Host-Related Factors as Targetable Drivers of Immunotherapy Response in Non-Small Cell Lung Cancer Patients

Despite some significant therapeutic breakthroughs leading to immunotherapy, a high percentage of patients with non-small cell lung cancer (NSCLC) do not respond to treatment on relapse, thus experiencing poor prognosis and survival. The unsatisfying results could be related to the features of the tumor immune microenvironment and the dynamic interactions between a tumor and immune infiltrate. Host-tumor interactions strongly influence the course of disease and response to therapies. Thus, targeting host-associated factors by restoring their physiologic functions altered by the presence of a tumor represents a new therapeutic approach to control tumor development and progression. In NSCLC, the immunogenic tumor balance is shifted negatively toward immunosuppression due to the release of inhibitory factors as well as the presence of immunosuppressive cells. Among these cells, there are myeloid-derived suppressor cells, regulatory T cells that can generate a tumor-permissive milieu by reprogramming the cells of the hosts such as tumor-associated macrophages, tumor-associated neutrophils, natural killer cells, dendritic cells, and mast cells that acquire tumor-supporting phenotypes and functions. This review highlights the current knowledge of the involvement of host-related factors, including innate and adaptive immunity in orchestrating the tumor cell fate and the primary resistance mechanisms to immunotherapy in NSCLC. Finally, we discuss combinational therapeutic strategies targeting different aspects of the tumor immune microenvironment (TIME) to prime the host response. Further research dissecting the characteristics and dynamic interactions within the interface host-tumor is necessary to improve a patient fitness immune response and provide answers regarding the immunotherapy efficacy, with the aim to develop more successful treatments for NSCLC

acetyl l carnitine is an anti angiogenic agent targeting the vegfr2 and cxcr4 pathways

Abstract Carnitines play an important role in the energy exchange in cells, and are involved in the transport of fatty acids across the inner mitochondrial membrane. l -Acetylcarnitine (ALCAR) is an acetic acid ester of carnitine that has higher bioavailability and is considered a fat-burning energizer supplement. We previously found that in serum samples from prostate cancer (PCa) patients, 3 carnitine family members were significantly decreased, suggesting a potential protective role of carnitine against PCa. Several studies support beneficial effects of carnitines on cancer, no study has investigated the activities of carnitine on tumor angiogenesis. We examined whether ALCAR acts as an "angiopreventive" compound and studied the molecular mechanisms involved. We found that ALCAR was able to limit inflammatory angiogenesis by reducing stimulated endothelial cell and macrophage infiltration in vitro and in vivo. Molecularly, we show that ALCAR downregulates VEGF, VEGFR2, CXCL12, CXCR4 and FAK pathways. ALCAR blocked the activation of NF-κB and ICAM-1 and reduced the adhesion of a monocyte cell line to endothelial cells. This is the first study showing that ALCAR has anti-angiogenic and anti-inflammatory properties and might be an attractive candidate for cancer angioprevention

Myeloid Derived Suppressor Cells Interactions With Natural Killer Cells and Pro-angiogenic Activities: Roles in Tumor Progression

Myeloid-derived suppressor cells (MDSCs) contribute to the induction of an immune suppressive/anergic, tumor permissive environment. MDSCs act as immunosuppression orchestrators also by interacting with several components of both innate and adaptive immunity. Natural killer (NK) cells are innate lymphoid cells functioning as primary effector of immunity, against tumors and virus-infected cells. Apart from the previously described anergy and hypo-functionality of NK cells in different tumors, NK cells in cancer patients show pro-angiogenic phenotype and functions, similar to decidual NK cells. We termed the pro-angiogenic NK cells in the tumor microenvironment “tumor infiltrating NK” (TINKs), and peripheral blood NK cells in cancer patients “tumor associated NK” (TANKs). The contribution of MDSCs in regulating NK cell functions in tumor-bearing host, still represent a poorly explored topic, and even less is known on NK cell regulation of MDSCs. Here, we review whether the crosstalk between MDSCs and NK cells can impact on tumor onset, angiogenesis and progression, focusing on key cellular and molecular interactions. We also propose that the similarity of the properties of tumor associated/tumor infiltrating NK and MDSC with those of decidual NK and decidual MDSCs during pregnancy could hint to a possible onco-fetal origin of these pro-angiogenic leukocytes

