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)

Observations on the morphological and functional similarity between embryonic or trophoblast tissues and tumors are very old. Over a period of time many investigators have created different hypotheses on the origin of cancerogenesis or tumor efficiency in relation to the host immune system. Some of these ideas have been rejected but many of them are still current. A presumption of the inefficiency of anti-tumor immunity in mammals due to the high similarity between trophoblast and embryonic cells (...) to tumor cells is very real. The mechanisms for the escape of tumors from the immune response are very similar to the mechanisms for the escape of a fetoplacental unit from the maternal immune response. The similarity between these two mechanisms is so great that any randomness must be banished. At the same time, an incidence of malignant tumors and the types of more frequent tumors in non-mammalian vertebrates is significantly different to that in mammals. Lastly, the mechanisms of anti-tumor immunity in mammals are substantially different from the mechanisms of anti-tumor immunity in other classes of vertebrates. These facts indicate that the immune system of mammals during anti-tumor immune response is tricked by the similarity between tumor cells and trophoblast or other placental cells. From this aspect, our conclusion is that anti-tumor immunity failure in mammals can be defined as an immunoreproductive phenomenon, which is developed under the evolutionary pressure of autoimmunity and reproductive effectiveness. (shrink)

Cancer cells exploit mechanisms to evade immune detection triggered by aberrant self‐nucleic acids (NA). PARP7, a key player in this immune evasion strategy, has emerged as a potential target for cancer therapy. PARP7 inhibitors reactivate NA sensing, resulting in type I interferon (IFN) signaling, programmed cell death, anti‐tumor immunity, and tumor regression. Cancer cells with elevated IFN‐stimulated gene (ISG) scores, representing a viral mimicry‐primed state, are particularly sensitive to PARP7 inhibition. This review focuses on the endogenous (...) sources of NA in cancer and the potential to exploit elevated aberrant self‐NA in cancer therapy. We describe strategies to increase cytoplamic NA levels, including targeting epigenetic control, DNA damage response, and mitochondrial function. We also discuss targeting RNA processing pathways, such as splicing and RNA editing, to enhance the immunostimulatory potential of existing NA. Combining PARP7 inhibitors with NA elevating strategies may improve cancer immunotherapy, especially for tumors with high ISG scores. (shrink)

The immune surveillance theory postulates that spontaneous tumors are normally rejected by the immune system and appear only when they override host‐immune recognition and rejection mechanisms. The present mini‐review describes a spontaneous tumor system, the reticulum cell sarcomas (RCS) in SJL/J mice, that is dependent on host tumor‐specific immune lymphocytes for growth. This continuous tumor‐specific response results in tumor progression and death of the host. This tumor system contradicts the basic concept of immune surveillance. We (...) propose as an explanation that some highly antigenic tumors, like the RCS, may have evolved in a non‐autonomous fashion but, nevertheless, have lost regulatory controls of cell proliferation. In the RCS system, the tumor expresses Class II MHC I‐E like specificities that are not expressed on the host cells and which selectively stimulate a subpopulation of I‐E specific T cells, the Vβ17a+ clonotype, leading to their expansion and continuous nurturing of the tumor via secreted lymphokines. This neoantigenic stimulation bypasses the tumor regulatory response that might have resulted if the tumor had not expressed neo‐antigens. Furthermore, passive administration of anti‐clonotypic antibody to tumor‐bearing mice results in tumor regression and long‐term survival through removal of the tumor reactive T cells. Thus, in this tumor system, immunosuppressive treatments are the prescription for tumor rejection. (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)

This article reviews recent findings that bear on the mechanism(s) of tumor‐specific Lyt‐1+2− T cell‐mediated tumor eradication in vivo A tumor‐immune Lyt‐1+2− T cell subset has been identified which is distinct from T cells mediating in vitro cytotoxicity (Lyt‐1+2+/1−2+). The Lyt‐1+2− cells have a crucial role in rejecting tumor cells when adoptively transferred into T cell‐deprived B cell mice. This indicates that Lyt‐1+2− T cells do not necessarily require recruitment of the host's cytotoxic T cell precursors (...) for implementation of in vivo immunity. Instead, this T cell subset exerts its anti‐tumor effect in collaboration with macrophages as shown with an in vivo tumor cell culture system utilizing a diffusion chamber. A pathway of Lyt‐1+2− T cell‐macrophage interaction leading to tumor cell killing is discussed in terms of its probable relevance to the eradication of tumor cell masses consisting of tumor cells expressing quantitatively and/or qualitatively different tumor antigens. (shrink)

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)

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)

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)

