Recently, the development of several strategies based on immunotherapy has raised hopes for a more promising way to treat cancer patients. Here, we describe how interleukin (IL)‐10, a seemingly unlikely candidate, stimulates the immune system in a particularly efficacious way. IL‐10, an omnipotent anti‐inflammatory cytokine, delivers an equally potent immune stimulation in the context of CD8+ T cells and tumor immunity. By activation of tumor‐resident, tumor‐specific CD8+ T cells, pegylated IL‐10 can induce rejection of large and metastasizing tumors (...) in mice. Here, we summarize the mechanisms of action of IL‐10, the reasons why the mechanisms may be crucial for the treatment of cancer patients, and the rationale for applying pegylated IL‐10 in the clinic. (shrink)

Cancer cells seem to exploit mechanisms that evolve as part of physiological tolerance, which is a complementary and often beneficial form of defense. The study of physiological systems of tolerance can therefore provide insights into the development of a state of host tolerance of cancer, and how to break it. Analysis of these models has the potential to improve our understanding of existing immunological therapeutic targets, and help to identify future targets and rational therapeutic combinations. The treatment of (...) cancer with immune checkpoint inhibitors aims to reverse the progression to tolerance of cancer, and achieve an immunogenic, rather than tolerogenic, homeostasis. Broadening the efficacy and durability of checkpoint inhibitors focuses on reversing tolerance and stimulating immunogenicity in the cancer, host, and environment. Two examples of important physiological states of tolerance that may inform tolerance of cancer are microbial infection and placental reproduction. These states of tolerance result from bilateral shaping of host and non‐self, akin to immunoediting in cancer, and offer reliable models to study the immune tolerance paradigm. (shrink)

Physiologically accurate mouse models of cancer are critical in the pre‐clinical development of novel cancer therapies. However, current standardized animal‐housing temperatures elicit chronic cold‐associated stress in mice, which is further increased in the presence of tumor. This cold‐stress significantly impacts experimental outcomes. Data from our lab and others suggest standard housing fundamentally alters murine physiology, and this can produce altered immune baselines in tumor and other disease models. Researchers may thus underestimate the efficacy of therapies that are benefitted (...) by immune responses. A potential mediator, norepinephrine, also underlies stress pathways common in mice and humans. Therefore, research into mechanisms connecting cold‐stress and norepinephrine signaling with immune depression in mice could highlight new combination therapies for humans to simultaneously target stress while stimulating anti‐tumor immunity. (shrink)

The question as to why some hosts can eradicate their tumors while others succumb to tumor‐progression remains unanswered. Here, a provocative concept is proposed that intrinsic differences in the T cell receptor (TCR) repertoire of individuals may influence the outcome of anti‐tumor immunity by affecting the frequency and/or variety of tumor‐reactive CD8 and/or CD4 tumor‐infiltrating lymphocytes. This idea implicates that the TCR repertoire in a given patient might not provide sufficiently different TCR clones that can recognize tumor antigens, namely, (...) “a hole in the TCR repertoire” might exist. This idea may provide a novel perspective to further dissect the mechanisms underlying heterogeneous anti‐tumor immune responses in different hosts. Besides tumor‐intrinsic heterogeneity and host microbiome, the various factors that may constantly shape the dynamic TCR repertoire are also discussed. Elucidating mechanistic differences in different individuals’ immune systems will allow to better harness immune system to design new personalized cancer immunotherapy. (shrink)

PurposeThis study aims to describe the adverse events following immunization of SARS-CoV-2 vaccination in cancer patients/survivors associated with their psychological distress.MethodsA cross-sectional study was conducted to assess AEFIs after the receipt of SARS-CoV-2 vaccines in cancer patients/survivors attending a university hospital in Malaysia. Psychological distress was measured using the Hospital Anxiety and Depression Scale before and after the first and second doses of COVID-19 vaccine.ResultsA total of 217 complete responses were received. Compared with before vaccination, both HADS Anxiety (...) and HADS Depression scores were significantly reduced after the first and second dose of the SARS-CoV-2 vaccine. Most of the participants had mild-or-moderate systemic and local AEFIs, with the most common being pain at the injection site, tiredness, and headache for both the first and second doses of the vaccine. Positive correlations between the total AEFI score and HADS-A and HADS-D scores were observed after the first dose of the SARS-CoV-2 vaccine. Similarly, positive associations were observed between the total AEFI score and HADS-A and HADS-D scores after the second dose of the SARS-CoV-2 vaccine.ConclusionMild-to-moderate AEFIs found in this study help address vaccine hesitancy in cancer patients/survivors. Receiving the SARS-CoV-2 vaccine had a positive effect on decreasing psychological distress in cancer patients/survivors. High severity of an AEFI was associated with higher anxiety and depressive symptoms. (shrink)

It has long been recognized that cancer onset and progression represent a type of reversion to an ancestral quasi‐unicellular phenotype. This general concept has been refined into the atavistic model of cancer that attempts to provide a quantitative analysis and testable predictions based on genomic data. Over the past decade, support for the multicellular‐to‐unicellular reversion predicted by the atavism model has come from phylostratigraphy. Here, we propose that cancer onset and progression involve more than a one‐off multicellular‐to‐unicellular (...) reversion, and are better described as a series of reversionary transitions. We make new predictions based on the chronology of the unicellular‐eukaryote‐to‐multicellular‐eukaryote transition. We also make new predictions based on three other evolutionary transitions that occurred in our lineage: eukaryogenesis, oxidative phosphorylation and the transition to adaptive immunity. We propose several modifications to current phylostratigraphy to improve age resolution to test these predictions. Also see the video abstract here: https://youtu.be/3unEu5JYJrQ. (shrink)