Differentiation of Mesenchymal Stem Cells Derived from Pancreatic Islets and Bone Marrow into Islet-Like Cell Phenotype

BACKGROUND:Regarding regenerative medicine for diabetes, accessible sources of Mesenchymal Stem Cells (MSCs) for induction of insular beta cell differentiation may be as important as mastering the differentiation process itself. METHODOLOGY/PRINCIPAL FINDINGS:In the present work, stem cells from pancreatic islets (human islet-mesenchymal stem cells, HI-MSCs) and from human bone marrow (bone marrow mesenchymal stem cells, BM-MSCs) were cultured in custom-made serum-free medium, using suitable conditions in order to induce differentiation into Islet-like Cells (ILCs). HI-MSCs and BM-MSCs were positive for the MSC markers CD105, CD73, CD90, CD29. Following this induction, HI-MSC and BM-MSC formed evident islet-like structures in the culture flasks. To investigate functional modifications after induction to ILCs, ultrastructural analysis and immunofluorescence were performed. PDX1 (pancreatic duodenal homeobox gene-1), insulin, C peptide and Glut-2 were detected in HI-ILCs whereas BM-ILCs only expressed Glut-2 and insulin. Insulin was also detected in the culture medium following glucose stimulation, confirming an initial differentiation that resulted in glucose-sensitive endocrine secretion. In order to identify proteins that were modified following differentiation from basal MSC (HI-MSCs and BM-MSCs) to their HI-ILCs and BM-ILCs counterparts, proteomic analysis was performed. Three new proteins (APOA1, ATL2 and SODM) were present in both ILC types, while other detected proteins were verified to be unique to the single individual differentiated cells lines. Hierarchical analysis underscored the limited similarities between HI-MSCs and BM-MSCs after induction of differentiation, and the persistence of relevant differences related to cells of different origin. CONCLUSIONS/SIGNIFICANCE:Proteomic analysis highlighted differences in the MSCs according to site of origin, reflecting spontaneous differentiation and commitment. A more detailed understanding of protein assets may provide insights required to master the differentiation process of HI-MSCs to functional beta cells based only upon culture conditioning. These findings may open new strategies for the clinical use of BM-MSCs in diabetes

Human induced pluripotent stem cells for skeletal muscle diseases

Regenerative medicine along with tissue engineering represent two closely related fields leading promising advances for the treatment of numerous musculoskeletal diseases and injuries. Nevertheless, new efforts are urgently needed to design a successful therapeutic approach for muscular disorders, aiming at identifying a functional stem cell population and biomaterial scaffolds in which cells and growth factors could be embedded. In this context, recent studies have suggested that reprogramming of somatic cells by defined transcription factors into induced pluripotent stem cells (iPS), as source for generating autologous muscle progenitor cells (MPs), overcomes several limitations related to adult myoblast therapy. The prospect of an unlimited cell source combined with properties such as a more proliferative capacity in vitro, suggesting a better regenerative capacity in vivo models, indicates that iPS could be a promising candidate for stem cell therapy to regenerate skeletal muscle. iPS have been shown to retain specific features that are remnants of epigenomes and transcriptomes of the donor tissue termed ‘epigenetic memory’. Given to these findings, during the first part of the present study, we generated iPS derived from skin fibroblasts and pericytes (known to have a remarkable myogenic capacity) from the same donor to determine whether the epigenetic memory could influence iPS properties, preferentially generating cells similar of the donor somatic cell type. Until now, different approaches have been reported to generate MPs from iPS. So far, these methods present limitations such as low efficiency/reproducibility and usually involve cell sorting for enrichment or forced expression of skeletal master genes risking undesired genetic recombination. Recently, substantial interest is mounting regarding extracellular vesicles (EVs) and their involvement in many cellular processes, including myogenesis. We explored the possibility to use EVs as "physiological liposomes" enriched with myogenic factors to trigger skeletal myogenesis. To this end, during the second part of the study we developed a new transgenic-free approach to obtain transplantable MPs by means of defined factors and extracellular vesicles (EVs) secreted from differentiated mouse skeletal myoblasts. We established a novel, robust stepwise protocol by treating iPS with a WNT agonist, CHIR 99021 and myotubes-derived EVs. Thus, this method has two main advantages: (i) studying molecular mechanisms of myogenesis which is overpassed in case of genetic manipulation; (ii) muscle progenitors are not terminally differentiated, and therefore have a better repair potential following transplantation. One of the major hurdles of stem cell therapy for skeletal muscle regeneration is the massive death following transplantation. Biomaterials exhibit immune protection properties and would ensure an artificial microenvironment which permits them to interact with host cells and exert their therapeutic benefits. With the purpose of a better engraftment, we employed Poly (ethylene glycol) (PEG) -fibrinogen hydrogel (PF) as cell carrier for skeletal muscle regeneration. When transplanted in a αsarcoglycan knockout/severe combined immunodeficiency beige (α-SGKO/SCIDbg) mice, PF-embedded myogenic progenitor cells exhibited stable long-term engraftment and participated in muscle regeneration by fusing with existing muscle fibers. Importantly, no teratoma and no abnormal structure were detected in the muscles transplanted with MPs Finally, our finding and differentiation system provide an effective method that facilitates further utilization of iPS

