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Abstract Relapsed/refractory (r/r) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) outcomes remain poor. A targeted cluster of differentiation (CD)33 × CD3 bispecific antibody, JNJ‐67571244, was assessed to identify the maximum tolerated dose (MTD), recommended phase II dose (RP2D), safety and tolerability, and preliminary clinical activity in patients with r/rAML or r/rMDS. This first‐in‐human, open‐label, phase I, dose‐escalation/dose‐expansion study included patients with r/rAML or r/rMDS who were ineligible for or had exhausted standard therapeutic options. JNJ‐67571244 was administered intravenously or subcutaneously using step‐up dosing until ≥1 discontinuation condition was met. Outcomes included safety/tolerability, preliminary clinical activity, and systemic pharmacokinetics and pharmacodynamics. The study was terminated after evaluating 10 dose‐escalation cohorts (n = 68) and before starting dose‐expansion. Overall, 11 (16.2%) patients experienced ≥1 dose‐limiting toxicity; all experienced ≥1 treatment‐emergent adverse event (TEAE; treatment related: 60 [88.2%]); and 64 (94.1%) experienced ≥1 TEAE of Grade ≥3 toxicity (treatment related: 28 [41.2%]). Although some patients had temporary disease burden reductions, no responses were seen. JNJ‐67571244 administration increased multiple cytokines, which coincided with incidence of cytokine release syndrome, infusion‐related reactions, and elevated liver function tests. A prolonged step‐up strategy was tested to improve tolerability, though this approach did not prevent hepatotoxicity. T‐cell activation following treatment suggested target engagement but did not correlate with clinical activity. Safely reaching the projected exposure level for JNJ‐67571244 efficacy was not achieved, thus MTD and RP2D were not determined.

Spontaneous remissions (SRs) in blastic plasmacytoid dendritic cell neoplasms (BPDCNs) are infrequent, poorly documented, and transient. We report a 40-year-old man presenting with bycitopenia and soft tissue infection. The bone marrow exhibited 3% abnormal cells. Immunophenotyping of these cells revealed the antigens CD45+ (dim), CD34+, CD117+, CD123+ (bright), HLA-DR+ (bimodal), CD56+ (bright), CD33+, CD13+, CD2+, and CD22+ (dim) and the partial expression of the CD10+, CD36+, and CD7+ antigens. All other myeloid, monocytic, and lymphoid antigens were negative. Genetic studies showed a complex karyotype and mutations in the TP53R337C and KRASG12D genes. On hospital admission, the patient showed a subcutaneous nodule on the right hand and left lower limb. Flow cytometry multiparameter (FCM) analysis showed the presence of 29% abnormal cells with the previously described immunophenotype. The patient was diagnosed with BPDCN. The patient was treated with broad-spectrum antibiotics for soft tissue infection, which delayed therapy for BPDCN. No steroids or chemotherapeutic or hypomethylating agents were administered. His blood cell counts improved and skin lesions disappeared, until the patient relapsed five months after achieving spontaneous remission. About 60% of abnormal cells were identified. No changes in immunophenotype or the results of genetic studies were observed. The patient underwent a HyperCVAD chemotherapy regimen for six cycles. Consolidation therapy was performed via allogeneic bone marrow transplantation with an HLA-unrelated donor. One year after the bone marrow transplant, the patient died due to the progression of his underlying disease, coinciding with a respiratory infection caused by SARS-CoV-2. In the available literature, SRs are often linked to infections or other stimulators of the immune system, suggesting that powerful immune activation could play a role in controlling the leukemic clone. Nevertheless, the underlying mechanism of this phenomenon is not clearly understood. We hypothesize that the immune system would force the leukemic stem cell (LSC) to undergo a state of quiescence. This loss of replication causes the LSC progeny to die off, resulting in the SR of BPDCN.

