Sociocultural incentives for cancer care implementation

The implementation and modification of cancer care systems in low- and middle-income countries (LMICs) to achieve Universal Health Coverage (UHC) for the entire population is usually accompanied not only by intensive and rapid changes in the delivery processes and system structure, but also by severe impact on human resources and sociocultural aspects of cancer care delivery. At the same time this is caused by and results in complex changes in clinical routines, in collaborative patterns among healthcare providers, professions and disciplines, as well as in the behavior of healthcare workers, patients or other stakeholders, and in the organization of cancer care [1]. Since allocation of qualitatively and quantitatively sufficient human resources to the entire population is a major challenge for cancer care in LIMCs, understanding of sociocultural incentives and their strategic use becomes of high importance [2]. These sociocultural incentives include various types of driving motivations that are not directly related to remuneration of healthcare service, such as free housing, access to professional education, social perception and appreciation, among others. Their importance is especially true for the care of patients with metastatic disease, given their vulnerability and particular clinical needs. Here we consider the impact of sociocultural incentives in this context

RASSF1A-Mediated Suppression of Estrogen Receptor Alpha (ERα)-Driven Breast Cancer Cell Growth Depends on the Hippo-Kinases LATS1 and 2

Around 70% of breast cancers express the estrogen receptor alpha (ERα). This receptor is of central importance for breast cancer development and estrogen-dependent tumor growth. However, the molecular mechanisms that are responsible for the control of ERα expression and function in the context of breast carcinogenesis are complex and not fully understood. In previous work, we have demonstrated that the tumor suppressor RASSF1A suppresses estrogen-dependent growth of breast cancer cells through a complex network that keeps ERα expression and function under control. We observed that RASSF1A mediates the suppression of ERα expression through modulation of the Hippo effector Yes-associated protein 1 (YAP1) activity. Here we report that RASSF1A-mediated alteration of YAP1 depends on the Hippo-kinases LATS1 and LATS2. Based on these results, we conclude that inactivation of RASSF1A causes changes in the function of the Hippo signaling pathway and altered activation of YAP1, and as a consequence, increased expression and function of ERα. Thus, the inactivation of RASSF1A might constitute a fundamental event that supports the initiation of ERα-dependent breast cancer. Furthermore, our results support the notion that the Hippo pathway is important for the suppression of luminal breast cancers, and that the tumor-suppressor function of RASSF1A depends on LATS1 and LATS2

CEMIP, a Promising Biomarker That Promotes the Progression and Metastasis of Colorectal and Other Types of Cancer

Originally discovered as a hypothetical protein with unknown function, CEMIP (cell migration-inducing and hyaluronan-binding protein) has been implicated in the pathogenesis of numerous diseases, including deafness, arthritis, atherosclerosis, idiopathic pulmonary fibrosis, and cancer. Although a comprehensive definition of its molecular functions is still in progress, major functions ascribed to CEMIP include the depolymerization of the extracellular matrix component hyaluronic acid (HA) and the regulation of a number of signaling pathways. CEMIP is a promising biomarker for colorectal cancer. Its expression is associated with poor prognosis for patients suffering from colorectal and other types of cancer and functionally contributes to tumor progression and metastasis. Here, we review our current understanding of how CEMIP is able to foster the process of tumor growth and metastasis, focusing particularly on colorectal cancer. Studies in cancer cells suggest that CEMIP exerts its pro-tumorigenic and pro-metastatic activities through stimulating migration and invasion, suppressing cell death and promoting survival, degrading HA, regulating pro-metastatic signaling pathways, inducing the epithelial–mesenchymal transition (EMT) program, and contributing to the metabolic reprogramming and pre-metastatic conditioning of future metastatic microenvironments. There is also increasing evidence indicating that CEMIP may be expressed in cells within the tumor microenvironment that promote tumorigenesis and metastasis formation, although this remains in an early stage of investigation. CEMIP expression and activity can be therapeutically targeted at a number of levels, and preliminary findings in animal models show encouraging results in terms of reduced tumor growth and metastasis, as well as combating therapy resistance. Taken together, CEMIP represents an exciting new player in the progression of colorectal and other types of cancer that holds promise as a therapeutic target and biomarker

Optimization of human, animal, and environmental health by using the One Health approach

Emerging diseases are increasing burdens on public health, negatively affecting the world economy, causing extinction of species, and disrupting ecological integrity. One Health recognizes that human, domestic animal, and wildlife health are interconnected within ecosystem health and provides a framework for the development of multidisciplinary solutions to global health challenges. To date, most health-promoting interventions have focused largely on single-sector outcomes. For example, risk for transmission of zoonotic pathogens from bush-meat hunting is primarily focused on human hygiene and personal protection. However, bush-meat hunting is a complex issue promoting the need for holistic strategies to reduce transmission of zoonotic disease while addressing food security and wildlife conservation issues. Temporal and spatial separation of humans and wildlife, risk communication, and other preventative strategies should allow wildlife and humans to co-exist. Upstream surveillance, vaccination, and other tools to prevent pathogen spillover are also needed. Clear multi-sector outcomes should be defined, and a systems-based approach is needed to develop interventions that reduce risks and balance the needs of humans, wildlife, and the environment. The ultimate goal is long-term action to reduce forces driving emerging diseases and provide interdisciplinary scientific approaches to management of risks, thereby achieving optimal outcomes for human, animal, and environmental health

A cautionary note: Toxicity of polyethylene glycol 200 injected intraperitoneally into mice

