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Abstract The human spleen contracts in response to stress‐induced catecholamine secretion, resulting in a temporary rise in haemoglobin concentration ([Hb]). Recent findings highlighted enhanced splenic response to exercise at high altitude in Sherpa, possibly due to a blunted splenic response to hypoxia. To explore the potential blunted splenic contraction in Sherpas at high altitude, we examined changes in spleen volume during hyperoxic breathing, comparing acclimatized Sherpa with acclimatized individuals of lowland ancestry. Our study included 14 non‐Sherpa (7 female) residing at altitude for a mean continuous duration of 3 months and 46 Sherpa (24 female) with an average of 4 years altitude exposure. Participants underwent a hyperoxic breathing test at altitude (4300 m; barrometric pressure = ∼430 torr; PO2 = ∼90 torr). Throughout the test, we measured spleen volume using ultrasonography and monitored oxygen saturation (SpO2). During rest, Sherpa exhibited larger spleens (226 ± 70 mL) compared to non‐Sherpa (165 ± 34 mL; P

Abstract Differences in the life history pathways (LHPs) of juvenile animals are often associated with differences in demographic rates in later life stages. For migratory animals, different LHPs often result in animals from the same population occupying distinct habitats subjected to different environmental drivers. Understanding how demographic rates differ among animals expressing different LHPs may reveal fitness trade‐offs that drive the expression of alternative LHPs and enable better prediction of population dynamics in a changing environment. To understand how demographic outcomes and their relationships with environmental variables differ among animals with different LHPs, we analyzed a long‐term (2006–2021) mark–recapture dataset for Chinook salmon (Oncorhynchus tshawytscha) from the Wenatchee River, Washington, USA. Distinct LHPs represented in this population include either remaining in the natal stream until emigrating to the ocean as a 1‐year‐old (natal‐reach rearing) or emigrating from the natal stream and rearing in downstream habitats for several months before completing the emigration to the ocean as a 1‐year‐old (downstream rearing). We found that downstream‐rearing fish emigrated to the ocean 19 days earlier on average and returned as adults from the ocean at higher rates. We detected a positive correlation between rate of return from the ocean by downstream‐rearing fish and coastal upwelling in their spring of outmigration, whereas for natal‐reach‐rearing fish we detected a positive correlation with sea surface temperature during their first marine summer. Different responses to environmental variability should lead to asynchrony in adult abundance among juvenile LHPs. A higher proportion of downstream‐rearing fish returned at younger ages compared with natal‐reach‐rearing fish, which contributed to variability in age at reproduction and greater mixing across generations. Our results demonstrate how diversity in juvenile LHPs is associated with heterogeneity in demographic rates during subsequent life stages, which can in turn affect variance in aggregate population abundance and response to environmental change. Our findings underscore the importance of considering life history diversity in demographic analyses and provide insights into the effects of life history diversity on population dynamics and trade‐offs that contribute to the maintenance of life history diversity.

Stream temperatures in the Pacific Northwest are projected to increase with climate change, placing additional stress on cold-water salmonids. We modeled the potential impact of increased stream temperatures on four anadromous salmonid populations in the Chehalis River Basin (spring-run and fall-run Chinook salmon Oncorhynchus tshawytscha, coho salmon O. kisutch, and steelhead O. mykiss), as well as the potential for floodplain reconnection and stream shade restoration to offset the effects of future temperature increases. In the Chehalis River Basin, peak summer stream temperatures are predicted to increase by as much as 3°C by late-century, but restoration actions can locally decrease temperatures by as much as 6°C. On average, however, basin-wide average stream temperatures are expected to increase because most reaches have low temperature reduction potential for either restoration action relative to climate change. Results from the life cycle models indicated that, without restoration actions, increased summer temperatures are likely to produce significant declines in spawner abundance by late-century for coho (-29%), steelhead (-34%), and spring-run Chinook salmon (-95%), and smaller decreases for fall-run Chinook salmon (-17%). Restoration actions reduced these declines in all cases, although model results suggest that temperature restoration alone may not fully mitigate effects of future temperature increases. Notably, floodplain reconnection provided a greater benefit than riparian restoration for steelhead and both Chinook salmon populations, but riparian restoration provided a greater benefit for coho. This pattern emerged because coho salmon tend to spawn and rear in smaller streams where shade restoration has a larger effect on stream temperature, whereas Chinook and steelhead tend to occupy larger rivers where temperatures are more influenced by floodplain connectivity. Spring-run Chinook salmon are the only population for which peak temperatures affect adult prespawn survival in addition to rearing survival, making them the most sensitive species to increasing stream temperatures.

Systemic sclerosis (SSc) is a rare and complex connective tissue disease associated with high morbidity and mortality. SSc is characterized by ischemic vasculopathy, cutaneous and visceral fibrosis and a dysimmune state (Denton and Khanna, 2017; Volkmann et al., 2023; Barnes and Mayes, 2012). We have derived induced pluripotent stem cell (iPSC) lines from two SSc patients aged 38 and 67 years with severe vascular phenotype. These iPSC lines expressed pluripotent markers, exhibited normal and stable genome, and differentiated into trilineage embryonic layers in teratoma formation assays. These SSc-specific iPSC lines can be differentiated into endothelial cells, providing a valuable model to elucidate vascular dysfunction and develop personalized therapeutic approaches., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Age is the most important risk factor for degenerative diseases such as osteoarthritis (OA). It is associated with the accumulation of senescent cells in joint tissues that contribute to the pathogenesis of OA, in particular through the release of senescence-associated secretory phenotype (SASP) factors. Mesenchymal stromal cells (MSCs) and their derived extracellular vesicles (EVs) are promising treatments for OA. However, the senoprotective effects of MSC-derived EVs in OA have been poorly investigated. Here, we used EVs from human adipose tissue-derived MSCs (ASC-EVs) in two models of inflammaging (IL1β)- and DNA damage (etoposide)-induced senescence in OA chondrocytes. We showed that the addition of ASC-EVs was effective in reducing senescence parameters, including the number of SA-β-Gal-positive cells, the accumulation of γH2AX foci in nuclei and the secretion of SASP factors. In addition, ASC-EVs demonstrated therapeutic efficacy when injected into a murine model of OA. Several markers of senescence, inflammation and oxidative stress were decreased shortly after injection likely explaining the therapeutic efficacy. In conclusion, ASC-EVs exert a senoprotective function both in vitro , in two models of induced senescence in OA chondrocytes and, in vivo , in the murine model of collagenase-induced OA.