In the atavistic model of cancer progression, tumor cell dedifferentiation is interpreted as a reversion to phylogenetically earlier capabilities. The more recently evolved capabilities are compromised first during cancer progression. This suggests a therapeutic strategy for targeting cancer: design challenges to cancer that can only be met by the recently evolved capabilities no longer functional in cancer cells. We describe several examples of this target‐the‐weakness strategy. Our most detailed example involves the immune system. The absence (...) of adaptive immunity in immunosuppressed tumor environments is an irreversible weakness of cancer that can be exploited by creating a challenge that only the presence of adaptive immunity can meet. This leaves tumor cells more vulnerable than healthy tissue to pathogenic attack. Such a target‐the‐weakness therapeutic strategy has broad applications, and contrasts with current therapies that target the main strength of cancer: cell proliferation. (shrink)

Cancer is generally defined as uncontrollable growth of cells caused by genetic aberrations and/or environmental factors. Yet contagious cancers also occur. The recent emergence of a contagious cancer in Tasmanian devils has reignited interest in transmissible cancers. Two naturally occurring transmissible cancers are known: devil facial tumour disease and canine transmissible venereal tumour. Both cancers evolved once and have then been transmitted from one individual to another as clonal cell lines. The dog cancer is ancient; having evolved (...) more than 6,000 years ago, while the devil disease was first seen in 1996. In this review I will compare and contrast the two diseases focusing on the life histories of the clonal cell lines, their evolutionary trajectories and the mechanisms by which they have achieved immune tolerance. A greater understanding of these contagious cancers will provide unique insights into the role of the immune system in shaping tumour evolution and may uncover novel approaches for treating human cancer. (shrink)

© 2015 Elsevier Inc.Postnatal organogenesis occurs in an immune competent environment and is tightly controlled by interplay between positive and negative regulators. Innate immune cells have beneficial roles in postnatal tissue remodeling, but roles for the adaptive immune system are currently unexplored. Here we show that adaptive immune responses participate in the normal postnatal development of a non-lymphoid epithelial tissue. Since the mammary gland is the only organ developing predominantly after birth, we utilized it as a powerful system to study (...) adaptive immune regulation of organogenesis. We found that antigen-mediated interactions between mammary antigen-presenting cells and interferon-γ -producing CD4+ T helper 1 cells participate in MG postnatal organogenesis as negative regulators, locally orchestrating epithelial rearrangement. IFNγ then affects luminal lineage differentiation. This function of adaptive immune responses, regulating normal development, changes the paradigm for studying players of postnatal organogenesis and provides insights into immune surveillance and cancer transformation. Plaks et al. (shrink)

It is well established that chronic infections can lead to cancer. Almost unknown is that, in contrast, acute brief viral and bacterial infections may have beneficial effects in cases of established neoplastic disease, while exposure to pathogenic products by infection, vaccination, and inhalation can cause prophylactic effects. In the following I will align evidence from case studies of spontaneous regression and from epidemiological studies with recent immunology to conclude that pathogenic substances belonging to the group of “pathogen‐associated molecular patterns” (...) can trigger the innate immune system to establish anti‐neoplastic immune responses. A better understanding of the protective role of the innate immune system might leverage considerable prophylactic potential. (shrink)

During tumor evolution, cancer cells use the tumor‐stroma crosstalk to reorganize the microenvironment for maximum robustness of the tumor. The success of immune checkpoint therapy foretells a new cancer therapy paradigm: an effective cancer treatment should not aim to influence the individual components of super complex intracellular interactomes (molecular targeting), but try to disrupt the intercellular interactions between cancer and stromal cells, thus breaking the tumor as a whole. Arguments are provided in favor of a hypothesis (...) that such interactions include formation of synapse‐like structures (interfaces) where the interacting cells are located at a distance of ∼10–15 nm. Within these interfaces, molecules initiating and strengthening the interaction are organized, and allow optimum cross‐signaling; a very confined intercellular space facilitates the concentration of secreted cytokines, enhancing the paracrine cross‐communication. These features of tumors form a druggable cancer hallmark the tumor‐stroma symbiotic crosstalk—which represents a new target for efficient cancer drug discovery. (shrink)

Here we review and discuss the link between regeneration capacity and tumor suppression comparing mammals (embryos versus adults) with highly regenerative vertebrates. Similar to mammal embryo morphogenesis, in amphibians (essentially newts and salamanders) the reparative process relies on a precise molecular and cellular machinery capable of sensing abnormal signals and actively reprograming or eliminating them. As the embryo's evil twin, tumor also retains common functional attributes. The immune system plays a pivotal role in maintaining a physiological balance to provide surveillance (...) against tumor initiation or to support its initiation and progression. We speculate that susceptibility to cancer development in adult mammals may be determined by the loss of an advanced regenerative capability during evolution and believe that gaining mechanistic insights into how regenerative capacity linked to tumor suppression is postnatally lost in mammals might illuminate an as yet unrecognized route to cancer treatment. (shrink)

