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Luisa Giaccone,1,2 Francesco Felicetti,3 Sara Butera,1,2 Danilo Faraci,1,2 Marco Cerrano,1,2 Margherita Dionisi Vici,3 Lucia Brunello,1,2 Nicoletta Fortunati,3 Enrico Brignardello,3,* Benedetto Bruno1,2,* 1Division of Hematology, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, University of Torino, Torino, Italy; 2Dipartimento di Biotecnologie Molecolari e Scienze per la Salute, University of Torino, Torino, Italy; 3Transition Unit for Childhood Cancer Survivors, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, University of Torino, Torino, Italy*These authors contributed equally to this workCorrespondence: Luisa GiacconeDivision of Hematology, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Via Genova 3, Torino 10126, ItalyTel +39 011-6334354Fax +39 011-6963737Email luisa.giaccone@unito.itAbstract: The increasing indications for allogeneic stem-cell transplant in patients with hematologic malignancies and non-malignant diseases combined with improved clinical outcomes have contributed to increase the number of long-term survivors. However, survivors are at increased risk of developing a unique set of complications and late effects, besides graft-versus-host disease and disease relapse. In this setting, the management capacity of a single health-care provider can easily be overwhelmed. Thus, to provide appropriate survivorship care, a multidisciplinary approach for the long-term follow-up is essential. This review aims at summarizing the most relevant information that a health-care provider should know to establish a follow-up care plan, in the light of individual exposures and risk factors, that includes all organ systems and considers the psychological burden of these patients.Keywords: long-term, complications, allografting

This paper examines how Descartes’ philosophy was presented and discussed in articles and reviews published in Mind from 1900 to 1947, a period in which this most prestigious British philosophical journal was edited by George F. Stout (until 1920) and then by George E. Moore (from 1921 to 1947). The survey deals with various aspects of the reception of Cartesian philosophy in the journal: articles devoted to several topics of Cartesian thought, critical notices and reviews of the secondary literature, discussions of twentieth-century English translations of Cartesian works. In line with the theoretical character of Mind, most of the interpreters discussed Cartesian philosophy with the aim either of checking its internal consistency or of proving how the Cartesian system might be rendered consistent with its own premises. In this respect, all the themes revolving around the problem of the Cartesian circle attracted the attention of commentators, and the intuitionist foundation of Cartesian theory was analyzed. Descartes’ metaphysics and natural philosophy were often evaluated from the perspective of contemporary philosophical debates, while their original historical context was neglected. Of particular relevance were issues like the mind-body problem, discussed at the beginning of the century in relation to developments in psychology, and the question of the existence of the external world, which was examined from various standpoints, metaphysically, epistemologically and from the point of view of linguistic analysis. Interest in Descartes was shown by many authors from major philosophers (such as Ward, Schiller, Taylor, Broad, Ryle) to lesser known scholars whose profiles and contributions are outlined. Through the angle of the Cartesian presence a sketch emerges of the rich and variegated philosophical scene of British culture in the first half of the twentieth century.

In Berkeley’s writings the topic of light is discussed in two different ways, within a theory of perception and within a metaphysics of nature of a Platonic stamp. In his first work, the original Essay for a New Theory of Vision (1709), light and colours are regarded as condition and object of vision; they are examined as contents of visual perception distinct from tangible perception. Light will be dealt with in a completely different manner in Berkeley’s last work, Siris (1744), in which a spiritualistic reading of the natural world is superimposed on modern science in general and on Newtonian physics in particular. In Siris, light (or invisible fire) is the instrument by which the causal activity of divine Intellect orders and permeates the natural world. A detailed analysis of the topic of light in the two aforementioned contexts shows inconsistencies and strained interpretations which derive from the apologetic use of the theory of vision in Berkeley’s early immaterialism and from the multi-layered and confused speculations of his late Siris. On the whole, Berkeley conceives light within the idealistic frame inherited from Platonic metaphysics of light; however, the specific themes examined in the Essay for a New Theory of Vision and in Siris derive from acquisitions of modern science, and are recast within a spiritualistic interpretation which intended both to neutralize scientific ideas through their phenomenistic reading and to exploit them for apologetic ends.

