Biomedical subjects

Burkhard Brandt

Publications and source records attributed to Burkhard Brandt.

At least 19 recordsLinked to original sources

PubMed2007

Cell cycle regulating proteins p21 and p27 in prognosis of oral squamous cell carcinomas.

Cyclin-dependent kinases (CDKs) and cyclin-dependent kinase inhibitors (CDKIs), such as p21 and p27, exert a direct control on the cell cycle. p21 and p27 are negative regulators of cyclin-dependent kinases and in this function they are negative check-point regulators of the cell cycle. We therefore aimed to evaluate p21 and p27 expression in oral squamous cell carcinomas (OSSC) to determine the value as a prognostic marker. One hundred and ninety-two patients with histologically proven, surgically treated squamous cell carcinoma of the oral cavity were eligible for the study and investigated for the expression of p21 and p27 by means of tissue microarrays (TMAs). Immunohistochemical screening under identical condition were carried out with antibodies against p21 and p27. Correlations between clinical features and the expression of the respective antibodies were evaluated statistically by Kaplan-Meier curves, log-rank and chi(2) tests. The expression of p21 correlated significantly with an increased prognosis in the log-rang test (p=0.01). No significant correlation was found between the expression of p27 and the overall survival rate. In multivariate Cox analysis, p27 was indicated as independent predictor of survival prognosis in the subgroup of nodal positive carcinomas, p27 positive tumours showed a significantly better survival prognosis (p=0.03). p21 and p27 in carcinoma of oral cavity seem to be predictive parameter in regulation and prognosis of squamous cell carcinomas. A p21 negative subgroup of OSCC may benefit from additional radio or radiochemotherapy.

Adult↗

PubMed2006

Mechanisms of egfr gene transcription modulation: relationship to cancer risk and therapy response.

The epidermal growth factor receptor (EGFR) plays a crucial role in growth, differentiation, and motility of normal as well as cancer cells. For predictive cancer diagnostics and therapeutic targeting of EGFR, it is important to know how the expression level of EGFR is controlled and related to receptor signaling. A novel transcriptional regulation mechanism has been described that depends on the length of a CA repeat in intron 1 [CA simple sequence repeat 1 (CA SSR I)] of the EGFR gene. Thereby, the number of CA repeats is inversely correlated to pre-mRNA synthesis. Indirect evidence for the importance of this mechanism includes the preferential occurrence of amplifications in cancer tissue harboring short CA repeats in this sequence and the discovery of distinct alleles in young breast cancer patients with a family history of the disease and in Japanese breast cancer patients. It can be postulated that the length of the CA repeat influences DNA bendability and, in consequence, the binding of repressor proteins. In summary, it seems that the CA SSR I represents an inherited variable for response to anti-EGFR therapies that could be determined before therapy. Moreover, the potential for synergistic effects with other polymorphism [e.g., EGFR R497K (HER-1 497K) and CCND1 A870G] leading to a simultaneous increase of EGFR signaling activity and expression should be investigated. From a practical perspective, assessment of the CA SSR I number of CA dinucleotide repeats as a predictor for clinical outcome is very attractive because it is a constant feature that does not change over time and can be easily measured in normal and cancer tissues (blood cells, skin, and tumor biopsies) in an assay that is technically simple, objective, and even quantitative.

Breast Neoplasms↗

PubMed2006

Asynchronous growth of prostate cancer is reflected by circulating tumor cells delivered from distinct, even small foci, harboring loss of heterozygosity of the PTEN gene.

The clinical value of prostate-specific antigen (PSA)-positive circulating tumor cells (CTCs) is still a matter of debate and it is also still unclear if these CTCs actually represent the primary tumor. Therefore, we isolated PSA-positive CTCs from the peripheral blood of patients suffering from multifocal cancers and did genetic profiling of each cancer focus by a multiplex PCR-based microsatellite analysis (D7S522, D8S522, NEFL, D10S541, D13S153, D16S400, D16S402, D16S422, and D17S855). In 17 of 20 prostate cancer cases, the loss of heterozygosity (LOH) pattern of the CTCs was identical with only one focus of the primary tumor. Moreover, in six cases, the LOH pattern suggested that smaller foci, down to 0.2 cm3, might deliver CTCs. Interestingly, the highest number of LOHs was observed at the marker D10S541 (85%), the PTEN gene, which was observed much less frequently in unifocal prostate cancer (48%). Furthermore, the infrequently occurring LOH in the BRCA1 gene (38%) was found in four of the five cases where a biochemical recurrence was seen within 3 years after prostatectomy. Therefore, the data might support the assumption that CTCs in prostate cancer are derived from distinct foci of a primary tumor. The size of the tumor focus is not related to the delivery of cells. Although the number of cases that were investigated in this study was small, it might be suggested that the LOH at distinct markers such as D10S541 and D17S855 represent the genes PTEN and BRCA1, which might be associated with the occurrence of CTCs in the peripheral blood of patients as well as an early biochemical recurrence.