In an instant classic paper ; 2002: 179–182) biologist Yuri Lazebnik deplores the poor effectiveness of the approach adopted by biologists to understand and “fix” biological systems. Lazebnik suggests that to remedy this state of things biologist should take inspiration from the approach used by engineers to design, understand, and troubleshoot technological systems. In the present paper I substantiate Lazebnik’s analysis by concretely showing how to apply the engineering approach to biological problems. I use an actual example of electronic circuit (...) troubleshooting to ground the thesis that, in engineering, the crucial phases of any non-trivial troubleshooting process are aimed at generating a mechanistic explanation of the functioning of the system, which makes extensive recourse to problem-driven qualitative reasoning possibly based on cognitive artifacts applied to systems that are known to have been designed for function. To show how to translate these findings into biological practice I consider a concrete example of biological model building and “troubleshooting”, aimed at the identification of a “fix” for the human immune system in presence of progressing cancer, autoimmune disease, and transplant rejection. The result is a novel immune system model—the danger model with regulatory cells— and new, original hypotheses concerning the development, prophylaxis, and therapy of these unwanted biological processes. Based on the manifest efficacy of the proposed approach, I suggest a refocusing of the activity of theoretical biologists along the engineering-inspired lines illustrated in the paper. (shrink)

Cancers rely on multiple, heterogeneous processes at different scales, pertaining to many biomedical fields. Therefore, understanding cancer is necessarily an interdisciplinary task that requires placing specialised experimental and clinical research into a broader conceptual, theoretical, and methodological framework. Without such a framework, oncology will collect piecemeal results, with scant dialogue between the different scientific communities studying cancer. We argue that one important way forward in service of a more successful dialogue is through greater integration of applied sciences (experimental (...) and clinical) with conceptual and theoretical approaches, informed by philosophical methods. By way of illustration, we explore six central themes: (i) the role of mutations in cancer; (ii) the clonal evolution of cancer cells; (iii) the relationship between cancer and multicellularity; (iv) the tumour microenvironment; (v) the immune system; and (vi) stem cells. In each case, we examine open questions in the scientific literature through a philosophical methodology and show the benefit of such a synergy for the scientific and medical understanding of cancer. (shrink)

Cancer chemotherapy has been the most common cancer treatment. However, it has side effects that kill both tumor cells and immune cells, which can ravage the patient’s immune system. Chemotherapy should be administered depending on the patient’s immunity as well as the level of cancer cells. Thus, we need to design an efficient treatment protocol. In this work, we study a feedback control problem of tumor-immune system to design an optimal chemotherapy strategy. For this, we first (...) propose a mathematical model of tumor-immune interactions and conduct stability analysis of two equilibria. Next, the feedback control is found by solving the Hamilton–Jacobi–Bellman equation. Here, we use an upwind finite-difference method for a numerical approximate solution of the HJB equation. Numerical simulations show that the feedback control can help determine the treatment protocol of chemotherapy for tumor and immune cells depending on the side effects. (shrink)

In this paper, we hypothesize that X chromosome-associated mechanisms, which affect X-linked genes and are behind the immunological advantage of females, may also affect X-linked microRNAs. The human X chromosome contains 10% of all microRNAs detected so far in the human genome. Although the role of most of them has not yet been described, several X chromosome-located microRNAs have important functions in immunity and cancer. We therefore provide a detailed map of all described microRNAs located on human and (...) mouse X chromosomes, and highlight the ones involved in immune functions and oncogenesis. The unique mode of inheritance of the X chromosome is ultimately the cause of the immune disadvantage of males and the enhanced survival of females following immunological challenges. How these aspects influence X-linked microRNAs will be a challenge for researchers in the coming years, not only from an evolutionary point of view, but also from the perspective of disease etiology. (shrink)

In this paper, we hypothesize that X chromosome‐associated mechanisms, which affect X‐linked genes and are behind the immunological advantage of females, may also affect X‐linked microRNAs. The human X chromosome contains 10% of all microRNAs detected so far in the human genome. Although the role of most of them has not yet been described, several X chromosome‐located microRNAs have important functions in immunity and cancer. We therefore provide a detailed map of all described microRNAs located on human and (...) mouse X chromosomes, and highlight the ones involved in immune functions and oncogenesis. The unique mode of inheritance of the X chromosome is ultimately the cause of the immune disadvantage of males and the enhanced survival of females following immunological challenges. How these aspects influence X‐linked microRNAs will be a challenge for researchers in the coming years, not only from an evolutionary point of view, but also from the perspective of disease etiology. (shrink)

In human cancers, histone methyltransferase SETDB1 (SET domain, bifurcated 1) is frequently overexpressed but its significance in carcinogenesis remains elusive. A recent study shows that SETDB1 downregulation induces de‐repression of retroelements and innate immunity in cancer cells. The possibility of SETDB1 functioning as a surveillant of retroelement expression is discussed in this study: the cytoplasmic presence of retroelement‐derived nucleic acids (RdNAs) drives SETDB1 into the nucleus by the RNA‐interference route, rendering the corresponding retroelement transcriptionally inert. These RdNAs could, (...) therefore, be signals of genome instability sent out for SETDB1 present in the cytoplasm to maintain genome integrity. (shrink)

Once regarded as cellular ‘debris’ extracellular vesicles (EVs) emerge as one of the most intriguing entities in cancer pathogenesis. Intercellular trafficking of EVs challenges the notion of cancer cell autonomy, and highlights the multicellular nature of such fundamental processes as stem cell niche formation, tumour stroma generation, angiogenesis, inflammation or immunity. Recent studies reveal that intercellular exchange mediated by EVs runs deeper than expected, and includes molecules causative for cancer progression, such as oncogenes (epidermal growth factor (...) receptor, Ras), and tumour suppressors (PTEN). The uptake of oncogenic EVs (oncosomes) by various cells may profoundly change their biology, signalling patterns and gene expression, and in some cases cause their overt tumorigenic conversion. Moreover, EVs circulating in blood and present in body fluids provide an unprecedented access to the molecular circuitry driving cancer cells, and new technologies are being developed to exploit this property as a source of unique cancer biomarkers. (shrink)

