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The mandibular interforaminal region has been considered safe for surgical procedures; nevertheless, the risk of injury to neurovascular structures, such as the mental foramen (MF) and its related structures (anterior loop [AL] and lingual foramina [LF]) should not be overlooked. The study aimed to evaluate the relative risk of injury to these structures during surgical procedures in the anterior region of the mandible based on cone-beam computed tomography (CBCT) scans. A retrospective cross-sectional and observational study was performed on 250 CBCTs from adults (18-69 years) with dentate jaws. Linear measurements of the MF, AL, and LF were evaluated to estimate the risk of injury to these structures during chin-related surgical procedures. The most frequent distance between the base of the mandible (BM) and MF was 8 mm (30.2%). In addition, 20.4% of the CTs had 6 mm from the vestibular cortical bone to the LF. The commonly found measurement from LF to the apex of the nearest tooth was 7 mm (24.0%); 64.2% of the CTs showed a 2-mm distance between the most distal point of the dental implant site to the most anterior point of the AL. Safety distances for genioplasty techniques (MF to mandible base > 6 mm, 96.6% [CI 95%, 95.0%-98.2%]) were observed. Considering the 5-mm cut-off point between the lower limit of a hypothetical bone graft and the chin, 65.4% (CI 95%, 58.9%-71.9%) of CTs were within this distance. Regarding the safety margin of 8 mm, 85.6% (CI 95%, 80.8%-90.4%) were up to this value. This study found safety margins for genioplasty and chin bone grafting surgical techniques that adopt a 5-mm cut-off point. Further similar studies assessing other surgical methods and employing larger samples from different geographical origins may contribute to this field of investigation.

Autism Spectrum Disorder (ASD) encompasses a wide range of neurodevelopmental conditions characterized by deficits in social interaction, communication and behavior. Current pharmacological options are limited and feature significant side effects. In this study, we conducted a retrospective, observational, and cross-sectional cohort study to evaluate the effects of Cannabidiol (CBD)-dominant, full-spectrum cannabis extract, containing Tetrahydrocannabinol (THC) in a ratio of 33:1 (CBD:THC), on non-syndromic children and adolescents (5-18 years old) with moderate to severe ASD. Thirty volunteers were recruited, underwent neuropsychological evaluations and were treated with individualized doses of CBD-dominant extract. Clinical assessments were conducted by the designated clinician. Additionally, parents or caregivers were independently interviewed to assess perceived treatment effects. We found significant improvements in various symptomatic and non-symptomatic aspects of ASD, with minimal untoward effects, as reported by both clinical assessments and parental perceptions. The observed improvements included increased communicative skills, attention, learning, eye contact, diminished aggression and irritability, and an overall increase in both the patient's and family's quality of life. Despite its limitations, our findings suggest that treatment with full-spectrum CBD-dominant extract may be a safe and effective option for core and comorbid symptoms of ASD, and it may also increase overall quality of life for individuals with ASD and their families.

Structural constraint approaches have been employed toward different ends in recent years, from augmenting the nucleophilicity in pyramidalized low-valent p-block compounds to enhancing the Lewis acidities at planarized tetravalent p-block elements. While previous studies exploited these effects separately, this work introduces a strategy to concatenate structural constraint approaches at individual stages of a reaction sequence in a row to unlock a synthetic path unattainable by conventional methodologies. The boosted nucleophilicity resulting from the constrained tetracoordinated calix[4]pyrrolato stannate(II) dianion enables the reductive formation of sterically unprotected acyclic aminocarbenes. These amino carbenes are stabilized at the concomitantly formed square-planar stannane(IV) as air-stable adducts. Transfer of the carbenes onto copper(I) by cooperativity of the calix[4]pyrrole ligand finalizes this protocol to hitherto unreported yet prototypical carbene complexes. Detailed spectroscopic and quantum theoretical analyses establish the synergy of structural constraints and element-ligand cooperation as the linchpin to this reaction path and its selectivity.

This study aimed to evaluate the scientific evidence on the effect of preemptive drug coadministration (PDC) for relieving inflammatory events (pain, swelling, and trismus) in mandibular third molar surgery. A PROSPERO-registered systematic review (CRD42022314546) was conducted according to the PRISMA guide. The searches were carried out in six primary databases and the gray literature. Studies not written in languages with the Latin alphabet (Roman) were excluded. Potential randomized controlled trials (RCTs) were screened for eligibility. Cochrane's Risk of Bias-2.0 (RoB) tool was assessed. A synthesis without meta-analysis (SWiM) based on a vote counting and an effect direction plot. Nine studies (low RoB) fulfilled the eligibility criteria and were included for data analysis, with a total of 484 patients. PDC mostly involved corticosteroids (Cort) and non-steroidal anti-inflammatory drugs (NSAIDs). PDC of Cort and other drugs mainly reduced pain scores (6 and 12 h postoperatively) and swelling (48 h postoperatively). PDC of NSAIDs and other drugs mainly reduced pain scores at 6, 8, and 24 h follow-up; swelling and trismus intensity ameliorated at 48 h postoperatively. The most frequently prescribed rescue medication was paracetamol, dipyrone, and paracetamol plus codeine. Results from individual studies have shown reduced consumption of ingested rescue analgesics. In summary, the available evidence from clinical trials included in this SWiM suggests that PDC may provide benefits in reducing the severity of inflammatory outcomes related to mandibular third molar surgery, especially the pain scores in the first hours after surgery, and the rescue analgesic consumption during the postoperative period., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The purpose of the study was to verify the effect of 4 weeks of a high-fructose diet (HFD) associated with aerobic training on the risk factors for cardiometabolic diseases. Twenty-one young adults were randomised into three groups: HFD (HFD: 1 g/kg body weight of fructose/day), high-glucose diet (HGD: 1 g/kg body weight of glucose/day) and high-fructose diet and exercise (HFDE: 1 g/kg body weight of fructose/day + 3 weekly 60-minute sessions of aerobic exercise). Before and after the 4 weeks of the intervention, blood samples were taken and flow-mediated dilatation, insulin resistance index, pancreatic beta cell functional capacity index, insulin sensitivity index and 24-h blood pressure were evaluated. HFD showed an increase in uric acid concentrations ( P = 0·040), and HGD and HFDE groups showed no changes in this outcome between pre- and post-intervention; however, the HFDE group showed increased uric acid concentrations from the middle to the end of the intervention ( P = 0·013). In addition, the HFD group showed increases in nocturnal systolic blood pressure (SBP) ( P = 0·022) and nocturnal diastolic blood pressure (DBP) ( P = 0·009). The HGD group exhibited decreases in nocturnal SBP ( P = 0·028) and nocturnal DBP ( P = 0·031), and the HFDE group showed a decrease in 24-h SBP ( P = 0·018). The consumption of 1 g/kg of fructose per day may increase uric acid concentrations and blood pressure in adults. Additionally, aerobic exercises along with fructose consumption attenuate changes in uric acid concentrations and prevent impairment in nocturnal blood pressure.

