There are well-established disparities in cancer incidence and outcomes by race/ethnicity that result from the interplay between structural, socioeconomic, socio-environmental, behavioural and ...biological factors. However, large research studies designed to investigate factors contributing to cancer aetiology and progression have mainly focused on populations of European origin. The limitations in clinicopathological and genetic data, as well as the reduced availability of biospecimens from diverse populations, contribute to the knowledge gap and have the potential to widen cancer health disparities. In this review, we summarise reported disparities and associated factors in the United States of America (USA) for the most common cancers (breast, prostate, lung and colon), and for a subset of other cancers that highlight the complexity of disparities (gastric, liver, pancreas and leukaemia). We focus on populations commonly identified and referred to as racial/ethnic minorities in the USA-African Americans/Blacks, American Indians and Alaska Natives, Asians, Native Hawaiians/other Pacific Islanders and Hispanics/Latinos. We conclude that even though substantial progress has been made in understanding the factors underlying cancer health disparities, marked inequities persist. Additional efforts are needed to include participants from diverse populations in the research of cancer aetiology, biology and treatment. Furthermore, to eliminate cancer health disparities, it will be necessary to facilitate access to, and utilisation of, health services to all individuals, and to address structural inequities, including racism, that disproportionally affect racial/ethnic minorities in the USA.
Human breastmilk contains pro- and anti-inflammatory compounds and hormones that can influence infant growth. However, little is known about the specific interrelationships between these compounds ...and whether their effects on infant growth may be influenced by pre-pregnancy weight status.
The purpose of this novel, prospective cohort study was to assess the interrelationships between pro-inflammatory cytokines (TNF-α, IL-6), hormones (insulin, leptin) and PUFAs (n-6, n-3) in blood and breastmilk in early postpartum between women with normal BMI (Group 1, n = 18; 18.5<BMI≤24.9 kg/m2) and with overweight/obesity (Group 2, n = 15; BMI≥25.0 kg/m2) before pregnancy to determine if these components correlated to infant growth measures at age 4-8 weeks.
Participants were robustly phenotyped along with their infants at 4-8 weeks postpartum. TNF-α, IL-6, insulin, leptin, and n-3 and n-6 PUFAs measured in blood and breastmilk and compared between pre-pregnancy BMI groups and with infant weight, length, head circumference and % fat mass.
Group 1 women had higher serum leptin (p<0.01) and breastmilk leptin (p<0.001) compared to Group 2. Other inflammatory markers, hormones, and total n-6, n-3 and n-6/n-3 ratio PUFAs were similar between pre-pregnancy BMI groups. No relationships were observed between whey inflammatory markers, hormones, PUFAs and growth measures in infants born to Group 2 women. However, TNF-α was positively related and, IL-6, leptin, insulin, total n-6, n-3 and n-6/n-3 PUFAs in whey breastmilk were negatively correlated to infant growth measures in infants born to Group 1 women (p<0.01).
Pro-inflammatory qualities of breastmilk were associated with infant growth measures regardless of maternal pre-pregnancy BMI. However, infants born to women with overweight or obesity demonstrated less responsive growth to breastmilk contents. More studies are needed to assess longitudinal effects of this impact.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Myeloid-derived suppressor cells (MDSC) promote tumor growth by blocking anti-tumor T cell responses. Recent reports show that MDSC increase fatty acid uptake and fatty acid oxidation (FAO) to ...support their immunosuppressive functions. Inhibition of FAO promoted a therapeutic T cell-mediated anti-tumor effect. Here, we sought to determine the mechanisms by which tumor-infiltrating MDSC increase the uptake of exogenous lipids and undergo metabolic and functional reprogramming to become highly immunosuppressive cells. The results showed that tumor-derived cytokines (G-CSF and GM-CSF) and the subsequent signaling through STAT3 and STAT5 induce the expression of lipid transport receptors with the resulting increase in the uptake of lipids present at high concentrations in the tumor microenvironment. The intracellular accumulation of lipids increases the oxidative metabolism and activates the immunosuppressive mechanisms. Inhibition of STAT3 or STAT5 signaling or genetic depletion of the fatty acid translocase CD36 inhibits the activation of oxidative metabolism and the induction of immunosuppressive function in tumor-infiltrating MDSC and results in a CD8
+
T cell-dependent delay in tumor growth. Of note, human tumor-infiltrating and peripheral blood MDSC also upregulate the expression of lipid transport proteins, and lipids promote the generation of highly suppressive human MDSC in vitro. Our data therefore provide a mechanism by which tumor-derived factors and the high lipid content in the tumor microenvironment can cause the profound metabolic and functional changes found in MDSC and suggest novel approaches to prevent or reverse these processes. These results could further enhance the efficacy of cancer immunotherapy.
