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Th1.17 characteristics of CD73+ CD4+ Teff based on the expression of CXCR3, CCR6, CRTH2, the migration in response to CXCL10 or CCL20 gradient and the MDR-1-specific Rhodamine 123 exclusion assay

Purpose: BRCA2 plays a central role in homologous recombination by loading RAD51 on DNA breaks. The objective of this study is to determine whether the location of mutations in the RAD51-binding domain (RAD51-BD; exon 11) of BRCA2 gene affects the clinical outcome of ovarian cancer patients.Experimental Design: A study cohort of 353 women with ovarian cancer who underwent genetic germline testing for BRCA1 and BRCA2 genes was identified. Progression-free survival (PFS), platinum-free interval (PFI), and overall survival (OS) were analyzed. The Cancer Genome Atlas (TCGA) cohort of ovarian cancer (n = 316) was used as a validation cohort.Results: In the study cohort, 78 patients were carriers of germline mutations of BRCA2. After adjustment for FIGO stage and macroscopic residual disease, BRCA2 carriers with truncating mutations in the RAD51-BD have significantly prolonged 5-year PFS [58%; adjusted HR, 0.36; 95% confidence interval (CI), 0.20–0.64; P = 0.001] and prolonged PFI (29.7 vs. 15.5 months, P = 0.011), compared with noncarriers. BRCA2 carriers with mutations located in other domains of the gene do not have prolonged 5-year PFS (28%, adjusted HR, 0.67; 95% CI, 0.42–1.07; P = 0.094) or PFI (19 vs. 15.5 months, P = 0.146). In the TCGA cohort, only BRCA2 carriers harboring germline or somatic mutations in the RAD51-BD have prolonged 5-year PFS (46%; adjusted HR, 0.30; 95% CI, 0.13–0.68; P = 0.004) and 5-year OS (78%; adjusted HR, 0.09; 95% CI, 0.02–0.38; P = 0.001).Conclusions: Among ovarian cancer patients, BRCA2 carriers with mutations located in the RAD51-BD (exon 11) have prolonged PFS, PFI, and OS. Clin Cancer Res; 24(2); 326–33. ©2017 AACR.

The production of CD73-derived adenosine (Ado) by Tregs has been proposed as a resistance mechanism to anti-PD-1 therapy in murine tumor models. We reported that human Tregs express the ectonucleotidase CD39, which generates AMP from ATP, but do not express the AMPase CD73. In contrast, CD73 defined a subset of effector CD4+ T cells (Teffs) enriched in polyfunctional Th1.17 cells characterized by expression of CXCR3, CCR6, and MDR1, and production of IL17A/IFNγ/IL22/GM-CSF. CD39+ Tregs selectively targeted CD73+ Teffs through cooperative degradation of ATP into Ado inhibiting and restricting the ability of CD73+ Teffs to secrete IL17A. CD73+ Teffs infiltrating breast and ovarian tumors were functionally blunted by Tregs expressing upregulated levels of CD39 and ATPase activity. Moreover, tumor-infiltrating CD73+ Teffs failed to express inhibitory immune checkpoints, suggesting that CD73 might be selected under pressure from immune checkpoint blockade therapy and thus may represent a nonredundant target for restoring antitumor immunity.Significance: Polyfunctional CD73+ T-cell effectors lacking other immune checkpoints are selectively targeted by CD39 overexpressing Tregs that dominate the breast tumor environment. Cancer Res; 78(13); 3604–18. ©2018 AACR.

Table S1: Multivariate Model of progression-free survival in the study cohort; Table S2: Multivariate Model of overall survival in the study cohort; Table S3: BRCA2 mutations in the study cohort; Figure S1: Flow diagram for selection of patients in the study cohort; Figure S2: A model for double-strand breaks repair by homologous recombination that depends on the location of mutation in BRCA2 gene.

