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Objectives To assess the frequency and diversity of extended spectrum β-lactamases (ESBLs) in the Champagne-Ardenne region France, and to identify genetic elements associated with the blaCTX-M genes. Methods During 2004, all the non-duplicate isolates of Pseudomonas aeruginosa and Acinetobacter baumannii resistant to ceftazidime and of Enterobacteriaceae intermediate or resistant to ceftazidime and/or cefotaxime, screening samples excluded, were collected in 10 public hospitals and 3 private clinics. bla genes were sequenced and blaCTX-M environment characterized by PCR mapping. Results In Enterobacteriaceae (138/21 861; 0.6%), ESBLs were predominantly TEM-24 (n = 52; 37.7%) and CTX-M-15 (n = 37; 26.8%). Three new enzymes were identified, CTX-M-61 (CTX-M-1 group), TEM- and SHV-type. A. baumannii (n = 5) produced VEB-1 and P. aeruginosa (n = 2) SHV-2a. ISEcp1 was detected in 22/27 strains, disrupted in 7 of them. The IS903-like element was downstream of blaCTX-M-14 and blaCTX-M-16. ISCR1 was found upstream of blaCTX-M-2 and blaCTX-M-9, and ISCR1 and blaCTX-M-2 were located on a sul1-type class 1 integron. In comparison with 2001–02, ESBL distribution among Enterobacteriaceae showed an increase in CTX-M-type (44.9% vs 3.7% P Escherichia coli CTX-M-15 and to the almost total disappearance of TEM-3 (0.9% vs 51.2%). E. coli was the most frequent species (50.0% vs 5.1% in 1998) despite a similar prevalence to that in 1998 (0.5% vs 0.2%). Conclusions A careful detection of blaCTX-M-type spread to other species would help to anticipate clonal endemics such as those observed in Enterobacter aerogenes TEM-24. [ABSTRACT FROM AUTHOR]

This paper studies the network structure and fragmentation of the Argentinean interbank market. The unsecured (CALL) and secured (REPO) markets are examined, applying complex network analysis. Results indicate that although the secured market has fewer participants, its nodes are more densely connected than the ones in the unsecured market. The interrelationships in the unsecured market are less stable, making its structure more volatile and vulnerable to negative shocks. The analysis identifies two hidden underlying subnetworks within the REPO market: one based on the transactions collateralized by Treasury bonds (REPO-T) and the other based on the operations collateralized by Central Bank (CB) securities (REPO-CB). The changes in monetary policy stance and monetary conditions seem to have a substantially smaller effect in the former submarket than in the latter one. The connectivity levels within the REPO-T market and its structure remain relatively unaffected by the (occasionally pronounced) swings in the other market segment. Hence, the REPO market shows signs of fragmentation in its inner structure, according to the type of collateral asset involved in the transactions, so the average REPO interest rate reflects the interplay between these two partially fragmented submarkets. The REPO market's mixed structure entails one of the main sources of differentiation with respect to the CALL market.

The representation of number symbols is assumed to be unique, and not shared with other ordinal sequences. However, little research has examined if this is the case, or whether properties of symbols (such as spatial complexity) affect ordinal learning. Two studies were conducted to investigate if the property of spatial complexity affects learning ordinal sequences. In Study 1, 46 adults made a series of judgements about two novel symbol sets (Gibson and Sunúz). The goal was to find a novel symbol set that could be ordered by spatial complexity. In Study 2, 84 adults learned to order nine novel symbols (Sunúz) with a paired comparison task, judging which symbol was 'larger' (whereby the larger symbol became physically larger as feedback), and were then asked to rank the symbols. Participants were assigned to either a condition where there was a relationship between spatial complexity and symbol order, or a condition where there was a random relationship. Of interest was whether learning an ordered list of symbols would be facilitated by the spatial complexity of the novel symbols. Findings suggest spatial complexity affected learning ability, and that pairing spatial complexity with relational information can facilitate learning ordinal sequences. This suggests that the implicit cognitive representation of number may be a more general feature of ordinal lists, and not exclusive to number per se.

Non-symbolic magnitude abilities are often claimed to support the acquisition of symbolic magnitude abilities, which, in turn, are claimed to support emerging math abilities. However, not all studies find links between non-symbolic and symbolic magnitude abilities, or between them and math ability. To investigate possible reasons for these different findings, recent research has analyzed differences in non-symbolic/symbolic magnitude abilities using latent class modeling and has identified four different magnitude ability profiles residing within the general magnitude ability distribution that were differentially related to cognitive and math abilities. These findings may help explain the different patterns of findings observed in previous research. To further investigate this possibility, we (1) attempted to replicate earlier findings, (2) determine whether magnitude ability profiles remained stable or changed over 1 year; and (3) assessed the degree to which stability/change in profiles were related to cognitive and math abilities. We used latent transition analysis to investigate stability/changes in non-symbolic and symbolic magnitude abilities of 109 5- to 6-year olds twice in 1 year. At Time 1 and 2, non-symbolic and symbolic magnitude abilities, number transcoding and single-digit addition abilities were assessed. Visuospatial working memory (VSWM), naming numbers, non-verbal IQ, basic RT was also assessed at Time 1. Analysis showed stability in one profile and changes in the three others over 1 year. VSWM and naming numbers predicted profile membership at Time 1 and 2, and profile membership predicted math abilities at both time points. The findings confirm the existence of four different non-symbolic–symbolic magnitude ability profiles; we suggest the changes over time in them potentially reflect deficit, delay, and normal math developmental pathways.

