The CARE System in Its Importance in Dealing with Today's Crises1.

The CARE system is a gift from Mother Nature, we have it in our biological heritage; it enables us humans-as a basic gift-to help each other in a large, life-serving context, and thus also to counterbalance destruction. It is about a basic human ability, linked to typical behaviour, but also about a basic human need for connectedness. In this paper, I would like to show how the CARE system can be activated as a collective attitude. The CARE system is strengthened by positive emotions. We are currently being affected by many crises and this triggers fear. How can we deal with this better? Fear is countered with hope and the associated positive emotions such as joy, awe, kama muta and others. These emotions and feelings can be consciously encouraged and placed alongside the feelings of fear. But also, when we share the feelings of grief with each other, it triggers an attitude of CARE. We can grieve together for the various experiences of loss that we go through-but we can also imagine together how we envisage a future that is worth living for everyone. An attitude in the sense of CARING has been practised in friendship for thousands of years. It would therefore be possible to move away from an attitude of competing and outdoing, to an attitude not only of recognition, care, and solidarity in human interaction, but also in our connection with nature.

Le système CARE (prendre soin) est un cadeau de Mère Nature, nous l'avons dans notre patrimoine biologique ; il nous permet, à nous les humains, en tant que don fondamental, de nous entraider dans un contexte vaste et vital et donc aussi de faire contrepoids à la destruction. Il s'agit d'une capacité humaine fondamentale, liée à un comportement typique, mais aussi du besoin humain fondamental d'être en lien. Dans cet article, j'aimerais montrer comment le système CARE peut être activé en tant qu'attitude collective. Le système CARE est renforcé par des émotions positives. Nous sommes actuellement touchés par de nombreuses crises, ce qui suscite la peur. Comment pouvons­nous mieux gérer cette situation ? La peur est contrée par l'espoir et les émotions positives qui y sont associées telles que la joie, la crainte, kama muta et autres. Ces émotions et ces sentiments peuvent être consciemment encouragés et placés à côté des sentiments de peur. Mais aussi, lorsque nous partageons les sentiments d'affliction les uns avec les autres, cela déclenche une attitude de BIENVEILLANCE. Nous pouvons faire ensemble le deuil dans diverses expériences de perte que nous traversons, mais nous pouvons aussi imaginer ensemble comment nous envisageons un avenir qui vaut la peine d'être vécu pour tous. Une attitude cultivant la BIENVEILLANCE est pratiquée dans l'amitié depuis des milliers d'années. Il serait donc possible de passer d'une attitude de compétition, et qui vise à supplanter, à une attitude non seulement de reconnaissance, d'attention et de solidarité dans l'interaction humaine, mais aussi dans notre relation avec la nature.

El sistema DE CUIDADO es un regalo de la Madre Naturaleza, lo tenemos en nuestra herencia biológica; nos permite a los humanos ­como regalo básico­ ayudarnos unos a otros en un contexto amplio, al servicio de la vida, y así también contrarrestar la destrucción. Se trata de una capacidad humana básica, vinculada al comportamiento típico, pero también de una necesidad humana básica de conexión. En este artículo, me gustaría mostrar cómo el sistema DE CUIDADO puede activarse como una actitud colectiva. El sistema DE CUIDADO se fortalece a través de emociones positivas. Actualmente nos vemos afectados por muchas crisis, y esto desencadena el miedo. ¿Cómo podemos afrontarlo mejor? El miedo se contrarresta con la esperanza y las emociones positivas asociadas, como la alegría, el asombro, el kama muta y otras. Estas emociones y sentimientos pueden fomentarse conscientemente y ocupar un lugar junto al miedo. Pero también, cuando compartimos los sentimientos de dolor con otros, se desencadena una actitud de CUIDADO. Podemos sentir juntos el dolor por las diversas experiencias de pérdida por las que pasamos, pero también podemos imaginar juntos un futuro que merezca la pena vivir para todos. Una actitud en el sentido de CUIDAR se practica en la amistad desde hace miles de años. Por lo tanto, sería posible pasar de una actitud de competencia y superación a una actitud no sólo de reconocimiento, cuidado y solidaridad en la interacción humana, sino también en nuestra conexión con la naturaleza.

RIPK1 and RIPK3 are positive prognosticators for cervical cancer patients and C2 ceramide can inhibit tumor cell proliferation in vitro.

