Association between diabetes and cancer. Current mechanistic insights into the association and future challenges.

Compelling pieces of epidemiological, clinical, and experimental research have demonstrated that Diabetes mellitus (DM) is a major risk factor associated with increased cancer incidence and mortality in many human neoplasms. In the pathophysiology context of DM, many of the main classical actors are relevant elements that can fuel the different steps of the carcinogenesis process. Hyperglycemia, hyperinsulinemia, metabolic inflammation, and dyslipidemia are among the classic contributors to this association. Furthermore, new emerging actors have received particular attention in the last few years, and compelling data support that the microbiome, the epigenetic changes, the reticulum endoplasmic stress, and the increased glycolytic influx also play important roles in promoting the development of many cancer types. The arsenal of glucose-lowering therapeutic agents used for treating diabetes is wide and diverse, and a growing body of data raised during the last two decades has tried to clarify the contribution of therapeutic agents to this association. However, this research area remains controversial, because some anti-diabetic drugs are now considered as either promotors or protecting elements. In the present review, we intend to highlight the compelling epidemiological shreds of evidence that support this association, as well as the mechanistic contributions of many of these potential pathological mechanisms, some controversial points as well as future challenges.

The First Population-Level Description of Women Diagnosed With Invasive Breast Cancer in Costa Rica From 2008 to 2012: A Cross-Sectional Study.

INTRODUCTION: Breast cancer is the leading cause of cancer-related deaths among women worldwide. In Costa Rica, it ranks first in incidence and fourth in terms of mortality. However, there is a lack of comprehensive information on treatment patterns and outcomes for breast cancer patients in Costa Rica. METHODS: This study utilized data from the National Tumor Registry, which was merged with the Costa Rica Social Security Fund (CCSS) to ensure comprehensive access to clinical information. The study is prospective and focused on patients diagnosed with breast cancer between January 2008 and December 2012. This combined dataset allowed for a more comprehensive analysis of patient characteristics, treatment patterns, and outcomes related to breast cancer in Costa Rica. RESULTS: Among the 4775 patients diagnosed during this period, 3160 met the inclusion criteria for our study. The average age at diagnosis was 59.1 years, with 32.5% of patients being over the age of 65. Most of the patients (55.4%) identified themselves as homemakers, while 46.5% underwent core needle biopsy for diagnosis. Approximately 60% of women were diagnosed with early-stage disease (IA, IIA, and IIB), while 1.7% had metastatic disease, mainly affecting the bone. The mean interval between diagnosis and surgery was 72 days. Most patients (88.7%) received surgery as their initial treatment, and over half (54.4%) received some form of adjuvant therapy. Additionally, 85.6% of patients completed their prescribed treatment. CONCLUSION: This study provides a comprehensive and detailed description of the characteristics and treatment patterns among breast cancer patients in Costa Rica. The findings contribute to our understanding of the disease in this population and can serve as a foundation for further research and improvement in breast cancer management and care.

Contribution of RAGE axis activation to the association between metabolic syndrome and cancer.

Far beyond the compelling proofs supporting that the metabolic syndrome represents a risk factor for diabetes and cardiovascular diseases, a growing body of evidence suggests that it is also a risk factor for different types of cancer. However, the involved molecular mechanisms underlying this association are not fully understood, and they have been mainly focused on the individual contributions of each component of the metabolic syndrome such as obesity, hyperglycemia, and high blood pressure to the development of cancer. The Receptor for Advanced Glycation End-products (RAGE) axis activation has emerged as an important contributor to the pathophysiology of many clinical entities, by fueling a chronic inflammatory milieu, and thus supporting an optimal microenvironment to promote tumor growth and progression. In the present review, we intend to highlight that RAGE axis activation is a crosswise element on the potential mechanistic contributions of some relevant components of metabolic syndrome into the association with cancer.

Healthy eating recommendations: good for reducing dietary contribution to the body's advanced glycation/lipoxidation end products pool?

The present review aims to give dietary recommendations to reduce the occurrence of the Maillard reaction in foods and in vivo to reduce the body's advanced glycation/lipoxidation end products (AGE/ALE) pool. A healthy diet, food reformulation and good culinary practices may be feasible for achieving the goal. A varied diet rich in fresh vegetables and fruits, non-added sugar beverages containing inhibitors of the Maillard reaction, and foods prepared by steaming and poaching as culinary techniques is recommended. Intake of supplements and novel foods with low sugars, low fats, enriched in bioactive compounds from food and waste able to modulate carbohydrate metabolism and reduce body's AGE/ALE pool is also recommended. In conclusion, the recommendations made for healthy eating by the Spanish Society of Community Nutrition (SENC) and Harvard University seem to be adequate to reduce dietary AGE/ALE, the body's AGE/ALE pool and to achieve sustainable nutrition and health.

