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Abstract Phosphorus pentamers (cyclo-P5) are unstable in nature but can be synthesized at the Ag(111) surface. Unlike monolayer black phosphorous, little is known about their electronic properties when in contact with metal electrodes, although this is crucial for future applications. Here, we characterize the atomic structure of cyclo-P5 assembled on Ag(111) using atomic force microscopy with functionalized tips and density functional theory. Combining force and tunneling spectroscopy, we find that a strong charge transfer induces an inward dipole moment at the cyclo-P5/Ag interface as well as the formation of an interface state. We probe the image potential states by field-effect resonant tunneling and quantify the increase of the local change of work function of 0.46 eV at the cyclo-P5 assembly. Our experimental approach suggest that the cyclo-P5/Ag interface has the characteristic ingredients of a p-type semiconductor-metal Schottky junction with potential applications in field-effect transistors, diodes, or solar cells.

The catalytically inactive caspase-8-homologous protein, c-FLIP, is a potent antiapoptotic protein highly expressed in various types of cancers. c-FLIP competes with caspase-8 for binding to the adaptor protein FADD (Fas-Associated Death Domain) following death receptors’ (DRs) activation via the ligands of the TNF-R family. As a consequence, the extrinsic apoptotic signaling pathway involving DRs is inhibited. The inhibition of c-FLIP activity in tumor cells might enhance DR-mediated apoptosis and overcome immune and anticancer drug resistance. Based on an in silico approach, the aim of this work was to identify new small inhibitory molecules able to bind selectively to c-FLIP and block its anti-apoptotic activity. Using a homology 3D model of c-FLIP, an in silico screening of 1880 compounds from the NCI database (National Cancer Institute) was performed. Nine molecules were selected for in vitro assays, based on their binding affinity to c-FLIP and their high selectivity compared to caspase-8. These molecules selectively bind to the Death Effector Domain 2 (DED2) of c-FLIP. We have tested in vitro the inhibitory effect of these nine molecules using the human lung cancer cell line H1703, overexpressing c-FLIP. Our results showed that six of these newly identified compounds efficiently prevent FADD/c-FLIP interactions in a molecular pull-down assay, as well as in a DISC immunoprecipitation assay. The overexpression of c-FLIP in H1703 prevents TRAIL-mediated apoptosis; however, a combination of TRAIL with these selected molecules significantly restored TRAIL-induced cell death by rescuing caspase cleavage and activation. Altogether, our findings indicate that new inhibitory chemical molecules efficiently prevent c-FLIP recruitment into the DISC complex, thus restoring the caspase-8-dependent apoptotic cascade. These results pave the way to design new c-FLIP inhibitory molecules that may serve as anticancer agents in tumors overexpressing c-FLIP.

The onset of deafblindness profoundly impacts both the individual with this condition and the individual’s family, including siblings. While current studies have primarily focused on the impact felt by parents or spouses, the distinct experiences of siblings have received comparatively less attention. This systematic review addresses the existing research gap regarding the psychological and social consequences experienced by siblings of individuals with deafblindness. A comprehensive search was conducted across multiple electronic databases, including PsycINFO, PsycARTICLES, Dissertations & Theses (on ProQuest), ERIC (Education Resources Information Center), International Bibliography of the Social Sciences (IBSS), Sociological Abstracts, Google Scholar, PubMed, and Cairn Info. Seven studies were identified as meeting the eligibility criteria for inclusion. The review revealed that siblings of individuals with deafblindness face psychological and social challenges, including emotions such as feelings of neglect, resentment, embarrassment, jealousy, and anxiety. Siblings also grapple with communication difficulties, contributing to feelings of exclusion and insecurity. In addition, these siblings take on significant responsibilities within the family and encounter obstacles in forming relationships outside the family. These findings underscore the need of interventions to improve the well-being of siblings of individuals with deafblindness by addressing their psycho-emotional needs and promoting positive social interactions. These findings align with studies conducted on siblings of children with other disabilities. However, additional research is crucial to investigate overlooked dimensions, particularly positive factors like coping mechanisms and resilience, that may influence the mental health and social experiences of these siblings.

