IL18 rs360717 and rs187238 genetic variants are associated with migraine diagnosis.

BACKGROUND: Migraine is a genetically determined disorder that predisposes to recurrent episodes of headache. Interleukin (IL)-18 is a pro-inflammatory cytokine that seems to play a role in migraine pathophysiology, and its genetic variants could potentially impact susceptibility to migraine. OBJECTIVE: To investigate the association between IL18 rs360717 and rs187238 genetic variants with migraine diagnosis and its clinical characteristics. METHODS: A case-control study was conducted with 152 people with migraine and 155 healthy controls, matched by sex, age, ethnicity, and body mass index. Clinical characteristics of migraine, as well as validated questionnaires regarding disability and impact of migraine, presence of allodynia, anxiety, depression, and hyperacusis were collected. Genotyping for IL18 rs360717 and rs187238 variants was performed using real-time polymerase chain reaction (qPCR) and TaqMan™ method. RESULTS: The IL18 rs360717A and rs187238G alleles were associated with increased chance of being diagnosed with migraine (OR = 1.53, 95%CI 1.05-2.24, p = 0.028 and OR = 1.46, 95%CI 1.00-2.14, p = 0.049, respectively). In the dominant model, the rs360717GA + AA genotypes were also associated with a higher chance of migraine than the GG genotype (OR = 1.69, 95%CI 1.05-2.73, p = 0.030). In women, in addition to the previous associations, there was also an effect of the variants on the chance of migraine in the codominant models and dominant models. Furthermore, among women, there was an influence on the prevalence of postdrome perception with rs360717GA + AA (OR = 3.04, 95%CI 1.10-8.42, p = 0.032) and rs187238CG + GG (OR = 2.97, 95%CI 1.08-8.21, p = 0.035). CONCLUSION: IL18 rs360717 and rs187238 variants were associated with migraine diagnosis and postdrome symptoms, especially in women. SIGNIFICANCE: This study has demonstrated that IL18 rs360717 and rs187238 variants play a role in migraine, influencing the chance of being diagnosed with migraine, particularly among women. There are prospects that IL18 variants could be considered potential genetic biomarkers for migraine.

The latency to awake from induced-obstructive sleep apnea is reduced in rats with chronic epilepsy.

OSA is known to increase the risk for SUDEP in persons with epilepsy, but the relationship between these two factors is not clear. Also, there is no study showing the acute responses to obstructive apnea in a chronic epilepsy model. Therefore, this study aimed to characterize cardiorespiratory responses to obstructive apnea and chemoreceptor stimulation in rats. In addition, we analyzed respiratory centers in the brain stem by immunohistochemistry. Epilepsy was induced with pilocarpine. About 30-60 days after the first spontaneous seizure, tracheal and thoracic balloons, and electrodes for recording the electroencephalogram, electromyogram, and electrocardiogram were implanted. Intermittent apneas were made by inflation of the tracheal balloon during wakefulness, NREM sleep, and REM sleep. During apnea, respiratory effort increased, and heart rate fell, especially with apneas made during wakefulness, both in control rats and rats with epilepsy. Latency to awake from apnea was longer with apneas made during REM than NREM, but rats with epilepsy awoke more rapidly than controls with apneas made during REM sleep. Rats with epilepsy also had less REM sleep. Cardiorespiratory responses to stimulation of carotid chemoreceptors with cyanide were similar in rats with epilepsy and controls. Immunohistochemical analysis of Phox2b, tryptophan hydroxylase, and NK1 in brain stem nuclei involved in breathing and sleep (retrotrapezoid nucleus, pre-Bötzinger complex, Bötzinger complex, and caudal raphe nuclei) revealed no differences between control rats and rats with epilepsy. In conclusion, our study showed that rats with epilepsy had a decrease in the latency to awaken from apneas during REM sleep, which may be related to neuroplasticity in some other brain regions related to respiratory control, awakening mechanisms, and autonomic modulation.

