Thyroid complications of SARS and coronavirus disease 2019 (COVID-19).

We have reviewed the available literature on thyroid diseases and coronavirus disease 2019 (COVID-19), and data from the previous coronavirus pandemic, the severe acute respiratory syndrome (SARS) epidemic. We learned that both SARS and COVID-19 patients had thyroid abnormalities. In the limited number of SARS cases, where it was examined, decreased serum T3, T4 and TSH levels were detected. In a study of survivors of SARS approximately 7% of the patients had hypothyroidism. In the previous evaluation evidence was found that pituitary function was also affected in SARS. Others suggested a hypothalamic-pituitary-adrenal axis dysfunction. One result published recently indicates that a primary injury to the thyroid gland itself may play a key role in the pathogenesis of thyroid disorders in COVID-19 patients, too. Subacute thyroiditis, autoimmune thyroiditis and an atypical form of thyroiditis are complications of COVID-19. Thyroid hormone dysfunction affects the outcome by increasing mortality in critical illnesses like acute respiratory distress syndrome, which is a leading complication in COVID-19. Angiotensin-converting enzyme 2 is a membrane-bound enzyme, which is also expressed in the thyroid gland and the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) uses it for docking, entering as well as replication. Based on the available results obtained in the SARS-CoV-2 pandemic, beside others, we suggest that it is necessary to monitor thyroid hormones in COVID-19.

PREDICTIVE VALUE OF SOMATIC MUTATIONS FOR THE DEVELOPMENT OF MALIGNANCY IN THYROID NODULES BY CYTOPATHOLOGY.

OBJECTIVE: The purpose of our prospective longitudinal study was to evaluate the predictive efficacy of genetic testing for malignancies in fine-needle aspiration biopsy samples that are cytologically benign at the time of biopsy. METHODS: A total of 779 aspirated cytological samples collected from thyroid nodules of 626 patients were included in a 3-year follow-up study. Consecutive patients with cytologically benign thyroid nodules by the Bethesda System for Reporting Thyroid Cytopathology were enrolled in the study. At enrollment, somatic 1-point nucleotide polymorphisms of BRAF and RAS family genes were tested by melting-point analysis, while RET/PTC and PAX8/PPAR-gamma rearrangements were examined by real-time polymerase chain reaction. The genetic test was considered to be positive if a somatic mutation was found. Malignant cytopathologic diagnoses were confirmed by histopathology. RESULTS: In samples collected from 779 thyroid nodules, there were 39 BRAF, 33 RAS mutations, and 1 RET/PTC rearrangements found at the beginning of the study. No PAX8/PPAR-gamma rearrangement was identified. There were 52 malignant thyroid tumors removed during follow-up, out of which 24 contained a somatic mutation. The specificity of the presence of somatic mutations for malignancies was as high as 93.3%, and sensitivity was 46.2%. The negative predictive value of genetic testing reached 96.0%. CONCLUSION: Our results show that our set of genetic tests can predict the appearance of malignancy in benign thyroid nodules (at the beginning of follow-up) with high specificity and strong negative predictive value. ABBREVIATIONS: BRAF = v-raf murine sarcoma viral oncogene homolog B1 FLUS = follicular lesion of undetermined significance FNAB = fine-needle aspiration biopsy FTC = follicular thyroid carcinoma HRAS = homologous to the oncogene from the Harvey rat sarcoma virus KRAS = homologous to the oncogene from the Kirsten rat sarcoma virus NRAS = first isolated from a human neuroblastoma/neuroblastoma RAS = viral oncogene homolog PAX8 = paired box 8 PCR = polymerase chain reaction PPAR-gamma = peroxisome proliferator-activated receptor gamma PTC = papillary thyroid carcinoma RAS = rat sarcoma RET = rearranged during transfection tyrosine-kinase proto-oncogene SM = somatic mutation SNP = single-nucleotide polymorphism.

