Horizontal running inside circular walls of Moon settlements: a comprehensive countermeasure for low-gravity deconditioning?

Long-lasting exposure to low gravity, such as in lunar settlements planned by the ongoing Artemis Program, elicits muscle hypotrophy, bone demineralization, cardio-respiratory and neuro-control deconditioning, against which optimal countermeasures are still to be designed. Rather than training selected muscle groups only, 'whole-body' activities such as locomotion seem better candidates, but at Moon gravity both 'pendular' walking and bouncing gaits like running exhibit abnormal dynamics at faster speeds. We theoretically and experimentally show that much greater self-generated artificial gravities can be experienced on the Moon by running horizontally inside a static 4.7 m radius cylinder (motorcyclists' 'Wall of Death' of amusement parks) at speeds preventing downward skidding. To emulate lunar gravity, 83% of body weight was unloaded by pre-tensed (36 m) bungee jumping bands. Participants unprecedentedly maintained horizontal fast running (5.4-6.5 m s-1) for a few circular laps, with intense metabolism (estimated as 54-74 mlO2 kg-1 min-1) and peak forces during foot contact, inferred by motion analysis, of 2-3 Earth body weight (corresponding to terrestrial running at 3-4 m s-1), high enough to prevent bone calcium resorption. A training regime of a few laps a day promises to be a viable countermeasure for astronauts to quickly combat whole-body deconditioning, for further missions and home return.

The work to swing limbs in humans versus chimpanzees and its relation to the metabolic cost of walking.

Compared to their closest ape relatives, humans walk bipedally with lower metabolic cost (C) and less mechanical work to move their body center of mass (external mechanical work, WEXT). However, differences in WEXT are not large enough to explain the observed lower C: humans may also do less work to move limbs relative to their body center of mass (internal kinetic mechanical work, WINT,k). From published data, we estimated differences in WINT,k, total mechanical work (WTOT), and efficiency between humans and chimpanzees walking bipedally. Estimated WINT,k is ~ 60% lower in humans due to changes in limb mass distribution, lower stride frequency and duty factor. When summing WINT,k to WEXT, between-species differences in efficiency are smaller than those in C; variations in WTOT correlate with between-species, but not within-species, differences in C. These results partially support the hypothesis that the low cost of human walking is due to the concerted low WINT,k and WEXT.

Identification of ADME genes polymorphic variants linked to trastuzumab-induced cardiotoxicity in breast cancer patients: Case series of mono-institutional experience.

BACKGROUND: Long-term survival induced by anticancer treatments discloses emerging frailty among breast cancer (BC) survivors. Trastuzumab-induced cardiotoxicity (TIC) is reported in at least 5% of HER2+BC patients. However, TIC mechanism remains unclear and predictive genetic biomarkers are still lacking. Interaction between systemic inflammation, cytokine release and ADME genes in cancer patients might contribute to explain mechanisms underlying individual susceptibility to TIC and drug response variability. We present a single institution case series to investigate the potential role of genetic variants in ADME genes in HER2+BC patients TIC experienced. METHODS: We selected data related to 40 HER2+ BC patients undergone to DMET genotyping of ADME constitutive variant profiling, with the aim to prospectively explore their potential role in developing TIC. Only 3 patients ("case series"), who experienced TIC, were compared to 37 "control group" matched patients cardiotoxicity-sparing. All patients underwent to left ventricular ejection fraction (LVEF) evaluation at diagnosis and during anti-HER2 therapy. Each single probe was clustered to detect SNPs related to cardiotoxicity. RESULTS: In this retrospective analysis, our 3 cases were homogeneous in terms of clinical-pathological characteristics, trastuzumab-based treatment and LVEF decline. We identified 9 polymorphic variants in 8 ADME genes (UGT1A1, UGT1A6, UGT1A7, UGT2B15, SLC22A1, CYP3A5, ABCC4, CYP2D6) potentially associated with TIC. CONCLUSION: Real-world TIC incidence is higher compared to randomized clinical trials and biomarkers with potential predictive value aren't available. Our preliminary data, as proof of concept, could suggest a predictive role of pharmacogenomic approach in the identification of cardiotoxicity risk biomarkers for anti-HER2 treatment.

