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Competing Interests: Nicolas Stocker reports lecture honoraria from AbbVie and AstraZeneca and congress invitations from BeiGene, Janssen, and Novartis, all outside the submitted work. Eolia Brissot reports research funding, honorarium, speaker's fees, and travel expenses from Novartis, Astellas, Alexion, Jazz Pharmaceuticals, Gilead, MSD, Keocyt, Amgen, Beigen, Pierre Fabre, Pfizer, Celgene/BMS, and Sanofi, all outside the submitted work. Rémy Duléry reports research funding from Ligue Contre le Cancer, Arthur Sachs, Monahan Foundation, Servier Foundation, Philippe Foundation, and DCP AP‐HP, honoraria from Novartis and Takeda, and nonfinancial support from Sanofi and Kite Pharma/Gilead, all outside the submitted work. Zoé Van de Wyngaert reported consulting fees from Janssen‐Cilag, BMS, and Sanofi. Antoine Capes reports honoraria from Takeda. Harry Sokol reports lecture fee, board membership, or consultancy from Amgen, Fresenius, IPSEN, Actial, Astellas, Danone, THAC, Biose, BiomX, Eligo, Immusmol, Adare, Nestle, Ferring, MSD, Bledina, Pfizer, Biocodex, BMS, Bromatech, Gilead, Janssen, Mayoli, Roche, Sanofi, Servier, Takeda, and Abbvie, has stocks from Enterome Bioscience, and is co‐founder of Exeliom Biosciences. Mohamad Mohty reports grants and lecture honoraria from Janssen, Sanofi, Maat Pharma, and JAZZ Pharmaceuticals, lecture honoraria from Celgene, Amgen, BMS, Takeda, and Pfizer, and grants from Roche, all outside the submitted work. Florent Malard reports lecture honoraria from Therakos/Mallinckrodt, BMS, MSD, Sanofi, Novartis, Astra Zeneca, and JAZZ Pharmaceuticals, all outside the submitted work. The other authors declare no competing financial interests.

Individuals with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have a high risk of developing other malignancies (OMs). The development of OMs may be associated with the advanced age of CLL/SLL patients, presence of a tumor-promoting microenvironment, immune alterations inherent to CLL/SLL, or chemotherapy. Importantly, the occurrence of OMs following frontline fludarabine, cyclophosphamide and rituximab (FCR) treatment is associated with a reduction in the overall survival (OS). This retrospective study included 108 CLL/SLL patients treated with FCR immunochemotherapy, as a first line treatment. With a median follow-up of 94.9 (6-222) months, 31% developed an OM or more, within a median of 61.8 months post-FCR initiation. The most common OMs were non-melanoma skin cancers (7%), Richter's syndrome (RS) (7%), myelodysplastic syndromes (6%), prostate cancer (4%), and acute myeloid leukemia (3%). Patients with OMs had shorter survival compared to those without (104.0 versus 149.0 months, P=0.02), with RS having the worst OS at 4.8 months (P<0.0001), followed by therapy-related myeloid neoplasia (t-MN) at 14.5 months. Although the onset of OMs in patients with CLL/SLL was observed after considerable delays, its impact on survival is significant in the immunochemotherapy era, necessitating a better understanding of these patterns to improve CLL/SLL management and guide future treatment strategies., Competing Interests: NS reports lecture honoraria from AbbVie, Astra Zeneca, and Janssen, all outside of the submitted work. FM reports lecture honoraria from Therakos/Mallinckrodt, Janssen, Biocodex, Sanofi, Jazz Pharmaceuticals, Gilead, and Astellas, all outside of the submitted work. TA reports lecture and/or consulting honoraria from Biotest and Amgen, all outside of the submitted work. MM reports grants and lecture honoraria from Janssen, Sanofi, Maat Pharma, and JAZZ Pharmaceuticals; lecture honoraria from Celgene, Amgen, BMS, Takeda, and Pfizer; and grants from Roche, all outside the submitted work. EB reports lecture honoraria from Novartis, Astellas, Alexion, Jazz Pharmaceuticals, Gilead/Kyte, MSD, Keocyt, Amgen, Pierre Fabre, BeiGene, all outside the submitted work. The other authors declare no competing financial interests.