When dissimilar images are presented to each eye, the images will alternate every few seconds in a phenomenon known as binocular rivalry. Recent research has found evidence of a bias towards one image at the initial ‘onset’ period of rivalry that varies across the peripheral visual field. To determine the role that visual field location plays in and around the fovea at onset, trained observers were presented small orthogonal achromatic grating patches at various locations across the central 3° of visual space for 1-s and 60-s intervals. Results reveal stronger bias at onset than during continuous rivalry, and evidence of temporal hemifield dominance across observers, however, the nature of the hemifield effects differed between individuals and interacted with overall eye dominance. Despite using small grating patches, a high proportion of mixed percept was still reported, with more mixed percept at onset along the vertical midline, in general, and in increasing proportions with eccentricity in the lateral hemifields. Results show that even within the foveal range, onset rivalry bias varies across visual space, and differs in degree and sensitivity to biases in average dominance over continuous viewing.

Introduction: Intracranial infections due to sinusitis and otitis, although rare, can progress rapidly and result in significant morbidity, necessitating multifaceted management including extended antibiotic therapy and surgical intervention. Predominantly affecting infants and older children, these infections have seen a perceived increase in incidence following the coronavirus disease 2019 (COVID-19) pandemic., Objectives: Our study aims to describe the clinical and epidemiological characteristics of intracranial infections secondary to sinusitis or otitis in the pediatric population and assess changes in incidence and clinical presentation post-pandemic. Specific objectives include analyzing neurosurgical management practices, the role of ENT-neurosurgery cooperation, incidence of epileptic seizures, and management of associated venous thrombosis., Materials and Methods: A retrospective multicentric study was conducted in hospitals across the Iberian Peninsula, including data from January 2018 to December 2022. Data were divided into pre-lockdown (January 2018 to March 2020) and post-lockdown (March 2020 to December 2022) periods for analysis., Results: The study included 60 pediatric cases (38 post-pandemic and 22 pre-pandemic). The average age was 9.8 years, with a male predominance (61.67%). Sinusitis was the most frequent cause (86%), and the frontal region was the most common site of infection (75%). Neurological symptoms were more prevalent post-pandemic (55.26% versus 23.68%). The primary pathogen was S. intermedius (29.6%). Most patients required neurosurgical intervention (81.7%), with a significant portion undergoing combined ENT-neurosurgery procedures (52.9%). The average antibiotic treatment duration was 6.6 weeks. Complications included venous sinus thrombosis (20%) and seizures (39.2%). Mortality was 3.3%., Conclusion: Although there was a perceived increase in cases post-pandemic, our study observed a normalization of incidence after the lockdown, with a decrease in diagnoses during confinement. The accepted antibiotic regimen lasts 6 weeks, extendable to 8 weeks in non-surgical patients, with at least 2 weeks of intravenous treatment. Sinus surgery combined with antibiotics may suffice to avoid craniotomy in some cases, while combined surgery has a lower reoperation rate in others. Anticoagulation should be individualized and discontinued upon recanalization. Prophylactic antiepileptic drug use remains controversial and should be tailored to patients with specific risk factors. Prolonged antiepileptic drug (AED) therapy may be warranted for those with early seizures and hemorrhagic lesions, whereas others may gradually taper off AEDs after the acute stage., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Extracellular ATP released from dying cells, including tumor cells, is a key mediator of inflammation and tolerance by binding to purinergic receptors on dendritic cells, resulting in inflammasome activation (via P2X7R), dendritic cell maturation (via P2Y11R), and Indoleamine-2,3-dioxygenase 1 upregulation. However, the regulation of ATP-driven Indoleamine-2,3-dioxygenase 1 expression in human dendritic cells has been poorly investigated. In this work we aimed to investigate the ATP-driven molecular regulation of Indoleamine-2,3-dioxygenase 1 expression via purinergic receptors and to provide an in-depth characterization of ATP-driven T regulatory cells induced by Indoleamine-2,3-dioxygenase 1-expressing dendritic cells. We identified P2Y11R as being responsible for ATP-driven Indoleamine-2,3-dioxygenase 1 upregulation, and non-canonical NF-kB as a molecular pathway associated with ATP-dependent Indoleamine-2,3-dioxygenase 1 induction through P2Y11R. Then we investigated - but did not confirm - an involvement of inflammasome machinery through P2X7R in Indoleamine-2,3-dioxygenase 1 upregulation. Finally, we evaluated the role of ATP catabolism via ATP ectonucleotidases, i.e. CD39 and CD73 and its main product adenosine, in regulating the generation of Indoleamine-2,3-dioxygenase 1-driven T regulatory cells. We found that ATP-driven Indoleamine-2,3-dioxygenase 1 upregulation is associated with CD73 upregulation and adenosine production. Additionally, ATP-treated Indoleamine-2,3-dioxygenase 1-positive mature dendritic cells induce PD-1-expressing bone fide suppressive T regulatory cells via adenosine A2AR. Collectively, a more in-depth understanding of ATP-driven immune-regulatory mechanisms through Indoleamine-2,3-dioxygenase 1 regulation in human dendritic cells leading to the induction of T regulatory cells can have clinical implications for the development of Indoleamine-2,3-dioxygenase 1 inhibitors in cancer patients, especially in combination with immunotherapy such as an anti-CD73 or adenosine receptor agonist and immunogenic chemotherapy., (© The Author(s) 2025. Published by Oxford University Press on behalf of Society for Leukocyte Biology.)

