May critical molecular cross-talk between indoleamine 2,3-dioxygenase (IDO) and arginase during human aging be targets for immunosenescence control?

BACKGROUND: This study aimed to identify novel plasma metabolic signatures with possible clinical relevance during the aging process. A biochemical quantitative phenotyping platform, based on targeted electrospray ionization tandem mass spectrometry technology, was used for the identification of any eventual perturbed biochemical pathway by the aging process in prospectively collected peripheral blood plasma from 166 individuals representing the population of São Paulo city, Brazil. RESULTS: Indoleamine 2,3-dioxygenase (IDO) activity (Kyn/Trp) was significantly elevated with age, and among metabolites most associated with elevations in IDO, one of the strongest correlations was with arginase (Orn/Arg), which could also facilitate the senescence process of the immune system. Hyperactivity of IDO was also found to correlate with increased blood concentrations of medium-chain acylcarnitines, suggesting that deficiencies in beta-oxidation may also be involved in the immunosenescence process. Finally, our study provided evidence that the systemic methylation status was significantly increased and positively correlated to IDO activity. CONCLUSIONS: In the present article, besides identifying elevated IDO activity exhibiting striking parallel association with the aging process, we additionally identified increased arginase activity as an underlying biochemical disturbance closely following elevations in IDO. Our findings support interventions to reduce IDO or arginase activities in an attempt to preserve the functionality of the immune system, including modulation of myeloid-derived suppressor cells (MDSCs), T cells, macrophages, and dendritic cells' function, in old individuals/patients.

Human Papillomavirus and Coronary Artery Disease in Climacteric Women: Is There an Association?

BACKGROUND: Cardiovascular diseases are leading causes of death worldwide. Recent studies suggest that infection by some viruses, including the human papillomavirus (HPV), may increase the risk of developing atheromatous lesions on coronary arteries. However, there is a lack of data regarding the possible association between HPV infection and coronary artery disease (CAD) in women. OBJECTIVE: To investigate whether HPV infection is associated with the occurrence of CAD among climacteric women. METHODS: The presence of CAD and cervical HPV DNA was investigated in 52 climacteric women. Social and demographic variables and metabolic profiles were also investigated. RESULTS: Among 27 women with CAD, 16 were positive for HPV, whereas 11 were negative. The presence of cervical HPV was strongly associated with CAD, after adjusting for demographic variables, health and sexual behaviors, comorbidities, and known cardiovascular risk factors. HPV-positive women showed a greater likelihood of having CAD (odds ratio [OR] = 3.74; 95% confidence interval [CI]: 1.16 to 11.96) as compared with HPV-negative women, particularly those infected with high-risk HPV types (OR = 4.90; 95% CI: 1.26 to 19.08). CONCLUSION: These results support the hypothesis that HPV infection might be associated with CAD among climacteric women, though further studies are needed to investigate the mechanisms involved.

Exploring the applicability of analysing X chromosome STRs in Brazilian admixed population.

Kinship and parentage analyses always involve one sample being compared to another sample or a few samples with a specific relationship question in mind. In most cases, the analysis of autosomal STR markers is sufficient to determine the genetic kinship. However, when genetic profiles are reconstructed from supposed relatives, for whom the family configuration available for analysis is deficient, the examination may be inconclusive. This study reports practical examples of actual cases analysing the efficiency of the chromosome X STR (STR-ChrX) markers. Three cases with different degrees of efficiency and impact were selected as follows: the identification of two charred bodies in a traffic accident, in which the family setting available was not complete, and one filiation analysis resulting from rape. This is the first paper reporting the use of the multiplex STR 12 ChrX in actual cases using the software Familias 1.8 and Brazilian regional frequency data. Our study clarifies the complex analysis using this powerful tool for professionals in the forensic science community, for both civil and criminal justice. We also discuss state-of-the-art ChrX STR markers and its implications and applications for legal procedures. The data presented here should be used in other studies of complex cases to improve the progress of the current justice system.

Unlocking the complete blood count as a risk stratification tool for breast cancer using machine learning: a large scale retrospective study.