A pathogenic connection between autoreactive T cells, fungal infection, and carcinogenesis has been demonstrated in studies of human autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy as well as in a mouse model in which kinase-dead Ikkα knock-in mice develop impaired central tolerance, autoreactive T cell–mediated autoimmunity, chronic fungal infection, and esophageal squamous cell carcinoma, which recapitulates APECED. IκB kinase α is one subunit of the IKK complex required for NF-κB activation. IKK/NF-κB is essential for central tolerance establishment by regulating the development of medullary thymic (...) epithelial cells that facilitate the deletion of autoreactive T cells in the thymus. In this review, we extensively discuss the pathogenic roles of inborn errors in the IKK/NF-κB loci in the phenotypically related diseases APECED, immune deficiency syndrome, and severe combined immunodeficiency; differentiate how IKK/NF-κB components, through mTEC, T cells/leukocytes, or epithelial cells, contribute to the pathogenesis of infectious diseases, autoimmunity, and cancer; and highlight the medical significance of IKK/NF-κB in these diseases. IKK/NF-κB regulates the expression of many genes that encode proteins involved in many crucial biological functions, such as immunity, tissue homeostasis, and fungal/bacterial/viral infections. Also, IKKα plays anti-tumor activities in many organs independently of NF-κB pathways. Thus, an inborn error in one of these gene loci can cause severe human diseases through these complicated mechanisms. (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)

Recent discoveries have suggested the concept that intracellular signals are the sum of multiple, site‐specified subsignals, rather than single, homogeneous entities. In the context of cancer, searching for compounds that selectively block subsignals essential for tumor progression, but not those regulating “house‐keeping” functions, could help in producing drugs with reduced side effects compared to compounds that block signaling completely. The Ras‐ERK pathway has become a paradigm of how space can differentially shape signaling. Today, we know that Ras proteins are (...) found in different plasma membrane microdomains and endomembranes. At these localizations, Ras is subject to site‐specific regulatory mechanisms, distinctively engaging effector pathways and switching‐on diverse genetic programs to generate different biological responses. The Ras effector pathway leading to ERKs activation is also under strict, space‐related regulatory processes. These findings may open a gate for aiming at the Ras‐ERK pathway in a spatially restricted fashion, in our quest for new anti‐tumor therapies. (shrink)

Mutations in DNA topoisomerase II are often correlated with drug‐resistance in tumor cell lines. Studies of topoisomerase II‐mediated drug‐resistance in various model systems, as well as the sequencing of such mutations from drug‐resistant tumors, have shed light on the functional domains of topoisomerase II, on how it interacts with inhibitors, and on the different mechanisms by which cells avoid the toxic effects of many clinically important anti‐tumor drugs.

A major problem in the treatment of cancer is the specific targeting of anti‐tumor drugs to these abnormal cells. Ideally, such a drug should act over short distances to minimize damage to healthy cells, and target subcellular compartments that have the highest sensitivity to the drug. Photosensitizers, alpha‐emitting radionuclides and many other medicines could be considered as such drugs if they possessed cellular and subcellular specificity. The author describes a novel approach of using modular recombinant transporters to target (...) photosensitizers and alpha‐emitting radionuclides to the nucleus, where their action is most pronounced, of cancer cells. Photosensitizer‐transporter conjugates have up to 3000 times greater efficacy than free photosensitizers and display cell specificity in contrast to free photosensitizers. Alpha‐emitting radionuclides, conjugated with the modular transporters, acquired similar properties. The different modules of the transporters are interchangeable, meaning that they can be tailored for particular applications. BioEssays 30:278–287, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Cancers have a formidable capacity to develop resistance to a large and diverse array of chemical, biologic, and physical anti‐neoplastic agents. This can be largely traced to the instability of the tumor cell genome, and the resultant ability of tumor cell populations to generate phenotypic variants rapidly. It is therefore argued that anti‐cancer strategies should be directed at eliminating those genetically stable normal diploid cells that are required for the progressive growth of tumors. Micro‐vascular endothelial cells (...) comprising the tumor vasculature represent such a normal cell target. Moreover, specificity for tumor associated vasculature by anti‐cancer agents may be achieved by virtue of the fact that many of the endothelial cells that comprise these blood vessels are in an immature, cycling, and ‘activated’ state, in contrast to the endothelial cells associated with normal tissue and organ blood vessels. (shrink)