In acute myeloid leukemia (AML), malignant cells surviving chemotherapy rely on high mRNA translation and their microenvironmental metabolic support to drive relapse. However, the role of translational reprogramming in the niche is unclear. Here, we found that relapsing AML cells increase translation in their bone marrow (BM) niches, where BM mesenchymal stromal cells (BMSCs) become a source of eIF4A-cap-dependent translation machinery that is transferred to AML cells via extracellular vesicles (EVs) to meet their translational demands. In two independent models of highly chemo-resistant AML driven by MLL-AF9 or FLT3-ITD (internal tandem duplication) and nucleophosmin (NPMc) mutations, protein synthesis levels increase in refractory AML dependent on nestin+ BMSCs. Inhibiting cap-dependent translation in BMSCs abolishes their chemoprotective ability, while EVs from BMSCs carrying eIF4A boost AML cell translation and survival. Consequently, eIF4A inhibition synergizes with conventional chemotherapy. Together, these results suggest that AML cells rely on BMSCs to maintain an oncogenic translational program required for relapse., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Subdural hematoma (SDH) typically occurs due to traumatic brain injury but can arise as a rare complication of procedures like endoscopic third ventriculostomy (ETV)., Case Presentation: We report an unusual case in a 9-year-old male with previous resection of a fourth-ventricle ependymoma at 2 years of age. Seven years post-surgery, he presented with worsening hydrocephalus and underwent ETV. One month later, he developed severe headaches and motor difficulties. Imaging revealed a significant right SDH, necessitating urgent drainage. Postoperative recovery was uneventful, and follow-up imaging showed resolution of the hematoma., Literature Review and Discussion: ETV is generally preferred for obstructive hydrocephalus due to lower complication rates compared to shunt procedures. However, cases of SDH post-ETV remain reported, albeit rarely. Potential mechanisms include altered cerebrospinal fluid dynamics and intraoperative vessel injury. This case aligns with literature findings and reinforces the importance of postoperative monitoring and prompt intervention in symptomatic cases to prevent complications., Conclusion: Clinicians should consider SDH in pediatric patients with new symptoms post-ETV. Further research should focus on understanding the risk factors and mechanisms for SDH development., Competing Interests: Declarations. Ethics approval: Ethical approval was not required for this study following national guidelines. Consent for publication: Written informed consent was obtained from the patient’s legal guardian to publish this case report. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Acute myeloid leukemia (AML) is an aggressive disease with a high relapse rate. In this study, we map the metabolic profile of CD34 + (CD38 low/- ) AML cells and the extracellular vesicle signatures in circulation from AML patients at diagnosis. CD34 + AML cells display high antioxidant glutathione levels and enhanced mitochondrial functionality, both associated with poor clinical outcomes. Although CD34 + AML cells are highly dependent on glucose oxidation and glycolysis for energy, those from intermediate- and adverse-risk patients reveal increased mitochondrial dependence. Extracellular vesicles from AML are mainly enriched in stem cell markers and express antioxidant GPX3, with their profiles showing potential prognostic value. Extracellular vesicles enhance mitochondrial functionality and dependence on CD34 + AML cells via the glutathione/GPX4 axis. Notably, extracellular vesicles from adverse-risk patients enhance leukemia cell engraftment in vivo. Here, we show a potential noninvasive approach based on liquid 'cell-extracellular vesicle' biopsy toward a redefined metabolic stratification in AML., Competing Interests: Competing interests: The authors declare no competing interests. Ethics: The research was approved by the institutional review board of the Area Vasta Emilia Centro (AVEC) Ethical Committee (approval code: 94/2016/O/Tess)., (© 2024. The Author(s).)

Acute myeloid leukemia (AML) is an aggressive hematologic neoplasia with a complex polyclonal architecture. Among driver lesions, those involving the FLT3 gene represent the most frequent mutations identified at diagnosis. The development of tyrosine kinase inhibitors (TKIs) has improved the clinical outcomes of FLT3 -mutated patients (Pt). However, overcoming resistance to these drugs remains a challenge. To unravel the molecular mechanisms underlying therapy resistance and clonal selection, we conducted a longitudinal analysis using a single-cell DNA sequencing approach (MissionBioTapestri® platform, San Francisco, CA, USA) in two patients with FLT3-mutated AML. To this end, samples were collected at the time of diagnosis, during TKI therapy, and at relapse or complete remission. For Pt #1, disease resistance was associated with clonal expansion of minor clones, and 2nd line TKI therapy with gilteritinib provided a proliferative advantage to the clones carrying NRAS and KIT mutations, thereby responsible for relapse. In Pt #2, clonal architecture was less complex, and 1st line TKI therapy with midostaurin was able to eradicate the leukemic clones. Our results corroborate previous findings about clonal selection driven by TKIs, highlighting the importance of a deeper characterization of individual clonal architectures for choosing the best treatment plan for personalized approaches aimed at optimizing outcomes.

Objectives: This study aimed to translate and test the psychometric properties of the Chase Nurse Manager Competency Instrument (CNMCI) among Italian nurse managers and to provide further support for the scale's validity testing., Methods: An instrument translation and cross-sectional validation study was conducted. The English version was translated into Italian using the translation method, which included pre-translation (establishing equivalence), initial translation, pretesting, review, and administration. From August 2022 to June 2023, 349 nurse managers were recruited through a web survey from 31 public and private healthcare organizations in North, Central, and Southern Italy. Validity assessments included content and structural validity. Reliability was evaluated using Cronbach's α coefficient and test-retest reliability., Results: The content validity confirmed all the items of the CNMCI in the Italian version, including the two measurement sections, "knowledge and understand" and "ability to implement and/or use." The instrument's item-content validity index (I-CVI) ranged from 0.83 to 1.00, while the scale-level content validity index (S-CVI) for both instrument sections was 0.97. The confirmatory factor analysis showed an acceptable fit. In the "knowledge and understand" section, Cronbach's α coefficient was 0.978, and in the "ability to implement and/or use" section, Cronbach's α coefficient was 0.976. The correlation coefficient between each dimension was 0.494-0.908. The test-retest reliability score was 0.82, suggesting good instrument consistency., Conclusions: Overall, the Italian CNMCI demonstrates good reliability and validity for measuring nurse managers' core competencies and supports the construct's multi-dimensionality. Also, our findings support the hierarchical nature of the factors, further supporting the validity of the instrument., Competing Interests: The authors declare that they have no competing interests., (© 2024 The Authors.)