The identification of pathways that control elimination of protein inclusions is essential to understand the cellular response to proteotoxicity, particularly in the nuclear compartment, for which our knowledge is limited. We report that stress-induced nuclear inclusions related to the nucleolus are eliminated upon stress alleviation during the recovery period. This process is independent of autophagy/lysosome and CRM1-mediated nuclear export pathways, but strictly depends on the ubiquitin-activating E1 enzyme, UBA1, and on nuclear proteasomes that are recruited into the formed inclusions. UBA1 activity is essential only for the recovery process but dispensable for nuclear inclusion formation. Furthermore, the E3 ligase HUWE1 and HSP70 are components of the ubiquitin/chaperone systems that promote inclusion elimination. The recovery process also requires RNA Pol I-dependent production of the lncRNA IGS 42 during stress. IGS 42 localises within the formed inclusions and promotes their elimination by preserving the mobility of resident proteins. These findings reveal a protein quality control system that operates within the nucleus for the elimination of stress-induced nucleolus-related inclusions., Competing Interests: Disclosure and competing interests statement. The authors declare no competing interests., (© 2024. The Author(s).)

Endoplasmic reticulum (ER) plasticity and ER-phagy are intertwined processes essential for maintaining ER dynamics. We investigated the interplay between two isoforms of the ER-phagy receptor FAM134B in regulating ER remodeling in differentiating myoblasts. During myogenesis, the canonical FAM134B1 is degraded, while its isoform FAM134B2 is transcriptionally upregulated. The switch, favoring FAM134B2, is an important regulator of ER morphology during myogenesis. FAM134B2 partial reticulon homology domain, with its rigid conformational characteristics, enables efficient ER reshaping. FAM134B2 action increases in the active phase of differentiation leading to ER restructuring via ER-phagy, which then reverts to physiological levels when myotubes are mature and the ER is reorganized. Knocking out both FAM134B isoforms in myotubes results in an aberrant proteome landscape and the formation of dilated ER structures, both of which are rescued by FAM134B2 re-expression. Our results underscore how the fine-tuning of FAM134B isoforms and ER-phagy orchestrate the ER dynamics during myogenesis providing insights into the molecular mechanisms governing ER homeostasis in muscle cells., Competing Interests: Disclosure and competing interests statement. The authors declare no competing interests., (© 2025. The Author(s).)

Background: Anti-CD19 CAR T-cells have revolutionized outcomes in relapsed/refractory large B-cell lymphomas. Long-term follow-up underscored the role of hematological toxicity in nonrelapse mortality, largely driven by infections, leading to the development of the CAR-HEMATOTOX (HT) score for predicting neutropenia. The European scientific community (EHA/EBMT) later reached a consensus, defining a new entity: immune effector cell-associated hematotoxicity (ICAHT)., Aims: To validate the ability of the HT score to predict ICAHT and survival., Methods: The CART-SIE is an ongoing multicenter prospective observational study collecting data on patients affected by B-cell lymphoma treated with commercial anti-CD19 CAR T-cells (ClinicalTrials.gov ID: NCT06339255)., Results: Since 2019 to 2024, 1002 consecutive patients were enrolled. Out of 746 patients infused, the HT score at infusion was evaluable in 389. Median age was 59 years (48-66). Patients with high HT score had greater disease burden and a greater need for bridge therapy. Patients with a HT HIGH score had a 4-fold higher risk of experiencing late ICAHT of grade≥3 (OR = 3.99, 95% CI = 1.16-13.77, P = .03). Patients with a HT HIGH score also showed lower overall response rates (ORR) and complete response rates (CRR) at 90 days (CRR at 90 days: 59% HT LOW versus 38% HT HIGH , OR = 0.42, 95% CI = 0.27-0.66, P = .0002; ORR at 90 days: 67% HT LOW versus 49% HT HIGH , OR = 0.47, 95% CI = 0.29-0.74, P = .001). Adjusted logistic models confirmed that the effect of HT score was independent from baseline characteristics. With a median follow-up of 18 months, patients with a HT HIGH score have lower OS and PFS (1-year OS: 78% HT LOW versus 62% HT HIGH , P = .0002; 1-year PFS: 49% versus 39%, P = .003). Adjusted Cox models confirmed that HT was an independent prognostic factor for OS. A high HT-score was found to be associated with higher risk of secondary primary malignancy (HR=2.8, 95% CI = 1.03-7.8, P = .04). A simplified version of HT (simpleHT), based solely on the platelet count and C-reactive protein at infusion, was calculated for 560 patients and proved significant in predicting both OS and PFS (1-year was 72% simpleHT LOW versus 37% simpleHT HIGH , P < .0001, 1-year PFS was 48% simpleHT LOW versus 22% simpleHT HIGH , P < .0001)., Conclusion: In our prospective real-world study, we validated the ability of the HT score to predict ICAHT and survival. SimpleHT identified a population at very high risk with an impaired progression free and overall survival., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