Breast carcinomas (BC) with osteoclast-like giant cells (OGC) are rare. Despite their distinct stromal features, their molecular characteristics remain unknown. Here, we report comprehensive clinico-pathological and molecular findings for 27 patients diagnosed with BC-OGC at Institut Curie between 2000 and 2021. Seventeen (63%) cases were invasive carcinomas of no special type (IC NST) with OGC (OGC-IC NST), four (15%) were mixed or multifocal cases with and without OGC (OGC-Mixed), and six (22%) were metaplastic carcinomas with OGC (OGC-MC). All OGC-IC NST and OGC-Mixed cases were ER+ HER2- tumors (most being luminal A based on transcriptomic subtyping, when available), while all OGC-MC were triple-negative. The median age at diagnosis was 46, 45 and 62 years for OGC-IC NST, OGC-Mixed and OGC-MC, respectively. Three patients developed distant metastases (one OGC-IC NST, two OGC-Mixed), one of whom died of metastatic disease (OGC-Mixed), and one other patient died of locally advanced disease (OGC-MC). Histopathological evaluation comparing 13 OGC-IC NST and 19 control IC NST without OGC confirmed that OGC-IC NST showed significantly higher density of vessels (by CD34 immunohistochemistry (IHC)), iron deposits (Perls stain), and CD68 and CD163-positive cell infiltrates. Genomic findings for nine OGC-IC NST and four OGC-MC were consistent with the underlying histologic subtype, including activating alterations of the PI3K/AKT/mTOR pathway in 7/13 cases. Using RNA-seq data, differential gene expression analysis between OGC-IC NST (n = 7) and control IC NST without OGC (n = 7) revealed significant overexpression of TNFSF11 (RANK-L), TNFRSF11A (RANK), CSF1 (M-CSF), CSF1R, and genes encoding osteoclastic enzymes (MMP9, ACP5, CTSK, CTSB) in OGC-IC NST, while OPG (osteoprotegerin) was underexpressed. We also confirmed for the first time RANK-L expression in BC with OGC by IHC (seen in 15 out of 16 cases, and only in 2 of 16 controls without OGC). These findings could offer a rationale for further investigating RANK-L as a therapeutic target in BC with OGC., (© 2022. The Author(s).)

Tamoxifen is a selective estrogen receptor (ER) modulator that is used to treat ER-positive breast cancer, but that at high doses kills both ER-positive and ER-negative breast cancer cells. We recapitulate this off-target effect in Caenorhabditis elegans, which does not have an ER ortholog. We find that different bacteria dramatically modulate tamoxifen toxicity in C. elegans, with a three-order of magnitude difference between animals fed Escherichia coli, Comamonas aquatica, and Bacillus subtilis. Remarkably, host fatty acid (FA) biosynthesis mitigates tamoxifen toxicity, and different bacteria provide the animal with different FAs, resulting in distinct FA profiles. Surprisingly these bacteria modulate tamoxifen toxicity by different death mechanisms, some of which are modulated by FA supplementation and others by antioxidants. Together, this work reveals a complex interplay between microbiota, FA metabolism and tamoxifen toxicity that may provide a blueprint for similar studies in more complex mammals., (© 2022. The Author(s).)

Nucleotidases contribute to the regulation of inflammation, coagulation, and cardiovascular activity. Exercise promotes biological adaptations, but its effects on nucleotidase activities and expression are unclear. The objective of this study was to review systematically the effects of exercise on nucleotidase functionality in healthy and unhealthy subjects. The MEDLINE, EMBASE, Cochrane Library, and Web of Science databases were searched to identify, randomized clinical trials, non-randomized clinical trials, uncontrolled clinical trials, quasi-experimental, pre-, and post-interventional studies that evaluated the effects of exercise on nucleotidases in humans, and was not limited by language and date. Two independent reviewers performed the study selection, data extraction, and assessment of risk of bias. Of the 203 articles identified, 12 were included in this review. Eight studies reported that acute exercise, in healthy and unhealthy subjects, elevated the activities or expression of nucleotidases. Four studies evaluated the effects of chronic training on nucleotidase activities in the platelets and lymphocytes of patients with metabolic syndrome, chronic kidney disease, and hypertension and found a decrease in nucleotidase activities in these conditions. Acute and chronic exercise was able to modify the blood plasma and serum levels of nucleotides and nucleosides. Our results suggest that short- and long-term exercise modulate nucleotidase functionality. As such, purinergic signaling may represent a novel molecular adaptation in inflammatory, thrombotic, and vascular responses to exercise., (© 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Transitions between epithelial and mesenchymal cellular states (EMT/MET) contribute to cancer progression. We hypothesize that EMT followed by MET promotes cell population heterogeneity, favouring tumour growth. We developed an EMT model by on and off exposure of epithelial EpH4 cells (E-cells) to TGFβ1 that mimics phenotypic EMT (M-cells) and MET. We aimed at understanding whether phenotypic MET is accompanied by molecular and functional reversion back to epithelia by using RNA sequencing, immunofluorescence (IF), proliferation, wound healing, focus formation and mamosphere formation assays as well as cell xenografts in nude mice. Phenotypic reverted epithelial cells (RE-cells) obtained after MET induction presented epithelial morphologies and proliferation rates resembling E cells. However, the RE transcriptomic profile and IF staining of epithelial and mesenchymal markers revealed a uniquely heterogeneous mixture of cell subpopulations with a high self-renewal ability. RE cell heterogeneity was stably maintained for long periods after TGFβ1 removal both in vitro and in large tumours derived from the nude mice. Overall, we show that phenotypic reverted epithelial cells (RE cells) do not return to the molecular and functional epithelial state and present mesenchymal features related to aggressiveness and cellular heterogeneity that favour tumour growth in vivo. This work strengthens epithelial cell reprogramming and cellular heterogeneity fostered by inflammatory cues as a tumour growth-promoting factor in vivo.

The purpose of this study was to summarize the evidence from randomized clinical trials on the effects of dance on fall risk in older adults through a systematic review with meta-analysis. Fall risk was assessed through timed up and go, Berg Balance Scale, or one-leg stand tests. Data are presented as mean differences for timed up and go test and standardized mean differences for Berg Balance Scale and one-leg stand tests between treatments with 95% confidence intervals, and calculations were performed using random effects models. Significance was accepted when p < .05. A significant difference was found between dance interventions and the control groups in the general analysis of fall risk assessed by timed up and go (mean differences: -1.446 s; 95% confidence interval [-1.586, -1.306]; p < .001) and Berg Balance Scale and one-leg stand tests (standardized mean differences: 0.737; 95% confidence interval [0.508, 0.966]; p < .001) in favor of the intervention group. Different dance interventions decreased the fall risk in older practitioners.

Background: The social diversity, heterogeneous culture, and inherent economic inequality factors in Latin America (LA) justify conducting a comprehensive analysis on the current status and future trends of peri-implant diseases and conditions. Thus, the aim of this Delphi study was to predict the future trends in the diagnosis and treatment of peri-implant diseases and conditions in LA countries for the year 2030., Methods: A Latin American steering committee and group of experts in implant dentistry validated a questionnaire including 64 questions divided into eight sections. The questionnaire was run twice with an interval of 45 days, with the results from the first round made available to all the participants in the second round. The results were expressed in percentages and data was analyzed describing the consensus level reached in each question., Results: A total of 221 experts were invited to participate in the study and a total 214 (96.8%) completed the two rounds. Moderate (65%-85%) to high consensus (≥ 85%) was reached in 51 questions (79.69%), except in the questions dealing with "prevalence", where no consensus was reached. High and moderate consensus was attained for all the questions in three fields (risk factors and indicators, diagnosis and treatment of peri-implant conditions and deficiencies, and prevention and maintenance)., Conclusions: The present study has provided relevant and useful information on the predictions in the diagnosis and treatment of peri-implant diseases with a high level of consensus among experts. Nevertheless, there is still a lack of agreement in certain domains., (© 2021 The Authors. Journal of Periodontology published by Wiley Periodicals LLC on behalf of American Academy of Periodontology.)

