densitometry and flow cytometry. Cycloheximide treatment did not diminish the up-regulation of MHC Class I after retroviral transfection, implicating a signal transduction pathway that does not require ongoing protein synthesis. Genistein pretreatment of cell cultures did diminish the up-regulation of MHC Class I, implicating a tyrosine kinase in the signaling cascade. Induction of MHC Class I in rat and human glioma cells after HSV TK retroviral gene therapy is a primary effect that is dependent on tyrosine kinase activity. Specific immune responses generated after transfection may represent an important general side effect of gene therapy protocols. Elucidation of the mechanism of immunomodulation after gene therapy will likely yield safer and more effective clinical protocols.

p53 activated by AND gate genetic circuit under radiation and hypoxia for targeted cancer gene therapy.

PubMed

Ding, Miao; Li, Rong; He, Rong; Wang, Xingyong; Yi, Qijian; Wang, Weidong

2015-09-01

Radio-activated gene therapy has been developed as a novel therapeutic strategy against cancer; however, expression of therapeutic gene in peritumoral tissues will result in unacceptable toxicity to normal cells. To restrict gene expression in targeted tumor mass, we used hypoxia and radiation tolerance features of tumor cells to develop a synthetic AND gate genetic circuit through connecting radiation sensitivity promoter cArG6 , heat shock response elements SNF1, HSF1 and HSE4 with retroviral vector plxsn. Their construction and dynamic activity process were identified through downstream enhanced green fluorescent protein and wtp53 expression in non-small cell lung cancer A549 cells and in a nude mice model. The result showed that AND gate genetic circuit could be activated by lower required radiation dose (6 Gy) and after activated, AND gate could induce significant apoptosis effects and growth inhibition of cancer cells in vitro and in vivo. The radiation- and hypoxia-activated AND gate genetic circuit, which could lead to more powerful target tumoricidal activity represented a promising strategy for both targeted and effective gene therapy of human lung adenocarcinoma and low dose activation character of the AND gate genetic circuit implied that this model could be further exploited to decrease side-effects of clinical radiation therapy. © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

Prostate Cancer Cells Express More Androgen Receptor (AR) Following Androgen Deprivation, Improving Recognition by AR-Specific T Cells.

PubMed

Olson, Brian M; Gamat, Melissa; Seliski, Joseph; Sawicki, Thomas; Jeffery, Justin; Ellis, Leigh; Drake, Charles G; Weichert, Jamey; McNeel, Douglas G

2017-12-01

Androgen deprivation is the primary therapy for recurrent prostate cancer, and agents targeting the androgen receptor (AR) pathway continue to be developed. Because androgen-deprivation therapy (ADT) has immmunostimulatory effects as well as direct antitumor effects, AR-targeted therapies have been combined with other anticancer therapies, including immunotherapies. Here, we sought to study whether an antigen-specific mechanism of resistance to ADT (overexpression of the AR) may result in enhanced AR-specific T-cell immune recognition, and whether this might be strategically combined with an antitumor vaccine targeting the AR. Androgen deprivation increased AR expression in human and murine prostate tumor cells in vitro and in vivo The increased expression persisted over time. Increased AR expression was associated with recognition and cytolytic activity by AR-specific T cells. Furthermore, ADT combined with vaccination, specifically a DNA vaccine encoding the ligand-binding domain of the AR, led to improved antitumor responses as measured by tumor volumes and delays in the emergence of castrate-resistant prostate tumors in two murine prostate cancer models (Myc-CaP and prostate-specific PTEN-deficient mice). Together, these data suggest that ADT combined with AR-directed immunotherapy targets a major mechanism of resistance, overexpression of the AR. This combination may be more effective than ADT combined with other immunotherapeutic approaches. Cancer Immunol Res; 5(12); 1074-85. ©2017 AACR . ©2017 American Association for Cancer Research.

FK506 attenuates thymic output in patients with myasthenia gravis

PubMed Central

Kuroda, Yukiko; Ueno, Shu-ichi; Matsui, Naoko; Kaji, Ryuji

2013-01-01

Introduction Myasthenia gravis (MG) is an antibody-mediated, T-cell-dependent autoimmune disease. The symptoms are caused by high-affinity IgG against the muscle acetylcholine receptor (AChR) at the neuromuscular junction. The production of these antibodies in B-cells depends on AChR-specific CD4+ T-cells and the thymus gland seems to play a significant role in the pathogenesis of MG. Altered thymic T-cell export seems to be associated with a pathological mechanism in myasthenia gravis. Tacrolimus (FK506) has recently been used to treat MG. Material and methods We examined the effects of tacrolimus on thymic T-cell export in patients with MG. Sixteen patients with nonthymomatous and/or thymectomized MG were treated with oral administrations of tacrolimus. To assess the effect of tacrolimus on the thymic output, we assayed the levels of T-cell receptor excision circle (TREC), a molecular marker of thymus emigrants. Results T-cell receptor excision circle was not significantly different from those in age-matched controls before tacrolimus therapy, but they were partially decreased 4 months after tacrolimus therapy. T-cell receptor excision circle levels were significantly decreased in the thymomatous group (p < 0.05), but not in the nonthymomatous group. Tacrolimus treatment significantly attenuated TREC levels in cultured CD4–CD8+ cells (p < 0.05), but total cell counts were not significantly changed. Conclusions These results indicate that TREC levels may become a marker of the curative effect of tacrolimus therapy for thymomatous MG, and that tacrolimus suppresses not only activating T-lymphocytes, but also naïve T-cells. PMID:24482655

Magnolol, a natural compound, induces apoptosis of SGC-7901 human gastric adenocarcinoma cells via the mitochondrial and PI3K/Akt signaling pathways.

