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Propulsion is a critical subsystem of many spacecraft1-4. For efficient propellant usage, electric propulsion systems based on the electrostatic acceleration of ions formed during electron impact ionization of a gas are particularly attractive5,6. At present, xenon is used almost exclusively as an ionizable propellant for space propulsion2-5. However, xenon is rare, it must be stored under high pressure and commercial production is expensive7-9. Here we demonstrate a propulsion system that uses iodine propellant and we present in-orbit results of this new technology. Diatomic iodine is stored as a solid and sublimated at low temperatures. A plasma is then produced with a radio-frequency inductive antenna, and we show that the ionization efficiency is enhanced compared with xenon. Both atomic and molecular iodine ions are accelerated by high-voltage grids to generate thrust, and a highly collimated beam can be produced with substantial iodine dissociation. The propulsion system has been successfully operated in space onboard a small satellite with manoeuvres confirmed using satellite tracking data. We anticipate that these results will accelerate the adoption of alternative propellants within the space industry and demonstrate the potential of iodine for a wide range of space missions. For example, iodine enables substantial system miniaturization and simplification, which provides small satellites and satellite constellations with new capabilities for deployment, collision avoidance, end-of-life disposal and space exploration10-14.
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Despite Peng and colleagues providing an extensive review of the clinical and laboratory aspects of CAR-T-associated coagulopathy, the current literature often lacks specificity in nomenclature and gradings, and the clinical implications of coagulopathy may remain unclear. Clear recommendations on stratification and prophylaxis are still required to standardize the clinical approach to this topic. Commentary on: Peng et al. Coagulation abnormalities associated with CAR-T therapy in hematological malignancies: A review. Br J Haematol 2024;205:420-428.
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Transtornos da Coagulação Sanguínea , Imunoterapia Adotiva , Humanos , Transtornos da Coagulação Sanguínea/etiologia , Transtornos da Coagulação Sanguínea/diagnóstico , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/complicações , Imunoterapia Adotiva/efeitos adversos , Receptores de Antígenos Quiméricos/uso terapêuticoRESUMO
Patients affected by multiple myeloma (MM) have an increased risk of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection and subsequent coronavirus (20)19 disease (COVID-19)-related death. The changing epidemiological and therapeutic scenarios suggest that there has been an improvement in severity and survival of COVID-19 during the different waves of the pandemic in the general population, but this has not been investigated yet in MM patients. Here we analyzed a large cohort of 1221 patients with MM and confirmed SARS-CoV-2 infection observed between February 2020, and August 2022, in the EPICOVIDEHA registry from 132 centers around the world. Median follow-up was 52 days for the entire cohort and 83 days for survivors. Three-hundred and three patients died (24%) and COVID-19 was the primary reason for death of around 89% of them. Overall survival (OS) was significantly higher in vaccinated patients with both stable and active MM versus unvaccinated, while only a trend favoring vaccinated patients was observed in subjects with responsive MM. Vaccinated patients with at least 2 doses showed a better OS than those with one or no vaccine dose. Overall, according to pandemic waves, mortality rate decreased over time from 34% to 10%. In multivariable analysis, age, renal failure, active disease, hospital, and intensive care unit admission, were independently associated with a higher number of deaths, while a neutrophil count above 0.5 × 109 /L was found to be protective. This data suggests that MM patients remain at risk of SARS-CoV-2 infection even in the vaccination era, but their clinical outcome, in terms of OS, has progressively improved throughout the different viral phases of the pandemic.
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COVID-19 , Mieloma Múltiplo , Humanos , SARS-CoV-2 , Pandemias , Mieloma Múltiplo/terapia , Sistema de RegistrosRESUMO
In patients with low-risk polycythemia vera, exposure to low-dose Ropeginterferon alfa-2b (Ropeg) 100 µg every 2 weeks for 2 years was more effective than the standard treatment of therapeutic phlebotomy in maintaining target hematocrit (HCT) (< 45%) with a reduction in the need for phlebotomy without disease progression. In the present paper, we analyzed drug survival, defined as a surrogate measure of the efficacy, safety, adherence, and tolerability of Ropeg in patients followed up to 5 years. During the first 2 years, Ropeg and phlebotomy-only (Phl-O) were discontinued in 33% and 70% of patients, respectively, for lack of response (12 in the Ropeg arm vs. 34 in the Phl-O arm) or adverse events (6 vs. 0) and withdrawal of consent in (3 vs. 10). Thirty-six Ropeg responders continued the drug for up to 3 years, and the probability of drug survival after a median of 3.15 years was 59%. Notably, the primary composite endpoint was maintained in 97%, 94%, and 94% of patients still on drug at 3, 4, and 5 years, respectively, and 60% of cases were phlebotomy-free. Twenty-three of 63 Phl-O patients (37%) failed the primary endpoint and were crossed over to Ropeg; among the risk factors for this failure, the need for more than three bloodletting procedures in the first 6 months emerged as the most important determinant. In conclusion, to improve the effectiveness of Ropeg, we suggest increasing the dose and using it earlier driven by high phlebotomy need in the first 6 months post-diagnosis.
