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An important health-related problem of obesity is reduced stance stability, leading to increased chance of falling. In the present experiment, we aimed to compare stability in quiet and in dynamic body balance between women with morbid obesity (n = 13, body mass index [BMI] > 40 Kg/m2, mean age = 38.85 years) and with healthy body weight (lean) (n = 13; BMI < 25 Kg/m2, mean age = 37.62 years), evaluating the extent to which quiet and dynamic balance stability are associated with plantar sensibility. Quiet stance was evaluated in different visual and support base conditions. The dynamic task consisted of rhythmic flexion—extension movements at the hip and shoulder, manipulating vision availability. The plantar sensibility threshold was measured through application of monofilaments on the feet soles. The results showed that the morbidly obese, in comparison with the lean women, had higher plantar sensibility thresholds, and a reduced balance stability in quiet standing. Mediolateral stance stability on the malleable surface was strongly correlated with plantar sensibility in the obese women. Analysis of dynamic balance showed no effect of obesity and weaker correlations with plantar sensibility. Our results suggest that reduced plantar sensibility in morbidly obese women may underlie their diminished stance stability, while dynamic balance control seems to be unaffected by their reduced plantar sensibility.

Background: Young breast cancer patients (pts) carrying a germline BRCA mutation (mBRCA) have similar outcomes as non-carriers. However, there is currently lack of evidence regarding the impact of mBRCA type and hormone receptor status on clinical behavior and outcomes of mBRCA breast cancer. We aim to address these questions in the largest dataset to date of young mBRCA breast cancer pts. Methods: This was an international, multicenter, hospital-based, retrospective cohort study. Women harboring deleterious germline mBRCA1 or mBRCA2 that received a diagnosis of stage I-III invasive early breast cancer at age ≤40 years between January 2000 and December 2012 were included. Baseline pts, tumor, and treatment characteristics, pattern and risk over time of disease-free survival (DFS) events, and survival outcomes (DFS, distant recurrence-free interval [DRFI] and overall survival [OS]) were compared between mBRCA1 and mBRCA2 pts overall and by hormone receptor status. Multivariate Cox proportional hazard models were used to compare hazard rates (HRs). Results: 1,236 young mBRCA breast cancer pts were included. Among 808 and 428 pts with mBRCA1 or mBRCA2, respectively, 191 (23.6%) and 356 (83.2%) had hormone receptor-positive tumors while 617 (76.4%) and 72 (16.8%) hormone receptor-negative disease (p Conclusions: In this large unique dataset, young mBRCA1 breast cancer pts had worse DFS than those with mBRCA2 mostly due to higher rates of second primary malignancies. Hormone receptor positivity had no positive prognostic value in young mBRCA breast cancer pts with a trend towards worse DRFI in those with hormone receptor-negative disease. These results provide important information for counseling young mBRCA breast cancer pts regarding treatment, prevention and follow-up care strategies. Citation Format: Matteo Lambertini, Marcello Ceppi, Anne-Sophie Hamy, Olivier Caron, Philip D. Poorvu, Estela Carrasco, Albert Grinshpun, Kevin Punie, Christine Rousset-Jablonski, Alberta Ferrari, Shani Paluch-Shimon, Angela Toss, Claire Senechal, Fabio Puglisi, Katarzyna Pogoda, Jose Alejandro Pérez-Fidalgo, Laura De Marchis, Riccardo Ponzone, Luca Livraghi, Maria Del Pilar Estevez-Diz, Cynthia Villarreal-Garza, Maria Vittoria Dieci, Florian Clatot, Francois P. Duhoux, Rossella Graffeo, Luis Teixeira, Octavi Córdoba, Amir Sonnenblick, Arlindo R. Ferreira, Ann H. Partridge, Antonio Di Meglio, Claire Saule, Fedro A. Peccatori, Marco Bruzzone, Lucia Del Mastro, Lieveke Ameye, Judith Balmaña, Hatem A. Azim, Jr. Clinical behavior and outcomes of BRCA-mutated breast cancer in young patients according to type of BRCA mutation and hormone receptor status: Results from an international cohort study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD10-06.