Acute myeloid leukemia (AML) is an aggressive heterogeneous disease characterized by several alterations of the immune system prompting disease progression and treatment response. The therapies available for AML can affect lymphocyte function, limiting the efficacy of immunotherapy while hindering leukemia-specific immune reactions. Recently, the treatment based on Venetoclax (VEN), a specific B-cell lymphoma 2 (BCL-2) inhibitor, in combination with hypomethylating agents (HMAs) or low-dose cytarabine, has emerged as a promising clinical strategy in AML. To better understand the immunological effect of VEN treatment, we characterized the phenotype and immune checkpoint (IC) receptors' expression on CD4 + and CD8 + T cells from AML patients after the first and second cycle of HMA in combination with VEN. HMA and VEN treatment significantly increased the percentage of naïve CD8 + T cells and TIM-3 + CD4 + and CD8 + T cells and reduced cytokine-secreting non-suppressive T regulatory cells (Tregs). Of note, a comparison between AML patients treated with HMA only and HMA in combination with VEN revealed the specific contribution of VEN in modulating the immune cell repertoire. Indeed, the reduction of cytokine-secreting non-suppressive Tregs, the increased TIM-3 expression on CD8 + T cells, and the reduced co-expression of PD-1 and TIM-3 on both CD4 + and CD8 + T cells are all VEN-specific. Collectively, our study shed light on immune modulation induced by VEN treatment, providing the rationale for a novel therapeutic combination of VEN and IC inhibitors in AML patients., 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 Corradi, Forte, Cristiano, Polimeno, Ciciarello, Salvestrini, Bandini, Robustelli, Ottaviani, Cavo, Ocadlikova and Curti.)

We report a rare clinical case of a malignant prolactinoma in which the exponential increase of prolactin levels with minimal tumor growth and no response to treatment led to diagnosis of abdominal, thoracic, and vertebral metastases., 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., (© 2024 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)

Current therapies for myeloproliferative neoplasms (MPNs) improve symptoms but have limited effect on tumor size. In preclinical studies, tamoxifen restored normal apoptosis in mutated hematopoietic stem/progenitor cells (HSPCs). TAMARIN Phase-II, multicenter, single-arm clinical trial assessed tamoxifen's safety and activity in patients with stable MPNs, no prior thrombotic events and mutated JAK2 V617F , CALR ins5 or CALR del52 peripheral blood allele burden ≥20% (EudraCT 2015-005497-38). 38 patients were recruited over 112w and 32 completed 24w-treatment. The study's A'herns success criteria were met as the primary outcome ( ≥ 50% reduction in mutant allele burden at 24w) was observed in 3/38 patients. Secondary outcomes included ≥25% reduction at 24w (5/38), ≥50% reduction at 12w (0/38), thrombotic events (2/38), toxicities, hematological response, proportion of patients in each IWG-MRT response category and ELN response criteria. As exploratory outcomes, baseline analysis of HSPC transcriptome segregates responders and non-responders, suggesting a predictive signature. In responder HSPCs, longitudinal analysis shows high baseline expression of JAK-STAT signaling and oxidative phosphorylation genes, which are downregulated by tamoxifen. We further demonstrate in preclinical studies that in JAK2V617F+ cells, 4-hydroxytamoxifen inhibits mitochondrial complex-I, activates integrated stress response and decreases pathogenic JAK2-signaling. These results warrant further investigation of tamoxifen in MPN, with careful consideration of thrombotic risk., (© 2023. The Author(s).)

Introduction: Extracellular vesicles (EVs) and particles (EPs) represent reliable biomarkers for disease detection. Their role in the inflammatory microenvironment of severe COVID-19 patients is not well determined. Here, we characterized the immunophenotype, the lipidomic cargo and the functional activity of circulating EPs from severe COVID-19 patients (Co-19-EPs) and healthy controls (HC-EPs) correlating the data with the clinical parameters including the partial pressure of oxygen to fraction of inspired oxygen ratio (PaO2/FiO2) and the sequential organ failure assessment (SOFA) score., Methods: Peripheral blood (PB) was collected from COVID-19 patients (n=10) and HC (n=10). EPs were purified from platelet-poor plasma by size exclusion chromatography (SEC) and ultrafiltration. Plasma cytokines and EPs were characterized by multiplex bead-based assay. Quantitative lipidomic profiling of EPs was performed by liquid chromatography/mass spectrometry combined with quadrupole time-of-flight (LC/MS Q-TOF). Innate lymphoid cells (ILC) were characterized by flow cytometry after co-cultures with HC-EPs or Co-19-EPs., Results: We observed that EPs from severe COVID-19 patients: 1) display an altered surface signature as assessed by multiplex protein analysis; 2) are characterized by distinct lipidomic profiling; 3) show correlations between lipidomic profiling and disease aggressiveness scores; 4) fail to dampen type 2 innate lymphoid cells (ILC2) cytokine secretion. As a consequence, ILC2 from severe COVID-19 patients show a more activated phenotype due to the presence of Co-19-EPs., Discussion: In summary, these data highlight that abnormal circulating EPs promote ILC2-driven inflammatory signals in severe COVID-19 patients and support further exploration to unravel the role of EPs (and EVs) in COVID-19 pathogenesis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Forte, Pellegrino, Trabanelli, Tonetti, Ricci, Cenerenti, Comai, Tazzari, Lazzarotto, Buratta, Urbanelli, Narimanfar, Alabed, Mecucci, La Manna, Emiliani, Jandus, Ranieri, Cavo, Catani and Palandri.)

