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Introduction: Chimeric antigen receptor T (CAR-T) cell therapy is an innovative technology that has shown promising results in clinical trials. Treatment is based on modifying the patient's own T cells to express artificial surface receptors to specifically recognize and attack the tumor cells., Objective: To synthesize available evidence on the incidence and management strategies of cytokine release syndrome in patients with diffuse large B-cell lymphoma who received CAR-T cell therapy., Methods: This is a systematic literature review. The search was conducted in the PubMed, Scopus, and Web of science databases. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The systematic review protocol is registered in the International Prospective Register of Systematic Reviews (PROSPERO) database under number CRD42022359258., Results: Nineteen studies were included with a total of 1193 patients who received CAR-T cell therapy. Of these patients, 804 (67%) developed some degree of cytokine release syndrome. The frequencies of Grade 3 and 4 cytokine release syndrome were 10% and 3%, respectively. The regimen most used in the management of the syndrome included tocilizumab and/or glucocorticoids., Conclusion: The results obtained in this review demonstrate high rates of cytokine release syndrome in patients with diffuse large B-cell lymphoma treated with CAR-T cell therapy, however these events are manageable, supporting the conclusion that this therapy is safe in these patients., Competing Interests: Conflicts of interest Authors declare no conflicts of interest., (Copyright © 2024 Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Preliminary studies suggest that creatine and guanidinoacetic acid (GAA) may function as moderate vasodilators, enhancing tissue oxygen saturation. However, the potential effects of this combination on brain oxygenation in humans remain unknown. Aim: The primary objective of this randomized controlled pilot trial was to assess cerebral blood oxygenation indices following a 7-day administration of a mixture containing creatine and GAA in healthy adults. Methods: Nineteen apparently healthy young adults (mean age 21.2 ± 0.4 years; 9 females) were randomly assigned to receive either a mixture (consisting of 2 g of creatine and 2 g of GAA) or a placebo in a crossover design. Oxygen saturation (SpO 2 ) and hemoglobin index (tHb) in the prefrontal cortex were assessed at rest (REST), during meditation that focused on mindful breathing (MED), during a three-component cognitive task (TASK), and during a post-task recovery (REC) before and after 7 days of supplementation. Results: Two-way ANOVA with repeated measures revealed statistically significant differences (treatment vs. time interaction) between interventions for SpO 2 during the REST ( F  = 5.733, P  = 0.028), MED ( F  = 5.897, P  = 0.026), and REC phases ( F  = 6.715, P  = 0.018), indicating that the creatine-GAA mixture was more effective than placebo in enhancing oxygen saturation in the prefrontal brain both before, during, and after a cognitive task. Conclusion: These promising findings are of considerable interest for nutritional neuroscience but require validation through well-designed longitudinal trials with larger sample sizes. The study is registered at ClinicalTrials.gov (NCT06371651)., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: SMO serves as a member of the Scientific Advisory Board on Creatine in Health and Medicine (AlzChem LLC). SMO co-owns patent “Supplements Based on Liquid Creatine” at the European Patent Office (WO2019150323 A1). SMO has received research support related to creatine during the past 36 months from the Serbian Ministry of Education, Science, and Technological Development; Provincial Secretariat for Higher Education and Scientific Research; Alzchem Group AG; ThermoLife International; and Hueston Hennigan LLP. SMO does not own stocks and shares in any organization. DZ and NT declare no known competing financial interests or personal relationships that could have appeared to influence the authorship of this paper.

