Search

Summary: Cancer-associated mesothelial cells (CAMCs) in the tumor microenvironment are thought to promote growth and immune evasion. We find that, in mouse and human ovarian tumors, cancer cells express anti-Müllerian hormone (AMH) while CAMCs express its receptor AMHR2, suggesting a paracrine axis. Factors secreted by cancer cells induce AMHR2 expression during their reprogramming into CAMCs in mouse and human in vitro models. Overexpression of AMHR2 in the Met5a mesothelial cell line is sufficient to induce expression of immunosuppressive cytokines and growth factors that stimulate ovarian cancer cell growth in an AMH-dependent way. Finally, syngeneic cancer cells implanted in transgenic mice with Amhr2−/− CAMCs grow significantly slower than in wild-type hosts. The cytokine profile of Amhr2−/− tumor-bearing mice is altered and their tumors express less immune checkpoint markers programmed-cell-death 1 (PD1) and cytotoxic T lymphocyte-associated protein 4 (CTLA4). Taken together, these data suggest that the AMH/AMHR2 axis plays a critical role in regulating the pro-tumoral function of CAMCs in ovarian cancer.

Abstract Background Attention‐deficit hyperactivity disorder (ADHD) is associated with white matter (WM) microstructure. Our objective was to investigate how WM microstructure is longitudinally related to symptom remission in adolescents and young adults with ADHD. Methods We obtained diffusion‐weighted imaging (DWI) data from 99 participants at two time‐points (mean age baseline: 16.91 years, mean age follow‐up: 20.57 years). We used voxel‐wise Tract‐Based Spatial Statistics (TBSS) with permutation‐based inference to investigate associations of inattention (IA) and hyperactivity‐impulsivity (HI) symptom change with fractional anisotropy (FA) at baseline, follow‐up, and change between time‐points. Results Remission of combined HI and IA symptoms was significantly associated with reduced FA at follow‐up in the left superior longitudinal fasciculus and the left corticospinal tract (CST; PFWE = 0.038 and PFWE = 0.044, respectively), mainly driven by an association between HI remission and follow‐up CST FA (PFWE = 0.049). There was no significant association of combined symptom decrease with FA at baseline or with changes in FA between the two assessments. Conclusions In this longitudinal DWI study of ADHD using dimensional symptom scores, we show that greater symptom decrease is associated with lower follow‐up FA in specific WM tracts. Altered FA thus may appear to follow, rather than precede, changes in symptom remission. Our findings indicate divergent WM developmental trajectories between individuals with persistent and remittent ADHD, and support the role of prefrontal and sensorimotor tracts in the remission of ADHD.

Background: Physical restraint is frequently used in intensive care units to prevent patients' life-threatening removal of indwelling devices. In France, their use is poorly studied. Therefore, to evaluate the need for physical restraint, we have designed and implemented a decision support tool., Aims: Besides describing the prevalence of physical restraint use, this study aimed to assess whether the implementation of a nursing decision support tool had an impact on restraint use and to identify the factors associated with this use., Study Design: A large observational, multicentre study with a repeated one-day point prevalence design was conducted. All adult patients hospitalized in intensive care units were eligible for this study. Two study periods were planned: before (control period) and after (intervention period) the deployment of the decision support tool and staff training. A multilevel model was performed to consider the centre effect., Results: During the control period, 786 patients were included, and 510 were in the intervention period. The prevalence of physical restraint was 28% (95% CI: 25.1%-31.4%) and 25% (95% CI: 21.5%-29.1%) respectively (χ 2  = 1.35; p = .24). Restraint was applied by the nurse and/or nurse assistant in 96% of cases in both periods, mainly to wrists (89% vs. 83%, p = .14). The patient-to-nurse ratio was significantly lower in the intervention period (1:3.0 ± 1 vs. 1:2.7 ± 0.7, p < .001). In multivariable analysis, mechanical ventilation was associated with physical restraint (aOR [95% CI] = 6.0 [3.5-10.2])., Conclusion: The prevalence of physical restraint use in France was lower than expected. In our study, the decision support tool did not substantially impact physical restraint use. Hence, the decision support tool would deserve to be assessed in a randomized controlled trial., Relevance to Clinical Practice: The decision to physically restrain a patient could be protocolised and managed by critical care nurses. A regular evaluation of the level of sedation could allow the most deeply sedated patients to be exempted from physical restraint., (© 2023 British Association of Critical Care Nurses.)