Background: . CD8 + Cytotoxic T lymphocytes play a key role in the pathogenesis of autoimmune diseases and clinical conditions such as graft versus host disease and graft rejection. Mesenchymal Stromal Cells (MSCs) are multipotent cells with tissue repair and immunomodulatory capabilities. Since they are able to suppress multiple pathogenic immune responses, MSCs have been proposed as a cellular therapy for the treatment of immune-mediated diseases. However, the mechanisms underlying their immunosuppressive properties are not yet fully understood. MSCs have the remarkable ability to sense tissue injury and inflammation and respond by donating their own mitochondria to neighboring cells. Whether mitochondrial transfer has any role in the repression of CD8 + responses is unknown., Methods and Results: . We have utilized CD8 + T cells from Clone 4 TCR transgenic mice that differentiate into effector cells upon activation in vitro and in vivo to address this question. Allogeneic bone marrow derived MSCs, co-cultured with activated Clone 4 CD8 + T cells, decreased their expansion, the production of the effector cytokine IFNγ and their diabetogenic potential in vivo. Notably, we found that during this interaction leading to suppression, MSCs transferred mitochondria to CD8 + T cells as evidenced by FACS and confocal microscopy. Transfer of MSC mitochondria to Clone 4 CD8 + T cells also resulted in decreased expansion and production of IFNγ upon activation. These effects overlapped and were additive with those of prostaglandin E2 secreted by MSCs. Furthermore, preventing mitochondrial transfer in co-cultures diminished the ability of MSCs to inhibit IFNγ production. Finally, we demonstrated that both MSCs and MSC mitochondria downregulated T-bet and Eomes expression, key transcription factors for CTL differentiation, on activated CD8 + T cells., Conclusion: . In this report we showed that MSCs are able to interact with CD8 + T cells and transfer them their mitochondria. Mitochondrial transfer contributed to the global suppressive effect of MSCs on CD8 + T cell activation by downregulating T-bet and Eomes expression resulting in impaired IFNγ production of activated CD8 + T cells., (© 2024. The Author(s).)

Patients with neuropathic pain often present with variable pain and nonpainful sensory qualities that could serve as outcomes in randomized clinical trials (RCTs). This study aimed to investigate the within-participant variability in the severity of these sensory qualities and whether the means of 7 daily pain quality assessments provide better assay sensitivity (ie, more sensitivity to treatment effects) than single-week recall-based assessments. This secondary analysis used data from an RCT of transcutaneous electrical nerve stimulation for chemotherapy-induced peripheral neuropathy (N = 142). Participants rated the severity of painful and nonpainful sensory qualities using 0 to 10 numeric rating scales daily for 1 week (24-hour recall) and 1 time at the end of each week (week recall) at trial baseline and endpoint (after 6 weeks of treatment). For pain quality assay sensitivity analyses, the 2 types of measures were used to 1) define the study sample (ie, how many participants met minimum baseline pain quality severity) and 2) calculate the observed effect sizes (ie, between-group differences in mean pain qualities) using analysis of covariances. The projected sample sizes required to detect the observed effect sizes in future clinical trials for hot/burning pain and cramping were substantially smaller using the daily mean outcome compared with week recall (ie, hot/burning pain: 153 vs 388, cramping: 121 vs 349), and only marginally larger for sharp/shooting pain (22 participants) with the daily mean outcome. Compared with single-week recall-based assessments of pain qualities, the mean of daily assessments may improve RCT assay sensitivity when used to define entry criteria and assess outcomes. PERSPECTIVE: This study suggests that means of daily pain quality assessments may improve assay sensitivity when used to define entry criteria and assess outcomes in clinical trials. This work may inform design of future clinical trials evaluating the intensity of different pain qualities., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Objectives: To assess the efficacy of a single intradiscal injection of allogeneic bone marrow mesenchymal stromal cells (BM-MSCs) versus a sham placebo in patients with chronic low back pain (LBP)., Methods: Participants were randomised in a prospective, double-blind, controlled study to receive either sham injection or intradiscal injection of 20 million allogeneic BM-MSC, between April 2018 and December 2022. The first co-primary endpoint was the rate of responders defined by improvement of the Visual Analogue Scale (VAS) for pain of at least 20% and 20 mm, or improvement of the Oswestry Disability Index (ODI) of 20% between baseline and month 12. The secondary structural co-primary endpoint was assessed by the disc fluid content measured by quantitative MRI T2, between baseline and month 12. Secondary endpoints included pain VAS, ODI, the Short Form (SF)-36 and the minimal clinically important difference in all timepoints (1, 3, 6, 12 and 24 months). We determined the immune response associated with allogeneic cell injection between baseline and 6 months. Serious adverse events (SAEs) were recorded., Results: 114 patients were randomised (n=58, BM-MSC group; n=56, sham placebo group). At 12 months, the primary outcome was not reached (74% in the BM-MSC group vs 69% in the placebo group; p=0.77). The groups did not differ in all secondary outcomes. No SAE related to the intervention occurred., Conclusions: While our study did not conclusively demonstrate the efficacy of allogeneic BM-MSCs for LBP, the procedure was safe. Long-term outcomes of MSC therapy for LBP are still being studied., Trial Registration Number: EudraCT 2017-002092-25/ClinicalTrials.gov: NCT03737461., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Objective: To explore the clinical relevance and assay sensitivity of using personalized outcomes using data from a randomized clinical trial (RCT) in people with chemotherapy induced peripheral neuropathy (CIPN)., Design: This study is a secondary analysis that leveraged data from a RCT of transcutaneous electrical stimulation for CIPN to test whether personalized outcomes could minimize potential floor effects and increase the assay sensitivity of pain clinical trials (ie, ability to detect a true treatment effect)., Setting: Participants were recruited for a RCT from community oncology clinics in the U.S., Participants: Adults with CIPN (N = 72) who reported on average ≥4 intensity (measured via a 7-day baseline diary) for at least one of the following pain qualities hot/burning pain, sharp/shooting pain and/or cramping., Methods: Personalized outcomes were defined based on participants' unique presentation of pain qualities at baseline, measured via 0-10 numeric rating scales (NRS), or ranking of the distress caused by the pain qualities. Analysis of covariance models estimated the treatment effect as measured by personalized and non-personalized outcomes., Results: The adjusted mean difference between groups was higher using personalized outcomes (ie, 1.21-1.25 NRS points) compared to a non-personalized outcome (ie, 0.97 NRS points), although the standardized effect sizes were similar between outcomes (0.49-0.54)., Conclusions: These results suggest that personalized pain quality outcomes could minimize floor effects, while providing similar assay sensitivity to non-personalized pain quality outcomes. Personalized outcomes better reflect an individual's unique experience, inherently providing more clinically relevant estimates of treatment effects. Personalized outcomes may be advantageous particularly for clinical trials in populations with high inter-individual variability in pain qualities., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Many patients with cancer experience cancer-related cognitive decline (CRCD). Previous studies have shown that elevated S100β, a calcium-binding protein commonly found in glial cells, can exhibit neurotoxic effects, including disruption of the blood-brain barrier (BBB). We studied changes in S100β levels in patients with breast cancer receiving chemotherapy, and the relationship to changes in cognitive function. A total of 505 women with breast cancer (mean (sd) age; 53.4 (53.6)) and 336 age-matched controls without cancer (52.8 (10.3)) were included from a nationwide study as part of the National Cancer Institute Community Oncology Research Program (NCORP). Both groups provided blood samples and completed neurocognitive assessments within 7 days before the patients with breast cancer received their first chemotherapy dose (pre-chemotherapy; T1) and within 1 month of their last chemotherapy administration (post-chemotherapy; T2). Utilizing a linear mixed model, multivariate linear regressions, and Spearman rank correlations (r s ), we investigated longitudinal changes in serum S100β concentrations and their relationships to changes in neurocognitive outcomes over time. We observed an increase in S100β for patients with breast cancer (p = 0.002), but not for controls without cancer over time (p = 0.683). Additionally, we identified subtle relationships between increases in serum S100β and worsening in cognitive performance on the Backward Counting test (r s  = 0.11, p = 0.041) and self-reported FACT-Cog Perceived Cognitive Abilities (r s  = -0.10, p = 0.025). Regression analyses adjusted for age, race, body-mass index (BMI), education, menopausal status, anxiety, and depression revealed a trend remained for the relationship of S100β with Backward Counting. In conclusion, we found that patients with breast cancer experience a significant increase in concentration of serum S100β over the course of chemotherapy. This increase is correlated with worsening in some neurocognitive outcomes from pre-to post-chemotherapy, with trending results remaining following adjustment for covariates., Competing Interests: None., (© 2024 Published by Elsevier Inc.)