Background: Reduced glutathione (GSH) is one of the main thiols involved in antioxidant defense. Changes in circulatory levels of GSH during exercise are associated with hyperthermia and dehydration. The mechanisms by which these alterations occur are not entirely known. We hypothesize that erythrocytes could be an important source of circulatory GSH during heat stress conditions. We performed two separate experiments to address this hypothesis., Methods: In the first experiment, we sought to investigate the impact of exercise in the heat and dehydration on erythrocyte levels of GSH. A total of 10 men performed 60 min of cycling at 60% VO 2 peak in the heat (38.0 ± 0.9 °C) or in a control temperate environment (23.0 ± 1.0 °C), both with and without dehydration. Relative humidity ranged from 50 to 70%. Blood samples were taken before and after exercise to measure GSH and oxidized (GSSG) glutathione. In the second experiment, erythrocytes were isolated from blood samples taken at rest and heated in vitro to determine the impact of heat on erythrocyte glutathione content. Tubes with erythrocytes were exposed to water baths at different temperatures; one tube was exposed to a water bath at 35 °C and the other tube to a water bath at 41 °C for a period of 30 min. After exposure to heat, plasma and erythrocytes were extracted for GSH and GSSG analyses., Results: Dehydration decreased circulatory GSH, regardless of ambient temperature (temperate and heat decreased 15.35% and 30.31%, respectively), resulting in an altered redox balance. Heat increased GSH levels in vitro., Conclusion: Our data suggest that dehydration decreases circulatory GSH levels regardless of environmental temperature. In addition, in vitro data suggests that erythrocytes may contribute to the release of GSH during exposure to heat stress.

Background: Statin use is highlighted as the most commonly utilized therapy for the treatment of dyslipidemias and can be considered as the most efficient pharmacological intervention for low-density lipoprotein (LDL) reduction. On the other hand, physical training can be considered an efficient and safe non-pharmacological strategy to promote improvements in lipid profile. However, the influence of statins on lipid adaptations arising from water-based training in populations with dyslipidemia is not known., Objectives: To analyze the influence of simvastatin use on lipid adaptations arising from water-based aerobics and resistance training in elderly women with dyslipidemia., Methods: Sixty-nine elderly (66.13 ± 5.13 years), sedentary, and dyslipidemic women, both non-users and users of simvastatin (20 mg and 40 mg), were randomized into the following 3 groups: water-based aerobic training (WA), water-based resistance training (WR), and control group (CG). Total duration of interventions, for all experimental groups consisted of 10 weeks, with 2 weekly sessions. Biochemical analyses were performed before the beginning of the interventions and repeated after the end of the trial. Generalized estimating equations were used to compare these data, setting α = 0.05., Results: In intention-to-treat analysis, the medicated participants obtained a greater magnitude of decrease in total cholesterol (TC) (-3.41 to -25.89 mg.dl-1; p = 0.038), LDL (-5.58 to -25.18 mg.dl-1; p = 0.007) and TC/HDL ratio (-0.37 to -0.61; p = 0.022) when compared to the non-medicated participants, and this decrease was statistically significant only in the WR group., Conclusions: Statin use enhances the adaptations promoted by water-based physical training in CT, LDL levels, and CT/HDL ratio, and it is more pronounced after WR.

Abstract: Vieira, AF, Umpierre, D, Teodoro, JL, Lisboa, SC, Baroni, BM, Izquierdo, M, and Cadore, EL. Effects of resistance training performed to failure or not to failure on muscle strength, hypertrophy, and power output: A systematic review with meta-analysis. J Strength Cond Res 35(4): 1165-1175, 2021-The aim of this review was to summarize the evidence from longitudinal studies assessing the effects induced by resistance training (RT) performed to failure (RTF) vs. not to failure (RTNF) on muscle strength, hypertrophy, and power output in adults. Three electronic databases were searched using terms related to RTF and RTNF. Studies were eligible if they met the following criteria: randomized and nonrandomized studies comparing the effects of RTF vs. RTNF on muscle hypertrophy, maximal strength, and muscle power in adults, and RT intervention ≥6 weeks. Results were presented as standardized mean differences (SMDs) between treatments with 95% confidence intervals, and calculations were performed using random effects models. Significance was accepted when p < 0.05. Thirteen studies were included in this review. No difference was found between RTF and RTNF on maximal strength in overall analysis (SMD: -0.08; p = 0.642), but greater strength increase was observed in RTNF considering nonequalized volumes (SMD: -0.34; p = 0.048). Resistance training performed to failure showed a greater increase in muscle hypertrophy than RTNF (SMD: 0.75; p = 0.005), whereas no difference was observed considering equalized RT volumes. No difference was found between RTF and RTNF on muscle power considering overall analysis (SMD: -0.20; p = 0.239), whereas greater improvement was observed in RTNF considering nonequalized RT volumes (SMD: -0.61; p = 0.025). Resistance training not to failure may induce comparable or even greater improvements in maximal dynamic strength and power output, whereas no difference between RTF vs. RTNF is observed on muscle hypertrophy, considering equalized RT volumes., (Copyright © 2021 National Strength and Conditioning Association.)

Introduction: The aim of the present study was to verify the effects of a Pilates training on total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), glucose and C-reactive protein (CRP) levels, as well as on functionality of postmenopausal women with dyslipidemia., Method: This randomized study involved 35 sedentary women with dyslipidemia, aged between 60 and 75 years. One group participated in a Pilates exercises training with two to four weekly sessions during 10 weeks (Pilates group, n = 20) and the other group did not perform any intervention (control group, n = 6). Biochemical analyses and functionality parameters were measured before and after the 10 weeks., Results: No significant differences were observed in TC, TG, LDL and HDL for both groups. Regarding glucose and CRP levels, significant reductions were observed in both groups after the intervention period. In functional parameters, both groups significantly increased their 30-s chair stand test values. On the other hand, only the Pilates group presented significant increments in the 6-min walk test (p < 0.05)., Conclusion: Pilates training did not change lipid or lipoprotein levels, but improved cardiorespiratory fitness of elderly women with dyslipidemia., Competing Interests: Declaration of competing interest The authors have not conflict of interest to report., (Copyright © 2020. Published by Elsevier Ltd.)

New Finding: What is the central question of this study? How does moderate-intensity aerobic exercise affect the behaviour of purinergic enzymes in sedentary, overweight and physically active subjects? What is the relationship between purinergic and inflammatory responses triggered by exercise? What is the main finding and its importance? Moderate-intensity aerobic exercise modifies the activity of purinergic enzymes and the levels of nucleotides and nucleosides. These results are similar in subjects with different biological characteristics. 5'-Nucleotidase activity and adenosine levels are associated with inflammatory responses. This study suggests that a purinergic pathway is related to the inflammatory responses triggered by exercise., Abstract: Purinergic signalling is a mechanism of extracellular communication that modulates events related to exercise, such as inflammation and coagulation. Herein, we evaluated the effects of acute moderate-intensity exercise on the activities of purinergic enzymes and plasma levels of adenine nucleotides in individuals with distinct metabolic characteristics. We analysed the relationship between purinergic parameters, inflammatory responses and cardiometabolic markers. Twenty-four healthy males were assigned to three groups: normal weight sedentary (n = 8), overweight sedentary (n = 8) and normal weight physically active (n = 8). The volunteers performed an acute session of moderate-intensity aerobic exercise on a treadmill at 70% of V ̇ O 2 peak ; blood samples were drawn at baseline, immediately post-exercise and at 1 h post-exercise. Immediately post-exercise, all subjects showed increases in ATP, ADP, AMP and p-nitrophenyl thymidine 5'-monophosphate hydrolysis, while AMP hydrolysis remained increased at 1 h after exercise. High-performance liquid chromatography analysis demonstrated lower levels of ATP and ADP at post- and 1 h post-exercise in all groups. Conversely, adenosine and inosine levels increased at post-exercise, but only adenosine remained augmented at 1 h after exercise in all groups. With regard to inflammatory responses, the exercise protocol increased tumour necrosis factor α (TNF-α) and interleukin 8 (IL-8) concentrations in all subjects, but only TNF-α remained elevated at 1 h after exercise. Significant correlations were found between the activity of 5'-nucleotidase, adenosine levels, V ̇ O 2 peak , triglyceride, TNF-α and IL-8 levels. Our findings suggest a purinergic signalling pathway that participates, at least partially, in the inflammatory responses triggered by acute moderate-intensity exercise. The response of soluble nucleotidases to acute moderate exercise appears to be similar between subjects of different biological profiles., (© 2021 The Authors. Experimental Physiology © 2021 The Physiological Society.)