Background: Time management practice is the act of influencing one's behavioural dimensions to complete as many tasks as possible within a specified amount of time. These behavioural dimensions include work organization and the continued application of time management techniques. Good time management, such as setting goals and priorities, as well as planning and delegating tasks, can facilitate productivity and success, contributing to work effectiveness, maintaining balance and job satisfaction. Conversely, poor time management has been associated with poor quality of work, low productivity, negative influence on the career path, and high levels of stress., Aim: The study aims to identify the strategies used by middle nurse managers in time management., Methods: A rapid review of biomedical databases was undertaken during the month of June 2021. The included studies were published in English and in Italian., Results: Findings reveal that the most used and effective time management strategies for nurse managers are setting goals, and priorities and delegating tasks. Other useful strategies also found to be fundamental are discussed in detail., Conclusion: A manager should prioritize the concept of planning, which can be counted as an efficient time management technique and educate himself on delegating. Time management has an impact not only on productivity and organizational success, but also on the balance between private and working life of managers.

Pituitary metastases are rare. Clinical presentation could range from asymptomatic to panhypopituitarism or local symptoms. We present a case report of a 43-year-old male patient with a new onset headache, visual disturbances, and panhypopituitarism. The investigation led to the diagnosis of pituitary metastasis as the first manifestation of underlying lung cancer., 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., (© 2022 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)

Epigenetic histone modifiers are key regulators of cell fate decisions in normal and malignant hematopoiesis. Their enzymatic activities are of particular significance as putative therapeutic targets in leukemia. In contrast, less is known about the contextual role in which those enzymatic activities are exercised and specifically how different macromolecular complexes configure the same enzymatic activity with distinct molecular and cellular consequences. We focus on KAT2A, a lysine acetyltransferase responsible for histone H3 lysine 9 acetylation, which we recently identified as a dependence in acute myeloid leukemia stem cells and that participates in 2 distinct macromolecular complexes: Ada two-A-containing (ATAC) and Spt-Ada-Gcn5-Acetyltransferase (SAGA). Through analysis of human cord blood hematopoietic stem cells and progenitors, and of myeloid leukemia cells, we identify unique respective contributions of the ATAC complex to regulation of biosynthetic activity in undifferentiated self-renewing cells and of the SAGA complex to stabilization or correct progression of cell type-specific programs with putative preservation of cell identity. Cell type and stage-specific dependencies on ATAC and SAGA-regulated programs explain multilevel KAT2A requirements in leukemia and in erythroid lineage specification and development. Importantly, they set a paradigm against which lineage specification and identity can be explored across developmental stem cell systems., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The necropsy made to two adult individuals of red deer shot in Sierra Nevada National Park revealed infestation by second- and third-instar larvae of the oestrid Pharyngomyia picta (Meigen 1824). The animals were shot in Dehesa de las Hoyas, about 2000 m above sea level. This is the first record of this parasite in Sierra Nevada National Park. Furthermore, the occurrence of adult P. picta at this altitude could indicate significant changes of the climatic conditions, now matching better the environmental requirements of this bot fly. Its monitoring may, therefore, be of great help for detecting global change signs., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Acute myeloid leukemia (AML) has been considered for a long time exclusively driven by critical mutations in hematopoietic stem cells. Recently, the contribution of further players, such as stromal and immune bone marrow (BM) microenvironment components, to AML onset and progression has been pointed out. In particular, mesenchymal stromal cells (MSCs) steadily remodel the leukemic niche, not only favoring leukemic cell growth and development but also tuning their responsiveness to treatments. The list of mechanisms driven by MSCs to promote a leukemia drug-resistant phenotype has progressively expanded. Moreover, the relative proportion and the activation status of immune cells in the BM leukemic microenvironment may vary by influencing their reactivity against leukemic cells. In that, the capacity of the stroma to re-program immune cells, thus promoting and/or hampering therapeutic efficacy, is emerging as a crucial aspect in AML biology, adding an extra layer of complexity. Current treatments for AML have mainly focused on eradicating leukemia cells, with little consideration for the leukemia-damaged BM niche. Increasing evidence on the contribution of stromal and immune cells in response to therapy underscores the need to hold the mutual interplay, which takes place in the BM. A careful dissection of these interactions will help provide novel applications for drugs already under experimentation and open a wide array of opportunities for new drug discovery.

