RAGE (Receptor for Advanced Glycation Endproducts), RAGE Ligands, and their role in Cancer and Inflammation

The Receptor for Advanced Glycation Endproducts [RAGE] is an evolutionarily recent member of the immunoglobulin super-family, encoded in the Class III region of the major histocompatability complex. RAGE is highly expressed only in the lung at readily measurable levels but increases quickly at sites of inflammation, largely on inflammatory and epithelial cells. It is found either as a membrane-bound or soluble protein that is markedly upregulated by stress in epithelial cells, thereby regulating their metabolism and enhancing their central barrier functionality. Activation and upregulation of RAGE by its ligands leads to enhanced survival. Perpetual signaling through RAGE-induced survival pathways in the setting of limited nutrients or oxygenation results in enhanced autophagy, diminished apoptosis, and (with ATP depletion) necrosis. This results in chronic inflammation and in many instances is the setting in which epithelial malignancies arise. RAGE and its isoforms sit in a pivotal role, regulating metabolism, inflammation, and epithelial survival in the setting of stress. Understanding the molecular structure and function of it and its ligands in the setting of inflammation is critically important in understanding the role of this receptor in tumor biology

Consensus Report of the 2015 Weinman International Conference on Mesothelioma.

On November 9 and 10, 2015, the International Conference on Mesothelioma in Populations Exposed to Naturally Occurring Asbestiform Fibers was held at the University of Hawaii Cancer Center in Honolulu, Hawaii. The meeting was cosponsored by the International Association for the Study of Lung Cancer, and the agenda was designed with significant input from staff at the U.S. National Cancer Institute and National Institute of Environmental Health Sciences. A multidisciplinary group of participants presented updates reflecting a range of disciplinary perspectives, including mineralogy, geology, epidemiology, toxicology, biochemistry, molecular biology, genetics, public health, and clinical oncology. The group identified knowledge gaps that are barriers to preventing and treating malignant mesothelioma (MM) and the required next steps to address barriers. This manuscript reports the group's efforts and focus on strategies to limit risk to the population and reduce the incidence of MM. Four main topics were explored: genetic risk, environmental exposure, biomarkers, and clinical interventions. Genetics plays a critical role in MM when the disease occurs in carriers of germline BRCA1 associated protein 1 mutations. Moreover, it appears likely that, in addition to BRCA1 associated protein 1, other yet unknown genetic variants may also influence the individual risk for development of MM, especially after exposure to asbestos and related mineral fibers. MM is an almost entirely preventable malignancy as it is most often caused by exposure to commercial asbestos or mineral fibers with asbestos-like health effects, such as erionite. In the past in North America and in Europe, the most prominent source of exposure was related to occupation. Present regulations have reduced occupational exposure in these countries; however, some people continue to be exposed to previously installed asbestos in older construction and other settings. Moreover, an increasing number of people are being exposed in rural areas that contain noncommercial asbestos, erionite, and other mineral fibers in soil or rock (termed naturally occurring asbestos [NOA]) and are being developed. Public health authorities, scientists, residents, and other affected groups must work together in the areas where exposure to asbestos, including NOA, has been documented in the environment to mitigate or reduce this exposure. Although a blood biomarker validated to be effective for use in screening and identifying MM at an early stage in asbestos/NOA-exposed populations is not currently available, novel biomarkers presented at the meeting, such as high mobility group box 1 and fibulin-3, are promising. There was general agreement that current treatment for MM, which is based on surgery and standard chemotherapy, has a modest effect on the overall survival (OS), which remains dismal. Additionally, although much needed novel therapeutic approaches for MM are being developed and explored in clinical trials, there is a critical need to invest in prevention research, in which there is a great opportunity to reduce the incidence and mortality from MM

Fear and loathing in the Caribbean: three studies of fear and cancer screening in Brooklyn's immigrant Caribbean subpopulations

