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Cancer drug resistance is an enormous problem. It is responsible for most relapses in cancer patients following apparent remission after successful therapy. Understanding cancer relapse requires an understanding of the processes underlying cancer drug resistance. This article discusses the causes of cancer drug resistance, the current combination therapies, and the problems with the combination therapies. The rational design of combination therapy is warranted to improve the efficacy. These processes must be addressed by finding ways to sensitize the drug-resistant cancers cells to chemotherapy, and to prevent formation of drug resistant cancer cells. It is also necessary to prevent the formation of cancer progenitor cells by epigenetic mechanisms, as cancer progenitor cells are insensitive to standard therapies. In this article, we emphasize the role for the rational development of combination therapy, including epigenetic drugs, in achieving these goals.

EMT and MET comprise the processes by which cells transit between epithelial and mesenchymal states, and they play integral roles in both normal development and cancer metastasis. This article reviews these processes and the molecular pathways that contribute to them. First, we compare embryogenesis and development with cancer metastasis. We then discuss the signaling pathways and the differential expression and down-regulation of receptors in both tumor cells and stromal cells, which play a role in EMT and metastasis. We further delve into the clinical implications of EMT and MET in several types of tumors, and lastly, we discuss the role of epigenetic events that regulate EMT/MET processes. We hypothesize that reversible epigenetic events regulate both EMT and MET, and thus, also regulate the development of different types of metastatic cancers.

The evolution process includes genetic alterations that started with prokaryotes and now continues in humans. A distinct difference between prokaryotic chromosomes and eukaryotic chromosomes involves histones. As evolution progressed, genetic alterations accumulated and a mechanism for gene selection developed. It was as if nature was experimenting to optimally utilize the gene pool without changing individual gene sequences. This mechanism is called epigenetics, as it is above the genome. Curiously, the mechanism of epigenetic regulation in prokaryotes is strikingly different from that in eukaryotes, mainly higher eukaryotes, like mammals. In fact, epigenetics plays a significant role in the conserved process of embryogenesis and human development. Malfunction of epigenetic regulation results in many types of undesirable effects, including cardiovascular disease, metabolic disorders, autoimmune diseases, and cancer. This review provides a comparative analysis and new insights into these aspects.

In efforts to reduce maternal and neonatal mortality, it is recommended that all pregnant women be counseled on signs of pregnancy related complications and neonatal illness. In resource limited settings, such counselling may be task-shifted to lay health workers. We conducted a community-based cross-sectional survey of community health workers/volunteers in North and East Kamagambo of the Rongo Sub- County of Migori County, Kenya, between January-April 2018. A survey tool was administered through face-to-face interviews to investigate the level of knowledge of obstetric and neonatal danger signs among community health workers in North Kamagambo after one year of participation in the Lwala program, as well as to evaluate baseline knowledge of community health volunteers in East Kamagambo at the beginning of Lwala's expansion and prior to their receiving training from Lwala. The North Kamagambo group identified more danger signs in each category. The percentage of participants with adequate knowledge in the pregnancy, postpartum, and neonatal categories was significantly higher in North Kamagambo than in East Kamagambo. Sixty percent of participants in North Kamagambo knew 3 or more danger signs in 3 or more categories, compared to 24% of participants in East Kamagambo. Location in North Kamagambo (OR 2.526, p=0.03) and a shorter time since most recent training (OR 2.291, p=0.025) were associated with increased knowledge. Our study revealed varying levels of knowledge among two populations of lay health workers. This study highlights the benefit of frequent trainings and placing greater emphasis on identified gaps in knowledge of the labor and postpartum periods. (Afr J Reprod Health 2020; 24[1]: 121-132). Afin de réduire la mortalité maternelle et néonatale, il est recommandé de conseiller toutes les femmes enceintes sur les signes de complications liées à la grossesse et de la maladie néonatale. Dans les milieux à ressources limitées, ces conseils peuvent être confiés à des agents de santé non professionnels. Nous avons mené une enquête transversale communautaire auprès des agents de santé communautaires / bénévoles dans le nord et l'est de Kamagambo du sous-comté de Rongo du comté de Migori, au Kenya, entre janvier et avril 2018. Un outil d'enquête a été administré par le biais des entretiens face à face pour enquêter sur le niveau de connaissance des signes de danger obstétricaux et néonatals chez les agents de santé communautaire de Kamagambo du Nord après un an de participation au programme Lwala ; ensuite pour évaluer les connaissances de base des volontaires de santé communautaire à Kamagambo de l'Est au début de l'expansion de Lwala et avant de recevoir une formation de Lwala. Le groupe de Kamagambo du Nord a identifié plus de signes de danger dans chaque catégorie. Le pourcentage de participants ayant des connaissances adéquates dans les catégories de la grossesse, du post-partum et du nouveau-né était significativement plus élevé à Kamagambo du Nord qu'à Kamagambo de l'Est. Soixante pour cent des participants à Kamagambo du Nord connaissaient 3 signes de danger ou plus dans 3 catégories ou plus, contre 24% des participants à Kamagambo de l'Est. La localisation à Kamagambo du Nord (OR 2,526, p = 0,03) et un temps plus court depuis la formation la plus récente (OR 2,291, p = 0,025) ont été associés à une connaissance accrue. Notre étude a révélé des niveaux de connaissances variables entre deux populations d'agents de santé non professionnels. Cette étude met en évidence les avantages des formations fréquentes et met davantage l'accent sur les lacunes identifiées dans la connaissance des périodes de travail et du post-partum. (Afr J Reprod Health 2020; 24[1]: 121-132).