La avicultura ornamental cumple un rol valioso en la preservación del acervo genético y cultural de las aves de corral en todo el mundo. En la ruralidad argentina, la crianza de aves de raza pura es una actividad ampliamente difundida, y se encuentra representada por las distintas asociaciones de aficionados. El “Standard Argentino de Perfección Avícola”, publicado por la Asociación Argentina de Criadores de Aves, Conejos y Abejas, en el año 1928 fue, y aún sigue siendo, el patrón de referencia para el desarrollo de esta actividad. Por promoción de la Comisión Avícola del Sur del Salado, y en colaboración con otras asociaciones y organizaciones del país, se resolvió revisar, reescribir y reeditar dicho estándar, incorporando nuevas razas, como es el caso de la única gallina sudamericana, prehispánica, conocida en la actualidad: la Gallina Mapuche (Gallus gallus domesticus). En el presente trabajo se hace una revisión, sistematización de tareas, recopilación de datos de investigación, análisis y elaboración del inédito “Primer Estándar de Perfeccionamiento Racial de la Gallina Mapuche”, en Argentina.

Abstract This study aimed to identify a recommended phase II dose and evaluate the safety, tolerability, pharmacokinetics/pharmacodynamics, and preliminary clinical activity of JNJ‐63709178, a CD123/CD3 dual‐targeting antibody, in patients with relapsed or refractory acute myeloid leukemia. Intravenous (i.v.) and subcutaneous (s.c.) administration of JNJ‐63709178 were evaluated. The i.v. infusions were administered once every 2 weeks (cohorts 1–5 [n = 17]) or twice weekly (cohorts 6–11 [n = 36]). A twice‐weekly s.c. dosing regimen with step‐up dosing was also studied (s.c. cohorts 1–2 [n = 9]). Treatment‐emergent adverse events (TEAEs) greater than or equal to grade 3 were observed in 11 (65%) patients in cohorts 1–5 and 33 (92%) patients in cohorts 6–11. At the highest i.v. dose (4.8 μg/kg), 5 (71%) patients discontinued treatment due to TEAEs. For s.c. administration (n = 9), eight (89%) patients experienced TEAEs greater than or equal to grade 3 and injection site reactions (≤ grade 3) emerged in all patients. At 4.8 μg/kg (i.v. and s.c.), the mean maximum serum concentrations were 30.3 and 3.59 ng/ml, respectively. Increases in multiple cytokines were observed following i.v. and s.c. administrations, and step‐up dosing strategies did not mitigate cytokine production or improve the safety profile and led to limited duration of treatment. Minimal clinical activity was observed across all cohorts. The i.v. and s.c. dosing of JNJ‐63709178 was associated with suboptimal drug exposure, unfavorable safety profiles, limited clinical activity, and inability to identify a recommended phase II dose.

The Varroa destructor mite infests Apis mellifera colonies and causes significant harm. Traditional treatments have become less effective because of mite resistance development and can also generate residues inside beehives. This study aimed to gauge the efficacy of a beehive-derived postbiotic in reducing V. destructor viability and to explore its synergies with organic compounds. Four lactic acid bacteria (LAB) species, Leuconostoc mesenteroides, Lactobacillus helsingborgensis, Bacillus velezensis, and Apilactobacillus kunkeei, were isolated and tested in a postbiotic form (preparations of inanimate microorganisms and/or their components) via bioassays. L. mesenteroides, L. helsingborgensis, and B. velezensis notably reduced the mite viability compared to the control, and they were further tested together as a single postbiotic product (POS). Further bioassays were performed to assess the impact of the POS and its combinations with oxalic acid and oregano essential oil. The simple products and combinations (POS/Oregano, POS/Oxalic, Oregano/Oxalic, and POS/Oregano/Oxalic) decreased the mite viability. The most effective were the oxalic acid combinations (POS/Oregano/Oxalic, Oxalic/Oregano, POS/Oxalic), showing significant improvements compared to the individual products. These findings highlight the potential of combining organic products as a vital strategy for controlling V. destructor infection. This study suggests that these combinations could serve as essential tools for combating the impact of mites on bee colonies.

Wnt signaling is a highly conserved pathway in evolution which controls important processes such as cell proliferation, differentiation and migration, both in the embryo and in the adult. Dysregulation of this pathway can favor the development of different types of cancer, such as acute myeloid leukemia and other hematological malignancies. Overactivation of this pathway may promote the transformation of pre-leukemic stem cells into acute myeloid leukemia stem cells, as well as the maintenance of their quiescent state, which confers them with self-renewal and chemoresistance capacity, favoring relapse of the disease. Although this pathway participates in the regulation of normal hematopoiesis, its requirements seem to be greater in the leukemic stem cell population. In this review, we explore the possible therapeutic targeting of Wnt to eradicate the LSCs of AML.