According to the dynamic dominance model, the left cerebral hemisphere is specialized for the control of intersegmental dynamics and the right hemisphere for impedance control. Our aim was to test predictions from the dynamic dominance model in children by comparing performance between the right (preferred) and left hands in aiming. Three groups were compared: 4-7, 8-11, and 18-38 years old. Results showed higher movement linearity in the performance with the right hand in all age groups (

Freezing of gait (FoG) is one of the main reasons for movement initiation disorders and abnormal coupling of posture and gait in Parkinson's disease (PD). Patients with FoG have poor postural control when compared to patients without FoG. However, the nature of the interrelationship between FoG and domains of postural control remains unknown. The aim of this study was to estimate the association between different domains of postural control and severity of FoG in patients with moderate-to-severe PD. Thirty patients with idiopathic PD with FoG (age range 45-80 years, Hoehn & Yahr stages 3 and 4) participated in the study. We evaluated objective (FoG-ratio during turning task) and subjective (New Freezing of Gait Questionnaire, NFoG-Q) measures of FoG severity, reactive postural adjustments in response to an external perturbation, first step anticipatory adjustment for step initiation and quiet standing stability. In the multiple regression analysis, step initiation was the strongest significant correlation of the NFoG-Q score explaining 23% of the variance of the assessment. For the objective FoG measure, mediolateral CoP amplitude in quiet standing and mediolateral CoP amplitude in step initiation explained 39% of the variance of the FoG-ratio. As main conclusions, this study identified the association between objective and subjective measure for FoG severity and postural control domains. The results support conducting step initiation training during rehabilitation of individuals with FoG.

The majority of clinical deaths in patients with triple-negative breast cancer (TNBC) are due to chemoresistance and aggressive metastases, with high prevalence in younger women of African ethnicity. Although tumorigenic drivers are numerous and varied, the drivers of metastatic transition remain largely unknown. Here, we uncovered a molecular dependence of TNBC tumors on the TRIM37 network, which enables tumor cells to resist chemotherapeutic as well as metastatic stress. TRIM37-directed histone H2A monoubiquitination enforces changes in DNA repair that rendered TP53-mutant TNBC cells resistant to chemotherapy. Chemotherapeutic drugs triggered a positive feedback loop via ATM/E2F1/STAT signaling, amplifying the TRIM37 network in chemoresistant cancer cells. High expression of TRIM37 induced transcriptomic changes characteristic of a metastatic phenotype, and inhibition of TRIM37 substantially reduced the in vivo propensity of TNBC cells. Selective delivery of TRIM37-specific antisense oligonucleotides using antifolate receptor 1–conjugated nanoparticles in combination with chemotherapy suppressed lung metastasis in spontaneous metastatic murine models. Collectively, these findings establish TRIM37 as a clinically relevant target with opportunities for therapeutic intervention.Significance:TRIM37 drives aggressive TNBC biology by promoting resistance to chemotherapy and inducing a prometastatic transcriptional program; inhibition of TRIM37 increases chemotherapy efficacy and reduces metastasis risk in patients with TNBC.

People with cerebral palsy (CP) often have difficulties related to maintaining body balance in their daily living activities. Accelerometers are low-cost wearable devices with potential use to objectively assess balance.What are the main characteristics and findings from protocols used in research aiming to investigate standing or dynamic body balance stability through trunk accelerometry in people with CP?We searched in December 2021 seven databases, Pubmed, Embase, Cochrane, Science Direct, Scopus, PEDro, and Lilacs, with descriptors related to cerebral palsy, accelerometer, and balance.Ten studies were included, with a total of 197 evaluated people with CP. These studies were classified as moderate or high methodological quality. We found convergence on the use of the sensor at the lumbar region (L3), with sampling frequency at 100 Hz. For balance assessment, 60 % of the reviewed studies used the 10-m walk test, while the other studies used different walking distances, or the quiet standing test. For data processing, the low-pass filter at 20 Hz has been used predominantly, and the most commonly used variable to evaluate balance stability has been root mean square of trunk acceleration. Children and adolescents with CP had higher acceleration values and greater gait complexity than typically developing children. Individuals with bilateral impairment had greater anteroposterior and mediolateral trunk accelerations than those with unilateral impairment. Trunk acceleration was shown to be sensitive to improvement in gait stability from interventions, and acceleration-based measures have been found to correlate with qualitative balance assessment tools.Trunk accelerometry in quiet posture and dynamic tasks was shown to be a valid and sensitive measurement to evaluate balance stability in children and adolescents with CP. It is a small, light, low-cost and easy-to-handle tool that is effective for measuring body balance on different tasks in this population.