Introduction: Pancreatic ductal adenocarcinoma (PDAC) represents the complexity of interaction between cancer and cells of the tumor microenvironment (TME). Immune cells affect tumor cell behavior, thus driving cancer progression. Cancer-associated fibroblasts (CAFs) are responsible of the desmoplastic and fibrotic reaction by regulating deposition and remodeling of extracellular matrix (ECM). As tumor-promoting cells abundant in PDAC ECM, CAFs represent promising targets for novel anticancer interventions. However, relevant clinical trials are hampered by the lack of specific markers and elusive differences among CAF subtypes. Indeed, while single-cell transcriptomic analyses have provided important information on the cellular constituents of PDACs and related molecular pathways, studies based on the identification of protein markers in tissues aimed at identifying CAF subtypes and new molecular targets result incomplete., Methods: Herein, we applied multiplexed Imaging Mass Cytometry (IMC) at single-cell resolution on 8 human PDAC tissues to depict the PDAC composing cells, and profiling immune cells, endothelial cells (ECs), as well as endocrine cells and tumor cells., Results: We focused on CAFs by characterizing up to 19 clusters distinguished by phenotype, spatiality, and interaction with immune and tumor cells. We report evidence that specific subtypes of CAFs (CAFs 10 and 11) predominantly are enriched at the tumor-stroma interface and closely associated with tumor cells. CAFs expressing different combinations of FAP, podoplanin and cadherin-11, were associated with a higher level of CA19-9. Moreover, we identified specific subsets of FAP + and podoplanin + /cadherin-11 + CAFs enriched in patients with negative prognosis., Discussion: The present study provides new general insights into the complexity of the PDAC microenvironment by defining phenotypic heterogeneities and spatial distributions of CAFs, thus suggesting different functions of their subtypes in the PDAC microenvironment., Competing Interests: LR reports grant/research funding to institution from Agios, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, IPSEN, Lilly, MSD, Nerviano Medical Sciences, Roche, Servier, Taiho Oncology, TransThera Sciences, and Zymeworks; consulting fees from AbbVie, AstraZeneca, Basilea, Bayer, Bristol Myers Squibb, Elevar Therapeutics, Exelixis, Genenta, Hengrui, Incyte, IPSEN, IQVIA, Jazz Pharmaceuticals, MSD, Nerviano Medical Sciences, Roche, Servier, Taiho Oncology, and Zymeworks; lecture fees from AstraZeneca, Bayer, Bristol Myers Squibb, Guerbet, Incyte, IPSEN, Roche, and Servier; and travel expenses from AstraZeneca. 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. 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. The reviewer MM declared a shared affiliation, with no collaboration, with the authors to the handling editor at the time of the review., (Copyright © 2024 Erreni, Fumagalli, D’Anna, Sollai, Bozzarelli, Nappo, Zanini, Parente, Garlanda, Rimassa, Terracciano, Biswas, Zerbi, Mantovani and Doni.)

Artificial intelligence (AI)-powered approaches are becoming increasingly used as histopathologic tools to extract subvisual features and improve diagnostic workflows. On the other hand, hi-plex approaches are widely adopted to analyze the immune ecosystem in tumor specimens. Here, we aimed at combining AI-aided histopathology and imaging mass cytometry (IMC) to analyze the ecosystem of non-small cell lung cancer (NSCLC). An AI-based approach was used on hematoxylin and eosin (H&E) sections from 158 NSCLC specimens to accurately identify tumor cells, both adenocarcinoma and squamous carcinoma cells, and to generate a classifier of tumor cell spatial clustering. Consecutive tissue sections were stained with metal-labeled antibodies and processed through the IMC workflow, allowing quantitative detection of 24 markers related to tumor cells, tissue architecture, CD45+ myeloid and lymphoid cells, and immune activation. IMC identified 11 macrophage clusters that mainly localized in the stroma, except for S100A8+ cells, which infiltrated tumor nests. T cells were preferentially localized in peritumor areas or in tumor nests, the latter being associated with better prognosis, and they were more abundant in highly clustered tumors. Integrated tumor and immune classifiers were validated as prognostic on whole slides. In conclusion, integration of AI-powered H&E and multiparametric IMC allows investigation of spatial patterns and reveals tissue relevant features with clinical relevance., Significance: Leveraging artificial intelligence-powered H&E analysis integrated with hi-plex imaging mass cytometry provides insights into the tumor ecosystem and can translate tumor features into classifiers to predict prognosis, genotype, and therapy response., (©2024 The Authors; Published by the American Association for Cancer Research.)

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. PDAC is characterized by a complex tumor microenvironment (TME), that plays a pivotal role in disease progression and resistance to therapy. Investigating the spatial distribution and interaction of TME cells with the tumor is the basis for understanding the mechanisms underlying disease progression and represents a current challenge in PDAC research. Imaging mass cytometry (IMC) is the major multiplex imaging technology for the spatial analysis of tumor heterogeneity. However, there is a dearth of reports of multiplexed IMC panels for different preclinical mouse models, including pancreatic cancer. We addressed this gap by utilizing two preclinical models of PDAC: the genetically engineered, bearing KRAS - TP53 mutations in pancreatic cells, and the orthotopic, and developed a 28-marker panel for single-cell IMC analysis to assess the abundance, distribution and phenotypes of cells involved in PDAC progression and their reciprocal functional interactions. Herein, we provide an unprecedented definition of the distribution of TME cells in PDAC and compare the diversity between transplanted and genetic disease models. The results obtained represent an important and customizable tool for unraveling the complexities of PDAC and deciphering the mechanisms behind therapy resistance.

