ABSTRACT
Despite lower rates and intensity of smoking, Black men experience a higher incidence of lung cancer compared to white men. The racial disparity in lung cancer is particularly pronounced in Chicago, a highly segregated urban city. Neighborhood conditions, particularly social stress, may play a role in lung tumorigenesis. Preliminary studies indicate that Black men residing in neighborhoods with higher rates of violent crime have significantly higher levels of hair cortisol, an indicator of stress response. To examine the relationship between social stress exposure and gene expression in lung tumors, we investigated glucocorticoid receptor (GR) binding in 15 lung tumor samples in relation to GR target gene expression levels and zip code level residential violent crime rates. Spatial transcriptomics and a version of ChIP sequencing known as CUT&RUN were used. Heatmap of genes, pathway analysis, and motif analysis were conducted at the statistical significance of P < 0.05. GR recruitment to chromatin was correlated with zip code level residential violent crime rate and overall GR binding increased with higher violent crime rates. Our findings suggest that exposure to residential violent crime may influence tumor biology via reprogramming GR recruitment. Prioritizing lung cancer screening in neighborhoods with increased social stress, such as high levels of violent crime, may reduce racial disparities in lung cancer. SIGNIFICANCE: Exposure to neighborhood violent crime is correlated with glucocorticoid signaling and lung tumor gene expression changes associated with increased tumor aggressiveness, suggesting social conditions have downstream biophysical consequences that contribute to lung cancer disparities.
Subject(s)
Lung Neoplasms , Receptors, Glucocorticoid , Residence Characteristics , Signal Transduction , Stress, Psychological , Violence , Receptors, Glucocorticoid/genetics , Receptors, Glucocorticoid/metabolism , Humans , Lung Neoplasms/genetics , Lung Neoplasms/epidemiology , Lung Neoplasms/metabolism , Male , Residence Characteristics/statistics & numerical data , Stress, Psychological/genetics , Stress, Psychological/epidemiology , Stress, Psychological/metabolism , Violence/statistics & numerical data , Violence/ethnology , Chicago/epidemiology , Black or African American/genetics , Black or African American/statistics & numerical data , Gene Expression Regulation, Neoplastic , Middle AgedABSTRACT
Cardiovascular diseases (CVDs) are one of the major causes of death globally. In addition to traditional risk factors such as unhealthy lifestyles (smoking, obesity, sedentary) and genetics, common environmental exposures, including persistent environmental contaminants, may also influence CVD risk. Per- and polyfluoroalkyl substances (PFASs) are a class of highly fluorinated chemicals used in household consumer and industrial products known to persist in our environment for years, causing health concerns that are now linked to endocrine disruptions and related outcomes in women, including interference of the cardiovascular and reproductive systems. In postmenopausal women, higher levels of PFAS are observed than in premenopausal women due to the cessation of menstruation, which is crucial for PFAS excretion. Because of these findings, we explored the association between perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), and perfluorobutanesulfonic acid in postmenopausal women from our previously established CVD study. We used liquid chromatography with tandem mass spectrometry, supported by machine learning approaches, and the detection and quantification of serum metabolites and proteins. Here, we show that PFOS can be a good predictor of coronary artery disease, whereas PFOA can be an intermediate predictor of coronary microvascular disease. We also found that the PFAS levels in our study are significantly associated with inflammation-related proteins. Our findings may provide new insight into the potential mechanisms underlying the PFAS-induced risk of CVDs in this population. This study shows that exposure to PFOA and PFOS is associated with an increased risk of cardiovascular disease in postmenopausal women. PFOS and PFOA levels correlate with amino acids and proteins related to inflammation. These circulating biomarkers contribute to the etiology of CVD and potentially implicate a mechanistic relationship between PFAS exposure and increased risk of cardiovascular events in this population.
