Major problems in cancer chemotherapy are toxicity, resistance, and cancer heterogeneity. A new theranostic paradigm has been proposed by the authors. Many million small molecules (SM) are bound to the proteins extracted from a patient's cancer. SM that also bind proteins extracted from normal human tissues are subtracted from the cancer protein bound SM leaving a large array of SM targeting many sites on each of the cancer biomarkers. Targeting many more than the conventional (...) 1 – 4 cancer biomarkers will reduce development of tumor resistance. After several cycles of selection and counter selection, DNA codes appended to the SM will be PCR amplified to provide templates for restricted libraries of the SM to improve selectivity and sensitivity. The large array of selected and counter selected SM assures that many of the compounds in the array will penetrate the cell membrane and bind to intracellular targets, low tumor resistance, low background for imaging, low therapeutic toxicity, and targeting of the diverse biomarkers present in the heterogeneous mixture of cells in primary and metastatic cancer. Theranostic use of radiolabeled SM binding many sites on many, not necessarily critical, biomarkers provides high cancer cell killing. Experiments to provide proof of principle of this novel concept suggested by the authors. -/- . (shrink)

Histone deacetylase inhibitors (HDACi) are in clinical trials against a variety of cancers. Despite early successes, results against the more common solid tumors have been mixed. How is it that so many cancers, and most normal cells, tolerate the disruption caused by HDACi‐induced protein hyperacetylation? And why are a few cancers so sensitive? Here we discuss recent results showing that human cells mount a coordinated transcriptional response to HDACi that mitigates their toxic effects. We present a hypothetical signaling system that (...) could trigger and mediate this response. To account for the existence of such a response, we note that HDACi of various chemical types are made by a variety of organisms to kill or suppress competitors. We suggest that the resistance response in human cells is a necessary evolutionary consequence of exposure to environmental HDACi. We speculate that cancers sensitive to HDACi are those in which the resistance response has been compromised by mutation. Identifying such mutations will allow targeting of HDACi therapy to potentially susceptible cancers. (shrink)

Chemotherapy is an important therapeutic approach for cancer treatment. However, drug resistance is an obstacle that often impairs the successful use of chemotherapies. Therefore, overcoming drug resistance would lead to better therapeutic outcomes for cancer patients. Recently, studies by our own and other groups have demonstrated that there is an intimate correlation between the loss of the F‐box and WD repeat domain‐containing 7 (FBW7) tumor suppressor and the incurring drug resistance. While loss of FBW7 sensitizes (...) cancer cells to certain drugs, FBW7‐/‐ cells are more resistant to other types of chemotherapies. FBW7 exerts its tumor suppressor function by promoting the degradation of various oncoproteins that regulate many cellular processes, including cell cycle progression, cellular metabolism, differentiation, and apoptosis. Since loss of the FBW7 tumor suppressor is linked to drug resistance, FBW7 may represent a novel therapeutic target to increase drug sensitivity of cancer cells to conventional chemotherapeutics. This paper thus focuses on the new functional aspects of FBW7 in drug resistance. (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)

Drugs targeting a single TK/RTK in the treatment of solid cancers has not had the same success seen in blood cancers. This is, in part, due to acquired resistance in solid cancers arising from a range of mechanisms including the upregulation of compensatory RTK signalling. Rather than attempting to inhibit individual compensatory RTK—requiring knowledge of which RTKs are upregulated in any given tumour—strategies to universally inhibit signalling from multiple RTKs may represent an effective alternative. Endosomal trafficking of RTKs is (...) a common conduit that can regulate signalling from multiple RTKs simultaneously. As such, we posit that targeting endosomal trafficking—in particular, aberrant post‐translational modifications in cancers that contribute to dysregulated endosomal trafficking—could inhibit oncogenic signalling driven by multiple RTKs and pave the way for the development of a novel class of inhibitors that shift the trafficking of RTKs to inhibit tumour growth. (shrink)

The presence and role of microbes in human cancers has come full circle in the last century. Tumors are no longer considered aseptic, but implications for cancer biology and oncology remain underappreciated. Opportunities to identify and build translational diagnostics, prognostics, and therapeutics that exploit cancer's second genome—the metagenome—are manifold, but require careful consideration of microbial experimental idiosyncrasies that are distinct from host‐centric methods. Furthermore, the discoveries of intracellular and intra‐metastatic cancer bacteria necessitate fundamental changes in describing clonal (...) evolution and selection, reflecting bidirectional interactions with non‐human residents. Reconsidering cancer clonality as a multispecies process similarly holds key implications for understanding metastasis and prognosing therapeutic resistance while providing rational guidance for the next generation of bacterial cancer therapies. Guided by these new findings and challenges, this Review describes opportunities to exploit cancer's metagenome in oncology and proposes an evolutionary framework as a first step towards modeling multispecies cancer clonality. Also see the video abstract here: https://youtu.be/-WDtIRJYZSs. (shrink)

Cancer stem cells (CSC) represent malignant cell subsets in hierarchically organized tumors, which are selectively capable of tumor initiation and self‐renewal and give rise to bulk populations of non‐tumorigenic cancer cell progeny through differentiation. Robust evidence for the existence of prospectively identifiable CSC among cancer bulk populations has been generated using marker‐specific genetic lineage tracking of molecularly defined cancer subpopulations in competitive tumor development models. Moreover, novel mechanisms and relationships have been discovered that link CSC to (...) cancer therapeutic resistance and clinical tumor progression. Importantly, proof‐of‐principle for the potential therapeutic utility of the CSC concept has recently been provided by demonstrating that selective killing of CSC through a prospective molecular marker can inhibit tumor growth. Herein, we review these novel and translationally relevant research developments and discuss potential strategies for CSC‐targeted therapy in the context of resistance mechanisms and molecular pathways preferentially operative in CSC. (shrink)