The impact of PARP inhibitors in the whole scenario of ovarian cancer management: A systematic review and network meta-analysis.

BACKGROUND: Carboplatin is still the cornerstone of the first-line treatment in advanced Epithelial Ovarian Cancer (aEOC) management and the clinical response to platinum-derived agents remains the major predictor of long-term outcomes. PATIENT AND METHODS: We aimed to identify the best treatment of the aEOC in terms of efficacy and safety, considering all treatment phases. A systematic literature search has been done to compare all treatments in aEOC population. Randomized trials with available survival and safety data published in the 2011-2022 timeframe were enclosed. Only trials reporting the BRCA or HRD (Homologous Recombination Deficiency) status were considered. DATA EXTRACTION AND SYNTHESIS: A ranking of treatment schedules on the progression-free survival (PFS) endpoint was performed. The random-effect model was used to elaborate and extract data. The Network Meta-Analysis (NMA) by Bayesian model was performed by STATA v17. Data on PFS were extracted in terms of Hazard ratio with relative confidence intervals. RESULTS: This NMA involved 18 trials for a total of 9105 patients. Within 12 treatment groups, we performed 3 different sensitivity analyses including "all comers" Intention to Treat (ITT) population, BRCA-mutated (BRCAm), and HRD subgroups, respectively. Considering the SUCRA-reported cumulative PFS probabilities, we showed that in the ITT population, the inferred best treatment was niraparib plus bevacizumab with a SUCRA of 96.7. In the BRCAm subgroup, the best SUCRA was for olaparib plus chemotherapy (96,9). The HRD population showed an inferred best treatment for niraparib plus bevacizumab (SUCRA 98,4). Moreover, we reported a cumulative summary of PARPi toxicity, in which different 3-4 grade toxicity profiles were observed, despite the PARPi "class effect" in terms of efficacy. CONCLUSIONS: Considering all aEOC subgroups, the best therapeutical option was identified as PARPi plus chemotherapy and/or antiangiogenetic agents, suggesting the relevance of combinatory approaches based on molecular profile. This work underlines the potential value of "chemo-free" regimens to prolong the platinum-free interval (PFI).

Metabolic cost and mechanical work of walking in a virtual reality emulator.

PURPOSE: The purpose of this study was to investigate the metabolic cost (C), mechanical work, and kinematics of walking on a multidirectional treadmill designed for locomotion in virtual reality. METHODS: Ten participants (5 females, body mass 67.2 ± 8.1 kg, height 1.71 ± 0.07 m, age 23.6 ± 1.9 years, mean ± SD) walked on a Virtuix Omni multidirectional treadmill at four imposed stride frequencies: 0.70, 0.85, 1.00, and 1.15 Hz. A portable metabolic system measured oxygen uptake, enabling calculation of C and the metabolic equivalent of task (MET). Gait kinematics and external, internal, and total mechanical work (WTOT) were calculated by an optoelectronic system. Efficiency was calculated either as WTOT/C or by summing WTOT to the work against sliding frictions. Results were compared with normal walking, running, and skipping. RESULTS: C was higher for walking on the multidirectional treadmill than for normal walking, running, and skipping, and decreased with speed (best-fit equation: C = 20.2-27.5·speed + 15.8·speed2); the average MET was 4.6 ± 1.4. Mechanical work was higher at lower speeds, but similar to that of normal walking at higher speeds, with lower pendular energy recovery and efficiency; differences in efficiency were explained by the additional work against sliding frictions. At paired speeds, participants showed a more forward-leaned trunk and higher ankle dorsiflexion, stride frequency, and duty factor than normal walking. CONCLUSION: Walking on a multidirectional treadmill requires a higher metabolic cost and different mechanical work and kinematics than normal walking. This raises questions on its use for gait rehabilitation but highlights its potential for high-intensity exercise and physical activity promotion.