Optimizing early breast cancer (BC) detection requires effective risk assessment tools. This retrospective study from Brazil showcases the efficacy of machine learning in discerning complex patterns within routine blood tests, presenting a globally accessible and cost-effective approach for risk evaluation. We analyzed complete blood count (CBC) tests from 396,848 women aged 40-70, who underwent breast imaging or biopsies within six months after their CBC test. Of these, 2861 (0.72%) were identified as cases: 1882 with BC confirmed by anatomopathological tests, and 979 with highly suspicious imaging (BI-RADS 5). The remaining 393,987 participants (99.28%), with BI-RADS 1 or 2 results, were classified as controls. The database was divided into modeling (including training and validation) and testing sets based on diagnostic certainty. The testing set comprised cases confirmed by anatomopathology and controls cancer-free for 4.5-6.5 years post-CBC. Our ridge regression model, incorporating neutrophil-lymphocyte ratio, red blood cells, and age, achieved an AUC of 0.64 (95% CI 0.64-0.65). We also demonstrate that these results are slightly better than those from a boosting machine learning model, LightGBM, plus having the benefit of being fully interpretable. Using the probabilistic output from this model, we divided the study population into four risk groups: high, moderate, average, and low risk, which obtained relative ratios of BC of 1.99, 1.32, 1.02, and 0.42, respectively. The aim of this stratification was to streamline prioritization, potentially improving the early detection of breast cancer, particularly in resource-limited environments. As a risk stratification tool, this model offers the potential for personalized breast cancer screening by prioritizing women based on their individual risk, thereby indicating a shift from a broad population strategy.

Biochemical phenotyping of paroxysmal nocturnal hemoglobinuria reveals solute carriers and ß-oxidation deficiencies.

INTRODUCTION: Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal disease of hematopoietic cells with a variable clinical spectrum characterized by intravascular hemolysis, high risk of thrombosis, and cytopenias. To understand the biochemical shifts underlying PNH, this study aimed to search for the dysfunctional pathways involved in PNH physiopathology by comparing the systemic metabolic profiles of affected patients to healthy controls and the metabolomic profiles before and after the administration of eculizumab in PNH patients undergoing treatment. METHODS: Plasma metabolic profiles, comprising 186 specific annotated metabolites, were quantified using targeted quantitative electrospray ionization tandem mass spectrometry in 23 PNH patients and 166 population-based controls. In addition, samples from 12 PNH patients on regular eculizumab maintenance therapy collected before and 24 hours after eculizumab infusion were also analyzed. RESULTS: In the PNH group, levels of the long-chain acylcarnitines metabolites were significantly higher as compared to the controls, while levels of histidine, taurine, glutamate, glutamine, aspartate and phosphatidylcholines were significantly lower in the PNH group. These differences suggest altered acylcarnitine balance, reduction in the amino acids participating in the glycogenesis pathway and impaired glutaminolysis. In 12 PNH patients who were receiving regular eculizumab therapy, the concentrations of acylcarnitine C6:1, the C14:1/C6 ratio (reflecting the impaired action of the medium-chain acyl-Co A dehydrogenase), and the C4/C6 ratio (reflecting the impaired action of short-chain acyl-Co A dehydrogenase) were significantly reduced immediately before eculizumab infusion, revealing impairments in the Acyl CoA metabolism, and reached levels similar to those in the healthy controls 24 hours after infusion. CONCLUSIONS: We demonstrated significant differences in the metabolomes of the PNH patients compared to healthy controls. Eculizumab infusion seemed to improve deficiencies in the acyl CoA metabolism and may have a role in the mitochondrial oxidative process of long and medium-chain fatty acids, reducing oxidative stress, and inflammation.

Evaluation of single nucleotide polymorphisms in microRNAs (hsa-miR-196a2 rs11614913 C/T) from Brazilian women with breast cancer.