Cranial and postcranial anatomy of a juvenile baurusuchid (Notosuchia, Crocodylomorpha) and the taxonomical implications of ontogeny.

Baurusuchidae comprises a clade of top-tier terrestrial predators and are among the most abundant crocodyliforms found in the Adamantina Formation, Bauru Basin, Brazil (Campanian-Maastrichtian). Here, we provide a detailed description of the cranial and postcranial osteology and myology of the most complete juvenile baurusuchid found to date. Although the preservation of juvenile individuals is somewhat rare, previously reported occurrences of baurusuchid egg clutches, a yearling individual, and larger, but skeletally immature specimens, comprise a unique opportunity to track anatomical changes throughout their ontogenetic series. Its cranial anatomy was resolved with the aid of a three-dimensional model generated by the acquisition of computed tomography data, and its inferred adductor mandibular musculature was compared to that of mature specimens in order to assess possible ontogenetic shifts. A subsequent phylogenetic analysis included the scoring of Gondwanasuchus scabrosus, the smallest baurusuchid species known to date, to evaluate its phylogenetic relations relative to a known juvenile. We find considerable differences between juveniles and adults concerning skull ornamentation and muscle development, which might indicate ontogenetic niche partitioning, and also anatomical and phylogenetic evidence that G. scabrosus corresponds to a young semaphoront lacking mature cranial features.

PCA and logistic regression in 2-[18F]FDG PET neuroimaging as an interpretable and diagnostic tool for Alzheimer's disease.

Objective.to develop an optimization and training pipeline for a classification model based on principal component analysis and logistic regression using neuroimages from PET with 2-[18F]fluoro-2-deoxy-D-glucose (FDG PET) for the diagnosis of Alzheimer's disease (AD).Approach.as training data, 200 FDG PET neuroimages were used, 100 from the group of patients with AD and 100 from the group of cognitively normal subjects (CN), downloaded from the repository of the Alzheimer's Disease Neuroimaging Initiative (ADNI). Regularization methods L1 and L2 were tested and their respective strength varied by the hyperparameter C. Once the best combination of hyperparameters was determined, it was used to train the final classification model, which was then applied to test data, consisting of 192 FDG PET neuroimages, 100 from subjects with no evidence of AD (nAD) and 92 from the AD group, obtained at the Centro de Diagnóstico por Imagem (CDI).Main results.the best combination of hyperparameters was L1 regularization andC≈ 0.316. The final results on test data were accuracy = 88.54%, recall = 90.22%, precision = 86.46% and AUC = 94.75%, indicating that there was a good generalization to neuroimages outside the training set. Adjusting each principal component by its respective weight, an interpretable image was obtained that represents the regions of greater or lesser probability for AD given high voxel intensities. The resulting image matches what is expected by the pathophysiology of AD.Significance.our classification model was trained on publicly available and robust data and tested, with good results, on clinical routine data. Our study shows that it serves as a powerful and interpretable tool capable of assisting in the diagnosis of AD in the possession of FDG PET neuroimages. The relationship between classification model output scores and AD progression can and should be explored in future studies.

Cannabidiol as an Adjunctive Treatment for Acute Bipolar Depression: A Pilot Study: Le cannabidiol comme traitement d'appoint de la dépression bipolaire aiguë : une étude pilote.

OBJECTIVE: The treatment of bipolar depression remains challenging due to the limited effective and safe therapeutic options available; thus, developing newer treatments that are effective and well tolerable is an urgent unmet need. The objective of the present trial was to test 150 to 300 mg/day of cannabidiol as an adjunctive treatment for bipolar depression. METHOD: A randomized, double-blind, placebo-controlled pilot study to assess the efficacy of adjunctive cannabidiol in bipolar depression was used. Efficacy parameters were changes in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to week 8. Secondary outcomes included response and remission rates, changes in anxiety and psychotic symptoms, and changes in functioning. Patients continued double-blind treatment until week 12 to monitor for adverse effects, laboratory analysis, and manic symptoms. Study registry: NCT03310593. RESULTS: A total of 35 participants were included. MADRS scores significantly decreased from baseline to the endpoint (placebo, -14.56; cannabidiol, -15.38), but there was no significant difference between the groups. Similarly, there were no other significant effects on the secondary outcomes. However, an exploratory analysis showed a significant effect of cannabidiol 300 mg/day in reducing MADRS scores from week 2 to week 8 (placebo, -6.64; cannabidiol, -13.72). There were no significant differences in the development of manic symptoms or any other adverse effects. CONCLUSION: Cannabidiol did not show significantly higher adverse effects than placebo. Despite the negative finding on the primary outcome, an exploratory analysis suggested that cannabidiol should be further studied in bipolar depression in higher doses of at least 300 mg/day and under research designs that could better control for high placebo response.