The challenges encountered in performing minimally invasive approaches, such as supraorbital minicraniotomy (SOMC), in services without adequate equipment are rarely reported in the literature. This study analyzes the viability of SOMC in the treatment of cerebral aneurysms, using exactly the same resources as pterional craniotomy (PC). The results of these two techniques are compared. 35 patients underwent SOMC, compared to 50 patients underwent CP (100 aneurysms in total), using the same microsurgical instruments. The following variables were compared: operative time, angiographic cure, length of intensive care unit stay during the post-operative period, surgical complications, length of hospital stay after surgery until hospital discharge, intraoperative aneurysm rupture, aesthetic satisfaction with the scar, and neurological status at discharge. SOMC had a significantly shorter operative time in relation to PC (213.9 ± 11.09 min and 268.6 ± 15.44 min, respectively) (p = 0.0081).With respect to the cosmetic parameters assessed by the Visual Analog Scale, the average for SOMC was 94.12 ± 1.92 points, and the average for PC was 83.57 ± 4.75 points (p = 0.036). SOMC was as effective as PC in relation to successful aneurysm clipping (p = 0.77). The SOMC technique did not show advantages over PC in any other variable. Even in a general neurosurgery service lacking a specific structure for minimally invasive surgeries, SOMC was feasible and effective for treating intracranial aneurysms, using the same set of microsurgical instruments used for PC, obtaining better results in operating time and cosmetic satisfaction.

Introduction: DICER1 is a member of RNase III family that has a pivotal role in the biogenesis of microRNAs, being important for normal development. Dysregulation of DICER1 has been described in different human tumours; however, there is insufficient data on the risk of thyroid cancer in the presence of germline DICER1 variants, particularly when focusing on the background of papillary thyroid carcinoma (PTC). For this purpose, we ascertained the presence of DICER1 variants in 502 (PTC) cases available from The Cancer Genome Atlas (TCGA) research network in a well-characterized pathological context., Material and Methods: in this study we analyzed 502 samples from 502 patients, described as PTC in the TCGA database. Tumour diagnoses were re-evaluated by 2 pathologists (S.C. and M.S.-S.) on slides available from the database, and clinicopathological and demographic data was examined. Data concerning germline and sporadic DICER1 gene variants as well as frequent mutations in the genes involved in thyroid carcinogenesis (e.g., RAS and BRAF V600E) was retrieved from the database., Results and Discussion: We report 1 new germline possibly pathogenic variant, besides 15 others already been identified in ClinVar. We found that the DICER1-positive PTC group more frequently includes PTC variants, namely the oncocytic, follicular, and aggressive (hobnail variant of PTC) variants. A previous association of DICER1 had been demonstrated, mainly with the follicular variant of PTC and follicular thyroid carcinomas. Tumours harbouring germline DICER1 mutations were more frequently "bilateral" and "encapsulated." The frequent association of DICER1 germline variants with other mutations associated with thyroid cancer can reflect an haploinsufficiency tumour suppressor gene function of DICER1, as suggested from the study of animal models., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2020 by European Thyroid Association Published by S. Karger AG, Basel.)

Probiotics form a promising strategy to maintain intestinal health. Milks fermented with probiotic strains, such as the Lactobacillus paracasei ST11, are largely commercialized in Brazil and form a low-cost alternative to probiotic pharmaceutical formulations. In this study, we assessed the probiotic effects of milk fermented by L. paracasei ST11 (administered through fermented milk) in a Salmonella typhimurium infection model in BALB/c mice. We observed in this murine model that the applied probiotic conferred protective effects against S. typhimurium infection, since its administration reduced mortality, weight loss, translocation to target organs (liver and spleen) and ileum injury. Moreover, a reduction in the mRNA expression of pro-inflammatory cytokines such as IFN-γ, IL-6, TNF-α and IL-17 in animals that received the probiotic before challenge was observed. Additionally, the ileum microbiota was better preserved in these animals. The present study highlights a multifactorial protective aspect of this commercial probiotic strain against a common gastrointestinal pathogen.

Brain metastases remain an unmet clinical need in breast oncology, being frequently found in HER2-overexpressing and triple-negative carcinomas. These tumors were reported to be highly cancer stem-like cell-enriched, suggesting that brain metastases probably arise by the seeding of cancer cells with stem features. Accordingly, we found that brain-tropic breast cancer cells show increased stem cell activity and tumorigenic capacity in the chick embryo choriallantoic membrane when compared to the parental cell line. These observations were supported by a significant increase in their stem cell frequency and by the enrichment for the breast cancer stem cell (BCSC) phenotype CD44 + CD24 -/low . Based on this data, the expression of BCSC markers (CD44, CD49f, P-cadherin, EpCAM, and ALDH1) was determined and found to be significantly enriched in breast cancer brain metastases when compared to primary tumors. Therefore, a brain (BR)-BCSC signature was defined (3-5 BCSC markers), which showed to be associated with decreased brain metastases-free and overall survival. Interestingly, this signature significantly predicted a worse prognosis in lymph node-positive patients, acting as an independent prognostic factor. Thus, an enrichment of a BCSC signature was found in brain metastases, which can be used as a new prognostic factor in clinically challenging breast cancer patients.

The prognostic impact of tumor-infiltrating lymphocytes (TILs) within invasive lobular carcinoma (ILC) remains to be better characterized. In estrogen receptor (ER)-negative invasive ductal carcinomas of no special type (IDC-NST), TILs are associated with good prognosis. The aim of this study was to examine TILs in ILC, with particular focus on prognostic and clinicopathologic features. A cohort comprising 459 consecutive ILCs diagnosed in a single institution from 2005 to 2008 met the eligibility criteria for this study. The percentage of tumor area occupied by TILs was quantified by two breast pathologists and categorized into three groups: no TILs, ≤5%, >5%. Clinicopathologic features were tested by Fisher's exact tests or Chi 2 tests. Overall survival (OS) and invasive disease-free survival (iDFS) were estimated by Kaplan-Meier and Cox proportional hazard statistics. There were 239 TIL-negative cases, 185 cases with ≤5% TILs, and 35 cases with >5% TILs. TILs were associated with younger age, larger tumors, lymph node involvement, poor Nottingham prognostic index, HER2 amplification, multinucleation, and prominent nucleoli (p < 0.05). Poor OS was significantly associated with increasing TILs in the univariate Cox proportional hazards model (p < 0.001) and Kaplan-Meier estimator (p < 0.05, log-rank test). Similar results were observed for iDFS (p = 0.004 for Cox univariate and p = 0.005 for log-rank test). Notably, TILs can identify a subset of ILC patients with poor OS independently of molecular subtype and lymph node metastases (multivariate Cox, p < 0.001, OS hazard ratio (HR) = 4.38 and HR = 6.15, for ≤5% and >5% TILs, respectively, vs. absence of TILs). Prominent nucleoli was the only nuclear feature associated with poor OS (p = 0.05) and iDFS (p = 0.05) in univariate Cox survival analysis. TILs represent a promising new morphologic biomarker associated with poor outcome of ILC, in contrast with that observed in ER-negative IDC-NST.

