Exploitation In Therapy Research Articles

Epigenetics in a Spectrum of Myeloid Diseases and Its Exploitation for Therapy.

Simple SummaryThe genome is stored in the limited space of the nucleus in a highly condensed form. The regulation of this packaging contributes to determining the accessibility of genes and is important for cell function. Genes affecting the genome’s packaging are frequently mutated in bone marrow cells that give rise to the different types of blood cells. Here, we first discuss the molecular functions of these genes and their role in blood generation under healthy conditions. Then, we describe how their mutations relate to a subset of diseases including blood cancers. Finally, we provide an overview of the current efforts of using and developing drugs targeting these and related genes.Mutations in genes encoding chromatin regulators are early events contributing to developing asymptomatic clonal hematopoiesis of indeterminate potential and its frequent progression to myeloid diseases with increasing severity. We focus on the subset of myeloid diseases encompassing myelodysplastic syndromes and their transformation to secondary acute myeloid leukemia. We introduce the major concepts of chromatin regulation that provide the basis of epigenetic regulation. In greater detail, we discuss those chromatin regulators that are frequently mutated in myelodysplastic syndromes. We discuss their role in the epigenetic regulation of normal hematopoiesis and the consequence of their mutation. Finally, we provide an update on the drugs interfering with chromatin regulation approved or in development for myelodysplastic syndromes and acute myeloid leukemia.

Prostaglandin E2 Receptor 4 (EP4) as a Therapeutic Target to Impede Breast Cancer-Associated Angiogenesis and Lymphangiogenesis.

Simple SummaryThe formation of new blood (angiogenesis) and lymphatic (lymphangiogenesis) vessels are major events associated with most epithelial malignancies, including breast cancer. Inflammation is a key mediator of both processes, hijacked by many cancers by the aberrant expression of the inflammation-associated enzyme cyclo-oxygenase (COX)-2. In this review, we focus on breast cancer and show that COX-2 is a major promoter of both events, primarily resulting from the activation of prostaglandin (PG) E receptor EP4 on tumor cells, tumor-infiltrating immune cells, and endothelial cells; and induction of oncogenic microRNAs. The COX-2/EP4 pathway also promotes additional events in breast cancer progression, such as cancer cell migration, invasion, and the stimulation of stem-like cells. Based on a combination of studies using multiple breast cancer models, we show that EP4 antagonists hold a major promise in breast cancer therapy in combination with other modalities including immune check-point inhibitors.The formation of new blood (angiogenesis) and lymphatic (lymphangiogenesis) vessels are major events associated with most epithelial malignancies, including breast cancer. Angiogenesis is essential for cancer cell survival. Lymphangiogenesis is critical in maintaining tumoral interstitial fluid balance and importing tumor-facilitatory immune cells. Both vascular routes also serve as conduits for cancer metastasis. Intratumoral hypoxia promotes both events by stimulating multiple angiogenic/lymphangiogenic growth factors. Studies on tumor-associated lymphangiogenesis and its exploitation for therapy have received less attention from the research community than those on angiogenesis. Inflammation is a key mediator of both processes, hijacked by many cancers by the aberrant expression of the inflammation-associated enzyme cyclo-oxygenase (COX)-2. In this review, we focus on breast cancer and showed that COX-2 is a major promoter of both events, primarily resulting from the activation of prostaglandin (PG) E receptor EP4 on tumor cells, tumor-infiltrating immune cells, and endothelial cells; and the induction of oncogenic microRNAs. The COX-2/EP4 pathway also promotes additional events in breast cancer progression, such as cancer cell migration, invasion, and the stimulation of stem-like cells. Based on a combination of studies using multiple breast cancer models, we show that EP4 antagonists hold a major promise in breast cancer therapy in combination with other modalities including immune check-point inhibitors.

The Multifaceted Roles of MSCs in the Tumor Microenvironment: Interactions With Immune Cells and Exploitation for Therapy.

The tumor microenvironment (TME) plays a critical role in tumorigenesis and is composed of different cellular components, including immune cells and mesenchymal stromal cells (MSCs). In this review, we will discuss MSCs in the TME setting and more specifically their interactions with immune cells and how they can both inhibit (immunosurveillance) and favor (immunoediting) tumor growth. We will also discuss how MSCs are used as a therapeutic strategy in cancer. Due to their unique immunomodulatory properties, MSCs isolated from perinatal tissues are intensely explored as therapeutic interventions in various inflammatory-based disorders with promising results. However, their therapeutic applications in cancer remain for the most part controversial and, importantly, the interactions between administered perinatal MSC and immune cells in the TME remain to be clearly defined.

Mesenchymal stem cells-based therapy as a potential treatment in neurodegenerative disorders: is the escape from senescence an answer?