PURPOSE Young women with germline BRCA mutations have unique reproductive challenges. Pregnancy after breast cancer does not increase the risk of recurrence; however, very limited data are available in patients with BRCA mutations. This study investigated the impact of pregnancy on breast cancer outcomes in patients with germline BRCA mutations. PATIENTS AND METHODS This is an international, multicenter, hospital-based, retrospective cohort study. Eligible patients were diagnosed between January 2000 and December 2012 with invasive early breast cancer at age ≤ 40 years and harbored deleterious germline BRCA mutations. Primary end points were pregnancy rate, and disease-free survival (DFS) between patients with and without a pregnancy after breast cancer. Pregnancy outcomes and overall survival (OS) were secondary end points. Survival analyses were adjusted for guarantee-time bias controlling for known prognostic factors. RESULTS Of 1,252 patients with germline BRCA mutations ( BRCA1, 811 patients; BRCA2, 430 patients; BRCA1/2, 11 patients) included, 195 had at least 1 pregnancy after breast cancer (pregnancy rate at 10 years, 19%; 95% CI, 17% to 22%). Induced abortions and miscarriages occurred in 16 (8.2%) and 20 (10.3%) patients, respectively. Among the 150 patients who gave birth (76.9%; 170 babies), pregnancy complications and congenital anomalies occurred in 13 (11.6%) and 2 (1.8%) cases, respectively. Median follow-up from breast cancer diagnosis was 8.3 years. No differences in DFS (adjusted hazard ratio [HR], 0.87; 95% CI, 0.61 to 1.23; P = .41) or OS (adjusted HR, 0.88; 95% CI, 0.50 to 1.56; P = .66) were observed between the pregnancy and nonpregnancy cohorts. CONCLUSION Pregnancy after breast cancer in patients with germline BRCA mutations is safe without apparent worsening of maternal prognosis and is associated with favorable fetal outcomes. These results provide reassurance to patients with BRCA-mutated breast cancer interested in future fertility.

O objetivo deste estudo foi avaliar a integração entre os componentes manual e postural em uma tarefa motora dual em resposta a perturbações que afetam a ambos os componentes. Foram avaliados oito adultos jovens em uma tarefa requisitando resposta reativa a uma perturbação postural causada por liberação de carga, enquanto apontando um laser continuamente para um alvo circular. As comparações foram feitas em função da combinação de dois fatores: (a) previsibilidade do momento da perturbação postural, com dica temporal versus sem dica; e (b) demanda de precisão da tarefa manual, contrastando alvos com diâmetros de 2 cm (alta restrição) versus 20 cm (baixa restrição). Os resultados revelaram que a previsibilidade do tempo de perturbação reduziu a amplitude de oscilação dos movimentos manuais e diminuiu a correlação entre respostas manuais e posturais, enquanto que o a amplitude de excursão do centro de pressão foi reduzida na condição de previsibilidade temporal da perturbação associada à baixa restrição da tarefa manual. Este estudo revela a factibilidade do método aqui empregado para avaliar a integração entre controle postural e de tarefas manuais, na busca de melhor compreender a regulação de ações duais dessa natureza realizadas frequentemente em nosso cotidiano.

BACKGROUND Exercises with motor complexity induce neuroplasticity in individuals with Parkinson's disease (PD), but its effects on freezing of gait are unknown. The objective of this study was to verify if adapted resistance training with instability - exercises with motor complexity will be more effective than traditional motor rehabilitation - exercises without motor complexity in improving freezing-of-gait severity, outcomes linked to freezing of gait, and brain function. METHODS Freezers were randomized either to the adapted resistance training with instability group (n = 17) or to the active control group (traditional motor rehabilitation, n = 15). Both training groups performed exercises 3 times a week for 12 weeks. The primary outcome was the New Freezing of Gait Questionnaire. Secondary outcomes were freezing of gait ratio (turning task), cognitive inhibition (Stroop-III test), motor signs (Unified Parkinson's Disease Rating Scale part-III [UPDRS-III]), quality of life (PD Questionnaire 39), anticipatory postural adjustment (leg-lifting task) and brain activation during a functional magnetic resonance imaging protocol of simulated anticipatory postural adjustment task. Outcomes were evaluated before and after interventions. RESULTS Only adapted resistance training with instability improved all the outcomes (P

Muscle fatigue accumulated during a soccer game can be a critical element to athletic performance. The aim of this study was to analyze the feasibility of evaluating the effect of muscle fatigue of the support leg in soccer players postural stability and muscular activation of the stabilizing muscles of the ankle in the performance of a power kick. Six university soccer players were evaluated. Muscular fatigue was induced by means of repeated oscillations of the swing leg. Results indicated that fatigue did not significantly affect velocity of the kicking leg and postural stability while kicking. Electromyographic analysis revealed that fatigue induced decreased activation of the medial gastrocnemius and increased activation of the soleus muscles in the period following foot-ball contact. These results show the feasibility of analyzing the effect of fatigue on dynamic balance and muscular activation in the performance of a power kicking task.

