Cancer stem cells (CSCs), also known as tumor-initiating cells, are characterized by an increased capacity for self-renewal, multipotency, and tumor initiation. While CSCs represent only a small ...proportion of the tumor mass, they significantly account for metastatic dissemination and tumor recurrence, thus making them attractive targets for therapy. Due to their ability to sustain in dormancy, chemo- and radiotherapy often fail to eliminate cancer cells with stemness properties. Recent advances in the understanding of the tumor microenvironment (TME) illustrated the importance of the immune contexture, determining the response to therapy and clinical outcome of patients. In this context, CSCs exhibit special properties to escape the recognition by innate and adaptive immunity and shape the TME into an immunosuppressive, pro-tumorigenic landscape. As CSCs sculpt the immune contexture, the phenotype and functional properties of the tumor-infiltrating immune cells in turn influence the differentiation and phenotype of tumor cells. In this review, we summarize recent studies investigating main immunomodulatory properties of CSCs and their underlying molecular mechanisms as well as the impact of immune cells on cancer cells with stemness properties. A deeper understanding of this bidirectional crosstalk shaping the immunological landscape and determining therapeutic responses will facilitate the improvement of current treatment modalities and the design of innovative strategies to precisely target CSCs.
In his The Idea of Human Rights, Charles Beitz offers a criticism of what he calls 'naturalistic' conceptions of human rights that has since become seminal. He argues that philosophers have largely ...ignored the actual practice of human rights for the purpose of their theories. As an alternative to these views, he develops a novel practical conception of human rights, whose methods take seriously the role human rights play within our international practice. While his criticism of naturalistic views remains brilliant, Beitz's alternative proposal has its own problems: it fails to explain the normative authority of human rights as a special class of rights, and it gives too much authority to contingent facts, thereby making human rights inherently static. It might at first seem as if these problems stem from the particular methodology Beitz employs. However, I show that this is not the case. The problems can be circumvented, I argue, by sticking to Beitz's methodology, but shifting the focus onto a different type of social practice that human rights function to govern. In order to make sense of human rights, we ought to regard them as necessary conditions of any scheme of just social cooperation.
Over the past 50 years, the number of overweight/obese people increased significantly, making obesity a global public health challenge. Apart from rare monogenic forms, obesity is a multifactorial ...disease, most likely resulting from a concerted interaction of genetic, epigenetic and environmental factors. Although recent studies opened new avenues in elucidating the complex genetics behind obesity, the biological mechanisms contributing to individual’s risk to become obese are not yet fully understood. Non-genetic factors such as eating behaviour or physical activity are strong contributing factors for the onset of obesity. These factors may interact with genetic predispositions most likely
via
epigenetic mechanisms. Epigenome-wide association studies or methylome-wide association studies are measuring DNA methylation at single CpGs across thousands of genes and capture associations to obesity phenotypes such as BMI. However, they only represent a snapshot in the complex biological network and cannot distinguish between causes and consequences. Intervention studies are therefore a suitable method to control for confounding factors and to avoid possible sources of bias. In particular, intervention studies documenting changes in obesity-associated epigenetic markers during lifestyle driven weight loss, make an important contribution to a better understanding of epigenetic reprogramming in obesity. To investigate the impact of lifestyle in obesity state specific DNA methylation, especially concerning the development of new strategies for prevention and individual therapy, we reviewed 19 most recent human intervention studies. In summary, this review highlights the huge potential of targeted interventions to alter disease-associated epigenetic patterns. However, there is an urgent need for further robust and larger studies to identify the specific DNA methylation biomarkers which influence obesity.
Cancer stem cells (CSCs) are pluripotent and highly tumorigenic cells that can re-populate a tumor and cause relapses even after initially successful therapy. As with tissue stem cells, CSCs possess ...enhanced DNA repair mechanisms. An active DNA damage response alleviates the increased oxidative and replicative stress and leads to therapy resistance. On the other hand, mutations in DNA repair genes cause genomic instability, therefore driving tumor evolution and developing highly aggressive CSC phenotypes. However, the role of DNA repair proteins in CSCs extends beyond the level of DNA damage. In recent years, more and more studies have reported the unexpected role of DNA repair proteins in the regulation of transcription, CSC signaling pathways, intracellular levels of reactive oxygen species (ROS), and epithelial–mesenchymal transition (EMT). Moreover, DNA damage signaling plays an essential role in the immune response towards tumor cells. Due to its high importance for the CSC phenotype and treatment resistance, the DNA damage response is a promising target for individualized therapies. Furthermore, understanding the dependence of CSC on DNA repair pathways can be therapeutically exploited to induce synthetic lethality and sensitize CSCs to anti-cancer therapies. This review discusses the different roles of DNA repair proteins in CSC maintenance and their potential as therapeutic targets.
