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)

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)

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)

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 (...) 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)

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)

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)

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)

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)

Gliomas are diffuse and invasive brain tumors with the nefarious ability to evade even seemingly draconian treatment measures. Here we introduce a simple mathematical model for drug delivery of chemotherapeutic agents to treat such a tumor. The model predicts that heterogeneity in drug delivery related to variability in vascular density throughout the brain results in an apparent tumor reduction based on imaging studies despite continual spread beyond the resolution of the imaging modality. We discuss a clinical example (...) for which the model-predicted scenario is relevant. The analysis and results suggest an explanation for the clinical problem of the long-standing confounding observation of shrinkage of the lesion in certain areas of the brain with continued growth in other areas. (shrink)

The corruption of public officials and institutions is one of the most obvious problems that affects developed and developing countries alike. Because this view is largely shared, most current studies of this phenomenon—‘political corruption’—have been dedicated either to measuring or counteracting the negative political, social, and economic effects that this form of corruption may have in society. Albeit significant and urgent, these studies have distracted the attention of commentators from a somewhat more basic analysis of the nature and wrongness of (...) this phenomenon. This lacuna has resulted in the formulation of a multiplicity of actions that address a very heterogeneous set of issues, including such diverse phenomena as bribery, embezzlement, institutional malfunctioning, the inadequacy of political leaders, and clientelism. This situation is unsatisfactory because it muddles important distinctions between different pathologies that may affect the public order. But it matters also for the design of anti-corruption strategies that risk to either misfire or be too vague by lacking a clear target and an account of the exact kind of wrong these strategies are meant to prevent and/or correct. In our research on this topic, we have addressed this issue by offering a normative analysis of political corruption as surreptitious public action. Our account explains the distinguishing traits of political corruption and makes sense of its inherent wrongness as a contradiction of the logic of publicity that undergirds political interactions in a rights-based system. In this chapter, we draw on this research and expand it with a view to enhancing the identification of relevant instances of political corruption and the design of policies to counteract them. (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 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)

Information transmission from tumor cells to non‐tumor cells in the surrounding microenvironment via microvesicles is a more recently studied form of intercellular signaling that can have a marked impact on the tumor microenvironment. Tumor‐derived microvesicles (TMVs) are packed with information including signaling proteins and nucleic acids, and can be taken up by target cells, enabling paracrine signaling. While previous research has focused on how vesicles released from pathologic cells differ from normal cells, the heterogeneity that (...) exists within the TMV population itself is not fully characterized, and only beginning to be appreciated. In this review, we summarize current understanding of the biogenesis and roles of shed TMVs in the tumor microenvironment, and speculate on the consequences for tumor cell signaling in light of the hypothesis that there exists variance within the TMV population. The analysis of differential signaling upon cell‐TMV interactions provides insights into potential mechanisms of intercellular communication. (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)

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 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)

Recent studies of prostate cancer and other tumor types have revealed significant support, as well as unexpected complexities, for the application of concepts from normal stem cell biology to cancer. In particular, the cell of origin and cancer stem cell models have been proposed to explain the heterogeneity of tumors during the initiation, propagation, and evolution of cancer. Thus, a basis of intertumor heterogeneity has emerged from studies investigating whether stem cells and/or non‐stem cells can serve as (...) cells of origin for cancer and give rise to tumor subtypes that vary in disease outcome. Furthermore, analyses of putative cancer stem cells have revealed the genetically diverse nature of cancers and expanded our understanding of intratumor heterogeneity and clonal evolution. Overall, the principles that have emerged from these stem cell studies highlight the challenges to be surmounted to develop effective treatment strategies for cancer. (shrink)