Introduction The hepatitis C virus (HCV) is a highly infectious and deadly disease, affecting some 58 million people worldwide. Of the 1.13 million people living in the Balearic Islands, Spain, about 1350 individuals have untreated HCV. Of these, about 1120 (83%) are estimated to be people who use drugs (PWUD), who are one of the key at-risk groups for HCV infection globally. Carrying out micro-elimination approaches focused on this population is crucial to achieve the WHO goal of eliminating HCV by 2030. Thus, the primary objective of this study is to validate a model of care that simplifies the screening and linkage to HCV care pathways for PWUD on the Balearic Islands.Methods and analysis This intervention study will be implemented across 17 sites, in 4 different settings: addiction service centres (n=12), non-governmental organisation centres (n=3), a mobile methadone unit and a prison, with an estimated 3725 participants. Together with the healthcare staff at each centre, the intervention protocols will be adapted, focusing on four phases: recruitment and testing; linkage to care; treatment for those who test positive; and monitoring of sustained virological response 12 weeks after treatment and reinfection. The primary outcomes will be the number of tested and treated individuals and the secondary outcomes will include individuals lost at each step in the cascade of care. Descriptive analysis and multivariable logistic regression of the data will be undertaken.Ethics and dissemination The Hospital Clínic Barcelona, Spain, Ethics Committee approved this study on 18 February 2021 (HCB/2020/2018). Findings will be disseminated through peer-reviewed publications, conference presentations and social media. The results of this study could provide a model for targeting PWUD for HCV testing and treatment in the rest of Spain and in other settings, helping to achieve the WHO HCV elimination goal.

Spontaneous remissions (SRs) in acute myeloid leukemia (AML) are infrequent, poorly documented and transient. Similarly, morphological and cytogenetic complete remissions (CR) under azacitidine treatment are scarce. We report a 71-year-old man with a secondary AML arising from essential thrombocythemia (ET), who developed an SR after discontinuation of azacitidine following a respiratory infection (four courses were administered). The distinctive feature of our case is the depth of the achieved CR, documented by next-generation sequencing (NGS) techniques. We also detected persistence of molecular lesions that might already have been present in the previous ET clone. Our patient relapsed 5 months after achieving CR. We conclude that our patient showed a spontaneous remission of his AML rather than an exquisite response to azacitidine. We hypothesize that the concurrent respiratory infection, or any other unknown trigger, might have activated his immune system forcing the leukemic stem cell to enter a quiescent state through a yet unexplained mechanism.

This work presents the development of an ADAS (advanced driving assistance system) focused on driver drowsiness detection, whose objective is to alert drivers of their drowsy state to avoid road traffic accidents. In a driving environment, it is necessary that fatigue detection is performed in a non-intrusive way, and that the driver is not bothered with alarms when he or she is not drowsy. Our approach to this open problem uses sequences of images that are 60 s long and are recorded in such a way that the subject’s face is visible. To detect whether the driver shows symptoms of drowsiness or not, two alternative solutions are developed, focusing on the minimization of false positives. The first alternative uses a recurrent and convolutional neural network, while the second one uses deep learning techniques to extract numeric features from images, which are introduced into a fuzzy logic-based system afterwards. The accuracy obtained by both systems is similar: around 65% accuracy over training data, and 60% accuracy on test data. However, the fuzzy logic-based system stands out because it avoids raising false alarms and reaches a specificity (proportion of videos in which the driver is not drowsy that are correctly classified) of 93%. Although the obtained results do not achieve very satisfactory rates, the proposals presented in this work are promising and can be considered a solid baseline for future works.

Secreted cytokine decoy receptors encoded by viruses can act as potent immune evasion proteins modulating antiviral immunity. Here Hernaez et al. show that cell surface binding is required for efficient evasion of the host response by a secreted virus encoded type I IFN decoy receptor of vaccinia and ectromelia virus using an in vivo model of infection.