Tumor‐infiltrating lymphocyte (TIL) therapy is a promising approach for treating refractory or advanced solid cancers by using autologous TILs harvested from cancer tissues. Despite the heterogeneity of cancer, TIL therapy can potentially produce a positive therapeutic response, including complete remission.After decades of research on lymphocyte functions, culture/expansion methods, therapeutic protocols, and multiple clinical trials, TIL therapy has finally reached a stage where it can be formally approved for clinical use.TIL therapy is expected to hold a unique position among (...) class='Hi'>anti‐cancer therapeutic options as a standard intervention. To successfully introduce TIL therapy into clinical settings, there is a need to expand therapeutic indications and set up the best protocols for cancer tissue sampling and manufacturing, and related clinical trials. Moreover, studies on next‐generation TIL therapy have already begun, and post‐approval real‐world data will promote and support further research. (shrink)

Tumor necrosis is a common histological feature and poor prognostic predictor in various cancers. Despite its significant clinical implications, the mechanism underlying tumor necrosis remains largely unclear due to lack of appropriate pre‐clinical modeling. We propose that tumor necrosis is a synergistic consequence of metabolic stress and inflammation, which lead to oxidative stress‐induced cell death, such as ferroptosis. As a natural consequence of tumor expansion, tumor cells are inevitably stripped of vascular supply, resulting in deprivation (...) of oxygen and nutrients. The resulting metabolic stress has commonly been considered the cause of tumor necrosis. Recent studies found that immune cells, such as neutrophils, when recruited to tumors, can directly trigger ferroptosis in tumor cells, suggesting that immune cells can be involved in amplifying tumor necrosis. This article will discuss potential mechanisms underlying tumor necrosis development and its impact on tumor progression as well as the immune response to tumors. (shrink)

The emergent Coronavirus Disease 2019 caused by the Severe Acute Respiratory Syndrome Coronavirus 2 could produce a maternal immune activation via the inflammatory response during gestation that may impair fetal neurodevelopment and lead to postnatal and adulthood mental illness and behavioral dysfunctions. However, so far, limited evidence exists regarding long-term physiological, immunological, and neurodevelopmental modifications produced by the SARS-CoV-2 in the human maternal-fetal binomial and, particularly, in the offspring. Relevant findings derived from epidemiological and preclinical models show that a MIA (...) is indeed linked to an increased risk of neurodevelopmental disorders in the offspring. We hypothesize that a gestational infection triggered by SARS-CoV-2 increases the risks leading to neurodevelopmental disorders of the newborn, which can affect childhood and the long-term quality of life. In particular, disruption of either the maternal or the fetal cholinergic anti-inflammatory pathway could cause or exacerbate the severity of COVID-19 in the maternal-fetal binomial. From a translational perspective, in this paper, we discuss the possible manifestation of a MIA by SARS-CoV-2 and the subsequent neurodevelopmental disorders considering the role of the fetal-maternal cytokine cross-talk and the CAP. Specifically, we highlight the urgent need of preclinical studies as well as multicenter and international databanks of maternal-fetal psychophysiological data obtained pre-, during, and post-infection by SARS-CoV-2 from pregnant women and their offspring. (shrink)

Niels Kaj Jerne has proposed the “immune network theory” of interactions among anti‐idiotypic antibodies, able to interfere with humoral responses to certain antigens. After the occurrence of the primary generation of antibodies, against an antigenic epitope, idiotypes of these antibodies induce anti‐idiotypic antibodies that modulate the intensity of the first response, and so on. Adverse effects following SARS‐COV‐2 COVID‐19 vaccines are occasionally similar to the symptoms of COVID‐19 infection. Rare events linked to SARS‐CoV‐2 vaccines also resemble some rarely (...) reported COVID‐19 complications. Safety data from product information by European Medicines Agency suggest that spectra do overlap for four main vaccines. The proposition is that vaccine events and COVID‐19 complications are related to anti‐idiotypic antibodies whose spatial shape can lead to interactions with ACE2 molecules, in individuals with a prolonged Spike protein synthesis. The vaccines target cells by their affinity to the vaccine vector, or to engulf lipid nanoparticles. Anti‐idiotypic antibodies shaped similarly to the Spike protein possibly interact with ACE2 molecules and cause diverse signs and symptoms. (shrink)

In his (1977) "Anomalous Monism and Kripke's Cartesian Intuitions," Colin McGinn argues that Donald Davidson's anomalous monism is untouched by Kripke's (1980) argument against the identity theory. The type-identity of the physical with the mental may very well fall at the feet of Kripke's powerful arguments, but a token identification, argues McGinn, is left standing due to the simple fact that token physicalism countenances a kind of imagined separation of token mental states with their corresponding token physical states. If McGinn (...) is correct, a full-blooded physicalism is consistent with Kripke's Cartesian intuitions regarding the non-identity of the mental and the physical. But I think McGinn is mistaken. In particular, McGinn misunderstands the nature of an "epistemic counterpart" of a token pain. So contrary to McGinn, token physicalism does not seem to be able to defend against Kripke after all. (shrink)