Subject(s)
Alkanesulfonic Acids , Caprylates , Cardiovascular Diseases , Environmental Pollutants , Fluorocarbons , Postmenopause , Humans , Fluorocarbons/blood , Fluorocarbons/toxicity , Female , Cardiovascular Diseases/chemically induced , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/blood , Postmenopause/blood , Middle Aged , Alkanesulfonic Acids/blood , Alkanesulfonic Acids/toxicity , Aged , Environmental Pollutants/blood , Environmental Pollutants/toxicity , Caprylates/blood , Caprylates/toxicity , Environmental Exposure/adverse effects , Risk FactorsABSTRACT
NAD+ is one of the most important metabolites for cellular activities, and its biosynthesis mainly occurs through the salvage pathway using the nicotinamide phosphoribosyl transferase (NAMPT) enzyme. The main nicotinamide adenine dinucleotide (NAD) consumers, poly-ADP-ribose-polymerases and sirtuins enzymes, are heavily involved in DNA repair and chromatin remodeling. Since cancer cells shift their energy production pathway, NAD levels are significantly affected. NAD's roles in cell survival led to the use of NAD depletion in cancer therapies. NAMPT inhibition (alone or in combination with other cancer therapies, including endocrine therapy and chemotherapy) results in decreased cell viability and tumor burden for many cancer types. Many NAMPT inhibitors (NAMPTi) tested before were discontinued due to toxicity; however, a novel NAMPTi, KPT-9274, is a promising, low-toxicity option currently in clinical trials.
Subject(s)
Neoplasms , Sirtuins , Humans , NAD/metabolism , Cytokines/metabolism , Neoplasms/drug therapy , DNA Repair , Sirtuins/geneticsABSTRACT
The potential effects of poly- and perfluoroalkyl substances (PFAS) are a recently emergent human and environmental health concern. There is a consistent link between PFAS exposure and cancer, but the mechanisms are poorly understood. Although epidemiological evidence supporting PFAS exposure and cancer in general is conflicting, there is relatively strong evidence linking PFAS and testicular germ cell tumors (TGCTs). However, no mechanistic studies have been performed to date concerning PFAS and TGCTs. In this report, the effects of the legacy PFAS perfluorooctanesulfonic acid (PFOS) and the newer "clean energy" PFAS lithium bis(trifluoromethylsulfonyl)imide (LiTFSi, called HQ-115), on the tumorigenicity of TGCTs in mice, TGCT cell survival, and metabolite production, as well as gene regulation were investigated. In vitro, the proliferation and survival of both chemo-sensitive and -resistant TGCT cells were minimally affected by a wide range of PFOS and HQ-115 concentrations. However, both chemicals promoted the growth of TGCT cells in mouse xenografts at doses consistent with human exposure but induced minimal acute toxicity, as assessed by total body, kidney, and testis weight. PFOS, but not HQ-115, increased liver weight. Transcriptomic alterations of PFOS-exposed normal mouse testes were dominated by cancer-related pathways and gene expression alterations associated with the H3K27me3 polycomb pathway and DNA methylation, epigenetic pathways that were previously showed to be critical for the survival of TGCT cells after cisplatin-based chemotherapy. Similar patterns of PFOS-mediated gene expression occurred in PFOS-exposed cells in vitro. Metabolomic studies revealed that PFOS also altered metabolites associated with steroid biosynthesis and fatty acid metabolism in TGCT cells, consistent with the proposed ability of PFAS to mimic fatty acid-based ligands controlling lipid metabolism and the proposed role of PFAS as endocrine disrupters. Our data, is the first cell and animal based study on PFAS in TGCTs, support a pro-tumorigenic effect of PFAS on TGCT biology and suggests epigenetic, metabolic, and endocrine disruption as potential mechanisms of action that are consistent with the non-mutagenic nature of the PFAS class.