Humans↗

PubMed2006

(CA)n microsatellite polymorphism of ERBB-1 in breast cancer.

The aim of this study was to determine polymorphism of repeated sequences (CA)(n) in the ERBB-1 gene. The study group included 197 breast cancer patients and 180 healthy women. DNA was isolated from fresh-frozen tumour tissue and from peripheral blood. ERBB-1 (CA)(n) microsatellite polymorphism was examined by polymerase chain reaction (PCR). A polymorphic simple sequence repeat region of 9-23 CA repeats was detected in both groups. Homozygotes comprised 22% and 34% of breast cancer patients and controls, respectively (P=0.009). An allelic imbalance (AI), mostly in the shorter allele, was found in 27% of breast cancer patients. AI occurrence was associated with the lack of oestrogen receptors in tumour cells (P=0.05); otherwise, there were no correlations between histoclinical features and (CA)(n) microsatellite polymorphism of ERBB-1. It was concluded that an allelic imbalance is a common feature in breast cancer patients and may coincide with the lack of oestrogen receptors in tumour cells. The clinical relevance of ERBB-1 microsatellite polymorphism in breast cancer remains to be established.

Allelic Imbalance↗

PubMed2006

Decay-accelerating factor (CD55): a versatile acting molecule in human malignancies.

The decay-accelerating factor (DAF, CD55) physiologically serves as an inhibitor of the complement system. Moreover, DAF is broadly expressed in malignant tumors. Here, DAF seems to dispose of several different functions reaching far beyond its immunological role, e.g., promotion of tumorigenesis, decrease of complement mediated tumor cell lysis, autocrine loops for cell rescue and evasion of apoptosis, neoangiogenesis, invasiveness, cell motility, and metastasis via oncogenic tyrosine kinase pathway activation, and specific seven-span transmembrane receptors (CD97) binding. Furthermore, DAF has already been included in diagnostic or therapeutic studies. Thereby, studies applying monoclonal anti-DAF antibodies and anti-DAF vaccination for a targeted therapy have been enrolled recently.

Animals↗

PubMed2006

HER2-positive circulating tumor cells indicate poor clinical outcome in stage I to III breast cancer patients.

PURPOSE: Early metastasis in node-negative breast cancer indicates that breast cancer cells obviously can bypass the lymph nodes and disseminate directly hematogenous to distant organs. For this purpose, we evaluated the prognostic value of blood-borne, HER2-positive circulating tumor cells (CTC) in the peripheral blood from 42 breast cancer patients with a median follow-up of 95 months. EXPERIMENTAL DESIGN: Cells were isolated by the patented combined buoyant density gradient and immunomagnetic separation procedure and analyzed by immunocytochemistry. RESULTS: We detected one to eight CTCs in the peripheral blood of 17 of 35 patients (48.6%) presenting no overt metastasis. As a positive control, 7 of 7 (100%) patients with metastatic disease presented positive. Healthy persons and patients (n = 32) operated for nonmalignant diseases presented negative for CTCs. The presence and frequency of HER2-positive CTCs correlated with a significantly decreased disease-free survival (P < 0.005) and overall survival (P < 0.05). Interestingly, in 12 patients with HER2-positive CTCs, the primary tumor was negative for HER2 as assessed by immunohistochemical score and fluorescence in situ hybridization. CONCLUSIONS: This study provides some evidence of a prognostic effect of HER2-positive CTCs in stage I to III breast cancer. Future studies have to determine the outcome of patients treated with HER2-targeting therapies with respect to HER2-positive CTC levels because it is not unlikely that high levels of HER2-positive CTCs reflect the activity of the tumor and may predict response to trastuzumab.