Background and Aim: Essential arterial hypertension is a risk factor for stroke, myocardial infarction, heart failure, and arterial aneurysm, which are related to the activation of platelets. Purinergic signaling has a central role in platelet aggregation. Although ATP and ADP can act as a proaggregant agent, adenosine inhibits platelet aggregation and reduces vascular injury. Physical exercise exhibits antiaggregant properties and can modulate purinergic system. The aim of this study was to evaluate the effect of 6 months of resistance training on purinergic system components in platelets and on platelet activation, hemodynamic and anthropometric parameters in hypertensive woman., Method: A total of 31 hypertensive and 28 normotensive middle-aged sedentary women were submitted to 6 months of resistance training. Purinergic enzymes activities were assessed in platelets; ATP and Tromboxane B2 (TXB2) levels were measured in serum. Blood pressure (BP), BMI, and body fat were also measured. All variables were statistically analyzed, considering P value less than 0.05., Results: Six months of resistance training was able to significantly reduce BP, ATP, and TXB2 levels as well as NTPDase, ecto-5'nucleotidase, and ADA activities in hypertensive group. After 6 months of resistance training, purinergic system components and TXB2 of hypertensive group were similar to normotensive group in platelets, demonstrating that resistance training was able to modulate platelet activation. A positive correlation was found between BP, enzyme activities, and levels of ATP and TXB2., Conclusion: Our findings demonstrated the relationship between purinergic signaling and platelet activation in hypertension and suggests that resistance training serve as tool to reduce platelet aggregation in hypertensive woman by modulating purinergic system., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Aim: To compare the outcomes of home-based and conventional hospital-based care for children newly diagnosed with type 1 diabetes mellitus., Methods: A descriptive study was conducted of all children newly diagnosed with diabetes mellitus at the Timone Hospital in Marseille, France, between November 2017 and July 2019. The patients received either home-based or in-patient hospital care. The primary outcome was the length of initial hospital stay. The secondary outcome measures were glycemic control in the first year of treatment, families' diabetes knowledge, the effect of diabetes on quality of life, and overall quality of care., Results: A total of 85 patients were included, 37 in the home-based care group and 48 in the in-patient care group. The initial length of hospital stay was 6 days in the home-based care group versus 9 days in the in-patient care group. Levels of glycemic control, diabetes knowledge and quality of care were comparable in the two groups despite a higher rate of socioeconomic deprivation in the home-based care group., Conclusion: Home-based care for children with diabetes is safe and effective. This new healthcare pathway provides good overall social care, especially for socioeconomically deprived families., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

The recognition of microbe and extracellular matrix (ECM) is a recurring theme in the humoral innate immune system. Fluid-phase molecules of innate immunity share regulatory roles in ECM. On the other hand, ECM elements have immunological functions. Innate immunity is evolutionary and functionally connected to hemostasis. Staphylococcus aureus ( S. aureus ) is a major cause of hospital-associated bloodstream infections and the most common cause of several life-threatening conditions such as endocarditis and sepsis through its ability to manipulate hemostasis. Biofilm-related infection and sepsis represent a medical need due to the lack of treatments and the high resistance to antibiotics. We designed a method combining imaging and microfluidics to dissect the role of elements of the ECM and hemostasis in triggering S. aureus biofilm by highlighting an essential role of fibrinogen (FG) in adhesion and formation. Furthermore, we ascertained an important role of the fluid-phase activation of fibrinolysis in inhibiting biofilm of S. aureus and facilitating an antibody-mediated response aimed at pathogen killing. The results define FG as an essential element of hemostasis in the S. aureus biofilm formation and a role of fibrinolysis in its inhibition, while promoting an antibody-mediated response. Understanding host molecular mechanisms influencing biofilm formation and degradation is instrumental for the development of new combined therapeutic approaches to prevent the risk of S. aureus biofilm-associated diseases.