Background: In ER+ HER2- metastatic breast cancer (MBC), activating ESR1 mutations (ESR1mut) confer resistance to aromatase inhibitors (AI) when used as single agent. The impact of ESR1mut, when detected at baseline (prior to the initiation of therapy), on the efficacy of first line combined AI- CDK4/6 inhibitor therapy remains however unknown. Methods: The PADA-1 phase 3 trial (NCT03079011) aims at evaluating the utility of monitoring the onset of ESR1mut in cell-free DNA (cfDNA) from patients (pts) receiving AI-palbociclib, as a biomarker to trigger a switch from AI to fulvestrant. Main inclusion criteria were pts with no prior therapy for MBC and with no overt resistance to AI (i.e. no adjuvant AI or adjuvant AI completed >12 months prior to the metastatic relapse). The present exploratory analysis evaluated the biological and clinical outcome of patients who tested positive for ESR1mut at baseline (before any treatment). Results: From 04/2017 to 01/2019, N=1017 ER+ HER2- MBC pts were included and had their cfDNA tested for ESR1mut at inclusion and during therapy (at 1 month and then every 2 months). N=33/1017 pts had a detectable circulating ESR1mut at inclusion (3.2%, 95%CI [2.2;4.5]), with a median allelic frequency (AF) of 2.5% (range: 0.1- 46%). First, we evaluated the kinetics of ESR1mut in the 33 ESR1mut-positive pts at inclusion. N=1 pt died after 1 month on treatment. In N=25/32 pts (78%), ESR1mut became undetectable (AF Conclusions: ESR1mut are rarely detected in the cfDNA of ER+ HER2- MBC patients with no overt resistance to AI. The quick ‘clearance’ of ESR1mut observed in most patients following treatment initiation and the observed 17.5 months-long median PFS both suggest that the AI palbociclib combination retain clinical activity in ESR1mut-positive MBC. However, in most patients, these mutations were eventually detected again later during therapy and ESR1mut- positivity was associated with a significantly shorter PFS, suggesting that ESR1mut positivity at baseline could accelerate the onset of resistance to AI-palbociclib. Funding: Pfizer Citation Format: François-Clément Bidard, Céline Callens, Florence Dalenc, Barbara Pistilli, Thibault de la Motte Rouge, Florian Clatot, Véronique D'Hondt, Luis Teixeira, Sibille Everhard, Hélène Vegas, Jérôme Lemonnier, Ivan Bieche, Anne Pradines, Jean-François Paitel, Dominique Spaeth, Jean-Luc Canon, Isabelle Moullet, Jean-Yves Pierga, Frédérique Berger, Thomas Bachelot, Suzette Delaloge. Clinical and biological efficacy of first line AI and palbociclib in ER+ HER2- MBC with detectable circulating ESR1 mutation prior to treatment initiation [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-11-22.

Purpose: Human telomerase reverse transcriptase (hTERT) is highly expressed in >85% of human tumors and is thus considered as a good tumor-associated antigen candidate for vaccine development. We conducted a phase I study to investigate the safety, tolerability, clinical response, and immunogenicity of INVAC-1, a DNA plasmid encoding a modified hTERT protein in patients with relapsed or refractory solid tumors. Patients and Methods: INVAC-1 was either administered by intradermal route followed by electroporation or by Tropis, a needle-free injection system. Safety and tolerability were monitored by clinical and laboratory assessments. Progression-free survival and overall survival were reported using Kaplan–Meier survival analysis. Immunogenicity was studied by ELISpot, Luminex, and Flow Cytometry. Results: Twenty-six patients were treated with INVAC-1 administered at three dose levels (100, 400, and 800 μg). Vaccination was well tolerated and no dose-limiting toxicity was reported. One treatment-related grade 3 SAE was reported. Fifty-eight percent of patients experienced disease stabilization. PFS was 2.7 months, median OS was 15 months, and 1-year survival was reached for 65% of patients. INVAC-1 vaccination stimulated specific anti-hTERT CD4 T-cell response as well as cytotoxic CD8 T-cell response. No evidence of peripheral vaccine-induced immunosuppression was observed. Conclusions: INVAC-1 vaccination was safe, well tolerated, and immunogenic when administered intradermally at the three tested doses in patients with relapsed or refractory cancers. Disease stabilization was observed for the majority of patients (58%) during the treatment period and beyond. See related commentary by Slingluff Jr, p. 529

People with Parkinson's disease (PwPD) showed impairments of balance control which can be aggravated by the presence of higher interlateral postural asymmetry caused by a distinct dopaminergic loss in the substantia nigra between cerebral hemispheres.We evaluate asymmetries between the more and the less affected leg in PwPD in responses to unanticipated stance perturbations.Sixteen 16 PwPD participated in the experiment that consisted of recovering a stable upright stance, keeping the feet in place, in response to a perturbation caused by a sudden release of a load equivalent to 7 % of the participant's body mass. Anterior displacement and velocity of the center of pressure (CoP), the latency of gastrocnemius medialis muscle (GM) activation onset, rate of GM activation, and normalized magnitude of muscular activation were analyzed.Analysis revealed significantly rate (p = 0.04) and magnitude (p = 0.02) higher activation of GM in the less affected limb. No significant effects of the leg were found for GM activation latency or CoP-related variables.There is a higher contribution of the less affected leg in automatic postural responses in PwPD.