Background: Gastric cancer is the fifth most common cancer and the third cause of global cancer mortality. CDX2 is an intestinal differentiation marker with prognostic value in gastric cancer and transcriptionally regulates the expression of glycoprotein A33 (GPA33) and liver intestine cadherin (LI-cadherin)., Methods: This study evaluated the clinical significance of the combined expression of CDX2 and its targets GPA33 and LI-cadherin in gastric cancer by fluorescence-based multiplex immunohistochemistry together with digital image analysis and chromogenic immunohistochemistry in 329 gastric cancer samples arranged in tissue microarrays. Additionally, publicly available RNA-seq expression data from 354 gastric cancer samples from the TCGA database were used to validate the immunohistochemistry results., Results: Expression of the three markers (CDX2, GPA33, and LI-cadherin) was strongly correlated, defining an intestinal differentiation panel. Low or negative protein expression of the intestinal differentiation panel identified patients with particularly poor overall survival, irrespective of the methodology used, and was validated in the independent series at the RNA-seq level., Conclusions: Expression of the intestinal differentiation panel (CDX2, GPA33, and LI-cadherin) defines a set of biomarkers with a strong biological rationale and favourable impact for prognostication of gastric cancer patients.

Aims: Congenital haemangiomas (CHs) can be subdivided into different subtypes [rapidly involuting CHs (RICHs), non-involuting CHs (NICHs), and partially involuting CHs (PICHs)]. During the first few days of life, RICHs may be associated with transient but sometimes marked thrombocytopenia. We sought to assess the histological aspects and clinicopathological correlations of the three subtypes., Methods and Results: We assessed the histopathological features of 10 RICHs, 25 NICHs, and 20 PICHs, described the patients' long-term clinical outcomes, and assessed clinicopathological correlations. All CHs were located in the dermis and hypodermis, and comprised both capillary lobules (with three distinct histopathological patterns) and extralobular large vessels. Most of the extralobular vessels were abnormal veins and abnormal lymphatic vessels. We did not observe significant correlations between the CH subtype, the histopathological pattern, and the time of the histopathological assessment. Interestingly, unexpected intralobular expression of podoplanin was found in neonatal biopsies of five RICHs and PICHs. Four of these five patients had concomitant thrombocytopenia. The podoplanin staining intensity decreased over time as the thrombocytopenia resolved and the tumour shrank., Conclusion: The histopathological features were similar in all three subtypes of CH, and were related to the time since disease onset; we consider that RICH, PICH and NICH form a single entity and differ only in their involuting potential. Along with the transient expression of intralobular podoplanin observed in some specimens from the newborn, the lobular architecture might lead to misdiagnosis of tufted haemangioma or kaposiform haemangioendothelioma., (© 2020 John Wiley & Sons Ltd.)

The objective of this study was to evaluate seminal plasma proteins from cattle and buffalo (Bubalus bubalis), to identify differences between related species. Sixteen buffaloes and 16 cattle between 30 and 60 months of age were used. Semen collection was performed by electroejaculation, followed by macroscopic and microscopic subjective analyses. After analysis, the samples were centrifuged at 800 g for 10 min, and the supernatant (seminal plasma) was recentrifuged at 10,000 g for 30 min at 4°C. The total protein concentration was determined by the Bradford method, and the proteins were digested in solution for mass spectrometry (nLC-MS/MS). Multivariate statistical analysis was used to evaluate the proteomics results by non-hierarchical clustering the considering exponentially modified protein abundance index (emPAI). Principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were used for clustering. Proteomics identified 78 proteins, and multivariate analysis showed 4 that were over-expressed in buffaloes (cystatin C, prosaposin, peptide YY and keratin type II cytoskeletal 5) and 9 in cattle (spermadhesin-1, seminal plasma protein PDC-109, ribonuclease 4, metalloproteinase inhibitor 2, acrosin inhibitor 1, seminal ribonuclease, C-type natriuretic peptide, angiogenin-1 and osteopontin). Among the proteins identified in seminal plasma, the C-type natriuretic peptide and metalloproteinase inhibitors were described for the first time in buffaloes. Some protease inhibitors were found over-expressed in buffaloes, and important proteins in seminal plasma of cattle were not identified or were found at lower expression levels in buffaloes, which can contribute to reproductive performance in this species., (© 2019 Blackwell Verlag GmbH.)

The objective of this study was to describe the dynamic changes in protein composition and protein abundance in amniotic and allantoic fluids from buffaloes during gestation. Amniotic and allantoic fluids were collected during the first, second and third trimesters of gestation. The foetuses were measured and weighed. Fluid samples were centrifuged at 800 g for 10 min and then at 10,000 g for 60 min at 4°C. The supernatant was collected to determine the total protein concentration. Based on total protein concentration, an aliquot (50 μg) was used for in-solution tryptic digestion, and mass spectrometry analysis (nano-LC-MS/MS) was performed. A multivariate statistical analysis of the proteomic data was conducted. Across the different stages of buffalo gestation, fifty-one proteins were found in the amniotic fluid, and twenty-one were found in the allantoic fluid. A total of twelve proteins were common among the stages, and four presented significant differences (VIP score α > 1). Fibronectin and alpha-1-antiproteinase were more abundant in the amniotic fluid than in the allantoic fluid. Alpha-2-macroglobulin and alpha-2-HS-glycoprotein were more abundant in the allantoic fluid than in the amniotic fluid. Alpha-2-macroglobulin participates in remodelling and growth of the uterus at beginning of the gestation (first trimester), and these findings indicate that can serve as a potential tool for the early diagnosis of pregnancy in buffaloes., (© 2019 Blackwell Verlag GmbH.)

Purpose: The addition of fructose to one or more meals daily may lead to increased postprandial lipemia (PPL). Aerobic exercise has been successful in preventing those increases; however, the duration of exercise effects is still unknown. The aim of this study was to evaluate the acute and residual effects of aerobic exercise and fructose ingestion on PPL., Methods: Twelve young and sedentary men completed a crossover blinded randomized trial. On day 0, they performed 45 min of aerobic exercise at 60% of VO 2peak , or 45 min of resting. On day 1, they received a high-fat meal together with one of the following conditions: (a) a fructose-rich beverage (FRUCT), or (b) exercise performed 13 h before the fructose-rich beverage ingestion (FRUCTEX), or (c) a dextrose-based beverage (DEX). On day 2, all subjects received a high-fat meal plus dextrose. Five blood samples were taken on days 1 and 2, to measure triglycerides (TG), HDL cholesterol, VLDL, total cholesterol (TC), glucose and insulin., Results: On day 1, the delta of the TG peak was higher for FRUCT compared to DEX condition (+ 73.7%; p = 0.019). Total area under the curve (AUC) of TG was lower on the condition FRUCTEX compared to FRUCT (+ 30%; p = 0.001). There was no effect of the beverages or the exercise on VLDL, TC, HDL and non-HDL cholesterol (p > 0.05). There were no differences found in any of the parameters assessed on day 2 (p > 0.05)., Conclusions: Fructose consumption (0.5 g/kg) severely increased postprandial TG on day 1, but not on day 2. Previous exercise performance could lead to ~ 30% reduction on the AUC of postprandial TG in 13 h, but not after 37 h followed by fructose consumption. The regularity of physical exercise practice seems to be essential to promote a constant hypolipemic effect.

