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Immune checkpoint inhibitors (ICIs) have revolutionized the current treatment landscape for cancer, yet the response rates of ICIs remain unmet. Synergistic with immunotherapy, low-dose radiotherapy (LDRT) has been demonstrated to activate anti-tumor immunity – a transition from traditional radiation therapy geared toward local radical treatment to a type of immunological adjuvant. As such, studies utilizing LDRT to enhance the efficacy of immunotherapy have been increasing preclinically and clinically. This paper reviews the recent strategies of using LDRT to overcome the resistance of ICIs, as well as providing potential opportunities in cancer treatment. Despite the potential of LDRT in immunotherapy is recognized, the mechanisms behind this form of treatment remain largely elusive. Thus, we reviewed history, mechanisms and challenges associated with this form of treatment, as well as different modes of its application, to provide relatively accurate practice standards for LDRT as a sensitizing treatment when combined with immunotherapy or radio-immunotherapy. [Display omitted] • We sheds new light on the history, mechanisms, as well as modes of application in LDRT. • We provided relatively accurate practice standards for LDRT as a sensitizing treatment. • We are trying to explore LDRT to overcome the resistance of ICIs. • We evaluated the potential and challenges associated with LDRT. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Engineering vaccine-based therapeutics for infectious diseases is highly challenging, as trial formulations are often found to be nonspecific, ineffective, thermally or hydrolytically unstable, and/or toxic. Vaccines have greatly improved the therapeutic landscape for treating infectious diseases and have significantly reduced the threat by therapeutic and preventative approaches. Furthermore, the advent of recombinant technologies has greatly facilitated growth within the vaccine realm by mitigating risks such as virulence reversion despite making the production processes more cumbersome. In addition, seroconversion can also be enhanced by recombinant technology through kinetic and nonkinetic approaches, which are discussed herein. Recombinant technologies have greatly improved both amino acid-based vaccines and DNA-based vaccines. A plateau of interest has been reached between 2001 and 2010 for the scientific community with regard to DNA vaccine endeavors. The decrease in interest may likely be attributed to difficulties in improving immunogenic properties associated with DNA vaccines, although there has been research demonstrating improvement and optimization to this end. Despite improvement, to the extent of our knowledge, there are currently no regulatory body-approved DNA vaccines for human use (four vaccines approved for animal use). This article discusses engineering DNA vaccines against infectious diseases while discussing advantages and disadvantages of each, with an emphasis on applications of these DNA vaccines. Statement of Significance This review paper summarizes the state of the engineered/recombinant DNA vaccine field, with a scope entailing "Engineering DNA vaccines against infectious diseases". We endeavor to emphasize recent advances, recapitulating the current state of the field. In addition to discussing DNA therapeutics that have already been clinically translated, this review also examines current research developments, and the challenges thwarting further progression. Our review covers: recombinant DNA-based subunit vaccines; internalization and processing; enhancing immune protection via adjuvants; manufacturing and engineering DNA; the safety, stability and delivery of DNA vaccines or plasmids; controlling gene expression using plasmid engineering and gene circuits; overcoming immunogenic issues; and commercial successes. We hope that this review will inspire further research in DNA vaccine development. [ABSTRACT FROM AUTHOR]

Immunotherapy has recently emerged as a promising treatment for multiple myeloma (MM). There are now several monoclonal antibodies that target specific surface antigens on myeloma cells or the checkpoints of immune and myeloma cells. Elotuzumab (targeting SLAMF7), daratumumab (targeting CD38), and pembrolizumab (targeting PD-1) have shown clinical activity in clinical studies with relapsed/refractory MM. Dendritic cell vaccination is a safe strategy that has shown some efficacy in a subset of myeloma patients and may become a crucial part of MM treatment when combined with immunomodulatory drugs or immune check-point blockade. Genetically engineered T cells, such as chimeric antigen receptor T cells or T cell receptor-engineered T cells, have also shown encouraging results in recent clinical studies of patients with MM. In this paper, we discuss recent progress in immunotherapy for the treatment of MM. [ABSTRACT FROM AUTHOR]

