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Algunos suelos agrícolas de Argentina evidencian procesos de acidificación. Este fenómeno puede tener efectos sobre el estado de la fracción mineral del suelo, particularmente el estado de cristalinidad de las arcillas. Por ello, se estudiaron suelos agrícolas de Argentina bajo siembra directa, no fertilizados y fertilizados con urea. Los resultados indican que suelos con pH más bajos (aquellos de ambientes húmedos y con mayor historia de fertilización nitrogenada) poseen mayores contenidos de Al activo. Esto podría haber sido producto de cierto grado de desnaturalización de los filosilicatos. La peor cristalización de las especies minerales de estos suelos habla a favor de cierto grado de desnaturalización de las mismas.

Background and Purpose: Proton Minibeam Radiation Therapy (pMBRT) is an unconventional radiation technique based on a strong modulation of the dose deposition. Due to its specific pattern, pMBRT involves several dosimetry (peak and valley doses, peak-to-valley dose ratio (PVDR)) and geometrical parameters (beam width, spacing) that can influence the biological response. This study aims at contributing to the efforts to deepen the comprehension of how the various parameters relate to central biological mechanisms, particularly anti-tumor immunity, and how these correlations affect treatment outcomes with the goal to fully unleash the potential of pMBRT. We also evaluated the effects of X-ray MBRT to further elucidate the influence of peak dose and dose heterogeneity., Methods and Materials: An orthotopic rat model of glioblastoma underwent several pMBRT configurations. The impact of different dosimetric parameters on survival and on the modulation of crucial mechanisms for pMBRT, such as immune response, was investigated. The latter was assessed by immunohistochemistry and flow cytometry at 7 days post-irradiation., Results: Survival was improved across the various pMBRT regimens via maintaining a minimum valley dose as well as a higher dose heterogeneity, which is driven by peak dose. While the mean dose did not impact immune infiltration, a higher PVDR promoted a less immunosuppressive microenvironment., Conclusions: Our results suggest that both tumor eradication, and immune infiltration are associated with higher dose heterogeneity. Higher dose heterogeneity was achieved by optimizing the peak dose, as well as maintaining a minimum valley dose. These parameters contributed to direct tumor eradication as well as reduction of immunosuppression, which is a departure from the more immunosuppressive tumor environment found in conventional proton therapy that delivers uniform dose distributions., 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.)

Particle therapy (PT) represents a significant advancement in cancer treatment, precisely targeting tumor cells while sparing surrounding healthy tissues thanks to the unique depth-dose profiles of the charged particles. Furthermore, their linear energy transfer and relative biological effectiveness enhance their capability to treat radioresistant tumors, including hypoxic ones. Over the years, extensive research has paved the way for PT's clinical application, and current efforts aim to refine its efficacy and precision, minimizing the toxicities. In this regard, radiobiology research is evolving toward integrating biotechnology to advance drug discovery and radiation therapy optimization. This shift from basic radiobiology to understanding the molecular mechanisms of PT aims to expand the therapeutic window through innovative dose delivery regimens and combined therapy approaches. This review, written by over 30 contributors from various countries, provides a comprehensive look at key research areas and new developments in PT radiobiology, emphasizing the innovations and techniques transforming the field, ranging from the radiobiology of new irradiation modalities to multimodal radiation therapy and modeling efforts. We highlight both advancements and knowledge gaps, with the aim of improving the understanding and application of PT in oncology., Competing Interests: 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., (© 2024 The Authors.)