BACKGROUND: Emerging evidence has shown that miRNAs are involved in human carcinogenesis as tumor suppressors or oncogenes. Single nucleotide polymorphisms (SNPs) located in pre-miRNAs may affect the processing and therefore, influence the expression of mature miRNAs. Previous studies generated conflicting results when reporting association between the hsa-miR-196a2 rs11614913 common polymorphism and breast cancer. METHODS: This study evaluated the hsa-miR-196a2 rs11614913 SNP in 388 breast cancer cases and 388 controls in Brazilian women. Polymorphism was determined by real-time PCR; control and experimental groups were compared through statistical analysis using the X2 or Fisher's exact tests. RESULTS: The analysis of the SNPs frequencies showed a significant difference between the groups (BC and CT) in regards to genotype distribution (χ2: p = 0.024); the homozygous variant (CC) was more frequent in the CT than in the BC group (p = 0.009). The presence of the hsa-miR-196a2 rs11614913 C/T polymorphism was not associated with histological grades (p = 0.522), axillary lymph node positive status (p = 0.805), or clinical stage (p = 0.670) among the breast cancer patients. CONCLUSIONS: The results of this study indicated that the CC polymorphic genotype is associated with a decreased risk of BC and the presence of the T allele was significantly associated with an increased risk of BC.

MspA1 polymorphism of the CYP17 gene in breast cysts.

OBJECTIVE: To study the prevalence of breast cysts in several age groups of the general female population and their association with the MspAI polymorphism of the gene CYP17. RESULTS: In 204 ultrasound tests, cysts were present in 22% of the studied population. The epidemiological-clinical profile of these women was Caucasian, aged 41-50 years, regular menstrual cycles, multiparous and complaining of mastalgia. The genetic distribution of polymorphisms of the gene displayed Hardy-Weinberg equilibrium and the wild homozygous phenotype was observed in 36.4% of the case group and in 37.6% of the control groups; the heterozygous phenotype was observed in 50% of the study group and 46.3% of control group and a mutated homozygous phenotype was seen in 13.6% of the study group and 16.1% of the controls. There was no statistically significant difference between the groups (p = 0.92). CONCLUSION: The prevalence and most of the epidemiological profile of breast cysts were in agreement with the literature. There was no statistically significant difference among the genotypic groups (wild homozygous, heterozygous and mutated homozygous), despite a slightly increased frequency of the mutated genotype in the control group. This difference indicates a trend of the MspAI polymorphism of the gene CYP17 to act as a protective factor against the development of breast cysts.

Evaluation of demographic, clinical characteristics, and genetic polymorphism as risk factors for pelvic organ prolapse in Brazilian women.

OBJECTIVE: Verify the association between genital prolapse, other risk factors and a polymorphism in exon 31 of the collagen III-a1 gene (COL3A1). SETTING: The etiology of genital prolapse is multifactorial, and genetic defects have been proposed. Also, there is evidence that changes in collagen may be responsible for defects in pelvic floor support. The exon 31 polymorphism results in structural changes in the triple helical of the collagen and appears to lead to abnormal synthesis of type III collagen. DESIGN: Basic science study. POPULATION: The studied group consisted of 107 patients with stage III and IV genital prolapse (POP-Q). The control group included 209 women with stage 0 and I prolapse. METHODS: After extracting genomic DNA from the peripheral blood, the exon 31 COL3A1 polymorphism was typed by restriction fragment length polymorphism analysis. MAIN OUTCOME MEASURES: Association between genital prolapse and exon 31 COL3A1 polymorphism. RESULTS: No statistically significant differences in genotype and allele frequencies were found between cases and controls (P = 0.75 and 0.66, respectively). Multiple logistic regression analyses identified age (OR = 1.05; 95%CI = 1.01-1.10), BMI (OR = 1.09; 95%CI = 1.01-1.17), presence of at least one vaginal delivery (OR = 7.22; 95%CI = 1.84-28.27), positive family history of POP (OR = 2.27; 95%CI = 1.05-4.93) and a macrosomic foetus (OR = 2.91; 95%CI = 1.24-6.79) as independent risk factors for genital prolapse. In contrast, the number of caesarean deliveries was found to be an independent protective factor (OR = 0.43; 95%CI = 0.24-0.78). CONCLUSIONS: The type III collagen exon 31 polymorphism is not a risk factor for pelvic genital prolapse in this sample.