Introduction: The enzymes Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) und 3 (RIPK3) as well as the protein Mixed lineage kinase domain like pseudokinase (pMLKL) play a role in the signaling cascade of necroptosis. This is a form of programmed cell death which is caspase-independent. High-risk human papilloma virus infection can inhibit necroptosis. Thereby, a persistent infection and consequently the development of cervical cancer can be triggered. Aim of this study was the analysis of the expression of RIPK1, RIPK3 and pMLKL in cervical cancer tissue and the evaluation of its prognostic value on overall survival, progression-free survival and additional clinical parameters. Methods: The expression of RIPK1, RIPK3, and pMLKL in cervical cancer tissue microarrays of n = 250 patients was analyzed immunohistochemically. Further, the effect of C2 ceramide on several cervical cancer cell lines (CaSki, HeLa, SiHa) was examined. C2 ceramide is a biologically active short-chain ceramide that induces necroptosis in human luteal granulosa cells. Results: Significantly longer overall survival and progression-free survival rates could be detected in cervical cancer patients expressing nuclear RIPK1 or RIPK3 alone or simultaneously (RIPK1 and RIPK3). Cell viability and proliferation was reduced through C2 ceramide stimulation of cervical cancer cells. Simultaneous stimulation of C2 ceramide and the pan-caspase inhibitor Z-VAD-fmk, or the RIPK1-inhibitor necrostatin-1, partly reversed the negative effect of C2 ceramide on cell viability. This observation could imply that caspase-dependent and -independent forms of cell death, including necroptosis, can occur. AnnexinV-FITC apoptosis staining induced a significant increase in apoptotic cells in CaSki and SiHa cells. The stimulation of CaSki cells with C2 ceramide led to a significant percentual increase in necrotic/intermediate (dying) cells after stimulation with C2 ceramide. In addition, after stimulation with C2 ceramide, CaSki and HeLa cells live cell imaging showed morphological changes which are common for necroptosis. Discussion: In conclusion, RIPK1 and RIPK3 are independent positive predictors for overall survival and progression-free survival in cervical cancer patients. C2 ceramide can reduce cell viability and proliferation in cervical cancer cells by inducing most likely both apoptosis and necroptosis.

A Tumor Microenvironment Model of Pancreatic Cancer to Elucidate Responses toward Immunotherapy.

Pancreatic cancer is a devastating malignancy with minimal treatment options. Standard-of-care therapy, including surgery and chemotherapy, is unsatisfactory, and therapies harnessing the immune system have been unsuccessful in clinical trials. Resistance to therapy and disease progression are mediated by the tumor microenvironment, which contains excessive amounts of extracellular matrix and stromal cells, acting as a barrier to drug delivery. There is a lack of preclinical pancreatic cancer models that reconstruct the extracellular, cellular, and biomechanical elements of tumor tissues to assess responses toward immunotherapy. To address this limitation and explore the effects of immunotherapy in combination with chemotherapy, a multicellular 3D cancer model using a star-shaped poly(ethylene glycol)-heparin hydrogel matrix is developed. Human pancreatic cancer cells, cancer-associated fibroblasts, and myeloid cells are grown encapsulated in hydrogels to mimic key components of tumor tissues, and cell responses toward treatment are assessed. Combining the CD11b agonist ADH-503 with anti-PD-1 immunotherapy and chemotherapy leads to a significant reduction in tumor cell viability, proliferation, metabolic activity, immunomodulation, and secretion of immunosuppressive and tumor growth-promoting cytokines.

3D Collagen-Nanocellulose Matrices Model the Tumour Microenvironment of Pancreatic Cancer.

Three-dimensional (3D) cancer models are invaluable tools designed to study tumour biology and new treatments. Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest types of cancer, has been progressively explored with bioengineered 3D approaches by deconstructing elements of its tumour microenvironment. Here, we investigated the suitability of collagen-nanocellulose hydrogels to mimic the extracellular matrix of PDAC and to promote the formation of tumour spheroids and multicellular 3D cultures with stromal cells. Blending of type I collagen fibrils and cellulose nanofibres formed a matrix of controllable stiffness, which resembled the lower profile of pancreatic tumour tissues. Collagen-nanocellulose hydrogels supported the growth of tumour spheroids and multicellular 3D cultures, with increased metabolic activity and matrix stiffness. To validate our 3D cancer model, we tested the individual and combined effects of the anti-cancer compound triptolide and the chemotherapeutics gemcitabine and paclitaxel, resulting in differential cell responses. Our blended 3D matrices with tuneable mechanical properties consistently maintain the growth of PDAC cells and its cellular microenvironment and allow the screening of anti-cancer treatments.

Kallikrein-Related Peptidase 6 Is Associated with the Tumour Microenvironment of Pancreatic Ductal Adenocarcinoma.

As cancer-associated factors, kallikrein-related peptidases (KLKs) are components of the tumour microenvironment, which represents a rich substrate repertoire, and considered attractive targets for the development of novel treatments. Standard-of-care therapy of pancreatic cancer shows unsatisfactory results, indicating the need for alternative therapeutic approaches. We aimed to investigate the expression of KLKs in pancreatic cancer and to inhibit the function of KLK6 in pancreatic cancer cells. KLK6, KLK7, KLK8, KLK10 and KLK11 were coexpressed and upregulated in tissues from pancreatic cancer patients compared to normal pancreas. Their high expression levels correlated with each other and were linked to shorter survival compared to low KLK levels. We then validated KLK6 mRNA and protein expression in patient-derived tissues and pancreatic cancer cells. Coexpression of KLK6 with KRT19, αSMA or CD68 was independent of tumour stage, while KLK6 was coexpressed with KRT19 and CD68 in the invasive tumour area. High KLK6 levels in tumour and CD68+ cells were linked to shorter survival. KLK6 inhibition reduced KLK6 mRNA expression, cell metabolic activity and KLK6 secretion and increased the secretion of other serine and aspartic lysosomal proteases. The association of high KLK levels and poor prognosis suggests that inhibiting KLKs may be a therapeutic strategy for precision medicine.