In this review, we discuss the application of mouse models to the identification and pre‐clinical validation of novel therapeutic targets in colorectal cancer, and to the search for early disease biomarkers. Large‐scale genomic, transcriptomic and epigenomic profiling of colorectal carcinomas has led to the identification of many candidate genes whose direct contribution to tumourigenesis is yet to be defined; we discuss the utility of cross‐species comparative ‘omics‐based approaches to this problem. We highlight recent progress in modelling late‐stage disease using (...) mice, and discuss ways in which mouse models could better recapitulate the complexity of human cancers to tackle the problem of therapeutic resistance and recurrence after surgical resection. (shrink)

Multidrug resistance resulting from expression of an energy‐dependent drug efflux pump encoded by the human MDR1 gene is a major impediment to effective cancer therapy. Pharmacologic intervention aimed at inhibiting this multidrug transporter should improve existing chemotherapy of human cancer, but drug development has been delayed by the difficulty and expense of developing valid animal models. Using recombinant DNA technology, a transgenic mouse has been engineered whose bone marrow is protected from the toxic effects of chemotherapy by (...) expression of the MDR1 gene. This animal system allows the rapid screening of drugs which inhibit the multidrug transporter and heralds a new era of using transgenic animals for pharmacologic screening. (shrink)

The information contained in DNA is not definitive, but modifiable. Indeed, the environment has the power to modify the genetic material expression without altering the DNA genes sequence. The principal environmental factors that work in this way, whether in a positive or in a negative way, are diet and stress with their ruling hormones, insulin and cortisol; these hormones are normally antagonists but, when they reach their respective resistances, they become the ubiquitary etiopathogenetic factors in bidirectional convergent relationship, each other (...) causing the disinhibition and development of low grade systemic inflammation that opens the door to a myriad of interconnected sets of problems. Among these problems the greater one is cancer, which represents the extreme junction between hyperinsulinemia and hypercortisolemia, just because cancer cells never become insulin resistant and/or cortisol resistant. (shrink)

Plasminogen activator inhibitor‐1 (PAI‐1) is a physiological inhibitor of urokinase (uPA), a serine protease known to promote cell migration and invasion. Intuitively, increased levels of PAI‐1 should be beneficial in downregulating uPA activity, particularly in cancer. By contrast, in vivo, increased levels of PAI‐1 are associated with a poor prognosis in breast cancer. This phenomenon is termed the “PAI‐1 paradox”. Many factors are responsible for the upregulation of PAI‐1 in the tumor microenvironment. We hypothesize that there is a (...) breast cancer predisposition to a more aggressive stage when PAI‐1 is upregulated as a consequence of Metabolic Syndrome (MetS). MetS exerts a detrimental effect on the breast tumor microenvironment that supports cancer invasion. People with MetS have an increased risk of coronary heart disease, stroke, peripheral vascular disease and hyperinsulinemia. Recently, MetS has also been identified as a risk factor for breast cancer. We hypothesize the existence of the “PAI‐1 cycle”. Sustained by MetS, adipocytokines alter PAI‐1 expression to promote angiogenesis, tumor‐cell migration and procoagulant microparticle formation from endothelial cells, which generates thrombin and further propagates PAI‐1 synthesis. All of these factors culminate in a chemotherapy‐resistant breast tumor microenvironment. The PAI‐1 cycle may partly explain the PAI‐1 paradox. In this hypothesis paper, we will discuss further how MetS upregulates PAI‐1 and how an increased level of PAI‐1 can be linked to a poor prognosis. BioEssays 29:1029–1038, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

According to the biomedical model of medicine, the subject of the illness event is the pathology rather than the person diagnosed with the disease. In this view, a body-self becomes a ‘patient’ body-object that can be enrolled in a therapeutic protocol, investigated, assessed, and transformed. How can it be possible for cancer patients to make sense of the opposite dimensions of their body-self and their body-diseased-object? Could a creative embodied approach enable the coping with trauma tied to the experience (...) of illness? By applying a phenomenological approach and auto-ethnographic analysis to the experience of cancer, this visual exploration provides support for rethinking the cancer event through a performative perspective. This work previews images and video material collected over ten years of haematological treatments, video dance performances and physical explorations. This work displays how processes of healing can be set in motion by creative embodied practices, physical explorations and unexpected journeys. By resisting the biomedical model and allowing the emergence of new meanings, it illustrates how dance and performative practices offer ground for transformation. (shrink)

Mutations in growth factor receptor signaling pathways are common in cancer cells, including the highly lethal brain tumor glioblastoma (GBM) where they drive tumor growth through mechanisms including altering the uptake and utilization of nutrients. However, the impact of changes in micro‐environmental nutrient levels on oncogenic signaling, tumor growth, and drug resistance is not well understood. We recently tested the hypothesis that external nutrients promote GBM growth and treatment resistance by maintaining the activity of mechanistic target of (...) rapamycin complex 2 (mTORC2), a critical intermediate of growth factor receptor signaling, suggesting that altered cellular metabolism is not only a consequence of oncogenic signaling, but also potentially an important determinant of its activity. Here, we describe the studies that corroborate the hypothesis and propose others that derive from them. Notably, this line of reasoning raises the possibility that systemic metabolism may contribute to responsiveness to targeted cancer therapies. (shrink)

In spite of the advances in our knowledge of cancer biology, most cancers remain not curable with present therapies. Current treatments consider cancer as resulting from uncontrolled proliferation and are non‐specific. Although they can reduce tumour burden, relapse occurs in most cases. This was long attributed to incomplete tumour elimination, but recent developments indicate that different types of cells contribute to the tumour structure, and that the tumour's cellular organization would be analogous to that of a normal tissue, (...) with a main mass of differentiating cells sensitive to anti proliferative agents, together with a small percentage of quiescent, resistant stem cells responsible for replenishing the tumour: the Cancer Stem Cells (CSCs). Anti‐CSCs targeted therapeutic agents would prevent tumour regeneration. New mouse models tailored to exploit this novel concept will be critical to develop CSC‐based anti‐cancer therapies. Here we review the biological basis and the therapeutic implications of the stem‐cell model of cancer. BioEssays 29:1269–1280, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