Interferon stimulated gene 15 (ISG15) encodes a ubiquitin‐like protein that is highly induced upon activation of interferon signaling and cytoplasmic DNA sensing pathways. As part of the innate immune system ISG15 acts to inhibit viral replication and particle release via the covalent conjugation to both viral and host proteins. Unlike ubiquitin, unconjugated ISG15 also functions as an intracellular and extra‐cellular signaling molecule to modulate the immune response. Several recent studies have shown ISG15 to also function in a diverse array of (...) cellular processes and pathways outside of the innate immune response. This review explores the role of ISG15 in maintaining genome stability, particularly during DNA replication, and how this relates to cancer biology. It puts forth the hypothesis that ISG15, along with DNA sensors, function within a DNA replication fork surveillance pathway to help maintain genome stability. (shrink)

The placenta invades the adjacent uterus and controls the maternal immune system, like a cancer invades surrounding organs and suppresses the local immune response. Intriguingly, placental and cancer cells are globally hypomethylated and share an epigenetic phenomenon that is not well understood – they fail to silence repetitive DNA sequences that are silenced in healthy somatic cells. In the placenta, hypomethylation of retrotransposons has facilitated the evolution of new genes essential for placental function. In cancer, hypomethylation is (...) thought to contribute to activation of oncogenes, genomic instability, and retrotransposon unsilencing; the latter, we postulate, is possibly the most important consequence. Activation of placental retrotransposon-derived genes in cancer underpins our hypothesis that hypomethylation of these genes drives cancer cell invasion. This alludes to an interesting paradox, that while placental retrotransposon-derived genes are essential for promoting early hominid life, the same genes promote disease-susceptibility and death through cancer. Placental and cancer cells fail to silence retrotransposons that are normally silenced in healthy tissues. This has created new genes that are essential for placental function, yet they are also expressed in cancer. We hypothesize that active retrotransposons are a double-edged sword, contributing both adaptive and deleterious functions to biology. (shrink)

The gut microbiota is an important component of the human body and its immune‐modulating and metabolic activities are critical to maintain good health. Gut microbes, however, are sensitive to changes in diet, exposure to antibiotics, or infections, all of which cause transient disruptions in the microbial composition, a phenomenon known as dysbiosis. It is now recognized that microbial dysbiosis is at the root of many gastrointestinal disorders. However, the mechanisms through which bacterial dysbiosis initiates disease are not fully understood. Microbially‐derived (...) metabolites and their role in disease have also attracted significant attention. Identification of cancer‐associated bacteria and understanding the contributions of microbial metabolism in health and disease are exciting but challenging areas that will allow defining microbial biomarkers for predicting gastrointestinal disorders. Understanding the complex interactions between gut microbiota, diet, host immune system and host genetics will be critical to developing more personalized therapies and approaches to treat disease. (shrink)

From the sixties on it has become clear how the human physical condition could be influenced by human behavior. Although hypothesis were lacking to understand these connections, nursing research especially proved how systematically introduced patient behavior during illness and hospitalization could induce better recovery results and better prognosis for the patient.Information andattitude proved to be crucial elements in these processes of improved patient expectations. It took less than two decades to get to the insights we have in 1994. Recent research (...) shows the interlocking mechanisms of nervous and endocrine systems with the immune system as significantly being influenced by behavior and especially psychic and or psychosocial stress.This special issue of Theoretical Medicine briefly describes the historical development with contributions on the most recent state of the scientific art. These developments are emphasized by discussion on the clinical reality of the (breast) cancer patient and recent findings on the complexity of the prevalence of cancer in epidemiology. An attempt is made to consider practical consequences of the actual knowledge if applied to patient care. (shrink)

The cyclic GMP‐AMP synthase–stimulator of interferon genes (cGAS‐STING) pathway is central for the initiation of anti‐tumoural immune responses. Enormous effort has been made to optimise the design and administration of STING agonists to stimulate tumour immunogenicity. However, in certain contexts the cGAS‐STING axis fuels tumourigenesis. Here, we review recent findings on the regulation of cGAS expression and activity. We particularly focus our attention on the DNA‐dependent protein kinase (DNA‐PK) complex, that recently emerged as an activator of inflammatory responses in tumour (...) cells. We propose that stratification analyses on cGAS and DNA‐PK expression/activation status should be carried out to predict treatment efficacy. We herein also provide insights into non‐canonical functions borne by cGAS and cGAMP, highlighting how they may influence tumourigenesis. All these parameters should be taken into consideration concertedly to choose strategies aiming to effectively boost tumour immunogenicity. (shrink)

Neddylation, a ubiquitylation‐like post‐translational modification, is catalyzed by a cascade composed of three enzymes: E1 activating enzyme, E2 conjugating enzyme, and E3 ligase with cullins as physiological substrates. Specifically, neddylation E2 UBE2M couples with E3 RBX1 to neddylate cullins 1–4, whereas neddylation E2 UBE2F couples with E3 RBX2/SAG to neddylate cullin 5, leading to activation of CRL1‐4 (Cullin‐RING ligases 1–4) and CRL5, respectively. While over‐activation of the neddylation‐CRLs axis occurs frequently in many human cancers, how neddylation‐CRLs regulate the function of (...) immune cells, particularly Treg cells was previously unknown. To this end, we recently performed Treg selective knockout of two neddylation E2s and two E3s, individually, driven by Foxp3‐Cre, and found that while the Ube2f‐Sag E2/E3 pair plays a minimal role, if any, the Ube2m‐Rbx1 pair is essential for the maintenance of Treg functionality, since their deletion triggers robust inflammatory response with autoimmune phenotypes. Milder phenotype severity upon Treg KO of upstream Ube2m than that of downstream Rbx1 strongly suggested that Rbx1 regulates Treg function in a manner dependent and independent of neddylation. (shrink)