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Policitemia Vera , Humanos , Policitemia Vera/tratamento farmacológico , Policitemia Vera/diagnóstico , Hematócrito , Fatores de Risco , Flebotomia , SangriaRESUMO
Evans syndrome (ES) is rare and mostly treated on a "case-by-case" basis and no guidelines are available. With the aim of assessing disease awareness and current management of adult ES, a structured survey was administered to 64 clinicians from 50 Italian participating centers. Clinicians had to be involved in the management of autoimmune cytopenias and were enrolled into the ITP-NET initiative. The survey included domains on epidemiology, diagnosis, and therapy of ES and was designed to capture current practice and suggested work-up and management. Thirty clinicians who had followed a median of 5 patients (1-45)/15 years responded. The combination of AIHA plus ITP was more common than the ITP/AIHA with neutropenia (p < .001) and 25% of patients had an associated condition, including lymphoproliferative syndromes, autoimmune diseases, or primary immunodeficiencies. The agreement of clinicians for each diagnostic test is depicted (i.e., 100% for blood count and DAT; only 40% for anti-platelets and anti-neutrophils; 77% for bone marrow evaluation). Most clinicians reported that ES requires a specific approach compared to isolated autoimmune cytopenias, due to either a more complex pathogenesis and a higher risk of relapse and thrombotic and infectious complications. The heterogeneity of treatment choices among different physicians suggests the need for broader harmonization.
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Patients with essential thrombocythemia (ET) are treated with once-daily low-dose aspirin to prevent thrombosis, but their accelerated platelet turnover shortens the antiplatelet effect. The short-term Aspirin Regimens in EsSential Thrombocythemia trial showed that twice-daily aspirin dosing restores persistent platelet thromboxane (TX) inhibition. However, the long-term pharmacodynamic efficacy, safety and tolerability of twice-daily aspirin remain untested. We performed a multicenter, randomized, open-label, blinded-endpoint, phase-2 trial in which 242 patients with ET were randomized to 100 mg aspirin twice- or once-daily and followed for 20 months. The primary endpoint was the persistence of low serum TXB2, a surrogate biomarker of antithrombotic efficacy. Secondary endpoints were major and clinically relevant non-major bleedings, serious vascular events, symptom burden assessed by validated questionnaires, and in vivo platelet activation. Serum TXB2 was consistently lower in the twice-daily versus once-daily regimen on 10 study visits over 20 months: median 3.9 ng/mL versus 19.2 ng/mL, respectively; p < .001; 80% median reduction; 95% CI, 74%-85%. No major bleeding occurred. Clinically relevant non-major bleedings were non-significantly higher (6.6% vs. 1.7%), and major thromboses lower (0.8% vs. 2.5%) in the twice-daily versus once-daily group. Patients on the twice-daily regimen had significantly lower frequencies of disease-specific symptoms and severe hand and foot microvascular pain. Upper gastrointestinal pain was comparable in the two arms. In vivo platelet activation was significantly reduced by the twice-daily regimen. In patients with ET, twice-daily was persistently superior to once-daily low-dose aspirin in suppressing thromboxane biosynthesis and reducing symptom burden, with no detectable excess of bleeding and gastrointestinal discomfort.