The major cause of death from cancer is the relentless growth of metastases that are resistant to conventional therapy. The pathogenesis of a metastasis is complex and requires that tumor cells complete a sequence of potentially lethal interactions with various host factors. The finding in 1973 that metastasis is selective process and the finding in 1977 that malignant neoplasms are heterogeneous and contain few preexisting metastatic subpopulations have added a new dimension to our understanding of cancer and its (...) spread. This understanding is now contributing to the design of better therapies against disseminated metastasis. (shrink)

Canadian and American population-based research concerning sexual and/or gender minority populations provides evidence of persistent breast and gynecologic cancer-related health disparities and knowledge divides. The Cancer's Margins research investigates the complex intersections of sexual and/or gender marginality and incommensurabilities and improvisation in engagements with biographical and biomedical cancer knowledge. The study examines how sexuality and gender are intersectionally constitutive of complex biopolitical mappings of cancer health knowledge that shape knowledge access and its mobilization in health and (...) treatment decision-making. Interviews were conducted with a diverse group of sexual and/or gender minority breast or gynecologic cancer patients. The LGBQ//T2 cancer patient narratives we have analyzed document in fine grain detail how it is that sexual and/or gender minority cancer patients punctuate the otherwise lockstep assemblage of their cancer treatment decision-making with a persistent engagement in creative attempts to resist, thwart and otherwise manage the possibility of discrimination and likewise, the probability of institutional erasure in care settings. Our findings illustrate the demands that cancer places on LGBQ//T2 patients to choreograph access to, and mobilization of knowledge and care, across significantly distinct and sometimes incommensurable systems of knowledge. (shrink)

Tumors are often viewed as unique entities with specific behaviors. However, tumors are a mixture of differentially evolved subpopulations of cells in constant Darwinian evolution, selecting the fittest clone and allowing it to outgrow the rest. As in the natural environment, the niche defines the properties the fittest clones must possess. Therefore, there can be multiple fit clones because of the various microenvironments inside a single tumor. Hypoxia is considered to be a major feature of the tumor microenvironment and is (...) a potential contributor to the cancer stem cell (CSC) phenotype and its enhanced tumorigenicity. The acidic microenvironment around hypoxic cells is accompanied by the activation of a subset of proteases that contribute to metastasis. Because of aberrant angiogenesis and the inaccessibility of their locations, hypoxic cells are less likely to accumulate therapeutic concentrations of chemotherapeutics that can lead to therapeutic resistance. Therefore, the targeting of the hypoxic CSC niche in combination with chemotherapy may provide a promising strategy for eradicating CSCs. In this review, we examine the cancer stem cell hypothesis and its relationship to the microenvironment, specifically to hypoxia and the subsequent metabolic switch and how they shape tumor behavior. (shrink)

Ovarian cancer is the most lethal gynecological malignancy and is often associated with both DNA repair deficiency and extensive metabolic reprogramming. While still emerging, the interplay between these pathways can affect ovarian cancer phenotypes, including therapeutic resistance to the DNA damaging agents that are standard‐of‐care for this tumor type. In this review, we will discuss what is currently known about cellular metabolic rewiring in ovarian cancer that may impact DNA damage and repair in addition to highlighting (...) how specific DNA repair proteins also promote metabolic changes. We will also discuss relevant data from other cancers that could be used to inform ovarian cancer therapeutic strategies. Changes in the choice of DNA repair mechanism adopted by ovarian cancer are a major factor in promoting therapeutic resistance. Therefore, the impact of metabolic reprogramming on DNA repair mechanisms in ovarian cancer has major clinical implications for targeted combination therapies for the treatment of this devastating disease. (shrink)

Oxidised bases, such as 8-oxo-guanine, occur in cellular DNA as a result of attack by oxygen free radicals. The cancer-protective effect of vegetables and fruit is attributed to the ability of antioxidants in them to scavenge free radicals, preventing DNA damage and subsequent mutation. Antioxidant supplements (e.g., β-carotene, vitamin C) increase the resistance of lymphocytes to oxidative damage, and a negative correlation is seen between antioxidant concentrations in tissues and oxidised bases in DNA. Large-scale intervention trials with β-carotene (...) have, however, led to increases in cancer. Recent measurements of the frequency of oxidised DNA bases indicate that earlier estimates were greatly exaggerated; there may be only a few thousand 8-oxo-guanines per cell. Convincing evidence for mutations resulting from oxidative damage, in tumours or cultured cells, is lacking. It seems that efficient antioxidant defences together with DNA repair maintain a steady-state level of damage representing minimal risk to cell or organism. BioEssays 21:238–246, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

Constructions of women’s activism as social service, volunteer, or charity work contribute to the relative invisibility of these forms of activism. The author conducted field research at an affiliate office of the Susan G. Komen Breast Cancer Foundation. She analyzes how these women volunteers resist the label “activist” at the same time that they engage in activities that resemble activism. The author also examines the reasons for their resistance to the term. Her analysis shows that implicit connections between (...) constructions of activism and gender shape the extent to which volunteers think of their work either as political or as activism. In light of Komen’s heteronormative gender ideology, the author concludes by raising questions about the relationships among gender, activism, and civic participation. (shrink)

Oxidised bases, such as 8-oxo-guanine, occur in cellular DNA as a result of attack by oxygen free radicals. The cancer-protective effect of vegetables and fruit is attributed to the ability of antioxidants in them to scavenge free radicals, preventing DNA damage and subsequent mutation. Antioxidant supplements (e.g., β-carotene, vitamin C) increase the resistance of lymphocytes to oxidative damage, and a negative correlation is seen between antioxidant concentrations in tissues and oxidised bases in DNA. Large-scale intervention trials with β-carotene (...) have, however, led to increases in cancer. Recent measurements of the frequency of oxidised DNA bases indicate that earlier estimates were greatly exaggerated; there may be only a few thousand 8-oxo-guanines per cell. Convincing evidence for mutations resulting from oxidative damage, in tumours or cultured cells, is lacking. It seems that efficient antioxidant defences together with DNA repair maintain a steady-state level of damage representing minimal risk to cell or organism. BioEssays 21:238–246, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