Immune effector cell-associated hematotoxicity (ICAHT) is a common toxicity associated with an important morbidity after chimeric antigen receptor (CAR)-T-cell therapy. Multiple factors seem to be involved in the development of severe ICAHT, making its management difficult. Here, we report three cases of severe ICAHT after axicabtagene-ciloleucel (axi-cel) for diffuse large B-cell lymphoma showing an expansion of large granular lymphocyte in the bone marrow with a CD3/CD57-positive non-CAR-T immunophenotype. We show that it is possible to treat them with low-dose steroids, obtaining a striking resolution of cytopenias with no deleterious impact on the underlying malignancy., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

The covalent Bruton tyrosine kinase inhibitors (iBTKs) have profoundly transformed the management of B-cell lymphoid malignancies, particularly chronic lymphocytic leukemia (CLL). These targeted therapies, with ibrutinib as the pioneer, have paved the way for significant improvement in the prognosis of many patients. With second-generation iBTKs such as acalabrutinib and zanubrutinib, the therapeutic landscape has expanded, offering potential new options for patients with CLL. This review focuses on the cardiovascular adverse effects associated with these treatments. It delves into the underlying pathophysiological mechanisms of these effects, highlighting the complex interactions between these molecules and the cardiovascular system. Additionally, it examines the frequency of adverse effects according to the type of iBTK, drawing on data from clinical trials and real-world clinical practice. Finally, the importance of close cardio-oncological monitoring is emphasized, with essential collaboration between hematologists and cardiologists. Strategies for screening and managing cardiovascular adverse effects are also discussed, emphasizing the need for a proactive approach in managing these complications. Experts propose a pragmatic follow-up of these patients, through a central illustration and a figure adapted from European cardio-oncology guidelines, to simplify hematologists' practice., (Copyright © 2024 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Purpose: Onco-nephrology is an emerging subspecialty aiming to better understand and prevent renal events in cancer patients. We assessed patients' knowledge about (1) oncological/hematological treatments induced renal toxicity and (2) kidney protective measures., Methods: Adult patients receiving systemic anti-tumor treatments in multiple day hospital units in France answered a self-administered questionnaire about their knowledge and expectations related to treatment-associated renal toxicity., Results: In total, 621 questionnaires were collected in 8 units from November 2021 to January 2022. Among respondents, 84.5% were treated for a solid tumor. Overall, 34.3% (n = 208) patients reported they had some knowledge about potential renal adverse events related to their anticancer treatment, and 38.5% (n = 234) about kidney protection measures. Their referring oncologist or hematologist represented the commonest source of knowledge (67.8%). Sufficient hydration was cited as a kidney protection measure by 93.2% (n = 218) of patients declaring some knowledge about renal toxicity; prevention of nausea/vomiting by 52.6% (n = 123). Consumption of still and alkaline water was chosen by respectively 64.4% (n = 400) and 16.8% (n = 104) of participants to correct dehydration. A majority of patients expressed strong interest for receiving more information about renal toxicity and prevention: median Likert scale score was 10/10 (Q1-Q3, 5-10), with online resources mentioned as the most desired source of information., Conclusion: One-third of patients declared they had some knowledge about potential renal toxicity of their oncologic treatment and the ways to prevent them, especially regarding hydration. However, a majority expressed interest for dedicated information, which conducted to the elaboration of free online educational sheets for patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Sexually transmitted infections (STIs) are a difficult health challenge for immunocompromised patients. Patients treated for several haematological malignancies have further compromised immune systems. Furthermore, many chemotherapies, alone or associated