Arthroscopic capsular release for frozen shoulder: when etiology matters.

PURPOSE: No therapeutic intervention is universally accepted for frozen shoulder, and the most effective management to restore motion and diminish pain has yet to be defined. The aim of this study was to investigate functional and psychological outcomes in patients who underwent arthroscopic capsular release for a frozen shoulder. METHODS: A retrospective study with prospective data collection was conducted with 78 patients suffering from frozen shoulder resistance to conservative treatment. Considering the etiology, there were 36 (46.2%) idiopathic, 31 (39.7%) postoperative, and 11 (14.1%) posttraumatic cases. Preoperatively, each patient was evaluated with the range of motion (ROM) assessment and the Constant-Murley score (CMS). At follow-up, the 4-point subjective satisfaction scale (SSS), the ROM assessment, the SF-12 questionnaire, the numerical rating scale (NRS) for the subjective assessment of pain, the CMS and the Hospital Anxiety and Depression Scale (HADS) were assessed. RESULTS: After a mean follow-up of 54.2 ± 22.3 months, ROM and CMS showed a statistically significant improvement between pre- and postoperative values (all p < 0.001). Before surgery, the mean CMS was 36.9% that of sex- and age-matched healthy individuals, and all patients showed a CMS lower than the normative data. At the final follow-up visit, the mean CMS was 99.9% that of sex- and age-matched healthy individuals, and 49 (62.8%) patients showed a CMS equal to or higher than the normative data. The mean increase in the CMS was 56.1 ± 8.3 points. The mean SSS, HADS-A, HADS-D, and NRS were 3.7 ± 0.5, 2.5 ± 1.6, 2.2 ± 1.3, and 2.2 ± 1.0, respectively. All patients returned to their previous level of work and sports activity after 2 and 2.5 months, respectively. The multivariate analysis showed the association between a higher postoperative CMS and the idiopathic etiology of a frozen shoulder (p = 0.004, ß = 3.971). No intraoperative complications occurred. Postoperatively, four patients (5.1%) were treated with intra-articular steroid injections to manage residual symptoms. One patient (1.3%) with a postoperative frozen shoulder showed persistent symptoms and underwent a new successful arthroscopic capsular release. CONCLUSION: High patient satisfaction and statistically significant ROM and CMS recovery can be achieved after arthroscopic capsular release to manage frozen shoulder. Better functional outcomes are expected when the etiology is idiopathic. Results can help surgeons identify the patients who will most benefit from surgery and should be discussed with the patient. LEVEL OF EVIDENCE: III.

First-line systemic treatment for hepatocellular carcinoma: A systematic review and network meta-analysis.

The rapid development of novel therapeutic options for advanced hepatocellular carcinoma (aHCC) has generated some uncertainty about the rational choice of the systemic upfront treatment. So far, a variety of therapeutic strategies have been investigated, including the combination of immunecheckpoint inhibitors and anti-VEGF. To identify the treatment that should be preferred as front-line approach, we compared the efficacy and toxicity of a variety of therapeutic strategies. With this aim, we performed a systematic review and a meta-analysis of randomized clinical trials. OS, PFS, ORR and tolerability outcomes were considered, and for each outcome the treatment ranking was evaluated by the surface under the cumulative rankings (SUCRAs). Combination of Camrelizumab + Rivoceranib scored the best in OS, followed by Sintilimab + Bevacizumab, whereas Lenvatinib + Pembrolizumab showed higher probability to be the best treatment in PFS and Sintilimab + Bevacizumab performed best in ORR. Finally, Durvalumab is the most tolerated treatment.

Complementary use of statistical parametric mapping and gait profile score to describe walking alterations in multiple sclerosis: a cross-sectional study.

