Development of multipurpose technologies products for pregnancy and STI prevention: update on polyphenylene carboxymethylene MPT gel development†.

Application of cell-based immunotherapy in organ transplantation to minimize the burden of immunosuppressive medication and promote allograft tolerance has expanded significantly over the past decade. Adoptively transferred regulatory immune cells prolong allograft survival and transplant tolerance in pre-clinical models. Many cell products are currently under investigation in early phase human clinical trials designed to assess feasibility and safety. Despite rapid advances in manufacturing practices, defining the appropriate protocol that will optimize in vivo conditions for tolerance induction remains a major challenge and depends heavily on understanding the fate, biodistribution, functional stability and longevity of the cell product after administration. This review focuses on in vivo detection and monitoring of various regulatory immune cell types administered for allograft tolerance induction in both pre-clinical animal models and early human clinical trials. We discuss the current status of various non-invasive methods for tracking regulatory cell products in the context of organ transplantation and implications for enhanced understanding of the therapeutic potential of cell-based therapy in the broad context of control of immune-mediated inflammatory disorders.

Gynecologic infections and colposcopy findings from a phase 3 efficacy and safety study of a contraceptive vaginal gel compared with nonoxynol-9

Immunotherapy against a variety of malignancies, including pleural-based malignancies, has shown promise in animal models and early human clinical trials, but successful efforts will need to address immuno-suppressive factors of the tumor and host, particularly certain cytokines and CD4+ CD25+ regulatory T cells (Treg). Here, we evaluated the cellular and cytokine components of malignant pleural effusions from 44 patients with previously diagnosed mesothelioma, non-small cell lung cancer (NSCLC), or breast cancer and found significant differences in the immune profile of pleural effusions secondary to mesothelioma vs. carcinoma. Although a high prevalence of functionally suppressive CD4+ CD25+ T cells was found in carcinomatous pleural effusions, mesothelioma pleural effusions contained significantly fewer CD4+ CD25+ T cells. Activated CD8+ T cells in pleural fluid were significantly more prevalent in mesothelioma than carcinoma. However, there is clear patient-to-patient variability and occasional mesothelioma patients with high percentages of CD4+ CD25+ pleural effusion T cells and low percentages of CD8+ CD25+ pleural effusion T cells can be identified. Mesothelioma pleural effusions contained the highest concentrations of the immuno-suppressive cytokine transforming growth factcor (TGF)-beta. Thus, the contribution of cellular and cytokine components of immuno-suppression associated with malignant pleural effusions varies by tumor histology and by the individual patient. These results have implications for the development of immunotherapy directed to the malignant pleural space, and suggest the need to tailor immunotherapy to overcome immunosuppressive mechanisms in tumor environments.

Fragile-X syndrome (FXS) patients display intellectual disability and autism spectrum disorder due to silencing of the X-linked, fragile-X mental retardation-1 (FMR1) gene. Dysregulation of cAMP metabolism is a consistent finding in patients and in the mouse and fly FXS models. We therefore explored if BPN14770, a prototypic phosphodiesterase-4D negative allosteric modulator (PDE4D-NAM) in early human clinical trials, might provide therapeutic benefit in the mouse FXS model. Daily treatment of adult male fmr1 C57Bl6 knock-out mice with BPN14770 for 14 days reduced hyperarousal, improved social interaction, and improved natural behaviors such as nesting and marble burying as well as dendritic spine morphology. There was no decrement in behavioral scores in control C57Bl6 treated with BPN14770. The behavioral benefit of BPN14770 persisted two weeks after washout of the drug. Thus, BPN14770 may be useful for the treatment of fragile-X syndrome and other disorders with decreased cAMP signaling.

Many patients with acute myeloid leukemia will eventually develop refractory or relapsed disease. In the absence of standard therapy for this population, there is currently an urgent unmet need for novel therapeutic agents. Targeted therapy with small molecule inhibitors represents a new therapeutic intervention that has been successful for the treatment of multiple tumors (e.g., gastrointestinal stromal tumors, chronic myelogenous leukemia). Hence, there has been great interest in generating selective small molecule inhibitors targeting critical pathways of proliferation and survival in acute myeloid leukemia. This review highlights a selective group of intriguing therapeutic agents and their presumed targets in both preclinical models and in early human clinical trials.