with haematopoietic stem-cell transplantation, make the body's natural barriers extremely fragile. STIs can negatively impact both patient morbidity and mortality. In this Series paper, we discuss Chlamydia trachomatis, Neisseria gonorrhoeae, syphilis, human immunodeficiency virus, herpes simplex virus, human papilloma virus, and hepatitis B virus, as we found them to be associated with increased risks for haematological malignancy treatments, either by incidence or by severity. Protective measures and vaccines for patients with haematological malignancies are also discussed. Large, well conducted studies should be encouraged, with the aim to systematically analyse the impacts of STIs in patients with haematological malignancies, especially given the difficulties that antimicrobial resistance can confer to patient management., Competing Interests: Declaration of interests TA declares consulting fees from Biotest and Amgen; honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events form Biotest; meeting or travel support from Biotest, Sandoz, Novartis, Astellas Pharma, and Viatris; and is responsible for the committee of the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (unpaid). NS declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, AbbVie, and Janssen. All authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Introduction: Angioimmunoblastic T-cell lymphoma (AITL) is a peripheral T-cell lymphoma characterized by a T follicular helper cell phenotype expressing PD-1 (programmed cell death-1). AITL exhibits a poor response to conventional chemotherapy, with a median 5-year overall survival of 44% and a progression-free survival of 32%. Relapse is common, resulting in a median overall survival of 6 months. Recurrent mutations are detected in genes regulating DNA methylation, including TET2, DNMT3A, and IDH2 variants, along with the prevalent RHOA G17V mutation. In this context, patients treated with the hypomethylating agent 5-azacytidine achieved overall response and complete response rates of 75% and 41%, respectively. We hypothesized that targeted therapies combining anti-PD-1 checkpoint blockers with hypomethylating agents could be efficient in AITL patients and less toxic than standard chemotherapy., Methods: Here, we report the efficacy of a regimen combining 5-azacytidine and nivolumab in nine relapsed or refractory AITL patients., Results: This regimen was well-tolerated, especially in elderly patients. The overall response rate was 78%, including four partial responses (44%) and three complete responses (33%). Allogeneic hematopoietic stem cell transplantation was performed in two patients who reached complete response., Discussion: These preliminary favorable results may serve as a basis for further investigation in prospective studies., 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 © 2024 Ricard, Cervera, Stocker, Corre, Van de Wyngaert, Banet, Marjanovic, Dulery, Bravetti, Joly, Baylatry and Coppo.)

We evaluated the impact of early recovery of mucosal-associated invariant T cells (MAIT) and gamma-delta (γδ) T cells, especially Vδ2 + T cells, on the clinical outcomes of 76 patients who underwent allogeneic hematopoietic cell transplantation (allo-HCT). MAIT cells were identified at day 20-30 post-transplant using flow cytometry and defined as CD3 + TCRVα7.2 + CD161 + . Two subsets of Vδ2 + T cells were analyzed according to the expression of CD26. The cytotoxicity profile of MAIT and Vδ2 + T cells was analyzed according to the intracellular expression of perforin and granzyme B, and intracellular IFN-γ was evaluated after in vitro activation. CD26 + Vδ2 + T cells displayed higher intracellular levels of IFN-γ, whereas CD26 - Vδ2 + T were found to be more cytotoxic. Moreover, MAIT cell frequency was correlated with the frequency of Vδ2 + T cells with a better correlation observed with Vδ2 + CD26 + than with the Vδ2 + CD26 - T cell subset. By using the composite endpoint graft-versus-host disease (GvHD)-free, relapse-free survival (GRFS) as the primary endpoint, we found that patients with a higher MAIT cell frequency at day 20-30 after allo-HCT had a significantly increased GRFS and a better overall survival (OS) and disease-free survival (DFS). Moreover, patients with a low CD69 expression by MAIT cells had an increased cumulative incidence of grade 2-4 acute GvHD (aGvHD). These results suggest that MAIT cell reconstitution may provide mitigating effects early after allo-HCT depending on their activation markers and functional status. Patients with a high frequency of Vδ2 + CD26 + T cells had a significantly higher GRFS, OS and DFS, but there was no impact on cumulative incidence of grade 2-4 aGVHD, non-relapse mortality and relapse. These results revealed that the impact of Vδ2 + T cells on the success of allo-HCT may vary according to the frequency of the CD26 + subset., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: Ibrutinib, a first-generation covalent Bruton's tyrosine kinase inhibitor (BTKi) was found to be a risk factor for the occurrence of invasive fungal complications. Acalabrutinib is a second-generation covalent BTKi used to treat B-cell malignancies. Healthy donor neutrophils incubated ex vivo with acalabrutinib lose ability to control Aspergillus conidia germination. In patients receiving acalabrutinib, the potential effect on neutrophil antifungal activity is unknown. Furthermore, only two cases of invasive aspergillosis have been reported during treatment with acalabrutinib, outside of a few cases in a clinical trial., Methods: We describe three new cases of invasive aspergillosis occurring within the first months of acalabrutinib therapy in patients with chronic lymphocytic leukemia. We used videomicroscopy and flow cytometry approaches to investigate the basic functional responses against Aspergillus of neutrophils from acalabrutinib-treated patients., Results: We showed an alteration in the anti-Aspergillus response after 1 month of acalabrutinb therapy: neutrophils lost their capacities of killing Aspergillus fumigatus germinating conidia and decreased their reactive oxygen species production when stimulated by Aspergillus., Conclusions: It is important to follow-up patients treated with acalabrutinib for the risk of aspergillosis as well as those treated with ibrutinib., Competing Interests: Declarations of Competing Interest The authors declare no conflict of interest in this study., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Human herpesvirus type 6 (HHV6) reactivation after haploidentical hematopoietic cell transplantation (HCT) with post-transplant cyclophosphamide (PT-Cy) has been scarcely studied, especially when antithymocyte globulin (ATG) is added to the graft-versus-host disease (GvHD) prophylaxis. We conducted a retrospective cohort study in 100 consecutive patients receiving haploidentical HCT with PT-Cy. We systematically monitored HHV6 DNA loads in blood samples on a weekly basis using quantitative PCR until day +100. The 100-day cumulative incidence of HHV6 reactivation was 54%. Clinically significant HHV6 infections were rare (7%), associated with higher HHV6 DNA loads, and had favorable outcomes after antiviral therapy. The main risk factor for HHV6 reactivation was a low absolute lymphocyte count (ALC) \< 290/µL on day +30 (68% versus 40%, p = 0.003). Adding ATG to PT-Cy did not increase the incidence of HHV6 reactivation (52% with ATG versus 79% without ATG, p = 0.12). Patients experiencing HHV6 reactivation demonstrated delayed platelet recovery (HR 1.81, 95% CI 1.07-3.05, p = 0.026), higher risk of acute grade II-IV GvHD (39% versus 9%, p \< 0.001) but similar overall survival and non-relapse mortality to the other patients. In conclusion, our findings endorse the safety of combining ATG and PT-Cy in terms of the risk of HHV6 reactivation and infection in patients undergoing haploidentical HCT. Patients with a low ALC on day +30 face a higher risk of HHV6 reactivation and may require careful monitoring., Competing Interests: FM reports lecture honoraria from Therakos/Mallinckrodt, Sanofi, JAZZ Pharmaceuticals, Gilead, Novartis, and Bristol Myers Squibb, all outside the submitted work. MM reports grants and lecture honoraria from Janssen, Sanofi, Maat Pharma and JAZZ Pharmaceuticals, lecture honoraria from Celgene, Amgen, BMS, Takeda, and Pfizer, grants from Roche, all outside the submitted work. RD reports research funding from Ligue contre le Cancer, Arthur Sachs, Monahan Foundation, Servier Foundation, Philippe Foundation, DCP AP-HP, honoraria from Novartis and Takeda, non-financial support from Kite Pharma / Gilead, all outside the submitted work. The other authors declare no competing financial interests.