Gait analysis is often used to study locomotor alterations in people with multiple sclerosis (PwMS), but the large number of extracted variables challenges the interpretability. In this paper, we analysed gait alterations by combining the Gait Profile Score (GPS), which summarizes kinematic locomotor deviations, and Statistical Parametric Mapping (SPM), which compares kinematics and kinetics over the whole gait cycle. Eleven PwMS and 11 speed-matched Healthy Controls (HC) underwent overground gait analysis. GPS were compared through independent-samples t-tests; sagittal-plane kinematics and power at hip, knee, and ankle were compared through SPM Hotelling's-T2 and SPM t-tests. Spearman's correlation coefficients (r) between GPS and clinical outcomes were also calculated. PwMS had higher GPS than HC (PwMS = 8.74 ± 2.13°; HC = 5.01 ± 1.41°;p < 0.001). Multivariate SPM found statistically significant differences at 0-49%, 70-80%, and 93-99% of stride (p < 0.05) and univariate analysis showed reduced ankle dorsiflexion, and lower knee flexion during pre-swing and swing. GPS correlated with Expanded Disability Status Scale (r = 0.65; 95%C.I.[0.04,0.91]; p = 0.04) and 2-Minute Walking Test (r = -0.65; 95%C.I.[-0.91,-0.04]; p = 0.04). GPS in conjunction with SPM revealed multi-joint kinematic alterations on sagittal plane involving distal joint angles, ankle and knee, during the stance phase with no changes at the proximal level. Gait deviations were more pronounced in PwMS with higher disability and walking limitations.

COVID-19 Containment Measures-a Step Back for Walking Mobility? A 2-Year, 60-Country Analysis of the Apple Mobility Data.

BACKGROUND: COVID-19 containment measures curb viral spread but may hamper walking mobility. As a low daily step count is associated with increased noncommunicable diseases and mortality, assessing the relationship between pandemic responses and walking mobility can help trade-off public health measures. We investigated the association between containment stringency and walking mobility across 60 countries in the period between January 21, 2020 and January 21, 2022 and modeled how this could impact mortality hazard. METHODS: Walking mobility was measured through the Apple Mobility Trends, containment measures stringency index through the Oxford COVID-19 response tracker (which considers local policies on closures, healthcare, and economy), and meteorological data by National Oceanic and Atmospheric Administration weather stations. Walking mobility was regressed over stringency in a mixed-effect model with weather variables as covariates. The impact of stringency on all-cause mortality due to reduced mobility was modeled based on regression results, prepandemic walking mobility, and the association between step count and all-cause mortality hazard. RESULTS: Across the 60 countries, the average stringency was 55 (9) (mean [SD]) out of 100. Stringency was negatively associated with walking mobility; a log-linear model fitted data better than a linear one, with a regression coefficient for stringency on ln (walking mobility) (95% confidence interval) of  -1.201 × 10-2 (-1.221 × 10-2 to -1.183 × 10-2). Increasing stringency, thus decreasing walking mobility, nonlinearly incremented the modeled all-cause mortality hazard by up to ∼40%. CONCLUSIONS: In this study, walking mobility was negatively associated with containment measures stringency; the relationship between stringency, mobility, and the subsequent impact on health outcomes may be nonlinear. These findings can help in balancing pandemic containment policies.

Comparison of three-dimensional body centre of mass trajectories during locomotion through zero- and one-dimensional statistics.

The trajectory of the body centre of mass (BCoM) during locomotion differs through speeds, gaits and pathological states; statistical methods are needed to compare it among different conditions. Here, ten participants walked on treadmill at 1.1 and 1.4 m/s; BCoM trajectories were obtained through stereophotogrammetry and expressed as Fourier series. Trajectories were compared among speeds using (i) zero-dimensional (0D) linear and circular tests for difference on amplitudes and phases of Fourier series harmonic, (ii) one-dimensional statistical parametric mapping (1D-SPM) t-tests on the anteroposterior, mediolateral and vertical axial components of the BCoM trajectory and (iii) 1D-SPM Hotelling's T2 test on the three-dimensional BCoM trajectory. Increasing speed increased the amplitude and decreased the phase of the fundamental (2nd) vertical harmonic. Coherently, the BCoM vertical trajectory featured greater displacement and a forward-shift, combined with greater displacement along the anteroposterior axis. Hotelling's T2 1D-SPM on the whole trajectory featured supra-threshold clusters at the transition between double and single support, and mid of the single support. 0D and 1D test yielded coherent and complementary results: 1D-SPM Hotelling's T2 is suitable to compare whole three-dimensional BCoM trajectories; however, when researchers hypothesize that conditions may impact specific harmonics or axial components, 0D or 1D-SPM t-tests are recommended.