Need for a true placebo for vaginal microbicide efficacy trials

Nanoemulsions (NEs) are high-energy oil-in-water emulsions smaller than 1,000 nm that disrupt the outer lipid membrane of pathogenic microbes [1–4]. Building on studies that demonstrated the potential of NE to prevent influenza infection [5], it was recognized that NE inactivated influenza virus generated greater immune responses than formalin inactivated influenza virus when administered intranasally [6]. Subsequent studies have demonstrated this material acts as a mucosal adjuvant with numerous antigens including recombinant anthrax protective antigen (PA) [7], killed-vaccinia virus [8], recombinant human immunodeficiency (HIV) gp120 [9], recombinant hepatitis B surface antigen (HBsAg) [10], and purified Burkholderia cenocepacia outer membrane protein (OMP) [11]. In addition, it was recognized that the surfactant in the NE is locked at the interface between the oil droplets and water and does not appear to denature proteins. This confers thermostability to the antigen [10, 12–14] and potentially allows for the elimination of the cold chain required for all currently available vaccines [15]. The mechanisms by which adjuvants enhance the immune response are starting to be elucidated and include improved antigen delivery as well as innate immune activation [16]. The NE adjuvant acts via both mechanisms as it enhances antigen uptake by dendritic cells (DCs) as well as activating Toll like receptors (TLR) 2 and 4; this enhances both humoral and cell-mediated Th1 and Th17 immune responses [17]. Importantly, NE mucosal adjuvant activity occurs without damaging the mucosal epithelium [10] and has been demonstrated to be safe and well tolerated in early phase human clinical trials (Stanberry, submitted). In this review, we will delineate the physical and chemical properties, mechanisms of activity, preclinical studies, and clinical experience available regarding mucosal NE adjuvants.

The targeting of tumor cell metabolism has emerged as an attractive candidate for chemotherapeutics. In particular, tumor cell mitochondria are dramatically reprogrammed to generate large amounts of biosynthetic intermediates to fuel cell division. We previously described a novel class of non-redox active lipoic acid analogs (“thioctoids”) which effect dramatic inactivation of the mitochondrial enzyme complex pyruvate dehydrogenase (PDH) (PMID:21769686). We have recently completed a comprehensive metabolomic study indicating that thioctoids down-regulate multiple mitochondria-associated enzymes. Each of these target enzymes are key control points for entry of carbon into the TCA cycle, including the alpha-ketoglutarate dehydrogenase complex and the branch-chain dehydrogenase/amino trasferase complex. In addition we will present data that reactive oxygen species (ROS) play a direct regulatory role in these inactivations and are a major contributor to the resultant cell cycle arrest and multiple cell death pathways which follow. Taken together, our results indicate that thioctoids are potent inhibitors of tumor cell mitochondrial energy metabolism, owing, apparently, to the central regulatory role of lipoic acid in mitochondrial lipoamide dehydrogenase-containing enzyme complexes. We hypothesize that thioctoids are ‘misread’ by these complexes resulting in increased levels of ROS leading to the further shutdown of redox-sensitive metabolic enzymes and ultimately cell death. As a consequence of these novel properties, thioctoids attack tumor-specific metabolism far more broadly and pervasively than other agents directed at individual metabolic steps or activities. Thioctoids are exceptionally well tolerated in animal studies and as a result may have high clinical potential. They are currently in early stage human clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1122. doi:1538-7445.AM2012-1122