Myeloid-derived suppressor cells (MDSC) producing arginase I are increased in the peripheral blood of patients with renal cell carcinoma (RCC). MDSC inhibit T-cell function by reducing the ...availability of L-arginine and are therefore considered an important tumor escape mechanism. We aimed to determine the origin of arginase I-producing MDSC in RCC patients and to identify the mechanisms used to deplete extracellular L-arginine. The results show that human MDSC are a subpopulation of activated polymorphonuclear (PMN) cells expressing high levels of CD66b, CD11b, and VEGFR1 and low levels of CD62L and CD16. In contrast to murine MDSC, human MDSC do not deplete L-arginine by increasing its uptake but instead release arginase I into the circulation. Activation of normal PMN induces phenotypic and functional changes similar to MDSC and also promotes the release of arginase I from intracellular granules. Interestingly, although activation of normal PMN usually ends with apoptosis, MDSC showed no increase in apoptosis compared with autologous PMN or PMN obtained from normal controls. High levels of VEGF have been shown to increase suppressor immature myeloid dendritic cells in cancer patients. Treatment of RCC patients with anti-VEGF antibody bevacizumab, however, did not reduce the accumulation of MDSC in peripheral blood. In contrast, the addition of interleukin-2 to the treatment increased the number of MDSC in peripheral blood and the plasma levels of arginase I. These results may provide new insights on the mechanisms of tumor-induced anergy/tolerance and may help explain why some immunotherapies fail to induce an antitumor response.
Helicobacter pylori (H. pylori) infection is a recognized risk factor for gastric cancer. The disease is one of the most common in the world and explains for a significant number of cancer cases and ...cancer-associated deaths worldwide. H. pylori infection induces huge array of responses at the gastric epithelial cells and the immune system, inducing both pro- and anti-inflammatory molecules that are intended to either perpetuate or control the infection. Despite the strong immune response, the infection is not cleared and can persist mostly without causing major significant discomfort in the human host. Among the mediators induced in response to the infection, microRNA (miRNA) have the potential to play a major impact on the outcome of the bacteria-host interaction. These miRNA are small 18-24 nucleotide long nucleotide molecules that can interact with mRNA molecules and block their translation into proteins or induce their degradation. Many efforts have been put into the generation of miRNA profiles and their role in gastric cancer. This has led to the identification of miRNA associated with promoting the inflammatory response initiated by the H. pylori infection, increasing the malignant progression of the gastric epithelium, and enhancing the invasiveness and migratory capacity of cancer cells. However, at the same time, several miRNA have been associated with events that are totally opposite, leading to reduced inflammation, inhibition of malignancy and increased apoptosis of transformed cells. In summary, as it is in many other examples, the role played by miRNA in gastric cancer is the results of a delicate balance between pro- and anti-cancer miRNA, and this balance is modified by the interaction of many players, many of which are still waiting to be discovered.
Estrogens may influence gastric cancer risk, but published studies are inconclusive. We therefore carried out a meta-analysis addressing the associations of gastric cancer in women with menstrual and ...reproductive factors and with use of estrogen- and antiestrogen-related therapies. Searches of PubMed up to June, 2011 and review of citations yielded a total of 28 independent studies, including at least one exposure of interest. Random effects pooled estimates of relative risk (RR) and corresponding 95% CIs were calculated for eight exposures reported in at least five studies, including: age at menarche, age at menopause, years of fertility, parity, age at first birth, oral contraceptive use, hormone replacement therapy (HRT), and tamoxifen treatment. Longer years of fertility (RR = 0.74, 95% CI: 0.63-0.86) and HRT (RR = 0.77; 95% CI: 0.64-0.92) were each associated with decreased gastric cancer risk. Conversely, tamoxifen treatment was associated with increased risk (RR = 1.82; 95% CI: 1.39-2.38). The other five exposures were not significantly associated. Our analysis supports the hypothesis that longer exposure to estrogen effects of either ovarian or exogenous origin may decrease risk of gastric cancer. Additional studies are warranted to extend this finding and to identify the underlying mechanisms.