Although chemotherapy is one of the most common treatments for cancer, it can be only partially successful. Drug resistance is the main cause of the failure of chemotherapy. In this work, we present a mathematical model to study the impact of both intrinsic and acquired resistances on chemotherapy effectiveness. Our simulations show that intrinsic resistance could be as dangerous as acquired resistance. In particular, our simulations suggest that tumors composed by even a small fraction of intrinsically (...) resistant cells may lead to an unsuccessful therapy very quickly. Our results emphasize the importance of monitoring both intrinsic and acquired resistances during treatment in order to succeed and the importance of doing more experimental and genetic research in order to develop a pretreatment clinical test to avoid intrinsic resistance. (shrink)

The transcriptional co‐activators YAP (or YAP1) and TAZ (or WWTR1) are frequently activated during the growth and progression of many solid tumors, including lung, colorectal, breast, pancreatic, and liver carcinomas as well as melanoma and glioma. YAP/TAZ bind to TEAD‐family co‐activators to drive cancer cell survival, proliferation, invasive migration, and metastasis. YAP/TAZ activation may also confer resistance to chemotherapy, radiotherapy, or immunotherapy. YAP‐TEAD cooperates with the RAS‐induced AP‐1 (FOS/JUN) transcription factor to drive tumor growth and cooperates with MRTF‐SRF (...) to promote activation of cancer‐associated fibroblasts, matrix stiffening, and metastasis. The key upstream repressor of YAP/TAZ activation is the Hippo (MST1/2‐LATS1/2) pathway and the key upstream activators are mechanically induced Integrin‐SRC and E‐cadherin‐AJUBA/TRIP6/LIMD1, growth factor induced PI3K‐AKT, and inflammation‐induced G‐protein coupled receptor (GPCR) signals, all of which antagonize the Hippo pathway. In this review, strategies to target YAP/TAZ activity in cancer are discussed along with the prospects for synergy with established pillars of cancer therapy. (shrink)

Certain sections ofJosiah Willard Gibbs's thermodynamics papers might be applicable to biological equilibrium and growth, normal or abnormal.Gibbs added terms⌆ Μ i dm i to the differential of the internal energy dε=tdη−pdΝ, where μi=δεδmi is the potential of substancem i , to provide for chemical as well as thermal and mechanical equilibrium. In this article a further generalization is suggested, to include biological equilibrium by adding to de terms of the form GdN, the variableN being the number of cells, where (...) G=δεδN is a “growth potential” that measures exactly the resistance toward spontaneous growth. The functionG, likeΜ i is intensive in nature except for a conversion factor dMdN ,M=⌆m i , affording possible insight into why incipient abnormal growth is often independent of the number of cells. Useful applications might follow from identities between δGδη,δGδv , or δGδmi and δtδN,−δpδN or δμiδN respectively. The following new function is studied, ζ¯=ζ−GN , a natural generalization of theGibbs free energy function ζ, the possibility of measuring it electrically, and comparison of its role with that of ζ for the possible experimental determination ofG. Gibbs's necessary and sufficient conditions for heterogeneous equilibrium ofn components inm phases are generalized and also modified to include broader restraining conditions like ∑mi=1δNj⩾o ,j=1,f,n, the > being characteristic of only living cellular phases. Careful appraisal of the term “biological stability” is followed by new criteria for stability, instability, and limits of stability, in terms of derivatives ofG, with possible medical applications. Three different sections of Gibbs's works tend to indicate that, for a biological phase, lower pressure usually increases its stability. The equation p′′−p′=σ , where σ=surface tension,p′, p′ = pressures,r, r′=radii of curvature, is applied to possible control of tissue growth at interfaces. Methods of altering the equilibrum between three phasesA, B, C by varying the interfacial tensionsσ AB ,σ BC ,σ AC , using relations like AB <σ AC + BC for stability of theA, B interface, suggest different means for shifting biological equilibrium between normal and abnormal cells through the introduction of new third phases at the interface. Various devices are mentioned for possible control of growth through proper channeling of surface or other equivalent forms of energy. (shrink)

Despite the remarkable achievements of novel targeted anti‐cancer drugs, most therapies only produce remission for a limited time, resistance to treatment, and relapse, often being the ultimate outcome. Drug resistance is due to highly efficient adaptive strategies utilized by cancer cells. Exogenous and endogenous stress stimuli are known to induce first‐line responses, capable of re‐establishing cellular homeostasis and determining cell fate decisions. Cancer cells may also mount second‐line adaptive strategies, such as the mutator response. Hypermutable (...) subpopulations of cells may expand under severe selective stress, thereby accelerating the emergence of adapted clones. As with first‐line protective responses, these strategies appear highly conserved, and are found in yeasts and bacteria. We hypothesize that evolutionarily conserved programs rheostatically regulate mutability in fluctuating environments, and contribute to drug resistance in cancer cells. Elucidating the conserved genetic and molecular mechanisms may present novel opportunities to increase the effectiveness of cancer therapies. (shrink)

Successful therapies to combat microbial diseases and cancers require incorporating ecological and evolutionary principles. Drawing upon the fields of ecology and evolutionary biology, we present a systems‐based approach in which host and disease‐causing factors are considered as part of a complex network of interactions, analogous to studies of “classical” ecosystems. Centering this approach around empirical examples of disease treatment, we present evidence that successful therapies invariably engage multiple interactions with other components of the host ecosystem. Many of these factors interact (...) nonlinearly to yield synergistic benefits and curative outcomes. We argue that these synergies and nonlinear feedbacks must be leveraged to improve the study of pathogenesis in situ and to develop more effective therapies. An eco‐evolutionary systems perspective has surprising and important consequences, and we use it to articulate areas of high research priority for improving treatment strategies. (shrink)

Estrogen receptor α (ERα) is a ligand‐dependent transcription factor that regulates the expression of estrogen‐responsive genes. Approximately 70% of patients with breast cancer are ERα positive. Estrogen stimulates cancer cell proliferation and contributes to tumor progression. Endocrine therapies, which suppress the ERα signaling pathway, significantly improve the prognosis of patients with breast cancer. However, the development of de novo or acquired endocrine therapy resistance remains a barrier to breast cancer treatment. Therefore, understanding the regulatory mechanisms (...) of ERα is essential to overcome the resistance to treatment. This review focuses on the regulation of ERα expression, including copy number variation, epigenetic regulation, transcriptional regulation, and stability, as well as functions from the point of view post‐translational modifications. (shrink)