Gastric Tumor Microenvironment.

A compelling body of evidence has demonstrated that gastric cancer has a very particular tumor microenvironment, a signature very suitable to promote tumor progression and metastasis. Recent investigations have provided new insights into the multiple molecular mechanisms, defined by genetic and epigenetic mechanisms, supporting a very active cross talk between the components of the tumor microenvironment and thus defining the fate of tumor progression. In this review, we intend to highlight the role of very active contributors at gastric cancer TME, particularly cancer-associated fibroblasts, bone marrow-derived cells, tumor-associated macrophages, and tumor-infiltrating neutrophils, all of them surrounded by an overtime changing extracellular matrix. In addition, the very active cross talk between the components of the tumor microenvironment, defined by genetic and epigenetic mechanisms, thus defining the fate of tumor progression, is also reviewed.

HMGB1 decreases CCR-2 expression and migration of M2 macrophages under hypoxia.

OBJECTIVE: The hypoxic milieu at tumor microenvironment is able to drive the behavior of infiltrating tumor cells. Considering that hypoxia-mediated HMGB1 release is known to promote tumor growth, as well to enhance the pro-tumoral profile of M2 macrophages by a RAGE-dependent mechanism, it is tempting to evaluate the potential contribution of HMGB1 under hypoxia to restrain M2 macrophages mobility. METHODS: CCR-2 expression was evaluated in M2 polarized macrophages by western blotting and immunocytochemistry. The secreted levels of CCL-2 and the migration capability were evaluated using an ELISA and a chemotaxis assay, respectively. RESULTS: HMGB1, under hypoxic conditions, markedly reduce both the production of CCL-2 and the expression of its receptor CCR-2; and reduced the migration capacity of M2 macrophages. CONCLUSIONS: These results provided new insights into the mechanisms that regulate M2 macrophages mobility at the tumor microenvironment.

Cr(VI) adsorption from aqueous solution by fungal bioremediation based using Rhizopus sp.

The highly toxic species of Chromium in its hexavalent state is an important hazard to the flora and fauna, causing a rupture in balance especially in aquatic environments. The removal of Cr(VI) ions from aqueous solutions using fungal biomass of Rhizopus sp. was investigated under batch experiments. The biomass was produced and treated with NaCl to compare pre-treated and untreated biosorbents capacity. Adsorption of Cr(VI) was investigated with a 23 experimental design to determine the best operational parameters including pH [2.0-4.0], temperature [20-40 °C] and agitation [50-150 rpm]. Maximum Cr(VI) uptake (99%) indicated that pH 2.0 is the optimal for Cr(VI) removal. Linear and non-linear kinetic models were evaluated. The best fitting for linear kinetics was the pseudo-second order linear equation and the Elovich model in its non-linear form, suggesting chemisorption as the controlling step of adsorption. Results followed Langmuir isotherm equation, the qm was 9.95 (mg·g-1) for Rhizopus sp. + NaCl. Thermodynamic parameters were calculated using the adsorption equilibrium constant obtained from Langmuir isotherm and indicated that the adsorption process was spontaneous and endothermic. The surface characteristics of the biomass were analyzed by Fourier transform infrared (FTIR) spectra; the analysis showed the involvement of amino groups in the bonding with Cr(VI). SEM and EDX analysis confirmed the presence of Cr in the biomass after adsorption. The results of these experiments may be utilized for modeling, simulation, and scale-up processes in the future.

Improving oral health in migrant and underserved populations: evaluation of an interactive, community-based oral health education program in Washington state.

OBJECTIVES: Oral health is one of the greatest unmet health needs of migrant farmworkers and many migrant workers lack basic oral health knowledge. This paper presents evaluation results for an oral health education program designed to both increase knowledge concerning oral health practices and to gain a better understanding of the knowledge, attitudes and behaviors regarding oral health among migrant workers. METHODS: We used a pre-post uncontrolled design to assess the impact of the education program on participant knowledge about oral health practices. Changes in knowledge were assessed using a paper and pencil survey given to participants before the session began (pre) and at the end of the session (post). The pre-post survey was supplemented by qualitative information in the form of participant self-reported barriers and facilitators, and figure drawings illustrating their feelings about the state of their own oral health. RESULTS: There were 311 participants in 12 workshops held in 2017 throughout Washington State. There were statistically significant increases in knowledge for all of the pre/post survey questions. Questions with particularly large improvements included: the results of having a mouth infection, factors causing oral health problems, and whether children in low-income families experience more tooth decay. CONCLUSIONS: An interactive, lay-led oral health education program can be an effective way to increase oral health knowledge in migrant populations. Recommendations for similar programs include using interactive approaches to engage participants, being open to learning and changing your own thinking, and using lay leaders for the education sessions.