20 years since the negotiation of the Palermo Protocol on Trafficking in 2000, the anti-trafficking field has gone from an early, almost exclusive preoccupation with sex work to addressing extreme exploitation in a range of labour sectors. While this might suggest a reduced focus on the nature of the work performed and a greater focus on the conditions under which it is performed, in reality, anti-trafficking discourse remains in the grip of polarised positions on sex work even as (...) the carceral effects of anti-trafficking law become evident and the Swedish model of criminalising the purchase of sexual services spreads. In this article, I demonstrate how despite the recent discursive shifts to ‘modern slavery’ and ‘forced labour’, the anti-trafficking transnational legal order itself reinforces, rather than diffuses cultures of sex work exceptionalism. The growing international sex workers’ movement has offered resistance, yet a closer look at the movement and the widespread support that it has garnered for decriminalisation from international organisations, while valuable, helps reveal the greatest cost yet of anti-trafficking discourse, namely, the inability of the sex workers’ movement to produce a sophisticated theory of regulation to reduce levels of exploitation within sex work, one which is commensurate with the informality and heterogeneity of sex markets the world over. Finally, to the extent that neoabolitionist projects derive legitimacy from interventions abroad, especially in the global South, I chronicle the edifice on which it rests in one such context, namely India, to demonstrate how countries in the global South are not merely conduits for the global North’s preoccupation with moral gentrification through neo-abolitionism, but rather, that the circuits of global governmentality while influential, are highly contingent, thus producing opportunities for creative forms of mobilisation by sex workers. (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)

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)

We propose a Condorcet-consistent voting method that we call Split Cycle. Split Cycle belongs to the small family of known voting methods satisfying the anti-vote-splitting criterion of independence of clones. In this family, only Split Cycle satisfies a new criterion we call immunity to spoilers, which concerns adding candidates to elections, as well as the known criteria of positive involvement and negative involvement, which concern adding voters to elections. Thus, in contrast to other clone-independent methods, Split Cycle mitigates (...) both “spoiler effects” and “strong no show paradoxes.”. (shrink)

Today in Europe we are witnessing a populist turn, we could even speak of a “populist moment” that signals the crisis of neoliberal democracy. According to Chantal Mouffe, “the populist moment” is the expression of a set of heterogeneous demands, which cannot be formulated in traditional right/left frontier. The battles of our time will be between right-wing and left-wing populism. Although the current state of liberal societies appears to favor the development of a Right project, Mouffe proves that just a (...) left-wing one can uphold any kind of radicalisation of democracy. The aim of this paper is to examine the reasons for the increasing success of populist parties in European countries and to consider whether the way the present crisis is manifesting is conducive to the growth of a populist narrative, especially in its right-wing variant. (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)

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)

There is currently a great debate about whether the holobiont, i.e. a multicellular host and its residential microorganisms, constitutes a biological individual. We propose that resident microorganisms have a general and important role in the individuality of the host organism, not the holobiont. Drawing upon the Equilibrium Model of Immunity, we argue that microorganisms are scaffolds of immune capacities and processes that determine the constituency and persistence of the host organism. A scaffolding perspective accommodates the contingency and heterogeneity (...) of resident microorganisms while accounting for their necessity and unifying contributions to host individuality. In our symbiotic view of life, holobionts may not be organisms or units of selection, but macroorganisms cannot persist nor function as individuals without their scaffolding microorganisms. (shrink)

This article discusses the debate about vaccination as a case of public scientific technological controversy. In the vaccination controversy there is a scientific question, the effectiveness of vaccines in the elimination of diseases; a question of risk assessment, possible adverse effects and the possibility that immunization causes idiopathic diseases; an ethical question, the balance of rights between the two groups and the limits of the freedom of choice of treatment; and a political issue, who must take decisions about immunization and (...) whether immunization should be mandatory. The results of the analysis of the controversy suggest that the attitudes of the anti-vaccination groups towards vaccination are largely explained by their worldview which comes majorly from New Age beliefs. This worldview causes differences in the interpretation of evidence, law, risk and science. (shrink)

This article discusses the debate about vaccination as a case of public scientific technological controversy. In the vaccination controversy there is a scientific question, the effectiveness of vaccines in the elimination of diseases; a question of risk assessment, possible adverse effects and the possibility that immunization causes idiopathic diseases; an ethical question, the balance of rights between the two groups and the limits of the freedom of choice of treatment; and a political issue, who must take decisions about immunization and (...) whether immunization should be mandatory. The results of the analysis of the controversy suggest that the attitudes of the anti-vaccination groups towards vaccination are largely explained by their worldview which comes majorly from New Age beliefs. This worldview causes differences in the interpretation of evidence, law, risk and science. (shrink)

