Dual Relief of T-lymphocyte Proliferation and Effector Function Underlies Response to PD-1 Blockade in Epithelial Malignancies

Although understanding of T-cell exhaustion is widely based on mouse models, its analysis in patients with cancer could provide clues indicating tumor sensitivity to immune checkpoint blockade (ICB). Data suggest a role for costimulatory pathways, particularly CD28, in exhausted T-cell responsiveness to PD-1/PD-L1 blockade. Here, we used single-cell transcriptomic, phenotypic, and functional approaches to dissect the relation between CD8+ T-cell exhaustion, CD28 costimulation, and tumor specificity in head and neck, cervical, and ovarian cancers. We found that memory tumor–specific CD8+ T cells, but not bystander cells, sequentially express immune checkpoints once they infiltrate tumors, leading, in situ, to a functionally exhausted population. Exhausted T cells were nonetheless endowed with effector and tumor residency potential but exhibited loss of the costimulatory receptor CD28 in comparison with their circulating memory counterparts. Accordingly, PD-1 inhibition improved proliferation of circulating tumor–specific CD8+ T cells and reversed functional exhaustion of specific T cells at tumor sites. In agreement with their tumor specificity, high infiltration of tumors by exhausted cells was predictive of response to therapy and survival in ICB-treated patients with head and neck cancer. Our results showed that PD-1 blockade–mediated proliferation/reinvigoration of circulating memory T cells and local reversion of exhaustion occur concurrently to control tumors

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Influence de divers aliments composés sur la croissance et la survie d'alevins de bars (Dicentrarchus labrax)

About twenty different prepared diets are given to young sea-basses weighing from 400 mg to a few grams, in 3 experiments, during which the growth and survival of the fish are regularly checked. The protein requirements of the species range around 47-SO % of the diet, and the energetic requirements seem to the covered by 11 to 12 % fat. The diets are mainly composed of fish meal. However fish autolysates and yeasts seem to give interesting results when incorporated into the diet.Une vingtaine d'aliments composés sont expérimentés sur de jeunes bars de 400 mg à quelques grammes, en trois séries de tests de grossissement où la croissance et la survie sont enregistrées régulièrement. Les besoins en protéines de l'espèce semblent être voisins de 47 â 50 7. du régime. La couverture énergétique paraît être assurée par un apport de 11 â 12 % de lipides. Les farines de poisson constituent la majeure partie de la ration. Cependant les autolysats de poisson et les levures apparaissent comme très intéressants à incorporer dans le régime

Brachypodium: a promising hub between model species and cereals

International audienceBrachypodium distachyon was proposed as a model species for genetics and molecular genomics in cereals less than 10 years ago. It is now established as a standard for research on C3 cereals on a variety of topics, due to its close phylogenetic relationship with Triticeae crops such as wheat and barley, and to its simple genome, its minimal growth requirement, and its short life cycle. In this review, we first highlight the tools and resources for Brachypodium that are currently being developed and made available by the international community. We subsequently describe how this species has been used for comparative genomic studies together with cereal crops, before illustrating major research fields in which Brachypodium has been successfully used as a model: cell wall synthesis, plant-pathogen interactions, root architecture, and seed development. Finally, we discuss the usefulness of research on Brachypodium in order to improve nitrogen use efficiency in cereals, with the aim of reducing the amount of applied fertilizer while increasing the grain yield. Several paths are considered, namely an improvement of either nitrogen remobilization from the vegetative organs, nitrate uptake from the soil, or nitrate assimilation by the plant. Altogether, these examples position the research on Brachypodium as at an intermediate stage between basic research, carried out mainly in Arabidopsis, and applied research carried out on wheat and barley, enabling a complementarity of the studies and reciprocal benefits

Restoring the reef: Coral restoration yields rapid impacts on certain fish assemblages

