Targeting ROS production through inhibition of NADPH oxidases.

NADPH oxidases (NOXs) are transmembrane enzymes that are devoted to the production of reactive oxygen species (ROS). In cancers, dysregulation of NOX enzymes affects ROS production, leading to redox unbalance and tumor progression. Consequently, NOXs are a drug target for cancer therapeutics, although current therapies have off-target effects: there is a need for isoenzyme-selective inhibitors. Here, we describe fully validated human NOX inhibitors, obtained from an in silico screen, targeting the active site of Cylindrospermum stagnale NOX5 (csNOX5). The hits are validated by in vitro and in cellulo enzymatic and binding assays, and their binding modes to the dehydrogenase domain of csNOX5 studied via high-resolution crystal structures. A high-throughput screen in a panel of cancer cells shows activity in selected cancer cell lines and synergistic effects with KRAS modulators. Our work lays the foundation for the development of inhibitor-based methods for controlling the tightly regulated and highly localized ROS sources.

Primary thromboprophylaxis in cancer outpatients - real-world evidence.

INTRODUCTION: Cancer-associated thrombosis (CAT) is a significant concern among patients with malignant diseases, leading to increased mortality. While current guidelines recommend primary thromboprophylaxis for venous thromboembolism (VTE) in medium-to-high-risk outpatients, this practice remains controversial. A better understanding of primary thromboprophylaxis is crucial, yet there is a lack of Real-World Evidence (RWE) in Portugal. AIMS: This RWE study aimed to elucidate primary thromboprophylaxis practices among cancer outpatients in Portugal. METHODS: A five-year observational multicentric study in eight Portuguese health institutions enrolled 124 adult cancer outpatients under primary thromboprophylaxis for VTE. The endpoints were CAT, bleeding, cancer progression and death. RESULTS: High thrombotic risk tumours were prevalent, with 57% (71) of the patients presenting with pancreatic and gastric cancers. Regarding primary thromboprophylaxis, 55% (68) received Low-Molecular-Weight Heparin (LMWH). VTE was presented in 11% (14) of the patients and major bleeding in 2% (2). Vascular compression, elevated D-dimer and previous VTE were significantly associated with VTE occurrence under primary thromboprophylaxis. The Onkotev model was shown to be the best risk assessment model (RAM) in this population (p = 0.007). CAT patients exhibited a lower progression-free survival than non-CAT patients (p = 0.021), while thrombosis did not influence overall survival (p = 0.542). CONCLUSION: Primary thromboprophylaxis in medium-to-high-risk cancer outpatients is a safe and effective practice in real-world settings. This study is the first Portuguese RWE on primary thromboprophylaxis, highlighting evidence for improving prophylactic strategies in this population.

Perceived stress modulates the activity between the amygdala and the cortex.

The significant link between stress and psychiatric disorders has prompted research on stress's impact on the brain. Interestingly, previous studies on healthy subjects have demonstrated an association between perceived stress and amygdala volume, although the mechanisms by which perceived stress can affect brain function remain unknown. To better understand what this association entails at a functional level, herein, we explore the association of perceived stress, measured by the PSS10 questionnaire, with disseminated functional connectivity between brain areas. Using resting-state fMRI from 252 healthy subjects spanning a broad age range, we performed both a seed-based amygdala connectivity analysis (static connectivity, with spatial resolution but no temporal definition) and a whole-brain data-driven approach to detect altered patterns of phase interactions between brain areas (dynamic connectivity with spatiotemporal information). Results show that increased perceived stress is directly associated with increased amygdala connectivity with frontal cortical regions, which is driven by a reduced occurrence of an activity pattern where the signals in the amygdala and the hippocampus evolve in opposite directions with respect to the rest of the brain. Overall, these results not only reinforce the pathological effect of in-phase synchronicity between subcortical and cortical brain areas but also demonstrate the protective effect of counterbalanced (i.e., phase-shifted) activity between brain subsystems, which are otherwise missed with correlation-based functional connectivity analysis.

In-situ acceleration-speed profile of an elite soccer academy: A cross-sectional study.