The parenteral administration of hydrophobic substances in vivo requires the use of organic solvents to ensure sufficient solubility and avoid precipitation. Dimethyl sulfoxide is commonly used for this purpose. Based on the common assumption that polyethylene glycol (PEG) is non-toxic, our local regulatory authorities recently recommended the use of PEG instead. However, mice injected intraperitoneally (i.p.) with PEG 200 at a dose of 8 mL/kg (i.e. 9 g/kg) did not tolerate PEG 200 well, and half of the animals had to be euthanized. Our results demonstrate that although PEG 200 is generally considered to be harmless, it can be toxic when injected i.p. and is painful for the recipient mice. Nevertheless, it can be used as a solvent for repeated i.p. injections in mice at a dose of 2 mL/kg (i.e. 2.25 g/kg) without obvious signs of systemic toxicity

Strategies for Wildlife Disease Surveillance

Epidemiologic surveillance is defined by the Centers for Disease Control and Prevention (CDC) as the ongoing systematic and continuous collection, analysis, and interpretation of health data\u27: The objective of surveillance is to generate data for rapid response to the detection of a disease of concern to apply prevention, control, or eradication measures as well as to evaluate such interventions. This is distinct from disease monitoring, which usually does not involve a particular response to disease detection. Surveillance for wildlife diseases has increased in importance due to the emergence and re-emergence of wildlife diseases that are threats to human, animal, and ecosystem health, or could potentially have a negative economic impact. It has been estimated that 75% of emerging human diseases are zoonotic in origin, of which the majority originate from wildlife (Taylor et al. 2001). However, there are unique challenges concerning wildlife disease surveillance such that disease and pathogens can be very difficult to detect and measure in wild animals. These challenges have been described previously (Wobeser 2006), but one of the primary issues is that disease in wildlife often goes unrecognized, especially in remote locations. Furthermore, sick and dead animals are very difficult to detect, as animals will disguise the signs of illness or hide when diseased. Carcasses from diseased animals are also rapidly removed by scavengers or will rapidly decompose, rendering them suboptimal for diagnostic purposes. There is also a lack of validated diagnostic tests for most wildlife disease agents as well as baseline data. The paucity of laboratory capacity with expertise in wildlife disease diagnostic investigation is also an impediment. Finally, surveillance networks for wildlife diseases that perform field investigations and report disease events are under-developed in most regions of the world. Despite these challenges, a number of very important epidemiological surveillance projects have been ongoing or recently developed, and some examples are described in this chapter. The examples are mostly drawn from the experiences of the U.S. Geological Survey National Wildlife Health Center (NWHC) and are provided to illustrate the different surveillance strategies and sampling techniques that can be used and have proven successful. Some future directions for wildlife disease surveillance are also suggested

RASSF1A Suppresses Estrogen-Dependent Breast Cancer Cell Growth through Inhibition of the Yes-Associated Protein 1 (YAP1), Inhibition of the Forkhead Box Protein M1 (FOXM1), and Activation of Forkhead Box Transcription Factor 3A (FOXO3A)

The estrogen receptor alpha (ERα) is expressed by the majority of breast cancers and plays an important role in breast cancer development and tumor outgrowth. Although ERα is well known to be a specific and efficient therapeutic target, the molecular mechanisms that are responsible for the control of ERα expression and function in the context of breast cancer initiation and progression are complex and not completely elucidated. In previous work, we have demonstrated that the tumor suppressor RASSF1A inhibits ERα expression and function in ERα-positive breast cancer cells through an AKT-dependent mechanism. Transcriptional activators such as forkhead box protein M1 (FOXM1) and forkhead transcription factor 3A (FOXO3A) and signaling pathways such as the Hippo pathway are also known to modulate ERα expression and activity. Here we report that RASSF1A acts as an inhibitor of ERα-driven breast cancer cell growth through a complex, hierarchically organized network that initially involves suppression of the Hippo effector Yes-associated protein 1 (YAP1), which is followed by inhibition of AKT1 activity, increased FOXO3A activity as well as a blockade of FOXM1 and ERα expression. Together our findings provide important new mechanistic insights into how the loss of RASSF1A contributes to ERα+ breast cancer initiation and progression

Extracellular regulation of BMP signaling: welcome to the matrix

Given its importance in development and homeostasis, bone morphogenetic protein (BMP) signaling is tightly regulated at the extra-and intracellular level. The extracellular matrix (ECM) was initially thought to act as a passive mechanical barrier that sequesters BMPs. However, a new understanding about how the ECM plays an instructive role in regulating BMP signaling is emerging. In this mini-review, we discuss various ways in which the biochemical and physical properties of the ECM regulate BMP signaling

Detection of Cellular Senescence Reveals the Existence of Senescent Tumor Cells within Invasive Breast Carcinomas and Related Metastases

Oncogene-induced senescence is thought to constitute a barrier to carcinogenesis by arresting cells at risk of malignant transformation. However, numerous findings suggest that senescent cells may conversely promote tumor growth and metastatic progression, for example, through the senescence-associated secretory phenotype (SASP) they produce. Here, we investigated the degree to which senescent tumor cells exist within untreated human primary breast carcinomas and whether the presence of senescent cancer cells in primary tumors is recapitulated in their matched lymph node metastases. For the detection of senescence, we used SA-β-galactosidase (SA-β-gal) staining and other senescence markers such as Ki67, p21, p53, and p16. In patients with invasive luminal A and B breast carcinomas, we found broad similarities in the appearance of cancer cells between primary tumors and their corresponding metastases. Analysis of lymph nodes from patients with other breast cancer subtypes also revealed senescent tumor cells within metastatic lesions. Collectively, our findings show that senescent tumor cells exist within primary breast carcinomas and metastatic lesions. These results suggest a potential role for senescent breast tumor cells during metastatic progression and raise the question as to whether the targeting of senescent tumor cells with anti-senescent drugs might represent a novel avenue for improved treatment of breast and other cancers