FMS-like tyrosine kinase 3 (FLT3) is among the most common driver genes recurrently mutated in acute myeloid leukemia (AML), accounting for approximately 30% of cases. Activating mutations of the FLT3 receptor include internal tandem duplications (ITD) that map to the auto-inhibitory juxtamembrane (JM) domain or point mutations within the tyrosine kinase domain (TKD). Several FLT3 tyrosine kinase inhibitors have been developed in the last few years, but midostaurin is currently the only one approved for the treatment of newly diagnosed patients harboring FLT3 mutations. Here we describe for the first time a novel in-frame deletion in exon 14 (JM domain) of the FLT3 gene, that we identified in a young woman with CBFb-MYH11-positive AML. We demonstrated that this novel FLT3 variant is pathogenic, since it is responsible for constitutive activation of FLT3 receptor. Finally, ex-vivo studies demonstrated that this novel mutation is sensitive to midostaurin., Competing Interests: AC was employed by Novartis, Pfizer, Abbvie and acted as speaker in Advisory Board for Novartis and Abbvie. CP was employed by Astellas, Amgen and acted as speaker in Advisory Board for Abbvie, Janssen, Novartis, Pfizer and Astellas. 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 © 2021 Bruno, Bandini, Patuelli, Robustelli, Venturi, Mancini, Forte, De Santis, Monaldi, Grassi, Chiurumbolo, Paolini, Cristiano, Papayannidis, Sartor, Nanni, Ottaviani, Curti, Cavo and Soverini.)

Dyeing vegetables with harmful compounds has become an alarming public health issue over the past few years. Excessive consumption of these dyed vegetables can cause severe health hazards, including cancer. Copper sulfate, malachite green, and Sudan red are some of the non-food-grade dyes widely used on vegetables by untrusted entities in the food supply chain to make them look fresh and vibrant. In this study, the presence and quantity of dye-based adulteration in vegetables are determined by applying 1 H-nuclear magnetic resonance (NMR) relaxometry. The proposed technique was validated by treating some vegetables in-house with different dyes and then soaking them in various solvents. The resulting solutions were collected and analyzed using NMR relaxometry. Specifically, the effective transverse relaxation time constant, T 2, eff , of each solution was estimated using a Carr-Purcell-Meiboom-Gill (CPMG) pulse sequence. Finally, the estimated time constants (i.e., measured signatures) were compared with a library of existing T 2, eff data to detect and quantify the presence of unwanted dyes. The latter consists of data-driven models of transverse decay times for various concentrations of each water-soluble dye. The time required to analyze each sample using the proposed approach is dye-dependent but typically no longer than a few minutes. The analysis results can be used to generate warning flags if the detected dye concentrations violate widely accepted standards for food dyes. The proposed low-cost detection approach can be used in various stages of a produce supply chain, including consumer household.

Blood cancers are a heterogeneous group of disorders including leukemia, multiple myeloma, and lymphoma. They may derive from the clonal evolution of the hemopoietic stem cell compartment or from the transformation of progenitors with immune potential. Extracellular vesicles (EVs) are membrane-bound nanovesicles which are released by cells into body fluids with a role in intercellular communication in physiology and pathology, including cancer. EV cargos are enriched in nucleic acids, proteins, and lipids, and these molecules can be delivered to target cells to influence their biological properties and modify surrounding or distant targets. In this review, we will describe the "smart strategy" on how blood cancer-derived EVs modulate tumor cell development and maintenance. Moreover, we will also depict the function of microenvironment-derived EVs in blood cancers and discuss how the interplay between tumor and microenvironment affects blood cancer cell growth and spreading, immune response, angiogenesis, thrombogenicity, and drug resistance. The potential of EVs as non-invasive biomarkers will be also discussed. Lastly, we discuss the clinical application viewpoint of EVs in blood cancers. Overall, blood cancers apply a 'vesicular intelligence' strategy to spread signals over their microenvironment, promoting the development and/or maintenance of the malignant clone.

Background: Myelofibrosis (MF) is a clonal disorder of hemopoietic stem/progenitor cells (HSPCs) with high prevalence in elderly patients and mutations in three driver genes (JAK2, MPL, or CALR). Around 10-15% of patients are triple-negative (TN) for the three driver mutations and display significantly worse survival. Circulating extracellular vesicles (EVs) play a role in intercellular signaling and are increased in inflammation and cancer. To identify a biomolecular signature of TN patients, we comparatively evaluated the circulating HSPCs and their functional interplay with the microenvironment focusing on EV analysis., Methods: Peripheral blood was collected from MF patients (n = 29; JAK2 V617F mutation, n = 23; TN, n = 6) and healthy donors (HD, n = 10). Immunomagnetically isolated CD34 + cells were characterized by gene expression profiling analysis (GEP), survival, migration, and clonogenic ability. EVs were purified from platelet-poor plasma by ultracentrifugation, quantified using the Nanosight technology and phenotypically characterized by flow cytometry together with microRNA expression. Migration and survival of CD34 + cells from patients were also analyzed after in vitro treatments with selected inflammatory factors, i.e. (Interleukin (IL)-1β, Tumor Necrosis Factor (TNF)-α, IL6) or after co-culture with EVs from MF patients/HD., Results: The absolute numbers of circulating CD34 + cells were massively increased in TN patients. We found that TN CD34 + cells show in vitro defective functions and are unresponsive to the inflammatory microenvironment. Of note, the plasma levels of crucial inflammatory cytokines are mostly within the normal range in TN patients. Compared to JAK2 V617F -mutated patients, the GEP of TN CD34 + cells revealed distinct signatures in key pathways such as survival, cell adhesion, and inflammation. Importantly, we observed the presence of mitochondrial components within plasma EVs and a distinct phenotype in TN-derived EVs compared to the JAK2 V617F -mutated MF patients and HD counterparts. Notably, TN EVs promoted the survival of TN CD34 + cells. Along with a specific microRNA signature, the circulating EVs from TN patients are enriched with miR-361-5p., Conclusions: Distinct EV-driven signals from the microenvironment are capable to promote the TN malignant hemopoiesis and their further investigation paves the way toward novel therapeutic approaches for rare MF.