Background: Anxiety, worry, and fear are among the most common emotional responses to the threat of disease and several studies have linked various fears to cancer preventive and detection behaviors. Cancer-related worry and fears about screening or its consequences are also characteristics that vary across ethnic groups and may be differentially linked to screening outcomes 1. Limiting the utility of this growing literature are at least two key considerations. First, little attention has been paid to documenting variation in cancer-related fears among subpopulations of persons of African descent, despite evidence that (a) rates of screening may vary among both male 2 and female 3 immigrants from islands in the Caribbean living in the United States and (b) incidence rates for cancers such as those of the prostate may be very high in men from Jamaica 4, Guadaloupe 5 and Trinidad and Tobago 6, as well as in immigrant groups in both the United Kingdom 7 and United States 8. Second, findings regarding the relations anxiety, cancer worry, and screening fear hold with screening behavior seen thus far have been inconsistent, in our view because anxieties stemming from different sources have different relations with behavior. In the emotions theory view, understanding the role of fear in health behavior in diverse groups is predicated on understanding the object or source of the fear 91011 for the simple reason that anxiety motivates avoidance of particular elicitors 1012. Research conducted within the U54 Comprehensive Cancer Partnership between Long Island University and Columbia University has produced several studies documenting differences in breast and prostate cancer screening frequencies among Caribbean subpopulations living in Brooklyn, New York 11213. A major concentration in this program of behavioral research has investigated whether trait anxiety, cancer worry, and screening-related fears vary across Caribbean subpopulations and whether these highly differentiated emotional responses independently predict screening behavior in multivariate models 12121314. Consistent with theory, we expected that fears pertaining to the screening context (e.g., fear of pain or the psychological implications of certain screens), would predict avoidance of the fear-inducing situation and thus be associated with less frequent screening. Conversely, where fears relate to the disease itself, greater fear should predict more frequent screening. Methods: Because of our overarching interest in the links between cancer and cancer-screening-related fears and cancer screening behaviors among the diverse groups of men and women living in Brooklyn, New York, we combined data from three community-based studies. Although measures and samples varied somewhat across studies, each study investigated the link between emotions and screening outcome in ethnic groups that included immigrants from islands in the Caribbean. Because of our interest in examining differences within traditional racial categories, we used a combination of (a) self-categorization based on a the traditional racial categories offered in the US Census together with (b) information regarding country of origin. Allowing a combination of self-reported racial categorization (tapping aspects of identity and minority status) in concert with shared birthplace to influence groupings increases the likelihood that participants share cultural and developmental characteristics thought to form part of ethnicity 15. We distinguished between Black men born in the United States (hereafter, U.S.-born African Americans), and those originating from countries in the English-speaking Caribbean (e.g., Trinidad & Tobago, Jamaica, Barbados). Immigrant and non-immigrant minority groups were contrasted with men self-identifying as "European or White/Non-Hispanic" who were born in the United States (hereafter, U.S.-born European American). In Study 1, stratified cluster-sampling was used to recruit 1364 women (aged between 50–70 years) from six ethnic groups: US-born African American, US-born European American, immigrants from islands in the English-speaking Caribbean (Jamaica, Barbados, Trinidad and Tobago), the Dominican Republic, Haiti, and Eastern Europe 1. In Study 2, 180 US-born African American, US-born European American and immigrant Jamaican men (aged between 40–70 years) were recruited using convenience sampling 13. In Study 3, 533 men (aged between 45–70 years) from four groups – US-born African American, US-born European American, and immigrant men from Jamaica and from Trinidad and Tobago – were recruited 12. In each study, participants provided background data, reported on screening history for either breast or prostate cancer, and completed a measure of trait anxiety, cancer worry, and/or screening fears. Results: As expected, we found differences among groups of African descent from the United States and the Caribbean. Although women from all groups screened at rates below those recommended, data from Study 1 showed that English-speaking Caribbean, Haitian and Dominican women screened less frequently than US-born African Americans and European Americans and that immigrant Eastern European women were also infrequent screeners (see Figure 1). Conversely, however, there were no differences in rates of self-reported prostate screening among men from the English-speaking Caribbean, US-born African Americans, or US-born European Americans in either Study 2 or Study 3. As expected, cancer-related emotional characteristics also varied across subpopulations (see Figure 2). Cancer worry was generally lower among women from the various Caribbean immigrant groups (Study 1) than it was among US-born African Americans or US-born European Americans. Fears regarding screening, however, varied somewhat differently. Fear of screening was higher among US-born African Americans and immigrant men from the English-speaking Caribbean (Studies 2 and 3) than among US-born European Americans. Consistent with the need to carefully measure fear-related constructs in the context of cancer behavior, however, our data also demonstrated that a specific fear related to concerns regarding threats to masculinity in the context of male screening strongly characterized the attitudes of men from the English-speaking Caribbean compared to the views of US-born European and US-born African Americans (Study 2). Finally, a combination of multiple regression and ANOVAs in each study showed that emotional characteristics independently predicted screening, in most cases even when background characteristics were controlled. Across studies, greater cancer worry predicted more frequent screening while fear of screening predicted less frequent screening. Figure 1 Number of cancer screens in prior 10 years Number of cancer screens in prior 10 years. DRE = digital rectal examination, PSA = prostate specific antigen test, Mamm = mammogram, CBE = clinical breast exam. Figure 2 Emotion characteristics related to screening Emotion characteristics related to screening. Trait = trait anxiety, Worry = cancer worry, Scr. Fr. = screening fear, and Em. Con. = emasculation concern. Conclusion: Data from three large-scale studies in Brooklyn, New York suggest that members of immigrant Caribbean subpopulations screen for breast and prostate cancer at very low rates; in most cases lower than those of either US-born African or US-born European Americans. Groups of Caribbean men and women also vary in the emotions they report regarding cancer and the screening process, generally revealing a pattern that is predictive of poorer screening. Coupled with the fact that emotion characteristics predicted screening outcomes even when controlling for other factors, data from these three studies suggest that the emotional responses Caribbean groups place them at risk for poor screening. Interventions that address these responses may offer the prospect of improving screening frequency in these disadvantaged groups. Competing interests: The authors declare that they have no competing interests. Authors' contributions: NSC and CM was involved in study design, analysis, interpretation/write up and critical revision of the manuscript. BA and DH in the analysis, interpretation and write up. AKJ, TU and LNB were involved in the interpretation and write up. PMR was part of the study design, analysis and interpretation/write up. JMM and AIN had part in the study design, analysis and critical revision whilst JSJ took part in critical revision