Lung cancer is one of the most common and deadliest cancers. Preclinical models are essential to study new therapies and combinations taking tumor genetics into account. We have established cell lines expressing the luciferase gene from lines with varied genetic backgrounds, commonly encountered in patients with pulmonary adenocarcinoma. We have characterized these lines by testing their response to multiple drugs. Thus, we have developed orthotopic preclinical mouse models of NSCLC with very high engraftment efficiency. These models allow the easy monitoring of tumor growth, particularly in response to treatment, and of tumor cells dissemination in the body. We show that concomitant treatment with osimertinib (3rd generation tyrosine kinase inhibitor targeting mutated EGFR) and bevacizumab (anti-angiogenic targeting VEGF) can have a beneficial therapeutic effect on EGFR-mutated tumors. We also show that the addition of afatinib to osimertinib-treated tumors in escape leads to tumor growth inhibition. No such effect is observed with selumetinib or simvastatin. These preclinical mouse models therefore make it possible to test innovative therapeutic combinations and are also a tool of choice for studying resistance mechanisms.

Abstract Electron-vibration coupling is of critical importance for the development of molecular electronics, spintronics, and quantum technologies, as it affects transport properties and spin dynamics. The control over charge-state transitions and subsequent molecular vibrations using scanning tunneling microscopy typically requires the use of a decoupling layer. Here we show the vibronic excitations of tetrabromotetraazapyrene (TBTAP) molecules directly adsorbed on Ag(111) into an orientational glassy phase. The electron-deficient TBTAP is singly-occupied by an electron donated from the substrate, resulting in a spin 1/2 state, which is confirmed by a Kondo resonance. The TBTAP•− discharge is controlled by tip-gating and leads to a series of peaks in scanning tunneling spectroscopy. These occurrences are explained by combining a double-barrier tunneling junction with a Franck-Condon model including molecular vibrational modes. This work demonstrates that suitable precursor design enables gate-dependent vibrational excitations of molecules on a metal, thereby providing a method to investigate electron-vibration coupling in molecular assemblies without a decoupling layer.

Léon Cordes (1913-1985) est imprégné d’un héritage culturel où se mêlent, de Minerve à Argeliers, le souvenir des cathares, la Croisade menée contre eux au XIIIème siècle, et, tout proche, celui de la révolte vigneronne de 1907. Dès les années 1930, il prend part à l’éclosion d’un occitanisme entièrement renouvelé, aux côtés de Charles Camproux, puis de Robert Lafont et Max Rouquette. Auteur de théâtre et rédacteur de revues, poète sensible, il revendique le profil singulier d’un paysan viscéralement lié à sa terre, mais maîtrisant toutes les disciplines littéraires pour s’engager par la création dans la défense et le développement d’une langue et d’une civilisation occitanes passionnément vécues. Le présent article, né de l’admiration et de l’amitié, s’efforce de restituer les grandes étapes d’un parcours insuffisamment reconnu, celui d’un écrivain-paysan dont le profond enracinement s’est accompagné d’une ouverture délibérée à la modernité. Resumit Léon Còrdas (1913-1985) es impregnat d’un eiretatge cultural ont se mesclan, de Menerba a Argeliers, lo sovenir dels catars, de la Crosada menada contra elis al segle XIIIen, e, tot proche lo de la granda revolta vinhairona de 1907. Tre las annadas 1930, participa a l’espeliment d’un occitanisme completament renovat, amb Carles Camprós, puèi Robert Lafont e Max Roqueta. Autor de teatre e redactor de revistas, poeta sensible, se reclama del perfil singular d’un païsan viscèralament ligat a sa terra, mas mestrejant totas las disciplinas literairas per s’engatjar al mejan de la creacion dins la defensa e lo desvolopament d’una lenga e d’una civilisacion occitans viscudas amb passion. Aquel article, nascut d’admiracion e d’amistat, vòl far reviure las grandas estapas d’un trajecte pas pro reconegut, lo d’un escrivan-païsan que son enrasigament prigond es ligat amb una dobertura volguda a la modernitat.