Purpose: Ventriculoatrial (VA) and ventriculopleural (VPL) shunts are used as alternatives when CSF diversion to the peritoneal compartment with a ventriculoperitoneal (VP) shunt is not possible. The objective of this study is to compare directly the shunt survival and complications for both procedures in this setting in children., Methods: A retrospective analysis of 54 consecutive patients who underwent VA (36) or VPL (18) shunt insertion between January 2002 and December 2017 was conducted., Results: The overall mean follow-up was 4.1 (SD 4.3) years, 2.8 (SD 4.1) for VPL and 4.7 (SD 4.4) for VA shunts, respectively (p = 0.11). Twenty-four (66.7%) patients in the VA group and 9 (50.0%) in the VPL group underwent shunt revision (p = 0.236); mean number of revisions was 2.2 (SD 3.0) and 0.94 (SD 1.4) in the VA and VPL groups (p = 0.079). Median time to failure was 8.5 (IQr 78, range 0-176) months for VA and 5.50 (IQr 36, range 0-60) for VPL shunts (log rank (Mantel-Cox) 0.832). Shunt survival at 3, 6, 12 and 30 months was 60.6, 51.5, 36.4 and 27.3%, respectively, for VA and 56.3, 43.8, 37.5 and 37.5% for VPL shunts (log rank (Mantel-Cox) test value 0.727). The infection rate was 13.8% for VA and 5.6% for VPL shunts (p = 0.358). Four patients with VPL shunts (22.2%) developed pleural effusions. Fourteen deaths (25.9%) were recorded during follow-up, 8 (22.2%) in the VA and 6 (33.3%) in the VPL group (p = 0.380); two of the deaths in the VA group were shunt-related., Conclusion: This study demonstrates that the outcomes of VA and VPL shunts, when used as second-line surgical treatment in paediatric hydrocephalus, were similar, as were the revision, infection and survival rates. The shorter longevity of these shunts compared with the general shunted population may reflect the complex nature of these children.

Like normal hematopoietic stem cells, leukemic stem cells depend on their bone marrow (BM) microenvironment for survival, but the underlying mechanisms remain largely unknown. We have studied the contribution of nestin + BM mesenchymal stem cells (BMSCs) to MLL-AF9-driven acute myeloid leukemia (AML) development and chemoresistance in vivo. Unlike bulk stroma, nestin + BMSC numbers are not reduced in AML, but their function changes to support AML cells, at the expense of non-mutated hematopoietic stem cells (HSCs). Nestin + cell depletion delays leukemogenesis in primary AML mice and selectively decreases AML, but not normal, cells in chimeric mice. Nestin + BMSCs support survival and chemotherapy relapse of AML through increased oxidative phosphorylation, tricarboxylic acid (TCA) cycle activity, and glutathione (GSH)-mediated antioxidant defense. Therefore, AML cells co-opt energy sources and antioxidant defense mechanisms from BMSCs to survive chemotherapy., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Theoretical models suggest multiple underlying pathways for ADHD and multiple risk factors' co-occurrence as impairing this population's affective, interpersonal, and behavioral adjustment. After comparing groups' executive functioning (EF) difficulties and attachment security with each parent, this study primarily aimed to examine four risk factors (ADHD, child-father attachment, child-mother attachment, EF) as possibly explaining children's socioemotional/behavioral measures (externalizing/internalizing behavior, social skills, negative mood regulation). Method : Participants were 100 children in Grades 5-6 (ages 11-12 years; M= 11.45 years, SD =.50): 50 with formally diagnosed ADHD, and 50 with typical development (TD). Instruments were children's self-report measures and teachers' evaluation. Results : Significant group differences emerged on all EF measures and attachment relationships, and most socioemotional/behavioral measures. Findings demonstrated the significant contribution of children's ADHD, parental attachments, and, partially, EF difficulties in explaining children's socioemotional/behavioral adjustment. Conclusion : Children with ADHD, compared to children with TD, reported significantly larger EF deficits and a significantly higher incidence of insecure attachment to the father as well as a lower sense of trust and closeness to the mother. Outcomes highlighted the role of children's four risk factors (ADHD, child-father attachment, child-mother attachment, EF) in explaining their socioemotional/behavioral adjustment. The EF deficits contributed only to intrapersonal maladjustment.

The impact of ruxolitinib therapy on evolution to blast phase (BP) in patients with myelofibrosis (MF) is still uncertain. In 589 MF patients treated with ruxolitinib, we investigated incidence and risk factors for BP and we described outcome according to disease characteristics and treatment strategy. After a median follow-up from ruxolitinib start of 3 years (range 0.1-7.6), 65 (11%) patients transformed to BP during (93.8%) or after treatment. BP incidence rate was 3.7 per 100 patient-years, comparably in primary and secondary MF (PMF/SMF) but significantly lower in intermediate-1 risk patients (2.3 vs 5.6 per 100 patient-years in intermediate-2/high-risk patients, P < .001). In PMF and SMF cohorts, previous interferon therapy seemed to correlate with a lower probability of BP (HR 0.13, P = .001 and HR 0.22, P = .02, respectively). In SMF, also platelet count <150 × 10 9 /l (HR 2.4, P = .03) and peripheral blasts ≥3% (HR 3.3, P = .004) were significantly associated with higher risk of BP. High-risk category according to dynamic International Prognostic Score System (DIPSS) and myelofibrosis secondary to PV and ET Collaboration Prognostic Model (MYSEC-PM predicted BP in patients with PMF and SMF, respectively. Median survival after BP was 0.2 (95% CI: 0.1-0.3) years. Therapy for BP included hypomethylating agents (12.3%), induction chemotherapy (9.2%), allogeneic transplant (6.2%) or supportive care (72.3%). Patients treated with supportive therapy had a median survival of 6 weeks, while 73% of the few transplanted patients were alive at a median follow-up of 2 years. Progression to BP occurs in a significant fraction of ruxolitinib-treated patients and is associated with DIPSS and MYSEC-PM risk in PMF and SMF, respectively., (© 2020 John Wiley & Sons Ltd.)