Glycemic fluctuations were compared throughout 10-week high-intensity training protocols in T1DM patients. Differences were compared using the rate of change in glycaemia during exercise (RoC E ). HIIT sessions led to lower RoC E in most weeks than other training protocols. The occurrence of level 1 hypoglycemia along sessions were similar among interventions., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background : The aim of this study was to perform a systematic review with meta-analysis and meta-regressions evaluating the effects of isolated strength training (ST), compared with a control group, on total cholesterol (TC), triglycerides (TG), low-density (LDL), high-density lipoprotein (HDL), C-reactive protein (CRP), and adiponectin of adults. Methods : Embase, PubMed, Cochrane, and Scopus data sources were searched up to May 2017. Clinical trials that compared ST with a control group of adults older than 18 years, which evaluated blood TC, TG, LDL, HDL, CRP, or adiponectin as an outcome were included. Random effect was used and the effect size (ES) was calculated by using the standardized mean difference with a 95% confidence interval. Results : ST promotes a reduction in TC (ES: -0.399; P  < .001), TG (ES: -0.204; P  = .002), LDL (ES: -0.451; P  < .001), and CRP (ES: -0.542; P  = .01) levels. In addition, ST is associated to an increase in HDL (ES: 0.363; P  < .001) and adiponectin concentrations (ES: 1.105; P  = .01). Conclusion : ST promotes decreases in TC, TG, LDL, and CRP levels and increases HDL and adiponectin concentrations. Thus, progressive ST could be a potential therapeutic option for improving abnormalities in lipid and inflammatory outcomes in adults.

Background : Regular exercise is recommended for the treatment of dyslipidemia. The aquatic environment presents some beneficial characteristics for patients suffering from dyslipidemia. However, it is unknown which modality promotes better results. This study aims to compare the effects of water-based aerobic training (WA) and water-based resistance training (WR) on lipid profile of dyslipidemic elderly women. Methods : Sixty-nine dyslipidemic elderly women participated in this 3-arm randomized controlled clinical trial with groups in parallel. The interventions were WA, WR, and control group, with 2 weekly sessions for 10 weeks. Total cholesterol (TC), triglycerides, low-density lipoprotein, high-density lipoprotein (HDL) levels, and TC/HDL ratio, were determined before and after interventions. Results : Intention-to-treat analysis showed that WA and WR participants obtained similar decreases in TC (-10.0% and -9.6%, respectively), triglycerides (-13.4% and -15.7%, respectively), low-density lipoprotein (-16.1% and -16.9%, respectively), TC/HDL (-16.9% and -23.4%, respectively) and increases in HDL (7.6% and 16.9%, respectively). The control group maintained their TC and low-density lipoprotein levels unchanged, whereas triglycerides and TC/HDL were increased (3.6% and 11.3%, respectively), and HDL decreases 4.8%. Conclusions : WA and WR improve similarly the lipid profile of dyslipidemic elderly women, representing interesting nonpharmacological tools in the treatment of dyslipidemia.

Centrosome amplification (CA) is a common feature of human tumours and a promising target for cancer therapy. However, CA's pan-cancer prevalence, molecular role in tumourigenesis and therapeutic value in the clinical setting are still largely unexplored. Here, we used a transcriptomic signature (CA20) to characterise the landscape of CA-associated gene expression in 9,721 tumours from The Cancer Genome Atlas (TCGA). CA20 is upregulated in cancer and associated with distinct clinical and molecular features of breast cancer, consistently with our experimental CA quantification in patient samples. Moreover, we show that CA20 upregulation is positively associated with genomic instability, alteration of specific chromosomal arms and C>T mutations, and we propose novel molecular players associated with CA in cancer. Finally, high CA20 is associated with poor prognosis and, by integrating drug sensitivity with drug perturbation profiles in cell lines, we identify candidate compounds for selectively targeting cancer cells exhibiting transcriptomic evidence for CA., Competing Interests: The authors have declared that no competing interests exist.

Aims: To investigate the effects of high-intensity interval training (HIIT) and/or strength training (ST) on inflammatory, oxidative stress (OS) and glycemic parameters in type 1 diabetes (T1DM) patients., Methods: After a 4-week control period, volunteers were randomly assigned to 10-week HIIT, ST or ST + HIIT protocol, performed 3×/week. Blood biochemistry, anthropometric, strength and cardiopulmonary fitness variables were assessed. Outcomes were analyzed via generalized estimating equations (GEE), with Bonferroni post hoc analysis., Results: ST, HIIT and ST + HIIT improved glycemic (HbA 1c and fasting glucose) and antioxidant parameters (total antioxidant capacity, catalase and superoxide dismutase activities), but not plasma inflammatory (C-reactive protein, TNF-α and IL-10) or OS markers (thiobarbituric acid-reactive substances, 8-hydroxy-2-deoxyguanosine and oxLDL) levels. Noteworthy, interventions reduced soluble receptors for advanced glycation end products levels. However, intracellular heat shock protein 70 content increased only after HIIT. While daily insulin dosage decreased only in the ST + HIIT group, all training models induced anthropometric and functional benefits., Conclusions: Similar benefits afforded by ST, HIIT or ST + HIIT in T1DM people are associated with enhanced antioxidant systems and glucose-related parameter, even in a few weeks. From a practical clinical perspective, the performance of ST + HIIT may be advised for additional benefits regarding insulin dosage reduction., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Basal-like breast cancer (BLBC) is a poor prognosis subgroup of triple-negative carcinomas that still lack specific target therapies and accurate biomarkers for treatment selection. P-cadherin is frequently overexpressed in these tumors, promoting cell invasion, stem cell activity and tumorigenesis by the activation of Src-Family kinase (SRC) signaling. Therefore, our aim was to evaluate if the treatment of BLBC cells with dasatinib, the FDA approved SRC inhibitor, would impact on P-cadherin induced tumor aggressive behavior., Methods: P-cadherin and SRC expression was evaluated in a series of invasive Breast Cancer and contingency tables and chi-square tests were performed. Cell-cell adhesion measurements were performed by Atomic Force Microscopy, where frequency histograms and Gaussian curves were applied. 2D and 3D cell migration and invasion, proteases secretion and self-renew potential were evaluated in vitro. Student's t-tests were used to determine statistically significant differences. The cadherin/catenin complex interactions were evaluated by in situ proximity-ligation assay, and statistically significant results were determined by using Mann-Whitney test with a Bonferroni correction. In vivo xenograft mouse models were used to evaluate the impact of dasatinib on tumor growth and survival. ANOVA test was used to evaluate the differences in tumor size, considering a confidence interval of 95%. Survival curves were estimated by the Kaplan-Meier's method, using the log-rank test to assess significant differences for mice overall survival., Results: Our data demonstrated that P-cadherin overexpression is significantly associated with SRC activation in breast cancer cells, which was also validated in a large series of primary tumor samples. SRC activity suppression with dasatinib significantly prevented the in vitro functional effects of P-cadherin overexpressing cells, as well as their in vivo tumorigenic and metastatic ability, by increasing mice overall survival. Mechanistically, SRC inhibition affects P-cadherin downstream signaling, rescues the E-cadherin/p120-catenin complex to the cell membrane, recovering cell-cell adhesion function., Conclusions: In conclusion our findings show that targeting P-cadherin/SRC signaling and functional activity may open novel therapeutic opportunities for highly aggressive and poor prognostic basal-like breast cancer.

This work aimed to evaluate the drought tolerance of transformed plants of the cultivar BRSMG Curinga that overexpress the rice phospholipase D α1 (OsPLDα1) gene. The productivity of independent transformation event plants of the OsPLDα1 gene was evaluated in an experiment where 19 days of water deficit were applied at the reproductive stage, a very strict growing condition for upland rice. The non-genetically modified cultivar (NGM) under drought treatment reduced productivity by 89% compared with that under irrigated treatment, whereas transformed plants (PLDα1&#95;E2) reduced productivity by only 41%. After the drought treatment, the PLDα1&#95;E2 plants productivity was five times greater than that of the NGM plant. Moreover, no adverse effects on growth and development of the transgenic plants were observed. Seven days after the resumption of irrigation, PLDα1&#95;E2 plants had higher stomatal conductance, greater photosynthetic rate, and transpiration rate than did NGM plants, as well as a higher expression level of the OsPLDα1 gene. A delay in the senescence process was observed in these PLDα1&#95;E2 plants, and this was determined for the recovery of photosynthesis, with greater expression of the Rubisco and lower expression of the SOD. This finding was suggestive of decreased oxidative stress, probably due to gas exchange by the partial closure of the stomata of these transformed plants, which prevented the formation of reactive oxygen species. OsPLDα1 gene overexpression resulted in a reduction in production loss under severe water deficit and revealed a possibility for the development of upland rice cultivars that are more tolerant to extreme drought conditions.