Over the last few years, oncolytic virus therapy has been recognised as a promising approach in cancer treatment, due to the potential of these viruses to induce systemic anti-tumour immunity and selectively killing tumour cells. However, the effectiveness of these viruses depends significantly on their interactions with the host immune responses, both innate and adaptive. In this article, we consider a mathematical approach to investigate the possible outcomes of the complex interactions between two extreme types of macrophages, effector (...) $$\hbox {CD8}^{+}$$ T cells and an oncolytic Vesicular Stomatitis Virus, on the growth/elimination of B16F10 melanoma. We discuss, in terms of VSV, $$\hbox {CD8}^{+}$$ and macrophages levels, two different types of immune responses which could ensure tumour control and eventual elimination. We show that both innate and adaptive anti-tumour immune responses, as well as the oncolytic virus, could be very important in delaying tumour relapse and eventually eliminating the tumour. Overall this study supports the use mathematical modelling to increase our understanding of the complex immune interaction following oncolytic virotherapies. However, the complexity of the model combined with a lack of sufficient data for model parametrisation has an impact on the possibility of making quantitative predictions. (shrink)

The human intestines are constantly under the influence of numerous pathological factors: enteropathogenic microorganisms, food antigens, physico‐chemical stress associated with digestion and bacterial metabolism, therefore it must be provided with a system of protection against adverse impact. Recent studies have shown that Paneth cells play a crucial role in maintaining homeostasis of the small intestines. Paneth cells perform many vital functions aimed at maintaining a homeostatic balance between normal microbiota, infectious pathogens and the human body, regulate the qualitative composition and (...) number of intestinal microorganisms, prevent the introduction of potentially pathogenic species, and protect stem cells from damage. Paneth cells take part in adaptive and protective‐inflammatory reactions. Paneth cells maintain dynamic balance between microbial populations, and the macroorganism, preventing the development of intestinal infections and cancer. They play a crucial role in gastrointestinal homeostasis and may be key factors in the etiopathological progression of intestinal diseases. (shrink)

Inflammatory immune cells, when activated, display much the same metabolic profile as a glycolytic tumor cell. This involves a shift in metabolism away from oxidative phosphorylation towards aerobic glycolysis, a phenomenon known as the Warburg effect. The result of this change in macrophages is to rapidly provide ATP and metabolic intermediates for the biosynthesis of immune and inflammatory proteins. In addition, a rise in certain tricarboxylic acid cycle intermediates occurs notably in citrate for lipid biosynthesis, and succinate, which activates the (...) transcription factor Hypoxia‐inducible factor. In this review we take a look at the emerging evidence for a role for the Warburg effect in the immune and inflammatory responses. The reprogramming of metabolic pathways in macrophages, dendritic cells, and T cells could have relevance in the pathogenesis of inflammatory and metabolic diseases and might provide novel therapeutic strategies. (shrink)

Human Papillomavirus (HPV) types are sexually transmitted infections that cause a number of human cancers. According to the competitive exclusion principle in ecology, HPV types that have lower transmission probabilities and shorter durations of infection should be outcompeted by more virulent types. This, however, is not the case, as numerous HPV types co-exist, some which are less transmissible and more easily cleared than others. This paper examines whether this exception to the competitive exclusion principle can be explained by the aggregation (...) of infection with HPV types, which results in patchy spatial distributions of infection, and what implications this has for the effect of vaccination on multiple HPV types. A deterministic transmission model is presented that models the patchy distribution of infected individuals using Lloyd’s mean crowding. It is first shown that higher aggregation can result in a reduced capacity for onward transmission and reduce the required efficacy of vaccination. It is shown that greater patchiness in the distribution of lower prevalence HPV types permits co-existence. This affirms the hypothesis that the aggregation of HPV types provides an explanation for the violation of the competitive exclusion principle. Greater aggregation of lower prevalence types has important implications where type-specific HPV vaccines also offer cross-protection against non-target types. It is demonstrated that the degree of cross-protection can be less than the degree of vaccine protection conferred against directly targeted types and still result in the elimination of non-target types when these non-target types are patchily distributed. (shrink)

The rapidly changing field of genetics affects society through advances in health-care and through implications of genetic research. This study addresses the impacts of new genetic discoveries and technologies on different segments of today's society. The book begins with a chapter on genetic complexity, and subsequent chapters discuss moral and ethical questions arising from today's genetics from the perspectives of health care professionals, the media, the general public, special interest groups and commercial interests.