Bispecific antibodies (BsAbs) are a new group of targeted therapies that are revolutionizing the treatment landscape of B-cell non-Hodgkin's lymphoma (B-NHL). In the relapsed/refractory setting, salvage chemotherapy and autologous stem cell transplantation are capable of curing 50% of patients, whereas the other half will have a dismal outcome with a median overall survival of less than 12 months. This unmet need reinforced the importance of innovative therapies like the BsAbs and CAR-T cell therapies. In this review, we delve into BsAbs in B-NHL from the preclinical development to clinical data in both refractory and frontline settings, and then discuss future perspectives., (© 2024. The Author(s).)

Immunotherapy (IT) is a major therapeutic strategy for lymphoma, significantly improving patient prognosis. IT remains ineffective for a significant number of patients, however, and exposes them to specific toxicities. The identification predictive factors around efficacy and toxicity would allow better targeting of patients with a higher ratio of benefit to risk. PRONOSTIM is a multicenter and retrospective study using the Clinical Data Warehouse (CDW) of the Greater Paris University Hospitals network. Adult patients with Hodgkin lymphoma or diffuse large-cell B lymphoma treated with immune checkpoint inhibitors or CAR T (Chimeric antigen receptor T) cells between 2017 and 2022 were included. Analysis of covariates influencing progression-free survival (PFS) or the occurrence of grade ≥3 toxicity was performed. In total, 249 patients were included. From this study, already known predictors for response or toxicity of CAR T cells such as age, elevated lactate dehydrogenase, and elevated C-Reactive Protein at the time of infusion were confirmed. In addition, male gender, low hemoglobin, and hypo- or hyperkalemia were demonstrated to be potential predictive factors for progression after CAR T cell therapy. These findings prove the attractiveness of CDW in generating real-world data, and show its essential contribution to identifying new predictors for decision support before starting IT.

Rhinoviruses and allergens, such as house dust mite are major agents responsible for asthma exacerbations. The influence of pre-existing airway inflammation on the infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is largely unknown. We analyse mechanisms of response to viral infection in experimental in vivo rhinovirus infection in healthy controls and patients with asthma, and in in vitro experiments with house dust mite, rhinovirus and SARS-CoV-2 in human primary airway epithelium. Here, we show that rhinovirus infection in patients with asthma leads to an excessive RIG-I inflammasome activation, which diminishes its accessibility for type I/III interferon responses, leading to their early functional impairment, delayed resolution, prolonged viral clearance and unresolved inflammation in vitro and in vivo. Pre-exposure to house dust mite augments this phenomenon by inflammasome priming and auxiliary inhibition of early type I/III interferon responses. Prior infection with rhinovirus followed by SARS-CoV-2 infection augments RIG-I inflammasome activation and epithelial inflammation. Timely inhibition of the epithelial RIG-I inflammasome may lead to more efficient viral clearance and lower the burden of rhinovirus and SARS-CoV-2 infections., (© 2023. The Author(s).)

SARS-CoV-2 enters human cells through its main receptor, angiotensin-converting enzyme 2 (ACE2), which constitutes a limiting factor of infection. Recent findings demonstrating novel ACE2 isoforms implicate that this receptor is regulated in a more complex way than previously anticipated. However, it remains unknown how various inflammatory conditions influence the abundance of these ACE2 variants. Hence, we studied expression of ACE2 messenger RNA (mRNA) and protein isoforms, together with its glycosylation and spatial localization in primary human airway epithelium upon allergic inflammation and viral infection. We found that interleukin-13, the main type 2 cytokine, decreased expression of long ACE2 mRNA and reduced glycosylation of full-length ACE2 protein via alteration of N-linked glycosylation process, limiting its availability on the apical side of ciliated cells. House dust mite allergen did not affect the expression of ACE2. Rhinovirus infection increased short ACE2 mRNA, but it did not influence its protein expression. In addition, by screening other SARS-CoV-2 related host molecules, we found that interleukin-13 and rhinovirus significantly regulated mRNA, but not protein of transmembrane serine protease 2 and neuropilin 1. Regulation of ACE2 and other host proteins was comparable in healthy and asthmatic epithelium, underlining the lack of intrinsic differences but dependence on the inflammatory milieu in the airways., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Competing Interests: Competing interests: None declared.