Genetic and environmental influence on thyroid gland volume and thickness of thyroid isthmus: a twin study

Objectives Decreased thyroid volume has been related to increased prevalence of thyroid cancer. Subjects and methods One hundred and fourteen Hungarian adult twin pairs (69 monozygotic, 45 dizygotic) with or without known thyroid disorders underwent thyroid ultrasound. Thickness of the thyroid isthmus was measured at the thickest portion of the gland in the midline using electronic calipers at the time of scanning. Volume of the thyroid lobe was computed according to the following formula: thyroid height*width*depth*correction factor (0.63). Results Age-, sex-, body mass index- and smoking-adjusted heritability of the thickness of thyroid isthmus was 50% (95% confidence interval [CI], 35 to 66%). Neither left nor right thyroid volume showed additive genetic effects, but shared environments were 68% (95% CI, 48 to 80%) and 79% (95% CI, 72 to 87%), respectively. Magnitudes of monozygotic and dizygotic co-twin correlations were not substantially impacted by the correction of covariates of body mass index and smoking. Unshared environmental effects showed a moderate influence on dependent parameters (24-50%). Conclusions Our analysis support that familial factors are important for thyroid measures in a general twin population. A larger sample size is needed to show whether this is because of common environmental (e.g. intrauterine effects, regional nutrition habits, iodine supply) or genetic effects.

Genetic and environmental influence on thyroid gland volume and thickness of thyroid isthmus: a twin study.

OBJECTIVES: Decreased thyroid volume has been related to increased prevalence of thyroid cancer. SUBJECTS AND METHODS: One hundred and fourteen Hungarian adult twin pairs (69 monozygotic, 45 dizygotic) with or without known thyroid disorders underwent thyroid ultrasound. Thickness of the thyroid isthmus was measured at the thickest portion of the gland in the midline using electronic calipers at the time of scanning. Volume of the thyroid lobe was computed according to the following formula: thyroid height*width*depth*correction factor (0.63). RESULTS: Age-, sex-, body mass index- and smoking-adjusted heritability of the thickness of thyroid isthmus was 50% (95% confidence interval [CI], 35 to 66%). Neither left nor right thyroid volume showed additive genetic effects, but shared environments were 68% (95% CI, 48 to 80%) and 79% (95% CI, 72 to 87%), respectively. Magnitudes of monozygotic and dizygotic co-twin correlations were not substantially impacted by the correction of covariates of body mass index and smoking. Unshared environmental effects showed a moderate influence on dependent parameters (24-50%). CONCLUSIONS: Our analysis support that familial factors are important for thyroid measures in a general twin population. A larger sample size is needed to show whether this is because of common environmental (e.g. intrauterine effects, regional nutrition habits, iodine supply) or genetic effects.

[The impact of thyroid function in women of reproductive age: infertility, pregnancy and the postpartum period]. / A pajzsmirigymuködés jelentosége fertilis korú nokben: meddoség, terhesség és a post partum idoszak.

This article reviews the management and diagnosis of thyroid dysfunction during pregnancy and postpartum, which was published by any of the endocrine societies in 2012. The author presents human data based on these clinical practice guidelines, however, there are also many unresolved questions. Especially, there are inconsistencies about screening using plasma TSH measurement. In pregnancy the main causes of hyperthyroidism are Graves's disease and gestational transient thyrotoxicosis. Generally, gestational transient thyrotoxicosis does not require medication, whereas Graves's disease needs antithyroid drug therapy. Postpartum thyroiditis occurs more frequently in antithyroid peroxidase-positive women, who should be screened using serum thyrotropin measurements at 6 to 12 gestation weeks and at 3 and 6 months postpartum. Because overt maternal hypothyroidism, due to autoimmune pathophysioloical mechanisms, negatively affects the fetus, timely recognition and treatment are important. The subclinical form of maternal hypothyroidism should also be treated. A link between thyroid dysfunction and infertility has been warranted.

CYP24A1 inhibition facilitates the anti-tumor effect of vitamin D3 on colorectal cancer cells.