IntroductionAn unprecedented amount of Earth Observations and in-situ data has become available in recent decades, opening up the possibility of developing scalable and practical solutions to assess and monitor ecosystems across the globe. Essential Biodiversity Variables are an example of the integration between Earth Observations and in-situ data for monitoring biodiversity and ecosystem integrity, with applicability to assess and monitor ecosystem structure, function, and composition. However, studies have yet to explore how such metrics can be organized in an effective workflow to create a composite Ecosystem Integrity Index and differentiate between local plots at the global scale.MethodsUsing available Essential Biodiversity Variables, we present and test a framework to assess and monitor forest ecosystem integrity at the global scale. We first defined the theoretical framework used to develop the workflow. We then measured ecosystem integrity across 333 forest plots of 5 km2. We classified the plots across the globe using two main categories of ecosystem integrity (Top and Down) defined using different Essential Biodiversity Variables.Results and discussion:We found that ecosystem integrity was significantly higher in forest plots located in more intact areas than in forest plots with higher disturbance. On average, intact forests had an Ecosystem Integrity Index score of 5.88 (CI: 5.53–6.23), whereas higher disturbance lowered the average to 4.97 (CI: 4.67–5.26). Knowing the state and changes in forest ecosystem integrity may help to deliver funding to priority areas that would benefit from mitigation strategies targeting climate change and biodiversity loss. This study may further provide decision- and policymakers with relevant information about the effectiveness of forest management and policies concerning forests. Our proposed method provides a flexible and scalable solution that facilitates the integration of essential biodiversity variables to monitor forest ecosystems.

Abstract Circulating tumor cells (CTC) have been studied in various solid tumors but clinical utility of CTC in small cell lung cancer (SCLC) remains unclear. The aim of the CTC-CPC study was to develop an EpCAM-independent CTC isolation method allowing isolation of a broader range of living CTC from SCLC and decipher their genomic and biological characteristics. CTC-CPC is a monocentric prospective non-interventional study including treatment-naïve newly diagnosed SCLC. CD56+ CTC were isolated from whole blood samples, at diagnosis and relapse after first-line treatment and submitted to whole-exome-sequencing (WES). Phenotypic study confirms tumor lineage and tumorigenic properties of isolated cells for the 4 patients analyzed with WES. WES of CD56+ CTC and matched tumor biopsy reveal genomic alteration frequently impaired in SCLC. At diagnosis CD56+ CTC were characterized by a high mutation load, a distinct mutational profile and a unique genomic signature, compared to match tumors biopsies. In addition to classical pathways altered in SCLC, we found new biological processes specifically affected in CD56+ CTC at diagnosis. High numeration of CD56+ CTC (> 7/ml) at diagnosis was associated with ES-SCLC. Comparing CD56+ CTC isolated at diagnosis and relapse, we identify differentially altered oncogenic pathways (e.g. DLL3 or MAPK pathway). We report a versatile method of CD56+ CTC detection in SCLC. Numeration of CD56+ CTC at diagnosis is correlated with disease extension. Isolated CD56+ CTC are tumorigenic and show a distinct mutational profile. We report a minimal gene set as a unique signature of CD56+ CTC and identify new affected biological pathways enriched in EpCAM-independent isolated CTC in SCLC.

Abstract Background The medium-term impact of the COVID-19 pandemic on the wellbeing of children and adolescents remains unclear. More than 2 years into the pandemic, we aimed to quantify the frequency and determinants of having been severely impacted by the COVID-19 pandemic and estimate its impact on health-related quality of life (HRQoL) and mental health. Methods Data was drawn from a population-based cohort of children and adolescents, recruited between December 2021 and June 2022, in Geneva, Switzerland. The Coronavirus impact scale was used to assess the multidimensional impact of the pandemic on children through parent’s report. A score higher than one standard deviation above the mean was deemed a severe impact. Parents additionally reported about their offspring HRQoL and mental health with validated scales. Determinants of having been severely impacted were assessed with logistic models, as were the associations between having experienced a severe impact and poor HRQoL or mental health. Results Out of 2101 participants aged 2–17, 12.7% had experienced a severe pandemic impact. Having a lasting health condition, a pandemic-related worsening of lifestyle habits or an unfavorable family environment were associated with having been severely impacted by the pandemic, while a previous anti-SARS-CoV-2 infection was not. Participants who had experienced a severe pandemic impact were more likely to present poor HRQoL (aOR = 3.1; 95% CI 2.3–4.4) and poor mental health (aOR = 3.9; 95% CI 2.5–6.2). Conclusion The COVID-19 pandemic may have persistent consequences on the wellbeing of children and adolescents, especially among those with health and family vulnerabilities.