Extracellular Vesicles from Skeletal Muscle Cells Efficiently Promote Myogenesis in Induced Pluripotent Stem Cells

The recent advances, offered by cell therapy in the regenerative medicine field, offer a revolutionary potential for the development of innovative cures to restore compromised physiological functions or organs. Adult myogenic precursors, such as myoblasts or satellite cells, possess a marked regenerative capacity, but the exploitation of this potential still encounters significant challenges in clinical application, due to low rate of proliferation in vitro, as well as a reduced self-renewal capacity. In this scenario, induced pluripotent stem cells (iPSCs) can offer not only an inexhaustible source of cells for regenerative therapeutic approaches, but also a valuable alternative for in vitro modeling of patient-specific diseases. In this study we established a reliable protocol to induce the myogenic differentiation of iPSCs, generated from pericytes and fibroblasts, exploiting skeletal muscle-derived extracellular vesicles (EVs), in combination with chemically defined factors. This genetic integration-free approach generates functional skeletal myotubes maintaining the engraftment ability in vivo. Our results demonstrate evidence that EVs can act as biological “shuttles” to deliver specific bioactive molecules for a successful transgene-free differentiation offering new opportunities for disease modeling and regenerative approaches

USING A QUEUING MODEL TO ANALYZE AND RECOMMEND CHANGES IN THE NEWS COMING SERVICE PERFORMANCE OF A NATIONAL MEDIA

The culture of media business service in Albania is being shaped day by day by giving up the old tradition of orientating itself toward the in-out flow rather than considering the out-in flow, meaning the greater importance of reader service that makes changes happen from outside, having them into focus. This empirical study focuses on solving a critical service problem in the news from the specific media we must concentrate on. In our case, it concerns measuring the performance of a queue service for the news coming service. It is the queue theory that helps us understand the problem modeling. Thus, performance analysis reaches out by testing the actual waiting time to improve the news manipulating time service, therefore business costs. The methodology used here is based on the Little Law, which relates the average arrival rate with the average waiting time (Poisson distribution) and item number in the queue, combined with the formula that calculates the total economic cost. The model is applied to our specific queue dataset. The data are obtained from one-month observations of news arrival time in a business organization that is focused on the media sector products. The results show that the business must employ another service channel (journalist)