Speed is an essential skill in sports performance and an important performance metric in talent identification. This study aims to evaluate and compare the sprint acceleration characteristics across different age groups in an elite soccer academy. A total of 141 elite academy soccer players were recruited to participate in the study, and they were assigned to their respective competitive age groups, ranging from under-14 to the B-team. An individual in-situ acceleration-speed (A-S) profile was assessed and derived from Global Position System (GPS) speed-acceleration raw data, from 10 consecutive football sessions, in the beginning of the season. The results showed that under-14 players exhibited significantly lower theoretical maximum speed (S0) (ηp2 = 0.215, p < 0.01) when compared with all other age groups. However, no differences were found between maximum theoretical acceleration (A0) and A-S slope between age groups. The results suggest that sprint mechanical profiles of young soccer athletes remain stable throughout their athletic development. Nevertheless, younger athletes have less capacity to apply horizontal force at higher speeds (S0).

Reliability of Maximal Strength and Peak Rate of Force Development in a Portable Nordic Hamstrings Exercise Device.

The Nordic hamstring exercise (NHE) is a very popular exercise used to improve eccentric strength and prevent injuries. The aim of this investigation was to assess the reliability of a portable dynamometer that measures maximal strength (MS) and rate of force development (RFD) during the NHE. Seventeen physically active participants (34.8 ± 4.1 years; n = 2 women and n = 15 men) participated. Measurements occurred on two different days separated by 48-72 h. Test-retest reliability was calculated for bilateral MS and RFD. No significant test-retest differences were observed in NHE (test-retest [95% CI, confidence interval]) for MS [-19.2 N (-67.8; 29.4); p = 0.42] and RFD [-70.4 N·s-1 (-178.4; 37.8); p = 0.19]. MS showed high reliability (intraclass correlation coefficient [ICC] [95% CI], =0.93 [0.80-0.97] and large within-subject correlation between test and retest [r = 0.88 (0.68; 0.95)]. RFD displayed good reliability [ICC = 0.76 (0.35; 0.91)] and moderate within-subject correlation between test and retest [r = 0.63 (0.22; 0.85)]. Bilateral MS and RFD displayed a coefficient of variation of 3.4% and 4.6%, respectively, between tests. The standard error of measurement and the minimal detectable change for MS was 44.6 arbitrary units (a.u.) and 123.6 a.u., and 104.6 a.u. and 290.0 a.u. for peak RFD. This study shows that MS and RFD can be measured for NHE using a portable dynamometer. However, not all exercises are suitable to apply to determine RFD, so caution must be taken when analyzing RFD during NHE.

Emotional status of children aged 7 to 17 of health workers and in the general population during the COVID-19 pandemic: A cross-sectional comparative study in Belgium.

Background: We assessed the mental health of children and adolescents aged 7 to 17 and their parents immediately after the first wave of the COVID-19 pandemic. Method: A survey online was conducted in Belgium between May 29th and August 31st 2020. Results: (1) Anxious and depressive symptoms were self-reported by one out of four children and hetero-reported by parents for one out of five children; (2) Anxiety scores were higher in children compared to adolescents; (3) Social introversion scores were significantly higher in adolescents compared to children; (4) No significant differences for anxio-depressive symptoms were found between healthcare worker parents and the other parents. Children's self- or hetero-reported symptoms were not found to be connected to parents' professional activities. Conclusions: This cross-sectional survey adds evidence to the impact the COVID-19 pandemic has had on children's and adolescents' emotional state, in particular on their levels of anxiety and depression.

Objectif: Nous avons évalué la santé mentale d'enfants et d'adolescents âgés de 7 à 17 ans et de leurs parents immédiatement après la première vague de la pandémie de COVID-19. Méthodologie: Une enquête en ligne a été réalisée en Belgique entre le 29 mai et le 31 août 2020. Résultats: (1) Les symptômes anxieux et dépressifs étaient auto-déclarés par un enfant sur quatre et hétéro-déclarés par les parents pour un enfant sur cinq ; (2) Les scores d'anxiété étaient plus élevés chez les enfants par rapport aux adolescents ; (3) Les scores d'introversion sociale étaient significativement plus élevés chez les adolescents par rapport aux enfants ; (4) Aucune différence significative pour les symptômes anxio-dépressifs n'a été trouvée entre les parents travailleurs de la santé et les autres parents. Les symptômes auto- ou hétéro-déclarés par les enfants ne se sont pas avérés être liés aux activités professionnelles des parents. Conclusions: Cette enquête transversale ajoute des preuves de l'impact de la pandémie de COVID-19 sur l'état émotionnel des enfants et des adolescents, en particulier sur leurs niveaux d'anxiété et de dépression.

