Aplastic anemia: immunosuppressive therapy in 2010

Acquired aplastic anemia (AA) is the typical bone marrow failure syndrome characterized by an empty bone marrow; an immune-mediated pathophysiology has been demonstrated by experimental works as well as by clinical observations. Immunusuppressive therapy (IST) is a key treatment strategy for aplastic anemia; since 20 years the standard IST for AA patients has been anti-thymocyte globuline (ATG) plus cyclosporine A (CyA), which results in response rates ranging between 50% and 70%, and even higher overall survival. However, primary and secondary failures after IST remain frequent, and to date all attempts aiming to overcome this problem have been unfruitful. Here we review the state of the art of IST for AA in 2010, focusing on possible strategies to improve current treatments. We also discuss very recent data which question the equality of different ATG preparations, leading to a possible reconsideration of the current standards of care for AA patients

Therapeutic Strategies in Pulmonary Hypertension

Pulmonary hypertension (PH) is a life-threatening condition characterized by elevated pulmonary arterial pressure. It is clinically classified into five groups: patients in the first group are considered to have pulmonary arterial hypertension (PAH) whereas patients of the other groups have PH that is due to cardiopulmonary or other systemic diseases. The management of patients with PH has advanced rapidly over the last decade and the introduction of specific treatments especially for PAH has lead to an improved outcome. However, despite the progress in the treatment, the functional limitation and the survival of these patients remain unsatisfactory and there is no cure for PAH. Therefore the search for an “ideal” therapy still goes on. At present, two levels of treatment can be identified: primary and specific therapy. Primary therapy is directed at the underlying cause of the PH. It also includes a supportive therapy consisting in oxygen supplementation, diuretics, and anticoagulation which should be considered in all patients with PH. Specific therapy is directed at the PH itself and includes treatment with vasodilatators such as calcium channel blockers and with vasodilatator and pathogenetic drugs such as prostanoids, endothelin receptor antagonists and phosphodiesterase type-5 inhibitors. These drugs act in several pathogenetic mechanisms of the PH and are specific for PAH although they might be used also in the other groups of PH. Finally, atrial septostomy and lung transplantation are reserved for patients refractory to medical therapy. Different therapeutic approaches can be considered in the management of patients with PH. Therapy can be established on the basis of both the clinical classification and the functional class. It is also possible to adopt a goal-oriented therapy in which the timing of treatment escalation is determined by inadequate response to known prognostic indicators

Correlation between Choriocapillaris Density and Retinal Sensitivity in Stargardt Disease

The aim of this work was to characterize the choriocapillaris (CC) in patients with Stargardt disease (STGD) using the swept source widefield optical coherence tomography angiography (SS WF OCTA) and to compare CC perfusion density to retinal sensitivity, analyzed using microperimetry (MP). This cross-sectional study included 9 patients (18 eyes) with STGD and central CC atrophy (stage 3 STGD). The CC was analyzed using SS WF OCTA and areas of different CC impairment were quantified and correlated with retinal sensitivity analyzed using MP. The main outcome measures were the percent perfused choriocapillaris area (PPCA), retinal sensitivity, and correlation between PPCA and retinal sensitivity. Seventeen eyes of 9 patients suffering from stage 3 STGD were analyzed. SS WF OCTA revealed a vascular rarefaction in central atrophic zones and a near atrophy halo of choriocapillaris impairment. In all eyes were noticed a central atrophy (CA) area with absolute absence of CC that corresponded to 0 dB points at MP, a near atrophy (NA) zone of PPCA impairment that included points with decreased sensitivity at MP and a distant from atrophy (DA) zone with higher PPCA and retinal sensitivity values. The mean difference of PPCA and retinal sensitivity between NA and CA and DA and CA was statistical significantly different (p < 0.01), the latter showing higher values. A direct relationship between PPCA and retinal sensitivity was found (p < 0.001). Choriocapillaris damage evaluated using SS WF OCTA correlates with MP, these data suggest that CC impairment may be a predictor of retinal function in patients with STGD