Adult↗

PubMed2006

Cytokeratin 8/18 expression indicates a poor prognosis in squamous cell carcinomas of the oral cavity.

BACKGROUND: Intermediary filaments are involved in cell motility and cancer progression. In a variety of organs, the expression of distinct intermediary filaments are associated with patient prognosis. In this study, we seeked to define the prognostic potential of cytokeratin and vimentin expression patterns in squamous cell carcinomas (SCC's) of the oral cavity. METHODS: 308 patients with histologically proven and surgically treated squamous cell carcinomas of the oral cavity were investigated for the immunohistochemical expression of a variety of intermediary filaments including high- and low-molecular weight cytokeratins (Ck's), such as Ck 5/6, Ck 8/18, Ck 1, CK 10, Ck 14, Ck 19 and vimentin, using the tissue microarray technique. Correlations between clinical features and the expression of Cytokeratins and vimentin were evaluated statistically by Kaplan-Meier curves and multivariate Cox regression analysis. RESULTS: The expression of Ck 8/18 and Ck 19 were overall significantly correlated with a poor clinical prognosis (Ck 8/18 p = 0.04; Ck19 p < 0.01). These findings could also be reproduced for Ck 8/18 in primary nodal-negative SCC's and held true in multivariate-analysis. No significant correlation with patient prognosis could be found for the expression of the other cytokeratins and for vimentin. CONCLUSION: The expression of Ck 8/18 in SCC's of the oral cavity is an independent prognostic marker and indicates a decreased overall and progression free survival. These results provide an extended knowledge about the role of intermediary filament expression patterns in SCC's.

Adult↗

PubMed2006

Amplifications of the epidermal growth factor receptor gene (egfr) are common in phyllodes tumors of the breast and are associated with tumor progression.

Phyllodes tumors of the breast are rare biphasic tumors with the potential for invasion and metastatic spread. An important role of the epidermal growth factor receptor (EGFR) in phyllodes tumors has been proposed. However, detailed pathogenetic mechanisms remained unclear. We investigated 58 phyllodes tumors of the breast (40 benign, 10 borderline and eight malignant) by means of egfr fluorescence in situ hybridization (FISH) and gene dosage PCR for a regulatory sequence within intron 1 of egfr. Immunohistochemical staining was performed for EGFR, p16, p21, p27, p53, c-myc, Cyclin A, Cyclin D1, Cyclin E, c-kit and Ki67. Immunopositivity for EGFR was detected in 19% of phyllodes tumors (75% of all malignant tumors) in stromal tumor cells but not in the epithelial component. Whole-gene amplifications were seen by FISH in 15.8% (in stromal cells only) and intron 1 amplifications by gene dosage PCR in as much as 41.8% of all phyllodes tumors. Significant correlations were seen between tumor grade on the one hand and EGFR overexpression (P=0.001) and intron 1 amplifications (P<0.05) on the other. EGFR overexpression further correlated positively with immunohistochemical staining for p53, p16, Cyclin A, Cyclin E, Ki67 and c-kit. Presence of intron 1 amplifications correlated with p16 (P<0.01), p21 (P=0.009) and p53 immunoreactivity (P<0.001). Neither EGFR overexpression nor whole-gene amplification was observed in a control series of 167 fibroadenomas and only one of 43 (2.3%) exhibited intron 1 amplification in gene dosage PCR. In conclusion, our results show for the first time that activating mutations in and overexpression of egfr are associated with the progression in grade of phyllodes tumors of the breast. The observed association between intron 1 amplification and overexpression of EGFR provides further insight into regulation mechanisms of EGFR overexpression.

Base Sequence↗

PubMed2006

The expression and action of decay-accelerating factor (CD55) in human malignancies and cancer therapy.

Decay-accelerating factor (DAF, CD55) is physiologically acting as an inhibitor of the complement system, but is also broadly expressed in malignant tumours. Here DAF seems to exert different functions beyond its immunological role such as e.g. promotion of tumorigenesis, decrease of complement mediated tumor cell lysis, autocrine loops for cell rescue and evasion of apoptosis, neoangiogenesis, invasiveness, cell motility, and metastasis via oncogenic tyrosine kinase pathways and specific seven-span transmembrane receptors (CD97) binding. Therefore, DAF has already become a target for therapy. In this paper we review the role of DAF in human malignancies as described in different basic, diagnostic and experimental therapeutic studies.