After allogeneic HSCT (allo-HSCT), the diversity of the intestinal microbiota significantly decreases. The changes can be rapid and are thought to be caused by chemotherapy, antibiotics, or intestinal inflammation. Most patients are exposed to prophylactic and therapeutic antibiotics during neutropenia and several patients are colonized by ESBL bacteria. We investigated the changes in gut microbiota composition in allo-HSCT, aiming at investigating if the acquisition of ESBL colonization may affect gut microbiome diversity during allo-HSCT. This was a single-center prospective pilot study. All patients consecutively admitted to the Haematological Unit of the City of Health and Science, Molinette Hospital in Turin, Italy, and undergoing allo-HSCT between August 2017 to August 2020 were enrolled in the study. Microbiome analysis on fecal samples were collected every 7 days from hospital admission to discharge and until 1 year after HSCT. 48 patients were enrolled in the study. At baseline 14 patients (29.16%) were colonized by MDR bacteria, mostly extended-spectrum beta-lactamase (ESBL)-producing gram negatives (N = 11; 78.57%). During allo-HSCT, one patient had a positive rectal swab for a carbapenemase-producing Klebsiella pneumoniae and eight patients lost the colonization during the hospital stay. Microbiota composition was compared between patients colonized by ESBL at baseline and non-colonized patients. Patients colonized by ESBL had a greater abundances of Bifidobacterium, Blautia, Clostridium, Coprococcus, L-Ruminococcus Mogibacteriaceae, Peptostreptococceae and Oscillospira, while non-colonized ESBL patients had a greater abundance of Actinomycetales, Staphylococcus and Sutterella. Moreover, microbiota composition of colonized by ESBL that retained colonization after HSCT showed an increased in abundances of Akkermansia, Dialister, Erysipelotrichaceae and Methanobrevibacter when compared with patients that become negative at rectal swabs. From a clinical perspective, the evolution of this prospective pilot study will be to investigate markers of gut barrier functions, SCFA productions and to correlate the predictivity of these parameters with risk of invasive infections and clinical outcomes in allo-HSCT population., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Transcription factors belonging to the large ethylene response factor (ERF) family are involved in plant responses to biotic and abiotic stresses. Among the ERFs, OCTADECANOID-RESPONSIVE ARABIDOPSIS 59 (ORA59) integrates ethylene and jasmonic acid signaling to regulate resistance to necrotrophic pathogens. The ERF group ERFVII encodes oxygen-labile proteins that are required for oxygen sensing and are stabilized by hypoxia established at the site of Botrytis (Botrytis cinerea) infection. Here, we show that ORA59 represses ERFVII protein activity to induce the expression of hypoxia-responsive genes in Arabidopsis (Arabidopsis thaliana). Moreover, inhibition of ethanol fermentation enhances plant tolerance to Botrytis, indicating a trade-off between the hypoxia and defense responses. In addition, ERFVII members and ORA59 are both involved in the downregulation of hypoxia-responsive genes during reoxygenation. Taken together, our results reveal that the ERFVII transcription factor-ORA59 module ensures that the multiple roles of ERFVII proteins are correctly balanced to favor plant tolerance to biotic or abiotic stresses., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society of Plant Biologists.)