For acute lymphoblastic leukemia (ALL) patients, total body irradiation (TBI)- based conditioning regimens are the first choice specially in young population. However, several studies have shown an equivalence in clinical outcomes with thiotepa-based conditioning regimen. We performed a retrospective study to evaluate the outcome of adult ALL patients who received allogeneic hematopoietic stem cell transplantation (allo-HCT) with a thiotepa-busulfan-fludarabine (TBF) myeloablative conditioning regimen with reduced toxicity. Fifty-five patients received a TBF regimen. The median age of the patients was 51 years (range, 17 to 72.4). Most patients had a diagnosis of B-ALL (93%) with 7% having T-ALL. Two - and 5-year overall survival was 73.2% and 64%, respectively. At 2 years, leukemia-free survival and GVHD-free, relapse-free survival were 59.5% and 57.6%, and at 5 years, 53.4% and 51.8%, respectively. The 5-year non-relapse mortality was 15%. The day 180 cumulative incidence (CI) of grade II-IV acute GVHD and grade III-IV acute GVHD were 38.2% and 5.5%, respectively. At 2 years, the CI of chronic GVHD and extensive chronic GVHD was 16.9% and 1.9%, respectively. Our study results do suggest that using TBF as the conditioning regimen in adult ALL patients is a promising option with acceptable toxicity., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Optogenetic gene therapies to restore vision are in clinical trials. Whilst current clinical approaches target the ganglion cells, the output neurons of the retina, new molecular tools enable efficient targeting of the first order retinal interneurons, the bipolar cells, with the potential to restore a higher quality of vision. Here we investigate retinal signaling and behavioral vision in blind mice treated with bipolar cell targeted optogenetic gene therapies. All tested tools, including medium-wave opsin, Opto-mGluR6, and two new melanopsin based chimeras restored visual acuity and contrast sensitivity. The best performing opsin was a melanopsin-mGluR6 chimera, which in some cases restored visual acuities and contrast sensitivities that match wild-type animals. Light responses from the ganglion cells were robust with diverse receptive-field types, inferring elaborate inner retinal signaling. Our results highlight the potential of bipolar cell targeted optogenetics to recover high-level vision in human patients with end-stage retinal degenerations., (© 2022. The Author(s).)

Purpose: This single-center retrospective study aims to assess the feasibility, safety, and tolerability of CareMin650, a new photobiomodulation device, for both preventing oral mucositis (OM) and reducing its severity in the setting of hematopoietic stem cell transplantation (HCT)., Methods: Patients who underwent autologous HCT for hematological malignancies between November 2020 and October 2021 could be included. Prophylactic photobiomodulation (PBM) was used daily from day 1 of conditioning until the day of neutrophil recovery at a dose of 3 J/cm 2 . Curative PBM was started at a dose of 6 J/cm 2 when at least one grade 1 OM had occurred. For each OM case, time of onset, National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0 grade for OM, analgesic dose, and time to resolution were reported., Results: Twenty-five consecutive patients were included. The median age was 58 years (range, 39-74) and 14 (56%) were male. Twenty-one patients (84%) received a high-dose melphalan conditioning regimen for multiple myeloma, and 4 (16%) patients received BEAM conditioning for aggressive lymphoma. A total of 178 CareMin650 sessions were performed, with a median of 7 days of application (range, 4-12), with no device-related adverse events (AEs). According to the NCI-CTCAE v5.0 scale, 76% (19 of 25) of patients presented grade 0 or 1 mucositis (no ulcers), five patients (20%) developed small ulcers (grade 2), and only one patient developed grade 4 mucositis. Satisfaction rates were high among patients and users., Conclusion: Photobiomodulation provides excellent safety and tolerance, as well as promising efficacy, both as a preventive and curative strategy, in patients undergoing autologous HCT., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Mesenchymal stem cells (mesenchymal stromal