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Aspirina , Esquema de Medicação , Hemorragia , Inibidores da Agregação Plaquetária , Trombocitemia Essencial , Humanos , Aspirina/administração & dosagem , Aspirina/uso terapêutico , Trombocitemia Essencial/tratamento farmacológico , Trombocitemia Essencial/sangue , Masculino , Pessoa de Meia-Idade , Feminino , Idoso , Adulto , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/uso terapêutico , Inibidores da Agregação Plaquetária/efeitos adversos , Hemorragia/induzido quimicamente , Tromboxano B2/sangue , Ativação Plaquetária/efeitos dos fármacos , Idoso de 80 Anos ou mais , Resultado do TratamentoRESUMO
The Detachment and Compartmentalization Inventory (DCI) is a valid and reliable self-report instrument that assesses these two distinct forms of dissociative symptoms. However, there is limited research on the cross-cultural validation of the DCI. Therefore, this study aimed to develop an Italian translation of the DCI and examine its internal structure and psychometric properties (including internal consistency, convergent validity, and test-retest reliability) within an Italian-speaking community sample. The sample consisted of 1276 adults (887 females; mean age: 29.57 ± 10.96 years), who completed the DCI and other self-report measures evaluating dissociative experiences and childhood trauma. Confirmatory factor analyses supported the original two-factor model (χ2169 = 1312.80, RMSEA = 0.073, 95%CI 0.069-0.077; CFI = 0.94; TLI = 0.94; SRMR = 0.04). Additionally, the DCI exhibited good internal consistency, test-retest reliability, and convergent validity with another measure of dissociation. The study also confirmed the association between DCI scores and the severity of childhood trauma. Finally, a Receiver Operating Characteristic (ROC) curve analysis demonstrated that the DCI effectively distinguishes individuals who screened positively for dissociative disorders. Overall, these findings indicate that the Italian translation of the DCI possesses satisfactory psychometric properties, suggesting its utility as a screening tool for assessing detachment and compartmentalization experiences.
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Transtornos Dissociativos , Psicometria , Humanos , Feminino , Itália , Masculino , Adulto , Reprodutibilidade dos Testes , Transtornos Dissociativos/psicologia , Autorrelato , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Adolescente , Inquéritos e QuestionáriosRESUMO
The efficacy and safety of thrombopoietin receptor agonists (TRAs) in older patients with primary immune thrombocytopenia (ITP) are unknown. We investigated TRA response and switch, thrombotic/hemorrhagic risk, and sustained responses off-treatment (SROTs) in 384 patients with ITP aged ≥60 years. After 3 months, 82.5% and 74.3% of eltrombopag- and romiplostim-treated patients, respectively, achieved a response; 66.7% maintained the response (median follow-up, 2.7 years). Eighty-five (22.2%) patients switched to the alternative TRA; although no cross-toxicity was observed, 83.3% of resistant patients had a response after the switch. Thirty-four major thromboses (3 fatal) and 14 major hemorrhages (none fatal) occurred in 18 and 10 patients, respectively, while on TRAs and were associated with thrombosis history (subdistribution hazard ratio, 2.04, P = .05) and platelet count <20 × 109/L (subdistribution hazard ratio, 1.69; P = .04), respectively, at TRA start. A recurrent event occurred in 15.6% of patients surviving thrombosis, in all cases but 1 during persisting TRA treatment (incidence rate, 7.7 per 100 patient-years). All recurrences occurred in the absence of adequate antithrombotic secondary prophylaxis. Sixty-two (16.5%) responding patients discontinued TRAs; 53 (13.8%) patients maintained SROTs, which were associated with TRA discontinuation in complete response (P < .001). Very old age (≥75 years; 41.1%) was associated with the more frequent start of TRAs in the persistent/acute phase but not with response or thrombotic/hemorrhagic risk. TRAs are effective in older patients with ITP, with no fatal hemorrhages and with SROTs in a significant portion of patients. Caution is warranted in patients with a history of thrombosis, and a careful risk/benefit balance should be considered.