Antigens, CD↗

PubMed2006

Improvements in the analysis strategy make single nucleotide polymorphism analysis a powerful tool in the detection and characterization of amplified chromosomal regions in human tumors.

OBJECTIVE: Single nucleotide polymorphism analysis (SNP) has recently been proposed as an alternative technique to comparative genomic hybridization (CGH) for defining loss of heterozygosity and gene copy number changes in a single experimental setup. In order to assess the potential of SNP analysis to complement or, ultimately, substitute CGH results, we applied both techniques to five primary tumor samples and two tumor cell lines. This was complemented by dilution experiments based on normal lymphocyte DNA to decipher the lower detection limit for genetic alterations. METHODS/RESULTS: Using an in-house software tool, we demonstrated that SNP analysis permits the generation of chromosomal alteration patterns that largely resemble conventional CGH ratio profiles of a given tumor/cell line. Moreover, compared to CGH, our SNP software tool allows a much more detailed definition of amplicon sizes and involved candidate genes. This advantage even persisted when the technique was applied to DNA with more than 60% of nontumor content. However, the detection of chromosomal losses is severely hampered by the presence of nontumor DNA so that the use of the SNP technique should be limited to tumor samples with more than 80% tumor DNA. CONCLUSION: SNP analysis is a very valuable tool for the detection and characterization of high-level chromosomal amplifications in the vast majority of primary tumor samples. Our software tool improves the analysis of SNP data and the presentation of the results, bridging the gap to existing CGH knowledge (http://bioinformatics.uni-muenster.de, 'Publications and Supplements').

Algorithms↗

PubMed2005

HIF1-alpha overexpression indicates a good prognosis in early stage squamous cell carcinomas of the oral floor.

BACKGROUND: Hypoxia-inducible factor 1 (HIF-1) is a transcription factor, which plays a central role in biologic processes under hypoxic conditions, especially concerning tumour angiogenesis. HIF-1alpha is the relevant, oxygen-dependent subunit and its overexpression has been associated with a poor prognosis in a variety of malignant tumours. Therefore, HIF-1alpha expression in early stage oral carcinomas was evaluated in relation to established clinico-pathological features in order to determine its value as a prognostic marker. METHODS: 85 patients with histologically proven surgically treated T1/2 squamous cell carcinoma (SCC) of the oral floor were eligible for the study. Tumor specimens were investigated by means of tissue micro arrays (TMAs) and immunohistochemistry for the expression of HIF-1. Correlations between clinical features and the expression of HIF-1 were evaluated by Kaplan-Meier curves, log-rank tests and multivariate Cox regression analysis. RESULTS: HIF-1alpha was frequently overexpressed in a probably non-hypoxia related fashion. The expression of HIF-1alpha was related with a significantly improved 5-year survival rate (p < 0.01) and a significantly increased disease free period (p = 0.01) independent from nodal status and tumour size. In primary node negative T1/T2 SCC of the oral floor, absence of HIF-1alpha expression specified a subgroup of high-risk patients (p < 0.05). CONCLUSION: HIF-1alpha overexpression is an indicator of favourable prognosis in T1 and T2 SCC of the oral floor. Node negative patients lacking HIF-1alpha expression may therefore be considered for adjuvant radiotherapy.

Adult↗

PubMed2005

Selective expression of a splice variant of decay-accelerating factor in c-erbB-2-positive mammary carcinoma cells showing increased transendothelial invasiveness.

By differential-display-PCR a subclone of the SK-BR-3 cell line with high in vitro transendothelial invasiveness was identified to express increased levels of a new alternative splice variant of decay-accelerating factor (DAF). DAF seems to play an important role in some malignant tumours since on the one hand the expression of complement inhibitors on the surface of tumour cells prevents the accumulation of complement factors and in consequence cell lysis. On the other hand, DAF has been identified as a ligand for the CD97 surface receptor which induces cell migration. Immunofluorescence procedures, Western blot analyses, and cDNA clone sequencing were employed to confirm the expression of DAF restricted to invasive tumour cells. Using a radioactive RNA-in situ hybridisation on freshly frozen tissue microarrays and RT-PCR on native tumour tissue, the expression of alternative spliced DAF mRNA was demonstrated in invasive breast cancer. Due to the fact that it could thereby not be detected in normal mammary tissues, it has to be confirmed in larger studies that the DAF splice variant might be a specific tumour marker for invasive breast cancer.