Since, it has become clear that individuality is not to be considered as a given, but rather as something which needs to be explained. How has individuality emerged through evolution, and how has it subsequently been maintained? In particular, why is it that multicellular organisms appeared and persisted, despite the obvious interest of each cell of favoring its own replication? Several biologists see the immune system as one of the key components for explaining the maintenance of multicellular organisms’ individuality. Indeed, (...) the immune system exerts a constant surveillance on all the constituents of the organism, including “cheaters” like tumor cells, which favor their own replication at the expense of the whole organism. In most cases, the immune system eliminates those cheaters. This is the “immune surveillance” hypothesis, first suggested by Burnet and Thomas. In this paper, I account for recent findings on immune surveillance in order to determine the precise role of the immune system in the emergence and maintenance of individuality. This investigation gives rise to a critical question for the domain of biological individuality: should immunity be considered as something unique to multicellular organisms? If it is indeed unique, should the multicellular organism be considered as an individual to a higher degree than any other living entity? If it is not unique, what precisely are the equivalents of the immune system in other living individuals? (shrink)

The tumor microenvironment (TME) plays a pivotal role in the behavior and development of solid tumors as well as shaping the immune response against them. As the tumor cells proliferate, the space they occupy and their physical interactions with the surrounding tissue increases. The growing tumor tissue becomes a complex dynamic structure, containing connective tissue, vascular structures, and extracellular matrix (ECM) that facilitates stimulation, oxygenation, and nutrition, necessary for its fast growth. Mechanical cues such as stiffness, solid (...) stress, interstitial fluid pressure (IFP), matrix density, and microarchitecture influence cellular functions and ultimately tumor progression and metastasis. In this fight, our body is equipped with T cells as its spearhead against tumors. However, the altered biochemical and mechanical environment of the tumor niche affects T cell efficacy and leads to their exhaustion. Understanding the mechanobiological properties of the TME and their effects on T cells is key for developing novel adoptive tumor immunotherapies. (shrink)

Host‐pathogen arms race is a universal, central aspect of the evolution of life. Most organisms evolved several distinct yet interacting strategies of anti‐pathogen defense including resistance to parasite invasion, innate and adaptive immunity, and programmed cell death (PCD). The PCD is the means of last resort, a suicidal response to infection that is activated when resistance and immunity fail. An infected cell faces a decision between active defense and altruistic suicide or dormancy induction, depending on whether (...) class='Hi'>immunity is “deemed” capable of preventing parasite reproduction and consequent infection of other cells. In bacteria and archaea, immunity genes typically colocalize with PCD modules, such as toxins‐antitoxins, suggestive of immunity‐PCD coupling, likely mediated by shared proteins that sense damage and “predict” the outcome of infections. In type VI CRISPR‐Cas systems, the same enzyme that inactivates the target RNA might execute cell suicide, in a case of ultimate integration of immunity and PCD. (shrink)

Since, it has become clear that individuality is not to be considered as a given, but rather as something which needs to be explained. How has individuality emerged through evolution, and how has it subsequently been maintained? In particular, why is it that multicellular organisms appeared and persisted, despite the obvious interest of each cell of favoring its own replication? Several biologists see the immune system as one of the key components for explaining the maintenance of multicellular organisms’ individuality. Indeed, (...) the immune system exerts a constant surveillance on all the constituents of the organism, including “cheaters” like tumor cells, which favor their own replication at the expense of the whole organism. In most cases, the immune system eliminates those cheaters. This is the “immune surveillance” hypothesis, first suggested by Burnet and Thomas. In this paper, I account for recent findings on immune surveillance in order to determine the precise role of the immune system in the emergence and maintenance of individuality. This investigation gives rise to a critical question for the domain of biological individuality: should immunity be considered as something unique to multicellular organisms? If it is indeed unique, should the multicellular organism be considered as an individual to a higher degree than any other living entity? If it is not unique, what precisely are the equivalents of the immune system in other living individuals? (shrink)

As the number of infections and mortalities from the SARS‐CoV‐2 pandemic continues to rise, the development of an effective therapy against COVID‐19 becomes ever more urgent. A few reports showing a positive correlation between BCG vaccination and reduced COVID‐19 mortality have ushered in some hope. BCG has been suggested to confer a broad level of nonspecific protection against several pathogens, mainly via eliciting “trained immunity” in innate immune cells. Secondly, BCG has also been proven to provide benefits in autoimmune (...) diseases by inducing tolerogenicity. Being an acute inflammatory disease, COVID‐19 requires a therapy that induces early priming of anti‐viral immune responses and regulates aberrant hyperactivity of innate‐immune cells. Here, we hypothesize that BCG can offer reliable spatiotemporal protection from COVID‐19 by triggering trained immunity and tolerogenesis, through multiple cellular pathways. We propose further research on BCG‐mediated immunoprotection, especially in vulnerable individuals, as a strategy to halt the progress of the SARS‐CoV‐2 pandemic. Also see the video abstract here https://youtu.be/P2D2RXfq6Vg. (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)

