Circular Business Model for Digital Health Solutions: Protocol for a Scoping Review

The circular economy reshapes the linear “take, make, and dispose” approach and evolves around minimizing waste and recapturing resources in a closed-loop system. The health sector accounts for 4.6% of global greenhouse gas emissions and has, over the decades, been built to rely on single-use devices and deal with high volumes of medical waste. With the increase in the adoption of digital health solutions in the health care industry, leading the industry into a new paradigm of how we provide health care, a focus must be put on the amount of waste that will follow. Digital health solutions will shape health care through the use of technology and lead to improved patient care, but they will also make medical waste more complex to deal with due to the e-waste component. Therefore, a transformation of the health care industry to a circular economy is a crucial cornerstone in decreasing the impact on the environment

A novel type of bispecific antibody with targeted depletion activity of soluble pro-tumoral factors in the tumor microenvironment for cancer therapy

L'objectif de cette thèse est de concevoir un nouveau type d’anticorps thérapeutiques bispécifiques pour éliminer de manière ciblée des facteurs solubles pro-tumoraux du microenvironnement tumoral selon un mécanisme de sweeping antibody via le ciblage du récepteur de la transferrine (TfR1). Le TfR1 est un récepteur surexprimé dans de nombreuses tumeurs. Il permet l’apport cellulaire en Fer selon un mécanisme FcRn-like. Le facteur soluble à éliminer choisi pour cette preuve de concept est l’interleukine (IL-6), une cytokine multifonctionnelle impliquée dans la progression tumorale. Trois formats d’anticorps différents bispécifiques ont été conçus à partir d’anticorps antagonistes internalisants ciblant le TfR1 et d’un anticorps anti-IL-6 non neutralisant à liaison pH-dépendante. Nous avons mis en évidence que (1) les 3 formats d’anticorps bispécifiques conservent les propriétés de liaison à l’IL-6 (liaison à pH physiologique mais pas à pH acide) et au TfR1 des anticorps parentaux (blocage de l’internalisation du ligand holo-transferrine via le TfR1) et (2) qu’ils permettent l’internalisation de l’IL-6 via le TfR1. L’activité sweeping a été évaluée in vitro par une comparaison des activités inhibitrices des anticorps bispécifiques et de la combinaison des anticorps parentaux sur des lignées cellulaires à croissance IL-6 dépendante (myélome XG-6 et XG-7) ou non (lymphome RAJI). L’élimination de l’IL-6 a également été mise en évidence in vivo en monitorant la concentation d’IL-6 dans le plasma de souris xénogreffées avec une lignée de cancer du pancréas productrice d’IL-6. Les résultats de cette thèse montrent qu’il est possible d’obtenir une activité sweeping TfR1-dépendante ce qui ouvre un large panel d’applications thérapeutiques dans le ciblage de facteurs solubles pro-tumoraux par l’utilisation de récepteurs tumeurs spécifiques-TfR1-like.The objective of this thesis is to design a new type of bispecific therapeutic antibodies to selectively eliminate soluble pro-tumoral factors from the tumor microenvironment by a sweeping antibody mechanism by targeting the transferrin receptor (TfR1). TfR1 is an overexpressed receptor in many tumors. It allows iron cell supply by a FcRn-like mechanism. The soluble factor chosen for this proof of concept is interleukin (IL-6), a multifunctional cytokine involved in tumor progression. Three different bispecific antibody formats have been developed based on internalizing antagonistic antibodies targeting TfR1 and a pH-dependent non neutralizing anti-IL-6 antibody. We highlight that (1) the 3 formats of bispecific antibodies retain the binding properties to IL-6 (binding at physiological pH but not at acidic pH) and TfR1 of parental antibodies (blocade of holo transferrine internalization) and (2) allow the internalization of IL-6 via TfR1. Sweeping activity was evaluated in vitro, by comparing the inhibitory activities of bispecific antibodies and the combination of parental antibodies on cell lines with IL-6 growth dependent (myeloma XG-6 and XG-7) or not (lymphoma RAJI). IL-6 elimination was also demonstrated in vivo by monitoring IL-6 elimination in the plasma of xenografted mice with an IL-6-producing pancreatic cancer line. The results of this thesis show that it is possible to obtain a TfR1-dependent sweeping activity, which opens up a wide range of therapeutic applications in the targeting of pro-tumor soluble factors by the use of specific TfR1-like tumor receptors