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Benzoatos , Hidrazinas , Púrpura Trombocitopênica Idiopática , Pirazóis , Receptores Fc , Receptores de Trombopoetina/antagonistas & inibidores , Proteínas Recombinantes de Fusão , Trombopoetina , Trombose , Idoso , Idoso de 80 Anos ou mais , Benzoatos/administração & dosagem , Benzoatos/efeitos adversos , Feminino , Seguimentos , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Humanos , Hidrazinas/administração & dosagem , Hidrazinas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/mortalidade , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Receptores Fc/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos , Estudos Retrospectivos , Trombopoetina/administração & dosagem , Trombopoetina/efeitos adversos , Trombose/induzido quimicamente , Trombose/mortalidadeRESUMO
Williams syndrome (WS) is a well-known genetic disorder caused by heterozygous microdeletions of the 7q11.23 chromosome region. The main clinical features of the syndrome are characteristic facial dysmorphisms, cardiovascular and endocrine anomalies, short stature, mild-to-moderate intellectual disability, and a recognizable cognitive and behavioral profile. Differently from large chromosomal imbalances and aneuploidies, mosaicism has only rarely been found in microdeletion syndromes, and mosaic cases with WS phenotype have never been reported. We here describe a 51-year-old female patient with the typical clinical features of WS, whose chromosomal microarray analysis and fluorescence in situ hybridization disclosed a 54%-68% germline mosaicism for 7q11.23 deletion.
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Síndrome de Williams , Feminino , Humanos , Síndrome de Williams/diagnóstico , Síndrome de Williams/genética , Hibridização in Situ Fluorescente , Mosaicismo , Análise em Microsséries , Fenótipo , Deleção CromossômicaRESUMO
OBJECTIVES: Polycythemia vera (PV) is an acquired clonal hematopoietic stem cell disorder characterized by the overproduction of red blood cells. It has long been underlined that there are differences in treatment patterns in routine practice. Therapeutic strategies have also expanded, and in recent years the JAK1/JAK2 inhibitor ruxolitinib has emerged as a second-line therapeutic option in patients who are intolerant to or resistant to hydroxyurea. Determining the impact of changes on practice patterns is of interest, especially for aspects that lack detailed guidance for management. METHODS: To gain insights into treatment patterns by clinicians treating patients with PV in Italy, we carried out a survey of 60 hematologists and transfusion specialists. The questions covered: treatment of low-risk patients, definition of significant leukocytosis, splenomegaly and excessive phlebotomies, resistance/intolerance to hydroxyurea, use of ruxolitinib, cytoreductive therapy, and vaccines. RESULTS: In general, the results of the survey indicate that there is a large heterogeneity in management of patients with PV across these areas. CONCLUSIONS: While helping to provide greater understanding of treatment patterns for patients with PV in Italy, our survey highlights the need for additional clinical studies to obtain more precise guidance for the routine care of patients with PV.
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Inibidores de Janus Quinases , Policitemia Vera , Humanos , Policitemia Vera/diagnóstico , Policitemia Vera/epidemiologia , Policitemia Vera/terapia , Hidroxiureia/uso terapêutico , Pirazóis/uso terapêutico , Janus Quinase 2 , Inibidores de Janus Quinases/uso terapêutico , Itália/epidemiologiaRESUMO
Interactions between childhood trauma (CT) and dissociation can contribute to psychiatric disturbances. We explored this phenomenon in relation to behavioral addictions (BAs) in a sample (n = 633) of young adults (age: 18-34 years). Self-report measures investigating CT, dissociation, and symptoms related to gambling disorder, internet gaming disorder, problematic social media use, exercise dependence and compulsive buying were used. Scales related to BAs were summarized into a single measure ("Total Behavioral Addiction Index" - TBAI) for inferential analyses. A model analyzing the direct and indirect effects of CT on TBAI through the mediation of pathological dissociation was performed, controlling for confounding factors. Measures on CT, dissociation, and TBAI were significantly associated with each other (all p < .001). The total effect of CT on TBAI was significant (B = 0.063; CI: 0.045; 0.081); pathological dissociation significantly mediated such association (B = 0.023; CI: 0.013; 0.036). Our findings support the possibility that the interaction between CT and dissociation contributes to increase disturbances related to BAs.