Consensus Report of the 2015 Weinman International Conference on Mesothelioma

On November 9 and 10, 2015, the International Conference on Mesothelioma in Populations Exposed to Naturally Occurring Asbestiform Fibers was held at the University of Hawaii Cancer Center in Honolulu, Hawaii. The meeting was cosponsored by the International Association for the Study of Lung Cancer, and the agenda was designed with significant input from staff at the U.S. National Cancer Institute and National Institute of Environmental Health Sciences. A multidisciplinary group of participants presented updates reflecting a range of disciplinary perspectives, including mineralogy, geology, epidemiology, toxicology, biochemistry, molecular biology, genetics, public health, and clinical oncology. The group identified knowledge gaps that are barriers to preventing and treating malignant mesothelioma (MM) and the required next steps to address barriers. This manuscript reports the group's efforts and focus on strategies to limit risk to the population and reduce the incidence of MM. Four main topics were explored: genetic risk, environmental exposure, biomarkers, and clinical interventions. Genetics plays a critical role in MM when the disease occurs in carriers of germline BRCA1 associated protein 1 mutations. Moreover, it appears likely that, in addition to BRCA1 associated protein 1, other yet unknown genetic variants may also influence the individual risk for development of MM, especially after exposure to asbestos and related mineral fibers. MM is an almost entirely preventable malignancy as it is most often caused by exposure to commercial asbestos or mineral fibers with asbestos-like health effects, such as erionite. In the past in North America and in Europe, the most prominent source of exposure was related to occupation. Present regulations have reduced occupational exposure in these countries; however, some people continue to be exposed to previously installed asbestos in older construction and other settings. Moreover, an increasing number of people are being exposed in rural areas that contain noncommercial asbestos, erionite, and other mineral fibers in soil or rock (termed naturally occurring asbestos [NOA] ) and are being developed. Public health authorities, scientists, residents, and other affected groups must work together in the areas where exposure to asbestos, including NOA, has been documented in the environment to mitigate or reduce this exposure. Although a blood biomarker validated to be effective for use in screening and identifying MM at an early stage in asbestos/NOA-exposed populations is not currently available, novel biomarkers presented at the meeting, such as high mobility group box 1 and fibulin-3, are promising. There was general agreement that current treatment for MM, which is based on surgery and standard chemotherapy, has a modest effect on the overall survival (OS), which remains dismal. Additionally, although much needed novel therapeutic approaches for MM are being developed and explored in clinical trials, there is a critical need to invest in prevention research, in which there is a great opportunity to reduce the incidence and mortality from MM