Background: Radiation-induced neurocognitive dysfunction is a major adverse effect of brain radiation therapy and has specific relevance in pediatric oncology, where serious cognitive deficits have been reported in survivors of pediatric brain tumors. Moreover, many pediatric patients receive proton therapy under general anesthesia or sedation to guarantee precise ballistics with a high oxygen content for safety. The present study addresses the relevant question of the potential effect of supplemental oxygen administered during anesthesia on normal tissue toxicity and investigates the anti-tumor immune response generated following conventional and FLASH proton therapy., Methods: Rats (Fischer 344) were cranially irradiated with a single high dose of proton therapy (15 Gy or 25 Gy) using FLASH dose rate proton irradiation (257 ± 2 Gy/s) or conventional dose rate proton irradiation (4 ± 0.02 Gy/s), and the toxicities in the normal tissue were examined by histological, cytometric and behavioral analysis. Glioblastoma-bearing rats were irradiated in the same manner and tumor-infiltrating leukocytes were quantified by flow cytometry., Results: Our findings indicate that supplemental oxygen has an adverse impact on both functional and anatomical evaluations of normal brain following conventional and FLASH proton therapy. In addition, oxygen supplementation in anesthesia is particularly detrimental for anti-tumor immune response by preventing a strong immune cell infiltration into tumoral tissues following conventional proton therapy., Conclusions: These results demonstrate the need to further optimize anesthesia protocols used in radiotherapy with the goal of preserving normal tissues and achieving tumor control, specifically in combination with immunotherapy agents., (© 2023. The Author(s).)