Despite the effectiveness of surgery or radiation therapy for the treatment of early-stage prostate cancer (PCa), there is currently no effective strategy for late-stage disease. New therapeutic targets are emerging; in particular, dsRNA receptors Toll-like receptor 3 (TLR3) and cytosolic helicases expressed by cancer cells, once activated, exert a pro-apoptotic effect in different tumors. We previously demonstrated that the synthetic analog of dsRNA poly(I:C) induces apoptosis in the androgen-dependent PCa cell line LNCaP in a TLR3-dependent fashion, whereas only a weak apoptotic effect is observed in the more aggressive and androgen-independent PCa cells PC3 and DU145. In this paper, we characterize the receptors and the signaling pathways involved in the remarkable apoptosis induced by poly(I:C) transfected by Lipofectamine (in-poly(I:C)) compared with the 12-fold higher free poly(I:C) concentration in PC3 and DU145 cells. By using genetic inhibition of different poly(I:C) receptors, we demonstrate the crucial role of TLR3 and Src in in-poly(I:C)-induced apoptosis. Therefore, we show that the increased in-poly(I:C) apoptotic efficacy is due to a higher binding of endosomal TLR3. On the other hand, we show that in-poly(I:C) binding to cytosolic receptors MDA5 and RIG-I triggers IRF3-mediated signaling, leading uniquely to the upregulation of IFN-β, which likely in turn induces increased TLR3, MDA5, and RIG-I proteins. In summary, in-poly(I:C) activates two distinct antitumor pathways in PC3 and DU145 cells: one mediated by the TLR3/Src/STAT1 axis, leading to apoptosis, and the other one mediated by MDA5/RIG-I/IRF3, leading to immunoadjuvant IFN-β expression. [ABSTRACT FROM AUTHOR]

Abstract: During recent decades there have been remarkable advances in biology, in which one of the most important discoveries is RNA interference (RNAi). RNAi is a specific post-transcriptional regulatory pathway that can result in silencing gene functions. Efforts have been done to translate this new discovery into clinical applications for disease treatment. However, technical difficulties restrict the development of RNAi, including stability, off-target effects, immunostimulation and delivery problems. Researchers have attempted to surmount these barriers and improve the bioavailability and safety of RNAi-based therapeutics by optimizing the chemistry and structure of these molecules. This paper aimed to describe the principles of RNA interference, review the therapeutic potential in various diseases and discuss the new strategies for in vivo delivery of RNAi to overcome the challenges. [Copyright &y& Elsevier]

Though aromatase inhibitors (AIs) are an essential part of estrogen receptor-positive (ER+) breast cancer therapy, many patients discontinue the medicine before their adjuvant therapy is completed because of the arthralgia which often accompanies the medicine. Up to half of women on AI therapy experience joint pain, and up to 20% will become non-compliant with the medicine because of the joint pain. Yet, very little is known about what causes AI-induced arthralgia (AIA), and there is no established, effective treatment for this difficult problem. It compromises survivors’ quality of life and leads to non-compliance. This paper will discuss AIA in depth, including potential etiologies, clinical significance, risk factors, and possible management solutions. Of note, this article presents one of the first proposed algorithms which clearly lays out a treatment plan for AIA, incorporating a variety of interventions which have been proven by the available literature. [ABSTRACT FROM PUBLISHER]