Alternative Splicing↗

PubMed2005

The origin of vimentin expression in invasive breast cancer: epithelial-mesenchymal transition, myoepithelial histogenesis or histogenesis from progenitor cells with bilinear differentiation potential?

Vimentin expression is a rather rare finding in invasive breast cancer, and is associated with high tumour invasiveness and chemoresistance. It is currently explained by two different biological theories: direct histogenetic derivation from myoepithelial cells, and epithelial-mesenchymal transition (EMT) reflecting the end-stage of breast cancer dedifferentiation. In this study we aimed to obtain further insights into the biological hallmarks of these vimentin-expressing breast cancers. We applied immunohistochemistry for vimentin and 15 other differentiation markers to a series of 364 invasive breast cancer cases, using tissue microarray technology. 7.7% of all tumours expressed vimentin. Almost all of these cases (19/21) were Grade 3 invasive ductal carcinomas, and the majority (13/21) of these were associated with a ductal in situ component. Vimentin expression was also seen in the respective in situ components and correlated positively with the expression of SMA, CD10, CK 5, p53, Mib-1 and EGFR. A negative correlation was seen for the expression of CK 8/18 and the oestrogen receptor. Vimentin-expressing carcinomas revealed a significantly higher average absolute number of cytogenetic alterations per case, but a significantly lower frequency of chromosome 16q losses compared to vimentin-negative cases. Our present results demonstrate that, despite analogies between vimentin-positive breast cancers and myoepithelial cells in their expression of differentiation-related proteins, neither myoepithelial histogenesis nor EMT can exclusively explain the biology of these distinct tumours. This is mainly supported by the significantly higher incidence of vimentin-expressing breast cancers compared to any other myoepithelial breast tumours and the fact that vimentin is already observed in ductal in situ components. We therefore propose the alternative hypothesis that vimentin-expressing breast carcinomas may derive from breast progenitor cells with bilinear (glandular and myoepithelial) differentiation potential.

Biomarkers, Tumor↗

PubMed2005

Effectiveness of hydroxyapatite-vancomycin bone cement in the treatment of Staphylococcus aureus induced chronic osteomyelitis.

In the field of local application of antimicrobials, a number of novel drugs and/or new drug delivery systems have been developed in recent years. The present study aimed to investigate hydroxyapatite cement (HAC) as a carrier for vancomycin in the treatment of chronic osteomyelitis due to Staphylococcus aureus strains with various mechanisms of resistance. The release of vancomycin from standard test cylinders was determined in vitro and the efficacy of the delivery system was measured in vivo using a rabbit model of chronic osteomyelitis. First, powdered HAC was mixed with vancomycin at 80, 160 and 240 mg/g. After hardening, formed cylinders were eluted in phosphate buffer and antibiotic release was measured by agar diffusion. High levels of release (1512+/-318 to 1937+/-336 microg/ml) were obtained for 12 to 20 days depending on the dosage of vancomycin. Additionally, bone infection was induced in the tibia of 30 New Zealand white rabbits by injecting either a methicillin-resistant S. aureus strain (MRSA) or a S. aureus strain with a small colony variant (SCV) phenotype. After 3 weeks (chronic infection), all animals were treated by debridement. Moreover, group 1 (challenged with SCVs) and group 2 (challenged with MRSA) were treated by filling the marrow with HAC alone, whereas in groups 3 (SCVs) and 4 (MRSA) the marrow was filled with HAC/vancomycin (160 mg/g). After 6 weeks all animals were sacrificed. At 3 weeks, pathogens were detected in 24 of 30 animals. All swabs of the control groups, positive for S. aureus on day 21, were also positive on day 42 and S. aureus strains recovered were shown to be clonal to the strains used for induction of osteomyelitis. By contrast, no growth was found in the treatment group following 7 days of incubation in BHI bouillon. HAC/vancomycin-treated animals showed no histological evidence of infection on day 42. In the other groups, different stages of chronic osteomyelitis were found histologically. No local or systemic side effects due to HAC or vancomycin were seen. HAC is an effective carrier material for antibiotic compounds even in refractory infections due to MRSA or S. aureus SCVs.

