Characterization of potential therapeutic targets in Leishmania infantum

Leishmaniasis is a parasitic disease caused by various species of Leishmania, which affects millions of people worldwide. Current treatments for leishmaniasis often present adverse effects and may not be effective against every Leishmania strain or form of the disease. Therefore, it is essential to explore new therapeutic approaches to combat the parasite. In this study, we focused on the PeBoW complex proteins homologous in Leishmania, which is involved in ribosomal biogenesis and plays a critical role in cancer development in mammalian cells. Recently, a homologue of the oncogene PES1 was found in Leishmania major, which plays a crucial role in parasite infectivity. Given this, we analyzed the possibility of using other PeBoW complex partner genes in Leishmania as therapeutic targets for leishmaniasis treatment. Specifically, our investigation aimed to characterize the partner WDR12 homologous in Leishmania infantum (LmjWDR12) as new therapeutic approach

HOW I TREAT RELAPSED MYELOMA

ABSTRACT Multiple myeloma (MM) is a plasma-cell malignancy leading to a significant lifeexpectancy shortening. Although the incorporation of the novel agents thalidomide, bortezomib and lenalidomide in the front-line therapy has resulted in significant improvement, almost all patients relapse, making the treatment of relapse a real challenge. In the present article, when and how to treat relapsed MM is discussed. Treatment can be safely delayed in a subset of patients with asymptomatic relapse, whereas those with symptomatic relapse, advanced disease at diagnosis or significant paraproteinemic increase require prompt rescue therapy. The benefit of re-treatment and the use of a sequential approach for successive relapses considering drug synergism are highlighted

Cardiopulmonary nematode infections in wild canids: Does the key lie on host-prey-parasite evolution?

©2019. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ This document is the Accepted, version of a Published Work that appeared in final form in Research in Veterinary Science. To access the final edited and published work see https://doi.org/10.1016/j.rvsc.2019.08.008Cardiopulmonary nematodes are among the most pathogenic parasites of domestic and wild canids. The aim of this study was to describe the species diversity, prevalence and infection intensity of these parasites in the Iberian wolf (Canis lupus signatus) and the red fox (Vulpes vulpes) in the northwest of the Iberian Peninsula. 257 foxes and 74 wolves were necropsied between 2008 and 2014. Four nematode species were identified: Angiostrongylus vasorum, Eucoleus aerophilus, Crenosoma vulpis and Filaroides hirthi. This last species was only found in wolves, being the first time that is cited worldwide in this wild canid. The overall parasite prevalence was significantly higher in foxes (70%) than in wolves (28%). Specifically, prevalences in foxes and wolves were, respectively, 43% and 22% for A. vasorum, 33% and 5% for E. aerophilus, and 30% and 9% for C. vulpis. The prevalence of F. hirthi was 16%. The A. vasorum intensity was significantly higher in foxes than in wolves. Differences between host species in the risk of infection would be associated to diverging feeding behavior, and possibly reflects a parasite-host adaptation related to host's hunting strategies and cardiorespiratory requirements. This study revealed an association between infection and environmental factors, and highlighted a wide variation in the spatial distribution of A. vasorum. Our results indicate that cardiopulmonary parasites are widespread in wild canids in northwest Spain, and further agrees with other studies indicating the expansion of A. vasorum in Europe and, therefore, the urgent need to investigate infection in dogs in sympatric areas

The Progress Test of the European Hematology Association: A New Tool for Continuous Learning

The European Hematology Curriculum, first launched in 2006, was created by the European Hematology Association (EHA) with the aim of harmonizing hema tology training in Europe. Its goals were to define the different areas hematologists are expected to cover during their training, and to establish the minimum recommended levels of competence that a hematology trainee should attain. EHA's education platform (EHA Campus) offers opportu nities for continuous learning for both trainees and specialists. Content is guided by the European Hematology Curriculum, which provides a structure for individual study and self-assess ment. To complete this organized learning environment, a tool for objective assessment of knowledge during and after specialist training was needed. In the spring of 2020, EHA started offering a progress test: a longitudinal test based on equivalent evalua tions given at fixed intervals, assessing developments in knowl edge. The EHA Progress Test was inspired by an earlier version developed by the Swedish Hematology Association in 2013, which has become widely used by specialist trainees and spe cialists in Sweden. Noticeable pedagogical effects, like targeted study efforts in weak knowledge areas, changes in clinical rota tions, and more have been reported in personal questionnaires

A serum microRNA signature associated with complete remission and progression after autologous stem-cell transplantation in patients with multiple myeloma

We have examined serum microRNA expression in multiple myeloma (MM) patients at diagnosis and at complete response (CR) after autologous stem-cell transplantation (ASCT), in patients with stable monoclonal gammopathy of undetermined significance, and in healthy controls. MicroRNAs were first profiled using TaqMan Human MicroRNA Arrays. Differentially expressed microRNAs were then validated by individual TaqMan MicroRNA assays and correlated with CR and progression-free survival (PFS) after ASCT. Supervised analysis identified a differentially expressed 14-microRNA signature. The differential expression of miR-16 (P = 0.028), miR-17 (P = 0.016), miR-19b (P = 0.009), miR-20a (P = 0.017) and miR-660 (P = 0.048) at diagnosis and CR was then confirmed by individual assays. In addition, high levels of miR-25 were related to the presence of oligoclonal bands (P = 0.002). Longer PFS after ASCT was observed in patients with high levels of miR-19b (6 vs. 1.8 years; P < 0.001) or miR-331 (8.6 vs. 2.9 years; P = 0.001). Low expression of both miR-19b and miR-331 in combination was a marker of shorter PFS (HR 5.3; P = 0.033). We have identified a serum microRNA signature with potential as a diagnostic and prognostic tool in MM