Tradução e adaptação transcultural do Questionário de Atividade Física Habitual

BACKGROUND: There has been a growing scientific interest on the interface between exercise and psychiatric disorders. However, there is a lack of self-report instruments to assess levels of physical activity adapted to Brazilian Portuguese. OBJECTIVE: To translate, assess the semantic equivalence of the Habitual Physical Activity Questionnaire and perform a non-psychometric pre-test with subjects (n = 30) from the Brazilian population, with different educational backgrounds. METHODS: The cross-cultural adaptation process consisted of two translations and back translations performed by two independent evaluators; an evaluation of the versions and the development of a synthetic version; and a commented pretest of the questionnaire. RESULTS: For each item of the instrument, the results of the four stages are reported. Most of the participants (91%) did not present any difficulties comprehending the items of the instrument. Further studies should be addressed to determine the adequacy of using this instrument in the less-educated population. We recommend that less instructed subjects be supervised while responding the questionnaire. DISCUSSION: The use of two translations versions, their critical appraisal and the assessment of the target population conceives more safety to the process of semantic equivalence.CONTEXTO: Atualmente há na literatura um crescente interesse na interface entre exercício físico e transtornos psiquiátricos. Apesar disso, ainda há uma deficiência de instrumentos de autorrelato para medir os níveis de atividade física dos pacientes. OBJETIVO: A tradução, a aferição da equivalência semântica e uma aplicação piloto (n = 30), sem pretensão psicométrica, do Questionário de Atividade Física Habitual, visando sua utilização na população brasileira de diferentes níveis de escolaridade. MÉTODOS: O processo envolveu duas traduções e retrotraduções realizadas por avaliadores independentes, avaliação das versões seguida da elaboração de uma versão síntese e pré-teste comentado. RESULTADOS: A maioria dos participantes (91%) não apresentou dificuldades de compreensão com o questionário. Para cada item do instrumento, apresentam-se os resultados das quatro etapas. Mais estudos são necessários para determinar a adequação para populações de baixa escolaridade. Os autores recomendam que sujeitos menos instruídos sejam supervisionados ao preencher o questionário. CONCLUSÕES: A utilização de duas versões de tradução e retrotradução, a discussão sobre a versão síntese e a interlocução com a população-alvo proporcionam maior segurança ao processo de equivalência semântica

A renewable energy and hydrogen storage system for residential electricity supply

Because of the intermittent behavior of renewable sources, efficient, reliable and clean energy storage technologies are needed to achieve a more stable and secure energy supply. In this context, hydrogen technologies play a key role because they can store large amount of energy for long time. In this study, a hydrogen-based electrical energy storage system, integrated with a solar power plant, is designed and analyzed from the energy perspective. The system consists of a photovoltaic power plant, an alkaline electrolysis unit, metal hydride tanks for hydrogen storage, a Li-ion battery unit and a polymer electrolyte membrane fuel cell module. The system is conceived for supplying a residential user. A numerical model is developed for sizing the system’s components and for evaluating their behaviors in terms of produced/stored electricity and hydrogen production. In this purpose, a sensitivity analysis varying PV plant size as well as the Li-ion battery capacity is performed for achieving the best compromise in terms of energy supply among all the considered power sources

The Polycomb Group Protein L3MBTL1 Represses a SMAD5-Mediated Hematopoietic Transcriptional Program in Human Pluripotent Stem Cells

SummaryEpigenetic regulation of key transcriptional programs is a critical mechanism that controls hematopoietic development, and, thus, aberrant expression patterns or mutations in epigenetic regulators occur frequently in hematologic malignancies. We demonstrate that the Polycomb protein L3MBTL1, which is monoallelically deleted in 20q- myeloid malignancies, represses the ability of stem cells to drive hematopoietic-specific transcriptional programs by regulating the expression of SMAD5 and impairing its recruitment to target regulatory regions. Indeed, knockdown of L3MBTL1 promotes the development of hematopoiesis and impairs neural cell fate in human pluripotent stem cells. We also found a role for L3MBTL1 in regulating SMAD5 target gene expression in mature hematopoietic cell populations, thereby affecting erythroid differentiation. Taken together, we have identified epigenetic priming of hematopoietic-specific transcriptional networks, which may assist in the development of therapeutic approaches for patients with anemia

Protein arginine methyltransferase 1 is a therapeutic vulnerability in multiple myeloma

Multiple myeloma (MM) is a devastating plasma cell malignancy characterized by the expansion of aberrant monoclonal plasma cells in the bone marrow, leading to severe clinical manifestations and poor prognosis, particularly in relapsed/refractory cases. Identifying novel therapeutic targets is crucial to improve treatment outcomes in these patients. In this study, we investigated the role of the protein arginine methyltransferase 1 (PRMT1) in MM pathogenesis and explored its potential as a therapeutic target. We observed that PRMT1, responsible for most asymmetric di-methylation in cells, exhibited the highest expression among PRMT family members in MM cell lines and primary MM cells. Importantly, PRMT1 expression was significantly elevated in relapsed/refractory patients compared to newly diagnosed patients. High expression of PRMT1 expression was strongly associated with poor prognosis. We found that genetic or enzymatic inhibition of PRMT1 impaired MM cell growth, induced cell cycle arrest, and triggered cell death. Treatment with MS023, a potent PRMT type I inhibitor, demonstrated a robust inhibitory effect on the viability of primary cells isolated from newly diagnosed and proteasome inhibitor-relapsed/refractory patients in a dose-dependent manner. Suppression of PRMT1 downregulated genes related to cell division and upregulated genes associated with apoptosis pathway. We also found that genes related to immune response and lymphocyte activation were significantly upregulated in PRMT1-suppressed cells. Notably, the activation status of T cells was strikingly enhanced upon co-culturing with PRMT1-KO MM cells. In vivo studies using a xenograft model revealed that targeting PRMT1 by either CRISPR/Cas9-mediated knockout or MS023 treatment significantly attenuated MM tumor growth and prolonged the survival of tumor-bearing mice. Histological analysis further confirmed increased apoptotic cell death in MS023-treated tumors. Collectively, our findings establish PRMT1 as an indispensable and novel therapeutic vulnerability in MM. The elevated expression of PRMT1 in relapsed/refractory patients underscores its potential as a target for overcoming treatment resistance. Moreover, our results highlight the efficacy of MS023 as a promising therapeutic agent against MM, offering new avenues for therapeutic approaches in relapsed/refractory MM