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Experiências Adversas da Infância , Comportamento Aditivo , Jogo de Azar , Humanos , Adulto Jovem , Adolescente , Adulto , Estudos Transversais , Comportamento Aditivo/diagnóstico , Comportamento Aditivo/psicologia , Jogo de Azar/psicologia , Transtornos DissociativosRESUMO
PURPOSE: Studies have shown significant associations of dissociative symptoms with both eating and addictive disorders; however, the different forms of dissociation have been relatively understudied in relation to food addiction (FA). The main aim of this study was to investigate the association of certain forms of dissociative experiences (i.e., absorption, detachment and compartmentalization) with FA symptoms in a nonclinical sample. METHODS: Participants (N = 755; 543 women; age range: 18-65; mean age: 28.22 ± 9.99 years) were evaluated using self-report measures of FA, dissociation, eating disturbances, and general psychopathology. RESULTS: Compartmentalization experiences (defined as pathological over-segregation of higher mental functions) were independently associated with FA symptoms (ß = 0.174; p = 0.013; CI = [0.008; 0.064]) even when confounding factors were controlled for. CONCLUSION: This finding suggests that compartmentalization symptoms can have a role in the conceptualization of FA, with such two phenomena possibly sharing common pathogenic processes. LEVEL OF EVIDENCE: Level V, cross-sectional descriptive study.
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Comportamento Aditivo , Dependência de Alimentos , Humanos , Feminino , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Estudos Transversais , AutorrelatoRESUMO
Essential thrombocythemia (ET) is characterized by abnormal megakaryopoiesis and enhanced thrombotic risk. Once-daily low-dose aspirin is the recommended antithrombotic regimen, but accelerated platelet generation may reduce the duration of platelet cyclooxygenase-1 (COX-1) inhibition. We performed a multicenter double-blind trial to investigate the efficacy of 3 aspirin regimens in optimizing platelet COX-1 inhibition while preserving COX-2-dependent vascular thromboresistance. Patients on chronic once-daily low-dose aspirin (n = 245) were randomized (1:1:1) to receive 100 mg of aspirin 1, 2, or 3 times daily for 2 weeks. Serum thromboxane B2 (sTXB2), a validated biomarker of platelet COX-1 activity, and urinary prostacyclin metabolite (PGIM) excretion were measured at randomization and after 2 weeks, as primary surrogate end points of efficacy and safety, respectively. Urinary TX metabolite (TXM) excretion, gastrointestinal tolerance, and ET-related symptoms were also investigated. Evaluable patients assigned to the twice-daily and thrice-daily regimens showed substantially reduced interindividual variability and lower median (interquartile range) values for sTXB2 (ng/mL) compared with the once-daily arm: 4 (2.1-6.7; n = 79), 2.5 (1.4-5.65, n = 79), and 19.3 (9.7-40; n = 85), respectively. Urinary PGIM was comparable in the 3 arms. Urinary TXM was reduced by 35% in both experimental arms. Patients in the thrice-daily arm reported a higher abdominal discomfort score. In conclusion, the currently recommended aspirin regimen of 75 to 100 once daily for cardiovascular prophylaxis appears to be largely inadequate in reducing platelet activation in the vast majority of patients with ET. The antiplatelet response to low-dose aspirin can be markedly improved by shortening the dosing interval to 12 hours, with no improvement with further reductions (EudraCT 2016-002885-30).
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Aspirina/administração & dosagem , Inibidores de Ciclo-Oxigenase/administração & dosagem , Inibidores da Agregação Plaquetária/administração & dosagem , Adulto , Idoso , Aspirina/farmacocinética , Ciclo-Oxigenase 1/sangue , Inibidores de Ciclo-Oxigenase/farmacologia , Método Duplo-Cego , Epoprostenol/urina , Humanos , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/farmacocinética , Trombocitemia Essencial/sangue , Trombocitemia Essencial/urinaRESUMO
Patients with Philadelphia-negative myeloproliferative neoplasm (MPN) are prone to the development of second cancers, but the factors associated with these events have been poorly explored. In an international nested case-control study, we recruited 647 patients with carcinoma, nonmelanoma skin cancer, hematological second cancer, and melanoma diagnosed concurrently or after MPN diagnosis. Up to 3 control patients without a history of cancer and matched with each case for center, sex, age at MPN diagnosis, date of diagnosis, and MPN disease duration were included (n = 1234). Cases were comparable to controls for MPN type, driver mutations and cardiovascular risk factors. The frequency of thrombosis preceding MPN was similar for cases and controls (P = .462). Thrombotic events after MPN and before second cancer were higher in cases than in controls (11.6% vs 8.1%; P = .013), because of a higher proportion of arterial thromboses (6.2% vs 3.7%; P = .015). After adjustment for confounders, the occurrence of arterial thrombosis remained independently associated with the risk of carcinoma (odds ratio, 1.97; 95% confidence interval, 1.14-3.41), suggesting that MPN patients experiencing arterial events after MPN diagnosis deserve careful clinical surveillance for early detection of carcinoma. This study was registered at www.clinicaltrials.gov as NCT03745378.