Interferon-gamma plasma levels and presence of mouse mammary tumor virus-like env gene: Implications on the pathogenesis of breast cancer.

Mouse mammary tumor virus (MMTV) is a retrovirus that has been associated with the development of breast cancer (BC) in mice. The identification of a 95% homologous gene sequence to MMTV in human BC samples has increased interest in this hypothesis. This virus in humans received the name of mouse mammary tumor virus-like (MMTV-like). Several cytokines may be involved in the interactions between MMTV and the immune system, such as interferon-gamma (IFN-γ), which can enhance Th1-mediated antitumor immune response but it can also play a protumorigenic role by transmitting antiapoptotic and proliferative signals. Little is known about the antiviral immune response in a microenvironment with the presence of MMTV-like in BC patients. Therefore, the purpose of the present study was to quantify the plasma levels of IFN-γ in the peripheral blood of 123 neoplasia-free donors and 98 BC patients of different molecular subtypes, by enzyme-linked immunosorbent assay (ELISA), and evaluate the association of these plasma levels with the detection of the MMTV-like env gene in tumor tissue. Correlation analyzes involving IFN-γ plasma levels and clinical-pathological parameters were performed by Kendall Tau-c test. In our study, a decrease in IFN-γ levels was observed in the group of BC patients (30.85 ± 57.49 pg/ml) compared to the control group (115.00 ± 176.80 pg/ml) (p < 0.0001). In the analysis by stratified BC molecular subtypes, Luminal-A (30.79 ± 61.04 pg/ml; p < 0.0001), Luminal-B (24.74 ± 25.78 pg/ml; p = 0.0188) and triple-negative (23.95 ± 40.45 pg/ml; p = 0.0005) had a lower plasma level compared to control group. There was no significant difference between IFN-γ plasma levels of MMTV-like DNA positive samples compared to MMTV-negative samples (p = 0.2056). In general BC, patients with larger tumor size had higher IFN-γ plasma levels (Tau-c = 0.202; p = 0.019). By analyzing the MMTV-like env negative samples, we could identify that IFN-γ plasma levels were higher in larger tumor size (Tau-c = 0.222; p = 0.020) and with greater lymph node involvement (Tau-c = 0.258; p = 0.042). Also, higher IFN-γ plasma levels were observed in patients with higher histopathological grades (Tau-c = 0.384; p = 0.019) in MMTV-like env positive samples. For the first time, we assessed the association between plasma levels of IFN-γ and the presence of the MMTV-like env gene in BC samples. However, more studies are needed to clarify whether the high levels of IFN-γ in MMTV-like env positive samples are reflecting a possible antiviral immune response or whether this cytokine is promoting tumor growth.

Impact of ZNF804A rs1344706 or CACNA1C rs1006737 polymorphisms on cognition in patients with severe mental disorders: A systematic review and meta-analysis.