Hemophilia A and B are rare X-linked genetic bleeding disorders due to a complete or partial deficiency in the coagulation factors VIII or IX, respectively. The main treatment for hemophilia is prophylactic and based on coagulation factor replacement therapies. These treatments have significantly reduced bleeding and improved the patients' quality of life. Nevertheless, repeated joint bleedings (hemarthroses), even subclinical hemarthroses, can lead to hemophilic arthropathy (HA). This disabling condition is characterized by chronic pain due to synovial inflammation, cartilage and bone destruction requiring ultimately joint replacement. HA resembles to rheumatoid arthritis because of synovitis but HA is considered as having similarities with osteoarthritis as illustrated by the migration of immune cells, production of inflammatory cytokines, synovial hypertrophy and cartilage damage. Various drugs have been evaluated for the management of HA with limited success. The objective of the review is to discuss new therapeutic approaches with a special focus on the studies that have investigated the potential of using mesenchymal stromal cells (MSCs) in the management of HA. A systematic review of the literature has been made. Most of the studies have focused on the interest of MSCs for the delivery of missing factors VIII or IX but in some studies, more insight on the effect of MSC injection on synovial inflammation or cartilage structure were provided and put in perspective for possible clinical applications., Competing Interests: Competing interests The authors declare no competing interests., (Copyright © 2024 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Age is the most important risk factor in degenerative diseases such as osteoarthritis (OA), which is associated with the accumulation of senescent cells in the joints. Here, we aimed to assess the impact of senescence on the therapeutic properties of extracellular vesicles (EVs) from human fat mesenchymal stromal cells (ASCs) in OA. We generated a model of DNA damage-induced senescence in ASCs using etoposide and characterized EVs isolated from their conditioned medium (CM). Senescent ASCs (S-ASCs) produced 3-fold more EVs (S-EVs) with a slightly bigger size and that contain 2-fold less total RNA. Coculture experiments showed that S-ASCs were as efficient as healthy ASCs (H-ASCs) in improving the phenotype of OA chondrocytes cultured in resting conditions but were defective when chondrocytes were proliferating. S-EVs were also impaired in their capacity to polarize synovial macrophages towards an anti-inflammatory phenotype. A differential protein cargo mainly related to inflammation and senescence was detected in S-EVs and H-EVs. Using the collagenase-induced OA model, we found that contrary to H-EVs, S-EVs could not protect mice from cartilage damage and joint calcifications, and were less efficient in protecting subchondral bone degradation. In addition, S-EVs induced a pro-catabolic and pro-inflammatory gene signature in the joints of mice shortly after injection, while H-EVs decreased hypertrophic, catabolic and inflammatory pathways. In conclusion, S-EVs are functionally impaired and cannot protect mice from developing OA., (© 2024. The Author(s).)

Objectives: This study aimed to estimate the prevalence of ANCA-associated vasculitis (AAV). That is, granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), in Southern France in 2018, and evaluate differences among Europeans and non-Europeans., Methods: This population-based, cross-sectional study used four sources (hospitals, community-based physicians, laboratories, National Health Insurance) to identify adults ≥15 years diagnosed with GPA, MPA or EGPA, living in Hérault and Gard in 2018. Cases were defined using the ACR/EULAR classification criteria, and if necessary, the European Medicines Agency algorithm. Prevalence estimates were standardised to the world population and capture-recapture analysis was used to assess the comprehensiveness of the estimation. The influence of geographical origin was evaluated., Results: A total of 202 patients were selected, with 86 cases of GPA (42.6%), 85 cases of MPA (42.1%) and 31 cases of EGPA (15.3%). The standardised prevalence estimates per million inhabitants for 2018 were: 103 (95%CI 84-125) for AAV, 48 (95%CI 35-64) for GPA, 39 (95%CI 28-53) for MPA and 16 (95%CI 9-26) for EGPA, 36 (95%CI 25-50) for anti-PR3 positive AAV, 46 (95%CI 34-61) for anti-MPO positive AAV, and 16 (95%CI 9-26) for ANCA-negative AAV. The global estimation of comprehensiveness by capture-recapture analysis was 80.5%. The number of AAV cases was higher for non-European residents (P = 0.001), particularly for MPA (P < 0.0001)., Conclusion: We provide a new estimate of AAV prevalence in France and show a higher prevalence of MPA in non-European patients., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Acute myocardial infarction (AMI) is the leading cause of cardiovascular death and remains the most common cause of heart failure. Reopening of the occluded artery, i.e., reperfusion, is the only way to save the myocardium. However, the expected benefits of reducing infarct size are disappointing due to the reperfusion paradox, which also induces specific cell death. These ischemia-reperfusion (I/R) lesions can account for up to 50% of final infarct size, a major determinant for both mortality and the risk of heart failure (morbidity). In this review, we provide a detailed description of the cell death and inflammation mechanisms as features of I/R injury and cardioprotective strategies such as ischemic postconditioning as well as their underlying mechanisms. Due to their biological properties, the use of mesenchymal stromal/stem cells (MSCs) has been considered a potential therapeutic approach in AMI. Despite promising results and evidence of safety in preclinical studies using MSCs, the effects reported in clinical trials are not conclusive and even inconsistent. These discrepancies were attributed to many parameters such as donor age, in vitro culture, and storage time as well as injection time window after AMI, which alter MSC therapeutic properties. In the context of AMI, future directions will be to generate MSCs with enhanced properties to limit cell death in myocardial tissue and thereby reduce infarct size and improve the healing phase to increase postinfarct myocardial performance.