PubMed

Rasul, Azhar; Yu, Bo; Khan, Muhammad; Zhang, Kun; Iqbal, Furhan; Ma, Tonghui; Yang, Hong

2012-04-01

Gastric cancer is the fourth most commonly diagnosed cancer with the second highest mortality rate worldwide. Surgery, chemotherapy and radiation therapy are generally used for the treatment of stomach cancer but only limited clinical response is shown by these therapies and still no effectual therapy for advanced gastric adenocarcinoma patients is available. Therefore, there is a need to identify other therapeutic agents against this life-threatening disease. Plants are considered as one of the most important sources for the development of anticancer drugs. Magnolol, a natural compound possesses anticancer properties. However, effects of Magnolol on human gastric cancer remain unexplored. The effects of Magnolol on the viability of SGC-7901 cells were determined by the MTT assay. Apoptosis, mitochondrial membrane potential and cell cycle were evaluated by flow cytometry. Protein expression of Bcl-2, Bax, caspase-3 and PI3K/Akt was analysed by Western blotting. Magnolol induced morphological changes in SGC-7901 cells and its cytotoxic effects were linked with DNA damage, apoptosis and S-phase arrest in a dose-dependent manner. Magnolol triggered the mitochondrial-mediated apoptosis pathway as shown by an increased ratio of Bax/Bcl-2, dissipation of mitochondrial membrane potential (ΔΨm), and sequential activation of caspase-3 and inhibition of PI3K/Akt. Additionally, Magnolol induced autophagy in SGC-7901 cells at high concentration but was not involved in cell death. Magnolol-induced apoptosis of SGC-7901 cells involves mitochondria and PI3K/Akt-dependent pathways. These findings provide evidence that Magnolol is a promising natural compound for the treatment of gastric cancer and may represent a candidate for in vivo studies of monotherapies or combination antitumor therapies.

Magnolol, a natural compound, induces apoptosis of SGC-7901 human gastric adenocarcinoma cells via the mitochondrial and PI3K/Akt signaling pathways

PubMed Central

RASUL, AZHAR; YU, BO; KHAN, MUHAMMAD; ZHANG, KUN; IQBAL, FURHAN; MA, TONGHUI; YANG, HONG

2012-01-01

Gastric cancer is the fourth most commonly diagnosed cancer with the second highest mortality rate worldwide. Surgery, chemotherapy and radiation therapy are generally used for the treatment of stomach cancer but only limited clinical response is shown by these therapies and still no effectual therapy for advanced gastric adenocarcinoma patients is available. Therefore, there is a need to identify other therapeutic agents against this life-threatening disease. Plants are considered as one of the most important sources for the development of anticancer drugs. Magnolol, a natural compound possesses anticancer properties. However, effects of Magnolol on human gastric cancer remain unexplored. The effects of Magnolol on the viability of SGC-7901 cells were determined by the MTT assay. Apoptosis, mitochondrial membrane potential and cell cycle were evaluated by flow cytometry. Protein expression of Bcl-2, Bax, caspase-3 and PI3K/Akt was analysed by Western blotting. Magnolol induced morphological changes in SGC-7901 cells and its cytotoxic effects were linked with DNA damage, apoptosis and S-phase arrest in a dose-dependent manner. Magnolol triggered the mitochondrial-mediated apoptosis pathway as shown by an increased ratio of Bax/Bcl-2, dissipation of mitochondrial membrane potential (ΔΨm), and sequential activation of caspase-3 and inhibition of PI3K/Akt. Additionally, Magnolol induced autophagy in SGC-7901 cells at high concentration but was not involved in cell death. Magnolol-induced apoptosis of SGC-7901 cells involves mitochondria and PI3K/Akt-dependent pathways. These findings provide evidence that Magnolol is a promising natural compound for the treatment of gastric cancer and may represent a candidate for in vivo studies of monotherapies or combination antitumor therapies. PMID:22139054

Sonodynamic therapy using water-dispersed TiO2-polyethylene glycol compound on glioma cells: comparison of cytotoxic mechanism with photodynamic therapy.

PubMed

Yamaguchi, Shigeru; Kobayashi, Hiroyuki; Narita, Takuhito; Kanehira, Koki; Sonezaki, Shuji; Kudo, Nobuki; Kubota, Yoshinobu; Terasaka, Shunsuke; Houkin, Kiyohiro