Clinical success with human hematopoietic stem cell (HSC) transplantation establishes a paradigm for regenerative therapies with other types of stem cells. However, it remains generally challenging to therapeutically treat tissues after engineering of stem cells in vitro. Recent studies suggest that stem and progenitor cells sense physical features of their niches. Here, we review biophysical contributions to lineage decisions, maturation, and trafficking of blood and immune cells. Polarized cellular contractility and nuclear rheology are separately shown to be functional markers of (...) a hematopoietic hierarchy that predict the ability of a lineage to traffic in and out of the bone marrow niche. These biophysical determinants are regulated by a set of structural molecules, including cytoplasmic myosin‐II and nuclear lamins, which themselves are modulated by a diverse range of transcriptional and post‐translational mechanisms. Small molecules that target these mechanobiological circuits, along with novel bioengineering methods, could prove broadly useful in programming blood and immune cells for therapies ranging from blood transfusions to immune attack of tumors. (shrink)

Judgments based on episodic memory are often thought to be immune to errors of misidentification (IEM). Yet there is a certain category of episodic memories, viz. observer memories, that seems to threaten IEM. In the resulting debate, some say that observer memories are a threat to the IEM enjoyed by episodic memory (Michaelian, 2021); others say that they pose no such threat (Fernández, 2021; Lin, 2020). In this paper, we argue for a middle way. First, we frame the debate, claiming (...) that the existing literature lacks a satisfying definition both of observer memories and of the precise issue of errors of identification in such memories. Then, we contribute to the debate by challenging an anti-separatist view about the relation between phenomenal and intentional features of observer memories that looms behind this debate. On this view, if the rememberer's self is a phenomenal feature of the memory, by implication it is also built into the intentional content. We reject this view and offer a moderate separatist account. Distinguishing between empirically-grounded species of observer memories, we say that the phenomenal self sometimes is, and sometimes is not built into the intentional content of the memory, and this results in different implications for IEM. (shrink)

The thesis addresses the issues of error through misidentification and immunity to error through misidentification in relation to the problem of the first person. First, it provides an explanation of error through misidentification. Secondly, it shows that there are two possible ways of understanding immunity to error through misidentification. It is then argued that the first understanding of immunity to error through misidentification leads to what is labelled "the trilemma about the self". That is to say, either (...) we provide an explanation of immunity to error through misidentification, but we subscribe to two contentious metaphysical views about the self-the Cartesian and the Idealist; or else we hold the view that the self is identical with a human being, but we have no explanation of immunity to error through misidentification. It is then shown that in order to solve the trilemma, a different understanding of immunity to error through misidentification must be offered. After discussing various possible understandings of immunity to error through misidentification, a sound account of it is finally provided. Moreover, it is shown how non-inferential, introspection-based mental self-ascriptions can comply with it, in such a way that they turn out to be logically immune to error through misidentification. Finally, by drawing on Evans' and Peacocke's accounts of the possession conditions of the first person concept-in which IEM I-judgements play a central role-, it is shown that it is a concept of a human being who thinks of herself as such. Hence, our first person concept is firmly anti-Cartesian and anti-Idealist. As a consequence, it is maintained that not only is there no need to hold the Cartesian and the Idealist metaphysics of the self in order to explain why some I-judgements can be immune to error through misidentification, but it is also argued that one can no longer be either Cartesian or Idealist. For that would expose one to conceptual incoherence. (shrink)

Contemporary discourses of management are full of encouragements to ‘expect the unexpected’ and to celebrate ‘the future of the future’. Many new public managerial technologies of change – such as steering labs, future games, and managerial performance arts – promise the co-creative ‘potentialization’ of employees, citizens and organizations. This paper approaches such potentialization technologies as immune mechanisms which serve to protect the social system from itself. From a perspective inspired by autopoietic systems theory, potentialization technologies provide autoimmunity by problematizing institutional (...) structures and providing ‘anti-structural’ space-times to facilitate transformation. There is a price to pay for this immune function, however, since these immune mechanisms cannot discriminate between productive and unproductive structures. By dissolving the certainty of the expectations that underlie the connectivity of diverse organizational operations, they risk harming the welfare systems that host them. (shrink)