ABSTRACT
Lithium Bis(trifluoromethanesulfonyl)imide (LiTFSI ie. HQ-115), a polymer electrolyte used in energy applications, has been detected in the environment, yet its health risks and environmental epigenetic effects remain unknown. This study aims to unravel the potential health risks associated with LiTFSI, investigate the role of DNA methylation-induced toxic mechanisms in its effects, and compare its hepatotoxic impact with the well-studied Perfluorooctanoic Acid (PFOA). Using a murine model, six-week-old male CD1 mice were exposed to 10 and 20 mg/kg/day of each chemical for 14 days as 14-day exposure and 1 and 5 mg/kg/day for 30 days as 30-day exposure. Results indicate that PFOA exposure induced significant hepatotoxicity, characterized by liver enlargement, and elevated serum biomarkers. In contrast, LiTFSI exposure showed lower hepatotoxicity, accompanied by mild liver injuries. Despite higher bioaccumulation of PFOA in serum, LiTFSI exhibited a similar range of liver concentrations compared to PFOA. Reduced Representative Bisulfite Sequencing (RRBS) analysis revealed distinct DNA methylation patterns between 14-day and 30-day exposure for the two compounds. Both LiTFSI and PFOA implicated liver inflammatory pathways and lipid metabolism. Transcriptional results showed that differentially methylated regions in both exposures are enriched with cancer/disease-related motifs. Furthermore, Peroxisome proliferator-activated receptor alpha (PPARα), a regulator of lipid metabolism, was upregulated in both exposures, with downstream genes indicating potential oxidative damages. Overall, LiTFSI exhibits distinct hepatotoxicity profiles, emphasizing the need for comprehensive assessment of emerging PFAS compounds.
Subject(s)
Chemical and Drug Induced Liver Injury , Fluorocarbons , Hydrocarbons, Fluorinated , Imides , Male , Animals , Mice , Lithium/metabolism , Lithium/pharmacology , Fluorocarbons/toxicity , Caprylates/toxicity , Epigenesis, Genetic , Liver , Chemical and Drug Induced Liver Injury/metabolismABSTRACT
Estrogen receptor-positive (ER+) breast tumors have a better overall prognosis than ER- tumors; however, there is a sustained risk of recurrence. Mounting evidence indicates that genetic and epigenetic changes associated with resistance impact critical signaling pathways governing cell metabolism. This review delves into recent literature concerning the metabolic pathways regulated in ER+ breast tumors by the availability of nutrients and endocrine therapies and summarizes research on how changes in systemic and gut microbial metabolism can affect ER activity and responsiveness to endocrine therapy. As targeting of metabolic pathways using dietary or pharmacological approaches enters the clinic, we provide an overview of the supporting literature and suggest future directions.
Subject(s)
Breast Neoplasms , Gastrointestinal Microbiome , Humans , Female , Breast Neoplasms/drug therapy , Antineoplastic Agents, Hormonal/pharmacology , Antineoplastic Agents, Hormonal/therapeutic use , Signal Transduction , Prognosis , Drug Resistance, NeoplasmABSTRACT
The pursuit of studying this subject is driven by the urgency to address the increasing global prevalence of Non-Alcoholic Fatty Liver Disease (NAFLD) and its profound health implications. NAFLD represents a significant public health concern due to its association with metabolic disorders, cardiovascular complications, and the potential progression to more severe conditions like non-alcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Liver estrogen signaling is important for maintaining liver function, and loss of estrogens increases the likelihood of NAFLD in postmenopausal women. Understanding the multifaceted mechanisms underlying NAFLD pathogenesis, its varied treatment strategies, and their effectiveness is crucial for devising comprehensive and targeted interventions. By unraveling the intricate interplay between genetics, lifestyle, hormonal regulation, and gut microbiota, we can unlock insights into risk stratification, early detection, and personalized therapeutic approaches. Furthermore, investigating the emerging pharmaceutical interventions and dietary modifications offers the potential to revolutionize disease management. This review reinforces the role of collaboration in refining NAFLD comprehension, unveiling novel therapeutic pathways, and ultimately improving patient outcomes for this intricate hepatic condition.