Background: Initially discovered for its ability to regenerate ear holes, the Murphy Roth Large (MRL) mouse has been the subject of multiple research studies aimed at evaluating its ability to regenerate other body tissues and at deciphering the mechanisms underlying it. These enhanced abilities to regenerate, retained during adulthood, protect the MRL mouse from degenerative diseases such as osteoarthritis (OA). Here, we hypothesized that mesenchymal stromal/stem cells (MSC) derived from the regenerative MRL mouse could be involved in their regenerative potential through the release of pro-regenerative mediators., Method: To address this hypothesis, we compared the secretome of MRL and BL6 MSC and identified several candidate molecules expressed at significantly higher levels by MRL MSC than by BL6 MSC. We selected one candidate, Plod2, and performed functional in vitro assays to evaluate its role on MRL MSC properties including metabolic profile, migration, and chondroprotective effects. To assess its contribution to MRL protection against OA, we used an experimental model for osteoarthritis induced by collagenase (CiOA)., Results: Among the candidate molecules highly expressed by MRL MSC, we focused our attention on procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2). Plod2 silencing induced a decrease in the glycolytic function of MRL MSC, resulting in the alteration of their migratory and chondroprotective abilities in vitro. In vivo, we showed that Plod2 silencing in MRL MSC significantly impaired their capacity to protect mouse from developing OA., Conclusion: Our results demonstrate that the chondroprotective and therapeutic properties of MRL MSC in the CiOA experimental model are in part mediated by PLOD2., (© 2024. The Author(s).)

We report molecular dynamics simulations of rhodamine entry into the central binding cavity of P-gp in the inward open conformation. Rhodamine can enter the inner volume via passive transport across the luminal membrane or lateral diffusion in the lipid bilayer. Entry into the inner volume is determined by the aperture angle at the apex of the protein, with a critical angle of 27° for rhodamine. The central binding cavity has an aqueous phase with a few lipids, which significantly reduces substrate diffusion. Within the central binding cavity, we identified regions with relatively weak binding, suggesting that the combination of reduced mobility and weak substrate binding confines rhodamine to enable the completion of the efflux cycle. Tariquidar, a P-gp inhibitor, aggregates at the lower arms of the P-gp, suggesting that inhibition involves steric hindrance of entry into the inner volume and/or steric hindrance of access of ATP to the nucleotide-binding domains.

Competing Interests: Competing interests: None declared.

Objective: While the incidence and type of blood malignancies are well documented amid primary Sjögren's syndrome patients (pSS), data focusing on solid neoplasms are more conflicting. We aimed to describe clinical, pathological, and immunological characteristics of pSS patients with cancers, along with the chronological interplay between the two conditions., Methods: Outcomes concerning both pSS and cancer were retrospectively collected from Montpellier University Hospital (tertiary center) between 2019 and 2020. pSS characteristics were compared to a control group of pSS patients without cancer., Results: A total of 165 patients with pSS were included: 55 patients with cancer (52 female, mean age 58.4 ± 10.4 years at pSS diagnosis; mean follow-up 10.5 ± 10.1 years, 12 patients had multiple cancers) and 110 controls without cancer. Characteristics of pSS patients with cancers were different from controls mostly for lymphoma prognosis factors. Among the 70 cancers, we recorded 55 solid neoplasms (whom 27 breast cancers and 8 lung cancers, and 82% of adenocarcinomas), with no evidence of disease at the end of follow-up in 85% of them. Among the 15 recorded blood malignancies, ten were lymphomas with an excellent prognosis. Regarding chronological interplay between cancer and pSS, most cancers (43%) were diagnosed close (± 5 years) to pSS diagnosis. Breast cancers were diagnosed before or close to pSS diagnosis (mean delay - 1.8 ± 13.0 years), at an early stage, with only two relapses (no cancer-related death), while lung cancers were diagnosed late after., Conclusions: The tight chronological interplay between breast cancer and pSS and the intriguing pathological and immunological pattern of pSS in these patients suggest a hypothesis of immune control of cancer., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The incidence of rheumatic diseases such as rheumatoid arthritis and osteoarthritis and injuries to articular cartilage that lead to osteochondral defects is predicted to rise as a result of population ageing and the increase in high-intensity physical activities among young and middle-aged people. Current treatments focus on the management of pain and joint functionality to improve the patient's quality of life, but curative strategies are greatly desired. In the past two decades, the therapeutic value of mesenchymal stromal cells (MSCs) has been evaluated because of their regenerative potential, which is mainly attributed to the secretion of paracrine factors. Many of these factors are enclosed in extracellular vesicles (EVs) that reproduce the main functions of parental cells. MSC-derived EVs have anti-inflammatory, anti-apoptotic as well as pro-regenerative activities. Research on EVs has gained considerable attention as they are a potential cell-free therapy with lower immunogenicity and easier management than whole cells. MSC-derived EVs can rescue the pathogenetic phenotypes of chondrocytes and exert a protective effect in animal models of rheumatic disease. To facilitate the therapeutic use of EVs, appropriate cell sources for the production of EVs with the desired biological effects in each disease should be identified. Production and isolation of EVs should be optimized, and pre-isolation and post-isolation modifications should be considered to maximize the disease-modifying potential of the EVs., (© 2023. Springer Nature Limited.)

The treatment of various disorders of the central nervous system (CNS) is often impeded by the limited brain exposure of drugs, which is regulated by the human blood-brain barrier (BBB). The screening of lead compounds for CNS penetration is challenging due to the biochemical complexity of the BBB, while experimental determination of permeability is not feasible for all types of compounds. Here we present a novel method for rapid preclinical screening of libraries of compounds by utilizing advancements in computing hardware, with its foundation in transition-based counting of the flux. This method has been experimentally validated for in vitro permeabilities and provides atomic-level insights into transport mechanisms. Our approach only requires a single high-temperature simulation to rank a compound relative to a library, with a typical simulation time converging within 24 to 72 h. The method offers unbiased thermodynamic and kinetic information to interpret the passive transport of small-molecule drugs across the BBB., (© 2023. The Author(s).)

