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Background NIS793 is a human IgG2 monoclonal antibody that binds to transforming growth factor beta (TGF-β). This first-in-human study investigated NIS793 plus spartalizumab treatment in patients with advanced solid tumors.Methods Patients received NIS793 (0.3–1 mg/kg every 3 weeks (Q3W)) monotherapy; following evaluation of two dose levels, dose escalation continued with NIS793 plus spartalizumab (NIS793 0.3–30 mg/kg Q3W and spartalizumab 300 mg Q3W or NIS793 20–30 mg/kg every 2 weeks [Q2W] and spartalizumab 400 mg every 4 weeks (Q4W)). In dose expansion, patients with non-small cell lung cancer (NSCLC) resistant to prior anti-programmed death ligand 1 or patients with microsatellite stable colorectal cancer (MSS-CRC) were treated at the recommended dose for expansion (RDE).Results Sixty patients were treated in dose escalation, 11 with NIS793 monotherapy and 49 with NIS793 plus spartalizumab, and 60 patients were treated in dose expansion (MSS-CRC: n=40; NSCLC: n=20). No dose-limiting toxicities were observed. The RDE was established as NIS793 30 mg/kg (2100 mg) and spartalizumab 300 mg Q3W. Overall 54 (49.5%) patients experienced ≥1 treatment-related adverse event, most commonly rash (n=16; 13.3%), pruritus (n=10; 8.3%), and fatigue (n=9; 7.5%). Three partial responses were reported: one in renal cell carcinoma (NIS793 30 mg/kg Q2W plus spartalizumab 400 mg Q4W), and two in the MSS-CRC expansion cohort. Biomarker data showed evidence of target engagement through increased TGF-β/NIS793 complexes and depleted active TGF-β in peripheral blood. Gene expression analyses in tumor biopsies demonstrated decreased TGF-β target genes and signatures and increased immune signatures.Conclusions In patients with advanced solid tumors, proof of mechanism of NIS793 is supported by evidence of target engagement and TGF-β pathway inhibition.Trial registration number NCT02947165.

Understanding the tumor microenviroment is important before it can be exploited therapeutically. Here, the authors use single cell sequencing to study stromal cells in mouse tumors and identify a subset of interferon-licensed cancer associated fibroblasts that appear after anti-TGFβ treatment.

The NF-κB family of transcription factors has emerged as a key player in the pathogenesis of multiple myeloma (MM). NF-κB is activated by at least two major signaling pathways. The classical pathway results in the activation of mainly RelA containing dimers, whereas the alternative pathway leads to the activation of RelB/p52 and RelB/p50 heterodimers. Activating mutations in regulators of the alternative pathway have been identified in 17% of MM patients. However, the status of RelB activation per se and its role in the regulation of cell survival in MM has not been investigated. Here, we reveal that 40% of newly diagnosed MM patients have a constitutive RelB DNA-binding activity in CD138(+) tumor cells, and we show an association with increased expression of a subset of anti-apoptotic NF-κB target genes, such as cIAP2. Furthermore, we demonstrate that RelB exerts a crucial anti-apoptotic activity in MM cells. Our findings indicate that RelB activation is key for promoting MM cell survival through the upregulation of anti-apoptotic proteins. Altogether, our study provides the framework for the development of new molecules targeting RelB in the treatment of MM.