Background: Immune checkpoints and their ligands are important actors of lymphocytes and monocytes activation's regulation. Their expression level within T cells changes with aging. Despite the major impact of aging on monocytes, there is no data about the expression of ICs on monocytes from old patients. The objective of our study is to describe the expression of ICs and their ligands on monocytes from young individuals compared to old patients., Methods: We included 18 old control (>75 years old), 10 young control (<55 years old) and 45 old patients with hip fracture (HF). Phenotypical and functional analyses were performed on cryopreserved PBMCs., Results: There is a differential expression of immune checkpoints and their ligands within monocyte subtypes regardless of age at baseline. After stimulation, a differential expression of immune checkpoints in young subjects but not in old subjects was observed which would be in favor of a regulation defect in old subjects. We hypothesize that this lack of regulation could partially explain the excess production of pro-inflammatory cytokines by the stimulated monocytes in old subjects. In HF, we also observe a differential expression of immune checkpoints, especially in old patients with a poor prognosis., Conclusion: Our results suggest that the immune regulation which should take place post-acute stress may be affected in old individuals., Competing Interests: Declaration of competing interest The authors have no conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)

Background: Very few data have been published on the use of subcutaneous implantable cardioverter-defibrillators (S-ICDs) in patients with congenital heart disease (CHD)., Objectives: The aim of this study was to analyze outcomes associated with S-ICDs in patients with CHD., Methods: This nationwide French cohort including all patients with an S-ICD was initiated in 2020 by the French Institute of Health and Medical Research. Characteristics at implantation and outcomes were analyzed in patients with CHD., Results: From October 12, 2012, to December 31, 2019, among 4,924 patients receiving an S-ICD implant in 150 centers, 101 (2.1%) had CHD. Tetralogy of Fallot, univentricular heart, and dextro-transposition of the great arteries represented almost one-half of the population. Patients with CHD were significantly younger (age 37.1 ± 15.4 years vs 50.1 ± 14.9 years; P < 0.001), more frequently female (37.6% vs 23.0%; P < 0.001), more likely to receive an S-ICD for secondary prevention (72.3% vs 35.9%; P < 0.001), and less likely to have severe systolic dysfunction of the systemic ventricle (28.1% vs 53.1%; P < 0.001). Over a mean follow-up period of 1.9 years, 16 (15.8%) patients with CHD received at least 1 appropriate shock, with all shocks successfully terminating the ventricular arrhythmia. The crude risk of appropriate S-ICD shock was twice as high in patients with CHD compared with non-CHD patients (annual incidences of 9.0% vs 4.4%; HR: 2.1; 95% CI: 1.3-3.4); however, this association was no longer significant after propensity matching (especially considering S-ICD indication, P = 0.12). The burden of all complications (HR: 1.2; 95% CI: 0.7-2.1; P = 0.4) and inappropriate shocks (HR: 0.9; 95% CI: 0.4-2.0; P = 0.9) was comparable in both groups., Conclusions: In this nationwide study, patients with CHD represented 2% of all S-ICD implantations. Our findings emphasize the effectiveness and safety of S-ICD in this particularly high-risk population. (S-ICD French Cohort Study [HONEST]; NCT05302115)., Competing Interests: Funding Support and Author Disclosures This study was supported by the French Institute of Health and Medical Research and Paris-Sudden Death Expertise Center, the French Society of Cardiology (Electrophysiology Working Group), and the French Federation of Cardiology. The Paris Sudden Death Expertise Center activities are supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), the University of Paris, Assistance Publique-Hôpitaux de Paris, Fondation Cœur et Artères, Global Heart Watch, Fédération Française de Cardiologie, Société Française de Cardiologie, and Fondation Recherche Medicale, as well as unrestricted grants from industrial partners (Abbott, Biotronik, Boston Scientific, Medtronic, MicroPort, ZOLL, and Schiller). Dr Waldmann has served as a consultant for Abbott and Medtronic. Dr Marijon has served as a consultant for Boston Scientific, Medtronic, ZOLL, and Abbott. Dr Ollitrault has received consulting fees from Abbott, Biotronik, Boston Scientific, and Medtronic. Dr Champ-Rigot has received consulting fees from Boston Scientific, Medtronic, and MicroPort CRM. Dr Garcia has received grants and honoraria from Boston Scientific. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Following acute stress such as trauma or sepsis, most of critically ill elderly patients become immunosuppressed and susceptible to secondary infections and enhanced mortality. We have developed a virus-based immunotherapy encoding human interleukin-7 (hIL-7) aiming at restoring both innate an adaptative immune homeostasis in these patients. We assessed the impact of this encoded hIL-7 on the ex vivo immune functions of T cells from PBMC of immunosenescent patients with or without hip fracture. T-cell ex vivo phenotyping was characterized in terms of senescence (CD57), IL-7 receptor (CD127) expression, and T cell differentiation profile. Then, post stimulation, activation status, and functionality (STAT5/STAT1 phosphorylation and T cell proliferation assays) were evaluated by flow cytometry. Our data show that T cells from both groups display immunosenescence features, express CD127 and are activated after stimulation by virotherapy-produced hIL-7-Fc. Interestingly, hip fracture patients exhibit a unique functional ability: An important T cell proliferation occurred compared to controls following stimulation with hIL-7-Fc. In addition, stimulation led to an increased naïve T cell as well as a decreased effector memory T cell proportions compared to controls. This preliminary study indicates that the produced hIL-7-Fc is well recognized by T cells and initiates IL-7 signaling through STAT5 and STAT1 phosphorylation. This signaling efficiently leads to T cell proliferation and activation and enables a T cell "rejuvenation." These results are in favor of the clinical development of the hIL-7-Fc expressing virotherapy to restore or induce immune T cell responses in immunosenescent hip fracture patients.