Intron retention-induced neoantigen load correlates with unfavorable prognosis in multiple myeloma

Neoantigen peptides arising from genetic alterations may serve as targets for personalized cancer vaccines and as positive predictors of response to immune checkpoint therapy. Mutations in genes regulating RNA splicing are common in hematological malignancies leading to dysregulated splicing and intron retention (IR). In this study, we investigated IR as a potential source of tumor neoantigens in multiple myeloma (MM) patients and the relationship of IR-induced neoantigens (IR-neoAg) with clinical outcomes. MM-specific IR events were identified in RNA-sequencing data from the Multiple Myeloma Research Foundation CoMMpass study after removing IR events that also occurred in normal plasma cells. We quantified the IR-neoAg load by assessing IR-induced novel peptides that were predicted to bind to major histocompatibility complex (MHC) molecules. We found that high IR-neoAg load was associated with poor overall survival in both newly diagnosed and relapsed MM patients. Further analyses revealed that poor outcome in MM patients with high IR-neoAg load was associated with high expression levels of T-cell co-inhibitory molecules and elevated interferon signaling activity. We also found that MM cells exhibiting high IR levels had lower MHC-II protein abundance and treatment of MM cells with a spliceosome inhibitor resulted in increased MHC-I protein abundance. Our findings suggest that IR-neoAg may represent a novel biomarker of MM patient clinical outcome and further that targeting RNA splicing may serve as a potential therapeutic strategy to prevent MM immune escape and promote response to checkpoint blockade

Safety and efficacy of plerixafor dose escalation for the mobilization of CD34+ hematopoietic progenitor cells in patients with sickle cell disease: interim results

Gene therapy for sickle cell disease is limited by the yield of hematopoietic progenitor cells that can be harvested for transduction or gene editing. We therefore performed a phase I dose-escalation study of the hematopoietic progenitor cell mobilizing agent plerixafor to evaluate the efficacy and safety of standard dosing on peripheral blood CD34+ cell mobilization. Of 15 patients enrolled to date, only one was chronically transfused and ten were on hydroxyurea. Of eight patients who achieved a CD34+ cell concentration >30 cells/μL, six were on hydroxyurea. There was no clear dose response to increasing plerixafor dosage. There was a low rate of serious adverse events; two patients developed vaso-occlusive crises, at the doses of 80 μg/kg and 240 μg/kg. Hydroxyurea may have contributed to the limited CD34+ mobilization by affecting baseline peripheral blood CD34 counts, which correlated strongly with peak peripheral blood CD34 counts. Plerixafor administration did not induce significant increases in the fraction of activated neutrophils, monocytes, or platelets. However, increased neutrophils positive for activated β2 integrin and Mac-1 were associated with serious adverse events. In summary, plerixafor was well tolerated but did not achieve consistent CD34+ cell mobilization in this cohort of patients, most of whom were being actively treated with hydroxyurea and only one was chronically transfused. The study will continue with escalation of the dose of plerixafor and modification of hydroxyurea administration. Clinicaltrials.gov identifier: NCT02193191

Pharmacologic targeting of the p62 ZZ domain enhances both anti-tumor and bone-anabolic effects of bortezomib in multiple myeloma

Multiple myeloma (MM) is a malignancy of plasma cells whose antibody secretion creates proteotoxic stress relieved by the N-end rule pathway, a proteolytic system that degrades N-arginylated proteins in the proteasome. When the proteasome is inhibited, protein cargo is alternatively targeted for autophagic degradation by binding to the ZZ-domain of p62/ sequestosome-1. Here, we demonstrate that XRK3F2, a selective ligand for the ZZ-domain, dramatically improved two major responses to the proteasome inhibitor bortezomib (Btz) by increasing: i) killing of human MM cells by stimulating both Btz-mediated apoptosis and necroptosis, a process regulated by p62; and ii) preservation of bone mass by stimulating osteoblast differentiation and inhibiting osteoclastic bone destruction. Co-administration of Btz and XRK3F2 inhibited both branches of the bimodal N-end rule pathway exhibited synergistic anti-MM effects on MM cell lines and CD138+ cells from MM patients, and prevented stromal-mediated MM cell survival. In mice with established human MM, co-administration of Btz and XRK3F2 decreased tumor burden and prevented the progression of MM-induced osteolytic disease by inducing new bone formation more effectively than either single agent alone. The results suggest that p62-ZZ ligands enhance the anti- MM efficacy of proteasome inhibitors and can reduce MM morbidity and mortality by improving bone health