Our moral convictions cannot, on the face of it, count in evidence against scientific claims with which they happen to conflict. Moral anti-realists of whatever stripe can explain this easily: science is immune to moral refutation because moral discourse is defective as a trustworthy source of true and objective judgments. Moral realists, they can add, are unable to explain this immunity. After describing how anti-realists might implement this reasoning, the paper argues that the only plausible realist comeback (...) turns on the practical nature of moral reasoning. This comeback, however, places significant constraints on the structure of evidence for moral judgments. These constraints cannot be met by coherentist defenders of reflective-equilibrium methodology or by anyone sympathetic to bottom-up, case-driven foundationalism, including those who claim we have perceptual or perception-like access to moral truths. Unfortunately for realists in these categories, alternative realism-friendly accounts of science’s apparent moral immunity are unpromising. These neither explain nor explain away our unwillingness to infer an is from an ought, as Hume might have put it. Science’s apparent immunity to moral refutation therefore poses a serious problem for any realist unhappy with top-down, theory-driven conceptions of the structure of moral evidence. (shrink)

Mycobacterium tuberculosis is the causative agent of pulmonary tuberculosis which has infected one third of the mankind and causes 2–3 million deaths worldwide each year. The persistence of the infection ensues from the ability of M. tuberculosis to subvert host immune responses in favor of survival and growth of mycobacteria in macrophages. The mechanisms by which M. tuberculosis manipulates the host immune system have only recently come to light. These activities are attributed to lipoarabinomannans (LAM) and their precursors lipomannans (LM), (...) two predominant glycolipids of M. tuberculosis cell wall. LM are able to skew anti‐mycobacterial immune responses into un‐protective ones, while LAM evoke immunosupression upon binding to macrophage and dendritic cell receptors specialized in binding to “self” host components. A newly emerging idea implicates plasma membrane rafts in LM and LAM signaling. Depending on acylation patterns, the glycolipids may either directly incorporate into the raft membrane via mannosylphosphatidylinositol anchors or interact with raft‐associated proteins to affect the assembly of receptor signaling complexes. BioEssays 30:943–954, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Abstract: Some first person statements, such as ‘I am in pain’, are thought to be immune to error through misidentification (IEM): I cannot be wrong that I am in pain because—while I know that someone is in pain—I have mistaken that person for myself. While IEM is typically associated with the self-ascription of psychological properties, some philosophers attempt to draw anti-Cartesian conclusions from the claim that certain physical self-ascriptions are also IEM. In this paper, I will examine whether some (...) physical self-ascriptions are in fact IEM, and—if they are—what role that fact is supposed to play in arguments for the anti-Cartesian claim that self-consciousness is consciousness of oneself as a material object. I will argue that if we accept the assumptions required to show that physical self-ascriptions are IEM, then IEM cannot play the role it needs to play in these anti-Cartesian arguments. (shrink)

The principle of non-combatant immunity protects non-combatants against intentional attacks in war. It is the most widely endorsed and deeply held moral constraint on the conduct of war. And yet it is difficult to justify. Recent developments in just war theory have undermined the canonical argument in its favour – Michael Walzer's, in Just and Unjust Wars. Some now deny that non-combatant immunity has principled foundations, arguing instead that it is entirely explained by a different principle: that of (...) necessity. In war, as in ordinary life, harms to others can be justified only if they are necessary. Attacking non-combatants, the argument goes, is never necessary, so never justified. Although often repeated, this argument has never been explored in depth. In this article, I evaluate the necessity-based argument for non-combatant immunity, drawing together theoretical analysis and empirical research on anti-civilian tactics in interstate warfare, counterinsurgency, and terrorism. (shrink)

Advances in the understanding of Ras oncoprotein function suggest novel points for anti‐tumor intervention. First, upstream‐acting guanine nucleotide exchange factors and SH2/SH3 domain‐containing adaptor proteins that link Ras with growth factor receptor tyrosine kinases have recently been characterized. Second, work on downstream‐acting Ras effector functions including the Ras GTPase‐activating protein (p120GAP) and the Raf kinase has revealed direct biochemical interactions that are functionally required for oncogenic Ras signalling. We summarize progress in these areas and discuss the potential for (...) novel applications to anti‐cancer chemotherapy. (shrink)