Association of amygdala size with stress perception: Findings of a transversal study across the lifespan.

Daily routines are getting increasingly stressful. Interestingly, associations between stress perception and amygdala volume, a brain region implicated in emotional behaviour, have been observed in both younger and older adults. Life stress, on the other hand, has become pervasive and is no longer restricted to a specific age group or life stage. As a result, it is vital to consider stress as a continuum across the lifespan. In this study, we investigated the relationship between perceived stress and amygdala size in 272 healthy participants with a broad age range. Participants were submitted to a structural magnetic resonance imaging (MRI) to extract amygdala volume, and the Perceived Stress Scale (PSS) scores were used as the independent variable in volumetric regressions. We found that perceived stress is positively associated with the right amygdala volume throughout life.

Assessment of preoperative axillary nodal disease burden: breast MRI in locally advanced breast cancer before, during and after neoadjuvant endocrine therapy.

BACKGROUND: Axillary lymph node (LN) metastasis is one of the most important predictors of recurrence and survival in breast cancer, and accurate assessment of LN involvement is crucial. Determining extent of residual disease is key for surgical planning after neoadjuvant therapy. The aim of the study was to evaluate the diagnostic reliability of MRI for nodal disease in locally advanced breast cancer patients treated with neoadjuvant endocrine therapy (NET). METHODS: Thirty-three clinically node-positive locally advanced breast cancer patients who underwent NET and surgery were prospectively enrolled. Two radiologists reviewed the axillary nodes at 3 separate time points MRI examinations at baseline (before the first treatment regimen), interim (following at least 2 months after the first cycle and prior to crossing-over), and preoperative (after the final administration of therapy and immediately before surgery). According to LN status after surgery, imaging features and diagnostic performance were analyzed. RESULTS: All 33 patients had a target LN reduction, the greatest treatment benefit from week 8 to week 16. There was a positive correlation between the maximal diameter of the most suspicious LN measured by MRI and pathology during and after NET, being highest at therapy completion (r = 0.6, P ≤ .001). Mean and median differences of maximal diameter of the most suspicious LN were higher with MRI than with pathology. Seven of 33 patients demonstrated normal posttreatment MRI nodal status (yrN0). Of these 7 yrN0, 3 exhibited no metastasis on final pathology (ypN0), 2 ypN1 and 2 ypN2. Reciprocally, MRI diagnosed 3 cases of ypN0 as yrN + . Diffusion -weighted imaging (DWI) was the only axillary node characteristic significant when associated with pathological node status (χ2(4) = 8.118, P = .072). CONCLUSION: Performance characteristics of MRI were not completely sufficient to preclude surgical axillary staging. To our knowledge, this is the first study on MRI LN assessment following NET in locally advanced breast cancer, and further studies with larger sample sizes are required to consolidate the results of this preliminary study. TRIAL REGISTRATION: Institutional Review Board approval was obtained (this current manuscript is from a prospective, open-label, randomized single-center cohort substudy of the NEOLETEXE trial). NEOLETEXE, a phase 2 clinical trial, was registered on March 23rd, 2015 in the National trial database of Norway and approved by the Regional Ethical Committee of the South-Eastern Health Region in Norway; registration number: REK-SØ-84-2015 .

Depression Among Portuguese Pregnant Women During Covid-19 Lockdown: A Cross Sectional Study.