cells; MSC)-based therapies remain a promising approach to treat degenerative and inflammatory diseases. Their beneficial effects were confirmed in numerous experimental models and clinical trials. However, safety issues concerning MSCs' stability and their long-term effects limit their implementation in clinical practice, including treatment of respiratory diseases such as asthma, chronic obstructive pulmonary disease, and COVID-19. Here, we aimed to investigate the safety of intranasal application of human adipose tissue-derived MSCs in a preclinical experimental mice model and elucidate their effects on the lungs. We assessed short-term (two days) and long-term (nine days) effects of MSCs administration on lung morphology, immune responses, epithelial barrier function, and transcriptomic profiles. We observed an increased frequency of IFNγ- producing T cells and a decrease in occludin and claudin 3 as a long-term effect of MSCs administration. We also found changes in the lung transcriptomic profiles, reflecting redox imbalance and hypoxia signaling pathway. Additionally, we found dysregulation in genes clustered in pattern recognition receptors, macrophage activation, oxidative stress, and phagocytosis. Our results suggest that i.n. MSCs administration to noninflamed healthy lungs induces, in the late stages, low-grade inflammatory responses aiming at the clearance of MSCs graft., Competing Interests: MT reports grant from National Science Centre, Poland, during the conduct of the study, grants from European Union funds, POWER 2014-2020, grants from National Centre for Research and Development, outside the submitted work. AJ and AZ reports grants and non-financial support from Ministry of Education and Science, Poland. CA reports research grants from the Swiss National Science Foundation, European Union (EU CURE), Novartis Research Institutes (Basel, Switzerland), Stanford University (Redwood City, Calif), and SciBase (Stockholm, Sweden), he is the Co-Chair for EAACI Guidelines on Environmental Science in Allergic diseases and Asthma, and serves on the Advisory Boards of Sanofi/Regeneron, Novartis, GlaxoSmithKline, and SciBase, and is the Editor-in-Chief of Allergy, outside the submitted work. MS reports grants from Swiss National Science Foundation, grants from GSK, grants from Novartis, personal fees from AstraZeneca, outside the submitted work. MM reports grants from National Centre for Research and Development, grant from Medical Research Agency, lecture fees from Astra Zeneca, Berlin-Chemie/Menarini, GSK, Takeda, Shire, Teva, Lek-Am, Celon, Sandoz, Pfizer, Hal Allergy, and had reimbursed conference costs and travel by Berlin-Chemie/Menarini, outside the submitted work. AE reports grant from National Science Centre, during the conduct of the study, grants from National Centre for Research and Development. 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 © 2022 Tynecka, Janucik, Niemira, Zbikowski, Stocker, Tarasik, Starosz, Grubczak, Szalkowska, Korotko, Reszec, Kwasniewski, Kretowski, Akdis, Sokolowska, Moniuszko and Eljaszewicz.)

In order to promote early rehabilitation, we proposed a system which provides full-body arm-leg training for patients in a bed-lying position. As the preliminary development, a platform for leg movement was investigated. An innovative system with four servo drives was designed and manufactured. An artificial leg frame was attached to the platform via belts. The positions of the hip and knee joints were recorded using potentiometers. Closed-loop PID position control algorithms were implemented for production of various stepping movements. Technical evaluation on a test participant showed that the platform tracked the circular trajectory of the foot in a supine-lying position with an area difference of 8.2%, and produced walking-like trajectories in the hip and knee joints in a side-lying position with a mean error of 10.6%. The mechanical structure can be resized, and the control system can be expanded, so as to produce 3-dimensional stepping movement in both arms and legs. This innovative platform combined with the closed-loop position control strategy shows the technical potential to be a promising full-body rehabilitation platform for the patients in the early post-injury stage.