Acidity, generated in hypoxia or hypermetabolic states, perturbs homeostasis and is a feature of solid tumors. That acid peripherally disperses lysosomes is a three‐decade‐old observation, yet one little understood or appreciated. However, recent work has recognized the inhibitory impact this spatial redistribution has on mechanistic target of rapamycin complex 1 (mTORC1), a key regulator of metabolism. This finding argues for a paradigm shift in localization of mTORC1 activator Ras homolog enriched in brain (RHEB), a conclusion several others have now independently (...) reached. Thus, mTORC1, known to sense amino acids, mitogens, and energy to restrict biosynthesis to times of adequate resources, also senses pH and, via dampened mTOR‐governed synthesis of clock proteins, regulates the circadian clock to achieve concerted responses to metabolic stress. While this may allow cancer to endure metabolic deprivation, immune cell mTOR signaling likewise exhibits pH sensitivity, suggesting that suppression of antitumor immune function by solid tumor acidity may additionally fuel cancers, an obstacle potentially reversible through therapeutic pH manipulation. (shrink)

The recent publication by Wylie et al. is reviewed, demonstrating that the p53 protein regulates the movement of transposons. While this work presents genetic evidence for a piRNA‐mediated p53 interaction with transposons in Drosophila and zebrafish, it is herein placed in the context of a decade or so of additional work that demonstrated a role for p53 in regulating transposons and other repetitive elements. The line of thought in those studies began with the observation that transposons damage DNA and p53 (...) regulates DNA damage. The presence of transposon movement can increase the rate of evolution in the germ line and alter genes involved in signal transduction pathways. Transposition can also play an important role in cancers where the p53 gene function is often mutated. This is particularly interesting as recent work has shown that de‐repression of repetitive elements in cancer has important consequences for the immune system and tumor microenvironment. (shrink)

Human papillomavirus (HPV) infection is the world’s most common sexually transmitted infection. It is a prerequisite for cervical cancer, the second most common cause of death in cancer among women worldwide, and is also believed to cause other anogenital and head and neck cancers. Vaccines that protect against the most common cancer-causing HPV types have recently become available, and different countries have taken different approaches to implementing vaccination. This paper examines the ethics of alternative HPV vaccination strategies. (...) It devotes particular attention to the major arguments for and against one strategy: voluntary, publicly funded vaccination for all adolescent boys and girls. This approach seems attractive because it would protect more people against cervical cancer and other HPV-related cancers than less inclusive alternatives, without the sacrifice of autonomy that a comparably broad compulsory programme would require. Also, the herd immunity that it would likely generate would protect those who remain unvaccinated, a major advantage from a justice perspective. However, there is a possibility that a HPV vaccination programme targeting all adolescents of both sexes is not considered sufficiently cost-effective. Also, it might pose more difficulties for achieving informed consent than comparable vaccination programmes against other diseases. Ultimately, society’s choice of HPV vaccination strategy requires careful consideration not only of the values at stake but also of available and emerging scientific evidence. (shrink)

Cellular senescence is an anti‐proliferative program that restricts the propagation of cells subjected to different kinds of stress. Cellular senescence was initially described as a cell‐autonomous tumor suppressor mechanism that triggers an irreversible cell cycle arrest that prevents the proliferation of damaged cells at risk of neoplastic transformation. However, discoveries during the last decade have established that senescent cells can also impact the surrounding tissue microenvironment and the neighboring cells in a non‐cell‐autonomous manner. These non‐cell‐autonomous activities are, in part, mediated (...) by the selective secretion of extracellular matrix degrading enzymes, cytokines, chemokines and immune modulators, which collectively constitute the senescence‐associated secretory phenotype. One of the key functions of the senescence‐associated secretory phenotype is to attract immune cells, which in turn can orchestrate the elimination of senescent cells. Interestingly, the clearance of senescent cells seems to be critical to dictate the net effects of cellular senescence. As a general rule, the successful elimination of senescent cells takes place in processes that are considered beneficial, such as tumor suppression, tissue remodeling and embryonic development, while the chronic accumulation of senescent cells leads to more detrimental consequences, namely, cancer and aging. Nevertheless, exceptions to this rule may exist. Now that cellular senescence is in the spotlight for both anti‐cancer and anti‐aging therapies, understanding the precise underpinnings of senescent cell removal will be essential to exploit cellular senescence to its full potential. (shrink)

In this chapter, the issue of information will be tackled from a "pathological" point of view, by considering living cells that have become cancerous and societies permeated by "psychological imbalances". The chapter focuses on the issue of fanaticism, whose cause is evidently related to the way of interpreting the world. The issue will revolve around immunity, identity, forms and communication. The chapter also considers some perspicacious analyses published in the 1960s by Jurgen Habermas. This unmissable philosopher has managed to (...) shed light on how science and technology have become ideologies, leading to societies guided by scientific modernism with two complementary aspects. The first one involves action as determined by the use of technological tools. The second one involves thinking, human conscience, and the sense of existence which, in the context of scientific modernism, are determined or at least guided by the use of technological tools and procedures founded on measuring and calculating science. (shrink)

Animal models play a crucial role in fundamental and medical research. Progress in the fields of drug discovery, regenerative medicine and cancer research among others are heavily dependent on in vivo models to validate in vitro observations, and develop new therapeutic approaches. However, conventional rodent and large animal experiments face ethical, practical and technical issues that limit their usage. The chick embryo represents an accessible and economical in vivo model, which has long been used in developmental biology, gene expression (...) analysis and loss/gain of function experiments. It is also an established model for tissue/cell transplantation, and because of its lack of immune system in early development, the chick embryo is increasingly recognised as a model of choice for mammalian biology with new applications for stem cell and cancer research. Here, we review novel applications of the chick embryo model, and discuss future developments of this in vivo model for biomedical research. (shrink)