INTRODUCTION: Coronavirus disease 2019 was declared as a pandemic on March 2020. Research on its psychological effects is still lacking. Perinatal depression is a medical complication of pregnancy, especially in situations of stress. In this study, we aimed to investigate the presence of symptoms of depression in pregnant women during the lockdown period in Portugal. METHODS: This study consisted in a cross-sectional study among Portuguese pregnant women, who completed an online self-report questionnaire between 25th April and 30th April 2020. An anonymous online questionnaire was developed to assess depression and concerns related to COVID-19. This study was approved by the IRB of Hospital Dona Estefânia and performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. Eligibility criteria included pregnant women, ≥ 18 years and living in Portugal. The primary outcome was to evaluate the presence of depressive symptoms and its association to socio-demographic characteristics and to concerns related to COVID-19. RESULTS: A total of 1698 pregnant women were enrolled. The mean age was 31.9 years. 82.4% felt a negative impact of the pandemic in the surveillance of pregnancy and 43% felt insufficient support. 26.3% showed "possible depression" according to the EPDS. A regression analysis revealed the possibility of depression increased as the concerns about COVID increased and was lower for women with support. The possibility of depression was higher for women with psychiatric medical history. CONCLUSION: This study demonstrated a significant increase in clinically significant depressive symptoms in pregnant women during the lockdown. It also revealed some of the socio-demographic characteristics of women at risk for depression. If left untreated, depression tends to persist, affecting the woman and also the child. Our findings suggest that COVID-19 represents a serious challenge for this population and reinforce the urgent need for early detection and intervention on mental health issues during pregnancy, especially during the pandemic.

Correlation between MRI morphological response patterns and histopathological tumor regression after neoadjuvant endocrine therapy in locally advanced breast cancer: a randomized phase II trial.

PURPOSE: To correlate MRI morphological response patterns with histopathological tumor regression grading system based on tumor cellularity in locally advanced breast cancer (LABC)-treated neoadjuvant with third-generation aromatase inhibitors. METHODS: Fifty postmenopausal patients with ER-positive/HER-2-negative LABC treated with neoadjuvant letrozole and exemestane given sequentially in an intra-patient cross-over regimen for at least 4 months with MRI response monitoring at baseline as well as after at least 2 and 4 months on treatment. The MRI morphological response pattern was classified into 6 categories: 0/complete imaging response; I/concentric shrinkage; II/fragmentation; III/diffuse; IV/stable; and V/progressive. Histopathological tumor regression was assessed based on the recommendations from The Royal College of Pathologists regarding tumor cellularity. RESULTS: Following 2 and 4 months with therapy, the most common MRI pattern was pattern II (24/50 and 21/50, respectively). After 4 months on therapy, the most common histopathological tumor regression grade was grade 3 (21/50). After 4 months an increasing correlation is observed between MRI patterns and histopathology. The overall correlation, between the largest tumor diameter obtained from MRI and histopathology, was moderate and positive (r = 0.50, P-value = 2e-04). Among them, the correlation was highest in type IV (r = 0.53). CONCLUSION: The type II MRI pattern "fragmentation" was more frequent in the histopathological responder group; and types I and IV in the non-responder group. Type II pattern showed the best endocrine responsiveness and a relatively moderate correlation between sizes obtained from MRI and histology, whereas type IV pattern indicated endocrine resistance but the strongest correlation between MRI and histology.

An Elegant Four-Helical Fold in NOX and STEAP Enzymes Facilitates Electron Transport across Biomembranes-Similar Vehicle, Different Destination.