Abstract: Our recent work (Séralini et al., 2012) remains to date the most detailed study involving the life-long consumption of an agricultural genetically modified organism (GMO). This is true especially for NK603 maize for which only a 90-day test for commercial release was previously conducted using the same rat strain (Hammond et al., 2004). It is also the first long term detailed research on mammals exposed to a highly diluted pesticide in its total formulation with adjuvants. This may explain why 75% of our first criticisms arising within a week, among publishing authors, come from plant biologists, some developing patents on GMOs, even if it was a toxicological paper on mammals, and from Monsanto Company who owns both the NK603 GM maize and Roundup herbicide (R). Our study has limits like any one, and here we carefully answer to all criticisms from agencies, consultants and scientists, that were sent to the Editor or to ourselves. At this level, a full debate is biased if the toxicity tests on mammals of NK603 and R obtained by Monsanto Company remain confidential and thus unavailable in an electronic format for the whole scientific community to conduct independent scrutiny of the raw data. In our article, the conclusions of long-term NK603 and Roundup toxicities came from the statistically highly discriminant findings at the biochemical level in treated groups in comparison to controls, because these findings do correspond in an blinded analysis to the pathologies observed in organs, that were in turn linked to the deaths by anatomopathologists. GM NK603 and R cannot be regarded as safe to date. [Copyright &y& Elsevier]

Abstract: This paper provides an overview of the legislations and regulatory approaches currently applied to the nonclinical safety assessment of human preventive vaccine products in three ICH regions, i.e., the EU, USA, and Japan. Perspectives of the three regions with regard to the various types of toxicity studies currently considered to assess the nonclinical safety of preventive vaccines are compared and described in more detail than in published guidelines. In addition, the common issues and current challenges in nonclinical safety assessment of preventive vaccines are discussed. [Copyright &y& Elsevier]

Abstract: Biologics are usually produced from live organisms, and the manufacturing process often involves a degree of natural variability. Characterization of biologics such as vaccines is inherently difficult due to the complex molecular structure of the antigens they contain and the presence of excipients such as preservatives and adjuvants that can interfere with testing. Therefore, each batch, lot, or serial produced must be tested before market release to ensure that the product complies with regulatory standards. This batch release testing emphasizes quality control of the final product and may be characterized by an extensive use of laboratory animals. The consistency approach is based upon the principle that the quality of a biologic is the result of the strict application of a quality system and consistent production. Subsequent batches are determined to be similar to clinically evaluated batches and therefore acceptable for release through the in-process testing that comprises this quality system. The European Centre for Validation of Alternative Methods (ECVAM) organized international workshops in 2006 and 2010 to discuss the consistency approach and its potential to reduce the number of animals used in testing of biological products. This paper provides an overview of these workshops. [Copyright &y& Elsevier]

Abstract: The future of manned space flight depends on an analysis of the numerous potential risks of travel into deep space. Currently no radiation dose limits have been established for these exploratory missions. To set these standards more information is needed about potential acute and late effects on human physiology from appropriate radiation exposure scenarios, including pertinent radiation types and dose rates. Cancer risks have long been considered the most serious late effect from chronic daily relatively low-dose exposures to the complex space radiation environment. However, other late effects from space radiation exposure scenarios are under study in ground-based accelerator facilities and have revealed some unique particle radiation effects not observed with conventional radiations. A comprehensive review of pertinent literature that considers tissue effects of radiation leading to functional detriments in specific organ systems has recently been published (NCRP National Council on Radiation Protection and Measurements. Information Needed to Make Radiation Protection Recommendations for Space Missions Beyond Low-Earth Orbit. Report #153, Bethesda, MD, 2006). This paper highlights the review of two non-cancer concerns from this report: cardiovascular and immunological effects. [Copyright &y& Elsevier]

This paper presents data from an investigation of the mode of action of five different crustacean immunostimulants presented to European lobster (Homarus gammarus) granulocytes cultured in vitro. The experiments were designed to test whether or not the immunostimulants could cause the short-term up-regulation of genes coding for immune proteins without causing the cells to degranulate. Quantitative measurements of mRNA transcript abundance were made using real-time PCR and it was first necessary to isolate the complete gene sequences coding for the proteins prophenoloxidase (proPO), β-1,3-glucan binding protein (βGBP) and β-actin (β-act) in the lobster. These sequences were used to design TaqMan™ primer and fluorescent probe sets. The presented data indicated that the majority of the tested immunostimulants did not induce the up-regulation of immune-related gene expression in the granulocytes in isolation. Alternative modes of action, including the in vivo up-regulation of gene expression in haemopoetic tissues, are discussed. [Copyright &y& Elsevier]