Survivin and telomerase expression in the uterine cervix of women with human papillomavirus-induced lesions.

INTRODUCTION: Infection by human papillomavirus is the most important risk factor in the pathogenesis of uterine cervical cancer. The aims of this study were to evaluate the expression of survivin protein and telomerase enzyme in samples of uterine cervix from women with human papillomavirus-induced lesions and to determine the relationship between survivin and telomerase expression and the different grades of cervical squamous intraepithelial neoplasia and invasive cervical carcinoma. METHODS: Biopsy samples from the uterine cervix of 105 women aged 18 to 80 years were analyzed. The patients were divided into 5 groups: WN group, 20 patients without neoplasia; CIN-1 group, 24 patients with grade 1 cervical intraepithelial neoplasia (CIN), grade 1; CIN-2 group, 20 patients with CIN grade 2; CIN-3 group, 24 patients with CIN, grade 3; and ICC group, 17 patients with invasive cervical carcinoma. Human papillomavirus detection, telomerase activity, and survivin expression were assessed using polymerase chain reaction (PCR), real-time PCR (RT-PCR), and immunochemistry, respectively. RESULTS: There was a significant increase in the expression of telomerase and survivin associated with the severity of the lesion. CONCLUSIONS: The results suggest that mechanisms that promote both cell proliferation (telomerase activity) and cell survival (survivin expression) are active in cervical cancer and its precursor lesions. There was a negative correlation between survivin expression and the number of PCR cycles necessary to detect telomerase activity in the total sample, achieving statistical significance in patients in the CIN-3 group.

Involvement of GDF-9, leptin, and IGF1 receptors associated with adipose tissue transplantation on fertility restoration in obese anovulatory mice.

The aim was to analyze the effect of adipose tissue transplantation on growth differentiation factor-9 (GDF-9), insulin growth factor 1 receptor (IGF1R), and leptin receptor (LEPR) protein expression in ovaries of obese anovulatory mice. Leptin-deficient female (ob/ob) and wild-type mice were divided into untreated ob/ob mice and gonadal white adipose tissue transplanted ob/ob mice, with evaluation after 7, 15, and 45 days and compared to control wild-type mice. The corporal weight and glycemia levels increased in the obese group concomitant with polymicrocyst formation and abundant estrone, mimicking anovulatory disease. In the treated group after 45 days, glycemia, weight, ovarian size, and number of follicles were decreased and corpora lutea were decreased. The analysis of GDF-9 revealed that, whereas control ovaries presented follicular localization, the obese ovary lacked this protein. On the other hand, obese ovaries showed elevated expression of IGF1R that was normalized after the transplantation. Finally, LEPR was reduced in obese ovaries, and adipose tissue transplantation was efficient in returning it to normal levels. In conclusion, the adipose tissue transplantation, especially after 45 days, seems to stimulate ovulation, supported by the fact that several proteins involved in ovulation returned to basal levels.

Disrupted cell cycle control in cultured endometrial cells from patients with endometriosis harboring the progesterone receptor polymorphism PROGINS.

Presently, little is understood about how endometriosis is established or maintained, or how genetic factors can predispose women to the disease. Because of the crucial role that the progesterone receptor polymorphism PROGINS plays in predisposing women to the development of endometriosis, we hypothesized that this variant may influence critical steps during endometrial cell metabolism that are involved in the pathogenesis of endometriosis. Eutopic endometria were collected from three sources: women with endometriosis who had a single PROGINS allele (from the progesterone receptor gene); women with endometriosis who had the wild-type progesterone receptor allele; and women without endometriosis who had the wild-type allele. Cells prepared from the eutopic endometria of these women were stimulated with both estradiol and progesterone, and then examined for cell proliferation, viability, and apoptosis. The cells from women with endometriosis that carried the PROGINS allele demonstrated increased proliferation, greater viability, and decreased apoptosis following progesterone treatment. In general, these parameters were very different as compared with those of women with endometriosis but without the PROGINS allele and women in the control group. This result indicates there is a reduced level of progesterone responsiveness in women who carry the PROGINS polymorphism. Because progesterone responsiveness is known to be an important characteristic of women with endometriosis, these data support the contention that the PROGINS polymorphism enhances the endometriosis phenotype.