Abstract Global climate changes may cause profound effects on species adaptation, particularly in ectotherms for whom even moderate warmer temperatures can lead to disproportionate heat failure. Still, several organisms evolved to endure high desert temperatures. Here, we describe the thermal tolerance survival and the transcriptomic heat stress response of three genera of desert (Cataglyphis, Melophorus, and Ocymyrmex) and two of temperate ants (Formica and Myrmica) and explore convergent and specific adaptations. We found heat stress led to either a reactive or a constitutive response in desert ants: Cataglyphis holgerseni and Melophorus bagoti differentially regulated very few transcripts in response to heat (0.12% and 0.14%, respectively), while Cataglyphis bombycina and Ocymyrmex robustior responded with greater expression alterations (respectively affecting 0.6% and 1.53% of their transcriptomes). These two responsive mechanisms—reactive and constitutive—were related to individual thermal tolerance survival and convergently evolved in distinct desert ant genera. Moreover, in comparison with desert species, the two temperate ants differentially expressed thousands of transcripts more in response to heat stress (affecting 8% and 12.71% of F. fusca and Myr. sabuleti transcriptomes). In summary, we show that heat adaptation in thermophilic ants involved changes in the expression response. Overall, desert ants show reduced transcriptional alterations even when under high thermal stress, and their expression response may be either constitutive or reactive to temperature increase.

Background: Children and adolescents are highly vulnerable to the impact of sustained stressors during developmentally sensitive times. We investigated how demographic characteristics intersect with socioeconomic dimensions to shape the social patterning of quality of life and mental health in children and adolescents, two years into the COVID-19 pandemic. Methods: We used data from the prospective SEROCoV-KIDS cohort study of children and adolescents living in Geneva (Switzerland, 2022). We conducted an intersectional Multilevel Analysis of Individual Heterogeneity and Discriminatory Accuracy by nesting participants within 48 social strata defined by intersecting sex, age, immigrant background, parental education and financial hardship in Bayesian multilevel logistic models for poor health-related quality of life (HRQoL, measured with PedsQL) and mental health difficulties (measured with the Strengths and Difficulties Questionnaire). Results: Among participants aged 2–17 years, 240/2096 (11.5%, 95%CI 10.1–12.9) had poor HRQoL and 105/2135 (4.9%, 95%CI 4.0–5.9) had mental health difficulties. The predicted proportion of poor HRQoL ranged from 3.4% for 6–11 years old Swiss girls with highly educated parents and no financial hardship to 34.6% for 12–17 years old non-Swiss girls with highly educated parents and financial hardship. Intersectional strata involving adolescents and financial hardship showed substantially worse HRQoL than their counterparts. Between-stratum variations in the predicted frequency of mental health difficulties were limited (range 4.4%–6.5%). Conclusions: We found considerable differences in adverse outcomes across social strata. Our results suggest that, post-pandemic, interventions to address social inequities in HRQoL should focus on specific intersectional strata involving adolescents and families experiencing financial hardship, while those aiming to improve mental health should target all children and adolescents.

The COVID-19 pandemic has dramatically changed psychotherapy practices. Psychotherapy around the world has shifted from predominantly face-to-face settings to overwhelmingly online settings since the beginning of the pandemic. Many studies have been published on this topic, but there has been no review of the literature focused on the experience of psychotherapists. Our goal was to identify the challenging issues of teletherapy, including the efficiency of online consultations and the extent to which they are accepted by therapists and patients. A PubMed literature search using the [(“Teletherapy” OR “Telebehavioral health” OR “telepsychotherapy”) AND (“COVID-19”)] search string retrieved 46 studies focused on mental health professionals, as detailed in a PRISMA flow diagram. Two reviewers independently screened the abstracts and excluded those that were outside the scope of the review. The selection of articles kept for review was discussed by all three authors. Overall, the review contributes to the description and evaluation of tele mental health services, including teletherapy, online counseling, digital mental health tools, and remote monitoring.

Catalytic methane combustion was carried out over YSZ, Pd/YSZ and Rh/YSZ between 200 and 700 °C. Despite similar light-off curves for Pd/YSZ and Rh/YSZ between 200 and 450 °C, isotopic exchange experiments using CD4 and 18O2 revealed different behaviour of both supported catalysts regarding the activation of reactant molecules. The use of C18O2 isotopic gas was shown to be more appropriate than 18O2 to evaluate the bulk oxygen mobility in YSZ at low temperatures. The exchange of gaseous CO2 with lattice YSZ oxygen atoms, which occurs via surface hydrogen carbonate intermediate species, allowed to demonstrate the contribution of bulk oxygen atoms of YSZ in Rh/YSZ at low temperatures.