Aging is the most prominent risk factor contributing to the development of neurodegenerative disorders. In the United States, over 35 million of elderly people suffer from age-related diseases. Aging impairs the self-repair ability of neuronal cells, which undergo progressive deterioration. Once initiated, this process hampers the already limited regenerative power of the central nervous system, making the search for new therapeutic strategies particularly difficult in elderly affected patients. So far, mesenchymal stem cells have proven to be a viable option to ameliorate certain aspects of neurodegeneration, as they possess high proliferative rate and differentiate in vitro into multiple lineages. However, accumulating data have demonstrated that during long-term culture, mesenchymal stem cells undergo spontaneous transformation. Transformed mesenchymal stem cells show typical features of senescence, including the progressive shortening of telomers, which results in cell loss and, as a consequence, hampered regenerative potential. These evidences, in line with those observed in mesenchymal stem cells isolated from old donors, suggest that senescence may represent a limit to mesenchymal stem cells exploitation in therapy, prompting scholars to either find alternative sources of pluripotent cells or to arrest the age-related transformation. In the present review, we summarize findings from recent literature, and critically discuss some of the major hurdles encountered in the search of appropriate sources of mesenchymal stem cells, as well as benefits arising from their use in neurodegenerative diseases. Finally, we provide some insights that may aid in the development of strategies to arrest or, at least, delay the aging of mesenchymal stem cells to improve their therapeutic potential.

The Therapeutic Potential of Modifying Inflammasomes and NOD-Like Receptors

Inflammasomes are the central processing units (CPUs) responsible for decoding and integrating signals of foreignness, damage, danger, and distress released by pathogens, cells, and tissues. It was initially thought that the inflammasomes participated only in pathogen recognition and in the pathogenesis of a few, rare, hereditary inflammatory disorders. On the contrary, it is now clear that they have a central role in the pathogenesis of basically all types of chronic inflammation, in metabolic diseases and cancer. So far, six or possibly eight inflammasome subtypes have been identified. Their main, but by no means exclusive, function is to catalyze conversion of pro-IL-1β and pro-IL-18 into their respective mature forms. However, the different inflammasome subtypes may also participate in additional responses, e.g., proliferation, regulation of glycolytic metabolism, or cell activation, albeit it is not clear whether these effects are still mediated through IL-1β release or via modulation of other caspase-1-dependent or -independent pathways. Central to inflammasome organization and activity are proteins belonging to the nucleotide binding domain, leucine-rich repeat, or NOD-like receptor family. One relevant exception is the AIM2 inflammasome. NOD-like receptors belong to the superfamily of pattern recognition receptors, a group of highly conserved molecules specialized in the recognition of invariant molecular patterns diffused across species. Given their potent proinflammatory activity, it is anticipated that inflammasome activation is tightly controlled. In this review, I will summarize essential features of the known NOD-like receptors, the basic molecular structure of inflammasomes, their participation in pathophysiological responses, and their possible exploitation for therapy.

NK cell-mediated immune response against cancer

The past fifteen years have witnessed great progress in our undestanding of how natural killer (NK) cells function, their role in innate defenses and their possible exploitation in therapy. This contribution traces the major advances in these formerly mysterious cells, from the first discovery of HLA-class I-specific inhibitory receptors to a more recent major breakgthrough that highlighted important perspectives and major expectations regarding the cure of life-threatening leukemias. The key role of "alloreactive" NK cells in eradicating acute myeloid leukemias and in preventing both graft rejection and graft-versus-host disease, led to a true revolution in bone marrow transplantation. Thus, it is now possible to search for appropriate HLA class I mismatches to set NK cells in action to cure high risk leukemias.

Exploitation in therapy and counselling: A breach of professional standards

Exploitation in therapy and counselling may occur in only a minority of cases, but when it does, its effects are potentially damaging to both the client and the profession. Exploitation in therapy may take the form of psychological, covert and overt abuse. The most reported form of abuse of the therapeutic relationship is of a sexual nature. However, psychological abuse usually forms the backdrop to sexual exploitation, preceding and perpetuating the sexual involvement. Sexual exploitation in therapy is an abuse of the power imbued in the therapist by nature of his professional role. It allows the therapist a sexual gratification which he would not have been likely to achieve outside the therapeutic relationship. The prevention of sexual exploitation in therapy is an issue of concern to training, employing and professional organisations who seek to maintain high standards of counselling delivery. Determining the variables which may contribute to exploitation is fundamental to avoiding its incidence. This paper discusses the factors underlying the use of therapy and counselling as a medium for therapist abuse. It examines (i) the prevailing conditions for abuse to occur, (ii) how the therapist overcomes client resistance, and (iii) the implications for the maintenance of professional standards.