It is being debated whether prostate-specific antigen (PSA)-based screening effectively reduces prostate cancer mortality. Some of the uncertainty could be related to deficiencies in the age-based ...PSA cut-off thresholds used in screening. Current study considered 2779 men with prostate cancer and 1606 men without a cancer diagnosis, recruited for various studies in New Zealand, US, and Taiwan. Association of PSA with demographic, lifestyle, clinical characteristics (for cases), and the aldo-keto reductase 1C3 (AKR1C3) rs12529 genetic polymorphisms were analysed using multiple linear regression and univariate modelling. Pooled multivariable analysis of cases showed that PSA was significantly associated with demographic, lifestyle, and clinical data with an interaction between ethnicity and age further modifying the association. Pooled multivariable analysis of controls data also showed that demographic and lifestyle are significantly associated with PSA level. Independent case and control analyses indicated that factors associated with PSA were specific for each cohort. Univariate analyses showed a significant age and PSA correlation among all cases and controls except for the US-European cases while genetic stratification in cases showed variability of correlation. Data suggests that unique PSA cut-off thresholds factorized with demographics, lifestyle and genetics may be more appropriate for prostate cancer screening.
There is evidence that tumor immunobiology and immunotherapy response may differ between African American and European American prostate cancer patients. Here, we determine if men of African descent ...harbor a unique systemic immune-oncological signature and measure 82 circulating proteins in almost 3000 Ghanaian, African American, and European American men. Protein signatures for suppression of tumor immunity and chemotaxis are elevated in men of West African ancestry. Importantly, the suppression of tumor immunity protein signature associates with metastatic and lethal prostate cancer, pointing to clinical importance. Moreover, two markers, pleiotrophin and TNFRSF9, predict poor disease survival specifically among African American men. These findings indicate that immune-oncology marker profiles differ between men of African and European descent. These differences may contribute to the disproportionate burden of lethal prostate cancer in men of African ancestry. The elevated peripheral suppression of tumor immunity may have important implication for guidance of cancer therapy which could particularly benefit African American patients.
The association between fatty acids and prostate cancer remains poorly explored in African-descent populations. Here, we analyze 24 circulating fatty acids in 2934 men, including 1431 prostate cancer ...cases and 1503 population controls from Ghana and the United States, using CLIA-certified mass spectrometry-based assays. We investigate their associations with population groups (Ghanaian, African American, European American men), lifestyle factors, the fatty acid desaturase (FADS) genetic locus, and prostate cancer. Blood levels of circulating fatty acids vary significantly between the three population groups, particularly trans, omega-3 and omega-6 fatty acids. FADS1/2 germline genetic variants and lifestyle factors explain some of the variation in fatty acid levels, with the FADS1/2 locus showing population-specific associations, suggesting differences in their control by germline genetic factors. All trans fatty acids, namely elaidic, palmitelaidic, and linoelaidic acids, associated with an increase in the odds of developing prostate cancer, independent of ancestry, geographic location, or potential confounders.
Abstract Ezrin is a scaffolding protein that is involved in oncogenesis by linking cytoskeletal and membrane proteins. Ezrin interacts with epidermal growth factor receptor (EGFR) in the cell ...membrane, but little is known about the effects of this interaction on EGFR signaling pathway. In this study, we established the biological and functional significance of ezrin-EGFR interaction in non–small cell lung cancer (NSCLC) cells. Endogenous ezrin and EGRF interaction was confirmed by co-immunoprecipitation and immunofluorescent staining. When expression of ezrin was inhibited, EGFR activity and phosphorylation levels of downstream signaling pathway proteins ERK and STAT3 were decreased. Cell fractionation experiments revealed that nuclear EGFR was significantly diminished in ezrin-knockdown cells. Consequently, mRNA levels of EGFR target genes AURKA , COX-2 , cyclin D1 , and iNOS were decreased in ezrin-depleted cells. A small molecule inhibitor of ezrin, NSC305787, reduced EGF-induced phosphorylation of EGFR and downstream target proteins, EGFR nuclear translocation, and mRNA levels of nuclear EGFR target genes similar to ezrin suppression. NSC305787 showed synergism with erlotinib in wild-type EGFR-expressing NSCLC cells, whereas no synergy was observed in EGFR-null cells. Phosphorylation of ezrin on Y146 was found as an enhancer of ezrin-EGFR interaction and required for increased proliferation, colony formation, and drug resistance to erlotinib. These findings suggest that ezrin-EGFR interaction augments oncogenic functions of EGFR and that targeting ezrin may provide a potential novel approach to overcome erlotinib resistance in NSCLC cells.
Background
Prior studies showed that neighborhood deprivation increases the risk of lethal prostate cancer. However, the role of neighborhood gentrification in prostate cancer development and outcome ...remains poorly understood. We examined the relationships of gentrification with prostate cancer and serum proteome‐defined inflammation and immune function in a diverse cohort.
Methods
The case–control study included 769 cases 405 African American (AA), 364 European American (EA) men and 1023 controls (479 AA and 544 EA), with 219 all‐cause and 59 prostate cancer‐specific deaths among cases. Geocodes were linked to a neighborhood gentrification index (NGI) derived from US Census data. Cox and logistic regression, and MANOVA, were used to determine associations between NGI, as continuous or quintiles (Q), and outcomes.