Mesenchymal stromal cells (MSCs) are characterized by an extraordinary capacity to modulate the phenotype and functional properties of various immune cells that play an essential role in the ...pathogenesis of inflammatory disorders. Thus, MSCs efficiently impair the phagocytic and antigen-presenting capacity of monocytes/macrophages and promote the expression of immunosuppressive molecules such as interleukin (IL)-10 and programmed cell death 1 ligand 1 by these cells. They also effectively inhibit the maturation of dendritic cells and their ability to produce proinflammatory cytokines and to stimulate potent T-cell responses. Furthermore, MSCs inhibit the generation and proinflammatory properties of CD4
T helper (Th)1 and Th17 cells, while they promote the proliferation of regulatory T cells and their inhibitory capabilities. MSCs also impair the expansion, cytokine secretion, and cytotoxic activity of proinflammatory CD8
T cells. Moreover, MSCs inhibit the differentiation, proliferation, and antibody secretion of B cells, and foster the generation of IL-10-producing regulatory B cells. Various cell membrane-associated and soluble molecules essentially contribute to these MSC-mediated effects on important cellular components of innate and adaptive immunity. Due to their immunosuppressive properties, MSCs have emerged as promising tools for the treatment of inflammatory disorders such as acute graft-versus-host disease, graft rejection in patients undergoing organ/cell transplantation, and autoimmune diseases.
Key points
The adrenal hormone aldosterone can stimulate K+ secretion during hyperkalaemia and Na+ reabsorption during hypovolaemia in the kidney.
Angiotensin II is thought to switch the ...physiological mode of action from K+ excretion towards Na+ retention, but how the regulation is achieved when angiotensin II levels are suppressed by high Na+ intake remains unknown.
We report that both dietary K+ depletion and dietary K+ loading provoke renal Na+ retention and increase blood pressure in Na+ replete mice, but these occur through different renal kinase signalling and Na+ transport pathways.
An angiotensin II‐ and aldosterone‐independent activation of the sodium‐chloride cotransporter NCC contributes to the blood pressure increase induced by K+ depletion, whereas the hypertensive response to K+ loading is dependent on neither aldosterone nor Na+ transport via the epithelial sodium channel ENaC.
These findings imply a major impact of K+ homeostasis on renal Na+ handling in the Na+ replete state and suggest a mechanism for the hypertensive effect of the Western diet (high Na+ and low K+) in humans.
A network of kinases, including WNKs, SPAK and Sgk1, is critical for the independent regulation of K+ and Na+ transport in the distal nephron. Angiotensin II is thought to act as a key hormone in orchestrating these kinases to switch from K+ secretion during hyperkalaemia to Na+ reabsorption during intravascular volume depletion, thus keeping disturbances in electrolyte and blood pressure homeostasis at a minimum. It remains unclear, however, how K+ and Na+ transport are regulated during a high Na+ intake, which is associated with suppressed angiotensin II levels and a high distal tubular Na+ load. We therefore investigated the integrated blood pressure, renal, hormonal and gene and protein expression responses to large changes of K+ intake in Na+ replete mice. Both low and high K+ intake increased blood pressure and caused Na+ retention. Low K+ intake was accompanied by an upregulation of the sodium‐chloride cotransporter (NCC) and its activating kinase SPAK, and inhibition of NCC normalized blood pressure. Renal responses were unaffected by angiotensin AT1 receptor antagonism, indicating that low K+ intake activates the distal nephron by an angiotensin‐independent mode of action. High K+ intake was associated with elevated plasma aldosterone concentrations and an upregulation of the epithelial sodium channel (ENaC) and its activating kinase Sgk1. Surprisingly, high K+ intake increased blood pressure even during ENaC or mineralocorticoid receptor antagonism, suggesting the contribution of aldosterone‐independent mechanisms. These findings show that in a Na+ replete state, changes in K+ intake induce specific molecular and functional adaptations in the distal nephron that cause a functional coupling of renal K+ and Na+ handling, resulting in Na+ retention and high blood pressure when K+ intake is either restricted or excessively increased.
What can international courts say when criminals ask, by what right do you try me? Some authors attempt to draw a connection between humanity's responsibility to call offenders to account and the ...harm humanity has suffered as a consequence of the offender's crimes. Others have argued that there need not be a special connection between those calling to account and the offenders, as the right to punish offenders is a general right each and every person has. Both lines of argument are ultimately unconvincing. Instead, I argue for a modified version of the second position which proposes a democratically based theory of responsibility for punishment held by international criminal law institutions.
