-With the high global prevalence of prostate cancer and associated mortalities, it is important to enhance current clinical practices for better prostate cancer outcomes. The current review is ...towards understanding the value of Zn towards this mission.
-General information on Zn in biology and multiple aspects of Zn involvement in prostate health and disease were referred to in PubMed.
-The most influential feature of Zn towards prostate health is its ability to retain sufficient citrate levels for a healthy prostate. Zn deficiencies were recorded in serum, hair, and prostate tissue of men with prostate cancer compared to non-cancer controls. Zn gut absorption, albumin binding, and storage compete with various factors. There are multiple associations of Zn cellular influx and efflux transporters, Zn finger proteins, matrix metalloproteinases, and Zn signaling with prostate cancer outcomes. Such Zn marker variations associated with prostate cancer recorded from biological matrices may improve algorithms for prostate cancer screening, prognosis, and management when coupled with standard clinical practices.
-The influence of Zn in prostatic health and disease is multidimensional, therefore more personalized Zn requirements may be beneficial. Several opportunities exist to utilize and improve understanding of Zn associations with prostate health and disease.
Androgen deprivation therapy (ADT) administered as a prostate cancer treatment is known to exert multiple side effects including bone deterioration leading to bone fracture. The current analysis is ...to evaluate the burden of fracture risk in the New Zealand prostate cancer (PCa) population treated with ADT, and to understand the subsequent risk of mortality after a fracture.
Using datasets created through linking records from the New Zealand Cancer Registry, National Minimal Dataset, Pharmaceutical Collection and Mortality Collection, we studied 25,544 men (aged ≥40 years) diagnosed with PCa between 2004 and 2012. ADT was categorised into the following groups: gonadotropin-releasing hormone (GnRH) agonists, anti-androgens, combined androgen blockade (GnRH agonists plus anti-androgens), bilateral orchiectomy, and bilateral orchiectomy plus pharmacologic ADT (anti-androgens and/or GnRH agonists).
Among patients receiving ADT, 10.8 % had a fracture compared to 3.2 % of those not receiving ADT (p < 0.0001). After controlling for age and ethnicity, the use of ADT was associated with a significantly increased risk of any fracture (OR = 2.83; 95 % CI 2.52-3.17) and of hip fracture requiring hospitalisation (OR = 1.82; 95 % CI 1.44-2.30). Those who received combined androgen blockade (OR = 3.48; 95 % CI 3.07-3.96) and bilateral orchiectomy with pharmacologic ADT (OR = 4.32; 95 % CI 3.34-5.58) had the greatest risk of fracture. The fracture risk following different types of ADT was confounded by pathologic fractures and spinal cord compression (SCC). ADT recipients with fractures had a 1.83-fold (95 % CI 1.68-1.99) higher mortality risk than those without a fracture. However, after the exclusion of pathologic fractures and SCC, there was no increased risk of mortality.
ADT was significantly associated with an increased risk of any fracture and hip fracture requiring hospitalisation. The excess risk was partly driven by pathologic fractures and SCC which are associated with decreased survival in ADT users. Identification of those at higher risk of fracture and close monitoring of bone health while on ADT is an important factor to consider. This may require monitoring of bone density and bone marker profiles.
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.
Abstract
Androgen deprivation therapy (ADT) for men with prostate cancer (PCa) results in accelerated bone loss and increased risk of bone fracture. The aim of the present study was to evaluate serum ...bone markers—sclerostin, Dickkopf-1 (DKK-1) and osteoprotegerin (OPG), in a cohort of 88 PCa patients without known bone metastases, managed with and without ADT, and to analyse their relationship with bone mineral density (BMD) and sex steroids. The cross-sectional analysis between acute-, chronic- and former-ADT groups and PCa controls showed that sclerostin and OPG levels significantly differed between them (
p
= 0.029 and
p
= 0.032). Groups contributing to these significant changes were recorded. There were no significant differences in serum DKK-1 levels across the four groups (
p
= 0.683). In the longitudinal analysis, significant % decreases within groups were seen for DKK-1 chronic-ADT (− 10.06%,
p
= 0.0057), former-ADT (− 12.77%,
p
= 0.0239), and in PCa controls group (− 16.73,
p
= 0.0022); and OPG levels in chronic ADT (− 8.28%,
p
= 0.003) and PCa controls group (− 12.82%,
p
= 0.017). However, % changes in sclerostin, DKK-1, and OPG did not differ significantly over 6-months across the evaluated groups. Sclerostin levels showed significant positive correlations with BMD at baseline in the ADT group, while in PCa controls this correlation existed at both baseline and 6-month time points. Sclerostin correlated negatively with testosterone in former ADT users and in PCa controls. Possible prognostic features denoted by parallel increases in sclerostin and BMD are discussed.
There is variable reporting on the benefits of a 200 μg/d selenium supplementation towards reducing prostate cancer impacts. The current analysis is to understand whether stratified groups receive ...supplementation benefits on prostate health.