There have been many criticisms of “nativism” in “Cartesian linguistics,” attacking positions that neither Chomsky nor any well-known generative grammarian has ever thought to defend. Shanker's polemic is no exception. It involves two spurious claims: Cartesian linguistics vitiates understanding language structure and use; nativism permits linguistic anthropology only to “validate” and “apply” generative principles. Briefly, Chomsky's outlines a language system, LS, of the human brain. LS reflexively discriminates and categorizes parts of the flux of human experience as “language,” and develops (...) complex abilities to infer and interpret this highly structured, and structurally peculiar, type of human production. There is nothing intrinsically different about LS – concerning innateness, evolution or universality – than the visual system, immune system, respiratory system, or any other complex biological system. Much polemic is driven by distaste for “innateness,” “genes,” and “evolution.” Historical and ideological reasons explain this aversion - some well-justified. None bear on universal grammar. Biologists believe all life consists of universal, highly structured codings of biological information. Still, biologists go on to explore diversity at many different levels. Similarly, linguistic anthropology can use generative grammar to better comprehend the diversity of languages and the cultural worlds they describe. This includes the very issues about proper names that Shanker highlights. (shrink)

The primary function of smooth muscle cells is to contract and alter the stiffness or diameter of hollow organs such as blood vessels, the airways and the gastrointestinal and urogenital tracts. In addition to purely structural functions, smooth muscle cells may play important metabolic roles, particularly in various inflammatory responses. In cell culture, these cells have been shown to be metabolically dynamic, synthesizing and secreting extracellular matrix proteins, glycosaminoglycans and a wide variety of cell–cell signaling proteins, such as interleukins, chemokines (...) and peptide growth factors. Secreted cell signaling proteins participate in the inflammatory response of smooth muscle‐containing organs, and some can also stimulate smooth muscle migration, proliferation and contraction. The cellular signaling pathways controlling synthesis of these signaling proteins are similar to those used by cells mediating innate immunity and may contribute to pathogenesis of diverse diseases including atherosclerosis, asthma, inflammatory bowel diseases and preterm labor. Appreciating the role of smooth muscle cells in these diseases may lead to better understanding of the beneficial effects of anti‐inflammatory drugs as well as identification of new targets for anti‐inflammatory therapy. BioEssays 26:646–655, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Some members of the Vienna Circle argued for a coherence theory of truth. Their coherentism is immune to standard objections. Most versions of coherentism are unable to show why a sentence cannot be true even though it fails to cohere with a system of beliefs. That is, it seems that truth may transcend what we can be warranted in believing. If so, truth cannot consist in coherence with a system of beliefs. The Vienna Circle's coherentists held, first, that sentences are (...) warranted by coherence with a system of beliefs. Next they drew upon their verification theory of meaning, a consequence of which is that truth cannot transcend what can be warranted. The coherence theory of knowledge and verificationism together entail that truth cannot transcend what can be warranted by coherence with a system of beliefs. The Vienna Circle's argument for coherentism is strong and anticipates contemporary anti-realism. (shrink)

This paper examines the politics behind algorithmic ordering in social media, focusing on the advertising logic behind them. This is explored through a practice I call rhythmedia – the way media companies render people, objects and their relations as rhythms and order them for economic purposes. As a case study I examine the way the Facebook Immune System algorithm orchestrates people’s mediated experience towards a desired rhythm while filtering out problematic rhythms. This anti-spam algorithm shows that it is important (...) for Facebook to understand people as rhythms and assemble a dynamic database from their mediated experiences, to convince advertisers that they know when and where people do things. People’s rhythms become a product that advertisers pay and bid for through Ad Auction to intervene in specific moments and shape people’s experience. Thus, the company can shape, manage, and filter specific rhythms to order sociality that brings more value. (shrink)

The mechanism(s) by which lentiviruses and related non‐oncogenic retroviruses (e.g. HTLV‐III, the etiologic agent of AIDS) escape immune surveillance, and thereby create long term progressive disease conditions, has been unknown until recently. Studies with two lentiviruses have begun to illuminate the mechanisms. In one, antigenic drift in the virus appears to be the primary mechanism of escape from immune surveillance; in the second, selective masking of the viral envelope glycoprotein epitope, which normally elicits neutralizing anti‐body, appears to provide the (...) means of escape. (shrink)

The expression of products encoded by the major histocompatibility complex (MHC) on tumor cells has recently been studied extensively. It has been found that many malignant tumor cells have their MHC antigens ‘switched‐off’ but that these antigens are re‐expressed following DNA‐mediated gene transfer, with increased tumor immunogenicity as a result and the consequence that these ‘transformed’ tumor cells are rejected in vivo.: This review will discuss approaches that have been taken to induce strong tumor‐specific (...) class='Hi'>immunity by the manipulation of MHC expression on tumor cells. (shrink)