Analyzing snapshot diversity patterns with the Neutral Theory can show functional groups’ effects on community assembly

International audienceA central question of community ecology is to understand how the interplay between processes of the Neutral Theory (e.g., immigration and ecological drift) and niche-based processes (e.g., environmental filtering, intra- and interspecific density dependence) shape species diversity in competitive communities. The articulation between these two categories of mechanisms can be studied through the lens of the intermediate organizational level of "functional groups" (FGs), defined as clusters of species with similar traits. Indeed, FGs stress ecological differences among species and are thus likely to unravel non-neutral interactions within communities. Here we presented a novel approach to explore how FGs affect species coexistence by comparing species and functional diversity patterns. Our framework considers the Neutral Theory as a mechanistic null hypothesis. It assesses how much the functional diversity deviates from species diversity in communities, and compares this deviation, called the "average functional deviation," to a neutral baseline. We showed that the average functional deviation can indicate reduced negative density dependence or environmental filtering among FGs. We validated our framework using simulations illustrating the two situations. We further analyzed tropical tree communities in Western Ghats, India. Our analysis of the average functional deviation revealed environmental filtering between deciduous and evergreen FGs along a broad rainfall gradient. By contrast, we did not find clear evidence for reduced density dependence among FGs. We predict that applying our approach to new case studies where environmental gradients are milder and FGs are more clearly associated to resource partitioning should reveal the missing pattern of reduced density dependence among FGs

ecolottery : Simulating and assessing community assembly with environmental filtering and neutral dynamics in R

International audience1. We introduce the R package ecolottery dedicated to quick and efficient simulation of communities undergoing local neutral dynamics with environmentally filtered immigration from a reference species pool (spatially implicit model). The package includes an Approximate Bayesian Computation (ABC) tool to estimate the param-eters of these processes. We present the rationale of the approach and show examples of simulations and ABC analysis. 2. The species in the reference pool differ in their abundances and trait values. Environmental filtering weights the probability of immigration success depending on trait values, while the descendants of established immigrants undergo neutral stochastic drift. The reference pool can be defined in a flexible way as representing, e.g. the composition of a broad biogeographical region, or available dispersers around local communities. The package provides a process-based alternative to the use of randomization-based null models. 3. The package proposes a coalescent-based simulation algorithm that presents sig-nificant advantages over alternative algorithms. It does not require simulating community dynamics from an initial state forward in time but does still allow measurement of the influence of environmental filtering. Because of its high calculation speed, this approach allows simulating many communities within a reasonable amount of time. 4. Diverse patterns of taxonomic, functional and phylogenetic compositions can be generated. The package can be used to explore the outcome of ecological and evolutionary processes playing at local and regional scales, and to estimate the parameters of these processes based on observed patterns

In situ visualization of aortic dissection propagation in notched rabbit aorta using synchrotron X-ray tomography

International audienceAortic dissection is a complex, intramural, and dynamic condition involving multiple mechanisms, hence, difficult to observe. In the present study, a controlled in vitro aortic dissection was performed using tension-inflation tests on notched rabbit aortic segments. The mechanical test was combined with conventional (cCT) and synchrotron (sCT) computed tomography for in situ imaging of the macro-and micro-structural morphological changes of the aortic wall during dissection. We demonstrate that the morphology of the notch and the aorta can be quantified in situ at different steps of the aortic dissection, and that the notch geometry correlates with the critical pressure. The phenomena prior to propagation of the notch are also described, for instance the presence of a bulge at the tip of the notch is identified, deforming the remaining wall. Finally, our method allows us to visualize for the first time the propagation of an aortic dissection in real-time with a resolution that has never previously been reached

Deep mutational engineering of broadly-neutralizing nanobodies accommodating SARS-CoV-1 and 2 antigenic drift

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From IB2 to IIIB locally advanced cervical cancers: report of a ten-year experience