Contemporary human papillomavirus genotyping and correlations to peniscopy, cytology, and histopatology on over 1000 males.

OBJECTIVES: To explore male human papillomavirus (HPV) contemporary genotyping epidemiology and correlations to peniscopy, cytology, and histopatology. METHODS: Medical records of patients who had been submitted to HPV infection screening with genotyping, peniscopy, cytology, and histopathology in a period of 2 years were reviewed. Frequency analysis and correlations between the diagnostic tools were established. RESULTS: Genotype of 1132 men resulted in 69.2% (784) positivity for HPV DNA, 78% classified as high risk of oncogenesis. Co-infections occurred in 429 (54.7%) and the most frequently identified types were HPV-6, HPV-42, and HPV-16, in 133 (17%), 94 (12%), and 86 (11%) patients, respectively. Positive/negative predictive values of peniscopy, cytology, and histopathology were 83/31%, 92/32%, and 87/33%, respectively. As a result, though significant, the correlations between genotype and non-molecular tests were poor. CONCLUSIONS: In the current contemporary representative male cohort, over two thirds are positive for human HPV DNA, 78% of high risk and with over half co-infections. Though significant, its correlation with non-molecular tests is poor and while the positive predictive values of peniscopy, cytology, and histopatology are between 83% and 92%, their negative predictive values are as low as 31% to 33%.

Biochemical phenotyping of multiple myeloma patients at diagnosis reveals a disorder of mitochondrial complexes I and II and a Hartnup-like disturbance as underlying conditions, also influencing different stages of the disease.

The aim of this study was to identify novel plasma metabolic signatures with possible relevance during multiple myeloma (MM) development and progression. A biochemical quantitative phenotyping platform based on targeted electrospray ionization tandem mass spectrometry technology was used to aid in the identification of any eventual perturbed biochemical pathway in peripheral blood plasma from 36 MM patients and 73 healthy controls. Our results showed that MM cases present an increase in short and medium/long-chain species of acylcarnitines resembling Multiple AcylCoA Dehydrogenase Deficiency (MADD), particularly, associated with MM advanced International Staging System (ISS). Lipids profile showed lower concentrations of phosphatidylcholine (PC), lysophosphatidylcholine (LPC) and sphingomyelins (SM) in the MM patients and its respective ISS groups. MM cases were accompanied by a drop in the concentration of essential amino acids, especially tryptophan, with a significant inverse correlation between the progressive drop in tryptophan with the elevation of ß2-microglobulin, with the increase in systemic methylation levels (Symmetric Arginine Dimethylation, SDMA) and with the accumulation of esterified carnitines in relation to free carnitine (AcylC/C0). Serotonin was significantly elevated in cases of MM, without a clear association with ISS. Kynurenine/tryptophan ratio demonstrates that the activity of dioxigenases is even higher in the cases classified as ISS 3. In conclusion, our study showed that MM patients at diagnosis showed metabolic disorders resembling both mitochondrial complexes I and II and Hartnup-like disturbances as underlying conditions, also influencing different stages of the disease.

Distinct pattern of one-carbon metabolism, a nutrient-sensitive pathway, in invasive breast cancer: A metabolomic study.