The post-acute impacts of COVID-19 in children and adolescents are not well understood. In this population-based study in Geneva, the authors find evidence of COVID-19-related symptom persistence beyond 12 weeks in adolescents, and identify chronic conditions and lower socioeconomic status as risk factors.

Summary: Antigen selection and prioritization represent crucial determinants of vaccines’ efficacy. Here, we compare two personalized dendritic cell-based vaccination strategies using whole-tumor lysate or neoantigens. Data in mouse and in cancer patients demonstrate that peptide vaccines using neoantigens predicted on the sole basis of in silico peptide-major histocompatibility complex (MHC) binding affinity underperform relative to whole-tumor-lysate vaccines. In contrast, effective in vitro peptide-MHC binding affinity and peptide immunogenicity significantly improve the prioritization of tumor-rejecting neoepitopes and result in more efficacious vaccines.

Abstract Climate change adaptation and mitigation strategies are gaining visibility and support. Decision-makers are defending the extension of large infrastructures that are low greenhouse gas (GHG) emitters, as a way to act quickly and massively without calling into question existing economic models. This situation depoliticizes these projects, masking their other ecological consequences such as their impacts on biodiversity. This article examines how promoters of these projects depoliticized its socio-technical futures while other actors re-politicized them. Using the example of the Seine Nord Europe Canal project, we show a politicization of the territorial future and a depoliticization of the environmental future. This depoliticization is based on the techno-optimist discourse promoting large-scale infrastructures as the only possible solution to the global ecological and climate crisis. It uses a selective framing of the environment that makes some elements visible and others invisible. We conducted semi-structured interviews with biodiversity stakeholders in the territories that would be impacted by the canal. Based on the concepts of environmental forms and motives, we reconstructed the environmental ontologies ignored by the dominant discourse and assembled them into three alternative scenarios. We present the method of investigation and identification of these motives and discuss the likelihood of the constructed scenarios participating in a re-politicization based on the reactions of various actors.

Breast cancer is one of the most prevalent cancers worldwide and pathologists are closely involved in establishing a diagnosis. Tools to assist in making a diagnosis are required to manage the increasing workload. In this context, artificial intelligence (AI) and deep-learning based tools may be used in daily pathology practice. However, it is challenging to develop fast and reliable algorithms that can be trusted by practitioners, whatever the medical center. We describe a patch-based algorithm that incorporates a convolutional neural network to detect and locate invasive carcinoma on breast whole-slide images. The network was trained on a dataset extracted from a reference acquisition center. We then performed a calibration step based on transfer learning to maintain the performance when translating on a new target acquisition center by using a limited amount of additional training data. Performance was evaluated using classical binary measures (accuracy, recall, precision) for both centers (referred to as "test reference dataset" and "test target dataset") and at two levels: patch and slide level. At patch level, accuracy, recall, and precision of the model on the reference and target test sets were 92.1% and 96.3%, 95% and 87.8%, and 73.9% and 70.6%, respectively. At slide level, accuracy, recall, and precision were 97.6% and 92.0%, 90.9% and 100%, and 100% and 70.8% for test sets 1 and 2, respectively. The high performance of the algorithm at both centers shows that the calibration process is efficient. This is performed using limited training data from the new target acquisition center and requires that the model is trained beforehand on a large database from a reference center. This methodology allows the implementation of AI diagnostic tools to help in routine pathology practice.