A standard way to move particles in a SMC sampler is to apply several steps of a MCMC (Markov chain Monte Carlo) kernel. Unfortunately, it is not clear how many steps need to be performed for optimal performance. In addition, the output of the intermediate steps are discarded and thus wasted somehow. We propose a new, waste-free SMC algorithm which uses the outputs of all these intermediate MCMC steps as particles. We establish that its output is consistent and asymptotically normal. We use the expression of the asymptotic variance to develop various insights on how to implement the algorithm in practice. We develop in particular a method to estimate, from a single run of the algorithm, the asymptotic variance of any particle estimate. We show empirically, through a range of numerical examples, that waste-free SMC tends to outperform standard SMC samplers, and especially so in situations where the mixing of the considered MCMC kernels decreases across iterations (as in tempering or rare event problems)., revised version

Significance Transmembrane signaling through G protein–coupled receptors (GPCRs), originally described as requiring coupling to intracellular G proteins, also uses G protein–independent pathways through β-arrestin recruitment. Biased ligands, by favoring one of the multiple bioactive conformations of GPCRs, allow selective signaling through either of these pathways. Here, we identified Serodolin as the first β-arrestin–biased agonist of the serotonin 5-HT 7 receptor. This new ligand, while acting as an inverse agonist on G s signaling, selectively induces ERK activation in a β-arrestin–dependent way. Importantly, we report that Serodolin decreases pain intensity caused by thermal, mechanical, or inflammatory stimuli. Our findings suggest that targeting the 5-HT 7 R with β-arrestin–biased ligand could be a valid alternative strategy to the use of opioids for the relief of pain.

In everyday life, humans face environments that feature uncertain and volatile or changing situations. Efficient adaptive behaviour must take into account uncertainty and volatility. Previous models of adaptive behaviour involve inferences about volatility that rely on complex and often intractable computations. Because such computations are presumably implausible biologically, it is unclear how humans develop efficient adaptive behaviours in such environments. Here, we demonstrate a counterintuitive result: simple, low-level inferences confined to uncertainty can produce near-optimal adaptive behaviour, regardless of the environmental volatility, assuming imprecisions in computation that conform to the psychophysical Weber law. We further show empirically that this Weber-imprecision model explains human behaviour in volatile environments better than optimal adaptive models that rely on high-level inferences about volatility, even when considering biologically plausible approximations of such models, as well as non-inferential models like adaptive reinforcement learning. Findling et al. present the Weber-imprecision model of decision-making, which operates on imprecise representations of uncertainty. It produces efficient adaptive behaviour regardless of environmental volatility and fits human behaviour better than optimal adaptive models.

The statistical analysis of the information generated by medical follow-up is a very important challenge in the field of personalized medicine. As the evolutionary course of a patient's disease progresses, his/her medical follow-up generates more and more information that should be processed immediately in order to review and update his/her prognosis and treatment. Hence, we focus on this update process through sequential inference methods for joint models of longitudinal and time-to-event data from a Bayesian perspective. More specifically, we propose the use of sequential Monte Carlo (SMC) methods for static parameter joint models with the intention of reducing computational time in each update of the full Bayesian inferential process. Our proposal is very general and can be easily applied to most popular joint models approaches. We illustrate the use of the presented sequential methodology in a joint model with competing risk events for a real scenario involving patients on mechanical ventilation in intensive care units (ICUs).

Objectives Description of fertility and prognosis of patients with borderline ovarian tumor (BOT) treated by fertility-sparing surgery through a longitudinal study from the French national cancer network. Methods All consecutive patients diagnosed with BOT from the French National Network dedicated to Ovarian Malignant Rare Tumors from 2010 and 2017 were selected. In 2018, an update was made by sending a questionnaire regarding recurrence and fertility to patients aged under 43 years at diagnosis and treated conservatively. We compared the characteristics of the patients with/without recurrence and with/without live birth. Results Fifty-two patients aged 18 to 42 years presented a desire of pregnancy. Thirty patients (58%) presented a FIGO IA tumor, and 20 patients were treated by bilateral cystectomies (38%). We observed at least one live birth for 33 patients (63%) and local recurrences in 20 patients (38%). Both recurrence and live birth in 17 patients (33%) were reported, with recurrence occurring before pregnancy, after a second fertility-sparing treatment, in half of the cases. No factors associated with recurrence or live birth in this study were identified. Moreover, in this population, both recurrence and live birth were independent of age, with a linear risk along time. Disease-free survival was worse for patients treated with bilateral cystectomy (n = 20, 38%), with no difference in terms of fertility. Conclusion Two third of the patients experienced life birth after conservation surgery. We did not highlight an age/time from surgery for which the risk of recurrence outweighs the chance of pregnancy and to radicalize surgery. Moreover, almost a quarter of the live birth occurred after recurrence, with no more further event to date in these patients. The results encourage to consider a second fertility-sparing surgery after local borderline recurrence in the case of pregnancy desire. All these decisions must be discussed in specialized multidisciplinary boards.