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Artérias/patologia , Transtornos Mieloproliferativos/patologia , Segunda Neoplasia Primária/patologia , Cromossomo Filadélfia , Trombose/patologia , Estudos de Casos e Controles , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Análise MultivariadaRESUMO
The combination of elotuzumab, lenalidomide, and dexamethasone (EloRd) enhanced the clinical benefit over Rd with a manageable toxicity profile in the ELOQUENT-2 trial, leading to its approval in relapsed/refractory multiple myeloma (RRMM). The present study is a 3-year follow-up update of a previously published Italian real-life RRMM cohort of patients treated with EloRd. This revised analysis entered 319 RRMM patients accrued in 41 Italian centers. After a median follow-up of 36 months (range 6-55), 236 patients experienced disease progression or died. Median progression-free survival (PFS) and overall survival (OS) were 18.4 and 34 months, respectively. The updated multivariate analyses showed a significant reduction of PFS and OS benefit magnitude only in cases with International Staging System stage III. Major adverse events included grade 3/4 neutropenia (18.5%), anemia (15.4%), lymphocytopenia (12.5%), and thrombocytopenia (10.7%), while infection rates and pneumonia were 33.9% and 18.9%, respectively. No new safety signals with longer follow-up have been observed. Of 319 patients, 245 (76.7%) reached at least a partial remission. A significantly lower response rate was found in patients previously exposed to lenalidomide. In conclusion, our study confirms that EloRd is a safe and effective regimen for RRMM patients, maintaining benefits across multiple unfavorable subgroups.
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Mieloma Múltiplo , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/efeitos adversos , Seguimentos , Humanos , Lenalidomida/uso terapêutico , Estudos Retrospectivos , Talidomida/efeitos adversosRESUMO
PUS3 encodes the pseudouridylate synthase 3, an enzyme catalyzing the formation of tRNA pseudouridine, which plays a critical role in tRNA structure, function, and stability. Biallelic pathogenic variants of PUS3 have been previously associated with severe intellectual disability, microcephaly, epilepsy, and short stature. We identified a novel homozygous PUS3 frameshift variant in a child with facial dysmorphisms, growth failure, microcephaly, retinal dystrophy, cerebellar hypoplasia, congenital heart defect, and right kidney hypoplasia. This patient further expands the phenotypic spectrum of PUS3-related disorders to include a more severe syndromic presentation.
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Deficiência Intelectual , Microcefalia , Malformações do Sistema Nervoso , Criança , Deficiências do Desenvolvimento/genética , Homozigoto , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Microcefalia/diagnóstico , Microcefalia/genética , FenótipoRESUMO
Ruxolitinib is approved for polycythemia vera (PV) patients after failure to previous cytoreductive therapy, based on durable results observed in phase 3 trials. We report a multicenter retrospective study demonstrating the efficacy and safety of ruxolitinib in real-life setting. Eighty-three patients were evaluated. Median follow-up was 24.5 months (IQR 14.0-29.3). At a 3-month response assessment, ruxolitinib provided significant benefit in reducing hematocrit (HCT) level (p < 0.001), phlebotomy requirement (p < 0.001), leucocytes (p = 0.044), and disease-related symptoms (p < 0.001). The exposure-adjusted rates (per 100 patient-years) of infectious complications, thromboembolic events, and secondary malignancies were 6.9, 3, and 3.7, respectively. Non-melanoma skin cancers (NMSC) were the most frequent (40%) SM type. Lymphoproliferative disorders were not detected. Five (6%) patients permanently discontinued ruxolitinib treatment and four (5%) evolved in myelofibrosis (MF), but none in acute leukemia. The rate of MF evolution per 100 patient-years of exposure was 2.8. In our experience, ruxolitinib confirmed its efficacy and safety outside of clinical trials.