Recent successes in developing small molecule degraders that act through the ubiquitin system have spurred efforts to extend this technology to other mechanisms, including the autophagosomal-lysosomal pathway. Therefore, reports of autophagosome tethering compounds (ATTECs) have received considerable attention from the drug development community. ATTECs are based on the recruitment of targets to LC3/GABARAP, a family of ubiquitin-like proteins that presumably bind to the autophagosome membrane and tether cargo-loaded autophagy receptors into the autophagosome. In this work, we rigorously tested the target engagement of the reported ATTECs to validate the existing LC3/GABARAP ligands. Surprisingly, we were unable to detect interaction with their designated target LC3 using a diversity of biophysical methods. Intrigued by the idea of developing ATTECs, we evaluated the ligandability of LC3/GABARAP by in silico docking and large-scale crystallographic fragment screening. Data based on approximately 1000 crystal structures revealed that most fragments bound to the HP2 but not to the HP1 pocket within the LIR docking site, suggesting a favorable ligandability of HP2. Through this study, we identified diverse validated LC3/GABARAP ligands and fragments as starting points for chemical probe and ATTEC development., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Secondary primary malignancies (SPM) have been reported after anti-BCMA or anti-CD19 chimeric antigen receptor (CAR)-T-cell therapies. While the cytotoxic effect of antecedent therapies, including chemotherapy and radiotherapy, has been well established, few data are available on risk related to CAR-T immunotherapies. The study aimed to analyse the incidence of SPM in 651 patients enrolled in the Italian prospective observational CART-SIE study. SPMs were documented in 4.3% (28/651), and the most frequent SPMs were haematological malignancies. In conclusion, the frequency of SPMs in our cohort of heavily pretreated patients receiving CAR-T was relatively low and consistent with previous studies., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Nuclear receptors (NRs) regulate transcription in response to ligand binding and NR modulation allows pharmacological control of gene expression. Although some NRs are relevant as drug targets, the NR1 family, which comprises 19 NRs binding to hormones, vitamins, and lipid metabolites, has only been partially explored from a translational perspective. To enable systematic target identification and validation for this protein family in phenotypic settings, we present an NR1 chemogenomic (CG) compound set optimized for complementary activity/selectivity profiles and chemical diversity. Based on broad profiling of candidates for specificity, toxicity, and off-target liabilities, sixty-nine comprehensively annotated NR1 agonists, antagonists and inverse agonists covering all members of the NR1 family and meeting potency and selectivity standards are included in the final NR1 CG set. Proof-of-concept application of this set reveals effects of NR1 members in autophagy, neuroinflammation and cancer cell death, and confirms the suitability of the set for target identification and validation., (© 2024. The Author(s).)

Oxygen is essential for plant growth and development. Hypoxia occurs in plants due to limited oxygen availability following adverse environmental conditions as well in hypoxic niches in otherwise normoxic environments. However, the existence and functional integration of spatiotemporal oxygen dynamics with plant development remains unknown. In animal systems dynamic fluctuations in oxygen availability are known as cyclic hypoxia. In this study, we demonstrate that cyclic fluctuations in internal oxygen levels occur in young emerging leaves of Arabidopsis plants. Cyclic hypoxia in plants is based on a mechanism requiring the ETHYLENE RESPONSE FACTORS type VII (ERFVII) that are central components of the oxygen-sensing machinery in plants. The ERFVII-dependent mechanism allows precise adjustment of leaf growth in response to carbon status and oxygen availability within plant cells. This study thus establishes a functional connection between internal spatiotemporal oxygen dynamics and developmental processes of plants., (Copyright © 2024 The Author. Published by Elsevier Inc. All rights reserved.)