In accordance with the critical women’s health literature recounting the ways that women are encouraged to submit themselves to various sorts of health “imperatives”, I investigate the messages tacitly conveyed to women in “campaigns for the cure” and breast cancer awareness efforts, which, I argue, overemphasizes a “positive attitude”, healthy lifestyle, and cure rather than prevention of this life-threatening disease. I challenge that the message of hope pervading breast cancer discourse silences the despair felt by many women, furthers (...) a tacit blaming for disease infliction via a rhetoric of personal responsibility, underemphasizes other cogent health determinants like environmental toxicity, and undermines legitimate critiques of current biomedical practices like widespread mammography. While finding a cure for breast cancer is a laudable and worthwhile healthcare goal that can understandably be shared by women’s health activists, corporate sponsors, and the medical community, this paper resists the current formation of campaigns for the cure and “pink ribbon activism” in general. (shrink)

Le terme de médecine personnalisée peut désigner indifféremment la médecine de précision et la médecine des systèmes. L’objectif de cet article est d’analyser les rapports entre ces deux faces de la médecine personnalisée, au prisme de l’histoire du développement des thérapies ciblées. Les thérapies ciblées ont été développées dans le cadre de la médecine de précision, en s’appuyant sur le concept d’addiction oncogénique et sur l’idée qu’à chaque biomarqueur permettant d’identifier un sous-type de cancer correspondrait un médicament précis. Ce (...) modèle a permis des succès thérapeutiques remarquables, mais a également rencontré des limites, notamment avec l’apparition des résistances aux thérapies ciblées. Pour mieux comprendre les raisons de ces limites, il me semble qu’il faut justement se tourner plutôt vers la médecine des systèmes. Je soutiens en particulier que cette dernière repose sur des concepts de robustesse et de redondance fonctionnelle, qui nous permettent de comprendre en quoi l’apparition des phénomènes de résistance est une conséquence inéluctable et non transitoire du développement des thérapies ciblées. Il s’agit donc de montrer comment la médecine des systèmes permet de penser différemment les stratégies thérapeutiques dans la prise en charge du cancer et l’évolution future de la médecine de précision. (shrink)

This is the text of the 2022 Boyle Lecture. After some acknowledgements, it introduces the theological problem of the suffering of nonhuman creatures in the natural world as described by evolutionary science. It sets aside the neo-Cartesian objection that this suffering should not be considered real. The lecture then considers, and initially rejects, theodicies based on some form of fall event. An account is offered based on the premise that Darwinian evolution was the only way God could have given rise (...) to a biological world containing the sorts of values we observe. Although this remains the preferred basis for an evolutionary theodicy, consideration is finally given to the extent to which certain phenomena, such as parasitism, cancers, and viral infections, might be thought to exhibit a resistance to the divine will. The tentative suggestion is made that this resistance might derive from temptation by spiritual powers, thus incorporating into an overall only-way account an element of angelic fallenness. (shrink)

Living with cancer: a state of perpetual emergency -- Notes -- References -- PART IV: Environmental aesthetics and resistance -- 12. The great turning -- 13. The underestimated power effects of the discourses and practices of the food justice movement -- Pessimist premise -- General system failure -- The transformative strength of the three Foucaults -- How practices and discourses of the food justice movement illustrate the three Foucaults -- The biopolitical disaster of industrial agriculture -- Via Campesina: (...) peasant knowledge, land and power -- Urban agriculture: eaters' resistance and practices for a new food system -- Slow Food: putting eaters' culture back into "agriculture" -- Conclusion: get your hands dirty! -- Acknowledgements -- References -- 14. Interrogating the neoliberal biopolitics of the sustainable development-resilience nexus -- The political genealogy of sustainable development -- From security to resilience -- The disastrous and politically debased subject of resilience -- Conclusion: development contra neoliberalism? -- References -- 15. The aesthetics of triage: Towards life beyond survival -- Mechanism of a triage -- Photographic triage -- The cinematic triage -- Beyond survival -- References -- 16. End piece: Dealing with disastrous life -- Extra/ordinary disasters -- Dread life -- Towards a new critical framework? -- References -- Index. (shrink)

Enhancement-line human genetic engineering has recurrently been targeted for bioethical discussion and is usually illustrated by examples alluding to a genetic technology that is far beyond our current possibilities. By discussing an ambitious project related to solid tumor cancers – multidrug resistance – the present paper places the question on a more realistic plane and draws bioethical conclusions to serve as guidelines in the field. The paper also establishes the inadequacy of the prevalent concept of genetic medicine as one (...) of substitution. (shrink)

Evolutionary theory assumed that mutations occur constantly, gradually, and randomly over time. This formulation from the “modern synthesis” of the 1930s was embraced decades before molecular understanding of genes or mutations. Since then, our labs and others have elucidated mutation mechanisms activated by stress responses. Stress‐induced mutation mechanisms produce mutations, potentially accelerating evolution, specifically when cells are maladapted to their environment, that is, when they are stressed. The mechanisms of stress‐induced mutation that are being revealed experimentally in laboratory settings provide (...) compelling models for mutagenesis that propels pathogen–host adaptation, antibiotic resistance, cancer progression and resistance, and perhaps much of evolution generally. We discuss double‐strand‐break‐dependent stress‐induced mutation in Escherichia coli. Recent results illustrate how a stress response activates mutagenesis and demonstrate this mechanism's generality and importance to spontaneous mutation. New data also suggest a possible harmony between previous, apparently opposed, models for the molecular mechanism. They additionally strengthen the case for anti‐evolvability therapeutics for infectious disease and cancer. (shrink)