Based on the Theory of Justice of John Rawls, this article analyses justice regarding the decisions of the Federal Supreme Court of Brazil (STF) related to public concessions of expensive medicines. This study focuses on constitutional principles like the universality and integrality in health care illuminated by the minimum existential and the reserve for contingencies. The study of the decisions of the Federal Supreme Court searched an equity approach and the consequences for the poor that depends on the public health system (SUS) to receive health care. Applying the analytical and synthetic methods, the analyses showed that the decisions are not fair in the same way John Rawls argues that because there is no protection of the minimum existential. Thus, there is a health injury to the poor that could be avoided by the theory of justice of John Rawls.

Individuals with Parkinson's disease (PD) and freezing of gait (FOG) have difficulty initiating and maintaining a healthy gait pattern; however, the relationship among FOG severity, gait initiation, and gait automaticity, in addition to the neural substrate of this relationship has not been investigated. This study investigated the association among FOG severity during turning (FOG-ratio), gait initiation (anticipatory postural adjustment [APA]), and gait automaticity (dual-task cost [DTC]), and the neural substrates of these associations. Thirty-four individuals with FOG of PD were assessed in the ON-medication state. FOG-ratio during a turning test, gait automaticity using DTC on stride length and gait speed, and APA during an event-related functional magnetic resonance imaging protocol to assess brain activity from the regions of interest (e.g., dorsolateral prefrontal cortex [DLPFC] and mesencephalic locomotor region [MLR]) were assessed in separated days. Results showed that FOG-ratio, APA amplitude, and DTC on stride length are negatively associated among them (P 0.05). APA amplitude and DTC on stride length explained 59% of the FOG-ratio variance (P 0.05). Although the activity of the right DLPFC and right MLR explained 55% of the FOG-ratio variance (P 0.05) and 30% of the DTC on stride length variance (P ≤ 0.05), only the activity of the right MLR explained 23% of the APA amplitude (P 0.05). FOG severity during turning, APA amplitude, and stride length automaticity are associated among them and share a similar locomotor substrate, as the MLR activity was a common brain region in explaining the variance of these variables.

EnglishBased on the Theory of Justice of John Rawls, this article analyses justice regarding the decisions of the Federal Supreme Court of Brazil (STF) related to public concessions of expensive medicines. This study focuses on constitutional principles like the universality and integrality in health care illuminated by the minimum existential and the reserve for contingencies. In the study of the STF decisions, we sought to verify the existence of analyses related to equity and, above all, to the consequences brought to the less favored, people who depend exclusively on SUS to obtain health treatments, no matter how basic they may be. Applying the analytical and synthetic methods, the analyses showed that the decisions are not fair in the same way John Rawls argues that because there is no protection of the minimum existential. Thus, there is a health injury to the poor that could be avoided by the theory of justice of John Rawls. portuguesO presente artigo objetiva analisar a justica das decisoes do Supremo Tribunal Federal (STF) sobre pedidos de medicamentos de alto custo com fundamento na teoria da justica como equidade de John Rawls. Este estudo tem como principal foco os principios constitucionais da universalidade e da integralidade do direito a saude, vistos sob a otica do minimo existencial e da reserva do possivel. No estudo das decisoes do STF, buscou-se verificar a existencia de analises relativas a equidade e, sobretudo, as consequencias trazidas aos menos favorecidos, pessoas que dependem exclusivamente do SUS para obtencao de tratamentos de saude, por mais basicos que sejam. Empregando os metodos analiticos e sinteticos, conclui-se que as decisoes analisadas se distanciam da justica como equidade proposta por Rawls, pois, em vista da escassez de recursos, nao privilegiam o minimo social, o que causa prejuizos aos menos favorecidos, justamente, o que Rawls tenta evitar com sua teoria.

Introduction Coronavirus disease 2019 resulted in a 30% mortality rate in patients with thoracic cancer. Given that patients with cancer were excluded from serum antisevere acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccine registration trials, it is still unknown whether they would develop a protective antispike antibody response after vaccination. This prospective vaccine monitoring study primarily aimed to assess humoral responses to the SARS-CoV-2 vaccine in patients with thoracic cancer. Methods SARS-CoV-2–spike antibodies were measured using the Abbot Architect SARS-CoV-2 immunoglobulin G immunoassay before the first injection of BNT162b2 mRNA vaccine, at week 4, and 2 to 16 weeks after the second vaccine dose administration. The factors associated with antibody response were analyzed. Results Overall, 306 patients, with a median age of 67.0 years (interquartile range: 58–74), were vaccinated. Of these, 283 patients received two vaccine doses at 28-day intervals. After a 6.7-month median follow-up, eight patients (2.6%) contracted proven symptomatic SARS-CoV-2 infection, with rapid favorable evolution. Of the 269 serologic results available beyond day 14 after the second vaccine dose administration, 17 patients (6.3%) were still negative (

