CD40-targeted adenoviral cancer vaccines: the long and winding road to the clinic

The ability of dendritic cells (DCs) to orchestrate innate and adaptive immune responses has been exploited to develop potent anti-cancer immunotherapies. Recent clinical trials exploring the efficacy of ex vivo modified autologous DC-based vaccines have reported some promising results. However, in vitro generation of autologous DCs for clinical administration, their loading with tumor associated antigens (TAAs) and their activation, is laborious and expensive, and, as a result of inter-individual variability in the personalized vaccines, remains poorly standardized. An attractive alternative approach is to load resident DCs in vivo by targeted delivery of TAAs, using viral vectors and activating them simultaneously. To this end, we have constructed genetically-modified adenoviral (Ad) vectors and bispecific adaptor molecules to retarget Ad vectors encoding TAAs to the CD40 receptor on DCs. Pre-clinical human and murine studies conducted so far have clearly demonstrated the suitability of a 'two-component' (i.e. Ad and adaptor molecule) configuration for targeted modification of DCs in vivo for cancer immunotherapy. This review summarizes recent progress in the development of CD40-targeted Ad-based cancer vaccines and highlights pre-clinical issues in the clinical translation of this approach.     

Promoting blood vessel growth in ischemic diseases: challenges in translating preclinical potential into clinical success

Angiogenic therapy, which involves the use of an exogenous stimulus to promote blood vessel growth, is an attractive approach for the treatment of ischemic diseases. It has been shown in animal models that the stimulation of blood vessel growth leads to the growth of the whole vascular tree, improvement of ischemic tissue perfusion and improved muscle aerobic energy metabolism. However, very few positive results have been gained from Phase 2 and 3 clinical angiogenesis trials. Many reasons have been given for the failures of clinical trials, including poor transgene expression (in gene-therapy trials) and instability of the vessels induced by therapy. In this Review, we discuss the selection of preclinical models as one of the main reasons why clinical translation has been unsuccessful thus far. This issue has received little attention, but could have had dramatic implications on the expectations of clinical trials. We highlight crucial differences between human patients and animal models with regards to blood flow and pressure, as well as issues concerning the chronic nature of ischemic diseases in humans. We use these as examples to demonstrate why the results from preclinical trials might have overestimated the efficacy of angiogenic therapies developed to date. We also suggest ways in which currently available animal models of ischemic disease could be improved to better mimic human disease conditions, and offer advice on how to work with existing models to avoid overestimating the efficacy of new angiogenic therapies.     

Cardiovascular stent design and vessel stresses: a finite element analysis

Intravascular stents of various designs are currently in use to restore patency in atherosclerotic coronary arteries and it has been found that different stents have different in-stent restenosis rates. It has been hypothesized that the level of vascular injury caused to a vessel by a stent determines the level of restenosis. Computational studies may be used to investigate the mechanical behaviour of stents and to determine the biomechanical interaction between the stent and the artery in a stenting procedure. In this paper, we test the hypothesis that two different stent designs will provoke different levels of stress within an atherosclerotic artery and hence cause different levels of vascular injury. The stents analysed using the finite-element method were the S7 (Medtronic AVE) and the NIR (Boston Scientific) stent designs. An analysis of the arterial wall stresses in the stented arteries indicates that the modular S7 stent design causes lower stress to an atherosclerotic vessel with a localized stenotic lesion compared to the slotted tube NIR design. These results correlate with observed clinical restenosis rates, which have found higher restenosis rates in the NIR compared with the S7 stent design. Therefore, the testing methodology outlined here is proposed as a pre-clinical testing tool, which could be used to compare and contrast existing stent designs and to develop novel stent designs.     