This survey on biotechnology and bioethics was carried out onnational random samples of the public and scientists in November2000-January 2000 throughout Japan, and attendees at theNovartis Life Science Forum held on 29 September, 1999 inTokyo. The sample size was 297, 370, and 74 respectively. Whilethere is better awareness of GMOs in 2000 compared to 1991; thetrend shows an increase in the perceived risks of GMOs followedby growing resistance in Japan. While a majority of personsbelieved genetic engineering would make life (...) better over the nexttwenty years , the proportion of respondents who thoughtgenetic engineering would make life worse over the next twentyyears doubled from 1997 to 2000 .Respondents were asked whether they had heard aboutapplications in several areas and the order of familiarity was: pest-resistant crops, human genes in bacteria, mouseto develop cancer, food and drinks, pigs with human hearts andpre-implantation diagnosis. A divide of opinion can be seen whenthe results on benefit, risk and moral acceptability of applicationsof biotechnology by the public are compared to the forum andscientist samples.A significant change in the acceptance of the public occurred in2000 where only 22% agreed on the moral acceptability of GMfood compared to 41% in 1997. In 2000 fewer people said they arewilling to buy genetically modified fruits that taste bettercompared to 1997 . The results show less public support foruse of gene therapy than 1993 and twice as many scientistsrejected gene therapy than they did in 1991.When asked whom is best placed to regulate modernbiotechnology, the respondents were overwhelmingly in favor ofinternational regulatory bodies, such as the United Nations andthe World Health Organization , rather than national bodies.The comparison between scientists and public is interesting,however the more enthusastic sample were participants from theNovartis Life Science Forum with its mixed occupations. (shrink)

The scientific discovery of a range of genetic mutations has meant that people with a strong family history of cancer can find out whether they are at risk of developing cancer well before they have any symptoms. Genetic testing has opened up the possibility for otherwise healthy mutation carriers to access prophylactic treatments in order to minimise their risk. These include surgery to remove at-risk body parts, treatment with cancer drugs, medical surveillance strategies, self-surveillance and change in (...) lifestyle. Clinical experience to date has shown considerable resistance to the uptake of medical preventative measures despite their promise of risk reduction. This paper provides a summary review of the available literature on the medical, psychological, counselling and social aspects of genetic testing and the use of risk-reducing treatments by people who have been diagnosed with a genetic predisposition to cancer. It acknowledges what has been learned from these approaches but points to the similarity of the philosophical underpinnings of most of the research. It concludes by tentatively making some suggestions, informed by the literature, about new directions for guiding our understanding the genetically at risk and the factors that influence their decision-making. (shrink)

The NHS is an institution of great importance to everybody in the UK - not only doctors, nurses and other health professionals, but also to patients, carers and their families. However, problems within the NHS are regularly reported in the media and we are all anxious about waiting lists, about whether potential illnesses will be identified treated in time, about bleeding to death on trollies in corridors or being struck down by antibiotic-resistant superbugs. This engaging book aims to explore and (...) simplify the issues from both sides of the NHS - professionals and patients - and to improve mutual understanding of the problems, which will hopefully spark an open debate about the future of health service provision. The book uses an innovative fictionalized account of the experiences of 'case study' individuals in the healthcare system, including a GP with depression, a woman with MS and a hospital manager whose wife has cancer. This book will be essential and enjoyable reading for anyone workingwithin the healthcare system, as well as patients and their families and anyone interested in the workings of the NHS. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:FDA Releases Draft Guidance on Regulation of Genetically Engineered AnimalsJohn P. Gluck (bio) and Mark T. Holdsworth (bio)On 18 September 2008, the U.S. Food and Drug Administration (FDA) issued a draft set of guidelines for those involved in developing genetically engineered animals with heritable recombinant DNA (rDNA) constructs and is requesting comment from industry and the public about their content. The document does not impose new regulations but details (...) how existing laws and regulations apply to genetically engineered (GE) animals and offers advice to developers on how to negotiate the laws in the most efficient and productive manner. The draft guidance document is not legally enforceable at this juncture, but the guidelines are recommendations reflecting the FDA's "current thinking on a topic."The modification of GE animals being developed for commercialization, which are the focus of the document, fall into six categories: modifications intended to (1) enhance food quality—e.g., faster growing fish and meats with better nutritional profiles; (2) improve animal health via increased resistance to disease—e.g., mastitis in dairy cattle and Bovine Spongiform Encephalopathy (BSE); (3) create so-called "biopharm" animals capable of producing therapeutic products such as insulin, clotting factors, and tissues for human transplantation; (4) reduce the barriers to human animal interaction—e.g., hypoallergenic pets; (5) develop valid animal models of human disease—e.g., Parkinson's disease, Lesh-Nyhan's syndrome, and cancer; and (6) improve production of industrial or consumer products such as fiber. The timing of the guidelines coincides with the FDA's belief in an expected boon in the number of GE animals approaching the stage of commercialization.The FDA's involvement in the approval process emerges from the new animal drug provisions of the Federal Food Drug and Cosmetic Act and the definition of what constitutes a drug. The Act defines a new animal drug as "an article (other than food) intended to affect the structure or any function of the body of... animals." A rDNA construct intended to affect the structure or function of an animal meets the definition of a new animal drug, regardless of whether the resulting GE animals are intended for human food or the production of pharmaceuticals or any other substances. [End Page 393]Before proceeding to a review of the draft guidelines, it is important briefly to set the controversies around GE animals in historical and ethical context.The Ethical DebateFrom its inception, the intentional genetic modification or genetic engineering of molecules, plants, and animals by the techniques of gene splicing has consistently elicited strong responses from both the scientific community and the public. There are some data to suggest that although the concerns of scientists fall primarily into the category of possible biohazards, those of the public also reflect great concern about the intrinsic moral issues, such as whether there is something fundamentally wrong with this line of work, making it a form of forbidden knowledge (see, e.g., Gaskell 1997). When news of Paul Berg's attempts in 1970 to graft the primate tumor virus (SV 40) onto the intestinal tract bacteria Escherichia coli for the purpose of studying how normal cells may be transformed into cancerous cells was shared with colleagues, he was strongly encouraged to reflect on the potential public health risks if somehow the altered bacteria broke containment and entered the environment. Thanks to Berg's leadership, these concerns soon resulted in conferences held in Asilomar, California, and New Hampton, New Hampshire, where the ethical responsibilities of microbiologists involved in this research were discussed. These initial discussions resulted in what has come to be known as "The Moratorium Letter" (Shattuck 1996) published in the journal Science in 1974. This letter, signed by 11 leaders in the field, actually recommended restrictions on several types of experiments that were considered to be particularly risky and stated "that adherence to our major recommendations will entail postponement or possibly abandonment of certain types of scientifically worthwhile experiments" (Berg 1974). An international conference on the issues came to similar conclusions about the need for a research moratorium for the sake of public safety. Recommendations arising from conference participants led to the formation of the National Institutes... (shrink)