Cancer-associated mesothelial cells (CAMCs) in the tumor microenvironment are thought to promote growth and immune evasion. We find that, in mouse and human ovarian tumors, cancer cells express anti-Müllerian hormone (AMH) while CAMCs express its receptor AMHR2, suggesting a paracrine axis. Factors secreted by cancer cells induce AMHR2 expression during their reprogramming into CAMCs in mouse and human in vitro models. Overexpression of AMHR2 in the Met5a mesothelial cell line is sufficient to induce expression of immunosuppressive cytokines and growth factors that stimulate ovarian cancer cell growth in an AMH-dependent way. Finally, syngeneic cancer cells implanted in transgenic mice with Amhr2 -/- CAMCs grow significantly slower than in wild-type hosts. The cytokine profile of Amhr2 -/- tumor-bearing mice is altered and their tumors express less immune checkpoint markers programmed-cell-death 1 (PD1) and cytotoxic T lymphocyte-associated protein 4 (CTLA4). Taken together, these data suggest that the AMH/AMHR2 axis plays a critical role in regulating the pro-tumoral function of CAMCs in ovarian cancer., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Eighty percent of the estimated 600 million domestic cats in the world are free-roaming. These cats typically experience suboptimal welfare and inflict high levels of predation on wildlife. Additionally, euthanasia of healthy animals in overpopulated shelters raises ethical considerations. While surgical sterilization is the mainstay of pet population control, there is a need for efficient, safe, and cost-effective permanent contraception alternatives. Herein, we report evidence that a single intramuscular treatment with an adeno-associated viral vector delivering an anti-Müllerian hormone transgene produces long-term contraception in the domestic cat. Treated females are followed for over two years, during which transgene expression, anti-transgene antibodies, and reproductive hormones are monitored. Mating behavior and reproductive success are measured during two mating studies. Here we show that ectopic expression of anti-Müllerian hormone does not impair sex steroids nor estrous cycling, but prevents breeding-induced ovulation, resulting in safe and durable contraception in the female domestic cat., (© 2023. The Author(s).)

The estrous cycle is regulated by rhythmic endocrine interactions of the nervous and reproductive systems, which coordinate the hormonal and ovulatory functions of the ovary. Folliculogenesis and follicle progression require the orchestrated response of a variety of cell types to allow the maturation of the follicle and its sequela, ovulation, corpus luteum formation, and ovulatory wound repair. Little is known about the cell state dynamics of the ovary during the estrous cycle and the paracrine factors that help coordinate this process. Herein, we used single-cell RNA sequencing to evaluate the transcriptome of >34,000 cells of the adult mouse ovary and describe the transcriptional changes that occur across the normal estrous cycle and other reproductive states to build a comprehensive dynamic atlas of murine ovarian cell types and states., Competing Interests: MM, MM, MC, HS, AK, NS, NN, SY, RS, MH, PD, BS, DP No competing interests declared, (© 2022, Morris, Meinsohn et al.)