2011-09-01

Sonodynamic therapy is expected to be a novel therapeutic strategy for malignant gliomas. The titanium dioxide (TiO(2)) nanoparticle, a photosensitizer, can be activated by ultrasound. In this study, by using water-dispersed TiO(2) nanoparticles, an in vitro comparison was made between the photodynamic and sonodynamic damages on U251 human glioblastoma cell lines. Water-dispersed TiO(2) nanoparticles were constructed by the adsorption of chemically modified polyethylene glycole (PEG) on the TiO(2) surface (TiO(2)/PEG). To evaluate cytotoxicity, U251 monolayer cells were incubated in culture medium including 100 μg/ml of TiO(2)/PEG for 3h and subsequently irradiated by ultraviolet light (5.0 mW/cm(2)) or 1.0MHz ultrasound (1.0 W/cm(2)). Cell survival was estimated by MTT assay 24h after irradiation. In the presence of TiO(2)/PEG, the photodynamic cytotoxic effect was not observed after 20 min of an ultraviolet light exposure, while the sonodynamic cytotoxicity effect was almost proportional to the time of sonication. In addition, photodynamic cytotoxicity of TiO(2)/PEG was almost completely inhibited by radical scavenger, while suppression of the sonodynamic cytotoxic effect was not significant. Results of various fluorescent stains showed that ultrasound-treated cells lost their viability immediately after irradiation, and cell membranes were especially damaged in comparison with ultraviolet-treated cells. These findings showed a potential application of TiO(2)/PEG to sonodynamic therapy as a new treatment of malignant gliomas and suggested that the mechanism of TiO(2)/PEG mediated sonodynamic cytotoxicity differs from that of photodynamic cytotoxicity. Copyright © 2011 Elsevier B.V. All rights reserved.

Intracellular delivery and passive tumor targeting of a self-assembled nanogel containing carborane clusters for boron neutron capture therapy.

PubMed

Kawasaki, Riku; Sasaki, Yoshihiro; Akiyoshi, Kazunari

2017-01-29

Boron neutron capture therapy, based on the release of thermal neutron irradiation from boron, is a targeted radiation therapy for cancer. Targeted and sufficient accumulation of boron in tumor cells to achieve cytotoxic efficacy and reduce off-target effects remains a challenge. Carborane has been investigated for use as a delivery agent in boron neutron capture therapy because of its high boron content and chemical stability; however, it is cytotoxic, making safe delivery difficult. The aim of this study was to investigate the potential of carborane-bearing pullulan nanogels to safely and effectively deliver boron to tumor cells in vitro and in vivo and, consequently, assess their potential as a boron neutron capture therapeutic. Murine fibrosarcoma cells (CMS5a) were used for in vitro investigations of nanogel cytotoxicity, cell uptake. A mouse fibrosarcoma xenograft model was used to investigate the bio-distribution of nanogels after intravenous administration. The nanogels produced no apparent cytotoxicity and underwent cell uptake in CMS5a cells after a 24 h incubation at up to 2000 μg/mL and 400 μg/mL, respectively. The internalized nanogels were localized around the nuclear membrane. The nanogels were administered intravenously to mice bearing fibrosarcoma xenografts. Nanogel tumor localization likely occurred through the enhanced permeation and retention effect. The nanogels successfully reduced the cytotoxicity of carborane, were internalized into tumor cells, acted as a dual-delivery therapeutic and accumulated in tumors in vivo. Consequently, they demonstrate significant potential as a boron neutron capture therapeutic. Copyright © 2016 Elsevier Inc. All rights reserved.

Carbon ion irradiation of the human prostate cancer cell line PC3: A whole genome microarray study

PubMed Central

SUETENS, ANNELIES; MOREELS, MARJAN; QUINTENS, ROEL; CHIRIOTTI, SABINA; TABURY, KEVIN; MICHAUX, ARLETTE; GRÉGOIRE, VINCENT; BAATOUT, SARAH

2014-01-01

Hadrontherapy is a form of external radiation therapy, which uses beams of charged particles such as carbon ions. Compared to conventional radiotherapy with photons, the main advantage of carbon ion therapy is the precise dose localization along with an increased biological effectiveness. The first results obtained from prostate cancer patients treated with carbon ion therapy showed good local tumor control and survival rates. In view of this advanced treatment modality we investigated the effects of irradiation with different beam qualities on gene expression changes in the PC3 prostate adenocarcinoma cell line. For this purpose, PC3 cells were irradiated with various doses (0.0, 0.5 and 2.0 Gy) of carbon ions (LET=33.7 keV/μm) at the beam of the Grand Accélérateur National d’Ions Lourds (Caen, France). Comparative experiments with X-rays were performed at the Belgian Nuclear Research Centre. Genome-wide gene expression was analyzed using microarrays. Our results show a downregulation in many genes involved in cell cycle and cell organization processes after 2.0 Gy irradiation. This effect was more pronounced after carbon ion irradiation compared with X-rays. Furthermore, we found a significant downregulation of many genes related to cell motility. Several of these changes were confirmed using qPCR. In addition, recurrence-free survival analysis of prostate cancer patients based on one of these motility genes (FN1) revealed that patients with low expression levels had a prolonged recurrence-free survival time, indicating that this gene may be a potential prognostic biomarker for prostate cancer. Understanding how different radiation qualities affect the cellular behavior of prostate cancer cells is important to improve the clinical outcome of cancer radiation therapy. PMID:24504141

Outcome From a Randomized Controlled Clinical Trial　- Improvement of Peripheral Arterial Disease by Granulocyte Colony-Stimulating Factor-Mobilized Autologous Peripheral-Blood-Mononuclear Cell Transplantation (IMPACT).