Altered cell metabolism is a hallmark of cancer and critical for its development. Particularly, activation of one-carbon metabolism in tumor cells can sustain oncogenesis while contributing to epigenetic changes and metabolic adaptation during tumor progression. We assessed whether increased one-carbon metabolism activity is a metabolic feature of invasive ductal carcinoma (IDC). Differences in the metabolic profile between biopsies from IDC (n = 47) and its adjacent tissue (n = 43) and between biopsies from different breast cancer subtypes were assessed by gas spectrometry in targeted (Biocrates Life Science ® ) and untargeted approaches, respectively. The metabolomics data were statistically treated using MetaboAnalyst 4.0, SIMCA P+ (version 12.01), Statistica 10 software and t test with p < 0.05. The Cancer Genome Atlas breast cancer dataset was also assessed to validate the metabolomic profile of IDC. Our targeted metabolomics analysis showed distinct metabolomics profiles between IDC and adjacent tissue, where IDC displayed a comparative enrichment of metabolites involved in one-carbon metabolism (serine, glycine, threonine, and methionine) and a predicted increase in the activity of pathways that receive and donate carbon units (i.e., folate, methionine, and homocysteine). In addition, the targeted and untargeted metabolomics analyses showed similar metabolomics profiles between breast cancer subtypes. The gene set enrichment analysis identified different transcription-related functions between IDC and non-tumor tissues that involved one-carbon metabolism. Our data suggest that one-carbon metabolism may be a central pathway in IDC and even in general breast tumors, representing a potential target for its treatment and prevention.

E-cadherin and metalloproteinase-1 and -7 polymorphisms in colorectal cancer.

PURPOSE: E-cadherin (CDH1) and metalloproteinase (MMP) polymorphisms could play a crucial role in cancer invasion. Our aim was to investigate the influence of the -160C/A CDH1, -1607ins/delG MMP-1 and -181A/G MMP-7 polymorphisms on the frequency and progression of colorectal cancer (CRC). EXPERIMENTAL DESIGN: A total of 130 patients with CRC and 130 noncancer controls were studied. The -160C/A CDH1, -1607ins/delG MMP-1 and -181A/G MMP-7 genotypes were analyzed by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: Patients with the 1G allele and a family history of CRC showed a six times higher risk of developing CRC (OR: 6.45, 95% CI: 2.02-20.6, p=0.001). The A/A CDH1 genotype was associated with a higher risk of metastatic disease (OR: 3.43, 95% CI: 1.27-9.27, p=0.023). A higher marginal risk of metastatic disease was observed for MMP-1 genotypes 1G/1G and 1G/2G (OR: 2.97, 95% CI: 0.93-9.47, p=0.098). CONCLUSIONS: The -160C/A CDH1, -1607ins/delG MMP-1 and -181A/G MMP-7 single nucleotide polymorphisms did not modify the risk of CRC development. Patients with the 1G/1G or 1G/2G genotype and a family history of CRC presented a higher risk of CRC. The AA CDH1 and 1G/1G and 1G/2G MMP-1 genotypes might be associated with advanced metastatic disease, but are not markers of lymphatic metastasis.

Association between the angiotensin-converting enzyme (insertion/deletion) and angiotensin II type 1 receptor (A1166C) polymorphisms and breast cancer among Brazilian women.

INTRODUCTION: We evaluated the association between components of the renin-angiotensin system and the development of breast cancer in a case-control study by means of angiotensin-converting enzyme (ACE) insertion/deletion (I/D) and angiotensin II type 1 (AT( 1))-receptor A1166C polymorphisms. METHODS: Genotyping was performed by PCR-RFLP (restriction fragment length polymorphism) or PCR (polymerase chain reaction) using genomic DNA extracted from buccal cells of subjects with (101 cases) or without (307 controls) breast cancer. RESULTS: The frequencies of genotypes for ACE were: DD, ID and II (in %: cases: 60; 20; 20; controls: 46; 37; 17; p=0.019, chi(2)); and for AT(1)receptor were:AA,AC and CC (in %: cases: 65; 30; 5; controls: 51; 44; 5; p=0.114, chi( 2)).The results suggested that the A1166C polymorphism was not associated with breast cancer risk. On the other hand, for the ACE (I/D), there seemed to be different risks for cancer between cases and controls. CONCLUSIONS: The ID genotype was less frequently associated with the disease than were the DD or II; that is, women with the ID genotype were 3.1 times less likely to develop breast cancer than those with the other genotypes.The ID genotype might be protective against breast cancer and the ACE (I/D) polymorphism a possible target for developing genetic markers for breast cancer.