OBJECTIVES: This systematic review and meta-analysis focussed on insights into the relationship between CACNA1C-rs1006737 and ZNF804A-rs1344706 polymorphisms and cognitive performance in schizophrenia (SCZ) spectrum and bipolar disorder (BD) and provide some contributions for clinical practice. METHODS: We searched the websites databases (PubMED, PsycINFO, Web of Science, EMBASE and Cochrane Library) using eligibility and exclusion criteria to capture all potential studies, based on PICO model and according to the PRISMA. RESULTS: Eight articles were included in this systematic review (five referring to CACNA1C-rs1006737 and three related to ZNF804A-rs1344706 polymorphisms), with a total of 5759 participants (1751 SCZ patients, 348 BD patients, 3626 controls and 34 first-degree relatives). The results demonstrated that the pooled effect of CACNA1C-rs1006737 (risk difference RD = 0.08; 95% CI 0.02-0.15) was associated with altered cognitive function in patients with severe mental disorders, but not ZNF804A-rs1344706 polymorphism (RD = 0.19; 95% CI 0.09-0.48. CONCLUSION: The present meta-analysis provides evidence regarding slight association between CACNA1C-rs1006737 polymorphisms and cognitive performance in severe mental disorders, indicating that cognitive impairment in severe mental disorders associated with the CACNA1C rs1006737 risk variants could only be expressed when interacting with environmental exposures. This study is registered with PROSPERO, number CRD42021246726.

Direct vascular contact is a hallmark of cerebral astrocytes.

Astrocytes establish extensive networks via gap junctions that allow each astrocyte to connect indirectly to the vasculature. However, the proportion of astrocytes directly associated with blood vessels is unknown. Here, we quantify structural contacts of cortical astrocytes with the vasculature in vivo. We show that all cortical astrocytes are connected to at least one blood vessel. Moreover, astrocytes contact more vessels in deeper cortical layers where vessel density is known to be higher. Further examination of different brain regions reveals that only the hippocampus, which has the lowest vessel density of all investigated brain regions, harbors single astrocytes with no apparent vascular connection. In summary, we show that almost all gray matter astrocytes have direct contact to the vasculature. In addition to the glial network, a direct vascular access may represent a complementary pathway for metabolite uptake and distribution.

Paleoneurology of Baurusuchus (Crocodyliformes: Baurusuchidae), ontogenetic variation, brain size, and sensorial implications.

Knowledge on crocodyliform paleoneurology has significantly improved with development of computed tomography. However, studies so far have been able to reconstruct brain endocasts based only on single specimens for each taxon. Here for the first time, we reconstructed brain endocasts for multiple fossil specimens of the same crocodyliform taxon (Baurusuchus), consisting of complete skulls of two medium sized specimens, one large adult, and a late juvenile. In addition, we were able to reconstruct the inner ear anatomy of a fragmentary skull using microtomography. We present estimates of brain size using simple models, based on modern Crocodylia, able to adapt brain to endocranial cavity ratios to expected ontogenetic variation instead of using fixed ratios. We also analyzed relative brain sizes, olfactory ratios, facial sensation, alert head posture, best hearing frequencies, and hearing range. The calculated endocranial volumes showed that they can be greatly altered by taphonomic processes, altering both total and partial endocranial volumes. Reconstructed endocasts are compatible with different degrees of occupation along the endocranial cavity and some of their characteristics might be useful as phylogenetic characters. The relative brain size of Baurusuchus seems to be small in comparison to modern crocodilians. Sensorial abilities were somewhat similar to modern crocodilians and hearing ranges and best mean frequencies remarkably similar to modern taxa, whereas olfactory ratio values are a little higher. Differing from its modern relatives, Baurusuchus hypothesized alert head posture is compatible with a terrestrial habit.

Genetic Polymorphisms of the TGFB1 Signal Peptide and Promoter Region: Role in Wilms Tumor Susceptibility?