This study aims to identify pathway involvement in the development of cisplatin (cis-diamminedichloroplatinum (II); CDDP) resistance in A549 lung cancer (LC) cells by utilizing advanced ...bioinformatics software. We developed CDDP-resistant A549 (A549/DDP) cells through prolonged incubation with the drug and performed RNA-seq on RNA extracts to determine differential mRNA and miRNA expression between A549/DDP and A549 cells. We analyzed the gene dysregulation with Ingenuity Pathway Analysis (IPA; QIAGEN) software. In contrast to prior research, which relied on the clustering of dysregulated genes to pathways as an indication of pathway activity, we utilized the IPA software for the dynamic evaluation of pathway activity depending on the gene dysregulation levels. We predicted 15 pathways significantly contributing to the chemoresistance, with several of them to have not been previously reported or analyzed in detail. Among them, the PKR signaling, cholesterol biosynthesis, and TEC signaling pathways are included, as well as genes, such as PIK3R3, miR-34c-5p, and MDM2, among others. We also provide a preliminary analysis of SNPs and indels, present exclusively in A549/DDP cells. This study's results provide novel potential mechanisms and molecular targets that can be explored in future studies and assist in improving the understanding of the chemoresistance phenotype.
Breast cancer is the most frequent cancer in women worldwide. It is classified into intrinsic subtypes characterized by different molecular profiles and prognosis. The prevalence of the different ...intrinsic subtypes varies between population groups. IHC surrogates based on the expression of the estrogen receptor, progesterone receptor, and HER2 have been widely used to study the distribution of intrinsic subtypes in non-Hispanic whites and African Americans, but data are limited for Hispanic/Latina women. Similarly, most studies analyzing gene expression profiles only include women of European descent. This review focuses on studies that describe the distribution of breast cancer subtypes in Hispanic/Latina women and highlights the need for more research in this population.
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The prevalence of gastric cancer is associated with several factors including geographical location, diet, and genetic background of the host. However, it is evident that infection with Helicobacter ...pylori (H. pylori) is crucial for the development of the disease. Virulence of the bacteria is also important in modulating the risk of the disease. After infection, H. pylori gains access to the gastric mucosa and triggers the production of cytokines that promote recruitment of inflammatory cells, probably involved in tissue damage. Once the infection is established, a cascade of inflammatory steps associated with changes in the gastric epithelia that may lead to cancer is triggered. H. pylori-induced gastritis and H. pylori-associated gastric cancer have been the focus of extensive research aiming to discover the underlying mechanisms of gastric tissue damage. This research has led to the association of host genetic components with the risk of the disease. Among these is the presence of single nucleotide polymorphisms (SNPs) in several genes, including cytokine genes, which are able to differentially modulate the production of inflammatory cytokines and then modulate the risk of gastric cancer. Interestingly, the frequency of some of these SNPs is different among populations and may serve as a predictive factor for gastric cancer risk within that specific population. However, the role played by other genetic modifications should not be minimized. Methylation of gene promoters has been recognized as a major mechanism of gene expression regulation without changing the primary structure of the DNA. Most DNA methylation occurs in cytosine residues in CpG dinucleotide, but it can also be found in other DNA bases. DNA methyltransferases add methyl groups to the CpG dinucleotide, and when this methylation level is too high, the gene expression is turned off. In H. pylori infection as well as in gastric cancer, hypermethylation of promoters of genes involved in cell cycle control, metabolism of essential nutrients, and production of inflammatory mediators, among others, has been described. Interestingly, DNA changes like SNPs or mutations can create CpG sites in sequences where transcription factors normally sit, affecting transcription.
In this chapter, we review the literature about the role of SNPs and methylation on H. pylori infection and gastric cancer, with big emphasis to the H. pylori role in the development of the disease due to the strong association between both.
COVID-19 ranges from asymptomatic in 35% of cases to severe in 20% of patients. Differences in the type and degree of inflammation appear to determine the severity of the disease. Recent reports show ...an increase in circulating monocytic-myeloid-derived suppressor cells (M-MDSC) in severe COVID 19 that deplete arginine but are not associated with respiratory complications. Our data shows that differences in the type, function and transcriptome of granulocytic-MDSC (G-MDSC) may in part explain the severity COVID-19, in particular the association with pulmonary complications. Large infiltrates by Arginase 1
G-MDSC (Arg
G-MDSC), expressing NOX-1 and NOX-2 (important for production of reactive oxygen species) were found in the lungs of patients who died from COVID-19 complications. Increased circulating Arg
G-MDSC depleted arginine, which impaired T cell receptor and endothelial cell function. Transcriptomic signatures of G-MDSC from patients with different stages of COVID-19, revealed that asymptomatic patients had increased expression of pathways and genes associated with type I interferon (IFN), while patients with severe COVID-19 had increased expression of genes associated with arginase production, and granulocyte degranulation and function. These results suggest that asymptomatic patients develop a protective type I IFN response, while patients with severe COVID-19 have an increased inflammatory response that depletes arginine, impairs T cell and endothelial cell function, and causes extensive pulmonary damage. Therefore, inhibition of arginase-1 and/or replenishment of arginine may be important in preventing/treating severe COVID-19.
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