Extracellular matrix glycation and receptor for advanced glycation end-products activation: a missing piece in the puzzle of the association between diabetes and cancer.

A growing body of epidemiologic evidence suggests that people with diabetes are at a significantly higher risk of many forms of cancer. However, the molecular mechanisms underlying this association are not fully understood. Cancer cells are surrounded by a complex milieu, also known as tumor microenvironment, which contributes to the development and metastasis of tumors. Of note, one of the major components of this niche is the extracellular matrix (ECM), which becomes highly disorganized during neoplastic progression, thereby stimulating cancer cell transformation, growth and spread. One of the consequences of chronic hyperglycemia, the most frequently observed sign of diabetes and the etiological source of diabetes complications, is the irreversible glycation and oxidation of proteins and lipids leading to the formation of the advanced glycation end-products (AGEs). These compounds may covalently crosslink and biochemically modify structure and functions of many proteins, and AGEs accumulation is particularly high in long-living proteins with low biological turnover, features that are shared by most, if not all, ECM proteins. AGEs-modified proteins are recognized by AGE-binding proteins, and thus glycated ECM components have the potential to trigger Receptor for advanced glycation end-products-dependent mechanisms. The biological consequence of receptor for advanced glycation end-products activation mechanisms seems to be connected, in different ways, to drive some hallmarks of cancer onset and tumor growth. The present review intends to highlight the potential impact of ECM glycation on tumor progression by triggering receptor for advanced glycation end-products-mediated mechanisms.

HMGB1 enhances the protumoral activities of M2 macrophages by a RAGE-dependent mechanism.

The monocyte-macrophage lineage shows a high degree of diversity and plasticity. Once they infiltrate tissues, they may acquire two main functional phenotypes, being known as the classically activated type 1 macrophages (M1) and the alternative activated type 2 macrophages (M2). The M1 phenotype can be induced by bacterial products and interferon-γ and exerts a cytotoxic effect on cancer cells. Conversely, the alternatively activated M2 phenotype is induced by Il-4/IL13 and promotes tumor cell growth and vascularization. Although receptor for advanced glycation end-products (RAGE) engagement in M1 macrophages has been reported by several groups to promote inflammation, nothing is known about the functionality of RAGE in M2 macrophages. In the current study, we demonstrate that RAGE is equally expressed in both macrophage phenotypes and that RAGE activation by high-mobility group protein box1 (HMGB1) promotes protumoral activities of M2 macrophages. MKN45 cells co-cultured with M2 macrophages treated with HMGB1 at different times displayed higher invasive abilities. Additionally, conditioned medium from HMGB1-treated M2 macrophages promotes angiogenesis in vitro. RAGE-targeting knockdown abrogates these activities. Overall, the present findings suggest that HMGB1 may contribute, by a RAGE-dependent mechanism, to the protumoral activities of the M2 phenotype.

The RAGE Axis: A Relevant Inflammatory Hub in Human Diseases.

In 1992, a transcendental report suggested that the receptor of advanced glycation end-products (RAGE) functions as a cell surface receptor for a wide and diverse group of compounds, commonly referred to as advanced glycation end-products (AGEs), resulting from the non-enzymatic glycation of lipids and proteins in response to hyperglycemia. The interaction of these compounds with RAGE represents an essential element in triggering the cellular response to proteins or lipids that become glycated. Although initially demonstrated for diabetes complications, a growing body of evidence clearly supports RAGE's role in human diseases. Moreover, the recognizing capacities of this receptor have been extended to a plethora of structurally diverse ligands. As a result, it has been acknowledged as a pattern recognition receptor (PRR) and functionally categorized as the RAGE axis. The ligation to RAGE leads the initiation of a complex signaling cascade and thus triggering crucial cellular events in the pathophysiology of many human diseases. In the present review, we intend to summarize basic features of the RAGE axis biology as well as its contribution to some relevant human diseases such as metabolic diseases, neurodegenerative, cardiovascular, autoimmune, and chronic airways diseases, and cancer as a result of exposure to AGEs, as well as many other ligands.