DNA mismatch repair is an important pathway of mutation avoidance. It also contributes to the cytotoxic effects of some kinds of DNA damage, and cells defective in mismatch repair are resistant, or tolerant, to the presence of some normally cytotoxic base analogues in their DNA. The absence of a particular mismatch binding function from some mammalian cells confers resistance to the base analogues O6‐methylguanine and 6‐thioguanine in DNA. Cells also acquire a spontaneous mutator phenotype as a consequence of this (...) defect. Impaired mismatch binding can cause an instability in DNA microsatellite regions that comprise repeated dinucleotides. Microsatellite DNA instability is common in familial and sporadic colon carcinomas as well as in a number of other tumours. Several independent lines of investigation have identified defects in mismatch repair proteins that are causally related to these cancers. (shrink)

Current debate and policy surrounding the use of genetic editing in humans often relies on a binary distinction between therapy and human enhancement. In this paper, we argue that this dichotomy fails to take into account perhaps the most significant potential uses of CRISPR-Cas9 gene editing in humans. We argue that genetic treatment of sporadic Alzheimer’s disease, breast- and ovarian-cancer causing BRCA1/2 mutations and the introduction of HIV resistance in humans should be considered within a new category of (...) genetic protection treatments. We find that if this category is not introduced, life-altering research might be unnecessarily limited by current or future policy. Otherwise ad hoc decisions might be made, which introduce a risk of unforeseen moral costs, and might overlook or fail to address some important opportunities. (shrink)

Enhancement-line human genetic engineering has recurrently been targeted for bioethical discussion and is usually (if not always) illustrated by examples alluding to a genetic technology that is far beyond our current possibilities. By discussing an ambitious project related to solid tumor cancers – multidrug resistance (MDR) – the present paper places the question on a more realistic plane and draws bioethical conclusions to serve as guidelines in the field. The paper also establishes the inadequacy of the prevalent concept of (...) genetic medicine as one of substitution. (shrink)

It is reasonable to assume that future generations will have the same concerns we have about combating disease and illness. Natural compounds have historically been potent sources of medications. Current synthetic identification and production processes are not generating the volume of novel medications predicted, which has prompted a call to return to diverse natural sources. Biodiversity loss threatens our ability to fight off current and future infections by removing powerful potential sources of biologically active compounds needed to spur medication development (...) for cancer, human immunodeficiency virus, and antibiotic resistant tuberculosis. International and economic policy should embrace principles of sustainable biodiversity while simultaneously providing market incentives for compliance and innovation in order to maximize the health and well-being of current and future generations. (shrink)

Both ethicists and lawyers accept that a provider – be it a researcher or a clinician – should provide sufficient information for a reasonable person to make an informed decision about whether they wish to go ahead with the proposed intervention or treatment.1 They are bound to do so both because they have an ethical responsibility to preserve the individual’s autonomous decision making, and, in many countries, because the law obliges them to. In this month’s issue of the JME, three (...) articles tackle ethical issues relating to consent in different contexts. Overarching these analyses is the pragmatic question of whether the process of taking consent in itself might alter the outcomes, and whether, in doing so, it can undermine the initial therapeutic or research goal – so creating another ethical question of what to prioritise. Psilocybin is entering Phase III trials to evaluate its effect on treatment resistant depression and cancer related depression and anxiety; earlier trials have shown sustained symptom reduction in these populations. Smith and Sisti examine whether a form of enhanced consent is ethically required for these drugs.2 They explore how to adequately consent for ‘therapeutic touch’ in a future altered state; the rare but significant mental health risks including trauma re-exposure; and the potential for a personality change given the intense experiences which many subjects have reported. They illustrate the potential for personality change with an example regarding the spiritual experiences which can occur with serotonergic psychedelics, and suggest that ‘agnostic or atheist patients may take the development of a newfound sense of spirituality or belief in God to …. (shrink)

Almost all biomedical research to date has relied upon mean measurements from cell populations, however it is well established that what it is observed at this macroscopic level can be the result of many interactions of several different single cells. Thus, the observable macroscopic ‘average’ cannot outright be used as representative of the ‘average cell’. Rather, it is the resulting emerging behaviour of the actions and interactions of many different cells. Single‐cell RNA sequencing (scRNA‐Seq) enables the comparison of the transcriptomes (...) of individual cells. This provides high‐resolution maps of the dynamic cellular programmes allowing us to answer fundamental biological questions on their function and evolution. It also allows to address medical questions such as the role of rare cell populations contributing to disease progression and therapeutic resistance. Furthermore, it provides an understanding of context‐specific dependencies, namely the behaviour and function that a cell has in a specific context, which can be crucial to understand some complex diseases, such as diabetes, cardiovascular disease and cancer. Here, we provide an overview of scRNA‐Seq, including a comparative review of emerging technologies and computational pipelines. We discuss the current and emerging applications and focus on tumour heterogeneity a clear example of how scRNA‐Seq can provide new understanding of a complex disease. Additionally, we review the limitations and highlight the need of powerful computational pipelines and reproducible protocols for the broader acceptance of this technique in basic and clinical research. (shrink)