Subject(s)
Non-alcoholic Fatty Liver Disease , Female , Humans , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/metabolism , Estrogens/metabolism , Liver/metabolism , Life StyleABSTRACT
Wnt ligand WNT4 is critical in female reproductive tissue development, with WNT4 dysregulation linked to related pathologies including breast cancer (invasive lobular carcinoma, ILC) and gynecologic cancers. WNT4 signaling in these contexts is distinct from canonical Wnt signaling yet inadequately understood. We previously identified atypical intracellular activity of WNT4 (independent of Wnt secretion) regulating mitochondrial function, and herein examine intracellular functions of WNT4. We further examine how convergent mechanisms of WNT4 dysregulation impact cancer metabolism. In ILC, WNT4 is co-opted by estrogen receptor α (ER) via genomic binding in WNT4 intron 1, while in gynecologic cancers, a common genetic polymorphism (rs3820282) at this ER binding site alters WNT4 regulation. Using proximity biotinylation (BioID), we show canonical Wnt ligand WNT3A is trafficked for secretion, but WNT4 is localized to the cytosol and mitochondria. We identified DHRS2, mTOR, and STAT1 as putative WNT4 cytosolic/mitochondrial signaling partners. Whole metabolite profiling, and integrated transcriptomic data, support that WNT4 mediates metabolic reprogramming via fatty acid and amino acid metabolism. Furthermore, ovarian cancer cell lines with rs3820282 variant genotype are WNT4 dependent and have active WNT4 metabolic signaling. In protein array analyses of a cohort of 103 human gynecologic tumors enriched for patient diversity, germline rs3820282 genotype is associated with metabolic remodeling. Variant genotype tumors show increased AMPK activation and downstream signaling, with the highest AMPK signaling activity in variant genotype tumors from non-White patients. Taken together, atypical intracellular WNT4 signaling, in part via genetic dysregulation, regulates the distinct metabolic phenotypes of ILC and gynecologic cancers. SIGNIFICANCE: WNT4 regulates breast and gynecologic cancer metabolism via a previously unappreciated intracellular signaling mechanism at the mitochondria, with WNT4 mediating metabolic remodeling. Understanding WNT4 dysregulation by estrogen and genetic polymorphism offers new opportunities for defining tumor biology, precision therapeutics, and personalized cancer risk assessment.
Subject(s)
Breast Neoplasms , Genital Neoplasms, Female , Humans , Female , Ligands , AMP-Activated Protein Kinases/metabolism , Genital Neoplasms, Female/genetics , Signal Transduction , Breast Neoplasms/genetics , Wnt4 Protein/genetics , Carbonyl Reductase (NADPH)/metabolismABSTRACT
African American (AA) women in the United States have a 40% higher breast cancer mortality rate than Non-Hispanic White (NHW) women. The survival disparity is particularly striking among (estrogen receptor positive) ER+ breast cancer cases. The purpose of this study is to examine whether there are racial differences in metabolic pathways typically activated in patients with ER+ breast cancer. We collected pretreatment plasma from AA and NHW ER+ breast cancer cases (AA n = 48, NHW n = 54) and cancer-free controls (AA n = 100, NHW n = 48) to conduct an untargeted metabolomics analysis using gas chromatography mass spectrometry (GC-MS) to identify metabolites that may be altered in the different racial groups. Unpaired t-test combined with multiple feature selection and prediction models were employed to identify race-specific altered metabolic signatures. This was followed by the identification of altered metabolic pathways with a focus in AA patients with breast cancer. The clinical relevance of the identified pathways was further examined in PanCancer Atlas breast cancer data set from The Cancer Genome Atlas Program (TCGA). We identified differential metabolic signatures between NHW and AA patients. In AA patients, we observed decreased circulating levels of amino acids compared to healthy controls, while fatty acids were significantly higher in NHW patients. By mapping these metabolites to potential epigenetic regulatory mechanisms, this study identified significant associations with regulators of metabolism such as methionine adenosyltransferase 1A (MAT1A), DNA Methyltransferases and Histone methyltransferases for AA individuals, and Fatty acid Synthase (FASN) and Monoacylglycerol lipase (MGL) for NHW individuals. Specific gene Negative Elongation Factor Complex E (NELFE) with histone methyltransferase activity, was associated with poor survival exclusively for AA individuals. We employed a comprehensive and novel approach that integrates multiple machine learning and statistical methods, coupled with human functional pathway analyses. The metabolic profile of plasma samples identified may help elucidate underlying molecular drivers of disproportionately aggressive ER+ tumor biology in AA women. It may ultimately lead to the identification of novel therapeutic targets. To our knowledge, this is a novel finding that describes a link between metabolic alterations and epigenetic regulation in AA breast cancer and underscores the need for detailed investigations into the biological underpinnings of breast cancer health disparities.