Animals↗

PubMed2005

3D-extravasation model -- selection of highly motile and metastatic cancer cells.

Extravasation has been described as a rate-limiting step in the process of hematogeneous metastasis formation. Thereby, transendothelial migration of tumor cells consists of a complex series of events involving multiple cell-cell and cell-matrix interactions. 3D-extravasation assays are valuable tools for the identification of genes, which are the key players at switchboards of the intracellular signaling pathways. In consequence, the combination of 3D-modeling and whole genome expression analysis lead to unravel molecular parameters which descripe distinct clinical phenotypes of cancer and therefore, work as prognosticators, predictors of therapy and new therapy targets.

Cell Movement↗

PubMed2005

In vitro and in vivo imaging of cell migration: two interdepending methods to unravel metastasis formation.

Metastasis development requires the migratory activity of tumor cells. It is therefore important to understand the molecular mechanisms of this migration in order to prevent metastasis development, which is the pernicious step in most solid tumor diseases. A lot of methods have been invented to investigate tumor cell migration, but not all are equally suited and no method alone is able to deliver a complete picture of tumor cell migration. We herein suggest a combination of three-dimensional in vitro and in vivo methods for the investigation of tumor cell migration and summarize the knowledge, which has been reached so far.

Animals↗

PubMed2005

Cytogenetic changes and loss of heterozygosity in atypical adenomatous hyperplasia, in carcinoma of the prostate and in non-neoplastic prostate tissue using comparative genomic hybridization and multiplex-PCR.

High grade prostatic intraepithelial neoplasia (PIN) and atypical adenomatous hyperplasia (AAH) are discussed to be precursors of prostate cancer (PC). Unlike high grade PIN the relation between AAH and PC is however unclear. In the present study we analyzed AAH, accompanying prostate carcinomas and carcinomas of the transitional zone after microdissection using comparative genomic hybridization (CGH) and multipelx-PCR with 10 microsatellite polymorphic markers. In every case non-neoplastic prostatic tissue was investigated for the same allelic imbalances. Two AAH showed allelic imbalances in multiplex-PCR. These imbalances did not correlate with the corresponding tumours and furthermore were different to the LOH found in the investigated prostate tumours of the transitional zone. One AAH showed loss on chromosome 22q. We found allelic imbalances in over 50% of non-neoplastic tissue adjacent to prostatic carcinoma. Our findings support the idea that AAH does not seem to be linked closely to PC and should not be considered as an obligate premalignant lesion.

Aged↗

PubMed2004

Modification of breast cancer risk in young women by a polymorphic sequence in the egfr gene.

The regulation of the epidermal growth factor receptor (egfr) gene in human cancer is not yet fully understood. Recent data on a polymorphic CA repeat located at the 5'-regulatory sequence in intron 1 of the egfr gene [egfr CA simple sequence repeat (SSR) I] point to a possible inheritance of cancer risk associated with the egfr gene. Furthermore, we have detected frequent allelic imbalances restricted to the egfr CA SSR I in breast cancer tissue and nontumorous breast tissue adjacent to invasive and in situ breast cancer representing amplifications. Therefore, we conducted a population-based case-control study to assess the relationship between the egfr polymorphism and breast cancer risk. Cases with a first primary breast cancer by age 50 years and age-matched population controls provided information on known and suspected risk factors. The allelic length of the egfr CA SSR was determined in 616 cases and 1072 population-sampled controls. Genotypes were categorized for analysis by allele length. Multivariate logistic regression was used to compare genotype distributions, accounting for other risk factors, and to investigate gene-environment interactions. We found a modifying effect, albeit no main effect, of the allelic length of the egfr polymorphism on breast cancer risk. The presence of two long alleles (>/==" BORDER="0">19 CA) was associated with a significantly elevated odds ratio (OR) of 10.4 [95% confidence interval (CI), 1.85-58.70] among women with a first-degree family history of breast cancer (P = 0.015 for interaction). The risk increase associated with high red meat consumption (OR, 10.68; 95% CI, 1.57-72.58) and the protective effect of high vegetable intake (OR, 0.07; 95% CI, 0.004-1.07) was also most pronounced among carriers of two long alleles (>/==" BORDER="0">19 CA). The length of the egfr CA SSR may increase the risk for familial breast cancers, and its effect could be modulated by dietary factors.

Adult↗