In 2014, Lord Saatchi launched his ultimately unsuccessful Medical Innovation Bill in the UK. Its laudable aim was to free doctors from the shackles that prevented them from providing responsible innovative treatment. Lord Saatchi’s principal contention was that current law was the unsurmountable barrier that prevented clinicians from delivering innovative treatments to cancer patients when conventional options had failed. This was because doctors feared that they might be sued or tried and convicted of gross negligence manslaughter if they deviated (...) from standard practice. Concerns about fear of the law and potential negative effects on medical practice are not new. Fear of litigation has been suggested as the reason for doctors practising “defensive medicine,” by opting for treatments regarded as “grievance-resistant,” rather than clinically indicated, for example, by ordering diagnostic tests or performing certain procedures, which are not strictly medically necessary. Whilst this claim is plausible and apparently accepted by the courts, there is limited empirical evidence in support of it so far as practitioners in the UK are concerned. In this paper, we report on our empirical research which provides a snapshot of medical opinion to begin to rectify this gap. We ran focus groups of different medical specialties, asking what these medical practitioners thought the barriers to medical innovation to be. We found that fear of the law was not the principal barrier to be lowered, and that the answer was far more multifaceted. (shrink)

Approaches to induce tumor differentiation often result in manageable and therapy‐naïve cellular states in cancer cells. This transformation is achieved by activating pathways that drive tumor cells away from plasticity, a state that commonly correlates with enhanced aggression, metastasis and resistance to therapy. Here, we discuss signaling pathways, epigenetics and non‐coding RNAs as three main regulatory levels with the potential to drive tumor differentiation and hence as potential targets in differentiation therapy approaches. The success of an effective therapeutic (...) regimen in one cancer, however, does not necessarily sustain across cancer types; a phenomenon largely resulting from heterogeneity in the genetic and physiological landscapes of tumor types necessitating an approach designed for each cancer's unique genetic and phenotypic build‐up. (shrink)

In spite of the numerous efforts made to control their transmission, parasite schistosomes still represent a serious public health concern and a major economic problem in many developing countries. Praziquantel (PZQ) is the drug of choice for the treatment of schistosomiasis and the only one that is available for mass chemotherapy. However, its widespread use and its inefficacy on juvenile parasites raise fears that schistosomes will develop drug resistance, and make the development of alternative drugs highly desirable. Protein tyrosine (...) kinases (PTKs) are key molecules that control cell differentiation and proliferation and they already represent important targets for molecular cancer therapy. The recent characterization in Schistosoma mansoni of several cytosolic and receptor PTKs, with properties similar but also divergent from their vertebrate counterparts, opens new perspectives for the development of novel strategies in chemotherapy of schistosomiasis, which could be based on the use of parasite‐specific tyrosine phosphorylation inhibitors. BioEssays 29:1281–1288, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Recent research shows that a faulty or sub‐optimally operating metabolic network can often be rescued by the targeted removal of enzyme‐coding genes – the exact opposite of what traditional gene therapy would suggest. Predictions go as far as to assert that certain gene knockouts can restore the growth of otherwise nonviable gene‐deficient cells. Many questions follow from this discovery: What are the underlying mechanisms? How generalizable is this effect? What are the potential applications? Here, I approach these questions from the (...) perspective of compensatory perturbations on networks. Relations are drawn between such synthetic rescues and naturally occurring cascades of reaction inactivation, as well as their analogs in physical and other biological networks. I specially discuss how rescue interactions can lead to the rational design of antagonistic drug combinations that select against resistance and how they can illuminate medical research on cancer, antibiotics, and metabolic diseases. Editor's suggested further reading in BioEssaysThe evolutionary context of robust and redundant cell biological mechanisms AbstractReprogramming cell fates: reconciling rarity with robustness Abstract. (shrink)

This survey on biotechnology and bioethics was carried out on national random samples of the public and scientists in November 2000-January 2000 throughout Japan, and attendees at the Novartis Life Science Forum held on 29 September, 1999 in Tokyo. The sample size was 297, 370, and 74 respectively. While there is better awareness of GMOs in 2000 compared to 1991; the trend shows an increase in the perceived risks of GMOs followed by growing resistance in Japan. While a majority (...) of persons believed genetic engineering would make life better over the next twenty years, the proportion of respondents who thought genetic engineering would make life worse over the next twenty years doubled from 1997 to 2000. Respondents were asked whether they had heard about applications in several areas and the order of familiarity was: pest-resistant crops, human genes in bacteria, mouse to develop cancer, food and drinks, pigs with human hearts and pre-implantation diagnosis. A divide of opinion can be seen when the results on benefit, risk and moral acceptability of applications of biotechnology by the public are compared to the forum and scientist samples.A significant change in the acceptance of the public occurred in 2000 where only 22% agreed on the moral acceptability of GM food compared to 41% in 1997. In 2000 fewer people said they are willing to buy genetically modified fruits that taste better compared to 1997. The results show less public support for use of gene therapy than 1993 and twice as many scientists rejected gene therapy than they did in 1991.When asked whom is best placed to regulate modern biotechnology, the respondents were overwhelmingly in favor of international regulatory bodies, such as the United Nations and the World Health Organization, rather than national bodies. The comparison between scientists and public is interesting, however the more enthusastic sample were participants from the Novartis Life Science Forum with its mixed occupations. (shrink)

B‐cell acute lymphoblastic leukaemia (B‐ALL) is a clonal malignant disease originated in a single cell and characterized by the accumulation of blast cells that are phenotypically reminiscent of normal stages of B‐cell differentiation. B‐ALL origin has been a subject of continuing discussion, given the fact that human disease is diagnosed at late stages and cannot be monitored during its natural evolution from its cell of origin, although most B‐ALLs probably start off with chromosomal changes in haematopoietic stem cells. However, the (...) cells responsible for maintaining the disease appear to differ between the different types of B‐ALLs and this remains an intriguing and exciting topic of research, since these cells have been posited to be responsible for resistance to conventional therapies, recurrence and dissemination. During the last years this problem has been addressed primarily by transplantation of purified subpopulations of human B‐ALL cells into immunodeficient mice. The results from these different reconstitution experiments and their interpretations are compared in this review in the context of normal B‐cell developmental plasticity. While the results from different research groups might appear mutually exclusive, we discuss how they could be reconciled with the biology of normal B‐cells and propose research avenues for addressing these issues in the future. (shrink)