AIM: The effects of vitamin D3 have been investigated on various tumors, including colorectal cancer (CRC). 25-hydroxyvitamin-D3-24-hydroxylase (CYP24A1), the enzyme that inactivates the active vitamin D3 metabolite 1,25-dihydroxyvitamin D3 (1,25-D3), is considered to be the main enzyme determining the biological half-life of 1,25-D3. During colorectal carcinogenesis, the expression and concentration of CYP24A1 increases significantly, suggesting that this phenomenon could be responsible for the proposed efficacy of 1,25-D3 in the treatment of CRC. The aim of this study was to investigate the anti-tumor effects of vitamin D3 on the human CRC cell line Caco-2 after inhibition of the cytochrome P450 component of CYP24A1 activity. METHODS: We examined the expression of CYP24A1 mRNA and the effects of 1,25-D3 on the cell line Caco-2 after inhibition of CYP24A1. Cell viability and proliferation were determined by means of sulforhodamine-B staining and bromodeoxyuridine incorporation, respectively, while cytotoxicity was estimated via the lactate dehydrogenase content of the cell culture supernatant. CYP24A1 expression was measured by real-time reverse transcription polymerase chain reaction. A number of tetralone compounds were synthesized to investigate their CP24A1 inhibitory activity. RESULTS: In response to 1,25-D3, CYP24A1 mRNA expression was enhanced significantly, in a time- and dose-dependent manner. Caco-2 cell viability and proliferation were not influenced by the administration of 1,25-D3 alone, but were markedly reduced by co-administration of 1,25-D3 and KD-35, a CYP24A1-inhibiting tetralone. Our data suggest that the mechanism of action of co-administered KD-35 and 1,25-D3 does not involve a direct cytotoxic effect, but rather the inhibition of cell proliferation. CONCLUSION: These findings demonstrate that the selective inhibition of CYP24A1 by compounds such as KD-35 may be a new approach for enhancement of the anti-tumor effect of 1,25-D3 on CRC.

The role of vitamin D, estrogen, calcium sensing receptor genotypes and serum calcium in the pathogenesis of prostate cancer.

INTRODUCTION: Prostate cancer is the second leading cause of cancer death among men in developed countries. Estrogen receptor-alpha (ER-α), vitamin D receptor (VDR), and the calcium-sensing receptor (CaSR), partly through their effects on calcium levels are implicated in the proliferation and carcinogenesis in the prostate gland. VDR, ER-α and CaSR genes show polymorphisms in humans that appear to have clinical significance in many pathological conditions, such as prostate cancer. Our aim was to evaluate the role of ER-α (PvuII, XbaI), VDR (BsmI) and CaSR (A986S) gene polymorphisms and serum calcium levels in the pathogenesis of prostate cancer. MATERIAL AND METHODS: Two hundred four patients with prostate cancer and 102 healthy controls were recruited into a hospital-based case control study. After genotyping, the relationship between the individual genotypes and prostate cancer was investigated. RESULTS: Both the ER-α XbaI and the VDR BsmI polymorphisms were significantly related to the risk of prostate cancer. An age adjusted logistic regression limited to controls and patients not receiving bisphosphonate therapy showed that higher corrected serum calcium and the VDR Bb/BB genotypes independently increased the risk of prostate cancer. CONCLUSIONS: ER-α XbaI and VDR BsmI genetic polymorphisms had a significant association with the risk of prostate cancer. Both VDR BsmI genotypes and serum calcium levels were independently related to the risk of prostate cancer, suggesting an influence of VDR on the development of this malignancy.

[Comparative study of somatic oncogene mutations in normal thyroid tissues and thyroid neoplasms]. / Szomatikus onkogén mutációk összehasonlító vizsgálata egészséges és tumoros pajzsmirigy-szövetmintákban.