572 men were supplemented with 200 µg/d selenium as selinized yeast for six months, and 481 completed the protocol. Selenium and prostate-specific antigen (PSA) levels were measured in serum at pre- and post-supplementation. Changes in selenium and PSA levels subsequent to supplementation were assessed with and without demographic, lifestyle, genetic and dietary stratifications.
The post-supplementation selenium (
= 0.002) and the gain in selenium (
< 0.0001) by supplementation were significantly dependent on the baseline selenium level. Overall, there was no significant correlation between changes in PSA and changes in selenium levels by supplementation. However, stratified analyses showed a significant inverse correlation between changes in PSA and changes in selenium in men below the median age (
= 0.048), never-smokers (
= 0.031), men carrying the GPX1 rs1050450 T allele (CT,
= 0.022 and TT,
= 0.011), dietary intakes above the recommended daily intake (RDI) for zinc (
< 0.05), and below the RDI for vitamin B12 (
< 0.001).
The current analysis shows the influence of life factors on prostate health benefits of supplemental selenium.
Inflammation is an essential immune response; however, chronic inflammation results in disease including Crohn's disease. Therefore, reducing the inflammation can yield a significant health benefit, ...and one way to achieve this is through diet. We developed a Mediterranean-inspired anti-inflammatory diet and used this diet in a 6-week intervention in a Crohn's disease population. We examined changes in inflammation and also in the gut microbiota. We compared the results of established biomarkers, C-reactive protein and the micronuclei assay, of inflammation with results from a transcriptomic approach.
Data showed that being on our diet for 6 weeks was able to reduce the established biomarkers of inflammation. However, using transcriptomics, we observed significant changes in gene expression. Although no single gene stood out, the cumulative effect of small changes in many genes combined to have a beneficial effect. Data also showed that our diet resulted in a trend of normalising the microbiota.
This study showed that our Mediterranean-inspired diet appeared to benefit the health of people with Crohn's disease. Our participants showed a trend for reduced markers of inflammation and normalising of the microbiota. The significant changes in gene expression after 6 weeks highlighted the increased sensitivity of using transcriptomics when compared to the established biomarkers and open up a new era of dietary intervention studies.
Dietary cancer and prevention using antimutagens Ferguson, Lynnette R; Philpott, Martin; Karunasinghe, Nishi
Toxicology (Amsterdam),
05/2004, Letnik:
198, Številka:
1
Journal Article, Conference Proceeding
Recenzirano
Many of the cancers common in the Western world, including colon, prostate and breast cancers, are thought to relate to dietary habits. Of the known risk factors, many will act through increasing the ...probability of mutation. Recognised dietary mutagens include cooked meat compounds,
N-nitroso compounds and fungal toxins, while high meat and saturated fat consumption, increasing rates of obesity, and regular consumption of alcohol and tobacco are all dietary trends that could indirectly enhance the probability of mutation. However, there are significant difficulties in implementing and sustaining major dietary changes necessary to reduce the population’s intake of dietary mutagens. Dietary antimutagens may provide a means of slowing progression toward cancer, and be more acceptable to the population. Consideration of genetic mechanisms in cancer development suggest several distinct targets for intervention. Strategies that reduce mutagen uptake may be the most simple intervention, and the one least likely to result in undesirable side effects. Certain (but not all) types of dietary fibres appear to reduce mutation through this mechanism, as may certain probiotics and large planar molecules such as chlorophyllin. Antioxidants have been suggested to scavenge free radicals, and prevent their interactions with cellular DNA. Small molecule dietary antioxidants include ascorbic acid, Vitamin E, glutathione, various polyphenols and carotenoids. We found a statistically significant relationship between colon cancer incidence and soil selenium status across different regions of New Zealand. Additionally, a study of middle-aged men suggested that blood selenium levels lower than 100
ng/ml were inadequate for repair or surveillance of oxidative (and other) DNA damage. We suggest that selenium will be an important antimutagen, at least in New Zealand, possibly through antioxidant effects associated with selenium’s role in enzymes associated with endogenous repair of DNA damage. Modulation of xenobiotic metabolizing enzymes is well recognised as cancer-protective, and is a property of various flavonoids and a number of sulfur-containing compounds. Many fruits and vegetables contain compounds that will protect against mutation and cancer by several mechanisms. For example, kiwifruit has antioxidant effects and may also affect DNA repair enzymes. Dietary folate may be a key factor in maintenance of methylation status, while enhanced overall levels of vitamins and minerals may retard the development of genomic instability. The combination of each of these factors could provide a sustainable intervention that might usefully delay the development of cancer in New Zealand and other populations. Although there are a range of potentially antimutagenic fruits, vegetables and cereals available to these populations, current intake is generally below the level necessary to protect from dietary or endogenous mutagens. Dietary supplementation may provide an alternative approach.