Purpose: FLASH radiation therapy (FLASH-RT) is a promising radiation technique that uses ultrahigh doses of radiation to increase the therapeutic window of the treatment. FLASH-RT has been observed to provide normal tissue sparing at high dose rates and similar tumor control compared with conventional RT, yet the biological processes governing these radiobiological effects are still unknown. In this study, we sought to investigate the potential immune response generated by FLASH-RT in a high dose of proton therapy in an orthotopic glioma rat model., Methods and Materials: We cranially irradiated rats with a single high dose (25 Gy) using FLASH dose rate proton irradiation (257 ± 2 Gy/s) or conventional dose rate proton irradiation (4 ± 0.02 Gy/s). We first assessed the protective FLASH effect that resulted in our setup through behavioral studies in naïve rats. This was followed by a comprehensive analysis of immune cells in blood, healthy tissue of the brain, and tumor microenvironment by flow cytometry., Results: Proton FLASH-RT spared memory impairment produced by conventional high-dose proton therapy and induced a similar tumor infiltrating lymphocyte recruitment. Additionally, a general neuroinflammation that was similar in both dose rates was observed., Conclusions: Overall, this study demonstrated that FLASH proton therapy offers a neuro-protective effect even at high doses while mounting an effective lymphoid immune response in the tumor., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Focal radiation therapy (RT) has attracted considerable attention as a combinatorial partner for immunotherapy (IT), largely reflecting a well-defined, predictable safety profile and at least some potential for immunostimulation. However, only a few RT-IT combinations have been tested successfully in patients with cancer, highlighting the urgent need for an improved understanding of the interaction between RT and IT in both preclinical and clinical scenarios. Every year since 2016, ImmunoRad gathers experts working at the interface between RT and IT to provide a forum for education and discussion, with the ultimate goal of fostering progress in the field at both preclinical and clinical levels. Here, we summarize the key concepts and findings presented at the Sixth Annual ImmunoRad conference., Competing Interests: MHBH is or has have been a recipient of research grants paid to UCSF or in-kind resources from Roche-Genentech, Varian Medical Systems, Eli Lilly, Pathway Innovations and has received fees for consulting from EMD-Serono, Varian Medical Systems, Genentech, Pathway Innovation, Scholar Rock. KHhas Honoraria: Arch Oncology (Inst), AstraZeneca (Inst), BMS (Inst), Boehringer Ingelheim (Inst), Codiak Biosciences (Inst), F-Star Therapeutics (Inst), Inzen Therapeutics (Inst), Merck Serono (Inst), MSD (Inst), Oncolys Biopharma (Inst), Pfizer (Inst), Replimune (Inst), VacV Biotherapeutics (Inst); Consulting or Advisory Role: Arch Oncology (Inst), AstraZeneca (Inst), BMS (Inst), Boehringer Ingelheim (Inst), Inzen Therapeutics (Inst), Merck Serono (Inst), MSD (Inst), Oncolys BioPharma (Inst), Replimune (Inst); Speakers’ Bureau: BMS (Inst), Merck Serono (Inst), MSD (Inst); Research Funding: AstraZeneca (Inst), Boehringer Ingelheim (Inst), Merck Sharp & Dohme (Inst), Replimune (Inst). FGH received Grant or Research Support Companies from Accuray inc, Bioprotect, Bristol-Myers Squibb, Roche-ImFlame/ImCore, Nanobiotix, AstraZeneca, Debio Pharmaceuticals, Seagen, Eisai, MSD; Grant or Research Support Foundations from Prostate Cancer Foundation, San Salvatore Foundation; Investigator or Co-Investigator Clinical Trials in Bristol-Myers Squibb; Consultations: Johnson & Johnson; Academic Collaborations: EORTC chairman Gynecology Cancer Group, ESMO Scientific Committee member for drug development, ASTRO Scientific Committee Annual Meeting. TH has Consulting: Synthetic Biologics, Novocure, Boston Scientific, Inivata, Merck, GSK; Scientific Advisory Board: PanTher Therapeutics (Equity), Lustgarten; Research Funding (Clinical Trials): Taiho, AstraZeneca, BMS, GSK, IntraOp, Ipsen. EJ reports other support from Abmeta and Adventris, personal fees from Achilles, Dragonfly, Mestag, The Medical Home Group, and Surgtx, other support from Parker Institute, grants and other support from the Lustgarten Foundation, Genentech, BMS, and Break Through Cancer outside the submitted work. SDK receives clinical funding from AstraZeneca, Genentech, and Ionis; she also receives preclinical research funding from Roche. KS is founder and consultant for Faeth Therapeutics and Transomic Technologies. CK is the co-recipient of a Sponsored Research Agreement from Ion Beam Applications (IBA). AM is funded by the Associazione Italiana per la Ricerca sul Cancro (AIRC IG 2018 Id.21763 and AIRC Programma di ricerca 5 per Mille 2019 Id.22737). MM declare grants from Boehringer Ingelheim, AC Biosciences and MSD outside the submitted work. ZSM has Scientific Advisory Board roles and equity options with Archeus Technologies and Seneca Therapeutics. JS owns stock and is a member of the Scientific Advisory Board of Surface Oncology, and is a member of the Scientific Advisory Board of Domain Therapeutics. RT has research grants to his institution from: Varian Medical Systems, Elekta Oncology, Accuray, Inc; scientific advisory board member for: Reflexion Medical, ImmuneSensor Therapeutics. AW acknowledge funding from AstraZeneca and imCORE. RW has stock and other ownership interests with Boost Therapeutics, Immvira LLC, Reflexion Pharmaceuticals, Coordination Pharmaceuticals Inc., Magi Therapeutics, Oncosenescence, Aqualung Therapeutics Corporation, and Cyntegron; he has served in a consulting or advisory role for Aettis Inc., AstraZeneca, Coordination Pharmaceuticals, Genus, Merck Serono S.A., Nano Proteagen, NKGen Biotech, Shuttle Pharmaceuticals, Highlight Therapeutics, S.L., Aqualung Therapeutics Corporation; he has research grants with Varian and Regeneron. RZ is scientific advisory board member of iTeos Therapeutics, receives research grant support from Bristol Myers Squibb and AstraZeneca, and is inventor on patent applications related to work on GITR, CTLA-4, and PD-1 (patent numbers: US20180244793A1; US10323091B2; WO2018106864A1; WO2019094352A1). SD has received compensation for consultant/advisory services from Lytix Biopharma, Mersana Therapeutics, EMD Serono, Ono Pharmaceutical, and Genentech, and research support from Lytix Biopharma and Boehringer-Ingelheim for unrelated projects. LG is/has been holding research contracts with Lytix Biopharma, Promontory and Onxeo, has received consulting/advisory honoraria from Boehringer Ingelheim, AstraZeneca, OmniSEQ, Onxeo, The Longevity Labs, Inzen, Imvax, Sotio, Promontory, Noxopharm, EduCom, and the Luke Heller TECPR2 Foundation, and holds Promontory stock options. ED reports grants and personal fees from Roche Genentech; grants from Servier; grants from AstraZeneca; grants and personal fees from Merck-Serono; grants from BMS; and grants from MSD outside the submitted work. SCF has Consultant: Bayer, Bristol Myers Squibb, Varian, ViewRay, Accuray, Elekta, Janssen, Regeneron, GlaxoSmithKline, Eisai, Astra Zeneca, MedImmune, Merck US, EMD Serono/Merck, Genentech/ROCHE, Boehringer Ingelheim, Nanobiotix and Grant/Research: support from: Bristol Myers Squibb, Varian, Regeneron, Merck, Celldex. All other authors have no conflict of interest to declare., (© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Purpose: Minibeam radiation therapy (MBRT) is an innovative technique that uses a spatial dose modulation. The dose distribution consists of high doses (peaks) in the path of the minibeam and low doses (valleys). The underlying biological mechanism associated with MBRT efficacy remains currently unclear and thus we investigated the potential role of the immune system after treatment with MBRT., Methods and Materials: Rats bearing an orthotopic glioblastoma cell line were treated with 1 fraction of high dose conventional radiation therapy (30 Gy) or 1 fraction of the same mean dose in MBRT. Both immunocompetent (F344) and immunodeficient (Nude) rats were analyzed in survival studies. Systemic and intratumoral immune cell population changes were studied with flow cytometry and immunohistochemistry (IHC) 2 and 7 days after the irradiation., Results: The absence of response of Nude rats after MBRT suggested that T cells were key in the mode of action of MBRT. An inflammatory phenotype was observed in the blood 1 week after irradiation compared with conventional irradiation. Tumor immune cell analysis by flow cytometry showed a substantial infiltration of lymphocytes, specifically of CD8 T cells and B cells in both conventional and MBRT-treated animals. IHC revealed that MBRT induced a faster recruitment of CD8 and CD4 T cells. Animals that were cured by radiation therapy did not suffer tumor growth after reimplantation of tumoral cells, proving the long-term immunity response generated after a high dose of radiation., Conclusions: Our findings show that MBRT can elicit a robust antitumor immune response in glioblastoma while avoiding the high toxicity of a high dose of conventional radiation therapy., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