Tumor necrosis factor (TNF) receptor associated factor 6 (TRAF6) is a crucial signaling molecule regulating a diverse array of physiological processes, including adaptive immunity, innate immunity, bone metabolism and the development of several tissues including lymph nodes, mammary glands, skin and the central nervous system. It is a member of a group of six closely related TRAF proteins, which serve as adapter molecules, coupling the TNF receptor (TNFR) superfamily to intracellular signaling events. Among the TRAF proteins, TRAF6 (...) is unique in that, in addition to mediating TNFR family signaling, it is also essential for signaling downstream of an unrelated family of receptors, the interleukin‐1 (IL‐1) receptor/Toll‐like receptor (IL‐1R/TLR) superfamily. Gene targeting experiments have identified several indispensable physiological functions of TRAF6, and structural and biochemical studies have revealed the potential mechanisms of its action. By virtue of its many signaling roles, TRAF6 represents an important target in the regulation of many disease processes, including immunity, inflammation and osteoporosis. BioEssays 25:1096–1105, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

I distinguish Local Constructivism (humans play a constitutive role in constructing some of the objects we have epistemic access to) from Global Constructivism (humans play a constitutive role in constructing all of the objects we have epistemic access to). I explicate and clarify Local Constructivism and show how the metaphysical concerns which motivate endorsing Local Constructivism about some objects (e.g. social objects, modal objects) differ from the epistemic and semantic concerns which motive endorsing Global Constructivism. I, then, examine the criticisms (...) Realists typically present against Constructivism. I argue that, although these criticisms undermine Global Constructivism, Local Constructivism is immune to them. If one has anti-Realist inclinations, but wishes to avoid the morass anti-Realism usually falls into (aka: anti-Realist Boogeyman), one should endorse Local, rather than Global, Constructivism. (shrink)

In Part I, this paper argues that Duncan Pritchard’s version of safety is incompatible with closure. In Part II I argue for an alternative theory that fares much better. Part I begins by reviewing past arguments concerning safety’s problems with closure. After discussing both their inadequacies and Pritchard’s response to them, I offer a modified criticism immune to previous shortcomings. I conclude Part I by explaining how Pritchard’s own arguments make my critique possible. Part II argues that most modal theories (...) of knowledge will run into problems similar to those found in Pritchard’s Anti-Luck Virtue Epistemology. I hence offer my own theory grounded in risk assessment and explain why and how it does much better. (shrink)

Thrombospondin (TSP‐1) is a large glycoprotein secreted by platelets and synthesized by many cell types, including endothelial and tumor cells. Although controversy exists about the biological function of TSP‐1, the following observations suggest that TSP‐1 may potentiate tumor progression. (1) Tumor metastases in mice are promoted by TSP‐1 and inhibited by anti‐TSP‐1 antibodies. (2) TSP‐1 promotes tumor cell adhesion, migration and invasion. (3) TSP‐1 promotes angiogenesis in the rat aorta model. (4) TSP‐1 up‐regulates the plasminogen (...) activator system through a mechanism involving the activation of TGF‐β1. (5) Human tumors express increased levels of the CSVTCG‐specific TSP‐1 receptor. (6) Tumor stroma is enriched in TSP‐1. (7) Cancer patients have high blood levels of TSP‐1. (8) Poor patient survival correlates with a higher expression of the CSVTCG‐specific TSP‐1 receptor on tumor cells. In this paper we discuss the evidence that TSP‐1 promotes tumor progression and present a hypothetical scheme for its mechanism of action. (shrink)

In Language, Logic, and Experience, Michael Luntley successfully employs a Kantian-style transcendental argument to refute Michael Dummett’s anti-realist view that we are incapable of grasping “recognition-transcendent” truth-conditions. But he also contends that his own purified version of antirealism is immune to thi s sort of attack. This version is purified because it is concerned solely with the question of whether a given statement possesses a determinate truth value, and thus with whether the reality it is about exists determinately. I (...) show that Kant’s original version of the argument (in the “Transcendental Analytic”) does in fact amount to a refutation of Luntleyan anti-realism. In particular, it demonstrates that the determinate existence of all past and present naturalistic states and events is a necessary condition of thought. Since Luntleyan anti-realism entails that many such states and events are indeterminate, it must be rejected. (shrink)

In Anti-Individualism and Knowledge Jessica Brown criticises views of content that combine Fregean Sense and anti-individualism. Brown assumes that all Fregean theories are motivated by a picture of the rational thinker as someone who will always have transparent access to the simple inferential consequences of his thoughts. This picture, Brown argues, is incompatible with anti-individualism about content. While traditional Fregean theories have indeed had such motivation, Brown’s mistake is in attributing this motivation to the modern Fregean (...) class='Hi'>anti-individualist. My goal in this paper is to bring to light a different, and seldom discussed, motivation for Fregean views of content which is immune to Browns objections. (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)