It is established that numerous somatic oncogene mutation (BRAF, NRAS, HRAS, KRAS) and gene translocations (RET/PTC, PAX8/PPAR-gamma) are associated with the development of thyroid cancer. In this study 22 intraoperative thyroid tissue samples (11 pathologic and 11 normal) were examined. Somatic single nucleotide polymorphisms were analyzed by LigthCycler melting method, while translocations were identified by real-time polymerase chain reaction technique. In tumorous sample 3 BRAF, 2 NRAS and one HRAS mutations were found, as well as one RET/PTC1 translocation. Results confirm international data showing that these oncogene mutations and translocations are linked to thyroid cancer. Cytological examination completed with genetic data may support the diagnosis of thyroid malignancies. In addition, genetic alterations may indicate malignant transformation and may become prognostic factors in future.

The protective role of bone morphogenetic protein-8 in the glucocorticoid-induced apoptosis on bone cells.

One of the side effects associated with glucocorticoid therapy is glucocorticoid-induced bone loss. Glucocorticoids partly detain bone formation via the inhibition of osteoblastic function, however, the exact mechanism of this inhibition remains elusive. In this study, we examined the effect of dexamethasone, an active glucocorticoid analogue, on cell viability and expression of bone remodelling-related genes in primary mouse calvarial and cloned MC3T3-E1 osteoblasts. Using sensitive biochemical assays, we demonstrated the apoptotic effect of dexamethasone on osteoblastic cells. Then, utilizing Taqman probe-based quantitative RT-PCR technology, gene expression profiles of 111 bone metabolism-related genes were determined. As a result of dexamethasone treatment we have detected significant apoptotic cell death, and six genes, including Smad3, type-2 collagen α-1, type-9 collagen α-1, matrix metalloproteinase-2, bone morphogenetic protein-4 and bone morphogenetic protein-8 showed (BMP-8) significant changes in their expression on a time- and concentration-dependent manner. BMP-8, (a novel player in bone-metabolism) exhibited a two orders of magnitude elevation in its mRNA level and highly elevated protein concentration by Western blot in response to dexamethasone treatment. The knockdown of BMP-8 by RNA interference significantly increased dexamethasone-induced cell death, confirming a protective role for BMP-8 in the glucocorticoid-induced apoptosis of osteoblasts. Our results suggest that BMP-8 might be an essential player in bone metabolism, especially in response to glucocorticoids.

[The role of vitamin D in the prevention and the additional therapy of cancers]. / A D-nap. A D-vitamin helye a daganatprevencióban és a kiegészíto kezelésben.

The active metabolite of vitamin D apart from a crucial role in maintaining mineral homeostasis and skeletal functions, has antiproliferative, apoptosis and differentiation inducing as well as immunomodulatory effects in cancer. It is well known that with increasing sunshine exposure the incidence of breast, prostate and colorectal cancer is decreasing. A number of in vitro and in vivo experiments documented the effects of vitamin D in the inhibition of the tumorigenesis. In studying the role of vitamin D in cancer, it is imperative to examine the potential pathways that control local tissue levels of vitamin D. The enzyme 24-hydroxylase converts the active vitamin D to inactive metabolite. Extra-renal production of this enzyme is observed and has been increasingly recognized as present in cancer cells. This enzyme is rate limiting for the amount of local vitamin D in cancer tissues and elevated expression is associated with an adverse prognosis. 24-hydroxylase may be a predictive marker of vitamin D efficacy in patients with cancer as an adjunctive therapy. There are many vitamin D analogs with no pronounced hypercalcemizing effects. Some analogs are in phase 1 and 2 clinical test, and they might have a role in the therapy of several types of cancer. At present our main task is to make an effort to decrease the vitamin D deficiency in Hungary. Speer G. The D-day. The role of vitamin D in the prevention and the additional therapy of cancers.

[Changes of gene expression and its role in pathogenesis in fibrous and non-fibrous dysplastic bone tissues in women]. / A génexpresszió változásai és patogenetikai jelentôségük fibrosus dysplasiás és nem fibrosus dysplasiás nôk csontszövetében.