Epithelial mesenchymal transition and resistance in endocrine-related cancers

Epithelial to mesencyhmal transition (EMT) has a central role in tumor metastasis and progression. EMT is regulated by several growth factors and pro-inflammatory cytokines. The most important role in this regulation could be attributed to transforming growth factor-β (TGF-β). In breast cancer, TGF-β effect on EMT could be potentiated by Fos-related antigen, oncogene HER2, epidermal growth factor, or mitogen-activated protein kinase kinase 5 – extracellular-regulated kinase signaling. Several microRNAs in breast cancer have a considerable role either in potentiation or in suppression of EMT thus acting as oncogenic or tumor suppressive modulators. At present, possibilities to target EMT are discussed but the results of clinical translation are still limited. In prostate cancer, many cellular events are regulated by androgenic hormones. Different experimental results on androgenic stimulation or inhibition of EMT have been reported in the literature. Thus, a possibility that androgen ablation therapy leads to EMT thus facilitating tumor progression has to be discussed. Novel therapy agents, such as the anti-diabetic drug metformin or selective estrogen receptor modulator ormeloxifene were used in pre-clinical studies to inhibit EMT in prostate cancer. Taken together, the results of pre-clinical and clinical studies in breast cancer may be helpful in the process of drug development and identify potential risk during the early stage of that process.     

WJSC 6th Anniversary Special Issues（2）:Mesenchymal stem cells Neurotrauma and mesenchymal stem cells treatment:From experimental studies to clinical trials

Mesenchymal stem cell(MSC)therapy has attracted the attention of scientists and clinicians around the world.Basic and pre-clinical experimental studies have highlighted the positive effects of MSC treatment after spinal cord and peripheral nerve injury.These effects are believed to be due to their ability to differentiate into other cell lineages,modulate inflammatory and immunomodulatory responses,reduce cell apoptosis,secrete several neurotrophic factors and respond to tissue injury,among others.There are many pre-clinical studies on MSC treatment for spinal cord injury(SCI)and peripheral nerve injuries.However,the same is not true for clinical trials,particularly those concerned with nerve trauma,indicating the necessity of more well-constructed studies showing the benefits that cell therapy can provide for individuals suffering the consequences of nerve lesions.As for clinical trials for SCI treatment the results obtained so far are not as beneficial as those described in experimental studies.For these reasons basic and pre-clinical studies dealing with MSC therapy should emphasize the standardization of protocols that could be translated to the clinical set with consistent and positive outcomes.This review is based on pre-clinical studies and clinical trials available in the literature from 2010 until now.At the time of writing this article there were 43 and 36 pre-clinical and 19 and 1 clinical trials on injured spinal cord and peripheral nerves,respectively.     

“Second-generation” stem cells for cardiac repair

Over the last years, stem cell therapy has emerged asan inspiring alternative to restore cardiac function after myocardial infarction. A large body of evidence has been obtained in this field but there is no conclusive data on the efficacy of these treatments. Preclinical studies and early reports in humans have been encouraging and have fostered a rapid clinical translation, but positive results have not been uniformly observed and when present, they have been modest. Several types of stem cells, manufacturing methods and delivery routes have been tested in different clinical settings but direct comparison between them is challenging and hinders further research. Despite enormous achievements, major barriers have been found and many fundamental issues remain to be resolved. A better knowledge of the molecular mechanisms implicated in cardiac development and myocardial regeneration is critically needed to overcome some of these hurdles. Genetic and pharmacological priming together with the discovery of new sources of cells have led to a "second generation" of cell products that holds an encouraging promise in cardiovascular regenerative medicine. In this report, we review recent advances in this field focusing on the new types of stem cells that are currently being tested in human beings and on the novel strategies employed to boost cell performance in order to improve cardiac function and outcomes after myocardial infarction.     

Combined therapies in osteoporosis: bisphosphonates and vitamin D-hormone analogs