The ankle plantar flexor muscles act synergistically to control quiet and dynamic body balance. Previous research has shown that the medial (MG) and lateral (LG) gastrocnemii, and soleus (SOL) are differentially activated as a function of motor task requirements. In the present investigation, we evaluated modulation of the plantar flexors' activation from feet orientation on the ground in an upright stance and the ensuing reactive response to a perturbation. A single group of young participants (n = 24) was evaluated in a task requiring initial stabilization of body balance against a backward pulling load (5% or 10% of body weight) attached to their trunk, and then the balance was suddenly perturbed, releasing the load. Four feet orientations were compared: parallel (0°), outward orientation at 15° and 30°, and the preferred orientation (M = 10.5°). Results revealed a higher activation magnitude of SOL compared to MG-LG when sustaining quiet balance against the 10% load. In the generation of reactive responses, MG was characterized by earlier, steeper, and proportionally higher activation than LG-SOL. Feet orientation at 30° led to higher muscular activation than the other orientations, while the activation relationship across muscles was unaffected by feet orientation. Our results support the conclusion of task-specific differential modulation of the plantar flexor muscles for balance control.

Post-transcriptional modifications of RNA constitute an emerging regulatory layer of gene expression. The demethylase fat mass- and obesity-associated protein (FTO), an eraser of N-6-methyladenosine (m(6)A), has been shown to play a role in cancer, but its contribution to tumor progression and the underlying mechanisms remain unclear. Here, we report widespread FTO downregulation in epithelial cancers associated with increased invasion, metastasis and worse clinical outcome. Both in vitro and in vivo, FTO silencing promotes cancer growth, cell motility and invasion. In human-derived tumor xenografts (PDXs), FTO pharmacological inhibition favors tumorigenesis. Mechanistically, we demonstrate that FTO depletion elicits an epithelial-to-mesenchymal transition (EMT) program through increased m(6)A and altered 3-end processing of key mRNAs along the Wnt signaling cascade. Accordingly, FTO knockdown acts via EMT to sensitize mouse xenografts to Wnt inhibition. We thus identify FTO as a key regulator, across epithelial cancers, of Wnt-triggered EMT and tumor progression and reveal a therapeutically exploitable vulnerability of FTO-low tumors.Fuks and colleagues report that downregulation of the FTO m(6)A RNA demethylase activates the Wnt pathway, promoting EMT-mediated progression of epithelial tumors and conferring sensitivity to Wnt inhibitors.