Subject(s)
Breast Neoplasms , Humans , Female , United States , Breast Neoplasms/pathology , Epigenesis, Genetic , Ethnicity , Metabolic Networks and Pathways , WhiteABSTRACT
Approximately 70% of human breast cancers express estrogen receptor-α (ERα), providing a potential target for endocrine therapy. However, 30% to 40% of patients with ER+ breast cancer still experience recurrence and metastasis, with a 5-year relative overall survival rate of 24%. In this study, we identified nicotinamide phosphoribosyltransferase (NAMPT), an important enzyme in nicotinamide adenine dinucleotide (NAD+) metabolism, to be increased in metastatic breast cancer (MBC) cells treated with fulvestrant (Fulv). We tested whether the blockade of NAD+ production via inhibition of NAMPT synergizes with standard-of-care therapies for ER+ MBC in vitro and in vivo. A synergistic effect was not observed when KPT-9274 was combined with palbociclib or tamoxifen or when Fulv was combined with other metabolic inhibitors. We show that NAMPT inhibitor KPT-9274 and Fulv works synergistically to reduce metastatic tumor burden. RNA-sequencing analysis showed that NAMPT inhibitor in combination with Fulv reversed the expression of gene sets associated with more aggressive tumor phenotype, and metabolomics analysis showed that NAMPT inhibition reduced the abundance of metabolites associated with several key tumor metabolic pathways. Targeting metabolic adaptations in endocrine-resistant MBC is a novel strategy, and alternative approaches aimed at improving the therapeutic response of metastatic ER+ tumors are needed. Our findings uncover the role of ERα-NAMPT crosstalk in MBC and the utility of NAMPT inhibition and antiestrogen combination therapy in reducing tumor burden and metastasis, potentially leading to new avenues of MBC treatment.
Subject(s)
Breast Neoplasms , Estrogen Receptor alpha , Humans , Female , Estrogen Receptor alpha/genetics , NAD/metabolism , Breast Neoplasms/genetics , Acrylamides , Cytokines/metabolism , Cell Line, TumorABSTRACT
The aim of the study is to determine the effect on death anxiety of loneliness in the elderly during the COVID-19 pandemic. The population of this study that is descriptive and cross-sectional type consist of 354 elderly who meet the inclusion criteria from three different associations operating for charitable purposes in a city center located in north-west Turkey. The average score of Loneliness Scale of Elderly (LSE) of the elderly was determined as 11.39 ± 5.31, and the average score of Death Anxiety Scale (DAS) of the elderly was determined as 8.54 ± 4.82. According to these results, it was found that the elderly experienced acceptable levels of loneliness and moderate death anxiety. A statistically significant difference was found in the LSE and DAS scores of the elderly according to their age, marital status, education status, chronic illness status and living at home with relatives. In addition, during the COVID-19 epidemic, the scale scores of the elderly who have increased worries, who have a hobby at home, and who communicate with their relatives via social media/mobile phones were found to be statistically significant (p < 0.05).
Subject(s)
COVID-19 , Aged , Humans , Cross-Sectional Studies , Loneliness , Pandemics , Educational Status , Anxiety , DepressionABSTRACT
The benefit of breast magnetic resonance imaging (MRI) in breast-conserving surgery (BCS) is unclear. Our study compared breast cancer patients with and without preoperative breast MRI and their long-term oncologic outcomes are reported. A total of 1378 BCS cases with early breast cancer between 1996 and 2017 were reviewed. Patients with carcinoma in situ or neoadjuvant treatment or having breast MRI after tumor excision were excluded. Of 1378 patients, 270 (19.5%) had preoperative MRI. There were no significant differences regarding T and N stage and molecular subtypes between the groups. Surgical margins were significantly wider in the breast MRI group. Five-year overall survival (OS) was 96.9% in the MRI group and 94.3% in the control group, and this difference was not significant (p=0.11). Five-year local-regional recurrence-free survival (LRFS) was not significantly different either (98.8% and 96.5%, respectively, p=0.41). When analyses were repeated only for patients with hormone receptor-negative or triple-negative breast cancer, there was still no significant difference in OS, LRFS, or disease-free survival. In conclusion, MRI does not seem necessary in all patients undergoing BCS. New prospective randomized controlled trials are needed to determine appropriate use of preoperative MRI and its effects on oncologic outcomes in early breast cancer patients.