2-Hydroxyglutarate (2HG) is a byproduct of the tricarboxylic acid (TCA) cycle and is readily detected in the tissues of healthy individuals. 2HG is found in two enantiomeric forms: S-2HG and R-2HG. Here, we investigate the differential roles of these two enantiomers in cluster of differentiation (CD)8 + T cell biology, where we find they have highly divergent effects on proliferation, differentiation, and T cell function. We show here an analysis of structural determinants that likely underlie these differential effects on specific α-ketoglutarate (αKG)-dependent enzymes. Treatment of CD8 + T cells with exogenous S-2HG, but not R-2HG, increased CD8 + T cell fitness in vivo and enhanced anti-tumor activity. These data show that S-2HG and R-2HG should be considered as two distinct and important actors in the regulation of T cell function., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Articular cartilage (AC)'s main function is to resist to a stressful mechanical environment, and chondrocytes are responding to mechanical stress for the development and homeostasis of this tissue. However, current knowledge on processes involved in response to mechanical stimulation is still limited. These mechanisms are commonly investigated in engineered cartilage models where the chondrocytes are included in an exogeneous biomaterial different from their natural extracellular matrix. The aim of the present study is to better understand the impact of mechanical stimulation on mesenchymal stromal cells (MSCs)-derived chondrocytes generated in their own extracellular matrix., Methods: A fluidic custom-made device was used for the mechanical stimulation of cartilage micropellets obtained from human MSCs by culture in a chondrogenic medium for 21 days. Six micropellets were positioned into the conical wells of the device chamber and stimulated with different signals of positive pressure (amplitude, frequency and duration). A camera was used to record the sinking of each micropellet into their cone, and micropellet deformation was analyzed using a finite element model. Micropellets were harvested at different time points after stimulation for RT-qPCR and histology analysis., Results: Moderate micropellet deformation was observed during stimulation with square pressure signals as mean von Mises strains between 6.39 and 14.35% were estimated for amplitudes of 1.75-14 kPa superimposed on a base pressure of 50% of the amplitude. The compression, tension and shear observed during deformation did not alter micropellet microstructure as shown by histological staining. A rapid and transient increase in the expression of chondrocyte markers (SOX9, AGG and COL2B) was measured after a single 30-min stimulation with a square pressure signal of 3.5 kPa amplitude superimposed on a minimum pressure of 1.75 kPa, at 1 Hz. A small change of 1% of cyclical deformations when using a square pressure signal instead of a constant pressure signal induced a fold change of 2 to 3 of chondrogenic gene expression. Moreover, the expression of fibrocartilage (COL I) or hypertrophic cartilage (COL X, MMP13 and ADAMTS5) was not significantly regulated, except for COL X., Conclusions: Our data demonstrate that the dynamic deformation of cartilage micropellets by fluidic-based compression modulates the expression of chondrocyte genes responsible for the production of a cartilage-like extracellular matrix. This lays the foundations for further investigating the chondrocyte mechanobiology and the cartilage growth under mechanical stimulation., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Senescent cells promote progressive tissue degeneration through the establishment of a combined inflammatory and trophic microenvironment. The cellular senescence state has therefore emerged as a central driving mechanism of numerous age-related diseases, including osteoarthritis (OA), the most common rheumatic disease. Senescence hallmarks are detectable in chondrocytes, synoviocytes and sub-chondral bone cells. This study investigates how the senescence-driven microenvironment could impact the cell fate of resident osteoarticular mesenchymal stromal/stem cells (MSCs) that are hence contributing to OA disease progression. For that purpose, we performed a comparative gene expression analysis of MSCs isolated from healthy donors that were in vitro chronically exposed either to interferon-gamma (IFN-γ) or Transforming Growth Factor beta 1 (TGFβ1), two archetypical factors produced by senescent cells. Both treatments reduced MSC self-renewal capacities by upregulating different senescence-driven cycle-dependent kinase inhibitors. Furthermore, a common set of differentially expressed genes was identified in both treated MSCs that was also found enriched in MSCs isolated from OA patients. These findings highlight an imprinting of OA MSCs by the senescent joint microenvironment that changes their matrisome gene expression. Altogether, this research gives new insights into OA etiology and points to new innovative therapeutic opportunities to treat OA patients.

Hemophilia is a rare congenital bleeding disorder caused by deficiency in coagulation factors VIII or IX, which is treated with prophylactic clotting factor concentrates. Nevertheless despite prophylaxis, spontaneous joint bleedings or hemarthroses still occur. The recurrent hemarthroses lead to progressive degradation of the joints and severe hemophilic arthropathy (HA) in patients with moderate and even mild forms of the disease. In absence of disease modifying treatment to stop or even delay HA progression, we aimed at evaluating the therapeutic potential of mesenchymal stromal cells (MSCs)-based therapy. We first developed a relevant and reproducible in vitro model of hemarthrosis relying on blood exposure of primary murine chondrocytes. We found that 30% whole blood for 4 days allowed to induce the characteristic features of hemarthrosis including low survival of chondrocytes, apoptosis induction, and dysregulation of chondrocyte markers in favor of a catabolic and inflammatory phenotype. We then evaluated the potential therapeutic effects of MSCs in this model using different conditions of coculture. Addition of MSCs improved the survival of chondrocytes when added either during the resolution or the acute phases of hemarthrosis and exerted a chondroprotective effect by enhancing the expression of anabolic markers, and reducing the expression of catabolic and inflammatory markers. We here provide the first proof-of-concept that MSCs may exert a therapeutic effect on chondrocytes under hemarthrosis conditions using a relevant in vitro model, thereby confirming a potential therapeutic interest for patients with recurrent joint bleedings., Competing Interests: The authors have no conflict of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Knee osteoarthritis (OA) is a degenerative joint disease of the knee that results from the progressive loss of articular cartilage. It is most common in the elderly and affects millions of people worldwide, leading to a continuous increase in the number of total knee replacement surgeries. These surgeries improve the patient's physical mobility, but can lead to late infection, loosening of the prosthesis, and persistent pain. We would like to investigate if cell-based therapies can avoid or delay such surgeries in patients with moderate OA by injecting expanded autologous peripheral blood derived CD34+ cells (ProtheraCytes ® ) into the articular joint. In this study we evaluated the survival of ProtheraCytes ® when exposed to synovial fluid and their performance in vitro with a model consisting of their co-culture with human OA chondrocytes in separate layers of Transwells and in vivo with a murine model of OA. Here we show that ProtheraCytes ® maintain high viability (>95%) when exposed for up to 96 hours to synovial fluid from OA patients. Additionally, when co-cultured with OA chondrocytes, ProtheraCytes ® can modulate the expression of some chondrogenic (collagen II and Sox9) and inflammatory/degrading (IL1β, TNF, and MMP-13) markers at gene or protein levels. Finally, ProtheraCytes ® survive after injection into the knee of a collagenase-induced osteoarthritis mouse model, engrafting mainly in the synovial membrane, probably due to the fact that ProtheraCytes ® express CD44, a receptor of hyaluronic acid, which is abundantly present in the synovial membrane. This report provides preliminary evidence of the therapeutic potential of CD34+ cells on OA chondrocytes in vitro and their survival after in vivo implantation in the knee of mice and merits further investigation in future preclinical studies in OA models., Competing Interests: CV, AG, MK, PH, and IG were employees and stockholders of CellProthera. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Vignon, Hilpert, Toupet, Goubaud, Noël, de Kalbermatten, Hénon, Jorgensen, Barbero and Garitaonandia.)