UNLABELLED: Fibrous dysplasia is an isolated skeletal disorder caused by a somatic activating mutation of GNAS1 gene with abnormal unmineralized matrix overproduction and extensive undifferentiated bone cell accumulation in fibro-osseous lesions. The aim of the investigation was to identify genes that are differently expressed in fibrous vs. non-fibrous human bone and to describe the relationships between these genes using multivariate data analysis. MATERIALS AND METHODS: Six bone tissue samples from fibrous dysplastic female patients and 7 bone tissue samples from non-fibrous dysplastic women were examined. The 6 female fibrous samples were taken from the fibrous dysplastic lesion itself while the control samples of 7 non-fibrous dysplastic females were taken from the femoral neck during the hip replacement procedure. The expression differences of selected 118 genes were analyzed in TaqMan probe based quantitative real-time RT-PCR system. RESULTS: The Mann-Whitney U test indicated significant differences in the expression of 27 genes of fibrous dysplasial and non fibrous dysplasial individuals (p≤0.05). Nine genes were significantly up-regulated in fibrous dysplasial women compared to non fibrous dysplasial ones and eighteen genes showed a down-regulated pattern. These significantly altered genes coding for minor collagen molecules, extracellular matrix digesting enzymes, transcription factors, adhesion molecules, growth factors, pro-inflammatory cytokines and lipid metabolism-affected substrates. Canonical variety analysis demonstrated that fibrous dysplastic and non fibrous dysplastic bone tissues can be distinguished by the multiple expression profile analysis of numerous genes controlled via a G-protein coupled pathway and BMP cascade as well as genes coding for extracellular matrix composing molecules. CONCLUSIONS: The significantly altered gene expression profile observed in the fibrous dysplastic human bone tissue may provide further insight into the pathogenetic process of fibrous degeneration of bone.

Gene expression patterns in the bone tissue of women with fibrous dysplasia.

Fibrous dysplasia is an isolated skeletal disorder caused by a somatic activating mutation of GNAS gene with abnormal unmineralized matrix overproduction and extensive undifferentiated bone cell accumulation in the fibro-osseous lesions. The aim of our investigation was to identify genes that are differently expressed in fibrous versus non-fibrous human bone and to describe the relationships between these genes using multivariate data analysis. Six bone tissue samples from female patients with fibrous dysplastia (FD) and seven bone tissue samples from women without FD (non-FD) were examined. The expression differences of selected 118 genes were analyzed by the TaqMan probe-based quantitative real-time RT-PCR system. The Mann-Whitney U-test indicated marked differences in the expression of 22 genes between FD and non-FD individuals. Nine genes were upregulated in FD women compared to non-FD ones and 18 genes showed a downregulated pattern. These altered genes code for minor collagen molecules, extracellular matrix digesting enzymes, transcription factors, adhesion molecules, growth factors, pro-inflammatory cytokines, and lipid metabolism-affected substrates. Canonical variates analysis demonstrated that FD and non-FD bone tissues can be distinguished by the multiple expression profile analysis of numerous genes controlled via a G-protein coupled pathway and BMP cascade as well as genes coding for extracellular matrix composing molecules. The remarkable changed gene expression profile observed in the fibrous dysplastic human bone tissue may provide further insight into the pathogenetic process of fibrous degeneration of bone.

[Verner-Morrison syndrome: a case study]. / Verner-Morrison-szindróma egy esete.

Verner and Morrison described a syndrome of watery diarrhea, hypokalemia, and achlorhydria (WDHA) in 1958. VIPomas producing high amounts of vasoactive intestinal peptide (VIP) commonly originate from the pancreas. Typical symptoms play a momentous role in the diagnosis of VIPoma. Diarrhea may persist for years before the diagnosis. Morbidity from untreated WDHA syndrome is associated with long-standing dehydration and with electrolyte and acid-base metabolism disorders, which may cause chronic renal failure. Assessment of specific marker (VIP) offers high sensitivity in establishing the diagnosis. Imaging modalities include endoscopic ultrasonography, computed tomography and magnetic resonance imaging, and particularly, scintigraphy with somatostatin analogues. Treatment options include resection of the tumor, chemotherapy or the reduction of symptoms with somatostatin analogues. Early diagnosis and management may affect survival of patients favorably. VIPoma cases may be associated with multiple endocrine neoplasia type 1.