T cells isolated from G-CSF-treated multiple myeloma patients are suitable for the generation of BCMA-directed CAR-T cells

Autologous cell immunotherapy using B cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR)-T cells is an effective novel treatment for multiple myeloma (MM). This therapy has only been used for relapsed and refractory patients, at which stage the endogenous T cells used to produce the CAR-T cells are affected by the immunosuppressive nature of advanced MM and/or side effects of previous therapies. An alternative pool of fitter T cells is found in leukocytoapheresis products that are routinely collected to obtain hematopoietic progenitor cells for autologous stem cell transplantation (ASCT) early in the treatment of MM. However, to mobilize the progenitor cells, patients are dosed with granulocyte colony-stimulating factor (G-CSF), which is reported to adversely affect T cell proliferation, function, and differentiation. Here, we aimed to first establish whether G-CSF treatment negatively influences T cell phenotype and to ascertain whether previous exposure of T cells to G-CSF is deleterious for anti-BCMA CAR-T cells. We observed that G-CSF had a minimal impact on T cell phenotype when added in vitro or administered to patients. Moreover, we found that CAR-T cell fitness and anti-tumor activity were unaffected when generated from G-CSF-exposed T cells. Overall, we showed that ASCT apheresis products are a suitable source of T cells for anti-BCMA CAR-T cell manufacture

Long-term Responders after autologous stem cell transplantation in multiple myeloma

Introduction: Multiple myeloma (MM) is considered an incurable hematological neoplasm. For transplant-eligible patients, initial treatment includes an induction phase followed by an autologous stem cell transplantation (ASCT). Despite the introduction of several drugs in the past years, relapses still occur. Nevertheless, some patients achieve sustained responses after successful induction treatment and ASCT. Methods: We retrospectively evaluated all patients diagnosed with MM in our institution who underwent induction treatment and ASCT between 1990 and 2015. The subset of patients who achieved a sustained response (any degree) for 5 or more years after ASCT without further treatment or signs of progression were distinguished as 'long-term responders' (LTRs). In the non-LTR group, a cohort referred to as 'prolonged responders' (PLRs) showed sustained response of at least 5 years after ASCT but eventually relapsed. We collected and analyzed clinical and laboratory data. Results: Two hundred and fifty patients were diagnosed with MM and received induction treatment and ASCT at our institution in the study period. Among them, 54 (21.6%) patients met the criteria for LTR. Some diagnostic features such as a younger age, female gender, ECOG performance status of 0, lower International Staging System (ISS) stage, lower bone marrow plasma cell infiltration, and lower serum levels of calcium, C-reactive protein, and lactate dehydrogenase (LDH) were found to be more prevalent in LTR. Female gender, an ECOG performance status of 0, a localized Durie-Salmon stage, an ISS of I-II, the absence of bone disease, and an LDH within normal range were also predictive of longer progression-free survival (PFS) and overall survival (OS) in the whole cohort. The depth of the response achieved after induction and ASCT as well as the administration of an IMID-based maintenance regimen may play a role in the differences observed on PFS between cohorts. A detectable M-protein with a monoclonal gammopathy of undetermined significance (MGUS)-like behavior was detected in one-third of LTR after ASCT. Although relapses continue to occur in patients who achieve a 5-year treatment-free period after ASCT, a plateau is observed in the survival curves at approximately 21 years of follow-up

Post-mortem neuropathologic examination of a 5-case series of CAR T-cell treated patients

Introduction: Chimeric antigen receptor (CAR) T-cell therapy is a promising immunotherapy for the treatment of refractory hematopoietic malignancies. Adverse events are common, and neurotoxicity is one of the most important. However, the physiopathology is unknown and neuropathologic information is scarce.Materials and methods: Post-mortem examination of 6 brains from patients that underwent CAR T-cell therapy from 2017 to 2022. In all cases, polymerase chain reaction (PCR) in paraffin blocks for the detection of CAR T cells was performed.Results: Two patients died of hematologic progression, while the others died of cytokine release syndrome, lung infection, encephalomyelitis, and acute liver failure. Two out of 6 presented neurological symptoms, one with extracranial malignancy progression and the other with encephalomyelitis. The neuropathology of the latter showed severe perivascular and interstitial lymphocytic infiltration, predominantly CD8+, together with a diffuse interstitial histiocytic infiltration, affecting mainly the spinal cord, midbrain, and hippocampus, and a diffuse gliosis of basal ganglia, hippocampus, and brainstem. Microbiological studies were negative for neurotropic viruses, and PCR failed to detect CAR T -cells. Another case without detectable neurological signs showed cortical and subcortical gliosis due to acute hypoxic-ischemic damage. The remaining 4 cases only showed a mild patchy gliosis and microglial activation, and CAR T cells were detected by PCR only in one of them.Conclusions: In this series of patients that died after CAR T-cell therapy, we predominantly found non-specific or minimal neuropathological changes. CAR T-cell related toxicity may not be the only cause of neurological symptoms, and the autopsy could detect additional pathological findings