In the world of clinic treatments, 3D-printed tissue constructs have emerged as a less invasive treatment method for various ailments. Printing processes, scaffold and scaffold free materials, cells used, and imaging for analysis are all factors that must be observed in order to develop successful 3D tissue constructs for clinical applications. However, current research in 3D bioprinting model development lacks diverse methods of successful vascularization as a result of issues with scaling, size, and variations in printing method. This study analyzes the methods of printing, bioinks used, and analysis techniques in 3D bioprinting for vascularization. These methods are discussed and evaluated to determine the most optimal strategies of 3D bioprinting for successful vascularization. Integrating stem and endothelial cells in prints, selecting the type of bioink according to its physical properties, and choosing a printing method according to physical properties of the desired printed tissue are steps that will aid in the successful development of a bioprinted tissue and its vascularization.

Osteoarthritis (OA) is the most prevalent rheumatic disease and a fast growing cause of disability. Current pharmacological treatments include antalgics and non-steroid anti-inflammatory drugs to control pain and inflammation as well as slow acting drugs such as intra-articular (IA) administration of hyaluronic acid. Oral supplementation or diet rich in polyunsaturated free fatty acids are proposed but evidence for benefit is still under debate. We here investigated the therapeutic potential of ARA 3000 BETA, an injectable copolymer of fatty acids, at the structural level in OA. Collagenase-induced osteoarthritis model was induced in C57BL/6 mice by collagenase injection into knee joint. Mice were treated with one or two IA or four intra-muscular injections (IM) of ARA 3000 BETA. At sacrifice, knee joints were recovered for cartilage analysis by confocal laser scanning microscopy (CLSM) and bone analysis by micro-computed tomography system. OA histological scoring was performed after safranin O/fast green staining. Histological analysis revealed a protective effect against cartilage degradation in treated knee joints after IM and IA administration. This was confirmed by CLSM with a significant improvement of all articular cartilage parameters, including thickness, volume and surface degradation whatever the administration route. A slight protective effect was also noticed on subchondral bone parameters and knee joint calcification after IM administration and to a lesser extent, two IA injections. We demonstrated the therapeutic efficacy of injectable ARA 3000 BETA in OA with a protection against cartilage and bone alterations providing the proof-of-concept that clinical translation might be envisioned to delay disease progression., (© 2023. The Author(s).)

Objective: Cartilage, as the majority of adult mammalian tissues, has limited regeneration capacity. Cartilage degradation consecutive to joint injury or aging then leads to irreversible joint damage and diseases. In contrast, several vertebrate species such as the zebrafish have the remarkable capacity to spontaneously regenerate skeletal structures after severe injuries. The objective of our study was to test the regenerative capacity of Meckel's cartilage (MC) upon mechanical injury in zebrafish and to identify the mechanisms underlying this process. Methods and Results: Cartilage regenerative capacity in zebrafish larvae was investigated after mechanical injuries of the lower jaw MC in TgBAC(col2a1a:mCherry) , to visualize the loss and recovery of cartilage. Confocal analysis revealed the formation of new chondrocytes and complete regeneration of MC at 14 days post-injury (dpi) via chondrocyte cell cycle re-entry and proliferation of pre-existing MC chondrocytes near the wound. Through expression analyses, we showed an increase of nrg1 expression in the regenerating lower jaw, which also expresses Nrg1 receptors, ErbB3 and ErbB2. Pharmacological inhibition of the ErbB pathway and specific knockdown of Nrg1 affected MC regeneration indicating the pivotal role of this pathway for cartilage regeneration. Finally, addition of exogenous NRG1 in an in vitro model of osteoarthritic (OA)-like chondrocytes induced by IL1β suggests that Nrg1/ErbB pathway is functional in mammalian chondrocytes and alleviates the increased expression of catabolic markers characteristic of OA-like chondrocytes. Conclusion: Our results show that the Nrg1/ErbB pathway is required for spontaneous cartilage regeneration in zebrafish and is of interest to design new therapeutic approaches to promote cartilage regeneration in mammals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sapède, Bahraoui, Abou Nassif, Barthelaix, Mathieu, Jorgensen and Djouad.)

Biopolymers are ideal candidates for the development of hydrogels for tissue engineering applications. However, chemical modifications are required to further improve their mechanical properties, in particular to cross-link them for long-lasting applications or biofabrication. Herein, we developed a novel gelatin-based hydrogel precursor, "GelmSi" which consist on modified gelatin with triethoxysilyl groups. Gelatin was chosen as starting material because of its biocompatibility and bioactivity, favouring cell adhesion and migration. Alkoxysilane moieties were introduced in a controlled manner on the lysine side chains of gelatin to obtain a hybrid precursor which reacts in physiological conditions, forming covalent siloxane bonds and allowing the formation of a three-dimensional chemical network. On the contrary to unmodified gelatin, siloxane covalent network dramatically increases the stiffness and the thermal stability of the resulting gelatin-based hydrogel, making it suitable for cell encapsulation and cell culture. The biorthogonality and versatility of the GelmSi hybrid hydrogel unlock a broad range of gelatin-based bioengineering applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Mesenchymal stem/stromal cells (MSCs) are multipotent cells with strong tissue repair and immunomodulatory properties. Due to their ability to repress pathogenic immune responses, and in particular T cell responses, they show therapeutic potential for the treatment of autoimmune diseases, organ rejection and graft versus host disease. MSCs have the remarkable ability to export their own mitochondria to neighboring cells in response to injury and inflammation. However, whether mitochondrial transfer occurs and has any role in the repression of CD4 + Th1 responses is unknown., Methods and Results: In this report we have utilized CD4 + T cells from HNT TCR transgenic mice that develop Th1-like responses upon antigenic stimulation in vitro and in vivo. Allogeneic bone marrow-derived MSCs reduced the diabetogenic potential of HNT CD4 + T cells in vivo in a transgenic mouse model of disease. In co-culture experiments, we have shown that MSCs were able to reduce HNT CD4 + T cell expansion, expression of key effector markers and production of the effector cytokine IFNγ after activation. This was associated with the ability of CD4 + T cells to acquire mitochondria from MSCs as evidenced by FACS and confocal microscopy. Remarkably, transfer of isolated MSC mitochondria to CD4 + T cells resulted in decreased T cell proliferation and IFNγ production. These effects were additive with those of prostaglandin E2 secreted by MSCs. Finally, we demonstrated that both co-culture with MSCs and transfer of isolated MSC mitochondria prevent the upregulation of T-bet, the master Th1 transcription factor, on activated CD4 + T cells., Conclusion: The present study demonstrates that transfer of MSC mitochondria to activated CD4 + T cells results in the suppression of Th1 responses in part by downregulating T-bet expression. Furthermore, our studies suggest that MSC mitochondrial transfer might represent a general mechanism of MSC-dependent immunosuppression., (© 2023. The Author(s).)