The aim of the present study was to investigate the rs1800468 (G-800A), rs1800469 (C-509T), rs1800470 (C29T), and rs1800471 (G74C) TGFB1 genetic polymorphisms and their haplotype structures in patients with Wilms Tumor (WT) and neoplasia-free controls. The genomic DNA was extracted from 35 WT patients and 160 neoplasia-free children, and the TGFB1 polymorphisms were genotyped by polymerase chain reaction, followed by restriction fragment length polymorphism. The haplotype structures were inferred, and permutation and logistic regression tests were performed to check for differences in haplotype distribution between the control and WT individuals. Positive associations were found in the recessive model for rs1800469 T allele (OR: 8.417; 95% CI: 3.177 to 22.297; P < 0.001) and for the rs1800470 C allele (OR: 3.000; 95% CI: 1.296 to 6.944; P = 0.01). Haplotype analysis revealed a significant negative association between GCTG and WT (OR: 0.236, 95% CI: 0.105 to 0.534; P = 0.0002); by contrast, the GTTG haplotype was associated with increased risk for WT (OR: 12.0; 95% CI: 4.202 to 34.270; P < 0.001). Furthermore, rs1800469 was negatively correlated with tumor size and a trend toward a positive correlation for capsular invasion was observed in the dominant model (Tau-b: -0.43, P = 0.02 and tau-b: 0.5, P = 0.06, respectively). This is the first study with rs1800468, rs1800469, rs1800470, and rs1800471 TGFB1 polymorphisms in WT, and our results suggest that the TGFB1 promoter and signal peptide region polymorphisms may be associated with WT susceptibility and clinical presentation.

An association between chronic life stressors prior to diagnosis of breast cancer.

The clinical course of breast cancer (BC) and survival depend on a wide range of risk factors. From the psychosomatic point of view, BC is one of the most studied type of cancer but there is no evidence available for this relation. Therefore, in the present study we evaluate the impact of chronic life stressors in BC patients. A total of 100 BC patients were invited to participate in an interview, when information about social parameters and emotional changes in the period prior to diagnosis were collected. The emotional changes were evaluated by the Holmes and Rahe's Stress Scale, which analyzes the difficulty required for a person to readjust to society after significant changes in their life. Clinicopathological parameters were obtained from the medical records. For all data, the level of significance adopted was p <0.05. It was observed that 55.2 % of the patients have a medium and 13.8 % were at high risk for disease development related to stressful events in the period prior to the BC diagnosis. The highest stress levels were presented by separated, divorced, or widowed patients compared to married (p <0.01) and single (p = 0.037) patients. The high-risk (HR) group had a lower proportion of positivity for estrogen receptor when compared to the low (LR) and moderate risk (MR) groups (p= 0.001). In addition, a binary logistic regression analysis was performed, and we found that the relationship between the estrogen receptor and the HR of chronic stress was independently associated with the histological type of BC and lymph nodes involvement. The relationship of stressful life experiences and BC is not well established, so our study collaborates with the literature to demonstrate the importance of stress as a factor associated with the development of BC.

A recurrent leiomyosarcoma of the buccal mucosa: An immunohistochemistry study and literature review.

Leiomyosarcoma is a rare type of cancer that affects smooth muscle tissue. Leiomyosarcomas are exceedingly rare in the oral cavity, particularly in the buccal mucosa. The diagnosis is challenging due to non-specific clinical features and significant overlap of morphological findings with several spindle cell tumors. We reported the clinicopathological and immunohistochemical features of a rare recurrent case of leiomyosarcoma in a 73-year-old female presenting clinically as a painful nodule on the posterior right buccal mucosa. Microscopically, the lesion showed atypical spindle cells arranged in a fascicular pattern and frequent mitotic figures. Immunohistochemistry showed strong positivity for vimentin, α-SMA, HHF35, h-caldesmon, and focal positivity for desmin. CD34 highlighted numerous blood vessels distributed throughout all tumor stroma. S-100 protein, myogenin, and pan-cytokeratin (AE1/AE3) were negative. Surgical excision followed by chemotherapy was carried out, and no recurrence was observed after 1 year of follow-up. Careful histopathological and immunohistochemistry analysis of these lesions is essential to ensure a correct diagnosis. Early surgical excision with tumor-free margins and prolonged follow-up is strongly recommended.

Diagnostic accuracy of perioperative electromyography in the positioning of pedicle screws in adolescent idiopathic scoliosis treatment: a cross-sectional diagnostic study.