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Background: Palbociclib (Pal) combined with an aromatase inhibitor (AI) is a standard of care as first line therapy in ER+ HER2- metastatic breast cancer (MBC). While ESR1 mutations (ESR1mut) are a characterized mechanism of resistance to AI as single agent, it remains unknown how these mutations, when detected prior to treatment initiation, may affect the efficacy of Pal+AI. In a subsidiary analysis of the first line PADA-1 trial, we report the ESR1mut detection rate at baseline and, in patients with ESR1mut detected at baseline, how ESR1 circulating tumor DNA levels changed after the first cycle of AI-Pal therapy. Methods: PADA-1 (NCT03079011) is a randomized phase III trial testing the clinical utility of real time ESR1mut detection (baseline, at 1 month and then every 2 months) in the blood of patients treated with AI-Pal (first step). Patients with rising ESR1mut in circulating tumor DNA (i.e. increasing or appearing mutations during first line AI-Pal therapy) are randomized in a second step between keeping AI-Pal or switching to Fulvestrant-Pal. Main inclusion criteria are patients with ER+ HER2- MBC, who never received adjuvant AI or completed adjuvant AI for >12 months, with neither prior therapy for MBC nor visceral crisis. ESR1mut are tracked in circulating DNA from up to 4ml of plasma by a ddPCR-based assay targeting E380, L536, Y537 and D538 hotspots (i.e. #90% of known ESR1 activating mutations) with #0.1% sensitivity (Bidard et al, AACR 2018 #3867). Results: From 04/2017 to 05/2018, 803 MBC patients have been included in 80 centers. Among these patients, ESR1mut were detected at baseline, prior to any systemic therapy, in 17 patients (2.1%, 95%CI=[1.3;3.3%]). ESR1mut levels ranged from 6 to 3959 copies/ml of plasma (median: 30 copies/ml); allelic frequency ranged from 0.3% to 47% (median=3.5%). ESR1mut were not associated with any of the tumor pathological characteristics (including PR status, primary TNM stage, number and type of metastatic sites); a non-significant association was observed with primary tumor grade (1.7% vs 4.1% in grade I-II vs III, Fisher: p=0.15). Among patients who received a prior adjuvant endocrine therapy, ESR1mut detection rate was lower in patients treated with tamoxifen (0.9% with any tamoxifen exposure vs 5.7% with no tamoxifen exposure; Yates Chi2: p=0.01) and observed only in patients treated with AI (4.9% with any AI exposure vs 0% with no AI exposure, Yates Chi2: p=0.009). Among the 17 patients with ESR1mut detected at baseline, only 4 patients had residual detectable ESR1mut detected after 1 month of AI-Pal therapy (3 of these 4 had decreased levels of ESR1 mutation). Conclusion: ESR1mut is a rare event in untreated AI-sensitive, ER+ HER2- MBC patients. Such detection is primarily associated with prior use of AI in the adjuvant setting. Interestingly, in most MBC patients with ESR1mut detected at baseline, ESR1mut became undetectable after 1 month of AI-Pal therapy, suggesting that this combination may retain early antitumor efficacy. Funding: Pfizer Citation Format: Bidard F-C, Pistilli B, Dalenc F, De la Motte Rouge T, Sabatier R, Frenel J-S, Ladoire S, Dubot C, Ferrero J-M, Levy C, Lortholary A, Stefani L, Mouret-Reynier M-A, Hardy A-C, Jacquin J-P, Grenier J, Chakiba C, Teixeira L, Soulie P, Everhard S, Lemonnier J, Jeannot E, Bieche I, Berger F, Pierga J-Y, Bachelot T, Delaloge S. Circulating ESR1 mutation detection rate and early decrease under first line aromatase inhibitor and palbociclib in the PADA-1 trial (UCBG-GINECO) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD2-06.

Imagética dos próprios movimentos tem mostrado induzir aprendizagem motora em adultos, porém são escassas evidências similares em crianças. O objetivo deste experimento foi avaliar o efeito da associação entre prática imagética e prática física em comparação com prática física pura em uma habilidade manual em crianças de 9-10 anos de idade. A tarefa consistiu em transportar um bloco e encaixá-lo em um suporte com rapidez e estabilidade, avaliando-se o tempo de movimento para completar os componentes de “alcance” e “transporte”. As crianças foram distribuídas em três grupos: (a) prática física (FIS) (240 tentativas), (b) combinação (COMB) de prática imagética (180 tentativas) e prática física (60 tentativas), e (c) controle (CON), com associação de rotação visual (180 tentativas) e prática física (60 tentativas). O desempenho foi avaliado imediatamente e 24 h após a prática. Os resultados indicaram que o grupo FIS obteve ganho persistente de desempenho no componente “transporte”, porém não no componente “alcance”, enquanto o grupo COMB alcançou ganho persistente de desempenho em ambos os componentes de movimento; não foram encontradas diferenças significantes para o grupo CON. Estes resultados sugerem que a prática imagética aprimora a representação mental da tarefa motora em crianças, enquanto que a prática física oferece informação de feedback sensorial sobre o os movimentos realizados. Como conclusão, nossos resultados sugerem que a combinação de prática física e imagética é um procedimento que pode ser mais efetivo do que prática física pura para aprendizagem motora em crianças.

L’immunothérapie représente une avancée récente et importante en cancérologie. Les inhibiteurs de checkpoints immunitaires, ciblant les protéines PD-1, PD-L1 et CTLA-4, sont les thérapies les plus prometteuses et sont utilisés dans la prise en charge de plusieurs cancers. Les toxicités associées à ces traitements sont généralement moins fréquentes et moins graves que celles associées aux chimiothérapies et à la plupart des thérapies ciblées. Cependant, il existe un certain nombre de toxicités spécifiques de ce type de traitement, qui peuvent parfois être sévères et dont les plus fréquentes sont les toxicités pulmonaire, digestive, endocrinienne et cutanée. Dans cette mise au point, nous reviendrons sur la fréquence, le mécanisme et les principes de traitement des différentes toxicités sévères associées à l’immunothérapie.