The ferric reductase superfamily comprises several oxidoreductases that use an intracellular electron source to reduce an extracellular acceptor substrate. NADPH oxidases (NOXs) and six-transmembrane epithelial antigen of the prostate enzymes (STEAPs) are iconic members of the superfamily. NOXs produce extracellular reactive oxygen species that exert potent bactericidal activities and trigger redox-signaling cascades that regulate cell division and differentiation. STEAPs catalyze the reduction of extracellular iron and copper which is necessary for the bioavailability of these essential elements. Both NOXs and STEAPs are present as multiple isozymes with distinct regulatory properties and physiological roles. Despite the important roles of NOXs and STEAPs in human physiology and despite their wide involvement in diseases like cancer, their mode of action at the molecular level remained incompletely understood for a long time, in part due to the absence of high-resolution models of the complete enzymes. Our two laboratories have elucidated the three-dimensional structures of NOXs and STEAPs, providing key insight into their mechanisms and evolution. The enzymes share a conserved transmembrane helical domain with an eye-catching hourglass shape. On the extracellular side, a heme prosthetic group is at the bottom of a pocket where the substrate (O2 in NOX, chelated iron or copper in STEAP) is reduced. On the intracellular side, the inner heme of NOX and the FAD of STEAP are bound to topological equivalent sites. This is a rare case where critical amino acid substitutions and local conformational changes enable a cofactor (heme vs FAD) swap between two structurally and functionally conserved scaffolds. The catalytic core of these enzymes is completed by distinct cytosolic NADPH-binding domains that are topologically unrelated (a ferredoxin reductase-like flavoprotein domain in NOX and a F420H2:NADP+-like domain in STEAP), feature different quaternary structures, and underlie specific regulatory mechanisms. Despite their differences, these domains all establish electron-transfer chains that direct the electrons from NADPH to the transmembrane domain. The multistep nature of the process and the chemical nature of the products pose considerable problems in the enzymatic assays. We learned that great care must be exerted in the validation of a candidate inhibitor. Multiple orthogonal assays are required to rule out off-target effects such as ROS-scavenging activities or nonspecific interference with the enzyme redox chain. The structural analysis of STEAP/NOX enzymes led us to further notice that their transmembrane heme-binding topology is shared by other enzymes. We found that the core domain of the cytochrome b subunits of the mitochondrial complex III and photosynthetic cytochrome b6f are closely related to NOXs and STEAPs and likely arose from the same ancestor protein. This observation expands the substrate portfolio of the superfamily since cytochromes b act on ubiquinone. The rigidly packed helices of the NOX/STEAP/cytochrome b domain contrast with the more malleable membrane proteins like ion channels or amino-acid transporters, which undergo large conformational changes to allow passage of relatively large metabolites. This notion of a rigid hourglass scaffold found an unexpected confirmation in the observation, revealed by structural comparisons, that an helical bundle identical to the NOX/STEAP/cytochrome b enzymes is featured by a de novo designed heme-binding protein, PS1. Apparently, nature and protein designers have independently converged to this fold as a versatile scaffold for heme-mediated reactions. The challenge is now to uncover the molecular mechanisms that implement the isozyme-specific regulation of the enzyme functions and develop much needed inhibitors and modulators for chemical biology and drug design studies.

Breast sarcoidosis: Clinical features, imaging, and histological findings.

Breast sarcoidosis is an extremely rare entity (about 1%). Conventional imaging significantly contributes to the detection of breast lesions, but it has been unable to establish a definite diagnosis. Histological examination should be mandatory, over imaging assessments, in order to confirm an early diagnosis and to avoid unjustified treatments. Malignancy should be excluded as a primary differential diagnosis. However, in the presence of granulomas, it is important to recognize other granulomatous disorders such as tuberculosis, Wegener's granulomatosis, or idiopathic granulomatous mastitis, since therapeutic strategies differ. This report clarifies the current clinical assessments and differential diagnosis of breast sarcoidosis.

The Adaptive Immune Landscape of the Colorectal Adenoma-Carcinoma Sequence.

BACKGROUND: The tumor immune microenvironment exerts a pivotal influence in tumor initiation and progression. The aim of this study was to analyze the immune context of sporadic and familial adenomatous polyposis (FAP) lesions along the colorectal adenoma-carcinoma sequence (ACS). METHODS: We analyzed immune cell counts (CD3+, CD4+, CD8+, Foxp3+, and CD57+), tumor mutation burden (TMB), MHC-I expression and PD-L1 expression of 59 FAP and 74 sporadic colorectal lesions, encompassing adenomas with low-grade dysplasia (LGD) (30 FAP; 30 sporadic), adenomas with high-grade dysplasia (22 FAP; 30 sporadic), and invasive adenocarcinomas (7 FAP; 14 sporadic). RESULTS: The sporadic colorectal ACS was characterized by (1) a stepwise decrease in immune cell counts, (2) an increase in TMB and MHC-I expression, and (3) a lower PD-L1 expression. In FAP lesions, we observed the same patterns, except for an increase in TMB along the ACS. FAP LGD lesions harbored lower Foxp3+ T cell counts than sporadic LGD lesions. A decrease in PD-L1 expression occurred earlier in FAP lesions compared to sporadic ones. CONCLUSIONS: The colorectal ACS is characterized by a progressive loss of adaptive immune infiltrate and by the establishment of a progressively immune cold microenvironment. These changes do not appear to be related with the loss of immunogenicity of tumor cells, or to the onset of an immunosuppressive tumor microenvironment.

The Transition from Child and Adolescent Mental Health Services (CAMHS) To Adult Mental Health Services (AMHS): What about Autism Spectrum Disorder?