The last several years have revealed increasing evidence of the immunomodulatory role of radiation therapy. Radiotherapy reshapes the tumoral microenvironment can shift the balance toward a more immunostimulatory or immunosuppressive microenvironment. The immune response to radiation therapy appears to depend on the irradiation configuration (dose, particle, fractionation) and delivery modes (dose rate, spatial distributions). Although an optimal irradiation configuration (dose, temporal fractionation, spatial dose distribution, etc.) has not yet been determined, temporal schemes employing high doses per fraction appear to favor radiation-induced immune response through immunogenic cell death. Through the release of damage-associated molecular patterns and the sensing of double-stranded DNA and RNA breaks, immunogenic cell death activates the innate and adaptive immune response, leading to tumor infiltration by effector T cells and the abscopal effect. Novel radiotherapy approaches such as FLASH and spatially fractionated radiotherapies (SFRT) strongly modulate the dose delivery method. FLASH-RT and SFRT have the potential to trigger the immune system effectively while preserving healthy surrounding tissues. This manuscript reviews the current state of knowledge on the immunomodulation effects of these two new radiotherapy techniques in the tumor, healthy immune cells and non-targeted regions, as well as their therapeutic potential in combination with immunotherapy., (Copyright © 2023 Elsevier Inc. All rights reserved.)

FLASH radiotherapy (FLASH-RT) and spatially fractionated radiation therapy (SFRT) are two new therapeutical strategies that use non-standard dose delivery methods to reduce normal tissue toxicity and increase the therapeutic index. Although likely based on different mechanisms, both FLASH-RT and SFRT have shown to elicit radiobiological effects that significantly differ from those induced by conventional radiotherapy. With the therapeutic potential having been established separately for each technique, the combination of FLASH-RT and SFRT could therefore represent a winning alliance. In this review, we discuss the state of the art, advantages and current limitations, potential synergies, and where a combination of these two techniques could be implemented today or in the near future., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The extra-embryonic yolk sac contains the first definitive multipotent hematopoietic cells, denominated erythromyeloid progenitors. They originate in situ prior to the emergence of hematopoietic stem cells and give rise to erythroid, monocytes, granulocytes, mast cells and macrophages, the latter in a Myb transcription factor-independent manner. We uncovered here the heterogeneity of yolk sac erythromyeloid progenitors, at the single cell level, and discriminated multipotent from committed progenitors, prior to fetal liver colonization. We identified two temporally distinct megakaryocyte differentiation pathways. The first occurs in the yolk sac, bypasses intermediate bipotent megakaryocyte-erythroid progenitors and, similar to the differentiation of macrophages, is Myb-independent. By contrast, the second originates later, from Myb-dependent bipotent progenitors expressing Csf2rb and colonize the fetal liver, where they give rise to megakaryocytes and to large numbers of erythrocytes. Understanding megakaryocyte development is crucial as they play key functions during vascular development, in particular in separating blood and lymphatic networks., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