Aldo-keto reductase 1C3 (AKR1C3) is known for multiple functions including its catalytic activity towards producing extra-testicular androgen. The present study is towards understanding interaction ...between biological, lifestyle and genetic impacts of AKR1C3 and their influence on clinical factors in a prostate cancer (PC) cohort from New Zealand (NZ).
Characteristics of 516 PC patients were collected from the Auckland Regional Urology Facility, NZ. These men were genotyped for the AKR1C3 rs12529 single nucleotide polymorphism (SNP). The leukocyte AKR1C3 activity was measured in a sub-cohort. Variability of leukocyte AKR1C3 activity between biological, lifestyle and clinical features as well as correlation between biological and clinical features were assessed with and without genetic stratification.
The leukocyte AKR1C3 activity was associated with age at diagnosis (0.51 vs 0.34 μM coumberol units for >69y vs ≤69y, P = 0.03); and with anatomic stage/prognostic grouping among the AKR1C3 rs12529 CC genotype carriers (0.50 vs 28 μM coumberol units among low- and high-risk groups respectively, P = 0.02). Significant correlation between leukocyte AKR1C3 activity and age at PC diagnosis was also observed (correlation coefficient 0.20 and P = 0.02). Ever- smoking impacted both age and PSA at PC diagnosis among AKR1C3 rs12529 GG and CG genotype carriers respectively. Age at diagnosis significantly correlated with PSA at diagnosis in the main (correlation coefficient 0.29, and P<0.001) and sub-cohorts (correlation coefficient 0.24, and P = 0.01); and those carrying the AKR1C3 rs12529 CG and GG genotypes in both the main (correlation coefficient 0.30, and P<0.001 and correlation coefficient 0.35, and P<0.001 respectively) and sub-cohorts (correlation coefficient 0.43, and P<0.001 and correlation coefficient 0.39, and P = 0.06 respectively); but not with those carrying the CC genotype.
Age dependent PSA thresholds in PC screening could have been valid only in men carrying the AKR1C3 rs12529 CG and GG genotypes in this NZ cohort.
Aldo-keto reductase 1C3 (AKR1C3) is an important oxidoreductase with multiple substrates, that are involved in producing extra-testicular androgens. Its activity is influenced by environmental ...exposures, as well as by genetic variants. These genetic variants could therefore produce variable testosterone levels and subsequent androgen receptor (AR) activation. This could lead to differential downstream production of the prostate-specific antigen (PSA). As PSA level is used for clinical evaluation of the prostate, these variations could impact prostate cancer (PC) diagnosis, as well as PC management outcomes. This review brings together information with regards to key functions of this enzyme, its relevance in PC, its transcriptional regulation, clinical aspects associated with genetics, differential regulation in cancer and cancer progression, and the types of AKR1C3 inhibitors with future therapeutic value.
Based on these discussions, hypotheses are forwarded for future applicability of this enzyme and its genetic variants in transformational medical practices in PC. Options for the use of personalised AKR1C3 inhibitor drugs for late stage PC are also discussed.
The prostate-specific antigen (PSA) based prostate cancer (PC) screening is currently being debated. The current assessment is to understand the variability of detecting high-risk PC in a NZ cohort ...in comparison to a US cohort with better PSA screening facilities. Aldo-keto reductase 1C3 (AKR1C3) is known for multiple functions with a potential to regulate subsequent PSA levels. Therefore, we wish to understand the influence of tobacco smoking and the AKR1C3 rs12529 gene polymorphism in this variability.
NZ cohort (n = 376) consisted of 94% Caucasians while the US cohort consisted of African Americans (AA), n = 202, and European Americans (EA), n = 232. PSA level, PC grade and stage at diagnosis were collected from hospital databases for assigning high-risk PC status. Tobacco smoking status and the AKR1C3 rs12529 SNP genotype were considered as confounding variables. Variation of the cumulative % high-risk PC (outcome variable) with increasing PSA intervals (exposure factor) was compared between the cohorts using the Kolmogorov-Smirnov test. Comparisons were carried out with and without stratifications made using confounding variables.
NZ cohort has been diagnosed at a significantly higher mean age (66.67± (8.08) y) compared to both AA (62.65±8.17y) and EA (64.83+8.56y); median PSA (NZ 8.90ng/ml compared to AA 6.86ng/ml and EA 5.80ng/ml); and Gleason sum (NZ (7) compared EA (6)) (p<0.05). The cumulative % high-risk PC detection shows NZ cohort with a significantly lower diagnosis rates at PSA levels between >6 - <10ng/ml compared to both US groups (p<0.05). These were further compounded significantly by smoking status and genetics.
High-risk PCs recorded at higher PSA levels in NZ could be due to factors including lower levels of PSA screening and subsequent specialist referrals for biopsies. These consequences could be pronounced among NZ ever smokers carrying the AKR1C3 rs12529 G alleles making them a group that requires increased PSA screening attention.
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