During the last two decades, the development of new, highly effective therapeutics (e.g. bisphosphonates, SERMs, strontium ranelate and PTH) has significantly extended the spectrum of osteoporosis therapy. However, the interest of combining bone-active agents and/or Vitamin D and calcium is still being debated, and is restricted to a very marginal set of compounds (Alendronate and native Vitamin D). On the other hand, Vitamin D-hormone analogs, calcitriol, and alfacalcidol, have repeatedly demonstrated their effectiveness in being valuable alternatives compared to native Vitamin D in this setting. A growing amount of data documents the pre-clinical and clinical efficacies of combinations of bisphosphonates with calcitriol, or with alfacalcidol in primary and secondary osteoporosis. This exhaustive review of the available animal and clinical data aimed at comparing the theoretical with demonstrated absolute and relative benefits of those therapeutic approaches. Most of the pre-clinical and clinical data in PMOP suggest significant, clinical improvements in response to combination therapies versus monotherapies in postmenopausal osteoporosis. As a investigated by most of the currently available trials, a daily dose of alendronate 10 mg or a weekly dose of Alendronate 70 m plus alfacalcidol 0.5-1.0 microg daily plus alfacalcidol 0.5 microg seems to surpass other combinations when BMD and bone metabolism markers are considered. A synergy with bisphosphonates in reducing the fracture episodes may lie in the pleiotropic effects of D-hormone analogs on musculoskeletal, immunological and neurological systems. Negative interactions between both drugs have not yet been reported, while a reduction of hypercalcuria episodes has been noted in combination therapies, as compared to monotherapies involving high doses of Vitamin D, calcitriol, or alfacalcidol. Based on the possible reduction of periodic safety checks of calcemia, an improved compliance could then be expected, which would, in turn, generate a better end result. However, to document this, long-term, high quality comparative studies with factorial designs are needed to determine which role this alternative should play in the management of postmenopausal, male, and glucocorticoid-induced osteoporosis.     

Trends in Aluminium‐Based Intercalation Batteries

Over the last decade, optimizing energy storage has become significantly important in the field of energy conversion and sustainability. As a result of immense progress in the field, cost‐effective and high performance batteries are imperative to meeting the future demand of sustainability. Currently, the best performing batteries are lithium‐ion based, but limited lithium (Li) resources make research into alternatives essential. In recent years, the performance of aluminium‐ion batteries has improved remarkably in all battery‐relevant metrics, which renders them a promising alternative. Compared with monovalent Li‐ion batteries, aluminium (Al) cations can carry three positive charges, which could result in higher energy densities. This review describes recent developments in Al‐based cathode materials. The major goal of this review is to highlight strengths and weaknesses of various different approaches and provide guidelines for future research.     

T cell-mediated graft-versus-leukemia reactions after allogeneic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation represents the only curative approach for many hematological malignancies. During the last years the impact of the conditioning regimen has been re-assessed. With the advent of reduced-intensity conditioning the paradigm has changed from cytoreduction executed by high-dose radio-chemotherapy to immunological surveillance of leukemia by donor cells. Distinct subsets of T cells and NK cells contribute to graft-versus-leukemia reactions. So far, cytotoxic T lymphocytes are the mainstay of allogeneic immunotherapy. Here, we summarise the current knowledge of T cell-mediated graft-versus-leukemia reactions and present results from pre-clinical and clinical studies of T cell-based adoptive immunotherapy. We address the issues of feasibility and specificity of adoptive immunotransfer from a clinical point of view and discuss the prerequisites for successful clinical applications. Finally, the prospects for immunological research that have evolved with the increasing use of reduced-intensity conditioning and allogeneic stem cell transplantation are highlighted.     

Wavelet thresholding with bayesian false discovery rate control

The false discovery rate (FDR) procedure has become a popular method for handling multiplicity in high-dimensional data. The definition of FDR has a natural Bayesian interpretation; it is the expected proportion of null hypotheses mistakenly rejected given a measure of evidence for their truth. In this article, we propose controlling the positive FDR using a Bayesian approach where the rejection rule is based on the posterior probabilities of the null hypotheses. Correspondence between Bayesian and frequentist measures of evidence in hypothesis testing has been studied in several contexts. Here we extend the comparison to multiple testing with control of the FDR and illustrate the procedure with an application to wavelet thresholding. The problem consists of recovering signal from noisy measurements. This involves extracting wavelet coefficients that result from true signal and can be formulated as a multiple hypotheses-testing problem. We use simulated examples to compare the performance of our approach to the Benjamini and Hochberg (1995, Journal of the Royal Statistical Society, Series B57, 289-300) procedure. We also illustrate the method with nuclear magnetic resonance spectral data from human brain.     