The aim of this study was to investigate the presence of methicillin-resistant Staphylococcus (MRS) strains in non-managed wild ungulates present in a typical Mediterranean forest in Spain. For this purpose, nasal swabs were obtained from 139 animals: 90 wild boar (Sus scrofa), 42 red deer (Cervus elaphus) and 7 fallow deer (Dama dama), which were subsequently pre-enriched in BHI+ NaCl (6.5%) (24 h/37 °C), and then seeded in Columbia blood agar (24 h/37 °C)). The presence of the mecA gene was investigated by PCR, first from the confluent and then from individual colonies. A total of 10 mecA+ colonies were obtained of which only seven showed phenotypic resistance to oxacillin/cefoxitin (methicillin resistance). All MRS strains belonged to the Staphylococcus sciuri group. Methicillin-resistant Staphylococcus aureus (MRSA) was not detected. In addition, a significant number of MRS strains showed resistance to other antimicrobials, mainly β-lactam (7/7), gentamicin (7/7), fusidic acid (6/7) and quinupristin-dalfopristin (6/7), showing an irregular correlation with their coding genes. The genetic profiles grouped the seven strains obtained according to the bacterial species but not in relation to the animal source or the geographical place of origin. The presence of SCCmec type III, common to animals and humans, has been detected in three of the strains obtained. In conclusion, the study reveals that the wild ungulates investigated play a role as potential reservoirs of multi-resistant strains of MRS. Such strains, due to their characteristics, can be easily transferred to other wild or domestic animal species and ultimately to humans through their products.

En el Programa Usos de Medios Interactivos (UMI) de la Universidad Nacional de General Sarmiento (UNGS) en Argentina, estamos desarrollando el “Estudio de procesos de apropiación de tecnologías por parte de niños y niñas de 6 a 8 años de edad”. Buscamos comprender las características que asumen esos procesos en un período de la infancia en el que se construyen las competencias de lectura y escritura. Presentamos en este artículo algunos resultados obtenidos a través de una encuesta a personas adultas a cargo de niños y niñas de ese tramo de edad. Abordamos tres dimensiones que adjudicamos teóricamente a la noción de hogar como entorno tecnocultural: disposición de tecnologías, dinámica de usos de tecnologías en el hogar y regulaciones sobre los usos de tecnologías. Comentamos aquí únicamente los usos de tecnologías (sobre todo internet) que, según las personas adultas, realizan los niños y las niñas en el contexto del hogar.

A better understanding of how signaling pathways govern cell fate is fundamental to advances in cancer development and treatment. The initialization of different tumors and their maintenance are caused by the deregulation of different signaling pathways and cancer stem cell maintenance. Quiescent stem cells are resistant to conventional chemotherapeutic treatments and, consequently, are responsible for disease relapse. In this review we focus on the conserved Hedgehog (Hh) signaling pathway which is involved in regulating the cell cycle of hematopoietic and leukemic stem cells. Thus, we examine the role of the Hh signaling pathway in normal and leukemic stem cells and dissect its role in acute myeloid leukemia. We explain not only the connection between illness and the signaling pathway but also evaluate innovative therapeutic approaches that could affect the outcome of patients with acute myeloid leukemia. We found that many aspects of the Hedgehog signaling pathway remain unknown. The role of Hh has only been proven in embryo and hematopoietic stem cell development. Further research is needed to elucidate the role of GLI transcription factors for therapeutic targeting. Glasdegib, an SMO inhibitor, has shown clinical activity in acute myeloid leukemia; however, its mechanism of action is not clear.

Vaccinia virus (VACV) encodes the soluble type I interferon (IFN) binding protein B18 that is secreted from infected cells and also attaches to the cell surface, as an immunomodulatory strategy to inhibit the host IFN response. By using next generation sequencing technologies, we performed a detailed RNA-seq study to dissect at the transcriptional level the modulation of the IFN based host response by VACV and B18. Transcriptome profiling of L929 cells after incubation with purified recombinant B18 protein showed that attachment of B18 to the cell surface does not trigger cell signalling leading to transcriptional activation. Consistent with its ability to bind type I IFN, B18 completely inhibited the IFN-mediated modulation of host gene expression. Addition of UV-inactivated virus particles to cell cultures altered the expression of a set of 53 cellular genes, including genes involved in innate immunity. Differential gene expression analyses of cells infected with replication competent VACV identified the activation of a broad range of host genes involved in multiple cellular pathways. Interestingly, we did not detect an IFN-mediated response among the transcriptional changes induced by VACV, even after the addition of IFN to cells infected with a mutant VACV lacking B18. This is consistent with additional viral mechanisms acting at different levels to block IFN responses during VACV infection.