PubMed

Horie, Takashi; Yamazaki, Seiji; Hanada, Sayaka; Kobayashi, Shuzo; Tsukamoto, Tatsuo; Haruna, Tetsuya; Sakaguchi, Katsuhiko; Sakai, Ken; Obara, Hideaki; Morishita, Kiyofumi; Saigo, Kenichi; Shintani, Yoshiaki; Kubo, Kohmei; Hoshino, Junichi; Oda, Teiji; Kaneko, Eiji; Nishikido, Masaharu; Ioji, Tetsuya; Kaneda, Hideaki; Fukushima, Masanori

2018-06-07

The clinical usefulness of peripheral blood (PB) mononuclear cell (MNC) transplantation in patients with peripheral arterial disease (PAD), especially in those with mild-to-moderate severity, has not been fully clarified.Methods and Results:A randomized clinical trial was conducted to evaluate the efficacy and safety of granulocyte colony-stimulating factor (G-CSF)-mobilized PBMNC transplantation in patients with PAD (Fontaine stage II-IV and Rutherford category 1-5) caused by arteriosclerosis obliterans or Buerger's disease. The primary endpoint was progression-free survival (PFS). In total, 107 subjects were enrolled. At baseline, Fontaine stage was II/III in 82 patients and IV in 21, and 54 patients were on hemodialysis. A total of 50 patients had intramuscular transplantation of PBMNC combined with standard of care (SOC) (cell therapy group), and 53 received SOC only (control group). PFS tended to be improved in the cell therapy group than in the control group (P=0.07). PFS in Fontaine stage II/III subgroup was significantly better in the cell therapy group than in the control group. Cell therapy-related adverse events were transient and not serious. In this first randomized, large-scale clinical trial of G-CSF-mobilized PBMNC transplantation, the cell therapy was tolerated by a variety of PAD patients. The PBMNC therapy was significantly effective for inhibiting disease progression in mild-to-moderate PAD.

Perspectives of boron-neutron capture therapy of malignant brain tumors

NASA Astrophysics Data System (ADS)

Kanygin, V. V.; Kichigin, A. I.; Krivoshapkin, A. L.; Taskaev, S. Yu.

2017-09-01

Boron neutron capture therapy (BNCT) is characterized by a selective effect directly on the cells of malignant tumors. The carried out research showed the perspective of the given kind of therapy concerning malignant tumors of the brain. However, the introduction of BNCT into clinical practice is hampered by the lack of a single protocol for the treatment of patients and the difficulty in using nuclear reactors to produce a neutron beam. This problem can be solved by using a compact accelerator as a source of neutrons, with the possibility of installation in a medical institution. Such a neutron accelerator for BNCT was developed at Budker Institute of Nuclear Physics, Novosibirsk. A neutron beam was obtained on this accelerator, which fully complies with the requirements of BNCT, as confirmed by studies on cell cultures and experiments with laboratory animals. The conducted experiments showed the relative safety of the method with the absence of negative effects on cell cultures and living organisms, and also confirmed the effectiveness of BNCT for malignant brain tumors.

IMMU-22. ADOPTIVE CELL THERAPY AGAINST DIPG USING DEVELOPMENTALLY REGULATED ANTIGENS

PubMed Central

Flores, Catherine; Gil, Jorge; Abraham, Rebecca; Pham, Christina; Wildes, Tyler; Moore, Ginger; Drake, Jeffrey; Dyson, Kyle; Mitchell, Duane

2017-01-01

Abstract INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) survival has remained static over decades and DIPG is now the main cause of brain tumor-related deaths in children. Immunotherapy has emerged as a treatment modality with the highest curative potential in patients with refractory malignancies. Our group has pioneered an adoptive cell therapy platform employing total tumor RNA pulsed dendritic cells to generate large amounts of polyclonal antigen-specific T cells in both human and murine systems. As DIPGs are embryonal tumors, our objective in this proposal is to identify a set of developmentally regulated antigens that are overexpressed during oncogenesis of DIPG in order to cause immunological rejection of this tumor without the need for tumor tissue. METHODS: We employ RNA-pulsed bone marrow-derived dendritic cells to ex vivo activate tumor-reactive T cells for use in adoptive cell therapy. Here we use either total RNA isolated from tumor tissue, (TTRNA) or developmental antigens (DevAg) RNA isolated from postnatal day 4 murine brain stem. Either TTRNA-T cells or DevAg-T cells were used in adoptive cell therapy against a preclinical model of DIPG. RESULTS: Pediatric brain tumors are bland relative to peripheral tumors in terms of high expression of immunogenic antigens. Since DIPG antigens remain largely uncharacterized, we used total RNA isolated from tumor cells to generate tumor-specific T cells to use for our therapeutic approach to first demonstrate that immune responses can be generated against this tumor. We also successfully generated immunity against DIPG in a preclinical model using DevAg-T cells for adoptive cell therapy. CONCLUSION: The region- and age- specific nature of DIPG suggests that the underlying pathophysiology likely involves dysregulation of a postnatal neurodevelopmental process which occurs in embryonal tumors. Here we leverage this and demonstrate that DIPG can be effectively treated using adoptive cell therapy against overexpressed developmentally regulated antigens.

Supercritical carbon dioxide-developed silk fibroin nanoplatform for smart colon cancer therapy.