The aim of this paper is to provide a theoretical framework to understand how multicellular systems realize functionally integrated physiological entities by organizing their intercellular space. From a perspective centered on physiology and integration, biological systems are often characterized as organized in such a way that they realize metabolic self-production and self-maintenance. The existence and activity of their components rely on the network they realize and on the continuous management of the exchange of matter and energy with their environment. One (...) of the virtues of the organismic approach focused on organization is that it can provide an understanding of how biological systems are functionally integrated into coherent wholes. Organismic frameworks have been primarily developed by focusing on unicellular life. Multicellularity, however, presents additional challenges to our understanding of biological systems, related to how cells are capable to live together in higher-order entities, in such a way that some of their features and behaviors are constrained and controlled by the system they realize. Whereas most accounts of multicellularity focus on cell differentiation and increase in size as the main elements to understand biological systems at this level of organization, we argue that these factors are insufficient to provide an understanding of how cells are physically and functionally integrated in a coherent system. In this paper, we provide a new theoretical framework to understand multicellularity, capable to overcome these issues. Our thesis is that one of the fundamental theoretical principles to understand multicellularity, which is missing or underdeveloped in current accounts, is the functional organization of the intercellular space. In our view, the capability to be organized in space plays a central role in this context, as it enables (and allows to exploit all the implications of) cell differentiation and increase in size, and even specialized functions such as immunity. We argue that the extracellular matrix plays a crucial active role in this respect, as an evolutionary ancient and specific (non-cellular) control subsystem that contributes as a key actor to the functional specification of the multicellular space and to modulate cell fate and behavior. We also analyze how multicellular systems exert control upon internal movement and communication. Finally, we show how the organization of space is involved in some of the failures of multicellular organization, such as aging and cancer. (shrink)

The integrated stress response (ISR) is a key determinant of tumorigenesis in response to oncogenic forms of stress like genotoxic, proteotoxic and metabolic stress. ISR relies on the phosphorylation of the translation initiation factor eIF2 to promote the translational and transcriptional reprogramming of gene expression in stressed cells. While ISR promotes tumor survival under stress, its hyperactivation above a level of tolerance can also cause tumor death. The tumorigenic function of ISR has been recently demonstrated for lung adenocarcinomas (LUAD) with (...) KRAS mutations. ISR mediates the translational repression of the dual‐specificity phosphatase DUSP6 to stimulate ERK activity and LUAD growth. The significance of this finding is highlighted by the strong anti‐tumor responses of ISR inhibitors in pre‐clinical LUAD models. Elucidation of the mechanisms of ISR action in LUAD progression via cell‐autonomous and immune regulatory mechanisms will provide a better understanding of its tumorigenic role to fully exploit its therapeutic potential in the treatment of a deadly form of cancer. (shrink)

Human papillomavirus (HPV) is one of the most common sexually transmitted infections. It is a leading cause of cervical cancer in women but the virus is increasingly being linked to several other cancers in men and women alike. Since the introduction of safe and effective but also expensive vaccines, many developed countries have implemented selective vaccination programs for girls. Some however argue that these programs should be expanded to include boys, since (1) HPV constitutes non-negligible health risks for boys (...) as well and (2) protected boys will indirectly also protect girls. In this paper we approach this discussion from an ethical perspective. First, on which moral grounds can one justify not reimbursing vaccination for the male sex? We develop an ethical framework to evaluate selective vaccination programs and conclude that, in the case of HPV, efficiency needs to be balanced against non-stigmatization, non-discrimination and justice. Second, if vaccination programs were to be expanded to boys as well, do the latter then also have a moral duty to become immunized? Two arguments in favor of such a moral duty are well known in vaccination ethics: the duty not to harm others and to contribute to the public good of public health. However, we argue that these are not particularly convincing in the context of HPV. In contrast, we believe a third, more powerful but also more controversial argument is possible. In our view, the sexual mode of transmission of HPV constitutes an additional reason to believe that boys in fact may have a moral obligation to accept vaccination. (shrink)

In Enhancing Evolution, leading bioethicist John Harris dismantles objections to genetic engineering, stem-cell research, designer babies, and cloning and makes an ethical case for biotechnology that is both forthright and rigorous. Human enhancement, Harris argues, is a good thing--good morally, good for individuals, good as social policy, and good for a genetic heritage that needs serious improvement. Enhancing Evolution defends biotechnological interventions that could allow us to live longer, healthier, and even happier lives by, for example, providing us with (...) class='Hi'>immunity from cancer and HIV/AIDS. Further, Harris champions the possibility of influencing the very course of evolution to give us increased mental and physical powers--from reasoning, concentration, and memory to strength, stamina, and reaction speed. Indeed, he says, it's not only morally defensible to enhance ourselves; in some cases, it's morally obligatory. In a new preface, Harris offers a glimpse at the new science and technology to come, equipping readers with the knowledge to assess the ethics and policy dimensions of future forms of human enhancement. (shrink)

The extent to which normal (nonmalignant) cells of the body can evolve through mutation and selection during the lifetime of the organism has been a major unresolved issue in evolutionary and developmental studies. On the one hand, stable multicellular individuality seems to depend on genetic homogeneity and suppression of evolutionary conflicts at the cellular level. On the other hand, the example of clonal selection of lymphocytes indicates that certain forms of somatic mutation and selection are concordant with the organism-level fitness. (...) Recent DNA sequencing and tissue physiology studies suggest that in addition to adaptive immune cells also neurons, epithelial cells, epidermal cells, hematopoietic stem cells and functional cells in solid bodily organs are subject to evolutionary forces during the lifetime of an organism. Here we refer to these recent studies and suggest that the expanding list of somatically evolving cells modifies idealized views of biological individuals as radically different from collectives. (shrink)