COVID-19 is caused by the infection of the lungs by SARS-CoV-2. Monoclonal antibodies, such as sotrovimab, showed great efficiency in neutralizing the virus before its internalization by lung epithelial cells. However, parenteral routes are still the preferred route of administration, even for local infections, which requires injection of high doses of antibody to reach efficacious concentrations in the lungs. Lung administration of antibodies would be more relevant requiring lower doses, thus reducing the costs and the side effects. But aerosolization of therapeutic proteins is very challenging, as the different processes available are harsh and trigger protein aggregation and conformational changes. This decreases the efficiency of the treatment, and can increase its immunogenicity. To address those issues, we developed a series of new excipients composed of a trehalose core, a succinyl side chain and a hydrophobic carbon chain (from 8 to 16 carbons). Succinylation increased the solubility of the excipients, allowing their use at relevant concentrations for protein stabilization. In particular, the excipient with 16 carbons (C 16 TreSuc) used at 5.6 mM was able to preserve colloidal stability and antigen-binding ability of sotrovimab during the nebulization process. It could also be used as a cryoprotectant, allowing storage of sotrovimab in a lyophilized form during weeks. Finally, we demonstrated that C 16 TreSuc could be used as an excipient to stabilize antibodies for the treatment against COVID-19, by in vitro and in vivo assays. The presence of C 16 TreSuc during nebulization preserved the neutralization capacity of sotrovimab against SARS-CoV-2 in vitro; an increase of its efficacy was even observed, compared to the non-nebulized control. The in vivo study also showed the wide distribution of sotrovimab in mice lungs, after nebulization with 5.6 mM of excipient. This work brings a solution to stabilize therapeutic proteins during storage and nebulization, making pulmonary immunotherapy possible in the treatment of COVID-19 and other lung diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Cell therapy is becoming established in many fields, including oncology with CAR-Ts or in regenerative medicine for cardiovascular diseases, diabetes or musculoskeletal disorders with mesenchymal stromal cells. These therapeutic cells are called advanced therapy medicinal products (ATMPs) and include all processes including cells manipulated to obtain reprogramming (iPS), to induce gene expression or by genome editing to modify the expression of a gene. The development of new biomaterial supports that can be 3D printed and take the desired shape of the target tissue before being colonised by the cellular elements necessary for their biological functions and replace the failing organ. All of these new technologies are driving innovation and the development of tomorrow&#8217;s bio-medicines. These new biotherapies will profoundly modify patient care in all areas, changing medical practices but with a considerable societal impact. Thus, the development and clinical research on cellular biotherapies are essential health issues but with a major ethical, societal and economic impact.

The annual "Antibody Industrial Symposium", co-organized by LabEx MAbImprove and MabDesign, held its 10th anniversary edition in Montpellier, France, on June 28-29, 2022. The meeting focused on new results and concepts in antibody engineering (naked, mono- or multi-specific, conjugated to drugs or radioelements) and also on new cell-based therapies, such as chimeric antigenic receptor (CAR)-T cells. The symposium, which brought together scientists from academia and industry, also addressed issues concerning the production of these molecules and cells, and the necessary steps to ensure a strong intellectual property protection of these new molecules and approaches. These two days of exchanges allowed a rich discussion among the various actors in the field of therapeutic antibodies.

Background: Mesenchymal stem/stromal cells (MSCs) have been widely used for their therapeutic properties in many clinical applications including osteoarthritis. Despite promising preclinical results showing the ability of MSC to reduce the clinical severity of osteoarthritis (OA) in experimental animal models, the benefits of intra-articular injection of MSC in OA patients are limited to the short term. In this regard, it is anticipated that improving the properties of MSC may collectively enhance their long-term beneficial effects on OA., Methods and Results: Recently, we have shown that PPAR β / δ inhibition using a commercially available antagonist in murine MSC increases their immunoregulatory potential in vitro as well as their therapeutic potential in an experimental murine arthritis model. Here, we relied on an innovative strategy to inhibit PPAR β / δ :NF- κ B TF65 subunit interaction in human MSC by designing and synthesizing an interfering peptide, referred to PP11. Through RT-qPCR experiments, we evidenced that the newly synthesized PP11 peptide reduced the expression level of PDK4 , a PPAR β / δ target gene, but did not modify the expression levels of ACOX1 and CPT1A , PPAR α target genes, and FABP4 , a PPAR γ target gene compared with untreated human MSC. Moreover, we showed that human MSCs pretreated with PP11 exhibit a significantly higher capacity to inhibit the proliferation of activated PBMC and to decrease the frequency of M1-like macrophages., Conclusions: We designed and synthesized an interfering peptide that potently and specifically blocks PPAR β / δ activity with concomitant enhancement of MSC immunoregulatory properties., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Gautier Tejedor et al.)

The pancreatic tumor microenvironment drives deregulated nutrient availability. Accordingly, pancreatic cancer cells require metabolic adaptations to survive and proliferate. Pancreatic cancer subtypes have been characterized by transcriptional and functional differences, with subtypes reported to exist within the same tumor. However, it remains unclear if this diversity extends to metabolic programming. Here, using metabolomic profiling and functional interrogation of metabolic dependencies, we identify two distinct metabolic subclasses among neoplastic populations within individual human and mouse tumors. Furthermore, these populations are poised for metabolic cross-talk, and in examining this, we find an unexpected role for asparagine supporting proliferation during limited respiration. Constitutive GCN2 activation permits ATF4 signaling in one subtype, driving excess asparagine production. Asparagine release provides resistance during impaired respiration, enabling symbiosis. Functionally, availability of exogenous asparagine during limited respiration indirectly supports maintenance of aspartate pools, a rate-limiting biosynthetic precursor. Conversely, depletion of extracellular asparagine with PEG-asparaginase sensitizes tumors to mitochondrial targeting with phenformin., (© 2022. The Author(s).)