The candidate oncogene CYP24A1: A potential biomarker for colorectal tumorigenesis.

The main autocrine/paracrine role of the active metabolite of vitamin D(3), 1alpha,25-dihydroxyvitamin D(3) (1,25-D(3)), is inhibition of cell growth and induction of cell differentiation and/or apoptosis. Synthesis and degradation of the secosteroid occurs not only in the kidney but also in normal tissue or malignant extrarenal tissues such as the colon. Because 25-hydroxyvitamin D(3) 24-hydroxylase (CYP24A1) is considered to be the main enzyme determining the biological half-life of 1,25-D(3), we have examined expression of the CYP24A1 mRNA (by real-time RT-PCR) and protein (by immunohistochemistry) in normal human colon mucosa, colorectal adenomas, and adenocarcinomas in 111 patients. Although 76% of the normal and benign colonic tissue was either completely devoid of or expressed very low levels of CYP24A1, in the majority of the adenocarcinomas (69%), the enzyme was present at high concentrations. A parallel increased expression of the proliferation marker Ki-67 in the same samples suggests that overexpression of CYP24A1 reduced local 1,25-D(3) availability, decreasing its antiproliferative effect.

Allelic variations of RANKL/OPG signaling system are related to bone mineral density and in vivo gene expression.

OBJECTIVE: Receptor activator of nuclear factor-kappaB ligand/osteoprotegerin (RANKL/OPG) signaling system plays a crucial role in the regulation of bone resorption. Polymorphic variations in the genes may have an influence on gene expression and bone metabolism. In the present study, we aimed to investigate the influence of RANKL/OPG allelic variations on the in vivo human gene expression of five genes, bone mineral density (BMD), and fracture incidence in Hungarian postmenopausal women. METHODS: Three hundred and sixty postmenopausal women (61.6+/-7.9 years) were genotyped. All together, five single nucleotide polymorphisms (SNPs) in the two genes have been investigated. In addition, bone samples from 17 examined subjects were acquired for gene expression studies. Bone densities and fracture data have also been collected. RESULTS: All two SNPs in OPG gene and three SNPs in RANKL gene showed correlation with BMD. Haplotype analysis of these genes gave similar results. The 'CCT' haplotype of RANKL promoter region, which was associated with decreased BMD, exhibited a significantly upregulated expression of RANKL mRNA, while the other haplotypes of RANKL or OPG 15 genes did not. No correlation between genetic variations and fracture data was found. CONCLUSION: We have demonstrated associations between RANKL and OPG haplotypes and BMD as well as between RANKL haplotypes and in vivo RANKL expression in a Hungarian postmenopausal population. Moreover, we have found a new RANKL haplotype associating with reduced BMD and increased in vivo RANKL expression in human bone tissue.

Abnormal glucose tolerance is associated with diminished postload change in leptin levels in women.

BACKGROUND: It is generally accepted that the metabolic effects of leptin are diminished in the obese due to leptin resistance. Hormone resistance may develop if diurnal (including meal-related) changes in hormone levels are disrupted. We sought to describe leptin changes after a 75 g oral glucose tolerance test (OGTT) in women with a prior diagnosis of gestational diabetes mellitus (a high risk group for the metabolic syndrome) compared to that in healthy controls. METHODS: In 2000 a retrospective cohort study was performed on women who had been diagnosed with gestational diabetes mellitus (WHO criteria 1985, n = 57) between 1996 and 1998 and on a healthy control female group (n = 36) all of whom had had a prior pregnancy without any diagnosis of diabetes. All the women underwent a standard 75 g OGTT. Serum leptin was measured by radioimmunoassay before and 90 min after the OGTT. RESULTS: Using multilevel models of change, fasting leptin levels were shown to be associated with body mass index; 10.1% (95% CI 8.1-12.1%) increase per 1 kg/m(2) increase in body mass index), homeostasis model assessment insulin sensitivity; 0.4% (95% CI 0.2-0.7%) decrease per 1% increase in insulin sensitivity); abnormal glucose tolerance (24% decrease, 95% CI 8-37%); and smoking (31% decrease, 95% CI 16-44%). Postload (90 min) leptin levels decreased significantly in women with normal glucose tolerance by 13% (95% CI 8-18%), while no significant change in postload leptin level was apparent in women with abnormal glucose tolerance (3% increase, 95% CI -4% to 29%). CONCLUSIONS: Disturbed leptin changes were found following an OGTT in women with abnormal glucose tolerance that might be either a cause or a consequence of leptin resistance.