Michael Nair-Collins and Franklin Miller are right to emphasise that, in order to deliberate responsibly about ethical and legal questions related to brain death and organ donation, it is crucial to answer the question of whether or not ‘brain death’i does indeed mark the biological death of the organism. Nonetheless, I disagree with the authors’ conclusion that brain death does not indicate the death of the human organism. Death can never be defined in merely biological terms, because any biological conception (...) of death relies on metaphysical presuppositions regarding what it means to be an ‘organism as a whole’, rather than an aggregate of cells and tissues. Death is a change in substance —that is, a change from one type of entity to another — not the cessation of all biological life. Organismal death occurs well before all of the organism’s parts irreversibly cease vital activity and decompose into inorganic matter. Biological life in some form can and usually does continue after organismal death at least for a time, with recent evidence indicating that animal cell networks continue to perform complex functions like stress response, immune response and inflammation response up to several days postmortem.1 With external support, many cells and tissues can continue to perform their functions ex vivo for long periods of time or even indefinitely.2 Henrietta Lax died in 1951, but cells derived from her cancerous cervical cells …. (shrink)

Misconceived Consent: Miguel has stage IV lung cancer. He has nearly exhausted his treatment options when his oncologist, Dr. Llewellyn, tells him about an experimental vaccine trial that may boost his immune response to kill cancer cells. Dr. Llewellyn provides Miguel with a consent form that explains why the study is being conducted, what procedures he will undergo, what the various risks and benefits are, alternative sources of treatment, and so forth. She even sits down with him, carefully (...) talks through the most important points, and gives him time to ask questions. Though it is a Phase 1 study and the chance that he will benefit is very low, Miguel happily agrees to take part. A week later, after the first experimental injection, she asks him if he is worried about the risks. “Risks?” he asks. “I’m sure this is safe—you’re a doctor, after all!”. (shrink)

Chronobiology, especially the study of circadian rhythms, provides a model scientific field in which philosophers can study how investigators from a variety of disciplines working at different levels of organization are each contributing to a multi-level account of the responsible mechanism. I focus on how the framework of mechanistic explanation integrates research designed to decompose the mechanism with efforts directed at recomposition that relies especially on computation models. I also examine how recently the integration has extended beyond basic research to (...) the processes through which the disruption of circadian rhythms contributes to disease, including various forms of cancer. Understanding these linkages has been facilitated by discoveries about how circadian mechanisms interact with mechanisms involved in other physiological processes, including the cell cycle and the immune system. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:A New Graduate Nurse’s StoryJill MountI was taking pre–med courses on the west coast when my mother was diagnosed with acute leukemia. I immediately finished out my classes, packed up my bags and cat and moved back to the town on the east coast where my parents lived. While my mother was fighting the leukemia, I spent many hours in her hospital room and I learned more about the (...) roles of doctors and nurses. Unlike what I had seen on television, where the doctors were always nearby and available to their patients, my mother’s doctors were seldom present. It was the nurses who spent the most time with my mother in the hospital. I wanted to care and be present for my patients like her nurses. So I decided to become a nurse. I didn’t realize that not all cancer units were like my mother’s where the nurses had time to really care for their patients.My mother’s attending doctor would visit her bedside once a day. The doctor would generally stand a few feet away from the foot of my mother’s bed and describe my mother’s latest blood counts. The doctor always seemed to keep her distance at the foot of the bed. As my mother’s series of chemotherapy treatments failed to put her in remission, the doctor would describe the next chemotherapy protocol that my mother would endure. My mother wanted desperately to live and she would keep copies of the blood counts her doctor provided her and would insist on trying the next round of chemotherapy, despite the list of grim side effects each seemed to come with. The doctor generally stayed an average of five minutes during these visits.My mother’s nurses, however, were a constant presence. I had not realized at the time that people are hospitalized primarily for nursing care. My mother was assigned several great nurses, who not only took her vital signs and administered her medications, but who seemed to care about her as a person as well. The nurses seemed to understand how difficult it was for my mother, a very independent person, not to have control over her health. To help her regain control, they provided her with guided visualizations. This was during the mid–eighties so they had her visualize her immune system as Pac–man eating all the cancer cells. My mother liked this because when she did the Pac– man visualizations, she felt she had some control directing her immune system to fight the disease.The nurses also provided my mother with emotional support. We were not a very physically affectionate family and the nurses encouraged us to give my mother hugs when she was not at risk for infections. They also gave her lots of back rubs. One of the nurses gave my mother a relaxation audiotape, which she listened to for hours, others provided her with poetry books. I believe it was partly the nurses’ physical and emotional care that enabled my mother to live as long and to fight the cancer for as long as she did. During the course of my mother’s illness, she received five rounds of chemotherapy over a period of ten months. Unfortunately her efforts to combat the cancer were unsuccessful and she died of complications of the disease and from the cumulative toxic side effects of the chemotherapy.After observing all the ways the nurses cared for my mother, I decided this was what I wanted to do and I decided to go to nursing school instead of medical school. I was able to apply my pre–med prerequisite courses to an accelerated nursing program [End Page E16] and I graduated with my bachelors in nursing after 18 months of nursing school.My nursing program emphasized the importance of viewing the patient as a whole person and not merely viewing them in terms of a particular disease or condition. Nursing school also reinforced how important nurse caring was for patients. I remember one of our exam questions focused on caring. The question was about a nurse walking into a patient’s room and finding the patient... (shrink)