3D Models for Ovarian Cancer.

The main reasons for the slow progress in improving survival outcomes for ovarian cancer are the 'one-size-fits-all' therapy and lack of clinically relevant experimental models that represent the advanced stages of the human disease. The interaction of tumour cells with their surrounding niche, the tumour microenvironment, influences the spread of ovarian cancer cells within the peritoneum and their responses to therapeutics. Scientists are increasingly using 3D cell culture models to dissect the role of the tumour microenvironment in cancer development and progression and the treatment of this disease. In this chapter, we will briefly describe the tumour microenvironment of ovarian cancer. Then, we will review some of the clinically relevant experimental approaches, such as spheroid, organoid and organotypic models, that have been developed for the 3D culture of ovarian cancer cells using different tools, including hydrogels, scaffolds and cancer-on-a-chip devices, to mimic selected components of the tumour microenvironment.

Inhibitor of apoptosis proteins are potential targets for treatment of granulosa cell tumors - implications from studies in KGN.

BACKGROUND: Granulosa cell tumors (GCTs) are derived from proliferating granulosa cells of the ovarian follicle. They are known for their late recurrence and most patients with an aggressive form die from their disease. There are no treatment options for this slowly proliferating tumor besides surgery and chemotherapy. In a number of tumors, analogs of the second mitochondria-derived activator of caspases (SMAC), alone or in combination with other molecules, such as TNFα, are evolving as new treatment options. SMAC mimetics block inhibitor of apoptosis proteins (IAPs), which bind caspases (e.g. XIAP), or activate the pro-survival NF-κB pathway (e.g. cIAP1/2). Expression of IAPs by GCTs is yet not fully elucidated but recently XIAP and its inhibition by SMAC mimetics in a combination therapy was described to induce apoptosis in a GCT cell line, KGN. We evaluated the expression of cIAP1 in GCTs and elucidated the effects of the SMAC mimetic BV-6 using KGN as a model. RESULTS: Employing immunohistochemistry, we observed cIAP1 expression in a tissue microarray (TMA) of 42 GCT samples. RT-PCR confirmed expression of cIAP1/2, as well as XIAP, in primary, patient-derived GCTs and in KGN. We therefore tested the ability of the bivalent SMAC mimetic BV-6, which is known to inhibit cIAP1/2 and XIAP, to induce cell death in KGN. A dose response study indicated an EC50 ≈ 8 µM for both, early (< 8) and advanced (> 80) passages, which differ in growth rate and presumably aggressiveness. Quantitative RT-PCR showed upregulation of NF-κB regulated genes in BV-6 stimulated cells. Blocking experiments with the pan-caspase inhibitor Z-VAD-FMK indicated caspase-dependence. A concentration of 20 µM Z-VAD-FMK was sufficient to significantly reduce apoptosis. This cell death was further substantiated by results of Western Blot studies. Cleaved caspase 3 and cleaved PARP became evident in the BV-6 treated group. CONCLUSIONS: Taken together, the results show that BV-6 is able to induce apoptosis in KGN cells. This approach may therefore offer a promising therapeutic avenue to treat GCTs.

Complexes and imagination.

Fantasies as imaginative activities are seen by Jung as expressions of psychic energy. In the various descriptions of active imagination the observation of the inner image and the dialogue with inner figures, if possible, are important. The model of symbol formation, as Jung describes it, can be experienced in doing active imagination. There is a correspondence between Jung's understanding of complexes and our imaginations: complexes develop a fantasy life. Complex episodes are narratives of difficult dysfunctional relationship episodes that have occurred repeatedly and are internalized with episodic memory. This means that the whole complex episode (the image for the child and the image for the aggressor, connected with emotions) is internalized and can get constellated in everyday relationship. Therefore inner dialogues do not necessarily qualify as active imaginations, often they are the expression of complex-episodes, very similar to fruitless soliloquies. If imaginations of this kind are repeated, new symbols and new possibilities of behaviour are not found. On the contrary, old patterns of behaviour and fantasies are perpetuated and become cemented. Imaginations of this kind need an intervention by the analyst. In clinical examples different kinds of imaginations are discussed.

Comments on 'the case of Melanie' and the reaction of Eduardo Gastelumendi.

Following an attempt to connect the theory of archetypes with the theory of primal phantasies, the commentary refers to how moments of complexity may be differentiated in terms of 'now moments' and concludes with an amplification of the 'black woman' in Melanie's dream related to a black woman in an important Austrian fairy tale.