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Policitemia Vera , Mielofibrose Primária , Humanos , Concentração de Íons de Hidrogênio , Nitrilas/uso terapêutico , Policitemia Vera/complicações , Mielofibrose Primária/diagnóstico , Pirazóis/efeitos adversos , Pirimidinas , Estudos RetrospectivosRESUMO
The lack of a randomized trial comparing carfilzomib (K) versus elotuzumab (Elo) associated with lenalidomide and dexamethasone (Rd) prompted us to assess the relative usefulness of one triplet over the other. Five independent retrospective cohorts of 883 relapsed/refractory multiple myeloma (RRMM) patients, including 300 EloRd and 583 KRd cases, outside clinical trials, entered this non-randomized comparison. KRd cohort accounted for a higher incidence of younger patients, cases with ≥3 lines of therapy, already exposed to lenalidomide, International Staging System (ISS) stage III, and abnormal lactic dehydrogenase (LDH) level compared with EloRd cohort. Moreover, cytogenetic risk categories, detected in roughly one-third of cases, were equally distributed between the two therapy arms. The probability of CR+VGPR response was significantly higher in KRd (n = 314, 53.9%) than in EloRd patients (n = 111, 37.0%). Likewise, the cumulative incidence function of CR+VGPR, taking into account the competitive risk of death, was significantly higher in KRd arm patients than those in the EloRd arm (p = .003). Moreover, KRd treatment significantly reduced the progression or death risk by 46% in an adjusted multivariate analysis (HR: 0.54, 95% CI 0.42-0.69, p < .0001). Finally, in an adjusted illness-progression/death model, the effect of KRd versus EloRd was of higher magnitude among those who achieved CR+VGPR (-39% hazard ratio reduction, p = .02) than among those who achieved < VGPR (-29% hazard ratio reduction, p = .007). With limitations characteristic to any retrospective analysis, this current clinical practice study's overall results demonstrated potential benefits of KRd therapy compared with EloRd. This observation may help the daily clinical practice.
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Mieloma Múltiplo , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona , Humanos , Lenalidomida , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Oligopeptídeos , Estudos Retrospectivos , Terapia de SalvaçãoRESUMO
BACKGROUND: Both mesenchymal stromal cells (MSCs) and acellular dermal matrices (ADMs) represent fascinating therapeutic tools in the wound healing scenario. Strategies aimed at combining these two treatment modalities are currently under investigation. Moreover, scarcity of quantitative, nondestructive techniques for quality assessment of engineered tissues poses great limitations in regenerative medicine and collagen autofluorescence-based imaging techniques are acquiring great importance in this setting. OBJECTIVE: Our goals were to assess the in vitro interactions between ADSCs and ADMs and to analyze extracellular-matrix production. METHODS: Adipose-derived MSCs (ADSC) were plated on 8-mm punch biopsies of a commercially available ADM (Integra®). Conventional histology with hematoxylin-eosin staining, environmental scanning electron microscopy, and confocal-laser scanning microscopy were used to obtain imaging of ADSC-seeded ADMs. Collagen production by ADSCs was quantified by mean fluorescence intensity (MFI), expressed in terms of positive pixels/field, obtained through ImageJ software processing of three-dimensional projections from confocal scanning images. Control conditions included: fibroblast-seeded ADM, ADSC- and fibroblast-induced scaffolds, and Integra® alone. RESULTS: ADSCs were efficiently seeded on Integra® and were perfectly incorporated in the pores of the scaffold. Collagen production was revealed to be significantly higher when ADSCs were seeded on ADM rather than in all other control conditions. Collagen autofluorescence was efficiently used as a surrogate marker of ECM production. CONCLUSIONS: Combined therapies based on MSCs and collagenic ADMs are promising therapeutic options for chronic wounds. Not only ADSCs can be efficiently seeded on ADMs, but ADMs also seem to potentiate their regenerative properties, as highlightable from fluorescence confocal imaging.
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Derme Acelular , Células-Tronco Mesenquimais , Colágeno , Imageamento Tridimensional , Microscopia ConfocalRESUMO
Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) represent a group of hematological disorders that are traditionally considered as indistinct slow progressing conditions; still, a subset of cases shows a rapid evolution towards myelofibrotic bone marrow failure. Specific abnormalities in the megakaryocyte lineage seem to play a central role in this evolution, especially in the bone marrow fibrosis but also in the induction of myeloproliferation. In this review, we analyze the current knowledge of prognostic factors of MPNs related to their evolution to myelofibrotic bone marrow failure. Moreover, we focused the role of the megakaryocytic lineage in the various stages of MPNs, with updated examples of MPNs in vitro and in vivo models and new therapeutic implications.