Effect of menopause on gene expression pattern in bone tissue of nonosteoporotic women.

OBJECTIVE: Menopausal changes influence the growth, differentiation, and metabolism of bone tissue. Hormonal deficiency at the time of menopause results in marked increases in bone resorption and formation, leading to rapid bone loss. The aim of our investigation was to determine genes characterized by significantly changed mRNA expression rates in postmenopausal versus premenopausal nonosteoporotic bone tissue and to describe the interrelationships among these genes using multivariate data analysis. METHODS: Ten bone tissue samples from postmenopausal nonosteoporotic women and seven bone tissue samples from premenopausal nonosteoporotic women were examined. The expression differences of 118 selected genes were analyzed in a TaqMan probe-based quantitative reverse transcriptase-polymerase chain reaction system. RESULTS: The Mann-Whitney U test indicated significant differences in the expression of 29 genes of postmenopausal and premenopausal nonosteoporotic women. Twenty-eight genes, including extracellular matrix molecules and digesting enzymes, genes belonging to the transforming growth factor-beta/bone morphogenic protein pathway, transcription factors, growth factors, and other candidate genes, were significantly up-regulated in postmenopausal women compared with premenopausal women. Only one gene (ENO1) showed down-regulation after menopause. Based on the multiple mRNA expression profiles of 118 genes, postmenopausal and premenopausal states could be differentiated by enhanced postmenopausal gene expression levels using principal components analysis. Canonical variates analysis demonstrated that postmenopausal and premenopausal nonosteoporotic bone tissues can be distinguished by expression analysis of genes controlled via estrogen receptor-alpha and genes coding for extracellular matrix molecules. CONCLUSIONS: The menopausal state of bone tissue has been unambiguously defined by its complex gene transcription pattern. Significant differences observed in the gene expression profiles of estrogen-deficient human bone tissue provide further insight into the process of postmenopausal changes of bone metabolism.

Effects of the lactase 13910 C/T and calcium-sensor receptor A986S G/T gene polymorphisms on the incidence and recurrence of colorectal cancer in Hungarian population.

BACKGROUND: Epidemiological studies suggested the chemopreventive role of higher calcium intake in colorectal carcinogenesis. We examined genetic polymorphisms that might influence calcium metabolism: lactase (LCT) gene 13910 C/T polymorphism causing lactose intolerance and calcium-sensing receptor (CaSR) gene A986S polymorphism as a responsible factor for the altered cellular calcium sensation. METHODS: 538 Hungarian subjects were studied: 278 patients with colorectal cancer and 260 healthy controls. Median follow-up was 17 months. After genotyping, the relationship between LCT 13910 C/T and CaSR A986S polymorphisms as well as tumor incidence/progression was investigated. RESULTS: in patient with colorectal cancer, a significantly higher LCT CC frequency was associated with increased distant disease recurrence (OR = 4.04; 95% CI = 1.71-9.58; p = 0.006). The disease free survival calculated from distant recurrence was reduced for those with LCT CC genotype (log rank test p = 0.008). In case of CaSR A986S polymorphism, the homozygous SS genotype was more frequent in patients than in controls (OR = 4.01; 95% CI = 1.33-12.07; p = 0.014). The number of LCT C and CaSR S risk alleles were correlated with tumor incidence (p = 0.035). The CCSS genotype combination was found only in patients with CRC (p = 0.033). CONCLUSION: LCT 13910 C/T and CaSR A986S polymorphisms may have an impact on the progression and/or incidence of CRC.