BACKGROUND: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder and a long-term condition that may require psychiatric life-long care. Transition from Child and Adolescent Mental Health Services (CAMHS) to Adult Mental Health Services (AMHS) possibly concerns a great portion of patients with ASD. This study focuses on transitional age youth (TAY) with ASD and proposes specific innovative tools to manage the transition process. SUBJECTS AND METHODS: This explorative study focuses on TAY with ASD. Data on socio-demographic characteristics and personal medical history was collected. Three self-rated questionnaires were used: the Health of The Nation Outcome Scales For Children And Adolescents (HoNOSCA-SR), to assess care need, the World Health Organization Quality of Life-BREF (WHOQOL-BREF) scale and the Transition Readiness and Appropriateness Measure (TRAM), to evaluate barriers to functioning. RESULTS: The sample was composed of 10 patients with ASD aged from 17 to 18. The majority of them were male (70%) and born in Belgium (60%). The median (interquartile range) age of ASD diagnosis was 16 (13-17). The comorbidity rate was 60% for psychiatric disorders and 30% for somatic diseases; 80% of the participants were under psychotropic drugs. The average questionnaires scores were respectively: HoNOSCA-SR = 21.63 (±9.90), WHOQOL-BREF physical health = 50.88 (±19.14), psychological health = 36.13 (±13.97), social relationships = 48.50 (±18.23) and environment = 59.38 (±14.08); TRAM's number of barriers to functioning were 4.25 (±1.39). CONCLUSIONS: These preliminary data, accompanied by current recommendations, allow to clarify the strategies to an optimal transition in ASD. Special insight is given to strategies to reach a well-managed transition from CAMHS to AMHS, such as the assessment of psychiatric and somatic comorbidities, the care need continuity, the elaboration, in advance, of a transition plan, the assessment of the barriers to functioning, and the involvement of young patients and their families.

Outpatient Care in Psychiatry for Transitional Age Youth (16 to 24 Years Old): Which Trajectories of Psychiatric Care in French-Speaking Belgium?

BACKGROUND: Transitional age youth (TAY) are a particularly at-risk population in mental health. They have specific needs, not currently covered between child and adolescent mental health services (CAMHS) and adult mental health services (AMHS), mainly because of existing barriers. This retrospective study was carried out to describe sociodemographic and clinical characteristics of patients who attended a new outpatient program specifically conceived for TAY in Brussels, Belgium. Outcomes related to trajectories of psychiatric care were analysed, such as leading symptom, consultation's referral and requester, and final orientation. SUBJECTS AND METHODS: The total sample included 243 patients aged from 16 to 24 years old who presented for care in this outpatient program between October 2019 and May 2021. Data were retrospectively extracted from each patient's electronic medical records. RESULTS: The sample was mainly composed by female participants; the average age was 18.7 (±2.0) years. General practitioner (18.9%), child and adolescent psychiatrist (18.1%), psychologist (11.5%) and adult psychiatrist (7.4%) referred patients. Leading symptoms were divided into three dimensions: internalizing (67.5%), externalizing (21.8%) and psychotic (10.7%) ones. After first assessment, 81.5% of youth were followed-up in our specific outpatient program. Overall, at the end of data collection, youth were orientated towards ongoing follow-up in this program (37%), AMHS care (21.8%), end of psychiatric care (17.3%) and CAMHS care (4.1%). 19.8% patients discontinued the proposed care. CONCLUSIONS: This psychiatric outpatient program for TAY represents an innovative contribution to reinforce CAMHS-AMHS interface in French-speaking Belgium. The analysis of trajectories in psychiatric care suggests positive outcomes of this TAY-tailored clinical program to achieve high quality standard of care in youth mental health. Future research and clinical implementation programs should further explore which factors influence decision-making process in TAY psychiatric assessment and care.

Accuracy of breast MRI in patients receiving neoadjuvant endocrine therapy: comprehensive imaging analysis and correlation with clinical and pathological assessments.