Orchids (Phalaenopsis spp.) growing in tropical and subtropical regions are epiphytes. As such, they grow on trees with the root system utilised to anchor themselves to tree branches. These roots are highly specialised, display a large diameter and are often green, suggesting the ability to carry out photosynthesis. However, the role of photosynthesis in orchid roots is controversial. Orchids that are leafless can photosynthesise in their roots, thus indicating that some orchid roots carry out photosynthesis in a similar manner to leaves. However, the primary site of photosynthesis in orchids are in their leaves, and the roots of epiphytic orchids may mostly conduct internal refixation of respiratory CO2 . Besides contributing to the overall carbon metabolism of orchid plants, oxygen produced through root photosynthesis may also be important by alleviating potential root hypoxia. The bulky tissue of most epiphytic orchid roots suggests that oxygen diffusion in these roots can be limited. Here, we demonstrate that the bulky roots of a widely commercially cultivated orchid belonging to the genus Phalaenopsis are hypoxic in the dark. These roots are photosynthetically active and produce oxygen when exposed to light, thus mitigating root hypoxia.

Selective autophagy of the endoplasmic reticulum (ER), known as ER-phagy, is an important regulator of ER remodeling and essential to maintain cellular homeostasis during environmental changes. We recently showed that members of the FAM134 family play a critical role during stress-induced ER-phagy. However, the mechanisms on how they are activated remain largely unknown. In this study, we analyze phosphorylation of FAM134 as a trigger of FAM134-driven ER-phagy upon mTOR (mechanistic target of rapamycin) inhibition. An unbiased screen of kinase inhibitors reveals CK2 to be essential for FAM134B- and FAM134C-driven ER-phagy after mTOR inhibition. Furthermore, we provide evidence that ER-phagy receptors are regulated by ubiquitination events and that treatment with E1 inhibitor suppresses Torin1-induced ER-phagy flux. Using super-resolution microscopy, we show that CK2 activity is essential for the formation of high-density FAM134B and FAM134C clusters. In addition, dense clustering of FAM134B and FAM134C requires phosphorylation-dependent ubiquitination of FAM134B and FAM134C. Treatment with the CK2 inhibitor SGC-CK2-1 or mutation of FAM134B and FAM134C phosphosites prevents ubiquitination of FAM134 proteins, formation of high-density clusters, as well as Torin1-induced ER-phagy flux. Therefore, we propose that CK2-dependent phosphorylation of ER-phagy receptors precedes ubiquitin-dependent activation of ER-phagy flux., (© 2023. The Author(s).)

Introduction: Extracorporal Photophoresis (ECP) is in clinical use for steroid-refractory and steroid-dependent acute GVHD (SR-aGVHD). Based on recent Phase-III study results, ruxolitinib has become the new standard of care for SR-aGVHD. Our aim was to collect comparative data between ruxolitinib and ECP in SR-aGVHD in order to improve the evidence base for clinical decision making., Methods: We asked EBMT centers if they were willing to participate in this study by completing a data form (Med-C) with detailed information on GVHD grading, -therapy, -dosing, -response and complications for each included patient., Results: 31 centers responded positively (14%) and we included all patients receiving alloSCT between 1/2017-7/2019 and treated with ECP or ruxolitinib for SR-aGVHD grades II-IV from these centers. We identified 53 and 40 patients with grades II-IV SR-aGVHD who were treated with ECP and ruxolitinib, respectively. We performed multivariate analyses adjusted on grading and type of SR-aGVHD (steroid dependent vs. refractory). At day+90 after initiation of treatment for SR-aGVHD we found no statistically significant differences in overall response. The odds ratio in the ruxolitinib group to achieve overall response vs. the ECP group was 1.13 (95% CI = [0.41; 3.22], p = 0.81). In line, we detected no statistically significant differences in overall survival, progression-free survival, non-relapse mortality and relapse incidence., Discussion: The clinical significance is limited by the retrospective study design and the current data can't replace prospective studies on ECP in SR-aGVHD. However, the present results contribute to the accumulating evidence on ECP as an effective treatment option in SR-aGVHD., Competing Interests: Author OP has previously received honoraria from Mallinckrodt Pharmaceuticals, but not for the current project. Author OP has received honoraria or travel support from Gilead, Jazz, MSD, Novartis and Pfizer. He has received research support from Incyte and Priothera. He is member of advisory boards to Equillium Bio, Jazz, Gilead, Novartis, MSD, Omeros, Priothera, Sanofi, Shionogi and SOBI. 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. This study received funding from Mallinckrodt Pharmaceuticals. The funder had the following involvement with the study: study design was done by EBMT experts and was approved by the funder; interpretation of data was discussed by EBMT experts and was communicated with the funder. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Penack, Peczynski, Boreland, Lemaitre, Afanasyeva, Kornblit, Jurado, Martinez, Natale, Pérez-Simón, Brunello, Avenoso, Klein, Ozkurt, Herrera, Wichert, Chiusolo, Gavriilaki, Basak, Schoemans, Koenecke, Moiseev and Peric.)