Abstract Background HIV patients face considerable acute and chronic healthcare needs and battling the HIV epidemic remains of the utmost importance. By focusing on health outcomes in relation to the cost of care, value-based healthcare (VBHC) proposes a strategy to optimize quality of care and cost-efficiency. Its implementation may provide an answer to the increasing pressure to optimize spending in healthcare while improving patient outcomes. This paper describes a pragmatic value-based healthcare framework for HIV care. Methods A value-based HIV healthcare framework was developed during a series of roundtable discussions bringing together 16 clinical stakeholder representatives from the Belgian HIV reference centers and 2 VBHC specialists. Each round of discussions was focused on a central question translating a concept or idea to the next level of practical implementation: 1) how can VBHC principles be translated into value-based HIV care drivers; 2) how can these value-based HIV care divers be translated into value-based care objectives and activities; and 3) how can value-based HIV care objectives and activities be translated into value-based care indicators. Value drivers were linked to concrete objectives and activities using a logical framework approach. Finally, specific, measurable, and acceptable structure, process and outcomes indicators were defined to complement the framework. Results Our framework identifies 4 core value areas where HIV care would benefit most from improvements: Prevention, improvement of the cascade of care, providing patient-centered HIV care and sustaining a state-of-the-art HIV disease management context. These 4 core value areas were translated into 12 actionable core value objectives. For each objective, example activities were proposed. Indicators are suggested for each level of the framework (outcome indicators for value areas and objectives, process indicators for suggested activities). Conclusions This framework approach outlines how to define a patient- and public health centered value-based HIV care paradigm. It proposes how to translate core value drivers to practical objectives and activities and suggests defining indicators that can be used to track and improve the framework’s implementation in practice.

Topological superconductivity emerging in one- or two-dimensional hybrid materials is predicted as a key ingredient for quantum computing. However, not only the design of complex heterostructures is primordial for future applications but also the characterization of their electronic and structural properties at the atomic scale using the most advanced scanning probe microscopy techniques with functionalized tips. We report on the topographic signatures observed by scanning tunneling microscopy (STM) of carbon monoxide (CO) molecules, iron (Fe) atoms and sodium chloride (NaCl) islands deposited on superconducting Pb(111). For the CO adsorption a comparison with the Pb(110) substrate is demonstrated. We show a general propensity of these adsorbates to diffuse at low temperature under gentle scanning conditions. Our findings provide new insights into high-resolution probe microscopy imaging with terminated tips, decoupling atoms and molecules by NaCl islands or tip-induced lateral manipulation of iron atoms on top of the prototypical Pb(111) superconducting surface.

In the context of climate change and sea-level rise, coastal realignment consists in reopening polders to marine waters to favor ‘nature-based’ mitigation measures. Such operations have consequences on biodiversity, which vary depending on the parameters studied and site features. In this study, a multimetric indicator aiming to evaluate and predict the potential ecological quality of sites undergoing a realignment operation was developed. This indicator is based on the combination of two tools, (i) a biological-capacity matrix to assess the importance of different habitats of a defined typology for taxonomical, patrimonial and functional parameters; (ii) habitat maps obtained by photointerpretation for past habitats, by machine learning using space-borne imagery for present habitats and by forecasting using submersion models for future habitats. The indicator is presented in the form of a radar chart, with each axis corresponding to one parameter of the biological-capacity matrix and highlighting its different values for different coastal-realignment scenarios or different time horizons.

Bells are made of bronze, an alloy of copper and tin. Art objects and musical instruments belong to tangible and intangible heritage. The effect of atmospheric alteration on their sound is not well documented. To address this question, alteration cycles of bronze specimens are performed in a chamber reproducing a realistic polluted coastal atmosphere. The corrosion layers are characterized by X-ray diffraction, electron microscopy and X-ray photoelectron spectrometry. The buried interface of the film (alloy-layer interface) is formed by a thin, adherent and micro-cracked layer, mainly composed of sulfates, copper oxide and chloride, on top of tin corrosion products. Near the atmosphere-film interface, less adherent irregular clusters of soot, calcite, gypsum and halite developed. Through these observations, an alteration scenario is proposed. To correlate the bronze corrosion effect on the bell sound, linear and nonlinear resonance experiments are performed on the corroded bronze specimens, where resonance parameters are monitored as a function of increasing driving force using a shaker. Results show that the corrosion effect on the acoustic properties can be monitored through the evolution of the acoustic nonlinear parameters (damping and resonance). These well-calibrated original experiments confirm the effect of corrosion on the acoustic properties of bronze.