BACKGROUND: To investigate in the conventional techniques of the pedicle screws using triggered screw electromyography (t-EMG), considering different threshold cutoffs: 10, 15, 20 25 mA, for predicting pedicle screw positioning during surgery of the adolescent with idiopathic scoliosis (AIS). METHODS: Sixteen patients (4 males, 12 females, average age 16.6 years) were included, with an average curve magnitude of 50 degrees and placement of 226 pedicle screws. Each screw was classified as "at risk for nerve injury" (ARNI) or "no risk for nerve injury" (NRNI) using CT and the diagnostic accuracy of EMG considering different threshold cutoffs (10,15, 20 and 25 mA) in the axial and Sagittal planes for predicting screw positions ARNI was investigated. RESULTS: The EMG exam accuracy, in the axial plane, 90.3% screws were considered NRNI. In the sagittal plane, 81% pedicle screws were considered NRNI. A 1-mA decrease in the EMG threshold was associated with a 12% increase in the odds of the screw position ARNI. In the axial and sagittal planes, the ORs were 1.09 and 1.12, respectively. At every threshold cutoff evaluated, the PPV of EMG for predicting screws ARNI was very low in the different threshold cutoff (10 and 15); the highest PPV was 18% with a threshold cutoff of 25 mA. The PPV was always slightly higher for predicting screws ARNI in the sagittal plane than in the axial plane. In contrast, there was a moderate to high NPV (78-93%) for every cutoff analyzed. CONCLUSIONS: EMG had a moderate to high accuracy for positive predicting value screws ARNI with increase threshold cutoffs of 20 and 25 mA. In addition, showed to be effective for minimizing false-negative screws ARNI in the different threshold cutoffs of the EMG in adolescent with idiopathic scoliosis (AIS).

Transforming growth factor beta 1 (TGFß1) plasmatic levels in breast cancer and neoplasia-free women: Association with patients' characteristics and TGFB1 haplotypes.

Transforming growth factor beta 1 (TGFß1) is a pleiotropic cytokine that acts in a context-dependent manner. In breast cancer (BC) this cytokine exerts subtype- and stage-specific roles, inhibiting poorly aggressive tumors while enhances the invasive potential of highly aggressive cancers. Single-nucleotide polymorphisms (SNPs) affecting TGFß1 production largely reflect this pattern of association, but studies investigating systemic TGFß1 levels in BC patients and their association with clinical features or SNPs produced conflicting conclusions. Therefore, the present work investigated plasmatic TGFß1 levels through enzyme linked immunosorbent assay (ELISA) in 341 individuals previously genotyped for four TGFB1 SNPs [G-800A (rs1800468), C-509T (rs1800469), T29C (rs1800470) and G74C (rs1800471)], encompassing 184 neoplasia-free women with clinical information regarding health status, 113 treatment-free pre-surgery BC patients and 44 treated BC patients. Results have shown that TGFß1 levels varied greatly in function of health status in neoplasia-free women, and disease-free individuals had higher TGFß1 levels than both treatment-free or treated BC patients. There was no correlation between TGFß1 with clinicopathological features in treatment-free BC general group, but it was negatively correlated with tumor size in luminal-B-HER2+ patients and with histopathological grade in triple-negative group. Also, TGFB1 ACTG haplotype (from G-800A to G74C) was associated with decreased TGFß1 levels compared to the reference GCTG haplotype, and regression analyses showed that this association was independent of age, health status or BC diagnosis. In conclusion, several factors may influence TGFß1 levels, and ACTG haplotype seems to be an important factor regulating TGFß1 production.

CCL5 protein level: influence on breast cancer staging and lymph nodes commitment.