The concept of cancer stem cells was proposed in the late 1990s. Although initially the idea seemed controversial, the existence of cancer stem cells is now well established. However, the process leading to the formation of cancer stem cells is still not clear and thus requires further research. This article discusses epigenetic events that possibly produce cancer progenitor cells from predisposed cells by the influence of their environment. Every somatic cell possesses an epigenetic signature in terms of histone modifications and DNA methylation, which are obtained during lineage-specific differentiation of pluripotent stem cells, which is specific to that particular tissue. We call this signature an epigenetic switch. The epigenetic switch is not fixed. Our epigenome alters with aging. However, depending on the predisposition of the cells of a particular tissue and their microenvironment, the balance of the switch (histone modifications and the DNA methylation) may be tilted to immortality in a few cells, which generates cancer progenitor cells.

Epigenetic regulation in eukaryotic and mammalian systems is a complex and emerging field of study. While histone modifications create an open chromatin conformation allowing for gene transcription, CpG methylation adds a further dimension to the expression of specific genes in developmental pathways and carcinogenesis. In this review, we will highlight DNA methylation as one of the distinct mechanisms for gene silencing and try to provide insight into the role of epigenetics in cancer progenitor cell formation and carcinogenesis. We will also introduce the concept of a dynamic methylation-demethylation system and the potential for the existence of a demethylating enzyme in this process. Finally, we will explain how re-expression of epigenetically silenced tumor suppressor genes could be exploited to develop effective drug therapies. In particular, we will consider how a combination therapy that includes epigenetic drugs could possibly kill cancer progenitor cells and reduce the chance of relapse following chemotherapy.

Breast cancer persists as the most common cause of cancer death in women worldwide. Ovarian cancer is also a significant source of morbidity and mortality, as the fifth leading cause of cancer death among women. This reflects the continued need for further understanding and innovation in cancer treatment. Though breast and ovarian cancer usually present as distinct clinical entities, the recent explosion of large-scale -omics research has uncovered many overlaps, particularly with respect to genetic and epigenetic alterations. We compared genetic, microenvironmental, stromal, and epigenetic changes common between breast and ovarian cancer cells, as well as the clinical relevance of these changes. Some of the most striking commonalities include genetic alterations of BRCA1 and 2, TP53, RB1, NF1, FAT3, MYC, PTEN, and PIK3CA; down regulation of miRNAs 9, 100, 125a, 125b, and 214; and epigenetic alterations such as H3K27me3, H3K9me2, H3K9me3, H4K20me3, and H3K4me. These parallels suggest shared features of pathogenesis. Furthermore, preliminary evidence suggests a shared epigenetic mechanism of oncogenesis. These similarities, warrant further investigation in order to ultimately inform development of more effective chemotherapeutics, as well as strategies to circumvent drug resistance.

Cancers have the ability to develop resistance to traditional therapies, and the increasing prevalence of these drug resistant cancers necessitates further research and treatment development. This paper outlines the current knowledge of mechanisms that promote or enable drug resistance, such as drug inactivation, drug target alteration, drug efflux, DNA damage repair, cell death inhibition, and the epithelial-mesenchymal transition, as well as how inherent tumor cell heterogeneity plays a role in drug resistance. It also describes the epigenetic modifications that can induce drug resistance and considers how such epigenetic factors may contribute to the development of cancer progenitor cells, which are not killed by conventional cancer therapies. Lastly, this review concludes with a discussion on the best treatment options for existing drug resistant cancers, ways to prevent the formation of drug resistant cancers and cancer progenitor cells, and future directions of study.

Epigenetic changes such as DNA methylation and histone methylation and acetylation alter gene expression at the level of transcription by upregulat-ing, downregulating, or silencing genes completely. Dysregulation of epigenetic events can be pathological, leading to cardiovascular disease, neurological disorders, metabolic disorders, and cancer development. Therefore, identifying drugs that inhibit these epigenetic changes are of great clinical interest. In this review, we summarize the epigenetic events associated with different disorders and diseases including cardiovascular, neurological, and metabolic disorders, and cancer. Knowledge of the specific epigenetic changes associated with these types of diseases facilitates the development of specific inhibitors, which can be used as epigenetic drugs. In this review, we discuss the major classes of epigenetic drugs currently in use, such as DNA methylation inhibiting drugs, bromodomain inhibitors, histone acetyl transferase inhibitors, histone deacetylase inhibitors, protein methyltransferase inhibitors, and histone methylation inhibitors and their role in reversing epigenetic changes and treating disease.

NF-κB is an evolutionarily conserved eukaryotic transcription factor that plays a role in many important developmental and immune-related processes by activating target gene expression. The goal of these experiments was to define the sequences required for a sea anemone NF-κB's intrinsic transactivation activity by using mutant proteins with serial deletions of the N- and C-terminal sequences. Deletion mutants were constructed that were missing the C-terminal 15, 32 or 47 amino acids (aa) or the N-terminal 17, 27 or 47 aa of the 440 aa NF-κB protein from the starlet sea anemone, Nematostella vectensis (Nv), a simple model organism in the phylum Cnidaria. These Nv-NF-κB mutants were expressed as GAL4 fusion proteins in yeast, and their transactivation activities were assessed by LacZ reporter gene assays. The deletion of 47 aa from either the N terminus or the C terminus of NF-κB completely inactivates the transactivation function of Nv-NF-κB. In addition, we identified proline-258 in the center of the protein as a key residue for the transactivation function of Nv-NF-κB. Taken together, these results demonstrate that non-conserved N- and C-terminal residues are both required for the transcriptional activating function of the sea anemone NF-κB protein, suggesting that it has a novel functional domain structure among known NF-κB proteins.