DNA vaccines, comprised of plasmid DNA encoding proteins from pathogens, allergens, and tumors, are being evaluated as prophylactic vaccines and therapeutic treatments for infectious diseases, allergies, and cancer; plasmids encoding normal human proteins are likewise being tested as vaccines and treatments for autoimmune diseases. Examples of in vivo prophylaxis and immunotherapy, based on different types of immune responses (humoral and cellular), in a variety of disease models and under evaluation in early phase human clinical trials are presented. Viral vectors continue to show better levels of expression than those achieved by DNA plasmid vectors. We have focused our clinical efforts, at this time, on the use of recombinant viral vectors for both vaccine as well as cytokine gene transfer studies. We currently have four clinical programs in cancer immunotherapy. Two nonspecific immunotherapy programs are underway that apply adenoviral vectors for the transfer of cytokine genes into tumors in situ. An adenovirus-IFN gamma construct (TG1042) is currently being tested in phase II clinical trials in cutaneous lymphoma. A similar construct, adenovirus-IL2 (TG1024), also injected directly into solid tumors, is currently being tested in patients with solid tumors (about one-half of which are melanoma). Encouraging results are seen in both programs. Two cancer vaccine immunotherapy programs focus on two cancer-associated antigens: human papilloma virus E6 and E7 proteins and the epithelial cancer-associated antigen MUC1. Both are encoded by a highly attenuated vaccinia virus vector [modified vaccinia Ankara (MVA)] and both are coexpressed with IL-2. Encouraging results seen in both of these programs are described.

BufferGel (ReProtect, LLC) is a vaginal gel with an acidic buffering action that was designed to prevent vaginal neutralization by semen. The purpose of this study was to evaluate the safety and tolerability of BufferGel (ReProtect, Limited Liability Company) applied vaginally either once or twice daily by 27 women who were at low risk for acquisition of human immunodeficiency virus (HIV). Participants initially used the product once daily for 14 days and then twice daily for 14 days; they underwent colposcopy before and after product exposure. BufferGel was well tolerated, although two-thirds of the participants reported at least 1 mild or moderate adverse experience. The most common adverse events were irritative genitourinary symptoms. Product use was discontinued after 3 adverse events. BufferGel was well tolerated in women at low risk for acquisition of HIV; toxicity was limited and occurred at frequencies similar to those in women who did not use any vaginal product and at levels lower than in women who used detergent-based microbicides.

Retinal pigment epithelium (RPE) differentiated from human induced pluripotent stem cells, called induced retinal pigment epithelium (iRPE), is being explored as a cell-based therapy for the treatment of retinal degenerative diseases, especially age-related macular degeneration. The success of RPE implantation is linked to the use of biomimetic scaffolds that simulate Bruch's membrane and promote RPE maturation and integration as a functional tissue. Due to difficulties associated with animal protein-derived scaffolds, including sterility and pro-inflammatory responses, current practices favor the use of synthetic polymers, such as polycaprolactone (PCL), for generating nanofibrous scaffolds. In this study, we tested the hypothesis that plant protein-derived fibrous scaffolds can provide favorable conditions permissive for the maturation of RPE tissue sheets in vitro. Our natural, soy protein-derived nanofibrous scaffolds exhibited a J-shaped stress-strain curve that more closely resembled the mechanical properties of native tissues than PCL with significantly higher hydrophilicity of the natural scaffolds, favoring in vivo implantation. We then demonstrate that iRPE sheets growing on these soy protein scaffolds are equivalent to iRPE monolayers cultured on synthetic PCL nanofibrous scaffolds. Immunohistochemistry demonstrated RPE-like morphology and functionality with appropriate localization of RPE markers RPE65, PMEL17, Ezrin, and ZO1 and with anticipated histotypic polarization of vascular endothelial growth factor and pigment epithelium-derived growth factor as indicated by enzyme-linked immunosorbent assay. Scanning electron microscopy revealed dense microvilli on the cell surface and homogeneous tight junctional contacts between the cells. Finally, comparative transcriptome analysis in conjunction with principal component analysis demonstrated that iRPE on nanofibrous scaffolds, either natural or synthetic, matured more consistently than on nonfibrous substrates. Taken together, our studies suggest that the maturation of cultured iRPE sheets for subsequent clinical applications might benefit from the use of nanofibrous scaffolds generated from natural proteins. Impact statement Induced retinal pigment epithelium (iRPE) from patient-derived induced pluripotent stem cells (iPSCs) may yield powerful treatments of retinal diseases, including age-related macular degeneration. Recent studies, including early human clinical trials, demonstrate the importance of selecting appropriate biomaterial scaffolds to support tissue-engineered iRPE sheets during implantation. Electrospun scaffolds show particular promise due to their similarity to the structure of the native Bruch's membrane. In this study, we describe the use of electroprocessed nanofibrous soy protein scaffolds to generate polarized sheets of human iPSC-derived iRPE sheets. Our evaluation, including RNA-seq transcriptomics, indicates that these scaffolds are viable alternatives to scaffolds electrospun from synthetic polymers.