Emerging and multifaceted potential contributions of polyphenols in the management of type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is recognized as a serious public health concern with a considerable impact on human life, long-term health expenditures, and substantial health losses. In this context, the use of dietary polyphenols to prevent and manage T2DM is widely documented. These dietary compounds exert their beneficial effects through several actions, including the protection of pancreatic islet ß-cell, the antioxidant capacities of these molecules, their effects on insulin secretion and actions, the regulation of intestinal microbiota, and their contribution to ameliorate diabetic complications, particularly those of vascular origin. In the present review, we intend to highlight these multifaceted actions and the molecular mechanisms by which these plant-derived secondary metabolites exert their beneficial effects on type 2 diabetes patients.

Empowering Agricultural Workers Through Community Health Worker-Led Pesticide Safety Workshops in Washington State.

Background: It is difficult to reach migrant or refugee agricultural workers about pesticide exposure prevention. Here, we describe a community health worker (CHW)-led pesticide exposure prevention workshop and the impact of this program among migrant and refugee workers in Washington state. Methods: A focus group of migrants and refugees participated in the development of a CHW-led Spanish language pesticide exposure prevention mobile phone app and workshop. Pre- and post-workshop surveys assessed pesticide training, knowledge, and characteristics. Results: Community health workers facilitated 28 workshops attended by 263 participants from 49 agricultural communities. Approximately 79% of participants reported no prior pesticide training. Significant improvements were observed in the proportion familiar with illnesses associated with pesticides, knowledge about pesticide definition, ability to correctly identify the content of pesticide labels, and the correct method to wash fruits and vegetables. Conclusions: Community health workers are effective in addressing the gaps in pesticide safety education and awareness among migrant and refugee communities. Further work is needed to assess how to better integrate a mobile phone app into this training and subsequent use of the knowledge.

Contributions of the receptor for advanced glycation end products axis activation in gastric cancer.

Compelling shreds of evidence derived from both clinical and experimental research have demonstrated the crucial contribution of receptor for advanced glycation end products (RAGE) axis activation in the development of neoplasms, including gastric cancer (GC). This new actor in tumor biology plays an important role in the onset of a crucial and long-lasting inflammatory milieu, not only by supporting phenotypic changes favoring growth and dissemination of tumor cells, but also by functioning as a pattern-recognition receptor in the inflammatory response to Helicobacter pylori infection. In the present review, we aim to highlight how the overexpression and activation of the RAGE axis contributes to the proliferation and survival of GC cells as and their acquisition of more invasive phenotypes that promote dissemination and metastasis. Finally, the contribution of some single nucleotide polymorphisms in the RAGE gene as susceptibility or poor prognosis factors is also discussed.

Community Health Worker-led Implementation of the Stanford Youth Diabetes Coaching Program in Underserved Latinx Communities.

BACKGROUND: The Stanford Youth Diabetes Coaching Program (SYDCP) is an evidence-based program led by health care professionals to teach healthy youth who then coach family members with diabetes or other chronic conditions. This purpose of this study is to evaluate a Community Health Worker (CHW)-led implementation of the SYDCP for low-income Latinx students from underserved agricultural communities. METHOD: CHWs were trained and virtually led 10 training sessions virtually during the COVID-19 for Latinx students who were recruited from high schools in agricultural regions of Washington state. Feasibility measures include recruitment, retention, class attendance, and successful coaching of a family member or friend. Acceptability was measured by responses on the post-training survey. Effectiveness was evaluated by pre-post changes in measures used in prior studies of the SYDCP such as level of activation and diabetes knowledge. RESULTS: Thirty-four students were recruited, 28 completed the training and 23 returned both pre- and post-surveys. Over 80% of students attended 7 or more classes. All met with a family or friend and 74% met with them weekly. Approximately 80% of the students rated the program's usefulness as "very good" or "excellent." Pre-post increases in diabetes knowledge, nutrition-related behaviors, resilience, and activation were significant and similar to those observed in prior published studies of the SYDCP. CONCLUSIONS: Findings support the feasibility, acceptability, and effectiveness of a CHW-led implementation of the SYDCP in underserved Latinx communities using a virtual remote model.

The RAGE/multiligand axis: a new actor in tumor biology.

The receptor for advanced glycation end-products (RAGE) is a multiligand binding and single-pass transmembrane protein which actively participates in several chronic inflammation-related diseases. RAGE, in addition to AGEs, has a wide repertoire of ligands, including several damage-associated molecular pattern molecules or alarmins such as HMGB1 and members of the S100 family proteins. Over the last years, a large and compelling body of evidence has revealed the active participation of the RAGE axis in tumor biology based on its active involvement in several crucial mechanisms involved in tumor growth, immune evasion, dissemination, as well as by sculpturing of the tumor microenvironment as a tumor-supportive niche. In the present review, we will detail the consequences of the RAGE axis activation to fuel essential mechanisms to guarantee tumor growth and spreading.