A SHORT ANALYSIS OF THE APPLICATION(S) OF INTELLIGENT AGENTS IN COMPUTER GAMES

The study of artificial intelligence techniques quickly moved to computer games, a sector in which they are of enormous practical utility. Artificial intelligence has advanced significantly in the last five decades. The concept of intelligent agents provides a crucial theoretical framework to compare numerous diverse methods to the smart, logical conduct of computer-controlled characters in games. Computer games represent one of the best environments for artificial intelligence research as they are typically designed to be played multiple times by many players and can thus be studied. Furthermore, advances in computer hardware have allowed game developers to create increasingly complex and engaging games that have forced computer scientists to produce even more creative solutions to complex problems. Artificial intelligence techniques are often used to make computer games more exciting and entertaining by providing the designers with the tools they need to create interactive characters capable of responding to the player\u27s actions. We can achieve behavior that resembles that of a human player, which is also preferred in games, by combining rationality with some restrictions on our agents\u27 skills. In addition, we can simulate behaviors observed in humans during social interaction between individuals or groups. In this paper we interpret, analyze, and bring a simple case study for using intelligent agents for computer games. From an interpretative literature review and a case study approach, we concluded that intelligent agents could improve the gameplay experience, gain insight into Artificial Intelligence behavior, and increase game difficulty

Microbiome and Prostate Cancer: A Novel Target for Prevention and Treatment

Growing evidence of the microbiome’s role in human health and disease has emerged since the creation of the Human Microbiome Project. Recent studies suggest that alterations in microbiota composition (dysbiosis) may play an essential role in the occurrence, development, and prognosis of prostate cancer (PCa), which remains the second most frequent male malignancy worldwide. Current advances in biological technologies, such as high-throughput sequencing, transcriptomics, and metabolomics, have enabled research on the gut, urinary, and intra-prostate microbiome signature and the correlation with local and systemic inflammation, host immunity response, and PCa progression. Several microbial species and their metabolites facilitate PCa insurgence through genotoxin-mediated mutagenesis or by driving tumor-promoting inflammation and dysfunctional immunosurveillance. However, the impact of the microbiome on PCa development, progression, and response to treatment is complex and needs to be fully understood. This review addresses the current knowledge on the host–microbe interaction and the risk of PCa, providing novel insights into the intraprostatic, gut, and urinary microbiome mechanisms leading to PCa carcinogenesis and treatment response. In this paper, we provide a detailed overview of diet changes, gut microbiome, and emerging therapeutic approaches related to the microbiome and PCa. Further investigation on the prostate-related microbiome and large-scale clinical trials testing the efficacy of microbiota modulation approaches may improve patient outcomes while fulfilling the literature gap of microbial–immune–cancer-cell mechanistic interactions

Cancer chemoprevention revisited: Cytochrome P450 family 1B1 as a target in the tumor and the microenvironment

Cancer chemoprevention is the use of synthetic, natural or biological agents to prevent or delay the development or progression of malignancies. Intriguingly, many phytochemicals with anti-inflammatory and anti-angiogenic effects, recently proposed as chemoprevention strategies, are inhibitors of Cytochrome P450 family 1B1 (CYP1B1), an enzyme overexpressed in a wide variety of tumors and associated with angiogenesis. In turn, pro-inflammatory cytokines were reported to boost CYP1B1 expression, suggesting a key role of CYP1B1 in a positive loop of inflammatory angiogenesis. Other well-known pro-tumorigenic activities of CYP1B1 rely on metabolic bioactivation of xenobiotics and steroid hormones into their carcinogenic derivatives. In contrast to initial in vitro observations, in vivo studies demonstrated a protecting role against cancer for the other CYP1 family members (CYP1A1 and CYP1A2), suggesting that the specificity of CYP1 family inhibitors should be carefully taken into account for developing potential chemoprevention strategies. Recent studies also proposed a role of CYP1B1 in multiple cell types found within the tumor microenvironment, including fibroblasts, endothelial and immune cells. Overall, our review of the current literature suggests a positive loop between inflammatory cytokines and CYP1B1, which in turn may play a key role in cancer angiogenesis, acting on both cancer cells and the tumor microenvironment. Strategies aiming at specific CYP1B1 inhibition in multiple cell types may translate into clinical chemoprevention and angioprevention approaches. (C) 2017 Elsevier Ltd. All rights reserved