Subject(s)
Mastectomy, Segmental , Triple Negative Breast Neoplasms , Humans , Mastectomy, Segmental/methods , Prospective Studies , Magnetic Resonance Imaging/methods , Disease-Free SurvivalABSTRACT
The COVID-19 spread rapidly all over the world and pandemic process has negatively affected nurses. Sleep disorders and depression are among these negative effects. Managers' awareness of problems experienced by nurses and taking precautions will increase employee and patient satisfaction and provide quality patient care. The study was conducted in descriptive, cross-sectional and correlational design to explain nurses' sleep quality and depression levels and relationship between them during the COVID-19 pandemic with 142 nurses who completed Personel Information Form, Pittsburgh Sleep Quality Index (PSQI) and Beck Depression Index (BDI). Sleep quality of nurses (64.8%) was poor, 33.1% had depression, and high school education, having a chronic illness and PSQI score increased the risk of depression level of nurses. Results highlight COVID-19 pandemic affected nurses' sleep quality and depression levels. All managers should be pioneers in providing psychological support to nurses and preparing and implementing a program for prevention of insomnia and depression.
ABSTRACT
Aim: This study investigated the effect of neoadjuvant chemotherapy (NAC) on stromal tumor-infiltrating lymphocytes (sTILs) and their treatment response. Materials & methods: 115 patients with pre-NAC core biopsies and post-NAC surgical resection specimens were reviewed. Results: There was no significant change between pre- and post-treatment sTILs. Both pre- and post-NAC sTILs were significantly lower in patients with luminal A subtype. An increase in sTILs was observed in 21 (25.9%) patients after NAC, a decrease in 29 (35.8%) and no change in 31 (38.3%; p = 0.07). Pretreatment sTIL density was independent predictor of pathological complete response in multivariate analyses (odds ratio: 1.025, 95% CI: 1.003-1.047; p = 0.023). Conclusion: High sTIL density in core biopsies was independently related to pathological complete response. In addition, ER appears to be the most crucial factor determining the rate of sTIL.
New studies have shown that the tumor microenvironment is critical in tumor behavior. Immune cells surrounding tumor cells are the main components of the tumor microenvironment. Our study aimed to investigate the change in immune cells before and after chemotherapy in breast cancer patients. Our study included 115 patients. All patients underwent chemotherapy before surgery to shrink the tumor. Tru-cut biopsy pieces and the breast tissue obtained after surgery were examined. The presence of estrogen or progesterone receptors on tumor cells decreased the number of immune cells surrounding the tumor cells. The number of immune cells did not decrease after chemotherapy. Another finding was that the greater the number of immune cells around the tumor, the more likely that the tumor would disappear after chemotherapy.
Subject(s)
Breast Neoplasms , Neoadjuvant Therapy , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Female , Humans , Lymphocytes, Tumor-Infiltrating/pathology , PrognosisABSTRACT
Development of targeted therapies will be a critical step towards reducing the mortality associated with triple-negative breast cancer (TNBC). To achieve this, we searched for targets that met three criteria: (1) pharmacologically targetable, (2) expressed in TNBC, and (3) expression is prognostic in TNBC patients. Since nuclear receptors have a well-defined ligand-binding domain and are thus highly amenable to small-molecule intervention, we focused on this class of protein. Our analysis identified TLX (NR2E1) as a candidate. Specifically, elevated tumoral TLX expression was associated with prolonged recurrence-free survival and overall survival for breast cancer patients with either estrogen receptor alpha (ERα)-negative or basal-like tumors. Using two TNBC cell lines, we found that stable overexpression of TLX impairs in vitro proliferation. RNA-Seq analysis revealed that TLX reduced the expression of genes implicated in epithelial-mesenchymal transition (EMT), a cellular program known to drive metastatic progression. Indeed, TLX overexpression significantly decreased cell migration and invasion, and robustly decreased the metastatic capacity of TNBC cells in murine models. We identify SERPINB2 as a likely mediator of these effects. Taken together, our work indicates that TLX impedes the progression of TNBC. Several ligands have been shown to regulate the transcriptional activity of TLX, providing a framework for the future development of this receptor for therapeutic intervention.