PubMed

Xie, Maobin; Fan, Dejun; Li, Yi; He, Xiaowen; Chen, Xiaoming; Chen, Yufeng; Zhu, Jixiang; Xu, Guibin; Wu, Xiaojian; Lan, Ping

2017-01-01

To deliver insoluble natural compounds into colon cancer cells in a controlled fashion. Curcumin (CM)-silk fibroin (SF) nanoparticles (NPs) were prepared by solution-enhanced dispersion by supercritical CO 2 (SEDS) (20 MPa pressure, 1:2 CM:SF ratio, 1% concentration), and their physicochemical properties, intracellular uptake efficiency, in vitro anticancer effect, toxicity, and mechanisms were evaluated and analyzed. CM-SF NPs (<100 nm) with controllable particle size were prepared by SEDS. CM-SF NPs had a time-dependent intracellular uptake ability, which led to an improved inhibition effect on colon cancer cells. Interestingly, the anticancer effect of CM-SF NPs was improved, while the side effect on normal human colon mucosal epithelial cells was reduced by a concentration of ~10 μg/mL. The anticancer mechanism involves cell-cycle arrest in the G 0 /G 1 and G 2 /M phases in association with inducing apoptotic cells. The natural compound-loaded SF nanoplatform prepared by SEDS indicates promising colon cancer-therapy potential.

Increased anti-tumor effects using IL2 with anti-TGFβ reveals competition between mouse NK and CD8 T cells

PubMed Central

Alvarez, Maite; Bouchlaka, Myriam N.; Sckisel, Gail D.; Sungur, Can M.; Chen, Mingyi; Murphy, William J.

2014-01-01

Due to increasing interest in the removal of immunosuppressive pathways in cancer, the combination of IL2 with antibodies to neutralize TGFβ, a potent immunosuppressive cytokine, was assessed. Combination immunotherapy resulted in significantly greater anti-tumor effects. These were correlated with significant increases in the numbers and functionality of NK cells, NK progenitors and activated CD8 T cells resulting in the observed anti-tumor effects. Combination immunotherapy was also accompanied with lesser toxicities than IL2 therapy alone. Additionally, we observed a dual competition between NK and activated CD8 T cells such that after immunotherapy, the depletion of either effector population resulted in the increased total expansion of the other population and compensatory anti-tumor effects. This study demonstrates the efficacy of this combination immunotherapeutic regimen as a promising cancer therapy and illustrates the existence of potent competitive regulatory pathways between NK and CD8 T cells in response to systemic activation. PMID:25000978

Interdependent IL-7 and IFN-γ signalling in T-cell controls tumour eradication by combined α-CTLA-4+α-PD-1 therapy

PubMed Central

Shi, Lewis Zhichang; Fu, Tihui; Guan, Baoxiang; Chen, Jianfeng; Blando, Jorge M.; Allison, James P.; Xiong, Liangwen; Subudhi, Sumit K.; Gao, Jianjun; Sharma, Padmanee

2016-01-01

Combination therapy with α-CTLA-4 and α-PD-1 has shown significant clinical responses in different types of cancer. However, the underlying mechanisms remain elusive. Here, combining detailed analysis of human tumour samples with preclinical tumour models, we report that concomitant blockade of CTLA-4 and PD-1 improves anti-tumour immune responses and synergistically eradicates tumour. Mechanistically, combination therapy relies on the interdependence between IL-7 and IFN-γ signalling in T cells, as lack of either pathway abrogates the immune-boosting and therapeutic effects of combination therapy. Combination treatment increases IL-7Rα expression on tumour-infiltrating T cells in an IFN-γ/IFN-γR signalling-dependent manner, which may serve as a potential biomarker for clinical trials with immune checkpoint blockade. Our data suggest that combining immune checkpoint blockade with IL-7 signalling could be an effective modality to improve immunotherapeutic efficacy. Taken together, we conclude that combination therapy potently reverses immunosuppression and eradicates tumours via an intricate interplay between IFN-γ/IFN-γR and IL-7/IL-7R pathways. PMID:27498556

Adoptive cellular therapy of cancer: exploring innate and adaptive cellular crosstalk to improve anti-tumor efficacy.

PubMed

Payne, Kyle K; Bear, Harry D; Manjili, Masoud H

2014-08-01

The mammalian immune system has evolved to produce multi-tiered responses consisting of both innate and adaptive immune cells collaborating to elicit a functional response to a pathogen or neoplasm. Immune cells possess a shared ancestry, suggestive of a degree of coevolution that has resulted in optimal functionality as an orchestrated and highly collaborative unit. Therefore, the development of therapeutic modalities that harness the immune system should consider the crosstalk between cells of the innate and adaptive immune systems in order to elicit the most effective response. In this review, the authors will discuss the success achieved using adoptive cellular therapy in the treatment of cancer, recent trends that focus on purified T cells, T cells with genetically modified T-cell receptors and T cells modified to express chimeric antigen receptors, as well as the use of unfractionated immune cell reprogramming to achieve optimal cellular crosstalk upon infusion for adoptive cellular therapy.

Application of proton boron fusion reaction to radiation therapy: A Monte Carlo simulation study

NASA Astrophysics Data System (ADS)

Yoon, Do-Kun; Jung, Joo-Young; Suh, Tae Suk

2014-12-01

Three alpha particles are emitted from the point of reaction between a proton and boron. The alpha particles are effective in inducing the death of a tumor cell. After boron is accumulated in the tumor region, the emitted from outside the body proton can react with the boron in the tumor region. An increase of the proton's maximum dose level is caused by the boron and only the tumor cell is damaged more critically. In addition, a prompt gamma ray is emitted from the proton boron reaction point. Here, we show that the effectiveness of the proton boron fusion therapy was verified using Monte Carlo simulations. We found that a dramatic increase by more than half of the proton's maximum dose level was induced by the boron in the tumor region. This increase occurred only when the proton's maximum dose point was located within the boron uptake region. In addition, the 719 keV prompt gamma ray peak produced by the proton boron fusion reaction was positively detected. This therapy method features the advantages such as the application of Bragg-peak to the therapy, the accurate targeting of tumor, improved therapy effects, and the monitoring of the therapy region during treatment.