Abstract Background Osimertinib is a third generation tyrosine kinase inhibitor (TKI) that targets the epidermal growth factor receptor (EGFR) in lung cancer. However, although this molecule is not subject to some of the resistance mechanisms observed in response to first generation TKIs, ultimately, patients relapse because of unknown resistance mechanisms. New relevant non-small cell lung cancer (NSCLC) mice models are therefore required to allow the analysis of these resistance mechanisms and to evaluate the efficacy of new therapeutic strategies. Methods Briefly, PC-9 cells, previously modified for luciferase expression, were injected into the tail vein of mice. Tumor implantation and longitudinal growth, almost exclusively localized in the lung, were evaluated by bioluminescence. Once established, the tumor was treated with osimertinib until tumor escape and development of bone metastases. Results Micro-metastases were detected by bioluminescence and collected for further analysis. Conclusion We describe an orthotopic model of NSCLC protocol that led to lung primary tumor nesting and, after osimertinib treatment, by metastases dissemination, and that allow the isolation of these small osimertinib-resistant micro-metastases. This model provides new biological tools to study tumor progression from the establishment of a lung tumor to the generation of drug-resistant micro-metastases, mimicking the natural course of the disease in human NSCLC patients.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are currently recommended as first-line treatment for advanced non-small-cell lung cancer (NSCLC) with EGFR-activating mutations. Third-generation (3rd G) EGFR-TKIs, including osimertinib, offer an effective treatment option for patients with NSCLC resistant 1st and 2nd EGFR-TKIs. However, the efficacy of 3rd G EGFR-TKIs is limited by acquired resistance that has become a growing clinical challenge. Several clinical and preclinical studies are being carried out to better understand the mechanisms of resistance to 3rd G EGFR-TKIs and have revealed various genetic aberrations associated with molecular heterogeneity of cancer cells. Studies focusing on epigenetic events are limited despite several indications of their involvement in the development of resistance. Preclinical models, established in most cases in a similar manner, have shown different prevalence of resistance mechanisms from clinical samples. Clinically identified mechanisms include EGFR mutations that were not identified in preclinical models. Thus, NRAS genetic alterations were not observed in patients but have been described in cell lines resistant to 3rd G EGFR-TKI. Mainly, resistance to 3rd G EGFR-TKI in preclinical models is related to the activation of alternative signaling pathways through tyrosine kinase receptor (TKR) activation or to histological and phenotypic transformations. Yet, preclinical models have provided some insight into the complex network between dominant drivers and associated events that lead to the emergence of resistance and consequently have identified new therapeutic targets. This review provides an overview of preclinical studies developed to investigate the mechanisms of acquired resistance to 3rd G EGFR-TKIs, including osimertinib and rociletinib, across all lines of therapy. In fact, some of the models described were first generated to be resistant to first- and second-generation EGFR-TKIs and often carried the T790M mutation, while others had never been exposed to TKIs. The review further describes the therapeutic opportunities to overcome resistance, based on preclinical studies.

Abstract Background CP12 is a small chloroplast protein that is widespread in various photosynthetic organisms and is an actor of the redox signaling pathway involved in the regulation of the Calvin Benson Bassham (CBB) cycle. The gene encoding this protein is conserved in many diatoms, but the protein has been overlooked in these organisms, despite their ecological importance and their complex and still enigmatic evolutionary background. Methods A combination of biochemical, bioinformatics and biophysical methods including electrospray ionization-mass spectrometry, circular dichroism, nuclear magnetic resonance spectroscopy and small X ray scattering, was used to characterize a diatom CP12. Results Here, we demonstrate that CP12 is expressed in the marine diatom Thalassiosira pseudonana constitutively in dark-treated and in continuous light-treated cells as well as in all growth phases. This CP12 similarly to its homologues in other species has some features of intrinsically disorder protein family: it behaves abnormally under gel electrophoresis and size exclusion chromatography, has a high net charge and a bias amino acid composition. By contrast, unlike other known CP12 proteins that are monomers, this protein is a dimer as suggested by native electrospray ionization-mass spectrometry and small angle X-ray scattering. In addition, small angle X-ray scattering revealed that this CP12 is an elongated cylinder with kinks. Circular dichroism spectra indicated that CP12 has a high content of α-helices, and nuclear magnetic resonance spectroscopy suggested that these helices are unstable and dynamic within a millisecond timescale. Together with in silico predictions, these results suggest that T. pseudonana CP12 has both coiled coil and disordered regions. Conclusions These findings bring new insights into the large family of dynamic proteins containing disordered regions, thus increasing the diversity of known CP12 proteins. As it is a protein that is more abundant in many stresses, it is not devoted to one metabolism and in particular, it is not specific to carbon metabolism. This raises questions about the role of this protein in addition to the well-established regulation of the CBB cycle. Choregraphy of metabolism by CP12 proteins in Viridiplantae and Heterokonta. While the monomeric CP12 in Viridiplantae is involved in carbon assimilation, regulating phosphoribulokinase (PRK) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) through the formation of a ternary complex, in Heterokonta studied so far, the dimeric CP12 is associated with Ferredoxin-NADP reductase (FNR) and GAPDH. The Viridiplantae CP12 can bind metal ions and can be a chaperone, the Heterokonta CP12 is more abundant in all stresses (C, N, Si, P limited conditions) and is not specific to a metabolism. Video Abstract