The article views the development of the Tartu–Moscow semiotic school from the analysis of texts to the study of spatial entities (semiosphere being most well known of them). It comes to light that ‘culture’ and ‘space’ have been such notions in Tartu–Moscow School to which, for instance, the ‘semiosphere’ does not add much. There are studied possibilities to join Uexküll’s and Lotman’s basic concepts (as certain grounds of Estonian semiotics) with Tartu–Moscow School’s treatment of culture and space through the notion (...) of ‘semiotic subject’. Such an approach allows to see transdisciplinarity, which has come to issue only during the last decade, already in the first conceptions of Tartu–Moscow School where transdisciplinarity revealed itself in the symbiotic use of ‘culture’ and ‘space’. (shrink)

It seems that eudaimonistic reconstructions of John Stuart Mill's conception of happiness have fallen prey to what they thought Mill should have done with regard to the role of pleasure in his notion of happiness. Insisting that utility and eudaimonia make conflicting claims, something which mirrors Mill's ‘conflicting loyalties’, they downgrade pleasure to just one of the ingredients of happiness. However, a closer look at Mill's intellectual development suggests otherwise. By focusing on Mill's radical background, this paper argues that pleasure (...) retains a central role in his conception of happiness – even from a eudaimonistic point of view. (shrink)

Summary John Stuart Mill's classic tale of disillusionment from a ‘narrow creed’, an overt as much as a covert theme of his Autobiography (London, 1873), has for many years served as a guide to the search for the causes and sources of his ‘enlargement-of-the-utilitarian-creed’ project. As a result, in analyses of Mill's mature views, Samuel Taylor Coleridge—and friends—commonly take centre stage in terms of influence, whereas John's father—James Mill—is reduced either to a supernumerary or a villain in the last act (...) of John's intellectual development. However, students of Mill's works should not take at face value the story presented in Autobiography. Mill's own emphasis on the role of his ‘new influences’ has led scholars to disregard the role of his ‘old influences’ in his attempt to create a broader theory of living—one which takes into account both the intellectual and the emotional capacities of individuals. A close look at key aspects of John Stuart Mill's ‘enlargement project’ suggests that James Mill may have played a more positive role than is usually acknowledged. A way into the intellectual affinity of the two Mills is the person they both kept returning to for guidance and inspiration throughout their lives: Plato. (shrink)

In this essay, I propose that DNA‐binding anti‐cancer drugs work more via chromatin disruption than DNA damage. Success of long‐awaited drugs targeting cancer‐specific drivers is limited by the heterogeneity of tumors. Therefore, chemotherapy acting via universal targets (e.g., DNA) is still the mainstream treatment for cancer. Nevertheless, the problem with targeting DNA is insufficient efficacy due to high toxicity. I propose that this problem stems from the presumption that DNA damage is critical for the anti‐cancer activity of (...) these drugs. DNA in cells exists as chromatin, and many DNA‐targeting drugs alter chromatin structure by destabilizing nucleosomes and inducing histone eviction from chromatin. This effect has been largely ignored because DNA damage is seen as the major reason for anti‐cancer activity. I discuss how DNA‐binding molecules destabilize chromatin, why this effect is more toxic to tumoral than normal cells, and why cells die as a result of chromatin destabilization. (shrink)

John Stuart Mill considered his A System of Logic , first published in 1843, the methodological foundation and intellectual groundwork of his later works in ethical, social, and political theory. Yet no book has attempted in the past to engage with the most important aspects of Mill's Logic . This volume brings together leading scholars to elucidate the key themes of this influential work, looking at such topics as his philosophy of language and mathematics, his view on logic, induction and (...) deduction, free will, argumentation, ethology and psychology, as well as his account of normativity, kinds of pleasure, philosophical and political method and the "Art of Life.". (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)