The contribution of cell-extrinsic factors in Acute Myeloid Leukemia (AML) generation and persistence has gained interest. Bitter taste receptors (TAS2Rs) are G protein-coupled receptors known for their primary role as a central warning signal to induce aversion toward noxious or harmful substances. Nevertheless, the increasing amount of evidence about their extra-oral localization has suggested a wider function in sensing microenvironment, also in cancer settings. In this study, we found that AML cells express functional TAS2Rs. We also highlighted a significant association between the modulation of some TAS2Rs and the poor-prognosis AML groups, i.e., TP53 - and TET2 -mutated, supporting a potential role of TAS2Rs in AML cell biology. Gene expression profile analysis showed that TAS2R activation with the prototypical agonist, denatonium benzoate, significantly modulated a number of genes involved in relevant AML cellular processes. Functional assay substantiated molecular data and indicated that denatonium reduced AML cell proliferation by inducing cell cycle arrest in G0/G1 phase or induced apoptosis via caspase cascade activation. Moreover, denatonium exposure impaired AML cell motility and migratory capacity, and inhibited cellular respiration by decreasing glucose uptake and oxidative phosphorylation. In conclusion, our results in AML cells expand the observation of cancer TAS2R expression to the setting of hematological neoplasms and shed light on a role of TAS2Rs in the extrinsic regulation of leukemia cell functions., (Copyright © 2020 Salvestrini, Ciciarello, Pensato, Simonetti, Laginestra, Bruno, Pazzaglia, De Marchi, Forte, Orecchioni, Martinelli, Bertolini, Méndez-Ferrer, Adinolfi, Di Virgilio, Cavo and Curti.)

Myelofibrosis (MF) is characterized by chronic inflammation and hyper-activation of the JAK-STAT pathway. Infections are one of the main causes of morbidity/mortality. Therapy with Ruxolitinib (RUX), a JAK1/2 inhibitor, may further increase the infectious risk. Monocytes are critical players in inflammation/immunity through cytokine production and release of bioactive extracellular vesicles. However, the functional behavior of MF monocytes, particularly during RUX therapy, is still unclear. In this study, we found that monocytes from JAK2V617F-mutated MF patients show an altered expression of chemokine (CCR2, CXCR3, CCR5) and cytokine (TNF-α-R, IL10-R, IL1β-R, IL6-R) receptors. Furthermore, their ability to produce and secrete free and extracellular vesicles-linked cytokines (IL1β, TNF-α, IL6, IL10) under lipopolysaccharides (LPS) stimulation is severely impaired. Interestingly, monocytes from RUX-treated patients show normal level of chemokine, IL10, IL1β, and IL6 receptors together with a restored ability to produce intracellular and to secrete extracellular vesicles-linked cytokines after LPS stimulation. Conversely, RUX therapy does not normalize TNF-R1/2 receptors expression and the LPS-driven secretion of free pro/anti-inflammatory cytokines. Accordingly, upon LPS stimulation, in vitro RUX treatment of monocytes from MF patients increases their secretion of extracellular vesicles-linked cytokines but inhibits the secretion of free pro/anti-inflammatory cytokines. In conclusion, we demonstrated that in MF the infection-driven response of circulating monocytes is defective. Importantly, RUX promotes their infection-driven cytokine production suggesting that infections following RUX therapy may not be due to monocyte failure. These findings contribute to better interpreting the immune vulnerability of MF and to envisaging strategies to improve the infection-driven immune response., (© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Growing evidence highlights the endocannabinoid (EC) system involvement in cancer progression. Lipid mediators of this system are secreted by hematopoietic cells, including the ECs 2-arachidonoyl-glycerol (2AG) and arachidonoyl-ethanolamide (AEA), the 2AG metabolite 1AG, and members of N-acylethanolamine (NAE) family-palmitoyl-ethanolamide (PEA) and oleoyl-ethanolamide (OEA). However, the relevance of the EC system in myeloproliferative neoplasms (MPN) was never investigated. We explored the EC plasma profile in 55 MPN patients, including myelofibrosis (MF; n = 41), polycythemia vera (PV; n = 9), and essential thrombocythemia (ET; n = 5) subclasses and in 10 healthy controls (HC). AEA, PEA, OEA, 2AG, and 1AG plasma levels were measured by LC-MS/MS. Overall considered, MPN patients displayed similar EC and NAE levels compared to HC. Nonetheless, AEA levels in MPN were directly associated with the platelet count. MF patients showed higher levels of the sum of 2AG and 1AG compared to ET and PV patients, higher OEA/AEA ratios compared to HC and ET patients, and higher OEA/PEA ratios compared to HC. Furthermore, the sum of 2AG and 1AG positively correlated with JAK2 V617F variant allele frequency and splenomegaly in MF and was elevated in high-risk PV patients compared to in low-risk PV patients. In conclusion, our work revealed specific alterations of ECs and NAE plasma profile in MPN subclasses and potentially relevant associations with disease severity.