We identified the anti-Mullerian hormone (also known as Müllerian inhibiting substance or MIS) as an inhibitory hormone that induces long-term contraception in mammals. The type II receptor to this hormone, AMHR2 (also known as MISR2), represents a promising druggable target for the modulation of female reproduction with a mechanism of action distinct from steroidal contraceptives. We designed an in vitro platform to screen and validate small molecules that can activate MISR2 signaling and suppress ovarian folliculogenesis. Using a bone morphogenesis protein (BMP)–response element luciferase reporter cell–based assay, we screened 5,440 compounds from a repurposed drug library. Positive hits in this screen were tested for specificity and potency in luciferase dose–response assays, and biological activity was tested in ex vivo Mullerian duct regression bioassays. Selected candidates were further evaluated in ex vivo follicle/ovary culture assays and in vivo in mice and rats. Here, we report that SP600125, CYC-116, gandotinib, and ruxolitinib can specifically inhibit primordial follicle activation and repress folliculogenesis by stimulating the MISR2 pathway.

Purpose: Monte Carlo modelling of SPECT imaging in Molecular Radiotherapy can improve activity quantification. Until now, SPECT modelling with GATE only considered circular orbit (CO) acquisitions. This cannot reproduce auto-contour acquisitions, where the detector head moves close to the patient to improve image resolution. The aim of this work is to develop and validate an auto-contouring step-and-shoot acquisition mode for GATE SPECT modelling., Methods: 177 Lu and 131 I SPECT experimental acquisitions performed on a Siemens Symbia T2 and GE Discovery 670 gamma camera, respectively, were modelled. SPECT projections were obtained for a cylindrical Jaszczak phantom and a lung and spine phantom. Detector head parameters (radial positions and acquisition angles) were extracted from the experimental projections to model the non-circular orbit (NCO) detector motion. The gamma camera model was validated against the experimental projections obtained with the cylindrical Jaszczak ( 177 Lu) and lung and spine phantom ( 131 I). Then, 177 Lu and 131 I CO and NCO SPECT projections were simulated to validate the impact of explicit NCO modelling on simulated projections., Results: Experimental and simulated SPECT images were compared using the gamma index, and were in good agreement with gamma index passing rate (GIPR) and gamma avg of 96.27%, 0.242 ( 177 Lu) and 92.89%, 0.36 ( 131 I). Then, simulated 177 Lu and 131 I CO and NCO SPECT projections were compared. The GIPR, gamma avg between the two gamma camera motions was 99.85%, 0.108 for 177 Lu and 75.58%, 0.6 for 131 I., Conclusion: This work thereby justifies the need for auto-contouring modelling for isotopes with high septal penetration., (Copyright © 2022 Associazione Italiana di Fisica Medica e Sanitaria. All rights reserved.)

Massive CD4+ T-cell depletion as well as sustained immune activation and inflammation are hallmarks of Human Immunodeficiency Virus (HIV)-1 infection. In recent years, an emerging concept draws an intriguing parallel between HIV-1 infection and aging. Indeed, many of the alterations that affect innate and adaptive immune subsets in HIV-infected individuals are reminiscent of the process of immune aging, characteristic of old age. These changes, of which the presumed cause is the systemic immune activation established in patients, likely participate in the immuno-incompetence described with HIV progression. With the success of antiretroviral therapy (ART), HIV-seropositive patients can now live for many years despite chronic viral infection. However, acquired immunodeficiency syndrome (AIDS)-related opportunistic infections have given way to chronic diseases as the leading cause of death since HIV infection. Therefore, the comparison between HIV-1 infected patients and uninfected elderly individuals goes beyond the sole onset of immunosenescence and extends to the deterioration of several physiological functions related to inflammation and systemic aging. In light of this observation, it is interesting to understand the precise link between immune activation and aging in HIV-1 infection to figure out how to best care for people living with HIV (PLWH)., (© 2022 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

There is a persistent bias toward higher prevalence and increased severity of coronavirus disease 2019 (COVID-19) in males. Underlying mechanisms accounting for this sex difference remain incompletely understood. Interferon responses have been implicated as a modulator of COVID-19 disease in adults and play a key role in the placental antiviral response. Moreover, the interferon response has been shown to alter Fc receptor expression and therefore may affect placental antibody transfer. Here, we examined the intersection of maternal-fetal antibody transfer, viral-induced placental interferon responses, and fetal sex in pregnant women infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Placental Fc receptor abundance, interferon-stimulated gene (ISG) expression, and SARS-CoV-2 antibody transfer were interrogated in 68 human pregnancies. Sexually dimorphic expression of placental Fc receptors, ISGs and proteins, and interleukin-10 was observed after maternal SARS-CoV-2 infection, with up-regulation of these features in placental tissue of pregnant individuals with male fetuses. Reduced maternal SARS-CoV-2–specific antibody titers and impaired placental antibody transfer were also observed in pregnancies with a male fetus. These results demonstrate fetal sex-specific maternal and placental adaptive and innate immune responses to SARS-CoV-2.