International audienceCoral reefs harbor one of the highest biodiversity on Earth but increasing disturbances have often led to rapid shifts from coral to algal states, prompting the development of conservation methods, including coral restoration. While most studies have focused on the medium and long-term effects of restoration on fish assemblages, less is known about its short-term effects (i.e., within one month) on associated communities. This study explored the short-term impacts (<1 month) of coral restoration, including four restoration conditions, on fish abundance, diversity, and assemblages in a marine educational area (a small coastal area managed by a scholl in the frame of an eco-citizen pedagogical program) in Bora, French Polynesia. Sixteen dead reef patches previously covered by macroalgae were grouped into four conditions as follows: four were non-restored (control condition), four were restored to 25% living coral cover (condition 25%), four to 50% living coral cover (condition 50%), and four were restored to 75% living coral cover (condition 75%). The abundance of fish at adult and juvenile stages was assessed, before and after coral restoration, using the fixed-point method for a period of 5 min on each of the 16 reef patches. Two successive observation periods were conducted for each patch: one focusing on more visible and mobile fish, and another on more cryptic species. Surveys were conducted one day and three days prior to restoration, and then 24 days and 28 days post-restoration. For adults, the difference in abundance, number of species, and diversity before and after restoration were not significant between the conditions. Similarly, for juveniles, no significant differences were observed when considering the conditions and restoration. Before restoration, the fish assemblages were randomly distributed between the four conditions for both adults and juveniles. After the restoration, the inter-conditions similarity decreased significantly for adults, but not for juveniles. Some species were associated with the more restored patches (Chaetodon citrinellus, Halichoeres trimaculatus, and Zanclus cornutus). Finaly, the restoration seemed to have variable effects depending on the trophic groups. Coral restoration has short-term effects on fish assemblages, indicating the effectiveness of restoration efforts even within a brief period. These rapid changes underscore the remarkable ability of adult fish to adapt to rapidly changing environments

Cancer brings forward oviposition in the fly Drosophila melanogaster

Abstract Hosts often accelerate their reproductive effort in response to a parasitic infection, especially when their chances of future reproduction decrease with time from the onset of the infection. Because malignancies usually reduce survival, and hence potentially the fitness, it is expected that hosts with early cancer could have evolved to adjust their life-history traits to maximize their immediate reproductive effort. Despite the potential importance of these plastic responses, little attention has been devoted to explore how cancers influence animal reproduction. Here, we use an experimental setup, a colony of genetically modified flies Drosophila melanogaster which develop colorectal cancer in the anterior gut, to show the role of cancer in altering life-history traits. Specifically, we tested whether females adapt their reproductive strategy in response to harboring cancer. We found that flies with cancer reached the peak period of oviposition significantly earlier (i.e., 2 days) than healthy ones, while no difference in the length and extent of the fecundity peak was observed between the two groups of flies. Such compensatory responses to overcome the fitness-limiting effect of cancer could explain the persistence of inherited cancer-causing mutant alleles in the wild. K E Y W O R D S cancer, fecundity, life-history strategy, reproductio

The importance of cancer cells for animal evolutionary ecology

Reciprocal interactions between hosts, their symbionts and their oncobiota (cancer cell communities) are yet to be studied in detail. Considering malignant cells in addition to the holobiont perspective allows greater understanding of the processes governing both host phenotypes and cancer dynamics

Bridge The Distance Between Breast Pathologists: When The Senopath Network Opens Up To The Telepathology