Many tumor cells express chemokines and chemokine receptors, and these molecules can contribute to distinct modes of metastasis processes. It is known that they play a crucial role in breast cancer (BC) tumorigenesis and progression. Considering this, it was investigated a possible role for C-Chemokine receptor type 5(CCR5) polymorphism (rs333/delta32) by conventional polymerase chain reaction (PCR) and CCL5 (C-C motif chemokine ligand 5) protein level by immunosorbent assay (ELISA) in 47 BC patients (resulting in 47 tumoral tissue samples and 47 adjacent normal tissue samples). There was a significant difference between CCL5 level in tumoral and adjacent normal tissues for the same BC patients (p < 0.0001). A significant association was also found for CCL5 level in relation to lymph nodes commitment (p = 0.03). Likewise, there was a significant difference in CCL5 level from tumor tissue of stage III in relation to stage I (p < 0.02). On the other hand, it was verified that CCR5-delta32 polymorphism presented no significant association in relation to CCL5 protein level. Considering the present findings, we suggest that CCL5 may be involved in BC staging and metastasis process.

The prevalence and clinical correlates of cannabis use and cannabis use disorder among patients with bipolar disorder: A systematic review with meta-analysis and meta-regression.

Bipolar disorder (BD) is commonly associated with comorbidities, especially substance use disorders. In light of this, the present review aimed to investigate the prevalence and clinical correlates of cannabis use in BD. Studies evaluating the prevalence of cannabis use among patients with BD and studies reporting a dichotomous sample of patients with cannabis use compared to those without the use were included. Meta-analyses using random-effects models were performed, and sources of heterogeneity were explored using meta-regression. The search resulted in 2918 publications, of which 53 were included. The prevalence of cannabis use was 24% (95%CI:18-29; k = 35; n = 51,756). Cannabis use was significantly associated with being younger, male, and single; having fewer years of education and an earlier onset of affective symptoms; and lifetime psychotic symptoms, suicide attempts, and use of tobacco, alcohol, and other substances. In conclusion, cannabis use present in almost one-quarter of patients with BD and is associated with factors that are highly relevant for both clinical practice and public health.

Transforming growth factor beta 1 (TGFß1) polymorphisms and haplotype structures have dual roles in breast cancer pathogenesis.

PURPOSE: Despite the documented dual role of TGFß1 in breast cancer (BC) pathogenesis, the subtype-specific influences of its polymorphisms remain undocumented. The present study investigated the effects of the TGFB1 promoter region (rs1800468 or G-800A and rs1800469 or C-509T) and signal peptide (rs1800470 or C29T and rs1800471 or G74C) single nucleotide polymorphisms (SNPs) and their haplotype structures on the susceptibility and clinicopathological presentation of BC subtypes. METHODS: TGFB1 genotypes were assessed by PCR-RFLP and haplotype structures were inferred for 323 BC patients and 405 neoplasia-free women, and case-control analyses were performed by logistic regression adjusted by age. Clinicopathological parameters (age at diagnosis, tumor size, histopathological grade, lymph node metastasis, proliferation index and disease stage) were tested for correlation with TGFB1 variants. All statistical analyses were two-tailed with an alpha level of 0.05. RESULTS: Variants related to increased TGFß1 production (C-509T SNP and GTCG haplotype) were associated with increased susceptibility to HER2+ tumors and correlated with worse prognostic parameters in HER2+ and triple-negative (TN) BCs, but correlated negatively to Ki67 in ER/PR+HER2- tumors. Conversely, low TGFß1 production variants (C29T SNP and GCTG haplotype) were protective against HER2+ tumors and correlated negatively with prognostic parameters in HER2+ and TN BCs, while indicating higher proliferation rates in ER/PR+HER2- tumors. Furthermore, the GCCG haplotype was associated with decreased susceptibility to ER/PR+HER2- tumors, but correlated positively with Ki67 in this subgroup. CONCLUSION: The present study indicates that TGFB1 variants have subtype-specific roles in BC and may switch from tumor suppressor to promoter during tumor development, consistent with TGFß1 dual role in BC pathogenesis.

Glutathione S-transferases deletions may act as prognosis and therapeutic markers in breast cancer.