Tailor-made and designed micro- and nanocarriers can bring significant benefits over their traditional macroscopic counterparts in drug delivery applications. For the successful loading and subsequent release of bioactive compounds, carriers should present a high loading capacity, trigger release mechanisms, biodegradability and biocompatibility. Hydrophobic drug molecules can accumulate in fat tissues, resulting in drawbacks for the patient’s recovery. To address these issues, we propose to combine the advantageous features of both host molecules (cyclodextrin) and calcium carbonate (CaCO3) particles in order to load hydrophobic chemicals. Herein, hybrid cyclodextrin-CaCO3 micro- to nano-particles have been fabricated by combining Na2CO3 solution and CaCl2 solution in the presence of an additive, namely poly (vinylsulfonic acid) (PVSA) or glycerol (gly). By investigating experimental parameters and keeping the Na2CO3 and CaCl2 concentrations constant (0.33 M), we have evidenced that the PVSA or gly concentration and mixing time have a direct impact on the final cyclodextrine-CaCO3 particle size. Indeed, by increasing the concentration of PVSA (5 mM to 30 mM) or gly (0.7 mM to 4 mM) or the reaction time (from 10 min to 4 h), particles with a size of 200 nm could be reached. Interestingly, the vaterite or calcite form could also be selected, according to the experimental conditions. We hypothesised that the incorporation of PVSA or gly into the precipitation reaction might reduce the nucleation rate by sequestering Ca2+. The obtained particles have been found to keep their crystal structure and surface charge after storage in aqueous media for at least 6 months. In the context of improving the therapeutic benefit of hydrophobic drugs, the developed particles were used to load the hydrophobic drug tocopherol acetate. The resulting particles are biocompatible and highly stable in a physiological environment (pH 7.4, 0.15 M NaCl). A selective release of the cargo is observed in acidic media (pH lower than 5).

BackgroundWe examined the determinants of adolescents' Health-Related Quality of Life (HRQoL) and psychological distress (self-reported and parent-reported) during the COVID-19 pandemic, using a random sample of the population of Geneva, Switzerland.MethodsData was drawn from participants aged 14-17 years, who participated with their families to a serosurvey conducted in November and December 2020. Adolescents' HRQoL was evaluated using the validated adolescent-reported KIDSCREEN-10 and parent-reported KINDL® scales. Psychological distress was assessed with self-reported sadness and loneliness, and using the KINDL® emotional well-being scale. Using generalized estimating equations, we examined the role of socio-demographic, family and behavioural characteristics in influencing adolescents' mental health status and wellbeing.ResultsAmong 240 adolescents, 11% had a low HRQoL, 35% reported sadness and 23% reported loneliness. Based on parents' perception, 12% of the adolescents had a low HRQoL and 16% a low emotional well-being. Being a girl (aOR = 3.20; 95%CI: 1.67-6.16), increased time on social media (aOR = 2.07; 95%CI: 1.08-3.97), parents' average to poor mood (aOR = 2.62; 95%CI: 1.10-6.23) and average to poor household financial situation (aOR = 2.31; IC95%: 1.01-6.10) were associated with an increased risk of sadness. Mismatches between adolescents' and their parents' perception of HRQoL were more likely for girls (aOR = 2.88; 95%CI: 1.54-5.41) and in households with lower family well-being (aOR = 0.91; 95%CI: 0.86-0.96).ConclusionsA meaningful proportion of adolescents experienced low well-being during the second wave of COVID-19, and average well-being was lower than pre-pandemic estimates. Adolescents living in underprivileged or distressed families seemed particularly affected. Monitoring is necessary to evaluate the long-term effects of the pandemic on adolescents.