Subject(s)
Triple Negative Breast Neoplasms , Animals , Epithelial-Mesenchymal Transition/genetics , Estrogen Receptor alpha/genetics , Humans , Ligands , Mice , Orphan Nuclear Receptors/therapeutic use , Receptors, Cytoplasmic and Nuclear/genetics , Triple Negative Breast Neoplasms/metabolismABSTRACT
Poly- and perfluoroalkylated substances (PFAS) are chemicals that persist and bioaccumulate in the environment and are found in nearly all human populations through several routes of exposure. Human occupational and community exposure to PFAS has been associated with several cancers, including cancers of the kidney, testis, prostate, and liver. While evidence suggests that PFAS are not directly mutagenic, many diverse mechanisms of carcinogenicity have been proposed. In this mini-review, we organize these mechanisms into three major proposed pathways of PFAS action-metabolism, endocrine disruption, and epigenetic perturbation-and discuss how these distinct but interdependent pathways may explain many of the proposed pro-carcinogenic effects of the PFAS class of environmental contaminants. Notably, each of the pathways is predicted to be highly sensitive to the dose and window of exposure which may, in part, explain the variable epidemiologic and experimental evidence linking PFAS and cancer. We highlight testicular and prostate cancer as models to validate this concept.
ABSTRACT
The median overall survival of patients with metastatic breast cancer is only 2-3 years, and for patients with untreated liver metastasis, it is as short as 4-8 months. Improving the survival of women with breast cancer requires more effective anti-cancer strategies, especially for metastatic disease. Nutrients can influence tumor microenvironments, and cancer metabolism can be manipulated via a dietary modification to enhance anti-cancer strategies. Yet, there are no standard evidence-based recommendations for diet therapies before or during cancer treatment, and few studies provide definitive data that certain diets can mediate tumor progression or therapeutic effectiveness in human cancer. This review focuses on metastatic breast cancer, in particular liver metastatic forms, and recent studies on the impact of diets on disease progression and treatment.
Subject(s)
Breast Neoplasms , Liver Neoplasms , Breast Neoplasms/drug therapy , Diet , Female , Humans , Liver Neoplasms/epidemiology , Liver Neoplasms/secondary , Neoplasm Metastasis , Tumor MicroenvironmentABSTRACT
No studies, to date, have scrutinized the role of a priori dietary patterns on prognosis following a head and neck squamous cell carcinoma (HNSCC) diagnosis. The purpose of this analysis was to evaluate the associations between adherence to six a priori defined diet quality indices (including AHEI-2010, aMED, DASH, and three low-carbohydrate indices) throughout the first 3 years of observation and all-cause and cancer-specific mortalities in 468 newly diagnosed HNSCC patients from the University of Michigan Head and Neck Specialized Program of Research Excellence (UM-SPORE). The dietary intake data were measured using a food frequency questionnaire administered at three annual time points commencing at study entry. Deaths and their causes were documented throughout the study using various data sources. Marginal structural Cox proportional hazards models were used to evaluate the role of diet quality, as a time-varying covariate, on mortality. There were 93 deaths from all causes and 74 cancer-related deaths adjudicated throughout the observation period. There was a strong inverse association between adherence to the AHEI-2010, all-cause mortality (HR Q5-Q1 :0.07, 95% CI:0.01-0.43, p trend:0.04), and cancer-specific mortality (HR Q5-Q1 :0.15, 95% CI:0.02-1.07, p trend:0.04). Other more modest associations were noted for the low-carbohydrate indices. In sum, higher adherence to the AHEI-2010 and a plant-based low-carbohydrate index throughout the first 3 years since diagnosis may bolster survival and prognosis in newly diagnosed patients with HNSCC.