Background How tandem autologous-allogeneic stem cell transplantation should be integrated in the treatment of multiple myeloma remains controversial. We examined the long-term outcome of patients with multiple myeloma managed with tandem autologous-allogeneic stem cell transplantation and present a prognostic factor analysis based on the experience of the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC).Design and Methods This French, retrospective, registry-based study included 146 patients who had undergone tandem autologous-allogeneic transplantation for multiple myeloma at 20 SFGM-TC centers between 1998 and 2010. The patients included in the study had fully completed the two steps of a planned tandem autologous-allogeneic transplantation. No treatment had to be administered between the autologous and allogeneic parts of the tandem procedure.Results Seventy-seven patients (53%) underwent tandem autologous-allogeneic transplantation as part of upfront treatment, i.e. after a single line of treatment not including autologous transplantation. The median follow-up from the allogeneic transplant was 47.5 months (range, 1.2–132 months). At 4 years, the overall survival and event-free survival rates were 48% (95% CI 39–57 %) and 27% (95% CI 19–36), respectively. Eighteen patients (12%) experienced grade III–IV acute graft-versus-host disease and 43 patients (30%) had chronic graft-versus-host disease. The transplant-related mortality rate at 1 year was 15% (95% CI 10–22). Patients receiving tandem transplantation as upfront treatment had significantly improved event-free survival (36% versus 11%; P=0.005) and overall survival (56% versus 34%; P=0.02). Donor’s age ≤50 years was associated with improved event-free survival (35% versus 16%; P=0.005) and overall survival (54% versus 41%; P=0.02). In the multivariable analysis, upfront tandem transplantation, donor’s age ≤50 years and full chimerism were independent prognostic factors for better outcome.Conclusions We confirmed the feasibility of tandem autologour-allogeneic transplantation in heavily treated patients with multiple myeloma. We identified younger donor’s age and upfront tandem transplantation as two independent prognostic factors for survival which could be further explored in prospective studies.

The evolution of metamorphic species may be constrained by different ecologies of the larval and adult stages. Here, Bardua et al. show that in frogs, adult ecology is more important than larval ecology for skull evolution, but species that don’t feed as tadpoles evolve faster than those that do.

Abstract Access to resources is a dynamic and multicausal process that determines the success and survival of a population. It is therefore often challenging to disentangle the factors affecting ecological traits like diet. Insular habitats provide a good opportunity to study how variation in diet originates, in particular in populations of mesopredators such as lizards. Indeed, high levels of population density associated with low food abundance and low predation are selection pressures typically observed on islands. In the present study, the diet of eighteen insular populations of two closely related species of lacertid lizards (Podarcis sicula and Podarcis melisellensis) was assessed. Our results reveal that despite dietary variability among populations, diet taxonomic diversity is not impacted by island area. In contrast, however, diet disparity metrics, based on the variability in the physical (hardness) and behavioral (evasiveness) properties of ingested food items, are correlated with island size. These findings suggest that an increase in intraspecific competition for access to resources may induce shifts in functional components of the diet. Additionally, the two species differed in the relation between diet disparity and island area suggesting that different strategies exist to deal with low food abundance in these two species. Finally, sexual dimorphism in diet and head dimensions is not greater on smaller islands, in contrast to our predictions.

Three alternatives have been proposed for the ecological state of the ancestral snake: fossorial (burrowing), aquatic, or terrestrial. Here, the authors use an integrative geometric morphometric approach that suggests evolution from terrestrial to fossorial in the most recent common ancestor of extant snakes.

Les capacités de préhension des catarrhiniens ont été largement étudiées dans le cadre de problématiques cognitives, fonctionnelles et évolutives. Une importante variabilité dans les types de saisies utilisés, incluant des stratégies longtemps décrites comme spécifiques des humains, a ainsi été mise en évidence. Cependant, bien que la préhension soit impliquée dans de nombreuses activités chez tous les primates, elle reste peu étudiée chez les platyrrhiniens et les strepsirrhiniens. Ces derniers constituent un groupe monophylétique à la base de l’arbre des primates, incluant environ 60 espèces présentant des caractéristiques morphologiques, sociales et écologiques différentes. Les strepsirrhiniens représentent donc un excellent modèle pour mieux comprendre les facteurs sociaux et écologiques conduisant à l’évolution des capacités de préhension. Cette étude vise à déterminer de manière quantitative les différentes stratégies comportementales adoptées par les strepsirrhiniens lors de la saisie de divers items alimentaires immobiles. A travers une approche comparative portant sur plus de 15 espèces, cette étude a également pour but de mieux comprendre les liens existants entre les facteurs écologiques et sociaux et la saisie manuelle. Les observations sont issues de l’analyse de vidéos réalisées au Duke University Lemur Center, chaque individu ayant été filmé dans son environnement habituel lors de ses repas sur une durée moyenne de 1,0 ± 0,1 heure permettant d’observer en moyenne 62 ± 5 saisies par individu. Cette étude montre que les saisies uni-manuelles, bien que stéréotypées, sont largement utilisées pour saisir des items alimentaires immobiles. Un effet important de la taille et de la consistance des items sur le choix du type de saisie est également mis en évidence. En effet, si une préférence significative pour les saisies avec la bouche est observée pour tous les autres items, les items grands et durs favorisent l’utilisation de la main. D’autre part, alors que le régime alimentaire et le type de locomotion ne semblent pas influencer significativement le type de saisie, cette propension à utiliser la main pour saisir des items grands et durs semble liée au degré d’arboricolisme et au type de transport des jeunes. Toutefois, les effets de lignée et les effets des facteurs écologiques et sociaux demeurent pour l’instant indissociables. L’augmentation prochaine de la taille de l’échantillon devrait permettre le renforcement des données et une meilleure différenciation des effets de lignées et des facteurs écologiques et sociaux conduisant à une augmentation de l’utilisation de la main pour saisir les objets grands et durs.Je remercie vivement le personnel du Duke Lemur Center et particulièrement David Brewer, Erin Ehmke et Kay Wesler pour leur assistance lors de la collecte des données.