Abstract Background Despite screening campaigns, cervical cancers remain among the most prevalent malignancies and carry significant mortality, especially in developing countries. Most studies report outcomes of patients receiving the usual standard of care. It is possible that these selected patients may not correctly represent patients in a real-world setting, which may be a limitation in interpreting outcomes. This study was undertaken to identify prognostic factors, management strategies and outcomes of locally advanced cervical cancers (LACC) treated in daily clinical practice. Methods Medical files of all consecutive patients treated with curative intent for LACC in a French Cancer Care Center between 2004 and 2014 were reviewed retrospectively. Results Ninety-four patients were identified. Performance status was ≥ 2 in 10.6%. Median age at diagnosis was 63.0. Based on the International Federation of Gynecology and Obstetrics classification, tumours were classified as follows: 10.6% IB2, 22.3% IIA, 51.0% IIB, 4.3% IIIA and 11.7% IIIB. Pelvic lymph nodes were involved in 34.0% of cases. Radiotherapy was delivered for all patients. Radiotherapy technique was intensity modulated radiation therapy or volumetric modulated arc therapy in 39.4% of cases. A concurrent cisplatin chemotherapy was delivered in 68.1% of patients. Brachytherapy was performed in 77.7% of cases. The recommended standard care (concurrent chemoradiotherapy with at least five chemotherapy cycles during radiotherapy, followed by brachytherapy) was delivered in 43.6%. The median overall treatment time was 56 days. Complete tumour sterilisation was achieved in 55.2% of cases. Mean follow-up was 54.3 months. Local recurrence rate was 18.1%. Five-year overall survival was 61.9% (95% Confident Interval (CI) = 52.3–73.2) and five-year disease-specific survival was 68.5% (95% CI = 59.2–79.2). Poor performance status, lymph nodes metastasis and absence of concurrent chemotherapy were identified as poor prognostic factors in multivariate analysis. Conclusions Less than 50% of patients received the standard care. Because LACC patients and disease are heterogeneous, treatment tailoring appears to be common in current clinical practice. However, guidelines for tailoring management are not currently available. More data about real-world settings are required in order to to optimise clinical trials’ aims and designs, and make them translatable in daily clinical practice. Trial registration retrospectively registered

Correction to: From IB2 to IIIB locally advanced cervical cancers: report of a ten-year experience

In the original publication [1] one author name was spelled incorrect

A recycling anti-transferrin receptor-1 monoclonal antibody as an efficient therapy for erythroleukemia through target up-regulation and antibody-dependent cytotoxic effector functions

International audienceTargeting transferrin receptor 1 (TfR1) with monoclonal antibodies is a promising therapeutic strategy in cancer as tumor cells often overexpress TfR1 and show increased iron needs. We have re-engineered six anti-human TfR1 single-chain variable fragment (scFv) antibodies into fully human scFv2-Fcγ1 and IgG1 antibodies. We selected the more promising candidate (H7), based on its ability to inhibit TfR1-mediated iron-loaded transferrin internalization in Raji cells (B-cell lymphoma). The H7 antibody displayed nanomolar affinity for its target in both formats (scFv2-Fcγ1 and IgG1), but cross-reacted with mouse TfR1 only in the scFv2-Fc format. H7 reduced the intracellular labile iron pool and, contrary to what has been observed with previously described anti-TfR1 antibodies, upregulated TfR1 level in Raji cells. H7 scFv2-Fc format elimination half-life was similar in FcRn knock-out and wild type mice, suggesting that TfR1 recycling contributes to prevent H7 elimination in vivo. In vitro, H7 inhibited the growth of erythroleukemia and B-cell lymphoma cell lines (IC50 0.1 µg/mL) and induced their apoptosis. Moreover, the Im9 B-cell lymphoma cell line, which is resistant to apoptosis induced by rituximab (anti-CD20 antibody), was sensitive to H7. In vivo, tumor regression was observed in nude mice bearing ERY-1 erythroleukemia cell xenografts treated with H7 through a mechanism that involved iron deprivation and antibody-dependent cytotoxic effector functions. Therefore, targeting TfR1 using the fully human anti-TfR1 H7 is a promising tool for the treatment of leukemia and lymphoma