Introduction/ Background In clinical practice, pathologists commonly face breast lesions, which are difficult to diagnose and which re- quire discussion. In Midi-Pyrénées, the largest region ofFrance, this problem has led us to develop in 2011 a peer group for breast diseases entitled SENOPATH. Aims In order to reduce second opinion delay, erase geographical barrier and provide continuing education, we aimed to introduce an effective online and outline telepathology system in the SENOPATH network. Methods A case review by SENOPATH can be requested by any pathologist in the Midi-Pyrénées region, by filling a form through the ONCOMIP network (organization dedicated to oncology in the Midi- Pyrénées region). The slides are sent for digitalization at The University Cancer Institute - Oncopole, using a Hamamatsu 2.0-RS scanner (until 2014) and a 3DHISTECH Pannoramic 250 scanner, then anonymized and transferred to a shared storage space at Toulouse Paul Sabatier University. Virtual slides can be seen before and/or after the meeting by members of the group by login in the online 3DHISTECHCaseCentervia the Imag’IN platform website. The group, who meets on a monthly basis, has recently developed a synchronized webinar  (using 3DHISTECH Case Center and Pannoramic Viewer) coupled with a conference call in order to ease the attendance of pathologists from remote pathology laboratories. A consensual diagnosis and final pathology report are issued for each case and sent to the referent clinician via the patient medical file securely hosted by ONCOMIP. Results From January 2012 to December 2015, 211 cases (39 in 2012, 50 in 2013, 75 in 2014 and 47 in 2015) have been reviewed during 43 meetings. Ten out of 43 meetings (23%) used telepathology. Sixty-one cases out of 211 (29%) were actually digitalized, mainly using theHamamatsu2.0-RS scanner. In average, the number of attending pathologists was9 to 10from 2012 to 2015. The average number of cases reviewed per meeting was 3 in 2012 and 5 between 2013 and 2015. Two main motives for review were identified: diagnostic ‘routine difficulty’ (equivocal or discordant cases, invasive vs in situ lesion, atypical vs malignant lesions, immunohistochemistry scoring pitfalls) or rare tumours. The rare tumour category included among others syringomatous tumour of the nipple, low-grade adenosquamous, myoepithelial, mucoepidermoid or secretory carcinomas, adenomyoepithelioma, atypical microglandular adenosis, sclerosing papillary hyperplasia without myoepithelium and periductal stromal tumour. Molecular analyses requested by the group and implemented in the diagnosis process mainly included immunohistochemistry and fluorescence in situ hybridization (HER2, ETV6, MAML2, MYB). The SENOPATH network committee review for difficult or rare lesions of the breast has considerably improved the pathologist’s network in our region. This working group is regularly requested by oncologists to solve difficult cases. Our aims for the next few years are 1/ to digitalize all of the cases reviewed by the SENOPATH network, 2/ to use telepathology facilities provided by the Imag’IN platform in order to widen the group to a national level, and 3/ to construct a growing online library of virtual slides for breast challenging lesions.

PD-1 blockade restores helper activity of tumor-infiltrating, exhausted PD-1hiCD39+ CD4 T cells

International audienceTumor antigen-specific CD4 T cells accumulate at tumor sites, evoking their involvement in antitumor effector functions in situ. Contrary to CD8 cytotoxic T lymphocyte exhaustion, that of CD4 T cells remains poorly appreciated. Here, using phenotypic, transcriptomic, and functional approaches, we characterized CD4 T cell exhaustion in patients with head and neck, cervical, and ovarian cancer. We identified a CD4 tumor-infiltrating lymphocyte (TIL) population, defined by high PD-1 and CD39 expression, which contained high proportions of cytokine-producing cells, although the quantity of cytokines produced by these cells was low, evoking an exhausted state. Terminal exhaustion of CD4 TILs was instated regardless of TIM-3 expression, suggesting divergence with CD8 T cell exhaustion. scRNA-Seq and further phenotypic analyses uncovered similarities with the CD8 T cell exhaustion program. In particular, PD-1hiCD39+ CD4 TILs expressed the exhaustion transcription factor TOX and the chemokine CXCL13 and were tumor antigen specific. In vitro, PD-1 blockade enhanced CD4 TIL activation, as evidenced by increased CD154 expression and cytokine secretion, leading to improved dendritic cell maturation and consequently higher tumor-specific CD8 T cell proliferation. Our data identify exhausted CD4 TILs as players in responsiveness to immune checkpoint blockade