Vertebrate limb morphology often reflects the environment due to variation in locomotor requirements. However, proximal and distal limb segments may evolve differently from one another, reflecting an anatomical gradient of functional specialization that has been suggested to be impacted by the timing of development. Here, we explore whether the temporal sequence of bone condensation predicts variation in the capacity of evolution to generate morphological diversity in proximal and distal forelimb segments across more than 600 species of mammals. Distal elements not only exhibit greater shape diversity, but also show stronger within-element integration and, on average, faster evolutionary responses than intermediate and upper limb segments. Results are consistent with the hypothesis that late developing distal bones display greater morphological variation than more proximal limb elements. However, the higher integration observed within the autopod deviates from such developmental predictions, suggesting that functional specialization plays an important role in driving within-element covariation. Proximal and distal limb segments also show different macroevolutionary patterns, albeit not showing a perfect proximo-distal gradient. The high disparity of the mammalian autopod, reported here, is consistent with the higher potential of development to generate variation in more distal limb structures, as well as functional specialization of the distal elements.

Vertebrate osteological collections provide comparative material for morphological analysis. Before being stored in the collection and studied by researchers, specimens are treated by preparators or curators and are cleaned. The preparation protocol employed ideally should not damage the material. Here, we explore the potential deformation of bones due to preparation using geometric morphometric methods. We focus both on intraspecific and interspecific variability. Our data on the scapular girdle of birds show that, at an intraspecific level, the effect of preparation on bone shape cannot be neglected. Paired and unpaired bones did not respond to the preparation process in the same way, possibly due to differences in function and their anatomical characteristics. Moreover, deformations due to preparation can be estimated by looking at the texture of the bone. At the interspecific level, we found no significant differences as the deformations induced by preparation are relatively small compared to differences among species. This study highlights the importance of carefully selecting preparation methods in order to avoid physical damage that could impact the shape of bones, especially for studies at the intraspecific level.

The challenging complexity of biological structures has led to the development of several methods for quantitative analyses of form. Bones are shaped by the interaction of historical (phylogenetic), structural, and functional constrains. Consequently, bone shape has been investigated intensively in an evolutionary context. Geometric morphometric approaches allow the description of the shape of an object in all of its biological complexity. However, when biological objects present only few anatomical landmarks, sliding semi-landmarks may provide good descriptors of shape. The sliding procedure, mandatory for sliding semi-landmarks, requires several steps that may be time-consuming. We here compare the time required by two different software packages (‘Edgewarp’ and ‘Morpho’) for the same sliding task, and investigate potential differences in the results and biological interpretation. ‘Morpho’ is much faster than ‘Edgewarp,’ notably as a result of the greater computational power of the ‘Morpho’ software routines and the complexity of the ‘Edgewarp’ workflow. Morphospaces obtained using both software packages are similar and provide a consistent description of the biological variability. The principal differences between the two software packages are observed in areas characterized by abrupt changes in the bone topography. In summary, both software packages perform equally well in terms of the description of biological structures, yet differ in the simplicity of the workflow and time needed to perform the analyses.