Microwave pumped high-efficient thermoacoustic tumor therapy with single wall carbon nanotubes.

PubMed

Wen, Liewei; Ding, Wenzheng; Yang, Sihua; Xing, Da

2016-01-01

The ultra-short pulse microwave could excite to the strong thermoacoustic (TA) shock wave and deeply penetrate in the biological tissues. Based on this, we developed a novel deep-seated tumor therapy modality with mitochondria-targeting single wall carbon nanotubes (SWNTs) as microwave absorbing agents, which act efficiently to convert ultra-short microwave energy into TA shock wave and selectively destroy the targeted mitochondria, thereby inducing apoptosis in cancer cells. After the treatment of SWNTs (40 μg/mL) and ultra-short microwave (40 Hz, 1 min), 77.5% of cancer cells were killed and the vast majority were caused by apoptosis that initiates from mitochondrial damage. The orthotopic liver cancer mice were established as deep-seated tumor model to investigate the anti-tumor effect of mitochondria-targeting TA therapy. The results suggested that TA therapy could effectively inhibit the tumor growth without any observable side effects, while it was difficult to achieve with photothermal or photoacoustic therapy. These discoveries implied the potential application of TA therapy in deep-seated tumor models and should be further tested for development into a promising therapeutic modality for cancer treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.

Combined influence of adjuvant therapy and interval after surgery on peripheral CD4+ T lymphocytes in patients with esophageal squamous cell carcinoma

PubMed Central

LING, YANG; FAN, LIEYING; DONG, CHUNLEI; ZHU, JING; LIU, YONGPING; NI, YAN; ZHU, CHANGTAI; ZHANG, CHANGSONG

2010-01-01

The aim of this study was to investigate possible differences in cellular immunity between chemo- and/or radiotherapy groups during a long interval after surgery in esophageal squamous cell carcinoma (ESCC) patients. Cellular immunity was assessed as peripheral lymphocyte subsets in response to chemotherapy (CT), radiotherapy (RT) and CT+RT by flow cytometric analysis. There were 139 blood samples obtained at different time points relative to surgery from 73 patients with ESCC. The changes in the absolute and relative proportions of lymphocyte phenotypes were significant among the adjuvant therapy groups. There were significant differences in the absolute counts of CD4+ and CD8+ T cells among the interval groups, and a lower CD4/CD8 ratio was found in patients following a prolonged interval. RT alone had a profound effect on the absolute counts of CD3+, CD4+ and CD8+ T cells compared with the other groups. CD4+ T cells exhibited a decreasing trend during a long interval, leading to a prolonged T-cell imbalance after surgery. Univariate analysis revealed that the interaction of the type of adjuvant therapy and the interval after surgery was correlated only with the percentage of CD4+ T cells. The percentage of CD4+ T cells can be used as an indicator of the cellular immunity after surgery in ESCC patients. However, natural killer cells consistently remained suppressed in ESCC patients following adjuvant therapy after surgery. These findings confirm an interaction between adjuvant therapy and the interval after surgery on peripheral CD4+ T cells, and implies that adjuvant therapy may have selective influence on the cellular immunity of ESCC patients after surgery. PMID:23136603

Low Temperature Plasma: A Novel Focal Therapy for Localized Prostate Cancer?

PubMed Central

Hirst, Adam M.; Frame, Fiona M.; Maitland, Norman J.; O'Connell, Deborah

2014-01-01

Despite considerable advances in recent years for the focal treatment of localized prostate cancer, high recurrence rates and detrimental side effects are still a cause for concern. In this review, we compare current focal therapies to a potentially novel approach for the treatment of early onset prostate cancer: low temperature plasma. The rapidly evolving plasma technology has the potential to deliver a wide range of promising medical applications via the delivery of plasma-induced reactive oxygen and nitrogen species. Studies assessing the effect of low temperature plasma on cell lines and xenografts have demonstrated DNA damage leading to apoptosis and reduction in cell viability. However, there have been no studies on prostate cancer, which is an obvious candidate for this novel therapy. We present here the potential of low temperature plasma as a focal therapy for prostate cancer. PMID:24738076

Low temperature plasma: a novel focal therapy for localized prostate cancer?

PubMed

Hirst, Adam M; Frame, Fiona M; Maitland, Norman J; O'Connell, Deborah

2014-01-01

Despite considerable advances in recent years for the focal treatment of localized prostate cancer, high recurrence rates and detrimental side effects are still a cause for concern. In this review, we compare current focal therapies to a potentially novel approach for the treatment of early onset prostate cancer: low temperature plasma. The rapidly evolving plasma technology has the potential to deliver a wide range of promising medical applications via the delivery of plasma-induced reactive oxygen and nitrogen species. Studies assessing the effect of low temperature plasma on cell lines and xenografts have demonstrated DNA damage leading to apoptosis and reduction in cell viability. However, there have been no studies on prostate cancer, which is an obvious candidate for this novel therapy. We present here the potential of low temperature plasma as a focal therapy for prostate cancer.