Interleukin-6 -174 G/C promoter polymorphism and nasal polyposis.

INTRODUCTION: Nasal polyposis is a chronic disease with unknown etiopathogenesis, although inflammatory mechanisms seem to play a role. One of several inflammatory mediators linked to nasal polyposis is Interleukin-6, which has a single nucleotide polymorphism -174 G/C that seems to promote an inflammatory reaction. OBJECTIVE: To compare the prevalence of the -174 G/C single nucleotide polymorphism between a group of patients with nasal polyposis and a control group. METHOD: Cross-sectional study with two groups (thirty two patients with nasal polyposis and fifty five controls) to investigate the -174 G/C polymorphism in blood samples. Asthma, aspirin intolerance and atopy were main exclusion criteria. IL-6 genotyping was performed using the PCR method with forward primer 5'-ATGCCAAGTGCTGAGTCACTA-3' and reverse primer 5'-GGAAAATCCCACATTTGATA-3', amplifying a 226-bp DNA fragment that contained the - 174 position. The amplified fragment can be cleaved by restriction enzyme NlaIII when the -174 position presented the C allele in two fragments of 117 and 109-bp, visualized by electrophoresis, classifying participants in GG, GC and CC. RESULTS: In the nasal polyposis group, 65.62% of the patients had the GG genotype, while in the control group, 41.82% had two G alleles, a statistically significant difference, with an odds ratio of 2.65. CONCLUSION: The -174 GG genotype was found more frequently in nasal polyposis patients than in controls, when asthma, aspirin intolerance and atopy were excluded.

Maternal glyphosate-based herbicide exposure alters antioxidant-related genes in the brain and serum metabolites of male rat offspring.

In response to the rapid development of genetically engineered glyphosate-tolerant crops, the use of glyphosate-based herbicides (GBHs), in agriculture, has increased substantially. Currently, it is estimated that 747 million kg of GBHs are applied per year. Although several epidemiological studies have demonstrated that there are health risks associated with GBH exposure, the effects these chemicals have on the oxidative and inflammatory response in the brain are still unclear. In fact, alterations in these processes could contribute to the development of neurological diseases, such as Alzheimer's disease and autism spectrum disorders. The present study exposed pregnant rats to GBH and evaluated changes in the expression of genes related to oxidnte defense and inflammation response and monitored the serum metabolome in the adult male offspring. Pregnant Wistar rats were administered distilled water or Roundup®, at either 5 and 50 mg/kg/day, (p.o.) from gestational day (GD) 18 to postnatal day (PND) 5. There was a significant increase in the gene expression levels of Neuroglobin (Ngb - oxygen storage and tissue protection) (105%, p = 0.031), Glutathione Peroxidase 1 (Gpx1 - oxidative stress) (95%, p = 0.005), Prostaglandin-Endoperoxidase Synthase 1 (Ptgs1 - inflammation) (109%, p = 0.033) and Hypoxia inducible factor 1 subunit alpha (Hif1α - oxygen sensor) (73%, p = 0.017), in the cerebellum of PND90 rats perinatally exposed to 50 mg GBH/kg/day. Moreover, both GBH-exposed groups displayed a significant decrease in the expression of Catalase (Cat - oxidative stress) (49%, p = 0.003; and 31% p = 0.050, respectively) expression, in the cortex. Serum metabolites analyses, from the same animals of each group, demonstrated that there were significant changes in the concentrations of lysophosphatidylcholine and phosphatidylcholine, which have been associated with neurodegenerative diseases. The results of the present study suggest GBH exposure during pregnancy alters the expression of genes associated with oxidant defense, inflammation and lipid metabolism. It is plausible that maternal GBH exposure could have lasting neuronal effects on the offspring later in life.

Reduced intestinal FADS1 gene expression and plasma omega-3 fatty acids following Roux-en-Y gastric bypass.