Càncer de mama; Genètica del càncer Cáncer de mama; Genética del cáncer Breast cancer; Cancer genetics Young breast cancer (BC) patients carrying a germline BRCA pathogenic variant (mBRCA) have similar outcomes as non-carriers. However, the impact of the type of gene (BRCA1 vs. BRCA2) and hormone receptor status (positive [HR+] vs. negative [HR−]) on clinical behavior and outcomes of mBRCA BC remains largely unknown. This is an international, multicenter, hospital-based, retrospective cohort study that included mBRCA patients diagnosed, between January 2000 and December 2012, with stage I–III invasive early BC at age ≤40 years. From 30 centers worldwide, 1236 young mBRCA BC patients were included. Among 808 and 428 patients with mBRCA1 or mBRCA2, 191 (23.6%) and 356 (83.2%) had HR+tumors, respectively (P

I explore a distinct perspective from that brought in the book by arguing that in postural control our organism selects the vigor of reactive responses guided by an optimization rule considering first the required postural response for balance recovery as indicated by afferent information from a myriad of sensory receptors, and second the history of previous responses to similar perturbations.

The microbial community interacting with a host can modulate the outcome of pathogenic infections. For instance, Wolbachia, one of the most prevalent invertebrate endosymbionts, strongly increases resistance of Drosophila melanogaster and other insect hosts, to many RNA viruses. D. melanogaster is also in continuous association with gut bacteria, whose role in antiviral immunity is poorly characterized. Here we asked how gut-colonizing bacteria impact viral titres and host survival, and how these interact with route of infection or Wolbachia presence. We compared germ-free flies and flies associated with two gut bacteria species recently isolated from wild flies (Acetobacter thailandicus and Lactobacillus brevis). We found that Wolbachia-conferred protection to both DCV or FHV is not affected by the presence or absence of these gut bacteria. Flies carrying A. thailandicus have lower DCV loads than germ-free flies, upon systemic infection, but reduced survival, indicating that these bacteria increase resistance to virus and decrease disease tolerance. Association with L. brevis, alone or in combination with A. thailandicus, did not lead to changes in survival to systemic infection. In contrast to the effect on systemic infection, we did not observe an impact of these bacteria on survival or viral loads after oral infection. Overall, the impact of gut-associated bacteria in resistance and tolerance to viruses was mild, when compared with Wolbachia. These results indicate that the effect of gut-associated bacteria to different viral infections, and different routes of infection, is complex and understanding it requires a detailed characterization of several parameters of infection.

In response to sudden perturbations of stance stability, muscles of both legs are activated for balance recovery. In conditions that one of the legs has a reduced capacity to respond, the opposite leg is predicted to compensate by responding more powerfully to restore stable upright stance. In this investigation, we aimed to evaluate between-leg compensatory control in automatic postural responses to sudden perturbations in a situation in which plantar flexor muscles of a single leg were fatigued. Young participants were evaluated in response to a series of perturbations inducing forward body sway, with a focus on activation of plantar flexor muscles: lateral and medial gastrocnemii and soleus. Muscular responses were analyzed through activation magnitude and latency of muscular activation onset. For evaluation of balance and postural stability, we also analyzed the center of pressure and upper trunk displacement and weight-bearing asymmetry between the legs. Responses were assessed in three conditions: pre-fatigue, under single-leg fatigue, and following the recovery of muscular function. Results showed (a) compensation of the non-fatigued leg through the increased magnitude of muscular activation in the first perturbation under fatigue; (b) adaptation in the non-fatigued leg over repetitive perturbations, with a progressive decrement of muscular activation over trials; and (c) maintenance of increased muscular activation of the non-fatigued leg following fatigue dissipation. These findings suggest that the central nervous system is able to modulate the descending motor drive individually for each leg's muscles apparently based on their potential contribution for the achievement of the behavioral aim of recovering stable body balance following stance perturbations.

People who are obese sustain very high foot pressures when standing, with potential consequences to their feet soles’ cutaneous sensibility. In the current investigation, we performed a detailed assessment of foot sole sensibility in women with morbid obesity ( n = 13; age = 38.85, SD = 8.09 years) status in comparison with leaner women ( n = 13; age = 37.62, SD = 7.10 years). We estimated tactile feet sole sensibility through graduated monofilament light touch applied at several hotspots of both feet soles, covering the toes, metatarsal heads, midfoot internal and lateral arches, and heel. Intergroup comparisons per foot sole region indicated significantly lower sensibility for the group with morbid obesity under the fifth and third metatarsal heads, midfoot lateral and internal arches and heel. We found a large variation across the sole regions, with the lowest difference between the obese and lean groups observed under the hallux (18%) and the largest difference observed under the lateral arch of the midfoot (76%). Correlation analyses between body weight and sensibility scores revealed a significant positive correlation among participants who were leaner ( rs = 0.56, p = 0.05) but not among participants who were obese ( rs = –0.06, p = 0.83). Mainly, our results showed that morbid obesity was associated with significantly higher cutaneous sensibility thresholds, with large variability of the sensibility deficit across different regions of both feet soles. Due to its functional relevance for body balance control, reduced sensibility thresholds among women who are morbidly obese may have implications for stance stability.