Over the past decade, tremendous progress has taken place in tumour immunotherapy, relying on the fast development of combination therapy strategies that target multiple immunosuppressive signaling pathways in the immune system of cancer patients to achieve a high response rate in clinical practice. Toll-like receptor 9 (TLR9) agonists have been extensively investigated as therapeutics in monotherapy or combination therapies for the treatment of cancer, infectious diseases and allergies. TLR9 agonists monotherapy shows limited efficacy in cancer patients; whereas, in combination with other therapies including antigen vaccines, radiotherapies, chemotherapies and immunotherapies exhibit great potential. Synthetic unmethylated CpG oligodeoxynucleotide (ODN), a commonly used agonist for TLR9, stimulate various antigen-presenting cells in the tumour microenvironment, which can initiate innate and adaptive immune responses. Novel combination therapy approaches, which co-deliver immunostimulatory CpG-ODN with other therapeutics, have been tested in animal models and early human clinical trials to induce anti-tumour immune responses. In this review, we describe the basic understanding of TLR9 signaling pathway; the delivery methods in most studies; discuss the key challenges of each of the above mentioned TLR9 agonist-based combination immunotherapies and provide an overview of the ongoing clinical trial results from CpG-ODN based combination therapies in cancer patients.

Recently, several clinical trials in acute stroke have failed to produce efficacy. This suggests that there is a large gap between results in human trials and in animal. Animal models may present on aspect of pathophysiology in patients. We have to know how similar and what aspect of animal models can be extrapolated to patients. It is a big question whether or not therapeutic time window between animal models and patients is similar. In some animal models, cerebral damage establishes within 6 hours of the MCA occlusion, and this indicates that it is impossible to cure cerebral damage when drug injection is administrered over a 6 hour pe-riod. Recently, some investigators demonstrated that in human penumbra disappears within 6 hours after ischemia and therapeutic time window is as narrow as that in animal models. Finally, in animal studies, effects of neuroprotective agents are evaluated by the size of cerebral damage and neurological deficits. In human trials, effects of these agents are evaluated by stroke scores in including Japan stroke scores. In stroke scores, consciousness, language ana paralysis are examined, but in animal models, only paralysis is examined. Data of neurological symptoms of animal studies do not accord with those in human trials.

The recent discovery of progenitor cells in peripheral blood that can differentiate into endothelial or vascular smooth muscle cells has led to the re-evaluation of many traditionally held beliefs about vascular biology. Most notably, concepts of vascular regeneration and repair, previously considered limited to the proliferation of existing differentiated cells within vascular tissue, have been expanded to include the potential for postnatal vasculogenesis. These cells have since been identified in the bone marrow, heart, skeletal muscle, and other peripheral tissues, including the vasculature itself. The significance of these cells lies not only in developing our understanding of normal vascular biology, but also in the insights they may provide into vascular diseases such as atherosclerosis. In addition, a potential role in therapeutics has already been explored in early clinical trials in humans. The mechanisms underlying the mobilization, target tissue integration, differentiation, and the observed therapeutic benefits of these cells are now being elucidated. It is these mechanisms, and the current understanding of the lineage of these cells, that constitutes the focus of this review.

Gravity‐induced coating flows of vaginal gel formulations: In vitro experimental analysis