We consider particle filters with weakly informative observations (or `potentials') relative to the latent state dynamics. The particular focus of this work is on particle filters to approximate time-discretisations of continuous-time Feynman--Kac path integral models -- a scenario that naturally arises when addressing filtering and smoothing problems in continuous time -- but our findings are indicative about weakly informative settings beyond this context too. We study the performance of different resampling schemes, such as systematic resampling, SSP (Srinivasan sampling process) and stratified resampling, as the time-discretisation becomes finer and also identify their continuous-time limit, which is expressed as a suitably defined `infinitesimal generator.' By contrasting these generators, we find that (certain modifications of) systematic and SSP resampling `dominate' stratified and independent `killing' resampling in terms of their limiting overall resampling rate. The reduced intensity of resampling manifests itself in lower variance in our numerical experiment. This efficiency result, through an ordering of the resampling rate, is new to the literature. The second major contribution of this work concerns the analysis of the limiting behaviour of the entire population of particles of the particle filter as the time discretisation becomes finer. We provide the first proof, under general conditions, that the particle approximation of the discretised continuous-time Feynman--Kac path integral models converges to a (uniformly weighted) continuous-time particle system., 36 pages, 9 figures

Background: Physical activity (PA) and psychosocial interventions are recommended management strategies for cancer-related fatigue (CRF). Randomized trials support the use of mind–body techniques, whereas no data show benefit for homeopathy or naturopathy. Methods: We used data from CANTO (ClinicalTrials.gov identifier: NCT01993498), a multicenter, prospective study of stage I–III breast cancer (BC). CRF, evaluated after primary treatment completion using the EORTC QLQ-C30 (global CRF) and QLQ-FA12 (physical, emotional, and cognitive dimensions), served as the independent variable (severe [score of ≥40/100] vs nonsevere). Outcomes of interest were adherence to PA recommendations (≥10 metabolic equivalent of task [MET] h/week [GPAQ-16]) and participation in consultations with a psychologist, psychiatrist, acupuncturist, or other complementary and alternative medicine (CAM) practitioner (homeopath and/or naturopath) after CRF assessment. Multivariable logistic regression examined associations between CRF and outcomes, adjusting for sociodemographic, psychologic, tumor, and treatment characteristics. Results: Among 7,902 women diagnosed from 2012 through 2017, 36.4% reported severe global CRF, and 35.8%, 22.6%, and 14.1% reported severe physical, emotional, and cognitive CRF, respectively. Patients reporting severe global CRF were less likely to adhere to PA recommendations (60.4% vs 66.7%; adjusted odds ratio [aOR], 0.82; 95% CI, 0.71–0.94; P=.004), and slightly more likely to see a psychologist (13.8% vs 7.5%; aOR, 1.29; 95% CI, 1.05–1.58; P=.014), psychiatrist (10.4% vs 5.0%; aOR, 1.39; 95% CI, 1.10–1.76; P=.0064), acupuncturist (9.8% vs 6.5%; aOR, 1.46; 95% CI, 1.17–1.82; P=.0008), or CAM practitioner (12.5% vs 8.2%; aOR, 1.49; 95% CI, 1.23–1.82; PP=.0001) and severe emotional CRF was associated with higher likelihood of psychologic consultations (aOR, 1.37; 95% CI, 1.06–1.79; P=.017). Conclusions: Uptake of recommendations to improve CRF, including adequate PA and use of psychosocial services, seemed suboptimal among patients with early-stage BC, whereas there was a nonnegligible interest in homeopathy and naturopathy. Findings of this large study indicate the need to implement recommendations for managing CRF in clinical practice.

We develop a (nearly) unbiased particle filtering algorithm for a specific class of continuous-time state-space models, such that (a) the latent process $X_t$ is a linear Gaussian diffusion; and (b) the observations arise from a Poisson process with intensity $\lambda(X_t)$. The likelihood of the posterior probability density function of the latent process includes an intractable path integral. Our algorithm relies on Poisson estimates which approximate unbiasedly this integral. We show how we can tune these Poisson estimates to ensure that, with large probability, all but a few of the estimates generated by the algorithm are positive. Then replacing the negative estimates by zero leads to a much smaller bias than what would obtain through discretisation. We quantify the probability of negative estimates for certain special cases and show that our particle filter is effectively unbiased. We apply our method to a challenging 3D single molecule tracking example with a Born and Wolf observation model., Comment: 34 pages, 14 figures