Hot topics in aging research: protein translation, 2009

In the last few years, links between regulation of mRNA translation and aging have been firmly established in invertebrate model organisms. This year, a possible relationship between mRNA translation and aging in mammals has been established with the report that rapamycin increases lifespan in mice. Other significant findings have connected translation control with other known longevity pathways and provided fodder for mechanistic hypotheses. Here, we summarize advances in this emerging field and raise questions for future studies.     

Advanced glycation of cellular proteins as a possible basic component of the “master biological clock”

During the last decade, evidence has been accumulating supporting the hypothesis that aging is genetically programmed and, therefore, precisely timed. This hypothesis poses a question: what is the mechanism of the biological clock that controls aging? Measuring the level of the advanced glycation end products (AGE) is one of the possible principles underlying the functioning of the biological clock. Protein glycation is an irreversible, non-enzymatic, and relatively slow process. Moreover, many types of cells have receptors that can measure AGE level. We propose the existence of a protein that has a lifespan comparable to that of the whole organism. Interaction of the advanced glycation end product generated from this protein with a specific AGE receptor might initiate apoptosis in a vitally important non-regenerating tissue that produces a primary juvenile hormone. This could result in the age-dependent decrease in the level of this hormone leading to aging of the organism.     

Circulating nucleic acids in plasma and serum (CNAPS) and its relation to stem cells and cancer metastasis: state of the issue

The presence of circulating cell-free nucleic acids has been demonstrated both in disease and health. In the last decade, a burst of papers about Circulating Nucleic Acids in Plasma and Serum (CNAPS) have been found in the literature, showing the scientific interest raised by this phenomenon and their putative clinical interest, especially in the field of cancer. Today, the detection of extracellular tumor-derived DNA and/or RNA is considered by many authors as a new molecular marker for situations such as cancer diagnosis, monitoring the outcome of a disease and, even, as a treatment response indicator. Furthermore, in some studies it has been suggested a possible role of tumor CNAPS in the development of metastasis. Specifically, the hypothesis known as the "genometastasis hypothesis" proposes that stem cells might be naturally transfected with dominant oncogenes as a result of dissemination of such genes in the plasma. On the other hand, current studies concerned with the biology of metastatic cells are increasingly being focused on the striking similarities found between these cells and stem cells. In this review we intend to expound and integrate two theories about metastatization: the "genometastasis hypothesis" and the idea of stem cells as cancer stem cells.     

What can genome-scale metabolic network reconstructions do for prokaryotic systematics?

It has recently been proposed that in addition to Nomenclature, Classification and Identification, Comprehending Microbial Diversity may be considered as the fourth tenet of microbial systematics [Staley JT (2010) The Bulletin of BISMiS, 1(1): 1–5]. As this fourth goal implies a fundamental understanding of microbial speciation, this perspective article argues that translation of bacterial genome sequences into metabolic features may contribute to the development of modern polyphasic taxonomic approaches. Genome-scale metabolic network reconstructions (GSMRs), which are the result of computationally predicted and experimentally confirmed stoichiometric matrices incorporating all enzyme and metabolite components encoded by a genome sequence, provide a platform that can illustrate bacterial speciation. As the topology and the composition of GSMRs are expected to be the result of adaptive evolution, the features of these networks may provide the prokaryotic taxonomist with novel tools for reaching the fourth tenet of microbial systematics. Through selected examples from the Actinobacteria, which have been inferred from GSMRs and experimentally confirmed after phenotypic characterisation, it will be shown that this level of information can be incorporated into modern polyphasic taxonomic approaches. In conclusion, three specific examples are illustrated to show how GSMRs will revolutionize prokaryotic systematics, as has previously occurred in many other fields of microbiology.     