Background: Recently a new system for reporting salivary gland fine-needle aspiration (FNA) cytology was proposed, the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC). Herein, we evaluated diagnostic accuracy of salivary gland FNA, comparing the system previously used in our hospital with the Milan system., Methods: Salivary gland specimens obtained between 2011 and 2017 were reclassified according to MSRSGC. Risk of malignancy for each diagnostic category was determined. Diagnostic yield of both classifications was evaluated., Results: The cases (n = 388) were classified according to the old system: nondiagnostic (n = 28), benign (n = 246), atypical (n = 36), neoplastic (n = 57), suspicious for malignancy (n = 7) and malignant (n = 14). The lesions were distributed according to the MSRSGC: nondiagnostic (n = 28), non-neoplastic (n = 89), atypia of undetermined significance (n = 39), benign neoplasm (n = 156), neoplasm of uncertain malignant potential (n = 55), suspicious for malignancy (n = 7) and malignant (n = 14). When considering only benign and malignant cases, both classifications showed the same sensitivity (62.5%), specificity (100%) and similar accuracy (95.8%). Comparison between the two systems showed no significant difference., Conclusions: Salivary gland FNA has high diagnostic accuracy and assists clinical management independently of the reporting system used, however, in some cases, the use of Milan system could be beneficial, since it allows an enhanced category stratification., (© 2018 Wiley Periodicals, Inc.)

Multigene signatures generate crucial prognostic information particularly useful for cancer patients where clinical parameters and traditional immunohistochemical markers alone lead to equivocal prognosis. Clinicians are now provided with molecular tools that assist in the outline of adjuvant therapies, namely helping decide on the extension of adjuvant endocrine therapy or on suppressing adjuvant chemotherapy in patients were toxic effects are particularly deleterious or when this treatment is fundamentally not needed. The importance of cancer multigene prognostic signatures is well elucidated in the guidelines for adjuvant systemic therapy in early-stage breast cancer and the guidelines on disease staging that are progressively integrating gene expression assays as classification biomarkers. In addition to the predictive and prognostic value, some genetic tests provide intrinsic subtyping classification. Herewith, we compare the molecular tests OncotypeDX, MammaPrint, Prosigna, EndoPredict, Breast Cancer Index, Mammostrat, and IHC4 and report the eligibility of each one in the suitable setting. Through to now, there is not a commercially available multigene test that makes recommendations regarding adjuvant treatment for HER-2 and triple negative breast cancers. Thus, these patients still receive adjuvant chemotherapy. Importantly, triple negative carcinomas are very heterogeneous regarding prognosis and new molecular signatures that decipher this very heterogeneous subgroup of breast cancer may improve the clinical management of the disease.

The aim of this study was to re-examine the chronic effect (>7 d) of fructose consumption on postprandial TAG, in adolescents and adults. The research was carried out in March 2017 and used different electronic databases, such as Medline ® (Pubmed®), Embase® and Cochrane. The review considered clinical trials (parallel or crossed) that evaluated the effect of fructose consumption for a period longer than 7 d, in humans. Two investigators independently performed data extraction. The outcome was the absolute delta of TAG concentration in a 4-h postprandial period. The results were presented with delta mean difference between treatments with 95 % CI. The calculations were made based on random-effect models. Statistical heterogeneity of treatment effects between studies was assessed by Cochrane's 'Q Test' and 'I 2' inconsistency test. The meta-analysis of the twelve selected interventions (n 318) showed that fructose generated larger variation (δ) of TAG concentrations during the postprandial period, compared with other carbohydrates (mean difference: 8·02 (95 % CI 0·46, 15·58) mg/dl (0·09 (95 % CI 0·01, 0·18) mmol/l); I 2: 74 %). High heterogeneity was generated almost exclusively by one study, and its withdrawal did not alter the result. We concluded that chronic consumption of fructose (>7 d) has a negative role on postprandial TAG in healthy adolescents and adults, as well as in overweight/obese individuals, but not in diabetics.

Centrosomes are the major microtubule organising centres of animal cells. Deregulation in their number occurs in cancer and was shown to trigger tumorigenesis in mice. However, the incidence, consequence and origins of this abnormality are poorly understood. Here, we screened the NCI-60 panel of human cancer cell lines to systematically analyse centriole number and structure. Our screen shows that centriole amplification is widespread in cancer cell lines and highly prevalent in aggressive breast carcinomas. Moreover, we identify another recurrent feature of cancer cells: centriole size deregulation. Further experiments demonstrate that severe centriole over-elongation can promote amplification through both centriole fragmentation and ectopic procentriole formation. Furthermore, we show that overly long centrioles form over-active centrosomes that nucleate more microtubules, a known cause of invasiveness, and perturb chromosome segregation. Our screen establishes centriole amplification and size deregulation as recurrent features of cancer cells and identifies novel causes and consequences of those abnormalities.

Background: Aerobic training has been widely indicated to patients with type 2 diabetes. However, there are still few studies comparing acute glycemic and blood pressure effects of different methods of aerobic training. The aim is to compare glycemic and pressure acute responses of continuous aerobic exercise to interval aerobic exercise in patients with type 2 diabetes., Materials and Methods: This study is a randomized, crossover clinical trial. Fourteen patients with type 2 diabetes performed two sessions of aerobic training with different methods (continuous and interval). Continuous session had duration of 35 minutes with intensity of 85-90% of heart rate corresponding to anaerobic threshold (HR AT ), while interval session had 45 minutes, with stimulus in intensity of 85-90% of HR AT with recovery in intensity under 85% of HR AT . Capillary glycemia, systolic and diastolic blood pressure were analyzed before and after the sessions., Results: Patients were 63.5 ± 9.8 years old. Glycemia was reduced in both sessions (p < 0.001). Only glycemia measured at 25 minutes after continuous session was not lower than pre-session values. Systolic blood pressure was also reduced in both sessions (p = 0.010) with similar behavior between them. In the diastolic blood pressure, there were differences only between the values measured immediately after exercise and the values measured 20 minutes (p = 0.002) and 30 minutes after exercise (p = 0.008)., Conclusion: Both continuous and interval aerobic exercise, in a same intensity, are effective for glycemic and pressure acute reductions in individuals with type 2 diabetes. For patients with greater risk of hypertension, we believe that the interval method is safer.

Studies of the role of actin in tumour progression have highlighted its key contribution in cell softening associated with cell invasion. Here, using a human breast cell line with conditional Src induction, we demonstrate that cells undergo a stiffening state prior to acquiring malignant features. This state is characterized by the transient accumulation of stress fibres and upregulation of Ena/VASP-like (EVL). EVL, in turn, organizes stress fibres leading to transient cell stiffening, ERK-dependent cell proliferation, as well as enhancement of Src activation and progression towards a fully transformed state. Accordingly, EVL accumulates predominantly in premalignant breast lesions and is required for Src-induced epithelial overgrowth in Drosophila. While cell softening allows for cancer cell invasion, our work reveals that stress fibre-mediated cell stiffening could drive tumour growth during premalignant stages. A careful consideration of the mechanical properties of tumour cells could therefore offer new avenues of exploration when designing cancer-targeting therapies.