Results
Adjusting for individual socioeconomic status (SES), continuous NGI was positively associated with prostate cancer among all men (odds ratio OR 1.07, 95% confidence interval CI 1.01–1.14). AA and low‐income men experienced the highest odds of prostate cancer when residing in tracts with moderate gentrification, whereas EA men experienced reduced odds of regional/metastatic cancer with increased gentrification in SES‐adjusted analyses. Continuous NGI also associated with mortality among men presenting with localized disease and low‐income men in SES‐adjusted Cox regression analyses. NGI was not associated with serum proteome‐defined chemotaxis, inflammation, and tumor immunity suppression.
Conclusions
Findings show that neighborhood gentrification associates with prostate cancer and mortality in this diverse population albeit associations were heterogenous within subgroups. The observations suggest that changing neighborhood socioeconomic environments may affect prostate cancer risk and outcome, likely through multifactorial mechanisms.
Abstract
Cancer health disparities remain stubbornly entrenched in the US health care system. The Affordable Care Act was legislation to target these disparities in health outcomes. Expanded access ...to health care, reduction in tobacco use, uptake of other preventive measures and cancer screening, and improved cancer therapies greatly reduced cancer mortality among women and men and underserved communities in this country. Yet, disparities in cancer outcomes remain. Underserved populations continue to experience an excessive cancer burden. This burden is largely explained by health care disparities, lifestyle factors, cultural barriers, and disparate exposures to carcinogens and pathogens, as exemplified by the COVID-19 epidemic. However, research also shows that comorbidities, social stress, ancestral and immunobiological factors, and the microbiome, may contribute to health disparities in cancer risk and survival. Recent studies revealed that comorbid conditions can induce an adverse tumor biology, leading to a more aggressive disease and decreased patient survival. In this review, we will discuss unanswered questions and new opportunities in cancer health disparity research related to comorbid chronic diseases, stress signaling, the immune response, and the microbiome, and what contribution these factors may have as causes of cancer health disparities.
Statins are associated with lower risk of gallstones due to anti-inflammatory effects. We assessed whether statins impact circulating inflammation among Chilean women with gallstones.
200 Mapuche ...women were matched on statin use and age to 200 non-Mapuche women in the Chile Biliary Longitudinal Study. We analyzed 92 inflammatory biomarkers using multivariable-adjusted regression models, random forests and pathway analyses.
Statins were not significantly associated with any inflammation marker when women were analyzed jointly or stratified by ancestry. No significant associations were found through random forest methods and pathway analyses.
We did not find significant associations between statin use and inflammation markers in women with gallstones, suggesting that statins do not reduce inflammation once gallstones have formed.
Statins are prescribed to lower cholesterol and can also decrease the risk of gallstone formation by reducing inflammation. We assessed whether statin use reduces inflammation among women who have already developed gallstones. We analyzed 92 inflammation markers among 400 women in Chile, including 200 women with Mapuche Amerindian ancestry and 200 women of Latina/European ancestry. We found that statin use was not correlated with inflammation in this group of women overall nor by ancestry. This may mean that statin use does not reduce inflammation in women who already were diagnosed with gallstones.
Sexually transmitted infections can reach the prostate gland where their harmful effects are mediated by innate immunity, including interferons. Humans are polymorphic for the germline dinucleotide ...variant, rs368234815-TT/ΔG, in the
gene encoding interferon λ4. Since the
ΔG allele has been linked to impaired viral clearance, we hypothesized that potential exposure to sexually transmitted pathogens, as assessed by the number of lifetime sexual partners, may increase prostate cancer risk in an
ΔG-dependent manner. Accordingly, we find that men with 10 or more sexual partners and at least one copy of
ΔG have a significantly increased risk of prostate cancer while those with the same number of partners but lacking
ΔG do not. Moreover, a test for effect modification shows a positive interaction between the number of lifetime partners and
ΔG in the development of aggressive prostate cancer. Based on these findings, we conclude that a gene-environment interaction between
ΔG and sexual activity may increase the risk of prostate cancer.
The aim of the current study was to determine the effects of the ERG small-molecule inhibitor YK-4-279 on ERG
prostate cancer patient-derived xenografts (PDX).
ERG activity was blocked using YK-4-279 ...in three subcutaneously-implanted ERG
(LuCaP 23.1, 86.2 and 35) and one ERG
(LuCaP 96) PDX. Treated animals tumor volume (TV), body weight (BW) and serum prostate-specific antigen (PSA) were compared to vehicle-treated control animals. Gene expression, proliferation, apoptosis, microvessel density and ERG expression were also assessed.
Administration of YK-4-279 decreased TV (p=0.026), proliferation (p=0.0038) and PSA (p=0.022) in Severe Combined Immunodeficiency (SCID) mice bearing LuCaP 23.1 tumors. LuCaP 86.2, LuCaP 35 and LuCaP 96 showed no significant changes in TV, or PSA. Mineralocorticoid receptor (MR) and MR-direct target genes were up-regulated in treatment-resistant LuCaP 86.2 and LuCaP 35 PDX.
YK-4-279 decreased ERG
LuCaP 23.1 tumor growth, but not LuCaP 86.2 and LuCaP 35 ERG
tumor growth.
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