From the Lab to Real Life: Monitoring Cardiorespiratory Fitness during the COVID-19 Pandemic through Wearable Devices. An Exploratory Longitudinal Study on Healthy Participants.

COVID-19 containment measures hampered population cardiorespiratory fitness (which can be quantified as peak oxygen consumption (V.O2peak)) and the possibility to assess it using laboratory-based techniques. Although it is useful to ascertain the V.O2peak recovery after lockdowns, the community and most scientific institutions were unable to evaluate it. Wearable devices may provide the opportunity to estimate cardiorespiratory fitness outside of the laboratory, without breaking self-isolation; herein, we explore the feasibility of this approach. Fifteen healthy participants were tested every 2 weeks for 10 weeks during a reduction of containment measures after a strict lockdown. Physical activity levels were measured using the International Physical Activity Questionnaire-Short Form (IPAQ-SF). V.O2peak was estimated through a previously validated test based on the speed of a 60 m sprint run, the baseline-to-peak heart rate (HR) variation, and the velocity of HR decay after the sprint, and measured through a wearable HR monitor. Participants increased physical activity from the end of lockdown (1833 [917-2594] MET-min/week; median [1st quartile-3rd quartile]) until the end of follow-up (2730 [1325-3380] MET-min/week). The estimated V.O2peak increased by 0.24 ± 0.19 mL/(min*kg*week) (regression coefficient ± standard error). Based on previous knowledge on the impact of inactivity on V.O2peak, our study indicates that a 10-week period of reducing the stringency of containment measures may not be sufficient to counteract the detrimental effects of the preceding lockdown.

miR-221/222 as biomarkers and targets for therapeutic intervention on cancer and other diseases: A systematic review.

Among deregulated microRNAs (miRs) in human malignancies, miR-221 has been widely investigated for its oncogenic role and as a promising biomarker. Moreover, recent evidence suggests miR-221 as a fine-tuner of chronic liver injury and inflammation-related events. Available information also supports the potential of miR-221 silencing as promising therapeutic intervention. In this systematic review, we selected papers from the principal databases (PubMed, MedLine, Medscape, ASCO, ESMO) between January 2012 and December 2020, using the keywords "miR-221" and the specific keywords related to the most important hematologic and solid malignancies, and some non-malignant diseases, to define and characterize deregulated miR-221 as a valuable therapeutic target in the modern vision of molecular medicine. We found a major role of miR-221 in this view.

Spns2 Transporter Contributes to the Accumulation of S1P in Cystic Fibrosis Human Bronchial Epithelial Cells.

The role of S1P in Cystic Fibrosis (CF) has been investigated since 2001, when it was first described that the CFTR channel regulates the inward transport of S1P. From then on, various studies have associated F508del CFTR, the most frequent mutation in CF patients, with altered S1P expression in tissue and plasma. We found that human bronchial epithelial immortalized and primary cells from CF patients express more S1P than the control cells, as evidenced by mass spectrometry analysis. S1P accumulation relies on two- to four-fold transcriptional up-regulation of SphK1 and simultaneous halving of SGPL1 in CF vs. control cells. The reduction of SGPL1 transcription protects S1P from irreversible degradation, but the excessive accumulation is partially prevented by the action of the two phosphatases that are up-regulated compared to control cells. For the first time in CF, we describe that Spns2, a non-ATP dependent transporter that normally extrudes S1P out of the cells, shows deficient transcriptional and protein expression, thus impairing S1P accrual dissipation. The in vitro data on CF human bronchial epithelia correlates with the impaired expression of Spns2 observed in CF human lung biopsies compared to healthy control.