The role of incretin-based therapies in prediabetes: a review.

PubMed

Ahmadieh, Hala; Azar, Sami T

2014-12-01

Prediabetes, a high-risk state for future development of diabetes, is prevalent globally. Abnormalities in the incretin axis are important in the progression of B-cell failure in type 2 diabetes. Incretin based therapy was found to improve B cell mass and glycaemic control in addition to having multiple beneficial effects on the systolic and diastolic blood pressure, weight loss in addition to their other beneficial effects on the liver and cardiovascular system. In prediabetes, several well-designed preventive trials have shown that lifestyle and pharmacologic interventions such as metformin, thiazolidinediones (TZD), acarbose and, nateglinide and orlistat, are effective in reducing diabetes development. In recent small studies, incretin based therapy (DPP IV inhibitors and GLP-1 agonists) have also been extended to patients with prediabetes since it was shown to better preserve B-cell function and mass in animal studies and in clinical trials and it was also shown to help maintain good long term metabolic control. Because of the limited studies and clinical experience, their side effects and costs currently guidelines do not recommend incretin-based therapies as an option for treatment in patients with prediabetes. With future clinical trials and studies they may be recommended for patients with impaired fasting glucose or impaired glucose tolerance. Copyright © 2014 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.

Inhibition of heme oxygenase-1 enhances the cytotoxic effect of gemcitabine in urothelial cancer cells.

PubMed

Miyake, Makito; Fujimoto, Kiyohide; Anai, Satoshi; Ohnishi, Sayuri; Nakai, Yasushi; Inoue, Takeshi; Matsumura, Yoshiaki; Tomioka, Atsushi; Ikeda, Tomohiro; Okajima, Eijiro; Tanaka, Nobumichi; Hirao, Yoshihiko

2010-06-01

Elevated heme oxygenase-1 (HO-1) is associated with resistance to chemo- and radiotherapy through anti-apoptotic function. The present study evaluated whether the HO-1 inhibitor, zinc protoporphyrin IX (ZnPP), enhances the cytotoxic effect of gemcitabine in urothelial carcinoma (UC). The in vitro cytotoxic effect of combination treatment of gemcitabine and ZnPP on UC cells was examined. The in vivo growth inhibitory effects of intraperitoneal administration of gemcitabine and/or ZnPP on mouse subcutaneous tumours were examined. The apoptotic changes were analysed with the detection of DNA fragmentation and cleaved caspase-3. HO-1 was up-regulated by both gemcitabine and irradiation treatment in vitro. ZnPP sensitised the UC cells to both therapies. Enhanced apoptosis was induced by the ZnPP combined with gemicitabine. ZnPP enhanced the antitumour effect of gemcitabine in vivo along with decreased numbers of proliferating cells and increased numbers of apoptotic cells. These findings suggest that ZnPP combined with gemcitabine or irradiation therapy may be an effective therapeutic modality for UC patients.

Synthesis of axially disubstituted silicon phthalocyanines and investigation of photodynamic effects on HCT-116 colorectal cancer cell line.

PubMed

Sarı, Ceren; Eyüpoğlu, Figen Celep; Değirmencioğlu, İsmail; Bayrak, Rıza

2018-05-15

Photodynamic therapy is one of the hot topics in cancer studies recently. Basically, photosensitizing chemical substrates which are stimulated by light having a specific wavelength cause fatal effect on different kind of cells in photodynamic therapy. In this study, axially 4-{[(1E)-2-furylmethylene]amino}phenol, 4-{[(1E)-2-thienylmethylene]amino}phenol and 4-{[(1E)-(4-nitro-2-thienyl)methylene]amino}phenol disubstituted silicon phthalocyanines were synthesized as Photosensitizers for photodynamic therapy in cancer treatment for the first time. The structural characterizations of these novel compounds were performed by a combination of FT-IR, 1 H-NMR, UV-vis and mass. All these newly prepared compounds did not show aggregation at the concentration range of 2 × 10 -6 -12 × 10 -6 M in tetrahydrofurane and also did not show aggregation in different organic solvents at 2 × 10 -6 M concentration. Phthalocyanines which are synthesized in this study are tested on HCT-116 colorectal cancer cells and stimulated by light has wavelength of 680 nm. The toxic effects on cancer cells which are caused by different concentrations of photosensitizing molecules have been examined and compared with the toxic effects on cancer cells that were kept in the dark. It is confirmed that these molecules caused toxic effects on colorectal cancer cells when they were stimulated by light but there was no toxic effect in the dark. Copyright © 2018. Published by Elsevier B.V.

Magselectofection: an integrated method of nanomagnetic separation and genetic modification of target cells.