The trypanosomatid Angomonas deanei is a model to study endosymbiosis. Each cell contains a single β-proteobacterial endosymbiont that divides at a defined point in the host cell cycle and contributes essential metabolites to the host metabolism. Additionally, one endosymbiont gene, encoding an ornithine cyclodeaminase (OCD), was transferred by endosymbiotic gene transfer (EGT) to the nucleus. However, the molecular mechanisms mediating the intricate host/symbiont interactions are largely unexplored. Here, we used protein mass spectrometry to identify nucleus-encoded proteins that co-purify with the endosymbiont. Expression of fluorescent fusion constructs of these proteins in A. deanei confirmed seven host proteins to be recruited to specific sites within the endosymbiont. These endosymbiont-targeted proteins (ETPs) include two proteins annotated as dynamin-like protein and peptidoglycan hydrolase that form a ring-shaped structure around the endosymbiont division site that remarkably resembles organellar division machineries. The EGT-derived OCD was not among the ETPs, but instead localizes to the glycosome, likely enabling proline production in the glycosome. We hypothesize that recalibration of the metabolic capacity of the glycosomes that are closely associated with the endosymbiont helps to supply the endosymbiont with metabolites it is auxotrophic for and thus supports the integration of host and endosymbiont metabolic networks. Hence, scrutiny of endosymbiosis-induced protein re-localization patterns in A. deanei yielded profound insights into how an endosymbiotic relationship can stabilize and deepen over time far beyond the level of metabolite exchange., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction and Objective: Cervical cancer is the fourth most prevalent type of cancer in the world. The tumor microenvironment of this disease is associated with the production of several cytokines, pro and anti-inflammatory, and with the purinergic signaling system so that changes in these components are observed throughout the pathological process. The aim of this review is to understand the pathophysiology of cervical cancer based on immunological processes and purinergic signaling pathways, in addition to suggesting possibilities of therapeutic targets., Materials and Methods: To make up this review, studies covering topics of cervical cancer, inflammation and purinergic system were selected from the Pubmed., Results: The main pro-inflammatory cytokines involved are IL-17, IL-1β, IL-6, and IL-18, and among the anti-inflammatory ones, IL-10 and TGF-β stand out. As new therapeutic targets, P2X7 and A2A receptors have been suggested, since blocking P2X7 would lead to reduced release of pro-inflammatory cytokines, and blocking A2A would increase activation of cytotoxic T lymphocytes in the context of tumor combat. The association between the immune system and the purinergic system, already known in other types of disease, also presents possibilities for a better understanding of biomolecular processes and therapeutic possibilities in the context of cervical cancer., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Thanks to its well-known neuroanatomy, limited brain size, complex behaviour, and the extensive genetic methods, Drosophila has become an indispensable model in neuroscience. A vast number of studies have focused on its olfactory system and the processing of odour information. Optogenetics is one of the recently developed genetic tools that significantly advance this field of research, allowing to replace odour stimuli by direct neuronal activation with light. This becomes a universal all-optical toolkit when spatially selective optogenetic activation is combined with calcium imaging to read out neuronal responses. Initial experiments showed a successful implementation to study the olfactory system in fish and mice, but the olfactory system of Drosophila has been so far precluded from an application. To fill this gap, we present here optogenetic tools to selectively stimulate functional units in the Drosophila olfactory system, combined with two-photon calcium imaging to read out the activity patterns elicited by these stimuli at different levels of the brain. This method allows to study the spatial and temporal features of the information flow and reveals the functional connectivity in the olfactory network., (© 2022. The Author(s).)

Cancer cases have increased significantly in Brazil and worldwide, with cutaneous melanoma (CM) being responsible for nearly 57,000 deaths in the world. Thus, this review article aims at exploring and proposed hypotheses with respect to the possibility that RA can be a promising and alternative compound to be used as an adjuvant in melanoma treatment, acting on purinergic signaling. The scarcity of articles evidencing the action of this compound in this signaling pathway requires further studies. Considering diverse evidence found in the literature, we hypothesize that RA can be an effective candidate for the treatment of CM acting as a modulating molecule of purinergic cellular pathway through P2X7 blocking, mitigating the Warburg effect, and as antagonic molecule of the P2Y12 receptor, reducing the formation of adhesive molecules that prevent adherence in tumor cells. In this way, our proposals for CM treatment based on targeting purinergic signaling permeate the integral practice, going from intracell to extracell. Undoubtedly, much is still to be discovered and elucidated about this promising compound, this paper being an interesting work baseline to support more research studies., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Acute secondary progressive multiple sclerosis (SPMS) is characterized by escalating neurological disability, with limited disease-modifying therapeutic options. A 48-year-old woman with acute SPMS being treated with interferon beta-1a and oral corticosteroids presented as a clinical outpatient with no disease-modifying effects after treatment. A decision was made to treat her with a combination of guanidinoacetate and creatine for 21 days. She had made clinical progress at follow-up, with the intensity of fatigue dropping from severe to mild. Magnetic resonance spectroscopy revealed increased brain choline, creatine, N-acetylaspartate, and glutathione. Patients with SPMS may benefit from guanidinoacetate-creatine treatment in terms of patient- and clinician-reported outcomes; this requires additional study.