BACKGROUND & AIMS: Roux-en-Y gastric bypass (RYGB) limits food ingestion and may alter the intestinal expression of genes involved in the endogenous synthesis of polyunsaturated fatty acids (PUFAs). These changes may decrease the systemic availability of bioactive PUFAs after RYGB. To study the impact of RYGB on the dietary ingestion and plasma concentration of PUFAs and on the intestinal expression of genes involved in their endogenous biosynthesis in severely obese women with type 2 diabetes. METHODS: Before, and 3 and 12 months after RYGB, obese women (n = 20) self-reported a seven-day dietary record, answered a food frequency query and provided plasma samples for alpha-linolenic (ALA), eicosapentaenoic (EPA), docosahexaenoic (DHA) and arachidonic (ARA) acid assessment by gas chromatography. Intestinal biopsies (duodenum, jejunum and ileum) were collected through double-balloon endoscopy before and 3 months after RYGB for gene expression analysis by microarray (Human GeneChip 1.0 ST array) and RT-qPCR validation. RESULTS: Compared to the preoperative period, patients had decreased intakes of PUFAs, fish and soybean oil (p < 0.05) and lower plasma concentrations of ALA and EPA (p < 0.001) 3 and 12 months after RYGB. FADS1 gene expression was lower in duodenum (RT-qPCR fold change = -1.620, p < 0.05) and jejunum (RT-qPCR fold change = -1.549, p < 0.05) 3 months following RYGB, compared to before surgery. CONCLUSION: RYGB decreased PUFA ingestion, plasma ALA and EPA levels, and intestinal expression of FADS1 gene. The latter encodes a key enzyme involved in endogenous biosynthesis of PUFAs. These data suggest that supplementation of omega-3 PUFAs may be required for obese patients undergoing RYGB. Clinical Trial Registry number and website: www.clinicaltrials.gov - NCT01251016; Plataforma Brasil - 19339913.0.0000.0068.

The catechol-O-methyltransferase (COMT) gene polymorphism and prevalence of uterine fibroids.

OBJECTIVE: To assess the possible association between the catechol-O-methyltransferase (COMT) polymorphism and uterine fibroids in Brazilian women. DESIGN: Case-control study. SETTING: Department of Gynecology; teaching hospital. PATIENT(S): One hundred twenty-four premenopausal women with fibroids, and 193 postmenopausal controls not presenting the disease. INTERVENTION(S): The subjects were classified as white or non-white (black and mulatto), and COMT genotypes were determined. DNA was extracted from the uterus of cases and from peripheral blood of controls and submitted to polymerase chain reaction (PCR) and agarose gel electrophoresis. MAIN OUTCOME MEASURE(S): The presence of the COMT polymorphism was recorded for all patients, and the frequency and distribution among cases and controls were compared according to race. Binomial log regression models were used to estimate odds-ratios (OR) for uterine volumes of <290 cm(3) (small fibroids) vs. those >290 cm(3) (large fibroids). Potential confounding variables (age, race and parity) were added to the model. RESULTS: Genotypes positive for the COMT polymorphism (heterozygous or mutant homozygous) were found in 45% of white and 28.9% of non-white women (p = .013) and the polymorphic allele frequencies in these groups were 27.2% and 16.3%, respectively (p = .006). However, there were no clear differences between patients and controls within the white subgroup with regard to the presence of COMT polymorphism-containing genotypes (41.5% vs. 46.0%, respectively) (p = .60), or for the polymorphic allele frequency (26.8% vs. 27.3%, respectively) (p = .92). For non-white women, there were also no differences between cases and controls for the frequency of polymorphic genotypes (28.9% vs. 28.9%, respectively) (p = .995), or for the polymorphic allele frequency (17.8 vs. 14.5, respectively) (p = .565). Estimated OR for small or large fibroids in association with the polymorphic allele revealed a positive association between the allele with lower activity and large fibroids (vs. small) (OR = 3.3; 95% confidence interval [CI] = 1.31-8.46). The adjusted OR was 4.35 (95% confidence interval [CI] = 1.58-11.9). CONCLUSIONS: The catechol-O-methyltransferase polymorphism is a risk factor for the development of large uterine fibroids in Brazilian women suffering from fibroids.