PubMed

Sanchez-Antequera, Yolanda; Mykhaylyk, Olga; van Til, Niek P; Cengizeroglu, Arzu; de Jong, J Henk; Huston, Marshall W; Anton, Martina; Johnston, Ian C D; Pojda, Zygmunt; Wagemaker, Gerard; Plank, Christian

2011-04-21

Research applications and cell therapies involving genetically modified cells require reliable, standardized, and cost-effective methods for cell manipulation. We report a novel nanomagnetic method for integrated cell separation and gene delivery. Gene vectors associated with magnetic nanoparticles are used to transfect/transduce target cells while being passaged and separated through a high gradient magnetic field cell separation column. The integrated method yields excellent target cell purity and recovery. Nonviral and lentiviral magselectofection is efficient and highly specific for the target cell population as demonstrated with a K562/Jurkat T-cell mixture. Both mouse and human enriched hematopoietic stem cell pools were effectively transduced by lentiviral magselectofection, which did not affect the hematopoietic progenitor cell number determined by in vitro colony assays. Highly effective reconstitution of T and B lymphocytes was achieved by magselectofected murine wild-type lineage-negative Sca-1(+) cells transplanted into Il2rg(-/-) mice, stably expressing GFP in erythroid, myeloid, T-, and B-cell lineages. Furthermore, nonviral, lentiviral, and adenoviral magselectofection yielded high transfection/transduction efficiency in human umbilical cord mesenchymal stem cells and was fully compatible with their differentiation potential. Upscaling to a clinically approved automated cell separation device was feasible. Hence, once optimized, validated, and approved, the method may greatly facilitate the generation of genetically engineered cells for cell therapies.

The effect of natural and synthetic fatty acids on membrane structure, microdomain organization, cellular functions and human health.

PubMed

Ibarguren, Maitane; López, David J; Escribá, Pablo V

2014-06-01

This review deals with the effects of synthetic and natural fatty acids on the biophysical properties of membranes, and on their implication on cell function. Natural fatty acids are constituents of more complex lipids, like triacylglycerides or phospholipids, which are used by cells to store and obtain energy, as well as for structural purposes. Accordingly, natural and synthetic fatty acids may modify the structure of the lipid membrane, altering its microdomain organization and other physical properties, and provoking changes in cell signaling. Therefore, by modulating fatty acids it is possible to regulate the structure of the membrane, influencing the cell processes that are reliant on this structure and potentially reverting pathological cell dysfunctions that may provoke cancer, diabetes, hypertension, Alzheimer's and Parkinson's disease. The so-called Membrane Lipid Therapy offers a strategy to regulate the membrane composition through drug administration, potentially reverting pathological processes by re-adapting cell membrane structure. Certain fatty acids and their synthetic derivatives are described here that may potentially be used in such therapies, where the cell membrane itself can be considered as a target to combat disease. This article is part of a Special Issue entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy. Copyright © 2013 Elsevier B.V. All rights reserved.

Targeting CD147 for T to NK Lineage Reprogramming and Tumor Therapy.

PubMed

Geng, Jie-Jie; Tang, Juan; Yang, Xiang-Min; Chen, Ruo; Zhang, Yang; Zhang, Kui; Miao, Jin-Lin; Chen, Zhi-Nan; Zhu, Ping

2017-06-01

CD147 is highly expressed on the surface of numerous tumor cells to promote invasion and metastasis. Targeting these cells with CD147-specific antibodies has been validated as an effective approach for lung and liver cancer therapy. In the immune system, CD147 is recognized as a co-stimulatory receptor and impacts the outcome of thymic selection. Using T cell-specific deletion, we showed here that in thymus CD147 is indispensable for the stable αβ T cell lineage commitment: loss of CD147 biases both multipotent DN (double negative) and fully committed DP (double positive) cells into innate NK-like lineages. Mechanistically, CD147 deficiency results in impaired Wnt signaling and expression of BCL11b, a master transcription factor in determining T cell identity. In addition, functional blocking of CD147 by antibody phenocopies genetic deletion to enrich NK-like cells in the periphery. Furthermore, using a melanoma model and orthotopic liver cancer transplants, we showed that the augmentation of NK-like cells strongly associates with resistance against tumor growth upon CD147 suppression. Therefore, besides its original function in tumorigenesis, CD147 is also an effective surface target for immune modulation in tumor therapy. Copyright © 2017. Published by Elsevier B.V.

Exploiting a Molecular Gleason Grade for Prostate Cancer Therapy

DTIC Science & Technology

2010-03-01

clinical effectiveness of chemotherapy. MAOA influences chemotherapy resistance 3 INTRODUCTION Despite numerous clinical trials conducted...therapy resistance. Although residual viable tumor cells were identified in each case, chemotherapy effects were evident. We previously reported the...found that MAOA expression was upregulated in prostate cancers in association with higher Gleason grades (11), but effects on modulating cytotoxic drug

Modelling hepatitis C therapy—predicting effects of treatment

PubMed Central

Perelson, Alan S.; Guedj, Jeremie

2015-01-01

Mathematically modelling HCV RNA changes measured in patients who receive antiviral therapy has yielded many insights into the pathogenesis and effects of treatment on the virus. By determining how rapidly HCV is cleared when viral replication is interrupted by a therapy, one can deduce how rapidly the virus is produced in patients before treatment. This knowledge, coupled with estimates of the HCV mutation rate, enables one to estimate the frequency with which drug resistant variants arise. Modelling HCV also permits the deduction of antiviral agent effectiveness at blocking HCV replication from the magnitude of the initial viral decline. One can also estimate the lifespan of an HCV infected cell from the slope of the subsequent viral decline and, determine the duration of therapy needed to cure infection. Our understanding of HCV RNA decline under IFN-based therapies needs to be revised in order to understand the HCV RNA decline kinetics seen when using direct-acting antiviral agents (DAAs). In this Review, we also discuss the unresolved issues involving understanding therapies with combinations of DAAs, such as whether a sustained virological response necessarily involves elimination of all infected cells PMID:26122475