Background: This paper evaluates the prognostic and predictive impact of protein expression of various molecular markers in high-risk breast cancer (HRBC) patients with >9 involved lymph nodes, who received different chemotherapy dose-intensification strategies within a prospective randomized WSG AM-01 trial. Materials and methods: Paraffin-embedded tumors from 236 patients, who were randomly assigned to dose-dense conventional chemotherapy with four cycles of E90C600 followed by three cycles of C600M40F600 every 2 weeks (DD) or a rapidly cycled tandem high-dose regimen with two cycles of E90C600 every 2 weeks followed by two cycles of E90C3000Thiotepa400 every 3 weeks (HD), were available for retrospective central pathological review (116 HD/120 DD). Expression of estrogen receptor (ER), progesterone receptor (PR), MIB-1, epidermal growth factor receptor, and Her-2/neu was evaluated immunohistochemically using tissue microarrays. Results were correlated with follow-up data and treatment effects by proportional hazard Cox regression models (including interaction analysis). Results: After a median follow-up of 61.7 months, 5-year event-free survival (EFS) as well as overall survival (OS) rates for the 236 patients were significantly better in the HD arm: EFS: 62% versus 41% [hazard ratio (HR) = 0.60, 95% CI 0.43–0.85, P = 0.004]; OS: 76% versus 61% (HR = 0.58, 95% CI 0.39–0.87, P = 0.007). In multivariate analysis, HD, tumor size Conclusion: Tandem HD improves both EFS and OS in HRBC. This therapy effect may be partly attributable to superior efficacy in the subgroup of triple-negative tumors and/or G3 with their poor prognostic marker profile. [ABSTRACT FROM AUTHOR]

As a result of the European ban of in-feed growth-promoting antibiotics, new strategies are being developed to increase the resistance to disease in farm animals. In pig production, this is of particular importance during the weaning transition when piglets are subjected to major stressful events, making them highly sensitive to digestive disorders. At this time, the development of both innate and adaptive immunity at the mucosal surface is critical in preventing the potential harmful effects of intestinal pathogenic agents. Strategies aiming at stimulating natural host defences through the use of substances able to modulate immune functions have gained increasing interest in animal research, and different bioactive components a priori sharing those properties have been the subject of in vivo nutritional investigations in pig. Among these, yeast derivates (b-glucans and mannans) are able to interact with immune cells, particularly phagocytic cells. However, studies where they have been fed to pigs have shown inconsistent results, suggesting that their ability to target the sensitive immune cells through the oral route is questionable. The plant extracts, which would benefit from a positive image in the public opinion, have also been tested. However, due to a lack of data on the bioactive components of particular plants and the large diversity of species, it has proved difficult to prepare extracts of equivalent potency and thus, the literature on their influence on pig immunity remains inconclusive. In considering piglet immunity and health benefits, the most promising results to date have been obtained with spray-dried animal plasma, whose positive effects would be provided by specific antibodies and nonspecific competition of some plasma components with bacteria for intestinal receptors. The major positive effect of spray-dried animal plasma is in reducing the infiltration of gut-associated lymphoid tissue by immune cells, which is likely to be the result of a decreased colonisation by potentially harmful bacteria. This review also highlights the limitations of some of the published in vivo studies on the immunomodulatory activity of certain feed additives. Among those, the lack of standardisation of extracts and the heterogeneity of piglet-rearing conditions (e.g. exposure to pathogens) are likely the most limiting. [ABSTRACT FROM AUTHOR]