A ribonucleopeptide world at the origin of life

The structural flexibility of RNA and its ability to store genetic information has led scientists to postulate that RNA could be the key molecule for the development of life on Earth, further leading to formulate the RNA world hypothesis that received a lot of success and acceptance after the discoveries of the last thirty‐five years. Despite its highly structural and functional significance, the difficulty in synthesizing the four nucleobases that form the RNA polymer from the same primordial soup, its low stability, and limited catalytic repertoire, make the RNA world hypothesis less convincing even though it remains the best explanation for the origin of life. An increasing number of scientists are becoming more supportive of a more realistic approach explaining the appearance of life. In this review, I propose an enhanced explanation for the appearance of life supported by recent discoveries and theories. Accordingly, amino acids and peptides associated with RNA (e.g., ribonucleopeptides) might have existed at the onset of RNA and might have played an important role in the continuous development of self‐sustaining biological systems. Therefore, in this review, I cover the most recent and relevant scientific investigations that propose a better understanding of the ribonucleopeptide world hypothesis and the appearance of life. Finally, I propose two hypotheses for a primitive translation machinery (PTM) that might have been formed of either a T box ribozyme or a ribopolymerase.     

Grand rounds at the National Institutes of Health: HDAC inhibitors as radiation modifiers, from bench to clinic

Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumour. Patients afflicted with this disease unfortunately have a very poor prognosis, and fewer than 5% of patients survive for 5 years from the time of diagnosis. Therefore, improved therapies to treat this disease are sorely needed. One such class of drugs that have generated great enthusiasm for the treatment of numerous malignancies, including GBM, is histone deacetylase (HDAC) inhibitors. Pre-clinical data have demonstrated the efficacy of various HDAC inhibitors as anticancer agents, with the greatest effects shown when HDAC inhibitors are used in combination with other therapies. As a result of encouraging pre-clinical data, numerous HDAC inhibitors are under investigation in clinical trials, either as monotherapies or in conjunction with other treatments such as chemotherapy, biologic therapy or radiation therapy. In fact, two actively studied HDAC inhibitors, vorinostat and depsipeptide, were recently approved for the treatment of refractory cutaneous T cell lymphoma. In this review, we first present a patient with GBM, and then discuss the pathogenesis, epidemiology and current treatment options of GBM. Finally, we examine the translation of pre-clinical studies that have demonstrated HDAC inhibitors as potent radiosensitizers in in vitro and in vivo models, to a phase II clinical trial combining the HDAC inhibitor, valproic acid, along with temozolomide and radiation therapy for the treatment of GBM.     

New insights on the comma-less theory

The comma-less hypothesis represents a theoretical effort to describe one of the steps in the early evolution of the translation apparatus. This hypothesis emphasizes the advantages that a RNY coding pattern would have provided in a primitive RNA adaptor-catalyst system. This theory has been debated for years, both in conceptual and statistical terms, and no consensus about its validity has been ascertained. In this work, a statistical model refuting this theory was reconsidered. This new approach eliminates the bias due to the absence of stop codons in the open reading frame, and to the amino acid composition of bacterial genes. The results obtained support the biological significance of the RNY coding pattern.     

New insights on the comma-less theory.

The comma-less hypothesis represents a theoretical effort to describe one of the steps in the early evolution of the translation apparatus. This hypothesis emphasizes the advantages that a RNY coding pattern would have provided in a primitive RNA adaptor-catalyst system. This theory has been debated for years, both in conceptual and statistical terms, and no consensus about its validity has been ascertained. In this work, a statistical model refuting this theory was reconsidered. This new approach eliminates the bias due to the absence of stop codons in the open reading frame, and to the amino acid composition of bacterial genes. The results obtained support the biological significance of the RNY coding pattern.     

Biologic response modifiers in gynecologic malignancies.

Biological therapy is currently being investigated in the treatment of a number of malignancies. The hypothesis for the use of this therapeutic modality involves an attempt to stimulate an already existent but perhaps suboptimal immune response to foreign protein, including tumor. Immunologic therapy appears to work best against small-volume disease, as indicated from animal studies. This condition is potentially achievable in advanced ovarian cancer, where surgery is capable of producing multi-log reduction in tumor mass, and thus immunotherapy may be an option in this disease. The attraction of biologic therapy in patients with ovarian cancer is the potential to treat relatively localized but often chemotherapy-resistant disease. In cervical cancer, the rationale for the use of interferon is somewhat different in that this disease may be a manifestation of a virally induced proliferative lesion. Thus, the antiviral properties of interferon are being investigated in both limited and advanced cervical cancer. Both of these hypothesis have pre-clinical data to support them. This paper presents the pre-clinical and clinical work currently available for consideration of future use.