International audience; A series of ferrocenyl-containing γ-hydroxy-γ-lactam tetramates were prepared in 2-3 steps through ring opening-ring closure (RORC) process of γ-ylidene-tetronate derivatives in the presence of ferrocenyl alkylamines. The compounds were screened in vitro for their antiplasmodial activity against chloroquine-sensitive (3D7) and chloroquine-resistant (W2) clones of P. falciparum, displaying activity in the range of 0.12-100 μM, with generally good resistance index. The most active ferrocene in these series exhibited IC50 equal to 0.09 μM (3D7) and 0.12 μM (W2). The low cytotoxicity of the ferrocenyl-containing γ-hydroxy-γ-lactam tetramates against Human Umbilical Vein Endothelial (HUVEC) cell line demonstrated selective antiparasitic activity. The redox properties of these ferrocene-derived tetramates were studied and physico-biochemical studies evidenced that these derivatives can exert potent antimalarial activities via a mechanism distinct from ferroquine.

BackgroundThe term uterine smooth muscle tumor of uncertain malignant potential (STUMP) indicates a rare, equivocal entity between benign leiomyomas and leiomyosarcomas. In the present study, we evaluated a comprehensive range of clinical, surgical, and pathological features in a large multicenter series of patients with STUMP to identify risk factors for recurrence.MethodsThis is a retrospective study performed by collecting consecutive cases diagnosed between January 2000 and December 2020 in five tertiary centers. Associations between STUMP recurrence and clinicopathological characteristics as well as surgical treatment modality were investigated.ResultsEighty-seven patients affected by STUMP were considered. Of them, 18 cases (20.7%) recurred: 11 as leiomyosarcoma (LMS) and 7 as STUMP. The mean time to recurrence was 79 months. We found that fragmentation/morcellation, epithelioid features, high mitotic count, Ki-67 value > 20%, progesterone receptor (PR) < 83%, and p16 diffuse expression were associated with higher risk of recurrence and shorter recurrence-free survival (RFS). Furthermore, morcellation/fragmentation and mitotic count remained independent risk factors for recurrence and shorter RFS after multivariate analysis, while the presence of epithelioid features was an independent risk factor for recurrence only.ConclusionsOur results suggest that morcellation is associated with risk of recurrence and shorter RFS, thus it should be avoided if a STUMP is suspected preoperatively. Epithelioid features, high proliferation activity, low PR expression, and diffuse p16 expression are also unfavorable prognostic factors, so patients presenting these features should be closely followed up.

ObjectiveSplenectomy is performed in 4–32% of cytoreductive surgeries for ovarian cancer. The objective of our study was to assess splenectomy and evaluate its impact on overall and disease-free survival.MethodsWe conducted a retrospective single-center study between January 2000 and December 2016. Patients who underwent a cytoreduction for epithelial ovarian cancer, regardless of stage and surgical approach, were eligible for the study. Patients deemed not operable were excluded from the study. Patients were stratified into two groups, splenectomy or no splenectomy. A univariate analysis followed by a multivariate analysis was conducted to evaluate the postoperative complications after splenectomy and the overall and disease-free survival.ResultsThis cohort included 464 patients. Disease stages, peritoneal carcinomatosis scores, and the rate of radical surgery (Pomel classification) were significantly higher in the splenectomy group, p=0.04, pConclusionSplenectomy may be considered an acceptable and safe procedure; however, with no impact on overall or disease-free survival. In addition, it is associated with longer hospital stay and longer time to chemotherapy.

Background We determined the prognostic impact of lymphovascular invasion (LVI) in a large, national, multicenter, retrospective cohort of patients with early breast cancer (BC) according to numerous factors. Patients and methods We collected data on 17 322 early BC patients treated in 13 French cancer centers from 1991 to 2013. Survival functions were calculated using the Kaplan–Meier method and multivariate survival analyses were carried out using the Cox proportional hazards regression model adjusted for significant variables associated with LVI or not. Two propensity score-based matching approaches were used to balance differences in known prognostic variables associated with LVI status and to assess the impact of adjuvant chemotherapy (AC) in LVI-positive luminal A-like patients. Results LVI was present in 24.3% (4205) of patients. LVI was significantly and independently associated with all clinical and pathological characteristics analyzed in the entire population and according to endocrine receptor (ER) status except for the time period in binary logistic regression. According to multivariate analyses including ER status, AC, grade, and tumor subtypes, the presence of LVI was significantly associated with a negative prognostic impact on overall (OS), disease-free (DFS), and metastasis-free survival (MFS) in all patients [hazard ratio (HR) = 1.345, HR = 1.312, and HR = 1.415, respectively; P < 0.0001], which was also observed in the propensity score-based analysis in addition to the association of AC with a significant increase in both OS and DFS in LVI-positive luminal A-like patients. LVI did not have a significant impact in either patients with ER-positive grade 3 tumors or those with AC-treated luminal A-like tumors. Conclusion The presence of LVI has an independent negative prognostic impact on OS, DFS, and MFS in early BC patients, except in ER-positive grade 3 tumors and in those with luminal A-like tumors treated with AC. Therefore, LVI may indicate the existence of a subset of luminal A-like patients who may still benefit from adjuvant therapy., Highlights • In a study of 17 322 early BC patients, LVI had a significant independent negative prognostic impact on survival. • LVI negatively impacted survival in almost every patient category and cancer subtype, with and without AC. • LVI did not have a negative survival impact in patients with ER+ grade 3 or with luminal A-like tumors with chemotherapy. • Results suggest a possible benefit of AC in LVI-positive luminal A-like patients.