Recent advances in cell reprogramming showed that OSKM induction is able to improve cell physiology in vitro and in vivo. Here, we show that a single short reprogramming induction is sufficient to prevent musculoskeletal functions deterioration of mice, when applied in early life. In addition, in old age, treated mice have improved tissue structures in kidney, spleen, skin, and lung, with an increased lifespan of 15% associated with organ-specific differential age-related DNA methylation signatures rejuvenated by the treatment. Altogether, our results indicate that a single short reprogramming early in life might initiate and propagate an epigenetically related mechanism to promote a healthy lifespan., (© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

During many years, chemo-immunotherapy fludarabine-cyclophosphamide-rituximab (FCR) was the gold standard for first line treatment of medically fit patients with symptomatic B-chronic lymphocytic leukemia (CLL). Over the last decade, targeted biotherapies have revolutionized the treatment of B-CLL patients and almost entirely supplanted FCR. However, no biomarker still exists to predict the complete remission (CR) with undetectable minimal residual disease (uMRD) in bone marrow (BM), which remains the best predictive factor for survival. MicroRNAs represent a class of molecular biomarkers which expression is altered in B-CLL. Our study aimed at identifying before treatment blood miRNAs that predict treatment outcome in previously untreated B-CLL patients (NCT01370772, https://clinicaltrials.gov/ct2/show/NCT01370772). Using hierarchical clustering of miRNA expression profiles discriminating 8 patients who achieved CR with BM uMRD from 8 patients who did not achieve CR and displayed detectable BM MRD, we identified 25 miRNAs differentially expressed before treatment. The expression of 11 miRNAs was further validated on a larger cohort (n=123). Based on the dosage of 5 miRNAs at diagnosis, a decision tree was constructed to predict treatment outcome. We identified 6 groups of patients with a distinct probability of being CR with BM uMRD to FCR treatment, ranging from 72% (miR-125b, miR-15b and miR-181c high) to 4% (miR-125b and miR-193b low). None of the patients displaying high expression levels of miR-125b, miR-15b and miR-181c relapsed during study follow-up. In contrast, patients with low miR-15b and high miR-412, or with low miR-125b and miR-193b, demonstrated significant low PFS. RNA sequencing of blood at diagnosis identified that patients relapsing after treatment are characterized by significant enrichment of gene signatures related to cell cycle, MYC target genes, metabolism and translation regulation. Conversely, patients achieving CR with BM uMRD displayed significant enrichment in genes related to communication between CLL cells and the microenvironment, immune system activation and upregulation of polycomb PRC2 complex target genes. Our results suggest that blood miRNAs are potent predictive biomarkers for FCR treatment efficacy and might be implicated in the FCR efficacy in B-CLL patients, providing new insight into unmet need for the treatment of B-CLL patients and identifying pathways predictive of patients' remission., Clinical Trial Registration: ClinicalTrials.gov, identifier NCT01370772., Competing Interests: Author GC received consultancy by Roche and BMS and honoraria from Roche, BMS, Jansen, Novartis and Gilead. Author ET received consultancy and honoraria from Janssen and Abbvie. Author SL received honoraria from Gilead, Janssen, Beigene, Abbvie, Astra Zeenca. Author OK was employed by Erasmus Mundus (2013-2016). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2022 Duroux-Richard, Gagez, Alaterre, Letestu, Khalifa, Jorgensen, Leprêtre, Tchernonog, Moreaux, Cartron and Apparailly.)

Objectives: Rheumatoid arthritis (RA) is a prevalent and disabling disease that is the source of significant direct and indirect costs. The current recommended therapeutic strategy is based on the rapid introduction of therapy with conventional Disease-Modifying Anti-Rheumatic Drugs (DMARDs) combined with regular disease monitoring by the rheumatologist. The onerous nature of such intense monitoring has motivated the development of new, less demanding strategies such as telemedicine. This study aimed to estimate the cost-effectiveness of the connected monitoring of RA patients initiating a new DMARD therapy versus conventional monitoring., Methods: An economic evaluation based on a randomized controlled trial of 89 patients was conducted. The patients in the intervention group (n=45) were monitored using a connected monitoring interface on a smartphone, while patients in the control group (n=44) were conventionally monitored. Health outcomes were measured as the gain in quality-adjusted life-years (QALYs), assessed using the EuroQol-5D questionnaire. Resource use and health outcomes were collected alongside the trial and at the six-month follow-up using application data and the related clinical case manager time, visits, hospitalisations, and transport records. These outcomes were valued using externally collected data on unit costs and QALY weights., Results: Compared to conventionally monitored patients, patients receiving connected monitoring had a slightly greater but not significant gain in the average QALY of 0.07. The economic analysis found that connected monitoring resulted in a significant cost reduction of 72€ (2927€ vs. 2999€, P&lt;0.01). The incremental cost-utility ratio of the intervention was equal to -1,029€ per QALY (95% CI: -32,033; +24,625) with a 97.8% chance of being cost-effective at a threshold of 30,000€ per QALY gained., Conclusion: Implementing EULAR recommendations for RA patients initiating a DMARD treatment using connected monitoring is more efficient and less expensive than conventional care., Clinical Trial Registration Number: ClinicalTrials.gov (NCT03005925)., (Copyright © 2022 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.)

Even prior to the COVID-19 pandemic, higher education was facing pressure both to modify traditional instruction practices to more learner-centered instruction and to meet the increased demand for flexible instruction (including hybrid and online). These pressures have increased the need for high quality, engaging content for instruction across all modalities (including in-person, hybrid, and online). To address this need of neuroscience educators, we developed the FUN Exchange, an online repository that is accessible to educators without a paid membership and that is endorsed by the Faculty of Undergraduate Neuroscience organization. Furthermore, the resource is community-driven, allowing educators to contribute and vet submissions to the Exchange. Hosted on AirTable, there are currently more than 475 resources available that are organized by resource type ranging from Class Activities to Simulation Exercises and that can be searched by subject area as well as key words. We believe the FUN Exchange can be a one-stop shop for educators interested in high-quality neuroscience teaching resources useful for all teaching modalities-in-person, hybrid, and online., (Copyright © 2022 Faculty for Undergraduate Neuroscience.)

Extracellular vesicles (EVs) are being widely investigated as acellular therapeutics in regenerative medicine applications. EVs isolated from mesenchymal stromal cells (MSCs) are by far the most frequently used in preclinical models for diverse therapeutic applications, including inflammatory, degenerative, or acute diseases. Although they represent promising tools as cell-free therapeutic agents, one limitation to their use is related to the batch-to-batch unreliability that may arise from the heterogeneity between MSC donors. Isolating EVs from MSCs derived from induced pluripotent stem cells (iMSCs) might allow unlimited access to cells with a more stable phenotype and function. In the present review, we first present the latest findings regarding the functional aspects of EVs isolated from iMSCs and their interest in regenerative medicine for the treatment of various diseases. We will then discuss future directions for their translation to clinics with good manufacturing practice implementation.