Axillary lymph node metastases represent the most powerful breast cancer prognostic factor, dictating disease staging and clinical therapeutic decisions. Nonetheless, breast cancer patients with positive lymph nodes still exhibit a heterogeneous behavior regarding disease progression. Stem-like subpopulations of cancer cells show high migratory and metastatic capacity, thus we hypothesize that breast cancer stem cell markers evaluation in metastasized lymph nodes could provide a more accurate prediction of patient's prognosis. Therefore, the expression profile of P-cadherin, CD44, and CD49f, which have been already associated to stem cell properties in breast cancer, has been evaluated by immunohistochemistry in a series of 135 primary tumors and matched axillary lymph node metastases from 135 breast cancer patients. Taking in consideration the expression of the stem cell markers only in axillary nodes, P-cadherin was the only biomarker significantly associated with poor disease-free and overall patient's survival. Moreover, although a concordant expression between primary tumors and matched lymph nodes has been found in the majority of the cases, a small but significant percentage displayed divergent expression (18.2-26.2%). Remarkably, although CD44 and CD49f changes between primary tumors and lymph node metastasis did not impact survival, the cases that were positive for P-cadherin in lymph node metastases being negative in the primary tumor, presented the worst disease-free and overall survival of the whole series. Accordingly, negative cases for this marker in the lymph nodes with positive expression in the matched breast carcinoma demonstrated a better prognosis, which overlapped with tumors that were negative in both sites. P-cadherin and CD49f gain of expression was mainly found in triple-negative carcinomas. Our results indicate for the first time that the evaluation of P-cadherin expression in lymph node metastases is an important predictor of disease outcome, being a putative valuable marker for axillary-based breast cancer decisions in the clinical practice.

This study aimed to verify the effect of aerobic exercise performed in the fasted v. fed states on fat and carbohydrate metabolism in adults. Searches were conducted in March 2015, and updated in July 2016, using PubMed®, Scopus and Cochrane databases (terms: 'fasting', 'exercise', 'aerobic exercise', 'substrate', 'energy metabolism', 'fat', 'glucose', 'insulin' and 'adult') and references from selected studies. Trials that compared the metabolic effects of aerobic exercise (duration ≤120 min) performed in the fasted v. fed states in adults were accepted. The outcomes evaluated were fat oxidation during exercise and the plasma concentrations of insulin, glucose and NEFA before and immediately after exercise; two independent reviewers extracted the data (A. F. V. and L. C.). The results were presented as weighted mean differences between treatments, with 95 % CI. Of 10 405 articles identified, twenty-seven studies - with a total of 273 participants - were included. There was a significant increase in fat oxidation during exercise performed in the fasted, compared with fed, state (-3·08 g; 95 % CI -5·38, -0·79; I 2 39·1 %). The weighted mean difference of NEFA concentrations was not significantly different between states (0·00 mmol/l; 95 % CI -0·07, 0·08; I 2 72·7 %). However, the weighted mean differences of glucose (0·78 mmol/l; 95 % CI 0·43, 1·14; I 2 90·8 %) and insulin concentrations (104·5 pmol/l; 95 % CI 70·8, 138·2; I 2 94·5 %) were significantly higher for exercise performed in the fed state. We conclude that aerobic exercise performed in the fasted state induces higher fat oxidation than exercise performed in the fed state.

P-cadherin is a classical cell-to-cell adhesion molecule with a homeostatic function in several normal tissues. However, its behaviour in the malignant setting is notably dependent on the cellular context. In some tumour models, such as melanoma and oral squamous cell carcinoma, P-cadherin acts as a tumour suppressor, since its absence is associated with a more aggressive cancer cell phenotype; nevertheless, the overexpression of this molecule is linked to significant tumour promoting effects in the breast, ovarian, prostate, endometrial, skin, gastric, pancreas and colon neoplasms. Herein, we review the role of P-cadherin in cancer cell invasion, as well as in loco-regional and distant metastatic dissemination. We focus in P-cadherin signalling pathways that are activated to induce invasion and metastasis, as well as cancer stem cell properties. The signalling network downstream of P-cadherin is notably dependent on the cellular and tissue context and includes the activation of integrin molecules, receptor tyrosine kinases, small molecule GTPases, EMT transcription factors, and crosstalk with other cadherin family members. As new oncogenic molecular pathways mediated by P-cadherin are uncovered, putative therapeutic options can be tested, which will allow for the targeting of invasion or metastatic disease, depending on the tumour model.

Mitochondria are central organelles for cellular metabolism. In cancer cells, mitochondrial oxidative phosphorylation (OXPHOS) dysfunction has been shown to promote migration, invasion, metastization and apoptosis resistance. With the purpose of analysing the effects of OXPHOS dysfunction in cancer cells and the molecular players involved, we generated cybrid cell lines harbouring either wild-type (WT) or mutant mitochondrial DNA (mtDNA) [tRNAmut cybrids, which harbour the pathogenic A3243T mutation in the leucine transfer RNA gene (tRNAleu)]. tRNAmut cybrids exhibited lower oxygen consumption and higher glucose consumption and lactate production than WT cybrids. tRNAmut cybrids displayed increased motility and migration capacities, which were associated with altered integrin-β1 N-glycosylation, in particular with higher levels of β-1,6-N-acetylglucosamine (GlcNAc) branched N-glycans. This integrin-β1 N-glycosylation pattern was correlated with higher levels of membrane-bound integrin-β1 and also with increased binding to fibronectin. When cultured in vitro, tRNAmut cybrids presented lower growth rate than WT cybrids, however, when injected in nude mice, tRNAmut cybrids produced larger tumours and showed higher metastatic potential than WT cybrids. We conclude that mtDNA-driven OXPHOS dysfunction correlates with increased motility and migration capacities, through a mechanism that may involve the cross talk between cancer cell mitochondria and the extracellular matrix., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Cancer stem cells are hypoxia-resistant and present a preponderant glycolytic metabolism. These characteristics are also found in basal-like breast carcinomas (BLBC), which show increased expression of cancer stem cell markers.Recently, we demonstrated that P-cadherin, a biomarker of BLBC and a poor prognostic factor in this disease, mediates stem-like properties and resistance to radiation therapy. Thus, the aim of the present study was to evaluate if P-cadherin expression was associated to breast cancer cell populations with an adapted phenotype to hypoxia., Methods: Immunohistochemistry was performed to address the expression of P-cadherin, hypoxic, glycolytic and acid-resistance biomarkers in primary human breast carcinomas. In vitro studies were performed using basal-like breast cancer cell lines. qRT-PCR, FACS analysis, western blotting and confocal microscopy were used to assess the expression of P-cadherin after HIF-1α stabilization, achieved by CoCl2 treatment. siRNA-mediated knockdown was used to silence the expression of several targets and qRT-PCR was employed to evaluate the effects of P-cadherin on HIF-1α signaling. P-cadherin high and low breast cancer cell populations were sorted by FACS and levels of GLUT1 and CAIX were assessed by FACS and western blotting. Mammosphere forming efficiency was used to determine the stem cell activity after specific siRNA-mediated knockdown, further confirmed by western blotting., Results: We demonstrated that P-cadherin overexpression was significantly associated with the expression of HIF-1α, GLUT1, CAIX, MCT1 and CD147 in human breast carcinomas. In vitro, we showed that HIF-1α stabilization was accompanied by increased membrane expression of P-cadherin and that P-cadherin silencing led to a decrease of the mRNA levels of GLUT1 and CAIX. We also found that the cell fractions harboring high levels of P-cadherin were the same exhibiting more GLUT1 and CAIX expression. Finally, we showed that P-cadherin silencing significantly decreases the mammosphere forming efficiency in the same range as the silencing of HIF-1α, CAIX or GLUT1, validating that all these markers are being expressed by the same breast cancer stem cell population., Conclusions: Our results establish a link between aberrant P-cadherin expression and hypoxic, glycolytic and acid-resistant breast cancer cells, suggesting a possible role for this marker in cancer cell metabolism.