Sample size estimation in locomotion kinematics and electromyography for statistical parametric mapping.

In biomechanics, kinematic and electromyographic data can be represented as one-dimensional (1D) waveforms and compared by using 1D hypothesis tests. These statistical techniques are increasingly applied in the study of locomotion. However, although widely agreed as a key step to obtain reliable and replicable findings, no a priori sample size estimation is usually conducted. This can also be done in 1D tests by calculating the statistical power - i.e., the probability of rejecting the null hypothesis when it is false - by using statistical parametric mapping. With the present study we characterised the parameters needed to estimate sample size in locomotion, and how they impact on statistical power in 1D tests. First, noise and signal in kinematics and electromyography were defined using experimental data on locomotion in physiological and pathological participants. Then, 1D power analysis was performed in representative conditions, and a dataset of tabulated sample sizes was generated. Kinematic and electromyographic data showed a smooth Gaussian noise, with amplitude and full-width-at-half-maximum depending on the physiological or pathological condition, and the considered joint or muscle. Given a certain noise, statistical power increased i) with greater signal amplitude and signal full-width-at-half-maximum, ii) when setting a region of interest and iii) when using a paired (vs. unpaired) study design. The present work provides initial benchmarks for appropriate sampling in 1D hypothesis testing, meant to evaluate statistical power in 1D tests and assists sample size estimation in studies on locomotion.

Vitreous composition modification after transpalpebral electrical stimulation of the eye: Biochemical analysis.

Electrical stimulation (ES) of the eye represents a therapeutic approach in various clinical applications ranging from retinal dystrophies, age-related macular degeneration, retinal artery occlusion and nonarteritic ischemic optic neuropathy. In clinical practice, ES of the eye is mainly performed with a transcorneal or transpalpebral approach. These procedures are non-invasive and well-tolerated by the patients, reporting only minimal and transient adverse events, while serious adverse effects were not observed. Despite the growing literature on animal models, only clinical parameters have been investigated in humans and few data are available about biochemical changes induced by ES of the eye. The purpose of this study is to investigate the possible mechanism that regulates the beneficial effects of ES on retinal cells function and survival in humans. 28 patients undergoing pars plana vitrectomy (PPV) for idiopathic epiretinal membrane (iERM) were randomly divided in two groups: 13 patients were treated with transpalpebral ES before surgery and 15 underwent surgery with no prior treatment. Vitreous samples were collected for biochemical analysis during PPV. ES treatment leads to a reduction in the vitreous expression of both proinflammatory cytokines, namely IL-6 and IL-8, and proinflammatory lipid mediators, such as lysophosphatidylcholine. Indeed, we observed a 70% decrease of lysophosphatidylcholine 18:0, which has been proven to exert the greatest proinflammatory activities among the lysophosphatidylcholine class. The content of triglycerides is also affected and significantly decreased following ES application. The vitreous composition of patients undergoing PPV for iERM displays significant changes following ES treatment. Proinflammatory cytokines and bioactive lipid mediators expression decreases, suggesting an overall anti-inflammatory potential of ES. The investigation of the mechanism by which this treatment alters the retinal neurons leading to good outcomes is essential for supporting ES therapeutic application in various types of retinal diseases.

Diagnóstico de carcinoma urotelial durante estudio de bacteremia por Streptococcus gordonii / Diagnosis of uroepithelial carcinoma during bacteremia by Streptococcus gordonii

Resumen La bacteremia por Streptococcus gordonii es infrecuente. Su aislamiento en hemocultivo traduce alta significancia clínica y debe dirigir el abordaje diagnóstico hacia la búsqueda de entidades subyacentes como neoplasias hematológicas, cardiopatías valvulares, neumonía, alteraciones estructurales de cabeza y cuello, inmunosupresión, y otras condiciones asociadas. No se han identificado reportes en pacientes con neoplasia de vías urinarias como posible condicionante de bacteremia por este agente. Se describe el caso de un paciente que, durante el estudio de bacteremia por este microorganismo, fue diagnosticado de carcinoma urotelial de alto grado.