PURPOSE: To assess the accuracy of magnetic resonance imaging (MRI) measurements in locally advanced oestrogen receptor-positive and human epidermal growth factor receptor 2-negative breast tumours before, during and after neoadjuvant endocrine treatment (NET) for evaluation of tumour response in comparison with clinical and pathological assessments. METHODS: This prospective study enrolled postmenopausal patients treated neoadjuvant with letrozole and exemestane given sequentially in an intra-patient cross-over regimen. Fifty-four patients were initially recruited, but only 35 fulfilled the inclusion criteria and confirmed to participate with a median age of 77. Tumours were scanned with MRI prior to treatment, during the eighth week of treatment and prior to surgery. Additionally, changes in longest diameter on clinical examination (CE) and tumour size at pathology were determined. Pre- and post-operative measurements of tumour size were compared in order to evaluate tumour response. RESULTS: The correlation between post-treatment MRI size and pathology was moderate and higher with a correlation coefficient (r) 0.64 compared to the correlation between CE and pathology r = 0.25. Post-treatment MRI and clinical results had a negligible bias towards underestimation of lesion size. Tumour size on MRI and CE had 0.82 cm and 0.52 cm lower mean size than tumour size measured by pathology, respectively. CONCLUSIONS: The higher correlation between measurements of residual disease obtained on MRI and those obtained with pathology validates the accuracy of imaging assessment during NET. MRI was found to be more accurate for estimating complete responses than clinical assessments and warrants further investigation in larger cohorts to validate this finding.

[Formula: see text] kinetics and energy contribution in simulated maximal performance during short and middle distance-trials in swimming.

PURPOSE: This study aims to analyze swimmers' oxygen uptake kinetics ([Formula: see text]K) and bioenergetic profiles in 50, 100, and 200 m simulated swimming events and determine which physiological variables relate with performance. METHODS: Twenty-eight well-trained swimmers completed an incremental test for maximal oxygen uptake (Peak-[Formula: see text]) and maximal aerobic velocity (MAV) assessment. Maximal trials (MT) of 50, 100, and 200-m in front crawl swimming were performed for [Formula: see text]K and bioenergetic profile. [Formula: see text]K parameters were calculated through monoexponential modeling and by a new growth rate method. The recovery phase was used along with the blood lactate concentration for bioenergetics profiling. RESULTS: Peak-[Formula: see text] (57.47 ± 5.7 ml kg-1 min-1 for male and 53.53 ± 4.21 ml kg-1 min-1 for female) did not differ from [Formula: see text]peak attained at the 200-MT for female and at the 100 and 200-MT for male. From the 50-MT to 100-MT and to the 200-MT the [Formula: see text]K presented slower time constants (8.6 ± 2.3 s, 11.5 ± 2.4 s and 16.7 ± 5.5 s, respectively), the aerobic contribution increased (~ 34%, 54% and 71%, respectively) and the anaerobic decreased (~ 66%, 46% and 29%, respectively), presenting a cross-over in the 100-MT. Both energy systems, MAV, Peak-[Formula: see text], and [Formula: see text] peak of the MT's were correlated with swimming performance. DISCUSSION: The aerobic energy contribution is an important factor for performance in 50, 100, and 200-m, regardless of the time taken to adjust the absolute oxidative response, when considering the effect on a mixed-group regarding sex. [Formula: see text]K speeding could be explained by a faster initial pacing strategy used in the shorter distances, that contributed for a more rapid increase of the oxidative contribution to the energy turnover.

Leucine metabolites do not attenuate training-induced inflammation in young resistance trained men.