Machine learning has allowed many systems that we interact with to improve performance and personalize. Recommender systems in particular are one of the largest users of machine learning in production environments that have improved performance of real-world systems. Learning in these interactive systems requires models that combine very diverse signals, including the logs of the interactive system (indicating if the intervention succeeded or failed) augmented with other data sources including: collaborative filtering, text, and image data. Bayesian inference is a compelling method to combine these diverse signals in a principled manner, but deployment of systems based on Bayesian principles remain challenging. The reward signal in the system logs is often uneven. Accurate estimation of reward is possible for exploiting actions, but often poor for other actions (exploration). Non-Bayesian methods such as inverse propensity score methods, the reinforce algorithm, and other heuristic-based approaches currently dominate practice. These commonly-used heuristics are often ineffective at leveraging diverse data. In contrast, Bayesian methods offer a principled, robust framework for learning from uneven signals and combining different types of information. Drawing upon the bandit and reinforcement learning community, in this workshop we will explore innovations in Bayesian inference for real world interactive systems, and consider advantages and limitations of the Bayesian approach.

Background Tumour features associated with isolated invasive breast cancer ipsilateral local recurrence (ILR) after breast conservative treatment (BCT) and consequences on overall survival (OS) are still debated. The aim of our study was to examine predictive factors of isolated ILR after BCT with in sano resection and whole breast irradiation as well as the impact of such an ILR on overall survival in a large multi-institutional cohort. Methods Patients were retrospectively identified from a large cohort of 23,375 consecutive patients who underwent BCT for invasive breast cancer in 16 cancer centres. End-points were ILR rate and OS. The impact of ILR on OS was assessed through multivariate analysis by logistic regression and Cox model, adjusted on ERs/Grade status (ERs+/Grade 1, ERs+/Grade 2, ERs+/Grade 3 and ERs-) and then on tumour subtypes. Results Of 15,570 patients, ILR rate was 3.1%. Cumulative ILR rates differed according to ERs/grade (ERs+/Grade2: HR=1.42, p=0.010; ERs+/Grade3: HR=1.41, p=0.067; ERs-: HR=2.14, p Impact of free interval time on OS among patients with ILR and among all patients p-valueHRInfSupILRno ILR 1 Conclusion ERs/Grade status, lack of endocrine therapy and tumour subtypes predict isolated ILR risk in patients treated with BCT. Short ILR-free-intervals represent a strong pejorative factor for OS. These results may help selecting initial treatment as well as tailoring ILR systemic chemotherapy. Citation Format: Houvenaeghel G, de Nonneville A, Cohen M, Classe J-M, Reyal F, Mazouni C, Chopin N, Martinez A, Daraï E, Coutant C, Colombo P-E, Gimbergues P, Chauvet M-P, Azuar A-S, Rouzier R, Tunon de Lara C, Murraciole X, Agostini A, Gonçalves A, Lambaudie E. Isolated ipsilateral local recurrence of breast cancer: Predictive factors and prognostic impact [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-08.

International audience; Pyridazino-1,3a,6a-triazapentalenes (PyTAP) are compact fused 6/5/5 tricyclic scaffolds which exhibit promising fluorescent properties. Chemically stable, they can be post-functionalized using standard Pd-catalyzed cross-coupling chemistry. Several original PyTAP bearing additional unsaturated substituents in positions 2 and 8 were synthetized and their spectroscopic properties analyzed. They have been successfully tested as fluorescent probes for cellular imaging.