Breast cancer (BC) is the main worldwide neoplasia in women. The metabolic balance between xenobiotic absorption and elimination rates plays an important role in preventing DNA damage and, consequently, tumor development. The glutathione S-transferases (GSTs), such as GSTM1 and GSTT1, and the NAD(P)H quinone oxidoreductase are important enzymes involved in phase II detoxification reactions. Deletions in GSTM1 and GSTT1, and single-nucleotide polymorphism (SNP) in NQO1 (rs1800655) have been investigated in cancer context, revealing conflicting results. The present study analyzed these genetic polymorphisms in 121 BC patients and 151 BC-free controls in order to verify if they could act as susceptibility modifiers and/or prognostic factors. Binary logistic regressions adjusted by age were performed to assess associations between allelic variants and interactions in polymorphisms combination with BC susceptibility, but no significant association was found. Genotypes distribution was also compared between BC subtypes, but no significant difference was observed (p > 0.05). GSTM1 deletion was significantly associated with histopathological grade, with a greater proportion of patients presenting grade III tumors (p = 0.007). Univariate analysis identified tumor size as the only clinicopathological parameter potentially associated with recurrence risk in patients that received adjuvant chemotherapy (p < 0.1). Thus, logistic regression analysis adjusted by tumor size revealed a positive association between GSTT1 deletion and recurrence risk in general BC (OR 4.25; p = 0.04), while GSTM1 was negatively associated with recurrence risk in ER/PR+HER2- samples (OR 0.07; p = 0.03). In conclusion, the present study indicated that GSTT1 deletion was associated with increased recurrence risk, while GSTM1 correlated with worst prognosis parameters at diagnosis, but was negatively associated with recurrence risk in luminal subtype samples.

The predictive value of transforming growth factor-ß in Wilms tumor immunopathogenesis.

Wilms tumor is the most common kidney malignancy in children, especially in children aged less than 6 years. Although therapeutic approach has reached successful rates, there is still room for improvement. Considering the tumor microenvironment, cytokines represent important elements of interaction and communication between tumor cells, stroma, and immune cells. In this regard, the transforming growth factor beta (TGF-ß) family members play significant functions in physiological and pathological conditions, particularly in cancer. By regulating cell growth, death, and immortalization, TGF-ß signaling pathways exert tumor suppressor effects in normal and early tumor cells. Thus, it is not surprising that a high number of human tumors arise due to alterations in genes coding for various TGF-ß signaling components. Understanding the ambiguous role of TGF-ß in human cancer is of paramount importance for the development of new therapeutic strategies to specifically block the metastatic signaling pathway of TGF-ß without affecting its tumor suppressive effect. In this context, this review attempt to summarize the involvement of TGF-ß in Wilms tumor.

The effect of Isabel grape addition on the physicochemical, microbiological and sensory characteristics of probiotic goat milk yogurt.

Goat milk is an attractive food because of its nutritional properties, easy digestibility and hypoallergenicity. Goat milk yogurt is an appropriate matrix for the inclusion of new ingredients such as probiotic cultures, fruit and its derivatives. Grapes are rich in polyphenols and recognized for their health benefits. The aim of this study was to improve the quality characteristics of probiotic goat milk yogurt by the addition of an Isabel grape (Vitis labrusca L.) preparation (IGP). For this, the influence of the addition of IGP on the physicochemical, microbiological and sensory characteristics of goat milk yogurt containing the probiotic Lactobacillus acidophilus LA-05 was evaluated during 28 days of refrigerated storage (5 ± 0.5 °C). Four yogurt formulations were prepared, each varying in the added IGP amount, as follows: Y0 (not containing IGP), YG15 (containing 15 g per 100 mL of IGP), YG20 (containing 20 g per 100 mL of IGP), and YG25 (containing 25 g per 100 mL of IGP). All formulations showed probiotic counts ranging from 7 to 8 log CFU mL-1 over the assessed storage period. The addition of 20 g per 100 mL of IGP affected positively the colour, viscosity, and sensory acceptance of the yogurt formulations. The production of goat milk yogurt containing L. acidophilus LA-05 and IGP is an option for developing a new goat dairy product with added value due to the inclusion of components with potential functional properties.