T cells are the predominant immune cell population in the pancreatic tumor microenvironment. High CD8
and Th1-polarized CD4
T cell infiltration is associated with prolonged survival in human ...pancreatic ductal adenocarcinoma (PDAC). However, the expression pattern of co-stimulatory and inhibitory receptors by PDAC-infiltrating T cells and their prognostic significance are not well defined. In this study, we employed multiplex immunofluorescence to investigate the intratumoral expression of the co-stimulatory receptor inducible T-cell co-stimulator (ICOS), the inhibitory receptors lymphocyte-activation gene 3 (LAG-3), programmed death 1 (PD-1), and V-domain immunoglobulin suppressor of T cell activation (VISTA) by tumor-infiltrating T cells (CD3) in a cohort of 69 patients with resected PDAC. T cells were enriched particularly within the stromal area and were highly heterogeneous across tumors. Further, T cells were associated with prolonged disease-free survival (DFS). However, LAG-3 expression by PDAC-infiltrating T cells was correlated with reduced DFS. Our study highlights the biological importance of LAG-3 expression by tumor-infiltrating T cells. LAG-3
T cells may represent a novel prognostic marker and a particularly attractive target for immunotherapeutic strategies in PDAC.
BackgroundPlasmacytoid dendritic cells (pDCs) play a key role in the induction and maintenance of antitumor immunity. Conversely, they can act as tolerogenic DCs by inhibiting tumor-directed immune ...responses. Therefore, pDCs may profoundly influence tumor progression. To gain novel insights into the role of pDCs in colon cancer, we investigated the frequency and clinical relevance of pDCs in primary tumor tissues from patients with colon cancer with different clinicopathological characteristics.MethodsImmunohistochemical stainings were performed to explore the frequency of tumor-infiltrating BDCA-2+ pDCs in patients with colon cancer. Statistical analyses were conducted to determine an association between the pDC density and clinicopathological characteristics of the patients. Furthermore, we used multiplex immunofluorescence stainings to evaluate the localization and phenotype of pDCs in stroma and tertiary lymphoid structures (TLS) of colon cancer tissues.ResultsAn increased density of infiltrating pDCs was associated with lower Union for International Cancer Control (UICC) stages. Furthermore, a higher pDC frequency was significantly correlated with increased progression-free and overall survival of patients with colon cancer. Moreover, a lower number of coloncancer-infiltrating pDCs was significantly and independently linked to worse prognosis. In addition, we found that a proportion of pDCs shows a nuclear expression of the transcription factor interferon regulatory factor 7 (IRF7), which is characteristic for an activated phenotype. In various tumor stroma regions, IRF7+ pDCs were located in the neighborhood of granzyme B-expressing CD8+ T cells. Moreover, pDCs were identified as a novel component of the T cell zone of colon cancer-associated TLS, which are major regulators of adaptive antitumor immunity. A proportion of TLS-associated pDCs displayed a nuclear IRF7 expression and was preferentially located close to CD4+ T cells.ConclusionsThese results indicate that higher densities of tumor-infiltrating pDCs are associated with prolonged survival of patients with colon cancer. Moreover, colon cancer-infiltrating pDCs may represent a novel prognostic factor. The colocalization of activated pDCs and T cells in tumor stroma and within TLS may contribute to the correlation between higher pDC densities and better prognosis. In addition, our findings may have implications for the design of novel immunotherapeutic strategies that are based on targeting colon cancer-infiltrating pDCs.
Background and Aims
In the CENTRAL trial context, we found diverse liver fat dynamics in response to different dietary interventions. Epigenetic mechanisms may contribute to the intraindividual ...variation. Moreover, genetic factors are involved in developing nonalcoholic fatty‐liver disease (NAFLD), a disease reflected by an increase in intrahepatic fat (IHF). In this exploratory analysis, we primarily aimed to examine the effect of lifestyle interventions on DNA‐methylation of NAFLD related genes associated with IHF.
Methods
For 120 participants from the CENTRAL trial, an 18‐month regimen of either low‐fat (LF) or Mediterranean‐low carbohydrate (MED/LC) diets, with or without physical activity (PA+/PA−), was instructed. Magnetic resonance imaging was used to measure IHF%, which was analysed for association with CpG specific DNA‐methylation levels of 41 selected candidate genes. Single‐nucleotide polymorphisms known to be associated with NAFLD within the studied genes were genotyped by TaqMan assays.
Results
At baseline, participants (92% men; body mass index = 30.2 kg/m2) had mean IHF of 10.7% (59% NAFLD). Baseline‐IHF% was inversely correlated with DNA‐methylation at individual CpGs within AC074286.1, CRACR2A, A2MP1, FARP1 (P < .05 for all multivariate models). FARP1 rs9584805 showed association with IHF, with the prevalence of NAFLD and baseline methylation level of the CpG site (cg00071727) associated with IHF%. Following 18‐month lifestyle intervention, differential DNA‐methylation patterns were observed between diets at cg14335324 annotated to A2MP1 (P = .04, LF vs. MED/LC), and differential DNA‐methylation between PA groups within AC074286.1, CRACR2A, and FARP1 CpGs (P < .05 for all, PA−vs. PA+).
Conclusions
This study suggests epigenetic markers for IHF and potential epigenetic remodeling after long‐term lifestyle interventions.
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