Objectives: Graft-versus-host disease (GVHD) of central nervous system is an atypical and rare manifestation of chronic GVHD, presenting with a heterogeneous spectrum of signs and symptoms. Diagnosis of neurological manifestations of GVHD can be highly challenging and remain associated with dismal prognosis, significant morbidity, and reduced quality of life., Case Presentation: In this report, we describe a 39-year-old woman developing neurological signs and symptoms 8 months after allogeneic HSCT magnetic resonance imaging showed multifocal hyperintense lesions involving the periventricular region and frontal subcortical white matter. There was no laboratory evidence of infective or malignant etiology, and the case was diagnosed as CNS-GVHD. The patient was treated with intravenous methylprednisolone pulse therapy and the clinical conditions gradually improved. After few months, patient symptoms progressed despite the addition of high-dose intravenous immunoglobulin, tacrolimus, and a new course of high dose steroids. To engage targeted therapy, the patient underwent brain biopsy that revealed a loss of myelin fibers, perivascular and diffuse infiltration of T cells, and macrophages associated with reactive gliosis, representing a demyelinating disease. We intensified treatment with cyclophosphamide and subsequently introduced ibrutinib as salvage strategy. Despite a magnetic resonance imaging showing great regression of the demyelinating lesions, patient's conditions deteriorated and she died 16 months after HSCT., Conclusions: CNS-GVHD is a rare complication of HSCT that is difficult to diagnose. Based on our experience, brain biopsy may represent a useful diagnostic tool when the clinical features of neurological symptoms are ambiguous or in patients without evidence of preceding chronic GVHD., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

In the present study we broadly explored the perception of physical and animated motion in bouncing-like scenarios through four experiments. In the first experiment, participants were asked to categorize bouncing-like displays as physical bounce, animated motion, or other. Several parameters of the animations were manipulated, that is, the simulated coefficient of restitution, the value of simulated gravitational acceleration, the motion pattern (uniform acceleration/deceleration or constant speed) and the number of bouncing cycles. In the second experiment, a variable delay at the moment of the collision between the bouncing object and the bouncing surface was introduced. Main results show that, although observers appear to have realistic representations of physical constraints like energy conservation and gravitational acceleration/deceleration, the amount of visual information available in the scene has a strong modulation effect on the extent to which they rely on these representations. A coefficient of restitution >1 was a crucial cue to animacy in displays showing three bouncing cycles, but not in displays showing one bouncing cycle. Additionally, bouncing impressions appear to be driven by perceptual constraints that are unrelated to the physical realism of the scene, like preference for simulated gravitational attraction smaller than g and perceived temporal contiguity between the different phases of bouncing. In the third experiment, the visible opaque bouncing surface was removed from the scene, and the results showed that this did not have any substantial effect on the resulting impressions of physical bounce or animated motion, suggesting that the visual system can fill-in the scene with the missing element. The fourth experiment explored visual impressions of causality in bouncing scenarios. At odds with claims of current causal perception theories, results indicate that a passive object can be perceived as the direct cause of the motion behavior of an active object., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Vicovaro et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)