Leucine metabolites may reduce training-induced inflammation; however, there is scant evidence for this assertion. We conducted a double-blind randomized controlled pragmatic trial where 40 male participants were allocated into 4 groups: α-hydroxyisocaproic acid group ([α-HICA], n = 10, Fat-free mass [FFM] = 62.0 ± 7.1 kg), ß-hydroxy-ß-methylbutyrate free acid group ([HMB-FA], n = 11, FFM = 62.7 ± 10.5 kg), calcium ß-hydroxy-ß-methylbutyrate group ([HMB-Ca], n = 9, FFM = 65.6 ± 10.1 kg) or placebo group ([PLA]; n = 10, FFM = 64.2 ± 5.7 kg). An 8-week whole-body resistance training routine (3 training sessions per week) was employed to induce gains in skeletal-muscle thickness. Skeletal muscle thickness (MT), one repetition maximum (1RM), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP) and tumour necrosis factor alpha (TNF-α) were assessed at baseline and at the end of weeks 4 and 8. Time-dependent increases were detected from baseline to week 8 for MT (vastus lateralis: p = 0.009; rectus femoris: p = 0.018), 1RM (back squat: α-HICA, 18.5% ± 18.9%; HMB-FA, 23.2% ± 16%; HMB-Ca, 10.5% ± 13.8%; PLA, 19.7% ± 9% and bench press: α-HICA, 13.8% ± 19.1%; HMB-FA, 15.5% ± 9.3%; HMB-Ca, 10% ± 10.4%; PLA, 14.4 ± 11.3%, both p < 0.001), IL-6, hsCRP (both p < 0.001) and TNF-α (p = 0.045). No differences were found between groups at any time point. No leucine metabolite attenuated inflammation during training. Additionally, backwards elimination regressions showed that no circulating inflammatory marker consistently shared variance with the change in any outcome. Using leucine metabolites to modulate inflammation cannot be recommended from the results obtained herein. Furthermore, increases in inflammatory markers, from training, do not correlate with any outcome variable and are likely the result of training adaptations.

Optimizing the Synthetic Route of Chromone-2-carboxylic Acids: A Step forward to Speed-Up the Discovery of Chromone-Based Multitarget-Directed Ligands.

6-Bromochromone-2-carboxylic acid (3) was synthesized by a microwave-assisted process. The optimization of the reaction was performed varying parameters, such as type of base/number of reagent equivalents, solvent, temperature and reaction time. The yield of the reaction was improved to 87%. The new synthetic route is versatile as several chromone-2-carboxylic acids (compounds 4B-10B) were obtained with good yields (54-93%). Only in the case of the nitro substituent (compound 11B), an ester was obtained instead of the desired carboxylic acid. Following this synthetic route chromone carboxylic acids can be attained with a high degree of purity, without the need of the tedious and expensive purification processes through column chromatography. The reaction is safe, cost-effective, fast and robust, and can be used in the development of concise and diversity-oriented libraries based on chromone scaffold. The overall study can be looked as a step forward to speed-up the discovery of chromone-based multitarget-directed ligands.

Long-term swimming training modifies acute immune cell response to a high-intensity session.

PURPOSE: Long-term training influence on athletes' immune cell response to acute exercise has been poorly studied, despite the complexity of both chronic and acute adaptations induced by training. The purpose of the study is to study the influence of a 4-month swimming training cycle on the immune cell response to a high-intensity training session, during 24 h of recovery, considering sex, maturity, and age group. METHODS: Forty-three swimmers (16 females, 14.4 ± 1.1 years; 27 males, 16.2 ± 2.0) performed a standardized high-intensity session, after the main competition of the first (M1), and second (M2) macrocycles. Blood samples were collected before (Pre), immediately after (Post), 2 h after (Post2h) and 24 h after (Post24h) exercise. Haemogram and lymphocytes subsets were assessed by an automatic cell counter and by flow cytometry, respectively. Subjects were grouped according to sex, competitive age groups, or pubertal Tanner stages. Results express the percentage of relative differences from Pre to Post, Post2h and Post24h. Upper respiratory symptoms (URS) and training load were quantified. RESULTS: At M2, we observed smaller increases of leukocytes (M1: 14.0 ± 36.3/M2: 2.33 ± 23.0%) and neutrophils (M1: 57.1 ± 71.6/M2: 38.9 ± 49.9%) at Post; and less efficient recoveries of total lymphocytes (M1: - 22.0 ± 20.1/M2: - 30.0 ± 18.6%) and CD19+ (M1: 4.09 ± 31.1/M2: - 19.1 ± 24.4%) at Post2h. At Post2h, the increment of CD4+/CD8+ was smaller in youth (M1: 21.5 ± 16.0/M2: 9.23 ± 21.4%), and bigger in seniors (M1: 3.68 ± 9.21/M2: 23.2 ± 15.0%); and at Post24h late pubertal swimmers' CD16+56+ recovered less efficiently (M1: - 0.66 ± 34.6/M2: - 20.5 ± 34.2%). CONCLUSIONS: The training cycle induced an attenuated immune change immediately after exercise and a less efficient recovery of total lymphocytes, involving an accentuated CD19+ decrease. The concomitant higher URS frequency suggests a potential immune depression and a longer interval of susceptibility to infection.