Abstract Streptococcus gordonii bacteremia is rare. Its isolation in blood culture translates into high clinical significance and the diagnostic approach should be directed towards the search for underlying entities such as hematologic malignancies, valvular heart disease, pneumonia, structural changes of the head and neck, immunosuppression and other related conditions. No reports have been identified in patients with urinary tract neoplasia as a possible condition of bacteremia by this agent. The case of a patient who was diagnosed with high-grade urothelial carcinoma during the study of bacteremia by this microorganism is described.

COVID-19 lockdown: Physical activity, sedentary behaviour and sleep in Italian medicine students.

AbstractCOVID-19 pandemic led many countries to implement lockdown measures. Italy declared lockdown from 9th March to 3rd May 2020, and universities shifted to online classes. Home confinement could prevent students from achieving the physical activity and sleep levels recommended for their psychophysical health, and medicine students are already known to be at risk of inactivity and reduced sleep due to their time-consuming curricula. This study aimed at describing medicine students' behaviours during lockdown and comparing them with pre-lockdown data and current recommendations. A cross-sectional questionnaire survey was conducted among 6th-year Italian medicine students (n = 714; age=25 ± 2 y; female: 62%; male: 38%) in October-November 2019. The same survey was repeated in 6th-year students during lockdown (n = 394; age=25 ± 2 y; female: 73%; male: 27%), and extended to 1st-5th year (total 1st-6th-year sample during lockdown: n = 1471; age=23 ± 2 y; female: 70%; male: 30%). International Physical Activity Questionnaire Short Form (IPAQ) and selected questions from Pittsburgh Sleep Quality Index were administered to evaluate physical activity, sitting and sleep time. Decreased physical activity, and increased sitting and sleep time were observed from pre- to during lockdown in 6th-year students (p<0.01). 1st-6th-year students featured 10 [8-12] hours sitting (median [Q1-Q3]) and an IPAQ score of 1170 [400-2348] MET-min/week. Even participants with higher physical activity featured high sitting time. Sleeping less than recommended (<7 h/night) was associated with more sitting time and less energies to perform daily activities. Strategies fostering compliance with current guidelines for physical activity, sedentary behaviour and sleep should be implemented, especially in case of a repeated or intermittent lockdown.

Activator protein-2 overexpression accounts for increased insulin receptor expression in human breast cancer.

Various studies have shown that the insulin receptor (IR) is increased in most human breast cancers, and both ligand-dependent malignant transformation and increased cell growth occur in cultured breast cells overexpressing the IR. However, although numerous in vivo and in vitro observations have indicated an important contributory role for the IR in breast cancer cell biology, the molecular mechanisms accounting for increased IR expression in breast tumors have not previously been elucidated. Herein, we did immunoblot analyses of nuclear protein from cultured breast cancer cells and normal and tumoral tissues from breast cancer patients combined with promoter studies by using a series of human wild-type and mutant IR promoter constructs. We provide evidence that IR overexpression in breast cancer is dependent on the assembly of a transcriptionally active multiprotein-DNA complex, which includes the high-mobility group A1 (HMGA1) protein, the developmentally regulated activator protein-2 (AP-2) transcription factor and the ubiquitously expressed transcription factor Sp1. In cultured breast cancer cells and human breast cancer specimens, the expression of AP-2 was significantly higher than that observed in cells and tissues derived from normal breast, and this overexpression paralleled the increase in IR expression. However, AP-2 DNA-binding activity was undetectable with the IR gene promoter, suggesting that transactivation of this gene by AP-2 might occur indirectly through physical and functional cooperation with HMGA1 and Sp1. Our findings support this hypothesis and suggest that in affected individuals, hyperactivation of the AP-2 gene through the overexpression of IR may play a key role in breast carcinogenesis.