In the embryo, the first hematopoietic cells derive from the yolk sac and are thought to be rapidly replaced by the progeny of hematopoietic stem cells. We used three lineage-tracing mouse models to show that, contrary to what was previously assumed, hematopoietic stem cells do not contribute significantly to erythrocyte production up until birth. Lineage tracing of yolk sac erythromyeloid progenitors, which generate tissue resident macrophages, identified highly proliferative erythroid progenitors that rapidly differentiate after intra-embryonic injection, persisting as the major contributors to the embryonic erythroid compartment. We show that erythrocyte progenitors of yolk sac origin require 10-fold lower concentrations of erythropoietin than their hematopoietic stem cell-derived counterparts for efficient erythrocyte production. We propose that, in a low erythropoietin environment in the fetal liver, yolk sac-derived erythrocyte progenitors efficiently outcompete hematopoietic stem cell progeny, which fails to generate megakaryocyte and erythrocyte progenitors., Competing Interests: Disclosures: The authors declare no competing interests exist., (© 2021 Soares-da-Silva et al.)

During embryonic development, multiple waves of hematopoietic progenitors with distinct lineage potential are differentially regulated in time and space. Two different waves of thymic progenitors colonize the fetal thymus where they contribute to thymic organogenesis and homeostasis. The origin, the lineage differentiation potential of the first wave, and their relative contribution in shaping the thymus architecture, remained, however, unclear. Here, we show that the first wave of thymic progenitors comprises a unique population of bipotent T and innatel lymphoid cells (T/ILC), generating a lymphoid tissue inducer cells (LTi's), in addition to invariant Vγ5+ T cells. Transcriptional analysis revealed that innate lymphoid gene signatures and, more precisely, the LTi-associated transcripts were expressed in the first, but not in the second, wave of thymic progenitors. Depletion of early thymic progenitors in a temporally controlled manner showed that the progeny of the first wave is indispensable for the differentiation of autoimmune regulator-expressing medullary thymic epithelial cells (mTECs). We further show that these progenitors are of strict hematopoietic stem cell origin, despite the overlap between lymphopoiesis initiation and the transient expression of lymphoid-associated transcripts in yolk sac (YS) erythromyeloid-restricted precursors. Our work highlights the relevance of the developmental timing on the emergence of different lymphoid subsets, required for the establishment of a functionally diverse immune system., (© 2021 by The American Society of Hematology.)

Macrophages are professional phagocytes from the innate arm of the immune system. In steady-state, sessile macrophages are found in adult tissues where they act as front line sentinels of infection and tissue damage. While other immune cells are continuously renewed from hematopoietic stem and progenitor cells (HSPC) located in the bone marrow, a lineage of macrophages, known as resident macrophages, have been shown to be self-maintained in tissues without input from bone marrow HSPCs. This lineage is exemplified by microglia in the brain, Kupffer cells in the liver and Langerhans cells in the epidermis among others. The intestinal and colon lamina propria are the only adult tissues devoid of HSPC-independent resident macrophages. Recent investigations have identified that resident macrophages originate from the extra-embryonic yolk sac hematopoiesis from progenitor(s) distinct from fetal hematopoietic stem cells (HSC). Among yolk sac definitive hematopoiesis, erythromyeloid progenitors (EMP) give rise both to erythroid and myeloid cells, in particular resident macrophages. EMP are only generated within the yolk sac between E8.5 and E10.5 days of development and they migrate to the fetal liver as early as circulation is connected, where they expand and differentiate until at least E16.5. Their progeny includes erythrocytes, macrophages, neutrophils and mast cells but only EMP-derived macrophages persist until adulthood in tissues. The transient nature of EMP emergence and the temporal overlap with HSC generation renders the analysis of these progenitors difficult. We have established a tamoxifen-inducible fate mapping protocol based on expression of the macrophage cytokine receptor Csf1r promoter to characterize EMP and EMP-derived cells in vivo by flow cytometry.