Contemporary sociosemiotics is a way to transcend borderlines between trends inside semiotics, and also other disciplines. Whereas semiotics has been considered as an interdisciplinary field of research par excellence, sociosemiotics can point directions at transdisciplinary research. The present article will try to conjoin the structural and the processual views on culture and society, binding them together with the notion of signification. The signification of space will illustrate the dynamic between both cultures and metacultures, and cultural mainstreams and subcultures. This paper (...) pays attention to the practice of sociocultural semiotisation of space and territorialisation by diverse examples and different sociocultural levels that imply semiotic cooperation between several members of groups that can be characterised as socii. We analyse territorialisation by graffiti, by furnishing spatial environment through artistic manners, by shaping the semiotic essence of cities through naming, renaming and translating street names, by pinning and structuring territories with monuments, by landmarking and mapping cultural space through individualisation of cities. We will see how principles of semiotisation of space are valid on different levels and how these principles form a transdisciplinary object of study as ‘semiotisation of space’, and how space can be regarded as a genuinely transdisciplinary research object. Individual, culture, and society are connected in such an object both as constituents and as a background of study. (shrink)

The article analyses the position of sociosemiotics in the paradigm of contemporary semiotics. Principles of studying sociocultural phenomena are discussed so as they have been set for analysing the inner mechanisms of sign systems in the semiology of F. de Saussure on the one hand, and for studying sign systems and semiotic units as related to referential reality in the semiotics of C. S. Peirce on the other hand. Three main issues are touched upon to define the scope of sociosemiotics: (...) the general methodology of sociosemiotics. its particular methods, and possible objects of analysis. The relevance of the features of objects in different humanitarian disciplines (cultural unit, historical fact, social fact, institutional fact, social process, etc.) is surveyed to define the object of study in sociosemiotics. Also, the article comments on the description of social organisations via cultural processes and on relations between an individual and society as controllable by social action models. (shrink)

Contemporary sociosemiotics is a way to transcend borderlines between trends inside semiotics, and also other disciplines. Whereas semiotics has been considered as an interdisciplinary field of research par excellence, sociosemiotics can point directions at transdisciplinary research. The present article will try toconjoin the structural and the processual views on culture and society, binding them together with the notion of signification. The signification of space willillustrate the dynamic between both cultures and metacultures, and cultural mainstreams and subcultures. This paper pays attention (...) to the practice of sociocultural semiotisation of space and territorialisation by diverse examples and different sociocultural levels that imply semiotic cooperation between several members of groups that can be characterised as socii. We analyse territorialisation by graffiti, by furnishing spatial environment through artistic manners, by shaping the semiotic essence of cities through naming, renaming and translating street names, by pinning and structuring territories with monuments, by landmarking and mapping cultural space through individualisation of cities. We will see how principles of semiotisation of space are valid on different levels (individual and social, formal and informal, democratic and hegemonic, cultural and subcultural) and how these principles form a transdisciplinary object of study as ‘semiotisation of space’, and how space can be regarded as a genuinely transdisciplinary research object. Individual, culture, and society are connected in such an object both as constituents and as a background of study. (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)

James Mill'sHistory of British India(1817) made a rather strange claim: first-hand experience of India was not vital in writing a history – potentially, it led to false ideas about its subject-matter: eyewitnesses are susceptible to bias. The historian was thus to perform his task as a judge: sifting through various testimonies to obtain a ‘more perfect’ conception of the whole than those who witnessed its various parts. Although strange, Mill's claim does not bewilder his readers: after all, Mill was a (...) ‘militant’ exponent of theorizing utilitarianism. I argue that such a reading of Mill's method is injudiciously restrictive. Not only did Mill draw on well-known methodological concerns in contemporary historiographical practice, not necessarily linked with Jeremy Bentham or the Scottish theoretical historiography, but he also seemed to adopt the vocabulary of forensic rhetoric, making his claim that his was a ‘judging’ history more literal than it has been supposed. (shrink)

The rise and fall of the historian of British India -- A classical education -- History, philosophy, and history -- Induction and deduction -- Rational persuasion -- Good government.